AU2003250581B2 - Derivatives of monosaccharides for drug discovery - Google Patents

Description

WO 2004/014929 PCT/AU2003/001008 1 DERIVATIVES OF MONOSACCHARIDES FOR DRUG DISCOVERY FIELD OF THE INVENTION This invention relates to new compounds and methods for the preparation of combinatorial libraries of potentially biologically active compounds based on natural and unnatural monosaccharides.

These compounds are functionalized, with a view to varying lipid solubility, size, function and other properties, with the particular aim of discovering novel drug or drug-like compounds, or compounds with useful properties. The invention provides intermediates, processes and synthetic strategies for the solution or solid phase synthesis of monosaccharides, variously functionalised about the sugar ring, including the addition of aromaticity and charge, the addition of pharmacophoric groups and the placement of amino acid and peptide side chain units or isosteres thereof.

BACKGROUND OF THE INVENTION In the field of drug discovery there is a constant need for novel scaffolds that enable the rational design of potentially bioactive molecules.

Carbohydrates have recently come under scrutiny as offering a source of scaffolds that allow for a high degree of substitution, and offer access to both functional and structural diversity. The nature of monosaccharide molecules is such that there are numerous different stereoisomers available that can provide access to a greater degree of molecular space than do the scaffolds presently employed in drug discovery.

Carbohydrate monomers predominantly contain hydroxyl groups but also may contain other functionalities such as an amino and/or carboxylate function. In essence, the concepts involved in drug discovery through carbohydrate based molecular and structural diversity, are twofold: The primary concept involves the exploitation of the high functional density found around the carbohydrate ring to display several different moieties of biological relevance. There is a dual significance to this substitution in that the substituents relative position around the ring may be varied in relation to each other and, (ii) each individual moiety may be substituted for a class of such moieties and therefore themselves may be varied (by example: an arginine WO 2004/014929 PCT/AU2003/001008 2 mimetic may be substituted at position 1, 2, 3, 4 or 5 around a ring in relation to other peptidomimetics, by the same token the arginine mimetic may represent a class of different arginine bioisosteres which may all be similarly substituted).

The second concept involves exploiting the structural diversity inherent in carbohydrate isomers. Each of the substituents around a carbohydrate ring may theoretically be presented in either an axial or equatorial configuration allowing access to hugely diverse molecular space. Many monosaccharides are naturally occurring, which aside from being useful in their own right, present themselves as cheap starting materials to access more exotic configurations.

There are other factors that promote carbohydrates as useful building blocks for drug discovery, for example the relative positions of the functional groups on the sugar rings are conveniently spaced such that they can effectively enable mimicry of (for example), peptide motifs such as peptidic turns and loops, as well as cyclic peptides.

The major difficulty encountered in attempts to employ monosaccharides as scaffolds, is associated with monosaccharide chemistry. In the past carbohydrate chemistry was considered arduous, protracted and not cost effective. Particularly, the degree of orthogonal protection group chemistry required to allow free access to any one of a monosaccharide's functional groups (usually five) was deemed too high to ever be effected in a commercially viable manner. As a corollary, the more easily effected peptide synthesis only requires a maximum three orthogonal protecting groups, additionally the conditions required for peptide synthesis are often milder, thus peptide synthesis has so far been able to be effected more easily than carbohydrate synthesis. Fortunately, recent developments in synthetic carbohydrate chemistry have begun to allow regular access to carbohydrates as molecular scaffolds. In a recent patent application (PCT AU00/00025) we disclosed a range of orthogonally protected building blocks suitable for oligosaccharide synthesis. The building blocks presented in this application are also suitable for use as intermediates in the synthesis of compounds of the present invention, and represent compounds and methods which define the state of the art.

WO 2004/014929 PCT/AU2003/001008 3 A large number of Carbohydrate based templates and scaffolds has now been published in the scientific literature. A review of the major contributions by Gruner et. al., (Chem. Rev., 2002, 102, p491-514) highlights this activity. Within the general literature, there are two distinct types of carbohydrate templates sugar amino acids and (ii) carbohydrate scaffolds.

Sugar amino acids are carbohydrates which contain both an amine function and a carboxylic acid function, and are used in place of amino acids in peptide type syntheses. The synthesis of monosaccharides for this purpose is exemplified by the work of Fleet (Tetrahedron, 1996, 52, p10711; Tetrahedron Assym., 1996, 7, p387; Tetrahedron Assym., 1996, 7, p157) and Le Merrer (Tet. Lett., 1995, 36, p6887) for furanoid sugars, and by Dondoni (J.Org.Chem., 1994, 59, p6404), Vogel Carbohyd. Chem., 1994, 13, p37) and Kessler (see chem rev. above) for pyranoid sugars.

Sugar amino acids have been used in peptide synthesis, and in the formation of linear oligomers for various biological purposes (see chem reviews above). Importantly, all of these compounds contain an amino function and a carboxylate function directly attached to the carbohydrate ring, and these functional groups are involved in amide bond forming processes which is the central concept in their use. The compounds of this type are distinctly different from the compounds of the present invention.

Carbohydrate scaffolds have also received considerable attention in the scientific literature, at least by way of desideratum. In concept, these compounds provide a chiral scaffold on which pharmaceutically active moieties are presented. This is the field of the present invention which adds to and is distinct from the state of the art.

The use of carbohydrates as scaffolds was promulgated by Hirschmann and co workers (Hirschmann et. al., J. Am. Chem. Soc., 114, 9217-9218, 1992) who employed this concept to develop a potent NK-1 receptor antagonist (Hirschmann et. al., J. Am. Chem. Soc., 115, 12550-12568, 1993), (Hirschmann et. al., J. Med. Chem., 39, 2441-2448, 1996). The fundamentals of this work have also been patented by Hirschmann et. al.

(PCT/US1994/012233).

WO 2004/014929 PCT/AU2003/001008 4 In a similar manner, Papageorgiou et al, have applied the concept to furanoid structures, developing weak somatostatin inhibitors in the process (Papageorgiou et. al., Bioorg. Med. Chem. Lett., 2, 135-140, 1992).

Weak inhibitors of integrin receptors and endothelin receptors have also been developed by applying this concept (Nicolaou, et. al, Tetrahedron, 1997, 53, p8751; Moitessier, et. al., Lett. Pep. Sci., 1998, Moitessier, et. al., Bioorg. Med. Chem., 2001, 9, p511.).

A number of other research groups have developed libraries of compounds based on this scaffold principle, and these groups are referred to in Gruner's review (vide supra). Despite the plethora of work to date, the compounds disclosed above have three common features which distinguish them from the current work: all of the substituents are attached to the scaffold through an oxygen linkage, (ii) the anomeric position is always an O glycoside, and (iii) all of the available hydroxyl positions are substituted.

These features, when taken together, place significant limitations on the utility of the compounds. For example, ether linkages provide considerable rotational freedom and it is generally accepted that rotational freedom often results in diminished biological activity (Murphy et. al., J. Org.

Chem., 68, 5692-5704, 2003). To this end, the present invention is directed to carbohydrate templates which have one or two amines directly attached to the carbohydrate ring, allowing the introduction of, for example, amide linked, sulfonamide linked, urea linked and carbamoyl linked moieties with significantly reduced rotational freedom and often better physical properties.

In a similar manner, the requisite for all of the positions to be substituted can lead to compounds of higher lipophillicity, higher molecular weight and lower solubility without imparting greater biological activity. In the present invention we disclose compounds with one or two hydroxyl positions unsubstituted, allowing generally improved solubility characteristics and lower molecular weights that would be expected for the corresponding fully substituted molecules.

WO 2004/014929 PCT/AU2003/001008 These two features represent significant improvements over compounds described in the literature and are the result of considerable new method developments by the inventors.

Of all the carbohydrate scaffold work reported in the scientific and patent literature to date, we have found few examples of amine containing scaffolds outside the sugar amino acid class. Kunz et. al. (WO 99/07718) have claimed 2-deoxy 2-amino sugars as scaffolds for drug discovery. This citation does not teach or exemplify a compound with an amine group directly attached to the ring in the two position or any other position.

