AU2003257259B2 - Compounds that interact with kinases - Google Patents

Description

WO 2004/022572 PCT/AU2003/001146 Compounds that Interact with Kinases FIELD OF THE INVENTION The invention is directed to classes of biologically active compounds that 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.

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 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 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 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 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 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 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 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 2 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.

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, Nature Tev. Drug Discovery, 1, 309-316, 2002). The specificity of published kinase inhibitors varies widely and it is apparent from the study of 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 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. 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.

Inhibitor Top 5 kinases inhibited concentration kinase and residual activity ML-9 MSK-1 ROCK-II SmMLCK S6K1 CDK2 100 M 14% 23% 25% 27% 38% LY 294002 PI3K CK2 PHK GSK3P SGK IM 13% 18% 44% 53% 72% HA1077 ROCK-II PRK2 MSK1 S6K1 PKA pM 7% 15% 19% 32% PP2 LCK CDK2 CK1 SAPK2a MKK1 M 1% 3% 6% 21% 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-II 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 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-Kib mitogen activated protein kinase activated protein kinase 1 b; PKCa protein kinase C alpha.

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.

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 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 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 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 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 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 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 acceptable derivative thereof Y X H H

~H

HO H OH /n formula I Wherein; n is 1 or 2, X is selected from the group consisting of: OR1, an unsubstituted 5 or 6 membered heterocyclic moiety, a substituted or 6 membered heterocyclic moiety, an unsubstituted 9 or o0 membered heterobicyclic moiety and a substituted 9 or 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, Y is selected from the group consisting of: an unsubstituted or 6 membered heterocyclic moiety; a substituted 5 or 6 membered heterocyclic moiety, an unsubstituted 9 or membered heterobicyclic moiety and a substituted 9 or membered heterobicyclic moiety; an amino acid, a dipeptide, and WO 2004/022572 WO 204/02572PCT/AU2003/001 146 6 0 7 R8

R

7 N

N-,N,

0 0 A B

R

1 RI /R

R

9

N

R2 N N1 1-11 c D

R

1 R 12

RI

N N R1-.

R

6 R 1 3 E F

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 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 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 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, 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, 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.

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 I and R12 may combine to form a cyclic structure, X may be selected from: OR1, N4N N N R2 R3 or

R

4 "N R

N

N

N N 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 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, 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 orC3 to C14 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from the group consisting of: (C0O)-OR4, and -(C=O)-NH-R4, WO 2004/022572 WO 204/02572PCT/AU2003/001 146 9 Y is selected from:

R

7

R

8 0 0 J" R 6 0 0 A B

R

1 1 /1 R N

N

R

1 4 N

R

13 C D N R1 N\H, N

H

N R

N,

At least one of R1 R14 may be 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 may be selected from the group consisting of: OH, NO, NO 2

NH-

2

N

3 halogen, OF 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 aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, alkyl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted.

X may comprise N4N

N

R2 R3 X may comprise R4, N R N N N N 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.

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.

2 0 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, CD117,

PBT.

The protein kinase may comprise VEGF-R2/KDR also known as VEGFR2, VEGFR-2 VEGFR, Hs.KDR, Hs.12337 FLK1 FLK-1.

The protein kinase may comprise EGF-R also known as ERBB1 ERBB, EGFRvlII.

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, 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.

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, 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, Y x YOX H H HO HH HO H OH n formula I WO 2004/022572 PCT/AU2003/001146 12 Wherein; n is 1, X is selected from: OR1,

NN

R2 R3 or

R

4 N R N N

NN

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 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, 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 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, R2 is selected from -(C=0)-NH-R4, Y is selected from the group consisting of: WO 2004/022572 WO 204/02572PCT/AU2003/001 146 13

R

7 R Re'~

R

6 0 0 A B

R

1 /R R N

N

R, N N-

R

13 C D

R,

/R

12

RI

N R1N

R

6

R

13 E r SN

H

N l\R 7

N

R

6 R6 is selected from the group consisting of H, CI to 07 alkyl, CI to 07 alkenyl, C1 to 07 alkynyl, C1 to 07 heteroalkyl, 06 to C14 aryl, C3 to 014 heteroaryl, 06 to 014 arylalkyl and 03 to 014 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 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, C6 to C14 heteroaryl, C6 to C14 heteroarylacyl, C6 to C14 arylalkyl or C6 to C14 heteroarylalkyl, -S-R6 or -O-R6, 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, 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.

R7 and R8 may combine to form a cyclic structure.

R6 and one of R7 or R8 may combine to form a cyclic structure.

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.

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 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, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted, X may be N

-N

I -R2

N

R3 or

R

4

/R

N

N

or -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.

Y may comprise E as described above.

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.

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.

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.

BEST MODE General Methods 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 equiv.) was added. The resulting solution was stirred at room temperature for h, then diluted with DCM (8 ml) and washed with 10 citric acid (2 x ml), saturated NaHCO 3 (2 x 5 ml), brine (5 ml) and water (5 ml). The solvent was removed in vacuo.

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 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 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 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.

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 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 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 2mL) then treated with TFA/DCM 1:1 (1mL) for 15 mins. The resin was filtered and washed with acetonitrile (1ml) (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 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 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 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 (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 3nitro-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 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.

