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:

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):

and pharmaceutically acceptable salts and solvates thereof, wherein: P ^x is selected from (P1 ), (P2) or (P3);

wherein R ^P1 and R ^P2 are each independently selected from

methyl, ethyl and -CH ₂ OMe;

R ^P3 is selected from the group consisting of:

(i) -CH ₂ R ^P6 , -CH ₂ CH ₂ R ^P6 , -CHMeR ^P6 , -C(Me) ₂ R ^P6 , -CH(R ^P6 ) ₂ , -CMe(R ^P6 ) ₂ , -C(C ₃ - 4cycloalkyl)R ^P6 , -C(=NH)R ^P6 , -CH ₂ C(=NH)R ^P6 , sec-butyl, 1-propynyl, -COOH,

trimethylsilyl(ethynyl),

(ii) C3-4 unsubstituted linear saturated alkyl,

(iii) C3-4 saturated cycloalkyl, optionally substituted with one C _1-3 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 C _1-3 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 C _1-3 linear saturated alkyl groups, R ^P4 is selected from linear, branched or cyclic C3 saturated alkyl groups, optionally substituted with a methyl group; m is 1 , 2 or 3; and R ^M is one or more optional substituents on the ring independently selected from

R ^pc when attached to a carbon atom adjacent the phosphorus atom, or

-OH, -OC _1-3 alkyl and R ^pc , when attached to other ring carbons;

R ^pc is selected from the group consisting of

C _1-3 alkyl, optionally substituted with one or more groups R ^PD ; and

oxo;

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

4-membered heterocyclyl or heteroaryl groups containing one or two heteroatoms selected from O and N, optionally substituted with one or two C _1-3 linear saturated alkyl groups,

-F,

-OH, -OMe, -OEt,

-SH, -SMe, -SEt,

-S(=0)H, -S(=0)Me, -S(=0)Et,

-SO2H, -S0 ₂ Me, -S0 ₂ Et,

-CH2OH, -CH ₂ OMe, -CH ₂ OEt,

-CH2SH, -CH ₂ SMe, -CH ₂ SEt,

-CH ₂ S(=0)H, -CH ₂ S(=0)Me, -CH ₂ S(=0)Et,

-CH ₂ S0 ₂ H, -CH ₂ S0 ₂ Me, -CH ₂ S0 ₂ Et,

-C(=0)OH, -C(=0)NH ₂ , -C(=0)NHMe, -C(=0)NMe ₂ ,

-NH ₂ , -NHMe, -NMe ₂ , -NMe ₃ ⁺ ,

-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me;

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

F,

OH and OC _1-3 alkyl;

R ^PE is selected from

methyl and oxo; R ^Au is selected from the groups (B1 ) to (B3):

wherein:

R ^NA is selected from the group consisting of

H;

linear or branched C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl,

C _4-6 heterocycloalkyl or heteroaryl, C _5-6 cycloalkenyl and C _5-6 heterocycloalkenyl optionally substituted with one or more groups R ^AL , and

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

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, R ^A1 , R ^A2 ,

-C(=0)N(R ^N1 )2, wherein 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; and

phenyl optionally substituted with one or more groups R ^A1 ,

-L ^s - and -L ^c - are each independently selected from

methylene or ethylene, optionally substituted with one or two groups R ^1A1 , and a single bond;

R ^SA is selected from the group consisting of

(i) C _5-6 cycloalkyi, heterocyclyl, aryl or heteroaryl groups and 8- to 10- membered bicyclyl or heterobicydyl groups, optionally substituted with one or more groups R ^A1 ; and

(ii) the groups (C1 ) to (C3)

wherein

E ^A is selected from the group consisting of: -0-R ^A2 ; -NH-R ^A2 ; -NR ^A ¾

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, R ^EB is absent, otherwise R ^EB 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 -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 ; when E ^B is E ^BA , R ^E1 and E ^BA 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 R ^AL , and

5- or 6-membered heteroaryl optionally substituted with one or more groups R ^A1 ;

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,

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; 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 , -

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 - 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 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, -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; when E ^D1 is Pro, R ^ED is absent, otherwise R ^ED is R ^E1 ;

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 ,

wherein R ^CAA is selected from the group consisting of

linear or branched C _{1 -6} alkyl, substituted with one or more groups R ^AL ,

C _3-6 cycloalkyl, aryl or heteroaryl, optionally substituted with one or more groups selected from V ^C1 , -CH ₂ V ^C1 , oxo, R ^AL , R ^A1 and R ^A2 ; wherein V ^C1 is a C _4-6 cycloalkyl or heterocyclyl group optionally substituted with one or more groups selected from oxo and R ^A1 ;

8- to 10-membered bicyclyl and biheterocyclyl, optionally substituted with one or more groups R ^A1 , when L ^c is methylene or ethylene, R ^CA is selected from R ^CAA and R ^CAB , wherein R ^CAB is selected from

C _2-6 alkenyl and C _2-6 alkynyl, optionally substituted with one or more groups R ^AL , or

C6 heterocyclyl attached to L ^c via a ring N atom, optionally substituted with one or more groups R ^A1 ; wherein R ^A1 is selected from the group consisting of

linear or branched C _{1 -6} alkyl, C _2-6 alkenyl or C _2-6 alkynyl optionally substituted with one or more groups R ^AL , wherein the alkyl chain is optionally interrupted by one or more atoms selected from O and S,

R ^A2 is selected from the group consisting of

linear or branched C _{1 -6} alkyl, C _2-6 alkenyl or C _2-6 alkynyl optionally substituted with one or more groups R ^AT , wherein the alkyl chain is optionally interrupted by one or more atoms selected from O and S,

OC _{1 -6} alkyl; C _3-6 cycloalkyl, C _4-6 heterocycloalkyl, C _5-6 cycloalkenyl or Cs-eheterocycloalkenyl optionally substituted with one or more groups R ^AT ,

phenyl optionally substituted with one or more groups R ^AR , and

C5-ioheteroaryl optionally substituted with one or more groups R ^AR ;

where 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

linear or branched C _{1 -6} alkyl optionally substituted with one or more groups R ^AT ;

R ^AR is selected from the group consisting of

linear or branched C _{1 -6} alkyl, C _2-6 alkenyl or C _2-6 alkynyl optionally substituted with one or more groups R ^AT ,

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 ,

-S0 ₂ NH ₂ , -S0 ₂ NH(C _1-3 alkyl) ₂ , -S0 ₂ N(C _1-3 alkyl) ₂ , -S0 ₂ (C _1-3 alkyl),

-NHCOH, -NHCO(C _1-3 alkyl), -N(C _1-3 alkyl)COH and -N(C _1-3 alkyl)CO(C _1-3 alkyl);

R ^1A1 is a linear or branched unsubstituted C _{1 -6} alkyl group.

In some embodiments,

R ^P3 is selected from the group consisting of:

(i) -CH ₂ R ^P6 , -CH ₂ CH ₂ R ^P6 , -CHMeR ^P6 , -C(Me) ₂ R ^P6 , -CH(R ^P6 ) ₂ , -CMe(R ^P6 ) ₂ , -

C(C ₃ -4cycloalkyl)R ^P6 , -C(=NH)R ^P6 , -CH ₂ C(=NH)R ^P6 , sec-butyl, 1 -propynyl, -COOH,

(ii) C ₃ -4 unsubstituted linear saturated alkyl,

(iii) C ₃ -4 saturated cycloalkyl, optionally substituted with one C _1-3 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 C _1-3 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 C _1-3 linear saturated alkyl groups,

and 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 or two C _1-3 linear saturated alkyl groups,

-OH, -OMe, -OEt,

-SH, -SMe, -SEt,

-S(=0)H, -S(=0)Me, -S(=0)Et,

-S0 ₂ H, -S0 ₂ Me, -S0 ₂ Et,

-CH ₂ OH, -CH ₂ OMe, -CH ₂ OEt,

-CH ₂ SH, -CH ₂ SMe, -CH ₂ SEt,

-CH ₂ S(=0)H, -CH ₂ S(=0)Me, -CH ₂ S(=0)Et,

-CH ₂ S0 ₂ H, -CH ₂ S0 ₂ Me, -CH ₂ S0 ₂ Et,

-C(=0)OH, -C(=0)NH ₂ , -C(=0)NHMe, -C(=0)NMe ₂ ,

-NH ₂ , -NHMe, -NMe ₂ , -NMe ₃ ⁺ ,

-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):

wherein P ^x is as defined elsewhere herein.

