AU2007295948A1 - Acetylenic compounds - Google Patents

Description

WO 2008/031157 PCT/AU2007/001353 -1 ACETYLENIC COMPOUNDS FIELD OF THE INVENTION 5 The present invention relates to a class of acetylenic compounds, to a method of preparing the acetylenic compounds, and to the polymerisation and therapeutic uses of the acetylenic compounds. The invention particularly relates to compounds containing two acetylenic moieties. 10 BACKGROUND OF THE INVENTION Compounds containing two acetylenic moieties (i.e. diyne compounds) are known to exhibit an array of interesting properties. For example, a range of compounds comprising a 3-ene-1,5-diyne structure, so called enediyne compounds, have been shown to have 15 potent antibiotic and anti-cancer properties. A variety of diyne alcohols have also been reported to have cytotoxic properties. In addition to presenting biological activity, diyne compounds have been employed as monomers in preparing polymeric materials. A unique class of polymeric materials that 20 may be prepared using diyne compounds are known as polydiacetylenes (PDA's). PDA's are typically prepared from conjugated diyne compounds. Polymerisation of conjugated diyne compounds (see Scheme 1 below) can afford highly conjugated -ene-yne- polymer backbones structured in the form of, for example, bulk single crystals, vesicles, and mono and multilayer films. RA RB 25 RA-CC-C C-RB

-*-C

25m Scheme 1: A simplified schematic representation of the polymerisation of a conjugated diyne compound, where RA and RB represent organic substituents and m is the number of repeat units of the polymer.

WO 2008/031157 PCT/AU2007/001353 -2 Perhaps the most notable property of PDA's is their ability to undergo dramatic chromogenic transitions (typically between blue, purple and red) upon being subjected to various stimuli, such as the binding of chemical or biological entities to the pendant side 5 groups of the PDA (affinochromism/biochromism), the exposure to heat (thermochromism), the application of stress (mechanochromism), and the exposure to a different chemical environment (chemochromism). PDA's also exhibit other unique properties such as strong structural anisotropy, high non linear optical susceptibility, and rapid optical responses, although their chromogenic transitions have been most widely 10 studied. The mechanism(s) behind the chromogenic transitions of PDA's is not yet fully understood. It has been proposed that the transitions may involve a transformation from the ene-yne-ene polymeric structure to a butatrienic type structure (i.e. a structure having 3 15 sequential double bonds). However, considerable doubt has been cast on this theory in the light of certain crystallographic studies and quantum chemical calculations. It would seem at present the most widely accepted explanation for the transitions involves some form of interplay between the conformation of the pendant side groups and the 20 polymer backbone. In particular, the absorption properties of the polymer backbone are believed to be strongly influenced by factors that alter its planarity, for example rotation about the C-C bonds of the polymer backbone. Rotation about the C-C bonds of the polymer backbone necessitates changes in the 25 conformation of the pendant side groups, and thus there exists a sensitive interplay between them. The side groups will have a preferred packing arrangement which dominates the intermolecular arrangement of the monomers in the unpolymerised form. Such a packing arrangement will generally be dictated by van der Waals, hydrogen bonding, electrostatic and/or u-stacking interactions. During polymerisation, the 30 propagating polymer backbone is believed to adopt a strained configuration due to steric constraints imposed by the non-covalent interactions of the pendant side groups.

WO 2008/031157 PCT/AU2007/001353 -3 Essentially, the packing energy of the pendant side groups is believed to be sufficiently high to create a barrier that prevents the polymer backbone from adopting a more relaxed form. Subjecting the resulting strained polymer conformation to one or more of the aforementioned stimuli can lead to a reorganisation of the pendant side groups and allow 5 the polymer backbone to adopt a more relaxed conformation through rotation about the C C bonds of the backbone, and thus alter the absorption characteristics of the polymer. Unlike polymerisation of many other unsaturated monomers, PDA's are prepared via topochemical polymerisation of the monomers in the solid state. In other words, the 10 polymerisation requires the ordered packing of the diyne monomers so as to present the acetylenic moieties in an appropriate spatial arrangement. A selection of diyne monomers are known to present a sufficiently ordered packing arrangement to enable polymerisation to proceed. Such monomers typically have end groups (often referred to as the "head" and "tail" of the monomer) that facilitate the alignment of the monomers to achieve the 15 required packing. For example, as shown in Scheme 2 below a compound such as 5,7 dodecadiynoic acid can self assemble into a one dimensional sheet type structure and provide the requisite alignment of the acetylenic moieties to be polymerised into a PDA. In this case, the carboxyl head and the alkyl tail of the compound are believed to facilitate its alignment into a suitably ordered packing arrangement. 20 WO 2008/031157 PCT/AU2007/001353 -4 0 H-a Self assemble o-H I ' 0 H-o Polymerisation O-H 0 0 H-0 O-H, H-0 H-0 OHa H-0 Scheme 2: Self assembly and polymerisation of 5,7-dodecadiynoic acid to form a PDA. 5 Notably, upon forming a suitably well ordered packing arrangement of diyne monomers, polymerisation can permanently knit certain aspects of the packed monomers to form PDA's with unique dimensions. Thus, polymerisation of monomers formed into large single crystals can provide for high molecular weight PDA's with highly linear backbones. Unique vesicular PDA structures and highly organised ultra thin PDA films (monolayers) WO 2008/031157 PCT/AU2007/001353 -5 may also be prepared. In view of such unique structural characteristics and their chromogenic properties, PDA's show great potential for use in applications such as micro and nano-devices, biosensors, strain gauges and colorimetric sensing surfaces to name but a few. 5 It would therefore be desirable to provide new diyne compounds that may add further versatility to this general class of compound. SUMMARY OF THE INVENTION 10 The present invention provides a diyne compound of general formula (I) 0 C /(R)n / _ _ X Y (W)-R 1 OH (I) 15 where X is OR or NR2R, R and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted 20 heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; R' is selected from H and an organic substituent; 25 n is selected from 0 or 1; q is selected from 0 or 1; and WO 2008/031157 PCT/AU2007/001353 -6 p is an integer ranging from 0 to 15, with the proviso that the compound is not: CHiC-CH=CH-(CH2)a-CEC-C-CEC--CC-(CH2)- C-CH(OH)-CO2H. 5 The invention also provides a method of preparing a diyne compound of general formula (I) C(R)n X Y (W)q-R OH (I) 10 said method comprising coupling a compound of general formula (II) with a compound of general formula (III) 0 C (R)n (W)q X Y H R 1 OH z (II) (III) 15 where X is OR 2 or NR 2

R

3 , R 2 and R3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted 20 heterocyclylene; WO 2008/031157 PCT/AU2007/001353 -7 W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; R' is selected from H and an organic substituent; 5 Z is a halogen; n is selected from 0 or 1; q is selected from 0 or 1; and p is an integer ranging from 0 to 15. 10 The invention provides a further method of preparing a diyne compound of general formula (I) 0 C (R)n / _ X Y (W)q-R OH (I) 15 said method comprising the diacetal deprotection of a compound of general formula (IV) OMe (R)n O Y (WgqR 1 0 OMe 0 (IV) where X is OR 2 or NR 2

R

3 , R 2 and R 3 are each independently selected from H and an 20 organic substituent or form together with N a heterocyclyl substituent; WO 2008/031157 PCT/AU2007/001353 R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; 5 W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene;

R

1 is selected from H and an organic substituent; n is selected from 0 or 1; 10 q is selected from 0 or 1; and p is an integer ranging from 0 to 15. Compounds of general formula (IV) are believed to be novel in their own right and therefore represent a further aspect of the invention. 15 Other methods for preparing compounds of general formula (I) are described below. In some embodiments of the invention, -(R)n-Y- of general formulae (I), (II), and (IV) is preferably -(CH 2 )-, where t is an integer ranging from 0 to 15, preferably an integer 20 ranging from 1 to 15. In some embodiments of the invention, in addition to or independent from -(R)n-Y- of general formulae (I), (II), and (IV) preferably being -(CH 2 )t-, q in -(W)q- of general formula (I), (III), and (IV) is preferably 1. When q is 1, in some embodiments of the 25 invention W is preferably -(CH 2 )p-,where p is an integer ranging from 0 to 15, preferably ranging from 1 to 15. In some embodiments of the invention general formula (I) may therefore be represented as general formula (IA): 30 WO 2008/031157 PCT/AU2007/001353 -9 Il

(CH

2 )t x OH

(CH

2 )p--R (IA) where X is OR 2 or NR 2

R

3 , R 2 and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; R1 is selected from H and an organic substituent; and 5 t and p are each independently an integer ranging from 0 to 15. In some embodiments of the invention, t and p are each independently an integer ranging from 1, 2, or 3 to 15. 10 Those skilled in the art will appreciate that the -(CH 2 )t- and -(CH 2 ),- features of general formula (IA) may also be transposed where appropriate to general formulae (II), (III), and (IV). Without wishing to be limited by theory, it is believed that locating a hydroxyl substituent 15 in the a (i.e. -2-) position relative to the carbonyl moiety in the structure of general formula (I) may provide the diyne compounds with further utility. In particular, it is believed that the a-OH substituent may give rise to hydrogen bonding interactions that lead to new and/or improved applications for such compounds. For example, the hydrogen bonding function and the increased hydrophilicity provided by the a-OH substituent is expected to 20 provide new and/or enhanced interactions with biological systems. At least the hydrogen bonding function of the a-OH substituent is also expected to influence the manner in which diyne compounds can self assemble and subsequently be polymerised. For example, and with reference to Scheme 3 below, a compound such as 2 25 hydroxy-5,7-dodecadiynoic acid is expected to self assemble into a unique 2-dimensional WO 2008/031157 PCT/AU2007/001353 -10 packing array comprising a series of stacked 1-dimensional sheet structures "A" - "E". The detail of sheet structures "B" - "E" in Scheme 3 has been omitted for clarity to reveal the expected hydrogen bonding provided by the a-OH substituent. E OX H D 5O HB H e/ H O o' H o' 5 H Scheme 3: Proposed self assembled structure of 2-hydroxy-5 ,7-dodecadiynoic acid. The influence of hydrogen bonding provided by the a-OH substituent is expected to vary 10 with different diyne compounds. Thus, the a-OH substituent may facilitate the formation of unique multi-dimensional packing arrangements such as that shown above in Scheme 3, relative to a diyne compound absent the a-OH substituent (see Scheme 2). The a-OH substituent may also promote self assembly in diyne compounds that would not otherwise be amenable to forming such a structure, or even enhance the integrity of an otherwise 15 unstable self assembled structure. Furthermore, the a-OH substituent provides the diyne compounds of general formula (I) with functionality that can take part in condensation polymerisation reactions. For example, where X in general formula (I) is OH, the diyne compounds may undergo self 20 condensation polymerisation and/or condensation polymerisation with one or more co monomers to yield a polyester polymer backbone having pendant diyne groups. The WO 2008/031157 PCT/AU2007/001353 - 11 pendant diyne groups may impart unique biological activity to the resulting polymer or function as a further reaction site. Other aspects of the invention are described in more detail below. 5 DETAILED DESCRIPTION OF THE INVENTION The substituent R can generally be selected from any divalent organic substituent. Preferably, R is a divalent form of a group selected from alkyl, alkenyl, alkynyl, aryl, acyl, 10 carbocyclyl, heterocyclyl, heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, acyloxy, carbocyclyloxy, heterocyclyloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, arylthio, acylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, alkylalkenyl, alkylalkynyl, alkylaryl, alkylacyl, alkylcarbocyclyl, alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkylacyloxy, 15 alkylcarbocyclyloxy, alkylheterocyclyloxy, alkylheteroaryloxy, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, alkylacylthio, alkylcarbocyclylthio, alkylheterocyclylthio, alkylheteroarylthio, alkylalkenylalkyl, alkylalkynylalkyl, alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylalkenylaryl, arylalkynylaryl, arylacylaryl, arylacyl, arylcarbocyclyl, arylheterocyclyl, arylheteroaryl, alkenyloxyaryl, alkynyloxyaryl, 20 aryloxyaryl, arylacyloxy, arylcarbocyclyloxy, arylheterocyclyloxy, arylheteroaryloxy, alkylthioaryl, alkenylthioaryl, alkynylthioaryl, arylthioaryl, arylacylthio, arylcarbocyclylthio, arylheterocyclylthio, and arylheteroarylthio. More preferably, R is a divalent form of any of the groups selected from C 1

-C

1 8 alkyl, C 2 25 C 18 alkenyl, C 2

-C

1 8 alkynyl, C 6

-C

18 aryl, C 1

-C

18 acyl, C 3

-C

18 carbocyclyl, C 2

-C

18 heterocyclyl, C 3

-C

18 heteroaryl, C 1

-C

1 8 alkyloxy, C 2

-C

18 alkenyloxy, C 2

-C

1 3 alkynyloxy,

C

6 -C1s aryloxy, C 1

-C

1 8 acyloxy, C 3

-C

1 8 carbocyclyloxy, C 2

-C

18 heterocyclyloxy, C 3

-C

18 heteroaryloxy, C 1

-C

18 alkylthio, C 2

-C

18 alkenylthio, C 2

-C

18 alkynylthio, C 6

-C

18 arylthio, C1-Cis acylthio, C3-Cis carbocyclylthio, C 2 -Ci 8 heterocyclylthio, C 3 -Ci 8 heteroarylthio, C 3 30 C 1 s alkylalkenyl, C 3

-C

18 alkylalkynyl, C 7

-C

24 alkylaryl, C 2

-C

18 alkylacyl, C 4

-C

1 8 alkylcarbocyclyl, C 3

-C

18 alkylheterocyclyl, C4-C 1 8 alkylheteroaryl, C 2

-C,

8 alkyloxyalkyl, WO 2008/031157 PCT/AU2007/001353 - 12 C 3

-C

18 alkenyloxyalkyl, C 3

-C

18 alkynyloxyalkyl, C 7

-C

24 aryloxyalkyl, C 2

-C

18 alkylacyloxy,

C

4

-C

18 alkylcarbocyclyloxy, C 3

-C

18 alkylheterocyclyloxy, C 4

-C

18 alkylheteroaryloxy, C 2 C 1 8 alkylthioalkyl, C 3

-C

18 alkenylthioalkyl, C 3

-C

18 alkynylthioalkyl, C7-C 24 arylthioalkyl,

C

2

-C

18 alkylacylthio, C 4

-C

18 alkylcarbocyclylthio, C 3

-C

18 alkylheterocyclylthio, C 4

-C

1 8 5 alkylheteroarylthio, C 4

-C

18 alkylalkenylalkyl, C 4

-C

1 8 alkylalkynylalkyl, C 8

-C

24 alkylarylalkyl, C 3

-C

18 alkylacylalkyl, C 13

-C

24 arylalkylaryl, C 14

-C

24 arylalkenylaryl, C 14 C 24 arylalkynylaryl, C 13

-C

24 arylacylaryl, C 7

-C

18 arylacyl, C 9

-C

18 arylcarbocyclyl, C 8

-C

18 arylheterocyclyl, C 9

-C

18 arylheteroaryl, Cs-Ci 8 alkenyloxyaryl, C 8

-C

18 alkynyloxyaryl, C 12 C 24 aryloxyaryl, C 7

-C

1 8 arylacyloxy, C 9

-C

1 8 arylcarbocyclyloxy, C 8

-C

18 10 arylheterocyclyloxy, C 9

-C

18 arylheteroaryloxy, C 7

-C

18 alkylthioaryl, C 8

-C

8 alkenylthioaryl, C 8

-C

18 alkynylthioaryl, C 12

-C

24 arylthioaryl, C 7

-C

18 arylacylthio, C 9

-C

1 8 arylcarbocyclylthio, C 8

-C

18 arylheterocyclylthio, and C 9

-C

18 arylheteroarylthio. Still more preferably, R is a divalent form of a group selected from alkyl (e.g. C-C 18 , C 1 15 C 6 , C 1

-C

5 , C 8

-C

18 , or C 9

-C

18 ), aryl (e.g. C 6

-C

18 ), heteroaryl (e.g. C 3

-C

18 ), carbocyclyl (e.g.

C

3

-C

18 ), heterocyclyl (e.g. C 2

-C

18 ), alkylaryl (e.g. C 7

-C

24 ), alkylheteroaryl (e.g. C 4

-C

18 ), alkylcarbocyclyl (e.g. C 4 -C18), and alkylheterocyclyl (e.g. C 3

-C

1 8). In the lists above defining divalent groups from which R may be selected, each alkyl, 20 alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, and heterocyclyl moiety may be optionally substituted. For avoidance of any doubt, where a given R group contains two or more of such moieties (e.g. alkylaryl), each of such moieties may be optionally substituted with one, two, three or more optional substituents as herein defined. 25 In the lists above defining divalent groups from which R may be selected, where a given R group contains two or more subgroups (e.g. [group A][group B]), the order of the subgroups are not intended to be limited to the order in which they are presented. Thus, an R group with two subgroups defined as [group A][group B] (e.g. alkylaryl) is intended to also be a reference to an R with two subgroups defined as [group B][group A] (e.g. 30 arylalkyl).

WO 2008/031157 PCT/AU2007/001353 - 13 Where R comprises an optionally substituted alkyl moiety, a preferred optional substituent includes where a -CH 2 - group in the alkyl chain is replaced by a group selected from -0-, -S-, -NRa-, -C(O)- (i.e. carbonyl), -C(0)0- (i.e. ester), and -C(O)NRa- (i.e. amide), where 5 Ra is as defined below. The substituents R1, R 2 and R 3 can generally be independently selected from H and any organic substituent. Preferably, R 1 , R 2 and R 3 are each independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, 10 optionally substituted aryl, optionally substituted alkylaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, and optionally substituted heteroaryl. R 1 may be further selected from optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryloxy, optionally substituted acyloxy, optionally substituted alkylthio, optionally substituted alkenylthio, 15 optionally substituted alkynylthio, optionally substituted arylthio, optionally substituted acyl, sulfoxide, sulfonyl, sulfonamide, amino, amido, carboxy ester, amino acid, and a peptide. More preferably, R', R 2 and R 3 are each independently selected from H, optionally 20 substituted C1 to C 18 alkyl, optionally substituted C 2 to C 1 8 alkenyl, optionally substituted

C

2 to C 1 s alkynyl, optionally substituted C 6 to C 18 aryl, optionally substituted C 3 to C 18 carbocyclyl, optionally substituted C 3 to C 18 heterocyclyl, and optionally substituted C 3 to

C

1 8 heteroaryl. R 1 may be further selected from optionally substituted C 1 to C 18 alkoxy, optionally substituted C 2 to C 1 8 alkenoxy, optionally substituted C 2 to C 18 alkynoxy, 25 optionally substituted C 6 to C 1 8 aryloxy, optionally substituted C 1 to C 18 acyloxy, optionally substituted C 1 to C 1 s alkylthio, optionally substituted C 2 to C 1 s alkynylthio, optionally substituted C 2 to C 18 alkynylthio, optionally substituted C 6 to C 18 arylthio, optionally substituted C 1 to C1s acyl, sulfoxide, sulfonyl, sulfonamide, amino, amido, carboxy ester, amino acid, and a peptide. 30 WO 2008/031157 PCT/AU2007/001353 - 14 Still more preferably, R', R 2 and R 3 are each independently selected from H, optionally substituted C 1 to C 18 alkyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted naphthyl, optionally substituted anthracenyl, optionally substituted pyridyl, optionally substituted pyrrolyl, optionally substituted thienyl, and optionally 5 substituted furanyl. Where X = NR 2

R

3 , R 2 and R? may form together with the N atom a heterocyclic organic substituent. The heterocyclyl substituent may be optionally substituted. The heterocyclyl substituent is preferably an optionally substituted C 1 to C 18 heterocyclyl substituent. 10 In some embodiments of the invention, n and q may each independently be 1. In some embodiments of the invention, the sum of t and p does not exceed 24. 15 In some embodiments of the invention, t is an integer ranging from 1 to 6, or ranging from 8 to 15. In some embodiments of the invention, the diyne compound of general formula (I) is not

CH

3

(CH

2 ) -C=C-CaC-(CH 2

)

7

-CH(OH)CO

2 H or CH 3

(CH

2 ) -C-C-C=-C-(CH 2

)

7 20 CH(OH)CO 2

CH(CH

3

)C

6

H

5 . As used herein, the term "alkyl", used either alone or in compound words denotes straight chain, branched or cyclic alkyl, preferably C 1

-

2 0 alkyl, e.g. C 1

.