The disclosures in Kunz's relate specifically to the use of glucose, galactose and mannose as scaffolds and the methods described are not generally applicable to other monosaccharide scaffolds. In contrast, the compounds of the present invention are all O glycosides which are further limited by a narrow range of unsubstituted substituents dictated by the low reactivity of the sugar hydroxyls under the synthetic conditions disclosed. It is apparent that this technology displays significant disadvantages to the present invention; the efficiencies of conversion, the range of potential substituents, the various inversion chemistries that introduce both alternate oxy and amino stereochemical orientations, and the versatile alkylative chemistries of the present invention represent significant improvements over the methods of Kunz's application. Particularly, the present invention provides stereoisomers of monosaccharides that have a nitrogen or a carbon atom attached to the ring in positions 3,4,5 and 6 of a monosaccharide or tetrahydrofurano/pyrano ring system. Of particular interest to the medicinal chemist is the inclusion of linking functionalities that are likely to be stable to physiological conditions thus allowing the drug to reach the desired target intact, or in an active form.

Despite the general paucity of amine containing carbohydrate scaffolds in the literature, there are many examples of monosaccharide building blocks and protected aminosugars employed for oligosaccharide synthesis. By way of example, US 4818816 discloses a compound 1-methyl-2carbobenzyloxy,3-benzyl glucosamine, a monosaccharide building block used in the synthesis of synthetic heparinoid oligomers. The compounds of the WO 2004/014929 PCT/AU2003/001008 6 present invention represent a significant departure from the simple building block type aminosugars, both in the diversity and complexity which is achievable. In order, to further distinguish the compounds of the present invention from the prior art, the use of standard amine protecting groups in carbohydrate synthesis is specifically excluded.

Sabesan (US patent 5,220,008) discloses a series of higher oligosaccharides as inhibitors on influenza. Within the claims of this patent, a partially protected monosaccharide (structure IV) is also disclosed. The compounds of this structure are protected monosaccharides for oligosaccharide synthesis which are known in the art and do not represent compounds for drug discovery.

Similarly, Alchemia Pty Ltd has disclosed in PCT/AU01/01307 building blocks, methods of syntheses, and final products relating to the employment of monosaccharide compounds as drug like molecules. The compounds of PCT/AU01/01307 are specifically directed at inhibitors of the muramyl cascade of enzymes and are hereby excluded from specification by the incorporation of this reference. A number of other publications relating to muramyl type compounds have appeared in the literature. Liu et. al. Biorg.

Med Chem Lett., 10, 2000, 1361-1363) present a series of compounds containing a benzyl glycoside at the anomeric position, an acetate at C-2 and a peptide homologated lactate at C-3 of a glucosamine scaffold. These compounds and those disclosed by Xiao (Peptides: Biol and Chem., Proc. 5 th Int. Chinese Peptide Symp., 1998 CA: 134:178795) represent compounds and methods which help define the art of carbohydrate chemistry but are not directly relevant to the present invention.

It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country.

OBJECT OF THE INVENTION In a first aspect, the invention comprises a compound of formula I being a derivative of a furanose or pyranose form of a monosaccharide, WO 2004/014929 PCT/AU2003/001008 7 H H .O 0 R1 H

H

R4< R2 n H H R3 formula I Wherein, n is 0 or 1; R1 is XR wherein, X is selected from O; S; S=O and SO 2 R is selected from the group consisting of C1 to C9 alkyl, C1 to C15 alkenyl, C1 to C15 alkynyl, C1 to C15 heteroalkyl, C6 to C15 aryl, C6 to C15 heteroaryl, C6 to C15 arylalkyl or C6 to C15 heteroarylalkyl which is optionally substituted, cyclic or acyclic, branched and/or linear, The groups R2 to R5 are selected from OH, OR and N(Y)Z such that: At least one of the groups R2 to R5 and not more than two of the groups R2 to R5 are OH, At least one of the groups R2 to R5 and not more than two of the groups R2 to R5 are OR, where R is defined above, with the proviso that when two of the groups R2 to R5 are OR, the R groups may not both be methyl or unsubstituted benzyl, At least one of the groups R2 to R5 and not more than two of the groups R2 to R5 are N(Y)Z, where Z is selected from hydrogen or R and Y is selected from the following, where G denotes the point of connection to the nitrogen atom in N(Y)Z, the N(Y)Z moieties may not be the same; WO 2004/014929 PCT/AU2003/001008 O O O OO 8 Rii R 11 -R G G G S R G- S N OR G \H OH O S 0 0 0 O G N G N G S N N GOR II H~ IO W W WV 0S S

NH

G R G SR G OR G

Q

w w w and the groups Q and W are independently selected from hydrogen or R as is defined above, and Q and W may combine to form a cycle, The groups Z and Y may combine to form a cycle, and The groups R1 to R5 may not combine together to form a cycle.

In a more particular form the invention resides in a compound as described above with the proviso that where two groups in the compound of formula I are N(Y)Z, these groups are different, with the further proviso that when either R2 or R5 is N(Y)Z, N(Y)Z may not be azido, acetyl, benzyloxycarbonyl or t-butoxycarbonyl,with the further proviso that when R2 is N(Y)Z, N(Y)Z may not be phthalimido, 4-[N-[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)-3-methylbutyl]-amino}benzyl ester (ODmab), N-1 -(4,4-dimethyl-2,6dioxocyclohexylidene)ethyl (Dde), 2,2,2-Trichloroethoxycarbonyl (Troc), 9- Fluorenylmethoxycarbonyl (Fmoc), or a 5-Acyl-1 ,3-dimethylbarbiturate type protecting group (DTPM) and with the further proviso that when the scaffold is of the 2-deoxy-2-aminoglucose configuration and R5 and R4 are both hydroxyl, R3 may not be a glycolate [-CH 2

-CO

2 H] or lactate ether [-CH(CH 3 )-CO2H] or an ester or amide derivative thereof.

WO 2004/014929 PCT/AU2003/001008 9 Suitably,the compound is a derivative of a furanose form of a monosaccharide, and wherein n is 0.

Suitably, the compound is a derivative of a furanose form of a monosaccharide, and wherein n is 0.

Suitably, the compound has n 1 ,at least one of the groups R2 to and not more than two of the groups R2 to R5 are N(Y)Z, where Z is selected from hydrogen or R and Y is selected from the following, where G denotes the point of connection to the nitrogen atom in N(Y)Z, the N(Y)Z moieties may not be the same; O O O O O G O R GR G S-R G N OR OH O H S O O O G N0 N N N- Q

N

Q 11 J LN--,IQ I H w w w 0 S S G R G LSR G OR And the groups Q and W are independently selected from hydrogen or R as is defined above, with the proviso that Y and Z may not both be hydrogen and where two groups in the compound of formula I are N(Y)Z, these groups are different, the groups Z and Y may combine to form a cycle, the groups R1 to R5 may not combine together to form a cycle, with the proviso that where two groups in the compound of formula I are N(Y)Z, these groups are different, with the further proviso that when either R2 or R5 is N(Y)Z, N(Y)Z may not be azido, acetyl, benzyloxycarbonyl or t-butoxycarbonyl,with the further proviso that when R2 is N(Y)Z, N(Y)Z may not be phthalimido, WO 2004/014929 PCT/AU2003/001008 dimethyl-2,6-dioxocyclo-hexylidene)-3-methylbutyl]-amino}benzyl ester (ODmab), N-l1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), 2,2,2- Trichloroethoxycarbonyl (Troc), 9-Fluorenylmethoxycarbonyl (Fmoc), or a Acyl-1,3-dimethylbarbiturate type protecting group (DTPM) with the further proviso that when the scaffold is of the 2-deoxy-2-aminoglucose configuration and R5 and R4 are both hydroxyl, R3 may not be a glycolate [-CH 2

-CO

2 H] or lactate ether [-CH(CH 3

)-CO

2 H] or an ester or amide derivative thereof.

Suitably the heteroarylalkyl is substituted by a moiety from the group consisting of OH, NO, NO 2

NH

2

N

3 halogen, CF 3

CHF

2

CH

2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may be further substituted, with the proviso that the group R may not be or contain another saccharide moiety, a peptide, protein or amino acid.