Another aspect of the invention provides a complex of formula VIII:

wherein 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.

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 (E ^S -SH, E ^SE -SeH or E ^N -NH respectively) with the gold atom of the gold(l) phosphine (P ^Y =Au) at a thiol or selenol group on the endogenous ligand or protein. As a result, -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).

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:

with a nitrogen containing derivative of general formula (Ι'):

wherein P ^x is as defined herein and R ^Au 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:

with a chloro(trialkyl phosphine) gold(l) complex of general formula

wherein P ^x is as defined herein and R ^Au 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:

with a chloro(trialkyl phosphine) gold(l) complex of general formula II:

wherein 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.

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 m ² ; in other embodiments the area of biofilm compared is 10 ^"5 m ² , 10 ^"4 m ² , or 10 ^"3 m ² . 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. 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. Examples of saturated alkyl groups include, but are not limited to, methyl (Ci), ethyl (C2), propyl (C3), butyl (C ₄ ), 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 (C ₄ ), n-pentyl (C5) and n-hexyl {Ce). Examples of 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: The term "C ₂ -6 alkenyl" as used herein, pertains to a C _2-6 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=CH ₂ ) and isopropenyl (1 -methylvinyl, -C(CH ₃ )=CH ₂ ). 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. Examples of C _3-6 cycloalkyl 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

Examples of monocyclic heterocycloalkyl groups include, but are not limited to, those derived from:

Ni : azetidine (C ₄ ), 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 (C ₄ ), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane

(tetrahydropyran) {Ce), dihydropyran {Ce), pyran {Ce); Si: thiirane (C3), thietane (C ₄ ), thiolane (tetrahydrothiophene) (C5), thiane

(tetrahydrothiopyran) {Ce);

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),

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). 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: 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 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.

Examples of 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 ).

Further embodiments

In some embodiments, P ^x is (P1 ).

In some embodiments, R ^P1 is methyl. In other embodiments, R ^P1 is ethyl. In some embodiments, R ^P1 is -CH ₂ OMe.

In some embodiments, 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.

In some embodiments, both R ^P1 and R ^P2 are methyl and R ^P3 is selected from the group consisting of:

(i) -CH ₂ R ^P6 , -CH ₂ CH ₂ R ^P6 , -CHMeR ^P6 , -C(Me) ₂ R ^P6 , -CH(R ^P6 ) ₂ , -CMe(R ^P6 ) ₂ , -C(C ₃ -4cycloalkyl)R ^P6 , -C(=NH)R ^P6 , -CH ₂ C(=NH)R ^P6 , 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 C _1-3 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 C _1-3 linear saturated alkyl groups.

In some embodiments, both R ^P1 and R ^P2 are methyl and R ^P3 is selected from the group consisting of:

-CH ₂ R ^P6 ,

C3 unsubstituted linear saturated alkyl, 4-membered heterocyclyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C _1-3 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 C _1-3 linear saturated alkyl groups.

In some embodiments, R ^P3 is selected from -CH ₂ R ^P6 , -CH ₂ CH ₂ R ^P6 , -CHMeR ^P6 ,

-C(Me) ₂ R ^P6 , -CH(R ^P6 ) ₂ , -CMe(R ^P6 ) ₂ , -C(C ₃ - ₄ cycloalkyl)R ^P6 , -C(=NH)R ^P6 and

-CH ₂ C(=NH)R ^P6 .

In some embodiments, R ^P3 is -COOH.

In some embodiments, R ^P3 is selected from sec-butyl and 1-propynyl.

In some embodiments, R ^P3 is trimethylsilyl(ethynyl).

In some embodiments, each R ^P6 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 C _1-3 linear saturated alkyl groups,

-F,

-OH, -OMe, -OEt,

-CH ₂ OH,

-C(=0)NH ₂ , -C(=0)NHMe, -C(=0)NMe ₂ ,

-NH ₂ , -NHMe, -NMe ₂ , -NMe ₃ ⁺ ,

-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.

In some embodiments, each R ^P6 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 C _1-3 linear saturated alkyl groups,

-OH, -OMe, -OEt,

-CH ₂ OH,

-C(=0)NH ₂ , -C(=0)NHMe, -C(=0)NMe ₂ ,

-NH ₂ , -NHMe, -NMe ₂ , -NMe ₃ ⁺ , -NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.

In some embodiments, each R ^P6 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 C _1-3 linear saturated alkyl groups,

-F,

-OH, -OMe, -OEt,

-CH2OH,

-C(=0)NH ₂ , -C(=0)NHMe, -C(=0)NMe ₂ ,

-NH2, -NHMe, -NMe ₂ , -NMe ₃ ⁺ ,

-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.

In some embodiments, each R ^P6 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 C _1-3 linear saturated alkyl groups,

-F,

-OH, -OMe, -OEt,

-CH2OH,

-C(=0)NH ₂ , -C(=0)NHMe, -C(=0)NMe ₂ ,

-NH ₂ , -NHMe, -NMe ₂ , -NMe ₃ ⁺ ,

-NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, R ^P6 is F. In some embodiments, each R ^P6 group is independently selected from -OH, -OMe and -OEt. In some embodiments, each R ^P6 group is independently selected from -SH, -SMe and -SEt. In some embodiments, each R ^P6 group is independently selected from -S(=0)H, -S(=0)Me and -S(=0)Et. In some embodiments, each R ^P6 group is independently selected from -S0 ₂ H, -S0 ₂ Me and -S0 ₂ Et. In some embodiments, each R ^P6 group is independently selected from -CH2OH, -ChbOMe and -ChbOEt. In some embodiments, each R ^P6 group is independently selected from - CH2OH and -CH ₂ OMe. In some embodiments, each R ^P6 group is independently selected from -CH2SH, -CH ₂ SMe and -CH ₂ SEt. In some embodiments, each R ^P6 group is independently selected from -CH2SH and -CH2SMe. In some embodiments, each R ^P6 group is independently selected from -CH ₂ S(=0)H, -CH ₂ S(=0)Me and -CH ₂ S(=0)Et. In some embodiments, each R ^P6 group is independently selected from -CH2S(=0)H and - CH2S(=0)Me. In some embodiments, 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.

In some embodiments, each R ^P6 group is independently selected from -C(=0)OH, - C(=0)NH ₂ , -C(=0)NHMe and -C(=0)NMe ₂ .

In some embodiments, each R ^P6 group is independently selected from -NH2, -NHMe, - NMe ₂ , -NMe ₃ ⁺ , -NHC(=0)H, -NHC(=0)Me, -NMeC(=0)H and -NMeC(=0)Me. In some embodiments, each R ^P6 group is independently -NH2. In some embodiments, each R ^P6 group is independently -NMe2.

In some embodiments, R ^P6 is not -CH20Me. In some embodiments, R ^P6 is not a 4- membered heteroaryl group.

In some embodiments, R ^P3 is -ChbOMe. In some embodiments, R ^P3 is -CH20Et. In some embodiments, R ^P3 is -CH ₂ C(=0)NH2. In some embodiments, R ^P3 is -CH ₂ NMe2. In some embodiments, R ^P3 is -CH2C(=0)NMe2. In some embodiments, R ^P3 is -CH2OH. In some embodiments, R ^P3 is -CH2CH2OH.