10 or C1.6. Examples of straight chain and branched alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec 25 butyl, t-butyl, n-pentyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1 methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3 dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2 trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3 dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4 30 dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6 methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- WO 2008/031157 PCT/AU2007/001353 - 15 methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Where an alkyl group is referred to generally as "propyl", butyl" etc, it will be understood 10 that this can refer to any of straight, branched and cyclic isomers where appropriate. An alkyl group may be optionally substituted by one or more optional substituents as herein defined. The term "alkenyl" as used herein denotes groups formed from straight chain, branched or 15 cyclic hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as previously defined, preferably C 2

-

20 alkenyl (e.g. C 2

-

10 or C 2

-

6 ). Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 20 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3 decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4 hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5 cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. An alkenyl group may be optionally substituted by one or more optional substituents as herein defined. 25 As used herein the term "alkynyl" denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to C 2

..

20 30 alkynyl (e.g. C2- 1 0 or C 2

-

6 ). Examples include ethynyl, 1-propynyl, 2-propynyl, and WO 2008/031157 PCT/AU2007/001353 -16 butynyl isomers, and pentynyl isomers. An alkynyl group may be optionally substituted by one or more optional substituents as herein defined. The term "halogen" ("halo") denotes fluorine, chlorine, bromine or iodine (fluoro, chloro, 5 bromo or iodo). Preferred halogens are chlorine, bromine or iodine. The term "aryl" (or "carboaryl)" denotes any of single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, 10 dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl, chrysenyl. Preferred aryl include phenyl and naphthyl. An aryl group may or may not be optionally substituted by one or more optional substituents as herein defined. The term "arylene" is intended to denote the divalent form of aryl. 15 The term "carbocyclyl" includes any of non-aromatic monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3

-

20 (e.g. C 3

..

10 or C 3

.

8 ). The rings may be saturated, e.g. cycloalkyl, or may possess one or more double bonds (cycloalkenyl) and/or one or more triple bonds (cycloalkynyl). Particularly preferred carbocyclyl moieties are 5-6-membered or 9-10 membered ring systems. Suitable examples include cyclopropyl, 20 cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctatetraenyl, indanyl, decalinyl and indenyl. A carbocyclyl group may be optionally substituted by one or more optional substituents as herein defined. The term "carbocyclylene" is intended to denote the divalent form of carbocyclyl. 25 The term "heterocyclyl" when used alone or in compound words includes any of monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3

-

20 (e.g.

C

3

..

10 or C 3 .8) wherein one or more carbon atoms are replaced by a heteroatom so as to provide a non-aromatic residue. Suitable heteroatoms include 0, N, S, P and Se, 30 particularly 0, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. The heterocyclyl group WO 2008/031157 PCT/AU2007/001353 -17 may be saturated or partially unsaturated, i.e. possess one or more double bonds. Particularly preferred heterocyclyl are 5-6 and 9-10 membered heterocyclyl. Suitable examples of heterocyclyl groups may include azridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2H-pyrrolyl, pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, 5 morpholinyl, indolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, thiomorpholinyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, pyrazolinyl, dioxalanyl, thiazolidinyl, isoxazolidinyl, dihydropyranyl, oxazinyl, thiazinyl, thiomorpholinyl, oxathianyl, dithianyl, trioxanyl, thiadiazinyl, dithiazinyl, trithianyl, azepinyl, oxepinyl, thiepinyl, indenyl, indanyl, 3H-indolyl, isoindolinyl, 4H-quinolazinyl, 10 chromenyl, chromanyl, isochromanyl, pyranyl and dihydropyranyl. A heterocyclyl group may be optionally substituted by one or more optional substituents as herein defined. The term "heterocyclylene" is intended to denote the divalent form of heterocyclyl. The term "heteroaryl" includes any of monocyclic, polycyclic, fused or conjugated 15 hydrocarbon residues, wherein one or more carbon atoms are replaced by a heteroatom so as to provide an aromatic residue. Preferred heteroaryl have 3-20 ring atoms, e.g. 3-10. Particularly preferred heteroaryl are 5-6 and 9-10 membered bicyclic ring systems. Suitable heteroatoms include, 0, N, S, P and Se, particularly 0, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by 20 different heteroatoms. Suitable examples of heteroaryl groups may include pyridyl, pyrrolyl, thienyl, imidazolyl, furanyl, benzothienyl, isobenzothienyl, benzofuranyl, isobenzofuranyl, indolyl, isoindolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, quinolyl, isoquinolyl, phthalazinyl, 1,5-naphthyridinyl, quinozalinyl, quinazolinyl, quinolinyl, oxazolyl, thiazolyl, isothiazolyl, isoxazolyl, triazolyl, 25 oxadialzolyl, oxatriazolyl, triazinyl, and furazanyl. A heteroaryl group may be optionally substituted by one or more optional substituents as herein defined. The term "heteroarylene" is intended to denote the divalent form of heteroaryl. The term "acyl" either alone or in compound words denotes a group containing the moiety 30 C=O (and not being a carboxylic acid, ester or aide) Preferred acyl includes C(0)-R, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocyclyl, or WO 2008/031157 PCT/AU2007/001353 - 18 heterocyclyl residue. Examples of acyl include formyl, straight chain or branched alkanoyl (e.g. C 1 20 ) such as acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, 5 octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and 10 naphthylbutanoyl]; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; 15 arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as 20 thiazolyglyoxyloyl and thienylglyoxyloyl. The R residue may be optionally substituted as described herein. The term "sulfoxide", either alone or in a compound word, refers to a group -S(O)Ry wherein RY is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, 25 heterocyclyl, carbocyclyl, and aralkyl. Examples of preferred RY include CI 2 oalkyl, phenyl and benzyl. The term "sulfonyl", either alone or in a compound word, refers to a group S(0)2-Ry, wherein RY is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, 30 heterocyclyl, carbocyclyl and aralkyl. Examples of preferred RY include CI20alkyl, phenyl and benzyl.

WO 2008/031157 PCT/AU2007/001353 - 19 The term "sulfonamide", either alone or in a compound word, refers to a group S(O)NRYRY wherein each RY is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, and aralkyl. Examples of preferred RY include C 1 . 5 2oalkyl, phenyl and benzyl. In a preferred embodiment at least one RY is hydrogen. In another form, both RY are hydrogen. The term, "amino" is used here in its broadest sense as understood in the art and includes groups of the formula NRaR wherein Ra and Rb may be any independently selected from 10 hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, arylalkyl, and acyl. Ra and Rb, together with the nitrogen to which they are attached, may also form a monocyclic, or polycyclic ring system e.g. a 3-10 membered ring, particularly, 5-6 and 9 10 membered systems. Examples of "amino" include NH 2 , NHalkyl (e.g. CI-2oalkyl), NHaryl (e.g. NHphenyl), NHaralkyl (e.g. NHbenzyl), NHacyl (e.g. NHC(O)CI-2oalkyl, 15 NHC(O)phenyl), Nalkylalkyl (wherein each alkyl, for example C1.

2 o, may be the same or different) and 5 or 6 membered rings, optionally containing one or more same or different heteroatoms (e.g. 0, N and S). The term "amido" is used here in its broadest sense as understood in the art and includes 20 groups having the formula C(O)NRaRb, wherein Ra and Rb are as defined as above. Examples of amido include C(0)NH 2 , C(O)NHalkyl (e.g. C1-2oalkyl), C(O)NHaryl (e.g. C(O)NHphenyl), C(O)NHaralkyl (e.g. C(O)NHbenzyl), C(O)NHacyl (e.g. C(0)NHC(O)C 1 -2oalkyl, C(O)NHC(0)phenyl), C(0)Nalkylalkyl (wherein each alkyl, for example C 1

-

20 , may be the same or different) and 5 or 6 membered rings, optionally 25 containing one or more same or different heteroatoms (e.g. 0, N and S). The term "carboxy ester" is used here in its broadest sense as understood in the art and includes groups having the formula CO 2 Rz, wherein Rz may be selected from groups including alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, aralkyl, and 30 acyl. Examples of carboxy ester include C0 2

C..

2 oalkyl, C0 2 aryl (e.g.. C02phenyl),

CO

2 aralkyl (e.g. CO 2 benzyl).

WO 2008/031157 PCT/AU2007/001353 -20 In this specification "optionally substituted" is taken to mean that a group may or may not be substituted or fused (so as to form a condensed polycyclic group) with one, two, three or more of organic and inorganic groups, including those selected from: alkyl, alkenyl, 5 alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, acyl, aralkyl, alkaryl, alkheterocyclyl, alkheteroaryl, alkcarbocyclyl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, halocarbocyclyl, haloheterocyclyl, haloheteroaryl, haloacyl, haloaryalkyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycarbocyclyl, hydroxyaryl, hydroxyheterocyclyl, hydroxyheteroaryl, hydroxyacyl, hydroxyaralkyl, alkoxyalkyl, 10 alkoxyalkenyl, alkoxyalkynyl, alkoxycarbocyclyl, alkoxyaryl, alkoxyheterocyclyl, alkoxyheteroaryl, alkoxyacyl, alkoxyaralkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, carbocyclyloxy, aralkyloxy, heteroaryloxy, heterocyclyloxy, acyloxy, haloalkoxy, haloalkenyloxy, haloalkynyloxy, haloaryloxy, halocarbocyclyloxy, haloaralkyloxy, haloheteroaryloxy, haloheterocyclyloxy, haloacyloxy, nitro, nitroalkyl, nitroalkenyl, 15 nitroalkynyl, nitroaryl, nitroheterocyclyl, nitroheteroayl, nitrocarbocyclyl, nitroacyl, nitroaralkyl, amino (NIH 2 ), alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, aralkylamino, diaralkylamino, acylamino, diacylamino, heterocyclamino, heteroarylamino, carboxy, carboxyester, amido, alkylsulphonyloxy, arylsulphenyloxy, alkylsulphenyl, arylsulphenyl, thio, alkylthio, alkenylthio, alkynylthio, 20 arylthio, aralkylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, acylthio, sulfoxide, sulfonyl, sulfonamide, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocarbocyclyl, aminoaryl, aminoheterocyclyl, aminoheteroaryl, aminoacyl, aminoaralkyl, thioalkyl, thioalkenyl, thioalkynyl, thiocarbocyclyl, thioaryl, thioheterocyclyl, thioheteroaryl, thioacyl, thioaralkyl, carboxyalkyl, carboxyalkenyl, carboxyalkynyl, carboxycarbocyclyl, 25 carboxyaryl, carboxyheterocyclyl, carboxyheteroaryl, carboxyacyl, carboxyaralkyl, carboxyesteralkyl, carboxyesteralkenyl, carboxyesteralkynyl, carboxyestercarbocyclyl, carboxyesteraryl, carboxyesterheterocyclyl, carboxyesterheteroaryl, carboxyesteracyl, carboxyesteraralkyl, amidoalkyl, amidoalkenyl, amidoalkynyl, amidocarbocyclyl, amidoaryl, amidoheterocyclyl, amidoheteroaryl, amidoacyl, amidoaralkyl, formylalkyl, 30 formylalkenyl, formylalkynyl, formylcarbocyclyl, formylaryl, formylheterocyclyl, formylheteroaryl, formylacyl, formylaralkyl, acylalkyl, acylalkenyl, acylalkynyl, WO 2008/031157 PCT/AU2007/001353 -21 acylcarbocyclyl, acylaryl, acylheterocyclyl, acylheteroaryl, acylacyl, acylaralkyl, sulfoxidealkyl, sulfoxidealkenyl, sulfoxidealkynyl, sulfoxidecarbocyclyl, sulfoxidearyl, sulfoxideheterocyclyl, sulfoxideheteroaryl, sulfoxideacyl, sulfoxidearalkyl, sulfonylalkyl, sulfonylalkenyl, sulfonylalkynyl, sulfonylcarbocyclyl, sulfonylaryl, sulfonylheterocyclyl, 5 sulfonylheteroaryl, sulfonylacyl, sulfonylaralkyl, sulfonamidoalkyl, sulfonamidoalkenyl, sulfonamidoalkynyl, sulfonamidocarbocyclyl, sulfonamidoaryl, sulfonamidoheterocyclyl, sulfonamidoheteroaryl, sulfonamidoacyl, sulfonamidoaralkyl, nitroalkyl, nitroalkenyl, nitroalkynyl, nitrocarbocyclyl, nitroaryl, nitroheterocyclyl, nitroheteroaryl, nitroacyl, nitroaralkyl, cyano, sulfate and phosphate groups. Optional substitution may also be taken 10 to refer to where a -CH 2 - group in a chain or ring is replaced by a group selected from -0-, -S-, -NRa-, -C(O)- (i.e. carbonyl), -C(O)O- (i.e. ester), and -C(O)NRa- (i.e. amide), where Ra is as defined herein. Preferred optional substituents include alkyl, (e.g. C 1

-

6 alkyl such as methyl, ethyl, propyl, 15 butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (e.g. methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (e.g.

C

1

-

6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halo, trifluoromethyl, trichloromethyl, tribromomethyl, hydroxy, phenyl (which itself may be 20 further substituted e.g., by C 1

.

6 alkyl, halo, hydroxy, hydroxyC.

6 alkyl, C 1

.

6 alkoxy, haloC 1

.

6 alkyl, cyano, nitro OC(O)C 1

.

6 alkyl, and amino), benzyl (wherein benzyl itself may be further substituted e.g., by C 1

.

6 alkyl, halo, hydroxy, hydroxyC1.

6 alkyl, C 1

.

6 alkoxy, haloC 1

.

6 alkyl, cyano, nitro OC(O)C 1

.

6 alkyl, and amino), phenoxy (wherein phenyl itself may be further substituted e.g., by C 1

.

6 alkyl, halo, hydroxy, hydroxyC1.

6 alkyl, C 1

.

6 alkoxy, 25 haloC 1

.

6 alkyl, cyano, nitro OC(O)C 1

.

6 alkyl, and amino), benzyloxy (wherein benzyl itself may be further substituted e.g., by C 1

.

6 alkyl, halo, hydroxy, hydroxyC1- 6 alkyl, C 1

.

6 alkoxy, haloC 1

.

6 alkyl, cyano, nitro OC(O)C 1

.

6 alkyl, and amino), amino, alkylamino (e.g. C 1

.

6 alkyl, such as methylamino, ethylamino, propylamino etc), dialkylamino (e.g. C 1

.

6 alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (e.g. NHC(O)CH 3 ), 30 phenylamino (wherein phenyl itself may be further substituted e.g., by C 1

.

6 alkyl, halo, hydroxy, hydroxyC 1

..

6 alkyl, C 1

.

6 alkoxy, haloC 1

..

6 alkyl, cyano, nitro OC(O)C 1

.

6 alkyl, and WO 2008/031157 PCT/AU2007/001353 -22 amino), nitro, formyl, -C(O)-alkyl (e.g. C 1

.

6 alkyl, such as acetyl), O-C(O)-alkyl (e.g. C 1 . 6 alkyl, such as acetyloxy), benzoyl (wherein the phenyl group itself may be further substituted e.g., by C 1

.

6 alkyl, halo, hydroxy hydroxyC 1

.

6 alkyl, C 1

.

6 alkoxy, haloC 1

,

6 alkyl, cyano, nitro OC(O)Ci- 6 alkyl, and amino), replacement of CH 2 with C=O, CO 2 H, CO 2 alkyl 5 (e.g. C 1

.

6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester), CO 2 phenyl (wherein phenyl itself may be further substituted e.g., by C 1

-

6 alkyl, halo, hydroxy, hydroxyl CI.

6 alkyl, C 1

.

6 alkoxy, halo C 1

.

6 alkyl, cyano, nitro OC(O)C 1

.

6 alkyl, and amino),

CONH

2 , CONHphenyl (wherein phenyl itself may be further substituted e.g., by C 1

..

6 alkyl, halo, hydroxy, hydroxyl C 1

.

6 alkyl, C 1

.

6 alkoxy, halo C 1

.

6 alkyl, cyano, nitro OC(O)C 1

.

6 10 alkyl, and amino), CONHbenzyl (wherein benzyl itself may be further substituted e.g., by

C

1

.

6 alkyl, halo, hydroxy hydroxyl C 1

.

6 alkyl, C 1

.

6 alkoxy, halo C 1

-

6 alkyl, cyano, nitro

OC(O)C

1

.

6 alkyl, and amino), CONHalkyl (e.g. C 1

.

6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl amide) CONHdialkyl (e.g. CI.

6 alkyl) aminoalkyl (e.g., HN C 1

.

6 alkyl-,

C

1

.

6 alkylHN-C.

6 alkyl- and (C 1

-

6 alkyl) 2

N-C-

6 alkyl-), thioalkyl (e.g., HS C 1

.

6 alkyl-), 15 carboxyalkyl (e.g., HO 2

CC

1

..

6 alkyl-), carboxyesteralkyl (e.g., Ci- 6 alkylO 2

CCI..

6 alkyl-), amidoalkyl (e.g., H 2 N(O)CC..6 alkyl-, H(C 1

-

6 alkyl)N(O)CC 1

.

