AU2003257259A1 - Compounds that interact with kinases - Google Patents

Description

WO 2004/022572 PCT/AU2003/001146 1 Compounds that Interact with Kinases FIELD OF THE INVENTION The invention is directed to classes of biologically active compounds that 5 interact in a pharmaceutically significant manner with protein kinases, and particularly to provide compounds suitable for the treatment of disorders mediated by protein kinase activity. The invention is also directed to treatment of the above mentioned disorders. The invention is also directed to the preparation of novel compounds per se. 10 BACKGROUND OF THE INVENTION The drug discovery landscape has been transformed by the genomics revolution. Advances in the understanding of biomolecular pathways and the roles they play in disease is generating vast numbers of targets for 15 therapeutic intervention. Protein kinases now represent an extensive and important class of therapeutic targets. Kinases are key components in almost all signal transduction pathways, modulating extracellular and intracellular signalling processes that mediate events such as cell growth and differentiation, metabolism and 20 apoptosis. Kinases do this by catalysing the transfer of a phosphate group from ATP to protein substrates. The pivotal role of kinases is emphasized by the fact that kinases represent the third most populous domain in the proteome. Kinases have been implicated in many diseases. Twenty percent of 25 oncogenes code for tyrosine kinases. Kinases play pivotal roles in many leukemias, tumours and other proliferative disorders. Other states involving kinases include inflammatory disorders such as psoriasis, cardiovascular diseases such as restenosis, viral induced diseases such as Kaposi's sarcoma, circulatory diseases such as atherosclerosis and fibroproliferative 30 diseases. Specific kinases are often implicated in particular disease states and therefore present themselves as potential targets for therapeutic intervention. The kinase family includes serine/threonine kinases and tyrosine WO 2004/022572 PCT/AU2003/001146 2 kinases, with the amino acid referring to the particular residue on a protein substrate that is phosphorylated. The tyrosine kinases can be further divided into receptor tyrosine kinases and non-receptor tyrosine kinases. Considering the rate of generation and nature of the targets currently 5 being deconvoluted by biologists, there is a need for the development of drug candidates, designed in a rational manner to purposely interact with selected targets, such as the kinases. From a drug discovery perspective, carbohydrate pyranose and furanose rings and their derivatives are well suited as templates. Each sugar 10 represents a three-dimensional scaffold to which a variety of substituents can be attached, usually via a scaffold hydroxyl group, although occasionally a scaffold carboxyl or amino group may be present for substitution. By varying the substituents, their relative position on the sugar scaffold, and the type of sugar to which the substituents are coupled, numerous highly diverse 15 structures are obtainable. An important feature to note with carbohydrates, is that molecular diversity is achieved not only in the type of substituents, but also in the three dimensional presentation. The different stereoisomers of carbohydrates that occur naturally, offer the inherent structural advantage of providing alternative presentation of substituents. We have developed a 20 system that allows the chemical synthesis of highly structurally and functionally diverse derivatised carbohydrate and tetrahydropyran structures, of both natural and unnatural origin. The diversity accessible is particularly augmented by the juxtaposition of both structural and functional aspects of the molecules. 25 A number of kinase inhibitors have appeared in the scientific literature to date. Many have entered human clinical trials and in two cases, Gleevac and Iressa, approval for the treatment of various tumours has been granted (Cohen, P., Nature Tev. Drug Discovery, 1, 309-316, 2002). The specificity of published kinase inhibitors varies widely and it is apparent from the study of 30 Gleevac that specificity for a single kinase is not a prerequisite for the inhibitor becoming a useful drug, indeed the inhibition of more than one kinase may be an advantage for therapeutic intervention. Despite some promiscuity in the target kinase being acceptable, it is generally considered desirable to have WO 2004/022572 PCT/AU2003/001146 3 good selectivity for the target kinase(s) over more general "housekeeping" kinases. Thus selectivity and inhibitor potency must be assessed on a case by case basis. The level of inhibition in cell based assays also shows considerable 5 variation from approximately 0.1 micromolar to over 100 micromolar as exemplified by the following table ( a more detailed study can be found in: Davies et. al., Biochem. J., 351, 95-105, 2000; and Bain et. al., Biochem. J., 371, 199-204, 2003). It is frequently the case that the most potent inhibitor is not the most suitable inhibitor for therapeutic purposes. 10 Inhibitor Top 5 kinases inhibited concentration kinase and residual activity ML-9 MSK-1 ROCK-Il SmMLCK S6K1 CDK2 100 RM 14% 23% 25% 27% 38% LY 294002 PI3K CK2 PHK GSK3P3 SGK 50 [M 13% 18% 44% 53% 72% HA1077 ROCK-II PRK2 MSK1 S6K1 PKA 20 p.M 7% 15% 19% 32% 35% PP2 LCK CDK2 CK1 SAPK2a MKK1 10 .M 1% 3% 6% 21% 55% Ro-31-8220 MAPKAPK1b MSK1 PKCa GSK3p S6K1 1 pM 2% 2% 3% 5% 6% MSK-1 = mitogen and stress activated protein kinase 1; ROCK-Il = Rho associated coiled coil forming protein kinase II; SmMLCK = smooth myosin light chain kinase; S6K1 = p70 S6 kinase; CDK2 = cyclin dependant kinase 2; P13K = phosphoinositide 3 kinase; CK2 = casein kinase 2; PHK = phosphorylase kinase; GSK3P = glycogen synthetase kinase 3p; SGK = 15 serum and glucocortin induced kinase; PRK2 = PKC related kinase 2; PKA = protein kinase A; LCK = T cell specific kinase; CK1 = casien kinase 1; SAPK2a = p38 kinase; MKK1 = mitogen activated protein kinase 1; MAPKAP-Ki b = mitogen activated protein kinase activated protein kinase I b; PKCu = protein kinase C alpha. 2 0 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. 25 WO 2004/022572 PCT/AU2003/001146 4 SUMMARY OF THE INVENTION Using the axioms of this drug discovery methodology, we synthesised several novel classes of chemotypes in an effort to develop drug candidates 5 against kinase targets. Kinases selected examples from the three different classes; serine/threonin kinase, tyrosine receptor kinase and tyrosine non-receptor kinase have been explored to determine the generality of the current invention. Compounds were tested within the industry standard concentration 10 range described above and have revealed potent and selective inhibitors against each selected kinase target. It is a general object of the invention to provide compounds suitable for the treatment of disorders mediated by protein kinase activity and in the treatment 15 of the above mentioned disorders. It is an optional object of the invention to provide a pharmaceutical formulation comprising at least one compound as described herein or a pharmaceutically acceptable salt thereof, together with one or more 20 pharmaceutically acceptable carriers, diluents or excipients. It is a further optional object of the invention to provide a method of treatment of a human or animal subject suffering from a disorder mediated by aberrant protein kinase activity which method comprises administering to the human or 25 animal subject an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof. It is a further object of the invention to prepare novel compounds per se 30 In one form, the invention comprises method of inhibiting or effecting protein kinase activity which comprises contacting a protein kinase with a compound of formula I being a derivative of a furanose or pyranose form of a monosaccharide, or a pharmaceutically WO 2004/022572 PCT/AU2003/001146 5 acceptable derivative thereof Y x H H / H HO H OH n formula I 5 Wherein; n is 1 or2, X is selected from the group consisting of: OR1, an unsubstituted 5 or 6 membered heterocyclic moiety, a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 10 membered heterobicyclic moiety and a substituted 9 or 10 membered heterobicyclic moiety, R1 is selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 15 heteroarylalkyl, Y is selected from the group consisting of: an unsubstituted 5 or 6 membered heterocyclic moiety; a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 20 membered heterobicyclic moiety; an amino acid, a dipeptide, and WO 2004/022572 PCT/AU2003/001146 I- N-- RN, R 6 O 0 A B

R

15 N RNRN R1214 R13 C D R15

R

1 2 R1, |N N N R 14 7 --.

R

6 R14 R 13 E F N H r N\ N R7 N m 1N 6

/G

WO 2004/022572 PCT/AU2003/001146 7 R6 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to 5 C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, with the proviso that R6, R7 and R8 are not all H, R9 is selected from H, or-(CO)-R6, R7, R8, R 1, R12, R14, are independently selected from the 10 group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl and C6 to C14 heteroarylalkyl, R13 is selected from the group consisting of :unsubstituted 15 phenyl unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, -S-R6 and -O-R6, 20 R15 is absent or is at least one substituent on the aromatic ring which are independently selected 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, 25 heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl. 30 R1 may be substituted, cyclic or acyclic, branched and/or linear. R7 and R8 may combine to form a cyclic structure.

WO 2004/022572 PCT/AU2003/001146 8 R6 and one of R7 or R8 may combine to form a cyclic structure. R11 and R12 may combine to form a cyclic structure, X may be selected from: OR1, N R2 N 5 R3 or

R

4 ,, R5 N N N / R1 and R3 are independently selected from the group 10 consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R4 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to 15 C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 20 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from the group consisting of: -(C=O)-R3, (C=O)-OR4, and -(C=O)-NH-R4, WO 2004/022572 PCT/AU2003/001146 9 Y is selected from: 0 R 7 N N N 0 0 A B R15

R

11 / R, 1 NRN / N N N R, N

R

13 C D

R

15 'N 1N-. E F N H /f" N N R7 N /G At least one of R1 - R14 may be substituted and these substituents and the substituents on the substituted 5 or 6 membered heterocyclic 5 moiety and the substituted 9 or 10 membered heterobicyclic moiety may be selected 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, WO 2004/022572 PCT/AU2003/001146 10 aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, alkyl, aminoheteroaryl, thioalkyl, thioaryl 5 or thioheteroaryl, which may optionally be further substituted. X may comprise N R2 R3 X may comprise

R

4 N, R 5 N N / /N N 10 X may comprise -OR1 Y may comprise A as described above. Y may comprise B as described above. Y may comprise C as described above. Y may comprise D as described above. 15 Y may comprise E as described above. Y may describe F as described above. Y may comprise G as described above. The protein kinase may comprise a serine or threonine kinase. The protein kinase may comprise a tyrosine kinase. 20 The protein kinase may comprise one or more of the isoforms of protein kinase C. The protein kinase may comprise Tie-2, also known as TEK, HPK-6 , TIE-2 VMCM, VMCM1.

WO 2004/022572 PCT/AU2003/001146 11 The protein kinase may comprise c-Kit also known as SCFR, CD1 17, PBT. The protein kinase may comprise VEGF-R2/KDR also known as VEGFR2, VEGFR-2, VEGFR, Hs.KDR, Hs.12337, FLK1 , FLK-1. 5 The protein kinase may comprise EGF-R also known as ERBB1 , ERBB, EGFRvIIl. The protein kinase may comprise Abl also known as c-abl , c-ABL, JTK7, p150, ABL1. The protein kinase may comprise MET also known as HGFR, C-MET, 10 RCCP2. The protein kinase may comprise, CDK2 also known as p34CDK2, p33CDK2, p33CDK2. The protein kinase may comprise PDGF also known as PDGFR1 , PDGFR, PDGF-R-beta, JTK12, CD140B, PDGFRB. 15 The protein kinase may comprise kinase, FGFR-1 also known as N-SAM, LOC51033, FLT2, FLJ14326, CEK, C-FGR, BFGFR, H5, H4, H3, H2, FLG. The protein kinase may comprise P38 MAP Kinase also known as p38alpha p38ALPHA, SAPK2a, SAPK2A, PRKM15, PRKM14, Mxi2, MXI2, 20 Exip, EXIP, CSPB1, CSBP2, CSBP1, p38, RK, P38, MAPK14. In another form, the invention comprises a compound of formula I which is a derivative of a furanose form of a monosaccharide of general formula I, 25 Y x H H H H O H OH n formula I WO 2004/022572 PCT/AU2003/001146 12 Wherein; n is 1, X is selected from: OR1, N N 5 R3 or

R

4 -N R 5 NA N NN / R1 and R3 are independently selected from the group o10 consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R4 is selected from the group consisting of: H, Cl to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 15 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 20 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from -(C=O)-R3, -(C=O)-OR4, -(C=O)-NH-R4, Y is selected from the group consisting of: WO 2004/022572 PCT/AU2003/001146 13 0

R

8

R

7 8 ReN N O O A B

R

15 s

R

1 , / R 6 R N N\ R12 N NR1 N4

R

13 C D

R

15 R 1 2 , R 11 N- N 1 N ,N

R

6 R 13 E F N H N R7 N

R

6 ReG R6 is selected from the group consisting of H, C1 to C7 alkyl, 5 C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, with the proviso that R6, R7 and R8 are not all H, R9 is selected from H, or-(CO)-R6, WO 2004/022572 PCT/AU2003/001146 14 R7, R8, R11, R12, R14, are independently selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to 5 C14 arylalkyl or C6 to C14 heteroarylalkyl, R13 is selected from the group consisting of: unsubstituted phenyl, unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, 10 C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, -S-R6 or -O-R6, R15 is absent or is at least one substituent on the aromatic ring which is independently selected from the group consisting of: OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, 15 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 20 acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl. R7 and R8 may combine to form a cyclic structure. R6 and one of R7 or R8 may combine to form a cyclic structure. 25 R11 and R12 may combine to form a cyclic structure. R1, R2, R3, R4 and R5 are optionally substituted, cyclic or acyclic, branched and/or linear. R2 and R3 may combine to form a ring structure. 30 R4 and R5 may combine to form a ring structure. At least one of R1 to R5 may be substituted with a substituent selected from the group, OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, WO 2004/022572 PCT/AU2003/001146 15 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, 5 hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted, X may be N pN I -R2 N 10 R3 or