In some embodiments, 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.

In some embodiments, R ^P3 is selected from C3-4 saturated cycloalkyi. In some

embodiments, 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.

In some embodiments, R ^P3 is selected from C3-4 unsubstituted saturated cycloalkyl. In some embodiments, R ^P3 is cyclopropyl. In some embodiments, R ^P3 is cyclobutyl.

In some embodiments, R ^P3 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 C _1-3 linear saturated alkyl group. In some embodiments, 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. In some embodiments, 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. In some embodiments, R ^P3 is selected from azetidyl and oxetanyl, optionally substituted with one or two methyl groups.

In some embodiments, 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.

In some embodiments, R ^P3 is not selected from C ₄ heterocyclyl groups having a single heteroatom.

In some embodiments, 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.

In some embodiments, R ^P3 is not pyridyl. In some embodiments, 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. In some embodiments, 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.

In some embodiments, 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.

In some embodiments, P ^x is selected from the groups:

In some embodiments, P ^x is the group (P2).

In some embodiments, 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.

In some embodiments, R ^P4 is cyclic C3 unsubstituted saturated alkyl. In some

embodiments, 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:

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 (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).

In some embodiments, R ^M is R ^pc . In some embodiments, R ^pc is methyl. In other embodiments, R ^pc is oxo.

In other embodiments, R ^M is OH. In other embodiments, R ^M is OMe.

In some embodiments, R ^PD is F. In some embodiments, R ^PD is OH. In some

embodiments, R ^PD is OMe.

In some embodiments, 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.

In some embodiments, P ^x is selected from the groups:

In some embodiments, P ^x is the group (P3).

In some embodiments, 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.

In some embodiments, 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

unsubstituted cyclic C3-4 saturated alkyl groups. In some embodiments, R ^P5 is cyclopropyl, optionally substituted with a methyl group. In some embodiments, R ^P5 is the group:

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, each of R ^P7 , R ^P8 , R ^P9 and R ^P1 ° are independently H.

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 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 .

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 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 .

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 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:

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 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 . 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:

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 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 . 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 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 . 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 the ring:

In some embodiments, R ^PE is methyl. In other embodiments, R ^PE is oxo.

In some embodiments, P ^x is selected from the groups:

In some embodiments,

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 ,

m is 3 and R ^M is absent,

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; and

R ^P6 and R ^Au are as defined above.

_R Au

In some embodiments, 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 .

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 -CO(C _{1 -6} alkyl) and -S0 ₂ R ^A2 .

In some embodiments R ^NA is unsubstituted linear or branched C _{1 -6} alkyl; and R ^NB is selected from -COR ^A2 and -S0 ₂ R ^A2 .

In some embodiments 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 .

In the above embodiments, R ^AL may be selected from

In the above embodiments, R ^AL may be selected from

In some embodiments 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 .

In some embodiments, 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 .

In some embodiments 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 . In some embodiments 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 . In some embodiments 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 .

In some embodiments 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 .

In some embodiments 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 .

In some embodiments -NR ^NA R ^NB is selected from

NR ^NA R ^NB

In some embodiments, -NR ^NA R ^NB is a 5- or 6-membered heterocycloalkyl or

heterocycloalkenyl group optionally substituted with one or more groups selected from oxo, =NH,

-C(=0)N(R ^N1 ) ₂ , wherein 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 ,

R ^A2 , and

R ^A1 . In some embodiments, -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

oxo, =NH,

-C(=0)N(R ^N1 ) ₂ , wherein 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 ,

R ^A2 , and

R ^A1 .

In some embodiments, -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

phenyl optionally substituted with one or more groups R ^A1 , and

R ^A1 .

In some embodiments, -NR ^NA R ^NB 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 -NR ^NA R ^NB ; 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 R ^A1 , and

R ^A1 .

In some embodiments, -NR ^NA R ^NB 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 -NR ^NA R ^NB ; substituted with one or two oxo groups and optionally further substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl; and

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).

In some embodiments, -NR ^NA R ^NB 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 -NR ^NA R ^NB ; substituted with one or two oxo groups and optionally further substituted with one or more groups selected from

C _1-3 alkyl; and

phenyl optionally substituted with one or more groups selected from F, CI, OH and 0(C _{1 -6} alkyl).

In some embodiments, -NR ^NA R ^NB is the group (A1 )

wherein

X ^N1 is selected from C=0 and CR ^4NA R ^4NB ;

X ^N2 is selected from O, CR ^4NA R ^4NB and NR ^X ; and

one of X ^N3 and X ^N4 is selected from C=0, CR ^4NA R ^4NB and S0 ₂ , with the other group of X ^N3 and X ^N4 being selected from CR ^4NA R ^4NB ;

wherein R ^x is selected from -H and -R ^A5 ;

each R ^4NA and R ^4NB is independently selected from

-H,

linear or branched Ci-4alkyl optionally substituted with one or more groups R ^AL , phenyl, optionally substituted with one or more groups R ^A1 ,

C _5-6 heteroaryl optionally substituted with one or more groups R ^A1 ,

independently geminal R ^4NA and R ^4NB 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 R ^AL , and

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 ;

and R ^A5 is selected from the group consisting of

linear or branched C _{1 -6} alkyl, C _2-6 alkenyl or C _2-6 alkynyl optionally substituted with one or more groups R ^AL ,

C _3-6 cycloalkyl or C4- ₆ heterocycloalkyl optionally substituted with one or more

groups R ^AT , phenyl, optionally substituted with one or more groups R ^A1 ,

C _5-6 heteroaryl optionally substituted with one or more groups R ^A1 , or

except when each of R ^P1 to R ^P3 is selected from ethyl, 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'

In some embodiments, -NR ^NA R ^NB is the group (A2)

wherein

V ^N1 is selected from C=0 and S0 ₂ ;

V ^N2 is selected from O, NR ^X and CR ^4NA R ^4NB ;

with the proviso that when V ^m is SO2, V ^N2 cannot be O;

wherein R ^x , R ^4NA and R ^4NB are as defined above.

In some embodiments, -NR ^NA R ^NB is the group (A4)

wherein

Z ^N1 is selected from C=0 and CR ^4NA R ^4NB ;

Z ^N2 and Z ^N3 are each independently selected from the group consisting of

O,

CR ^4NA R ^4NB , C=0 and

NR ^X ,

with the proviso that any two adjacent groups of Z ^N1 to Z ^N4 cannot both be O, cannot both be C=0 and cannot both be NR ^X ;

Z ^N4 is selected from CR ^4NA R ^4NB , and NR ^X ; and Z ^N5 is selected from C=0 and SO2;

with R ^4NA , R ^4NB and R ^x being as defined above. some embodiments, -NR ^NA R ^NB is the group (A5)

wherein

a dotted line indicates that a bond may be present or absent; and W ¹ to W ⁴ are each independently selected from CH and CR ^A1 .

In some embodiments, -NR ^NA R ^NB is the group (A6)

wherein

W ⁵ to W ⁸ are each independently selected from CH and CR'

In some embodiments, -NR ^NA R ^NB is selected from

In some embodiments, -NR ^NA R ^NB is selected from a 5- or 6-membered heteroaryl group optionally substituted with one or more groups selected from

oxo, =NH,

-C(=0)N(R ^N1 ) ₂ , wherein 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 ,

R ^A2 , and

R ^A1 .

In some embodiments, -NR ^NA R ^NB 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 R ^A1 ,

R ^A2 , and

R ^A1 .

In some embodiments, -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

oxo, =NH,

-C(=0)N(R ^N1 ) ₂ , wherein 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 ,

R ^A2 , and

R ^A1 . In some embodiments, -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

oxo, =NH,

-C(=0)N(R ^N1 ) ₂ , wherein 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 ,

R ^A2 , and

R ^A1 .

In some embodiments, -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 .