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 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 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 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, 1M hydrazine hydrate in DMF was substituted for methanolic 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 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 Boc protected amino acid is made by dissolving the amino acid in methanol and water (0.5ml/mmol) and adding an aqueous solution of Cs 2

CO

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 with the cesium salt (5eq) in dry DMF (4ml/g of resin) and stirred at 50°C for 24 hours. The resin is drained and washed with DMF, DMF/H 2 0 x 3), MeOH/H 2 0 x 3) and MeOH (x 3) and then dried in vacuo.

General Method 12- Reductive amination: 6 eq of aldehyde is dissolved in TMOF/THF 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 2ml) is added to the resin and shaken overnight at room temperature. The resin is then drained and washed with lo THF/MeOH x 3 DMF/MeOH x DCM/MeOH x 3) and DCM.

General Method 13- Urea formation: In a gloved box, the resin is swelled in DIPEA/DCM, a solution of triphosgene (2eq in 1.2ml of dry DCM) was added to the resin in two batches and shaken for 1 hour. The resin is washed with dry DCM (1ml 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 DCM (x 3) and MeOH (x 3) and dried.

2o General Method 14 base catalysed ring closure: The resin was treated with a solution of MeOH/NEt 3 2ml) and heated to 600C overnight. The resin is drained (collecting the filtrate) and washed with MeOH, (1 ml), DCM (1ml), MeOH (1ml) and DCM (1ml). The filtrates are combined and the solvent removed in vacuo. The process is then repeated.

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 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 R1X (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 rt for 12h, then washed with DMF s (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 OC. The solution was stirred at 0°C for 30 mins. The solution was syringed out leaving the 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 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-alkvlation: Bromoacetylated resin produced by 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 DIPEA (10eq) in NMP (1ml/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.

General Method 20- Nitro reduction: The resin was swelled in DCM (1.5ml/100mg) and a solution of K 2

CO

3 (10eq) 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 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 100°C overnight. The resin was filtered and washed with DMF, DCM and MeOH and dried in vacuo.

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 (1ml) 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.

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 and washed with DCM. The filtrate was concentrated under reduced pressure to afford the crude residue.

General Method 24- Biological assays: Compounds were tested in vitro as follows.

Recombinant protein kinases, which were expressed as fusion proteins in SF9 insect cells or E. coil, 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.

All kinase assays except for p38a (see below) were performed in 96well micro-titre plates. The assay components included assay buffer, ATP, test compound, enzyme and substrate.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 23 The assay for all enzymes (except for the PKQ .see below contained mM HEPES-NaOH, pH 7.5, 3 mM MVGICI 2 3 mM MnC1 2 3 4tM Naorthovanadate, 1 mM DTT, 0.1 11M [7- 33 p]-ATP (approx. 5x1 05 cpm per well).

The assay for the PKCs contained 60 mM HEPES-NaOH, pH 7.5, 1 mM EDTA, 1.25 mM EGTA, 5 mM M90l 2 ,1.32 mM CaC1 2 5 jig/ml Phosphatidlylserine, I jig/mI 1.2 Dioleyl-glycerol, 1.2 mM DTT, 50 jig/mI

PEG

2 00 0 0 0.1 4iM 33 P]-ATP (approx, 5 x1 0 5 cpm per well).

The table below details the amounts of enzyme and substrate that were used lo per well: ft Kinase Screenpoollf Enzyme Substrate Substra te I 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 Rallpha FGF-RI 1 75 Poly(Glu, Tyr) 4 :1 500 6 CDK2ICycA 2 10 .Histone HI 250 7 MET 7 100 Poly(Glu, Tyr) 4 :1 125 8 VEGF-R2 2 50 Poly(Glu, Tyr) 4 :1 125 9 ABIL 1 10 Poly(Ala, Glu, Lys, 250 PKC-betal 1 13 Histone Hi 500 The reaction cocktails were incubated at 30 0 C for 80 minutes. The reaction was stopped with 50 lal of 2% H 3 P0 4 plates were aspirated and washed twice with 200 jil of H 2 0 or 0.9% 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 NanoCarrier Tm 2080 format. In these assays 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 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 (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) Only data where the Z' value was >0.5 was used.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 1: NHBz NHBz KN N O R H N

H

2 N 0 OC(.J. OKN: <N 1-In=1lor2 .14IT 0 R Hw NH 2 (4NH 2 H0 2 CUJ N N O R H N H 0 N i~n H 0 0

N:]N

n=1 or 2 H Hnl Hd~> H1-Iln1 r General Method 1, General Method 2, General Method 3.

Analysis of some typical example compounds 0 CH 3 HNH 2 H0 2 0 N H 0N NJ Hc H 4 Isomer A: proton (400 MHz: DMVSO) 2.38 (dt, J 5.0, 6H, CH 2

CH

2 2.65 J 15.0 Hz, I H, OH 3 3.85-3.95 (in, 2H, H2 or H3 or H4), 4.05 (dd, J 3.0, 8.0 Hz, I H, 4.10 (dd, J 3.0, 8.0 Hz, 1IH, H5b), 4.30 (in, 1IH, OH), 4.65 (dd, J 5.0 Hz, 1 H, H2 or H3 or H4), 5.87 J 4.0 Hz, I1H, Hi1), 8.30 1 H, ArH), 8.45 1 H, ArH).