R

4 ,N R 5 N1 N / /N' N or -OR1. 15 Y may comprise A as described above. Y may comprise B as described above. Y may comprise C as described above. Y may comprise D as described above. Y may comprise E as described above. 20 Y may comprise F as described above. Y may comprise G as described above. The compounds of the invention may be mixed with a pharmaceutical WO 2004/022572 PCT/AU2003/001146 16 acceptable carrier, adjuvant, or vehicle which may comprise a-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof. 5 The pharmaceutical derivative may comprise a salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention, although no limitation is meant thereby. 10 Compounds of the invention may be administered orally such as by means of a tabled, powder, liquid, emulsion, dispersion and the like; by inhalation; topically such as by means of a cream, ointment, salve etc; and as a suppository, although no limitation is meant thereby. 15 BEST MODE General Methods 20 General Method 1- Amide bond formation: To a solution of an acid in DMF (0.3 ml, 0.35 M, 1.0 equiv.) at room temperature was added a solution of HBTU in DMF (0.3 ml, 0.42 M, 1.2 equiv.) followed by DIPEA (2.5 equiv.). After 10 min., a solution of the desired amine in DMF (0.3 ml, 0.37 M, 1.05 25 equiv.) was added. The resulting solution was stirred at room temperature for 2.5 h, then diluted with DCM (8 ml) and washed with 10 % citric acid (2 x 5 ml), saturated NaHCO 3 (2 x 5 ml), brine (5 ml) and water (5 ml). The solvent was removed in vacuo. 30 General Method 2- Ester Hydrolysis: A solution of the ester (0.1 mmoles) in THF (0.5 ml) was treated with a solution of lithium hydroxide in water (0.5 ml, 0.45 M, 2.1 equiv.). The resulting mixture was stirred at room temperature overnight, then evaporated to dryness under reduced pressure to provide the WO 2004/022572 PCT/AU2003/001146 17 corresponding carboxyllic acid as the lithium salt. The residue is redissolved in either ethyl acetate or dichloromethane and washed with a small quantity of 10% citric acid solution, followed by drying of the organic layer and removal of the solvents in vacuo to yield the desired carboxylic acid. In cognate 5 experiments sodium hydroxide or potassium hydroxide has been substituted for lithium hydroxide to for the corresponding sodium or potassium salts in comparable yields. Methanol and dioxane have been substituted for THF as the reaction solvent with comparable results. 10 General Method 3a - Removal of acid labile protecting groups (isopropylidene and BOC)- solution phase: The compound was dissolved in acetonitrile and treated with 90/10 trifluoroacetic acid-water (2ml) and monitored by t.l.c for reaction completeness. Reaction times vary considerably from 15 minutes at RT to 6 hours at RT. When complete, the 15 mixture was concentrated under reduced pressure and co-evaporating from acetonitrile. The crude products were resuspended in water-acetonitrile and lyophilised then purificatied by reverse phase C-18 HPLC using a solvent gradient of water/acetonitrile to afford the desired product as white solids. In cognate experiments, 50/50 trifluoroacetic acid - water has been used with 20 similar efficiency. General Method 3b - Removal of acid labile protecting groups (isopropylidene and BOC) and cleavage from resin - solid phase: The resin bound compound (approx. 200mg of resin) was washed with DCM (2x 25 2mL) then treated with TFA/DCM 1:1 (1 mL) for 15 mins. The resin was filtered and washed with acetonitrile (1 ml) (filtrates collected). This procedure was repeated for a second cycle. The filtrates were evaporated under a stream of nitrogen. The residue was redissolved in water (1 ml) and agitated for 3h. After this time, the solution was lyophilised to afford the crude products 30 which were purified as described above. General Method 4- removal of an Fmoc protecting group: The Fmoc protected compound on resin (12 g of resin, 0.7 mmol/g, 8.4 mmol) was WO 2004/022572 PCT/AU2003/001146 18 washed with DMF (2 x 120 ml), then treated with 20 % piperidine in DMF (120 ml) and shaken at r.t. for 30 min. The resin was drained and washed with DMF (2 x 120 ml). The reaction was repeated and the resin was drained, washed with DMF (2 x 120 ml), DCM (2 x 120 ml), MeOH (2 x 120 ml) and 5 ether (2 x 120 ml), and dried in vacuo for 2 h. General Method 5- coupling of fluoro-nitro-benzoic acid: Resin bound substrate was washed under N 2 with dry DCM (1 x 80 ml, 1 x 60 ml). To a solution of 4-fluoro-3-nitrobenzoic acid (9.3 g, FW 185.09, 50.2 mmol, 6 10 equiv.) in dry DCM (60 ml) and dry DMF (9 ml) at r.t. and under N 2 was added 1,3-diisopropylcarbodiimide (DIC, 3.9 ml, d 0.806, FW 126.20, 24.9 mmol, 3 equiv.). The solution was stirred for 10 min., then added to the resin followed by 4-(dimethylamino)pyridine (DMAP, 102 mg, FW 122.17, 0.83 mmol, 0.1 equiv.). The resin was then shaken at r.t. for 3 h, drained, washed with DMF 15 (4 x 120 ml), DCM (3 x 120 ml) and ether (2 x 120 ml), and dried in vacuo overnight. The coupling procedure may be repeated in the event of a positive ninhydrin test. General Method 6- nucleophillic aromatic displacment: Resin bound 3 20 nitro-4-fluoro-benzoate XI (200 mg, 0.14 mmol) was washed under N 2 with dry DMF (2 ml) or dry DMSO (2 ml), then treated with a solution of the nucleophile (0.42 mmol, 3 equiv.) and diisopropylamine (DIPEA, 0.146 ml, d 0.742, FW, 129.25, 0.84 mmol, 6 equiv.) in dry DMF (2 ml)or dry DMSO (2 ml) and shaken at r.t. o/n. The resin was drained and washed with DMF (3 x 2 25 ml) and DCM (3 x 2 ml). In the case of DMSO as solvent, the reaction was warmed to 60 oC. The nucleophile may be any suitable primary or secondary aliphatic or aromatic amine, or a thiol. In an alternative experiment, the nucleophile was bound to the solid support and treated with an excess of ortho-fluoro-nitrobenzyl derivatives under similar conditions. 30 General Method 7- reduction of an aromatic nitro group: The resin bound substrate (0.14 mmol) was washed with DMF (2 x 2 ml) and then suspended in DMF (0.7 ml) to which was added a solution of SnCI 2 .2H 2 0 in DMF (0.7 ml, WO 2004/022572 PCT/AU2003/001146 19 2 M, 1.40 mmol, 10 equiv.). The resin was shaken at r.t. o/n, then washed with DMF (5 x 2 ml), DCM (3 x 2 ml) and MeOH (5 x 2 ml). General Method 8 preparation and reaction of an acid chloride: Resin 5 bound substrate (0.14 mmol) was washed with DCM (2 x 2 ml) and then under N 2 with dry DCM (2 x 2 ml). A suspension of the of sugar-acid building blocks (0.42 mmol, 3 equiv.) in dry DCM (2 ml) was treated with triphosgene (42 mg, FW 296.75, 0.14 mmol, 1 equiv.) followed by collidine (0.159 ml, d 0.917, FW 121.18, 1.20 mmol, 8.6 equiv.). An effervescence was observed 10 and a solution formed. After 1 min., this solution was added to the resin bound substrate and the resin was shaken at r.t. for 3 h. The resin was drained and washed with DCM (5 x 2 ml) and MeOH (3 x 2 ml). General Method 9 cleavage of adenosine N-benzoyl group: The 15 adenosine-containing products were treated with saturated ammonia in methanol (4 ml) at r.t. o/n. The solvent was removed in vacuo and the product was again treated with sat NH 3 in MeOH at r.t. o/n. The solvent was removed in vacuo and compounds purified as described above. In an alternative proceedure, 1 M hydrazine hydrate in DMF was substituted for methanolic 20 ammonia. The latter procedure is particularly useful for benzoate removal on solid support. General Method 10- benzimidazole synthesis: Resin bound substrate (approx. 200mg, 0.14mmol) was treated with a solution of an aldehyde (5.0 25 equivalents) in N-methylpyrrolidine (NMP) (4ml) and heated to 45-500C overnight. The resins were subsequently washed with DMF (3x4mL), DCM (3x4mL), MeOH (3x4mL), ether (3x4mL) and dried in vacuo overnight. General Method 11- Cesium carboxylate coupling: The cesium salt of the 30 Boc protected amino acid is made by dissolving the amino acid in methanol (5ml/mmol) and water (0.5ml/mmol) and adding an aqueous solution of 20% CS2CO 3 until pH 7 is reached. The solvent is removed in vacuo and the material is freeze-dried overnight to give a white powder. The resin is treated WO 2004/022572 PCT/AU2003/001146 20 with the cesium salt (5eq) in dry DMF (4ml/g of resin) and stirred at 500C for 24 hours. The resin is drained and washed with DMF, DMF/H 2 0 (1:1; x 3), MeOH/H 2 0 (1:1; x 3) and MeOH (x 3) and then dried in vacuo. 5 General Method 12- Reductive amination: 6 eq of aldehyde is dissolved in TMOF/TFFHF (1:1; 2ml) and added to the resin (200mg) and shaken at room temperature for 3-4 hours. The resin is drained and a solution of NaCNBH 3 (2eq) in THF/MeOH/AcOH (9:1:0.1; 2ml) is added to the resin and shaken overnight at room temperature. The resin is then drained and washed with o10 THF/MeOH (1:3; x 3, DMF/MeOH (1:3; x 3), DCM/MeOH (1:3; x 3) and DCM. General Method 13- Urea formation: In a gloved box, the resin is swelled in 10% DIPEA/DCM, a solution of triphosgene (2eq in 1.2ml of dry DCM) was 15 added to the resin in two batches and shaken for 1 hour. The resin is washed with dry DCM (1 ml x 2) and a solution of the amine (1.1 eq) and DIPEA (2.2eq) in 1.5ml of dry DCM was added and shaken for 30 minutes. The resin is drained and washed with DMF (x 3), DCM (x 3) and MeOH (x 3) and dried. 20 General Method 14 base catalysed ring closure: The resin was treated with a solution of MeOH/NEt 3 (9:1; 2ml) and heated to 600C overnight. The resin is drained (collecting the filtrate) and washed with MeOH, (1 ml), DCM (1 ml), MeOH (1 ml) and DCM (1 ml). The filtrates are combined and the solvent removed in vacuo. The process is then repeated. 25 General Method 15- Thiourea formation: Resin bound substrate was washed under N 2 with dry THF (3 x 30 mL) then thiocarbonyl diimidazole (2.49g, 14 mmol) in dry THF (70 mL, conc = 0.2M) was added and the resin was shaken at rt for 12h. The resin was filtered, washed with THF (3 x 30 30 mL), DMF (2 x 30 mL), DCM (2 x 30 ml), DCM/MeOH (30 mL), MeOH (30 mL) and dried in vacuo. General Method 16-S alkylation of an isothiourea: The reactions were WO 2004/022572 PCT/AU2003/001146 21 performed in Bodhan Miniblocks. The resin bound thiourea compound resin(200 mg) was washed under N 2 with dry DMF (2 x 2 mL). Alkyl halide R'X (0.7 mmol) in dry DMF (1 mL) was added followed by DIPEA (1.4 mmol) in dry DMF (1 mL). The resin was shaken at rtfor 12h, then washed with DMF 5 (3 x 2 mL), DCM (3 x 2 mL), DCM/MeOH 1:1 (2 x 2 mL), MeOH (2 x 2 mL). General Method 17- bromoacetylation: To bromoacetic acid (7.76g) in dry DCM (40 mL) was added slowly DIC (4.4 mL) at 0 'C. The solution was stirred at 0 0 C for 30 mins. The solution was syringed out leaving the 10 precipitated urea. Resin bound substrate was washed under N 2 with dry DMF then swollen in dry DMF (1 mL). The bromoacetic anhydride solution in dry DCM (1 ml) was added and the resin was shaken at rt for 1 hrs. The resin was filtered, washed 15 with dry DMF (3x 3 mL) under N 2 (glove box) and dry DCM (2 x 3 mL). Excess DCM was drained applying positive pressure of N 2 . The resin was carried through the next step immediately. General Method 18- N-alkylation: Bromoacetylated resin produced by 20 general method 17 is added to a sugar amine building block (5eq) in DMF (1 mL). The resin was shaken at rt for 16h then filtered, washed with DMF, DCM, DCM/MeOH and dried in vacuo. General Method 19- Dichloro-Nitropyrimidine addition: The resin was swelled in NMP and a solution of 4,6-Dichloro-5-nitropyrimidine (5eq) and 25 DIPEA (10eq) in NMP (lml/100mg resin) was added and shaken at room temperature overnight (solution turned deep orange-red). The resin was drained under nitrogen and washed with dry DMF and dry DCM until filtrate is colourless and dried in vacuo. 30 General Method 20- Nitro reduction: The resin was swelled in DCM (1.5ml/100mg) and a solution of K 2

CO

3 (10 Oeq) and Na 2

S

2 0 4 (8eq) in H 2 0 (0.75ml/100mg) was added. Viologen (0.4eq) was then added turning the solution deep blue. The resin was then shaken vigourously for 72 hours. The WO 2004/022572 PCT/AU2003/001146 22 resin was then drained and washed with an aqueous solution of 1% AcOH, THF, DMF and DCM and dried in vacuo. General Method 21- Aldehyde cyclisation: A solution of the aldehyde (5eq) 5 in NMP with 1% AcOH (800pl/100mg resin) was added to the dry resin in a test tube. The tube was sealed but allowed to vent with a needle in the top. The resin was heated at 100C overnight. The resin was filtered and washed with DMF, DCM and MeOH and dried in vacuo. 10 General Method 22- Acid Chloride Acylation: Resin bound substrate was washed under N 2 with dry DCM then swollen in DIPEA (20eq)/DCM (1 mL). A solution of acid chloride (10eq) in DCM (1mi) was added and the resin was shaken at rt for 24h. The resin was washed with DMF, DMF/MeOH, DCM, DCM/MeOH, MeOH and dried in vacuo. 15 General Method 23- Reaction with the isocyanates and the resin cleavage: The resin was taken up in DCE and cooled to 0 oC followed by isocyanate (4 eq) addition. After 30 minutes, 10% TFA/DCM was added followed by shaking for 1 hour at room temperature. The resin was filtered 20 and washed with DCM. The filtrate was concentrated under reduced pressure to afford the crude residue. General Method 24- Biological assays: 25 Compounds were tested in vitro as follows. Recombinant protein kinases, which were expressed as fusion proteins in SF9 insect cells or E. coll, were used for all in vitro assays. The purity and identity of each kinase was checked by SDS-PAGE/silver staining and by western blot analysis with specific antibodies. 30 All kinase assays except for p38a (see below) were performed in 96 well micro-titre plates. The assay components included assay buffer, ATP, test compound, enzyme and substrate.

WO 2004/022572 PCT/AU2003/001146 23 The assay for all enzymes (except for the PKC.see below contained 60 mM HEPES-NaOH, pH 7.5, 3 mM MgCI 2 , 3 mM MnCl 2 , 3 pM Na orthovanadate, 1 mM DTT, 0.1 pM [y- 3 3 P]-ATP (approx. 5x105 cpm per well). The assay for the PKCs contained 60 mM HEPES-NaOH, pH 7.5, 1 5 mM EDTA, 1.25 mM EGTA, 5 mM MgCI 2 , 1.32 mM CaCl 2 , 5 gg/ml Phosphatidylserine, 1 pg/ml 1.2 Dioleyl-glycerol, 1.2 mM DTT, 50 jtg/ml

PEG

20000 , 0.1 p.M [y- 33 P]-ATP (approx. 5 x10 5 cpm per well). The table below details the amounts of enzyme and substrate that were used 10 per well: # Kinase Screenpool # Enzyme Substrate Substra te (ng/50plI) (ng/50/, 1 KIT 1 50 Poly(Glu, Tyr) 4 :1 125 2 EGF-R 4 50 Poly(Glu, Tyr) 4 :1 125 3 TIE2 3 100 Poly(Glu, Tyr) 4 :1 125 4 PDGF- 3 100 Poly(Glu, Tyr) 4 :1 500 Ralpha 5 FGF-R1 1 75 Poly(Glu, Tyr) 4 :1 500 6 CDK2/CycA 2 10 Histone H1 250 7 MET 7 100 Poly(Glu, Tyr) 4 :1 125 8 VEGF-R2 2 50 Poly(Glu, Tyr) 4 :1 125 9 ABL 1 10 Poly(Ala, Glu, Lys, 250 Tyr) 6

:

2

:

5 :1 10 PKC-betal 1 13 Histone H1 500 The reaction cocktails were incubated at 300C for 80 minutes. The reaction was stopped with 50 p1l of 2% (v/v) H 3

PO

4 , plates were aspirated and washed 15 twice with 200 pl of H 2 0 or 0.9% (w/v) NaCI. Incorporation of 33 Pi was determined with a microplate scintillation counter. The mitogen-activated protein kinase p38a assays were done in a proprietary microassay NanoCarrierTM 2080 format. In these assays 20 phosphorylation was detected by a phospho-substrate specific monoclonal antibody in an indirect competition assay. The degree of binding of the antibody to the phospho-substrate was measured by fluorescence WO 2004/022572 PCT/AU2003/001146 24 polarization using 2D-FIDA anisotrophy. In these experiments the final concentration of the enzyme was 1.6nM and the substrate was 2pM. All data is presented as residual activity, which is the activity of the 5 enzyme in the presence of the stipulated concentration of inhibitor or compound. 100% activity is the maximum activity of the enzyme in the absence of any inhibitor or compound. In all experiments the Z' value was calculated according to Zhang et al 10 (J-H Zhang, T.D.Y Chung, K. R. Oldenburg (1999) Journal of Biomolecular Screening 4:67-73) using the standard deviations and mean values of the positive and negative controls. Z' = 1-( 3 *Stdevneg + 3 *Stdevpos)/(Meanpos-Meanneg) 15 Only data where the Z' value was >0.5 was used.

WO 2004/022572 PCT/AU2003/001146 25 Example 1: NHBz NHBz N "l N O R H N ,0 N~ N RO2Cq~IthNKN

H

2 NN 0N O - n=1 or2 1-II (b)

HO

2 R NH 2

NH

2 H2CN N < ON HO2C H N N -N Y(c) "NN ' n H 0 N* -- N n H 0N N n=1 or 2 HO" ' H -V n=1 or 2 1>I 1-II 5 (1-a) General Method 1, (1-b) General Method 2, (1-c) General Method 3. Analysis of some typical example compounds O CH 3

HNH

2 HO2 N N H02C -I HOC H 0 NN 10 H 'OH 4 Isomer A : proton (400 MHz: DMSO) 2.38 (dt, J 5.0, 6H, CH 2

CH

2 ), 2.65 (d, J 15.0 Hz, IH, CH 3 ), 3.85-3.95 (m, 2H, H2 or H3 or H4), 4.05 (dd, J3.0, 8.0 Hz, 1H, H5a), 4.10 (dd, J3.0, 8.0 Hz, 1H, H5b), 4.30 (m, 1H, CH), 4.65 (dd, J5.0, 15 5.0 Hz, 1H, H2 or H3 or H4), 5.87 (d, J 4.0 Hz, 1H, H1), 8.30 (s, 1H, ArH), 8.45 (s, 1 H, ArH). Isomer B : proton (400 MHz: DMSO) 2.42 (dt, J 5.0, 6H, CH 2

CH

2 ), 2.75 (d, J 15.0 Hz, 1H, CH 3 ), 3.85-3.95 (m, 2H, H2 or H3 or H4), 4.05 (dd, J 3.0, 8.0 Hz, 1H, H5a), 4.10 (dd, J3.0, 8.0 Hz, 1H, H5b), 4.30 (m, 1H, CH), 4.65 (dd, J5.0, WO 2004/022572 PCT/AU2003/001146 26 5.0 Hz, 1H, H2 or H3 or H4), 5.92 (d, J 4.0 Hz, 1H, H1), 8.35 (s, 1 H, ArH), 8.50 (s, 1 H, ArH). Example 2: 5 '0 /N-N H o ,N--N H2N

CONH

2

R

3 0 2 C N N CONH2

N

N

(a) N H CH R O R 1 R' S0 2-1 O O R COOH COOH j(b) O)n ON N O-N(C) Oo N S N

CONH

2 N - CONH 2 HO OH R R O R 2-IV 2-Ill R 1 =phenyl, Rl=propyl (2-a) General Method 1, (2-b) General Method 2, (2-c) General Method 3. Analysis of some typical example compounds 10 O N=N

HO

2 C N 0\H 4p NH,

E

k Z H PhNH

CO

2 H HO OH 32 proton (400 MHz: D 2 0) 2.36-2.55 (m, 5H, alkyl H), 2.57-2.76 (m, 1H, alkyl H), 3.31-3.48 (m, 2H, H5), 3.98-4.07 (m, 1H, H4), 4.45-4.56 (m, 2H, H3, 15 NCHCO), 4.69-4.75 (m, 2H, H2), 5.57 (d, J2.4 Hz, 1H, H1), 7.32-7.40 (m, 2H, PhH), 7.41-7.53 (m, 3H, PhH). O N-N