The compound may be immobilized to a support. The support may be soluble or insoluble. Non-limiting examples of insoluble supports include derivatised polystyrene, tentagel, wang resin, MBHA resin, aminomethylpolystyrene, rink amide resin etc. Non-limiting examples of soluble supports include DOX-mpeg, polyethylene glycol etc.

DETAILED DESCRIPTION Embodiments of the invention will be described with reference to the following examples. Where appropriate, the following abbreviations are used.

Ac Acetyl DTPM 5-Acyl-1,3-dimethylbarbiturate Ph Phenyl TBDMS t-Butyldimethylsilyl TBDPS t-Butyldiphenylsilyl WO 2004/014929 Bn Bz Me

DCE

DCM

Tf Ts

IDMVF

DMAP

L.LI-DMT

IDMVSO

DTT

IDMVTST

TBAF

PCTAJ2003OO1008 benzyl benzoyl methyl I 2-dichloroethane dichioromethane, methylene chloride trifluoromethanesulfonyl 4-methylphenylsulfonyl, p-toluenesulfonyl N, N-dimethylformamide N,N-dimethylaminopyridine Li]1-dimethoxytoluene, benzaldehyde dimethyl acetal d imethylsulfoxide dithiothreitol Dimethyl(methylthio)sulphoniumtrifluoro- methanesuiphonate tetra-n-butylammonium fluoride Part A: Preparation of building blocks: In order to fully enable the invention, we detail below methods for the preparation of certain building blocks used in the preparation of the compounds of the invention. The building blocks described are suitable for both solution and solid phase synthesis of the compounds of the invention.

Example A: Synthesis of a 2,4 dinitrogen containing Galactopyranoside Building Block WO 2004/014929 PCT/AU20031001008 12 OH Ph Ph C O 0) 0 0 NHDTPM NHDTPM NHDTPM A-1 A-2 A-3 N OTBDPS OTBDPS OH BzO V) 0o Mei v) QO m NHDTPM NHDTPM N HDTPM A-6 A-5 A-4 Conditions: LI.]-dimethoxytoluene (EQL-DMT), p-toluenesulphonic acid (TsOH), acetonitrile (MeCN), 76()C, 85%; (ii) Benzoylchloride (BzCI), triethylamine; DCM, 99%; (iii) methanol (MeOH)/MeCN/water, TsOH, 750C, 98%; (iv) t-butyldiphenylsilylchloride (TBDPS-CI), imidazole, pyridine, 120 0

C,

99% Tf 2 O, pyridine, DCM, 0 0 C, 1 NaN 3 DMF, l6hr, RT, 99%.

WO 2004/014929 PCT/AU20031001008 13 Example B: Synthesis of a 3-nitrogen containing Gul oyranoside Building Block Ph- Ph 0 0 0y0OH HO SMe -o*-rl4 OBzCl 3IBC

N

3 OBzCI B-1 B-2 B-3 0 SMe

N

3 OBzCI B-4 Conditions: tritluoromethanesulfonic anhydride (Tf 2 pyridine, -20 0

C,

dichioromethane (DCM), 1 hour, 100%, sodium azide (NaN 3

NN-

dimethylformnamide (DMF), 50 0 C, 5 hours, quantitative; (ii) TsOH, MeCN/ MeOH/water 90 0 C, 6 hours, 88%(iii) TBDPSCI, OMAIP, pyridine, 120 0 C, 12 hours, 93% Example C: Synthesis of a 2,6-dinitrogen substituted Glucopyranoside Building Block OH

N

3 z 0 SMe F&OSMe NHDTPM

NHDTPM

A-4 c-1 Conditions: Tosylchlodride, pyridine, RT, 24 hours, 33%(b) NaN 3

DMF,

RT, 168 hours.

WO 2004/014929 PCT/AU20031001008 14 Example D: Synthesis of a 2-nitrogen containing Tallopyranoside Building Block D-1 D-2 OH P -0N 3(iv) TBDPSO -0 .~SMe TBDPSO SMe OBz O:Q _3

TBDPSOS~

Conditions: TBDPSCI, imidazole, 1 ,2-DCE, refiux; (ii) NaOMelMeOH; (iii) (a) Tf 2 O, pyridine, -200C, DOM, 1 hour, NaN 3 DMF, 5000, 5 hours; (iv) TsOH, MeCN/MeOH/water; benzoylchloride, DMAP, I 2-DOE, -200C.

WO 2004/014929 PCT/AU20031001008 Example E: Synthesis of two 3-nitrogen containing Altropyranoside Building Block HO OH 0 O HOI~ 0i qc HO~ HO S~e- E-1 E-2 E-3 PhOMe HO O~n-OMe HO 0SMe

N

3 E-7 0 O~n-OMe

N

3 0 7o0 OBn-OMe E-4 TBDPSO OBz (vi HO ~L SMe

N

3 Conditions: cyciohexanone dimethylacetal, TsQH, MeCN; (ii) pmethoxybenzaldehyde dimethylacetal, TsOH, MeCN; (iii) DIBAL, diethyl ether; (iv) Tf 2 Q, pyridine, -20 0 C, DCM, 1 hour, NaN 3 DMF, 50 0 C, hours; TsOH, MeCN/MeOH/water; (vi) TBDPSCI, DMAP, 1,2-DCE; (vii) (a) CAN, BzCI, OMAP, 1,2-DCE, TsOH, MeCN/MeOH/water; (viii) TBDPSCI, DMAP, I ,2-DCE.

WO 2004/014929 PCT/AU20031001008 16 Example F: Synthesis of a 2-nitrogen containing Glucopyrangside Building Block Ph Ph HO~ 0 0 HO) 0 0 HO SMe-* HO Se BzO

N

3

N

3

N

3

TBDPSO-

HO iv BzOA OSMe -4 (iv)

N

3

HO

H

Bz, SMe F-4

N

3 Conditions: EID-DMT, TsOH, MeCN; 0ii) I ,2-DCE, BzCI, DMAP; (Ni) TsOH, MeOH/MeCN; (iv) TBDPS-CI, DMAP, I 7 2-DCE.

HO 0TBDPSO-~ HO SmeHO

N

3 H O P-1 F6 N 3

TBDPSO

BzO~~ HO- SMe

N

3

TBDPSO-

HO

Bzo o e

N

3 F-7 F-6 Conditions: TBDPSCI, DMAP, pyridine, 120 0 C, 0.5 hours, (Bu)2SnO, MeOH; b. Benzoylchloride, RT, 24 hour; 81 (ii) a.

WO 2004/014929 PCT/AU20031001008 17 Example G: Synthesis of a 2-nitrogen containing Allopvranoside Building Block Ph Ph Ph 0 MSO 0 SMe

N

3 NS

N

F-2 G-1 OBz N G-2 HODPS 0(iv) HO (i) HOSMe -HO 0 -SMe I~

N

3 O~zOBz N 3 G-4 G-3 Conditions: DCM/pyridine, MsCI, DMAP, 000; (ii) sodium benzoate, dimethylsulphoxide (DMSO), I 4OC; (iii) TsOH, MeOH/MeCN/water; (iv) TBDPS-CI, imidazole, 0CM, 1 hour, reflux.

WO 2004/014929 PCT/AU20031001008 18 Example H: Synthesis of a 3-nitroglen containing Allopyranoside Building Block

OH

0 0- H-1 0i 0

N

3 0 H-2

(V)

H-6

H-S

(Vii) -SMe OiX) H-7 H-8 H-9 Conditions: Tf 2 O, pyridine, DCM; NaN 3 DMF; (ii) acetone, (iii) Ac 2

O,

pyridine; (iv) hexamethyldisilazane, 12, CH 3

-S-S-CH

3 NaOMe/MeOH; (vi) TsOH, E.F-dimnethoxytoluene, MeCN; (vii) benzoylch lo ride, 1,2-DOE, pyridine, DMAP; (viii) TsOH, MeOH, H 2 0, MeCN; (ix) TBDPS-CI, imidazole, 1,2-DCE.