6 alkyl-), formylalkyl (e.g., OHCCi- 6 alkyl-), acylalkyl (e.g., C 1

.

6 alkyl(O)CC 1

.

6 alkyl-), nitroalkyl (e.g., 0 2

NC

1

..

6 alkyl-), sulfoxidealkyl (e.g., R(O)SC 1

..

6 alkyl, such as C 1

.

6 alkyl(O)SCI.

6 alkyl-), sulfonylalkyl (e.g.,

R(O)

2

SC-

6 alkyl- such as C 1

.

6 alkyl(O) 2

SC

1

.

6 alkyl-), sulfonamidoalkyl (e.g., 2

HRN(O)SC

1 . 20 6 alkyl, H(C 1

.

6 alkyl)N(O)SC 1

.

6 alkyl-). The term "heteroatom" or "hetero" as used herein in its broadest sense refers to any atom other than a carbon atom which may be a member of a cyclic organic group. Particular examples of heteroatoms include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, 25 selenium and tellurium, more particularly nitrogen, oxygen and sulfur. As used herein, the term "amino acid" refers to compounds having an amino group and a carboxylic acid group. The amino acid may be a naturally or non-naturally occurring and may be proteogenic or non-proteogenic. The amino acid may also be an L-amino acid, D 30 amino acid, a-amino acid, or a P-amino acid.

WO 2008/031157 PCT/AU2007/001353 - 23 Suitable naturally occurring proteogenic amino acids are shown in Table 1 together with their one letter and three letter codes. Table 1: List of naturally occurring proteogenic amino acids Amino Acid one letter code three letter code L-alanine A Ala L-arginine R Arg L-asparagine N Asn L-aspartic acid D Asp L-cysteine C Cys L-glutamine Q Gln L-glutamic acid E Glu glycine G Gly L-histidine H His L-isoleucine. I Ile L-leucine L Leu L-lysine K Lys L-methionine M Met L-phenylalanine F Phe L-proline P Pro L-serine S Ser L-threonine T Thr L-tryptophan W Trp L-tyrosine Y Tyr L-valine V Val 5 Suitable non-proteogenic or non-naturally occurring amino acids may be prepared by techniques known in the art such as side chain modification or by total synthesis. As used herein, the term "peptide" refers to any of various natural or synthetic compounds 10 containing two or more amino acids covalently linked by the carboxyl group of one amino WO 2008/031157 PCT/AU2007/001353 -24 acid to the amino group of another. For monovalent substituents, terms written as "[groupA] [group B]" refer to group A when linked by a divalent form of group B. For example, "[group A][alkyl]" refers to a 5 particular group A (such as hydroxy, amino, etc.) when linked by divalent alkyl, i.e. alkylene (e.g. hydroxyethyl is intended to denote HO-CH 2 -CH-). Thus, terms written as "[group]oxy" refer to a particular group when linked by oxygen, for example, the terms "alkoxy" or "alkyloxy", "alkenoxy" or "alkenyloxy", "alkynoxy" or alkynyloxy", "aryloxy" and "acyloxy", respectively, denote alkyl, alkenyl, alkynyl, aryl and acyl groups as 10 hereinbefore defined when linked by oxygen. Similarly, terms written as "[group]thio" refer to a particular group when linked by sulfur, for example, the terms "alkylthio", "alkenylthio", alkynylthio" and "arylthio", respectively, denote alkyl, alkenyl, alkynyl and aryl groups as hereinbefore defined when linked by sulfur. 15 Reference to the phrase "a divalent form of a group selected from" is intended to mean that the specified group is a divalent radical. Thus, a divalent alkyl group is in effect an alkylene group (e.g. -CH 2 -). Similarly, the divalent form of the group alkylaryl may, for example, be represented by -(C 6

H

4

)-CH

2 -, a divalent alkylarylalkyl group may, for example, be represented by -CH 2

-(C

6

H

4

)-CH

2 -, a divalent alkyloxy group may, for 20 example, be represented by -CH 2 -0-, and a divalent alkyloxyalkyl group may, for example, be represented by -CH 2 -0-CH 2 -. Where the term "optionally substituted" is used in combination with such a divalent group, that group may or may not be substituted or fused as hereinbefore described. Where the divalent group comprises two or more subgroups, for example [group A] [group B] [group C] (e.g. alkylarylalkyl), if viable one or 25 more of such subgroups may be optionally substituted. Those skilled in the art will appreciate that compounds of general formulae (I), (lA), and (II) at least contain one chiral centre- at the carbon atom to which the a-OH substituent is attached. Accordingly, general formulae (I), (IA) and (II) may give rise to stereoisomers. 30 Enantiomerically pure forms and racemic mixtures of these compounds are contemplated by the present invention.

WO 2008/031157 PCT/AU2007/001353 - 25 In accordance with one embodiment of the invention, diyne compounds of general formula (I) are prepared by coupling a compound of general formula (II) with a compound of general formula (III). Any suitable coupling reactions may be employed. The Z group in 5 general formula (III) is preferably iodo, and in this case coupling of the compounds results in the liberation of HI. A suitable coupling reaction may be performed according to a procedure outlined in Synthetic Communications, 16(7), 847 (1986) in which the compounds to be coupled were combined in an aqueous solution of potassium hydroxide comprising methanol, copper(I)chloride, ethylamine (70% aqueous solution) and 10 hydroxylamine hydrochloride. Those skilled in the art will appreciate that this type of coupling reaction may not be suitable for all compounds of general formula (II) and (III). If the reaction pathway is unsuitable, it is expected that a person skilled in the art could determine an alternative pathway. For example, if the reaction could not be performed using a particular ester of formula (II) (i.e. where X = OR2), it might be possible to 15 perform the reaction using the corresponding acid form of formula (II) (i.e. where X = OH), with the resulting reaction product subsequently being converted into the required ester using techniques well known in the art. Compounds of general formula (II) may be prepared using any suitable technique. One 20 approach might involve the reaction sequence outlined below in Scheme 4 in which a compound of general formula (V) is converted to the a-OH derivative (VI) through deprotonation with lithium diisopropylamide (LDA) in tetrahydrofuran (THF) and direct oxygenation according to a procedure outlined in J. Org. Chem., Vol. 40, No. 22, 1975, 3253. The resulting compound of general formula (VI) can then be desilylated through 25 reaction with tetrabutylammoniumfluoride in THF according to a procedure outlined in J. Org. Chem., Vol. 53, No. 8, 1988, 1617. Those skilled in the art will appreciate that such a reaction pathway may not be suitable for all compounds of general formula (V). If the reaction pathway is unsuitable, it is expected that a person skilled in the art could determine an alternative pathway. For example, if the reaction could not be performed 30 using a particular ester of formula (V) (i.e. where X = OR 2 ), it might be possible to perform the reaction using the corresponding acid form of formula (IV) (i.e. where X = WO 2008/031157 PCT/AU2007/001353 - 26 OH), with the resulting reaction product subsequently being converted into the required ester using techniques well known in the art. 0 02 LDA 11 C (R)n THF /C (R)n X Y Si- 00 CO (V) (VI) 0 n-Bu 4 NF, THF, C (R)n Room temp., Ar X Y~ -- H OH (II) 5 Scheme 4: Preparation of a compound of general formula (II), where X, R, Y and n are as hereinbefore defined. A compound of general formula (V) may be prepared using any suitable technique. One 10 approach might involve the reaction sequence outlined below in Scheme 5 in which a compound of general formula (VII) is reacted with (trimethylsilyl)acetylene (VIII) in the presence of n-butyl lithium (n-BuLi), hexamethylphosphoramide (HMPA) and THF at -78'C under argon according to a procedure outlined in Organic Letters 2004, Vol. 6, No. 20, 3601. In this case, Z is preferably bromo. (Trimethylsilyl)acetylene (VIII) may be 15 obtained commercially or prepared using techniques known in the art. Those skilled in the art will appreciate that such a reaction pathway may not be suitable for all compounds of general formula (VII). If the reaction pathway is unsuitable, it is expected that a person skilled in the art could determine an alternative pathway. For example, if the reaction could not be performed using a particular ester of formula (VII) (i.e. where X = OR 2 ), it 20 might be possible to perform the reaction using the corresponding acid form of formula (VII) (i.e. where X = OH), with the resulting reaction product subsequently being converted into the required ester using techniques well known in the art.

WO 2008/031157 PCT/AU2007/001353 -27 0 0 n-BuLi 11 C (R) THF/HMPA C Rn Y-Z -78 0 C, Ar x (VII) (VIII) (V) 5 Scheme 5: Preparation of a compound of general formula (V), where X, R, Y, n and Z are as hereinbefore defined. A compound of general formula (VII) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 6 in which a 10 compound of general formula (IX) is subjected to a Jones oxidation using chromium trioxide and sulfuric acid according to a procedure outlined in J. Chem. Soc. 1949, 604. The resulting acid compound of formula (VIIA) may then be used directly as compound (VII) (i.e. where X = OH), or if required converted using techniques known in the art into the appropriate specific form of general formula (VII). 15 H Jones Oxidation O \ CrO 3

/H

2

SO

4 H C R)ln Y-Z V \; \Y-Z (IX) (VIIA) Scheme 6: Preparation of a compound of general formula (VIIA) (i.e. compound (VII) where X = OH), where R, Y, n and Z are as hereinbefore defined. 20 An alternative approach to preparing a compound of general formula (V) might involve the reaction sequence outlined below in Scheme 7 in which a compound of general formula (X) is reacted with (trimethylsilyl)chloride (XI) in the presence of n-BuLi, THF at -78 0 C according to a procedure outlined in J. Med. Chem. 2005, 48, 1849. 25 (Trimethylsilyl)chloride (XI) may be obtained commercially or prepared using techniques WO 2008/031157 PCT/AU2007/001353 -28 known in the art. Those skilled in the art will appreciate that such a reaction pathway may not be suitable for all compounds of general formula (X). If the reaction pathway is unsuitable, it is expected that a person skilled in the art could determine an alternative pathway. For example, if the reaction could not be performed using a particular ester of 5 formula (X) (i.e. where X = OR 2 ), it might be possible to perform the reaction using the corresponding acid form of formula (X) (i.e. where X = OH), with the resulting reaction product subsequently being converted into the required ester using techniques well known in the art. H 0 n-BuLi R) C (Rn +c THF C i I ~'/ \~I-780C X 10 (X) (XI) (V) Scheme 7: Alternative preparation for a compound of general formula (V), where X, R, Y, and n are as hereinbefore defined. 15 A compound of general formula (X) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 8 in which a compound of general formula (XII) is subjected to a Jones oxidation with chromium trioxide and sulfuric acid according to a procedure outlined in J. Chem. Soc. 1949, 604. The resulting acid compound of formula (XA) may then be used directly as compound (X) 20 (i.e. where X = OH), or if required converted using techniques known in the art into the appropriate specific form of general formula (X).

WO 2008/031157 PCT/AU2007/001353 -29 H O H Jones Oxidation 11 CrO 3

/H

2

SO

4 H C (R)n H O (R)n \ (XII) (XA) Scheme 8: Preparation of a compound of general formula (XA), (i.e. compound (X) 5 where X = OH) where R, Y, and n are as hereinbefore defined. A compound of general formula (XII) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 9 in which a compound of general formula (XIII) is converted into a compound of general formula 10 (XII) using lithium in the presence of 1,3-diaminopropane according to a procedure outlined in Can. J. Chem. Vol. 62, 1984. (R)n H

Y-CH

3 Li H 1 ,3-diaminopropane H (R)n (XIII) (XII) 15 Scheme 9: Preparation of a compound of general formula (XII), where R, Y, n are as hereinbefore defined. A compound of general formula (XIII) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 10 in which a 20 compound of general formula (XIV) is reacted with a compound of general formula (XV) in the presence of lithium, ammonia, and [Fe(N0 3

)

3 ].9H 2 0 according to a procedure outlined in Tetrahedron 60 (2004), 5237. Haloalkenes of general formula (XV) may be obtained commercially or prepared using techniques known in the art.

WO 2008/031157 PCT/AU2007/001353 -30 H Li (R)n (R)n NH 3 H

Y-CH

3 H \0\/ z Y-CH 3 H -/1\ (XIV) (XV) (XIII) Scheme 10: Preparation of a compound of general formula (XIII), where R, Y, n and Z 5 are as hereinbefore defined. A compound of general formula (III) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 11 in which a compound of general formula (XVI) is deprotonated with n-BuLi and halogenated in THF 10 according to a procedure outlined in Preparative Acetylenic Chemistry: Elsevier: Amsterdam 1988. Compounds of general formula (XVI) may be obtained commercially or can be prepared using techniques known in the art. (W)q R-(W)q n-BuLi, Z 2 R THF z H (XVI) H 15 Scheme 11: Preparation of a compound of general formula (III), where R', W, q, and Z are as hereinbefore defined. Reaction Schemes 4 - 11 above depict reaction sequences that can be used in preparing a 20 compound of general formula (I). Those skilled in the art will appreciate that aide compounds of general formula (I) (i.e. where X = NR 2

R

3 ) could be readily prepared from acid compounds of general formula (I) (i.e. where X = OH). For example, standard peptide coupling reaction conditions could be employed where acid compounds of formula WO 2008/031157 PCT/AU2007/001353 -31 (I) are reacted with R2-NH 2 (where R2 is as hereinbefore defined) as shown below in Scheme 12. Such reaction conditions will generally require the a-OH substituent to be protected, for example with a trimethylsilyl or triisopropylsilyl group. It will of course be possible to perform such reactions on suitable intermediate compounds used in the 5 preparation of compounds of general formula (I), such as those depicted in Schemes 4-8 above. O

R

2

-NH

2 + 1 R) HO Y (W)q-R' Protecting group EDC, HOBt, HBTU, DIPEA, DMF, 2-3 hrs, room temp., pH5-6 Deprotection O R2 C (R) \ / YRx NH Y (W)q-R OH (I, where X = NR 2 ) Scheme 12: Preparation of a compound of general formula (I), where X = NHR 2 , R, R', 10 R 2 , Y, W, n and q are as hereinbefore defined. As used herein, EDC = 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide, HOBt = N Hydroxybenzotriazole, HBTU = O-Benzotriazole-NN,N',N'-tetramethyl-uronium hexafluoro-phosphate, DIPEA = diisopropylethyamine, and DMF = dimethylformamide. 15 In accordance with a further embodiment of the invention, diyne compounds of general formula (I) are prepared by the diacetal deprotection of a compound of general formula WO 2008/031157 PCT/AU2007/001353 -32 (IV). By the term "diacetal deprotection" is meant that the diacetal moiety of general formula (IV) is involved in a reaction with a reagent that gives rise to the X-C(O) CH(OH)- moiety of general formula (I). 5 Those skilled in the art will appreciate that the conditions employed to promote the diacetal deprotection will dictate the functionality of substituent X in general formula (I). Thus, acid mediated diacetal deprotection can provide for the acid form of general formula (I) (i.e. where X = OH). For example, a compound of general formula (IV) may be reacted with trifluoroacetic acid (TFA) in water. Diacetal deprotection using an appropriate 10 alcohol R 2 -OH (where R 2 is as hereinbefore defined) can provide the ester form of general formula (I) (i.e. where X = OR 2 ). In this case, it may be necessary to perform the reaction in the presence of a halo-silane such as trimethysilylchloride. Diacetal deprotection using an appropriate amine R 2

R

3 NH (where R 2 and R 3 are as hereinbefore defined) can provide for an amide form of general formula (I) (i.e. where X = NR 2

R

3 ). In this case, it may be 15 necessary to perform the reaction by activiating the amine with a Grignard reagent such as i-PrMgCl. Preparing compounds of general formula (I) using this methodology therefore provides a relatively efficient pathway to produce a broad range of the 2-hydroxy-diyne compounds. As will be discussed in more detail below, this methodology also provides a convenient route for preparing enantiomerically pure compounds of general formula (I) 20 through use of an enantiomerically pure butane-2,3-diacetal protected glycolic acid moiety. Compounds of general formula (IV) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 13 in which a compound of general formula (XVII) is alkylated with a halo diyne compound (preferably 25 an iodo diyne compound) of general formula (XVIII) using lithium bis(trimethylsilyl)amide (LHMDS) and excess electophile according to a procedure outlined in Org. Biomol. Chem., 2004, 2, 3608.

WO 2008/031157 PCT/AU2007/001353 - 33 OMe o O + Z (R -Y(W)q-Rl OMe 0 (XVIII) (XVII) 1) LHMDS 2) CH 3 COOH THF OMe (R)n O Y (W)q-R 1 OMe O (IV) Scheme 13: Preparation of a compound of general formula (IV), where R, Y, W, R', n and q are as hereinbefore defined. 5 A compound of formula (XVII) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 14 in which glycolic acid (XIX) is protected with 2,3-dimethoxybutadiene (XX) in the presence of catalytic amounts of triphenylphosphine hydrobromide according to a procedure outlined 10 in Org. Biomol. Chem., 2004, 2, 3608. 2,3-dimethoxybutadiene (XX) may be obtained commercially or prepared using techniques known in the art such as that described in J. C. S. Perkin 1, 1979, 1893. O OH OMe OMe + PPh 3 x HBr OH OMe CH 2 Cl 2 OMe 0 (XIX) (XX) (XVi1) 15 Scheme 14: Preparation of a compound of formula (XVII).

WO 2008/031157 PCT/AU2007/001353 -34 One approach to preparing enantiomerically pure compounds of general formula (I) might involve a reaction sequence similar to that outlined in Scheme 13 above in which an enantiomerically pure form of butane-2,3-diacetal protected glycolic acid is alkylated with a halo diyne compound. Diacetal deprotection of the resulting alkylated product can then 5 yield enantiomerically pure compounds of general formula (I). Enantiomerically pure butane-2,3-diacetal protected glycolic acid may be prepared using any suitable technique. One approach might involve the reaction sequences outlined below in Scheme 15 in which (S)-3-chloropropane-1,2-diol (XXI) is converted in a three step 10 synthesis to yield (S,S)butane-2,3-diacetal protected glycolic acid (XXII) according to a procedure outlined in Org. Biomol. Chem., 2004, 2, 3608. An analogous three step synthesis may be performed using (R)-3-chloropropane-1,2-diol (XXIII) to yield (R,R)butane-2,3-diacetal protected glycolic acid (XXIV). OMe HO CI O2? OMe 0 (XXI) (XXII) OMe HO CI , OR OH 0 OMe 15 (XXIII) (XXIV) Scheme 15: Preparation of enantiomerically pure butane-2, 3-diacetal protected glycolic acids (XXII) and (XXIV). 20 Compounds of general formula (XVIII) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 16 in which a compound of general formula (XXV) is converted into its corresponding halo derivative by reacting it with triphenylphosphine, imidazole and halogen according to a procedure outlined in J. Org. Chem. 2005, 70, 3898. In this case, the halogen is preferably iodine.