HO

2 C H 2 N NH a -\ H \J Ph H2 Ph HO OH 38 20 proton (400 MHz: D 2 0) 2.26-2.40 (m, 4H, alkyl H),2.73 (dd, J 14.0, 8.0 Hz, WO 2004/022572 PCT/AU2003/001146 27 1 H, CHaPh), 2.88 (dd, J 14.0, 6.2 Hz, 1 H, CHbPh), 3.30 (dd, J 14.6, 4.6 Hz, 1 H, H5a), 3.42 (dd, J 14.6, 3.8 Hz, 1H, H5b), 3.96-4.02 (m, 1H, H4), 4.26 (t, J 5.8 Hz, 1 H, H3), 4.36 (t, J 7.4 Hz, 1 H, NCHCO), 5.52 (d, J 2.8 Hz, 1 H, H1), 7.02-7.20 (m, 5H, PhH), 7.35 (d, J 6.4 Hz, 2H, PhH), 7.42-7.54 (m, 3H, PhH). O N:N O K. Y=i Ph NH2 HO OH HN 0 6CF3 50 proton (400 MHz: D20) 1.76-1.87 (m, 1H, alkyl H), 1.96-2.08 (m, 1H, alkyl H), 2.30-2.41 (m, 6H, alkyl H), 3.43 (d, J 4.4 Hz, 2H, H5), 4.06 (q, J 5.2 Hz, 1 H, o10 H4), 4.26 (dd, J9.0, 5.2 Hz, 1H, H3), 4.40 (t, J5.6 Hz, 1H, NCHCO), 4.69 4.74 (m, 1H, H2), 5.54 (d, J3.2 Hz, 1H, H1), 7.2.8-7.48 (m, 8H, PhH), 7.65 (s, 1H, PhH). 0 N:N H0 2 C - N 'N N 0 H L- Pr NH 2

CO

2 H HO OH s15 33 proton (400 MHz: D20) 0.77 (t, J 7.4 Hz, 3H, CH 2

CH

3 ), 1.42-1.56 (m, 2H,

CH

2

CH

3 ),2.37-2.53 (m, 5H, alkyl H), 2.58 (dd, J 15.4, 5.4 Hz, 1H, alkyl H), 2.89 (t, J7.6 Hz, 2H, ArCH 2 ), 3.30-3.46 (m, 2H, H5), 4.07-4.15 (m, 1H, H4), 4.42-4.53 (m, 2H, H3, NCHCO), 4.70-4.75 (m, 2H, H2), 5.87 (d, J 2.8 Hz, 1 H, 20 H1). O N:N

HO

2 C 2N N 0 - H ? Pr Ph HO OH 37 proton (400 MHz: D20) 0.78 (t, J7.2 Hz, 3H, CH 2

CH

3 ), 1.38-1.46 (m, 2H, 25 CH 2

CH

3 ),2.34 (bs, 4H, alkyl H), 2.70 (t, J 10.2 Hz, 1H, ArCHa), 2.74-2.96 (m, WO 2004/022572 PCT/AU2003/001146 28 3H, ArCHb, CH 2 Ph), 3.25-3.45 (m, 2H, H5), 4.02-4.12 (m, 1H, H4), 4.18-4.25 (m, 2H, H3), 4.29-4.38 (m, 1H, NCHCO), 5.83 (bs, 1H, H1), 6.99-7.20 (m, 5H, PhH). O N=N

HO

2 C 2 o H P-. Fr NH 2 HN O OH HN 0 5 6hCF 3 51 proton (400 MHz: D 2 0) 0.73 (t, J7.4 Hz, 3H, CH 2

CH

3 ), 1.36-1.50 (m, 2H,

CH

2

CH

3 ), 1.73-1.85 (m, 1 H, alkyl H), 1.88-2.03 (m, 1 H, alkyl H), 2.28-2.45 (m, 6H, alkyl H), 2.84 (q, J7.5 Hz, 2H, ArCH 2 ), 3.42 (d, J4.4 Hz, 2H, H5), 4.10 o10 4.20 (m, 2H, H3, H4), 4.38 (t, J5.4 Hz, 1H, NCHCO), 5.84 (d, J2.8 Hz, 1H, H1), 7.34-7.52 (m, 3H, ArH), 7.65 (s, 1 H, ArH).

WO 2004/022572 PCT/AU2003/001146 29 Some typical peptide arms Ila-Ilr used in step a of examples 1 and 2 O H O H O N OH IIa OH O 0 Ile H 0 O. IIb O0 Ilf OH 0 "0 N~ 0:' 0l 0N 0 0" OOHO 0 g 00 H H N O H OH N O I0d

OH

WO 2004/022572 PCT/AU2003/001146 30 Example 3: RINK -N-Fmoc (a) O-RINK -NH 2 H 3-I 3-II (b) o 0 3-IV NAr (d) 3-I F

NO

2 H

NO

2 (e) (c) o 0 O-RK-H .. R'4R N 3-V " "N V H " NAr 3-t()3-V y N

NH

2 H NO 2 H H0O2 R2 H(g) O2 IX, X, XI, (shown below) 0 3-VII - N (h) H 2 NOC R HN H -2 o (i) N R 0 3-VIIL " O0 HO OH R2 (3-a) General Method 4, (3-b) General Method 5, (3-c) General Method 6 5 (using reagents ArNH 2 and DMSO), (3-d) General Method 6 (using reagents ArCH 2

NH

2 and DMF as solvent), (3-e) General Method 7, (3-f) General Method 7, (3-g) General Method 8, (3-h) General Method 3b, effects ring closure, deprotection and cleavage from resin, (3-i) General Method 9, only required for adenine containing compounds. 10 WO 2004/022572 PCT/AU2003/001146 31 Blocks IX, X and X 0 N N

NH

2 ox IX0 X HO N O o 0 0 0NH 2 Ix x XI 5 Analysis of a typical example compound Br

H

2 NOC N N NH2 N NU1 \NH HO OH 355 10 proton (400 MHz: d 6 DMSO) 4.92 (q, J4.4 Hz, 1H, H2 or H3), 4.98 (q, J 5.1 Hz, 1H, H2 or H3), 5.33 (d, J4.0 Hz, 1H, H4), 5.54 (d, J 16.8 Hz, 1H, CHaPh), 5.62 (d, J 17.2 Hz, 1H, CHbPh), 5.77 (d, J 5.3 Hz, 1H, OH), 5.80 (d, J 5.4 Hz, 1H, OH), 6.10 (d, J5.3 Hz, 1H, H1), 6.96 (d, J7.9 Hz, 1H, PhH), 7.09 (t, J7.8 Hz, 1H, PhH), 7.24 (bs, 2H, NH 2 ), 7.27 (bs, 1H, PhH), 7.29 (s, 1H, CONHa), 15 7.36 (d, J 8.9 Hz, 1H, PhH), 7.47 (d, J 8.3 Hz, 1H, ArH), 7.78 (dd, J 8.5, 1.6 Hz, 1 H, ArH), 7.98 (bs, 2H, ArH, CONHb), 8.31 (d, J 1.2 Hz, 1 H, ArH), 8.37 (s, 1 H, ArH). 20 WO 2004/022572 PCT/AU2003/001146 32 Example 4: 0 RINK -F 4-I RINK -N H (C)

NO

2 N NH 0 HET 4-Ha: HET=a (d) NO 2 4-ic: HET=c O O 4-Id: HET=d 0N O RINK -N ~H SNH 0 HET 4-IIIa

NH

2 4

"

Il e 4-1I1c (e) 4-IIId RIN 0 HET N- NH4-IVa H2NtI F N 0N H E 4 V a Ri d 0 4-IVc I N 4-IVd o (f), (g)

H

2 N NN HET 4V

R

1 HO OH 4-Vd 5 (4-c) General Method 6 using a sugar amine, (4-d) General Method 7, (4-e) General Method 10, (4-f) General Method 3b, (4-g) General Method 9, only required for adenine containing compounds. Exemplary Aldehydes used in step 4-e. Benzaldehyde, 3-Bromobenzaldehyde, m-Tolualdehyde, 2 10 Methoxybenzaldehyde, p-Tolualdehyde, 4-Dimethylaminobenzaldehyde, 4 Cyanobenzaldehyde, 1,2,3,6-tetrahydrobenzaldehyde, Indole-3 carboxaldehyde, 2-naphthaldehyde, 3-methyl thiophene-2-carboxaldehyde, cyclohexane carboxaldehyde, pyrrole-2-carboxaldedhyde, phenyl acetaldehyde, 4-(2-pyridyl)benzaldehyde, a,a,a-trifluoro-o-tolualdehyde, 2,5- WO 2004/022572 PCT/AU2003/001146 33 dimethylbenzaldeyde, 3,5-difluorobenzaldehyde, 2-fluorobenzaldehyde, 4 fluoro-3-(trifluoromethyl)benzaldehyde. Example 5: N=N N=N O FmocHN N CO 2 H (a) FmocHN ON N 'NH RI R coNK oNHo 5-III 5-I 5-II

NO

2 R- ( C) R 0 0 0 0 A -5-IV (d)

R

2

R

2 r N=N 0 ~ N=N 0 fO / > NH (e) . / NH 2

R

3 0 "0 R db 5-6 O R 3 HO OH 5 /O 5-VII 5-VIII (5-a) General Method 1, (5-b) General Method 4, (5-c) General Method 6, (5 d) General Method 7, (5-e) General Method 3b 10 Analysis of some typical example compounds N=N O N N

NH

2 N

NH

2 Me HO OH OMe proton (400 MHz: d 6 DMSO) 2.41 (s, 3H, CH 3 ), 3.83 (s, 3H, OCH 3 ), 4.34-4.53 (m, 4H, H2, H3, H4, H5a), 4.75 (d, J 13.2 Hz, 1H, H5b), 5.80 (s, 1H, H1), 6.97 15 (d, J 8.8 Hz, 2H, ArH), 7.39-7.47 (m, 2H, ArH), 7.51 (bs, 1 H, NHa), 7.57-7.67 (m, 3H, ArH), 7.69-7.75 (m, 1 H, ArH), 7.79 (bs, 1 H, NHb).

WO 2004/022572 PCT/AU2003/001146 34 Me N N 0 N N. N NH2 HO OH OH proton (400 MHz: d 6 DMSO) 0.77 (t, J 7.4 Hz, 3H, CH 2

CH

3 ), 1.40 (q, J 7.1 Hz, 2H, CH 2

CH

3 ), 2.37 (s, 3H, ArCH 3 ), 2.84-2.98 (m, 2H, ArCH 2 ), 4.38-4.52 5 (m, 4H, H2, H3, H4, H5a), 4.70 (bd, J 14.4 Hz, 1IH, H5b), 5.80 (s, 1 H, HI), 6.85 (d, J 8.0 Hz, 2H, ArH), 7.27 (bs, 2H, NHa, ArH), 7.48-7.60 (m, 4H, ArH), 7.78 (bs, I1H, NHb). N=N 0O N

NH

2 HO OH/\ OBn OMe proton (400 MHz: d 6 DMSO) 3.77 (s, 3H, OCH 3 ), 4.35-4.46 (m, 3H, H2, H3, 10o H4), 4.57 (bdd, J 14.8, 6.4 Hz, 1H, H5a), 4.84 (bd, J 14.8 Hz, 1H, H5b), 5.05 (d, J 11.6 Hz, 1 H, OCHa), 5.11 (d, J 11.6 Hz, 1 H, OCHb), 5.34 (s, 1 H, HI), 6.96-7.04 (m, 4H, ArH), 7.20 (d, J 8.8 Hz, 2H, ArH), 7.30-7.46 (m, 7H, ArH), 7.54 (bs, 1 H, NHa), 7.60 (d, J8.8 Hz, 2H, ArH), 7.63-7.68 (m, 1H, ArH), 7.71 7.78 (m, 1 H, ArH), 7.90 (bs, 1 H, NHb). 15 WO 2004/022572 PCT/AU2003/001146 35 Example 6: 0 H N NH 0R2

NH

2 (a) 6-1 o o (b) 0 NHR4 N0 2 6-4l1 o F

R

4 = Bz, H N R = NH N CONH2 (c) Ra 2 NO 6- II NHR 0 H- NH-'( ,OR oNH (d) I RHN-N O RI HzN R2 0 N HN I "OH OH S6-V N NHR RI Conditions: (a) general method 5 (b) general method 6; (c) general method 7, general method 10; (d) general method 9 for adenosine containing 5 compounds only, general method 3b. 10 WO 2004/022572 PCT/AU2003/001146 36 Example 7: BzO CO'CN NaOMHe Ho .

0 CN 2,2-dimethoxypropaneHO .( CN Bz Bz MeOH O OH H 2 SO4, acetone 6~ 7-I 7-I SMsCI PY NHz N"% 0 "1H BrCH 2

CO

2 Me N 3 N cN NaN Mso- 0 cN Sc2 M e Zn / THF DMF oo0 7-VI oo ooHF 00 HCI . 7-V 7-IV THF O O t 0 NH2 N3 CO2Me BzCl, py co2Me BuOCOCN o NH 2 lb N 3 - N.(%YOco2tBu HO OH Bzo OBz Cu(acac) 2 ] BzO OBz CO 2 Me 5 mol % 7-IX 7-VIII 7-VI 1) R'NHNH 2 83 2) H + R \N-N Rt N-N N,

C

O 2 H T N C O B u . CO 2 Me DCM CO 2 Me BzO OBz BzO OBz 7-XI 7-X 1) HBTU, DIPEA, DMF 2) (NH 2 RRN R\ N-N .O-RK Ri N-N .o NO H N3 N 3' NH -- [ " " L r NH -- < - co 2 Me THF - Co 2 H BzO OBz HO OH 7-XIII 7-XII 1) HBTU, DIPEA, DMF 2) R 2

NH

2 Ri\N-N o RN-N 0 0 BzCI, py N3N-O - N3 Fy N- 00NHR CONHR BzO OBz 7-XV HO OH 7-XIV zooz7-XV 7-XIV SDTT R1 N-N O H2N NH CONHR BzO OBz 7-XVI WO 2004/022572 PCT/AU2003/001146 37 Example 8: R R O Boc-N OH + CS 2

CO

3 (a) Boc- OCs (a) Bo c H O Ho Boo R 8-I O J (b) R2: 0 " d -11Y NH R' NH 0 N.. (C) 0NNH 2 Ra R O R2 0(d) 8I 0N (e(f 0 Ra=B,C,D,E 0 0 O ' N- R 2 R HN-R 2 O 8-IV 8-V (g)l R' O N N-R2 RO 8-VI (8-a) General Method 11, (8-b) General Method 3b, (8-c) General Method 12, 5 (8-d) General Method 13, (8-e) General Method 14, (8-f) General Method 3a, (8-g) General Method 9 for adenosine containing compounds. Analysis of some typical example compounds CIs)C NH 2 N0 N N 1 Hd bH 10 220 Isomer 1: proton NMR (400MHz,d 6 -DMSO): 8: 8.46 (s, 1 H, H-6); 8.26 (d, 1H, H-8); 7.93 (s, 2H, NH 2 ); 7.37-7.31 (m, 6h); 7.15-7.08 (m, 5H); 6.92 (d, 1H, J=6Hz); 5.86 WO 2004/022572 PCT/AU2003/001146 38 (d, 1H, J=5.6Hz, H-1); 4.70-4.64 (m, 2H, containing H-2 and Hplald); 4.39 (d, I H, J=16Hz, Hp2ald); 4.20 (t, 1 H, J= 4.8Hz, Ha); 4.04-3.96 (m, 2H, containing H-3, H-5A); 3.59 (d, 1 H, J=6.8Hz, H-4); 2.97 (m, 2H, containing HPI, H0 2 ). Isomer 2: 5 proton NMR (400MHz,d 6 -DMSO): 8: 8.42 (s, 1H, H-6); 8.22 (d, 1H, H-8); 7.75 (s, 2H, NH 2 ); 7.38-7.30 (m, 6h); 7.17-7.11 (m, 5H); 6.98-6.96 (m,lH, J=6Hz); 5.82 (d, 1H, J=5.6Hz, H-1); 4.72-4.64 (m, 2H, containing H-2 and Hplald); 4.40 (d, 1H, J=16.4Hz, Hp2ald); 4.21 (t, 1H, J= 4.4Hz, Ha); 4.08 (t, 1 H, J=4.4Hz, H 3); 3.97 (q, 1H, J=6.4, 10.4Hz, H-5A); 3.65 (dd, 1H, J=6.4, 14.4Hz, H-4); 3.54 10 (dd, 1 H, J=7.6, 14.4, H-5A); 2.98 (d, 2H, J=4.8Hz containing Ho 1 , Hp2). S

NH

2 NON NN 0 0 Hd bH 221 Isomer 1: proton NMR (400MHz,d 6 -DMSO): 8: 8.48 (s, 1H, H-6); 8.27 (s, 1H, H-8); 7.45 15 (d, 1 H, J=4.4Hz); 7.40 (d, I H, J=4.8Hz); 7.24-7.09 (m, 4H); 7.05-7.02 (m, 1H); 6.97-6.91 (m, 2H); 5.84 (d, 1H, J=6.4Hz, H-1); 4.86 (d, 1H, J=16Hz, Hplald); 4.66-4.63 (m, 1H, H-2); 4.45 (d, 1H, J=16Hz, Hp2ald); 4.21 (t, 1H, J=4.4Hz, Ha); 4.03 (t, 1H, J=3.6Hz, H-3); 3.98-3.92 (m, 1H, H-5A); 3.19 (q, 1H, J=5.2, 9.2Hz Hp1); 3.05-3.01 (m, 1H, Hp2). 20 Isomer 2: proton NMR (400MHz,d 6 -DMSO): 8: 8.47 (s, 1 H, H-6); 8.26 (s, 1 H, H-8); 7.44 (d, 1H, J=4Hz); 7.41 (d, 1H, J=4.8Hz); 7.24-7.09 (m, 4H); 7.05-7.02 (m, 1H); 6.97-6.91 (m, 2H); 5.82 (d, 1H, J=6.4Hz, H-1); 4.88 (d, 1H, J=16Hz, Hplald); 4.66-4.63 (m, 1H, H-2); 4.45 (d, 1H, J=16Hz, Hi2aid); 4.22 (t, 1H, J=4.4Hz, Ha); 25 4.06 (t, IH, J=4Hz, H-3); 3.98-3.92 (m, 1H, H-5A); 3.22 (q, 1H, J=5.2, 9.2Hz Hpl); 3.05-3.01 (m, 1H, H02).

