WO2018220171A1 - Gold compounds and their use in therapy - Google Patents

Gold compounds and their use in therapy Download PDF

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WO2018220171A1
WO2018220171A1 PCT/EP2018/064452 EP2018064452W WO2018220171A1 WO 2018220171 A1 WO2018220171 A1 WO 2018220171A1 EP 2018064452 W EP2018064452 W EP 2018064452W WO 2018220171 A1 WO2018220171 A1 WO 2018220171A1
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groups
group
alkyl
optionally substituted
biofilm
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PCT/EP2018/064452
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French (fr)
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Nigel Paul King
Jonathan Raymond Powell
Gabriel NEGOITA-GIRAS
Joseph Michael WATTS
Alicia Galván ÁLVAREZ
Lucie Juliette GUETZOYAN
Joshua Robert FREEM
Philip Graham CLARKE
Alan Naylor
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Auspherix Limited
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    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
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    • C07F9/02—Phosphorus compounds
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    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6551—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a four-membered ring
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    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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Definitions

  • the present invention relates to gold(l)-phosphine compounds, their use as inhibitors of growth of Gram-positive and/or Gram-negative bacteria, and their use for the prevention and/or treatment of a disease or disorder selected from fungal infections, Protozoal infections, inflammatory diseases, proliferative diseases and viral diseases.
  • the present invention also relates to using such compounds for the prevention and/or treatment of bacterial infection, or the prevention and/or treatment of a disease or disorder selected from fungal infections, Protozoal infections, inflammatory diseases, proliferative diseases and viral diseases.
  • AMR antimicrobial resistance
  • Inorganic Biochem., 2003, 95, 208-220 discloses triphenyl phosphine compounds with a variety of ligands with antibacterial activity against Gram-positive organisms, and Aguinagalde, L, et al., J. Antimicrob. Chemother., 2015, 70(9), 2608-2617 discloses six triethyl phosphine compounds with antibacterial activity against Gram-positive organisms.
  • Gold(l) is a soft Lewis acid and preferentially complexes with soft donor atoms such as sulfur, selenium and phosphorous.
  • soft donor atoms such as sulfur, selenium and phosphorous.
  • complexes used clinically include gold thiomalate, aurothioglucose and auranofin:
  • Auranofin a second generation orally bioavailable gold(l) based treatment for rheumatoid arthritis (RA), has been identified as inhibiting the in vitro growth of S. aureus (Oxford strain) with an MIC of 0.6-0.9 ⁇ g/mL and V. cholerae with an MIC of 2.5 ⁇ g/mL.
  • the fungal infections caused by the above include candidiasis, cryptococcosis, histoplasmosis, blastomycosis, paracoccoidiomycosis, coccidioidomycosis, aspergillosis, extracutaneous sporotrichosis, and mucormycosis (Ellis D., J Antimicrob Chemother. 2002 Feb;49 Suppl 1 :7-10).
  • the diverse eukaryotic subgroup Protozoa contains many pathogenic species of clinical relevance. Despite being more commonly associated with infection in low-middle income countries, incidences of enteric protozoal infection have increased in high income countries over recent years (Artemis Efstratiou et al., Water Research. (2017), (1 14) :pp14-22). Resistance to antiparasitic agents has been reported in several species (Genetu Bayih A et al., Clin Microbiol Rev. (2017) 30(3):647-669. doi: 10.1 128/CMR.001 1 1 -16; Squire SA et al., Parasit Vectors. (2017), 20;10(1 ):195; Arjen M.
  • Clinically relevant protozoa include, Trypanosoma cruzi, T brucei, Leshmania spp., Dientamoeba fragilis, Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica, Naeglaeri fowleri, Acanthomoeba, Balamuthia mandrillaris, Plasmodium spp., Babesia microti, Cryptosporidium parvum, Cycolspora cayetanensis, Cystoisopora belli, Toxoplasma gondii, Sarcocystis spp., and Balantidium coll.
  • a first aspect of the invention is a compound according to formula (I):
  • P x is selected from (P1 ), (P2) or (P3);
  • R P1 and R P2 are each independently selected from
  • R P3 is selected from the group consisting of:
  • R pc is selected from the group consisting of
  • R P5 is selected from linear or branched unsubstituted C1-4 saturated alkyl groups, or cyclic C3-4 saturated alkyl groups optionally substituted with a methyl group; each R P6 group is independently selected from
  • R P7 and R P8 are each independently selected from H and methyl or together for an oxo group
  • R P9 and R P1 ° are each independently selected from H and methyl or together for an oxo group
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form either
  • a 4- or 5-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally mono-substituted with a group R PE , or
  • a 6-membered heterocyclic ring including 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups R PE ;
  • R PD is selected from the group consisting of
  • R PE is selected from
  • R Au is selected from the groups (B1 ) to (B3):
  • R NA is selected from the group consisting of
  • R NB is selected from -COR A2 and -S0 2 R A2 ; or R NA and R NB together with the nitrogen atom to which they are attached form
  • oxo NH, R A1 , R A2 ,
  • each R N1 is independently selected from R N2 and -OR N3 , wherein R N2 and R N3 are each independently selected from linear unsubstituted C 1 -6 alkyl;
  • -L s - and -L c - are each independently selected from
  • R SA is selected from the group consisting of
  • E A is selected from the group consisting of: -0-R A2 ; -NH-R A2 ; -NR A 3 ⁇ 4
  • R E1 is selected from H and linear or branched C 1-3 alkyl
  • E B is selected from: E BA ; -CO-E B1 -NR EA R E2 and -CO-E B2 -E B3 -NR EB R E2 ; wherein E B1 , E B2 and E B3 are D- or L-amino acid residues independently selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -CO-, -NR EA R E2 and -NR EB R E2 groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality; when E B1 is Pro, R EA is absent, otherwise R EA is R E1 ; when E B3 is Pro
  • E c is selected from: -OH; -OR A2 ; -NH 2 ; NHR A2 ; NR A2 2 and -NR EC1 -E c1 -COR EC2 ; wherein E C1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys,
  • - NR EC1 - and -COR EC2 groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality; when E C1 is Pro, R EC1 is absent, otherwise R EC1 is R E1 ; wherein the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH 2 , -CONHR A2 , -
  • R E1 and -COOR A2 and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C 1-3 alkyl) and - OCOCHs;
  • R EC2 is selected from -OR E9 , -NH 2 , -NHR A2 and -NR A2 R E1 ;
  • R E3 and R E4 are independently selected from -H and -CH3; when R E1 is H and E c is -OC 1-3 alkyl, -NH 2 or -NHC 1-3 alkyl, E D is selected from -H, and -CO-E D1 -NR ED R E6 , otherwise, E D is selected from: -R E5 , and -CO-E D1 -NR ED R E6 ; wherein E D1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the - NR ED R E6 - and -CO- groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid
  • R E2 , R E5 and R E6 are independently selected from -H and -COCH 3 ;
  • R E7 , R E8 and R E9 are each independently selected from -H and -R A2 ; when L c is a single bond, R CA is R CAA ,
  • R CAA is selected from the group consisting of
  • V C1 is a C 4-6 cycloalkyl or heterocyclyl group optionally substituted with one or more groups selected from oxo and R A1 ;
  • R CA is selected from R CAA and R CAB , wherein R CAB is selected from
  • R A2 is selected from the group consisting of
  • N is substituted by 2 R A2 groups
  • the N and the R A2 groups may together form a N- containing C 5-6 heterocycloalkyl group, optionally substituted with one or two groups selected from linear unsubstituted C 1 -6 alkyl;
  • R 1 A1 is selected from linear or branched unsubstituted C 1-3 alkyl
  • R AL is selected from the group consisting of
  • R AR is selected from the group consisting of
  • R AT is selected from the group consisting of -OCOC 1-3 alkyl, -OCONH 2 , -OCONHC 1-3 alkyl, -OCON(C 1-3 alkyl) 2 , -NH 2 , -NHC 1-3 alkyl, -N(C 1-3 alkyl) 2 ,
  • R 1A1 is a linear or branched unsubstituted C 1 -6 alkyl group.
  • R P3 is selected from the group consisting of:
  • each R P6 group is independently selected from
  • the first aspect of the invention also provides a compound according to formula (I) for use in the prevention or treatment of a bacterial infection.
  • the first aspect of the invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prevention of a bacterial infection.
  • the first aspect of the invention further provides a method of treatment of a human or animal patient afflicted with a bacterial infection, comprising administering to said patient an effective amount of a pharmaceutical composition containing a compound of formula (I).
  • the bacterial infection prevented and/or treated may be infection by one or more Gram-positive bacteria.
  • the bacterial infection prevented and/or treated may be infection by one or more Gram-negative bacteria.
  • the bacterial infection prevented and/or treated may be infection by one or more multi-drug resistant bacteria.
  • the first aspect may also relate to the treatment of fungal infection, e.g. by providing a compound of formula (I) for use in the prevention or treatment of a fungal infection.
  • the fungal infection prevented and/or treated may be an infection selected from candidiasis, cryptococcosis, histoplasmosis, blastomycosis, paracoccoidiomycosis, coccidioidomycosis, aspergillosis, extracutaneous sporotrichosis, and mucormycosis.
  • the fungal infection prevented and/or treated may be an infection caused by a fungus selected from Candida spp, Aspergillus fumigatus, Mucor, Rhizopus, Absidia,
  • the first aspect may also relate to the prevention and/or treatment of a Protozoal infection, e.g. by providing a compound of formula (I) for use in the prevention or treatment of a Protozoal infection.
  • the invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of a Protozoal infection. Methods of preventing or treating such diseases are also provided.
  • the Protozoal infection prevented and/or treated may be an infection caused by Protozoa selected from Trypanosoma cruzi, T brucei, Leshmania spp., Dientamoeba fragilis, Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica, Naeglaeri fowleri,
  • the first aspect may also relate to the prevention and/or treatment of an inflammatory disease.
  • the first aspect may also relate to the prevention and/or treatment of a disease selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis.
  • the invention provides a compound of formula (I) for use in the prevention or treatment of an inflammatory disease, for example a disease selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis.
  • the invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of an inflammatory disease, for example a disease selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis.
  • an inflammatory disease for example a disease selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis.
  • the first aspect may also relate to the prevention and/or treatment of a proliferative disease, for example cancer.
  • the invention provides a compound of formula (I) for use in the prevention or treatment of a proliferative disease, for example cancer, for example a cancer selected from ovarian, skin, breast, lung, prostate, colorectal, lymphomas, bladder, uterine, kidney and blood cancers including leukaemia, lymphoma and myeloma.
  • the invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of a proliferative disease, for example cancer, for example a cancer selected from ovarian, skin, breast, lung, prostate, colorectal, lymphomas, bladder, uterine, kidney and blood cancers including leukaemia, lymphoma and myeloma.
  • a proliferative disease for example cancer, for example a cancer selected from ovarian, skin, breast, lung, prostate, colorectal, lymphomas, bladder, uterine, kidney and blood cancers including leukaemia, lymphoma and myeloma.
  • a proliferative disease for example cancer, for example a cancer selected from ovarian, skin, breast, lung, prostate, colorectal, lymphomas, bladder, uterine, kidney and blood cancers including leukaemia, lymphoma and myeloma.
  • Methods of preventing or treating such diseases are also provided.
  • the invention provides a compound of formula (I) for use in the prevention or treatment of a viral disease, for example a disease caused by the human immunodeficiency virus (HIV) / AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV).
  • a viral disease for example a disease caused by the human immunodeficiency virus (HIV) / AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV).
  • the invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of a viral disease, for example a disease caused by the human immunodeficiency virus (HIV / AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV).
  • a viral disease for example a disease caused by the human immunodeficiency virus (HIV / AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV).
  • HCV human immunodeficiency virus
  • RSV respiratory syncytial virus
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • Compounds of the present invention may also be used to treat conditions by interaction, e.g. binding to thioredoxin reductase (TrxR), glutathione peroxidase (GSPx), ⁇ kinase (IKK) complex, cathepsins and type I iodothyronine deiodinase.
  • a third aspect of the present invention provides a pharmaceutical composition comprising a compound of the second aspect of the invention.
  • the pharmaceutical composition may also comprise a pharmaceutically acceptable diluent or excipient.
  • the third aspect of the present invention also provides the use of a compound of the second aspect of the invention in a method of therapy.
  • Another aspect of the invention provides a compound according to formula (II):
  • Another aspect of the invention provides a complex of formula VIII:
  • P x is as defined elsewhere herein, and E is a residue of a thiol-containing, selenol-containing or NH-containing endogenous ligand or protein.
  • compounds according to certain aspects of the invention may act as prodrugs which decompose within the body by cleavage of the Au-S bond and its replacement with an endogenous ligand or protein, such as those entrained within the blood of an organism.
  • an endogenous ligand or protein such as those entrained within the blood of an organism.
  • These may be, for example, thiol-containing, selenol-containing or NH-containing (e.g. an amide or a DNA base) ligand.
  • the resultant complexes i.e. complexes according to formula VIII
  • -E has a structure selected from -S-E s ,-Se-E SE and -N-E N , where E s is the remainder of the thiol-containing endogenous ligand or protein (connected to Au via the S atom of a reacted thiol group), E SE is the remainder of the selenol-containing endogenous ligand or protein (connected to Au via the Se atom of a reacted selenol group) and E N is the remainder of the NH- containing endogenous ligand or protein (connected to Au via the N atom of a reacted NH group).
  • endogenous indicates a ligand or protein originating within the body of a subject organism, such as within the body of a human subject.
  • Any ligand or protein containing an -SH, -SeH or -NH group may react with the gold(l) phosphine to provide a compound according to formula VIII.
  • Examples of the groups -E are provided below.
  • E is a residue of an endogenous low molecular weight thiol selected from cysteine (Cys), cysteinylglycine (CysGly) homocysteine (Hey), and glutathione (GSH, L-v-glutamyl-L-cysteinyl-glycine), N-acetylcysteine, thioglycolic acid, v- glutamyl-cysteine, cysteinyl-glycine, lipoic acid and Coenzyme A.
  • E is a residue of an endogenous low molecular weight selenol such as selenocysteine.
  • E is a residue of an endogenous protein selected from human serum albumin, thioredoxin reductase (TrxR), glutathione peroxidase (GSPx), ⁇ kinase (IKK) complex, cathepsins and type I iodothyronine deiodinase.
  • TrxR thioredoxin reductase
  • GSPx glutathione peroxidase
  • IKK ⁇ kinase
  • E may be a residue of an organism specific thiol-containing or selenol- containing endogenous ligand or protein such as mycothiol (present in Actinomycetes), bacillithiol (present in Firmicutes), ⁇ -Glu-Cys (present in halobacteria and lactic acid bacteria), trypanothione (present in trypanosomes), ergothioneine (present in
  • Another aspect of the invention is a compound according to formula VIII for use in the prevention or treatment of a bacterial infection.
  • Another aspect is the use of a compound according to formula VIII in the manufacture of a medicament for the prevention or treatment of a bacterial infection.
  • Another aspect is a method of preventing or treating a bacterial infection in a human or animal, comprising administering to said patient an effective amount of a pharmaceutical composition containing a compound of formula VIII.
  • Another aspect may relate to the treatment of fungal infection, e.g. by providing a compound of formula VIII for use in the prevention or treatment of a fungal infection.
  • Another aspect of the invention is a compound obtained by a method of synthesis as described herein.
  • Another aspect of the invention is a compound obtainable by a method of synthesis as described herein.
  • a compound which is obtained or obtainable by a method of reacting a gold(l) complex of formula II:
  • P x is as defined herein and R Au is the group (B1 ).
  • a compound which is obtained or obtainable by a method of reacting a compound of general formula III, IV, V, VI or IX:
  • P x is as defined herein and R Au is the group (B3).
  • Further aspects of the invention relate generally to the use of the compounds of the present invention to inhibit microbial growth, sensitize the inhibition of microbial growth, inhibit biofilm formation or development, disrupt existing biofilms, reduce the biomass of a biofilm, and sensitize a biofilm and microorganisms within the biofilm to an antimicrobial agent.
  • the invention relates to a method for inhibiting biofilm formation, comprising exposing a biofilm-forming microorganism to an effective amount of a compound of the invention.
  • a compound of the invention is coated, impregnated or otherwise contacted with a surface or interface susceptible to biofilm formation.
  • the surface is a surface of a medical device such as: medical or surgical equipment, an implantable medical device or prosthesis (for example, venous catheters, drainage catheters (e.g.
  • the biofilm or biofilm-forming microorganism is on a bodily surface of a subject and exposure of the biofilm or biofilm-forming microorganism to a compound of the invention is by administration of the compound of the invention to the subject.
  • the biofilm or biofilm-forming microorganism may be associated with an infection, disease or disorder suffered by the subject or to which the subject is susceptible.
  • a medical device such as those exemplified above coated or impregnated with a compound of the invention is provided.
  • the invention in another aspect relates to a method for reducing the biomass of a biofilm and/or promoting the dispersal of microorganisms from a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention.
  • the invention relates to a method for dispersing or removing, removing, or eliminating a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention.
  • the biofilm is an existing, preformed or established biofilm.
  • the invention relates to a method for killing microorganisms within a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention.
  • the biofilm is an existing, preformed or established biofilm.
  • the invention relates to a method of sensitizing a microorganism in a biofilm to an antimicrobial agent by exposing the biofilm to an effective amount of a compound of the invention.
  • the antimicrobial agent is an antibiotic (e.g. rifampicin, gentamicin, erythromycin, lincomycin, linezolid or vancomycin) or an antifungal agent.
  • the invention relates to a compound of the invention for use in a method of dispersing, removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, killing microorganisms within a biofilm, sensitizing a microorganism in a biofilm to an antimicrobial agent, treating or preventing an infection, disease or disorder caused by a biofilm, inhibiting the growth of a microbial persister cell, killing a microbial persister cell, or treating or preventing an infection, disease or disorder caused by or associated with a microbial persister cell.
  • the invention in another aspect relates to a compound of the invention for use in a method of treating or preventing an infection, disease or disorder treatable by dispersing, removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, killing microorganisms within a biofilm, sensitizing a microorganism in a biofilm to an infection, disease or disorder treatable by dispersing, removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, killing microorganisms within a biofilm, sensitizing a microorganism in a biofilm to an
  • the biofilm comprises bacteria, such as, for example, multi-drug resistant bacteria.
  • the bacteria are Gram-positive bacteria.
  • the bacteria are Gram-negative bacteria.
  • the biofilm comprises, consists essentially of, or consists of S. aureus. In some aspects, the S.
  • the biofilm comprises, consists essentially of, or consists of A. baumannii. In other embodiments, the biofilm comprises, consists essentially of, or consists of K. pneumoniae. In other embodiments, the biofilm comprises, consists essentially of, or consists of one or more of the bacteria listed in Table 1 herein. In further embodiments, the biofilms comprise bacterial species, including but not limited to, Staphylococcus spp., Streptococcus spp., Enterococcus spp., Listeria spp.
  • Clostridium spp. Klebsiella spp., Acinetobacter spp., Pseudomonas spp., Burkholderia spp., Erwinia spp., Haemophilus spp., Neisseria spp., Escherichia spp, Enterobacter spp., Vibrio spp. and/or Actinobacillus spp.
  • biofilm comprises lower eukaryotes, such as yeast, fungi, and filamentous fungi, including, but not limited to Candida spp., Pneumocystis spp.,
  • Saccharomyces spp. Malassezia spp., Trichosporon spp. and Cryptococcus spp.
  • Example species include C. albicans, C. glabrata, C. parapsilosis, C. dubliniensis, C. krusei, C. tropicalis, A. fumigatus, and C. neoforms.
  • the biofilm may comprise one species of microorganism, or comprise two or more species of microorganism, i.e. be a mixed species biofilm.
  • the mixed species biofilms may include two or more species of bacteria, two or more species of lower eukaryote (e.g. two or more fungal species, such as unicellular fungi, filamentous fungi and/or yeast), and/or both bacteria and lower eukaryotes, such as one or more species of bacteria and one or more species of lower eukaryotes.
  • the methods, uses and compositions provided herein are applicable to biofilms comprising one or more species of bacteria and one or more species of fungi, such as a yeast, unicellular fungi and/or filamentous fungi.
  • the mixed species biofilm may thus comprise 2, 3, 4, 5, 10, 15, 20 or more species of microorganism, and the microorganisms within the biofilm may be bacteria and/or lower eukaryotes, such as unicellular fungi, filamentous fungi and/or yeast.
  • the compounds of the invention can act together with other antimicrobial agents, allowing for increased efficacy of anti-microbial action. Accordingly, for any aspect described herein comprising exposing a biofilm, biofilm-forming microorganism, or a microbial persister cell to a compound of the invention, the present invention provides a
  • biofilm or biofilm-forming microorganism comprising exposing the biofilm or biofilm-forming microorganism to a combination of compounds of the invention and at least one additional antimicrobial agent, such as, for example, an antibiotic or an anti-fungal agent.
  • the antibiotic is selected from rifampicin, gentamicin, erythromycin, lincomycin and vancomycin.
  • the methods described herein may be performed, for example, in vivo, ex vivo, or in vitro.
  • Phosphines primarily function as Lewis bases, interacting with metals as ⁇ donor ligands through the lone pair of electrons on the phosphorus atom. They also can accept electron density from metal into P-C o * antibonding orbitals. The magnitude of these two bonding interactions depends on the substituents on the phosphine and the electron density at the metal center. Consequently, the skilled person understands that the metal-phosphine bonds are not of pure single or double character, but rather something between the two extremes. Any representation herein of the Au-P bond as a single or double bond is merely provided as an approximation and cannot be taken as implying that the bond in fact exists as a traditional 'single' or 'double' bond. The way the Au(l)-phosphine bonds are shown herein is a formalization and in principle other representations could be used, e.g. a single bond (line) between the Au(l) center and the phosphine atom.
  • Microbe / Microorganism The terms "microbe / microorganism” as used herein pertain to bacteria and lower eukaryotes, such as fungi, including yeasts, unicellular fungi and filamentous fungi.
  • Antimicrobial agent The term “antimicrobial agent” as used herein pertains to any agent that, alone or in combination with another agent, is capable of killing or inhibiting the growth of one or more species of microorganism.
  • Antimicrobial agents include, but are not limited to, antibiotics, antifungals, detergents, surfactants, agents that induce oxidative stress, bacteriocins and antimicrobial enzymes (e.g. lipases, proteinases, pronases and lyases) and various other proteolytic enzymes and nucleases, peptides and phage.
  • Reference to an antimicrobial agent includes reference to both natural and synthetic antimicrobial agents.
  • antimicrobial agents include fluoroquinolones, aminoglycosides, glycopeptides, lincosamides, cephalosporins and related beta-lactams, macrolides, nitroimidazoles, penicillins, polymyxins, tetracyclines, and any combination thereof.
  • the methods of the present invention can employ acedapsone; acetosulfone sodium; alamecin; alexidine; amdinocillin; amdinocillin pivoxil; amicycline; amifloxacin; amifloxacin mesylate; amikacin; amikacin sulfate; aminosalicylic acid;
  • aminosalicylate sodium amoxicillin; amphomycin; ampicillin; ampicillin sodium; apalcillin sodium; apramycin; aspartocin; astromicin sulfate; avilamycin; avoparcin; azithromycin; azlocillin; azlocillin sodium; bacampicillin hydrochloride; bacitracin; bacitracin methylene disalicylate; bacitracin zinc; bambermycins; benzoylpas calcium; berythromycin; betamicin sulfate; biapenem; biniramycin; biphenamine hydrochloride; bispyrithione magsulfex; butikacin; butirosin sulfate; capreomycin sulfate; carbadox; carbenicillin disodium;
  • cefbuperazone cefdinir; cefepime; cefepime hydrochloride; cefetecol; cefixime;
  • cefmenoxime hydrochloride cefmetazole; cefmetazole sodium; cefonicid monosodium; cefonicid sodium; cefoperazone sodium; ceforanide; cefotaxime sodium; cefotetan;
  • cefuroxime sodium cephacetrile sodium; cephalexin; cephalexin hydrochloride;
  • cephaloglycin cephaloridine; cephalothin sodium; cephapirin sodium; cephradine;
  • cetocycline hydrochloride cetophenicol; chloramphenicol; chloramphenicol palmitate; chloramphenicol pantothenate complex; chloramphenicol sodium succinate; chlorhexidine phosphanilate; chloroxylenol; chlortetracycline bisulfate; chlortetracycline hydrochloride; cinoxacin; ciprofloxacin; ciprofloxacin hydrochloride; cirolemycin; clarithromycin; clinafloxacin hydrochloride; clindamycin; clindamycin hydrochloride; clindamycin palmitate hydrochloride; clindamycin phosphate; clofazimine; cloxacillin benzathine; cloxacillin sodium; chlorhexidine, cloxyquin; colistimethate sodium; colistin sulfate; coumermycin; coumermycin sodium; cyclacillin; cycloserine
  • levofuraltadone levopropylcillin potassium; lexithromycin; lincomycin; lincomycin hydrochloride; lomefloxacin; lomefloxacin hydrochloride; lomefloxacin mesylate;
  • loracarbef mafenide; meclocycline; meclocycline subsalicylate; megalomicin potassium phosphate; mequidox; meropenem; methacycline; methacycline hydrochloride;
  • methenamine methenamine; methenamine hippurate; methenamine mandelate; methicillin sodium; metioprim; metronidazole hydrochloride; metronidazole phosphate; mezlocillin; mezlocillin sodium; minocycline; minocycline hydrochloride; mirincamycin hydrochloride; monensin; monensin sodiumr; nafcillin sodium; nalidixate sodium; nalidixic acid; natainycin;
  • nebramycin neomycin palmitate; neomycin sulfate; neomycin undecylenate; netilmicin sulfate; neutramycin; nifuiradene; nifuraldezone; nifuratel; nifuratrone; nifurdazil;
  • nifurimide nifiupirinol; nifurquinazol; nifurthiazole; nitrocycline; nitrofurantoin; nitromide; norfloxacin; novobiocin sodium; ofloxacin; onnetoprim; oxacillin and oxacillin sodium; oximonam; oximonam sodium; oxolinic acid; oxytetracycline; oxytetracycline calcium; oxytetracycline hydrochloride; paldimycin; parachlorophenol; paulomycin; pefloxacin; pefloxacin mesylate; penamecillin; penicillins such as penicillin G benzathine, penicillin G potassium, penicillin G procaine, penicillin G sodium, penicillin V, penicillin V benzathine, penicillin V hydrabamine, and penicillin V potassium; pentizidone sodium; phenyl aminosalicylate; piperacillin sodium
  • quindecamine acetate quinupristin; racephenicol; ramoplanin; ranimycin; relomycin; repromicin; rifabutin; rifametane; rifamexil; rifamide; rifampin; rifapentine; rifaximin;
  • rolitetracycline rolitetracycline
  • rolitetracycline nitrate rosaramicin; rosaramicin butyrate
  • rosaramicin propionate rosaramicin sodium phosphate
  • rosaramicin stearate rosoxacin
  • roxarsone roxithromycin
  • sancycline sanfetrinem sodium
  • sarmoxicillin sarpicillin
  • scopafungin sisomicin; sisomicin sulfate; sparfloxacin; spectinomycin hydrochloride; spiramycin;
  • stallimycin hydrochloride steffimycin; streptomycin sulfate; streptonicozid; sulfabenz; sulfabenzamide; sulfacetamide; sulfacetamide sodium; sulfacytine; sulfadiazine;
  • sulfadiazine sodium sulfadoxine; sulfalene; sulfamerazine; sulfameter; sulfamethazine; sulfamethizole; sulfamethoxazole; sulfamonomethoxine; sulfamoxole; sulfanilate zinc; sulfanitran; sulfasalazine; sulfasomizole; sulfathiazole; sulfazamet; sulfisoxazole;
  • temocillin tetracycline
  • tetracycline hydrochloride tetracycline phosphate complex
  • tetroxoprim thiamphenicol; thiphencillin potassium; ticarcillin cresyl sodium; ticarcillin disodium; ticarcillin monosodium; ticlatone; tiodonium chloride; tobramycin; tobramycin sulfate; tosufloxacin; trimethoprim; trimethoprim sulfate; trisulfapyrimidines;
  • troleandomycin trospectomycin sulfate; tyrothricin; vancomycin; vancomycin
  • hydrochloride virginiamycin; zorbamycin; bifonazolem; butoconazole; clotrimazole;
  • econazole fenticonazole; isoconazole; ketoconazole; miconazolel omoconazolel oxiconazolel sertaconazolel sulconazolel tioconazolel; albaconazole; fluconazole;
  • Biofilm The term "biofilm” as used herein pertains to any three-dimensional, matrix- encased microbial community displaying multicellular characteristics. Accordingly, the term biofilm includes surface-associated biofilms as well as biofilms in suspension, such as floes and granules. Biofilms may comprise a single microbial species or may be mixed species complexes, and may include bacteria as well as fungi, algae, protozoa, or other microorganisms.
  • reducing the biomass of a biofilm is used herein to mean reducing the biomass of an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the biofilm biomass of the area immediately before exposure to a compound of the invention.
  • the "biomass” is the mass of cells present in the area of biofilm in addition to the extracellular polymeric substance (EPS) of the biofilm matrix.
  • the "biomass” is only the mass of cells present in the area of biofilm (that is, the mass of the EPS is not counted as “biomass”).
  • the biomass of the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the biofilm biomass of the area immediately before exposure to a compound of the invention, the mass of the otherwise identical area of a biofilm which has not been exposed to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the biofilm biomass of the area immediately before exposure to a compound of the invention.
  • the area of biofilm compared is 10 "6 m 2 ; in other embodiments the area of biofilm compared is 10 "5 m 2 , 10 "4 m 2 , or 10 "3 m 2 .
  • a biofilm whose biomass has been reduced by at least 95% is deemed to have been "eliminated”, “dispersed” or “removed”.
  • a biofilm whose biomass has been reduced by at least 99% is deemed to have been “eliminated”, “dispersed” or “removed”.
  • a biofilm whose biomass has been reduced by at least 99.9% is deemed to have been "eliminated", "dispersed” or “removed”.
  • the change in biofilm biomass is assessed by a method comprising the steps of: i) washing the area of biofilm to remove non-adherent (planktonic) microorganisms, ii) assessing the area of biofilm biomass (i.e. the biomass "immediately before exposure to a compound of the invention"), iii) exposing the area of biofilm (or an otherwise identical area) to an effective amount of a compound of the invention for a period of time (for example, 24 hours), iv) washing the biofilm to remove non-adherent (planktonic) microorganisms, and v) assessing the area of biofilm biomass to obtain the 'post-exposure' biomass.
  • Promoting the dispersal of microorganisms from a biofilm is used herein to mean reducing the number of microorganisms present in an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the number of microorganisms present in the area immediately before exposure to a compound of the invention.
  • the number of microorganisms in the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the number of microorganisms present in the area immediately before exposure to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the number of microorganisms present in the area immediately before exposure to a compound of the invention.
  • microorganisms in an area of biofilm is assessed by a method comprising the steps of: i) washing the biofilm to remove non-adherent (planktonic) microorganisms, ii) counting the remaining microorganisms to obtain a 'pre-exposure' microorganism count (i.e. the count "immediately before exposure to a compound of the invention"), iii) exposing the biofilm to an effective amount of a compound of the invention for a period of time (for example, 24 hours), iv) washing the biofilm to remove non-adherent (planktonic) microorganisms, and v) counting the remaining microorganisms to obtain the 'post-exposure' microorganism count.
  • a method comprising the steps of: i) washing the biofilm to remove non-adherent (planktonic) microorganisms, ii) counting the remaining microorganisms to obtain a 'pre-exposure' microorgan
  • a biofilm where number of microorganisms in an area has been reduced by at least 95% is deemed to have been "eliminated”, “dispersed” or “removed”.
  • a biofilm where number of microorganisms in an area has been reduced by at least 99% is deemed to have been “eliminated”, “dispersed” or “removed”.
  • a biofilm where number of microorganisms in an area has been reduced by at least 99.9% is deemed to have been "eliminated", “dispersed” or "removed”.
  • Killing microorganisms within a biofilm is used herein to mean reducing the number of live microorganisms present in an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the number of live microorganisms present in the area immediately before exposure to a compound of the invention.
  • the biofilm is an existing, preformed or established biofilm.
  • the number of live microorganisms in the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the number of live microorganisms present in the area immediately before exposure to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the number of live microorganisms present in the area immediately before exposure to a compound of the invention.
  • the change in number of microorganisms in an area of biofilm is assessed by a method comprising the steps of: i) washing the area biofilm to remove non-adherent (planktonic) microorganisms, ii) manually disperse the biofilm into solution (using, for example, scraping, sonication, and vortexing), iii) prepare serial dilutions, plate, and culture to estimate the number of colony forming unit (cfu) in the area of biofilm, iv) provide an otherwise identical area of biofilm and expose it to an effective amount of a compound of the invention for a period of time (for example, 24 hours), v) manually disperse the biofilm and estimate cfu as described above to obtain the 'post-exposure' microorganism count.
  • the viability of the biofilm can be also assessed by allowing the biofilm to re-grow in compound free medium and assessing planktonic growth.
  • Dispersal The term "dispersal" as used here
  • microorganisms making up a biofilm means the process of detachment and separation of cells and a return to a planktonic phenotype or behaviour of the dispersing cells.
  • Exposing means generally bringing into contact with. Exposure of a biofilm or biofilm-forming microorganism to an agent (e.g. a compound of the invention) includes administration of the agent to a subject harbouring the agent.
  • an agent e.g. a compound of the invention
  • the biofilm or biofilm-forming microorganisms are exposed to a compound of the invention by coating, impregnating or otherwise contacting a surface or interface susceptible to biofilm formation to an effective amount of the compound.
  • Surfaces that may be exposed, coated, or impregnated with a compound of the invention include those present in a range of industrial and domestic settings, including but not limited to, domestic, medical or industrial settings (e.g.
  • Inhibiting refers to any microbiocidal or microbiostatic activity of an agent (e.g. a compound of the invention) or composition. Such inhibition may be in magnitude and/or be temporal or spatial in nature. Inhibition of the growth of a microorganism by an agent can be assessed by measuring growth of the microorganism in the presence and absence of the agent.
  • the growth can be inhibited by the agent by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more compared to the growth of the same microorganism that is not exposed to the agent.
  • inhibiting and variations thereof such as “inhibition” and “inhibits” as used herein in relation to biofilms means complete or partial inhibition of biofilm formation and/or development and also includes within its scope the reversal of biofilm development or processes associated with biofilm formation and/or development. Further, inhibition may be permanent or temporary. The inhibition may be to an extent (in magnitude and/or spatially), and/or for a time, sufficient to produce the desired effect. Inhibition may be prevention, retardation, reduction or otherwise hindrance of biofilm formation or development. Such inhibition may be in magnitude and/or be temporal or spatial in nature.
  • Inhibition of the formation or development of a biofilm by a compound of the invention can be assessed by measuring biofilm mass or microbial growth in the presence and absence of a compound of the invention.
  • the formation or development of a biofilm can be inhibited by a compound of the invention by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more compared to the formation or development of a biofilm that is not exposed to a compound of the invention.
  • Sensitize The terms "sensitize” or “sensitizing” as used herein mean making a biofilm or microorganisms within a biofilm more susceptible to an antimicrobial agent.
  • the sensitizing effect of a compound of the invention, on a biofilm or microorganisms within the biofilm can be measured as the difference in the susceptibility of the biofilm or microorganisms (as measured by, for example, microbial growth or biomass of the biofilm) to a second antimicrobial agent with and without administration of the compound.
  • the sensitivity of a sensitized biofilm or microorganism i.e.
  • a biofilm or microorganism exposed to an agent such as a compound of the invention) to a antimicrobial agent can be increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500% or more compared to the sensitivity of an unsensitized biofilm or microorganism (i.e. a biofilm or microorganism not exposed to the agent).
  • sensitizing effect of a compound of the invention on a biofilm or microorganisms within the biofilm can be measured by the difference in Minimum Inhibitory Concentration (MIC) of a second antimicrobial administered either in combination with a compound of the invention, or alone.
  • MIC Minimum Inhibitory Concentration
  • the MIC of a combination of a compound of the invention and the second antimicrobial is at least 10% lower than the MIC of the second antimicrobial administered alone; such as at least 20% lower, at least 30% lower, at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower, at least 90% lower, at least 95% lower, at least 99% lower, or at least 99.9% lower than the MIC of the second antimicrobial administered alone.
  • the sensitization of a microorganism may also occur outside of a biofilm.
  • Surface includes both biological surfaces and non- biological surfaces. Biological surfaces typically include surfaces both internal (such as organs, tissues, cells, bones and membranes) and external (such as skin, hair, epidermal appendages, seeds, plant foliage) to an organism. Biological surfaces also include other natural surfaces such as wood or fibre.
  • a non-biological surface may be any artificial surface of any composition that supports the establishment and development of a biofilm. Such surfaces may be present in industrial plants and equipment, and include medical and surgical equipment and medical devices, both implantable and non-implantable.
  • a surface may be porous (such as a membrane) or non-porous, and may be rigid or flexible.
  • Infection, disease or disorder caused by a biofilm / infection, disease or disorder caused by or associated with a microbial persister cell The term "Infection, disease or disorder caused by a biofilm” as used herein is used to describe conditions, diseases and disorders associated with, characterised by, or caused by biofilms and biofilm-forming microorganisms. Similarly, the term “Infection, disease or disorder caused by or associated with a microbial persister cell” as used herein is used to describe conditions, diseases and disorders associated with, characterised by, or caused by microbial persister cells.
  • microbial infections are known to be associated with biofilm formation and/or persister cells, such as cellulitis, impetigo, mastitis, otitis media, bacterial endocarditis, sepsis, toxic shock syndrome, urinary tract infections, pulmonary infections (including pulmonary infection in patients with cystic fibrosis), pneumonia, dental plaque, dental caries, periodontitis, bacterial prostatitis and infections associated with surgical procedures or burns.
  • cellulitis impetigo, mastitis, otitis media, bacterial endocarditis, sepsis, toxic shock syndrome, urinary tract infections, pulmonary infections (including pulmonary infection in patients with cystic fibrosis), pneumonia, dental plaque, dental caries, periodontitis, bacterial prostatitis and infections associated with surgical procedures or burns.
  • pulmonary infections including pulmonary infection in patients with cystic fibrosis
  • pneumonia including pulmonary infection in patients with cystic fibrosis
  • dental plaque dental caries
  • periodontitis bacterial prosta
  • epidermidis cause or are associated with cellulitis, impetigo, mastitis, otitis media, bacterial endocarditis, sepsis, toxic shock syndrome, urinary tract infections, pulmonary infections (including pulmonary infection in patients with cystic fibrosis), pneumonia, dental plaque, dental caries and infections associated with surgical procedures or burns.
  • K. pneumoniae can cause or be associated with pneumonia, sepsis, community-acquired pyogenic liver abscess (PLA), urinary tract infection, and infections associated with surgical procedures or burns.
  • A. baumannii can cause or be associated with bacteremia, pneumonia, meningitis, urinary tract infection, and infections associated with wounds.
  • aeruginosa can cause or be associated with respiratory tract infections (including pneumonia), skin infections, urinary tract infections, bacteremia, infection of the ear (including otitis media, otitis externa and otitis interna), endocarditis and bone and joint infections such as osteomyelitis.
  • Candida spp. such as C. albicans, Cryptococcus spp. such as C. neoformans, as well as other fungi such as Trichosporon spp., Malassezia spp., Blastoschizomyces spp., Coccidioides spp. and Saccharomyces spp. (e.g. S. cerevisiae) may cause or be associated with infections related to the implantation or use of medical or surgical devices, such as catheterization or implantation of heart valves.
  • Persister cell(s) The term "persister cell(s)" as used herein pertains to metabolic variants of wild type microbial cells that are phenotypically characterized by their slow growth rate, which is typically 30%, 25%, 20%, 15%, 10%, 5% or less of the growth rate of the wild- type counterpart.
  • the persister cells are dormant and have, for example, no detectable cell division in a 24 hour period. Further, persister cells typically form colonies that are approximately 30%, 25%, 20%, 15%, 10%, 5% or less of the size of the colonies formed by their wild-type counterparts.
  • Reference to persister cells includes reference to persister cells of any microbial genera or species, including, but not limited to, bacterial and lower eukaryotic, such as fungal, including yeast, persister cells.
  • the persister cell is a Gram-negative bacterium.
  • the persister cell is a Gram-positive bacterium.
  • Exemplary persister cells include, but are not limited to, those of Staphylococcus spp., such as S. aureus, S. epidermidis, and S.
  • Pseudomonas spp. such as P. aeruginosa
  • Burkholderia spp. such as B. cepacia and B. pseudomallei
  • Salmonella serovars including Salmonella Typhi
  • Vibrio spp. such as V. cholerae
  • Shigella spp. Brucella spp.
  • B. melitensis Escherichia spp.
  • Lactobacillus spp. such as L. acidophilus
  • Serratia spp. such as S. marcescens
  • Neisseria spp. such as N. gonorrhoeae, as well as Candida spp., such as C.
  • C 1 -6 alkyl The term "C 1 -6 alkyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having from 1 to 6 carbon atoms.
  • saturated alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), propyl (C3), butyl (C 4 ), pentyl (C5) and hexyl ⁇ Ce).
  • saturated linear alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), n-propyl (C3), n-butyl (C 4 ), n-pentyl (C5) and n-hexyl ⁇ Ce).
  • saturated branched alkyl groups include iso-propyl (C3), iso-butyl (C 4 ), sec-butyl (C 4 ), tert-butyl (C 4 ), iso-pentyl (C5), neopentyl (C5), iso-hexyl ⁇ Ce) and neohexyl (Ce).
  • C 2-6 alkenyl refers to a C 2-6 alkyl group having one or more carbon-carbon double bonds.
  • C 2-6 alkynyl The term "C 2-6 alkynyl” as used herein, pertains to a C 2-6 alkyl group having one or more carbon-carbon triple bonds. Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH) and 2-propynyl (propargyl, -CH2-C ⁇ CH).
  • C 3-6 cycloalkyl the term “C 3-6 cycloalkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic core having 3, 4, 5 or 6 atom in the cyclic core all of which are carbon atoms.
  • C 3-6 cycloalkyl examples include, but are not limited to, cyclopropyl, cyclohexyl and cyclopentyl.
  • C 5-6 cycloalkenyl The term “C 5-6 cycloalkenyl” as used herein, pertains to a C 3-6 cycloalkyl group having one or more carbon-carbon double bonds.