WO 2004/014929 PCT/AU20031001008 19 Example 1: Syntheses of two 2-nitrogen containing Tallopyranoside Building Blocks with hydroxyls in the 3 or 4 positions.

0 ~S0

OH

0

~TBDPS

0 Me 1-2 HOZ b~ 1 -3 BzO OTBDPS HO L SMe v) 1-6 BzO OTBDPS PAO -ESMe o BD:M NzO Conditions: Tf 2 O/Py, NaN 3 DMF; (ii) TsOH, MeOH/MeCN/water; (iii) BzCI, DMAP, 1,2-OCE; (iv) phenoxyacetyl-CI (PACI)/pyridine; (b) Bz 2 O/Pyridine; MeNH 2

ITHF.

WO 2004/014929 PCT/AU20031001008 Example J: Synthesis of nitrogen containing furanoside Building Blocks j- OH

TBDPSO

0HO J-2 -0 0 -0\O TBDPSO TBDPSO PMBO J-6' N 3 ,J-3 -0 (vi)0 %kB TBDPSO

N

3

N

3 O0 PM BO J-6 "OBz 0~A a\\ TBDPS PMBO J- N 3 Conditions: 2,2-dimethoxypropane, TsOH, DMF; TBDPSi-CI, Imidazole, DMF; (ii) Tf 2 OfPy, NaN 3 DMF; (iii) TsOH, MeOH/MeCN/water; Benzoyl chloride, pyridine, DCM; (iv) 4-methoxybenzyl chloride, NaH, DMF; (a)TBAF, THE; Tf 2 O/Py, NaN 3 DMF; TsOH, MeOH/MeCN/water;, Benzoyl chloride, pyridine, DCM; (vi) TsOH, MeOH/MeCN/water; Benzoyl chloride, pyridine, DCM; R-OH or R-SH, boron trifluoride diethyl etherate, DCM, molecular sieves; Tf 2 OfPy, NaN 3

DMF;

WO 2004/014929 PCT/AU20031001008 21 Example K: Synthesis of a 3-nitrogen containing Gulopyranoside Building Block (ii)

U

(vi) O13z OTBDPS OBZ OTBDPS 0 (Vii)0 SMe ~UIb~~SMe

N

3

N

3 L OH 0 K-7 K-8 Conditions: trifluoromethanesu Ifonic anhyd ride (Wf 2 pyridine, -20 0

C,

dichloromethane (DCM), 1 hour, 100%, sodium azide (NaN 3

NN-

dimethylformamide (D MF), 5000, 5 hours, quantitative; (ii) NaOH/H2OITH FIMeOH, 99%; (iii) Levulinic acid, N, N'-dicyclohexyldiimide, DMAP, 0CM, quantitative; (iv) TsOH, MeCN/ MeOH/water (1 5:15:1), 5000, 16 hours, 56%; TBDPSCI, DMAP, pyridine, 12000, 2 hours, (vi) Benzoylch lo ride, pyridine, RT, 2 hour, 95%; (vii) hydrazine acetate, 0CM.

Part B: Immobilization to solid support and glycosylation: The compounds of the present invention may be conveniently prepared in solution phase or on a solid support. Because a free hydroxyl group is always present in the compounds of the invention, it is convenient to immobilize the WO 2004/014929 PCT/AU2003/001008 22 building blocks to the solid support through a hydroxy function which will become the free hydroxyl group in the final compounds. Many of the building blocks described above have a free hydroxyl in the 4 position which is suitable for immobilization. Where a free hydroxyl is desired in a different position, a protection/deprotection sequence is first performed.

Example L: Alternative immobilization positions TBDPSO-- TBDPSO TBDPSO--\ HSO SMSe SMe Me PMBO SMe PMBO SM OBz N OBz N OH N G-4 L-1 L-2 PMBO 0SMe OBz N 3 L-3 Conditions: 4-methoxybenzyl chloride, NaH, DMF, workup with citric acid (ii) NaOMe/MeOH/THF; (iii) TBAF/THF; HOAc to neutral pH Example M: Glycosvlation of anomeric position In most cases the thiomethyl glycoside building block containing one free hydroxyl group can be used in glycosylation reactions without resorting to protection of the free hydroxyl. An excess of the alcohol acceptor is typically employed. Where a thiol is to be glycosylated, the acceptor alcohol is in short supply or results are not satisfactory, the thiomethyl glycoside donor may first be converted to the bromo sugar or imidate, and these donors used for glycosylation. Alternatively, glycosylation can be effected with the fully protected precursor e.g. K-2, if significant side reaction is observed with the free hydroxy donors e.g. K-3, K-4, G-4.

WO 2004/014929 PCT/AU2003/001008 23 In a typical proceedure, 1 mmol of donor (eg G-4, K-2, K-3, K-4, A-6, B-4, C-1 etc) is dissolved in anhydrous dichloromethane 8 mL and an equal weight of dry 4A molecular sieves is added. The mixture is stirred for 30 minutes at room temperature then 4 mmol of the acceptor alcohol is added followed by addition of DMTST solution (6 equivalents in 12ml of DCM). The reaction is monitored by t.l.c. When the reaction is complete, triethylamine (1.2 mmol) is added. The mixture is diluted with 100 mL dichloromethane and extracted with sodium bicarbonate (10% aqueous), citric acid (10% aqueous) and sodium chloride (sat. solution), dried over magnesium sulfate and solvents removed in vacuo.

The crude material is chromatographed on silica gel prior to immobilisation or in the case of K-2 removal of one of the alcohol protecting groups.

In an alternative proceedure, 1 mmol of donor in dichloromethane 8 mL is first treated with bromine to yield the crude sugar halide. This solution is washed breifly with 5% sodium thiosulfate, dried over magnesium sulfate and the solvents removed in vacuo. The crude sugar halide is used directly as above with silver triflate as the activating agent in place of DMTST. Both alcohols and thiols are amenable to glycosylation by this method.

Example N: Immobilization onto solid phase Wang resin (13.3 g; 0.85 mmol/g, p-Benzyloxybenzyl Alcohol polystyrenedivinylbenzene resin) was dried in the vacuum oven overnight in 500 ml round bottom flask. The flask was place under nitrogen atmosphere then dry DCM (133 ml) and trichloroacetonitrile (20 ml) was added. The mixture was cooled with ice bath while gently stirred. After 15 minutes of cooling DBU (1.3 ml) was added drop wise in 15 minutes, the resulting mixture was stirred for one hour with ice bath cooling. The resin was collected by filtering, washed with DMF, THF and DCM (3x each). The resin was dried in the vacuum oven over P 2 0 5 for 24 hours to afford 15 grams of TriChloroAcetimidate Wang (TCA-Wang) resin.

The resin was packed under nitrogen and stored at 4°C.

Yield 100%; loading ca. 0.754 mmol/g.

WO 2004/014929 PCT/AU2003/001008 24 (Alternative resins may be used).

Glycosylated building blocks containing one free hydroxyl are immobilised onto TCA-Wang resin. In a typical proceedure, TCA Wang resin (3.6 gram) was dried in vacuum oven overnight then washed with anhydrous THF (3x36 ml) under nitrogen atmosphere. Building block (3 equiv.) was added followed by addition of anhydrous DCM (18 ml). The reaction mixture was shaken for 5 minutes (until all alcohol was dissolved), and BF 3 .Et 2 0 (0.35 ml, 1 equvalent) was added. The reaction mixture was shaken vigorously for ten minutes and drained; the resin was washed with DCM (3x30 ml), DMF (3x30 ml), THF (3x30 ml) and dried.

Part C: Library preparation: The compounds of the invention are prepared by sequential deprotection and ligation chemistries either on solid support or in solution phase. The following typical chemistries may be employed as required.