WO 2004/022572 PCT/AU2003/001146 39 S NH 2 N N N o Hd bH 202 proton NMR (400MHz,d 6 -DMSO): 8:8.37 (s, 1H, H-6); 8.12 (s, H, H-8); 7.63 (t, 4H, J=8.4Hz); 7.46 (t, 2H, J=7.6Hz); 7.36-7.27 (m, 5H); 5.87 (d, 1H, 5 J=5.6Hz, H-1); 5.53 (d, 1H, J=6.4Hz); 5.35 (d, 1 H, J=4.8), 4.78 (q, 1 H, J=5.2, 10.4Hz); 4.51 (s, 2H), 4.17-4.08 (m, 2H); 3.92 (s, 2H); 3.82-3.77 (m, 1H); 3.70-3.64 (m, 1H). Cl Cil O O ,N N'III ~ NH 2 N N N Hd bH o10 proton NMR (400MHz,d 6 -DMSO): 8: 7.78 (s, 1H); 7.42 (s, 1H); 7.08 (d, IH, J=4Hz); 6.88 (d, 1H, J=3.6Hz); 5.77 (d, 1 H, J=2.8Hz); 4.62-4.60 (m, 1H); 4.54 (s, 2H); 4.39 (t, 1H, J=5.2Hz); 4.16 (q, 1H, J=6, 11.6Hz); 3.85 (d, 2H, J=5.2Hz); 3.62-3.57 (m, 1H); 3.53-3.48 (m, 1H); 3.02-2.90 (m, 3H); 1.54-1.48 (m, 2H); 0.86-0.83 (m, 3H). 15

NNH

2 NN N N 0 737 Isomer 1: WO 2004/022572 PCT/AU2003/001146 40 proton NMR (400MHz,d 6 -DMSO): 8:8.40 (s, 1H); 8.18 (s, 1H); 7.62 (s, 2H); 7.56 (d, 2H, J=7.6Hz); 7.44 (t, 2H, J= 3.6Hz); 7.37 (t, 3H, J=8.4Hz); 7.27-7.25 (m, 3H); 7.20-7.18 (m, 2H); 7.08 (d, 2H, J=8Hz); 5.87 (d, 1H, J=5.6Hz); 4.76 (d, 1H, J=15.6Hz); 4.67 (t, 1H, J= 5.6Hz); 4.30 (d, 1H, J=15.6Hz); 4.23 (t, 1H, 5 J=4.4Hz); 4.04-4.00 (m, 2H); 3.70-3.59 (m, 2H); 3.18-3.04 (m, 2H). Isomer 2: proton NMR (400MHz,d 6 -DMSO): 8: 8.39 (s, 1H); 8.20 (s, 1H); 7.81 (s, 2H); 7.61 (d, 2H, J=7.2Hz); 7.52 (d, 2H, J= 8Hz); 7.45 (t, 3H, J=7.2Hz); 7.35-7.26 (m, 5H); 7.21 (dd, 4H, J=6.8, 15.6); 5.83 (d, 1H, J=6Hz); 4.78 (d, 1H, 10 J=15.6Hz); 4.69 (t, 1H, J=5.2Hz); 4.30 (d, 1H, J= 15.6Hz); 4.25 (t, 1H, J=4.4Hz); 4.11 (t, 1H, J=4.4Hz); 4.02-3.98 (m, 2H); 3.21-3.06 (m, 2H); 3.18 3.04 (m, 2H). CI N NH N )N KNN J -C 0 0 Hd bH 750 15 Isomer 1 proton NMR (400MHz,d 6 -DMSO): 8: 8.46 (s, 1H); 8.25 (s, 1H); 7.63 (d, 4H, J=7.2Hz); 7.52 (t, 2H, J= 7.6Hz); 7.44-7.36 (m, 5H); 7.28 (d, 2H, J=8.4Hz); 7.16 (d, 2H, J=8.4Hz); 5.95 (d, 1H, J=5.6Hz); 4.79-4.73 (m, 2H); 4.40-4.33 (m, 2H); 4.13-4.07 (m, 2H); 3.78-3.70 (m, 2H); 3.26-3.11 (m, 2H). 20 Isomer 2 proton NMR (400MHz,d 6 -DMSO): 8: 8.26 (s, 1H); 8.07 (s, 1H); 7.55 (d, 2H, J=7.4Hz); 7.45 (d, 2H, J=8.4Hz); 7.39 (t, 5H, J= 7.6Hz); 7.30 (d, 2H, J=8Hz); 7.17 (d, 2H, J=8.4Hz); 7.11 (d, 2H, J=8.4Hz); 5.77 (d, 1H, J=5.6Hz); 5.50 (s, 1H); 5.26 (s, 1H); 4.67-4.63 (m, 2H); 4.25-4.22 (m, 2H); 4.06 (t, 1H, J=8Hz); 25 3.95 (q, 1H, J=6.8, 10.4Hz); 3.67-3.48 (m, 2H); 3.18-2.99 (m, 2H).

WO 2004/022572 PCT/AU2003/001146 41 Example 9:

-NH

2 RINK amide PS resin NzN (a RH 0 0 9-la: RI=P 9-Ib: RI=Pr QI- N - 'N, 0 lNH NN R2 .... "'OH - $,.N R2,, ) R0 (b R 9-19-III (c so, 0 \

R

3 (d) HO OH R 3 N 9-IV 9-V Conditions: (a) general method 1; (b) (i) MsCI, DCM, (ii) Tryptamine 5 derivative, DMF (c) R 3 CHO, 25% TFA/DCM, rt; (d) general method 3b. Example 10: 1/NO 2 FmOcN

R

a O S02 02 NO2 HN N-S O Oo O H R, N-Fmoc R R110 'Fmoc 0OH H10-V H R 3 10-Il 10-1

R

2 N R2 R 3 01)-o N-S NO 2 2 N 0N - On O i . 0" 0 (d) . Oo" 0 10-V R,

R

a 10-VI R, (e) R 2 NN 0 R O Hd H O10-VII WO 2004/022572 PCT/AU2003/001146 42 Conditions: (a) (i) general method 4, (ii) o-nitrobenzenesulfonyl chloride, DCM, DIPEA, 3 hours, RT; (b) PPh 3 , aminoalcohol, DEAD, 24 hr; (c) (i) general method 4, (ii) general method 12; (d) (i) Na PhS

-

, DMF, 12 hours, RT (ii) general method 13 where the amine is intramolecular, (e) general method 5 3b. Example 11:

R

2 R (3O NH2 ()O-T7 R3 11-I MsO R 3 ! 11-II 0 ".,,,OH (b) N OO O N S O 0R 0 11-IV NHBOC -V NH 2 O (d) HN R2 R1 N 0R3 11-VI 10 Conditions: (a) DMF, DIPEA; (b) general method 1; (c) general method 3b; (d) reflux in toluene.

WO 2004/022572 PCT/AU2003/001146 43 Example 12:

R

h 12-II H N-Fmoc 0 NH2 H H R 3 N _ )N-r N N-Fmoc (b) H (a) - H 12-I OH 12-III H R 3 H R 3

R

2 H R 3

R

2

NH

2 (C)

N-

/ (d) NT]NO 12-IV 12-V HN 0i,. R 2 O NkN OR, 12-VI Ra 12-VII Conditions: (a) aldehyde, TMOF/THF; (b) general method 4; (c) general 5 method 12; (d) ) (i) Na+PhS

-

, DMF, (ii) general method 13 where the second amine is intramolecular; (e) general method 3b Example 13: S R 2 S R NHN 2 N HN N NR2 Br O R RI R 4 R R 13-IV 13-I 13-II o 13-III +

R

2 N Ri R 3 N S S N R 4 N R 2 R R4 H DH c) R 4 N' R 3

R

4 OHRH 13-V 13-VI OH H 10 Conditions: (a) R2-Isothiocyanate, DCM; (b) Bromoketone, DMF; (c) general method 3b WO 2004/022572 PCT/AU2003/001146 44 Example 14: R2

H

2 N 0 R 2 'N 0 (0 R 1 (a)_ (b) R 3 N 14-1 14-H0 0 : 14-I R2 SR(c) O HO OH 14-IV 5 Conditions: (a) R 2 CHO, TMOF, THF; (b) R 3 -CO-CI, NEt 3 ; (c) general method 3b. Example 15:

H

2 N RI HO N 1 N R H (b) O 15-I 15-I R 1

R

2 O R , R2 15-III L R2 R4) 15-IV 10 Conditions: (a) Epoxide, DIEA, DMF; (b) CDI, DCM; (c) general method 3b.

WO 2004/022572 PCT/AU2003/001146 45 Example 16: R2 R2

R

1 k 0 R

H

2

N

R

(a) N N CO, R 16-Id - -(b) N N' 0 R H 2R 3 R 4 16-I 0R 3

R

4 HO OH 16-III 0 0 0 eg: O6 Etc 5 Conditions: (a) R 3

-CO-CO-R

4 , NH 4 OAc, R 2 -CHO; (b) general method 3b Example 17: o R R 2 -->-N 0 I 0

H

2 N (a 2 N R (b)

R

3 N , O- OO S O O17-II O R R2 6 O 17-I 3o 17- HS O 17-IV OH 17-III

R

3 0

R

2 HO OH 17-V 10 Conditions: (a) R 2 CHO, TMOF, THF; (b) mercapto acetic acid; (c) general method 3b. 15 WO 2004/022572 PCT/AU2003/001146 46 Example 18: Intermediate from example 4 (4-111 a,c,d) S(a) 0 0-FRINK]HN 0 Ra (b) s 1" HN 0 R (c) N e (d) S 6o 0 18-II 0

H

2 N " R 0 -Ra IV S H6 OH (18-a) General Method 15, (18-b) General Method 16, (18-c) General Method 5 9, hydrazine/DMF conditions for adenosine containing compounds only, (18 d) General Method 3b Exemplary yield and crude product purity Ra=adenosine 10 Purity of Compound crude cpds (%, by ELSD) yield (%) 86 96 33 87 92 33 88 84 31 89 98 31 90 97 27 91 96 46 92 92 35 WO 2004/022572 PCT/AU2003/001146 47 93 87 28 94 86 34 95 98 40 96 85 33 97 95 35 98 94 45 99 97 39 100 98 39 101 96 40 102 98 47 103 63 23 104 90 38 105 96 31 106 95 49 107 98 46 108 41 18 109 89 38 110 89 41 111 81 18 112 20 12 113 15 8 114 35 12 115 95 22 116 84 42 117 97 39 118 88 34 119 77 25 120 92 44 Analysis of some typical example compounds 0

H

2 N N NH 2 N/ S HO OH 18-1 5 proton (400MHz, d -DMSO): 8.29 (s, 1H, H-8), 8.11 (s, 1H, H-2), 8.00 (d, 1H, J = 1.5 Hz, Ar-H), 7.87 (broad s, 1 H, NH), 7.61 (dd, 1 H, J = 1.5, 8.6 Hz, Ar-H), 7.41 (d, 1H, J= 8.6 Hz, ArH), 7.30 (broad s, 2H, NH), 7.21 (broad s, 1H, NH), 5.86 (d, 1H, J = 5.1 Hz, H'-1), 5.61 (d, 1H, J = 6.0 Hz, OH), 5.45 (d, 1H, J = 5.4 Hz, OH), 4.72 (qua, 1H, J = 5.2 Hz, H'-2 or H'-3), 4.54 (dd, J = 15.2, 4.7 10 Hz, H'-5), 4.47 (dd, 1H, J= 15.2, 7.4 Hz, H'-5), 4.31 (qua, 1H, J=4.7 Hz, H'-3 WO 2004/022572 PCT/AU2003/001146 48 or H'-2), 4.29 (dt, 1 H, J = 4.7, 7.4 Hz). carbon (100MHz, d 6 -DMSO): 168.7, 156.6, 154.8, 153.2, 149.8, 142.9, 140.4, 139.3, 128.4, 121.9, 119.8, 117.6, 109.8, 88.5, 82.7, 73.5, 71.8, 46.9. 0 H2N 0 --- -- N H N111111: N H 2 NN N Nzz 7 N S HO OH 115 proton (400MHz, d 6 -DMSO): 8.38 (s, 1H, H-8), 8.15 (s, 1H, H-2), 7.95 (broad s, I H, NH), 7.64 (d, 1 H, J = 1.5 Hz, Ar-H), 7.54 (dd, 1 H, J = 1.5, 8.3 Hz, Ar-H), 7.31 (d, 1 H, J= 8.5 Hz, Ar-H), 7.30 (broad s, I H, NH), 7.25 (broad s, 1 H, NH), 10 5.85 (d, 1H, J= 6.3 Hz, H'-1), 5.54 (d, 1H, J = 6.2 Hz, OH), 5.38 (d, 1H, J = 5.1 Hz, OH), 4.82 (qua, 1H, J = 5.8 Hz, H'-3 or H'-2), 4.70 (dd, 1H, J = 4.6, 13.8 Hz, H'-5), 4.49-4.38 (m, 2H, H'-5 + H'-4), 4.35 (m, 1H, H'), 2.10 (s, 3H,

CH

3 ). carbon (100MHz, d6-DMSO): 170.2, 167.9, 156.6, 153.2, 150.0, 140.4, 135.9, 15 131.1, 129.6, 122.3, 119.8, 110.0, 109.7, 87.8, 82.4, 73.2, 71.9, 46.9, 31.5. 0

H

2 N N NH 2 N Nzz Nz- k- N- N S HO OH 116 proton (400MHz, d 6 -DMSO): 8.30 (s, 1H, H-8), 8.11 (s, 1H, H-1), 8.08 (d, 1H, 20 J= 1.5 Hz, Ar-H), 7.59 (broad s, 1H, NH), 7.63 (dd, 1H, J= 1.5, 8.3 Hz, Ar-H), 7.43 (d, 1H, J = 8.3 Hz, Ar-H), 7.31 (broad s, 2H, NH 2 ), 7.22 (broad s, 1H, NH), 5.87 (d, 1H, J= 5.0 Hz, H'-1), 5.63 (d, 1H, J= 5.8 Hz, OH), 5.46 (d, 1H, J = 5.4 Hz, OH), 4.75 (qua, 1H, J = 5.0 Hz, H'-2 or H'-3), 4.54 (dd, 1H, J = 4.7, 15.3 Hz, H'-5), 4.48 (dd, 1H, J = 7.6, 15.3 Hz, H'-5), 4.34 (qua, 1H, J = 25 4.7 Hz, H'-2 or H'-3), 4.25 (dt, 1H, J = 4.7, 7.4 Hz, H'-4), 3.24 (qua, 2H, J = 7.3 Hz, CH 2 ), 1.32 (t, 3H, J = 7.3 Hz, CH 3

).

WO 2004/022572 PCT/AU2003/001146 49 carbon (100MHz, d 6 -DMSO): 168.7, 156.6, 153.8, 153.2, 149.8, 143.0, 140.4, 139.1, 128.4, 121.9, 119.8, 117.6, 109.9, 88.5, 82.7, 73.4, 71.8, 46.9, 27.2, 15.6. 5 Yield and purity of crude products Ra = 0

-

/

NH

2 R, Purity of Crude cpds (%, by Compound# R 1 ELSD) yield (%) 121 Ph 96.9 38 122 Ph 94.8 5 123 Ph 96.7 31 124 Ph 97.8 34 125 Ph 50.6 38 126 Ph 97.3 21 127 Ph 98.3 41 128 Ph 97.7 26 129 Ph 97.7 14 130 Ph 96.7 28 131 Ph 91.1 23 132 Ph 97.9 39 133 Ph 96.9 36 134 Ph 89.0 31 135 Ph 97.5 33 136 Ph 96.4 22 137 Ph 97.0 30 138 Ph 96.7 28 139 Ph 84.6 23 140 Ph 83.3 24 141 Ph 97.1 28 142 Ph 97.0 27 143 Ph 95.3 35 144 Ph 72.8 25 145 Ph 88.6 30 146 Ph 85.7 8 147 Ph 66.3 23 148 Ph 68.1 25 149 Ph 26.1 15 150 Ph 97.7 7 151 Ph 99.1 5 152 Ph 97.8 6 153 Ph 48.4 17 WO 2004/022572 PCT/AU2003/001146 50 154 Ph 95.6 26 155 Ph 96.0 31 156 Ph 74.50 2 157 Ph 7.9 3 158 Ph 53.6 17 159 Pr 96.4 12 160 Pr 98.2 37 161 Pr 96.8 20 162 Pr 96.9 36 163 Pr 97.4 19 164 Pr 96.4 36 165 Pr 96.7 27 166 Pr 97.2 24 167 Pr 96.8 17 168 Pr 95.0 33 169 Pr 82.1 15 170 Pr 95.8 34 171 Pr 97.0 37 172 Pr 97.4 23 173 Pr 96.8 33 174 Pr 96.9 37 175 Pr 96.9 41 176 Pr 96.9 28 177 Pr 89.9 7 178 Pr 98.2 35 179 Pr 97.3 37 180 Pr 96.4 36 181 Pr 93.7 28 182 Pr 80.7 26 183 Pr 96.6 36 184 Pr 97.7 36 185 Pr 60.2 21 186 Pr 86.9 33 187 Pr 39.7 15 188 Pr 97.2 2 189 Pr 99.5 60 190 Pr 98.4 4 191 Pr 60.0 5 192 Pr 96.0 34 193 Pr 96.7 36 194 Pr 95.4 12 195 Pr 17.0 2 196 Pr 80.5 11 WO 2004/022572 PCT/AU2003/001146 51 Analysis of a typical example compounds 0