Isomer B :proton (400 MHz: DMVSO) 2.42 (dt, J 5.0, 6H, CH 2

CH

2 2.75 J 15.0 Hz, I H, OH 3 3.85-3.95 (in, 2H, H2 or H3 or H4), 4.05 (dd, J 3.0, 8.0 Hz, 1H, H5a), 4.10 (dd, J 3.0, 8.0 Hz, 1 H, H5b), 4.30 (in, 1IH, OH), 4.65 (dd, J WO 2004/022572 WO 204/02572PCT/AU2003/001 146 26 Hz, 1IH, H2 or H3 or H4), 5.92 J 4.0 Hz, 1 H, Hi1), 8.35 1 H, ArH), 8.50 1 H, ArH).

Example 2: R 1 phenyl, Rlpropyl General Method 1, General Method 2, General Method 3.

Analysis of some typical example compounds 1 0 0 N -N 0 H0 2 C -N VO -N o H I Ph NH 2 CO0 2 H HO OH 32 proton (400 MHz: D 2 0) 2.36-2.55 (in, 5H, alkyl 2.57-2.76 (in, 1 H, alkyl H), 3.31-3.48 (mn, 2H, H5), 3.98-4.07 (mn, 1IH, H4), 4.45-4.56 (in, 2H, H3, NCHCO), 4.69-4.75 (mn, 2H, H2), 5.57 J 2.4 Hz, 1 H, HI), 7.32-7.40 (mn, 2H, PhH), 7.41-7.53 (mn, 3H, PhH).

O N=N 0 H0 2 C H PhNH 2 Ph HO OH 38 proton (400 MHz: D 2 0) 2.26-2.40 (mn, 4H, alkyl 2.73 (dd, J 14.0, 8.0 Hz, WO 2004/022572 WO 204/02572PCT/AU2003/001 146 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, I H, H5a), 3.42 (dd, J 14.6, 3.8 Hz, I H, H5b), 3.96-4.02 (in, I H, H4), 4.26 J 5.8 Hz, 1 H, H3), 4.36 J 7.4 Hz, I H, NCHCO), 5.52 J 2.8 Hz, I H, Hi), 7.02-7.20 (in, 5H, PhH), 7.35 J 6.4 Hz, 2H, PhH), 7.42-7.54 (in, 3H, Ph H).

o N=N 0 H0 2 C N 02 0 H X.JPhNH HO OH 6CF, proton (400 MHz: 020) 1.76-1.87 (in, 1 H, alkyl 1.96-2.08 (in, 1 H, alkyl H), 2.30-2.41 (in, 6H, alkyl 3.43 J 4.4 Hz, 2H, H5), 4.06 J 5.2 Hz, 1 H, H4), 4.26 (dd, J 9.0, 5.2 Hz, I H, H3), 4.40 J 5.6 Hz, I H, NOHO), 4.69- 4.74 (in, I H, H2), 5.54 J 3.2 Hz, 1IH, Hi1), 7.2.8-7.48 (in, 8H, PhH), 7.65 (s, I1H, PhH).

o N--N0 H02C 0

CO

2 H H-1 OH 33 proton (400 MHz: 020) 0.77 J 7.4 Hz, 3H, CH 2

CH

3 ),1I.42-1.56 (in, 2H,

CH

2

CH

3 2.37-2.53 (in, 5H, alkyl 2.58 (dd, J 15.4, 5.4 Hz, 1 H, alkyl H), 2.89 J 7.6 Hz, 2H, ArCH 2 3.30-3.46 (in, 2H, H5), 4.07-4.15 (mn, 1 H, H4), 4.42-4.53 (mn, 2H, H3, NCHCO), 4.70-4.75 (mn, 2H, H2), 5.87 J 2.8 Hz, I H, HI1).

0 N-N0 H02C 0 N~

NH

2 Ph HO OH 37 proton (400 MHz: D20) 0.78 J 7.2 Hz, 3H, CH 2

CH

3 1.38-1.46 (mn, 2H,

CH

2

CH

3 2.34 (bs, 4H, alkyl 2.70 J 10.2 Hz, I1H, ArCH 2 2.74-2.96 (in, WO 2004/022572 WO 204/02572PCT/AU2003/001 146 28 3H, ArCHb, CH 2 Ph), 3.25-3.45 (in, 2H, H5), 4.02-4.12 (in, 1IH, H4), 4.18-4.25 (in, 2H, H3), 4.29-4.38 (in, 1 H, NCHCO), 5.83 (bs, 1IH, HI1), 6.99-7.20 (in, PhH).

0 N N 0 H0 2 CN 0N HN 0 (t.INCF, 51 proton (400 MHz: 020) 0.73 J 7.4 Hz, 3H, CH 2

CH

3 1.36-1.50 (in, 2H,

CH

2

CH

3 1.73-1.85 (mn, I H, alkyl 1.88-2.03 (mn, 1IH, alkyl 2.28-2.45 (in, 6H, alkyl 2.84 J 7.5 Hz, 2H, ArCH 2 3.42 J 4.4 Hz, 2H, H5), 4.10- 4.20 (mn, 2H, H3, H4), 4.38 J 5.4 Hz, 1 H, NCHCO), 5.84 J 2.8 Hz, 1IH, Hi), 7.34-7.52 (mn, 3H, ArH), 7.65 1 H, ArH).