Removal of a tert-butyldiphenylsilyl: The resin bound building block is suspended in dry THF/methanol (20/1 v/v) mixture containing 10 equivalents of tetra-n-butylammonium fluoride. The mixture is stirred at 65 0 C for 24 hours, drained; the resin is filtered, washed with dimethylformamide followed by THF and finally dichloromethane. In an alternative procedure, TBAF may be conveniently replaced by HF.pyridine and the reaction effected in plastic ware. The TBAF may also be replaced by HF."proton sponge" complex with good results.

Removal of a benzoate, p-chlorobenzoate or other ester protecting group: The resin bound building block is suspended in dry THF and methanol (3/1 v/v) mixture and sodium methoxide (0.5 equivalents) is added. The mixture is shaken for 24 hours, drained and re-treated with fresh reagents for further 24 hours. The resin is filtered, washed with dimethylformamide followed by THF and finally dichloromethane.

WO 2004/014929 PCT/AU2003/001008 Removal of a p-methoxvbenzvl groupl The resin bound building block is suspended in DCM and a small amount of water is added (approx followed by 2,3-dichloro-5,6-dicyanobenzoquinone equivalents). The mixture is shaken for 3 hours drained and re-treated with fresh reagent for a further 3 hours. The resin is filtered, washed with THF followed by methanol and finally dichloromethane.

Etherification of hydroxyl position: Resin bound building block which has previously had a hydroxyl group deprotected is washed three times and then suspended in anhydrous DMF and 3 equivalents of potassium t-butoxide added (alternative bases may be employed), shaken and drained after 5 minutes followed by the alkylating agent (3 equivalents) in DMF. The mixture is shaken for 10 minutes, drained and retreated twice more with fresh reagents as above. The resin is filtered, washed with dimethylformamide followed by THF and finally dichloromethane.

Reduction of an azide: The resin bound building block is suspended in dry DMF; 5 equivalents of DTT (1,4-dithio-DL-threitol) and 3 equivalents of potassium tert-butoxide (alternative bases may be employed) are added. The mixture is agitated under nitrogen atmosphere for 24 hours, drained and the resin is washed with dimethylformamide followed by THF and finally dichloromethane.

Removal of a DTPM group: The resin bound building block is suspended in DMF and hydrazine hydrate (50/1 v/v) mixture, agitated 2 hours, drained and the resin is washed with dimethylformamide followed by THF and finally dichloromethane Amide formation: A solution of a suitable carboxylic acid (10 equivalents) in dry DMF is treated with HBTU (10 equivalents) and di-isopropylethylamine (10 equivalents) and shaken for 5 minutes. This solution is then added to a suspension of Resin WO 2004/014929 PCT/AU2003/001008 26 bound building block, which has previously had an amine group deprotected in DMF and the mixture shaken for 30 minutes. After this time the resin is drained and treated once more with fresh reagent for 30 minutes. The resin is filtered, washed with DMF followed by methanol and finally dichloromethane. If desired, quantitative ninhydrin assay may be performed to determine that the reaction is complete. Alternative coupling systems including HOAT, EDC/NHS or anhydrides may be employed to similar effect.

Urea and thiourea formation: Isocyanates and thioisocyanates may be purchased or prepared by reaction of the corresponding amine with triphosgene, diphosgene, phosgene or thiophosgene as appropriate according to standard procedures as outlined in "Organic Functional Group Preparation" Vol 1, 2 n d Ed., Sandier and Karo, Academic Press, ISBN:0-12-618601-4 pp 359 to 375.

Resin bound building block which has previously had an amine group deprotected is suspended in anhydrous THF and 2 equivalents of the isocyanate or thioisocyanate added, followed immediately by triethylamine (1 equivalent). The mixture is shaken for 2 hours and may be exothermic depending on the scale and reactivity of the isocyanate or thioisocyanate used, drained and re-treated with fresh reagents for a further 2 hours. The resin is filtered, washed with THF followed by methanol and finally dichloromethane.

Carbamate formation: Chloroformates and imidoylformates may be purchased or prepared by reaction of the corresponding alcohol with phosgene or carbonylbisimidazole as appropriate according to standard procedures as outlined in "Organic Functional Group Preparation" Vol I, 2 nd Ed., Sandier and Karo, Academic Press, ISBN:0- 12-618601-4 pp 359 to 375.

Resin bound building block which has previously had an amine group deprotected is suspended in anhydrous THF and 2 equivalents of the WO 2004/014929 PCT/AU2003/001008 27 chloroformate or imidoylformate added, followed immediately by triethylamine (1 equivalent). The mixture is shaken for 2 hours and may be exothermic depending on the scale and reactivity of the isocyanate or thioisocyanate used, drained and re-treated with fresh reagents for a further 2 hours. The resin is filtered, washed with THF followed by methanol and finally dichloromethane.

Sulfonamide formation: Resin bound building block which has previously had an amine group deprotected is suspended in anhydrous THF or DMF and 2 equivalents of the sulfonyl chloride added, followed immediately by triethylamine (2 equivalent).

The mixture is shaken for 2 hours, drained and re-treated with fresh reagents for a further 2 hours. The resin is filtered, washed with THF or DMF followed by methanol and finally dichloromethane.

Removal of Fmoc: The resin bound building block is suspended in piperidine /DMF v/v) mixture and stirred 1 hours, drained and repeated once more; the resin is filtered, washed with dimethylformamide followed by THF and finally dichloromethane.

Guanidine formation: The resin bound building block is suspended in dry DMF containing 3 equivalents of 3,5-dimethylpyrazolyl formamidinium nitrate and 15 equivalents of DIPEA. The mixture is stirred at 65 0 C for 24 hours, drained; the resin is filtered, washed with dimethylformamide followed by THF and finally dichloromethane.

Cleavage of resin bound product: The resin bound compound is suspended in dry DCM containing 20% TFA and 20% Et 3 SiH. The mixture is stirred at RT for 3 hours and the aliquot was collected; the resin was washed with dry DCM and all the DCM solutions were WO 2004/014929 PCTAJ2Of3IOO1008 28 combined, evaporated to dryness under reduced vacuo to furnish the desired product.

WO 2004/014929 PCT/AU20031001008 29 Libraries of compounds of the invention have been prepared based on the following scaffolds: Scaffold W1 derived from A-6 N R 5

R

4 0 0-

R

3 0NR

NR

2 Scaffold W3 derived from C-1 SC O\R2 R4

R,

Scaffold W5 derived from E-9 E-7

OR

4

OR

~~R1

NR

3

OR

2 Scaffold W2 derived from B-4 or K-8

OR/OR

OR2

R

3 0) -X affold W4 derived from D-5 or 1-6 R0

R

4 00

R

R

3 0 N R 2 Scaffold W6 derived from F-5 or F-7 Scaffold W7 derived from G-4

R

5

R

4 O 0 R,

NR

3

OR

2 Scaffold W8 derived from H-9

R

5

N

R

3 0 O0R 2 Scaffold W10 derived from J-6 Scaffold W9 derived from J-4

R

3 0 NR 2 Scaffold W1 I derived from J-7 WO 2004/014929 PCT/AU20031001008 The following groups are exemplary of moieties in position R1, where the wavey line indicates the point of attachment to the carbohydrate ring: X2 X3 X4 X8 X6 X7 X9 Xl 2 0'N0 X1 8

H

N, NH 2 0 X19

NH

0 2 0 WO 2004/014929 WO 204/04929PCT/A1J20031001008 31 X21 X22 X23 X24 /o-S

CF

3 X26 X27

-NO

2 X28 X28 X29 WO 2004/014929 PCT/AU2003/001008 32 The following groups are exemplary of ether linked moieties, where the wavey line indicates the point of attachment to an oxygen on the carbohydrate ring: Methyl Ethyl Y1 Y2 Y3 Y4 Cl Y6