WO 2008/031157 PCT/AU2007/001353 -35 Compounds of general formula (XXV) may be obtained commercially or prepared using techniques known in the art, for example by copper catalysed coupling of acetylenic alcohols with iodo-alkynes according to a procedure outlined in Tetrahedron Letters, 1996, Vol. 37, No. 16, 2763. 5 (R)n PPh 3 , imidazole, z 2 (R)n / \ Z HO Y (W)g-R' CH 2 C1 2 Z Y (VOq-R (XXV) (XVIII) Scheme 16: Preparation of a compound of general formula (XVIII), where R, Y, W, Z, n and q are as hereinbefore defined. 10 Depending upon the nature of substituents X, R, Y, W, and R 1 in general formula (I), it may be preferable that the compound be prepared by alternative synthetic routes to those described above in Schemes 4-16. For example, where -(R)n-Y- in general formula (I) represents a divalent ester moiety, for example such as -CH 2 -0-C(O)-CH 2 -, it may be preferable that such compounds of general formula (I) (conveniently represented by 15 general formula (IB)) be prepared according to a reaction sequence outlined below in Scheme 17 in which a compound of general formula (XXVI) is reduced (for example with NaBH 4 ) to afford a compound of general formula (IB). O O /C\ /\ /0 __ _ HO C 0 (VV)q-RI 0i (XXVI) NaBH 4 reduction O O HO O - (W)q-RI OH (IB) 20 Scheme 17: Preparation of a compound of general formula (IB), where -(R)a-Y- and X in general formula (I) are -CH 2 -0-C(O)-CH 2 - and OH, respectively, and where W, R 1 and q are as hereinbefore defined.

WO 2008/031157 PCT/AU2007/001353 -36 A compound of general formula (XXVI) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 18 in which a compound of general formula (XXVII) is subjected to a Jones oxidation with chromium 5 trioxide and sulfuric acid according to a procedure outlined in J. Chem. Soc. 1949, 604. 0 E 0 _ _ _ _ _ _R KO

(WV-R

1 OH -OH (XXVII) I Jones Oxidation O 0 HO C C>O C ~~~ ~~ (W)-R 1 0 (XXVI) Scheme 18: Preparation of a compound of general formula (XXVI), where W, R 1 and q 10 are as hereinbefore defined. A compound of general formula (XXVII) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 19 in which a compound of general formula (XXVIII) is treated with an acidic resin such as Amberlyst 5 1 5 in ethanol.

WO 2008/031157 PCT/AU2007/001353 - 37 -- O C_~ (V)g-R 1 E0 (XXVIII) Amberlyst 15 95% EtOH 0 O C (W)q-R 1 --- OH -OH (XXVII) Scheme 19: Preparation of a compound of general formula (XXVII), where W, R' and q are as hereinbefore defined. 5 A compound of general formula (XXVIII) may be prepared using any suitable technique. One approach might involve the reaction sequence outlined below in Scheme 20 in which a compound of general formula (XXIX) is esterified with a compound of general formula (XXX). Compounds of general formulae (XXIX) and (XXX) may be obtained 10 commercially or can be prepared using techniques known in the art. HO O HO (W)q-R (XXX) Esterification (XX)

(-H

2 0) O 0 ~(W)q-R 1 -O0 -o (XXVIII) Scheme 20: Preparation of a compound of general formula (XXVIII), where W, R' and q 15 are as hereinbefore defined.

WO 2008/031157 PCT/AU2007/001353 - 38 Where -(R)a-Y- in general formula (I) represents a divalent ether moiety, for example such as -CH 2 -0-(CH 2

)

2 -, it may be preferable that such compounds of general formula (I) (conveniently represented by general formula (IC)) be prepared according to a reaction 5 sequence outlined below in Scheme 21 in which a compound of general formula (XXXI) is reduced (for example with NaBH 4 ) to afford a compound of general formula (IC). 0 HO C 0 ~~ (W)q-R 1 1! (XXXI) NaBH 4 reduction O HO O/~~ (W)q-R OH (IC) 10 Scheme 21: Preparation of a compound of general formula (IC), where -(R),-Y- and X in general formula (I) are -CH 2 -0-(CH 2

)

2 - and OH, respectively, and where W, R 1 and q are as hereinbefore defined. Compounds of general formula (XXXI) may be prepared using any suitable technique. 15 One approach might involve the reaction sequence outlined below in Scheme 22 in which a compound of general formula (XXXII) is brominated, for example with PPh 3 Br 2 , to afford a compound of general formula (XXXIII) which in turn may undergo a condensation reaction with a compound of general formula (XXX) liberating HBr to afford a compound of general formula (XXXIV) which in turn may be subjected to treatment 20 with an acidic resin such as Amberlyst 15 in ethanol to afford a compound of general formula (XXXV) which in turn may be subjected to a Jones oxidation using chromium trioxide and sulfuric acid according to a procedure outlined in J. Chem. Soc. 1949, 604 to afford a compound of general formula (XXXI).

WO 2008/031157 PCT/AU2007/001353 -39 (W)q-R 1 (W)q-R 1 HO (XXXII) Br (XXXIII) PPh 3 Br 2 ____ - (WV)q-Rl NaH

-

DMF HO 0 0 - (XXXIV) X (XXX) Amberlyst 15 95% EtOH -~ (WMg-R1 O 0 (XXXV) Jones Oxidation HO C O -- (W)q R 1 - OH II 0 (XXXI) Scheme 22: Preparation of a compound of general formula (XXXI), where W, R' and q are as hereinbefore defined. 5 Those skilled in the art will appreciate that the reaction pathways outlined above in Schemes 17-22 may not be suitable for all compounds of the general formulae outlined therein. If the reaction pathway is unsuitable, it is expected that a person skilled in the art could determine an alternative pathway. 10 Compounds contemplated by the present invention are expected to be suitable for treating a disease or condition of a subject. Subjects to be treated include mammalian subjects: humans, primates, livestock animals (including cows, horses, sheep, pigs and goats), companion animals (including dogs, cats, rabbits, guinea pigs), and captive wild animals. Laboratory animals such as rabbits, mice, rats, guinea pigs and hamsters are also 15 contemplated as they may provide a convenient test system. Preferably the subject is a human subject.

WO 2008/031157 PCT/AU2007/001353 - 40 Accordingly, the invention also provides a method of treating a disease or condition in a subject comprising administration to said subject an effective amount of a compound of general formula (I) 5 0 C(R)n X Y (W)q-R 1 OH (I) where X is OR2 or NR 2

R

3 , R 2 and R3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; 10 R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted 15 heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; R' is selected from H and an organic substituent; n is selected from 0 or 1; q is selected from 0 or 1; and 20 p is an integer ranging from 0 to 15.

WO 2008/031157 PCT/AU2007/001353 -41 As used herein, "treating a disease or condition" can refer to either: prophylactic treatment (e.g. preventing or delaying the onset of the disease or condition, or symptoms thereof, or otherwise diminishing the extent or severity of symptoms before symptoms of the disease or condition are apparent); or therapeutic treatment (e.g. alleviation of one or more 5 symptoms, or halting, reversing or otherwise slowing down the progression of one or more symptoms of the disease/condition or the severity thereof). The compounds described herein may be administered in, as appropriate, a treatment or inhibitory effective amount. A treatment effective amount is intended to include an 10 amount which, when administered according to the desired dosing regimen, achieves a desired therapeutic effect, including one or more of: alleviating the symptoms of, preventing or delaying the onset of, inhibiting or slowing the progression of, or halting or reversing altogether the onset or progression of the particular disease or condition being treated. 15 Suitable dosage amounts and dosing regimens to achieve this can be determined by the attending physician and may depend on the particular disease or condition being treated, the severity of the disease or condition as well the general age, health and weight of the subject. 20 Compounds of general formula (I) may be administered in a single dose or a series of doses. While it is possible for such compounds to be administered alone, it is preferable to present the compound(s) as a composition, preferably as a pharmaceutical composition, with one or more pharmaceutically accepted adjuvants. 25 Thus, the present invention further relates to the use of a compound of general formula (I) or a pharmaceutically acceptable salt or prodrug thereof, WO 2008/031157 PCT/AU2007/001353 -42 C (R)n X Y (W)q-R 1 OH (I) where X is OR or NR2R, R2 and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; 5 R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted 10 heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; R' is selected from H and an organic substituent; n is selected from 0 or 1; q is selected from 0 or 1; and 15 p is an integer ranging from 0 to 15, in the manufacture of a medicament for treating a disease or condition in a subject. Formulation constituents of such compositions are well known to those skilled in the art, see for example, Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing, 20 1990. The composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, anti fungal and anti-bacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions may also include other supplementary physiological active agents. 25 WO 2008/031157 PCT/AU2007/001353 - 43 The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including dermal, buccal and sublingual), vaginal or parental (including subcutaneous, intramuscular, intravenous and 5 intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient 10 with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Compositions suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active 15 ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine 20 the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g. inert diluent), preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The 25 tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. 30 WO 2008/031157 PCT/AU2007/001353 - 44 Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable 5 liquid carrier. Compositions suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like. Suitable carriers include mineral oil, propylene 10 glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Transdermal patches may also be used to administer the compounds of the invention. 15 Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter, glycerin, gelatin or polyethylene glycol. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active 20 ingredient such carriers as are known in the art to be appropriate. Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; 25 and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and 30 suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

WO 2008/031157 PCT/AU2007/001353 -45 It should be understood that in addition to the compounds of the invention, the compositions may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include 5 such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include corn starch, methyleellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil 10 of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, 15 sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate. The present invention also relates to prodrugs of general formula (I). Any compound that is a prodrug of a compound of formula (I) is within the scope and spirit of the invention. 20 The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo, either enzymatically or hydrolytically, to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free thiol or hydroxy group is converted into an ester, such as an acetate, or where a free amino group is converted into an amide. Procedures for 25 acylating the compounds of the invention, for example to prepare ester and amide prodrugs, are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base. Other conventional procedures for the selection and preparation of suitable prodrugs are known in the art and are described, for example, in WO 00/23419, Design ofProdrugs, 30 Hans Bundgaard, Ed., Elsevier Science Publishers, 1985, and The Organic Chemistry of WO 2008/031157 PCT/AU2007/001353 - 46 Drug Design and Drug Action, Chapter 8, pp 352-401, Academic press, Inc., 1992, the contents of which are incorporated herein by reference. Compounds in accordance with the invention may also be polymerised to provide unique 5 PDA's. Accordingly, the present invention also provides a method of preparing a polydiacetylene, said method comprising polymerising one or more diyne compounds of general formula (I) 0 C(R)n x Y (W)q-R OH 10 (1) where X is OR 2 or NR 2

R

3 , R 2 and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; 15 Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted 20 heterocyclylene; R1 is selected from H and an organic substituent; n is selected from 0 or 1; q is selected from 0 or 1; and p is an integer ranging from 0 to 15. 25 WO 2008/031157 PCT/AU2007/001353 -47 The compounds may be conveniently polymerised using techniques known in the art for polymerising diacetylene compounds. For example, crystallisation and Langmuir-Blodgett techniques may be employed. 5 Langmuir-Blodgett techniques have been used in the art to prepare monolayer and multilayer PDA films. This technique typically involves spreading a thin layer of diyne monomer on a water surface in a solvent such as chloroform. The solvent rapidly evaporates, which causes the monomers to align with respect to each other and the water surface. A substrate (such as glass or mica) is then brought upwards through the surface of 10 the water, while a computer controlled movable barrier compresses the layer of monomer on the surface of the water so as to keep a constant pressure. This results in the deposition of a highly ordered monolayer of monomers onto the substrate. This process can be repeated to build up several layers. These layers can then be photopolymerised to form extremely thin films of PDA on the substrate. 15 PDA's formed using Langmuir-Blodgett techniques can have limited application as they are typically formed on a substrate. The resulting polymer can then be difficult to remove for use independent of the substrate. Polymerisation of diyne compounds in crystalline form can advantageously overcome this problem. In order to obtain PDA's using this 20 technique, it is necessary to obtain precursor crystal phases of the diyne compounds having a suitable molecular packing. The diyne compounds may be crystallised from an appropriate solvent, from the melt, or from vapour diffusion, so as to provide the monomer crystal phase that can be polymerised. 25 Where solvent crystallisation is employed, a variety of solvents may be used. For example, solvents such as alkyl esters of monocarboxylic acids, alkyl alcohols, paraffins, olefins, benzene, alkylated benzenes, ethers, ketones, petroleum ether, halogenated hydrocarbons, and water may be used. Examples of specific solvents include, but are not limited to, ethylacetate, methyl propionate, methanol, ethanol, butanol, isopropenol, 30 hexane, heptane, 1,4-dimethylheptane, toluene, xylene, trimethylbenzene, ethyl ether, isopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, acetone, WO 2008/031157 PCT/AU2007/001353 - 48 ethylmethylketone, chloroform, dichloromethane, trichloroethane, and mixtures thereof. Crystallisation may, for example, be conducted at room temperature by the evaporation of solutions containing from about 0.0001 to about 0.5, and preferably about 0.002 to about 5 0.2, parts by weight of monomer per parts by weight of solvent or solvent blend. Other conventional recrystallisation techniques may also be used, such as sublimation or by cooling a saturated solution to sufficiently low temperature (typically at or above room temperature) where crystallisation occurs. 10 Suitable crystals may also be grown from the melt using conventional techniques known in the art. The crystalline form of the diyne compounds may then be polymerised by subjecting the 15 monomeric crystals to actinic radiation, heat or mechanical stress. When polymerised by heat, the monomeric crystals will typically be subjected to a temperature below the melting point of the crystals and the decomposition temperature of the resulting polymer. Examples of actinic radiation include, but are not limited to, visible, ultra violet, and 20 gamma radiation. The resulting PDA's may be purified by using a suitable solvent to extract any non polymerised diyne compounds. 25 PDA's formed using the crystallisation technique may advantageously be liquid phase processable in that they may be either melt processable, solution processable or both. In addition to undergoing polymerisation via the conjugated diyne moiety to form PDA's, compounds of general formula (I) may also undergo condensation polymerisation via the 30 X-C(O)-CH(OH)- moiety to yield unique polyesters or polyesteramides having a polymer backbone that presents pendent diyne groups.

WO 2008/031157 PCT/AU2007/001353 -49 Diyne compounds of general formula (I) may undergo autocondensation polymerisation and/or condensation polymerisation with one or more comonomers. In such reactions, X in general formula (I) will generally be -OR 2 as hereinbefore defined. To participate in 5 such reactions, those skilled in the art will appreciate that in compounds of general formula (I) where X = OR 2 , at least R 2 must be sufficiently low in molecular weight to yield a volatile leaving group that can be removed from the reaction mixture and thereby force the reaction in favour of polymerisation. In this case, R 2 will generally be selected from H and an organic substituent having 1 - 6 carbon atoms, such as a C 16 alkyl substituent, 10 preferably a C 1 3 alkyl substituent. The invention therefore also provides a method of preparing a polyester or polyesteramide comprising polymerising one or more diyne compounds of general formula (I). 15 Where X in general formula (I) provides a suitable acid or ester derivative capable of undergoing a condensation reaction, those skilled in the art will appreciate that the a-OH substituent can enable such compounds to undergo autocondensation and form a corresponding polyester polymer backbone with pendent diyne groups. Alternatively, such compounds may undergo condensation polymerisation with one or more other 20 comonomers to yield a copolyester or polyesteramide polymer backbone having pendent diyne groups. Suitable comonomers that may be used to prepare copolyesters or polyesteramides as hereinbefore described include, but are not limited to, 2-hydroxyethanoic acid, 2 25 hydroxypropanoic acid, 3-hydroxypropanoic acid, 2-hydroxybutanoic acid, 3 hydroxybutanoic acid, 4-hydroxybutanoic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-hydroxyhexanoic acid, 2-hydroxypalmitic acid, 2 hydroxystrearic acid, 2-hydroxyoleic acid, propiolactone, gamma-butyrolactone, beta butyrolactone, caprolactone caprolactam, alpha- and beta-amino acids, 2-bromoethanoic 30 acid, 2-bromoethanyl bromide, 2-bromopropanoic acid, 2-bromopropanyl bromide, 2 bromobutanoic acid, 2-bromobutanyl bromide, 2-bromoethanyl chloride, 2- WO 2008/031157 PCT/AU2007/001353 -50 bromopropionyl chloride, 2-bromohexanyl bromide, 2-bromohexanyl chloride, 2 bromostearyl bromide, 2-bromostearyl chloride, and combinations thereof. Those skilled in the art will appreciate that polyesters and polyesteramides of the type 5 described above can also be prepared via ring-opening polymerisation reactions similar to that used to prepare polyesters such as poly(glycolic acid) and poly(lactic acid) and polyamides such as polycaprolactam. Thus, compounds of general formula (I) may be used to prepare cyclic esters comprising two or more ester groups within the cycle (i.e. dilactones or higher cyclic esters) through autocondensation of the -X group with the a-OH 10 group, or condensation of the -X and a-OH moieties with one or more other comonomers. More specifically, compounds of general formula (I) may be used to prepare cyclic esters through autocondensation of the a-OH and -C(O)OR2 moieties, or condensation of the a OH and -C(O)OR 2 moieties with one or more other comonomers. 15 Suitable comonomers for making the cyclic esters include, but are not limited to, 2 hydroxyethanoic acid, 2-hydroxypropanoic acid, 3-hydroxypropanoic acid, 2 hydroxybutanoic acid, 3-hydroxybutanoic acid, 4-hydroxybutanoic acid, 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-hydroxyhexanoic acid, 2 hydroxypalmitic acid, 2-hydroxystearic acid, 2-hydroxyoleic acid, 2-bromoethanoic acid, 20 2-bromoethanyl bromide, 2-bromopropanoic acid, 2-bromopropanyl bromide, 2 bromobutanoic acid, 2-bromobutanyl bromide, 2-bromoethanyl chloride, 2 bromopropionyl chloride, 2-bromohexanyl bromide, 2-bromohexanyl chloride, 2 bromostearyl bromide, 2-bromostearyl chloride, and mixtures thereof. 25 Accordingly, the invention also provides a method of preparing a polyester or polyesteramide, said method comprising polymerising by ring opening polymerisation a cyclic ester having two or more ester groups within the cycle, wherein at least one of said ester groups is the cyclised condensate of a compound of general formula (I). 30 By the phrase "cyclised condensate of a compound of general formula (I)", it will be appreciated from the discussion above and further comments below that it is intended to WO 2008/031157 PCT/AU2007/001353 - 51 define the reaction product resulting from a compound of general formula (I) having undergone condensation through the -X and a-OH moieties so as to form at least part of the cyclic ester. 5 In other words, the cyclised condensate of a compound of general formula (I) may be depicted as the residue structure shown below in Scheme 23, where the dashed lines represent the remainder of the cyclic ester structure. I I(R)n-Y (W)q-Rl 10 ----- Scheme 24: The residue of a compound of general formula (I) in a cyclic ester which has been formed through condensation of the -X and a-OH moieties, where R, Y, W, R 1 , n. and q are as hereinbefore defined. 15 Thus, by "at least one of the ester groups in the cyclic ester" being the cyclised condensate of a compound of general formula (I) is meant that at least part of the cycle of the ester is formed by the residue structure shown in Scheme 24. The cyclic ester may therefore have a structure represented by general formula (ID), 20 WO 2008/031157 PCT/AU2007/001353 - 52 k r o=-C/ I (R)n-Y (Wq -R1 K (ID) where r is an integer ranging from 1 to about 6, preferably from 1 to about 4; k is an integer ranging from 0 to about 5, preferably from 1 to 3, such that when k is 0, r is at least 5 2 and such that the sum of r and k is no greater than about 6; K is selected from H and an optionally substituted alkyl group, preferably from H and a C 1 6 alkyl group; D is selected from optionally substituted alkylene and optionally substituted alkenylene, preferably from optionally substituted CI1 0 alkylene and optionally substituted C 2

.