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 29 Some typical peptide arms hla-llr used in step a of examples 1 and 2 0H 0 0 H 0 N o N OH Ila 'N- 0 1- N OH 0 0 le 0H 0 0 H 0

OH

N

OH

0 Ih

OHI

OH

0 Id WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Exampjle 3: O4RIN -N-Fmc -NH 3-1 3-11(b O- 0 O-FRiNKJ-N 34V N~A 3IlF

NO

2 H 311 N0 2

(C)

0 0 3-IH--N .11R 1 0-MfI I- N Ar

NH

2 H 3V N0 2

H

IX, X, XI, (shown below) 0 3-VIIN HN

H

0- 0

AN

(i)

H

2 NOC N\ R' 3-VIII HO OH General Method 4, General Method 5, General Method 6 (using reagents ArNH 2 and DMVSO), General Method 6 (using reagents ArCH 2

NH

2 and DMF as solvent), General Method 7, (34f) General Method 7, General Method 8, General Method 3b, effects ring closure, deprotection and cleavage from resin, General Method 9, only required for adenine containing compounds.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 31 Blocks IX, X and Xl

N

HO NHBz 6z N N Ix 1-1 NH 2 0x Analysis of a typical example compound Br

H

2 NOC4 N

NH

N rN NH

N

355 lo proton (400 M Hz: d 6 DMSO) 4.92 J 4.4 Hz, 1IH, H2 or H3), 4.98 J 5.1 Hz, 1IH, H2 or H3), 5.33 J 4.0 Hz, 1 H, H4), 5.54 J 16.8 Hz, 1 H, CHaPh), 5.62 J 17.2 Hz, I H, CHbPh), 5.77 J 5.3 Hz, I1H, OH), 5.80 J 5.4 Hz, I1H, OH), 6.10 J 5.3 Hz, 1lH, Hi), 6.96 J 7.9 Hz, 1 H, PhH), 7.09 J 7.8 Hz, 1H, PhH), 7.24 (bs, 2H, NH 2 7.27 (bs, I H, PhH), 7.29 I H, CONHa,), 7.36 J 8.9 Hz, 1 H, PhH), 7.47 J 8.3 Hz, I H, ArH), 7.78 (dd, J 8.5, 1.6 Hz, 1 H, ArH), 7.98 (bs, 2H, ArH, CONHb), 8.31 J 1.2 Hz, 1 H, ArH), 8.37 (s, I H, ArH).

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 4: 0 F 4-1

NO,

JNH 0 HET

NO

2 z 0 0O> 4-11a: HETha 4-Tic: HET~c 4-lid: HET~d 4-111a 4-111C 4-111d -x 0 H ET 4-Va W 4-Vc

R

1 Hd OH 4-Vd General Method 6 using a sugar amine, General Method 7, (4-e) General Method 10, General Method 3b, General Method 9, only required for adenine containing compounds.

Exemplary Aldehydes used in step 4-e.

Benzaldehyde, 3-Bromobenzaldehyde, m-Tolualdehyde, 2- Methoxybenzaldehyde, p-Tolualdehyde, 4-Dimethylaminobenzaldehyde, 4- Cyanobenzaldehyde, 1 ,2,3,6-tetrahyd robenzaldehyde, I ndole-3carboxaldehyde, 2-naphthaldehyde, 3-methyl thiophene-2-carboxaldehyde, cyclohexane carboxaldehyde, pyrrole-2-carboxaldedhyde, phenyl acetaldehyde, 4-(2-pyridyl)benzaldehyde, ca,ca,c-trifluoro-o-toluaidehyde, WO 2004/022572 WO 204/02572PCT/AU2003/001 146 33 dimethylbenzaldeyde, 3,5-difluorobenzaldehyde, 2-fluorobenzaldehyde, 4fluoro-3-(trifluoromethyl)benzaldehyde.

Examp~le

N=N

FmcHN~

CO

2

H

0 0 5-1 0-FR1K NH25-111 5-I1

NO

2 H R (c) H2N~k 0~ 0

N=-

0~

R

General Method 1, General Method 4, General Method 6, d) General Method 7, General Method 3b Analysis of some typical example compounds

NH,

Me OMe proton (400 MHz: d 6 DMSO) 2.41 3H, OH 3 3.83 3H, OCH 3 4.34-4.53 (in, 4H, H2, H3, H4, H5a), 4.75 J 13.2 Hz, 1lH, H5b), 5.80 1lH, Hi1), 6.97 is J 8.8 Hz, 2H, ArH), 7.39-7.47 (in, 2H, ArH), 7.51 (bs, 1 H, NHa), 7.57-7.67 (mn, 3H, ArH), 7.69-7.75 (in, 1 H, ArH), 7.79 (bs, 1 H, NHb).

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 34 Me N N 0

OH

proton (400 MHz: d 6 DMSO) 0.77 J 7.4 Hz, 3H, CH 2

CH

3 1.40 J 7.1 Hz, 2H, CH 2

CH

3 2.37 3H, ArCH 3 2.84-2.98 (in, 2H, ArCH 2 4,38-4.52 (mn, 4H, H2, H3, H4, H5a), 4.70 (bd, J 14.4 Hz, I H, H5b), 5.80 1IH, HI1), 6.85 J 8.0 Hz, 2H, ArH), 7.27 (bs, 2H, NHa, ArH), 7.48-7.60 (mn, 4H, ArH), 7.78 (bs, 1IH, NHb).