H

2 N N:N 0

NH

2 S HO bH

NO

2 138 proton (400MHz, d 6 -DMSO): 8.13 (d, 1H, J= 1.3 Hz, Ar-H), 8.09 (d, 1H, J= 5 8.7 Hz, Ar-H), 7.93 (broad s, 1 H, NH), 7.86 (broad s, 1H, NH), 7.70 (dd, 1H, J = 1.3, 8.4 Hz, Ar-H), 7.64 (d, 1 H, J = 8.7 Hz, Ar-H), 7.50-7.30 (m, 5H, Ar-H), 7.28 (d, 1H, J = 8.5 Hz, Ar-H), 7.25 (broad s, 1H, NH), 5.75 (d, 1H, J = 5.48 Hz, OH), 5.53 (d, 1H, J = 6.4 Hz, OH), 5.37 (d, 1H, J = 1.7 Hz, H'-1), 4.75 4.60 (m, 3H, CH + CH 2 ), 4.54-4.40 (m, 2H, CH), 4.30-4.23 (m, 2H, CH). 10 Carbon (100MHz, d 6 -DMSO): 167,6, 161.1, 152.2, 146.2 145.3, 141.8, 138.9, 138.2, 138.1, 129.9, 129.7, 129.4, 127.8, 127.7, 125.0, 123.2, 121.3,116.9, 108.8, 89.7, 82.3, 74., 71.8, 46.3, 34.7. Example 19: 3-VI I (a) N (b) HN H (b) Br O 0 HN H Ra 0 H -- (c),(d) O o R 19-II N S N N Ra

NH

2 Hd bOH 15 19-111 WO 2004/022572 PCT/AU2003/001146 52 (19-a) General Method 17, (19-b) General Method 18, (19-c) General Method 9 for adenosine containing compounds only, (19-d) General Method 3b. R \0.1% formic acid R \ N CHaCN/H 2 0 S- NN"°R N oR

NH

2 HO OH NH 2 H OHO 5OH 5 19-III 19-IV Retention time, observed mass, yield Compound 2 components 19-111 and 19-IV 312 Rt= 4.24min (M+H)*=516 (26%), Rt= 4.75min (M+H)+=544 (72%) 313 Rt= 4.80min (M+H) =550 (3%), Rt= 5.28min (M+H)+=578 (72%) 314 Rt= 4.52min (M+H) t =546 (23%), Rt= 4.96min (M+H)+=574 (74%) 315 Rt= 4.70min (M+H)+=530 (11%), Rt= 5.17min (M+H)+=558 (88%) 316 Rt= 4.69min (M+H)*= (2%), Rt= 5.23 min (M+H)'= (19%) 317 Rt= 5.82min (M+H) =572 (22%), Rt= 6.26min (M+H) =544 (78%) 318 Rt=4.81min (M+H)+=596 (73%), Rt=5.40min (M+H)+=624 (27%) 319 Rt=4.68min (M+H) =530 (2%), Rt=5.15min (M+H)+=558 (98%) 320 Rt=5.92min (M+H)+=608 (25%), Rt=6.37min (M+H) =636 (75%) 321 Rt=5.97 min (M+H)+=622 (52%), Rt= 6.48min (M+H)+=650 (48%) 322 Rt= 5.74min (M+H)+=592 (43%), Rt=6.27min (M+H)+=620 (57%) 323 Rt= 5.15min (M+H) =569 (14%), Rt= 5.98min (M+H) = 597(86%) 324 Rt= 5.63min (M+H)+=603 (46%), Rt= 6.62min (M+H)

+

= 631(52%) 325 Rt= 5.34min (M+H)+=599 (23%), Rt= 6.20min (M+H) =627 (77%) 326 Rt= 5.51 min (M+H) =583 (38%), Rt= 6.38min (M+H) =611 (62%) 327 Rt= 5.58min (M+H)+=603 (90%), Rt= 6.46min (M+H) =631 (8%) WO 2004/022572 PCT/AU2003/001146 53 328 Rt= 6.54min (M+H) =625 (55%), Rt= 7.41min (M+H) =653 (45%) 329 Rt= 5.77min (M+H) =647 (31%), Rt= 6.66min (M+H) =677 (55%) 330 Rt= 5.59min (M+H) =612 (28%), Rt=6.20 min (M+H) =640 (61%) 331 Rt= 5.51min (M+H) =583 (22%), Rt= 6.31 min (M+H) =611 (78%) 332 Rt= 6.57min (M+H)+=661 (42%), Rt= 7.50min (M+H) =689 (58%) 333 Rt= 6.75min (M+H) =675 (38%), Rt=7.62 min (M+H) =703 (60%) 334 Rt=6.56min (M+H)+=645 (55%), Rt= 7.38min (M+H)+=673 (44%) 335 Rt= 5.03min (M+H) =535 (17%), Rt= 5.77min (M+H) =563 (82%) 335 Rt= 5.58min (M+H) =569 (11%), Rt= 6.35min (M+H) =597 (87%) 336 Rt= 5.26min (M+H) =565 (15%), Rt= 6.0min (M+H) =593 (84%) 337 Rt= 5.33min (M+H) =5.49 (12%), Rt= 6.04min (M+H) 4 =577 (88%) 338 Rt= 5.41min (M+H) =569 (79%), Rt= 6.27min (M+H) =597 (5%) 339 Rt= 6.44min (M+H) =591 (36%), Rt= 7.29min (M+H) += 619(64%) 340 Rt= 5.67 (M+H) =615 (18%), Rt= 6.46min (M+H) =643 (79%) 341 Rt=6.51 min (M+H) =591 (8%) 342 Rt= 5.37min (M+H) =549 (25%), Rt= 6.20min (M+H) =577 (75%) 343 Rt= 6.54min (M+H) =627 (19%), Rt= 7.40min (M+H)+=655 (81%) 344 Rt= 6.64min (M+H) =641 (30%), Rt= 7.52min (M+H)+=669 (69%) 345 Rt=6.41 min (M+H) =611 (58%), Rt=7.26 min (M+H) =639 (42%) 5 WO 2004/022572 PCT/AU2003/001146 54 Example 20: 0 (a) (b) -- R

-

N,

NO

2 H -Nf'R H N CI 20-I O N -- R O-N R NN (c) NN NH 2 - i R 2 (d) [ii ' N N N 0 H H (e) NR R HNR O 20-IV HNR N N O R2 HO OH 20-V 5 (20-a) General Method 12, (20-b) General Method 19, (20-c) General Method 6, (20-d) General Method 20, (20-e) General Method 21, (20-f) General Method 9 for adenosine containing compounds only, then General Method 3b for all compounds. 10 Analysis of some typical example compounds: NH2 N N N 718 WO 2004/022572 PCT/AU2003/001146 55 proton NMR (400MHz,d 6 -DMSO): 5:8.37 (s, 1 H); 8.24 (s, 1H); 7.57 (d, 2H, J=8.8Hz); 7.35 (d, 2H, J=7.2Hz); 7.30 (t, 2H, J=7.6Hz); 7.21 (t, 2H, J=7.2Hz), 6.77 (d, 2H, J=8.8Hz), 5.81 (d, I H, J=4.4Hz); 4.71-4.63(m, 3H), 4.64 (t, 1 H, J=4.8Hz); 4.46-4.38 (m, 2H); 4.33-4.30 (m, 1H), 3.76 (s, 3H). 5 0 o No N H 726 Beta isomer: proton NMR (400MHz,d 6 -DMSO): 5: 8.27 (s, 1H), 7.88 (s, 1 H), 7.55-7.41 (m, 10 6H); 7.28 (dd, 2H, J=1.2, 7.6Hz); 6.84 (d, 2H, J=8.8Hz); 5.31 (d, 1H, J=2Hz); 4.66 (d, 1 H, J=11.2Hz); 4.51 (s, 1H); 4.41-4.32 (m, 3H); 3.97-3.88 (m, 3H); 2.98 (s, 3H); 1.73-1.66 (m, 2H); 1.39-1.26 (m, 12H); 0.87-0.84 (m, 3H). Alpha isomer: proton NMR (400MHz,d 6 -DMSO): 8: 8.25 (s, 1H), 7.82 (d, 3H, J=8.4Hz); 7.51 15 7.46 (m, 6H); 7.11 (d, 2H, J=8.8Hz); 5.43 (d, 1 H, J=4.4Hz); 4.91 (s, 1H); 4.37 (s, 1H); 4.23 (q, 1 H, J=5.6, 8.8Hz); 4.06 (t, 2H, J=6.4Hz); 3.79 (s, 3H); 1.77 1.70 (m, 2H); 1.44-1.26 (m, 12H); 0.87-0.84 (m, 3H). 20 25 WO 2004/022572 PCT/AU2003/001146 56 Example 21:

OCH

3 N O CHO N(a) 0 N NHBz PL-FMP resin 21-I (b) N NHBzN H N N (c) 2N NHBz

N

2 0 2 N \/=/ R 9 O OR j NO 2 OO 21-IlI )21-II (d21-IVe) 21-V (21-a) General Method 12, (21-b) General Method 6, (21-c) General Method 5 7, (21-d) General Method 1 or 22, (21-e) General Method 9, (21-f) General Method 3-b then General Method 3a. Analysis of some typical example compounds: C NH2 C

N/-

(f)/ N () NH 2 NN NN R2O H OH OH

OCH

3 10 920 21-TV 21-V (21-a)proton (400MHz, d6-DMSO): 8.36 (s, 1H, H-8), 8.25 6, (21H, H-2), 7.88 (s, 2Hod ARCH)7, (21-d) General Method I or 22CH), 6.84(21-e) General Method 9J=8.8Hz, A(21-fCH), 5.85 (dGeneral Method 3-b then General Method 3a. Analysis of some typical example compounds: 1H, J= 3.6Hz, H'-1), 4.73 (dd, 1H, J=3.5, 15.8Hz, CH), 4.57-4.64 (m, 2H, CH2), 4.36 (t, 1 H, J= 5.6 Hz, CH), 4.22 (m, 1 H, H'-4), 3.80 (s, 3H, OCH3). 15 c1 NH 2 C' K4N N NN ON N OH OH 0CH 3 10 920 proton (400MHz, d 6 -DMSO): 8.36 (s, I H, H-8), 8.25 (s, 1 H, H-2), 7.88 (s, 2H, ArCH), 7.62 (d, 2H, J= 8.8Hz, ArCH), 6.84 (d, 2H, J=8.8Hz, ArCH), 5.85 (d, IH, J= 3.6Hz, H'-1), 4.73 (dd, IH, J=3.5, 15.8Hz, OH), 4.57-4.64 (in, 2H,

OH

2 ), 4.36 (t, 1 H, J= 5.6 Hz, CH), 4.22 (in, I H, H'-4), 3.80 (s, 3H, OCH 3 ). 15 WO 2004/022572 PCT/AU2003/001146 57 Example 22: SOH 0 NHBz O H (a ) O 0 . N H 2 H 0 Hz

,HR

1 Hk 6 N N) b22-1 o0<o0 22 (2.5 eq) 22-II (b) NHBz NHBz 0- 0 0h oo oo R2 22-IV 22-111 (d), (e) 2 NH2 0 N 5e I N N. O Ph'N- :C N

R

2 0 HO OH 22-V 5 (22-a) General Method 1, general method 4 (22-b) General Method 12, (22-c) General Method 23, (22-d) General Method 9, (22-e) General Method 3-a. Analysis of some typical example compounds:

NH

2 0 N N N N N 0,0 10( H a bH 10 741 WO 2004/022572 PCT/AU2003/001146 58 Isomer1: proton NMR (400MHz,d 6 -DMSO): 8: 8.48 (s, 1H); 8.17 (s, 1H); 7.39-7.22 (m, 6H); 7.11 (d, 2H, J=7.6Hz); 6.86 (d, 2H, J=6.8Hz); 5.93 (d, 1H, J=4.8Hz); 4.67 (t, 1 H, J=4.8Hz); 4.59 (t, 1 H, J=3.6Hz); 4.34 (t, 1 H, J=5.2Hz); 4.22 (q, 1H, 5 J=4.8, 10Hz); 4.00 (dd, 1H, J=6.8, 15.2Hz); 3.76 (dd, 1H, J=7.6, 14.8Hz); 3.26 (dd, 1H, J=4.4, 14Hz); 3.05 (dd, 1H, J=3.6, 14.4Hz). Isomer2: proton NMR (400MHz,d 6 -DMSO): 8: 8.59 (s, 1H); 8.31 (s, 1H); 7.38-7.23 (m, o10 5H); 7.11-7.06 (m, 3H); 6.88 (d, 2H, J=6.8Hz); 5.97 (d, 1H, J=6Hz); 4.84 (t, 1H, J=4.8Hz); 4.50 (t, 1 H, J=3.6Hz); 4.25-4.22 (m, 2H); 4.14 (dd, 1H, J=3.6, 14.8Hz); 3.23 (dd, 1H, J=5.2, 14.4Hz); 3.00 (dd, 1H, J=2.8, 14Hz).

NH

2 0 N N N N C

-

0 / Hd 5 15 935 Isomer 1: proton NMR (400MHz,d 6 -DMSO): 8: 10.94 (s, 1H); 8.59 (s, 1H); 8.26 (s, 1H); 7.48 (d, 1H, J=8Hz); 7.32-7.26 (m, 4H); 7.10 (s, 1H); 7.06 (t, 1H, J=7.6Hz); 6.93 (t, 1 H, J=7.6Hz); 6.69-6.67 (mn, 2H); 5.95 (d, 1 H, J=5.2Hz); 4.66 (t, 1H, 20 J=5.6Hz); 4.54 (t, 1H, J=3.2Hz); 4.33 (t, 1H, J=4.8Hz); 4.25 (q, 1H, J=5.2, 10.8Hz); 4.00 (dd, 1H, J=6.4, 15.2Hz); 3.76 (dd, 1H, J=4, 14.8Hz); 3.37-3.25 (m, 2H). Isomer 2: 25 proton NMR (400MHz,d 6 -DMSO): a: 10.95 (s, 1H); 8.68 (s, 1H); 7.43 (d, 1 H, J=8Hz); 7.32 (d, 2H, J=8Hz); 7.27-7.25 (m, 2H); 7.09 (s, 1H); 7.06 (t, 1H, J=8Hz); 6.92 (t, 1 H, J=8Hz); 6.70 (dd, 2H, J=3.6, 7.6Hz); 5.99 (d, 1 H, WO 2004/022572 PCT/AU2003/001146 59 J=5.6Hz); 4.81 (t, 1 H, J=5.2Hz); 4.47 (t, 1H, J=3.2Hz); 4.29-4.22 (m, 2H); 4.12 (dd, 1H, J=4.4, 14.8Hz); 3.68 (dd, 1H, J=8.4, 14.8Hz); 3.36 (dd, 1H, J=5.2, 15.2Hz); 3.24 (dd, 1 H, J=2.4, 15.2Hz).

NH

2 0 N N N NN 0 Hd 'oH N 5 H 948 Isomer 1: proton NMR (400MHz,d 6 -DMSO): 8:8.96 (s, 1H); 8.49 (s, 1H); 8.03 (s, 1H); 7.73 (d, 2H, J=10.8Hz); 7.67 (d, 2H, J=7.2Hz); 7.49 (t, 2H, J=7.6Hz); 7.40 o10 7.35 (m, 2H); 7.34 (d, 2H, J=8.4Hz); 5.95 (d, 1H, J=5.6Hz); 4.70 (t, 1H, J=5.2Hz); 4.65 (t, 1H, J=4.4Hz); 4.31 (t, 1 H, J=4.8Hz); 4.27-4.23 (m, 1H); 3.95 (dd, 1H, J=7.6, 15.2Hz); 3.77 (dd, 1H, J=4, 14.8Hz); 3.26-3.24 (m, 2H). Isomer 2: 15 proton NMR (400MHz,d 6 -DMSO): 8: 8.97 (s, 1H); 8.51 (s, 1H); 7.82 (s, 1H); 7.73 (d, 2H, J=8.8Hz); 7.67 (d, 2H, J=7.2Hz); 7.49 (t, 2H, J=7.2Hz); 7.40-7.35 (m, 2H); 7.25 (d, 2H, J=8.4Hz); 5.95 (d, 1 H, J=5.6Hz); 4.79 (t, 1H, J=4.8Hz); 4.62 (t, 1H, J=5.6Hz); 4.27-4.22 (m, 2H); 4.16 (dd, 1 H, J=4, 14.8Hz); 3.33 3.21 (m, 2H). 20 WO 2004/022572 PCT/AU2003/001146 60 Example 23: Part A N=N NN 0 FmocHN YN / C0 2 H (a) FmocHN s J NH /< RK 23-11 23-I (b) R2 N=N O N=N O NO2 NH I (C) H2N N NH-O

R

2

R

2 1 R, NN 0 N=N O N NI OHNN NH N~~- H- l 6l, NH-O R R S 23-V 23-VI

NH

2 NHBn (g), (h) R N= N N- N N-% / CONH 2 R HO OH 5 NHBn 23-VII (23-a) General Method 1, (23-b) General Method 4, (23-c) General Method 6, (23-d) General Method 10, (23-e) General Method 4 or General Method 20, (23-f) General Method 12. (23-g) General Method 9. (23-h) General Method o10 3a.