  • C 4-6 heterocycloalkyl The term "C 4 -6 heterocycloalkyl” as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 4 to 6 ring atoms, of which from 1 to 3 are ring heteroatoms selected from O, S and N. In this context, the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms
  • monocyclic heterocycloalkyl groups include, but are not limited to, those derived from:
  • Ni azetidine (C 4 ), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline,
  • O1 oxetane (C 4 ), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane
  • O2 dioxolane (C5), dioxane ⁇ Ce);
  • N 2 imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine ⁇ Ce);
  • N1O1 tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5),
  • N1S1 thiazoline (C5), thiazolidine (C5), thiomorpholine ⁇ Ce);
  • N2O1 oxadiazine (Ce);
  • O1S1 oxathiole (C5) and oxathiane (thioxane) ⁇ Ce); and,
  • C 5-6 heterocycloalkenyl The term "C 5-6 heterocycloalkenyl" as used herein, pertains to a C 5-6 heterocycloalkyl group having one or more carbon-carbon or carbon-nitrogen double bonds.
  • Heterobicyclyl refers to a bicyclic ring, wherein 1 , 2, or 3 ring carbons are replaced with a heteroatom selected from the group consisting of O, S and N.
  • one of the rings is aromatic.
  • both of the rings are aromatic.
  • neither ring is aromatic.
  • the bicylic rings may be spiro or fused.
  • Examples of a heterobicyclic group include, but are not limited to, 2,5-diaza-bicyclo[2.2.1 ]hept-2-yl, 7-aza-bicyclo[2.2.1]hept- 7-yl, 1 ,3-dihydro-isoindolyl, 3,4-dihydro-1 H-isoquinolinyl, octahydro-cyclopenta[c]pyrrolyl and the like
  • C 5-6 heteroaryl the term C 5-6 heteroaryl as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of an aromatic structure having between one and three atoms that are not carbon forming part of said ring. Wherein, those atoms that are not carbon can be chosen independently from the list nitrogen, oxygen and sulphur.
  • C 5-6 heteroaryl groups include, but are not limited to, groups derived from: Ni : pyridine (C 6 );
  • N1O1 oxazole (C5), isoxazole (C5);
  • N2O1 oxadiazole (furazan) (C5); N2S1: thiadiazole (C 5 )
  • N2 imidazole (1 ,3-diazole) (C5), pyrazole (1 ,2-diazole) (C5), pyridazine (1 ,2-diazine) ⁇ Ce), pyrimidine (1 ,3-diazine) ⁇ Ce) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) ⁇ Ce); N 3 : triazole (C 5 ).
  • P x is (P1 ).
  • R P1 is methyl. In other embodiments, R P1 is ethyl. In some embodiments, R P1 is -CH 2 OMe.
  • R P2 is methyl. In other embodiments, R P2 is ethyl. In some embodiments, R P2 is -CH 2 OMe. In some embodiments, both R P1 and R P2 are methyl. In other embodiments, both R P1 and R P2 are ethyl. In further embodiments, R P1 is methyl and R P2 is ethyl. In further embodiments, both R P1 and R P2 are -CH 2 OMe.
  • both R P1 and R P2 are methyl and R P3 is selected from the group consisting of:
  • both R P1 and R P2 are methyl and R P3 is selected from the group consisting of:
  • 6-membered heteroaryl groups containing one to four (preferably two to four) heteroatoms independently selected from O and N, optionally substituted with one or two C 1-3 linear saturated alkyl groups.
  • R P3 is selected from -CH 2 R P6 , -CH 2 CH 2 R P6 , -CHMeR P6 ,
  • R P3 is -COOH.
  • R P3 is selected from sec-butyl and 1-propynyl.
  • R P3 is trimethylsilyl(ethynyl).
  • each R P6 group is independently selected from
  • each R P6 group is independently selected from
  • each R P6 group is independently selected from
  • each R P6 group is independently selected from
  • each R P6 group is independently selected from 4-membered heterocyclyl or heteroaryl groups containing one or two heteroatoms selected from O and N, optionally substituted with one C 1-3 linear saturated alkyl group.
  • each R P6 group is independently selected from 4-membered heterocyclyl groups containing one heteroatom selected from O and N, optionally substituted with one C 1-3 linear saturated alkyl group.
  • each R P6 group is independently selected from - CH2SO2H, -CH 2 S0 2 Me and -CH 2 S0 2 Et. In some embodiments, each R P6 group is independently selected from -CH2SO2H and -ChbSC ⁇ Me.
  • each R P6 group is independently -NH2.
  • each R P6 group is independently -NMe2.
  • R P6 is not -CH20Me. In some embodiments, R P6 is not a 4- membered heteroaryl group.
  • R P3 is selected from C3-4 unsubstituted linear saturated alkyl groups. In some embodiments, R P3 is n-propyl. In some embodiments, R P3 is n-butyl.
  • R P3 is selected from C3-4 saturated cycloalkyi.
  • R P3 is selected from C3 saturated cycloalkyi groups, optionally substituted with one C 1-3 linear saturated alkyl group. In some embodiments, R P3 is selected from C 4 saturated heterocyclyl groups containing one or two heteroatoms independently selected from O and N, optionally substituted with one C 1-3 linear saturated alkyl group. In some embodiments, R P3 is selected from unsubstituted C3-4 saturated cycloalkyl groups.
  • R P3 is selected from C3-4 unsubstituted saturated cycloalkyl. In some embodiments, R P3 is cyclopropyl. In some embodiments, R P3 is cyclobutyl.
  • R P3 is selected from 4- or 5-membered heterocyclyl or
  • R P3 is selected from 4-membered heterocyclyl or heterocycloalkenyl groups containing one or two heteroatoms independently selected from O and N, optionally substituted with one C 1-3 linear saturated alkyl group.
  • R P3 is selected from 5-membered heterocyclyl or heterocycloalkenyl groups containing one or two heteroatoms independently selected from O and N, optionally substituted with one C 1-3 linear saturated alkyl group.
  • R P3 is selected from azetidyl and oxetanyl, optionally substituted with one or two methyl groups.
  • R P3 is selected from 5-membered heterocyclyl groups or heterocycloalkenyl containing two heteroatoms independently selected from O and N, optionally substituted with one C 1-3 linear saturated alkyl group. In some embodiments, R P3 is selected from dioxalanyl, optionally substituted with one or two methyl groups.
  • R P3 is not selected from C 4 heterocyclyl groups having a single heteroatom.
  • R P3 is selected from 5- or 6-membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C 1-3 linear saturated alkyl groups. In some embodiments, R P3 is selected from 5- or 6-membered heteroaryl groups containing two to four heteroatoms independently selected from O and N, optionally substituted with one or two C 1-3 linear saturated alkyl groups. In some embodiments, the 5- or 6-membered heteroaryl group is unsubstituted.
  • R P3 is not pyridyl.
  • R P3 is selected from 5-membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C 1-3 linear saturated alkyl groups.
  • R P3 is selected from 6-membered heteroaryl groups containing two to four heteroatoms independently selected from O and N, optionally substituted with one or two C 1-3 linear saturated alkyl groups.
  • R P1 is methyl, R P2 is methyl or ethyl and R P3 and R Au are as defined above. In some embodiments, R P1 is methyl, R P2 is methyl and R P3 and R Au are as defined above.
  • P x is selected from the groups:
  • P x is the group (P2).
  • R P4 is linear unsubstituted C3 saturated alkyl. In some embodiments, R P4 is n-propyl. In some embodiments, R P4 is linear C3 saturated alkyl, substituted with a methyl group. In some embodiments, R P4 is selected from n-butyl and isobutyl. In some embodiments, R P4 is branched C3 unsubstituted saturated alkyl. In some embodiments, R P4 is isopropyl. In some embodiments, R P4 is branched C3 saturated alkyl, substituted with a methyl group. In some embodiments, R P4 is selected from t-butyl and sec-butyl.
  • R P4 is cyclic C3 unsubstituted saturated alkyl.
  • R P4 is cyclopropyl. In some embodiments, R P4 is cyclic C3 saturated alkyl, substituted with a methyl group. In some embodiments, R P4 is the group:
  • m is 1 . In other embodiments, m is 2. In some embodiments, m is 1 or 2. In other embodiments, m is 3.
  • the ring in (P2) is unsubstituted (R M is absent). In other embodiments, there is one R M substituent on the ring in (P2). In further embodiments, there are two R M substituents on the ring in (P2).
  • R M is R pc . In some embodiments, R pc is methyl. In other embodiments, R pc is oxo.
  • R M is OH. In other embodiments, R M is OMe.
  • R PD is F. In some embodiments, R PD is OH. In some
  • R PD is OMe
  • m is 1 or 2
  • R M is absent and R P4 is selected from linear, branched or cyclic C3 saturated alkyl groups, optionally substituted with a methyl group.
  • P x is selected from the groups:
  • P x is the group (P3).
  • R P5 is selected from linear or branched unsubstituted C1-4 saturated alkyl groups. In some embodiments, R P5 is selected from methyl, isopropyl and t-butyl.
  • R P5 is selected from cyclic C3-4 saturated alkyl groups, optionally substituted with a methyl group. In some embodiments, R P5 is selected from
  • R P5 is cyclopropyl, optionally substituted with a methyl group. In some embodiments, R P5 is the group:
  • R P7 and R P8 are independently H. In some embodiments, one of R P7 and R P8 is H and the other is methyl.
  • R P9 and R P1 ° are each independently H. In some embodiments, one of R P9 and R P1 ° is H and the other is methyl.
  • each of R P7 , R P8 , R P9 and R P1 ° are independently H.
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form a 4- or 5-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the
  • phosphorus atom optionally substituted with one or two groups R PE .
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form a 4- or 5-membered heterocyclic ring including 1 heteroatom independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups R PE .
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form a 4-membered heterocyclic ring including 1 heteroatom independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups R PE . In some embodiments, the ring is unsubstituted. In some embodiments, R F1 and R F2 , together with the two carbon atoms to which they are attached and the phosphorus atom, form a ring selected from:
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form a 5-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups R PE .
  • the ring is unsubstituted.
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form a ring selected from:
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form a 6-membered heterocyclic ring including 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups R PE .
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form a 6-membered heterocyclic ring including 2 heteroatoms each independently selected from O in addition to the phosphorus atom, optionally substituted with one or two groups R PE .
  • the ring is unsubstituted.
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form the ring:
  • R PE is methyl. In other embodiments, R PE is oxo.
  • P x is selected from the groups:
  • P x is selected from the groups (P1 ), (P2) and (P3),
  • R P1 is methyl
  • R P2 is methyl or ethyl
  • R P3 is -CH 2 R P6 ,
  • R P4 and R P5 are each methyl
  • R P7 to R P1 ° are each H
  • R F1 and R F2 together with the two carbon atoms to which they are attached and the phosphorus atom, form a 6-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally mono-substituted with a methyl group;
  • R P6 and R Au are as defined above.
  • R Au is selected from the groups (B1 ) and (B2). In some embodiments, R Au is the group (B1 ), i.e. the group -NR NA R NB . In some embodiments R NA is linear or branched C 1 -6 alkyl optionally substituted with one or more groups R AL ; and R NB is selected from -COR A2 and -S0 2 R A2 .
  • R NA is linear or branched C 1 -6 alkyl optionally substituted with one or more groups R AL ; and R NB is selected from -CO(C 1 -6 alkyl) and -S0 2 R A2 .
  • R NA is unsubstituted linear or branched C 1 -6 alkyl; and R NB is selected from -COR A2 and -S0 2 R A2 .
  • R NA is unsubstituted linear or branched C 1 -6 alkyl; and R NB is selected from -CO(C 1 -6 alkyl) and -S0 2 R A2 .
  • R AL may be selected from
  • R AL may be selected from
  • R NA is Cs-eheteroaryl, optionally substituted with one or more groups R A1 ; and R NB is selected from -COR A2 and -S0 2 R A2 .
  • R NA is Csheteroaryl, optionally substituted with one or more groups R A1 (e.g. C 1 -6 alkyl, such as methyl); and R NB is selected from -COR A2 and -S0 2 R A2 .
  • R NA is Ceheteroaryl, optionally substituted with one or more groups R A1 (e.g. C 1 -6 alkyl, such as methyl); and R NB is selected from -COR A2 and -S0 2 R A2 .
  • R A is C 1-3 alkyl substituted by phenyl or C 5-6 heteroaryl, which groups may optionally be substituted with one or more groups R A1 ; and R B is selected from -COR A2 and -S0 2 R A2 .
  • R NA is C 1-3 alkyl (e.g. methyl) substituted by Csheteroaryl which is optionally substituted with one or more groups R A1 ; and R NB is selected from -COR A2 and -S0 2 R A2 .
  • R NA is C 1-3 alkyl (e.g. methyl) substituted b+y Ceheteroaryl which is optionally substituted with one or more groups R A1 ; and R NB is selected from -COR A2 and -S0 2 R A2 .
  • R NA is C 1-3 alkyl (e.g. methyl) substituted by phenyl which is optionally substituted with one or more groups R A1 ; and R NB is selected from -COR A2 and -S0 2 R A2 .
  • -NR NA R NB is a 5- or 6-membered heterocycloalkyl or
  • each R N1 is independently selected from R N2 and -OR N3 , wherein R N2 and R N3 are each independently selected from linear unsubstituted C 1 -6 alkyl; phenyl optionally substituted with one or more groups R A1 ,
  • -NR NA R NB is a 5- or 6-membered heterocycloalkyl or
  • heterocycloalkenyl group containing up to two heteroatoms in the ring selected from N, O and S in addition to the N atom of -NR NA R NB ; optionally substituted with one or more groups selected from
  • each R N1 is independently selected from R N2 and -OR N3 , wherein R N2 and R N3 are each independently selected from linear unsubstituted C 1 -6 alkyl; phenyl optionally substituted with one or more groups R A1 ,
  • -NR NA R NB is a 5- or 6-membered heterocycloalkyl or
  • heterocycloalkenyl group containing up to two heteroatoms in the ring selected from N, O and S in addition to the N atom of -NR NA R NB ; substituted with one or two oxo groups and optionally further substituted with one or more groups selected from
  • -NR NA R NB is a 5- or 6-membered heterocycloalkyl or
  • -NR NA R NB is a 5- or 6-membered heterocycloalkyl or
  • phenyl optionally substituted with one or more groups selected from F, CI, Br, CN, OH, 0(C 1 -6 alkyl), COOH and COO(C 1 -6 alkyl).
  • -NR NA R NB is a 5- or 6-membered heterocycloalkyl or
  • phenyl optionally substituted with one or more groups selected from F, CI, OH and 0(C 1 -6 alkyl).
  • -NR NA R NB is the group (A1 )
  • X N2 is selected from O, CR 4NA R 4NB and NR X ;
  • R x is selected from -H and -R A5 ;
  • each R 4NA and R 4NB is independently selected from
  • Ci-4alkyl optionally substituted with one or more groups R AL , phenyl, optionally substituted with one or more groups R A1 ,
  • R 4NA and R 4NB groups may be joined to form a 5- or
  • R 4NA groups independently two vicinal R 4NA groups may be joined to form a 5- or 6-membered alicyclic, heteroalicyclic, aromatic or heteroaromatic group optionally substituted with one or more groups R A1 ;
  • R A5 is selected from the group consisting of
  • R A5 may be joined to a vicinal R 4NA or R 4NB group to form a 5- or 6-membered heterocyclic or heteroaromatic group optionally substituted with one or more groups R'
  • -NR NA R NB is the group (A2)
  • V N2 is selected from O, NR X and CR 4NA R 4NB ;
  • V N2 cannot be O;
  • R x , R 4NA and R 4NB are as defined above.
  • -NR NA R NB is the group (A4)
  • Z N2 and Z N3 are each independently selected from the group consisting of
  • R 4NA , R 4NB and R x being as defined above.
  • -NR NA R NB is the group (A5)
  • W 1 to W 4 are each independently selected from CH and CR A1 .
  • -NR NA R NB is the group (A6)
  • W 5 to W 8 are each independently selected from CH and CR'
  • -NR NA R NB is selected from
  • -NR NA R NB is selected from a 5- or 6-membered heteroaryl group optionally substituted with one or more groups selected from
  • each R N1 is independently selected from R N2 and -OR N3 , wherein R N2 and R N3 are each independently selected from linear unsubstituted C 1 -6 alkyl; phenyl optionally substituted with one or more groups R A1 ,
  • -NR NA R NB is selected from a 5- or 6-membered heteroaryl group optionally substituted with one or more groups selected from
  • -NR NA R NB is selected from a 5- or 6-membered heteroaryl group containing up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of -NR NA R NB ; optionally substituted with one or more groups selected from
  • each R N1 is independently selected from R N2 and -OR N3 , wherein R N2 and R N3 are each independently selected from linear unsubstituted C 1 -6 alkyl; phenyl optionally substituted with one or more groups R A1 ,
  • -NR NA R NB is selected from a 5-membered heteroaryl group containing up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of -NR NA R NB ; optionally substituted with one or more groups selected from
  • each R N1 is independently selected from R N2 and -OR N3 , wherein R N2 and R N3 are each independently selected from linear unsubstituted C 1 -6 alkyl; phenyl optionally substituted with one or more groups R A1 ,
  • -NR NA R NB is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of -NR A R B ; optionally substituted with one or more groups R A1 .
  • -NR NA R NB is selected from a 5-membered heteroaryl group containing one or two heteroatoms in the ring in addition to the N atom of -NR A R B , the heteroatoms being N atoms; wherein the heteroaryl group is optionally substituted with one or more groups selected from
  • -NR NA R NB is selected from a 5-membered heteroaryl group containing one heteroatom in the ring in addition to the N atom of -NR NA R NB , wherein both heteroatoms are N atoms; and wherein the heteroaryl group is optionally substituted with one or more groups selected from
  • -NR NA R NB is selected from a 5-membered heteroaryl group containing two heteroatoms in the ring in addition to the N atom of -NR NA R NB , wherein both heteroatoms are N atoms; and wherein the heteroaryl group is optionally substituted with one or more groups selected from
  • -NR NA R NB is selected from a 5-membered heteroaryl group containing one or two heteroatoms in the ring in addition to the N atom of -NR NA R NB , the heteroatoms being N atoms; wherein the heteroaryl group is optionally substituted with one or more groups selected from
  • -NR NA R NB is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of -NR NA R NB ;
  • -NR NA R NB is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of -NR NA R NB ;
  • -NR NA R NB is the group (A3)
  • one group from Y N1 to Y N4 is CR 3 , another is N and the remainder are independently selected from CR 3 and N; wherein R 3 is selected from:
  • R 3 is selected from:
  • R 3 is selected from linear, branched or cyclic C 1 -6 alkyl optionally substituted with one group R AL . In some embodiments, R 3 is selected from linear, branched or cyclic unsubstituted C 1 -6 alkyl. In some embodiments, R 3 is selected from linear C 1-3 saturated alkyl.
  • -NR NA R NB is the group (A7)
  • Y N5 , Y N6 and Y N7 are selected from N and CR Y1 ; and the other two of Y N5 , Y N6 and Y N7 are each independently selected from CR Y1 ; wherein R Y1 is selected from -H;
  • -NR NA R NB is the group (A7), wherein Y N5 and Y N7 are each independently selected from CR Y1 , and Y N6 is selected from N, CH and CR Y1 , wherein R ' is selected from:
  • -NR NA R NB is the group (A7), wherein Y N5 and Y N7 are each independently selected from CR Y1 , and Y N6 is selected from N, CH and CR Y1 , wherein R ' is selected from:
  • -NR NA R NB is the group (A7), wherein Y N5 and Y N7 are each independently selected from CR Y1 , and Y N6 is selected from N, CH and CR Y1 , wherein R Y1 is selected from:
  • -NR NA R NB is the group (A7), wherein Y N5 and Y N7 are each independently selected from CR Y1 , and Y N6 is selected from N, CH and CR Y1 , wherein R Y1 is methyl or ethyl.
  • Y N6 is CH.
  • -NR NA R NB is the group (A7), wherein one of Y N5 , Y N6 and Y N7 is selected from N and CH; a second of Y N5 , Y N6 and Y N7 is CH and the third of Y N5 , Y N6 and Y N7 is selected from CH and CR Y1 ; wherein R Y1 is selected from
  • P x is (P1 ); R P1 and R P2 are each independently selected from methyl and ethyl;
  • R P3 is selected from
  • R z is selected from the group consisting of
  • Y N5 , Y N6 and Y N7 are selected from N and CR Y1 ; and the other two of Y N5 , Y N6 and Y N7 are each independently selected from CR Y1 ; wherein R Y1 is selected from -H;
  • -NR NA R NB is selected from
  • NR NA R NB is an imidazolyl group, bearing a C substituent which the group (D1 )
  • R B1 is selected from the group consisting of
  • R B2 is selected from -H, and linear or branched and
  • R B3 is selected from the group consisting of
  • -NR NA R NB is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from
  • the 8- to 10-membered heterobicyclyl group includes up to three heteroatoms in the bicyclic system in addition to the N atom of -NR NA R NB , for example one, two or three heteroatoms, each independently selected from N and O. In some embodiments, the 8- to 10-membered heterobicyclyl group includes up to three heteroatoms in the bicyclic system in addition to the N atom of -NR NA R NB , for example one, two or three heteroatoms, each independently selected from N. In some embodiments, the 8- to 10-membered heterobicyclyl group includes two heteroatoms in the bicyclic system in addition to the N atom of -NR NA R NB , each independently selected from N.
  • -NR NA R NB is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or two groups selected from
  • -NR NA R NB is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or two groups selected from
  • -NR NA R NB is a 9-membered heterobicyclyl group optionally substituted with one or more groups selected from
  • -NR NA R NB is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from
  • a "5,6" fused ring system indicates a bicyclic ring system in which a 5-membered ring is fused to a 6-membered ring.
  • -NR NA R NB is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from
  • -NR NA R NB is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from
  • -NR NA R NB is a 10-membered 6,6 fused heterobicyclyl group optionally substituted with one or more groups selected from
  • -NR NA R NB is selected from
  • R P1 and R P2 are methyl
  • R P3 is selected from the group consisting of:
  • 6-membered heteroaryl groups containing one to four (preferably two to four) heteroatoms independently selected from O and N, optionally substituted with one or two C 1-3 linear saturated alkyl groups;
  • R Au is the group (B1 ).
  • R P1 and R P2 are methyl
  • R P3 is selected from the group consisting of:
  • 6-membered heteroaryl groups containing one to four (preferably two to four) heteroatoms independently selected from O and N, optionally substituted with one or two C 1-3 linear saturated alkyl groups;
  • R Au is the group -NR NA R NB , wherein -NR NA R NB is selected from a 5-membered heteroaryl group containing up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of -NR NA R NB ; optionally substituted with one or more groups selected from
  • each R N1 is independently selected from R N2 and -OR N3 , wherein R N2 and R N3 are each independently selected from linear unsubstituted C 1 -6 alkyl; phenyl optionally substituted with one or more groups R A1 ,
  • the compound according to formula (I) is selected from:
  • -L s - is unsubstituted methylene. In other embodiments, -L s - is unsubstituted ethylene. In some embodiments, -L s - is a single bond.
  • -L s - is methylene substituted with one or two groups R 1A1 . In other embodiments, -L s - is ethylene substituted with one or two groups R 1A1 .
  • R 1A1 is selected from linear C 1-3 alkyl. In some embodiments, R 1A1 is methyl.
  • R SA is selected from linear C 1-3 alkyl. In some embodiments, R 1A1 is methyl.
  • R SA is selected from C 5-6 cycloalkyl, heterocyclyl, aryl or heteroaryl groups and 8- to 10- membered bicyclyl or heterobicyclyl groups, optionally substituted with one or more groups R A1 .
  • R SA is (S1 ):
  • one of Y S1 , Y S2 , Y S3 , Y S4 and Y S9 is N.
  • Y S1 is N and Y S2 , Y S3 , Y S4 and Y S9 are CH. In others of these
  • Y S3 is N and Y S1 , Y S2 , Y S4 and Y S9 are CH.
  • Y S4 is N and Y S1 , Y S2 , Y S3 and Y S9 are CH.
  • (S1 ) is pyridyl.
  • two of Y S1 , Y S2 , Y S3 , Y S4 and Y S9 are N.
  • Y S1 , Y S4 and Y S9 are CH and Y S2 and Y S3 are N.
  • Y S2 , Y S4 and Y S9 are CH and Y S1 and Y S3 are N.
  • Y S3 , Y S4 and Y S9 are CH and Y S1 and Y S2 are N.
  • Y S1 and Y S4 are N and Y S2 , Y S3 and Y S9 are CH.
  • Y S2 and Y S4 is N and Y S1 , Y S3 , and Y S9 are CH. In others of these embodiments, Y S3 and Y S4 are N and Y S1 , Y S2 and Y S9 are CH. In others of these embodiments, Y S3 and Y S9 are N and Y S1 , Y S2 and Y S4 are CH.
  • (S1 ) is selected from pyrimidinyl, pyridazinyl and pyrazinyl. In some embodiments, all of Y S1 , Y S2 , Y S3 , Y S4 and Y S9 are CH, i.e. (S1 ) is phenyl.
  • R SA is (S2):
  • V is O. In other of these embodiments, V is is selected from H and C 1-3
  • R° 1 is H. In others of these embodiments,
  • R° 1 is C 1-3 unbranched alkyl, e.g. methyl, ethyl, n-propyl.
  • V is N-C02-R C2 , where R C2 is either C 1-3 unbranched alkyl or C3-4 branched alkyl.
  • R C2 is C 1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl.
  • R C2 is C3-4 branched alkyl, i.e. /sopropyl, /sobutyl, sec-butyl and tert-butyl.
  • V is N-R N2 , where R N2 is C 1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl. In some embodiments, R N2 is methyl.
  • R SA is (S3):
  • X is NH. In others of these embodiments, X is O. In some of these embodiments, all of Y S5 , Y se , Y S7 and Y S8 are CH. In others of these embodiments, one of Y S5 , Y se , Y S7 and Y S8 is N. In some of these embodiments, Y S5 may be N. In some of these embodiments Y se may be N. In some of these embodiments Y S7 may be N. In some of these embodiments Y S8 may be N. In some embodiments, R SA is (S4):
  • R C1 is 0-R° 2 .
  • R° 2 is C 1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl.
  • R C1 is NHR N1 . In some of these embodiments, R N1 is H. In others of these embodiments, R N1 is C 1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl.
  • R C4 and R C5 are both H.
  • R C4 is H and R C5 is Me.
  • R C4 and R C5 are both Me.
  • R SA is (S5):
  • R C3 is C 1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl. In others of these embodiments R C3 is C2H4CO2H.
  • n is an integer from 4 to 8. In some of these embodiments
  • n is 7 or 8.
  • R SA is a 5-membered heteroaromatic group containing up to 4 heteroatoms selected from N, O and S, at least one of which being N.
  • R SA is a 5-membered heteroaromatic group containing up to 4 heteroatoms selected from N and O, at least one of which being N.
  • R SA is a 5-membered heteroaromatic group connected to sulfur at a ring carbon and containing up to 4 heteroatoms selected from N, O and S, at least one of which being N.
  • R SA is a 5-membered heteroaromatic group containing up to 4 heteroatoms selected from N.
  • R SA is unsubstituted tetrazolyl.
  • R SA is a 5-membered heteroaromatic group containing at least one heteroatom selected from N, O and S optionally N-substituted with one or more groups selected from
  • linear or branched C 1 -6 alkyl optionally substituted with one or more groups R AL .
  • R SA is a 5-membered heteroaromatic group containing at least one heteroatom selected from N, O and S optionally N-substituted with one or more groups selected from
  • R SA is a 5-membered heteroaromatic group containing at least one heteroatom selected from N, O and S optionally N-substituted with one or more methyl groups, and optionally C-substituted with one or more methyl groups. In some embodiments, R SA is selected from
  • R SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
  • R SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
  • R SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
  • R SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
  • R SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
  • R SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
  • R SA is selected from 6-membered aromatic carbocyclic groups ortho- and/or mefa-substituted with one or more groups selected from
  • R SA is selected from
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups R A1 . In some embodiments, R SA is selected from 6-membered heteroaryl group containing two nitrogen atoms, substituted with one or more groups R A1 .
  • R SA is selected from 6-membered heteroaryl group containing one nitrogen atom, substituted with one or more groups R A1 .
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one nitrogen atom, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing two nitrogen atoms, substituted with one group independently selected from the group consisting of
  • R SA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
  • R SA is selected from
  • R SA is selected from 8- to 10-membered heterobicyclyl groups containing one or more heteroatoms independently selected from N, O and S. In some embodiments, R SA is selected from 8- to 10-membered heterobicyclyl groups containing one or more heteroatoms each independently selected from N.
  • R SA is selected from 8- to 10-membered heterobicyclyl groups containing one, two or three heteroatoms independently selected from N, O and S.
  • R SA is selected from 8- to 10-membered heterobicyclyl groups containing one or two heteroatoms independently selected from N and O.
  • R SA is selected from 9-membered heterobicyclyl groups containing one or two heteroatoms independently selected from N, O and S. In some embodiments, R SA is selected from 9-membered heterobicyclyl groups containing one, two or three heteroatoms independently selected from N, O and S, connected to sulfur through a ring carbon atom.
  • the heterobicyclyl group is a heteroaromatic group.
  • R SA is selected from 8- to 10-membered heterobicyclyl groups containing one or more heteroatoms independently selected from N, O and S, wherein the heterobicyclyl group is substituted with one or more groups independently selected from R A1 .
  • R SA is selected from
  • R SA is the group
  • Z S3 is selected from the group consisting of CH 2 , CHF and CF2;
  • Z S1 , Z S2 , Z S4 and Z S5 is selected from the group consisting of
  • Z S1 , Z S2 , Z S4 and Z S5 are independently selected from the group consisting of
  • the ring contains 0 or 1 oxygen atoms, that nitrogen atoms cannot be in a 1 ,2 or 1 ,3 relationship to each other, and that when Z S1 or Z S5 is N, L s cannot be a single bond.
  • Z S3 is selected from the group consisting of Chb, CHF and CF2; one of Z S1 , Z S2 , Z S4 and Z S5 is selected from the group consisting of
  • Z S1 , Z S2 , Z S4 and Z S5 are CH2.
  • Z S3 is selected from the group consisting of CH2, CHF and CF2;
  • R SA is
  • R SA is the grou
  • one of Q 1 to Q 4 is selected from the group consisting of
  • N-CO-R A2 N-CO-NHR A2 , N-S0 2 -R A2 and N-C0 2 -R M ;
  • one of Q 1 to Q 4 is selected from the group consisting of
  • one of Q 1 to Q 4 is selected from the group consisting of
  • R SA is the grou (C1 )
  • E A is selected from the group consisting of
  • E A1 , E A2 and E A3 are D- or L-amino acid residues independently selected from Ala, Asn, Asp, Gin, Glu, Gly, His, lie, Leu, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -NR EA1 - and -COR EA2 groups represent terminals of the alpha or pendent functionality of the amino acids respectively;
  • amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality
  • R EA1 when E A2 is Pro, R EA1 is absent, otherwise R EA1 is R E1 ; the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHR A2 , -CONR A2 R E1 and -COOR A2 ; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C 1-3 alkyl) and -OCOCH 3 ; and when E A2 and E A3 are present and E A3 is not Pro the nitrogen of the amide bond between E A2 and E A3 may be optionally substituted with R E1 ;
  • R EA2 is selected from -OR E7 , -NH 2 , -NHR A2 and -NR A2 R E1 ;
  • R E7 is selected from -H and -R A2 ;
  • R E1 is selected from H and linear or branched C 1-3 alkyl.
  • E A is selected from the group consisting of
  • E A is selected from -NR EA1 -E A1 -COR EA2 .
  • E A is selected from the group consisting of
  • R EA2 is selected from -OR E7 .
  • R EA2 is selected from -IMH2, -NHR A2 and -NR A2 R E1 .
  • R EA2 is selected from -NH 2 .
  • L s is methylene and E A is selected from the group consisting of In some embodiments, L s is methylene and E A is selected from the group consisting of -NH-R A2 , and In some embodiments, L s is methylene and E A is selected from the group consisting of -0( C 1-3 alkyl),
  • L s is methylene and E A is selected from the group consisting of -NH-(C 1-3 alkyl), and
  • L s is methylene and E A is selected from the group consisting of -NH-CH 3 , and
  • R SA is
  • R SA is selected from the roup (C2)
  • R E1 is selected from H and linear or branched C 1-3 alkyl
  • E B is selected from -CO-E B2 -E B3 -N R EB R E2 ,
  • E B1 , E B2 and E B3 are D- or L-amino acid residues independently selected from Ala, Asn, Asp, Gin, Glu, Gly, His, lie, Leu, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -CO-, -NR EA R E2 and -NR EB R E2 groups represent terminals of the alpha or pendent functionality of the amino acids;
  • amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality
  • the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHR A2 , -CONR A2 R E1 and - COOR A2 ; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C 1-3 alkyl) and -OCOCH3; and when E B2 and E B3 are present and E B2 is not Pro the nitrogen of the amide bond between E B2 and E B3 may be optionally substituted with R E1 ;
  • R E2 is selected from -H and -COCH3;
  • E B is selected from E BA .
  • E B is selected from
  • E B is -CO-E B1 -NR EA R E2 .
  • R E2 is -H.
  • R E2 is -COCH3.
  • R E1 is -H. In some embodiments of the group (C2), R E1 is methyl. In some embodiments, R SA is the group (C3)
  • R E1 is selected from H and linear or branched C 1-3 alkyl
  • E c is selected from
  • E C1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -NR EC1 - and -COR EC2 groups represent terminals of the alpha or pendent functionality of the amino acids;
  • amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality
  • R EC1 when E C1 is Pro, R EC1 is absent, otherwise R EC1 is R E1 ;
  • the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH 2 , -CONHR A2 , -CONR A2 R E1 and - COOR A2 ; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C 1-3 alkyl) and -OCOCH 3 ;
  • R EC2 is selected from -OR E9 , -NH 2 , -NHR A2 and -NR A2 R E1 ;
  • R E3 and R E4 are independently selected from -H and -CH3;
  • E D is selected from
  • E D1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -
  • NR ED R E6 - and -CO- groups represent terminals of the alpha or pendent functionality of the amino acids
  • amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality
  • acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHR A2 , -CONR A2 R E1 and -COOR A2 ; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C 1-3 alkyl) and -OCOCH3; wherein R E5 and R E6 are independently selected from -H and -COCH3;
  • R A is not L-cysteine
  • E c is selected from
  • E c is selected from
  • E c is selected from E D is -CO-E D1 -NR ED R E6 .
  • E c is -NR EC1 -E c1 -COR EC2 ;
  • E D is -CO-E D1 -NR ED R E6 .
  • R E3 and R E4 are the same. In some embodiments, R E3 and R E4 are both -H. In some embodiments, R E3 and R E4 are both methyl. In some embodiments of the group (C3), R E1 is -H. In some embodiments, R SA is
  • R SA is the grou (C4)
  • Z 6 is selected from N-CO-R A2 and N-CO-NHR A2 ;
  • R Z6 is one or two optional methyl substituents.
  • R Au is the group (B3), i.e. the group -C ⁇ C-L C -R CA .
  • L c is the group (B3), i.e. the group -C ⁇ C-L C -R CA .
  • -L c - is unsubstituted methylene. In other embodiments, -L c - is unsubstituted ethylene. In some embodiments, -L c - is a single bond. In some embodiments, -L c - is methylene substituted with one or two groups R 1A1 . In other embodiments, -L c - is ethylene substituted with one or two groups R 1A1 .
  • R 1A1 is selected from C 1-3 linear unsubstituted alkyl. In some embodiments, R 1A1 is methyl.
  • -L c - is a single bond and R CA is R CAA .
  • -L c - is methylene or ethylene optionally substituted with one or more groups R 1A1 and R CA is selected from R CAA and R CAB .
  • R CAA is selected from linear or branched C 1 -6 alkyl, substituted with one or more groups R AL .
  • R CAA is methyl, substituted with one or more groups R AL .
  • R CAA is methyl, substituted with -NR A2 2. In some embodiments, R CAA is methyl, substituted with -N(C 1 -6 alkyl) 2 .
  • R CAA is methyl, substituted with one or more groups R AL , wherein R AL is selected from
  • R CAA is methyl, substituted with one or more groups R AL , wherein R AL is selected from
  • R CAA is ethyl, substituted with one or more groups R AL , wherein R AL is selected from In some embodiments, R CAA is branched C3-4alkyl, substituted with one or more groups R AL .
  • R CAA is selected from:
  • R CAA is the roup (D1 )
  • R B1 is selected from the group consisting of
  • R B2 is selected from -H, and linear or branched Ci-4alkyl
  • R B3 is selected from the group consisting of
  • L c is a single bond and R CAA is
  • R CAA is C3-5cycloalkyl, optionally substituted with one or more groups R AL .
  • R AL may be selected from
  • R CAA is selected from 8- to 10-membered bicyclyl and biheterocyclyl, optionally substituted with one or more groups R A1 .
  • R CAA is 9-membered biheterocyclyl including two or more heteroatoms selected from N and O.
  • R CAA is selected from
  • R CAA is selected from 5-membered heteroaryl containing one or more heteroatoms selected from N, O and S, optionally N-substituted with one or more groups R A2 and/or C-substituted with one or more groups R A1 . In some embodiments, R CAA is selected from 5-membered heteroaryl containing one or more heteroatoms selected from N and O, optionally N-substituted with one or more groups R A2 .
  • R CAA is selected from 5-membered heteroaryl containing one or more heteroatoms independently selected from N and O, optionally N-substituted with one or more groups selected from linear or branched C 1 -6 alkyl.
  • R CAA is selected from 5-membered heteroaryl containing two heteroatoms independently selected from N and O, optionally N-substituted with one or more groups R A2 .
  • R CAA is selected from 5-membered heteroaryl containing two heteroatoms independently selected from N and O, optionally N-substituted with one or more groups selected from linear or branched C 1 -6 alkyl.
  • R CAA is selected from
  • R CAA is selected from the group consisting of (D2) to (D4):
  • W 1B is selected from the group consisting of N and C;
  • W C1 and W 1A are each independently selected from the group consisting of NH, NR A2 , O and S;
  • W C2 to W C4 , W 2A to W 4A and W 2B to W 5B are each independently selected from the group consisting of CH, CR A1 and N.
  • R CAA is -COOH.
  • R CAA is -COOR A2 , wherein R A2 is selected from linear or branched C 1 -6 alkyl. In some of these embodiments, R A2 may be selected from linear or branched C 1-3 alkyl. In further embodiments, R A2 may be selected from linear C 1-3 alkyl, e.g. methyl, ethyl.
  • R CAA is -CONH2.
  • R CAA is selected from -CONHR A2 , wherein R A2 is selected from linear or branched C 1 -6 alkyl. In some of these embodiments, R A2 may be selected from linear or branched C 1-3 alkyl. In further embodiments, R A2 may be selected from linear C 1-3 alkyl, e.g. methyl, ethyl.
  • R CAA is selected from -CONR A2 2, where R A2 may be as expressed above.
  • R CAA is selected from
  • R CAA is selected from
  • R CAA is the group (D5)
  • V 6 is selected from the group consisting of CH and CR A2 ;
  • V 1 to V 5 are independently selected from the group consisting of
  • V 1 to V 5 are independently selected from the group consisting of
  • R A6 is selected from the group consisting of
  • any two adjacent groups from V to V 5 cannot both be SO2, cannot both be CO, and a CO or O group cannot be adjacent to an SO2 group, and cannot both be NR A6 .
  • R CAA is the group (D5) wherein V 6 is selected from CH and CR A2 , one of V 1 to V 5 is selected from CHF, CF 2 , O, S0 2 , NH and NR A2 and the remainder of V 1 , V 2 , V 4 and V 5 are CH 2 .
  • R CAA is the group (D5) wherein V 6 is selected from CH and CR A2 , V 3 is selected from CH 2 , CHF, CF 2 , O, S0 2 , NH and NR A2 and V 1 , V 2 , V 4 and V 5 are CH 2 .
  • R CAA is the group (D5) wherein V 6 is CH, V 3 is selected from CH 2 , CHR A1 , CR A1 2 , O, S0 2 , NH and NR A2 and V 1 , V 2 , V 4 and V 5 are CH 2 .
  • R CAA is the group (D6)
  • a first group from X 1 to X 5 is selected from the group consisting of
  • Y is selected from one of the groups (D7) to (D9);
  • L v is selected from methylene, and a single bond
  • V 12 , Y 1 and Z 1 are each independently selected from the group consisting of CH, CR 1A1 and N;
  • V 7 to V 11 are independently selected from the group consisting of
  • V 7 to V 11 are independently selected from the group consisting of
  • V 7 to V 11 being selected from the group consisting of
  • any two adjacent groups from V 7 to V 11 cannot both be CO and cannot both be NR A7 ; and a CO or O group cannot be adjacent to an S0 2 group;
  • one of Y 2 to Y 5 is selected from the group consisting of
  • two further groups of Y 2 to Y 5 are independently selected from the group consisting of
  • any two adjacent groups from Y 2 to Y 5 cannot both be CO and cannot both be NR A7 ; and a CO group cannot be adjacent to an S0 2 group; when Z 1 is N, Z 2 , Z 3 and Z 4 are each independently selected from the group consisting of
  • Z 1 is CH or CR 1A1
  • one of Z 2 , Z 3 and Z 4 is NR A7 and the remaining two positions are independently selected from the group consisting of CH 2 , CHR 1A1 and CR 1A1 2;
  • R A7 is selected from the group consisting of
  • a second and third group from X 1 to X 5 is selected from the group consisting of
  • X 1 to X 5 are each independently selected from the group consisting of
  • R CAB is selected from
  • V nor V 5 can be NR A6 and that any two adjacent groups cannot be both O, CO, NR A6 or SO2; and that a CO or O group cannot be adjacent to an SO2 group.
  • R CAA is the group (D6) wherein three groups from X 1 , X 2 , X 3 , X 4 and X 5 are CH; a further group is selected from CH and N and the fifth group is N.
  • R AA is selected from pyridyl and diazinyls (e.g. pyrazinyl, pyrimidnyl and pyridazinyl).
  • R CAA is the group (D6) wherein four groups from X 1 , X 2 , X 3 , X 4 and X 5 are CH and the fifth group is CR A1 .
  • R CAA is selected from the group (D6) wherein four groups from X 1 , X 2 , X 3 , X 4 and X 5 are CH and the fifth group is CR A1 , wherein R A1 is selected from the group consisting of C 1 -6 alkyl wherein the alkyl chain is interrupted with one S atom,
  • R CAA is the group (D6) wherein four groups from X 1 , X 2 , X 3 , X 4 and X 5 are CH and the fifth group is CR A1 , wherein R A1 is selected from the group consisting of C 1 -6 alkyl wherein the alkyl chain is interrupted with one S atom,
  • R CAA is the group (D6) wherein four groups from X 1 , X 2 , X 3 , X 4 and X 5 are CH and the fifth group is CR A1 , wherein R A1 is selected from the group consisting of
  • R CAA is the group (D6) wherein three groups from X 1 , X 2 , X 3 , X 4 and X 5 are CH and the remaining two groups are independently CR A1 , wherein R A1 is selected from the group consisting of
  • R CAA is the group (D6) wherein three groups from X 1 , X 2 , X 3 , X 4 and X 5 are CH and the remaining two groups are independently CR A1 , wherein R A1 is selected from the group consisting of

Abstract

Compound of formula (I) and pharmaceutically acceptable salts and solvates thereof are described, wherein: Px selected from (P1), (P2) or (P3); The compounds are useful in the prevention or treatment of a bacterial infection.