N=N 0 N6

NH

2 OBn OMe proton (400 MHz: d 6 DMSO) 3.77 3H, OCH 3 4.35-4.46 (mn, 3H, H2, H3, lo H4), 4.57 (bdd, J 14.8, 6.4 Hz, 1IH, H5a), 4.84 (bd, J 14.8 Hz, 1 H, H5b), 5.05 J 11.6 Hz, 1H, OCHa), 5.11 J 11.6 Hz, I H, OCHb), 5.34 1H, Hi), 6.96-7.04 (mn, 4H, ArH), 7.20 J 8.8 Hz, 2H, ArH), 7.30-7.46 (in, 7H, ArH), 7.54 (bs, 1IH, NHa), 7.60 J 8.8 Hz, 2H, ArH), 7.63-7.68 (in, 1IH, ArH), 7.71 7.78 (in, 1 H, ArH), 7.90 (bs, 1 H, NHb).

WO 2004/022572 PCT/AU2003/001 146 Examile 6: 0 NH 0 R 2

NH,

H NH 0 R, oNH 1(b) 0NR

NO

2 6-Il1

N

0 F

N

R4 Bz, H NH 0R, 0 NH N OONH 2

NHHRR

0 0 R 0 HN- "~OH

OH

6-V N Y NHR Conditions: general method 5 general method 6; general method 7, general method 10; general method 9 for adenosine containing compounds only, general method 3b.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 7- Bzo-*N,')CN NaOMe Ho-N4 0 CN 2,-iehxpop n O C BzO OzHO OH H 2 S0 4 0ctn 0 7-11 1 7-1I 0NH 2 Z 1 CO 2 Me K7-VI

IHCI

TH F MsCI py MsO-'-jyCN BrCH 2

CO

2 Me 0 CN NaN 3 Zn THF 0-0 DMF 7-V CO Me BzCI, py HO OH 7-Vil

N

3 Y/I.~C2Me BzO OBz 7-VII t BuOCOCN 00 NH 2 N3C2B [Cu(acac) 2 E3,0 O z O 2

M

5 mol 7-IX 1) R'1 I2) H+

NIHNH

2 83

CO

2 Me BzO OBz 7-XI 1)HBTUDIPEA,

DMF

2) jj~-NH 2 TFA N,0 0B DOM -C0 2 Me szo OBz 7-X N-N 0

CO

2 Me BzO OBz 7-XII

RIN

CONHR'

Bz0 013z 7-XV

SDTT

H

2 N

H-

O ONHR' BZO OBz 7-XVI LiOH, N3 0

N-<

THF CO 2

H

HO OH 7-XIIL S1) HBTU, DIPEA, DMF 2) R 2

NH

2 Bz2lpy N< N RN 0

CONHR'

HCOoH 7-XIV WO 2004/022572 WO 204/02572PCT/AU2003/001 146 37 Example 8: Boo-N -YOH 082003 Bo- OCS N, o H 0 H 0 BoY 8 -01R R-(c) (b) I NH 2 -j R Ra R 2:~ 0 0 Ra=B,C,D,E N R 8-V 8-Iv 0 R 0kN- 8-V1 General Method 11, General Method 3b, General Method 12, s General Method 13, General Method 14, General Method 3a, General Method 9 for adenosine containing compounds.

Analysis of some typical example compounds

\/NH

2 N 0 N N 0 db 220 Isomer 1: proton NMR (400MHz,d 6 -DMSO): 6: 8.46 1 H, 8.26 1 H, 7.93 2H, NH- 2 7.37-7.31 (in, 6h); 7.15-7.08 (in, 5H); 6.92 1H, J=6Hz 5.86 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 38 1 H, J=5.6Hz, 4.70-4.64 (in, 2H, containing H-2 and HPl 8 Id); 4.39 (di, I H, J1l 6Hz, HP2a11d); 4.20 1 H, J= 4.8Hz, 4.04-3.96 (in, 2H, containing H-3, H-5A); 3.59 (di, 1IH, J=6.8Hz, 2.97 (in, 2H, containing Ho 1 H02).

Isomer 2: proton NMR (400MHz,d 6 -DMSO): 6: 8.42 I H, 8.22 (ci, I1H, 7.75 2H, NH 2 7.38-7.30 (in, 6h); 7.17-7.11 (in, 5H); 6.98-6.96 (mn,IH, J=6Hz); 5.82 (di, 1H, J=5.6Hz, 4.72-4.64 (in, 2H, containing H-2 and HplaJd); 4.40 1 H, J=1 6.4Hz, HP2ard); 4.21 1IH, J= 4.4Hz, 4.08 1IH, J=4.4Hz, H- 3.97 1IH, J=6.4, 10.4Hz, H-5A); 3.65 (dcl, I H, J=6.4, 14.4Hz, 3.54 lo (dci, 1IH, J=7.6, 14.4, H-5A); 2.98 (di, 2H, J=4.8Hz containing Hol, H0 2

NH

2 NON LN N 221 Isomer 1: proton NMR (400MHz,d 6 -DMSO): 6: 8.48 1 H, 8.27 I H, 7.45 (di, 1H, J=4.4Hz); 7.40 (di, I H, J=4.8Hz); 7.24-7.09 (mn, 4H); 7.05-7.02 (mn, 1IH); 6.97-6.91 (mn, 2H); 5.84 (di, I H, J=6.4Hz, 4.86 (ci, 1IH, J=l 6Hz, Hpild); 4.66-4.63 (mn, I1H, 4.45 1 H, J=lI6Hz, Hj02ajd); 4.21 1IH, J=4.4Hz, 4.03 I1H, J=3.6Hz, 3.98-3.92 (mn, I H, H-5A); 3.19 1IH, J=5.2, 9.2 Hz Isomer 2: proton NMR (400MHz,d 6 -DMSO): 6: 8.47 1 H, 8.26 1 H, 7.44 (di, I1H, J=4Hz); 7.41 (ci, 1IH, J=4.8 Hz); 7.24-7.09 (in, 4 7.05-7.02 (in, I H); 6.97-6.91 (in, 2H); 5.82 (di, I H, J=6.4Hz, 4.88 (di, I H, Jl6Hz, HPla1d); 4.66-4.63 (in, I H, 4.45 (di, I1H, J=lI6Hz, H52 2 Id); 4.22 1 H, J=4.4Hz, Ha); 4.06 1 H, J=4Hz, 3.98-3.92 (mn, 1 H, 3.22 1IH, J=5.2, 9.2Hz Hp1); 3.05-3.01 (in, I H, H0 2 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 39