In some embodiments, -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

linear, branched or cyclic C _{1 -6} alkyl optionally substituted with one group R ^AL ,

F, CI, Br,

-CN,

-CF ₃ , -CF ₂ H, -CH ₂ F,

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ .

In some embodiments, -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

linear, branched or cyclic C _{1 -6} alkyl optionally substituted with one group R ^AL ,

F, CI, Br,

-CN,

-CF ₃ , -CF ₂ H, -CH ₂ F,

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ . In some embodiments, -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

linear, branched or cyclic C _{1 -6} alkyl optionally substituted with one group R ^AL ,

F, CI, Br,

-CN,

-CF ₃ , -CF ₂ H, -CH ₂ F,

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ .

In some embodiments, -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

linear, branched or cyclic C _{1 -6} alkyl optionally substituted with one group R ^AL ,

F, CI, Br,

-CN,

-CF ₃ , -CF ₂ H, -CH ₂ F,

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ .

In some embodiments, -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 ;

optionally substituted with one or more groups selected from

linear or branched unsubstituted C _{1 -6} alkyl,

F, CI, Br,

-CN

-CF ₃ , -CF ₂ H, -CH ₂ F,

-OH, -0(C _{1 -6} alkyl),

-COOH and -COO(C _{1 -6} alkyl).

In some embodiments, -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 ;

optionally substituted with one or more groups selected from linear or branched unsubstituted C _{1 -6} alkyl,

-CN

-CF ₃ , -CF2H and -CH ₂ F. some embodiments, -NR ^NA R ^NB is the group (A3)

wherein

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:

linear, branched or cyclic C _{1 -6} alkyl optionally substituted with one group R ^AL ,

F, CI, Br,

-CN,

-CFs, -CF2H, -CH2F,

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ .

In some embodiments, R ³ is selected from:

linear, branched or cyclic C _{1 -6} alkyl optionally substituted with one group R ^AL , F,

-CN,

-CFs,

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ .

In some embodiments, 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.

In some embodiments, -NR ^NA R ^NB is the group (A7)

wherein one of Y ^N5 , Y ^N6 and Y ^N7 is 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;

C _{1 -6} linear or branched alkyl, optionally substituted with one or two groups R ^A1 ; C _3-6 unsubstituted cycloalkyl;

-F, -CI, -Br,

-CN,

-CFs, -CF ₂ H, -CH ₂ F,

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ .

In some embodiments, -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:

C _{1 -6} linear or branched alkyl, optionally substituted with one or two groups R ^A1 ; C _3-6 unsubstituted cycloalkyl;

-F, -CI, -Br,

-CN,

-CFs, -CF ₂ H, -CH ₂ F,

-OH, -0( C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ .

In some embodiments, -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:

C _{1 -6} linear or branched unsubstituted alkyl;

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ . In some embodiments, -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:

C _{1 -6} linear or branched unsubstituted alkyl, preferably C _1-3 linear or branched unsubstituted alkyl.

In some embodiments, -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.

In some embodiments, Y ^N6 is CH.

In some embodiments, -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

-H;

C _{1 -6} linear or branched alkyl, optionally substituted with one or two groups R ^A1 ; C _3-6 unsubstituted cycloalkyl;

-F, -CI, -Br,

-CN,

-CFs, -CF ₂ H, -CH ₂ F,

-OH, -0(C _{1 -6} alkyl),

-COOH, -COO(C _{1 -6} alkyl) and -CON(C _{1 -6} alkyl) ₂ . In some embodiments, P ^x is (P1 ); R ^P1 and R ^P2 are each independently selected from methyl and ethyl;

R ^P3 is selected from

methyl, ethyl, n-propyl,

-Q ^A , -CH ₂ Q ^A , -(CH ₂ ) ₂ Q ^A ,

wherein Q ^A is selected from

cyclopropyl,

4- or 5-membered heterocycloalkyi groups containing one or two heteroatoms selected from NR ^Z , O and S, and

4- or 5-membered cycloalkyl groups;

wherein R ^z is selected from the group consisting of

H, C _1-3 alkyl, COCi. ₃ alkyl and S0 ₂ C _1-3 alkyl; and

-NR ^A R ^B is the group (A7),

wherein one of Y ^N5 , Y ^N6 and Y ^N7 is 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;

C _{1 -6} linear or branched alkyl, optionally substituted with one or two groups R ^A1 ; C _3-6 unsubstituted cycloalkyl;

In some embodiments, -NR ^NA R ^NB is selected from

In some embodiments, NR ^NA R ^NB is an imidazolyl group, bearing a C substituent which the group (D1 )

(i.e. ethyl substituted by COR ⁸³ and NR ^B1 R ^B2 ) wherein

R ^B1 is selected from the group consisting of

-H,

-COR ^A2 , -CONR ^A2 , C0 ₂ R ^A2 , and

-S0 ₂ R ^A2 ;

R ^B2 is selected from -H, and linear or branched and

R ^B3 is selected from the group consisting of

-OH, -OR ^A2 ,

-NH ₂ , -NHR ^A2 and -NR ^A2 ₂ . In some embodiments, -NR ^NA R ^NB 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 R ^A1 ,

R ^A2 and

R ^A1 .

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 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.

In some embodiments, -NR ^NA R ^NB is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or two groups selected from

linear or branched C _{1 -6} alkyl optionally substituted with one or more groups R ^AL ,

-OH, -OR ^A2 ,

-CF ₃ , -CN, -NO2,

-COR ^A2 , -COOH, -COOR ^A2 , -CONH2, -CONHR ^A2 , -CONR ^A2 ₂ , and

oxo.

In some embodiments, -NR ^NA R ^NB is selected from an 8- to 10-membered heterobicyclyl group optionally substituted with one or two groups selected from

-COR ^A2 , -COOH, -COOR ^A2 , -CONH ₂ , -CONHR ^A2 , and -CONR ^A2 ₂ .

In some embodiments, -NR ^NA R ^NB is a 9-membered heterobicyclyl group optionally substituted with one or more groups selected from

oxo,

phenyl optionally substituted with one or more groups R ^A1 ,

R ^A2 and

R ^A1 . In some embodiments, -NR ^NA R ^NB 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 R ^A1 ,

R ^A2 and

R ^A1 .

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, -NR ^NA R ^NB is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from

oxo,

linear or branched C _{1 -6} alkyl,

-F, -CI, -Br,

-CN,

-OH, -0(C _{1 -6} alkyl),

-COOH and -COO(C _{1 -6} alkyl). In some embodiments, -NR ^NA R ^NB is a 9-membered 5,6 fused heterobicyclyl group optionally substituted with one or more groups selected from

oxo,

linear or branched C _{1 -6} alkyl,

-OH and -0(C _{1 -6} alkyl).

In some embodiments, -NR ^NA R ^NB is a 10-membered 6,6 fused heterobicyclyl group optionally substituted with one or more groups selected from

oxo, and

R ^A1 .

In some embodiments, -NR ^NA R ^NB is selected from

In some embodiments, both R ^P1 and R ^P2 are methyl, R ^P3 is selected from the group consisting of:

-CH ₂ R ^P6 ,

C3 unsubstituted linear saturated alkyl,

4-membered heterocyclyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C _1-3 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 C _1-3 linear saturated alkyl groups; and

R ^Au is the group (B1 ).

In some embodiments, both R ^P1 and R ^P2 are methyl, R ^P3 is selected from the group consisting of:

-CH ₂ R ^P6 ,

C3 unsubstituted linear saturated alkyl, 4-membered heterocyclyl containing one or two heteroatoms independently selected from O and N, optionally substituted with one C _1-3 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 C _1-3 linear saturated alkyl groups; and

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

oxo, =NH,

-C(=0)N(R ^N1 ) ₂ , wherein 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 ,

R ^A2 , and

R ^A1 .