WO 2004/022572 PCT/AU2003/001146 61 Part B R R N(i) N NN 0 _ _N-- N NH-0 Ph Ph 23-V 23-VIII

NH

2 NHCOPh R\ N=N N N CONH 2 S Ph HO OH NHCOPh 23-IX (23-i) General Method 22, (23-j) General Method 3-a 5 Part-C

R

1

R

1 NN H (k) NN o N02 " . Ph NH2 Ph 0 0 0 0 OO 23-IV OO 23-X 1(i) RI N:N RN:N 0 N N-'' CONH 2 W N' / NH-Q Ph NH- Ph N HO OH O 23-XI N - 23-XII 23-XI RR22 (23-k) General Method 7, (23-1) General Method 17, followed by treatment of 10 the resins with a 1.43 Molar solution (-10 equivalents) of piperazine in dry DMF at room temperature overnight. The resin was then drained, washed (2 x DMF and 3 x DCM) and then dried in vacuo, General Method 12; (23-m) WO 2004/022572 PCT/AU2003/001146 62 General Method 3-a. Analysis of a typical example compounds: N F 0I a /CONH 2 NN N HO OH OMe NHBn 968 5 proton (400 MHz: d 6 DMSO) 3.79 (s, 3H, OCH 3 ), 4.30 (bs, 2H, H2, H3), 4.43 (bd, J 6.0 Hz, 3H, H4, NCH 2 Ph), 4.65 (dd, J 15.6, 6.2 Hz, 1H, H5a), 4.91 (d, J 14.8 Hz, 1H, H5b), 5.35 (s, 1H, H1), 6.64 (d, J8.8 Hz, 2H, ArH), 6.98 (d, J8.8 Hz, 2H, ArH), 7.19 (d, J8.8 Hz, 2H, ArH), 7.22-7.36 (m, 5H, ArH, NHa), 7.42 7.56 (m, 5H, ArH), 7.71 (t, J7.6 Hz, 2H, ArH), 7.82 (bs, 1H, NHb). 10 C I N N N O'/

CONH

2 N- 0 04Ph Z 11 HO OH NHCOPh proton (400 MHz: d 6 DMSO) 4.24-4.31 (m, I1H, H4), 4.38 (dd, J 7.4, 5.0 Hz, I H, H3), 4.47 (dd, J4.4, 1.6 Hz, I H, H2), 4.50 (dd, J 15.6, 7.6 Hz, I H, H5a), 4.76 (dd, J 15.6, 2.8 Hz, 1 H, H5b), 5.33 (d, J 1.2 Hz, IH, HI), 7.29 (dd, J7.8, 15 1.4 Hz, 2H, ArH), 7.40-7.62 (mn, 8H, ArH, ArCONHa), 7.68 (d, J 8.4 Hz, 2H, ArH), 7.83 (s, IH, ArCONHb), 7.88 (d, J 8.8 Hz, 2H, ArH), 7.91-7.99 (m, 3H, ArH), 10.46 (s, IH, ArNHCOPh).

WO 2004/022572 PCT/AU2003/001146 63 Example 24: o o (c) O (d) 0" 0 NHN o 24-I O O N 00 N ,NHBoc -24-II N N (e) R N N NNH2 NC 0 N N 24-IH H0 H 5 (24-a) General Method 1, (24-b) General Method 4, (24-c) General Method 12, (24-d) General Method 13, (24-e) General Method 3-b. Analysis of some typical example compounds: 0 cl N NH 2 cl HoeN OH 10 954 proton (d6-DMSO, 400MHz): 8.51 (s, 1H, H-2/8), 8.31 (s, 1H, H-2/8), 7.60 7.05 (m, 8H, ArCH), 5.86 (d, 1H, J=5.6,Hz, H'-I), 4.67 (t, 1H, J=5.5Hz, H' 2/3), 4.64 (d, 1H, JAB=16.1Hz, HA-), 4.39 (d, 1H, JAB=16.1Hz, HB-), 4.34 (t, 1 H, J=5.1Hz, H-2/3), 4.09 (t, 1 H, J=4.2Hz, ), 3.99 (m, 1 H, H'-4), 3.67 (dd, 1 H, 15 J=5.8Hz, 14.0Hz, HA), 3.58 (dd, 1H, J=7.6, 14.0Hz, HB), 3.14 (dd, 1H, J=5.1, 14.4Hz, H'-5A), 3.02 (dd 1H, J=4.6, 14.4Hz, H'-53).

WO 2004/022572 PCT/AU2003/001146 64 0 O N NH N- N N / OH 960 proton (d 6-DMSO, 400MHz): 8.48 (s, 1H, H-2/8), 8.29 (s, 1 H, H-2/8), 7.57 7.00 (m, 8H, ArCH), 5.88 (d, 1 H, J=5.8Hz, H'-1), 4.68 (t, J=5.2Hz, H'-), 4.60 5 (d, 1H, JAB=16.1Hz, H-), 4.38 (d, 1H, JAB=16.1Hz, H), 4.34 (t, 1H, J=5.1Hz, H ), 4.07 (t, 1H, J=4.6Hz, H), 4.01 (m, 1H, H'-4), 3.64 (d, 2H, AB system, H-), 3.12 (dd, 1H, J=5.2, 14.6Hz, HA-), 3.01 (dd, 1H, J=4.4, 14.6Hz, HB-). Exemplary compounds of the Invention: 10 The substructures A-H listed below are substituents in the field R1 in the libraries of compounds that follow.

NH

2 NHBz O O N N N N NH 2 N NH 2 N N A B C D 0 0 0 N N e N NH 2 N" NH 2 / NH 2 OMe N a \ \N NN E F G C H OMe 15 Others substiuents referred to in the following libraries may be subsequently found in the text at the end of examples.

WO 2004/022572 PCT/AU2003/001146 65 Example 25: R2HN" 0 R 1 HO" ""OH R1 R2 R (on Comp. ISOMER arm) 1 A Ila-1 Land D H 2 A IIb-1 Land D H 3 A Iic-1 L and D H 4 A lid-1 Land D H 5 A lie-1 L H 6 A lie-1 D H 7 A Ilf-1 L and D H 8 A Ig-1 L and D H 9 A IIh-1 L and D H 10 A Il-1 L and D H 11 A IIj-1 L and D H 12 A Ilk-1 L and D H 13 A I1-1 L and D H 14 A o10-1 L H 15 A |10-1 D H 16 B jla-1 L and D methyl 17 B lib-1 L and D methyl 18 B Iic-1 L and D methyl 19 B lid-1 L and D methyl 20 B lie-1 L and D H 21 B |If-1 L and D H 22 B IIh-1 L and D methyl 23 B hi-1 L and D ethyl 24 B j -1 L and D ethyl 25 B Ilk-1 L and D methyl 26 B |r-I L and D methyl 27 B I1- Land D methyl 28 B 110o-1 L and D methyl 29 B lip-1 L and D methyl 30 B IIq-1 Land D methyl WO 2004/022572 PCT/AU2003/001146 66 Example 26: R2HN"," R1

HO

' OH R (on Comp. R1 R2 Isomer arm) 31 C Ila-1 Land D H 32 C IIb-I L and D H 33 D lib-1 L and D H 34 C 11ic-1 L and D H 35 C lid-1 L and D H 36 D lid-1 Land D H 37 D lie-1 L and D H 38 C le-1 L and D H 39 D lIf-1 Land D H 40 C Ilf-1 Land D H 41 D 1Ig-1 L and D H 42 C IIh-1 L and D H 43 D IIh-1 Land D H 44 C Ili-I1 L H 45 D Il-1 L H 46 C 1lj-1 L H 47 D lij-1 L H 48 C Ilk-1 Land D H 49 D Ilk-1 Land D H 50 C ilr-1 L H 51 D IIr-1 L H 52 C Il-1 L H 53 D lI-1 L H 54 c IIn-1 L H 55 D IIn-1 L H 56 C 110o-1 L H 57 D 110o-1 L H 58 c lip-1 L H 59 D lip-1 L H 60 c IIq-1 L H 61 D lq-1 L H 62 C lib-1 L H 63 D lib-1 L H 64 C lie-1 L H 65 D lie-1 L H WO 2004/022572 PCT/AU2003/001146 67 O 0 0 0 O, H, H, RO N RO N (L) and (D) O CH 3 (L) and (D) 0 Ila-1 lie-1 I 0 0 H 0 N _ (L) and (D) O O IIb-1 OH 0 OR Ilf-1 0 H 0 0H 0 RO' N RO N (L) and (D) O (L) and (D) O Ic-1 0 OH Ig-i NH H H 0 A H, N ON RO ROR () (L) and (D) O Ild-1 IIh-1 I (L)and(D) O WO 2004/022572 PCT/AU2003/001146 68 00 H 0 H N RO Ni RO (L) and (D) (L) and (D) o H 0 / -NH RO NI ON IIn-1 Cl / 0 0 O 0 IIj-1 O H (L) and (D) RO N (L) and (D) 0 N NH RO NH Io-1 (L) and (D) O Ilk-i 0 0 O-H N "0 N H RO (L) and (D) 0 0H 0 ON / NH -1 O FC (L) and (D) Il-1

F

3

H

3 CO N 0 O H 0 -0-H N OH 0 R O N RO N (L) and (D) 0 (L) and (D) 0 IIm-1

H

3 C- -N Iq-1

F

3 C / N 0 O O -0 -H H 0 N RO

F

3 0 IIr-1 N O (L) and (D) - H WO 2004/022572 PCTIAU2003/001146 69 Example 27: H R2. O R3 1N)

-

O H RI R4 O H& ! OH Comp. R1 R2 R3 R4 66 A a4 v2 11 67 A [37 v2 Y1 68 A 36 v2 21 69 A ,5 v2 I 70 A K4 v2 1 71 A ca4 v2 a4 72 A 37 v2 a4 73 A 36 v2 a4 74 A (5 v2 a4 75 A K4 v2 a4 76 A a4 al 11 77 A 37 a 1 1 78 A 136 al El 79 A ,5 al ,1 80 A K4 al 1 81 A o4 01 01 82 A 37 al al 83 A 36 al cal 84 A X5 al al 85 A rx4 al al 5 Example 28: 0

H

2 N N 0 RI N= 2S HO OH Comp. RI R2 86 A pl 87 A f1 88 A P2 89 A 82 90 A 1 91 A Kl WO 2004/022572 PCT/AU2003/001146 70 92 A s1 93 A o)l 94 A s2 95 A cr1 96 A 03 97 A 72 98 A y3 99 A 82 100 A s3 101 A K2 102 A 72 103 A s4 104 A 04 105 A y4 106 A P5 107 A o1 108 A 73 109 A 2 110 A VI 111 A v2 112 A v3 113 A v4 114 A 11 115 A v5 116 A v6 117 A s5 118 A 6 119 A v7 120 A ,1 Example 29: 0

H

2 N /R HO O NRS Ha O bH Comp. R1 R2 121 C al1 WO 2004/022572 PCT/AU2003/001146 71 122 C pl 123 C yl 124 C 02 125 C 81 126 C 1i 127 C Ic 128 C 7tl 129 C 01 130 C s2 131 C al 132 C P3 133 C y2 134 C y3 135 C 82 137 C s3 137 C 2 138 C it2 139 c s4 140 C P4 141 c y4 142 C P5 143 C 1 144 C %3 145 C 2 146 C v1 147 C v2 148 C v3 149 C v4 150 C 1 151 C v5 152 C v6 153 C pl 154 C 5 155 C 86 156 C p2 157 C v7 158 C X1 159 D a1 160 D p1 WO 2004/022572 PCT/AU2003/001146 72 161 D yl 162 D P2 163 D 81 164 D 81 165 D Kl 166 D E1 167 D aO)1 168 D c2 169 D a1 170 D P3 171 D 72 172 D 73 173 D 82 174 D s3 175 D K2 176 D 72 177 D 84 178 D P4 179 D 74 180 D P5 181 D 1l 182 D 73 183 D 2 184 D vI 185 D v2 186 D v3 187 D v4 188 D 1 189 D v5 190 D v6 191 D pl 192 D F5 193 D s6 194 D p2 195 D v7 196 D X,1 WO 2004/022572 PCT/AU2003/001146 73 Example 30: 0

R

2 -N N RI R3 0 & Comp. R1 R2 R3 197 A 4 1 198 A l l 199 A 1 1 200 A s5 l 201 A s2 202 A 1 l 203 A 2 1 204 A 1 1 205 A 1 1 206 A T2 91 207 A g2 1 208 A 87 1 209 A g3 1 210 A 72 1 211 A 75 l 212 A 74 cl 213 A 01 al 214 A 41 al 215 A s5 al 216 A s2 cl 217 A a1 al 218 A a2 al 219 A [L al 220 A r1 al 221 A T2 al 222 A 87 al 223 A 93 al 224 A y2 al 225 A y5 al 226 C 74 91 227 C pl pl 228 C 1 pl 229 C 85 l WO 2004/022572 PCT/AU2003/001146 74 230 C jpl pl 231 C il l 232 C T2 _1 233 C 42 Jl 234 C 7 1 235 C p3 w1 236 C y2 W1 237 C y5 , 1 238 C (1 al 239 C s5 al 240 c E2 al 241 C al al 242 C a2 al 243 C Id al 244 C T al 245 C v2 al 246 C g2 al 247 C s7 l 248 C p3 al 249 C y2 al 250 C y5 al 251 D r4 al 252 D l al 253 D s2 i1 254 D al1 Example 31: O

H

2 N N0 R N= R2 HO OH Comp. R1 R2 255 A a2 256 A 43 257 A D6 258 A 01 259 A 68 260 A X2 WO 2004/022572 PCT/AU2003/001146 75 261 A y3 262 A %4 263 A v8 264 A 08 265 A 7r5 266 A g4 267 A g5 268 A r3 269 A a3 270 A 4 271 A 03 272 A p9 273 A g6 274 C 42 275 C 06 276 C (pl 277 C 01 278 C X2 279 C 3 280 C X4 281 C v8 282 C D8 283 C 75 284 C g4 285 C g5 286 C r3 287 C a3 288 C T4 289 C a3 290 C 9 291 C g6 292 D 02 293 D (2 294 D 06 295 D (pl 296 D 01 297 D 88 298 D X2 299 D X3 300 D X4 301 D v8 WO 2004/022572 PCTIAU2003/001146 76 302 D 08 303 D nc5 304 D gv4 305 D g5 306 D v3 307 D 03 308 D c4 309 D 03 310 D P9 311 D g6 Example 32: R3 0 R1 IN /~.~ R1H bH

H

2 N 0 5 Comp. R1 R2 R3 312 A 12 a4 313 A E2 P6 314 A E2 X5 315 A X2 69 316 A 12 7 317 A Z2 810 318 A xy1 02 319 A Z2 E11 320 A Z2 X6 321 A 1 X4 322 A Z2 c3 323 C E2 a4 324 C 2 06 325 C 2 X5 326 C 2 C9 327 C 1 07 328 C pl slO 329 C 2 02 330 C 2 3 WO 2004/022572 PCT/AU2003/001146 77 331 c Z2 E11 332 C Z2 X6 333 C Z2 X4 334 C l Y3 335 D ,2 a4 336 D Y2 P6 337 D E2 X5 338 D Z2 P9 339 D l P7 340 D 12 10 341 D Z2 02 342 D Y2 611 343 D 12 X6 344 D M2 X4 345 D 1 3 Example 33: N/R2 HO2//R1

H

2 N N H bH 5 Comp. R1 R2 346 A 75 347 D X5 348 A C9 349 D 69 350 A X6 351 D 77 352 A al 353 C al 354 D al 355 A 03 356 C 03 357 D 03 358 A y3 359 C 73 360 D 73 361 A 04 WO 2004/022572 PCT/AU2003/001146 78 362 C 04 363 D 04 364 A 71 365 C yl 366 D Yl 367 A s3 368 C E3 369 D 3 370 A X1 371 C X1 372 D X1 373 A 85 374 C c5 375 D 85 376 A I 377 C K1 378 D Ki 379 A 01 380 C 01 381 D 01 382 A 2 383 C r,2 384 D r,2 385 A a5 386 C a5 387 D a5 388 A pl0 389 C 10 390 D 010 391 A 76 392 C 7 6 393 D y6 394 A v2 395 C v2 396 D v2 WO 2004/022572 PCT/AU2003/001146 79 Example 34: 0

H

2 N N 0 R N= R2 HO b H Comp. R1 R2 397 A 01 398 C 01 399 D 01 400 A a4 401 A sl1 402 A X8 403 A E9 404 A (3 405 A co2 406 A a6 407 A i7 408 A j3 409 A *4 410 A z7 411 A g8 412 A al 413 A 1sO 414 A K3 415 A 612 416 A 77 417 A 78 418 A 79 419 C a4 420 C 811 421 C X8 422 C 89 423 C ,3 424 C o2 425 c a6 426 C [t7 427 C 3 WO 2004/022572 PCT/AU2003/001146 80 428 C c4 429 C 7 430 C 16 431 C xal 432 C 810 433 C 3 434 C s12 435 C y7 436 C y8 437 C y9 438 D a4 439 D E11 440 D X8 441 D 89 442 D a3 443 D o2 444 D a6 445 D g7 446 D 3 447 D c4 448 D 7 449 D g8 450 D al 451 D 810 451 D 3 453 D 812 454 D y7 455 D 8 456 D 9 Example 35: O

H

2 N' R2 HO' "OH OH 5 WO 2004/022572 PCT/AU2003/001146 81 Comp. R1 R2 457 D 01 458 D P8 459 D 73 460 D g6 461 D 99 Example 36: 0

H

2 N N.N 0 RI R2 O OH 5 Comp. R1 R2 462 D s2 463 D al 464 D 82 465 D 4 466 D O1 Example 37:: R3 0 R R2 HO ObH Compound No. R1 R2 R3 467 E X3 E3 468 E g6 Z3 469 E y2 E3 470 E X3 l 471 E 6 1 472 E a3 gI 473 E X4 W1 WO 2004/022572 PCT/AU2003/001146 82 474 E 72 91 475 C X3 , 1 476 C g6 j1 477 C a3 W1 478 C X4 pl 479 C x2 pl 480 A y3 gl 481 A g6 W1 482 A a3 w1 483 A X4 wl 484 A 2 l Example 38:

NH

2 0 0 R R3 N R R2 HO OH Compound No R1 R2 R3 485 A _ 5 pl 486 A X9 . l 487 A _ 7 91 488 A X10 91 489 A 11 pl 490 A X12 9l 491 A X13 9l 492 A X1 4 II1 493 A X15 pl 494 A X16 11 495 A X17 91 496 A X18 .l1 497 A 71 9 W1 498 A X23 l 499 A a4 1 500 A X20 Wl 501 A 4 l 502 A 311 91 503 A X21 1l 504 A _22 l WO 2004/022572 PCT/AU2003/001146 83 505 C 75 yl 506 C 2,9 y 1 507 C X7 W1 508 C 10 Y1 509 C 711 W1 510 C X1 2 gl 511 C X 1 3 Wl 512 C X14 Wl 513 C - 15 W1 514 C 716 W1 515 C X17 j1 516 C 718 , 1 517 C 7,19 gl 518 C 7_X23 1 519 C 4 Wl 520 C 720 pl 521 C - 4 l1 522 C $1l pl 523 C - 21 p1 524 C 722 1 525 D X5 1 526 D _ 9 l 527 D 7 7 Wl 528 D _ 10 l 529 D _ 11 91 530 D 712 Y1 531 D 713 Y1 532 D 714 wl 533 D X15 Wl 534 D Z16 W1 535 D X17 W1 536 D x18 , l 537 D X19 1/ 538 D X23 11 539 D a4 pl 540 D X20 Wl 541 D (4 91 542 D pl1 yl 543 D 721 , 1 544 D 722 , l 545 A X5 X1 WO 2004/022572 PCT/AU2003/001146 84 546 A x9 x 9

-

1 547 A X7 X 7

-

1 548 A X10 710-1 549 A 11 X11-1 550 A X12 X12-1 551 A lX13 X13-1 552 A X14 X14-1 553 A X1 5 X15-1 554 A X16 X16-1 555 A X17 X17-1 556 A X18 X18-1 557 A X19 X19- 1 558 A X23 X23-1 559 A a4 a4-1 560 A X20 X20-1 561 A ,4 44-1 562 A Pl11 P4 563 A X22 X22-1 564 C X5 X1 565 C X9 X9-1 566 C X7 X 7

-

1 567 C XO1 X10-1 568 C x11 X11-1 569 C 712 712-1 570 C 7 1 3 X13-1 571 C 714 X14-1 572 C X15 X15-1 573 C X16 X1 6 -1 574 C X 1 7 X17-1 575 C X18 X1 8 -1 576 C X19 X19-1 577 C X 2 3 X23-1 578 C 04 a4-1 579 C y20 X20-1 580 C 44 (4-1 581 C 13l1 P4 582 C X22 X22-1 583 D X5 X1 584 D X9 X9-1 585 D X7 X 7 -1 586 D lO0 X10-1 WO 2004/022572 PCT/AU2003/001 146 85 588 D x12 z1 2 -1 589 D X13 _X1 3 -1 590 D Y,14 X1 4 -1 591 D X15 X15-1 592 D 16 X16-1 593 D ~17 X17-1 594 D Y, 8 x1 8 -1 595 D X19 X19-1 596 D xj23 x 2 3 -1 597 D a4 ay4-1 598 D 4 4-1 599 0 431 f{ 600D 22 x 2 2 -1 Example 39: 0

R

2 -- N 0 R3 Compound No RI R2 R3 601 A 41 al 602 A s5 azl 603 A s2 a 604 A cxl l 605 A c2 xl 606 A g3 al 607 E -c2 axl 608 E g axl 609 E [t cl 610 E y5 al 5 WO 2004/022572 PCT/AU2003/001146 86 Example 40: R5 R4 N 0 RI R3 R2 HO OH Compound No R1 R2 R3 R4 R5 611 C 74 1 p1 612 F 75 l1 91 613 D X5 l Wl 614 C 75 l pl 615 G 75 W1 jl 616 H 75 M1 1 617 F 75 x5 pl 618 D 75 K5 l 619 C 75 .5 Kl 620 G 75 K5 pl 621 H 75 K5 l 622 F X5 1 v5 623 D 75 Wl v5 624 C y5 ~l v5 625 G 75 _l v5 626 H X5 gl v5 627 F X5 312 012 628 D X5 012 12 629 C X5 312 P12 630 G X5 P12 P12 631 H 5 1312 312 632 F X18 V1 W1 633 D X18 41 1 634 C ;18 1 j1 635 G X18 1 W1 636 H X18 p1l gl 637 F 718 r5 1 638 D X18 5 639 C X18 5 640 G X18 K5 1 641 H X18 r,5 '1 642 F X18 W1 v5 WO 2004/022572 PCT/AU2003/001 146 87 643 D X18 gi v5 644 C X18 Wl v5 645 G X18 Wl v5 646 H X18 Tl v5 647 F X18 12 P12 648 D X18 P12 012 649 C X18 f312 01 650 G I x18 P12 P1 651 H X18 P12 P12 652 F X4 Wl X1 653 D0 X N'l 655 H Y, 'V 1 X1 656 F X4 r,5 1y 657 D X4 0 c 658___ ___ X4K L 659___ G__ X4-5 K 660___ H X4__ r,5 661__ F 4W v5 662 D X v~ v5 663____ ____ X4 W v5 664_G__C4_ jl v5 66 H x4XV v5 666____ F____X ____ 12 P12 667 D X4 12 P12 668____X4 P12 12 669 G X4 12 01 670 H 7,4 P12 012 671 F X5 X1 Nwl W 672 0 x5 X1 W{l wl~ 673 C X5 X1 Wl Wj 674 G X5 XI 'VI W 675 H X5 X1 VI 21lL 676 F X5 Xl 0 ly 677 D X5 Xl 0 W 678 C X5 X1 -K5 679 G X5 X1 K5 1l 680 H X5 Xl 0( xyl 681 F X5 XI W~l v5 682 D X5 X1 w4 v5 683 C 7,5 X 1 1l V5 684 G X5 X1 W v5 WO 2004/022572 PCTIAU2003/001 146 88 685 H X5 Y, I v5 687 D X5 X1 P312 12 688 G X5 X1 P312 12 689 H X5 X 1312 01 690 F X18 X18-1 ijl Wj 691 C XIS X18-1 N' 1 wpj 692 G X1 8 X18-1 N'l 1l 693 H X18 X18-1 NW 1 W 694 H X18 XlS8-1 r,5 W 695 F X18 X 1 8 -1 Wi V5 696 C X18 Xl18-1 yj v5 697 D x18 x18-1 wi v5 698 G X18 X18-1 wj4 v5 699 - H X18 Xl 8 -1 IVL v5 700 - F X18 X18-1 1312 P1 701 D X18 X18-1 1312 P12 702 C x18 X18-1 j312 P12 703 G X18 X18-1 f312 P1 704 H Xl8 X1 8 -1 1312 012 705 F X4~ X 24 TI Wf 706 C y,4 X 24

N'

1 I 707 G X4 X24 Mf 1 WNl 708 H x4 x24 mN' 1 Wl 709 F X4 x2 0 W5 710 D X4 X 24 K5 W 711 C X4 X 2 4 r, W 712 H X4 X2 ic5 713 D X4 X2 N' 1 v5 714 F x4 X2 1312 P12 WO 2004/022572 PCTIAU2003/001146 89 Example 41: N 0 HN N R1 R3 R2 HO OH Compound No. R1 R2 R3 715 A Z5 al 716 C X5 al 717 A X3 al 718 C 3 ccl 719 A a3 al 720 C c3 al 721 A _ 5 v5 722 C X5 v5 723 C X5 v5 724 A y3 v5 725 C X3 v5 726 C X3 v5 727 A cr3 v5 728 C cr3 v5 729 C c3 v5 Example 42: 03J~ 5 O HO OH Compound No R1 R2 R3 730 A 02 al 731 A E5 al 732 A 03 al 733 A X19 al 734 A X1 al 735 A ylO al 736 A 45 al 737 A a1 al 738 A X4-1 al WO 2004/022572 PCT/AU2003/001146 90 739 A plo0 al 740 A 02 al 741 A a4 al 742 A a8 ul 743 A R2 02 744 A e5 P2 745 A P3 P2 746 A 719 02 747 A Y,1 02 748 A YO1 P2 749 A 45 02 750 A a1 02 751 A X4-1 p2 752 A p10 02 753 A 2 02 754 A a4 02 755 A ,8 P2 756 A J2 S5 757 A F5 s5 758 A 03 E5 759 A 719 E5 760 A X1 65 761 A 710 e5 762 A (5 s5 763 A a1 e5 764 A y4-1 65 765 A o10 65 766 A 02 s5 767 A a4 s5 768 A o8 s5 769 A 02 1 770 A s5 1 771 A 3 1 772 A 1 1 773 A y710 1 774 A t1 1 775 A X4-1 1 776 A p10 , 1 777 A 2 1 778 A a4 1 779 A A8 1 WO 2004/022572 PCT/AU2003/001146 91 780 A P2 x1 781 A P2 (5 782 A s5 jl 783 A s5 45 784 A P3 . l 785 A p3 45 786 A X1 p1 787 A 71 45 788 A 710 . l 789 A y710 5 790 A 45 . l 791 A (5 45 792 A a1 91 793 A a1 (5 794 A X4-1 yl 795 A p10 pl 796 A 10 45 797 A 2 pl 798 A 2 45 799 A a8 45 800 A a8 45 801 A Pl2 l 802 A 65 C1 803 A P3 o1 804 A X19 )1 805 A 1 col1 806 A X19 91 807 A Xl9 45 808 A 2 o1 809 A 10 71 810 A 2 . 1 811 A a4 y1 812 A 8 71 813 A R2 K.2 814 A 5 r,2 815 A 03 x2 816 A X19 K2 817 A l1 2 818 A y10 <2 819 A 75 2 820 A a1 _ 2 WO 2004/022572 PCT/AU2003/001146 92 821 A %4-1 K2 822 A 410 K2 823 A 2 K2 824 A (4 K2 825 A a8 r,2 826 A 02 r2 827 A s5 r2 828 A 03 r2 829 A X19 T2 830 A 71 c2 831 A ylO v2 832 A X5 r2 833 A 01 "2 834 A X4-1 -2 835 A 410 r2 836 A 02 u2 837 A a4 c2 838 A a8 'r2 839 A P2 T2 840 A s5 g2 841 A 03 p2 842 A X19 p2 843 A X1 g2 844 A YO10 2 845 A X5 . 2 846 A g2 [2 847 A y4-1 g2 848 A 1 lO g92 849 A 2 g2 850 A a4 g2 851 A a8 g2 852 A 02 %1 853 A s5 X1 854 A 03 X1 855 A X19 X1 856 A X1 X1 857 A 10 X1 858 A _ 5 X1 859 A al 71 860 A _ 4-1 X1 861 A _ 2 1 WO 2004/022572 PCT/AU2003/001146 93 862 A a4 X1 863 A a8 Y1 864 A 2 Z4 865 A s5 Z4 866 A P3 Z4 867 A X19 Z4 868 A _ 1 Z4 869 A y710 4 870 A X5 F4 871 A a1 E4 872 A X4-1 E4 873 A g10 Z4 874 A 02 E4 875 A a4 E4 876 A a8 Z4 877 A al v1 878 A a1 v2 879 A al v9 880 A v4 al 881 A v4 y2 882 A v4 c2 883 A v4 'cl 884 A x1 v4 885 A p7-1 al 886 A p.7-1 y2 887 A p7-1 c2 888 A p7-1 r1 889 A g7-1 X1 890 A 710 61 891 A 75 ol 892 A al ol 893 A x4-1 ol 894 A 410 Ol 895 A a4 l01 896 A A8 ol 897 A J2 71 898 A 5 1 899 A P3 yl 900 A X19 y71 901 A X1 71 902 A ylO 71 WO 2004/022572 PCT/AU2003/001146 94 903 A 45 y1 904 A 01 71 905 A 74-1 l71 906 A I11 1 907 A il1 2 908 A v4 g3 909 A cal crl 910 A a1 02 911 A a1 E5 Example 43: R3 R4 - 0 N. NR1 R2 H 0H Compound No R1 R2 R3 R4 912 A X4 91 1l 913 A X5 41 W1 914 A X18 71 x1 915 A X5 w1 v5 916 A X18 gl v5 917 A X5 <5 W1 918 A X4 K5 Tl 919 A 71 8 K5 pl 920 A 75 0312 12 921 A 4 312 1312 922 A X18 312 P312 WO 2004/022572 PCT/AU2003/001146 95 Example 44: R3O R2 HO OH Compound No R1 R2 R3 923 A al c4 924 A al P6 925 A al 69 926 A al 16 927 A al a3 928 A a1 X8 929 A l a4 930 A 71 P6 931 A 1 9 932 A 1 K6 933 A l a3 934 A 91 X8 935 A g7-1 a4 936 A g7-1 06 937 A g7-1 69 938 A g7-1 r6 939 A g7-1 a3 940 A 7-1 %8 941 A p13 a4 942 A 913 P6 943 A g13 69 944 A g13 K6 945 A g13 a3 946 A g13 ,8 947 A al a4 948 A al 136 949 A g7-1 a4 950 A p7-1 136 951 A _7-1 a3 952 A t13 cr3 953 A p13 Z_8 WO 2004/022572 PCT/AU2003/001146 96 Example 45: R3 RO R2 • ) HO OH Compound No R1 R2 R3 954 A P4 al 955 A p2 al 956 A s3 al 957 A y2 al 958 A 71 al 959 A 3 al 960 A p4 al 961 A P2 al 962 A 3 al 963 A y2 oal 964 A y1 al 965 A P3 al Example 46: R4 R3 HO' OH 5 NHR2 Compound No R1 R2 R3 R4 966 C al 71 l 967 G cal 1 1 968 H al 1 1 969 C cl 15 pl 970 G cl <5 p1 971 H al K5 p1 972 C al p1 v5 973 G al p1 v5 974 H al 1l v5 WO 2004/022572 PCT/AU2003/001146 97 975 C al 012 P312 976 G l 1312 012 977 h al 0312 12 Example 47: o

H

2 N R3N N R1 R2 Hd OH Compound No. R1 R2 R3 978 A a2 c2-1 979 A (2 (2-1 980 A 06 P2 981 A 01 03 982 A c8 81 983 A 08 P3 984 A 75 71 985 A r3 c1 986 A c3 a3-1 987 A r4 c2 988 A 0a3 1al 989 C X2 X2-1 990 C X3 (3-1 991 C X4 X 4

-

1 992 C v8 vI 993 C 5 [t 5

-

1 994 C "3 -1 995 C r4 "2 996 C 46 g6-1 997 D "2 a2-1 998 D 42 42-1 999 D 6 02 1000 D p1 (p1-1 X4-1 (X 2 4 1001 D 4 ) 1002 D v8 vI 1003 D c4 "2 WO 2004/022572 PCT/AU2003/001146 98 1004 D a3 1al 1005 D 09 09-1 1006 D g6 _ _6-1 1007 A X2 X2-1 Example 48: 0