NH,

0 0 Hd bH 202 proton NMIR (400MHz,d 6 -DMSO): a: 8.37 I1H, 8.12 1 H, 7.63 4H, J=8.4Hz); 7.46 2H, J=7.6Hz); 7.36-7.27 (in, 5H); 5.87 1 H, J=5.6Hz, 5.53 I1H, J=6.4Hz); 5.35 I H, 4.78 1IH, J=5.2, 10.4Hz); 4.51 2H), 4.17-4.08 (in, 2H); 3.92 2H); 3.82-3.77 (in, 1IH); 3.70-3.64 (mn, I H).

cI 0 0 N Pi ll\ NH 2 1-400 bH proton NMVR (400MHz,d 6 ,-DMSO): 8: 7.78 1H); 7.42 1H); 7.08 I H, J=4Hz); 6.88 1IH, J=3.6Hz); 5.77 I H, J=2.8Hz); 4.62-4.60 (in, I 4.54 2H); 4.39 I H, J=5.2Hz); 4.16 1 H, J=6, 11.6Hz); 3.85 2H, J=5.2Hz); 3.62-3.57 (in, 1 3.53-3.48 (mn, I 3.02-2.90 (mn, 3H); 1.54-1.48 (in, 2H); 0.86-0.83 (in, 3H).

737 Isomer 1: WO 2004/022572 WO 204/02572PCT/AU2003/001 146 proton NMR (400MHz,d 6 -DMSO): 8: 8.40 1IH); 8.18 1IH); 7.62 2H); 7.56 2H, J=7.6Hz); 7.44 2H, J= 3.6Hz); 7.37 3H, J=8.4Hz); 7.27-7.25 (in, 3H); 7.20-7.18 (in, 2H); 7.08 2H, J=8Hz); 5.87 1IH, J=5.6Hz); 4.76 1IH, J=15.6Hz); 4.67 1H, J= 5.6Hz); 4.30 1IH, J1l5.6Hz); 4.23 1H, s J=4.4Hz); 4.04-4.00 (in, 2H); 3.70-3.59 (in, 2H); 3.18-3.04 (mn, 2H).

I somer 2: proton NMR (400MHz,d 6 -DMSO): 8: 8.39 1 8.20 1 7.81 2H); 7.61 2H, J=7.2Hz); 7.52 2H, J= 8Hz); 7.45 3H, J=7.2Hz); 7.35-7.26 (in, 5H); 7.21 (dd, 4H, J=6.8, 15.6); 5.83 1IH, J=6Hz); 4.78 1IH, lo J=1 5.6Hz); 4.69 1IH, J=5.2Hz); 4.30 I H, J= 15.0Hz); 4.25 1IH, J=4.4Hz); 4.11 1IH, J=4.4Hz); 4.02-3.98 (in, 2H); 3.21-3.06 (in, 2H); 3.18- 3.04 (mn, 2H).

cI

NH

2 N N N N 0 0 Hd bH 750 Isomer 1 proton NMVR (400MHz,d 6 -DMSO): 5: 8.46 1 8.25 1 7.63 4H, J=7.2Hz); 7.52 2H, J= 7.6Hz); 7.44-7.36 (in, 5H); 7.28 2H, J=8.4Hz); 7.16 2H, J=8.4Hz); 5.95 I1H, J=5.6Hz); 4.79-4.73 (in, 2H); 4.40-4.33 (mn, 2H); 4.13-4.07 (mn, 2H); 3.78-3.70 2H); 3.26-3.11 (mn, 2H).

Isomer 2 proton NMVR (400MHz,d 6 -DMSO): 8: 8.26 1IH); 8.07 I 7.55 2H, J=7.4Hz); 7.45 2H, J=8.4Hz); 7.39 5H, J= 7.6Hz); 7.30 2H, J=8Hz); 7.17 2H, J=8.4Hz); 7.11 2H, J=8.4Hz); 5.77 1H, J=5.6Hz); 5.50 (s, 1H); 5.26 I 4.67-4.63 (in, 2H); 4.25-4.22 (in, 2H); 4.06 1IH, J=-8Hz); 3.95 I H, J=6.8, 10.4Hz); 3.67-3.48 (mn, 2H); 3.18-2.99 (mn, 2H).

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 9: 3-NH, (a) RINK amnide PS resin 0 0 9-1b: RI=Pr C) N I OH 00 9-IT (b) 3-NH N-N

R

2 0 N$j~ 0\ R, 9Il H N H1 2 N N--N 0

R

1

I-

N

2 0~ HO H R N 'A R3H 9-TV 9-V Conditions: general method 1; MsCI, 0CM, (ii) Tryptamine derivative, DMF R 3 CHO, 25% TFA/DCM, rt; general method 3b.