Description

GOLD COMPOUNDS AND THEIR USE IN THERAPY
The present invention relates to gold(l)-phosphine compounds, their use as inhibitors of growth of Gram-positive and/or Gram-negative bacteria, and their use for the prevention and/or treatment of a disease or disorder selected from fungal infections, Protozoal infections, inflammatory diseases, proliferative diseases and viral diseases. The present invention also relates to using such compounds for the prevention and/or treatment of bacterial infection, or the prevention and/or treatment of a disease or disorder selected from fungal infections, Protozoal infections, inflammatory diseases, proliferative diseases and viral diseases.
The global rise of bacteria and other microorganisms resistant to antibiotics and antimicrobials in general, poses a major threat. Deployment of massive quantities of antimicrobial agents into the human ecosphere during the past 60 years has introduced a powerful selective pressure for the emergence and spread of antimicrobial-resistant bacterial pathogens. The World Health Organization has highlighted antimicrobial resistance (AMR) as an issue of global concern in 2014. AMR is now present in all parts of the world with the incidence of antibiotic resistance (ABR) in bacteria that cause common infections (e.g. pneumonia, bloodstream infections and urinary tract infections) rendering many historically efficacious antibiotics ineffective. Of particular concern are hospital-acquired infections caused by highly resistant bacteria such as the ESKAPE pathogens {Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species), Escherichia coli, Coagulase-negative staphylococci and Clostridium difficile. Additionally, failure of last resort third-generation cephalosporins for the treatment of gonorrhea has now been reported in 10 countries raising the possibility that gonorrhea may soon become untreatable in the absence of new antibacterial agents.
The biological activity of gold(l) and gold(lll) complexes has been studied historically and salts of both have been demonstrated to possess antimicrobial activity against a range of pathogens. Gold(l) complexes have historically been reported as having antibacterial activity against Gram-positive organisms. (Glisic, B.D. & Djuran M.I., Dalton Trans., 2014, 43, 5950-5969). For example, Nomiya (Nomiya, K., et al., J. Inorganic Biochem., 2003, 95, 208-220) discloses triphenyl phosphine compounds with a variety of ligands with antibacterial activity against Gram-positive organisms, and Aguinagalde, L, et al., J. Antimicrob. Chemother., 2015, 70(9), 2608-2617 discloses six triethyl phosphine compounds with antibacterial activity against Gram-positive organisms.
Gold(l) is a soft Lewis acid and preferentially complexes with soft donor atoms such as sulfur, selenium and phosphorous. Examples of such complexes used clinically include gold thiomalate, aurothioglucose and auranofin:
Figure imgf000004_0001
Auranofin, a second generation orally bioavailable gold(l) based treatment for rheumatoid arthritis (RA), has been identified as inhibiting the in vitro growth of S. aureus (Oxford strain) with an MIC of 0.6-0.9 μg/mL and V. cholerae with an MIC of 2.5 μg/mL. These observations reinforce multiple literature reports of the antimicrobial activity of auranofin and other gold(l) compounds against a range of bacterial pathogens (Madeira, JM., Inflammopharmacology, 2012, 20, 297-306; Jackson-Rosario, S, J. Biol. Inorg. Chem., 2009, 14(4), 507-519; Novelli, F., Farmaco, 1999, 54, 232-236; Shaw, CF, Chem Rev., 1999, 99(9), 2589-2600; Rhodes, MD, J. Inorg. Biochem., 1992, 46, 129-142 and Fricker, SP, Transition Met. Chem., 1996, 21 , 377-383). Auranofin has not been shown to have any significant activity against the majority of Gram-negative bacteria.
WO 2015/181551 A1 and WO 2015/181550 A1 in the name of Auspherix Limited, incorporated herein by reference, describe certain gold(l) phosphine compounds and their use as inhibitors of growth of Gram-positive and/or Gram-negative bacteria.
Co-pending applications PCT/EP2016/079679, PCT/EP2016/079680 and
PCT/EP2016/079681 (published as WO 2017/093543, WO 2017/093544 and WO
2017/093545 respectively) describe certain gold(l) phosphine compounds and their use as inhibitors of growth of Gram-positive and/or Gram-negative bacteria. There are approximately 300 species of fungi which are pathogenic to humans and resistance to antifungal agents is increasing, making treatment of mycotic infection challenging (https://www.cdc.gov/fungal/diseases/index.html). Invasive fungal infections are a significant cause of morbidity and mortality in healthcare and community settings. Pathogenic fungal infections are commonly associated with but not limited to Candida spp, Aspergillus fumigatus, Mucor, Rhizopus, Absidia, Cunninghamella (Lee F.Y.; Mossad S.B.; Adal K.A. (1999). "Pulmonary mucormycosis: the last 30 years". Arch Intern Med. 159 (12): 1301-9), Cryptococcus neoformans, C. gattii (Vallabhaneni S et al., Emerg Infect Dis. 2015 Oct [date cited], http://dx.doi.org/10.3201/eid21 10.150249), Pneumocystis jirovecii (Harris JR et al., Curr Fung Infect Rep 2010;4:229-37), Blastomyces dermatitidis (Saccente M et al., Clin Microbiol Rev. 2010 Apr;23(2):367-81 ), Coccidioides immitis, Coccidioides posadasii, Histoplasma capsulatum, Sporothrix schenckii, Aspergillus flavus, Fusarium spp., Alternaria spp., Curvularia spp., and Acremonium spp. (Bharathi MJ et al., Indian J Ophthalmol. 2003;51 :315-21 ).
The fungal infections caused by the above include candidiasis, cryptococcosis, histoplasmosis, blastomycosis, paracoccoidiomycosis, coccidioidomycosis, aspergillosis, extracutaneous sporotrichosis, and mucormycosis (Ellis D., J Antimicrob Chemother. 2002 Feb;49 Suppl 1 :7-10).
The diverse eukaryotic subgroup Protozoa contains many pathogenic species of clinical relevance. Despite being more commonly associated with infection in low-middle income countries, incidences of enteric protozoal infection have increased in high income countries over recent years (Artemis Efstratiou et al., Water Research. (2017), (1 14) :pp14-22). Resistance to antiparasitic agents has been reported in several species (Genetu Bayih A et al., Clin Microbiol Rev. (2017) 30(3):647-669. doi: 10.1 128/CMR.001 1 1 -16; Squire SA et al., Parasit Vectors. (2017), 20;10(1 ):195; Arjen M. Dondorp et al., Trends in Parasitology (2017) 33(5):353-363) and this demonstrates the need for new drugs to target a growing threat to human health. Clinically relevant protozoa include, Trypanosoma cruzi, T brucei, Leshmania spp., Dientamoeba fragilis, Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica, Naeglaeri fowleri, Acanthomoeba, Balamuthia mandrillaris, Plasmodium spp., Babesia microti, Cryptosporidium parvum, Cycolspora cayetanensis, Cystoisopora belli, Toxoplasma gondii, Sarcocystis spp., and Balantidium coll.
A first aspect of the invention is a compound according to formula (I):
Figure imgf000006_0001
and pharmaceutically acceptable salts and solvates thereof, wherein: Px is selected from (P1 ), (P2) or (P3);
Figure imgf000006_0002
wherein RP1 and RP2 are each independently selected from
methyl, ethyl and -CH2OMe;
RP3 is selected from the group consisting of:
(i) -CH2RP6, -CH2CH2RP6, -CHMeRP6, -C(Me)2RP6, -CH(RP6)2, -CMe(RP6)2, -C(C3- 4cycloalkyl)RP6, -C(=NH)RP6, -CH2C(=NH)RP6, sec-butyl, 1-propynyl, -COOH,
trimethylsilyl(ethynyl),
(ii) C3-4 unsubstituted linear saturated alkyl,
(iii) C3-4 saturated cycloalkyl, optionally substituted with one C1-3 linear saturated alkyl group;
(iv) 4- or 5-membered heterocyclyl or heterocycloalkenyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group,
(v) 5-or 6-membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups, RP4 is selected from linear, branched or cyclic C3 saturated alkyl groups, optionally substituted with a methyl group; m is 1 , 2 or 3; and RM is one or more optional substituents on the ring independently selected from
Rpc when attached to a carbon atom adjacent the phosphorus atom, or
-OH, -OC1-3alkyl and Rpc, when attached to other ring carbons;
Rpc is selected from the group consisting of
C1-3alkyl, optionally substituted with one or more groups RPD; and
oxo;
RP5 is selected from linear or branched unsubstituted C1-4 saturated alkyl groups, or cyclic C3-4 saturated alkyl groups optionally substituted with a methyl group; each RP6 group is independently selected from
4-membered heterocyclyl or heteroaryl groups containing one or two heteroatoms selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
-F,
-OH, -OMe, -OEt,
-SH, -SMe, -SEt,
-S(=0)H, -S(=0)Me, -S(=0)Et,
-SO2H, -S02Me, -S02Et,
-CH2OH, -CH2OMe, -CH2OEt,
-CH2SH, -CH2SMe, -CH2SEt,
-CH2S(=0)H, -CH2S(=0)Me, -CH2S(=0)Et,
-CH2S02H, -CH2S02Me, -CH2S02Et,
-C(=0)OH, -C(=0)NH2, -C(=0)NHMe, -C(=0)NMe2,
-NH2, -NHMe, -NMe2, -NMe3 +,
-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me;
RP7 and RP8 are each independently selected from H and methyl or together for an oxo group; RP9 and RP1° are each independently selected from H and methyl or together for an oxo group;
RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form either
a 4- or 5-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally mono-substituted with a group RPE, or
a 6-membered heterocyclic ring including 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups RPE;
RPD is selected from the group consisting of
F,
OH and OC1-3alkyl;
RPE is selected from
methyl and oxo; RAu is selected from the groups (B1 ) to (B3):
Figure imgf000008_0001
wherein:
RNA is selected from the group consisting of
H;
linear or branched C1 -6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl,
C4-6heterocycloalkyl or heteroaryl, C5-6cycloalkenyl and C5-6heterocycloalkenyl optionally substituted with one or more groups RAL, and
RNB is selected from -CORA2 and -S02RA2; or RNA and RNB together with the nitrogen atom to which they are attached form
a 5- or 6-membered heteroaryl, heterocycloalkyi or heterocycloalkenyl group or 8- to 10-membered heterobicydyl group, optionally substituted with one or more groups selected from
oxo, =NH, RA1, RA2,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; and
phenyl optionally substituted with one or more groups RA1,
-Ls- and -Lc- are each independently selected from
methylene or ethylene, optionally substituted with one or two groups R1A1, and a single bond;
RSA is selected from the group consisting of
(i) C5-6 cycloalkyi, heterocyclyl, aryl or heteroaryl groups and 8- to 10- membered bicyclyl or heterobicydyl groups, optionally substituted with one or more groups RA1; and
(ii) the groups (C1 ) to (C3)
Figure imgf000009_0001
wherein
EA is selected from the group consisting of: -0-RA2; -NH-RA2; -NRA¾
RE1 is selected from H and linear or branched C1-3alkyl; EB is selected from: EBA; -CO-EB1-NREARE2 and -CO-EB2-EB3-NREBRE2; wherein EB1, EB2 and EB3 are D- or L-amino acid residues independently selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -CO-, -NREARE2 and -NREBRE2 groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality; when EB1 is Pro, REA is absent, otherwise REA is RE1; when EB3 is Pro, REB is absent, otherwise REB is RE1; wherein the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, - CONRA2RE1 and -COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and - OCOCH3; and when EB2 and EB3 are present and EB2 is not Pro the nitrogen of the amide bond between EB2 and EB3 may be optionally substituted with RE1; when EB is EBA, RE1 and EBA together with the nitrogen atom to which they are attached form a group selected from:
5- or 6-membered saturated heterocyclyl optionally substituted with one or more groups RAL, and
5- or 6-membered heteroaryl optionally substituted with one or more groups RA1;
Ec is selected from: -OH; -ORA2; -NH2; NHRA2; NRA2 2 and -NREC1-Ec1-COREC2; wherein EC1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys,
Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the - NREC1- and -COREC2 groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality; when EC1 is Pro, REC1 is absent, otherwise REC1 is RE1; wherein the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, -
CONRA2RE1 and -COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and - OCOCHs; REC2 is selected from -ORE9, -NH2, -NHRA2 and -NRA2RE1;
RE3 and RE4 are independently selected from -H and -CH3; when RE1 is H and Ec is -OC1-3alkyl, -NH2 or -NHC1-3alkyl, ED is selected from -H, and -CO-ED1-NREDRE6, otherwise, ED is selected from: -RE5, and -CO-ED1-NREDRE6; wherein ED1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the - NREDRE6- and -CO- groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality; wherein the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, -CONRA2RE1 and -COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and -OCOCH3; when ED1 is Pro, RED is absent, otherwise RED is RE1;
RE2, RE5 and RE6 are independently selected from -H and -COCH3;
RE7, RE8 and RE9 are each independently selected from -H and -RA2; when Lc is a single bond, RCA is RCAA,
wherein RCAA is selected from the group consisting of
linear or branched C1 -6alkyl, substituted with one or more groups RAL,
C3-6 cycloalkyl, aryl or heteroaryl, optionally substituted with one or more groups selected from VC1, -CH2VC1, oxo, RAL, RA1 and RA2; wherein VC1 is a C4-6 cycloalkyl or heterocyclyl group optionally substituted with one or more groups selected from oxo and RA1;
8- to 10-membered bicyclyl and biheterocyclyl, optionally substituted with one or more groups RA1,
Figure imgf000012_0002
when Lc is methylene or ethylene, RCA is selected from RCAA and RCAB, wherein RCAB is selected from
C2-6alkenyl and C2-6alkynyl, optionally substituted with one or more groups RAL, or
C6 heterocyclyl attached to Lc via a ring N atom, optionally substituted with one or more groups RA1; wherein RA1 is selected from the group consisting of
linear or branched C1 -6alkyl, C2-6alkenyl or C2-6alkynyl optionally substituted with one or more groups RAL, wherein the alkyl chain is optionally interrupted by one or more atoms selected from O and S,
Figure imgf000012_0001
RA2 is selected from the group consisting of
linear or branched C1 -6alkyl, C2-6alkenyl or C2-6alkynyl optionally substituted with one or more groups RAT, wherein the alkyl chain is optionally interrupted by one or more atoms selected from O and S,
OC1 -6alkyl; C3-6cycloalkyl, C4-6heterocycloalkyl, C5-6cycloalkenyl or Cs-eheterocycloalkenyl optionally substituted with one or more groups RAT,
phenyl optionally substituted with one or more groups RAR, and
C5-ioheteroaryl optionally substituted with one or more groups RAR;
where N is substituted by 2 RA2 groups, the N and the RA2 groups may together form a N- containing C5-6 heterocycloalkyl group, optionally substituted with one or two groups selected from linear unsubstituted C1 -6 alkyl;
R1 A1 is selected from linear or branched unsubstituted C1-3alkyl;
RAL is selected from the group consisting of
linear or branched C1 -6alkyl optionally substituted with one or more groups RAT;
Figure imgf000013_0001
RAR is selected from the group consisting of
linear or branched C1 -6alkyl, C2-6alkenyl or C2-6alkynyl optionally substituted with one or more groups RAT,
Figure imgf000013_0002
RAT is selected from the group consisting of
Figure imgf000013_0003
-OCOC1-3alkyl, -OCONH2, -OCONHC1-3alkyl, -OCON(C1-3alkyl)2, -NH2, -NHC1-3alkyl, -N(C1-3alkyl)2,
-S02NH2, -S02NH(C1-3alkyl)2, -S02N(C1-3alkyl)2, -S02(C1-3alkyl),
-NHCOH, -NHCO(C1-3alkyl), -N(C1-3alkyl)COH and -N(C1-3alkyl)CO(C1-3alkyl);
R1A1 is a linear or branched unsubstituted C1 -6 alkyl group.
In some embodiments,
RP3 is selected from the group consisting of:
(i) -CH2RP6, -CH2CH2RP6, -CHMeRP6, -C(Me)2RP6, -CH(RP6)2, -CMe(RP6)2, -
C(C3-4cycloalkyl)RP6, -C(=NH)RP6, -CH2C(=NH)RP6, sec-butyl, 1 -propynyl, -COOH,
(ii) C3-4 unsubstituted linear saturated alkyl,
(iii) C3-4 saturated cycloalkyl, optionally substituted with one C1-3 linear saturated alkyl group;
(iv) 4- or 5-membered heterocyclyl or heterocycloalkenyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group,
(v) 5-or 6-membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
and each RP6 group is independently selected from
4-membered heterocyclyl or heteroaryl groups containing one or two heteroatoms selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
-OH, -OMe, -OEt,
-SH, -SMe, -SEt,
-S(=0)H, -S(=0)Me, -S(=0)Et,
-S02H, -S02Me, -S02Et,
-CH2OH, -CH2OMe, -CH2OEt,
-CH2SH, -CH2SMe, -CH2SEt,
-CH2S(=0)H, -CH2S(=0)Me, -CH2S(=0)Et,
-CH2S02H, -CH2S02Me, -CH2S02Et,
-C(=0)OH, -C(=0)NH2, -C(=0)NHMe, -C(=0)NMe2,
-NH2, -NHMe, -NMe2, -NMe3 +,
-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me. The first aspect of the invention also provides a compound according to formula (I) for use in the prevention or treatment of a bacterial infection. The first aspect of the invention also provides the use of a compound of formula (I) in the manufacture of a medicament for the treatment and/or prevention of a bacterial infection. The first aspect of the invention further provides a method of treatment of a human or animal patient afflicted with a bacterial infection, comprising administering to said patient an effective amount of a pharmaceutical composition containing a compound of formula (I).
In the first aspect, the bacterial infection prevented and/or treated may be infection by one or more Gram-positive bacteria. The bacterial infection prevented and/or treated may be infection by one or more Gram-negative bacteria. In the first aspect, the bacterial infection prevented and/or treated may be infection by one or more multi-drug resistant bacteria. The first aspect may also relate to the treatment of fungal infection, e.g. by providing a compound of formula (I) for use in the prevention or treatment of a fungal infection.
The fungal infection prevented and/or treated may be an infection selected from candidiasis, cryptococcosis, histoplasmosis, blastomycosis, paracoccoidiomycosis, coccidioidomycosis, aspergillosis, extracutaneous sporotrichosis, and mucormycosis.
The fungal infection prevented and/or treated may be an infection caused by a fungus selected from Candida spp, Aspergillus fumigatus, Mucor, Rhizopus, Absidia,
Cunninghamella, Cryptococcus neoformans, C. gattii, Pneumocystis jirovecii,
Blastomyces dermatitidis, Coccidioides immitis, Coccidioides posadasii, Histoplasma capsulatum, Sporothrix schenckii, Aspergillus flavus, Fusarium spp., Alternaria spp., Curvularia spp., and Acremonium spp.
The first aspect may also relate to the prevention and/or treatment of a Protozoal infection, e.g. by providing a compound of formula (I) for use in the prevention or treatment of a Protozoal infection. In some embodiments, the invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of a Protozoal infection. Methods of preventing or treating such diseases are also provided. The Protozoal infection prevented and/or treated may be an infection caused by Protozoa selected from Trypanosoma cruzi, T brucei, Leshmania spp., Dientamoeba fragilis, Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica, Naeglaeri fowleri,
Acanthomoeba, Balamuthia mandrillaris, Plasmodium spp., Babesia microti,
Cryptosporidium parvum, Cycolspora cayetanensis, Cystoisopora belli, Toxoplasma gondii, Sarcocystis spp., and Balantidium coli.
The first aspect may also relate to the prevention and/or treatment of an inflammatory disease. For example, the first aspect may also relate to the prevention and/or treatment of a disease selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis. In some embodiments, the invention provides a compound of formula (I) for use in the prevention or treatment of an inflammatory disease, for example a disease selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis. In some embodiments, the invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of an inflammatory disease, for example a disease selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis. Methods of preventing or treating such diseases are also provided.
The first aspect may also relate to the prevention and/or treatment of a proliferative disease, for example cancer. In some embodiments, the invention provides a compound of formula (I) for use in the prevention or treatment of a proliferative disease, for example cancer, for example a cancer selected from ovarian, skin, breast, lung, prostate, colorectal, lymphomas, bladder, uterine, kidney and blood cancers including leukaemia, lymphoma and myeloma. In some embodiments, the invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of a proliferative disease, for example cancer, for example a cancer selected from ovarian, skin, breast, lung, prostate, colorectal, lymphomas, bladder, uterine, kidney and blood cancers including leukaemia, lymphoma and myeloma. Methods of preventing or treating such diseases are also provided. The first aspect may also relate to the prevention and/or treatment of a viral disease. In some embodiments, the invention provides a compound of formula (I) for use in the prevention or treatment of a viral disease, for example a disease caused by the human immunodeficiency virus (HIV) / AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV). In some embodiments, the invention provides the use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of a viral disease, for example a disease caused by the human immunodeficiency virus (HIV / AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV). Methods of preventing or treating such diseases are also provided.
Compounds of the present invention may also be used to treat conditions by interaction, e.g. binding to thioredoxin reductase (TrxR), glutathione peroxidase (GSPx), ΙκΒ kinase (IKK) complex, cathepsins and type I iodothyronine deiodinase. A third aspect of the present invention provides a pharmaceutical composition comprising a compound of the second aspect of the invention. The pharmaceutical composition may also comprise a pharmaceutically acceptable diluent or excipient. The third aspect of the present invention also provides the use of a compound of the second aspect of the invention in a method of therapy.
Another aspect of the invention provides a compound according to formula (II):
Figure imgf000017_0001
wherein Px is as defined elsewhere herein.
Another aspect of the invention provides a complex of formula VIII:
Figure imgf000017_0002
wherein Px is as defined elsewhere herein, and E is a residue of a thiol-containing, selenol-containing or NH-containing endogenous ligand or protein.
Without wishing to be bound by theory, it is believed that compounds according to certain aspects of the invention, such as those according to formulae (I) or (II), may act as prodrugs which decompose within the body by cleavage of the Au-S bond and its replacement with an endogenous ligand or protein, such as those entrained within the blood of an organism. These may be, for example, thiol-containing, selenol-containing or NH-containing (e.g. an amide or a DNA base) ligand. The resultant complexes (i.e. complexes according to formula VIII) may then exert a therapeutic effect as described herein (see Crooke et al., Biochemical Pharmacology, 1986, Vol. 35, No. 20, 3423-3431 and Snyder et al., Biochemical Pharmacology, 1986, Vol. 35, No. 6, 923-932).
E is a "residue of a thiol-containing, selenol-containing or NH-containing endogenous ligand or protein", in other words E is a ligand formed from the reaction of a thiol- containing, selenol-containing or NH-containing endogenous ligand or protein (ES-SH, ESE-SeH or EN-NH respectively) with the gold atom of the gold(l) phosphine (PY=Au) at a thiol or selenol group on the endogenous ligand or protein. As a result, -E has a structure selected from -S-Es,-Se-ESE and -N-EN, where Es is the remainder of the thiol-containing endogenous ligand or protein (connected to Au via the S atom of a reacted thiol group), ESE is the remainder of the selenol-containing endogenous ligand or protein (connected to Au via the Se atom of a reacted selenol group) and EN is the remainder of the NH- containing endogenous ligand or protein (connected to Au via the N atom of a reacted NH group).
It will be understood that the term "endogenous" indicates a ligand or protein originating within the body of a subject organism, such as within the body of a human subject.
Any ligand or protein containing an -SH, -SeH or -NH group may react with the gold(l) phosphine to provide a compound according to formula VIII. Examples of the groups -E are provided below.
In some embodiments, E is a residue of an endogenous low molecular weight thiol selected from cysteine (Cys), cysteinylglycine (CysGly) homocysteine (Hey), and glutathione (GSH, L-v-glutamyl-L-cysteinyl-glycine), N-acetylcysteine, thioglycolic acid, v- glutamyl-cysteine, cysteinyl-glycine, lipoic acid and Coenzyme A. In some embodiments, E is a residue of an endogenous low molecular weight selenol such as selenocysteine. In some embodiments, E is a residue of an endogenous protein selected from human serum albumin, thioredoxin reductase (TrxR), glutathione peroxidase (GSPx), ΙκΒ kinase (IKK) complex, cathepsins and type I iodothyronine deiodinase.
In some cases, E may be a residue of an organism specific thiol-containing or selenol- containing endogenous ligand or protein such as mycothiol (present in Actinomycetes), bacillithiol (present in Firmicutes), γ-Glu-Cys (present in halobacteria and lactic acid bacteria), trypanothione (present in trypanosomes), ergothioneine (present in
mycobacteria), coenzyme M or coenzyme B (present in methanogenic Archaea). Another aspect of the invention is a compound according to formula VIII for use in the prevention or treatment of a bacterial infection. Another aspect is the use of a compound according to formula VIII in the manufacture of a medicament for the prevention or treatment of a bacterial infection. Another aspect is a method of preventing or treating a bacterial infection in a human or animal, comprising administering to said patient an effective amount of a pharmaceutical composition containing a compound of formula VIII. Another aspect may relate to the treatment of fungal infection, e.g. by providing a compound of formula VIII for use in the prevention or treatment of a fungal infection.
Another aspect of the invention is a compound obtained by a method of synthesis as described herein.
Another aspect of the invention is a compound obtainable by a method of synthesis as described herein.
For example, in some embodiments a compound is provided which is obtained or obtainable by a method of reacting a gold(l) complex of formula II:
Figure imgf000019_0001
with a nitrogen containing derivative of general formula (Ι'):
Figure imgf000020_0001
wherein Px is as defined herein and RAu is the group (B1 ).
In some embodiments a compound is provided which is obtained or obtainable by a method of reacting a compound of general formula III, IV, V, VI or IX:
Figure imgf000020_0002
with a chloro(trialkyl phosphine) gold(l) complex of general formula
Figure imgf000020_0003
wherein Px is as defined herein and RAu is the group (B2).
In some embodiments a compound is provided which is obtained or obtainable by a method of reacting a compound of general formula X or XI:
Figure imgf000021_0001
with a chloro(trialkyl phosphine) gold(l) complex of general formula II:
Figure imgf000021_0002
wherein Px is as defined herein and RAu is the group (B3). Further aspects of the invention relate generally to the use of the compounds of the present invention to inhibit microbial growth, sensitize the inhibition of microbial growth, inhibit biofilm formation or development, disrupt existing biofilms, reduce the biomass of a biofilm, and sensitize a biofilm and microorganisms within the biofilm to an antimicrobial agent.
In one aspect the invention relates to a method for inhibiting biofilm formation, comprising exposing a biofilm-forming microorganism to an effective amount of a compound of the invention. In some embodiments a compound of the invention is coated, impregnated or otherwise contacted with a surface or interface susceptible to biofilm formation. In some embodiments, the surface is a surface of a medical device such as: medical or surgical equipment, an implantable medical device or prosthesis (for example, venous catheters, drainage catheters (e.g. urinary catheters), stents, pacemakers, contact lenses, hearing- aids, percutaneous glucose sensors, dialysis equipment, drug-pump related delivery cannula, prostheses such as artificial joints, implants such as breast implants, heart valves, medical fixation devices such as rods, screws, pins, plates, or devices for wound repair such as sutures, and wound dressings such as bandages). In particular embodiments, the biofilm or biofilm-forming microorganism is on a bodily surface of a subject and exposure of the biofilm or biofilm-forming microorganism to a compound of the invention is by administration of the compound of the invention to the subject. In such instances, the biofilm or biofilm-forming microorganism may be associated with an infection, disease or disorder suffered by the subject or to which the subject is susceptible. In a related aspect of the invention, a medical device (such as those exemplified above) coated or impregnated with a compound of the invention is provided.
In another aspect the invention relates to a method for reducing the biomass of a biofilm and/or promoting the dispersal of microorganisms from a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention.
In yet another aspect the invention relates to a method for dispersing or removing, removing, or eliminating a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention. In some embodiments the biofilm is an existing, preformed or established biofilm.
In a further aspect the invention relates to a method for killing microorganisms within a biofilm, comprising exposing the biofilm to an effective amount of a compound of the invention. In some embodiments the biofilm is an existing, preformed or established biofilm.
In a yet further aspect the invention relates to a method of sensitizing a microorganism in a biofilm to an antimicrobial agent by exposing the biofilm to an effective amount of a compound of the invention. In some embodiments the antimicrobial agent is an antibiotic (e.g. rifampicin, gentamicin, erythromycin, lincomycin, linezolid or vancomycin) or an antifungal agent.
In one aspect the invention relates to a compound of the invention for use in a method of dispersing, removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, killing microorganisms within a biofilm, sensitizing a microorganism in a biofilm to an antimicrobial agent, treating or preventing an infection, disease or disorder caused by a biofilm, inhibiting the growth of a microbial persister cell, killing a microbial persister cell, or treating or preventing an infection, disease or disorder caused by or associated with a microbial persister cell. In another aspect the invention relates to a compound of the invention for use in a method of treating or preventing an infection, disease or disorder treatable by dispersing, removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, killing microorganisms within a biofilm, sensitizing a microorganism in a biofilm to an
antimicrobial agent, inhibiting the growth of a microbial persister cell, killing a microbial persister cell, or treating or preventing an infection, disease or disorder caused by or associated with a microbial persister cell. In some aspects, the biofilm comprises bacteria, such as, for example, multi-drug resistant bacteria. In some aspects the bacteria are Gram-positive bacteria. In some aspects the bacteria are Gram-negative bacteria. In particular examples, the biofilm comprises, consists essentially of, or consists of S. aureus. In some aspects, the S.
aureus is methicillin-resistant S. aureus (MRSA). In some embodiments, the biofilm comprises, consists essentially of, or consists of A. baumannii. In other embodiments, the biofilm comprises, consists essentially of, or consists of K. pneumoniae. In other embodiments, the biofilm comprises, consists essentially of, or consists of one or more of the bacteria listed in Table 1 herein. In further embodiments, the biofilms comprise bacterial species, including but not limited to, Staphylococcus spp., Streptococcus spp., Enterococcus spp., Listeria spp. and Clostridium spp., Klebsiella spp., Acinetobacter spp., Pseudomonas spp., Burkholderia spp., Erwinia spp., Haemophilus spp., Neisseria spp., Escherichia spp, Enterobacter spp., Vibrio spp. and/or Actinobacillus spp.
In some aspects, biofilm comprises lower eukaryotes, such as yeast, fungi, and filamentous fungi, including, but not limited to Candida spp., Pneumocystis spp.,
Coccidioides spp., Aspergillus spp., Zygomycetes spp., Blastoschizomyces spp.,
Saccharomyces spp., Malassezia spp., Trichosporon spp. and Cryptococcus spp.
Example species include C. albicans, C. glabrata, C. parapsilosis, C. dubliniensis, C. krusei, C. tropicalis, A. fumigatus, and C. neoforms.
The biofilm may comprise one species of microorganism, or comprise two or more species of microorganism, i.e. be a mixed species biofilm. The mixed species biofilms may include two or more species of bacteria, two or more species of lower eukaryote (e.g. two or more fungal species, such as unicellular fungi, filamentous fungi and/or yeast), and/or both bacteria and lower eukaryotes, such as one or more species of bacteria and one or more species of lower eukaryotes. For example, the methods, uses and compositions provided herein are applicable to biofilms comprising one or more species of bacteria and one or more species of fungi, such as a yeast, unicellular fungi and/or filamentous fungi. The mixed species biofilm may thus comprise 2, 3, 4, 5, 10, 15, 20 or more species of microorganism, and the microorganisms within the biofilm may be bacteria and/or lower eukaryotes, such as unicellular fungi, filamentous fungi and/or yeast.
The compounds of the invention can act together with other antimicrobial agents, allowing for increased efficacy of anti-microbial action. Accordingly, for any aspect described herein comprising exposing a biofilm, biofilm-forming microorganism, or a microbial persister cell to a compound of the invention, the present invention provides a
corresponding further aspect comprising exposing the biofilm or biofilm-forming microorganism to a combination of compounds of the invention and at least one additional antimicrobial agent, such as, for example, an antibiotic or an anti-fungal agent. In particular examples, the antibiotic is selected from rifampicin, gentamicin, erythromycin, lincomycin and vancomycin.
The methods described herein may be performed, for example, in vivo, ex vivo, or in vitro. The Gold-Phosphine Bond
Phosphines primarily function as Lewis bases, interacting with metals as σ donor ligands through the lone pair of electrons on the phosphorus atom. They also can accept electron density from metal into P-C o* antibonding orbitals. The magnitude of these two bonding interactions depends on the substituents on the phosphine and the electron density at the metal center. Consequently, the skilled person understands that the metal-phosphine bonds are not of pure single or double character, but rather something between the two extremes. Any representation herein of the Au-P bond as a single or double bond is merely provided as an approximation and cannot be taken as implying that the bond in fact exists as a traditional 'single' or 'double' bond. The way the Au(l)-phosphine bonds are shown herein is a formalization and in principle other representations could be used, e.g. a single bond (line) between the Au(l) center and the phosphine atom.
Definitions
Microbe / Microorganism: The terms "microbe / microorganism" as used herein pertain to bacteria and lower eukaryotes, such as fungi, including yeasts, unicellular fungi and filamentous fungi. Antimicrobial agent: The term "antimicrobial agent" as used herein pertains to any agent that, alone or in combination with another agent, is capable of killing or inhibiting the growth of one or more species of microorganism. Antimicrobial agents include, but are not limited to, antibiotics, antifungals, detergents, surfactants, agents that induce oxidative stress, bacteriocins and antimicrobial enzymes (e.g. lipases, proteinases, pronases and lyases) and various other proteolytic enzymes and nucleases, peptides and phage.
Reference to an antimicrobial agent includes reference to both natural and synthetic antimicrobial agents. Examples of antimicrobial agents include fluoroquinolones, aminoglycosides, glycopeptides, lincosamides, cephalosporins and related beta-lactams, macrolides, nitroimidazoles, penicillins, polymyxins, tetracyclines, and any combination thereof. For example, the methods of the present invention can employ acedapsone; acetosulfone sodium; alamecin; alexidine; amdinocillin; amdinocillin pivoxil; amicycline; amifloxacin; amifloxacin mesylate; amikacin; amikacin sulfate; aminosalicylic acid;
aminosalicylate sodium; amoxicillin; amphomycin; ampicillin; ampicillin sodium; apalcillin sodium; apramycin; aspartocin; astromicin sulfate; avilamycin; avoparcin; azithromycin; azlocillin; azlocillin sodium; bacampicillin hydrochloride; bacitracin; bacitracin methylene disalicylate; bacitracin zinc; bambermycins; benzoylpas calcium; berythromycin; betamicin sulfate; biapenem; biniramycin; biphenamine hydrochloride; bispyrithione magsulfex; butikacin; butirosin sulfate; capreomycin sulfate; carbadox; carbenicillin disodium;
carbenicillin indanyl sodium; carbenicillin phenyl sodium; carbenicillin potassium;
carumonam sodium; cefaclor; cefadroxil; cefamandole; cefamandole nafate; cefamandole sodium; cefaparole; cefatrizine; cefazaflur sodium; cefazolin; cefazolin sodium;
cefbuperazone; cefdinir; cefepime; cefepime hydrochloride; cefetecol; cefixime;
cefmenoxime hydrochloride; cefmetazole; cefmetazole sodium; cefonicid monosodium; cefonicid sodium; cefoperazone sodium; ceforanide; cefotaxime sodium; cefotetan;
cefotetan disodium; cefotiam hydrochloride; cefoxitin; cefoxitin sodium; cefpimizole;
cefpimizole sodium; cefpiramide; cefpiramide sodium; cefpirome sulfate; cefpodoxime proxetil; cefprozil; cefroxadine; cefsulodin sodium; ceftazidime; ceftibuten; ceftizoxime sodium; ceftriaxone sodium; cefuroxime; cefuroxime axetil; cefuroxime pivoxetil;
cefuroxime sodium; cephacetrile sodium; cephalexin; cephalexin hydrochloride;
cephaloglycin; cephaloridine; cephalothin sodium; cephapirin sodium; cephradine;
cetocycline hydrochloride; cetophenicol; chloramphenicol; chloramphenicol palmitate; chloramphenicol pantothenate complex; chloramphenicol sodium succinate; chlorhexidine phosphanilate; chloroxylenol; chlortetracycline bisulfate; chlortetracycline hydrochloride; cinoxacin; ciprofloxacin; ciprofloxacin hydrochloride; cirolemycin; clarithromycin; clinafloxacin hydrochloride; clindamycin; clindamycin hydrochloride; clindamycin palmitate hydrochloride; clindamycin phosphate; clofazimine; cloxacillin benzathine; cloxacillin sodium; chlorhexidine, cloxyquin; colistimethate sodium; colistin sulfate; coumermycin; coumermycin sodium; cyclacillin; cycloserine; dalfopristin; dapsone; daptomycin;
demeclocycline; demeclocycline hydrochloride; demecycline; denofungin; diaveridine; dicloxacillin; dicloxacillin sodium; dihydrostreptomycin sulfate; dipyrithione; dirithromycin; doxycycline; doxycycline calcium; doxycycline fosfatex; doxycycline hyclate; droxacin sodium; enoxacin; epicillin; epitetracycline hydrochloride; erythromycin; erythromycin acistrate; erythromycin estolate; erythromycin ethylsuccinate; erythromycin gluceptate; erythromycin lactobionate; erythromycin propionate; erythromycin stearate; ethambutol hydrochloride; ethionamide; fleroxacin; floxacillin; fludalanine; flumequine; fosfomycin; fosfomycin tromethamine; fumoxicillin; furazolium chloride; furazolium tartrate; fusidate sodium; fusidic acid; ganciclovir and ganciclovir sodium; gentamicin sulfate; gloximonam; gramicidin; haloprogin; hetacillin; hetacillin potassium; hexedine; ibafloxacin; imipenem; isoconazole; isepamicin; isoniazid; josamycin; kanamycin sulfate; kitasamycin;
levofuraltadone; levopropylcillin potassium; lexithromycin; lincomycin; lincomycin hydrochloride; lomefloxacin; lomefloxacin hydrochloride; lomefloxacin mesylate;
loracarbef; mafenide; meclocycline; meclocycline subsalicylate; megalomicin potassium phosphate; mequidox; meropenem; methacycline; methacycline hydrochloride;
methenamine; methenamine hippurate; methenamine mandelate; methicillin sodium; metioprim; metronidazole hydrochloride; metronidazole phosphate; mezlocillin; mezlocillin sodium; minocycline; minocycline hydrochloride; mirincamycin hydrochloride; monensin; monensin sodiumr; nafcillin sodium; nalidixate sodium; nalidixic acid; natainycin;
nebramycin; neomycin palmitate; neomycin sulfate; neomycin undecylenate; netilmicin sulfate; neutramycin; nifuiradene; nifuraldezone; nifuratel; nifuratrone; nifurdazil;
nifurimide; nifiupirinol; nifurquinazol; nifurthiazole; nitrocycline; nitrofurantoin; nitromide; norfloxacin; novobiocin sodium; ofloxacin; onnetoprim; oxacillin and oxacillin sodium; oximonam; oximonam sodium; oxolinic acid; oxytetracycline; oxytetracycline calcium; oxytetracycline hydrochloride; paldimycin; parachlorophenol; paulomycin; pefloxacin; pefloxacin mesylate; penamecillin; penicillins such as penicillin G benzathine, penicillin G potassium, penicillin G procaine, penicillin G sodium, penicillin V, penicillin V benzathine, penicillin V hydrabamine, and penicillin V potassium; pentizidone sodium; phenyl aminosalicylate; piperacillin sodium; pirbenicillin sodium; piridicillin sodium; pirlimycin hydrochloride; pivampicillin hydrochloride; pivampicillin pamoate; pivampicillin probenate; polymyxin b sulfate; porfiromycin; propikacin; pyrazinamide; pyrithione zinc;
quindecamine acetate; quinupristin; racephenicol; ramoplanin; ranimycin; relomycin; repromicin; rifabutin; rifametane; rifamexil; rifamide; rifampin; rifapentine; rifaximin;
rolitetracycline; rolitetracycline nitrate; rosaramicin; rosaramicin butyrate; rosaramicin propionate; rosaramicin sodium phosphate; rosaramicin stearate; rosoxacin; roxarsone; roxithromycin; sancycline; sanfetrinem sodium; sarmoxicillin; sarpicillin; scopafungin; sisomicin; sisomicin sulfate; sparfloxacin; spectinomycin hydrochloride; spiramycin;
stallimycin hydrochloride; steffimycin; streptomycin sulfate; streptonicozid; sulfabenz; sulfabenzamide; sulfacetamide; sulfacetamide sodium; sulfacytine; sulfadiazine;
sulfadiazine sodium; sulfadoxine; sulfalene; sulfamerazine; sulfameter; sulfamethazine; sulfamethizole; sulfamethoxazole; sulfamonomethoxine; sulfamoxole; sulfanilate zinc; sulfanitran; sulfasalazine; sulfasomizole; sulfathiazole; sulfazamet; sulfisoxazole;
sulfisoxazole acetyl; sulfisboxazole diolamine; sulfomyxin; sulopenem; sultamricillin;
suncillin sodium; talampicillin hydrochloride; teicoplanin; temafloxacin hydrochloride;
temocillin; tetracycline; tetracycline hydrochloride; tetracycline phosphate complex;
tetroxoprim; thiamphenicol; thiphencillin potassium; ticarcillin cresyl sodium; ticarcillin disodium; ticarcillin monosodium; ticlatone; tiodonium chloride; tobramycin; tobramycin sulfate; tosufloxacin; trimethoprim; trimethoprim sulfate; trisulfapyrimidines;
troleandomycin; trospectomycin sulfate; tyrothricin; vancomycin; vancomycin
hydrochloride; virginiamycin; zorbamycin; bifonazolem; butoconazole; clotrimazole;
econazole; fenticonazole; isoconazole; ketoconazole; miconazolel omoconazolel oxiconazolel sertaconazolel sulconazolel tioconazolel; albaconazole; fluconazole;
isavuconazole; itraconazole; posaconazole; ravuconazole; terconazole; voriconazole;. abafungin; amorolfin; butenafine; naftifine; terbinafine; anidulafungin; caspofungin; and micafungin. Biofilm: The term "biofilm" as used herein pertains to any three-dimensional, matrix- encased microbial community displaying multicellular characteristics. Accordingly, the term biofilm includes surface-associated biofilms as well as biofilms in suspension, such as floes and granules. Biofilms may comprise a single microbial species or may be mixed species complexes, and may include bacteria as well as fungi, algae, protozoa, or other microorganisms.