Particular embodiments of the invention are shown in the examples. In some

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

In some embodiments, -L ^s - is unsubstituted methylene. In other embodiments, -L ^s - is unsubstituted ethylene. In some embodiments, -L ^s - is a single bond.

In some embodiments, -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 .

In some embodiments, R ^1A1 is selected from linear C _1-3 alkyl. In some embodiments, R ^1A1 is methyl. R ^SA

In some embodiments, 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 . In some embodiments, R ^SA is (S1 ):

In some embodiments, one of Y ^S1 , Y ^S2 , Y ^S3 , Y ^S4 and Y ^S9 is N. In some of these embodiments, Y ^S1 is N and Y ^S2 , Y ^S3 , Y ^S4 and Y ^S9 are CH. In others of these

embodiments, Y ^S3 is N and Y ^S1 , Y ^S2 , Y ^S4 and Y ^S9 are CH. In others of these embodiments, Y ^S4 is N and Y ^S1 , Y ^S2 , Y ^S3 and Y ^S9 are CH. In these embodiments, (S1 ) is pyridyl.

In some embodiments, two of Y ^S1 , Y ^S2 , Y ^S3 , Y ^S4 and Y ^S9 are N. In some of these embodiments, Y ^S1 , Y ^S4 and Y ^S9 are CH and Y ^S2 and Y ^S3 are N. In others of these embodiments, Y ^S2 , Y ^S4 and Y ^S9 are CH and Y ^S1 and Y ^S3 are N. In others of these embodiments, Y ^S3 , Y ^S4 and Y ^S9 are CH and Y ^S1 and Y ^S2 are N. In some of these embodiments, Y ^S1 and Y ^S4 are N and Y ^S2 , Y ^S3 and Y ^S9 are CH. In others of these embodiments, 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. In these embodiments, (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. In some embodiments, R ^SA is (S2):

In some of these embodiments, V is O. In other of these embodiments, V is is selected from H and C _1-3

unbranched alkyl. In some of these embodiments, R° ¹ is H. In others of these

embodiments, R° ¹ is C _1-3 unbranched alkyl, e.g. methyl, ethyl, n-propyl.

In other of these embodiments, V is N-C02-R ^C2 , where R ^C2 is either C _1-3 unbranched alkyl or C3-4 branched alkyl. In some of these embodiments, R ^C2 is C _1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl. In others of these embodiments, R ^C2 is C3-4 branched alkyl, i.e. /sopropyl, /sobutyl, sec-butyl and tert-butyl.

In other of these embodiments, 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.

In some of these embodiment, there are no optional methyl substituents (represented by R ^ce ).

In other of these embodiments, there is a single methyl substituent represented by R ^ce . In other of these embodiments, there are two methyl substituents represented by R ^ce .

In some embodiments, R ^SA is (S3):

In some of these embodiments, 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):

In some of these embodiments, R ^C1 is 0-R° ² . R° ² is C _1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl.

In others of these embodiments, 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.

In some of these embodiments, R ^C4 and R ^C5 are both H.

In other of these embodiments, R ^C4 is H and R ^C5 is Me.

In other of these embodiments, R ^C4 and R ^C5 are both Me.

In some embodiments, R ^SA is (S5): In some of these embodiments, R ^C3 is C _1-3 unbranched alkyl, i.e. methyl, ethyl, n-propyl. In others of these embodiments R ^C3 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, 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.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, R ^SA is a 5-membered heteroaromatic group containing up to 4 heteroatoms selected from N.

In some embodiments, R ^SA is unsubstituted tetrazolyl.

In some embodiments, 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 C _1-3 alkyl;

and optionally C-substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl optionally substituted with one or more groups R ^AL .

In some embodiments, 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

methyl and ethyl

and optionally C-substituted with one or more groups selected from

linear or branched C _1-3 alkyl. In some embodiments, 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

In some embodiments, R ^SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl, optionally substituted with one or more groups R ^AL ,

In some embodiments, R ^SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl, optionally substituted with one or more groups R ^AL ,

In some embodiments, R ^SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl, optionally substituted with one or more groups R ^AL ,

In some embodiments, R ^SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl, optionally substituted with one or more groups R ^AL ,

In some embodiments, R ^SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl, optionally substituted with one or more groups R ^AL ,

In some embodiments, R ^SA is selected from 6-membered aromatic carbocyclic groups substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl, optionally substituted with one or more groups R ^AL ,

In some embodiments, R ^SA is selected from 6-membered aromatic carbocyclic groups ortho- and/or mefa-substituted with one or more groups selected from

linear or branched C _{1 -6} alkyl, optionally substituted with one or more groups R ^AL ,

and/or para-substituted with a group selected from

linear or branched C _{1 -6} alkyl, optionally substituted with one or more groups R ^AL ,

In some embodiments, R ^SA is selected from

In some embodiments, 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 .

In some embodiments, R ^SA is selected from 6-membered heteroaryl group containing one nitrogen atom, substituted with one or more groups R ^A1 .

In some embodiments, 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

linear or branched C _1-6 alkyl,

In some embodiments, 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

linear or branched C _{1 -6} alkyl,

In some embodiments, 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

linear or branched C _{1 -6} alkyl,

In some embodiments, 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

linear or branched C _{1 -6} alkyl,

-CH ₂ OH, -CH ₂ 0(C _1-3 alkyl),

-COOH, -COO(C _1-3 alkyl), -CONH ₂ , -CONH(C _1-3 alkyl), -CON(C _1-3 alkyl) ₂ ,

-OCO(C _1-3 alkyl), -OCONH ₂ , -OCONH(C _1-3 alkyl), -OCON(C _1-3 alkyl) ₂ ,

-NH ₂ , -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ ,

-NHCOH, -NHCO(C _1-3 alkyl), -N(C _1-3 alkyl)COH and -N(C _1-3 alkyl)CO(C _1-3 alkyl).

In some embodiments, 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

linear or branched C _{1 -6} alkyl,

-F. -CI,

-OH, -0(C _1-3 alkyl),

-CF ₃ ,

-CO(C _1-3 alkyl),

-CH ₂ OH, -CH ₂ 0(C _1-3 alkyl),

-COOH, -COO(C _1-3 alkyl), -CONH ₂ , -CONH(C _1-3 alkyl), -CON(C _1-3 alkyl) ₂ ,

-NH ₂ , -NH(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ ,

-NHCOH, -NHCO(C _1-3 alkyl) and -N(C _1-3 alkyl)COH.

In some embodiments, 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

methyl,

-F. -CI,

-OH, -OMe,

-CF ₃ ,

-COMe,

-CH ₂ OH, -CH ₂ OMe,

-COOH, -COOMe, -CONH ₂ , -CONHMe, -CONMe ₂ ,

-NH ₂ , -NHMe, -NMe ₂ ,

-NHCOH, -NHCOMe and -NMeCOH.

In some embodiments, 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

methyl, -F. -CI,

-OH, -OMe,

-CF ₃ ,

-COMe,

-CH2OH, -CH ₂ OMe,

-COOH and -COOMe,

In some embodiments, 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

-COOH, -CON(C _{1 -6} alkyl) ₂ , -COO(C _{1 -6} alkyl),

-CONH2, and

-CFs.

In some embodiments, 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

-COOH, -CON(Me) ₂ , -COO(Me),

-CONH2, and

-CFs.

In some embodiments, 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

-COOH, -CON(Me) ₂ , -COO(Me), and -CONH ₂ .

In some embodiments, R ^SA 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 -CONH ₂ .

In some embodiments, 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

-CONH ₂ , and

-CF ₃ . In some embodiments R ^SA is selected from

In some embodiments, 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.

In some embodiments, R ^SA 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, R ^SA is selected from 8- to 10-membered heterobicyclyl groups containing one or two heteroatoms independently selected from N and O.

In some embodiments, 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.

In some embodiments, the heterobicyclyl group is a heteroaromatic group.

In some embodiments, 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 .