Example k R N-Fmoc OH

H

10-1I' 1o-tv R2, 0 2 NO 2 R-\N R N-S Q-0o-- V R, h 1 R21 Rl\ 0 R O-VI

R,

0 R 1 b WO 2004/022572 WO 204/02572PCT/AU2003/001 146 42 Conditions: general method 4, (ii) o-nitrobenzenesulfonyl chloride, DCM, DIPEA, 3 hours, RT; PPh 3 aminoalcohol, DEAD, 24 hr; (i) general method 4, (ii) general method 12; Na+PhS-, DMF, 12 hours, RT (ii) general method 13 where the amine is intramolecular, general method s 3b.

Example 11:

R,

NH

2

OR

0~ H 3 6~

R

3

R,

R

2 'o R- 2

OH

N N j 11-TV NHBOC 11V NH 2 0 HN R, 0N 0R, 11-Vi Conditions: DMF, DIPEA; general method 1; general method 3b; (d) reflux in toluene.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 12: 0

NH

2 12-1

OH

R

3 12- H N-F (a) H R 3 N- -U N F o 12-111 H R 3

R

2 12-V H R 3 N NH 2

(C)

12-IV H R 3

R

2 N

HN

Oi, 12-VI

R

3 t- 12-VII Conditions: aldehyde, TMOF/THF; general method 4; general method 12; Na+PhS-, DMF, (ii) general method 13 where the second amine is intramolecular; general method 3b Example 13:

H

2 N HN O~ Br RI

R

1 R 4 )r 13-1 13-1T 0 3 13-111 Rl 3 3 N4 N Rl 2 1M-V

RN

s NI 41-

RN'R

2 Rl 3 Rl 4

OH-IC

0

R

1 13-VTI 6H bH Rl 3

S

13-V

RI

1 Conditions: R2-lsothiocyanate, 0CM; Bromoketone, DMF; general method 3b WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 14:

H

2 N 0 (a) 14-1I

R

3 N 0 R 1 0 14-Il R N 0R, 0 Hd bH 14-IV Conditions: R 2 CHO, TMOF, THE; R 3 -CO-CI, NEt 3 generaJ method 3b.

Example

H

2 N 0

I

6 jb ~J R, R 2

R

2 HO~r N R

RH

0

R

2 Hd

OH

Conditions: Epoxide, DIEA, DMF; CDI, DCM; general method 3b.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 16:

R

2 02 0 R 1 0 R HN(a) N' N 16-1I

R

3

R

4 H6 OH 16-111 0 0 eg:t Conditions: R 3

-CO-CO-R

4

NH

4 OAc, R 2 -CHO; general method 3b Example 17:

H

2 N 0 17-1 17-11

HS-I

OH

17-11I 0

R

3 0 R S4 z: R2 0 17-IV R3 0 5 N 0 R

R

2 H C OH 17-V Conditions: R 2 CHO, TMOF, THE; mercapto acetic acid; general method 3b.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 46 Example 18: Intermediate from example 4 (4-111 a,c,d) I(a)0 O j- HN N 0 Re

HN-

0 S 1 j R -j N 0 Re I(d) FS 6K 18-HI1 0

H

2 N 0 Ra N'q .K 18-W1 IS H6 OH (18-a) General Method 15, (18-b) General Method 16, (18-c) General Method 9, hydrazine/DMF conditions for adenosine containing compounds only, (18d) General Method 3b Exemplary yield and crude Product purity Ra=adenosine Purity of Compound crude cpds (,by ELSD) yield(% 86 96 33 87 92 33 88 84 31 89 98 31 97 27 91 96 46 92 92 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 47 93 87 28 94 86 34 98 96 85 33 97 95 98 94 99 97 39 100 98 39 101 96 102 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 ill 81 18 112 20 12 113 15 8 114 35 12 115 95 22 116 84 42 117 97 39 118 88 34 119 77 120 92 44 Analysis of some typical example compounds 0

H

2

N

N NH 2 HN- S H6 OH 18-1 proton (400MHz, d 6 -DMSO): 8.29 1 H, 8.11 1 H, 8.00 I H, 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 I H, J =8.6 Hz, ArH), 7.30 (broad s, 2H, NH), 7.21 (broad s, I H, NH), 5.86 1IH, J 5.1 Hz, 5.61 I H, J =6.0 Hz, OH), 5.45 1IH, J 5.4 Hz, OH), 4.72 (qua, 1 H, J 5.2 Hz, H'-2 or 4.54 (dd, J 15.2, 4.7 Hz, 4.47 (dd, 1 H, J 15.2, 7.4 Hz, 4.31 (qua, 1 H, J 4.7 Hz, H'-3 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 48 or 4.29 (dt, 1 H, J 4.7, 7.4 Hz).

carbon (100OMHz, d'-DMSO): 168.7, 156.6, 154.8, 153.2, 149.8, 142.9, 1404, 139.3, 128.4, 121.9, 119.8, 117.6, 109.8, 88.5, 82.7, 73.5, 71.8, 46.9.