Reducing the biomass of a biofilm: The term "reducing the biomass of a biofilm" is used herein to mean reducing the biomass of an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the biofilm biomass of the area immediately before exposure to a compound of the invention. In some embodiments the "biomass" is the mass of cells present in the area of biofilm in addition to the extracellular polymeric substance (EPS) of the biofilm matrix. In some embodiments the "biomass" is only the mass of cells present in the area of biofilm (that is, the mass of the EPS is not counted as "biomass"). In some embodiments the biomass of the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the biofilm biomass of the area immediately before exposure to a compound of the invention, the mass of the otherwise identical area of a biofilm which has not been exposed to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the biofilm biomass of the area immediately before exposure to a compound of the invention. In some embodiments the area of biofilm compared is 10"6 m2; in other embodiments the area of biofilm compared is 10"5 m2, 10"4 m2, or 10"3 m2. In some embodiments a biofilm whose biomass has been reduced by at least 95% is deemed to have been "eliminated", "dispersed" or "removed". In some embodiments a biofilm whose biomass has been reduced by at least 99% is deemed to have been "eliminated", "dispersed" or "removed". In some embodiments a biofilm whose biomass has been reduced by at least 99.9% is deemed to have been "eliminated", "dispersed" or "removed". In some embodiments the change in biofilm biomass is assessed by a method comprising the steps of: i) washing the area of biofilm to remove non-adherent (planktonic) microorganisms, ii) assessing the area of biofilm biomass (i.e. the biomass "immediately before exposure to a compound of the invention"), iii) exposing the area of biofilm (or an otherwise identical area) to an effective amount of a compound of the invention for a period of time (for example, 24 hours), iv) washing the biofilm to remove non-adherent (planktonic) microorganisms, and v) assessing the area of biofilm biomass to obtain the 'post-exposure' biomass.
Promoting the dispersal of microorganisms from a biofilm: The term "promoting the dispersal of microorganisms from a biofilm" is used herein to mean reducing the number of microorganisms present in an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the number of microorganisms present in the area immediately before exposure to a compound of the invention. In some embodiments the number of microorganisms in the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the number of microorganisms present in the area immediately before exposure to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the number of microorganisms present in the area immediately before exposure to a compound of the invention. In some embodiments the change in number of
microorganisms in an area of biofilm is assessed by a method comprising the steps of: i) washing the biofilm to remove non-adherent (planktonic) microorganisms, ii) counting the remaining microorganisms to obtain a 'pre-exposure' microorganism count (i.e. the count "immediately before exposure to a compound of the invention"), iii) exposing the biofilm to an effective amount of a compound of the invention for a period of time (for example, 24 hours), iv) washing the biofilm to remove non-adherent (planktonic) microorganisms, and v) counting the remaining microorganisms to obtain the 'post-exposure' microorganism count. In some embodiments a biofilm where number of microorganisms in an area has been reduced by at least 95% is deemed to have been "eliminated", "dispersed" or "removed". In some embodiments a biofilm where number of microorganisms in an area has been reduced by at least 99% is deemed to have been "eliminated", "dispersed" or "removed". In some embodiments a biofilm where number of microorganisms in an area has been reduced by at least 99.9% is deemed to have been "eliminated", "dispersed" or "removed".
Killing microorganisms within a biofilm: The term "killing microorganisms within a biofilm" is used herein to mean reducing the number of live microorganisms present in an area of a biofilm exposed to an effective amount of a compound of the invention as compared to the number of live microorganisms present in the area immediately before exposure to a compound of the invention. In some embodiments the biofilm is an existing, preformed or established biofilm. In some embodiments the number of live microorganisms in the area of a biofilm exposed to an effective amount of a compound of the invention is at least 10% less than the number of live microorganisms present in the area immediately before exposure to a compound of the invention, for example, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% less than the number of live microorganisms present in the area immediately before exposure to a compound of the invention. In some embodiments the change in number of microorganisms in an area of biofilm is assessed by a method comprising the steps of: i) washing the area biofilm to remove non-adherent (planktonic) microorganisms, ii) manually disperse the biofilm into solution (using, for example, scraping, sonication, and vortexing), iii) prepare serial dilutions, plate, and culture to estimate the number of colony forming unit (cfu) in the area of biofilm, iv) provide an otherwise identical area of biofilm and expose it to an effective amount of a compound of the invention for a period of time (for example, 24 hours), v) manually disperse the biofilm and estimate cfu as described above to obtain the 'post-exposure' microorganism count. The viability of the biofilm can be also assessed by allowing the biofilm to re-grow in compound free medium and assessing planktonic growth. Dispersal: The term "dispersal" as used herein pertains to any to a biofilm and
microorganisms making up a biofilm means the process of detachment and separation of cells and a return to a planktonic phenotype or behaviour of the dispersing cells.
Exposing: The term "exposing" as used herein means generally bringing into contact with. Exposure of a biofilm or biofilm-forming microorganism to an agent (e.g. a compound of the invention) includes administration of the agent to a subject harbouring the
microorganism or biofilm, or otherwise bringing the microorganism or biofilm into contact with the agent itself, such as by contacting a surface on which the biofilm or biofilm- forming microorganism are present with the agent. In some embodiments, the biofilm or biofilm-forming microorganisms are exposed to a compound of the invention by coating, impregnating or otherwise contacting a surface or interface susceptible to biofilm formation to an effective amount of the compound. Surfaces that may be exposed, coated, or impregnated with a compound of the invention include those present in a range of industrial and domestic settings, including but not limited to, domestic, medical or industrial settings (e.g. medical and surgical devices, and surfaces within hospitals, processing plants and manufacturing plants), as well as internal and external surfaces of the body of a subject. In the present disclosure the terms "exposing", "administering" and "contacting" and variations thereof may, in some contexts, be used interchangeably. Inhibiting: The term "inhibiting" and variations thereof such as "inhibition" and "inhibits" as used herein in relation to microbial growth refers to any microbiocidal or microbiostatic activity of an agent (e.g. a compound of the invention) or composition. Such inhibition may be in magnitude and/or be temporal or spatial in nature. Inhibition of the growth of a microorganism by an agent can be assessed by measuring growth of the microorganism in the presence and absence of the agent. The growth can be inhibited by the agent by at least or about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more compared to the growth of the same microorganism that is not exposed to the agent.
The term "inhibiting" and variations thereof such as "inhibition" and "inhibits" as used herein in relation to biofilms means complete or partial inhibition of biofilm formation and/or development and also includes within its scope the reversal of biofilm development or processes associated with biofilm formation and/or development. Further, inhibition may be permanent or temporary. The inhibition may be to an extent (in magnitude and/or spatially), and/or for a time, sufficient to produce the desired effect. Inhibition may be prevention, retardation, reduction or otherwise hindrance of biofilm formation or development. Such inhibition may be in magnitude and/or be temporal or spatial in nature. Inhibition of the formation or development of a biofilm by a compound of the invention can be assessed by measuring biofilm mass or microbial growth in the presence and absence of a compound of the invention. The formation or development of a biofilm can be inhibited by a compound of the invention by at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more compared to the formation or development of a biofilm that is not exposed to a compound of the invention. Sensitize: The terms "sensitize" or "sensitizing" as used herein mean making a biofilm or microorganisms within a biofilm more susceptible to an antimicrobial agent. The sensitizing effect of a compound of the invention, on a biofilm or microorganisms within the biofilm can be measured as the difference in the susceptibility of the biofilm or microorganisms (as measured by, for example, microbial growth or biomass of the biofilm) to a second antimicrobial agent with and without administration of the compound. The sensitivity of a sensitized biofilm or microorganism (i.e. for example, a biofilm or microorganism exposed to an agent such as a compound of the invention) to a antimicrobial agent can be increased by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500% or more compared to the sensitivity of an unsensitized biofilm or microorganism (i.e. a biofilm or microorganism not exposed to the agent). In some embodiments sensitizing effect of a compound of the invention on a biofilm or microorganisms within the biofilm can be measured by the difference in Minimum Inhibitory Concentration (MIC) of a second antimicrobial administered either in combination with a compound of the invention, or alone. For example, in some embodiments the MIC of a combination of a compound of the invention and the second antimicrobial is at least 10% lower than the MIC of the second antimicrobial administered alone; such as at least 20% lower, at least 30% lower, at least 40% lower, at least 50% lower, at least 60% lower, at least 70% lower, at least 80% lower, at least 90% lower, at least 95% lower, at least 99% lower, or at least 99.9% lower than the MIC of the second antimicrobial administered alone. The sensitization of a microorganism may also occur outside of a biofilm. Surface: The term "surface" as used herein includes both biological surfaces and non- biological surfaces. Biological surfaces typically include surfaces both internal (such as organs, tissues, cells, bones and membranes) and external (such as skin, hair, epidermal appendages, seeds, plant foliage) to an organism. Biological surfaces also include other natural surfaces such as wood or fibre. A non-biological surface may be any artificial surface of any composition that supports the establishment and development of a biofilm. Such surfaces may be present in industrial plants and equipment, and include medical and surgical equipment and medical devices, both implantable and non-implantable.
Further, for the purposes of the present disclosure, a surface may be porous (such as a membrane) or non-porous, and may be rigid or flexible.
Infection, disease or disorder caused by a biofilm / infection, disease or disorder caused by or associated with a microbial persister cell: The term "Infection, disease or disorder caused by a biofilm" as used herein is used to describe conditions, diseases and disorders associated with, characterised by, or caused by biofilms and biofilm-forming microorganisms. Similarly, the term "Infection, disease or disorder caused by or associated with a microbial persister cell" as used herein is used to describe conditions, diseases and disorders associated with, characterised by, or caused by microbial persister cells. For example, a variety of microbial infections are known to be associated with biofilm formation and/or persister cells, such as cellulitis, impetigo, mastitis, otitis media, bacterial endocarditis, sepsis, toxic shock syndrome, urinary tract infections, pulmonary infections (including pulmonary infection in patients with cystic fibrosis), pneumonia, dental plaque, dental caries, periodontitis, bacterial prostatitis and infections associated with surgical procedures or burns. For example, S. aureus and S. epidermidis cause or are associated with cellulitis, impetigo, mastitis, otitis media, bacterial endocarditis, sepsis, toxic shock syndrome, urinary tract infections, pulmonary infections (including pulmonary infection in patients with cystic fibrosis), pneumonia, dental plaque, dental caries and infections associated with surgical procedures or burns. In other examples, K. pneumoniae can cause or be associated with pneumonia, sepsis, community-acquired pyogenic liver abscess (PLA), urinary tract infection, and infections associated with surgical procedures or burns. In further examples, A. baumannii can cause or be associated with bacteremia, pneumonia, meningitis, urinary tract infection, and infections associated with wounds. In still further examples, P. aeruginosa can cause or be associated with respiratory tract infections (including pneumonia), skin infections, urinary tract infections, bacteremia, infection of the ear (including otitis media, otitis externa and otitis interna), endocarditis and bone and joint infections such as osteomyelitis. Candida spp. such as C. albicans, Cryptococcus spp. such as C. neoformans, as well as other fungi such as Trichosporon spp., Malassezia spp., Blastoschizomyces spp., Coccidioides spp. and Saccharomyces spp. (e.g. S. cerevisiae) may cause or be associated with infections related to the implantation or use of medical or surgical devices, such as catheterization or implantation of heart valves.
Persister cell(s): The term "persister cell(s)" as used herein pertains to metabolic variants of wild type microbial cells that are phenotypically characterized by their slow growth rate, which is typically 30%, 25%, 20%, 15%, 10%, 5% or less of the growth rate of the wild- type counterpart. In some embodiments, the persister cells are dormant and have, for example, no detectable cell division in a 24 hour period. Further, persister cells typically form colonies that are approximately 30%, 25%, 20%, 15%, 10%, 5% or less of the size of the colonies formed by their wild-type counterparts. Reference to persister cells includes reference to persister cells of any microbial genera or species, including, but not limited to, bacterial and lower eukaryotic, such as fungal, including yeast, persister cells. In some examples, the persister cell is a Gram-negative bacterium. In some examples, the persister cell is a Gram-positive bacterium. Exemplary persister cells include, but are not limited to, those of Staphylococcus spp., such as S. aureus, S. epidermidis, and S.
capitis; Pseudomonas spp. such as P. aeruginosa; Burkholderia spp. such as B. cepacia and B. pseudomallei; Salmonella serovars, including Salmonella Typhi; Vibrio spp. such as V. cholerae; Shigella spp.; Brucella spp. such as B. melitensis; Escherichia spp. such as E. coli; Lactobacillus spp. such as L. acidophilus; Serratia spp. such as S. marcescens; Neisseria spp. such as N. gonorrhoeae, as well as Candida spp., such as C. albicans. C1 -6 alkyl: The term "C1 -6 alkyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated hydrocarbon compound having from 1 to 6 carbon atoms. Examples of saturated alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5) and hexyl {Ce).
Examples of saturated linear alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), n-propyl (C3), n-butyl (C4), n-pentyl (C5) and n-hexyl {Ce). Examples of saturated branched alkyl groups include iso-propyl (C3), iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5), neopentyl (C5), iso-hexyl {Ce) and neohexyl (Ce). C2-6 alkenyl: The term "C2-6 alkenyl" as used herein, pertains to a C2-6 alkyl group having one or more carbon-carbon double bonds. Examples of unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH2), 1 -propenyl (-CH=CH-CH3), 2-propenyl (allyl, -CH-CH=CH2) and isopropenyl (1 -methylvinyl, -C(CH3)=CH2). C2-6 alkynyl: The term "C2-6 alkynyl" as used herein, pertains to a C2-6 alkyl group having one or more carbon-carbon triple bonds. Examples of unsaturated alkynyl groups include, but are not limited to, ethynyl (-C≡CH) and 2-propynyl (propargyl, -CH2-C≡CH). C3-6 cycloalkyl: the term "C3-6 cycloalkyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated cyclic core having 3, 4, 5 or 6 atom in the cyclic core all of which are carbon atoms. Examples of C3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclohexyl and cyclopentyl. C5-6 cycloalkenyl: The term "C5-6 cycloalkenyl" as used herein, pertains to a C3-6 cycloalkyl group having one or more carbon-carbon double bonds. C4-6 heterocycloalkyl: The term "C4-6 heterocycloalkyl" as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 4 to 6 ring atoms, of which from 1 to 3 are ring heteroatoms selected from O, S and N. In this context, the prefixes denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms
Examples of monocyclic heterocycloalkyl groups include, but are not limited to, those derived from:
Ni : azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline,
2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), piperidine {Ce), dihydropyridine {Ce), tetrahydropyridine {Ce);
O1: oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane
(tetrahydropyran) {Ce), dihydropyran {Ce), pyran {Ce); Si: thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiane
(tetrahydrothiopyran) {Ce);
O2: dioxolane (C5), dioxane {Ce);
N2: imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine {Ce);
N1O1: tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (C5),
dihydroisoxazole (C5), morpholine {Ce), tetrahydrooxazine {Ce), dihydrooxazine {Ce), oxazine {Ce);
N1S1: thiazoline (C5), thiazolidine (C5), thiomorpholine {Ce);
N2O1: oxadiazine (Ce);
O1S1: oxathiole (C5) and oxathiane (thioxane) {Ce); and,
N1O1S1: oxathiazine {Ce). C5-6 heterocycloalkenyl: The term "C5-6 heterocycloalkenyl" as used herein, pertains to a C5-6 heterocycloalkyl group having one or more carbon-carbon or carbon-nitrogen double bonds.
Heterobicyclyl: The term "heterobicyclyl" as used herein, pertains to a bicyclic ring, wherein 1 , 2, or 3 ring carbons are replaced with a heteroatom selected from the group consisting of O, S and N. In some embodiments, one of the rings is aromatic. In some embodiments, both of the rings are aromatic. In some embodiments, neither ring is aromatic. The bicylic rings may be spiro or fused. Examples of a heterobicyclic group include, but are not limited to, 2,5-diaza-bicyclo[2.2.1 ]hept-2-yl, 7-aza-bicyclo[2.2.1]hept- 7-yl, 1 ,3-dihydro-isoindolyl, 3,4-dihydro-1 H-isoquinolinyl, octahydro-cyclopenta[c]pyrrolyl and the like C5-6 heteroaryl: the term C5-6 heteroaryl as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of an aromatic structure having between one and three atoms that are not carbon forming part of said ring. Wherein, those atoms that are not carbon can be chosen independently from the list nitrogen, oxygen and sulphur.
Examples of C5-6 heteroaryl groups include, but are not limited to, groups derived from: Ni : pyridine (C6);
N1O1: oxazole (C5), isoxazole (C5);
N2O1: oxadiazole (furazan) (C5); N2S1: thiadiazole (C5)
N2: imidazole (1 ,3-diazole) (C5), pyrazole (1 ,2-diazole) (C5), pyridazine (1 ,2-diazine) {Ce), pyrimidine (1 ,3-diazine) {Ce) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) {Ce); N3: triazole (C5).
Further embodiments
In some embodiments, Px is (P1 ).
In some embodiments, RP1 is methyl. In other embodiments, RP1 is ethyl. In some embodiments, RP1 is -CH2OMe.
In some embodiments, RP2 is methyl. In other embodiments, RP2 is ethyl. In some embodiments, RP2 is -CH2OMe. In some embodiments, both RP1 and RP2 are methyl. In other embodiments, both RP1 and RP2 are ethyl. In further embodiments, RP1 is methyl and RP2 is ethyl. In further embodiments, both RP1 and RP2 are -CH2OMe.
In some embodiments, both RP1 and RP2 are methyl and RP3 is selected from the group consisting of:
(i) -CH2RP6, -CH2CH2RP6, -CHMeRP6, -C(Me)2RP6, -CH(RP6)2, -CMe(RP6)2, -C(C3-4cycloalkyl)RP6, -C(=NH)RP6, -CH2C(=NH)RP6, sec-butyl, 1-propynyl, -COOH, trimethylsilyl(ethynyl),
(ii) C3-4 unsubstituted linear saturated alkyl,
(iii) C3-4 saturated cycloalkyl;
(iv) 4- or 5-membered heterocyclyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group, and
(v) 5-or 6-membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups.
In some embodiments, both RP1 and RP2 are methyl and RP3 is selected from the group consisting of:
-CH2RP6,
C3 unsubstituted linear saturated alkyl, 4-membered heterocyclyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group, and
6-membered heteroaryl groups containing one to four (preferably two to four) heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups.
In some embodiments, RP3 is selected from -CH2RP6, -CH2CH2RP6, -CHMeRP6,
-C(Me)2RP6, -CH(RP6)2, -CMe(RP6)2, -C(C3-4cycloalkyl)RP6, -C(=NH)RP6 and
-CH2C(=NH)RP6.
In some embodiments, RP3 is -COOH.
In some embodiments, RP3 is selected from sec-butyl and 1-propynyl.
In some embodiments, RP3 is trimethylsilyl(ethynyl).
In some embodiments, each RP6 group is independently selected from
4-membered heterocyclyl or heteroaryl groups containing one heteroatom selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
-F,
-OH, -OMe, -OEt,
-CH2OH,
-C(=0)NH2, -C(=0)NHMe, -C(=0)NMe2,
-NH2, -NHMe, -NMe2, -NMe3 +,
-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.
In some embodiments, each RP6 group is independently selected from
4-membered heterocyclyl or heteroaryl groups containing one heteroatom selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
-OH, -OMe, -OEt,
-CH2OH,
-C(=0)NH2, -C(=0)NHMe, -C(=0)NMe2,
-NH2, -NHMe, -NMe2, -NMe3 +, -NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.
In some embodiments, each RP6 group is independently selected from
4-membered heterocyclyl groups containing one or two heteroatoms selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
-F,
-OH, -OMe, -OEt,
-CH2OH,
-C(=0)NH2, -C(=0)NHMe, -C(=0)NMe2,
-NH2, -NHMe, -NMe2, -NMe3 +,
-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.
In some embodiments, each RP6 group is independently selected from
4-membered heterocyclyl or heteroaryl groups containing one heteroatom selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
-F,
-OH, -OMe, -OEt,
-CH2OH,
-C(=0)NH2, -C(=0)NHMe, -C(=0)NMe2,
-NH2, -NHMe, -NMe2, -NMe3 +,
-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.
In some embodiments, each RP6 group is independently selected from 4-membered heterocyclyl or heteroaryl groups containing one or two heteroatoms selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group.
In some embodiments, each RP6 group is independently selected from 4-membered heterocyclyl groups containing one heteroatom selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group.
In some embodiments, RP6 is F. In some embodiments, each RP6 group is independently selected from -OH, -OMe and -OEt. In some embodiments, each RP6 group is independently selected from -SH, -SMe and -SEt. In some embodiments, each RP6 group is independently selected from -S(=0)H, -S(=0)Me and -S(=0)Et. In some embodiments, each RP6 group is independently selected from -S02H, -S02Me and -S02Et. In some embodiments, each RP6 group is independently selected from -CH2OH, -ChbOMe and -ChbOEt. In some embodiments, each RP6 group is independently selected from - CH2OH and -CH2OMe. In some embodiments, each RP6 group is independently selected from -CH2SH, -CH2SMe and -CH2SEt. In some embodiments, each RP6 group is independently selected from -CH2SH and -CH2SMe. In some embodiments, each RP6 group is independently selected from -CH2S(=0)H, -CH2S(=0)Me and -CH2S(=0)Et. In some embodiments, each RP6 group is independently selected from -CH2S(=0)H and - CH2S(=0)Me. In some embodiments, each RP6 group is independently selected from - CH2SO2H, -CH2S02Me and -CH2S02Et. In some embodiments, each RP6 group is independently selected from -CH2SO2H and -ChbSC^Me.
In some embodiments, each RP6 group is independently selected from -C(=0)OH, - C(=0)NH2, -C(=0)NHMe and -C(=0)NMe2.
In some embodiments, each RP6 group is independently selected from -NH2, -NHMe, - NMe2, -NMe3 +, -NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me. In some embodiments, each RP6 group is independently -NH2. In some embodiments, each RP6 group is independently -NMe2.
In some embodiments, RP6 is not -CH20Me. In some embodiments, RP6 is not a 4- membered heteroaryl group.
In some embodiments, RP3 is -ChbOMe. In some embodiments, RP3 is -CH20Et. In some embodiments, RP3 is -CH2C(=0)NH2. In some embodiments, RP3 is -CH2NMe2. In some embodiments, RP3 is -CH2C(=0)NMe2. In some embodiments, RP3 is -CH2OH. In some embodiments, RP3 is -CH2CH2OH.
In some embodiments, RP3 is selected from C3-4 unsubstituted linear saturated alkyl groups. In some embodiments, RP3 is n-propyl. In some embodiments, RP3 is n-butyl.
In some embodiments, RP3 is selected from C3-4 saturated cycloalkyi. In some
embodiments, RP3 is selected from C3 saturated cycloalkyi groups, optionally substituted with one C1-3 linear saturated alkyl group. In some embodiments, RP3 is selected from C4 saturated heterocyclyl groups containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group. In some embodiments, RP3 is selected from unsubstituted C3-4 saturated cycloalkyl groups.
In some embodiments, RP3 is selected from C3-4 unsubstituted saturated cycloalkyl. In some embodiments, RP3 is cyclopropyl. In some embodiments, RP3 is cyclobutyl.
In some embodiments, RP3 is selected from 4- or 5-membered heterocyclyl or
heterocycloalkenyl groups containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group. In some embodiments, RP3 is selected from 4-membered heterocyclyl or heterocycloalkenyl groups containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group. In some embodiments, RP3 is selected from 5-membered heterocyclyl or heterocycloalkenyl groups containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group. In some embodiments, RP3 is selected from azetidyl and oxetanyl, optionally substituted with one or two methyl groups.
In some embodiments, RP3 is selected from 5-membered heterocyclyl groups or heterocycloalkenyl containing two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group. In some embodiments, RP3 is selected from dioxalanyl, optionally substituted with one or two methyl groups.
In some embodiments, RP3 is not selected from C4 heterocyclyl groups having a single heteroatom.
In some embodiments, RP3 is selected from 5- or 6-membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups. In some embodiments, RP3 is selected from 5- or 6-membered heteroaryl groups containing two to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups. In some embodiments, the 5- or 6-membered heteroaryl group is unsubstituted.
In some embodiments, RP3 is not pyridyl. In some embodiments, RP3 is selected from 5-membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups. In some embodiments, RP3 is selected from 6-membered heteroaryl groups containing two to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups.
In some embodiments, RP1 is methyl, RP2 is methyl or ethyl and RP3 and RAu are as defined above. In some embodiments, RP1 is methyl, RP2 is methyl and RP3 and RAu are as defined above.
In some embodiments, Px is selected from the groups:
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
In some embodiments, Px is the group (P2).
In some embodiments, RP4 is linear unsubstituted C3 saturated alkyl. In some embodiments, RP4 is n-propyl. In some embodiments, RP4 is linear C3 saturated alkyl, substituted with a methyl group. In some embodiments, RP4 is selected from n-butyl and isobutyl. In some embodiments, RP4 is branched C3 unsubstituted saturated alkyl. In some embodiments, RP4 is isopropyl. In some embodiments, RP4 is branched C3 saturated alkyl, substituted with a methyl group. In some embodiments, RP4 is selected from t-butyl and sec-butyl.
In some embodiments, RP4 is cyclic C3 unsubstituted saturated alkyl. In some
embodiments, RP4 is cyclopropyl. In some embodiments, RP4 is cyclic C3 saturated alkyl, substituted with a methyl group. In some embodiments, RP4 is the group:
Figure imgf000045_0001
In some embodiments, m is 1 . In other embodiments, m is 2. In some embodiments, m is 1 or 2. In other embodiments, m is 3.
In some embodiments, the ring in (P2) is unsubstituted (RM is absent). In other embodiments, there is one RM substituent on the ring in (P2). In further embodiments, there are two RM substituents on the ring in (P2).
In some embodiments, RM is Rpc. In some embodiments, Rpc is methyl. In other embodiments, Rpc is oxo.
In other embodiments, RM is OH. In other embodiments, RM is OMe.
In some embodiments, RPD is F. In some embodiments, RPD is OH. In some
embodiments, RPD is OMe.
In some embodiments, m is 1 or 2, RM is absent and RP4 is selected from linear, branched or cyclic C3 saturated alkyl groups, optionally substituted with a methyl group.
In some embodiments, Px is selected from the groups:
Figure imgf000046_0001
In some embodiments, Px is the group (P3).
In some embodiments, RP5 is selected from linear or branched unsubstituted C1-4 saturated alkyl groups. In some embodiments, RP5 is selected from methyl, isopropyl and t-butyl.
In some embodiments, RP5 is selected from cyclic C3-4 saturated alkyl groups, optionally substituted with a methyl group. In some embodiments, RP5 is selected from
unsubstituted cyclic C3-4 saturated alkyl groups. In some embodiments, RP5 is cyclopropyl, optionally substituted with a methyl group. In some embodiments, RP5 is the group:
Figure imgf000047_0001
In some embodiments, RP7 and RP8 are independently H. In some embodiments, one of RP7 and RP8 is H and the other is methyl.
In some embodiments, RP9 and RP1° are each independently H. In some embodiments, one of RP9 and RP1° is H and the other is methyl.
In some embodiments, each of RP7, RP8, RP9 and RP1° are independently H.
In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a 4- or 5-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the
phosphorus atom, optionally substituted with one or two groups RPE.
In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a 4- or 5-membered heterocyclic ring including 1 heteroatom independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups RPE.
In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a 4-membered heterocyclic ring including 1 heteroatom independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups RPE. In some embodiments, the ring is unsubstituted. In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a ring selected from:
Figure imgf000047_0002
In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a 5-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups RPE. In some embodiments, the ring is unsubstituted. In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a ring selected from:
Figure imgf000048_0001
In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a 6-membered heterocyclic ring including 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally substituted with one or two groups RPE. In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a 6-membered heterocyclic ring including 2 heteroatoms each independently selected from O in addition to the phosphorus atom, optionally substituted with one or two groups RPE. In some embodiments, the ring is unsubstituted. In some embodiments, RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form the ring:
Figure imgf000048_0002
In some embodiments, RPE is methyl. In other embodiments, RPE is oxo.
In some embodiments, Px is selected from the groups:
Figure imgf000049_0001
In some embodiments,
Px is selected from the groups (P1 ), (P2) and (P3),
RP1 is methyl, RP2 is methyl or ethyl,
RP3 is -CH2RP6,
m is 3 and RM is absent,
RP4 and RP5 are each methyl,
RP7 to RP1° are each H,
RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a 6-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally mono-substituted with a methyl group; and
RP6 and RAu are as defined above.
RAu
In some embodiments, RAu is selected from the groups (B1 ) and (B2). In some embodiments, RAu is the group (B1 ), i.e. the group -NRNARNB. In some embodiments RNA is linear or branched C1 -6alkyl optionally substituted with one or more groups RAL; and RNB is selected from -CORA2 and -S02RA2.
In some embodiments RNA is linear or branched C1 -6alkyl optionally substituted with one or more groups RAL; and RNB is selected from -CO(C1 -6alkyl) and -S02RA2.
In some embodiments RNA is unsubstituted linear or branched C1 -6alkyl; and RNB is selected from -CORA2 and -S02RA2.
In some embodiments RNA is unsubstituted linear or branched C1 -6alkyl; and RNB is selected from -CO(C1 -6alkyl) and -S02RA2.
In the above embodiments, RAL may be selected from
Figure imgf000050_0001
In the above embodiments, RAL may be selected from
Figure imgf000050_0002
In some embodiments RNA is Cs-eheteroaryl, optionally substituted with one or more groups RA1; and RNB is selected from -CORA2 and -S02RA2.
In some embodiments, RNA is Csheteroaryl, optionally substituted with one or more groups RA1 (e.g. C1 -6 alkyl, such as methyl); and RNB is selected from -CORA2 and -S02RA2.
In some embodiments RNA is Ceheteroaryl, optionally substituted with one or more groups RA1 (e.g. C1 -6 alkyl, such as methyl); and RNB is selected from -CORA2 and -S02RA2. In some embodiments RA is C1-3alkyl substituted by phenyl or C5-6heteroaryl, which groups may optionally be substituted with one or more groups RA1; and RB is selected from -CORA2 and -S02RA2. In some embodiments RNA is C1-3alkyl (e.g. methyl) substituted by Csheteroaryl which is optionally substituted with one or more groups RA1; and RNB is selected from -CORA2 and -S02RA2.
In some embodiments RNA is C1-3alkyl (e.g. methyl) substituted b+y Ceheteroaryl which is optionally substituted with one or more groups RA1; and RNB is selected from -CORA2 and -S02RA2.
In some embodiments RNA is C1-3alkyl (e.g. methyl) substituted by phenyl which is optionally substituted with one or more groups RA1; and RNB is selected from -CORA2 and -S02RA2.
In some embodiments -NRNARNB is selected from
Figure imgf000051_0001
NRNARNB
In some embodiments, -NRNARNB is a 5- or 6-membered heterocycloalkyl or
heterocycloalkenyl group optionally substituted with one or more groups selected from oxo, =NH,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; phenyl optionally substituted with one or more groups RA1,
RA2, and
RA1. In some embodiments, -NRNARNB is a 5- or 6-membered heterocycloalkyl or
heterocycloalkenyl group containing up to two heteroatoms in the ring selected from N, O and S in addition to the N atom of -NRNARNB; optionally substituted with one or more groups selected from
oxo, =NH,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; phenyl optionally substituted with one or more groups RA1,
RA2, and
RA1.
In some embodiments, -NRNARNB is a 5- or 6-membered heterocycloalkyl or
heterocycloalkenyl group containing up to two heteroatoms in the ring selected from N, O and S in addition to the N atom of -NRNARNB; substituted with one or two oxo groups and optionally further substituted with one or more groups selected from
phenyl optionally substituted with one or more groups RA1, and
RA1.
In some embodiments, -NRNARNB is a 5- or 6-membered heterocycloalkyl or
heterocycloalkenyl group containing one heteroatom in the ring selected from N, O and S in addition to the N atom of -NRNARNB; substituted with one or two oxo groups and optionally further substituted with one or more groups selected from
phenyl optionally substituted with one or more groups RA1, and
RA1.
In some embodiments, -NRNARNB is a 5- or 6-membered heterocycloalkyl or
heterocycloalkenyl group containing one heteroatom in the ring selected from N, O and S in addition to the N atom of -NRNARNB; substituted with one or two oxo groups and optionally further substituted with one or more groups selected from
linear or branched C1 -6alkyl; and
phenyl optionally substituted with one or more groups selected from F, CI, Br, CN, OH, 0(C1 -6alkyl), COOH and COO(C1 -6alkyl).
In some embodiments, -NRNARNB is a 5- or 6-membered heterocycloalkyl or
heterocycloalkenyl group containing one heteroatom in the ring selected from N, O and S in addition to the N atom of -NRNARNB; substituted with one or two oxo groups and optionally further substituted with one or more groups selected from
C1-3alkyl; and
phenyl optionally substituted with one or more groups selected from F, CI, OH and 0(C1 -6alkyl).
In some embodiments, -NRNARNB is the group (A1 )
Figure imgf000053_0001
wherein
XN1 is selected from C=0 and CR4NAR4NB;
XN2 is selected from O, CR4NAR4NB and NRX; and
one of XN3 and XN4 is selected from C=0, CR4NAR4NB and S02, with the other group of XN3 and XN4 being selected from CR4NAR4NB;
wherein Rx is selected from -H and -RA5;
each R4NA and R4NB is independently selected from
-H,
linear or branched Ci-4alkyl optionally substituted with one or more groups RAL, phenyl, optionally substituted with one or more groups RA1,
C5-6heteroaryl optionally substituted with one or more groups RA1,
independently geminal R4NA and R4NB groups may be joined to form a 5- or
6-membered alicyclic or 5- or 6- membered heteroalicyclic group optionally substituted with one or more groups RAL, and
independently two vicinal R4NA groups may be joined to form a 5- or 6-membered alicyclic, heteroalicyclic, aromatic or heteroaromatic group optionally substituted with one or more groups RA1;
and RA5 is selected from the group consisting of
linear or branched C1 -6alkyl, C2-6alkenyl or C2-6alkynyl optionally substituted with one or more groups RAL,
C3-6cycloalkyl or C4-6heterocycloalkyl optionally substituted with one or more
groups RAT, phenyl, optionally substituted with one or more groups RA1,
C5-6heteroaryl optionally substituted with one or more groups RA1, or
except when each of RP1 to RP3 is selected from ethyl, RA5 may be joined to a vicinal R4NA or R4NB group to form a 5- or 6-membered heterocyclic or heteroaromatic group optionally substituted with one or more groups R'
In some embodiments, -NRNARNB is the group (A2)
Figure imgf000054_0001
wherein
VN1 is selected from C=0 and S02;
VN2 is selected from O, NRX and CR4NAR4NB;
with the proviso that when Vm is SO2, VN2 cannot be O;
wherein Rx, R4NA and R4NB are as defined above.
In some embodiments, -NRNARNB is the group (A4)
Figure imgf000054_0002
wherein
ZN1 is selected from C=0 and CR4NAR4NB;
ZN2 and ZN3 are each independently selected from the group consisting of
O,
CR4NAR4NB, C=0 and
NRX,
with the proviso that any two adjacent groups of ZN1 to ZN4 cannot both be O, cannot both be C=0 and cannot both be NRX;
ZN4 is selected from CR4NAR4NB, and NRX; and ZN5 is selected from C=0 and SO2;
with R4NA, R4NB and Rx being as defined above. some embodiments, -NRNARNB is the group (A5)
Figure imgf000055_0001
wherein
a dotted line indicates that a bond may be present or absent; and W1 to W4 are each independently selected from CH and CRA1.
In some embodiments, -NRNARNB is the group (A6)
Figure imgf000055_0002
wherein
W5 to W8 are each independently selected from CH and CR'
In some embodiments, -NRNARNB is selected from
Figure imgf000056_0001
Figure imgf000057_0001
In some embodiments, -NRNARNB is selected from a 5- or 6-membered heteroaryl group optionally substituted with one or more groups selected from
oxo, =NH,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; phenyl optionally substituted with one or more groups RA1,
RA2, and
RA1.
In some embodiments, -NRNARNB is selected from a 5- or 6-membered heteroaryl group optionally substituted with one or more groups selected from
phenyl optionally substituted with one or more groups RA1,
RA2, and
RA1.
In some embodiments, -NRNARNB is selected from a 5- or 6-membered heteroaryl group containing up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of -NRNARNB; optionally substituted with one or more groups selected from
oxo, =NH,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; phenyl optionally substituted with one or more groups RA1,
RA2, and
RA1. In some embodiments, -NRNARNB is selected from a 5-membered heteroaryl group containing up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of -NRNARNB; optionally substituted with one or more groups selected from
oxo, =NH,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; phenyl optionally substituted with one or more groups RA1,
RA2, and
RA1.
In some embodiments, -NRNARNB is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of -NRARB; optionally substituted with one or more groups RA1.
In some embodiments, -NRNARNB is selected from a 5-membered heteroaryl group containing one or two heteroatoms in the ring in addition to the N atom of -NRARB, the heteroatoms being N atoms; wherein the heteroaryl group is optionally substituted with one or more groups selected from
linear, branched or cyclic C1 -6alkyl optionally substituted with one group RAL,
F, CI, Br,
-CN,
-CF3, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2.
In some embodiments, -NRNARNB is selected from a 5-membered heteroaryl group containing one heteroatom in the ring in addition to the N atom of -NRNARNB, wherein both heteroatoms are N atoms; and wherein the heteroaryl group is optionally substituted with one or more groups selected from
linear, branched or cyclic C1 -6alkyl optionally substituted with one group RAL,
F, CI, Br,
-CN,
-CF3, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2. In some embodiments, -NRNARNB is selected from a 5-membered heteroaryl group containing two heteroatoms in the ring in addition to the N atom of -NRNARNB, wherein both heteroatoms are N atoms; and wherein the heteroaryl group is optionally substituted with one or more groups selected from
linear, branched or cyclic C1 -6alkyl optionally substituted with one group RAL,
F, CI, Br,
-CN,
-CF3, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2.
In some embodiments, -NRNARNB is selected from a 5-membered heteroaryl group containing one or two heteroatoms in the ring in addition to the N atom of -NRNARNB, the heteroatoms being N atoms; wherein the heteroaryl group is optionally substituted with one or more groups selected from
linear, branched or cyclic C1 -6alkyl optionally substituted with one group RAL,
F, CI, Br,
-CN,
-CF3, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2.
In some embodiments, -NRNARNB is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of -NRNARNB;
optionally substituted with one or more groups selected from
linear or branched unsubstituted C1 -6alkyl,
F, CI, Br,
-CN
-CF3, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH and -COO(C1 -6alkyl).
In some embodiments, -NRNARNB is selected from a 5-membered heteroaryl group containing up to three N atoms in the ring in addition to the N atom of -NRNARNB;
optionally substituted with one or more groups selected from linear or branched unsubstituted C1 -6alkyl,
-CN
-CF3, -CF2H and -CH2F. some embodiments, -NRNARNB is the group (A3)
Figure imgf000060_0001
wherein
one group from YN1 to YN4 is CR3, another is N and the remainder are independently selected from CR3 and N; wherein R3 is selected from:
linear, branched or cyclic C1 -6alkyl optionally substituted with one group RAL,
F, CI, Br,
-CN,
-CFs, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2.
In some embodiments, R3 is selected from:
linear, branched or cyclic C1 -6alkyl optionally substituted with one group RAL, F,
-CN,
-CFs,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2.
In some embodiments, R3 is selected from linear, branched or cyclic C1 -6alkyl optionally substituted with one group RAL. In some embodiments, R3 is selected from linear, branched or cyclic unsubstituted C1 -6alkyl. In some embodiments, R3 is selected from linear C1-3 saturated alkyl.
In some embodiments, -NRNARNB is the group (A7)
Figure imgf000061_0001
wherein one of YN5, YN6 and YN7 is selected from N and CRY1; and the other two of YN5, YN6 and YN7 are each independently selected from CRY1; wherein RY1 is selected from -H;
C1 -6 linear or branched alkyl, optionally substituted with one or two groups RA1; C3-6 unsubstituted cycloalkyl;
-F, -CI, -Br,
-CN,
-CFs, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2.
In some embodiments, -NRNARNB is the group (A7), wherein YN5 and YN7 are each independently selected from CRY1, and YN6 is selected from N, CH and CRY1, wherein R' is selected from:
C1 -6 linear or branched alkyl, optionally substituted with one or two groups RA1; C3-6 unsubstituted cycloalkyl;
-F, -CI, -Br,
-CN,
-CFs, -CF2H, -CH2F,
-OH, -0( C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2.
In some embodiments, -NRNARNB is the group (A7), wherein YN5 and YN7 are each independently selected from CRY1, and YN6 is selected from N, CH and CRY1, wherein R' is selected from:
C1 -6 linear or branched unsubstituted alkyl;
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2. In some embodiments, -NRNARNB is the group (A7), wherein YN5 and YN7 are each independently selected from CRY1, and YN6 is selected from N, CH and CRY1, wherein RY1 is selected from:
C1 -6 linear or branched unsubstituted alkyl, preferably C1-3 linear or branched unsubstituted alkyl.
In some embodiments, -NRNARNB is the group (A7), wherein YN5 and YN7 are each independently selected from CRY1, and YN6 is selected from N, CH and CRY1, wherein RY1 is methyl or ethyl.
In some embodiments, YN6 is CH.
In some embodiments, -NRNARNB is the group (A7), wherein one of YN5, YN6 and YN7 is selected from N and CH; a second of YN5, YN6 and YN7 is CH and the third of YN5, YN6 and YN7is selected from CH and CRY1; wherein RY1 is selected from
-H;
C1 -6 linear or branched alkyl, optionally substituted with one or two groups RA1; C3-6 unsubstituted cycloalkyl;
-F, -CI, -Br,
-CN,
-CFs, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2. In some embodiments, Px is (P1 ); RP1 and RP2 are each independently selected from methyl and ethyl;
RP3 is selected from
methyl, ethyl, n-propyl,
-QA, -CH2QA, -(CH2)2QA,
wherein QA is selected from
cyclopropyl,
4- or 5-membered heterocycloalkyi groups containing one or two heteroatoms selected from NRZ, O and S, and
4- or 5-membered cycloalkyl groups;
wherein Rz is selected from the group consisting of
H, C1-3alkyl, COCi.3alkyl and S02C1-3alkyl; and
-NRARB is the group (A7),
wherein one of YN5, YN6 and YN7 is selected from N and CRY1; and the other two of YN5, YN6 and YN7 are each independently selected from CRY1; wherein RY1 is selected from -H;
C1 -6 linear or branched alkyl, optionally substituted with one or two groups RA1; C3-6 unsubstituted cycloalkyl;
Figure imgf000063_0001
In some embodiments, -NRNARNB is selected from
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000065_0001
In some embodiments, NRNARNB is an imidazolyl group, bearing a C substituent which the group (D1 )
Figure imgf000065_0002
(i.e. ethyl substituted by COR83 and NRB1 RB2) wherein
RB1 is selected from the group consisting of
-H,
-CORA2, -CONRA2, C02RA2, and
-S02RA2;
RB2 is selected from -H, and linear or branched
Figure imgf000065_0003
and
RB3 is selected from the group consisting of
-OH, -ORA2,
-NH2, -NHRA2 and -NRA2 2. In some embodiments, -NRNARNB is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or more groups selected from
oxo,
phenyl optionally substituted with one or more groups RA1,
RA2 and
RA1.