10 alkenylene; j is selected from 0 or 1; and R, Y, W, R', n, q, and p are as hereinbefore defined. 10 Those skilled in the art will appreciate that when k in formula (ID) is 0, structure (ID) is intended to represent a situation where a compound of formula (I) has undergone autocondensation to form the cyclic ester. In this case, r must be at least 2. Similarly, it will be appreciated that when k in formula (ID) is at least 1, structure ID is intended to 15 represent a situation where a compound of formula (I) has undergone condensation with a suitable comonomer to form the cyclic ester. Those skilled in the art will also appreciate that integers r and k in compounds of general formula (ID) may vary depending on the specific starting compounds and the technique 20 used to make the compound. For example, where a comonomer such as lactic acid has been used to form the cyclic structure, r may be 1 and the remainder of the cycle will be formed by the condensed residue or the "cyclised condensate" of the lactic acid comonomer as shown below in Scheme 24. With reference to formula (ID), in the WO 2008/031157 PCT/AU2007/001353 -53 structure shown below in Scheme 24 both r and k are 1, K is methyl and j is 0. ZO \ (R)n-Y (W)g-R1 O==C C==0 5 Scheme 24: A cyclic ester formed through condensation of the -X and a-OH moieties of a compound of general formula (I) with lactic acid, where R, Y, W, R', n. and q are as hereinbefore defined. In a given compound of formula (ID), r will typically vary between 1, 2, 3, 4, and possibly 10 5 and 6. A mixture of cyclic compounds having different ring sizes may also be formed. The cyclic esters may undergo ring opening polymerisation with itself or with one or more other cyclic ester or cyclic amide comonomers. As a comonomer, such cyclic esters or cyclic amides may contain one or more ester or amide groups, respectively, that define the 15 cycle. Suitable cyclic esters or cyclic amides for use as a comonomer include, but are not limited to, caprolactone, lauryllactone, caprolactam, lauryllactam and mixtures thereof. Polyester or polyesteramide products of compounds of general formula (I) are expected to have a number of useful applications. For example, the pendent diyne groups may provide 20 these polymers with unique biological activity. The pendent diyne groups of the polymer products may also act as a site for further reaction that will enable the polymers to be functionalised or modified for use in specific applications. For example, metathesis chemistry may be used to modify the pendent diyne 25 groups. The invention also therefore provides a polymer product comprising a polymerised residue of a compound of general formula (I) WO 2008/031157 PCT/AU2007/001353 -54 C (R)n X Y (W)q-R 1 OH (I) where X is OR or NR 2

R

3 , R 2 and R 3 are each independently selected from H and an 5 organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; 10 W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene;

R

1 is selected from H and an organic substituent; n is selected from 0 or 1; 15 q is selected from 0 or 1; and p is an integer ranging from 0 to 15. By reference to a compound of general formula (I) being a "polymerised residue" in a polymer product is meant that a compound of general formula (I) has taken part in a 20 polymerisation reaction to become incorporated within a polymeric structure. In other words, the compound has functioned as a monomer in a polymerisation reaction. The present invention will hereinafter be further described with reference to the following non-limiting examples. 25 WO 2008/031157 PCT/AU2007/001353 - 55 EXAMPLES General: Proton NMR spectra were obtained on Bruker AV400 and Bruker AV200 spectrometer operating at 400 MHz and 200 MHz, respectively. All spectra were obtained 5 at 23'C unless specified. Chemical shifts are reported in parts per million (ppm) on the 6 scale and relative to the chloroform peak at 7.26 ppm (1H). Oven dried glassware was used in all reactions carried out under an inert atmosphere (either dry nitrogen or argon). All starting materials and reagents were obtained commercially unless otherwise stated. Removal of solvents "under reduced pressure" refers to the process of bulk solvent 10 removal by rotary evaporation (low vacuum pump) followed by application of high vacuum pump (oil pump) for a minimum of 30 min. Analytical thin layer chromatography (TLC) was performed on plastic- or aluminium-backed Merck Kieselgel KG60F 25 4 silica plates and visualised using short wave ultraviolet light, potassium permanganate or phosphomolybdate dip. Flash chromatography was performed using 230-400 mesh Merck 15 Silica Gel 60 under positive pressure. Tetrahydrofuran and dichloromethane were obtained from a solvent dispensing system under an inert atmosphere. All other reagents and solvents were used as purchased. Example 1 20 Part A: Synthesis of 11-Trimethylsilanyl-undec-10-ynoic acid 0 H O" Si 25 A solution of undec-10-ynoic acid (5 g, 27.43 mmol) in anhydrous THF (200 ml) at -78"C was treated with n-BuLi (1.6 M in hexane, 37.72 ml, 60.35 mmol, 2.2 mol equiv.). After stirring for 2 min trimethylsilyl chloride (10.76 ml, 85.04 mmol, 9.24 g, 3.1 mol equiv.) was added. The reaction mixture was allowed to warm slowly to 25'C and was stirred for 1 hr. The reaction was quenched with the addition of aqueous 2 N HCl (50 ml) and WO 2008/031157 PCT/AU2007/001353 - 56 extracted with CH 2 Cl 2 (3 x 50 ml). The organic layer was dried over Na 2

SO

4 , filtered and concentrated. Column chromatography (SiO 2 , EtOAc-hexane 2:1) afforded the acid (5.3 g, 20.83 mmol, 76 %) as a white solid: 'H-NMR (CDCl 3 , 400 MHz): 6[ppm]= 0.61 (9H, s), 1.17 - 1.39 (8H, in), 1.41 - 1.53 (2H, 5 m), 1.55 - 1.68 (2H, m), 2.17 (2H, t, J= 6.5 Hz), 2.35 (2H, t, J= 6.5 Hz) Part B: Synthesis of 2-Hydroxy-11-trimethylsilanyl-undec-10-vnoic acid 0 HO OH Si 10 Dry diisopropylamine (6.71 ml, 4.85 g, 47.91 mmol, 2.3 equiv) and dry THF (100 ml) were introduced into an argon-swept flask and cooled to 0"C. N-BuLi (1.6 M in hexane, 27.34 ml, 43.74 mmol, 2.1 mol equiv.) was introduced in a fine stream. The mixture was then stirred for 15-30 min. A solution of 11 -trimethylsilanyl-undec- 10-ynoic acid (5.3 g, 15 20.83 mmol) in THF (20 ml) was added with continued cooling and stirring. The stirring was continued for 30 min at 0"C and then at 50C for 1.5 hr. The reaction was cooled to room temperature and oxygen was bubbled through the solution for 30 min. The reaction was quenched with water (200 ml) and acidified with 5 N aqueous HCl to pH 1. The aqueous mixture was extracted with diethyl ether (3 x 50 ml) then the combined organic 20 layers were washed with saturated NaCl solution, dried over Na 2

SO

4 , filtered and concentrated. The crude product was reacted on without further purification. 'H-NMR (CDCl 3 , 400 MHz): S[ppm]= 0.62 (9H, s), 1.21 - 1.69 (12H, in), 2.15 (2H, t, J= 6.8 Hz), 4.13 (lH, dd, J= 13.5, 3.2 Hz) WO 2008/031157 PCT/AU2007/001353 - 57 Part C: Synthesis of 2-Hydroxy-11-trimethylsilanyl-undec-10-ynoic acid methyl ester 0 Me,'O 0 OH Si 1 5 To a solution of 2-hydroxy-11 -trimethylsilanyl-undec-10-ynoic acid (4.8 g, 17.74 mmol) was dissolved in dry Methanol (100 ml) under an argon atmosphere trimethylsilyl chloride (11.22 ml, 9.64 g, 88.74 mmol, 5 equiv) was added. The mixture was stirred at room temperature for 12 hr. The methanol was removed under reduced pressure and the residue submitted to column chromatography (SiO 2 , EtOAc-Hexane 1:2). Purification afforded 10 the methyl ester (2.67 g, 9.40 mmol, 53 %) as a clear oil: 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.62 (9H, s), 1.19 - 1.67 (12H, in), 2.17 (2H, t, J 6.9 Hz), 3.71 (3H, s), 4.13 (1H, dd, J= 13.5, 3.2 Hz) Part D: Synthesis of 2-Hydroxy-undec-10-ynoic acid methyl ester 15 0 Me,'O 0 OH H To a solution of 2-hydroxy-11-trimethylsilanyl-undec-10-ynoic acid methyl ester (1.4 g, 4.92 mmol) in dry THF (20 ml) was added tetrabutylammonium fluoride (1.0 M in THF, 20 7.38 ml, 7.38 mmol, 1.5 equiv). The dark solution was stirred at room temperature for 3 h and then diluted with water. The mixture was extracted with diethyl ether (3 x 30 ml) and the combined organic layers were dried over Na 2

SO

4 . Removal of the solvent left an oil that was used without further purification. This intermediate was not characterized prior to use. 25 WO 2008/031157 PCT/AU2007/001353 - 58 Part E: Synthesis of 1-Iodo-hept-1-yne 5 N-BuLi (1.6 M in hexane, 25.34 ml, 40.55 mmol, 1.3 equiv was added slowly to a solution of hept-l-yne (4.08 ml, 31.19 mmol) in dry THF at 20'C under argon and was stirred for 1 hr. The mixture was then cooled to 40"C and treated with iodide. After stirring for 12 hr at room temperature the reaction mixture was quenched with saturated NH 4 Cl (100 ml) solution and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were 10 washed with saturated sodium thiosulfate solution, and dried over Na 2

SO

4 . Removal of the solvent left an oil that was used without further purification. 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.88 (311, t, J= 7.5 Hz), 1.32 - 1.59 (6H, m), 2.35 (2H, t, J= 6.9 Hz) 15 Part F: Synthesis of 2-Hydroxy-octadeca-10, 12-divnoic acid 0 HO ' 6 H OHN 2-hydroxy-undec-10-ynoic acid methyl ester (1.04 g, 4.92 mmol, 0.5 equiv) was suspended 20 in a solution of 5 ml 10 % potassium hydroxide in water and hydroxylamine hydrochloride (34.2 mg, 0.49 mmol, 0.05 equiv) was added. Then a catalyst consisting of a solution of Copper(I)chloride (0.155 g, 1.57 mmol, 0.16 equiv) in 1.5 g 70 % aqueous ethylamine was added. A yellow precipitate formed immediately. A solution of 1-iodo-hept-1-yne (2.19 g, 9.84 mmol) in 10 ml methanol was then added dropwise with stirring. The suspension was 25 stirred for 1 hour after the addition. The reaction mixture was acidified by the addition of 2.5 N HCl, filtered and the filtrate and precipitate were washed with diethyl ether (3 x 20 ml). The combined ether layers were washed with water (20 ml), sodium thiosulfate solution (20 ml), water (20 ml) and sodium chloride solution (20 ml). After drying over Na 2

SO

4 the solvents were removed under reduced pressure. The residue was induced to WO 2008/031157 PCT/AU2007/001353 -59 crystallise by scratching under petroleum ether. The crystals of the product were filtered of and recrystallised giving (0.53 g, 1.81 mmol, 37 %). 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.88 (3H, t, J= 7.5 Hz), 1.17 - 1.55 (14H, m), 1.56 - 1.71 (2H, m), 1.75 - 1.81 (2H, m), 2.23 (4H, m), 4.21. 5 Example 2 Part A: Synthesis of Pentadeca-8,10-divn-1-ol HO 10 To a stirred solution of 1-iodo-hex-1-yne (6.2 g, 29.80 mmol) and non-8-yn-1-ol (2.46 g, 17.53 mmol) in pyrrolidine (50 ml) under an argon atmosphere, was added copper(I) iodide (2.98 mmol, 0.57 g). After stirring at room temperature for 30 min, the mixture was 15 hydrolysed with a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The organic extract was dried over MgSO 4 and the solvent was removed in vacuo. Column chromatography (SiO 2 , EtOAc-hexane: 2:1) gave 3.35 g (15.19 mmol, 87 %) of pure pentadeca-8,10-diyn-1-ol. 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.89 (3H, t, J = 7.3 Hz), 1.26 - 1.62 (14H, m), 2.24 20 (4H, t, J = 6.6 Hz), 3.62 (2H, t, J = 7.0 Hz) Part B: Synthesis of 15-Iodo-pentadeca-5,7-divne 25 To a solution of pentadeca-8,10-diyn-1-ol (2.6 g, 11.80 mmol), triphenylphosphine (3.4 g, 12.98 mmol) and imidazole (0.96 g, 14.16 mmol) in CH 2 C1 2 (60 ml), was added iodine (3.14 g, 12.39 mmol) in small portions at -10 deg. The solution was stirred at -10 C for 1 hr before it was quenched with sat aqueous Na 2

S

2 0 3 (80 ml). The organic phase was WO 2008/031157 PCT/AU2007/001353 - 60 separated and the aqueous phase was extracted with CH 2 C1 2 (3 x 80 ml). The combined organic phases were dried over Na 2

SO

4 and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (SiO 2 , gradient eluent 0 % to 2 % EtOAc in hexanes) to provide pure 15-iodo-pentadeca-5, 7-diyne 3.60 g (10.88 5 mmol, 92 %). 'H-NMR (CDCl 3 , 400 MHz): 6[ppm]= 0.90 (3H, t, J = 7.3 Hz), 1.22 - 1.58 (12H, m), 1.81 (2H, quint, J = 7.2 Hz), 2.24 (4H, t, J= 6.6 Hz), 3.18 (2H, t, J = 7.0 Hz) Part C: Synthesis of 2, 3-Dimethoxy-1,3-butadiene-diene 10 MeO MeO:( A mixture of biacetyl (17.2 g, 0.2 mol), absolute methanol (25 ml, 1.25 mol), trimethyl orthofornate (63.6 g, 0.6 mol) and concentrated sulfuric acid (95 drops) was refluxed for 15 10 h. The excess of reagents were distilled of and the remaining liquid was vacuum distilled. Ammonium dihydrogenphosphate (25 mg) and a few crystals of hydroquinone were added and the liquid was heated at 100 deg to 110 deg. Methanol slowly distilled over, together with some remaining orthoformate. The temperature was raised (160 deg to 170 deg) and the colourless oily liquid collected between 129 deg and 132 deg (17.3 g or 20 76 % of crude diene). Redistillation gave 2,3-dimethoxy-1, 3-butadiene (15.5 g, 68 %), b. p. 132 deg - 132.5 deg. 1 H-NMR (CDCl 3 , 400 MHz): 6[ppm] = 3.57 (6H, s), 4.02 (2H, d, J = 1.5 Hz), 4.57 (2H, d, J= 1.5 Hz) WO 2008/031157 PCT/AU2007/001353 -61 Part D: Synthesis of (±) 5,6-DimethoxV-5,6-dimethyl-[1, 4ldioxane-2-one OMe 0 OMe 5 Triphenylphosphine hydrobromide (165 mg, 0.48 mmol) was added to a stirred solution of hydroxy-acetic acid (270 mg, 3.55 mmol) and 2,3-dimethoxy-1,3-butadiene (490 mg, 2.29 mmol) in CH 2 C1 2 (10 ml) at room temperature. After 3 h, the reaction mixture was diluted with CH 2 Cl 2 (20 ml). The organic phase was washed with saturated aqueous NaHCO 3 (20 ml), dried (Na 2

SO

4 ), filtered and concentrated in vacuo. The residue was purified by flash 10 chromatography (hexane-EtOAc 4:1) to give the lactone as a white solid (559 mg, 83 %). 'H-NMR (CDCl 3 , 400 MHz): 6[ppm] = 1.38 (3H, s), 1.49 (3H, s), 3.30 (3H, s), 3.43 (3H, s), 4.14 (1H, d, J = 17.6 Hz), 4.28 (1H, d, J = 17.6) Part E: Synthesis of (±) 5, 6-Dimethoxy-5, 6-dimethyl-3-pentadeca-8, 10-divnvl-[1, 41 15 dioxan-one OMe -- O MeO O Lithium bis(trimethylsilyl)amide (IM in THF, 1.0 ml) was added to a stirred solution of 20 5,6-Dimethoxy-5,6-dimethyl-[1, 4] dioxan-2-one (200 mg, 1.05 mmol) in THF (5 ml) at 78 deg. After 15 min 15-Iodo-pentadeca-5,7-diyne (1.04 g, 3.15 mmol) was added and the solution stirred at -78 deg for 1 h and then warmed to -20 deg for 2.5 h. The reaction was quenched at -20 deg with acetic acid (0.148 ml, 2.1 mmol), Et 2 O was added and the precipitated salts removed by filtration through a plug of silica. The crude product was 25 purified column chromatography (SiO 2 , Et 2 O-petrol 8:1) to give the lactone as a colourless oil 0.17 g (0.44 mmol, 42 %).