In some embodiments, R ^SA is selected from

In some embodiments, R ^SA is the group

wherein

Z ^S3 is selected from the group consisting of CH ₂ , CHF and CF2;

one of Z ^S1 , Z ^S2 , Z ^S4 and Z ^S5 is selected from the group consisting of

the remainder of Z ^S1 , Z ^S2 , Z ^S4 and Z ^S5 are independently selected from the group consisting of

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 Z ^S1 or Z ^S5 is N, L ^s cannot be a single bond.

In some embodiments, 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

CH ₂ , CHR ^AL and CR ^AL ₂ ; and

the remainder of Z ^S1 , Z ^S2 , Z ^S4 and Z ^S5 are CH2.

In some embodiments, Z ^S3 is selected from the group consisting of CH2, CHF and CF2; and

the remainder of Z ^S1 , Z ^S2 , Z ^S4 and Z ^S5 are CH2. In some embodiments, R ^SA is

In some embodiments, R ^SA is the grou

wherein

one of Q ¹ to Q ⁴ is selected from the group consisting of

O,

NH, NR ^A2 ,

CH ₂ , CHR ^AL , CR ^AL 2,

N-CO-R ^A2 , N-CO-NHR ^A2 , N-S0 ₂ -R ^A2 and N-C0 ₂ -R ^M ; and

the remainder of Q ¹ to Q ⁴ are independently selected from the group consisting of

CH ₂ , CHR ^AL and CR ^AL 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 Q ¹ or Q ⁴ is N, L ^s cannot be a single bond.

In some embodiments, one of Q ¹ to Q ⁴ is selected from the group consisting of

O,

NH, NR ^A2 ,

CH ₂ , CHR ^AL and CR ^AL ₂ ; and

the remainder of Q ¹ to Q ⁴ are independently selected from the group consisting of

CH ₂ , CHR ^AL and CR ^AL ₂ .

In some embodiments, one of Q ¹ to Q ⁴ is selected from the group consisting of

CH ₂ , CHR ^AL and CR ^AL ₂ ; and

the remainder of Q ¹ to Q ⁴ are CH ₂ .

In some embodiments, R ^SA is the grou (C1 )

wherein

E ^A is selected from the group consisting of

wherein 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;

the amino acid residues Asp and Glu may form amide bonds from either the alpha or pendent carboxylic acid functionality;

when E ^A1 is Pro, R ^EA1 is absent, otherwise R ^EA1 is R ^E1 ;

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 ; and

R ^E1 is selected from H and linear or branched C _1-3 alkyl.

In some embodiments, E ^A is selected from the group consisting of

In some embodiments, E ^A is selected from -NR ^EA1 -E ^A1 -COR ^EA2 .

In some embodiments, E ^A is selected from the group consisting of

In some embodiments, R ^EA2 is selected from -OR ^E7 .

In some embodiments, R ^EA2 is selected from -IMH2, -NHR ^A2 and -NR ^A2 R ^E1 .

In some embodiments, R ^EA2 is selected from -NH ₂ . In some embodiments, 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),

-NH-(C _1-3 alkyl), and

-N(C _1-3 alkyl) ₂ .

In some embodiments, L ^s is methylene and E ^A is selected from the group consisting of -NH-(C _1-3 alkyl), and

-N(C _1-3 alkyl) ₂ .

In some embodiments, L ^s is methylene and E ^A is selected from the group consisting of -NH-CH ₃ , and

-N(CH ₃ ) ₂ .

In me embodiments, R ^SA is

In some embodiments, R ^SA is selected from the roup (C2)

wherein

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 ,

wherein 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;

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 -H;

when E ^B3 is Pro, R ^EB is absent, otherwise R ^EB 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, -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; and

when E ^B is E ^BA , R ^E1 and E ^BA 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 R ^AL , and

5- or 6-membered saturated heteroaryl optionally substituted with one or more groups R ^A1 .

In some embodiments, E ^B is selected from E ^BA .

In some embodiments, E ^B is selected from

-CO-E ^B1 -NR ^EA R ^E2 , and

-CO-E ^B2 -E ^B3 -N R ^EB R ^E2 . In some embodiments, E ^B is -CO-E ^B1 -NR ^EA R ^E2 .

In some embodiments, R ^E2 is -H.

In some embodiments, R ^E2 is -COCH3.

In some embodiments of the group (C2), R ^E1 is -H. In some embodiments of the group (C2), R ^E1 is methyl. In some embodiments, R ^SA is the group (C3)

wherein

R ^E1 is selected from H and linear or branched C _1-3 alkyl;

E ^c is selected from

-OH,

-OR ^A2

-IMH2, NHR ^A2 , NR ^A2 2 and

. _{N R} ECI. _E CI. _CO REC2

wherein 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;

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 ;

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;

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

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 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, -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;

when E ^D1 is Pro, R ^ED is absent, otherwise R ^ED is -H; and

with the proviso that R ^A is not L-cysteine.

In some embodiments, E ^c is selected from

E ^D is selected from

In some embodiments, E ^c is selected from

E ^D is selected from

In some embodiments, E ^c is selected from E ^D is -CO-E ^D1 -NR ^ED R ^E6 .

In some embodiments, E ^c is -NR ^EC1 -E ^c1 -COR ^EC2 ; and

E ^D is -CO-E ^D1 -NR ^ED R ^E6 .

In some embodiments, 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

In some embodiments, R ^SA is the grou (C4)

wherein

Z ⁶ is selected from N-CO-R ^A2 and N-CO-NHR ^A2 ; and

R ^Z6 is one or two optional methyl substituents.

Particular embodiments of the invention are shown in the examples.

In some embodiments, R ^Au is the group (B3), i.e. the group -C≡C-L ^C -R ^CA . L ^c

In some embodiments, -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 .

In some embodiments, R ^1A1 is selected from C _1-3 linear unsubstituted alkyl. In some embodiments, R ^1A1 is methyl.

_R CA

In some embodiments, -L ^c - is a single bond and R ^CA is R ^CAA .

In some embodiments, -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 . ftCAA

In some embodiments, R ^CAA is selected from linear or branched C _{1 -6} alkyl, substituted with one or more groups R ^AL .

In some embodiments, R ^CAA is methyl, substituted with one or more groups R ^AL .

In some embodiments, R ^CAA is methyl, substituted with -NR ^A2 2. In some embodiments, R ^CAA is methyl, substituted with -N(C _{1 -6} alkyl) ₂ .

In some embodiments, R ^CAA is methyl, substituted with one or more groups R ^AL , wherein R ^AL is selected from

In some embodiments, R ^CAA is methyl, substituted with one or more groups R ^AL , wherein R ^AL is selected from

-F,

In some embodiments, 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 .

In some embodiments, R ^CAA is selected from:

In certain embodiments, R ^CAA is the roup (D1 )

(i.e. ethyl substituted by COR ⁶³ and NR ^B1 R ^B2 ) wherein

R ^B1 is selected from the group consisting of

R ^B2 is selected from -H, and linear or branched Ci-4alkyl; and

R ^B3 is selected from the group consisting of

In some embodiments, L ^c is a single bond and R ^CAA is

In some embodiments, R ^CAA is C3-5cycloalkyl, optionally substituted with one or more groups R ^AL . In these embodiments, R ^AL may be selected from

In some embodiments, R ^CAA is selected from 8- to 10-membered bicyclyl and biheterocyclyl, optionally substituted with one or more groups R ^A1 .

In some embodiments, R ^CAA is 9-membered biheterocyclyl including two or more heteroatoms selected from N and O.

In some embodiments, R ^CAA is selected from

In some embodiments, 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 .

In some embodiments, 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.

In some embodiments, 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 .

In some embodiments, 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.

In some embodiments, R ^CAA is selected from

In some embodiments, 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. In some embodiments, R ^CAA is -COOH.

In some embodiments, 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.

In some embodiments, R ^CAA is -CONH2.

In some embodiments, 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.