In some embodiments, the 8- to 10-membered heterobicyclyl group includes up to three heteroatoms in the bicyclic system in addition to the N atom of -NRNARNB, for example one, two or three heteroatoms, each independently selected from N and O. In some embodiments, the 8- to 10-membered heterobicyclyl group includes up to three heteroatoms in the bicyclic system in addition to the N atom of -NRNARNB, for example one, two or three heteroatoms, each independently selected from N. In some embodiments, the 8- to 10-membered heterobicyclyl group includes two heteroatoms in the bicyclic system in addition to the N atom of -NRNARNB, each independently selected from N.
In some embodiments, -NRNARNB is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or two groups selected from
linear or branched C1 -6alkyl optionally substituted with one or more groups RAL,
-OH, -ORA2,
-CF3, -CN, -NO2,
-CORA2, -COOH, -COORA2, -CONH2, -CONHRA2, -CONRA2 2, and
oxo.
In some embodiments, -NRNARNB is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or two groups selected from
-CORA2, -COOH, -COORA2, -CONH2, -CONHRA2, and -CONRA2 2.
In some embodiments, -NRNARNB is a 9-membered heterobicyclyl group optionally substituted with one or more groups selected from
oxo,
phenyl optionally substituted with one or more groups RA1,
RA2 and
RA1. In some embodiments, -NRNARNB is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from
oxo,
phenyl optionally substituted with one or more groups RA1,
RA2 and
RA1.
Herein, a "5,6" fused ring system indicates a bicyclic ring system in which a 5-membered ring is fused to a 6-membered ring.
In some embodiments, -NRNARNB is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from
oxo,
linear or branched C1 -6alkyl,
-F, -CI, -Br,
-CN,
-OH, -0(C1 -6alkyl),
-COOH and -COO(C1 -6alkyl). In some embodiments, -NRNARNB is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from
oxo,
linear or branched C1 -6alkyl,
-OH and -0(C1 -6alkyl).
In some embodiments, -NRNARNB is a 10-membered 6,6 fused heterobicyclyl group optionally substituted with one or more groups selected from
oxo, and
RA1.
In some embodiments, -NRNARNB is selected from
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
In some embodiments, both RP1 and RP2 are methyl, RP3 is selected from the group consisting of:
-CH2RP6,
C3 unsubstituted linear saturated alkyl,
4-membered heterocyclyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group, and
6-membered heteroaryl groups containing one to four (preferably two to four) heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups; and
RAu is the group (B1 ).
In some embodiments, both RP1 and RP2 are methyl, RP3 is selected from the group consisting of:
-CH2RP6,
C3 unsubstituted linear saturated alkyl, 4-membered heterocyclyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group, and
6-membered heteroaryl groups containing one to four (preferably two to four) heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups; and
RAu is the group -NRNARNB, wherein -NRNARNB is selected from a 5-membered heteroaryl group containing up to three heteroatoms in the ring selected from N, O and S in addition to the N atom of -NRNARNB; optionally substituted with one or more groups selected from
oxo, =NH,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; phenyl optionally substituted with one or more groups RA1,
RA2, and
RA1.
Particular embodiments of the invention are shown in the examples. In some
embodiments, the compound according to formula (I) is selected from:
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
In some embodiments, -Ls- is unsubstituted methylene. In other embodiments, -Ls- is unsubstituted ethylene. In some embodiments, -Ls- is a single bond.
In some embodiments, -Ls- is methylene substituted with one or two groups R1A1. In other embodiments, -Ls- is ethylene substituted with one or two groups R1A1.
In some embodiments, R1A1 is selected from linear C1-3 alkyl. In some embodiments, R1A1 is methyl. RSA
In some embodiments, RSA is selected from C5-6 cycloalkyl, heterocyclyl, aryl or heteroaryl groups and 8- to 10- membered bicyclyl or heterobicyclyl groups, optionally substituted with one or more groups RA1. In some embodiments, RSA is (S1 ):
Figure imgf000077_0001
In some embodiments, one of YS1, YS2, YS3, YS4 and YS9 is N. In some of these embodiments, YS1 is N and YS2, YS3, YS4 and YS9 are CH. In others of these
embodiments, YS3 is N and YS1, YS2, YS4 and YS9 are CH. In others of these embodiments, YS4 is N and YS1, YS2, YS3 and YS9 are CH. In these embodiments, (S1 ) is pyridyl.
In some embodiments, two of YS1, YS2, YS3, YS4 and YS9 are N. In some of these embodiments, YS1, YS4 and YS9 are CH and YS2 and YS3 are N. In others of these embodiments, YS2, YS4 and YS9 are CH and YS1 and YS3 are N. In others of these embodiments, YS3, YS4 and YS9 are CH and YS1 and YS2 are N. In some of these embodiments, YS1 and YS4 are N and YS2, YS3 and YS9 are CH. In others of these embodiments, YS2 and YS4 is N and YS1, YS3, and YS9 are CH. In others of these embodiments, YS3 and YS4 are N and YS1, YS2 and YS9 are CH. In others of these embodiments, YS3 and YS9 are N and YS1, YS2 and YS4 are CH. In these embodiments, (S1 ) is selected from pyrimidinyl, pyridazinyl and pyrazinyl. In some embodiments, all of YS1 , YS2, YS3, YS4 and YS9 are CH, i.e. (S1 ) is phenyl. In some embodiments, RSA is (S2):
Figure imgf000078_0001
In some of these embodiments, V is O. In other of these embodiments, V is is selected from H and C1-3
Figure imgf000078_0002
unbranched alkyl. In some of these embodiments, R°1 is H. In others of these
embodiments, R°1 is C1-3 unbranched alkyl, e.g. methyl, ethyl, n-propyl.
In other of these embodiments, V is N-C02-RC2, where RC2 is either C1-3 unbranched alkyl or C3-4 branched alkyl. In some of these embodiments, RC2 is C1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl. In others of these embodiments, RC2 is C3-4 branched alkyl, i.e. /sopropyl, /sobutyl, sec-butyl and tert-butyl.
In other of these embodiments, V is N-RN2, where RN2 is C1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl. In some embodiments, RN2 is methyl.
In some of these embodiment, there are no optional methyl substituents (represented by Rce).
In other of these embodiments, there is a single methyl substituent represented by Rce. In other of these embodiments, there are two methyl substituents represented by Rce.
In some embodiments, RSA is (S3):
Figure imgf000079_0001
In some of these embodiments, X is NH. In others of these embodiments, X is O. In some of these embodiments, all of YS5, Yse, YS7 and YS8 are CH. In others of these embodiments, one of YS5, Yse, YS7 and YS8 is N. In some of these embodiments, YS5 may be N. In some of these embodiments Yse may be N. In some of these embodiments YS7 may be N. In some of these embodiments YS8 may be N. In some embodiments, RSA is (S4):
Figure imgf000079_0002
In some of these embodiments, RC1 is 0-R°2. R°2 is C1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl.
In others of these embodiments, RC1 is NHRN1. In some of these embodiments, RN1 is H. In others of these embodiments, RN1 is C1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl.
In some of these embodiments, RC4 and RC5 are both H.
In other of these embodiments, RC4 is H and RC5 is Me.
In other of these embodiments, RC4 and RC5 are both Me.
In some embodiments, RSA is (S5):
Figure imgf000079_0003
In some of these embodiments, RC3 is C1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl. In others of these embodiments RC3 is C2H4CO2H.
In some of these embodiments n is an integer from 4 to 8. In some of these
embodiments, n is 7 or 8.
In some embodiments, RSA is a 5-membered heteroaromatic group containing up to 4 heteroatoms selected from N, O and S, at least one of which being N.
In some embodiments, RSA is a 5-membered heteroaromatic group containing up to 4 heteroatoms selected from N and O, at least one of which being N.
In some embodiments, RSA is a 5-membered heteroaromatic group connected to sulfur at a ring carbon and containing up to 4 heteroatoms selected from N, O and S, at least one of which being N.
In some embodiments, RSA is a 5-membered heteroaromatic group containing up to 4 heteroatoms selected from N.
In some embodiments, RSA is unsubstituted tetrazolyl.
In some embodiments, RSA is a 5-membered heteroaromatic group containing at least one heteroatom selected from N, O and S optionally N-substituted with one or more groups selected from
linear C1-3alkyl;
and optionally C-substituted with one or more groups selected from
linear or branched C1 -6alkyl optionally substituted with one or more groups RAL.
In some embodiments, RSA is a 5-membered heteroaromatic group containing at least one heteroatom selected from N, O and S optionally N-substituted with one or more groups selected from
methyl and ethyl
and optionally C-substituted with one or more groups selected from
linear or branched C1-3alkyl. In some embodiments, RSA is a 5-membered heteroaromatic group containing at least one heteroatom selected from N, O and S optionally N-substituted with one or more methyl groups, and optionally C-substituted with one or more methyl groups. In some embodiments, RSA is selected from
Figure imgf000081_0001
In some embodiments, RSA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
linear or branched C1 -6alkyl, optionally substituted with one or more groups RAL,
Figure imgf000081_0002
In some embodiments, RSA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
linear or branched C1 -6alkyl, optionally substituted with one or more groups RAL,
Figure imgf000081_0003
Figure imgf000082_0001
In some embodiments, RSA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
linear or branched C1 -6alkyl, optionally substituted with one or more groups RAL,
Figure imgf000082_0002
In some embodiments, RSA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
linear or branched C1 -6alkyl, optionally substituted with one or more groups RAL,
Figure imgf000082_0003
In some embodiments, RSA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
linear or branched C1 -6alkyl, optionally substituted with one or more groups RAL,
Figure imgf000082_0004
In some embodiments, RSA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from
linear or branched C1 -6alkyl, optionally substituted with one or more groups RAL,
Figure imgf000083_0003
In some embodiments, RSA is selected from 6-membered aromatic carbocyclic groups ortho- and/or mefa-substituted with one or more groups selected from
linear or branched C1 -6alkyl, optionally substituted with one or more groups RAL,
Figure imgf000083_0001
and/or para-substituted with a group selected from
linear or branched C1 -6alkyl, optionally substituted with one or more groups RAL,
Figure imgf000083_0002
In some embodiments, RSA is selected from
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups RA1. In some embodiments, RSA is selected from 6-membered heteroaryl group containing two nitrogen atoms, substituted with one or more groups RA1.
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one nitrogen atom, substituted with one or more groups RA1.
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
linear or branched C1-6alkyl,
Figure imgf000086_0002
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
linear or branched C1 -6alkyl,
Figure imgf000087_0001
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one nitrogen atom, substituted with one or more groups independently selected from the group consisting of
linear or branched C1 -6alkyl,
Figure imgf000087_0002
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
linear or branched C1 -6alkyl,
Figure imgf000087_0003
-CH2OH, -CH20(C1-3alkyl),
-COOH, -COO(C1-3alkyl), -CONH2, -CONH(C1-3alkyl), -CON(C1-3alkyl)2,
-OCO(C1-3alkyl), -OCONH2, -OCONH(C1-3alkyl), -OCON(C1-3alkyl)2,
-NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2,
-NHCOH, -NHCO(C1-3alkyl), -N(C1-3alkyl)COH and -N(C1-3alkyl)CO(C1-3alkyl).
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
linear or branched C1 -6alkyl,
-F. -CI,
-OH, -0(C1-3alkyl),
-CF3,
-CO(C1-3alkyl),
-CH2OH, -CH20(C1-3alkyl),
-COOH, -COO(C1-3alkyl), -CONH2, -CONH(C1-3alkyl), -CON(C1-3alkyl)2,
-NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2,
-NHCOH, -NHCO(C1-3alkyl) and -N(C1-3alkyl)COH.
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
methyl,
-F. -CI,
-OH, -OMe,
-CF3,
-COMe,
-CH2OH, -CH2OMe,
-COOH, -COOMe, -CONH2, -CONHMe, -CONMe2,
-NH2, -NHMe, -NMe2,
-NHCOH, -NHCOMe and -NMeCOH.
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
methyl, -F. -CI,
-OH, -OMe,
-CF3,
-COMe,
-CH2OH, -CH2OMe,
-COOH and -COOMe,
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
-COOH, -CON(C1 -6alkyl)2, -COO(C1 -6alkyl),
-CONH2, and
-CFs.
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
-COOH, -CON(Me)2, -COO(Me),
-CONH2, and
-CFs.
In some embodiments, RSA is selected from 6-membered heteroaryl group containing two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
-COOH, -CON(Me)2, -COO(Me), and -CONH2.
In some embodiments, RSA is selected from 6-membered heteroaryl group containing two nitrogen atoms, substituted with one group independently selected from the group consisting of
-COOH, -CON(Me)2, -COO(Me), and -CONH2.
In some embodiments, RSA is selected from 6-membered heteroaryl group containing one or two nitrogen atoms, substituted with one or more groups independently selected from the group consisting of
-CONH2, and
-CF3. In some embodiments RSA is selected from
Figure imgf000090_0001
In some embodiments, RSA is selected from 8- to 10-membered heterobicyclyl groups containing one or more heteroatoms independently selected from N, O and S. In some embodiments, RSA is selected from 8- to 10-membered heterobicyclyl groups containing one or more heteroatoms each independently selected from N.
In some embodiments, RSA is selected from 8- to 10-membered heterobicyclyl groups containing one, two or three heteroatoms independently selected from N, O and S.
In some embodiments, RSA is selected from 8- to 10-membered heterobicyclyl groups containing one or two heteroatoms independently selected from N and O.
In some embodiments, RSA is selected from 9-membered heterobicyclyl groups containing one or two heteroatoms independently selected from N, O and S. In some embodiments, RSA is selected from 9-membered heterobicyclyl groups containing one, two or three heteroatoms independently selected from N, O and S, connected to sulfur through a ring carbon atom.
In some embodiments, the heterobicyclyl group is a heteroaromatic group.
In some embodiments, RSA is selected from 8- to 10-membered heterobicyclyl groups containing one or more heteroatoms independently selected from N, O and S, wherein the heterobicyclyl group is substituted with one or more groups independently selected from RA1.
In some embodiments, RSA is selected from
Figure imgf000091_0001
In some embodiments, RSA is the group
Figure imgf000091_0002
wherein
ZS3 is selected from the group consisting of CH2, CHF and CF2;
one of ZS1, ZS2, ZS4 and ZS5 is selected from the group consisting of
Figure imgf000091_0003
the remainder of ZS1, ZS2, ZS4 and ZS5 are independently selected from the group consisting of
Figure imgf000091_0004
O;
with the provisos that the ring contains 0 or 1 oxygen atoms, that nitrogen atoms cannot be in a 1 ,2 or 1 ,3 relationship to each other, and that when ZS1 or ZS5 is N, Ls cannot be a single bond.
In some embodiments, ZS3 is selected from the group consisting of Chb, CHF and CF2; one of ZS1, ZS2, ZS4 and ZS5 is selected from the group consisting of
CH2, CHRAL and CRAL 2; and
the remainder of ZS1, ZS2, ZS4 and ZS5 are CH2.
In some embodiments, ZS3 is selected from the group consisting of CH2, CHF and CF2; and
the remainder of ZS1, ZS2, ZS4 and ZS5 are CH2. In some embodiments, RSA is
Figure imgf000092_0001
In some embodiments, RSA is the grou
Figure imgf000092_0002
wherein
one of Q1 to Q4 is selected from the group consisting of
O,
NH, NRA2,
CH2, CHRAL, CRAL2,
N-CO-RA2, N-CO-NHRA2, N-S02-RA2 and N-C02-RM; and
the remainder of Q1 to Q4 are independently selected from the group consisting of
CH2, CHRAL and CRAL 2; with the proviso that the ring contains 0 or 1 oxygen atoms, that the ring contains 0 or 1 nitrogen atoms, and that when Q1 or Q4 is N, Ls cannot be a single bond.
In some embodiments, one of Q1 to Q4 is selected from the group consisting of
O,
NH, NRA2,
CH2, CHRAL and CRAL 2; and
the remainder of Q1 to Q4 are independently selected from the group consisting of
CH2, CHRAL and CRAL 2.
In some embodiments, one of Q1 to Q4 is selected from the group consisting of
CH2, CHRAL and CRAL 2; and
the remainder of Q1 to Q4 are CH2.
In some embodiments, RSA is the grou (C1 )
Figure imgf000093_0001
wherein
EA is selected from the group consisting of
Figure imgf000093_0002
wherein EA1, EA2 and EA3 are D- or L-amino acid residues independently selected from Ala, Asn, Asp, Gin, Glu, Gly, His, lie, Leu, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -NREA1- and -COREA2 groups represent terminals of the alpha or pendent functionality of the amino acids respectively;
the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality;
when EA1 is Pro, REA1 is absent, otherwise REA1 is RE1;
when EA2 is Pro, REA1 is absent, otherwise REA1 is RE1; the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, -CONRA2RE1 and -COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and -OCOCH3; and when EA2 and EA3 are present and EA3 is not Pro the nitrogen of the amide bond between EA2 and EA3 may be optionally substituted with RE1;
REA2 is selected from -ORE7, -NH2, -NHRA2 and -NRA2RE1;
RE7 is selected from -H and -RA2; and
RE1 is selected from H and linear or branched C1-3alkyl.
In some embodiments, EA is selected from the group consisting of
Figure imgf000094_0001
In some embodiments, EA is selected from -NREA1-EA1-COREA2.
In some embodiments, EA is selected from the group consisting of
Figure imgf000094_0002
In some embodiments, REA2 is selected from -ORE7.
In some embodiments, REA2 is selected from -IMH2, -NHRA2 and -NRA2RE1.
In some embodiments, REA2 is selected from -NH2. In some embodiments, Ls is methylene and EA is selected from the group consisting of
Figure imgf000094_0003
In some embodiments, Ls is methylene and EA is selected from the group consisting of -NH-RA2, and In some embodiments, Ls is methylene and EA is selected from the group consisting of -0( C1-3alkyl),
-NH-(C1-3alkyl), and
-N(C1-3alkyl)2.
In some embodiments, Ls is methylene and EA is selected from the group consisting of -NH-(C1-3alkyl), and
-N(C1-3alkyl)2.
In some embodiments, Ls is methylene and EA is selected from the group consisting of -NH-CH3, and
-N(CH3)2.
In me embodiments, RSA is
Figure imgf000095_0001
In some embodiments, RSA is selected from the roup (C2)
Figure imgf000095_0002
wherein
RE1 is selected from H and linear or branched C1-3alkyl;
EB is selected from
Figure imgf000095_0003
-CO-EB2-EB3-N REBRE2,
wherein EB1, EB2 and EB3 are D- or L-amino acid residues independently selected from Ala, Asn, Asp, Gin, Glu, Gly, His, lie, Leu, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -CO-, -NREARE2 and -NREBRE2 groups represent terminals of the alpha or pendent functionality of the amino acids;
the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality;
when EB1 is Pro, REA is absent, otherwise REA is -H;
when EB3 is Pro, REB is absent, otherwise REB is -H;
the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, -CONRA2RE1 and - COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and -OCOCH3; and when EB2 and EB3 are present and EB2 is not Pro the nitrogen of the amide bond between EB2 and EB3 may be optionally substituted with RE1;
RE2 is selected from -H and -COCH3; and
when EB is EBA, RE1 and EBA together with the nitrogen atom to which they are attached form a group selected from
5- or 6-membered saturated heterocyclyl optionally substituted with one or more groups RAL, and
5- or 6-membered saturated heteroaryl optionally substituted with one or more groups RA1.
In some embodiments, EB is selected from EBA.
In some embodiments, EB is selected from
-CO-EB1-NREARE2, and
-CO-EB2-EB3-N REBRE2. In some embodiments, EB is -CO-EB1-NREARE2.
In some embodiments, RE2 is -H.
In some embodiments, RE2 is -COCH3.
In some embodiments of the group (C2), RE1 is -H. In some embodiments of the group (C2), RE1 is methyl. In some embodiments, RSA is the group (C3)
Figure imgf000097_0001
wherein
RE1 is selected from H and linear or branched C1-3alkyl;
Ec is selected from
-OH,
-ORA2
-IMH2, NHRA2, NRA22 and
.N RECI.ECI.COREC2
wherein EC1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -NREC1- and -COREC2 groups represent terminals of the alpha or pendent functionality of the amino acids;
the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality;
when EC1 is Pro, REC1 is absent, otherwise REC1 is RE1;
the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, -CONRA2RE1 and - COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and -OCOCH3;
REC2 is selected from -ORE9, -NH2, -NHRA2 and -NRA2RE1;
RE3 and RE4 are independently selected from -H and -CH3;
when RE1 is H and Ec is -OC1-3alkyl, -NH2 or -NHC1-3alkyl, ED is selected from
-H, and
-CO-ED1-NREDRE6 otherwise, ED is selected from
Figure imgf000098_0001
wherein ED1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -
NREDRE6- and -CO- groups represent terminals of the alpha or pendent functionality of the amino acids;
wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality;
wherein the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, -CONRA2RE1 and -COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and -OCOCH3; wherein RE5 and RE6 are independently selected from -H and -COCH3;
when ED1 is Pro, RED is absent, otherwise RED is -H; and
with the proviso that RA is not L-cysteine.
In some embodiments, Ec is selected from
Figure imgf000098_0002
ED is selected from
Figure imgf000098_0003
In some embodiments, Ec is selected from
Figure imgf000098_0004
ED is selected from
Figure imgf000098_0005
In some embodiments, Ec is selected from
Figure imgf000098_0006
ED is -CO-ED1-NREDRE6.
In some embodiments, Ec is -NREC1-Ec1-COREC2; and
ED is -CO-ED1-NREDRE6.
In some embodiments, RE3 and RE4 are the same. In some embodiments, RE3 and RE4 are both -H. In some embodiments, RE3 and RE4 are both methyl. In some embodiments of the group (C3), RE1 is -H. In some embodiments, RSA is
Figure imgf000099_0001
In some embodiments, RSA is the grou (C4)
Figure imgf000099_0002
wherein
Z6 is selected from N-CO-RA2 and N-CO-NHRA2; and
RZ6 is one or two optional methyl substituents.
Particular embodiments of the invention are shown in the examples.
Figure imgf000100_0001
Figure imgf000101_0001
In some embodiments, RAu is the group (B3), i.e. the group -C≡C-LC-RCA. Lc
In some embodiments, -Lc- is unsubstituted methylene. In other embodiments, -Lc- is unsubstituted ethylene. In some embodiments, -Lc- is a single bond. In some embodiments, -Lc- is methylene substituted with one or two groups R1A1. In other embodiments, -Lc- is ethylene substituted with one or two groups R1A1.
In some embodiments, R1A1 is selected from C1-3 linear unsubstituted alkyl. In some embodiments, R1A1 is methyl.
RCA
In some embodiments, -Lc- is a single bond and RCA is RCAA.
In some embodiments, -Lc- is methylene or ethylene optionally substituted with one or more groups R1A1 and RCA is selected from RCAA and RCAB. ftCAA
In some embodiments, RCAA is selected from linear or branched C1 -6alkyl, substituted with one or more groups RAL.
In some embodiments, RCAA is methyl, substituted with one or more groups RAL.
In some embodiments, RCAA is methyl, substituted with -NRA22. In some embodiments, RCAA is methyl, substituted with -N(C1 -6alkyl)2.
In some embodiments, RCAA is methyl, substituted with one or more groups RAL, wherein RAL is selected from
Figure imgf000102_0001
In some embodiments, RCAA is methyl, substituted with one or more groups RAL, wherein RAL is selected from
-F,
Figure imgf000103_0005
In some embodiments, RCAA is ethyl, substituted with one or more groups RAL, wherein RAL is selected from
Figure imgf000103_0001
In some embodiments, RCAA is branched C3-4alkyl, substituted with one or more groups RAL.
In some embodiments, RCAA is selected from:
Figure imgf000103_0002
In certain embodiments, RCAA is the roup (D1 )
Figure imgf000103_0003
(i.e. ethyl substituted by COR63 and NRB1 RB2) wherein
RB1 is selected from the group consisting of
Figure imgf000103_0004
RB2 is selected from -H, and linear or branched Ci-4alkyl; and
RB3 is selected from the group consisting of
Figure imgf000104_0004
Figure imgf000104_0001
In some embodiments, Lc is a single bond and RCAA is
In some embodiments, RCAA is C3-5cycloalkyl, optionally substituted with one or more groups RAL. In these embodiments, RAL may be selected from
Figure imgf000104_0002
In some embodiments, RCAA is selected from 8- to 10-membered bicyclyl and biheterocyclyl, optionally substituted with one or more groups RA1.
In some embodiments, RCAA is 9-membered biheterocyclyl including two or more heteroatoms selected from N and O.
In some embodiments, RCAA is selected from
Figure imgf000104_0003
In some embodiments, RCAA is selected from 5-membered heteroaryl containing one or more heteroatoms selected from N, O and S, optionally N-substituted with one or more groups RA2 and/or C-substituted with one or more groups RA1. In some embodiments, RCAA is selected from 5-membered heteroaryl containing one or more heteroatoms selected from N and O, optionally N-substituted with one or more groups RA2.
In some embodiments, RCAA is selected from 5-membered heteroaryl containing one or more heteroatoms independently selected from N and O, optionally N-substituted with one or more groups selected from linear or branched C1 -6alkyl.
In some embodiments, RCAA is selected from 5-membered heteroaryl containing two heteroatoms independently selected from N and O, optionally N-substituted with one or more groups RA2.
In some embodiments, RCAA is selected from 5-membered heteroaryl containing two heteroatoms independently selected from N and O, optionally N-substituted with one or more groups selected from linear or branched C1 -6alkyl.
In some embodiments, RCAA is selected from
Figure imgf000105_0001
In some embodiments, RCAA is selected from the group consisting of (D2) to (D4):
Figure imgf000105_0002
W1B is selected from the group consisting of N and C;
WC1 and W1A are each independently selected from the group consisting of NH, NRA2, O and S;
WC2 to WC4, W2A to W4A and W2B to W5B are each independently selected from the group consisting of CH, CRA1 and N. In some embodiments, RCAA is -COOH.
In some embodiments, RCAA is -COORA2, wherein RA2 is selected from linear or branched C1 -6alkyl. In some of these embodiments, RA2 may be selected from linear or branched C1-3alkyl. In further embodiments, RA2 may be selected from linear C1-3alkyl, e.g. methyl, ethyl.
In some embodiments, RCAA is -CONH2.
In some embodiments, RCAA is selected from -CONHRA2, wherein RA2 is selected from linear or branched C1 -6alkyl. In some of these embodiments, RA2 may be selected from linear or branched C1-3alkyl. In further embodiments, RA2 may be selected from linear C1-3alkyl, e.g. methyl, ethyl.
In some embodiments, RCAA is selected from -CONRA22, where RA2 may be as expressed above.
In some embodiments, RCAA is selected from
Figure imgf000106_0001
In some embodiments, RCAA is selected from
Figure imgf000107_0001
In some embodiments, RCAA is the group (D5)
Figure imgf000107_0002
wherein V6 is selected from the group consisting of CH and CRA2;
two of V1 to V5 are independently selected from the group consisting of
Figure imgf000107_0005
two further groups of V1 to V5 are independently selected from the group consisting of
Figure imgf000107_0003
with the remaining group of V to V5 being selected from the group consisting of
Figure imgf000107_0004
wherein RA6 is selected from the group consisting of
Figure imgf000107_0006
provided that any two adjacent groups from V to V5 cannot both be SO2, cannot both be CO, and a CO or O group cannot be adjacent to an SO2 group, and cannot both be NRA6.
In some embodiments, RCAA is the group (D5) wherein V6 is selected from CH and CRA2, one of V1 to V5 is selected from CHF, CF2, O, S02, NH and NRA2 and the remainder of V1 , V2, V4 and V5 are CH2. In some embodiments, RCAA is the group (D5) wherein V6 is selected from CH and CRA2, V3 is selected from CH2, CHF, CF2, O, S02, NH and NRA2 and V1, V2, V4 and V5 are CH2.
In some embodiments, RCAA is the group (D5) wherein V6 is CH, V3 is selected from CH2, CHRA1, CRA1 2, O, S02, NH and NRA2 and V1, V2, V4 and V5 are CH2.
In some embodiments RCAA is selected from
Figure imgf000108_0001
In some embodiments L-RA is selected from:
Figure imgf000108_0002
In some embodiments, RCAA is the group (D6)
Figure imgf000108_0003
wherein
a first group from X1 to X5 is selected from the group consisting of
CH, CRA1 , and
CY, wherein Y is selected from one of the groups (D7) to (D9);
Figure imgf000109_0001
wherein Lv is selected from methylene, and a single bond;
V12, Y1 and Z1 are each independently selected from the group consisting of CH, CR1A1 and N;
two of V7 to V11 are independently selected from the group consisting of
Figure imgf000109_0004
two further groups of V7 to V11 are independently selected from the group consisting of
Figure imgf000109_0003
with the remaining group of V7 to V11 being selected from the group consisting of
Figure imgf000109_0002
provided that any two adjacent groups from V7 to V11, cannot both be CO and cannot both be NRA7; and a CO or O group cannot be adjacent to an S02 group;
one of Y2 to Y5 is selected from the group consisting of
Figure imgf000109_0005
two further groups of Y2 to Y5 are independently selected from the group consisting of
Figure imgf000109_0006
with the remaining group of Y2 to Y5 being selected from the group consisting of
Figure imgf000109_0007
provided that any two adjacent groups from Y2 to Y5 cannot both be CO and cannot both be NRA7; and a CO group cannot be adjacent to an S02 group; when Z1 is N, Z2, Z3 and Z4 are each independently selected from the group consisting of
CH2, CHR1A1 and CR1A1 2;
when Z1 is CH or CR1A1 , one of Z2, Z3 and Z4 is NRA7 and the remaining two positions are independently selected from the group consisting of CH2, CHR1A1 and CR1A12;
wherein RA7 is selected from the group consisting of
Figure imgf000110_0002
a second and third group from X1 to X5 is selected from the group consisting of
CH, and CRA1;
and the remainder of X1 to X5 are each independently selected from the group consisting of
N and CH;
with the proviso that X1 and X5 are not C-CN.
In some embodiments, RCAB is selected from
C2-6alkenyl and C2-6alkynyl, optionally substituted with one or more groups RAL, or the group (D5) wherein V6 is N and three of V1 to V5 are independently selected from CH2, CHRA1 and CRA12, with the remaining two groups being independently selected from
Figure imgf000110_0001
provided that neither V nor V5 can be NRA6 and that any two adjacent groups cannot be both O, CO, NRA6 or SO2; and that a CO or O group cannot be adjacent to an SO2 group.
In some embodiments, RCAA is the group (D6) wherein three groups from X1, X2, X3, X4 and X5 are CH; a further group is selected from CH and N and the fifth group is N. In these embodiments therefore RAA is selected from pyridyl and diazinyls (e.g. pyrazinyl, pyrimidnyl and pyridazinyl).
In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CRA1.
In some embodiments, RCAA is selected from the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CRA1, wherein RA1 is selected from the group consisting of C1 -6alkyl wherein the alkyl chain is interrupted with one S atom,
Figure imgf000111_0001
In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CRA1 , wherein RA1 is selected from the group consisting of C1 -6alkyl wherein the alkyl chain is interrupted with one S atom,
Figure imgf000111_0004
In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CRA1 , wherein RA1 is selected from the group consisting of
Figure imgf000111_0002
In some embodiments, RCAA is the group (D6) wherein three groups from X1, X2, X3, X4 and X5 are CH and the remaining two groups are independently CRA1, wherein RA1 is selected from the group consisting of
Figure imgf000111_0003
Figure imgf000112_0002
In some embodiments, RCAA is the group (D6) wherein three groups from X1, X2, X3, X4 and X5 are CH and the remaining two groups are independently CRA1, wherein RA1 is selected from the group consisting of
-F, -CN
-OH and -ORA2.
In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CY, wherein Y is the group (D7)
Figure imgf000112_0001
wherein Lv is methylene or a single bond; V7, V8, V9 and V10 are each independently selected from CH2 and CHR1A1; V9 is selected from O, NH, NR1A1 and S02; and V12 is selected from CH and N.
In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CY, wherein Y is the group (D7); wherein Lv is methylene or a single bond; V7, V8, V9 and V10 are each independently selected from CH2 and C H RIAI . V9 is selected from O, NH, NR1A1 and S02; and V12 is N.
In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CY, wherein Y is the group (D8)
Figure imgf000113_0001
wherein Lv is methylene or a single bond; Y2, Y3, Y4 and Y5 are each independently selected from CH2 and CHR1A1; and Y1 is selected from CH and N.
In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CY, wherein Y is the group (D8); wherein Lv is methylene or a single bond; Y2, Y3, Y4 and Y5 are each independently selected from CH2 and CHR1A1; and Y1 is N.
In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CY, wherein Y is the group (D9)
Figure imgf000113_0002
wherein Lv is methylene or a single bond; one of Z2, Z3, and Z4 is NRA7, and the other two of Z2, Z3, and Z4 are each independently selected from CH2 and CHR1A1 ; and Z1 is selected from CH and N. In some embodiments, RCAA is the group (D6) wherein four groups from X1, X2, X3, X4 and X5 are CH and the fifth group is CY, wherein Y is the group (D9); wherein Lv is methylene or a single bond; Z2, Z3, and Z4 are each independently selected from CH2 and CHR1A1; and Z1 is N. In the above embodiments where one of X1, X2, X3, X4 and X5 is CY, R1A1 may be methyl.
In some embodiments, RCAA is the group (D6) wherein a first group from X1 to X5 is selected from the group consisting of
CH, CRA1 , and
CY, wherein Y is selected from one of the groups (D7) to (D9);
a second and third group from X1 to X5 is selected from the group consisting of
CH, and CRA1;
and the remainder of X1 to X5 are each N.
In some embodiments, RCAA is the group (D6) wherein a first group from X1 to X5 is selected from the group consisting of
CH and CRA1,
a second and third group from X1 to X5 is CH;
a fourth group from X1 to X5 is N;
and the final group from X1 to X5 is selected from CH and N.
In some embodiments, RCAA is the group (D6) wherein a first group from X1 to X5 is selected from the group consisting of
CH and CRA1, wherein RA1 is selected from -COOH, -COORA2, -CONH2,
-CONHRA2 and -CONRA2 2;
a second and third group from X1 to X5 is CH;
a fourth group from X1 to X5 is N;
and the final group from X1 to X5 is selected from CH and N.
In some embodiments, RCAA is phenyl, optionally mono- or di-substituted with groups independently selected from
Figure imgf000114_0001
and
Figure imgf000115_0001
In some embodiments, RCAA is phenyl, optionally mono- or di-substituted with groups independently selected from
Figure imgf000115_0002
In some embodiments, RCAA is phenyl, optionally mono- or di-substituted with groups independently selected from
-OMe,
-COOH,
Figure imgf000115_0003
In some embodiments, RCAA is phenyl, optionally mono-substituted with
independently selected from
-OMe,
-COOH,
Figure imgf000115_0004
In some embodiments, RCAA is unsubstituted phenyl. In some embodiments, RCAA is selected from
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
In some embodiments, L-RCAA is selected from
Figure imgf000122_0001
Figure imgf000123_0001
In some embodiments, the compounds according to formula (I) is selected from:
Figure imgf000123_0002
In some embodiments, the compounds according to formula (II) is selected from:
Figure imgf000123_0003
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Bacterial infections
Bacteria that cause infection of humans include, but are not limited to, those set out below in Table 1 .
Figure imgf000128_0001
Figure imgf000129_0001
The bacterial infection prevented and/or treated by compounds of the present invention may be infection by one or more Gram-positive bacteria. Furthermore, the compounds of the present invention may be selective for one or more Gram-positive bacteria over Gram- negative bacteria. Thus, compounds of the present invention may show no significant inhibition of growth of Gram-negative bacteria.
The bacterial infection prevented and/or treated by compounds of the present invention may be infection by one or more Gram-negative bacteria. Furthermore, the compounds of the present invention may be selective for one or more Gram-negative bacteria over Gram-positive bacteria. Thus, compounds of the present invention may show no significant inhibition of growth of Gram-positive bacteria.
Furthermore, the compounds of the present invention may inhibit the growth of both Gram-positive bacteria and Gram-negative bacteria.
Representative examples of Gram-positive bacteria include Staphylococcus (e.g. S.
aureus, S. epidermis), Enterococci (e.g. E. faecium, E. faecalis), Clostridia (e.g. C.
difficile), Propionibacteria (e.g. P. acnes) and Streptococcus.
Bacterial infections in animals are, for example, described in "Pathogenesis of Bacterial Infections in Animals", edited by Carlton L. Gyles, John F. Prescott, J. Glenn Songer, and Charles O. Thoen, published by Wiley-Blackwell (Fourth edition, 2010 - ISBN 978-0-8138- 1237-3), which is hereby incorporated by reference. Many are the same as listed above for humans.
Combinations
Treatments as described herein may be in combination with one or more known antibiotics, examples of which are described below:
(a) Aminoglyosides: Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin,
Tobramycin, Paromomycin, Streptomycin; Spectinomycin;
(b) Ansamycins: Geldanamycin, Herbimycin, Rifaximin;
(c) Carbacephem:Loracarbef;
(d) Cabapenems: Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem;
(e) 1 st generation Cephlasporins: Cefadroxil, Cefazolin, Cefalotin or Cefalothin, Cefalexin;
(f) 2nd generation Cephlasporins: Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime;
(g) 3rd generation Cephlasporins: Cefixime, Cefdinir, Cefditoren, Cefoperazone,
Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone;
(h) 4th generation Cephlasporins: Cefepime;
(i) 5th generation Cephlasporins: Ceftaroline fosamil, Ceftobiprole, Ceftolozane- tazobactam, Ceftaroline;
(j) Glycopeptides: Teicoplanin, Vancomycin, Telavancin, Dalbavancin, Oritavancin;
(k) Lincosamides: Clindamycin, Lincomycin
(I) Lipopeptide: Daptomycin
(m) Macrolides: Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spiramycin, Rifabutin; Fidaxomicin;
(n) Monobactams: Aztreonam;
(o) Nitrofurans: Furazolidone, Nitrofurantoin;
(p) Oxazolidonones: Linezolid, Posizolid, Radezolid, Torezolid, Tedizolid, Tedizolid phosphate;
(q) Penicillins: Amoxicillin, Ampicillin, Aziocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V,
Piperacillin, Temocillin, Ticarcillin;
(r) Polypeptides: Bacitracin, Colistin, Polymyxin B, Polymyxin E (colistin);
(s) Quinolones: Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin,
Grepafloxacin, Sparfloxacin, Temafloxacin; (t) Sulfonamides: Mafenide, Sulfacetamide, Sulfadiazine, Silver sulfadiazine,
Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine,
Sulfisoxazole, Trimethoprim-Sulfamethoxazole, Sulfonamidochrysoidine;
(u) Tetracylines: Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline;
(v) Antibodies: bezlotoxumab;
(w) Νοη-β-lactam β-lactamase inhibitors: avibactam;
(x) Quinolines: Bedaquiline; and
(y) Combinations: ceftazidime-avibactam, colistin-ceftazidime, colistin-rifabutin.
Treatments as described herein may also be in combination with one or more known anti-fungal, anti-Protozoal, anti-inflammatory, anti-proliferative or anti-viral agents.
General Experimental
The invention also provides a process for the preparation of a compound of formula IA:
Figure imgf000131_0001
which comprises reacting a compound of general formula I':
Figure imgf000131_0003
with chloro(trialkyl phosphine) gold(l) complexes of general formula II:
Figure imgf000131_0002
The invention also provides a process for the preparation of a compound of formula IB:
Figure imgf000132_0001
which comprises reacting a compound of general formula III, IV, V, VI or IX:
Figure imgf000132_0002
with a chloro(trialkyl phosphine) gold(l) complex of general formula II:
Figure imgf000132_0003
The invention also provides a process for the preparation of a compound of formula IC:
Figure imgf000132_0004
comprising reacting a compound of general formula X or XI:
Figure imgf000133_0001
with a chloro(trialkyl phosphine) gold(l) complex of general formula II:
Figure imgf000133_0002
Isomers, Salts and Solvates
Isomers
Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").
Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers", as used herein, are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH3, is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH2OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., Ci-7alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl). The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.
Figure imgf000134_0001
Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1H, 2H (D), and 3H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any isotopic form, including 160 and 180; Au may be in any isotopic forms, including 197Au and 195Au; S may be in any isotopic forms, including 32S, 33S, 34S and 36S; P may be in any isotopic forms, including 31P, 33P and 32P; and the like. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g. fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
Regioisomers
In some cases, the structural assignments for compounds described herein may be unconfirmed due to regioisomerism. When a reactant exists in multiple interchangeable tautomeric forms, the product may be one of a number of regioisomers (each regioisomer resulting from the reaction of a different tautomeric form), or a mixture of these forms. For example, the substituted pyrazole compound below exists in the tautomeric forms (A) and (B) shown:
Figure imgf000134_0002
, where R' represents a group that is not H. When this substituted pyrazole compound reacts with a gold(l) phosphine chloride reactant CI-Au=PR3, reaction may occur with either tautomer, producing the following two distinct regioisomeric products (Α') and (Β'):
Figure imgf000135_0001
It is possible that these may interconvert in solution (as described in Nomiya, 1998) - any analytical approach used may indicate only one of the possible regioisomers, although the actual product formed may more correctly be assigned as (Α'), (Β') or a mixture of the two.
Thus, when a structure is assigned herein as a compound which could exist as multiple regioisomers due to reaction of a gold(l) phosphine chloride with a reactant which exists in multiple interchangeable tautomeric forms, the skilled person will understand that the actual product may in fact be one or more of the regioisomers, and the disclosure of such compounds herein extends to all such regioisomers individually and as mixtures in any relative amount.
The specific compounds described herein which may exist as multiple regioisomers for this reason are indicated below.
Salts
It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge, et al., J. Pharm. Sc/'., 66, 1-19 (1977).
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Α 3. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4+) and substituted ammonium ions (e.g., NHsR+, NhbF^, NHR3+, NR4 +). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine,
ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH3)4 +.
If the compound is cationic, or has a functional group which may be cationic (e.g., -IMH2 may be -NhV), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. Unless otherwise specified, a reference to a particular compound also include salt forms thereof.
Solvates
It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. Unless otherwise specified, a reference to a particular compound also include solvate forms thereof. The Subject/Patient
The subject/patient may be an animal, mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a monotreme (e.g., duckbilled platypus), a rodent
(e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.
Furthermore, the subject/patient may be any of its forms of development, for example, a foetus. In one preferred embodiment, the subject/patient is a human.