WO 2008/031157 PCT/AU2007/001353 - 62 'H-NMR (CDC1 3 , 400 MHz): S[ppm]= 0.89 (3H, t, J = 7.2 Hz), 1.25 - 1.56 (14H, m), 1.38 (3H, s), 1.47 (3H, s), 1.85 (2H, quart, J = 6.2 Hz), 2.23 (4H, quart, J = 5.9 Hz), 3.30 (3H, s), 3.41 (3H, s), 4.13 (1H, t, J = 5.8 Hz) 5 Part F: Synthesis of 2-hydroxy-heptadeca-10, 12-divnoic acid methyl ester

HO

0 O (1) 5,6-Dimethoxy-5,6-dimethyl-3-pentadeca-8,10-diynyl-[1,4] dioxan-one (0.15 g, 0.38 10 mmol) was dissolved in a 0.3 M solution of trimethylsilyl chloride (2.29 mmol, 0.249 g) in Methanol (7 ml) and stirred at room temperature for 25 min. The reaction was concentrated in vacuo giving the pure product in 95 % yield (0.36 mmol, 105 mg). 'H-NMR (CDCl 3 , 400 MHz): 6[ppm] = 0.90 (3H, t, J= 7.3 Hz), 1.22 - 1.56 (14H, m), 1.56 - 1.69 (1H, m), 1.71-1.84 (1H, m), 2.00 - 2.55 (1H, br), 3.79 (3H, s), 4.18 (1H, dd, J= 15 3.4, J 2 = 7.7) Part G: Synthesis of 2-hydroxy-heptadeca-10, 12-divnoic acid

HO

O HO 20 (i) 5,6-Dimethoxy-5, 6-dimethyl-3-pentadeca-8,10-diynyl-[1,4] dioxan-one (0.15 g, 0.38 mmol) was dissolved in a solution of TFA-H20 (9:1, 5 ml) and stirred at room temperature for 45 min. NaOH (2.5 M, 5 ml) was added, the mixture stirred for 15 min, and then extracted with CH 2 C1 2 (20 ml). The aqueous layer was acidified with 3N HCl, extracted WO 2008/031157 PCT/AU2007/001353 - 63 with EtOAc (10 ml), dried (MgSO 4 ) and concentrated in vacuo to give the pure product in 91 % yield (0,35 mmol, 96 mg). 'H-NMR (CDCl 3 , 400 MHz): S[ppm]= 0.89 (3H, t, J = 7.2 Hz), 1.21 - 1.54 (14H, m), 1.58 - 1.72 (lH, m), 1.75-1.87 (1H, m), 4.18 (1H, dd, J' = 3.4, J 2 = 7.7), 10.2-10.8 (2H, br) 5 Example 3 Part A: Crystallisation of 2-hydroxy-heptadeca-10,12-diynoic acid 10 A solution of 2-hydroxy-heptadeca-10,12-diynoic acid (100 mg, 0.36 mmol) in methanol (30 ml) was reduced in volume to 1 ml under vacuum at 40C and had added to it a hydrochloric acid solution in tetrahydrofuran (1 M aq. HCl, 20 ml in 20 ml THF). The solution was stirred overnight at room temperature, after which the solvent was removed to give a clear oil. This was dissolved in dichloromethane (1 ml) into which hexane was then 15 introduced by slow vapour diffusion in a sealed system at -10 C. After 3 days well-formed crystals of 2-hydroxy-heptadecadiynoic acid had appeared in the dichloromethane. Part B: Polymerisation of single crystals of 2-hydroxy-heptadeca-10,12-divnoic acid 20 Several single crystals prepared as outlined in Part A above were taken and exposed to UV radiation (254 nm) from a small handheld lamp. After a few second's exposure the crystals turned a deep blue. Upon exposure to organic solvents or high temperatures the crystals turned a deep red colour. After storage at -1 OC for a week, the clear crystals had taken on a light blue hue, due to the thermal polymerisation of the diacetylene groups. 25 WO 2008/031157 PCT/AU2007/001353 - 64 Example 4 Part A: Synthesis of 4-[(Trimethylsilvl)ethynyllbenzaldehyde 0 H 5 TMS A deaerated solution of 24.5 g (132 mmol) of 4-bromobenzaldehyde and 1.00 g of triphenylphosphine in 300 ml of anhydrous triethylamine was treated with 20.0 g (204 mmol) of ethynyltrimethylsilane and then 0.3 g of palladium(II)acetate under argon. The 10 mixture was heated at reflux for 2 h, cooled and filtered to give 24.Og (100 %) of triethylamine hydrobromide. The filtrate was concentrated to an oil which solidified into long needles. The crude material was dissolved in hexane and filtered through silica gel to give 26.3 g (130 mmol, 98.6 %) of 4-[(trimethylsilyl)ethynyl]benzaldehyde. The material was used in the next step without any further purification. 15 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.21(s, 9 H), 7.60 (q, 4 H, J = 7.0 Hz), 9.85 (s, 1 H) Part B: Synthesis of 4- [(Trimethylsilyl)ethynyl-phenyll methanol 20 TMS OH To a stirred solution of 4-[(trimethylsilyl)ethynyl]benzaldehyde (0.50 g, 2.47 mmol) in dry ethanol (10 ml) was added sodium borohydride (0.32 g, 8.50 mmol). The reduction was 25 almost instantaneous at room temperature. The reaction mixture was carefully quenched with half-saturated aqueous ammonium chloride solution (30 ml) and extracted with dichloromethane (2 x 20 ml). The combined organic layers were washed with saturated WO 2008/031157 PCT/AU2007/001353 - 65 brine (2 x 15 ml), dried over MgS04, filtered and concentrated under reduced pressure to yield 4-[(trimethylsilyl)ethynyl-phenyl]methanol (0.47 g, 2.32 mmol, 94%). The material was used in the next step without any further purification. 'H-NMR (CDCl 3 , 200 MHz): 8[ppm] = 0.25 (s, 9H), 1.65 (t, 1H, J= 5.9 Hz), 4.69 (d, 2H, J 5 = 5.8 Hz), 7.29 (d, 2H, J = 8.3 Hz), 7.46 (d, 2H, J = 8.3 Hz) Part C: Synthesis of (4-Ethynyl-phenyl)-methanol H OH H 10 4-[(Trimethylsilyl)ethynyl-phenyl]methanol (0.47 g, 2.30 mmol) was treated with potassium carbonate (0.34 g, 2.47 mmol) in 10 ml of methanol under argon at room temperature for 2 h. The solution was quenched with half saturated aqueous ammonium chloride solution (30 ml) and extracted with ether (2 x 25 ml). The combined organic 15 layers were washed with saturated brine (2 x 20 ml), dried over MgS04, filtered and concentrated under reduced pressure giving the product as a pale yellow oil in quantitative yield. The material was used in the next step without any further purification. 1H-NMR (CDCl 3 , 200 MHz): S[ppm] = 1.67 (tr, 1H, J = 5.9 Hz), 4.71 (d, 2H, J = 5.9 Hz), 7.32 (d, 2H, J = 8.5 Hz), 7.50 (d, 2H, J= 8.5 Hz) 20 Part D: Synthesis of (4-Dodeca-1,3-divnyl-phenyl)-methanol OH 25 A solution of (4-ethynyl-phenyl)-methanol (0.50 g, 3.78 mmol) and 1-iododecyne (3.00 g, 11.4 mmol) in degassed piperidine (10 ml) was cooled to 0C under argon.

WO 2008/031157 PCT/AU2007/001353 - 66 Copper(I)chloride (14.0 mg, 0.38 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 1 h the reaction mixture was quenched with half saturated aqueous ammonium chloride solution (30 ml) and extracted with diethyl ether (2 x 20 ml). The combined organic layers were washed with saturated brine (2 x 20 ml), dried 5 over Na 2

SO

4 , filtered and concentrated under reduced pressure. Chromatography on silica (15 % ethyl acetate in PET-spirit) gave (4-dodeca-1,3-diynyl-phenyl)-methanol (0.44 g, 1.63 mmol). 'H-NMR (CDC1 3 , 200 MHz): 6[ppm] = 0.85 (tr, 3H, J = 6.7 Hz), 1.75 - 1.17 (in, 13 H), 2.36 (tr, 2H, J = 6.9 Hz), 4.70 (d, 2H, J= 5.9 Hz), 7.30 (d, 2H, J = 8.2 Hz), 7.47 (d, 2H, J= 10 8.2 Hz) Part E: Synthesis of 1-Bromomethyl-4-dodeca-1,3-divnvl-benzene Br 15 To a solution of (4-dodeca-1,3-diynyl-phenyl)-methanol (2.97 g, 11.0 mmol) and pyridine (17.7 mmol, 1.40 ml) in acetonitrile (30 ml) was added at 0"C in 10 min solid PPh 3 Br 2 (6.10 g, 14.40 mmol). After stirring at room temperature for 1 h (disappearance of alcohol is checked by TLC), the reaction mixture was filtered through a short pad of silica gel and 20 rinsed with ether-pentane 1/10 ( 200 ml) to give the pure bromide (3.10 g, 9.36 mmol, 85 'H-NMR (CDCl 3 , 400 MHz): 6[ppm] = 0.88 (tr, 3H, J = 6.0 Hz), 1.67 - 1.11 (in, 12H), 2.36 (tr, 2H, J = 6.8 Hz), 4.46 (s, 2H), 7.32 (d, 2H, J = 8.3 Hz), 7.44 (d, 2H, J = 8.3 Hz) WO 2008/031157 PCT/AU2007/001353 - 67 Part F: Synthesis of 3-(4-Dodeca-1,3-divnvl-benzvl)-5,6-dimethoxv-5,6-dimethvl [1,41dioxan-2-one OMe 0 OMe 0 5 Lithium bis(trimethylsilyl)amide (1M in THF, 3.12 ml) was added to a stirred solution of 5,6-dimethoxy-5,6-dimethyl-[I, 4] dioxan-2-one (0.59 g, 3.12 mmol) in THF (20 ml) at 78'C. After 15 min 1-bromomethyl-4-dodeca-1,3-diynyl-benzene (3.10 g, 9.36 mmol) was added and the solution stirred at -78'C for 1 h and then warmed to -20'C for 2.5 h. The 10 reaction was quenched at -20'C with acetic acid (0.36 ml, 6.24 mmol) then Et 2 O (20 ml) was added and the precipitated salts were removed by filtration through a plug of silica. The crude product was purified by column chromatography (SiO 2 , Et 2 O-petrol, 8:1) to give the lactone as a colourless oil (1.21 g, 2.75 mmol, 88 %). 'H-NMR (CDCl 3 , 400 MHz): 6[ppm] = 0.89 (tr, 3H, J = 6.6 Hz), 1.46 - 1.22 (m, 16H), 15 1.62 - 1.52 (m, 2H), 2.35 (tr, 2H, J = 7.0 Hz), 3.06 (s, 3H), 3.15 (d, 2H, J = 5.5 Hz), 3.24 (s, 3H), 4.37 (tr, 1H, J = 5.0 Hz), 7.22 (d, 2H, J = 8.3 Hz), 7.38 (d, 2H, J = 8.3 Hz) Part G: Synthesis of 3-(4-Dodeca-1,3-divnvl-phenyl)-2-hydroxy-propionic acid 200 HO OH 20 3-(4-Dodeca-1,3-diynyl-benzyl)-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (0.15 g, 0.38 mmol) was dissolved in a solution of TFA-H 2 0 (9:1, 5 ml) and stirred at room temperature for 45 min. NaOH (2.5 M, 5 ml) was added, the mixture stirred for 15 min and 25 then extracted with CH 2 Cl 2 (3 x 20 ml). The combined organic layers were washed with 3 WO 2008/031157 PCT/AU2007/001353 -68 N HC1, dried (MgSO 4 ) and concentrated in vacuo to give the pure product in 91 % yield (0,35 mmol, 96 mg). 'H-NMR (CDCl 3 , 200 MHz): S[ppm] = 0.88 (tr, 3H, J = 6.2 Hz), 1.68 - 1.07 (m, 12 H), 2.35 (tr, 2H, J = 6.8 Hz), 2.98 (dd, 1H, J = 14.0 Hz, J = 7.0 Hz), 3.21 (dd, 1H, J = 14 Hz, J 5 = 3.9 Hz), 4.51 (dd, 1H, J = 7.0 Hz, J = 3.9 Hz), 7.20 (d, 2H, J = 8.1 Hz), 7.42 (d, 2H, J = 8.1 Hz) Part H: Synthesis of 3-(4-Dodeca-1,3-diynyl-phenyl)-2-hydroxy-propionic acid methyl ester 10 0/ O H 3-(4-Dodeca-1,3-diynyl-benzyl)-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (0.15 g, 0.34 mmol) was dissolved in a 0.5 M solution of TMS-chloride in MeOH (5 ml, 2.5 mmol) 15 and stirred at room temperature for 30 min. The reaction was diluted with saturated aqueous NaHCO 3 (20 ml), the aqueous layer extracted with CH 2 Cl 2 (3 x 20 ml), dried (MgSO 4 ) and concentrated in vacuo to give the ester as a yellow oil (0.11 g, 0.32 mmol, 94 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.89 (tr, 3H, J = 6.2 Hz), 1.61 - 1.20 (m, 12H), 20 2.35 (tr, 2H, J = 7.0 Hz), 2.72 (d, 1H, J = 5.9 Hz), 2.95 (dd, 1H, J = 14.0 Hz, J = 7.0 Hz), 3.11 (dd, 1H, J= 14.0 Hz, J = 3,9 Hz), 3.77 (s, 3H), 4.44 (ddd, 1H, J = 4.5 Hz, J= 6.2 Hz, J = 10.4 Hz), 7.15 (d, 2H, J = 8.1 Hz), 7.40 9d, 2H, J= 8.1 Hz) WO 2008/031157 PCT/AU2007/001353 -69 Part I: Synthesis of N-Benzvl-3-(4-dodeca-1,3-divnvl-phenyl)-2-hydroxy propionamide OH 5 3-(4-Dodeca-1,3-diynyl-benzyl)-5,6-dimethoxy-5,6-dimethyl-[1,4]dioxan-2-one (0.15 g, 0.34 mmol) was dissolved in benzylamine (5 ml) and stirred at room temperature for 120 h. The reaction was concentrated in vacuo to yield the amide as a white solid (0.16 mmol, 0.06 g, 47 %). 10 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.87 (tr, 3H, J = 6.8 Hz), 1.62 - 1.24 (m, 12 H), 2.36 (tr, 2H, J = 7.0 Hz), 3.01 - 2.75 (br, 1H), 3.11 (dd, 1H, J = 13.8 Hz, J = 3.1 Hz), 3.28 (dd, 1H, J = 13.8 Hz, J = 3.3 Hz), 3.88 (s, 1H), 4.39-4.29 (m, 2H), 4.80 (d, 1H, J = 15.3 Hz), 7.42 -7.12 (m, 1OH). 15 Example 5 Part A: Synthesis of Synthesis of 11-iodo-undec-10-yn-1-ol HO 20 A 2.5 molar solution of n-butyl lithium in hexane (68.3 mmol, 27.3 ml) was added slowly to a solution of undec-10-yn-l-ol (5.00 g, 29.7 mmol) in dry THF (500 ml) at -20'C under argon and stirred for 1 h. The reaction mixture was cooled to -40'C and treated with iodine (38.6 mmol, 9.80 g). After stirring for 12 h at room temperature the reaction mixture was 25 quenched with half saturated ammonium chloride solution (1000 ml) and extracted with diethyl ether (2 x 300 ml). The combined organic layers were washed with half saturated sodium thiosulfate solution (2 x 200 ml) and saturated brine (2 x 20 ml), dried over WO 2008/031157 PCT/AU2007/001353 - 70 Na 2

SO

4 , filtered and concentrated under reduced pressure giving 11-iodo-undec-10-yn-1-ol in quantitative yield. The material was used in the next step without any further purification. 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 1.73 - 1.18 (m, 14 H), 2.34 (tr, 2H, J = 7.0 Hz), 5 3.62 (tr, 2H, J = 6.6 Hz) Part B: Synthesis of 13-Phenyl-trideca-10, 12-diyn-1-ol 10 A solution of of 11 -iodo-undec-10-yn-1-ol (29.7 mmol, 8.74 g) and ethynyl benzene (89.1 mmol, 9.80 ml) in degassed piperidine (50 ml) was cooled to 0"C under argon. Copper(I)iodide (0.57 g, 2.97 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 1 h the reaction mixture was quenched with half 15 saturated aqueous ammonium chloride solution (200 ml) and extracted with diethyl ether (2 x 200 ml). The combined organic layers were washed with saturated brine (2 x 200 ml), dried over Na 2

SO

4 , filtered and concentrated under reduced pressure. Chromatography on silica (15 % ethyl acetate in PET-spirit) gave 13-phenyl-trideca-10, 12-diyn-l-ol (4.98 g, 18.6 mmol). 20 'H-NMR (CDCl 3 , 200 MHz): 6[ppm] = 1.66 - 1.07 (in, 14 H), 2.36 (tr, 2H, J = 6.8 Hz), 3.64 (2H, J = 5.5 Hz, J= 6.4 Hz), 7.36 - 7.22 (m, 3 H), 7.52 - 7.42 (in, 2 H) WO 2008/031157 PCT/AU2007/001353 - 71 Part C: Synthesis of (13-Iodo-trideca-1,3-divnyl)-benzene 5 To a solution of 13-phenyl-trideca-10, 12-diyn-l-ol (0.50 g, 1.86 mmol), PPh 3 (0.54 g, 2.05 mmol) imidazole (0.15 g, 2.23 mmol) in CH 2 Cl 2 (50 ml) was added 12 (0.50 g, 1.95 mmol) in small portions at -10 C. The solution was stirred at -10 C for 1 h before it was quenched with saturated aqueous Na 2

S

2 0 3 (30 ml). The organic phase was separated and the aqueous phase was extracted with CH 2 Cl 2 (3 x 20 ml). The combined organic phases 10 were dried over Na 2