YOH

0

OH

Y8

NH

2 Y12a Br CF3 Yi3

OH

Y19 Y17 Y18 WO 2004/014929 WO 204/04929PCT/A1J20031001008 .N0 2 Octyl, Y21 Y22 Y23 Y24 Y26

YN

Y27

N

N

N

ti

N

H

Y28Y2 Y29 WO 2004/014929 PCT/AU20031001008 34 The following groups are exemplary of amine Iinkdd moieties, where the wavey line indicates the point of attachment to a nitrogen on the carbohydrate ring: 0 0 0 y y

NH

2

NH

2 0 Z4 0

NH

2 Z5 0 Z6 V7 Z8 0 z1 0 0 Z1 3 0

NH

Z1 4 Z17 Z18 WO 2004/014929 WO 204/04929PCT/A1J20031001008

NH

0NH

NH

2 0

OH

Z29 0 WO 2004/014929 PCT/AU20031001008 z 36 00

CF

3 1N l 34 0 0 N CF 3 ZZ36 H Z37 NH I9 CF 3 Z38 Z39 Z41 Z42 WO 2004/014929 WO 204/04929PCT/A1J20031001008 0

H

Z43 H

H

Z48 0 Z49

/N

NH2 0 0

HN

zso Z51 0

NH

0 NH 2

HN

Z52 N H 0? NHBoc

HN

Z54 WO 2004/014929 WO 204/04929PCT/A1J20031001008

-NH

HNHBoc 0

N

NH

2 Z56 Z57 Z58

H

Z59 0

H

Z\

N.

A NH 2 WO 2004/014929 WO 204/04929PCT/A1J20031001008 Exemplary library compounds: Compound Scaffold RI Number R2 R3 R4

I

1 W6 il- Z43 Y3 [OH Y21 2 W6 X36 Z44 Y3 OH Y22 3 W6 X9l _Z45 Y3 OH Y23 4 W6 -Xl Z46 Y3 OH Y24 W6 XI Z47 Y3 OH 6 W6 XI Z48 Y3 OH Y26 7 W6 XI Z49 Y3 OH Y27 8 W6 X1 Z50 Y3 OH Y28 9 W6 Xl Z51 Y3 OH Y29 W6 X1 Z52 Y3 OH 11 W6 X1 Z53 Y3 OH Y21 12 W6 XI Z54 Y3 OH Y22 13 W6 XI Z56 Y3 OH Y23 14 W6 Xl Z56 Y3 OH Y24 W6 Xl Z57 Y3 OH 16 W6 XI Z58 Y3 OH Y26 17 W6 Xl Z59 Y3 OH Y27 18 W6 XI Z60 Y3 OH Y28 19 W6 X3 Z12 Y9 OH Y29 W6 X3 Z29 Y9 OH 21 W6 X3 Z12 Y9 OH Y12 22 W6 X3 Z29 Y9 OH Y12 23 W6 X3 Z13 Y9 OH Y8 24 W6 33 Z26 Y9 OH Y8 25W6 X3 -Z13 Y3 OH YIO 26 W6 3 3- Z26 Y3 OH YIO 27 W6 X34- -Z3 Y3 OH Y8 28 Z17 WO 2004/014929 WO 204/04929PCT/A1J20031001008 29 W6 X4 Z3V3- OH Ylo W6 X4 Z17 Y3 OH Yb-- 31 W6 X4 Z12 Y3 OH Y9 32 W6 X4 Z29 Y3 OH Y9 33 W6 X4 Z3 Y12 OH Y8 34 W6 X4 Z17 Y12 OH Y8 W6 X4 Z3 Y12 OH YIo 36 W6 X4 Z17 Y12 OH Ybo 37 W6 X4 Z12 Y12 OH Y9 38 W6 X4 Z29 Y12 OH Y9 39 W6 X4 Z3 Y8 OH Y3 W6 X4 Z17 Y8 OH Y3 41 W6 X4 Z3 Y8 OH Y12 42 W6 X4 Z17 Y8 OH Y12 43 W6 X4 Z13 Y8 OH Y9 44 W6 X4 Z26 Y8 OH Y9 W6 X4 Z3 Y10 OH Y3 46 W6 X4 Z17 Y10 OH Y3 47 W6 X4 Z3 Ylo OH Y12 48 W6 X4 Z17 YIo OH Y12 49 W6 X4 Z13 '(10 OH Y9 W6 X4 Z26 YIO0 OH Y9 51 W6 X4 Z12 Y9 OH Y3 52 W6 X4 Z29 Y9 OH Y3 53 W6 X4Z12 Y9 OH yl12 54 W6 X4 Z29 OH YI 2 W6 X4 Z13 Y9 OH '(9 56 W6 X4Z26 Y9 OH '(9 57 W6 X4 Z13 YS OH 58 -W6- X4 Z26 Y9 OH 59 W6 Xi4 Z3 YOHY8 WO 2004/014929 WO 204/04929PCT/A1J20031001008 W6 X4 Z17 Y2 OH Y8 61 W6 X4 Z3 Y2 OH Ylo 62 W6 X4 Z17 Y2 OH YIo 63 W6 XR4 Z12 Y2- OH Y9 64 W6 X4 Z29 Y2 OH Y9 W6 X4 Z3 Y8 OH Yi 66 W6 XIO Z17 Y8 OH Yi 67 W6 XIO Z3 Y8 OH Y2 68 W6 XIO Z17 Y8 OH Y2 69 W6 XIO ZI YB OH Y9 W6 XIO Z4 YB OH Y9 71 W6 XIO Z3 Ybo OH YI 72 W6 XIO Z17 Y10 OH YI 73 W6 XIO Z3 Ybo OH Y2 74 W6 XIO Z17 Y10 OH Y2 W6 XIO ZI YIo OH Y9 76 W6 XIO Z4 Ylo OH Y9 77 W6 XIO0 Z12 Y9 OH YI 78 W6 XIO0 Z29 Y9 OH YI 79 W6 XIO0 Z12 Y9 OH Y2 W6 XIO Z29 Y9 OH Y2 81 W6 XIO0 ZI Y9 OH Y9 82 W6 XIO Z4 Y9 OH Y9 83 W6 Xis ZiI Yb OH Y17 84 W6 xi 5 Z4 Y9 OH YIo W8 X6 Y8 Z33 OH Y9 86 W8 X6 YIo Z24 OH Y1 9 87 W8 X6 Y7 ZI8 OH Y12 88 W8 X9 Y9 Z25 OH Y3 89 W8 X9 Y19 ZI OH Y4 W8 X9 Y12 Z20 OH Y13 WO 2004/014929 WO 204/04929PCT/A1J20031001008 91 W8 X12 Y3 Z25 OH Y17 92 W8 X12 Y4 Z20 OH Yi 1 93 W8 X12 Y13 Z20 OH Y1 8 94 W8 XIO Y17 Z36 OH Y8 W8 XIO YII Z42 OH Y1 0 96 W8 XIO Y18 Z18 OH Y1 3 97 WI X6 Z33 Y4 Z37 OH 98 WI X6 Z37 OH Z33 Y3 99 WI1 X6 Z42 OH Z18 Y3 100 WI X9 Z33 Y4 Z37 OH 101 WI X9 Z37 OH Z33 Y3 102 WI X9 Z42 OH Z18 Y3 103 WI X12 Z33 Y4 Z37 OH 104 W11 X12 Z37 OH Z33 Y3 105 WI X12 Z42 OH Z18 Y3 106 W6 (12 ZII1 Y5 OH YI 107 W6 X12 ZI6 Y5 OH YI 108 W6 X12 Z5 Y5 OH YI 109 W6 X12 ZiI Y17 OH YI 110 W6 X1 2 ZI6 Y17 OH YI il16X116 Y1 H Y 112W6 X2 Z YOH1 113W6 X2 Z6 YOH1 114W6 X2 5 YOHi 115X12 Z YOH1 116 W6 X1 2 ZI6 Y4 OH Yi 117 W X2 5 YOH1 118 X i 5 H Y 119 -W6- X9 ZIG YV5- OH Y1 120 W- X9 Z5 Y5 OH Yi 121 W6 X9 ZiI Y17 OH Y1 WO 2004/014929 WO 204/04929PCT/A1J20031001008 122 W6 X9 f16- Y17 OH YI 123 W6 X9 i5 Y1 7 OH Vi 124 W6 X9 ZIl Y3 OH VI 125 W6 X9 Z16 Y3 OH Vi 126 W6 X9 Z5 Y3 OH YI 127 W6 X9 ZiI Y4 OH VI 128 W6 X9 ZI6 Y4 OH VI 129 W6 X9 Z5 Y4 OH VI 130 W6 X12 ZiI VI OH Vs 131 W6 X12 Z16 VI OH 132 W6 X12 Z5 VI OH 133 W6 X1 9 Z28 VI OH Y3 134 W6 Xi 9 Z13 YI OH Y17 135 W6 Xi 9 Z13 Y17 OH VI 136 W6 X3 Z29 Y12 OH Y9 137 W6 X3 Z17 Y8 OH Y3 138 W6 X3 Z17 Y8 OH Y12 139 W7 X12 ZiI VII OH YI 140 W7 X12 Z16 Y15 OH VI 141 W7' X12 M3 Y16 OH YI 142 W7 X8 ZII YII OH VI 143 W7 X8 ZIG V15 OH VI 145 W7' X8 Z3 Y16 OH VI 146 W7 XI 5 ZII VII OH VI 147 W7' X15 Z16 Y15 OH VI 148 W7 XIS Z3 Y16 OH Vi 149 W' X17 ZiI Y4 OH YI 150 W7' X15 Z7 OH Y4 Y17 151 W' XIS Z31 OH Y4 Y17 152 W7 X15 Z9 OH Y4 Y17 153 W' Xis Z32 OH Y4 Y17 WO 2004/014929 WO 204/04929PCT/A1J20031001008 154 T T X15 Z42 155 W X15 37 Y2 YIjO 156 W6 X15 Z37 20 YI OH 157 W6 X1l 4 Z42 Y6 Y8 OH 158 W6 X4 Z37 Y20 Y78 OH 159 W6 X6 Z17 Y8 Y3 OH 160 W2 XBOH Z13 Y4 YI 161 W2 X8 OH Z16 Y4 YI 162 W3 X15 Z36 Y4 OH Z37 163 W3 X5 zli Y4 OH Z33 164 W3 X5 Z8 Y4 OH Z24 165 W3 X5 Z36 Y4 OH Z37 166 W3 xi ZiI OH OH Z33 167 W3 xi Z8 OH OH Z24 168 W3 xi Z36 OH OH Z37 169 W3 X15 ZiI Y4 OH Z33 170 W3 X16 Z8 Y4 OH Z24 171 W4 X12 ZIO Y4 Y8 OH 172 W4 X12 Z41 Y8 Y3 OH 173 W5 X8 Y17 Z13 Y4 OH 174 W5 X8 Y17 Z16 Y4 OH 175 W9 X22 Y4 Z3 Absent OH 176 W9 X23 Y5 Zi I Absent OH 177 W9 X26 Y8 Z3 Absent -OH 178 W9 X21 Y17 ZiI Absent OH 179 WIO X3 Y6 OH Absent 180 W10 X6 Y12 OH Absent 181 WIO XIO Y19 OH Absent 182 Wil X6 Z25 OH Absent Y6 183 WII X8 Z30 OH Absent IY12 184 WII XIO Z40 OH Absent Y19 WO 2004/014929 PCT/AU20031001008 Exemplary synthesis of compound 85 (W6-X15-ZII-YI-OH-Y17) on solid phase.