Dosage and Formulation
The dosage administered to a patient will normally be determined by the prescribing physician and will generally vary according to the age, weight and response of the individual patient, as well as the severity of the patient's symptoms and the proposed route of administration. However, in most instances, an effective therapeutic daily dosage will be in the range of from about 0.05 mg/kg to about 100 mg/kg of body weight and, preferably, of from 0.05 mg/kg to about 5 mg/kg of body weight administered in single or divided doses. In some cases, however, it may be necessary to use dosages outside these limits.
While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The formulations, both for veterinary and for human medical use, of the present invention comprise a compound of formula (I) in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredient(s). The carrier(s) must be 'acceptable' in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Conveniently, unit doses of a formulation contain between 0.1 mg and 1 g of the active ingredient. Preferably, the formulation is suitable for administration from one to six, such as two to four, times per day. For topical administration, the active ingredient preferably comprises from 1 % to 2% by weight of the formulation but the active ingredient may comprise as much as 10% w/w. Formulations suitable for nasal or buccal administration, such as the self-propelling powder-dispensing formulations described hereinafter, may comprise 0.1 to 20% w/w, for example about 2% w/w of active ingredient.
The formulations include those in a form suitable for oral, ophthalmic, rectal, parenteral (including subcutaneous, vaginal, intraperitoneal, intramuscular and intravenous), intraarticular, topical, nasal or buccal administration. The toxicity of certain of the compounds in accordance with the present invention will preclude their administration by systemic routes, and in those, and other, cases opthalmic, topical or buccal administration, and in particular topical administration, is preferred for the treatment of local infection.
Formulations of the present invention suitable for oral administration may be in the form of discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. The active ingredient may also be in the form of a bolus, electuary or paste. For such formulations, a range of dilutions of the active ingredient in the vehicle is suitable, such as from 1 % to 99%, preferably 5% to 50% and more preferably 10% to 25% dilution. Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.
Formulations suitable for parenteral administration comprise a solution, suspension or emulsion, as described above, conveniently a sterile aqueous preparation of the active ingredient that is preferably isotonic with the blood of the recipient.
Formulations suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient, which may be in a microcrystalline form, for example, in the form of an aqueous microcrystalline suspension or as a micellar dispersion or suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient particularly for both intra-articular and ophthalmic administration.
Formulations suitable for topical administration include liquid or semi-liquid preparations such as liniments, lotions or applications; oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. For example, for ophthalmic administration, the active ingredient may be presented in the form of aqueous eye drops, as for example, a 0.1 -1.0% solution.
Drops according to the present invention may comprise sterile aqueous or oily solutions. Preservatives, bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric salts (0.002%), benzalkonium chloride (0.01 %) and chlorhexidine acetate (0.01 %). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol. Lotions according to the present invention include those suitable for application to the eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide or preservative prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol, or a softener or moisturiser such as glycerol or an oil such as castor oil or arachis oil.
Creams, ointments or pastes according to the present invention are semi-solid
formulations of the active ingredient in a base for external application. The base may comprise one or more of a hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil such as a vegetable oil, eg almond, corn, arachis, castor or olive oil; wool fat or its derivatives; or a fatty acid ester of a fatty acid together with an alcohol such as propylene glycol or macrogols. The formulation may also comprise a suitable surface- active agent, such as an anionic, cationic or non-ionic surfactant such as a glycol or polyoxyethylene derivatives thereof. Suspending agents such as natural gums may be incorporated, optionally with other inorganic materials, such as silicaceous silicas, and other ingredients such as lanolin.
Formulations suitable for administration to the nose or buccal cavity include those suitable for inhalation or insufflation, and include powder, self-propelling and spray formulations such as aerosols and atomisers. The formulations, when dispersed, preferably have a particle size in the range of 10 to 200μηη.
Such formulations may be in the form of a finely comminuted powder for pulmonary administration from a powder inhalation device or self-propelling powder-dispensing formulations, where the active ingredient, as a finely comminuted powder, may comprise up to 99.9% w/w of the formulation. Self-propelling powder-dispensing formulations preferably comprise dispersed particles of solid active ingredient, and a liquid propellant having a boiling point of below 18°C at atmospheric pressure. Generally, the propellant constitutes 50 to 99.9% w/w of the formulation whilst the active ingredient constitutes 0.1 to 20% w/w. for example, about 2% w/w, of the formulation.
The pharmaceutically acceptable carrier in such self-propelling formulations may include other constituents in addition to the propellant, in particular a surfactant or a solid diluent or both. Especially valuable are liquid non-ionic surfactants and solid anionic surfactants or mixtures thereof. The liquid non-ionic surfactant may constitute from 0.01 up to 20% w/w of the formulation, though preferably it constitutes below 1 % w/w of the formulation. The solid anionic surfactants may constitute from 0.01 up to 20% w/w of the formulation, though preferably below 1 % w/w of the composition.
Formulations of the present invention may also be in the form of a self-propelling formulation wherein the active ingredient is present in solution. Such self-propelling formulations may comprise the active ingredient, propellant and co-solvent, and advantageously an antioxidant stabiliser. Suitable co-solvents are lower alkyl alcohols and mixtures thereof. The co-solvent may constitute 5 to 40% w/w of the formulation, though preferably less than 20% w/w of the formulation. Antioxidant stabilisers may be incorporated in such solution-formulations to inhibit deterioration of the active ingredient and are conveniently alkali metal ascorbates or bisulphites. They are preferably present in an amount of up to 0.25% w/w of the formulation.
Formulations of the present invention may also be in the form of an aqueous or dilute alcoholic solution, optionally a sterile solution, of the active ingredient for use in a nebuliser or atomiser, wherein an accelerated air stream is used to produce a fine mist consisting of small droplets of the solution.
In addition to the aforementioned ingredients, the formulations of this invention may include one or more additional ingredients such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives eg
methylhydroxybenzoate (including anti-oxidants), emulsifying agents and the like. A particularly preferred carrier or diluent for use in the formulations of this invention is a lower alkyl ester of a Cie to C24 mono-unsaturated fatty acid, such as oleic acid, for example ethyl oleate. Other suitable carriers or diluents include capric or caprylic esters or triglycerides, or mixtures thereof, such as those caprylic/capric triglycerides sold under the trade name Miglyol, eg Miglyol 810. Embodiments of the invention will now be described by way of example only.
Examples
Analytical Methods
Analysis of products and intermediates was performed using reverse phase analytical HPLC-MS using the parameters set out below.
HPLC Analytical Methods:
AnalpH2_MeOH_4min: Phenomenex Luna C18 (2) 3 μηι, 50 x 4.6 mm; A = water + 0.1 % formic acid; B = MeOH + 0.1 % formic acid; 45°C; %B: 0.0 min 5%, 1 .0 min 37.5%, 3.0 min 95%, 3.5 min 95%, 3.51 min 5%, 4.0 min 5%; 2.25 mL/min.
Preparative HPLC Methods
Reverse Phase Preparative HPLC-MS: Mass-directed purification by preparative LC-MS using a preparative C-18 column (Phenomenex Luna C18 (2), 100 x 21 .2 mm, 5 μηη).
Generic Acidic Conditions:
A = water + 0.1 % formic acid; B = MeOH + 0.1 % formic acid; 20°C; %B: 0.0 min Initial between 2% and 50%, 0.1 min % as per Initial, 7.0 min between 40% and 95%, 9.0 min 95%, 10.0 min 95%, 10.1 min back to Initial %; 12.0 min Initial %; 20.0 mL/min.
Generic Basic Conditions:
A = water pH 9 (Ammonium Bicarbonate 10 mM); B = MeOH; 20°C; %B: 0.0 min Initial between 2% and 50%, 0.1 min % as per Initial, 7.0 min between 40% and 95%, 9.0 min 95%, 10.0 min 95%, 10.1 min back to Initial %; 12.0 min Initial %; 20.0 mL/min.
NMR was also used to characterise final compounds. NMR spectra were obtained Bruker Advance 400, Bruker DRX 400 or Jeol 400 ECS at room temperature unless otherwise stated. 1H NMR spectra are reported in ppm and referenced to either tetramethylsilane (0.00 ppm), DMSO-d6 (2.50 ppm), CDCI3 (7.26 ppm) or CD3OD (3.31 ppm). 31P NMR spectra are reported in ppm and referenced to phosphoric acid (0.00 ppm). Abbreviations Used
For the examples below as well as throughout the application, the following abbreviations have the following meanings. If not defined, the terms have their generally accepted meanings.
°C Degrees Celsius
AC2O Acetic anhydride
app Apparent
aq. Aqueous
br Broad
d Doublet
DABCO 1 ,4-Diazabicyclo[2,2,2]octane
dba Dibenzylideneacetone
DCM Dichloromethane
DIPEA /V,/V-Diisopropylethylamine
dm Doublet of multiplets
DMSO Dimethyl sulfoxide
Et Ethyl
EtOAc Ethyl acetate
EtOH Ethanol
Et20 Diethyl ether
Eq. Equivalent(s)
g Gram(s)
h Hour(s)
HATU 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-£>]pyridinium 3-oxide hexafluorophosphate
HCI Hydrochloric acid
HPLC High-performance liquid chromatography
J Coupling constant
K2CO3 Potassium carbonate
KOH Potassium hydroxide
LC-MS Liquid chromatography-mass spectrometry
m Multiplet
M Molar
Me Methyl
MeCN Acetonitrile MeOH Methanol
mg Milligram(s)
MgS04 Magnesium sulfate
min Minute(s)
mL Millilitre(s)
mmol Millimole(s)
N Normal
NaH Sodium hydride
NaOH Sodium hydroxide
NaOMe Sodium methoxide
nBuLi n-Butylithium
NMR Nuclear Magnetic Resonance
ppm Parts per million
Pr Propyl
q Quartet
qn Quintet
rt Room temperature
sat. Saturated
s Singlet
SPE Solid Phase Extraction
TBAF Tetrabutylammonium fluoride
TCEP Tris(2-carboxyethyl)phosphine
TEA Triethylamine
THF Tetrahydrofuran
TLC Thin layer chromatography
TMS Trimethylsilyl
TsCI 4-Toluenesulfonyl chloride
t Triplet
w/v Weight/volume
Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene Example 1 - Synthesis of phosphine liqands, qold(l) chlorides and other intermediates: Dimethylphosphine borane 1-2
Figure imgf000144_0001
Cerium(lll) chloride (30.2 g, 122.5 mmol) was suspended in THF (200 mL) and stirred at rt for 1 h. Sodium borohydride (5.6 g, 148.5 mmol) was then added and the suspension stirred at rt for a further 1 h. The reaction was cooled to 0°C at which point dimethylphosphine oxide 1-1 (5.8 g, 74.2 mmol) dissolved in THF (30 mL) was added dropwise followed by lithium aluminium hydride (1 M in THF, 97 mL, 97 mmol) also dropwise. The reaction was stirred at rt overnight. The reaction was cooled to 0°C, diluted with Et20 (50 mL) then quenched with water (25 mL) and aq. HCI (3N, 170 mL). The layers were separated and the aqueous phase was extracted with Et.20 (3 x 250 mL) and the combined organic extracts washed with brine (sat., 250 mL), dried over MgSC and filtered. Concentration in vacuo gave the crude product as a colourless oil (4.5 g, 58.6 mmol, 79%). 1 H-NMR (400 MHz, CDCI3): δ ppm 4.88 (1 H, dm, J = 357.2 Hz), 1.42 (6H, dd, J = 6.0, 1 .5 Hz), 0.59 (3H, qdd, J = 96.6, 16.5, 6.0 Hz). 31P-NMR (162 MHz, CDCI3): δ ppm -29.34 (dm, J = 357.2 Hz).
Dimethylpropylphosphine gold (I) chloride 1-4
Figure imgf000144_0002
(a) Dimethylpropylphosphine borane 1-3
Dimethylphosphine borane 1-2 (700 mg, 9.2 mmol) was dissolved in THF (15 mL) and the colourless solution cooled to 0°C. NaH (60% dispersion in mineral oil, 553 mg, 13.8 mmol) was added portionwise, whereupon effervescence was observed. The opaque reaction was stirred at 0°C for 10 min then at rt for 30 min and cooled to 0°C whereupon 1 -bromopropane (1.3 mL, 13.8 mmol) was added in one portion. The reaction mixture was stirred at rt overnight then cooled to 0°C and water was added and the phases separated. The aqueous phase was extracted with Et.20 (2 x 30 mL) and the combined organic extracts washed with brine (sat., 50 mL), dried over MgS04 and filtered. Concentration in vacuo gave a mixture of the starting material and product (-1 :1 by 1H NMR). The mixture was dissolved in THF (15 mL) and the colourless solution cooled to 0°C. NaH (60% dispersion in mineral oil, 553 mg, 13.8 mmol) was added portionwise, whereupon effervescence was observed. The opaque reaction was stirred at 0°C for 10 min then at rt for 30 min and cooled to 0°C whereupon 1 -bromopropane (1.3 mL, 13.8 mmol) was added in one portion. The reaction mixture was stirred at rt overnight. The reaction mixture was cooled to 0°C and water was added and the phases separated. The aqueous phase was extracted with Et^O (2 x 30 mL) and the combined organic extracts washed with brine (sat., 50 mL), dried over MgS04 and filtered. Concentration in vacuo gave the desired product (785 mg, 6.7 mmol, 72%).
(b) Dimethylpropylphosphine gold(l) chloride 1-4
Dimethylpropylphosphine borane 1-3 (785 mg, 6.7 mmol) was dissolved in THF (20 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (2.2 g, 19.9 mmol) was added and the reaction sealed with a Teflon screw cap. The mixture was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath and adding chloro(tetrahydrothiophene)gold(l) (2.1 g, 6.7 mmol) and dry DCM (20 mL). After stirring at rt overnight the reaction was diluted with DCM (30 mL) and water (30 mL) and the phases separated. The aqueous phase was extracted with DCM (2 x 40 mL) and the combined organic extracts washed with brine (sat., 100 mL), dried over MgS04 and filtered. Concentration in vacuo gave the crude product as a brown oil which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil eluting with 20% to 50% EtOAc / isohexane) to provide the title compound as a light purple solid (720 mg, 2.1 mmol, 32%). 1 H-NMR (400 MHz, DMSO-d6): δ ppm 1 .95-1.85 (2H, m), 1 .60 (6H, d, J = 1 1.5 Hz), 1 .60-1 .48 (2H, m), 1.04 (3H, t, J = 7.3 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 2.24 (s). (Dimethylphosphino)methanol gold(l) chloride 1-6, (methoxymethyl)dimethylphosphine gold(l) chloride 1-8 and (ethoxymethyl)dimethylphosphine gold(l) chloride 1-10
Figure imgf000146_0001
(a) (Dimethylphosphino)methanol borane 1-5
Dimethylphosphine borane /-2 (1 .3 g, 17.2 mmol) was dissolved in THF (70 ml.) and the colourless solution cooled to 0°C. NaH (60% dispersion in mineral oil, 1 .1 g, 27.5 mmol) was added portionwise, whereupon effervescence was observed. The opaque reaction was stirred at 0°C for 10 min then at rt for 30 min and cooled to 0°C whereupon paraformaldehyde (825 mg, 27.5 mmol) was added in one portion. The reaction mixture was stirred at rt for 3 h. The reaction was cooled to 0°C, quenched with aq. HCI (0.5N, 50 ml_). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 70 ml.) and the combined organic extracts were dried over MgSC and filtered. Concentration in vacuo gave the crude product as a colourless oil which was purified by column chromatography (Biotage Isolera Four, 100 g KP-Sil eluting with isohexane to 66% EtOAc / isohexane) to provide the title compound as a colourless solid (1.8 g, 16.5 mmol, 96%). 1H-NMR (400 MHz, CDCI3): δ ppm 3.96 (2H, s), 1.90 (1 H, br s), 1.38 (6H, d, J = 10.5 Hz), 0.92 (3H, dq, J = 95.3, 15.6 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 8.06 (q, J = 56.7 Hz).
(b) (Dimethylphosphino)methanol gold(l) chloride 1-6
(Dimethylphosphino)methanol borane 1-5 (847 mg, 8.0 mmol) was dissolved in THF (21 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (2.7 g, 24.0 mmol) was added and the reaction sealed with a Teflon screw cap. The mixture was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath and adding chloro(tetrahydrothiophene)gold(l) (2.573 g, 8.0 mmol) and dry DCM (21 mL). After stirring at rt overnight the reaction was diluted with DCM (10 mL) and filtered through a pad of celite eluting with DCM. Concentration in vacuo gave the crude product which was washed with Et.20 and MeOH to provide the title compound as a light orange solid (783 mg, 2.4 mmol, 30%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 5.70 (1 H, app q, J = 6.0 Hz), 4.00 (2H, d, J = 6.0 Hz), 1 .55 (6H, d, J = 1 1.4 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 3.45 (s).
(c) (Methoxymethyl)dimethylphosphine borane 1-7
(Dimethylphosphino)methanol borane 1-5 (876 mg, 8.3 mmol) was dissolved in THF (35 mL) and the colourless solution cooled to 0°C. NaH (60% dispersion in mineral oil, 529 mg, 13.2 mmol) was added portionwise, whereupon effervescence was observed. The opaque reaction was stirred at 0°C for 10 min then at rt for 30 min and cooled to 0°C whereupon iodomethane (1.029 mL, 16.5 mmol) was added dropwise. The reaction mixture was stirred at rt overnight then cooled to 0°C and quenched with water (35 mL). The layers were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL) and the combined organic extracts were washed with brine (sat., 150 mL), dried over MgS04 and filtered. Concentration in vacuo gave the crude product as white solid (813 mg, 6.8 mmol, 82%). (d) (Methoxymethyl)dimethylphosphine gold(l) chloride 1-8
(Methoxymethyl)dimethylphosphine borane /-7 (813 mg, 6.8 mmol) was dissolved in THF (20 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (1 .5 g, 13.2 mmol) was added and the reaction sealed with a Teflon screw cap. The mixture was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath and adding chloro(tetrahydrothiophene)gold(l) (2.7 g, 8.5 mmol) and dry DCM (20 mL). After stirring at rt overnight the reaction was diluted with DCM (30 mL) and water (30 mL) and the phases separated. The aqueous phase was extracted with DCM (2 x 40 mL) and the combined organic extracts washed with brine (sat., 100 mL), dried over MgS04 and filtered. Concentration in vacuo gave the crude product as a brown oil which was purified by column chromatography (Biotage Isolera Four, 100 g KP-Sil eluting with 20% to 66% EtOAc / isohexane) to provide the title compound as a purple solid (1 .1 g, 3.3 mmol, 50%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 4.00 (2H, d, J = 2.3 Hz), 3.42 (3H, s), 1.60 (6H, d, J = 1 1 .9 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm -0.24 (s). (e) (Ethoxymethyl)dimethylphosphine borane 1-9
(Dimethylphosphino)methanol borane 1-5 (922 mg, 8.7 mmol) was dissolved in THF (40 mL) and the colourless solution cooled to 0°C. NaH (60% dispersion in mineral oil, 558 mg, 13.9 mmol) was added portionwise, whereupon effervescence was observed. The opaque reaction was stirred at 0°C for 10 min then at rt for 30 min and cooled to 0°C whereupon iodoethane (1 .4 mL, 17.4 mmol) was added dropwise. The reaction mixture was stirred at rt overnight. The reaction was cooled to 0°C, quenched with water (40 mL). The layers were separated and the aqueous phase was extracted with Et.20 (2 x 50 mL) and the combined organic extracts were washed with brine (sat., 150 mL), dried over MgS04 and filtered. Concentration in vacuo gave the crude product as a light yellow oil (1.2 g, 8.6 mmol, 99%).
(f) (Ethoxymethyl)dimethylphosphine gold(l) chloride 1-10
(Ethoxymethyl)dimethylphosphine borane 1-9 (940 mg, 7.0 mmol) was dissolved in THF (20 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (2.6 g, 21.0 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath and adding chloro(tetrahydrothiophene)gold(l) (2.3 g, 7.0 mmol) and dry DCM (20 mL). After stirring at rt overnight the reaction was diluted with DCM (30 mL) and filtered through a pad of celite eluting with DCM. Concentration in vacuo gave the crude product which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil eluting with isohexane to 50% EtOAc / isohexane) to provide the title compound as a light purple solid (1.9 g, 5.3 mmol, 75%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 4.03 (2H, d, J = 1.8 Hz), 3.61 (2H, q, J = 6.9 Hz), 1 .59 (6H, d, J = 1 1 .9 Hz), 1 .15 (3H, t, J = 6.9 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm -0.03 (s).
1-(Dimethylphosphino)-N,N-dimethylmethanamine gold(l) chloride 1-14
Figure imgf000149_0001
(a) 1-(Dimethylphosphino)-N,N-dimethylmethanamine oxide 1-12
To a solution of /V./V./V./V-tetramethylendiamine (12.0 mL, 88.0 mmol) in dry Et20 (120 mL) under nitrogen was added acetyl chloride (13.8 mL, 194.0 mmol) dropwise at rt. The reaction mixture was stirred at rt for 1 h and the resulting white solid {1-11) collected by filtration, washed under nitrogen with dry Et20 (2 x 100 mL) and then suspended in dry THF (100 mL). Dimethylphosphine oxide 1-1 (5.0 g, 64.0 mmol) was dissolved in THF (150 mL) and the colourless solution cooled to 0°C. NaH (60% dispersion in mineral oil, 3.7 g, 94.0 mmol) was added portionwise, whereupon effervescence was observed. The opaque reaction was stirred at 0°C for 10 min then at rt for 1 .5 h and cooled to 0°C. This mixture was added dropwise at 0°C to a suspension of 1-11 in THF previously prepared and the resulting mixture stirred at rt overnight. The reaction mixture was then cooled to 0°C, water (200 mL) was added and the phases separated. The aqueous phase was washed with Et.20 (2 x 150 mL) and concentrated in vacuo to give the crude product as a yellow oil which was purified by SCX column (2 x 50 g cartridges, eluting with 3.5N NHs/MeOH) to provide the title compound as a yellow solid (4.7 g, 34.4 mmol, 54%).
(b) 1-(Dimethylphosphino)-N,N-dimethylmethanamine borane 1-13
Cerium(lll) chloride (13.8 g, 246.5 mmol) was suspended in THF (150 mL) and stirred at rt for 1 h. Sodium borohydride (3.9 g, 102.0 mmol) was then added and the suspension stirred at rt for a further 1 h. The reaction was cooled to 0°C at which point 1 - (dimethylphosphino)-/V,/V-dimethylmethanamine oxide 1-12 (4.7 g, 34.4 mmol) dissolved in THF (30 mL) was added dropwise followed by lithium aluminium hydride (1 M in THF, 45.0 ml_, 45.0 mmol) also dropwise. The reaction was stirred at rt overnight then cooled to 0°C, diluted with Et20 (50 mL) and quenched with water (25 mL) and aq. NaOH (10%, 50 mL). The layers were separated and the aqueous phase was extracted with Et20 (3 x 200 mL) and the combined organic extracts washed with brine (sat., 500 mL), dried over MgSCu and filtered. Concentration in vacuo gave the crude product as white solid (3.9 g, 29.2 mmol, 86%).
(c) 1-(Dimethylphosphino)-N,N-dimethylmethanamine gold(l) chloride 1-14
1 -(Dimethylphosphino)-/V,/V-dimethylmethanamine borane 1-13 (365 mg, 2.8 mmol) was dissolved in THF (8 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (1 .0 g, 9.0 mmol) was added and the reaction sealed with a Teflon screw cap. The mixture was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath and adding chloro(tetrahydrothiophene)gold(l) (1 .1 g, 3.4 mmol) and dry DCM (8 mL). After stirring at rt overnight the reaction was diluted with DCM (10 mL) and filtered through a pad of celite washing with DCM. Concentration in vacuo gave the crude product which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil eluting with DCM to 6% MeOH / DCM). The light pink solid obtained was washed with Et20 (5 x 10 mL) to provide the title compound as a white solid (389 mg, 1 .1 mmol, 40%). 1 H-NMR (400 MHz, DMSO-d6): δ ppm 3.07 (2H, d, J = 3.7 Hz), 2.40 (6H, s), 1.57 (6H, d, J = 1 1 .4 Hz). 31 P-NMR (162 MHz, DMSO-d6): δ ppm -5.36 (s).
Dimethyl(oxetan-3-ylmethyl)phosphine gold(l) chloride 1-16
Figure imgf000150_0001
(a) Dimethyl(oxetan-3-ylmethyl)phosphine borane 1-15
Dimethylphosphine borane 1-2 (700 mg, 9.3 mmol) was dissolved in THF (23 mL) and the colourless solution cooled to 0°C. NaH (60% in mineral oil, 1 .9 g, 46.0 mmol) was added in one portion, whereupon effervescence was observed. The opaque mixture was stirred at rt for 10 min whereupon 3-(bromomethyl)oxetane (1.4 g, 9.3 mmol) was added in one portion. When TLC had indicated completion of the reaction, brine (sat., 40 mL) and Et- OAc (40 mL) were added and the phases separated. The aqueous phase was extracted with EtOAc (2 x 40 mL) and the combined organic extracts washed with brine (sat., 40 mL) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude material which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil eluting with isohexane to 75% EtOAc / isohexane) provided the title compound as a white solid (1.0 g, 7.1 mmol, 76%).
(b) Dimethyl(oxetan-3-ylmethyl)phosphine gold(l) chloride 1-16
Dimethyl(oxetan-3-ylmethyl)phosphine borane 1-15 (1.0 g, 6.9 mmol) was dissolved in THF (50 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (2.3 g, 20.8 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath and adding chloro(tetrahydrothiophene)gold(l) (2.8 g, 8.6 mmol). After stirring at rt overnight the reaction was diluted with sat. brine / EtOAc (1 :1 , 100 mL) and the layers separated. The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic extracts washed with brine (sat., 50 mL) and dried over MgS04 before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a dark grey solid which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil eluting with EtOAc) to provide the title compound as a white solid (1.2 g, 3.3 mmol, 48%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 4.69 (2H, dd, J = 7.8, 5.5 Hz) , 4.42 (2H, app t, J = 6.4 Hz), 3.25 (1 H, m), 2.37 (2H, dd, J = 1 1.9, 7.8 Hz), 1.58 (6H, d, J = 1 1.9 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm -1.56 (s).
Dimethyl(oxetan-3-yl)phosphine gold(l) chloride 1-18
Figure imgf000151_0001
(a) Dimethyl(oxetan-3-yl)phosphine borane 1-17
Dimethylphosphine borane 1-2 (55% wt. in THF, 1.3 g, 9.2 mmol) was dissolved in THF (60 mL) and the colourless solution cooled to 0°C. NaH (60% in mineral oil, 1 .6 g, 40.5 mmol) was added in one portion, whereupon effervescence was observed. The opaque reaction was stirred at rt for 20 min whereupon 3-bromooxetane (1.52 mL, 18.4 mmol) was added in one portion. When TLC had indicated completion of the reaction, the reaction was cooled to 0°C and MeOH added until effervescence has ceased. The solvent was removed in vacuo and the crude residue taken up in DCM (100 mL) and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude material which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil column eluting with isohexane to 50% EtOAc / isohexane) to provide the title compound as a colourless oil (630 mg, 4.7 mmol, 51 %).
(b) Dimethyl(oxetan-3-yl)phosphine gold(l) chloride 1-18
Dimethyl(oxetan-3-yl)phosphine borane 7 (630 mg, 4.7 mmol) was dissolved in toluene (10 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (1 .5 g, 4.7 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100°C and stirred at this temperature for 18 h before adding to a cooled (0°C) suspension of chloro(tetrahydrothiophene)gold(l) (1.7 g, 5.3 mmol) in DCM (5 mL) which had been degassed with nitrogen. After stirring at rt for 4 h the reaction was diluted with DCM and washed with water. The aqueous phase was extracted with DCM and the combined organic extracts passed through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product which was purified by column chromatography (Biotage Isolera Four, 100 g KP-Sil, eluting with isohexane to 50% EtOAc / isohexane) to provide the title compound as an off-white solid (853 mg, 2.4 mmol, 51 %). 1H-NMR (400 MHz, DMSO-d6): δ ppm 4.82 (2H, ddd, J = 18.8, 8.7, 6.4 Hz), 4.57 (2H, dt, J = 18.8, 6.4 Hz), 3.63 (1 H, m), 1.66 (6H, d, J = 1 1.5 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 8.43 (s).
Dimethyl-(2-pyridyl)-phosphine gold(l) chloride 1-20
Figure imgf000152_0001
(a) Dimethyl-(2-pyridyl)-phosphine borane 1-19
Dimethylphosphine borane 1-2 (700 mg, 9.2 mmol) was dissolved in THF (25 mL) and the colourless solution cooled to 0°C. NaH (60% dispersion in mineral oil, 1 .1 g, 27.6 mmol) was added portionwise, whereupon effervescence was observed. The opaque mixture was stirred at 0°C for 10 min then at rt for 30 min and cooled to 0°C whereupon 2- fluoropyridine (2.4 mL, 27.6 mmol) was added in one portion. The reaction mixture was stirred at rt overnight, cooled to 0°C and water (10 mL) was added and then the mixture concentrated in vacuo to give a light yellow solid. The crude material was taken up in EtOAc (30 mL) and water (30 mL). The aqueous phase was extracted with EtOAc (2 x 30 mL) and the combined organic extracts were dried over MgS04 and filtered. Concentration in vacuo gave the product as a brown liquid (1 .1 g, 7.4 mmol, 80%).
(b) Dimethyl-(2-pyridyl)-phosphine gold(l) chloride 1-20
Dimethyl-(2-pyridyl)-phosphine borane 1-19 (1 .1 g, 7.4 mmol) was dissolved in anhydrous THF (10 mL) and the solution degassed with nitrogen for 5 min. DABCO (2.5 g, 22.1 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath. Chloro(tetrahydrothiophene)gold(l) (2.5 g, 9.2 mmol) was suspended in anhydrous DCM (20 mL), cooled to 0°C and degassed with nitrogen for 5 min. Dropwise addition of the phosphine solution described above immediately turned the mixture dark brown/black in colour. After stirring at rt overnight the reaction was filtered through celite and washed with DCM (50 mL). Concentration of the filtrate gave an orange gum which was purified by column chromatography (Biotage Isolera Four, 25 g KP-Sil eluting with isohexane to 50% acetone / isohexane) to provide the title compound as a light orange solid (1.5 g, 4.0 mmol, 54%). 1H-NMR (400 MHz, DMSO-d6) δ ppm: 8.79 (1 H, d, J = 5.0 Hz), 8.06-7.88 (2H, m), 7.56 (1 H, m), 1.93 (6H, d, J = 1 1.7 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 6.47 (s).
Dimethyl-(2,6-pyrimidyl)-phosphine gold(l) chloride 1-22
Figure imgf000153_0001
(a) Dimethyl-(2,6-pyrimidyl)-phosphine borane 1-21
Dimethylphosphine borane 1-2 (700 mg, 9.2 mmol) was dissolved in THF (25 mL) and the colourless solution cooled to 0°C. NaH (60% dispersion in mineral oil, 1 .1 g, 27.6 mmol) was added portionwise, whereupon effervescence was observed. The opaque mixture was stirred at 0°C for 10 min then at rt for 30 min and cooled to 0°C whereupon 2- chloropyrimidine (3.2 g, 27.6 mmol) was added in one portion. The reaction mixture was stirred at rt overnight, cooled to 0°C and water (10 mL) was added. The mixture was then concentrated in vacuo to give a red solid which was taken up in EtOAc (30 mL) and water (30 mL). The aqueous phase was extracted with EtOAc (2 x 30 mL) and the combined organic extracts were dried over MgS04 and filtered. Concentration in vacuo gave a red oil which was purified by column chromatography (Biotage Isolera Four, 25 g KP-Sil eluting with isohexane to 60% EtOAc / isohexane) to provide the title compound as a white solid (720 mg, 4.7 mmol, 51 %).
(b) Dimethyl-(2,6-py midyl)-phosphine gold(l) chloride 1-22
Dimethyl-(2,6-pyrimidyl)-phosphine borane 1-21 (720 mg, 4.7 mmol) and DABCO (1.6 g, 14.0 mmol) were taken up in anhydrous THF (10 mL) and degassed with nitrogen for 10 min and then sealed with a Teflon screw cap. The reaction mixture was then heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath. Chloro(tetrahydrothiophene)gold(l) (4.29 g, 13.4 mmol) was suspended in anhydrous DCM (25 mL), cooled in an ice bath and then degassed with nitrogen for 10 min. The phosphine solution was then added dropwise to the suspension of chloro(tetrahydrothiophene)gold(l), before the reaction mixture was warmed to rt and stirred overnight under nitrogen. The black reaction mixture was filtered through celite and washed with DCM (50 mL). Concentration of the filtrate gave the crude product as a light yellow solid which was purified by column chromatography (Biotage Isolera Four, 100 g KP-Sil eluting with isohexane to acetone) to give the desired product as an off-white solid (241 mg, 0.65 mmol) along with -75% pure product (335 mg). The impure fractions were re-purified by column chromatography (Biotage Isolera Four, 10 g KP-Sil eluting with isohexane to 75% acetone / isohexane) to give the desired product as an off-white solid (99 mg, 0.27 mmol). Combined yield: (340 mg, 0.91 mmol, 20%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.99 (2H, d, J = 5.0 Hz), 7.64 (1 H, td, J = 4.75, 3.75 Hz), 1 .99 (6H, d, J = 1 1 .9 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 8.49 (s).
Ethyldimethyphosphine gold(l) chloride 1-24
Figure imgf000154_0001
(a) Ethyldimethylphosphine borane 1-23
Dimethylphosphine borane 1-2 (585 mg, 7.7 mmol) was dissolved in THF (19 mL) and the colourless solution cooled to 0°C. NaH (60% in mineral oil, 1 .5 g, 38.4 mmol) was added in one portion, whereupon effervescence was observed. The opaque reaction was stirred at rt for 5 min whereupon iodoethane (0.77 mL, 9.6 mmol) was added in one portion. When TLC had indicated completion of the reaction, water (30 mL) and EtOAc (30 mL) were added and the phases separated. The aqueous phase was extracted with EtOAc (2 x 40 mL) and the combined organic extracts washed with brine (sat., 40 mL) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude material as a pale yellow oil. Purification by column chromatography (Biotage Isolera Four, 50 g KP-Sil eluting with isohexane to 20% EtOAc / isohexane) provided the title compound as a white solid (797 mg, 6.9 mmol, 90%).
(b) Ethyldimethylphosphine gold(l) chloride 1-24
Ethyldimethylphosphine borane 1-23 (225 mg, 2.0 mmol) was dissolved in THF (5 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (640 mg, 6.0 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath and adding a solution of chloro(tetrahydrothiophene)gold(l) (640 mg, 2.0 mmol) in DCM (5 mL). After stirring at rt for 18 h the reaction was diluted with DCM (10 mL) and water (10 mL) and the phases separated. The aqueous phase was extracted with DCM (2 x 20 mL) and the combined organic extracts washed with brine (sat., 20 mL) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a brown oil which was purified by column chromatography (Biotage Isolera Four, 25 g KP- Sil eluting with 25% to 60% EtOAc / isohexane) to provide the title compound as a white solid (265 mg, 0.82 mmol, 41 %). 1 H NMR (400 MHz, CDCI3): δ ppm 1 .85 (2H, dq, J = 10.9, 7.6 Hz), 1.57 (6H, d, J = 1 1.1 Hz), 1 .26 (3H, dt, J = 20.5, 7.6 Hz). 31P-NMR (162 MHz, CDCIs): δ ppm 4.07 (s). 4-Methyl-[1 ,4]oxaphosphinane gold (I) chloride 1-27
Figure imgf000156_0001
(a) [2-(2-Bromo-ethoxy)-ethyl]dimethyl-5-phosphane borane 1-25
To a solution of diethyl methylphosphonate (3 mL, 20.8 mmol) in dry THF (50 mL) was added lithium aluminium hydride (1 M in THF, 19.7 mL, 19.7 mmol) at 0°C. The reaction was stirred between 0°C and 10°C for 20 min. The reaction mixture was cooled to 0°C whereupon borane-THF complex (1 M in THF, 19.7 mL, 19.7 mmol) was added dropwise over the course of 10 min and the reaction stirred between 0°C and 10°C for an additional 20 min. The reaction was then cooled to -78°C and nBuLi (1.6M in hexane, 12.3 mL, 19.7 mmol) was added over 5 min and stirring continued at -78°C for 30 min. 1-Bromo-2- (2-bromoethoxy)ethane (2.5 mL, 19.7 mmol) was then added over the course of 1 min and the reaction mixture allowed to warm to rt and stirred for a further 18 h. The reaction was cooled to 0°C and aq. HCI (3N, 30 mL) added slowly. The mixture was stirred until effervescence has ceased. EtOAc (150 mL) was added to the reaction and the layers separated. The aqueous phase was extracted with EtOAc (3 x 100 mL) and the combined organic extracts washed with brine (sat.) and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a colourless oil which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil eluting with isohexane to 75% EtOAc / isohexane) to provide the title compound as a colourless oil (876 mg, 4.1 mmol, 21 %). (b) 4-Methyl-[1,4]oxaphosphinaneborane 1-26
[2-(2-Bromo-ethoxy)-ethyl]dimethyl-5-phosphane borane 1-25 (866 mg, 4.0 mmol) was dissolved in THF (41 mL) and the colourless solution cooled to 0°C. NaH (60% in mineral oil, 196 mg, 4.9 mmol) was added in one portion, whereupon effervescence was observed. The opaque reaction was stirred at rt for 5 h whereupon TLC indicated the reaction had not gone to completion. Further NaH (60% in mineral oil, 236 mg, 5.9 mmol) was added in one portion and the reaction stirred at rt for an additional 36 h. The reaction was quenched with brine (sat., 50 ml.) and EtOAc (50 ml.) added. The phases were separated and the aqueous phase extracted with EtOAc (3 x 50 ml.) and the combined organic extracts washed with brine (sat., 40 ml.) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude material as a pale yellow oil. Purification by column chromatography (Biotage Isolera Four, 25 g KP-Sil eluting with isohexane to 75% EtOAc / isohexane) provided the title compound as a colourless oil (300 mg, 2.3 mmol, 55%). (c) 4-Methyl-[1 ,4]oxaphosphinane gold(l) chloride 1-27
Prepared according to a procedure similar to that described for dimethyl(oxetan-3- ylmethyl)phosphine gold(l) chloride 1-16 starting from 4-methyl- [1 ,4]oxaphosphinaneborane 1-26 (285 mg, 2.2 mmol) to provide the title compound as a white solid (443 mg, 1 .3 mmol, 57%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 4.01-3.89 (2H, m), 3.82-3.72 (2H, m), 2.22-2.15 (2H, m), 2.1 1 -2.01 (2H, m), 1 .78 (3H, d, J = 1 1 .9 Hz). 31 P-NMR (162 MHz, DMSO-d6): δ ppm -5.36 (s).
Isopropyldimethylphosphine gold(l) chloride 1-29
Figure imgf000157_0001
(a) Isopropyldimethylphosphine borane 1-28
Dimethylphosphine borane 1-2 (576 mg, 7.6 mmol) was dissolved in THF (50 ml.) and the colourless solution cooled to 0°C. NaH (60% in mineral oil, 1 .3 g, 33.4 mmol) was added in one portion, whereupon effervescence was observed. The opaque reaction was stirred at rt for 10 min whereupon 2-iodopropane (1 .1 ml_, 1 1 .4 mmol) was added in one portion. When TLC had indicated completion of the reaction, the reaction was cooled to 0°C and MeOH added until effervescence has ceased. The reaction was diluted with water and DCM and the phases separated. The aqueous phase was extracted with DCM and the combined organic extracts passed through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude material which was purified by column chromatography (Biotage Isolera Four, 50g KP-Sil column eluting with isohexane to 25% EtOAc / isohexane) to provide the title compound as a white solid (524 mg, 4.4 mmol, 59%).
(b) Isopropyldimethylphosphine gold(l) chloride 1-29
Isopropyldimethylphosphine borane 1-28 (524 mg, 4.4 mmol) was dissolved in toluene (10 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (1 .4 g, 4.4 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100°C and stirred at this temperature for 18 h before adding to a cooled, degassed (nitrogen) suspension of chloro(tetrahydrothiophene)gold(l) (1 .6 g, 4.9 mmol) in DCM (5 mL) at 0°C. After stirring at rt for 4 h the reaction was diluted with EtOAc and washed with brine (sat., 3 x) The organic phase was passed through a phase separator cartridge (Biotage) and concentrated in vacuo to give the crude product which was purified by column chromatography (Biotage Isolera Four, 25 g KP-Sil, eluting with 25% to 60% EtOAc / isohexane) to provide the title compound as a white solid (680 mg, 2.0 mmol, 46%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 2.10 (1 H, m), 1.60 (6H, d, J = 1 1.0 Hz), 1 .12 (6H, dd, J = 18.8, 6.9 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 18.48 (s).
Diethylmethylphosphine gold(l) chloride 1-32
Figure imgf000158_0001
(a) Diethylmethylphosphine borane 1-31
Diethylchlorophosphine 1-30 (4.0 g, 32.1 mmol) was dissolved in THF (50 mL) and the colourless solution cooled to 0°C. MeMgCI (3M in THF, 10.7 mL, 32.1 mmol) was added dropwise, then the reaction was warmed to rt and stirred for 3 h. The reaction mixture was cooled to 0°C whereupon borane-THF complex (1 M in THF, 32.1 mL, 32.1 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with Et.20 (150 mL), then quenched with water (50 mL). The layers were separated and the organic phase was washed with water (2 x 30 mL) and brine (sat., 30 mL), dried (MgS04), filtered and concentrated to give a white solid containing the desired product and inorganic impurities. The crude material was taken up in DCM (50 mL), filtered and concentrated to give the desired product as a colourless, clear solid (3.2 g, 30.7 mmol, 96%).
(b) Diethylmethylphosphine gold(l) chloride 1-32
Prepared according to a procedure similar to that described for ethyldimethylphosphine gold(l) chloride 1-24 starting from diethylmethylphosphine borane 1-31 (385 mg, 3.2 mmol) to provide the title compound as a white solid (475 mg, 1.4 mmol, 44%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 2.00-1.78 (4H, m), 1 .53 (3H, d, J = 1 1.4 Hz), 1 .05 (6H, dt, J = 19.8, 7.7 Hz) ppm. 31P-NMR (162 MHz, DMSO-d6): δ ppm 20.58 (s).
1 -Methylphospholane gold (I) chloride 1-35
Figure imgf000159_0001
(a) 1 -Methylphospholane borane 1-34
The £>/s-Grignard reagent was prepared by treating magnesium (1.0 g, 40.0 mmol) with 1 ,4-dibromobutane 1-33 (4.3 g, 20.0 mmol) in dry THF (50 ml.) and heating at 65°C for 3 h. A cooled (10°C) solution of dichloromethyl phosphine (2.3 g, 20 mmol) in dry THF (25 ml.) was added dropwise maintaining a temperature of 10°C. The mixture was stirred overnight at rt. Borane-THF complex (1 M, 20 ml_, 20 mmol) was added dropwise and the reaction mixture stirred for additional 4 h. The reaction mixture was poured onto a mixture of ice (200 g) and aq. HCI (2M, 100 ml.) with vigorous stirring. The aqueous phase was extracted with DCM (3 x 100 ml.) and the combined organic extracts dried over MgS04. Concentration in vacuo gave the crude product as a yellow oil which was purified by column chromatography (Biotage Isolera Four eluting with isohexane to 20% EtOAc / isohexane) to provide the title compound as a colourless oil (700 mg, 6.0 mmol, 30%).