SO

4 and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography [Gradient eluent 0% to 2% EtOAc in hexane] to provide the iodide in as a pale yellow oil (0.43 g, 61 %). 'H-NMR (CDCl 3 , 200 MHz): S[ppm] = 1.66 - 1.05 (m, 13 H), 1.91 - 1.68 (m, 2H), 2.36 (tr, 2H, J = 6.8 Hz), 3.19 (tr, 2H, J = 7.0 Hz), 7.38 -7.24 (m, 3H), 7.53 - 7.42 (m, 2H) 15 Part D: Synthesis of 5,6-Dimethoxy-5,6-dimethyl-3-(13-phenyl-trideca-10,12-divnvl) [1,41dioxan-2-one O Me 0 20 Lithium bis(trimethylsilyl)amide (1M in THF, 2.36 ml) was added to a stirred solution of 5,6-dimethoxy-5,6-dimethyl-[1, 4] dioxan-2-one (0.50 g, 2.36 mmol) in THF (20 ml) at 78*C. After 15 min (13-iodo-trideca-1,3-diynyl)-benzene (2.98 g, 7.88 mmol) was added and the solution stirred at -78'C for 1 h and then warmed to -20'C for 2.5 h. The reaction 25 was quenched at -20'C with acetic acid (0.31 ml, 5.26 mmol) then Et 2 O (20 ml) was added and the precipitated salts removed by filtration through a plug of silica. The crude product WO 2008/031157 PCT/AU2007/001353 - 72 was purified through column chromatography (SiO 2 , Et 2 O-petrol, 8:1) to give the lactone as a colourless oil 0.41 g (0.92 mmol, 39 %). 'H-NMR (CDCl 3 , 400 MHz): 6[pprm] = 1.60 - 1.23 (in, 20H), 1.86 (quart, 2H, J = 7.8 Hz), 2.36 (tr, 2H, J = 7.0 Hz), 3.30 (s, 3H), 3.42 (s, 3H), 7.37 - 7.26 (in, 3H), 7.51-7.46 (in, 2H) 5 Part E: Synthesis of 2-hydroxy-15-phenyl-pentadeca-12,14-divnoic acid OH 10 5,6-Dimethoxy-5,6-dimethyl-3-(13-phenyl-trideca-10,12-diynyl)-[1,4]dioxan-2-one (0.15 g, 0.38 mmol) was dissolved in a solution of TFA-H 2 0 (9:1, 5 ml) and stirred at room temperature for 45 min. NaOH (2.5 M, 5 ml) was added, the mixture stirred for 15 min, and then extracted with CH 2 C1 2 (20 ml). The aqueous layer was acidified with 3 N HCl, extracted with EtOAc (10 ml), dried (MgS04) and concentrated in vacuo to give the pure 15 product in 91 % yield (0.35 mmol, 96.0 mg). 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 1.62-1.22 (in, 14H), 1.79-1.62 (m, 1H), 1.92-1.77 (m, 1H), 2.36 (t, J = 7.02 Hz, 2H), 4.28 (dd, J = 7.2 Hz, J = 4.1 Hz , 1H), 7.35-7.27 (m, 3H), 7.53-7.42 (in, 2H) WO 2008/031157 PCT/AU2007/001353 - 73 Part F: Synthesis of 2-hydroxy-15-phenyl-pentadeca-12,14-dinoic acid isopropyl ester OH 5 5,6-Dimethoxy-5,6-dimethyl-3-(13-phenyl-trideca-10,12-diynyl)-[1,4]dioxan-2-one (0.10 g, 0.27 mmol) was dissolved in a 0.50 M solution of TMS chloride in 'PrOH (5 ml, 2.5 mmol) and heated to reflux at 80'C for 45 h. The reaction was diluted with saturated aqueous NaHCO 3 (20 ml), the aqueous layer extracted with CH 2 C1 2 (3 x 10 ml), dried 10 (MgSO 4 ) and concentrated in vacuo to give the ester as a yellow oil (85.0 mg, 0.23 mmol, 86%). 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = 1.81 - 1.23 (m, 22H), 2.35 (tr, 2H, J = 7.0 Hz), 2.75 (br, 1H), 4.12 (dd, 1 H, J = 4.3 Hz, J = 2.2 Hz), 5.10 (hept, 1H, J = 6.3 Hz), 7.35 - 7.26 (m, 3H), 7.50 - 7.46 (m, 2H) 15 Part G: Synthesis of 2-hydroxy-1-morpholin-4-vl-15-phenyl-pentadeca-12,1 4 -divn-1 one N 20 5,6-Dimethoxy-5,6-dimethyl-3-(13-phenyl-trideca-10,12-diynyl)-[1,4]dioxan-2-one (0.08 g, 0.18 mmol) was dissolved in morpholine (5 ml) and stirred at room temperature for 48 h. The reaction was concentrated in vacuo to yield the amide as a colourless oil (0.15 mmol, 60 mg, 83 %).

WO 2008/031157 PCT/AU2007/001353 - 74 'H-NMR (CDC1 3 , 400 MHz): S[ppm] = 1.46-1.21 (m, 12H), 1.62-1.51 (m, 2H), 1.77-1.65 (m, 2H), 2.36 (t, J = 7.0 Hz, 2H), 3.78-3.55 (m, 8H), 4.38 (t, J = 7.1 Hz, 1H), 7.36-7.24 (m, 3H), 7.50-7.44 (m, 2H) 5 Example 6 Part A: Synthesis of 2-hydroxy-pent-4-ynoic acid 0 HO OH 10 Propargylglycine (1.50 g, 13.3 mmol, 1.00 mol equiv.) was dissolved in 1 M H 2 S0 4 (52.0 ml) and cooled to -2'C. An aqueous solution of sodium nitrite (40% (w/w), 6.6 ml) was added dropwise, keeping the temperature below 1 0 0 C. After the addition was complete, the reaction mixture was held at 0C for 3 h and then allowed to warm to 23'C and stirred 16 15 h. The reaction mixture was extracted with MTBE (3 x 75 ml), the combined organic phases were dried over Na 2

SO

4 and evaporated to give 2-hydroxy-pent-4-ynoic acid as a yellow oil (1.00 g, 66 %) which was used without further purification. 'H-NMR (CDC1 3 , 400 MHz): S[ppm] = 2.11 (tr, 1H, J = 2.6 Hz), 2.73 (ddd, 1H, J = 17.0 Hz, J = 5.3 Hz, J = 2.6 Hz), 2.81 (ddd, 1H, J = 17.0 Hz, J = 4.8 Hz, J = 2.6 Hz), 4.43 (tr, 20 1H, 5.1 Hz) WO 2008/031157 PCT/AU2007/001353 - 75 Part B: 2-hydroxy-pentadeca-4,6-divnoic acid 0 H O OH 5 2-hydroxy-pent-4-ynoic (1.00 g, 8.76 mmol) was dissolved in 10% (w/w) aqueous KOH solution (10 ml). CuCl (2.19 mmol, 216 mg) in ethylamine (6 ml) (70% aqueous solution) was added, followed by hydroxylamine hydrochloride (0.43 mmol, 30.0 mg). To this yellow solution was added 1-iodo-dec-1-yne (11.4 mmol, 3.00 g) dissolved in 10 ml of methanol. On addition of the iodoalkyne the reaction mixture turned blue and then yellow 10 on addition of few drops of 10% (w/w) aqueous hydroxylamine hydrochloride solution. These steps, repeated until all the iodoalkyne reacted, were completed in 15 min. The reaction mixture was then acidified with 30% (w/w) HCl and extracted with diethyl ether. An analytical sample of the crude product was obtained by recrystallisation from hexane. The crude product was converted to the methyl ester without further purification. 15 'H-NMR (CDCl 3 , 400 MHz): S[ppm] = (tr, 3H, J = 6.7 Hz), 1.42 - 1.19 (in, 10H), 1.51 (quint, 2H, J = 6.8 Hz), 2.24 (tr, 2H, J = 7.0 Hz), 2.78 (dd, 1H, J = 17.4 Hz, J = 5.4 Hz), 2.88 (dd, 1H, J= 17.4 Hz, J = 3.6 Hz), 4.07 - 3.01 (br, 2H), 4.40 (tr, 1H, J = 4.9 Hz) Part C: 2-hydroxy-pentadeca-4,6-divnoic acid methyl ester 20 0 H O O 2-hydroxy-pentadeca-4,6-diynoic acid (0.10 g, 0.38 mmol) was dissolved in methanol (5 ml). TMS chloride (0.50 ml) was added under argon and the reaction mixture was stirred WO 2008/031157 PCT/AU2007/001353 - 76 over night at room temperature. Excess methanol and TMS chloride was removed under reduced pressure and the product was obtained as a yellow oil in quantitative yields. 'H-NMR (CDCl 3 , 400 MHz): 6[ppm] = 0.88 (tr, 3H, J = 6.3 Hz), 1.38 - 1.22 (m, 1OH), 1.51 (quint, 2H, J = 6.8 Hz), 2.23 (tr, 2H, J = 7.0 Hz), 2.72 (dd, 1H, J = 17.3 Hz, J = 5.3 5 Hz), 2.79 (dd, 1H, J = 17.3 Hz, J = 5.5 Hz), 4.32 (tr, 1H, J = 5.0 Hz) Example 7 Part A: Synthesis of 3-methyl-6-trideca-2,4-divnvl-[1,41 dioxane-2,5-dione 10 0 Triethylamine (24.3 mmol, 3.39 ml) was added dropwise under argon to a 0C solution of 2-hydroxy-pentadeca-4,6-diynoic acid (1.52 g, 6.07 mmol) and 2-bromo-propionyl 15 bromide (9.75 mmol, 1.03 ml) in dry THF (150 ml). After stirring at 0C over night, the white solid was removed by filtration and the filtrate was condensed. The residual brown oil and additional triethylamine (24.3 mmol, 3.39 ml) were dissolved in acetone and refluxed over night. After removing the solvent in vacuo , the residue was redissolved in diethyl ether (200 ml) washed with 0.5 M HCl (3 x 200 ml) and saturated NaHCO 3 (3 x 20 200 ml) and dried over MgSO 4 . Removal of the ether gave a brown oil which was purified three times by column chromatography (SiO 2 , 85/15 hexane-ethyl acetate) to give (0.02 g, 0.07 mmol, 1.1 %) of a brown oil. 1 H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.89 (tr, 3H, J = 6.4 Hz), 1.21 - 1.64 (m, 17H), 2.13 - 1.93 (br, 1H), 2.24 (tr, 2H, J = 6.9 Hz), 2.62 - 2.93 (m, 2H), 4.89 - 5.10 9m, 2H) 25 WO 2008/031157 PCT/AU2007/001353 - 77 Example 8 Part A: Synthesis of 8-Trimethylsilanyl-oct-7-ynoic acid I " 0 Si 5 HO A solution of oct-7-ynoic acid (5.00 g, 35.70 mmol) in anhydrous THF (200 ml) at -78"C was treated with n-BuLi (1.6 M in hexane, 49.1 ml, 78.5 mmol, 2.20 mol equiv.). After stirring for 2 min trimethylsilyl chloride (14.0 ml, 110 mmol, 12.0 g, 3.10 mol equiv.) was 10 added. The reaction mixture was allowed to warm slowly to 25 0 C and was stirred for 1 h. The reaction was quenched with the addition of aqueous 2 N HCl (50 ml) and extracted with CH 2 Cl 2 (3 x 50 ml). The organic layer was dried over Na 2

SO

4 , filtered and concentrated. Column chromatography (SiO 2 , EtOAc-hexane, 2:1) afforded the acid (5.98 g, 28.2 mmol, 79 %) as a white solid. 15 1 H-NMR (CDCl 3 , 400 MHz): S[ppm] = 0.61 (9H, s), 1.17 - 1.71 (6H, in), 2.19 (2H, t, J 6.6 Hz), 2.33 (2H, t, J= 6.4 Hz) Part B: Synthesis of 2-Hydroxy-8-Trimethylsilanyl-oct-7-ynoic acid O si' 20 OH Dry diisopropylamine (8.32 ml, 6.01 g, 59.4 mmol, 2.30 mol equiv.) and dry THF (100 ml) were introduced into an argon-swept flask and cooled to 0"C. N-BuLi (1.6 M in hexane, 33.9 ml, 54.2 mmol, 2.10 mol equiv.) was introduced in a fine stream. The mixture was 25 then stirred for 15-30 min. A solution of 8-trimethylsilanyl-oct-7-ynoic acid (5.90 g, 25.9 mmol) in THF (20 ml) was added with continued cooling and stirring. The stirring was continued for 30 min at 0C and then at 50"C for 1.5 h. The reaction was cooled to room temperature and oxygen was bubbled through the solution for 30 min. The reaction was WO 2008/031157 PCT/AU2007/001353 - 78 quenched with water (200 ml) and acidified with 5 N aqueous HCI to pH 1. The aqueous mixture was extracted with diethyl ether (3 x 50 ml), the combined organic layers were washed with saturated NaCl solution, dried over Na 2

SO

4 , filtered and concentrated. The crude product was reacted on without further purification. 5 'H-NMR (CDCl 3 , 400 MHz): 8[ppm] = 0.61 (9H, s), 1.17 - 1.65 (6H, m), 2.15 (2H, t, J 6.8 Hz), 4.17 (1H, dd, J= 13.4, 3.3 Hz) Part C: Synthesis of 2-Hydroxy-8-Trimethylsilanyl-oct-7-ynoic acid methyl ester 0 Si

N

0 -1 10 OH To a solution of 2-hydroxy-8-trimethylsilanyl-oct-7-ynoic acid (4.42 g, 19.4 mmol) was dissolved in dry methanol (100 ml) under an argon atmosphere. Trimethylsilyl chloride (12.2 ml, 10.5 g, 96.7 mmol, 5 mol equiv.) was added. The mixture was stirred at room 15 temperature for 12 h. The methanol was removed under reduced pressure and the residue submitted to column chromatography (SiO 2 , EtOAc-Hexane, 1:2). Purification afforded the methyl ester (2.58 g, 10.7 mmol, 55 %) as a clear oil. 'H-NMR (CDCl 3 , 400 MHz): 6[ppm] = 0.63 (9H, s), 1.22 - 1.70 (6H, in), 2.15 (2H, t, J 6.8 Hz), 3.70 (3H, s), 4.14 (lH, dd, J= 13.5, 3.3 Hz) 20 Part D: Synthesis of 2-Hydroxy-oct-7-ynoic acid methyl ester 0 OH 25 To a solution of 2-hydroxy-8-trimethylsilanyl-oct-7-ynoic acid methyl ester (2.13 g, 8.80 mmol) in dry THF (20 ml) was added tetrabutylammonium fluoride (1.0 M in THF, 13.2 ml, 13.2 mmol, 1.5 mol equiv.). The dark solution was stirred at room temperature for 3 h WO 2008/031157 PCT/AU2007/001353 - 79 and then diluted with water. The mixture was extracted with diethyl ether (3 x 30 ml) and the combined organic layers were dried over Na 2

SO

4 . Removal of the solvent left an oil that was used without further purification. This intermediate was not characterized prior to use. 5 Part E: Synthesis of 1-Iodo-oct-1-Yne 10 N-BuLi (1.6 M in hexane, 25.3 ml, 40.6 mmol, 1.3 mol equiv.) was added slowly to a solution of oct-1-yne (3.44 g, 31.2 mmol) in dry THF at 20'C under argon and was stirred for 1 h. The mixture was then cooled to 40'C and treated with iodine (34.3 mmol, 8.68 g, 1.1 mol equiv.). After stirring for 12 h at room temperature the reaction mixture was quenched with saturated NH 4 C1 (100 ml) solution and extracted with ethyl acetate (3 x 50 15 ml). The combined organic layers were washed with saturated sodium thiosulfate solution and dried over Na 2

SO

4 . Removal of the solvent left an oil that was used without further purification. 'H-NMR (CDCl3, 400 MHz): 6[ppm] = 0.88 (3H, t, J= 7.5 Hz), 1.31 - 1.63 (8H, m), 2.35 (2H, t, J= 6.9 Hz) 20 Part F: Synthesis of 2-Hydroxy-hexadeca-7, 9-divnoic acid 0 HO OH 25 2-hydroxy-oct-7-ynoic acid methyl ester (0.98 g, 5.77 mmol, 0.5 mol equiv.) was suspended in a solution of 5 ml 10 % (w/w) potassium hydroxide in water and hydroxylarnine hydrochloride (40.0 mg, 0.57 mmol, 0.05 mol equiv.) was added. Then a catalyst consisting of a solution of copper(I)chloride (0.41 g, 2.81 mmol, 0.16 mol equiv.) WO 2008/031157 PCT/AU2007/001353 - 80 in 1.90 g 70 % aqueous ethylamine was added. A yellow precipitate formed immediately. A solution of 1-iodo-oct-1-yne (2.72 g, 11.5 mmol) in 10 ml methanol was added dropwise with stirring. The suspension was stirred for 1 h after the addition. The reaction mixture was acidified by the addition of 2.5 N HCl, filtered and the filtrate and precipitate were 5 washed with diethyl ether (3 x 20 ml). The combined ether layers were washed with water (20 ml), sodium thiosulfate solution (20 ml), water (20 ml) and sodium chloride solution (20 ml). After drying over Na 2

SO

4 the solvents were removed under reduced pressure. The residue was induced to crystallise by scratching under petroleum ether. The crystals of the product were filtered of and recrystallised giving (0.53 g, 2.02 mmol, 35 %). 10 'H-NMR (CDCl 3 , 400 MHz): 6[ppm] = 0.88 (3H, t, J= 7.4 Hz), 1.14- 1.58 (12H, m), 1.59 - 1.73 (2H, m), 1.75 - 1.85 (2H, in), 2.25 - 2.37 (4H, in), 4.21 (iH, dd, J= 13.5, 3.2 Hz) Part G: Synthesis of 2-Hydroxy-hexadeca-7, 9-divnoic acid methyl ester 0K 15 OH To a solution of 2-hydroxy-hexadeca-7, 9-diynoic acid (0.10 g, 0.38 mmol) was dissolved in dry methanol (10 ml) under an argon atmosphere. Trimethylsilyl chloride (5 mol equiv.) was added. The mixture was stirred at room temperature for 12 h. The methanol was 20 removed under reduced pressure and the residue submitted to column chromatography (SiO 2 , EtOAc-Hexane 1:2). Purification afforded the methyl ester as a clear oil in quantitative yields. 1 H-NMR (CDCl 3 , 400 MHz): S[ppm]= 0.88 (3H, t, J= 7.4 Hz), 1.14 - 1.58 (12H, in), 1.59 - 1.73 (2H, in), 1.75 - 1.85 (2H, in), 2.25 - 2.37 (411, in), 4.21 (1H, dd, J= 13.5, 3.2 Hz) 25 WO 2008/031157 PCT/AU2007/001353 - 81 Example 9 Part A: Synthesis of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl octadeca-6,8-diynoate 5 0 Octadeca-6,8-diynoic acid, prepared via previously described methods (1.54 g, 5.57 mmol) was dissolved in toluene (200 ml) and had added to it solketal (excess, 30 ml) and p 10 toluenesulfonic acid (10 mg). The solution was heated at reflux using a Dean-Stark apparatus for 24 hours. Following this, the toluene was removed under reduced pressure at 70'C, dissolved in dichloromethane (200 ml), washed with water (2 x 200 ml) and brine (1 x 200 ml). The organic layer was dried over Na 2

SO

4 and the product purified over silica (eluted with 3:1 ethylacetate:hexane). Removal of the solvent gave the product as a light 15 yellow oil (1.05 g, 2.69 mmol, 48 %). 'H-NMR (CDCl 3 , 400 MHz): 0.88 (3H, t), 1.25-1.43 (12H, in), 1.37 (6H, s), 1.63 (2H, in), 2.13 (2H, in), 2.34 (2H, t), 3.74 (1H, t), 4.05-4.18 (3H, in), 4.31 (1H, in).