TBDPSO

HO

M

BzO

N

3

TBDPSO-

N

3 W6 TBDPSO TBDPSO OV) 0XI 5 0X15 NN3 TBDPSO 1 w MeO-~'X5

N

3 HO~ (vi) OX1

N

3 WO 2004/014929 PCT/AU20031001008 46 Y17 (vii)i 0e- X15 MeO~ 0X1

N

3 NH Y17 Y17 \0(ix) \0 W O 0 X15 0 O-7tr Me NNHFmoc HN- N H 00 Cl Y17 0 0 (xi) M e O O 0 Q MeO- 5

HN

HN X -NH 0 X \NH

NH,

0

NH

2

HN

HN C 2 ,H,,C1N 4 0 6 Exact Mass: 556.21 Conditions: a. Br 2 DCM; b. 4-Chlorobenzylalcohol, AgOTf, 0CM; (ii) TCA-Wang resin, BF 3 .Et 2 O, 0CM, THF; (iii) NaOMe, THE, MeOH; (iv) a. KOBut, DMF; b. lodomethane, DMF; HF.'proton sponge', AcOH, DMF, 6500; (vi) a.

KOBu', DMF; b. 2-bromomethyl-naphthalene, DMF; (vii) I 4-Dithio-DL-threitol, KOBut, DMF; (viii) HBTU, Fmoc-Gly-OH, DIPEA, DMF; (ix) piperidine! DMF 3,5-dimethylpyrazolyl formamidinium nitrate, DIPEA, DMF; (xA) TFA, Et 3 SiH, DCM.

WO 2004/014929 PCT/A1J20031001008 LCMVS method: Time water% 0.00 95.0 1.00 95.0 7.00 0.0 12.00 0.

acetonitrile% 5.0 2.000 5.0 2.000 100.0 2.000 Flow (mi/mmn) 2.000 100.0 M+H 557.3; Rt 3.98 min WO 2004/014929 PCT/AU20031001008 48 Exemplarv synthesis of compound 159 (W6-Z1 7-Y8-Y3-OH) in solution phase: MeO Ho-O HON -OHO

N

3 t OMe MeO 0 HO 0 X-1N 3 0;70N 3

OPMB

0

H

P- '-O0 0 BccHN

OH

(vi)0

ONH

H

2

N

Conditions: 4-Methoxybenzaldehyde dimethylacetal, TsOH, CH 3 CN; (ii) NaH tert-butyl bromnoacetate, DMF; (iii) NaBH 3 CN, TFA, DMF; (iv) KoBut, BnBr, DMF; a. Zn, NH 4 CI, MeOH, H 2 0; b. HBTU, 3-Boc-NH-benzoic acid, DIPEA, DMF; (vi) CH 3 CN, H 2 0, TsQH.

It should be appreciated that various changes and modifications can be made to the embodiments without departing from the spirit and scope of the invention.

Claims (21)

1. A compound of formula I being a derivative of a furanose or pyranose form of a monosaccharide, H H R 5 H H R4 \R2 n H H R3 formula I Wherein, n is 0 or 1; R1 is XR wherein, X is selected from 0; S; S=0 and SO 2 R is selected from the group consisting of C1 to C9 alkyl, C1 to C15 alkenyl, C1 to C15 alkynyl, C1 to C15 heteroalkyl, C6 to C15 aryl, C6 to heteroaryl, C6 to C15 arylalkyl or C6 to C15 heteroarylalkyl which is optionally substituted, cyclic or acyclic, branched and/or linear, the groups R2 to R5 are selected from OH, OR and N(Y)Z such that: at least one of the groups R2 to R5 and not more than two of the groups R2 to R5 are OH, at least one of the groups R2 to R5 and not more than two of the groups R2 to R5 are OR, where R is defined above, with the proviso that when two of the groups R2 to R5 are OR, OR is an ether type moiety and the R groups may not both be methyl or unsubstituted benzyl, at least one of the groups R2 to R5 and not more than two of the groups R2 to R5 are N(Y)Z, where Z is selected from hydrogen or R and Y is selected from the following, where G denotes the point of connection to the nitrogen atom in N(Y)Z, the N(Y)Z moieties may not be the same; AkENDED SHEE" IPEWI PCT/AU03/01008 Received 10 August 2004 O I I GOH OH 0 OR GI' 0 11? 0 0 G-~O N OR H S G N/Q I w 0 0 H I W 0 G -OR 0 G R S S NH G SR G OR G N W and the groups Q and W are independently selected from hydrogen or R as is defined above, and Q and W may combine to form a cycle, the groups Z and Y may combine to form a cycle, the groups R1 to R5 may not combine together to form a cycle, with the proviso that where two groups in the compound of formula I are N(Y)Z, these groups are different, with the further proviso that when either R2 or R5 is N(Y)Z, N(Y)Z may not be trifluoroacetamido, acetamido, benzyloxycarbonylamino or t-butoxycarbonylamino, with the further proviso that when R2 is N(Y)Z, N(Y)Z may not be phthalimido, 4 4 -dimethyl-2,6-dioxocyclo-hexylidene)-3- methylbutyl]-amino}benzyl ester (ODmab), N-1-(4,4-dimethyl-2,6- dioxocyclohexylidene)ethyl (Dde), 2,2,2-Trichloroethoxycarbonyl (Troc), 9- Fluorenylmethoxycarbonyl (Fmoc), or a 5-Acyl-1,3-dimethylbarbiturate type protecting group (DTPM), with the further proviso that when the compound is of the 2- deoxy-2-aminoglucose configuration and R5 and R4 are both hydroxyl, R3 may not be a glycolate IPB^AU WO 2004/014929 PCT/AU2003/001008 51 CH 2 -CO 2 H] or lactate ether [-CH(CH 3 )-CO 2 H] or an ester or amide derivative thereof.