In some embodiments, R ^CAA is selected from -CONR ^A2 2, where R ^A2 may be as expressed above.

In some embodiments, R ^CAA is selected from

In some embodiments, R ^CAA is selected from

In some embodiments, R ^CAA is the group (D5)

wherein V ⁶ is selected from the group consisting of CH and CR ^A2 ;

two of V ¹ to V ⁵ are independently selected from the group consisting of

two further groups of V ¹ to V ⁵ are independently selected from the group consisting of

with the remaining group of V to V ⁵ being selected from the group consisting of

wherein R ^A6 is selected from the group consisting of

provided that 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 .

In some embodiments, 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 . In some embodiments, 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 .

In some embodiments, 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 .

In some embodiments R ^CAA is selected from

In some embodiments L-R ^A is selected from:

In some embodiments, R ^CAA is the group (D6)

wherein

a first group from X ¹ to X ⁵ is selected from the group consisting of

CH, CR ^A1 , and

CY, wherein Y is selected from one of the groups (D7) to (D9);

wherein 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;

two of V ⁷ to V ¹¹ are independently selected from the group consisting of

two further groups of V ⁷ to V ¹¹ are independently selected from the group consisting of

with the remaining group of V ⁷ to V ¹¹ being selected from the group consisting of

provided that 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

with the remaining group of Y ² to Y ⁵ being selected from the group consisting of

provided that 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

CH ₂ , CHR ^1A1 and CR ^1A1 ₂ ;

when 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;

wherein 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

CH, and CR ^A1 ;

and the remainder of X ¹ to X ⁵ are each independently selected from the group consisting of

N and CH;

with the proviso that X ¹ and X ⁵ are not C-CN.

In some embodiments, R ^CAB is selected from

C _2-6 alkenyl and C _2-6 alkynyl, optionally substituted with one or more groups R ^AL , or the group (D5) wherein V ⁶ is N and three of V ¹ to V ⁵ are independently selected from CH2, CHR ^A1 and CR ^A1 2, with the remaining two groups being independently selected from

provided that neither 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.

In some embodiments, 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. In these embodiments therefore R ^AA is selected from pyridyl and diazinyls (e.g. pyrazinyl, pyrimidnyl and pyridazinyl).

In some embodiments, 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 .

In some embodiments, 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,

In some embodiments, 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,

In some embodiments, 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

In some embodiments, 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

In some embodiments, 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

-F, -CN

-OH and -OR ^A2 .

In some embodiments, 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 CY, wherein Y is the group (D7)

wherein L ^v is methylene or a single bond; V ⁷ , V ⁸ , V ⁹ and V ¹⁰ are each independently selected from CH ₂ and CHR ^1A1 ; V ⁹ is selected from O, NH, NR ^1A1 and S0 ₂ ; and V ¹² is selected from CH and N.

In some embodiments, 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 CY, wherein Y is the group (D7); wherein L ^v is methylene or a single bond; V ⁷ , V ⁸ , V ⁹ and V ¹⁰ are each independently selected from CH ₂ and _{C H R} IAI . _V 9 _is selected from O, NH, NR ^1A1 and S0 ₂ ; and V ¹² is N.

In some embodiments, 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 CY, wherein Y is the group (D8)

wherein L ^v is methylene or a single bond; Y ² , Y ³ , Y ⁴ and Y ⁵ are each independently selected from CH ₂ and CHR ^1A1 ; and Y ¹ is selected from CH and N.

In some embodiments, 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 CY, wherein Y is the group (D8); wherein L ^v is methylene or a single bond; Y ² , Y ³ , Y ⁴ and Y ⁵ are each independently selected from CH2 and CHR ^1A1 ; and Y ¹ is N.

In some embodiments, 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 CY, wherein Y is the group (D9)

wherein L ^v is methylene or a single bond; one of Z ² , Z ³ , and Z ⁴ is NR ^A7 , and the other two of Z ² , Z ³ , and Z ⁴ are each independently selected from CH ₂ and CHR ^1A1 ; and Z ¹ is selected from CH and N. In some embodiments, 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 CY, wherein Y is the group (D9); wherein L ^v is methylene or a single bond; Z ² , Z ³ , and Z ⁴ are each independently selected from CH ₂ and CHR ^1A1 ; and Z ¹ is N. In the above embodiments where one of X ¹ , X ² , X ³ , X ⁴ and X ⁵ is CY, R ^1A1 may be methyl.

In some embodiments, R ^CAA is the group (D6) wherein a first group from X ¹ to X ⁵ is selected from the group consisting of

CH, CR ^A1 , and

CY, wherein Y is selected from one of the groups (D7) to (D9);

a second and third group from X ¹ to X ⁵ is selected from the group consisting of

CH, and CR ^A1 ;

and the remainder of X ¹ to X ⁵ are each N.

In some embodiments, R ^CAA is the group (D6) wherein a first group from X ¹ to X ⁵ is selected from the group consisting of

CH and CR ^A1 ,

a second and third group from X ¹ to X ⁵ is CH;

a fourth group from X ¹ to X ⁵ is N;

and the final group from X ¹ to X ⁵ is selected from CH and N.

In some embodiments, R ^CAA is the group (D6) wherein a first group from X ¹ to X ⁵ is selected from the group consisting of

CH and CR ^A1 , wherein R ^A1 is selected from -COOH, -COOR ^A2 , -CONH ₂ ,

-CONHR ^A2 and -CONR ^A2 ₂ ;

a second and third group from X ¹ to X ⁵ is CH;

a fourth group from X ¹ to X ⁵ is N;

and the final group from X ¹ to X ⁵ is selected from CH and N.

In some embodiments, R ^CAA is phenyl, optionally mono- or di-substituted with groups independently selected from

and

In some embodiments, R ^CAA is phenyl, optionally mono- or di-substituted with groups independently selected from

In some embodiments, R ^CAA is phenyl, optionally mono- or di-substituted with groups independently selected from

-OMe,

-COOH,

In some embodiments, R ^CAA is phenyl, optionally mono-substituted with

independently selected from

-OMe,

-COOH,

In some embodiments, R ^CAA is unsubstituted phenyl. In some embodiments, R ^CAA is selected from

In some embodiments, L-R ^CAA is selected from

In some embodiments, the compounds according to formula (I) is selected from:

In some embodiments, the compounds according to formula (II) is selected from:

Bacterial infections

Bacteria that cause infection of humans include, but are not limited to, those set out below in Table 1 .

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) 2 ^nd generation Cephlasporins: Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime;

(g) 3 ^rd generation Cephlasporins: Cefixime, Cefdinir, Cefditoren, Cefoperazone,

Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone;

(h) 4 ^th generation Cephlasporins: Cefepime;

(i) 5 ^th 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:

which comprises reacting a compound of general formula I':

with chloro(trialkyl phosphine) gold(l) complexes of general formula II:

The invention also provides a process for the preparation of a compound of formula IB:

which comprises reacting a compound of general formula III, IV, V, VI or IX:

with a chloro(trialkyl phosphine) gold(l) complex of general formula II:

The invention also provides a process for the preparation of a compound of formula IC:

comprising reacting a compound of general formula X or XI:

with a chloro(trialkyl phosphine) gold(l) complex of general formula II:

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.

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 ¹ H, ² H (D), and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; O may be in any isotopic form, including ¹⁶ 0 and ¹⁸ 0; Au may be in any isotopic forms, including ¹⁹⁷ Au and ¹⁹⁵ Au; S may be in any isotopic forms, including ³² S, ³³ S, ³⁴ S and ³⁶ S; P may be in any isotopic forms, including ³¹ P, ³³ P and ³² P; 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:

, 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'):

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 Ca ²⁺ and Mg ²⁺ , 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 ⁺ , NR ₄ ⁺ ). 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. ¹ H NMR spectra are reported in ppm and referenced to either tetramethylsilane (0.00 ppm), DMSO-d6 (2.50 ppm), CDCI ₃ (7.26 ppm) or CD ₃ OD (3.31 ppm). ³¹ P 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

Et ₂ 0 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)

MgS0 ₄ 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

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 Et ₂ 0 (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, CDCI ₃ ): 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). ³¹ P-NMR (162 MHz, CDCI ₃ ): δ ppm -29.34 (dm, J = 357.2 Hz).