WO 2008/031157 PCT/AU2007/001353 - 82 Part B: Synthesis of 2,3-dihydroxypropyl octadeca-6,8-divnoate OH OH 5 (2,2-dimethyl-1,3-dioxolan-4-yl)methyl octadeca-6,8-diynoate (400 mg, 1.02 mmol) was dissolved in acetonitrile (40 ml) and had added to it Amberlyst 15 resin (200 mg) and was heated at reflux overnight. After filtering to remove the Amberlyst resin, the abetonitrile was removed under reduced pressure to give an oil from which the product precipitated as 10 a white solid upon cooling. This collected on a filter paper and washed with a very small amount of cold hexane (300 mg, 0.857 mmol, 85 %). 1 H-NMR (Acetone-d6, 400 MHz): 0.88 (3H, t), 1.22-1.52 (18H, m), 1.60 (2H, in), 2.12 (2H, in), 2.29 (2H, in), 3.54 (1.5H, in), 3.68 (0.5H, m), 3.82 (1H, in), 4.10 (2H, 2 x dd), 4.86 and 5.07 (br m from 2 x OH) 15 Part C: Synthesis of 3-(octadeca-6,8-divnoyloxy)-2-oxopropanoic acid HO 0 20 2,3-dihydroxypropyl octadeca-6,8-diynoate (300 mg, 0.838 mmol) was dissolved in acetone (40 ml) and had Jones reagent added to it dropwise with vigorous stirring until an orange colour persisted. The chromium salts that formed during the reaction were filtered off and the filtrate was then carefully neutralised with ispropanol. The solvent was WO 2008/031157 PCT/AU2007/001353 -83 removed under reduced pressure to give a green oil which was dissolved in dichloromethane (50 ml) and washed with water (50 ml). The organic layer was dried over Na 2

SO

4 and the solvent removed under reduced pressure to give a light green oil which was used in the next step without further purification. 5 Part D: Synthesis of 2-hydroxy-3-(octadeca-6,8-diynoyloxv)propanoic acid OH HO 0 10 Crude 3-(octadeca-6,8-diynoyloxy)-2-oxopropanoic acid (193 mg, 0.530 mmol) was dissolved in THF (20 ml). NaBH 4 (25 mg, 0.66 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was neutralised with water (200 ml) then extracted with diethyl ether (3 x 100 ml). The ether extracts were combined and dried over Na 2

SO

4 , then the solvent removed under reduced pressure to give an oil from which a 15 white waxy solid precipitated. The solid was collected and purified using silica chromatography by loading onto the column, washing with pentane:ethylacetate (2:1, 3 column volumes), ethyl acetate (1 column volume) then eluting with ethanol (Abs, 2 column volumes). Yield 23 mg, 7 %. 'H-NMR (CDCl 3 , 400 MHz): 0.89 (3H, t), 1.17 1.84 (18H, m, br), 2.08 - 2.35 (6H, m, br), 3.64 (2H, in), 4.16 (1H from OH, s, br), 4.25 20 (1H, t) Example 10 Part A: Biological Testing - General procedure 25 1 mg of either compound 1 or compound 2 in 100 pl DMSO were added to 2 ml Luria broth (giving a concentration of 1.8 mM) and inoculated with E. coli DH5a cells (5 x 10 4 WO 2008/031157 PCT/AU2007/001353 - 84 cells/mL). The mixture was shaken overnight at 37'C and diluted and plated for single colonies after 12 h. Control experiments (using 100 pl DMSO and no active compounds) were carried out under identical conditions. 5 Each compound was tested four times Part B: Biological Testingz - Results Number Structure Expt 1 Expt 2 Expt 3 Expt 4 Mean survival survival survival survival survival 1 48 45 81 71 61 OH 2 18 81 46 71 54 OH DMSO 100 100 100 100 100 10 Both compounds show activity against E. coli DH5a cells. The control experiment (using only DMSO) demonstrates that the 2-hydroxy-diyne compounds are responsible for the biological activity. Throughout this specification and the claims which follow, unless the context requires 15 otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), 20 or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (31)

1. A diyne compound of general formula (I) 0 X Y (W)q-R 1 OH 5 (I) where X is OR or NR 2 R 3 , R 2 and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; 10 Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted 15 heterocyclylene; R 1 is selected from H and an organic substituent; n is selected from 0 or 1; q is selected from 0 or 1; and p is an integer ranging from 0 to 15, 20 with the proviso that the compound is not: CHC--CH:=CH-(CH2)3-CEEEC-C EC -C EEC -(CH2),-C-C C-CH(OH)-CO2H,

2. The diyne compound of general formula (I), wherein R is a divalent form of a group selected from alkyl, alkenyl, alkynyl, aryl, acyl, carbocyclyl, heterocyclyl, 25 heteroaryl, alkyloxy, alkenyloxy, alkynyloxy, aryloxy, acyloxy, carbocyclyloxy, heterocyclyloxy, heteroaryloxy, alkylthio, alkenylthio, alkynylthio, arylthio, acylthio, WO 2008/031157 PCT/AU2007/001353 -86 carbocyclylthio, heterocyclylthio, heteroarylthio, alkylalkenyl, alkylalkynyl, alkylaryl, alkylacyl, alkylcarbocyclyl, alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkylacyloxy, alkylcarbocyclyloxy, alkylheterocyclyloxy, alkylheteroaryloxy, alkylthioalkyl, 5 alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, alkylacylthio, alkylcarbocyclylthio, alkylheterocyclylthio, alkylheteroarylthio, alkylalkenylalkyl, alkylalkynylalkyl, alkylarylalkyl, alkylacylalkyl, arylalkylaryl, arylalkenylaryl, arylalkynylaryl, arylacylaryl, arylacyl, arylcarbocyclyl, arylheterocyclyl, arylheteroaryl, alkenyloxyaryl, alkynyloxyaryl, aryloxyaryl, arylacyloxy, arylcarbocyclyloxy, 10 arylheterocyclyloxy, arylheteroaryloxy, alkylthioaryl, alkenylthioaryl, alkynylthioaryl, arylthioaryl, arylacylthio, arylcarbocyclylthio, arylheterocyclylthio, and arylheteroarylthio.

3. The diyne compound according to claim 2, wherein R is a divalent form of any of 15 the groups selected from Ci-C 18 alkyl, C 2 -C 18 alkenyl, C 2 -C 1 8 alkynyl, C 6 -Ci 8 aryl, CI-C 1 8 acyl, C 3 -C 18 carbocyclyl, C 2 -Ci 8 heterocyclyl, C 3 -C 18 heteroaryl, C 1 -C 1 8 alkyloxy, C 2 -C 18 alkenyloxy, C 2 -C 1 8 alkynyloxy, C 6 -Ci 8 aryloxy, C 1 -C 18 acyloxy, C 3 -Ci 8 carbocyclyloxy, C 2 -C 18 heterocyclyloxy, C 3 -CI 8 heteroaryloxy, C 1 -C 1 8 alkylthio, C 2 -C 18 alkenylthio, C 2 -Ci 8 alkynylthio, C 6 -CI 8 arylthio, CI-C 1 8 acylthio, 20 C 3 -C 18 carbocyclylthio, C 2 -Ci 8 heterocyclylthio, C 3 -C 18 heteroarylthio, C 3 -C 18 alkylalkenyl, C 3 -C 1 8 alkylalkynyl, C 7 -C 24 alkylaryl, C 2 -C 18 alkylacyl, C 4 -C 1 8 alkylcarbocyclyl, C 3 -C 18 alkylheterocyclyl, C 4 -Ci 8 alkylheteroaryl, C 2 -C 18 alkyloxyalkyl, C 3 -C 18 alkenyloxyalkyl, C 3 -C 1 8 alkynyloxyalkyl, C 7 -C 24 aryloxyalkyl, C 2 -C 18 alkylacyloxy, C 4 -C 18 alkylcarbocyclyloxy, C 3 -Ci 8 alkylheterocyclyloxy, C 4 25 C 1 8 alkylheteroaryloxy, C 2 -C 1 8 alkylthioalkyl, C 3 -Ci 8 alkenylthioalkyl, C 3 -C 18 alkynylthioalkyl, C 7 -C 24 arylthioalkyl, C 2 -C 18 alkylacylthio, C 4 -CI 8 alkylcarbocyclylthio, C 3 -C 1 8 alkylheterocyclylthio, C 4 -Ci 8 alkylheteroarylthio, C 4 C 1 alkylalkenylalkyl, C 4 -C 1 8 alkylalkynylalkyl, C 8 -C 24 alkylarylalkyl, C 3 -C 1 8 alkylacylalkyl, C 13 -C 24 arylalkylaryl, C 14 -C 24 arylalkenylaryl, C 14 -C 24 30 arylalkynylaryl, C 13 -C 24 arylacylaryl, C 7 -Ci 8 arylacyl, C 9 -C 18 arylcarbocyclyl, C 8 -Ci 8 arylheterocyclyl, C 9 -Ci 8 arylheteroaryl, C 8 -Ci 8 alkenyloxyaryl, C 8 -Ci 8 WO 2008/031157 PCT/AU2007/001353 - 87 alkynyloxyaryl, C 1 2 -C 24 aryloxyaryl, C 7 -CI 8 arylacyloxy, C 9 -Ci 8 arylcarbocyclyloxy, C 8 -C 18 arylheterocyclyloxy, C 9 -CI 8 arylheteroaryloxy, C7-CI 8 alkylthioaryl, C 8 -CI 8 alkenylthioaryl, C 8 -Ci 8 alkynylthioaryl, C 12 -C 24 arylthioaryl, C 7 -Cis arylacylthio, C 9 C 18 arylcarbocyclylthio, C 8 -Ci 8 arylheterocyclylthio, and C 9 -Ci 8 arylheteroarylthio. 5

4. The diyne compound according to claim 2, wherein R is a divalent form of a group selected from alkyl, heteroaryl, carbocyclyl, heterocyclyl, alkylaryl, alkylheteroaryl, alkylcarbocyclyl, and alkylheterocyclyl. 10

5. The diyne compound according to any one of claims 1 to 4, wherein when R comprises an alkyl moiety and a -CH 2 - group in the alkyl moiety is replaced by a group selected from -0-, -S-, -NRa-, -C(O)-, -C(O)0-, and -C(O)NRa-, where Ra is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, arylalkyl, and acyl. 15

6. The diyne compound according to any one of claims 1 to 5, wherein R', R 2 and R 3 are each independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alkylaryl, optionally substituted carbocyclyl, optionally 20 substituted heterocyclyl, and optionally substituted heteroaryl.

7. The diyne compound according to any one of claims 1 to 5, wherein R 1 is selected from optionally substituted alkoxy, optionally substituted alkenoxy, optionally substituted alkynoxy, optionally substituted aryloxy, optionally substituted acyloxy, 25 optionally substituted alkylthio, optionally substituted alkenylthio, optionally substituted alkynylthio, optionally substituted arylthio, optionally substituted acyl, sulfoxide, sulfonyl, sulfonamide, amino, amido, carboxy ester, amino acid, and a peptide. WO 2008/031157 PCT/AU2007/001353 - 88

8. A method of preparing a diyne compound of general formula (I) 0 C(R)n / _ _ X Y (W)q-RI OH (I) 5 said method comprising coupling a compound of general formula (II) with a compound of general formula (III) 0 C (R)n (W)q X Y lY H RI OH z (II) (III) 10 where X is OR 2 or NR 2 R 3 , R 2 and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted 15 heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; R 1 is selected from H and an organic substituent; 20 Z is a halogen; WO 2008/031157 PCT/AU2007/001353 - 89 n is selected from 0 or 1; q is selected from 0 or 1; and p is an integer ranging from 0 to 15. 5

9. A method of preparing a diyne compound of general formula (I) 0 C (R)n / _ X Y (W~g-R 1 OH (I) said method comprising the diacetal deprotection of a compound of general formula 10 (IV) OMe (R)n 0 Y (W)q-R 1 OMe O (IV) where X is OR 2 or NR 2 R 3 , R 2 and R 3 are each independently selected from H and an 15 organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; 20 W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted WO 2008/031157 PCT/AU2007/001353 - 90 heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; R1 is selected from H and an organic substituent; n is selected from 0 or 1; 5 q is selected from 0 or 1; and p is an integer ranging from 0 to 15.

10. The method according to claim 8 or 9, wherein the diyne compound is selected from a diyne compound according to any one of claims 1 to 7. 10

11. A method of treating a disease or condition in a subject comprising administration to said subject an effective amount of a diyne compound of general formula (I) 0 C(R)n X Y (W)q-RI OH (I) 15 where X is OR2 or NR2R, R 2 and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted 20 heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; 25 R' is selected from H and an organic substituent; n is selected from 0 or 1; WO 2008/031157 PCT/AU2007/001353 - 91 q is selected from 0 or 1; and p is an integer ranging from 0 to 15.

12. Use of a diyne compound of general formula (I) or a pharmaceutically acceptable 5 salt or prodrug thereof O C(R)n X Y (W)q-R OH (I) where X is OR 2 or NR 2 R 3 , R 2 and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; 10 R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted 15 heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; R 1 is selected from H and an organic substituent; n is selected from 0 or 1; q is selected from 0 or 1; and 20 p is an integer ranging from 0 to 15, in the manufacture of a medicament for treating a disease or condition in a subject.

13. A method according to claim 11 or a use according to claim 12, wherein the diyne compound is selected from a diyne compound according to any one of claims 1 to 7. 25 WO 2008/031157 PCT/AU2007/001353 - 92

14. A method of preparing a polydiacetylene, said method comprising polymerising one or more diyne compounds of general formula (I) C (R)n X Y (W)q-R 1 OH (I) 5 where X is OR 2 or NR 2 R 3 , R 2 and R3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted 10 heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene;

15 R 1 is selected from H and an organic substituent; n is selected from 0 or 1; q is selected from 0 or 1; and p is an integer ranging from 0 to 15. 20 15. The method according to claim 14, wherein the one or more diyne compounds are selected from diyne compounds according to any one of claims 1 to 7.

16. The method according to claim 14 or 15, wherein -(R)"-Y- and -(W)q- of general formula (I) are -(CH 2 )t- and -(CH 2 )p-, respectively, where t and p are each 25 independently an integer ranging from 0 to 15. WO 2008/031157 PCT/AU2007/001353 - 93

17. The method according to any one of claims 14 to 16, wherein polymerisation of the one or more diyne compounds is preceded by their crystallisation or formation into a monolayer or multilayer film. 5

18. A method of preparing a polyester or polyesteramide, said method comprising polymerising one or more diyne compounds of general formula (I) C(R)n X) Y (W)q-R 1 OH (I) 10 where X is OR 2 , and R 2 is selected from H and an organic substituent; R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; 15 W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; R 1 is selected from H and an organic substituent; n is selected from 0 or 1; 20 q is selected from 0 or 1; and p is an integer ranging from 0 to 15.

19. The method according to claim 18, wherein the one or more compounds of general formula (I) undergo autocondensation polymerisation to form the polyester. 25 WO 2008/031157 PCT/AU2007/001353 -94

20. The method according to claim 18, wherein the one or more compounds of general formula (I) undergo condensation polymerisation with one or more comonomers to form the polyester or polyesteramide. 5

21. The method according to claim 18, wherein the one or more comonomers are selected from 2-hydroxypropanoic acid, 3-hydroxypropanoic acid, 2 hydroxybutanoic acid, 3-hydroxybutanoic acid, 4-hydroxybutanoic acid, 2 hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2 hydroxyhexanoic acid, 2-hydroxypalmitic acid, 2-hydroxystrearic acid, 2 10 hydroxyoleic acid, propiolactone, gamma-butyrolactone, beta-butyrolactone, caprolactone, caprolactam, alpha- and beta-amino acids, 2-bromoethanoic acid, 2 bromoethanyl bromide, 2-bromopropanoic acid, 2-bromopropanyl bromide, 2 bromobutanoic acid, 2-bromobutanyl bromide, 2-bromoethanyl chloride, 2 bromopropionyl chloride, 2-bromohexanyl bromide, 2-bromohexanyl chloride, 2 15 bromostearyl bromide, 2-bromostearyl chloride, and combinations thereof.

22. A method of preparing a polyester or polyesteramide, said method comprising polymerising by ring opening polymerisation a cyclic ester having two or more ester groups within the cycle, wherein at least one of said ester groups is the cyclised 20 condensate of a diyne compound of general formula (I) C(R)n / _ _ _ _ X Y (W)q-R 1 OH (I) where X is OR 2 , and R 2 is selected from H and an organic substituent; 25 R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted WO 2008/031157 PCT/AU2007/001353 - 95 heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted 5 heterocyclylene; R' is selected from H and an organic substituent; n is selected from 0 or 1; q is selected from 0 or 1; and p is an integer ranging from 0 to 15. 10

23. The method according to claim 22, wherein the cyclic ester is prepared by autocondensation of compounds of general formula (I).

24. The method according to claim 22, wherein the cyclic ester is prepared by 15 condensation of a compound of general formula (I) with one or more comonomers.

25. The method according to any one of claim 24, wherein the one or more comonomers are selected from 2-hydroxypropanoic acid, 3-hydroxypropanoic acid, 2 hydroxybutanoic acid, 3-hydroxybutanoic acid, 4-hydroxybutanoic acid, 2 20 hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2 hydroxyhexanoic acid, 2-hydroxypalmitic acid, 2-hydroxystrearic acid, 2 hydroxyoleic acid, 2-bromoethanoic acid, 2-bromoethanyl bromide, 2 bromopropanoic acid, 2-bromopropanyl bromide, 2-bromobutanoic acid, 2 bromobutanyl bromide, 2-bromoethanyl chloride, 2-bromopropionyl chloride, 2 25 bromohexanyl bromide, 2-bromohexanyl chloride, 2-bromostearyl bromide, 2 bromostearyl chloride, and combinations thereof.

26. The method according to any one of claims 22 to 25, wherein the cyclic ester undergoes ring opening polymerisation with itself to form the polyester. 30 WO 2008/031157 PCT/AU2007/001353 - 96

27. The method according to any one of claims 22 to 25, wherein the cyclic ester undergoes ring opening polymerisation with one or more cyclic ester and/or cyclic amide comonomers to form the polyester or polyester aide. 5

28. The method according to claim 27, wherein the one or more cyclic ester and cyclic amide comonomers are selected from caprolactone, lauryllactone, caprolactam, lauryllactam and mixtures thereof.

29. The method according to any one of claims 18 to 28, wherein the one or more diyne 10 compounds are selected from a diyne compound according to any one of claims 1 to 7 when X is not NR 2 R 3 .

30. A polymer product comprising polymerised residue of a diyne compound of general formula (I) 15 0 C (R)n xY - (W)q-R' OH (I) where X is OR2 oNR 2 R 3 , R 2 and R 3 are each independently selected from H and an organic substituent or form together with N a heterocyclyl substituent; 20 R is a divalent organic substituent; Y is selected from -CH 2 -, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; W is selected from -(CH 2 )p-, optionally substituted arylene, optionally substituted 25 heteroarylene, optionally substituted carbocyclylene, and optionally substituted heterocyclylene; WO 2008/031157 PCT/AU2007/001353 - 97 R' is selected from H and an organic substituent; n is selected from 0 or 1; q is selected from 0 or 1; and p is an integer ranging from 0 to 15. 5

31. The polymer product according to claim 30, wherein the diyne compound is selected from a diyne compound according to any one of claims 1 to 7.