2. The compound of claim 1 which is a derivative of a pyranose form of a monosaccharide and wherein n is 1.

3. The compound of claim 1 which is a derivative of a furanose form of a monosaccharide, and wherein n is 0.

4. The compound of claim 2, wherein n is 1, at least one of the groups R2 to R5 and not more than two of the groups R2 to R5 are N(Y)Z, where Z is selected from hydrogen or R and Y is selected from the following, where G denotes the point of connection to the nitrogen atom in N(Y)Z, the N(Y)Z moieties may not be the same; 0 IH OH O R G O 0 0 0 O O G S- HN- OR H S G N I W 0 0 I Q H W 0 G-^^LR S S G- SR G I'OR and the groups Q and W are independently selected from hydrogen or R as is defined above, with the proviso that Y and Z may not both be hydrogen and '1 52 Swhere two groups in the compound of formula I are N(Y)Z, these groups are different, C the groups Z and Y may combine to form a cycle, the groups R1 to R5 may not combine together to form a cycle, with the proviso that where two groups in the compound of formula I are N(Y)Z, 00 Sthese groups are different, Swith the further proviso that when either R2 or R5 is N(Y)Z, N(Y)Z t' may not be trifluoroacetamido, acetamido, benzyloxycarbonylamino or t- O butoxycarbonylamino, with the further proviso that when R2 is N(Y)Z, N(Y)Z may not be phthalimido, -(4,4-dimethyl-2,6-dioxocyclo-hexylidene)-3-methylbutyl]- amino}benzyl ester (ODmab), N-1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), 2,2,2-Trichloroethoxycarbonyl (Troc), 9-Fluorenylmethoxycarbonyl (Fmoc), or a 5-Acyl-1,3-dimethylbarbiturate type protecting group (DTPM), with the further proviso that when the scaffold is of the 2-deoxy-2-aminoglucose configuration and R5 and R4 are both hydroxyl, R3 may not be a glycolate [-CH 2 CO 2 H] or lactate ether [-CH(CH 3 )-CO 2 H] or an ester or amide derivative thereof. The compound of any one of claim 1-4 wherein the heteroarylalkyl is substituted by a moiety from the group consisting of OH, NO, NO 2 NH 2 N 3 halogen, CF 3 CHF 2 CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may be further substituted, with the proviso that the group R may not be or contain another saccharide moiety, a peptide, protein or amino acid. WO 2004/014929 PCT/AU2003/001008 53

6. The compound of claim 1 which comprises, as a precursor N OTBDPS BzO LSMe NHDTPM

7. The compound of claim 1, which comprises as a precursor O- OTBDPS SMe N 3 OBzCI

8. The compound of claim 1, which comprises as a precursor N 3 HzO O SMe NHDTPM

9. The compound of claim 1, which comprises as a precursor OBz TBDPSO SMe The compound of claim 1, which comprises as a precursor TBDPSO OBn-OMe HO SMe N3 N 3

11. The compound of claim 1, which comprises as a precursor TBDPSO OBz HO~ SMe N 3 WO 2004/014929 PCT/AU2003/001008 54

12. The compound of claim 1, which comprises as a precursor TBDPSO- BO 0 SMe HO N 3

13. The compound of claim 1, which comprises as a precursor TBDPSO O BzMe N 3

14. The compound of claim 1, which comprises as a precursor TBDPSO HO SMe OBz N 3 The compound of claim 1, which comprises as a precursor TBDPSO- HO0 SMe ^^^LSMe N 3 OBz

16. The compound of claim 1, which comprises as a precursor OTBDPS BzO SMe

17. The compound of claim 1, which comprises as a precursor BzO jOTBDPS HO E-SMe HO WO 2004/014929 PCT/AU2003/001008

18. The compound of claim 1, which comprises as a precursor O,,,,,OBz TBDPSO N3 'Bz

19. The compound of claim 1, which comprises as a precursor N 3 .111 PMBO 'OBz

20. The compound of claim 1, which comprises as a precursor TBDPSO PMBO N 3

21. The compound of claim 1, which comprises as a precursor OBz OTBDPS SMe N 3 OH

22. The compound of claim 1 which is immobilised to a support.

23. The compound of claim 22, wherein the compound is immobilised to the support through a hydroxyl group. 24 The compound of claim 23, wherein the support is selected from the group consisting of derivatised polystyrene, tentagel, wang resin, MBHA resin, aminomethylpolystyrene, rink amide resin DOX-mpeg and polyethylene glycol. WO 2004/014929 PCTIAIJ2003OO1008 56 The compound of claim 1, wherein R1 is selected from the group consisting of xi X2 X3 X4 X X 6 0X X8 o I xi X1 l0 1 OH XI 2 CF 3 00 XISI OH O H 0 0 X16 X1 7 NO 2 00 H Ny NH- 2 2 Xl 9 0X20 NH WO 2004/014929 57 0 Cl X21 PCT/A1J20031001008 X22 X23 X24 X26 X27 NO 2 X28 X29 0 WO 2004/014929 WO 204/04929PCT/A1J20031001008

26. The compound of claim 1, wherein selected from the group consisting of Methyl Ethyl YI Y2 Y30 one of the R moieties in OR is Y4 a cl VY6 OH 0 A,)-"OH Y8 NH 2 Y9 Y12a Br I r- -YI CF 3 Y1 3 OH Y19 Y1 8 WO 2004/014929 WO 204/04929PCT/A1J20031001008 Octyl Y21 NO 2 Y23 Y22 0 H Y24 Y26 Y27 N I7 1 N 0 N- N H Y28Y2 Y29 4S C The compound of claim 1, wherein Y is selected from the group consisting of 0 ZI 0 Z4 0 NH 2 Z2 0 NH Z5 0 yk NH 2 Z3 0 Z6 0 0 zia 0 OH Z120 U 0 NH Z13 Z14 0 0 NH N NH 2 H 5 Z18 WO 2004/014929 WO 204/04929PCT/A1J20031001008 NH 0 NH NH 2 Z28 0 NH N NH 2 Z31 WO 2004/014929 PCT/AU20031001008 62 00 CF 3 H y l Z34 0 0 N CF 3 Z36 H Z37 NH 0 F CF 3 H Z38 Z39 S CF 3 H 0/ NyN, Z41 NH N CF 3 Z42 WO 2004/014929 WO 204/04929PCT/A1J20031001008 Z44 H HH Z46 Z47 Z48 0 Z49 )/NH 0 NH 2 HN Z51 0 0NH HN -N H H NH 2 Z52 NH 0 NHBoc HN NHBoc HN Z64 WO 2004/014929 WO 204/04929PCT/A1J20031001008 64 -N H NHBoc 0 HN Z56 H N NH 2 Z57 Z58 Z69