(b) 1 -Methylphospholane gold(l) chloride 1-35
Prepared according to a procedure similar to that described for ethyldimethylphosphine gold(l) chloride 1-24 starting from 1-methylphospholane borane 1-34 (1 16 mg, 1 .0 mmol) to provide the title compound as an off-white solid (200 mg, 0.6 mmol, 60%). 1H-NMR (400 MHz, CDCIs): δ ppm 2.35-2.19 (2H, m), 2.03-1 .85 (6H, m), 1 .55 (3H, d, J = 10.6). 31P- NMR (162 MHz, CDCIs): δ ppm 1 1 .82 (s).
Tert-butyldimethylphosphine gold(l) chloride 1-37
Figure imgf000160_0001
7~ert-butyldimethylphosphine borane 1-36 (970 mg, 7.13 mmol) was dissolved in THF (50 mL) and the solution degassed with nitrogen for 5 min. DABCO (2.53 g, 22.56 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 100°C and stirred at this temperature for 4 h before cooling in an ice bath and adding a solution of chloro(tetrahydrothiophene)gold(l) (2.83 g, 7.48 mmol) in 50 mL dry DCM. After stirring at rt overnight the reaction was diluted with EtOAc (100 mL) and water (100 mL), filtered, and the phases separated. The aqueous phase was extracted with EtOAc (2 x 100 mL) and the combined organic extracts were dried by passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a grey/black solid which was purified by column chromatography (Biotage SP1 , 100 g KP- Sil eluting with 25% to 75% EtOAc / isohexane) to provide the title compound as a white solid (1 .43 g, 4.00 mmol, 56%). 1 H-NMR (400 MHz, CDCI3): δ ppm 1.51 (6H, dd, J = 10.5, 1 .8 Hz), 1.22 (9H, dd, J = 16.49, 1.4 Hz). 31P-NMR (162 MHz, CDCI3): δ ppm 25.2 (s).
1-(Dimethylphosphino)-N,N,N-trimethylmethanaminium iodide gold(l) chloride 1-38
Figure imgf000160_0002
1 -(Dimethylphosphino)-/V,/V-dimethylmethanamine gold(l) chloride 1-14 (64 mg, 0.2 mmol) was dissolved in anhydrous DCM (1 mL) under nitrogen and methyliodide (0.1 mL, 1 .8 mmol) was added dropwise. The reaction mixture was stirred at rt overnight. Concentration in vacuo gave the product as a purple solid (90 mg, 0.2 mmol, 99%). 1H- NMR (400 MHz, DMSO-d6): δ ppm 4.29 (2H, d, J = 7.8 Hz), 3.36 (9H, s), 1 .78 (6H, d, J = 1 1.0 Hz).31P-NMR (162 MHz, DMSO-d6): δ ppm 1 .02 (s). (2-(Dimethylamino)ethyl)dimethylphosphine gold(l) chloride 1-42
Figure imgf000161_0001
(a) (2-(Dimethylamino)ethyl)dimethylphosphine oxide 1-40
Dimethylphosphinic chloride 1-39 (865 mg, 7.7 mmol), was dissolved in anhydrous THF (20 mL) and cooled to -78°C. Vinyl magnesium bromide (1 M in THF, 9 mL, 9.0 mmol) was added dropwise whereupon the opaque reaction was allowed to gradually warm to rt and stir at this temperature for 18 h. The now orange reaction mixture was transferred to a sealed tube and dimethylamine (2M in MeOH, 4.5 mL, 9.0 mmol) along with MeOH (10 mL) were added in one portion. The reaction was sealed and subsequently heated at 80°C for 4 h at which point LC-MS (AnalpH2_MeOH_4min) indicated completion of the reaction. The solvent was removed in vacuo to provide the crude product, which was divided into two equal portions. One portion was purified by SCX column (25 g cartridge, eluting with 0.5N NH3/MeOH) to provide the title compound as a brown oil which crystallised upon standing. The other portion was dissolved in water and extracted with DCM. LC-MS (AnalpH2_MeOH_4min) indicated the product was located in the aqueous phase, thus the aqueous phase was concentrated in vacuo to provide the title compound as a brown oil. The material from the SCX purification and the aqueous work up were combined to provide the title compound as a brown oil which crystallised upon standing (1.04 g, 6.9 mmol, 90%).
(b) (2-(Dimethylamino)ethyl)dimethylphosphine borane 1-41
Cerium(lll) chloride (4.9 g, 20.0 mmol) was suspended in THF (30 mL) and stirred at rt for 1 h. Sodium borohydride (756 mg, 20.0 mmol) was then added and the suspension stirred at rt for a further 1 h. The reaction was cooled to 0°C at which point (2-(dimethylamino)ethyl)dimethylphosphine oxide 1-40 (1.0 g, 6.7 mmol) dissolved in THF (30 mL) was added dropwise followed by lithium aluminium hydride (1 M in THF, 7 mL, 7.0 mmol) also dropwise. The reaction was stirred at rt overnight. The reaction was then added dropwise to aq. HCI (6N, 100 mL) and ice and the resultant bi-phasic mixture extracted with DCM. The combined organic extracts were washed with brine (sat.), dried over MgSC and filtered. Concentration in vacuo gave the product as an orange solid (207 mg, 1.4 mmol, 20%).
(c) (2-(Dimethylamino)ethyl)dimethylphosphine gold(l) chloride 1-42
(2-(Dimethylamino)ethyl)dimethylphosphine borane 1-41 (200 mg, 1.4 mmol) was dissolved in toluene (12 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (461 mg, 4.1 mmol) was added and the reaction sealed with a Teflon screw cap. The reaction was heated to 90°C and stirred at this temperature for 16 h before cooling in an ice bath and adding chloro(tetrahydrothiophene)gold(l) (440 mg, 1 .4 mmol). After stirring at rt for 4 h the reaction was diluted with water / DCM (1 :1 ) and the layers separated. The aqueous phase was extracted with DCM and the combined organic extracts washed with brine (sat.) before passing through a phase separator cartridge (Biotage). Concentration in vacuo gave the crude product as a pink solid which was purified by column chromatography (Biotage Isolera Four, 10 g KP-Sil eluting with DCM to 10% MeOH / DCM) to provide the title compound as a light brown solid (87 mg, 0.24 mmol, 17%). 1H-NMR (400 MHz, CDCI3): δ ppm 2.68 (2H, app qn, J = 7.3 Hz), 2.32 (6H, s), 2.06 (2H, m), 1 .63 (6H, d, J = 1 1.1 Hz). 31 P-NMR (162 MHz, CDCI3): δ ppm -0.58 (s).
5-(2-Methoxycarbonyl-ethylsulfanyl)-pyrimidine-4-carboxylic acid methyl ester 1-45
Figure imgf000162_0001
(a) 5-Bromo-pyrimidine-4-carboxylic acid dimethylamide 1-44
5-Bromo-4-pyrimidine carboxylic acid 1-43 (410 mg, 2.0 mmol) and dimethylamine hydrochloride (329 mg, 4.0 mmol) were combined and suspended in DCM (13 mL). DIPEA (1 .1 mL, 6.1 mmol) was added followed by HATU (1 .1 g, 2.9 mmol) and the reaction stirred at rt overnight. The reaction was diluted with DCM and washed with water and the layers separated. The aqueous fraction was extracted with DCM (x 2) and the combined organic extracts passed through a phase separator cartridge (Biotage) and concentrated in vacuo. The residue was purified by column chromatography (Biotage, Isolera 4, 50 g KP-Sil, eluting with 50% EtOAc / isohexane to EtOAc) to afford the title compound as a pale yellow oil (353 mg, 1 .5 mmol, 76%).
(b) 5-(2-Methoxycarbonyl-ethylsulfanyl)-pyrimidine-4-carboxylic acid methyl ester 1-45 A mixture 5-bromo-pyrimidine-4-carboxylic acid dimethylamide 1-44, (353 mg, 1.53 mmol), methyl-3-mercaptopropionate (187 uL, 1 .7 mmol), Pd2(dba)3 (56 mg, 0.06 mmol), Xantphos (71 mg, 0.12 mmol), DIPEA (534 uL, 3.1 mmol) and dioxane (12 mL) was degassed with nitrogen and the mixture heated at 1 10°C until LC-MS (AnalpH2_MeOH_4min) indicated completion of the reaction. The reaction mixture was concentrated in vacuo and the residue diluted with EtOAc (100 mL) before being washed with aq. NH4CI (sat., 30 mL), aq. NaHCOs (sat., 30 mL) and brine (sat., 30 mL). The organic phase was dried over MgS04 before being concentrated in vacuo. The residue was purified by column chromatography (Biotage, Isolera 4, 100 g KP-Sil, eluting with isohexane to 50% EtOAc / isohexane) to afford the title compound as a yellow oil (130 mg, 0.48 mmol, 31 %).
(S)-2-Acetylamino-4-[(R)-1-(ethoxycarbonylmethyl-carbamoyl)-2-mercapto- ethylcarbamoyl]-butyric acid ethyl ester 1-48
Figure imgf000163_0001
(a) (S)-2-Acetylamino-4-[(R)- 1 -(ethoxycarbonylmethyl-carbamoyl)-2-mercapto- ethylcarbamoyl]-butyric acid ethyl ester oxidised 1-47
L-Glutathione oxidised 1-46 (800 mg, 1 .3 mmol) was suspended in anhydrous EtOH (20 mL) and the mixture cooled to 0°C before thionyl chloride (1.5 mL, 20.5 mmol) was added dropwise. The mixture was stirred at rt for 3 days then evaporated to dryness to afford the intermediate tetra-ester as confirmed by 1H-NMR (CD3OD). The crude intermediate was suspended in THF (25 mL), and DIPEA (2.3 mL, 13.1 mmol) added in one portion. Acetic anhydride (1.3 mL, 13.1 mmol) was added dropwise and the mixture stirred at rt for 4 h after which time DMF (20 mL) was added and the mixture stirred at rt for an additional 16 h. Concentration in vacuo provided a crude product which was purified by column chromatography (Biotage Isolera Four, 10 g KP-Sil, eluting with DCM to 10% MeOH / DCM) to provide the title compound as a white solid (946 mg, 1.2 mmol, 89%).
(b) (S)-2-Acetylamino-4-[(R)- 1 -(ethoxycarbonylmethyl-carbamoyl)-2-mercapto- ethylcarbamoyl]-butyric acid ethyl ester 1-48
(S)-2-Acetylamino-4-[(f?)-1-(ethoxycarbonylmethyl-carbamoyl)-2-mercapto- ethylcarbamoyl]-butyric acid ethyl ester oxidised /-47 (100 mg, 0.12 mmol) and TCEP.HCI (177 mg, 0.62 mmol) were dissolved in MeOH / water (1 :1 , 4 mL) and stirred at rt for 18 h. The mixture was concentrated in vacuo and the crude residue partitioned between DCM (15 mL) and water (15 mL). The layers were separated and the aqueous phase extracted with DCM (2 x 15 mL). The organic extracts were combined and passed through a phase separator cartridge (Biotage) and concentrated in vacuo to provide the title compound as a white solid (93 mg, 0.23 mmol, 92%).
Dimethyl(prop-1-yn-1-yl)phosphine gold(l) chloride 1-51
Figure imgf000164_0001
(a) Dimethyl(prop-1 -yn- 1 -yl)phosphine borane 1-50
Dimethylchlorophosphine 1-49 (1 M in THF, 15 mL, 15.0 mmol) was cooled to -78°C whereupon 1-propynylmagnesium bromide (0.5M in THF, 33 mL, 16.5 mmol) was added dropwise. The mixture was then warmed to rt, stirred for 4 h and then cooled to 0°C whereupon borane-THF complex (1 M in THF, 22.5 mL, 22.5 mmol) was added. The resulting mixture was stirred at rt overnight then diluted with DCM (40 mL) and quenched with water (25 mL). The layers were separated and the aqueous phase extracted with DCM (2 x 30 mL). The organic extracts were then combined, passed through a phase separator cartridge (Biotage) and concentrated in vacuo to give a crude product which was purified by column chromatography (Biotage Isolera Four, 100 g KP-Sil, eluting with isohexane to 25% EtOAc / isohexane) to provide the title compound as a colourless oil (876 mg, 7.7 mmol, 51 %).
(b) Dimethyl (prop- 1 -yn- 1 -yl)phosphine gold(l) chloride 1-51
Dimethyl(prop-1-yn-1 -yl)phosphine borane 1-50 (876 mg, 7.7 mmol) was dissolved in toluene (15 mL) and the colourless solution degassed with nitrogen for 5 min. DABCO (2.6 g, 23.1 mmol) was added and the mixture sealed with a Teflon screw cap and heated to 1 10°C. After stirring at this temperature for 16 h the mixture was cooled in an ice bath andchloro(tetrahydrothiophene)gold(l) (2.7 g, 8.5 mmol) added in one portion. After stirring at rt for 4 h the mixture was diluted with DCM (40 mL) and water (30 mL) and the phases separated. The aqueous phase was extracted with DCM (2 x 40 mL) and the organic extracts combined and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave a crude product which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil, eluting with 25% to 50% EtOAc / isohexane) to provide the title compound as a white solid (1.1 g, 3.3 mmol, 44%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 2.10 (3H, d, J = 4.1 Hz), 1 .86 (6H, d, J = 1 1 .9 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm -24.33 (s).
Dimethyl((trimethylsilyl)ethynyl)phosphine gold(l) chloride 1-52
Figure imgf000165_0001
Dimethylchlorophosphine 1-49 (1 M in THF, 15 mL, 15.0 mmol) was cooled to -78°C whereupon lithium (trimethylsilyl)acetylide (0.5M in THF, 33.0 mL, 16.5 mmol) was added dropwise. The mixture was warmed to rt, stirred for 4 h then split into two equal portions. One portion was added to a stirring suspension of chloro(tetrahydrothiophene)gold(l) (2.4 g, 7.5 mmol) in DCM (10 mL) at rt and the mixture stirred at rt overnight. The resulting mixture was then poured into water and extracted with DCM (x 3) and the organic extracts combined and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave a crude product which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil, eluting with isohexane to 30% EtOAc / isohexane) to provide the title compound as a white solid (1.0 g, 2.6 mmol, 35%). 1 H- NMR (400 MHz, DMSO-d6): δ ppm 1.89 (6H, d, J = 12.4 Hz), 0.23 (9H, s). 31P-NMR (162 MHz, DMSO-d6): δ ppm -24.24 (s).
Cyclopropyldimethylphosphine g id(l) chloride 1-54
Figure imgf000166_0001
(a) Cyclopropyldimethylphosphine borane 1-53
Dimethylchlorophosphine 1-49 (1 M in THF, 15 mL, 15.0 mmol) was cooled to 0°C whereupon cyclopropylmagnesium bromide (0.5M in THF, 45 mL, 22.5 mmol) was added dropwise. The mixture was warmed to rt, stirred for 4 h then cooled to 0°C whereupon borane-THF complex (1 M in THF, 30.0 mL, 30.0 mmol) was added. The mixture was stirred at rt overnight, diluted with Et.20 (40 mL) and then quenched with water (75 mL). The layers were separated and the aqueous phase extracted with Et^O (2 x 150 mL) before the organic extracts were combined, washed with brine (sat.), dried over MgS04 and concentrated in vacuo. The crude product was purified by column chromatography (Biotage Isolera Four, 340 g KP-Sil, eluting with pentane to 55% Et^O / pentane) to provide the title compound as a white solid (1 .2 g, 9.8 mmol, 65%). (b) Cyclopropyldimethylphosphine gold(l) chloride 1-54
Prepared according to a procedure similar to that described for dimethyl-(2,6-pyrimidyl)- phosphine gold(l) chloride 1-22 starting from cyclopropyldimethylphosphine borane 1-53 (1.2 g, 9.8 mmol) to provide the title compound as an off-white solid (1.8 g, 5.4 mmol, 55%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 1.67 (6H, d, J = 1 1.9 Hz), 1 .12 (1 H, m), 0.91 -0.84 (2H, m), 0.69-0.60 (2H, m). 31P-NMR (162 MHz, DMSO-d6): δ ppm 22.05 (s).
2-(Dimethylphosphineyl)oxazole gold(l) chloride 1-55
Figure imgf000167_0001
To a stirred solution of oxazole (0.33 mL, 5.0 mmol) in THF (10 mL) at -78°C was added nBuLi (1 .6M in hexanes, 3.4 mL, 5.5 mmol) dropwise and the mixture allowed to warm gradually to rt. After stirring at this temperature for 1 h the mixture was cooled to -78°C and dimethylchlorophosphine 1-49 (1 M in THF, 7.5 mL, 7.5 mmol) was added dropwise. The mixture was then allowed to warm gradually to rt and stirred at this temperature for 2 h before cooling to 0°C whereupon a suspension of chloro(tetrahydrothiophene)gold(l) (1.9 g, 6.0 mmol) in DCM (10 mL) was added in one portion. The resulting mixture was stirred at rt for 18 h whereupon MeOH (5 mL) was added to quench the excess dimethylchlorophosphine and the mixture filtered through a pad of celite. The filtrate was concentrated in vacuo to afford a crude product as a yellow solid which was purified by recrystallisation (MeOH / DCM) to provide the title compound as a white solid (450 mg, 1 .2 mmol, 25%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 8.51 (1 H, s), 7.55 (1 H, s), 2.02 (6H, d, J = 12.4 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm -4.63 (s).
(Fluoromethyl)dimethylphosphlne gold(l) chloride 1-58
Figure imgf000167_0002
(a) (Dimethylphosphineyl)methyl 4-methylbenzenesulfonate borane 1-56
A solution of (dimethylphosphino)methanol borane 1-5 (2.0 g, 18.7 mmol) in DCM (100 mL) was cooled to 0°C and 4-toluenesulfonyl chloride (4.3 g, 22.4 mmol) added followed by triethylamine (3.1 mL, 22.4 mmol). The mixture was allowed to warm gradually to rt and was then stirred at this temperature for 18 h. The reaction was quenched with water and the layers separated. The aqueous phase was extracted with DCM and the organic extracts combined and dried over MgSC before the solvent was removed in vacuo to afford a crude product as a colourless oil. Purification by column chromatography (Biotage Isolera Four, 100 g KP-Sil, eluting with isohexane to 80% EtOAc / isohexane) provided the title compound as a colourless oil (2.7 g, 10.3 mmol, 55%).
(b) (Fluoromethyl)dimethylphosphlne borane 1-57
TBAF (1 M in THF, 20.6 ml_, 20.6 mmol) was added to a stirred solution of (dimethylphosphineyl)methyl 4-methylbenzenesulfonate borane 1-56 (2.7 g, 10.3 mmol) in THF (20 ml_). The mixture was then stirred at rt for 3 days then concentrated in vacuo to afford a crude product as an orange oil. Purification by column chromatography (Biotage Isolera Four, 50 g KP-Sil, eluting with isohexane to EtOAc) provided the title compound as a white solid (300 mg, 2.8 mmol, 27%).
(c) (Fluoromethyl)dimethylphosphlne gold(l) chloride 1-58
Prepared according to a procedure similar to that described for dimethyl-(2,6-pyrimidyl)- phosphine gold(l) chloride 1-22 starting from (fluoromethyl)dimethylphosphlne borane 1-57 (300 mg, 2.8 mmol) to provide the title compound as an off-white solid (1 15 mg, 0.35 mmol, 13%). 1 H-NMR (400 MHz, DMSO-d6): δ ppm 5.18 (2H, d, J = 46.7 Hz), 1 .68 (6H, d, J = 1 1.9 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 2.42 (d, J = 50.5 Hz). 19F-NMR (376 MHz, DMSO-d6): δ ppm -240.26 (dt, J = 52.0, 47.7 Hz).
1 -Methylphosphetane gold(l) chloride 1-62
Figure imgf000168_0001
(a) (3-Bromopropyl)(methyl)phosphine borane 1-60 A solution of dimethyl methylphosphonate 1-59 (2.8 mL, 26.0 mmol) in THF (60 mL) was cooled to 0°C and lithium aluminium hydride (1 M in THF, 25.0 mL, 25.0 mmol) added dropwise over 15 min. The mixture was stirred at this temperature for 15 min at which time borane-THF complex (1 M in THF, 25.0 mL, 25.0 mmol) was added dropwise over 5 min. The mixture was stirred at this temperature for 15 min whereupon it was cooled to - 78°C and nBuLi (1 .6M in THF, 15.6 mL, 25.0 mmol) added over 10 min. The mixture was allowed to warm gradually to 0°C and was stirred at this temperature for 30 min before the addition of 1 ,3-dibromopropane (2.5 mL, 25.0 mmol) in one portion. The mixture was stirred at 0°C for 20 min then at rt for 18 h before cooling back to 0°C whereupon the reaction was quenched slowly with aq. HCI (3N, 100 mL). The aqueous phase was then extracted with EtOAc (3 x 100 mL) and the organic extracts combined, washed with brine (sat., 50 mL) and passed through a phase separator cartridge (Biotage) before concentrating in vacuo to afford a crude product as a yellow oil. Purification by column chromatography (Biotage Isolera Four, 50 g KP-Sil, eluting with isohexane to 50% EtOAc / isohexane) provided the title compound as a colourless oil (697 mg, 3.8 mmol, 15%).
(b) 1 -Methylphosphetane borane 1-61
A solution of (3-bromopropyl)(methyl)phosphine borane 1-60 (667 mg, 3.6 mmol) in THF (45 mL) was cooled to 0°C whereupon NaH (60% dispersion in mineral oil, 600 mg, 10.0 mmol) was added in one portion. The mixture was stirred at 0°C for 20 min before being allowed to warm to rt. After stirring at this temperature for 18 h, brine (sat., 20 mL) was added slowly followed by EtOAc (30 mL) and the layers separated. The aqueous phase was extracted with EtOAc (2 x 40 mL) and the organic extracts combined and passed through a phase separator cartridge (Biotage) and concentrated in vacuo. The resulting residue was purified by column chromatography (Biotage Isolera Four, 25 g KP-Sil, eluting with isohexane to 20% EtOAc / isohexane) to afford the title compound as a colourless oil (21 1 mg, 2.1 mmol, 58%).
(c) 1 -Methylphosphetane gold(l) chloride 1-62
Prepared according to a procedure similar to that described for dimethyl-(2,6-pyrimidyl)- phosphine gold(l) chloride 1-22 starting from 1 -methylphosphetane borane 1-61 (142 mg,
I .4 mmol) to provide the title compound as a white solid (90 mg, 0.3 mmol, 20%). 1 H- NMR (400 MHz, CDCI3): δ ppm 2.86-2.57 (4H, m), 2.32-2.21 (2H, m), 1.95 (3H, d, J =
I I .9 Hz). 31P-NMR (162 MHz, CDCI3): δ ppm 31 .68 (s).
1 -Ethylphosphetane gold(l) chloride 1-65
Figure imgf000170_0001
(a) 1 -Ethylphosphetane borane 1-64
A solution of diethyl ethylphosphonate 1-63 (12.1 mL, 75.0 mmol) in THF (15 mL) was cooled to -20°C whereupon lithium aluminium hydride (1 M in THF, 82.5 mL, 82.5 mmol) was added dropwise over the course 15 min. The mixture was stirred at this temperature for an additional 15 min at which time borane-THF complex (1 M in THF, 75 mL, 75.0 mmol) was added dropwise over the course of 5 min. The mixture was stirred at this temperature for 15 min, then cooled to -78°C and nBuLi (1 .6M in THF, 103 mL, 165.0 mmol) added over the course of 15 min. The mixture was allowed to warm gradually to 0°C and stirred at this temperature for 30 min before the addition of 1 ,3-dibromopropane (7.6 mL, 75.0 mmol) in one portion. The mixture was stirred at 0°C for 30 min then at rt for 18 h and was then slowly diluted with aq. HCI (2N, 200 mL) and the aqueous phase extracted with EtOAc (3 x 200 mL). The organic extracts were combined, washed with brine (sat., 250 mL), dried over Na2S04 and then concentrated in vacuo to afford a crude product as a light-yellow oil. Purification by column chromatography (Biotage Isolera Four, 100 g KP-Sil, eluting with isohexane to 50% EtOAc / isohexane) provided the title compound as a colourless oil (1.3 g, 12.0 mmol, 16%).
(b) 1 -Ethylphosphetane gold(l) chloride 1-65
Prepared according to a procedure similar to that described for dimethyl-(2,6-pyrimidyl)- phosphine gold(l) chloride 1-22 starting from 1 -ethylphosphetane borane 1-64 (1 .0 g, 9.6 mmol) to provide the title compound as a light-purple solid (1.3 g, 3.7 mmol, 39%). 1 H- NMR (400 MHz, CDCI3): δ ppm 2.94-2.46 (4H, m), 2.42-2.12 (4H, m), 1.28 (3H, dt, J = 20.7, 7.7 Hz). 31P-NMR (162 MHz, CDCI3): δ ppm 45.76 (s).
1 -Cyclopropylphosphetane gold(l) chloride 1-69
Figure imgf000171_0001
(a) Diethyl cyclopropylphosphonate 1-67
A solution of diethyl chlorophosphate 1-66 (5.0 mL, 34.6 mmol) in THF (50 mL) was cooled to -78°C and cyclopropylmagnesium bromide (1 M in 1 -methyl-THF, 36.3 mL, 36.3 mmol) added over the course of 10 min. The mixture was stirred at -78°C for 5 min and then allowed to warm to rt with stirring for a further 18 h. The mixture was then diluted with Et.20 (50 mL) and slowly poured into aq. NH4CI (sat.). The layers were separated and the aqueous phase extracted with Et20 (75 mL) before the organic extracts were combined, dried over MgS04 and concentrated in vacuo to provide the title compound as a yellow oil (6.3 g - contains 7% THF by 1H-NMR) which was used in the subsequent step without further purification.
(b) 1 -Cyclopropylphosphetane borane 1-68
Prepared according to a procedure similar to that described for 1-ethylphosphetane borane 1-64 starting from diethyl cyclopropylphosphonate 1-67 (6.3 g, from previous step) to provide the title compound as a pale-yellow oil (805 mg, 6.3 mmol, 18% over two- steps). (c) 1 -Cyclopropylphosphetane gold(l) chloride 1-69
Prepared according to a procedure similar to that described for dimethyl-(2,6-pyrimidyl)- phosphine gold(l) chloride 1-22 starting from 1 -cyclopropylphosphetane borane 1-68 (800 mg, 6.3 mmol) to provide the title compound as an off-white solid (330 mg, 1 .0 mmol, 15%). 1H-NMR (400 MHz, CDC ): δ ppm 2.82-2.29 (6H, m), 1 .34 (1 H, m), 1 .16-1.02 (2H, m), 0.93-0.83 (2H, m). 31P-NMR (162 MHz, CDCI3): δ ppm 61.39 (s).
1 -Isopropylphosphetane gold(l) chloride 1-72
Figure imgf000172_0001
(a) Diethyl isopropylphosphonate 1-70
Prepared according to a procedure similar to that described for diethyl cyclopropylphosphonate 1-67 starting from diethyl chlorophosphate 1-66 (2 mL, 13.8 mmol) and isopropylmagnesium chloride LiCI complex (1 .3M in THF, 1 1.2 mL, 14.5 mmol) to provide the title compound as a colourless oil (1.9 g, 8.8 mmol, 64%).
(b) 1 -Isopropylphosphetane borane 1-71
Prepared according to a procedure similar to that described for 1-ethylphosphetane borane 1-64 starting from diethyl isopropylphosphonate 1-70 (7.0 g, 38.8 mmol) to provide the title compound as a colourless oil (910 mg, 7.0 mmol, 18%).
(c) 1 -Isopropylphosphetane gold(l) chloride 1-72
Prepared according to a procedure similar to that described for dimethyl-(2,6-pyrimidyl)- phosphine gold(l) chloride 1-22 starting from 1 -isopropylphosphetane borane 1-71 (910 mg, 7.0 mmol) to provide the title compound as a light-purple solid (1 .2 g, 3.4 mmol, 49%). 1H-NMR (400 MHz, CDCI3): δ ppm 2.76 (1 H, m), 2.69-2.20 (6H, m), 1 .25 (6H, dd, J = 19.5, 7.1 Hz). 31P-NMR (162 MHz, CDC ): δ ppm 58.13 (s).
1 ,3-Dimethylphosphetane gold(l) chloride 1-74
Figure imgf000172_0002
(a) 1 ,3-Dimethylphosphetane borane 1-73 Prepared according to a procedure similar to that described for 1-ethylphosphetane borane 1-64 starting from dimethyl methylphosphonate 1-59 (1.2 g, 9.4 mmol) and 1 ,3- dibromo-2-methylpropane (2.1 g, 9.4 mmol) to provide the title compound as a colourless oil (274 mg, 2.4 mmol, 25%) which was isolated as an ca. 1 :1 mixture of cis/trans isomers.
(b) 1 ,3-Dimethylphosphetane gold(l) chloride 1-74
Prepared according to a procedure similar to that described for dimethyl-(2,6-pyrimidyl)- phosphine gold(l) chloride 1-22 starting from 1 ,3-dimethylphosphetane borane 1-73 (274 mg, 2.4 mmol, as an ca. 1 :1 mixture of cis/trans isomers) to provide the title compound as a white solid (210 mg, 0.6 mmol, 27%) which was isolated as an ca. 1 :1 mixture of cis/trans isomers. 1H-NMR (400 MHz, CDCI3): δ ppm 3.22 (0.5H, m), 3.07 (0.5H, m), 2.63 (1 H, m), 2.40-2.24 (2H, m), 2.08 (1 H, m), 1.92 (1.5H, d, J = 1 1.4 Hz), 1.86 (1.5H, d, J = 1 1.9 Hz), 1.28 (1.5H, d, J = 6.4 Hz), 1.26 (1 .5H, d, J = 6.0 Hz). 31 P-NMR (162 MHz, CDCIs): δ ppm 15.23 (s) & 5.95 (s) (1 :1 ). tert-Butyldiethylphosphine gold(l) chloride 1-75
Figure imgf000173_0001
Diethylchlorophosphine 1-30 (1.0 g, 7.2 mmol) was cooled to 0°C and tert- butylmagnesium chloride (1 M in THF, 7.2 ml_, 7.2 mmol) was added dropwise. The mixture was then warmed to rt, stirred for 1 h and added to a stirring suspension of chloro(tetrahydrothiophene)gold(l) (2.3 g, 7.2 mmol) in DCM (20 ml_). After stirring at this temperature overnight, the mixture was diluted with water and extracted with DCM (2 x 15 ml.) and the organic extracts combined and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave a crude product which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil, eluting with 60% EtOAc / isohexane to EtOAc) to provide the title compound as a white solid (2.4 g, 6.3 mmol, 88%). 1H-NMR (400 MHz, CDCIs): δ ppm 1.96-1 .67 (4H, m), 1 .35-1 .20 (15H, m). 31 P-NMR (162 MHz, CDCIs): δ ppm 56.94 (s). tert-Butyl(ethyl)(methyl)phosphine gold(l) chloride 1-77
Figure imgf000174_0001
tert-Butyldichlorophosphine 1-76 (1.0 g, 6.3 mmol) was dissolved in THF (30 mL) and the solution cooled to -78°C. Ethylmagnesium chloride (2.7M in THF, 2.3 mL, 6.3 mmol) was added dropwise and the mixture stirred at -78°C for 10 min before being allowed to warm to rt. After stirring for a further 30 min, the mixture was cooled back to -78°C and methylmagnesium chloride (3M in THF, 2.1 mL, 6.3 mmol) was added dropwise. The mixture was allowed to warm to rt and stirred for 30 min before a solution of chloro(tetrahydrothiophene)gold(l) (2.1 g, 6.6 mmol) in DCM (20 mL) was added over 2 min. The mixture was stirred at this temperature for 18 h and was then diluted with water (25 mL) and extracted with DCM (3 x 50 mL) before the organic extracts were combined and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave a crude product which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil, eluting with isohexane to 75% EtOAc / isohexane) to provide the title compound as an off-white solid (1.5 g, 4.2 mmol, 67%). 1H-NMR (400 MHz, CDCI3): δ ppm 1.91-1.66 (2H, m), 1.46 (3H, d, J = 10.1 Hz), 1 .24 (3H, dt, J = 19.2, 7.8 Hz), 1.22 (9H, d, J = 16.0 Hz). 31 P-NMR (162 MHz, CDCI3): δ ppm 41.01 (s).
Diisopropyl(methyl)phosphine gold(l) chloride 1-79
Figure imgf000174_0002
A solution of chlorodiisopropylphosphine 1-78 (0.5 mL, 3.3 mmol) in THF (10 mL) was cooled to -78°C and methylmagnesium chloride (3M in THF, 1.1 mL, 3.3 mmol) added dropwise. The mixture was stirred at -78°C for 5 min before being allowed to warm to rt. After stirring for a further 30 min, a solution of chloro(tetrahydrothiophene)gold(l) (1.1 g, 3.4 mmol) in DCM (10 mL) was added over 2 min and the resulting mixture stirred at this temperature for 18 h. The mixture was then diluted with water (25 ml_), extracted with DCM (3 x 50 ml.) and the organic extracts combined and passed through a phase separator cartridge (Biotage). Concentration in vacuo gave a crude product which was purified by column chromatography (Biotage Isolera Four, 50 g KP-Sil, eluting with isohexane to 75% EtOAc / isohexane) to provide the title compound as a white solid (646 mg, 1.8 mmol, 54%). 1H-NMR (400 MHz, CDCI3): δ ppm 2.17-2.04 (2H, m), 1 .42 (3H, d, J = 10.1 Hz), 1.26 (6H, dd, J = 18.3, 6.9 Hz), 1 .18 (6H, dd, J = 16.9, 6.9 Hz). 31 P-NMR (162 MHz, CDCIs): δ ppm 41 .46 (s). 2-(Dimethylphosph neyl)-1 -methyl-1 H-imidazole gold(l) chloride 1-80
Figure imgf000175_0001
Prepared according to a procedure similar to that described for 2- (dimethylphosphineyl)oxazole gold(l) chloride 1-55 starting from /V-methylimidazole (0.4 ml_, 5.0 mmol). However, in this case the crude product was divided into two approximately equal portions. The first portion was triturated with Et.20 and the resulting solid washed with DCM (2x). The first DCM washing was concentrated and then purified by column chromatography (Biotage Isolera Four, 10 g KP-Sil, eluting with DCM to 20% MeOH / DCM) to afford the title compound as a white solid (45.6 mg, 1 .2 mmol, 5%). 1H- NMR (400 MHz, DMSO-d6): δ ppm 7.49 (1 H, m), 7.14 (1 H, br s), 4.02 (3H, s), 1.96 (6H, d, J = 1 1.9 Hz). 31 P-NMR (162 MHz, DMSO-d6): δ ppm -15.03 (s).
The second DCM washing was also concentrated and the residue purified by column chromatography, as described above, to give an additional batch of product (275 mg). Finally, the second portion of crude product from the reaction was triturated with Et^O and the resulting solid washed with DCM. The DCM was concentrated and the residue purified by column chromatography, as described above, to give a third batch of product (320 mg) 2-(Dimethylphosphaneyl)-N,N-dimethylacetamide gold(l) chloride 1-82
Figure imgf000176_0001
(a) 2-(Dimethylphosphaneyl)-N,N-dimethylacetamide borane 1-81
Prepared according to a procedure similar to that described for ethyldimethylphosphine borane 1-23 starting from 2-chloro-/V,/V-dimethylacetamide (396 mg, 3.1 mmol) (except reaction performed at rt) to provide the title compound as a colourless oil (231 mg, 1.2 mmol, 84%).
(b) 2-(Dimethylphosphaneyl)-N,N-dimethylacetamide gold(l) chloride 1-82
2-(Dimethylphosphaneyl)-/V,/V-dimethylacetamide borane 1-81 (231 mg, 1 .2 mmol) and DABCO (404 mg, 3.6 mmol) were dissolved in anhydrous THF (8 mL) and degassed with nitrogen for 10 min. The reaction was sealed and heated at 100°C for 4 h before cooling to rt. Meanwhile, chloro(tetrahydrothiophene)gold(l) (391 mg, 1 .2 mmol) was suspended in anhydrous DCM (8 mL) and degassed with nitrogen for 10 min and then added to the solution of phosphine and the mixture stirred at rt overnight. The mixture was then diluted with EtOAc (20 mL) and water (20 mL) and the phases separated. The aqueous phase was extracted with EtOAc (2 x 30 mL) and the organic extracts combined and dried over MgS04. Concentration in vacuo provided a crude product as an orange solid which was purified by column chromatography (Biotage Isolera Four, 25 g KP-Sil eluting with DCM to 5% MeOH / DCM) to provide the title compound as a brown solid (contaminated with 2% DABCO). The material was dissolved in MeOH and passed through an SPE cartridge (2g, Isolute SCX-2 cartridge, Biotage) and the filtrate subsequently concentrated in vacuo. The residue was dissolved in DCM and washed with water and aq. NaHC03 (sat.) to provide the title compound as a brown solid (170.2 mg, 0.43 mmol, 36%). 1H-NMR (400 MHz, CDCIs): δ ppm 3.15 (3H, s), 3.03 (2H, d, J = 1 1 .0 Hz), 2.98 (3H, s), 1.75 (6H, d, J = 1 1.0 Hz). 31 P-NMR (162 MHz, CDCIs): δ ppm -3.07 (s).
1 -( 1 H-lmidazol-2-yl)-N,N-dimethylmethanamine 1-84
Figure imgf000177_0001
lmidazole-2-carboxaldehyde 1-83 (1 g, 10.4 mmol) was suspended in MeOH (10 ml.) and dimethylamine (40% aq. solution, 9.2 ml_, 72.8 mmol) added in one portion. To the now yellow solution at rt, was added NaBhU (1.2 g, 31 .2 mmol) portionwise over the course of 3 min. The reaction was then heated at 65°C for 2 h after which time it was allowed to cool to rt and was then stirred at this temperature for a further 16 h. The mixture was then concentrated in vacuo and the residue partitioned between EtOAc and brine. The layers were separted and the aqueous phase extracted with EtOAc (3 x 40 ml.) and DCM (3 x 40 ml_). The EtOAc washings were discarded and the DCM extracts passed through a phase separator cartridge (Biotage) before concentrating in vacuo to provide the title compound as a white solid, (171.0 mg, 1 .4 mmol, 13%).
Synthesis of N, S and C-linked phosphine qold(l) complexes:
General procedures
General procedure A - to prepare W-linked and S-linked gold(l) phosphines
To a stirred suspension of the appropriate nitrogen (A//-/)-containing ligand or thiol (1.0 eq.) and the appropriate phosphine gold(l) chloride (1 .0 eq.) in anhydrous MeOH at rt was added NaOH (s) or NaOMe (0.5M in MeOH) or KOH (s) (1 .1 to 3.0 eq.) as a solution in anhydrous MeOH. The reaction mixture was stirred at rt overnight. The volatile solvents were removed in vacuo to afford a residue which was then treated in one of the following ways:
A1 ) The residue was suspended in DCM and sonicated. The resultant white precipitate was removed by filtration and the filtrate reduced under a stream of nitrogen or compressed air. The resulting residue was then dried under high vacuum for a period of time (24 to 72 h). If the product was sufficiently pure by 1H and 31P NMR, no further purification was required.
A2) The residue was suspended in DCM and sonicated. The resultant white precipitate was removed by filtration and the filtrate reduced under a stream of nitrogen or compressed air. The resulting residue was then dried under high vacuum for a period of time (24 to 72 h). If the product was impure by 1H and 31 P NMR it was purified by triturating with Et.20 or another suitable solvent / combination of solvents.
A3) The residue was then dried under high vacuum for a period of time (24 to 72 h) to provide the product. If the product was impure by 1H and 31P-NMR it was purified by trituration with Et^O or another suitable solvent / combination of solvents.
A4) The residue was treated with aq. HCI (0.1 N) or water and the product extracted with DCM. The organic extracts were combined then dried over MgS04, filtered and evaporated to provide the product. If the product was impure by 1H and 31P-NMR it was further purified by trituration with Et^O or another suitable solvent / combination of solvents.
Example: Synthesis of gold(l) complex 11
Figure imgf000178_0001
To a stirred suspension of pyrazole (21 mg, 0.31 mmol) and dimethyl(oxetan-3- yl)phosphine gold(l) chloride 1-18 (108 mg, 0.31 mmol) in anhydrous MeOH (4 mL) at rt was added NaOH (18.5 mg, 0.46 mmol) as a solution in anhydrous MeOH (2 mL). The reaction mixture was stirred at rt overnight. The solvents were removed in vacuo and the residue suspended in DCM (4 mL) and sonicated. The resulting white precipitate was removed by filtration and the filtrate reduced under a stream of nitrogen. The resulting gum was then dried under high vacuum for 24 h to afford the title compound as a colourless gum (106 mg, 0.28 mmol, 90%).
General procedure B - to prepare S-linked gold(l) phosphines
To a suspension of the appropriate phosphine gold(l) chloride (1 .0 eq.) in EtOH at 0°C was added a solution of appropriate thiol (1 .0 eq.) in EtOH and 10% (w/v) aq. K2CO3. The reaction mixture was stirred at 0°C or rt for 1 h and then heated at 50°C overnight before cooling to rt. The reaction was then continued in one of the following ways: B1 ) The resulting white precipitate was collected by filtration and the solid was washed with EtOH and water. The solid was dried under high vacuum (24 to 72 h) to provide the product. If required, the product was further purified by triturating with DCM. B2) The solvent was removed in vacuo or under a stream of nitrogen or compressed air and the residue dissolved in DCM. Water was added, the phases were separated and the aqueous phase extracted with DCM. The organic phases were combined, dried over MgS04 and filtered. Concentration in vacuo provided the product. If required, the product was further purified by triturating with Et.20.
Example: Synthesis of gold(l) complex 24
Figure imgf000179_0001
1 -(Dimethylphosphino)-/V,/V-dimethylmethanamine gold(l) chloride 1-14 (101 mg, 0.29 mmol) was suspended in EtOH (1 ml.) and to this mixture was added a solution of 1 7- benzimidazole-2-thiol (43 mg, 0.29 mmol) in EtOH (1 ml.) and aq. K2C03 (10% w/v, 1 ml.) in one portion. The reaction was heated to 50°C and stirred at this temperature overnight. The reaction was then cooled to rt, the solvent removed in vacuo and the residue dissolved in DCM (10 ml_). Water (10 ml.) was added, the phases were separated and the aqueous phase extracted with DCM (2 x 10 ml_). The organic phases were combined, dried over MgS04 and filtered. Concentration in vacuo provided the crude product which was purified by triturating with Et20. The solid was collected and dried under high vacuum for 24 h to provide the title compound as a light brown solid (1 10 mg, 0.24 mmol, 83%).