Dimethylpropylphosphine gold (I) chloride 1-4

(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 MgS0 ₄ and filtered. Concentration in vacuo gave a mixture of the starting material and product (-1 :1 by ¹ H 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 MgS0 ₄ 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 MgS0 ₄ 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). ³¹ P-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

(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%). ¹ H-NMR (400 MHz, CDCI ₃ ): 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). ³¹ P-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%). ¹ H-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). ³¹ P-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 MgS0 ₄ 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 MgS0 ₄ 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%). ¹ H-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). ³¹ P-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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm -0.03 (s).

1-(Dimethylphosphino)-N,N-dimethylmethanamine gold(l) chloride 1-14

(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 Et ₂ 0 (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 Et ₂ 0 (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 Et ₂ 0 (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 Et ₂ 0 (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 Et ₂ 0 (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

(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 MgS0 ₄ 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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm -1.56 (s).

Dimethyl(oxetan-3-yl)phosphine gold(l) chloride 1-18

(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 %). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm 8.43 (s).

Dimethyl-(2-pyridyl)-phosphine gold(l) chloride 1-20

(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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm 6.47 (s).

Dimethyl-(2,6-pyrimidyl)-phosphine gold(l) chloride 1-22

(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 MgS0 ₄ 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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm 8.49 (s).

Ethyldimethyphosphine gold(l) chloride 1-24

(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, CDCI ₃ ): 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). ³¹ P-NMR (162 MHz, CDCIs): δ ppm 4.07 (s). 4-Methyl-[1 ,4]oxaphosphinane gold (I) chloride 1-27

(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%). ¹ H-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

(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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm 18.48 (s).

Diethylmethylphosphine gold(l) chloride 1-32

(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 (MgS0 ₄ ), 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%). ¹ H-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. ³¹ P-NMR (162 MHz, DMSO-d ₆ ): δ ppm 20.58 (s).

1 -Methylphospholane gold (I) chloride 1-35

(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 MgS0 ₄ . 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%). ¹ H-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). ³¹ P- NMR (162 MHz, CDCIs): δ ppm 1 1 .82 (s).

Tert-butyldimethylphosphine gold(l) chloride 1-37

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, CDCI ₃ ): δ ppm 1.51 (6H, dd, J = 10.5, 1 .8 Hz), 1.22 (9H, dd, J = 16.49, 1.4 Hz). ³¹ P-NMR (162 MHz, CDCI3): δ ppm 25.2 (s).

1-(Dimethylphosphino)-N,N,N-trimethylmethanaminium iodide gold(l) chloride 1-38

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%). ¹ H- 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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm 1 .02 (s). (2-(Dimethylamino)ethyl)dimethylphosphine gold(l) chloride 1-42

(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 NH ₃ /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%). ¹ H-NMR (400 MHz, CDCI ₃ ): 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-carboxyl ic acid methyl ester 1-45

(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. NH ₄ CI (sat., 30 mL), aq. NaHCOs (sat., 30 mL) and brine (sat., 30 mL). The organic phase was dried over MgS0 ₄ 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-carbamoy l)-2-mercapto- ethylcarbamoyl]-butyric acid ethyl ester 1-48

(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 ¹ H-NMR (CD ₃ OD). 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

(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%). ¹ H-NMR (400 MHz, DMSO-d6): δ ppm 2.10 (3H, d, J = 4.1 Hz), 1 .86 (6H, d, J = 1 1 .9 Hz). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm -24.33 (s).

Dimethyl((trimethylsilyl)ethynyl)phosphine gold(l) chloride 1-52

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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm -24.24 (s).

Cyclopropyldimethylphosphine g id(l) chloride 1-54

(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 MgS0 ₄ 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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm 22.05 (s).

2-(Dimethylphosphineyl)oxazole gold(l) chloride 1-55

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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm -4.63 (s).

(Fluoromethyl)dimethylphosphlne gold(l) chloride 1-58

(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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm 2.42 (d, J = 50.5 Hz). ¹⁹ F-NMR (376 MHz, DMSO-d6): δ ppm -240.26 (dt, J = 52.0, 47.7 Hz).

1 -Methylphosphetane gold(l) chloride 1-62

(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, CDCI ₃ ): δ ppm 2.86-2.57 (4H, m), 2.32-2.21 (2H, m), 1.95 (3H, d, J =

I I .9 Hz). ³¹ P-NMR (162 MHz, CDCI ₃ ): δ ppm 31 .68 (s).

1 -Ethylphosphetane gold(l) chloride 1-65

(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 Na2S0 ₄ 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, CDCI ₃ ): δ ppm 2.94-2.46 (4H, m), 2.42-2.12 (4H, m), 1.28 (3H, dt, J = 20.7, 7.7 Hz). ³¹ P-NMR (162 MHz, CDCI3): δ ppm 45.76 (s).

1 -Cyclopropylphosphetane gold(l) chloride 1-69

(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 Et ₂ 0 (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 ¹ H-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%). ¹ H-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). ³¹ P-NMR (162 MHz, CDCI3): δ ppm 61.39 (s).

1 -Isopropylphosphetane gold(l) chloride 1-72

(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%). ¹ H-NMR (400 MHz, CDCI ₃ ): δ ppm 2.76 (1 H, m), 2.69-2.20 (6H, m), 1 .25 (6H, dd, J = 19.5, 7.1 Hz). ³¹ P-NMR (162 MHz, CDC ): δ ppm 58.13 (s).

1 ,3-Dimethylphosphetane gold(l) chloride 1-74

(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. ¹ H-NMR (400 MHz, CDCI ₃ ): 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

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%). ¹ H-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

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%). ¹ H-NMR (400 MHz, CDCI ₃ ): 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, CDCI ₃ ): δ ppm 41.01 (s).

Diisopropyl(methyl)phosphine gold(l) chloride 1-79

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%). ¹ H-NMR (400 MHz, CDCI ₃ ): 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

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%). ¹ H- 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

(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 MgS0 ₄ . 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%). ¹ H-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

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 ¹ H and ³¹ P 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 ¹ H 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 ¹ H and ³¹ P-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 ¹ H and ³¹ P-NMR it was further purified by trituration with Et^O or another suitable solvent / combination of solvents.

Example: Synthesis of gold(l) complex 11

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 MgS0 ₄ 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

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. K ₂ C0 ₃ (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 MgS0 ₄ and filtered. Concentration in vacuo provided the crude product which was purified by triturating with Et ₂ 0. 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 MgS0 ₄ 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

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 MgS0 ₄ 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. K ₂ C0 ₃ (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 ¹ H 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 ¹ H and ³¹ P NMR it was purified by triturating with Et.20 or another suitable solvent / combination of solvents. Example: Synthesis of gold(l) complex 106

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:

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

5-(2-Methoxycarbonyl-ethylsulfanyl)-pyrimidine-4-carboxyl ic 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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO-d6): δ ppm 8.78 (s). The following compounds were made using this method:

Synthesis of gold(l) complex 140

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%). ¹ H-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). ³¹ P-NMR (162 MHz, DMSO- d6): δ ppm 38.60 (s) Example 2

Growth Media

Tryptic Soy Broth

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

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)

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 5x10 ⁷ cfu/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.

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 5x10 ² - 2.5x10 ³ 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:

C. albicans ATCC 10231 MIC ₉₀ values

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 5x10 ² - 2.5x10 ³ cells/mL (Yeast) and 0.4x10 ⁴ - 5x10 ⁴ 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.

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