H

2 N o0 R3 '1 R2 HO DH 5 Compound No. R1 R2 R3 1008 A a4 al 1009 A 811 s3 1010 A 78 X8-1 1011 A s9 s5 1012 A s2 E1 1013 A a6 a6-1 1014 A x3 2 1015 A c4 _c5 1016 A a7 a7-1 1017 A aOl 5 1018 A 810 s2 1019 A 3 7 1020 A 812 87 1021 A y7 y4 1022 A 78 y8-1 1023 A 79 y5 1024 C a4 cal 1025 C 01 03 1026 C 811 s3 1027 C X8 %8-1 1028 C s9 s5 1029 C s3 81 1030 C a6 a6-1 WO 2004/022572 PCT/AU2003/001146 99 1031 C 3 02 1032 C r4 'C5 1033 C c7 a7-1 1034 C al a5 1035 C s810 s2 1036 C K3 7 1037 C s12 s7 1038 C 77 y4 1039 C 78 y8-1 1040 C Y9 y5 1041 D a4 al 1042 D 01 03 1043 D sll s3 1044 D X8 X8-1 1045 D E9 s5 1046 D s2 e1 1047 D a6 a6-1 1048 D 3 2 1049 D 7 ca7-1 1050 D 10 s2 1051 D K3 7 1052 D 612 7 1053 D 77 4 1054 D y8 y8-1 1055 D y9 5 WO 2004/022572 PCT/AU2003/001146 100 Example 49: Selected activity data tested at 25 micromolar except ! tested at 2.5 micromolar. compound number EGF-R c-Kit VEGF ABL MET PDGFalpha CDK2 Tie2 PKC P38 100 69 52 58 109 88 106 70 42 80 146 94 53 101 115 78 127 270 71 142 212 23 12 10 41 46 38 25 1 26 223 22 109 11 24 31 17 40 0 10 246 15 6 8 30 27 28 26 -1 13 279 66 17 31 6 72 85 20 12 80 345 58 40 54 74 87 82 67 41 65 456 96 92 96 107 103 113 28 91 104 466 84 55 72 110 102 104 114 88 87 486! 24 45 96 100 488! 34 136 82 100 508! 12 17 16 100 528! 12 44 26 101 604 27 13 18 49 46 46 30 3 50 100 605 20 18 14 55 54 56 26 5 27 100 658! 20 55 5 99 659! 17 63 8 94 668! 16 1 669! 11 34 1 97 670! 9 23 1 718! 7 8 1 725! 6 10 912 88 38 44 96 88 96 119 72 96 70 Blank = not determined. The following lists examples of compound numbers that demonstrate activity 5 EGF-R inhibitors at 25 micromolar: 470,471,472,478, 480,604, 605, 611, 100, 198,205,207,209,212, 213,214, 215, 216, 218,211,220, 221,222, 223,224,225,227,233,235,238,240,241,246,248,254,273,279,291, 334,345,350,386,391,392,393: o10 c-Kit inhibitors at 25 micromolar: 470, 471,472,473,474, 480, 482,483,484, 604,605,611,912,486,488,501,504,508,528,606,607,608,609,610, 654,657,658,659,660,663,664,665,666,667,668,669,670,99,100, 103,104,108,109,110,122,125,127,130,131,132,133,135,136,137, 138, 139, 140,143,144,145,146,148, 154, 155, 163, 168, 169, 170,173, 15 174,175,177,178,180,181,183,184,186,192,193,198,204,205,207, 209,212,213,214,217,218,211,220,221,222,225,227,233,235,238, 240,241,246,248,254,:228,242,244,245,247,250,252,253,260,261, 262,271,264,273,279,282,286,289,291,299,309,321,322,332,333, 334,345,346,362,370,377,378,379,386,398,403,404,408,427,458, 20 459,460,462,463,464,465,466: VEGF-R2 inhibitors at 25 micromolar: 472, 478,, 480,482, 483, 484, 604, 605,611,912,486,505,508,528,604,605,606,608,658,659,660,667, WO 2004/022572 PCT/AU2003/001146 101 668,669, 670, 100, 198,205, 207, 209, 211,212,214,215, 216,218,220, 221,222,223,224,225,227,233,235,238,244,246,252,254,256,271, 273,279,291,345,370,371,379,403,466: 5 ABL inhibitors at 25 micromolar: 470,478,480, 604, 605, 611,107, 127, 135, 152, 156, 157, 158, 159, 191,207, 212, 214,215,220,221,223,224,225, 233,246,273,279,291,299,330,334,345,397: MET inhibitors at 25 micromolar: 470,480,604, 605, 207, 212, 214,217, 220, lo 221,223,224,225,233,238,246,279,291: PDGF-Ralpha inhibitors at 25 micromolar: 470, 604, 605,207, 212, 214,215,220,221,223,224, 225, 233,246, 202,271,321,334, 370: 15 CDK2 inhibitors at 25 micromolar: 470,472, 478, 604, 605, 611, 32,100, 205, 207,209,212,213,214,215,216,218,219,220,221,222,223,224,225, 233,246,273,279,291,334,345,456: Tie2 inhibitors at 25 micromlar: 470, 471,472, 474,478, 480, 604, 605, 611, 20 912,508,528,534,535,604,605,606,607,608,609,610,654,657,658, 659, 660, 667, 668, 669,670, 71, 91, 92, 99,100,101,103, 104,106,107, 108,109,113,114,127,131,135,136,138,139,143,144,145,146,151, 152,153,154,155,160,168,177,178,183,192,198,205,207,209,211, 212,217,214,215,216,218,220,221,222,223,224,225,227,231,233, 25 235,238,240,241,244,246,248,250,252,254,256,271,273,279,291, 333,334,345,376,379,446,457,459: PK-C inhibitors at 25 micromolar: 470,471,472,474,478, 480,604, 605, 611,2,205,207,209,212,213,214,215,216,218,219,220,221,222,223, 30 224,225,233,246,299,321,333,334,345,379: FGF-R1 inhibitors at 25 micromolar: 604, 605, 611,100,104, 198, 205, 207, 211,212,214,215,216,217,218,220,221,222,223,224,225,227,233, 238,246,248,254,273,279,291,345: 35 WO 2004/022572 PCTIAU2003/001 146 102 Tables of Substituents: K ~ N K H3 al 11F C I el F3i N02 Icil' F CH3 CN C(0H 3

)

3 I l y3 6 3 co 1 ,2 'N3f32 52

H

3 C CH 3 CI 'N ICI' H3 I-S OH 3 F F

CF

3

NO

2

OH

3 cl7 P35 ic2 7c2 e4 4 H3C-H 3 C 'N I-

H

3 C v2 H3C CH HH 3 0

H

3

OH

3

H

3 C O H F 3 0 v5 060H 3 4 , WO 2004/022572 PCTIAU2003/001 146 103 'N Sc w4 N ,C- '-CH 'N2 ' N / N HC 'N CHO p2 g3 N y 5 (Y2 'N CHO ' P6 Br e8 3 X2 HOC 0& f601 X8 'NCI ' CI 'N,' HOC I--,- CCI A P37 138 715 H C N C'N ' 5 S3 a3 M4 J.L4 goK6 1312 FC K6 WO 2004/022572 PCTIAU2003/001 146 104 ci - F N / f33 9 H 3 0--/ g6 N- 2 0

H

3 C,, HH N'C 0 H3C.O qT1 H3 B C H30-O

H

3 0 Bra4 H % 1 OH d 02 ell

H

3 C . Br" XX703 Br04 c5 CI I OH 3 NC 010 'y6 X8o2 ac6

OH

3 \S NH

CF

3 g7 'r0 4 g8 3

OH

3 F F I F 3 C()

OH

3 F c12 y7y 8 P9 9 5 WO 2004/022572 PCT/AU2003/001146 105

H

3 CO 0~ 0H Co 9- 1 10-1 X11-1 X12-1 H3OK HH3HCO HC' OCH 3 C0O OC: H 3 C CH X13-1 X1 4 -1 X 1 5 -1 H3CO CH, X16-1

H

3 CO H CCO O 'cr ~HO" I HC))

OCH

3 0 X1 7

-

1 18-1 19-1 2 0

-

1 OH

H

3 CO HOC

X

2 1-1 x 22- 1 x23-1 311 X24 (X4-1) o 04-1 H 44-1 oMe X7-1 Jll WO 2004/022572 PCTIAU2003/001 146 106 0j, H 3 CO 0 I I~

(OH

2

)

8

OCH

3 OH

Z

9 -1 ,1- Xl1-1 y,12

H

3 C00 H 3 C00 OCH, HCO OCH 3 H 0CH OCH 3 OH X13-1 Xt4 1 51 HC X610H

H

3 00

H

3 00-N HO Z81 H 3 C0 a1- X17-1 I X 2 0 -1 OH

H

3 C00 -, _ O~ HOa y2 1 -1 Z 2 -112 NN g 41H 41 l WO 2004/022572 PCT/AU2003/001146 107 3-1 a2-1 42-1 X3-1 R5-1 g6-1 Z8-1 91l-1 P9-1 a6-1 v5 'NN a 7 - 1 C7 7 8 -1,7 1 0 p 3 N pl12 Throughout the specification and the claims (if present), unless the context requires otherwise, the term "comprise", or variations such as 5 "comprises" or "comprising", will be understood to apply the inclusion of the stated integer or group of integers but not the exclusion of any other integer or group of integers. It should be appreciated that various other changes and modifications can be made to any embodiment described without departing from the spirit 10 and scope of the invention

Claims (66)

1. A method of inhibiting or effecting protein kinase activity which comprises contacting a protein kinase with a compound of formula I being a derivative of a furanose or pyranose form of a 5 monosaccharide, or a pharmaceutically acceptable salt thereof Y x H H H HO H OH n formula I Wherein; 10 nis 1 or2, X is selected from the group consisting of : OR1, an unsubstituted 5 or 6 membered heterocyclic moiety, a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 15 membered heterobicyclic moiety, R1 is selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, 20 Y is selected from the group consisting of an unsubstituted 5 or 6 membered heterocyclic moiety; a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or 10 membered heterobicyclic moiety and a substituted 9 or 10 membered heterobicyclic moiety; an amino acid, a dipeptide, and WO 2004/022572 PCT/AU2003/001146 109 R 8 0 O R R R7 O O R 6 R 0 0 A B R15 R1, R6 N R12 N R N N R 13 C D R 15 R 1 2 R, N R6N R 1 4 R13 E F N H / N\ N N R7 N R6 G WO 2004/022572 PCT/AU2003/001146 110 R6 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to 5 C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, with the proviso that R6, R7 and R8 are not all H, R9 is selected from H, or-(CO)-R6, R7, R8, R11, R12, R14, are independently selected from the 10 group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, CI to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl and C6 to C14 heteroarylalkyl, R13 is selected from the group consisting of :unsubstituted 15 phenyl unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, -S-R6 and -O-R6, 20 R15 is absent or is at least one substituent on the aromatic ring which are independently selected 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, 25 heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl and thioheteroaryl. 30

2. The method of claim 1, wherein R1 is substituted, cyclic or acyclic, branched and/or linear. WO 2004/022572 PCT/AU2003/001146 111

3. The method of claim 1, wherein R7 and R8 combine to form a cyclic structure.

4. The method of claim 1, wherein R6 and one of R7 or R8 combine to 5 form a cyclic structure.

5. The method of claim 1, wherein R 11 and R12 combine to form a cyclic structure, 10

6. The method of claim 1, wherein X is selected from: OR1, N pN N R2 R3 or R 4 , R 5 NN NN 15 / R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to 20 C14 arylalkyl and C3 to C14 heteroarylalkyl, R4 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 WO 2004/022572 PCT/AU2003/001146 112 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl,.C6 to C14 arylalkyl or C3 to C14 5 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from the group consisting of: -(C=O)-R3, (C=O)-OR4, and -(C=O)-NH-R4, Y is selected from: WO 2004/022572 PCT/AU2003/001146 113 RR 0 Ra R

7 S N R 0 0N R 6 ~ R 0 0 A B R1s R 1 1 R, R 13 C D R 1 5 R 11 R12R N 'N R<N-.. R 6 N R14 R 13 E F N H N R7 N G 5 7 The method of claim 6, wherein at least one of R1 to R5 is substituted, cyclic or acyclic, branched and/or linear.

8. The method of claim 6, wherein R7 and R8 combine to form a cyclic WO 2004/022572 PCT/AU2003/001146 114 structure.

9. The method of claim 6, wherein R6 and one of R7 or R8 combine to form a cyclic structure. 5

10. The method of claim 6, wherein R11 and R1 2 combine to form a cyclic structure.

11. The method of claim 1 and claim 6 wherein at least one of R1 - R14 10 is substituted and these substituents and the substituents on the substituted 5 or 6 membered heterocyclic moiety and the substituted 9 or 10 membered heterobicyclic moiety are selected 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, 15 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, alkyl, aminoaryl, 20 aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted.

12. The method of claim 1 wherein the group X is IR2 R3 25

13. The method of claim 1, wherein the group X is WO 2004/022572 PCT/AU2003/001146 115 R 4 ,N R 5 N N N N /

14. The method of claim 1, wherein X is -ORI

15. The method of claim 12 wherein the group Y is R 7 o O R8 R 6 0 s A

16. The method of claim 13 wherein the group Y is R7 O R8 o R6 0 A

17. The method of claim 12 wherein Y is R7 R6 O. B 10

18. The method of claim 13, wherein Y is WO 2004/022572 PCT/AU2003/001146 116 R 8 0 R7 O R6 _ 0 B

19. The method of claim 12, wherein Y is R1,_ /R RIO N R I_ /RIo 9 R12 N C

20. The method of claim 13 wherein Y is R 11 R / RIO N / N R 1 2 N 5 C

21. The method of claim 12, wherein Y is R 1 1 N R13 D

22. The method of claim 13, wherein Y is WO 2004/022572 PCT/AU2003/001146 117 R 1 5 R, N N R13 D

23. The method of claim 12, wherein Y is R 15 N R14 E

24. The method of claim 13, wherein Y is R15 R1 5 E

25. The method of claim 12, wherein Y is WO 2004/022572 PCT/AU2003/001146 118 R,Rl R12 R N N R 1 4 R 13 F

26. The method of claim 13, wherein Y is .RI, R12 I N R, N - N R14 R 13 F

27. The method of claim 12, wherein Y is N H r N \ N R7 N RN 5 G

28. The method of claim 13, wherein Y is N H N G

29. The method of claim 1 wherein the protein kinase is a serine or threonine kinase. 10

30. The method of claim 1 wherein the protein kinase is a tyrosine WO 2004/022572 PCT/AU2003/001146 119 kinase.

31. The method of claim 1 wherein the protein kinase is one or more of the isoforms of protein kinase C.

32. The method of claim 1 wherein the protein kinase is Tie-2, also 5 known as TEK, HPK-6, TIE-2, VMCM, VMCMI.

33. The method of claim 1 wherein the protein kinase is c-Kit also known as SCFR, CD117, PBT.

34. The method of claim 1 wherein the protein kinase is VEGF R2/KDR also known as VEGFR2, VEGFR-2, VEGFR, Hs.KDR, 10 Hs.12337, FLK1 , FLK-1.

35. The method of claim 1 wherein the protein kinase is EGF-R also known as ERBB1 , ERBB, EGFRvlII.

36. The method of claim 1 wherein the protein kinase is Abl also known as c-abl , c-ABL, JTK7, p150, ABLI. 15

37. The method of claim 1 wherein the protein kinase is MET also known as HGFR, C-MET, RCCP2.

38. The method of claim 1 wherein the protein kinase is, CDK2 also known as p34CDK2, p33CDK2, p33CDK2.

39. The method of claim 1 wherein the protein kinase is PDGF also 20 known as PDGFR1 , PDGFR, PDGF-R-beta, JTK12, CD140B, PDGFRB.

40. The method of claim 1 wherein the protein kinase is FGFR-1 also known as N-SAM , LOC51033, FLT2, FLJ14326, CEK, C-FGR, BFGFR, H5, H4, H3, H2, FLG. 25

41. The method of claim 1 wherein the protein kinase is P38 MAP Kinase also known as p38alpha, p38ALPHA, SAPK2a, SAPK2A, PRKM15, PRKM14, Mxi2, MXI2, Exip, EXIP, CSPB1, CSBP2, CSBP1, p38, RK, P38, MAPK14. 30

42. A compound of formula I which is a derivative of a furanose form of a monosaccharide of general formula I, WO 2004/022572 PCT/AU2003/001146 120 Y x H H HO H OH ) n formula I Wherein; n is 1, X is selected from: OR1, 5 N N N R2 R 3 or R 4 , R 5 N N NN / 10 R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, R4 is selected from the group consisting of: H, C1 to C7 15 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, Cl to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to WO 2004/022572 PCT/AU2003/001146 121 C14 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 5 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from -(C=O)-R3, -(C=O)-OR4, -(C=O)-NH-R4, Y is selected from the group consisting of: R 7 R, 0 0 R, R 7 ReN N 0 O A B Rjs C D R1 R 1 5R12 R I N N N14 1 E F N H N R7 N RRG RN / N WO 2004/022572 PCT/AU2003/001146 122 R6 is selected from the group consisting of H, CI to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to 5 C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl, with the proviso that R6, R7 and R8 are not all H, R9 is selected from H, or-(CO)-R6, R7, R8, R11, R12, R14, are independently selected from the 10 group consisting of: H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, R13 is selected from the group consisting of: unsubstituted 15 phenyl, unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C1 to C7 alkenyl, C1 to C7 alkynyl, C1 to C7 acyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C6 to C14 arylacyl, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, -S-R6 or -O-R6, 20 R15 is absent or is at least one substituent on the aromatic ring which is independently selected 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, 25 heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl. 30

43. The compound of claim 42, wherein R7 and R8 combine to form a cyclic structure. WO 2004/022572 PCT/AU2003/001146 123

44. The compound of claim 42, wherein R6 and one of R7 or R8 combine to form a cyclic structure.

45. The compound of claim 42, wherein R11 and R12 combine to form a 5 cyclic structure.

46. The compound of claim 42, wherein the groups R1, R2, R3, R4 and R5 are optionally substituted, cyclic or acyclic, branched and/or linear. 10

47. The compound of claim 42, wherein R2 and R3 combine to form a ring structure.

48. The compound of claim 42, wherein the groups R4 and R5 combine 15 to form a ring structure.

49. A compound of claim 42 in which at least one of R1 to R14 is substituted with a substituent selected from the group, OH, NO, NO 2 , NH 2 , N 3 , halogen, CF 3 , CHF 2 , CH 2 F, nitrile, alkoxy, aryloxy, 20 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 25 acid, heteroaryloxy, aminoalkyl, alkyl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted,

50. The compound of claim 42 in which the group X is WO 2004/022572 PCT/AU2003/001146 124 N4N I R2 N R 3

51. The compound of claim 42 in which the group X is R 4 ,N R 5 N N < N N / 5

52. The compound of claim 42 in which the group X is -OR1.

53. The compound of claim 50 wherein Y is R7 O R8 R6 A

54. The compound of claim 51 wherein Y is R7 O R8 o R6 0 A 10

55. The compound of claim 50, wherein Y is WO 2004/022572 PCT/AU2003/001146 125 R8 o R7N R 6 0 B

56. The compound of claim 51, wherein Y is R 8 0 R 7 R6 O B 5

57. The compound of claim 50, wherein Y is R, /Rio N RI 2 N C

58. The compound of claim 51, wherein Y is R12 C 10

59. The compound claim 50, wherein Y is WO 2004/022572 PCT/AU2003/001146 126 R 1 4 R 13 D

60. The compound claim 51, wherein Y is R15 N Rx14 \ R13 D 5

61. The compound of claim 50, wherein Y is R15 N R 14 E

62. The compound of claim 51, wherein Y is WO 2004/022572 PCT/AU2003/001146 127 R15 N RN R14X E

63. The compound of claim 50, wherein Y is R 11 R 1 2 \ RN N R"14 \ r1 R13 F 5

64. The compound of claim 51, wherein Y is R 11 R12 \ , N N R 1 3 F

65. The compound claim 50, wherein Y is N H N R7 NN R6n i G

66. The compound claim 51, wherein Y is WO 2004/022572 PCT/AU2003/001146 128 N H r N \ N R7 N /G