General procedure C - to prepare C-linked (acetylenic) gold(l) phosphines
The appropriate phosphine gold(l) chloride (1.0 eq.) and the appropriate acetylene (1.0 eq.) were dissolved in anhydrous MeOH and NaOMe (0.5 M in MeOH, 1 .1 to 1 .2 eq.) or NaOH (s) (1.2 eq.) added dropwise/portionwise. The reaction mixture was stirred at rt overnight. The reaction was continued in one of the following ways: C1 ) The solvent was removed in vacuo and the residue dissolved in DCM. Water was added the phases separated and the aqueous phase extracted with DCM. The organic phases were combined, dried over MgS04 and filtered. Concentration in vacuo gave the desired product.
C2) The precipitate was collected by filtration and washed with MeOH and Et.20 to provide the desired product.
Example: Synthesis of acetylene gold(l) complex 5
Figure imgf000180_0001
Dimethylpropylphosphine gold(l) chloride 1-4 (100 mg, 0.3 mmol) and phenylacetylene (0.033 ml_, 0.3 mmol) were dissolved in anhydrous MeOH (6 ml.) and NaOMe (0.5M in MeOH, 0.7 ml_, 0.36 mmol) added dropwise. The reaction mixture was stirred at rt overnight. The solvent was removed in vacuo and the residue dissolved in DCM (10 ml_). Water (10 ml.) was added, the phases were separated and the aqueous phase extracted with DCM (2 x 10 ml_). The organic phases were combined, dried over MgS04 and filtered. Concentration in vacuo gave the title compound as a yellow oil (1 12 mg, 0.28 mmol, 93%).
General procedure D - to prepare W-linked & S-linked gold(l) phosphines
To a suspension of the appropriate phosphine gold(l) chloride (1 .0 eq.) in EtOH at 0°C was added a solution of the appropriate nitrogen (A//-/)-containing ligand or thiol (1.0 eq.) in EtOH and 10% (w/v) aq. K2C03 (4.3 to 7.1 eq.). The reaction mixture was stirred at 0°C for 1 h or at rt for 1 h or at rt overnight. The reaction was then continued in one of the following ways:
D1 ) The reaction was diluted with water and the product extracted with DCM. The organic extracts were combined then passed through a phase separator cartridge (Biotage) and the solvent evaporated to provide the product. If the product was impure by 1H and 31 P NMR it was purified by triturating with Et^O or another suitable solvent / combination of solvents.
D2) The reaction was diluted with water, acidified to pH 3-5 with aq. HCI (0.5 - 1 N) and the product extracted with DCM. The organic extracts were combined then passed through a phase separator cartridge (Biotage) and the solvent evaporated to provide the product. If the product was impure by 1H and 31P NMR it was purified by triturating with Et.20 or another suitable solvent / combination of solvents. Example: Synthesis of gold(l) complex 106
Figure imgf000181_0001
1 -Methylphosphetane gold(l) chloride 1-62 (81 mg, 0.25 mmol) and thiosalicylic acid (39 mg, 0.25 mmol) were suspended in EtOH (2 mL). K2CO3 (aq., 10% w/v, 2 mL) was added and the mixture stirred at 0°C for 1 h. The reaction was poured into water (10 mL) and acidified to pH 4 with aq. HCI (1 N). The aqueous phase was extracted with DCM (3 x 20 mL) and the organic extracts combined and passed through a phase separator cartridge (Biotage). Concentration in vacuo afforded the title compound as a yellow gum (95 mg, 0.20 mmol, 86%).
The following compounds were synthesised using one of the above methods:
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
General method E - to prepare S-linked gold(l) phosphines The appropriate protected thiol (1.0 eq.) was dissolved in MeOH and 10% (w/v) aq. NaOH (4.0 to 13.0 eq.) was added in one portion. The mixture was heated to 100°C in a microwave reactor for a period of time (45 min to 1 h), whereupon the mixture was cooled to 0°C and the appropriate phosphine gold(l) chloride (1 .0 eq.) was added in one portion. The reaction was stirred at 0°C for 1 h before it was diluted with water and the product extracted with DCM. The organic extracts were combined then passed through a phase separator cartridge (Biotage) and the solvent evaporated to provide the product.
Example: Synthesis of gold(l) complex 63
Figure imgf000213_0001
5-(2-Methoxycarbonyl-ethylsulfanyl)-pyrimidine-4-carboxylic acid methyl ester 1-45 (24.3 mg, 0.09 mmol) was dissolved in MeOH (2 mL) before the addition of aq. NaOH (10% w/v, 0.5 mL). The reaction mixture was then heated to 100°C for 1 h in a microwave. The reaction mixture was then cooled to 0°C followed by the addition of (2-(dimethylamino)ethyl)dimethylphosphine gold(l) chloride 1-42 (33.0 mg, 0.09 mmol) in one portion, then stirred at 0°C for 1 h. The reaction was poured into water (10 mL), then extracted with DCM (3 x 10 mL). The combined organic extracts were passed through a phase separator cartridge (Biotage) and evaporated to dryness to provide the product as a light brown solid (39 mg, 0.076 mmol, 85%). 1H-NMR (400 MHz, DMSO-d6): δ ppm 8.96 (1 H, s), 8.71 (1 H, s), 2.97 (3H, s), 2.75 (3H, s), 2.59-2.52 (2H, m), 2.21-2.10 (8H, m), 1 .61 (6H, d, J = 1 1 .0 Hz). 31P-NMR (162 MHz, DMSO-d6): δ ppm 8.78 (s). The following compounds were made using this method:
Figure imgf000213_0002
Figure imgf000214_0001
Figure imgf000215_0002
Synthesis of gold(l) complex 140
Figure imgf000215_0001
Triethylphosphine gold(l) chloride 1-85 (80 mg, 0.23 mmol) and (S)-2-acetylamino-4-[(f?)- 1-(ethoxycarbonylmethyl-carbamoyl)-2-mercapto-ethylcarbamoyl]-butyric acid ethyl ester 1-48 (93 mg, 0.23 mmol) were dissolved in anhydrous DCM (10 mL) and cooled to 0°C before adding triethylamine (96 μί mL, 0.69 mmol) in one portion. The mixture was stirred at 0°C for 1 h before diluting with water (10 mL) and extracting with DCM (2x10 mL). The organic extracts were combined then passed through a phase separator cartridge (Biotage) and concentrated in vacuo to provide the title compound as a colourless gum (153 mg, 0.21 mmol, 91%).1H-NMR (400 MHz, DMSO-d6): δ ppm 8.25 (1H, d, J = 7.3 Hz), 8.17 (1H, t, J= 5.6 Hz), 7.85 (1H, d, J = 7.8 Hz), 4.32-4.12 (2H, m), 4.07 (2H, q, J = 7.3 Hz), 4.06 (2H, q, J= 7.3 Hz), 3.78 (2H, d, J= 5.6 Hz), 3.10 (1H, dd, J= 12.8, 5.0 Hz), 2.88 (1H, dd, J= 12.8, 8.7 Hz), 2.30-2.07 (2H, m), 1.94-1.80 (11H, m), 1.17 (3H, t, J= 7.3 Hz), 1.16 (3H, t, J= 7.3 Hz), 1.09 (9H, dt, J= 18.5, 7.6 Hz).31P-NMR (162 MHz, DMSO- d6): δ ppm 38.60 (s) Example 2
Growth Media
Tryptic Soy Broth
Figure imgf000215_0003
Figure imgf000216_0003
Directions for use: Dissolve 30 g of the medium in one litre of purified water, mix thoroughly, and then autoclave at 121 °C for 15 minutes.
Luria Broth
Figure imgf000216_0001
Directions for use: Dissolve components in 1 litre of distilled or deionized water and sterilize by autoclaving at 121 °C for 15 minutes.
Mueller Hinton II Broth (Cation-Adjusted)
Figure imgf000216_0002
Directions for use: Dissolve components in 1 litre of distilled or deionized water and sterilize by autoclaving at 121 °C for 15 minutes.
Growth assay for S. aureus.
Stock solution of the test compounds (20mg/ml) in dimethyl sulfoxide (DMSO) were serially diluted in DMSO and each diluted compound added in duplicate to a 96-well plate to a final DMSO concentration of 2% (v/v). An overnight culture of S. aureus (Oxford strain) grown in tryptic soy broth (TSB) was diluted to approximately 5x107cfu/ml and 150μΙ of this sample was added to each well of the 96-well plates. Control wells included an 'untreated' control with bacteria in TSB in the presence of 2% DMSO and a negative sample (containing 150μΙ TSB growth media in the presence of 2% DMSO). Plates were incubated in a shaking incubator at 37°C for 22-24 hours and bacterial growth assessed by absorbance at a wavelength of 595nm. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of compound that inhibited growth compared to the no-treatment control.
Variation of growth assays for:
Klebsiella pneumoniae or E. coli (ATCC 25922): use of 1/100 overnight dilution to set up assay, medium used: Luria broth (LB); incubation without shaking.
P. aeruginosa (ATCC 27853): use of 1/100 overnight dilution to set up assay, medium used: Cation adjusted Mueller Hinton broth (CaMHB); incubation without shaking.
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Example 3
Compounds were screened against C. albicans ATCC 10231 to determine MIC90 values. Each compound was tested in duplicate and Fluconazole was included as a reference standard of care (S.O.C) antifungal drug.
Methods and Materials
Yeast Strain
C. albicans ATCC 10231 was procured, propagated and stored according to the American Type Culture Collection (ATCC) recommendations. According to the Clinical and Laboratory Standards Institute (CLSI) guideline (M27A3E) the desired input for antifungal susceptibility testing is 5x102 - 2.5x103 cells/mL. All prepared inoculums were enumerated to ensure this input range was adhered to. Reference antifungal control
Fluconazole (P13D035, Alfa Aesar) was included in each batch of compound testing as a reference S.O.C antifungal drug. All microdilutions were prepared in 100% DMSO (BP231-100, Fisher). Media
C. albicans ATCC 10231 was cultured from a glycerol vial of known cellular density. The inoculum for each assay was prepared in sterile water and added directly to the assay plate containing 2X RPMI 1640 (31800-022, Gibco) supplemented with 2% glucose (D16- 500, Fisher) at pH 6.95, as per CLSI guidelines.
Experimental Protocol
All test compounds were dissolved in 100% DMSO (BP231 -100, Fisher) and tested at a top dose of 25 μg/mL in a 2-fold, 12-point dilution series. Compounds were transferred from the drug plate to a Corning Costar 3370 assay plate in duplicate. The original drug stocks and working stocks were stored at -20°C. Each batch of compound testing included a negative and positive growth control plate, in addition, to Fluconazole tested in duplicate at a top test concentration of 64 μg/mL.
Assay plates were incubated at 35°C for 24 hours, cells were then re-suspended and an absorbance read was taken at 530 nm using a Spectramax i3x plate reader (Molecular Devices). Assay plates were re-incubated for an additional 24 hours and the process was repeated to obtain a 48 hour end point read.
Results
The compounds tested displayed excellent reproducibility and the following quality parameters were assessed for each batch of compounds tested: Z' > 0.5, CV <10% and a high signal to background ratio.
All batches of compounds tested passed the quality parameters and the MlCgo range for Fluconazole was within CLSI guidelines as tabulated below:
Figure imgf000224_0001
C. albicans ATCC 10231 MIC90 values
Figure imgf000224_0002
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Compounds were screened against C. albicans ATCC 10231 , C. glabrata AMRI-0314, and A. fumigatus ATCC MYA-3627 to determine MIC90 values. Each compound was tested in duplicate with Fluconazole and Voriconazole as reference standard of care (S.O.C) antifungal drugs. After submission of the initial testing, Auranofin was tested again in triplicate.
Methods and Materials
Strains
C. albicans ATCC 10231 , C. glabrata AMRI-0314, and A. fumigatus ATCC MYA-3627 were procured, propagated and stored according to ATCC recommendations. According to CLSI guideline (M27A3E) the desired input for antifungal susceptibility testing is 5x102 - 2.5x103 cells/mL (Yeast) and 0.4x104 - 5x104 CFU/mL (Fungi). All prepared inoculums were enumerated to ensure this input range was adhered to. Reference antifungal control
Fluconazole (P13D035, Alfa Aesar) was included in each batch of compound testing for the two yeast strains as a reference S.O.C antifungal drug. Voriconazole (Sigma 458670010) was included in each batch of compound testing for the Aspergillus strain as a reference S.O.C antifungal drug. All microdilutions were prepared in 100% DMSO (BP231-100, Fisher).
Media C. albicans ATCC 10231 and C. glabrata AMRI-0314 were cultured from glycerol vials of known cellular density. A. fumigatus ATCC MYA-3627 was cultured from a glycerol stock onto a potato dextrose agar plate (PDA, BD Difco 254920) for 5 - 7 days before the mature conidia were harvested for the assay. The inoculum for each assay was prepared in sterile water and added directly to the assay plate containing 2X RPMI 1640 (31800- 022, Gibco) supplemented with 2% glucose (D16-500, Fisher) at pH 6.95, as per CLSI guidelines.
Experimental Protocol
All test compounds were dissolved in 100% DMSO (BP231 -100, Fisher) and tested at a top dose of 200 μg/mL in a 2-fold, 12-point dilution series. Compounds were transferred from the drug plate to a Corning Costar 3370 assay plate in duplicate. The original drug stocks and working stocks were stored at -20°C. Each batch of compound testing included negative and positive growth controls, in addition, to Fluconazole and Voriconazole tested in duplicate at a top test concentration of 64 μg/mL.
Assay plates were incubated at 35°C for 24 hours, yeast cells were then re-suspended and an absorbance read was taken at 530 nm using a Spectramax i3x plate reader (Molecular Devices). The Aspergillus cells were read as is without resuspension. Assay plates were re-incubated for an additional 24 hours and the process was repeated to obtain a 48 hour end point read.
Results
The compounds tested displayed excellent reproducibility and the following quality parameters were assessed for each batch of compounds tested: Z' > 0.5, CV <10% and a high signal to background ratio.
All batches of compounds tested passed the quality parameters and the MICgo ranges for Fluconazole or Voriconazole were within CLSI guidelines as tabulated below.
Figure imgf000228_0001
Figure imgf000228_0002
Figure imgf000229_0001
MIC90 ranges were taken from 24 hour and 48 hour reads on Candida spp. as per CLSI guidelines
MIC90 ranges were taken from a 48 hour read on A. fumigatus as per CLSI guidelines.
References
Figure imgf000229_0002

Claims

1 . A compound of formula (I):
Figure imgf000230_0001
and pharmaceutically acceptable salts and solvates thereof, wherein: Px is selected from (P1 ), (P2) or (P3);
Figure imgf000230_0002
wherein RP1 and RP2 are each independently selected from
methyl, ethyl and -CH2OMe;
RP3 is selected from the group consisting of:
(i) -CH2RP6, -CH2CH2RP6, -CHMeRP6, -C(Me)2RP6, -CH(RP6)2, -CMe(RP6)2, -C(C3. 4cycloalkyl)RP6, -C(=NH)RP6, -CH2C(=NH)RP6, sec-butyl, 1-propynyl, -COOH,
trimethylsilyl(ethynyl),
(ii) C3-4 unsubstituted linear saturated alkyl,
(iii) C3-4 saturated cycloalkyl, optionally substituted with one C1-3 linear saturated alkyl group;
(iv) 4- or 5-membered heterocyclyl or heterocycloalkenyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group, (v) 5-or 6-membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
RP4 is selected from linear, branched or cyclic C3 saturated alkyl groups, optionally substituted with a methyl group; m is 1 , 2 or 3; and RM is one or more optional substituents on the ring independently selected from
Rpc when attached to a carbon atom adjacent the phosphorus atom, or
-OH, -OC1-3alkyl and Rpc, when attached to other ring carbons;
Rpc is selected from the group consisting of
C1-3alkyl, optionally substituted with one or more groups RPD; and
oxo;
RP5 is selected from linear or branched unsubstituted C1-4 saturated alkyl groups, or cyclic C3-4 saturated alkyl groups optionally substituted with a methyl group; each RP6 group is independently selected from
4-membered heterocyclyl or heteroaryl groups containing one or two heteroatoms selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
-F,
-OH, -OMe, -OEt,
SH, -SMe, -SEt,
S(=0)H, -S(=0)Me, -S(=0)Et,
S02H, -S02Me, -S02Et,
CH2OH, -CH2OMe, -CH2OEt,
CH2SH, -CH2SMe, -CH2SEt,
CH2S(=0)H, -CH2S(=0)Me, -CH2S(=0)Et,
CH2S02H, -CH2S02Me, -CH2S02Et,
C(=0)OH, -C(=0)NH2, -C(=0)NHMe, -C(=0)NMe2,
NH2, -NHMe, -NMe2, -NMe3 +,
NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me; RP7 and RP8 are each independently selected from H and methyl or together for an oxo group;
RP9 and RP1° are each independently selected from H and methyl or together for an oxo group;
RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form either
a 4- or 5-membered heterocyclic ring including 1 or 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, optionally mono-substituted with a group RPE, or
a 6-membered heterocyclic ring including 2 heteroatoms each independently selected from O and N in addition to the phosphorus atom, substituted with one or two groups RPE;
RPD is selected from the group consisting of
F,
OH and OC1-3alkyl;
RPE is selected from
methyl and oxo;
RAu is selected from the groups (B1 ) to (B3):
Figure imgf000232_0001
wherein:
RNA is selected from the group consisting of linear or branched C1 -6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C4-6heterocycloalkyl or heteroaryl, C5-6cycloalkenyl and
C5-6heterocycloalkenyl optionally substituted with one or more groups RAL, and
RNB is selected from -CORA2 and -S02RA2; or RNA and RNB together with the nitrogen atom to which they are attached form
a 5- or 6-membered heteroaryl, heterocycloalkyi or heterocycloalkenyl group or 8- to 10-membered heterobicyclyl group, optionally substituted with one or more groups selected from
oxo, =NH, RA1, RA2,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; and
phenyl optionally substituted with one or more groups RA1,
-Ls- and -Lc- are each independently selected from
methylene or ethylene, optionally substituted with one or two groups R1A1, and a single bond;
RSA is selected from the group consisting of
(i) C5-6 cycloalkyi, heterocyclyl, aryl or heteroaryl groups and 8- to 10- membered bicyclyl or heterobicyclyl groups, optionally substituted with one or more groups RA1; and (ii) the groups (C1 ) to (C3)
Figure imgf000233_0001
wherein EA is selected from the group consisting of: -0-RA2; -NH-RA2; -NRA¾
RE1 is selected from H and linear or branched C1-3alkyl;
EB is selected from: EBA; -CO-EB1-NREARE2 and -CO-EB2-EB3-NREBRE2; wherein EB1, EB2 and EB3 are D- or L-amino acid residues independently selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the -CO-, -NREARE2 and -NREBRE2 groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality; when EB1 is Pro, REA is absent, otherwise REA is RE1; when EB3 is Pro, REB is absent, otherwise REB is RE1; wherein the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, - CONRA2RE1 and -COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and - OCOCH3; and when EB2 and EB3 are present and EB2 is not Pro the nitrogen of the amide bond between EB2 and EB3 may be optionally substituted with RE1; when EB is EBA, RE1 and EBA together with the nitrogen atom to which they are attached form a group selected from:
5- or 6-membered saturated heterocyclyl optionally substituted with one or more groups RAL, and
5- or 6-membered heteroaryl optionally substituted with one or more groups RA1;
Ec is selected from: -OH; -ORA2; -NH2; NHRA2; NRA2 2 and -NREC1-Ec1-COREC2; wherein EC1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys, Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the - NREC1- and -COREC2 groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality; when EC1 is Pro, REC1 is absent, otherwise REC1 is RE1; wherein the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, - CONRA2RE1 and -COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and - OCOCH3;
REC2 is selected from -ORE9, -NH2, -NHRA2 and -NRA2RE1; RE3 and RE4 are independently selected from -H and -CH3; when RE1 is H and Ec is -OC1-3alkyl, -NH2 or -NHC1-3alkyl, ED is selected from -H, and -CO-ED1-NREDRE6, otherwise, ED is selected from: -RE5, and -CO-ED1-NREDRE6; wherein ED1 is a D- or L-amino acid residue selected from Ala, Arg, Asn, Asp, Cys,
Gin, Glu, Gly, His, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, wherein the - NREDRE6- and -CO- groups represent terminals of the alpha or pendent functionality of the amino acids; wherein the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality; wherein the acid functionality of Asp and Glu not forming an amide bond may be present as the corresponding amides or esters selected from -CONH2, -CONHRA2, - CONRA2RE1 and -COORA2; and the hydroxyl side chain groups of Ser, Thr and Tyr may be present as their corresponding alkoxy or acetate groups selected from -0(C1-3alkyl) and - OCOCH3; when ED1 is Pro, RED is absent, otherwise RED is RE1;
RE2, RE5 and RE6 are independently selected from -H and -COCH3; RE7, RE8 and RE9 are each independently selected from -H and -RA2; when Lc is a single bond, RCA is RCAA,
wherein RCAA is selected from the group consisting of
linear or branched C1 -6alkyl, substituted with one or more groups RAL,
C3-6 cycloalkyl, aryl or heteroaryl, optionally substituted with one or more groups selected from VC1, -CH2VC1, oxo, RAL, RA1 and RA2; wherein VC1 is a C4-6 cycloalkyl or heterocyclyl group optionally substituted with one or more groups selected from oxo and RA1;
8- to 10-membered bicyclyl and biheterocyclyl, optionally substituted with one or more groups RA1,
Figure imgf000236_0002
when Lc is methylene or ethylene, RCA is selected from RCAA and RCAB, wherein RCAB is selected from
C2-6alkenyl and C2-6alkynyl, optionally substituted with one or more groups RAL, or C6 heterocyclyl attached to Lc via a ring N atom, optionally substituted with one or more groups RA1; wherein RA1 is selected from the group consisting of
linear or branched C1 -6alkyl, C2-6alkenyl or C2-6alkynyl optionally substituted with one or more groups RAL, wherein the alkyl chain is optionally interrupted by one or more atoms selected from O and S,
Figure imgf000236_0001
RA2 is selected from the group consisting of linear or branched C1 -6alkyl, C2-6alkenyl or C2-6alkynyl optionally substituted with one or more groups RAT, wherein the alkyl chain is optionally interrupted by one or more atoms selected from O and S,
O C1 -6alkyl;
C3-6cycloalkyl, C4-6heterocycloalkyl, C5-6cycloalkenyl or Cs-eheterocycloalkenyl optionally substituted with one or more groups RAT,
phenyl optionally substituted with one or more groups RAR, and
C5-ioheteroaryl optionally substituted with one or more groups RAR;
where N is substituted by 2 RA2 groups, the N and the RA2 groups may together form a N- containing C5-6 heterocycloalkyi group, optionally substituted with one or two groups selected from linear unsubstituted C1 -6 alkyl;
R1 A1 is selected from linear or branched unsubstituted C1-3alkyl; RAL is selected from the group consisting of
linear or branched C1 -6alkyl optionally substituted with one or more groups RAT;
Figure imgf000237_0001
RAR is selected from the group consisting of
linear or branched C1 -6alkyl, C2-6alkenyl or C2-6alkynyl optionally substituted with one or more groups RAT,
Figure imgf000237_0002
RAT is selected from the group consisting of
-F, -CN, -OH, -OC1-3alkyl, oxo,
-CF3, -CF2H, -COC1-3alkyl,
-COOH, -COOC1-3alkyl, -CONH2, -CONHC1-3alkyl, -CON(C1-3alkyl)2,
-OCOC1-3alkyl, -OCONH2, -OCONHC1-3alkyl, -OCON(C1-3alkyl)2,
-NH2, -NHC1-3alkyl, -N(C1-3alkyl)2,
-S02NH2, -S02NH(C1-3alkyl)2, -S02N(C1-3alkyl)2, -S02(C1-3alkyl),
-NHCOH, -NHCO(C1-3alkyl), -N(C1-3alkyl)COH and -N(C1-3alkyl)CO(C1-3alkyl); R1A1 is a linear or branched unsubstituted C1 -6 alkyl group.
2. A compound according to claim 1 , wherein RP3 is selected from the group consisting of
-CH2RP6, -CH2CH2RP6, -CHMeRP6, -C(Me)2RP6, -CH(RP6)2, -CMe(RP6)2, -C(C3- 4cycloalkyl)RP6, -C(=NH)RP6, -CH2C(=NH)RP6, sec-butyl, 1-propynyl, -COOH, C3-4 unsubstituted linear saturated alkyl,
C3-4 unsubstituted saturated cycloalkyl,
5-membered heterocyclyl or heterocycloalkenyl groups containing two heteroatoms independently selected from O and N, optionally substituted with one C1-3 linear saturated alkyl group;
5- membered heteroaryl groups containing one to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups, and
6- membered heteroaryl groups containing two to four heteroatoms independently selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups; and each RP6 group is independently selected from
4-membered heterocyclyl groups containing one heteroatom selected from O and N, optionally substituted with one or two C1-3 linear saturated alkyl groups,
-OH, -OMe, -OEt,
-CH2OH,
-C(=0)NH2, -C(=0)NHMe, -C(=0)NMe2,
-NH2, -NHMe, -NMe2, -NMe3 +,
-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.
3. A compound according to claim 1 or 2, wherein Px is the group (P1 ).
4. A compound according to claim 3, wherein both RP1 and RP2 are methyl.
5. A compound according to claim 3, wherein both RP1 and RP2 are ethyl.
6. A compound according to claim 3, wherein RP1 is methyl and RP2 is ethyl.
7. A compound according to any one of claims 3 to 6, wherein RP3 is selected from -CH2RP6, -CH2CH2RP6, -CHMeRP6, -C(Me)2RP6, -CH(RP6)2, -CMe(RP6)2, -C(C3-
4cycloalkyl)RP6, -C(=NH)RP6 and -CH2C(=NH)RP6.
8. A compound according to any one of claims 3 to 7, wherein Px is selected from the groups:
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
9. A compound for use according to claim 1 or 2, wherein Px is the group (P2).
10. A compound according to claim 9, wherein RP4 is selected from isopropyl, n-propyl, cyclopropyl, tert-butyl, sec-butyl, n-butyl and iso-butyl.
1 1. A compound according to claim 9, wherein RP4 is selected from isopropyl, n- and cyclopropyl.
12. A compound according to any one of claims 9 to 1 1 , wherein RM is absent.
13. A compound according to any one of claims 7 to 10, wherein Px is selected from the groups:
Figure imgf000243_0001
14. A compound according to claim 1 or 2, wherein Px is the group (P3).
15. A compound according to claim 14, wherein RP5 is methyl.
16. A compound according to claim 14 or 15, wherein RP7 and RP8 are each independently hydrogen.
17. A compound according to any one of claims 14 to 16, wherein RP9 and RP1° are each independently hydrogen.
18. A compound according to any one of claims 14 to 17, wherein RF1 and RF2, together with the two carbon atoms to which they are attached and the phosphorus atom, form a 4- or 5-membered heterocyclic ring including 1 or 2 heteroatoms each
independently selected from O and N in addition to the phosphorus atom, optionally mono-substituted with a methyl group.
19. A compound according to any one of claims 14 to 18, wherein Px is selected from the roups:
Figure imgf000244_0001
20. A compound according to any one of claims 1 to 19, wherein RAu is the group (B1 ).
21. A compound according to claim 20, wherein RNA and RNB together with the nitrogen atom to which they are attached form a 5- or 6-membered heteroaryl group, optionally substituted with one or more groups selected from
oxo, =NH, RA1, RA2,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; and phenyl optionally substituted with one or more groups RA1.
22. A compound according to claim 21 , wherein RNA and RNB together with the nitrogen atom to which they are attached form a 5-membered heteroaryl group.
23. A compound according to claim 20, wherein RNA and RNB together with the nitrogen atom to which they are attached form an 8- to 10-membered heterobicyclyl group, optionally substituted with one or more groups selected from
oxo, =NH, RA1, RA2,
-C(=0)N(RN1)2, wherein each RN1 is independently selected from RN2 and -ORN3, wherein RN2 and RN3 are each independently selected from linear unsubstituted C1 -6alkyl; and
phenyl optionally substituted with one or more groups RA1.
24. A compound according to claim 20, wherein -NRNARNB is the group (A3)
Figure imgf000245_0001
wherein
one group from YN1 to YN4 is CR3, another is N and the remainder are
independently selected from CR3 and N; wherein R3 is selected from
linear, branched or cyclic C1 -6alkyl optionally substituted with one group RAL,
F, CI, Br,
-CN,
-CF3, -CF2H, -CH2F,
-OH, -0(C1 -6alkyl),
-COOH, -COO(C1 -6alkyl) and -CON(C1 -6alkyl)2.
25. A compound according to claim 20, wherein -NRNARNB is selected from
Figure imgf000246_0001
Figure imgf000247_0001
26. A compound according to any one of claims 1 to 19, wherein RAu is the group (B2).
27. A compound according to claim 26, wherein -Ls- is a single bond.
28. A compound according to claim 26 or 27, wherein RSA is selected from the group consisting of C5-6 cycloalkyl, heterocyclyl, aryl or heteroaryl groups and 8- to 10- membered bicyclyl or heterobicyclyl groups, optionally substituted with one or more groups RA1.
29. A compound according to any one of claims 26 to 27, wherein RSA is a 5- membered heteroaromatic group containing up to 4 heteroatoms selected from N, O and S, at least one of which being N.
30. A compound according to claim 29, wherein the up to 4 heteroatoms are selected from N and O, at least one of which being N.
31. A compound according to claim 29, wherein the 5-membered heteroaromatic group is connected to sulfur at a ring carbon.
32. A compound according to any one of claims 29 to 31 , wherein the 5-membered heteroaromatic group contains up to 4 heteroatoms selected from N.
33. A compound according to claim 20, wherein LS-RSA is selected from
Figure imgf000248_0001
34. A compound according to claim 26, wherein RSA is selected from 8- to 10- membered bicyclyl or heterobicyclyl groups, optionally substituted with one or two groups RA1.
35. A compound according to claim 26, wherein RSA is the group (S3)
Figure imgf000249_0001
wherein one of YS5, YS6, YS7 and YS8 is selected from CH and N, and the others are CH; and X is independently selected from NH, S and O.
36. A compound according to any one of claims 1 to 19, wherein RAu is the group (B3).
37. A compound according to claim 36, wherein -Lc- is a single bond.
38. A compound according to claim 36 or 37, wherein RCA is selected from C3-6 cycloalkyi, aryl or heteroaryl, optionally substituted with one or more groups selected from VC1, -CH2VC1, oxo, RAL, RA1 and RA2; wherein VC1 is a C4-6 cycloalkyi or heterocyclyl group optionally substituted with one or more groups selected from oxo and RA1.
39. A compound according to claim 38, wherein RCA is selected from C3-6 aryl or heteroaryl, optionally substituted with one or more groups selected from RAL.
40. A compound according to claim 39, wherein RCA is phenyl.
41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40.
42. A pharmaceutical composition according to claim 41 , which also comprises a pharmaceutical acceptable diluent or excipient.
43. A compound according to any one of claims 1 to 40 for use in therapy.
44. A compound according to any one of claims 1 to 40, for use in the prevention or treatment of a bacterial infection.
45. A compound for use according to claim 44, wherein the bacterial infection prevented and/or treated is infection by one or more Gram-positive bacteria.
46. A compound for use according to claim 44, wherein the bacterial infection prevented and/or treated is infection by one or more Gram-negative bacteria.
47. A compound according to any one of claims 1 to 40, for use in the prevention or treatment of a fungal infection.
48. A compound for use according to claim 47, wherein the fungal infection is selected from candidiasis, cryptococcosis, histoplasmosis, blastomycosis, paracoccoidiomycosis, coccidioidomycosis, aspergillosis, extracutaneous sporotrichosis, and mucormycosis.
49. A compound for use according to claim 47, wherein the fungal infection is an infenction caused by a fungus selected from Candida spp, Aspergillus fumigatus, Mucor, Rhizopus, Absidia, Cunninghamella, Cryptococcus neoformans, C. gattii, Pneumocystis jirovecii, Blastomyces dermatitidis, Coccidioides immitis, Coccidioides posadasii, Histoplasma capsulatum, Sporothrix schenckii, Aspergillus flavus, Fusarium spp., Alternaria spp., Curvularia spp., and Acremonium spp.
50. A compound according to any one of claims 1 to 40, for use in the prevention or treatment of a Protozoal infection.
51. A compound for use according to claim 50, wherein the Protozoal infection is an infection caused by Protozoa selected from Trypanosoma cruzi, T brucei, Leshmania spp., Dientamoeba fragilis, Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica, Naeglaeri fowleri, Acanthomoeba, Balamuthia mandrillaris, Plasmodium spp., Babesia microti, Cryptosporidium parvum, Cycolspora cayetanensis, Cystoisopora belli, Toxoplasma gondii, Sarcocystis spp., and Balantidium coli.
52. A compound according to any one of claims 1 to 40, for use in the prevention or treatment of an inflammatory disease.
53. A compound for use according to claim 52, wherein the inflammatory disease is selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis.
54. A compound according to any one of claims 1 to 40, for use in the prevention or treatment of a proliferative disease, such as cancer.
55. A compound for use according to claim 54, wherein the proliferative disease is a cancer selected from ovarian, skin, breast, lung, prostate, colorectal, lymphomas, bladder, uterine, kidney and blood cancers including leukaemia, lymphoma and myeloma.
56. A compound according to any one of claims 1 to 40, for use in the prevention or treatment of a viral disease.
57. A compound for use according to claim 56, wherein the viral disease caused by the human immunodeficiency virus (HIV) / AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV).
58. Use of a compound according to any one of claims 1 to 40 in the manufacture of a medicament for the prevention or treatment of a fungal infection.
59. Use according to claim 58, wherein the fungal infection is selected from
candidiasis, cryptococcosis, histoplasmosis, blastomycosis, paracoccoidiomycosis, coccidioidomycosis, aspergillosis, extracutaneous sporotrichosis, and mucormycosis.
60. Use according to claim 58, wherein the fungal infection is an infenction caused by a fungus selected from Candida spp, Aspergillus fumigatus, Mucorales, Mucor,
Rhizopus, Absidia, Cunninghamella, Cryptococcus neoformans, C. gattii, Pneumocystis jirovecii, Blastomyces dermatitidis, Coccidioides immitis, Coccidioides posadasii,
Histoplasma capsulatum, Sporothrix schenckii, Aspergillus flavus, Fusarium spp., Alternaria spp., Curvularia spp., and Acremonium spp.
61. Use of a compound according to any one of claims 1 to 40 in the manufacture of a medicament for the prevention or treatment of a Protozoal infection.
62. Use according to claim 61 , wherein the Protozoal infection is an infection caused by Protozoa selected from Trypanosoma cruzi, T brucei, Leshmania spp., Dientamoeba fragilis, Giardia lamblia, Trichomonas vaginalis, Entamoeba histolytica, Naeglaeri fowleri, Acanthomoeba, Balamuthia mandrillaris, Plasmodium spp., Babesia microti,
Cryptosporidium parvum, Cycolspora cayetanensis, Cystoisopora belli, Toxoplasma gondii, Sarcocystis spp., and Balantidium coli.
63. Use of a compound according to any one of claims 1 to 40 in the manufacture of a medicament for the prevention or treatment of an inflammatory disease.
64. Use according to claim 63, wherein the inflammatory disease is selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis.
65. Use of a compound according to any one of claims 1 to 40 in the manufacture of a medicament for the prevention or treatment of a proliferative disease, such as cancer.
66. Use according to claim 65, wherein the proliferative disease is a cancer selected from ovarian, skin, breast, lung, prostate, colorectal, lymphomas, bladder, uterine, kidney and blood cancers including leukaemia, lymphoma and myeloma.
67. Use of a compound according to any one of claims 1 to 40 in the manufacture of a medicament for the prevention or treatment of a viral disease.
68. A compound for use according to claim 67, wherein the viral disease caused by the human immunodeficiency virus (HIV) /AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV).
69. A method of preventing or treating a disease or disorder selected from fungal infections, protozoal infections, inflammatory diseases, proliferative diseases and viral diseases.
70. A method according to claim 69, which is a method of preventing or treating a fungal infection selected from candidiasis, cryptococcosis, histoplasmosis, blastomycosis, paracoccoidiomycosis, coccidioidomycosis, aspergillosis, extracutaneous sporotrichosis and, mucormycosis.
71. A method according to claim 69, which is a method of preventing or treating a Protozoal infection caused by Protozoa selected from Trypanosoma cruzi, T brucei,
Leshmania spp., Dientamoeba fragilis, Giardia lamblia, Trichomonas vaginalis,
Entamoeba histolytica, Naeglaeri fowleri, Acanthomoeba, Balamuthia mandrillaris, Plasmodium spp., Babesia microti, Cryptosporidium parvum, Cycolspora cayetanensis, Cystoisopora belli, Toxoplasma gondii, Sarcocystis spp., and Balantidium coli.
72. A method according to claim 69, which is a method of preventing or treating an inflammatory disease selected from chronic airway inflammation, tumor growth and metastasis, rheumatoid arthritis, inflammatory bowel disease, renal and corneal transplant rejection, and atopic dermatitis and psoriasis.
73. A method according to claim 69, which is a method of preventing or treating a proliferative disease selected from ovarian cancer, skin cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, lymphomas, bladder cancer, uterine cancer, kidney cancer and blood cancers including leukaemia, lymphoma and myeloma.
74. A method according to claim 69, which is a method of preventing or treating a viral disease caused by the human immunodeficiency virus (HIV) / AIDS, the respiratory syncytial virus (RSV), the hepatitis A virus (HAV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) or the influenza A virus (IAV).
75. A method for reducing the biomass of a biofilm, the method comprising exposing the biofilm to an effective amount of a compound as described in any one of claims 1 to 40.
76. A method for promoting the dispersal of microorganisms from a biofilm, the method comprising exposing the biofilm to an effective amount of a compound as described in any one of claims 1 to 40.
77. A method for killing a microorganism within a biofilm, comprising exposing the biofilm to an effective amount of a compound as described in any one of claims 1 to 40.
78. A method of sensitizing a microorganism in a biofilm to an antimicrobial agent by exposing the biofilm to an effective amount of a compound as described in any one of claims 1 to 40.
79. The method according to any one of claims 75 to 78, wherein the biofilm is an established biofilm.
80. A method for inhibiting the formation of a biofilm, the method comprising exposing the biofilm to an effective amount of a compound as described in any one of claims 1 to 40.
81. The method according to claim 80 wherein the compound as described in any one of claims 1 to 40 is coated, impregnated or otherwise contacted with a surface or interface susceptible to biofilm formation.
82. The method according to claim 81 , wherein the surface is a surface of medical or surgical equipment, an implantable medical device, implant, or prosthesis
83. A method of removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, sensitizing a microorganism in a biofilm to an antimicrobial agent, killing a microorganism within a biofilm, treating or preventing an infection, disease or disorder caused by a biofilm, inhibiting the growth of a microbial persister cell, killing a microbial persister cell, or treating or preventing an infection, disease or disorder caused by or associated with a microbial persister cell; the method comprising exposing the biofilm to an effective amount of a compound as described in any one of claims 1 to 40.
84. A method for killing microbial persister cells, or inhibiting the growth of microbial persister cells, comprising exposing the persister cell to an effective amount of a compound as described in any one of claims 1 to 40.
85. Use of a compound of a compound as described in any one of claims 1 to 40 to remove or eliminate an existing biofilm, inhibit biofilm formation, reduce the biomass of a biofilm, promote the dispersal of microorganisms from a biofilm, sensitize a
microorganism in a biofilm to an antimicrobial agent, kill a microorganism within a biofilm, treat or prevent an infection, disease or disorder caused by a biofilm, inhibit the growth of a microbial persister cell, kill a microbial persister cell, or treat or prevent an infection, disease or disorder caused by or associated with a microbial persister cell.
86. A compound as described in any one of claims 1 to 40 for use in a method of removing or eliminating an existing biofilm, inhibiting biofilm formation, reducing the biomass of a biofilm, promoting the dispersal of microorganisms from a biofilm, sensitizing a microorganism in a biofilm to an antimicrobial agent, killing a microorganism within a biofilm, treating or preventing an infection, disease or disorder caused by a biofilm, inhibiting the growth of microbial persister cells, killing microbial persister cells, or treating or preventing an infection, disease or disorder caused by or associated with microbial persister cells.
87. The method according to any one of claims 75 to 84, the use according to claim 85, or the compound according to claim 86, wherein the biofilm comprises bacteria, or the microbial persister cells are bacteria.
88. The method according to any one of claims 75 to 84, the use according to claim 85, or the compound according to claim 86, wherein the bacteria are Gram-positive bacteria.
89. The method according to any one of claims 75 to 84, the use according to claim 85, or the compound according to claim 86, wherein the bacteria are Staphylococcus spp.
90. The method according to any one of claims 75 to 84, the use according to claim 85, or the compound according to claim 86, wherein the bacteria are multi-drug resistant bacteria.
91. The method according to any one of claims 75 to 84, the use according to claim 85, or the compound according to claim 86 wherein the bacteria are small colony variants.
92. The method according to any one of claims 75 to 84, the use according to claim 85, or the compound according to claim 86, comprising further administering at least one additional antimicrobial agent.
93. A medical device coated or impregnated with a compound as described in any one of claims 1 to 40.
94. A compound according to formula (II):
Figure imgf000256_0001
wherein Px is as defined in any one of claims 1 to 40.
95. A compound according to formula VIII:
Figure imgf000256_0002
wherein Px is as defined in any one of claims 1 to 40, and
E is a residue of a thiol-containing or selenol-containing endogenous ligand or protein.
96. A method of making a compound of formula (I):
Figure imgf000256_0003
wherein Px is as defined in any one of claims 1 to 40 and RAu is the group (B1 ) as defined in any one of claims 1 to 40, comprising reacting a gold(l) complex of formula II:
Figure imgf000256_0004
with a nitrogen containing derivative of general formula (Ι'):
Figure imgf000257_0001
97. A method of synthesising a compound of formula I
Figure imgf000257_0002
wherein Px is as defined in any one of claims 1 to 40 and RAu is the group (B2) as defined in any one of claims 1 to 40, which comprises reacting a compound of general formula III, IV, V, VI or IX:
Figure imgf000257_0003
with a chloro(trialkyl phosphine) gold(l) complex of general formula II:
Figure imgf000257_0004
98. A method of making a compound of formula (I):
Figure imgf000257_0005
wherein Px is as defined in any one of claims 1 to 40 and RAu is the group (B3) as defined in any one of claims 1 to 40, comprising reacting a compound of general formula X or XI:
Figure imgf000258_0001
with a chloro(trialkyl phosphine) gold(l) complex of general formula II:
Figure imgf000258_0002
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