0

H

2 N rN

NH

2

N

/S HO

OH

115 proton (400MHz, d 6 -DMSO): 8.38 I H, 8.15 I1H, 7.95 (broad s, I H, NH), 7.64 1IH, J 1.5 Hz, Ar-H), 7.54 (dd, 1IH, J 1.5, 8.3 Hz, Ar-H), 7.31 1 H, J =8.5 Hz, Ar-H), 7.30 (broad s, I H, N 7.25 (broad s, 1 H, N H), 5.85 1 H, J =6.3 Hz, 5.54 I H, J 6.2 Hz, OH), 5.38 1IH, J 5.1 Hz, OH), 4.82 (qua, 1IH, J 5.8 Hz, H'-3 or 4.70 (dd, I H, J 4.6, 13.8 Hz, 4.49-4.38 (in, 2H, H'-5 4.35 (in, I H, 2.10 3H,

CH

3 carbon (100MHz, d 6 -DMSO): 170.2, 167.9, 156.6, 153.2, 150.0, 140.4, 135.9, is 131.1, 129.6, 122.3, 119.8, 110.0, 109.7, 87.8, 82.4, 73.2, 71.9, 46.9, 3 0 o,

NH

2 Nzv SHO OH 116 proton (400MHz, d 6-DMSO): 8.30 1IH, 8.11 1IH, 8.08 1IH, J 1.5 Hz, Ar-H), 7.59 (broad s, I H, NH), 7.63 (dd, 1IH, J 1.5, 8.3 Hz, Ar-H), 7.43 1H, J 8.3 Hz, Ar-H), 7.31 (broad s, 2H, NH 2 7.22 (broad s, 1H, NH), 5.87 1 H, J =5.0 Hz, 5.63 1 H, J =5.8 Hz, OH), 5.46 1 H, J 5.4 Hz, OH), 4.75 (qua, I H, J 5.0 Hz, H'-2 or 4.54 (dd, 1 H, J 4.7, 15.3 Hz, 4.48 (dd, 1IH, J 7.6, 15.3 Hz, 4.34 (qua, 1IH, J 4.7 Hz, H'-2 or 4.25 (dt, I1H, J 4.7, 7.4 Hz, 3.24 (qua, 2H, J 7.3 Hz, OH 2 .32 3H, J 7.3 Hz, OH: 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.

Yield and purity of crude products Ra INH2 R1 Compound# 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 Purity of Crude cpds by

ELSD)

96.9 94.8 96.7 97.8 50.6 97.3 98.3 97.7 97.7 96.7 91.1 97.9 96.9 89.0 97.5 96.4 97.0 96.7 84.6 83.3 97.1 97.0 95.3 72.8 88.6 85.7 66.3 68.1 26.1 97.7 99.1 97.8 48.4 yield 38 31 34 38 21 41 26 14 28 23 39 36 31 33 22 28 23 24 28 27 8 23 7 6 17 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 95.6 96.0 74.50 7.9 53.6 96.4 98.2 96.8 96.9 97.4 96.4 96.7 97.2 96.8 95.0 82.1 95.8 97.0 97.4 96.8 96.9 96.9 96.9 89.9 98.2 97.3 96.4 93.7 80.7 96.6 97.7 60.2 86.9 39.7 97.2 99.5 98.4 60.0 96.0 96.7 95.4 17.0 80.5 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 51 Analysis of a typical example compounds 0 HN W: 0

NH

2 SHO OHb

NO,

138 proton (400MHz, d 6 -DMSO): 8.13 1 H, J 1.3 Hz, Ar-H), 8.09 1 H, J= s 8.7 Hz, Ar-H), 7.93 (broad s, I H, N 7.86 (broad s, 1 H, N 7.70 (dd, I H, J 1.3, 8.4 Hz, Ar-H), 7.64 I H, J =8.7 Hz, Ar-H), 7.50-7.30 (in, 5H, Ar-H), 7.28 I H, J 8.5 Hz, Ar-H), 7.25 (broad s, 1 H, N 5.75 1 H, J 5.48 Hz, OH), 5.53 1 H, J =6.4 Hz, OH), 5.37 1 H, J =1.7 Hz, 4.75- 4.60 (in, 3H, CH OH 2 4.54-4.40 (mn, 2H, OH), 4.30-4.23 (in, 2H, OH).

ic Carbon (I100MHz, d'-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 0

R

H

HN H 9- 0 HN H

R

19-L

N

N

N

NH

2 Hci bH 19-11T WO 2004/022572 WO 204/02572PCT/AU2003/001 146 52 (19-a) General Method 17, (19-b) General Method 18, (19-c) Genera! Method 9 for adenosine containing compounds only, (19-d) General Method 3b.

[RI1 0.1% formic adcd I II9

NCHCN/H

2 0

N

HN

NH

2 HNObH NH, H O H0 OH 19-Ill 19-IV Retention time, observed mass, yield Compound j2 components 19-111 and 19-IV 312 Rt= 4.24mmn (M+H)+=516 Rt= 4.75mmn (M+H)+=544 (72%) 313 Rt= 4.80mmn (M+H)'=550 Rt= 5.28min (M+H)+=578 (72%) 314 Rt= 4.52min (M+H) t =546 4.96min (M+H) 4 '=574 (74%) 315 Rt= 4.70mmn (M+H)+=530 (11 5.17min (M+H)+=558 (88%) 316 Rt= 4.69min 5.23 min (19%) 317 Rt= 5.82mmn (M+H)+=572 6.26min (M+H)+=544 (78%) 318 Rt=4.8l min (M+H)+=596 Rt=5.40min (M+H)+=624 (27%) 319 Rt=4.68min (M+H)+=530 (M+H)+=558 (98%) 320 Rt=5.92min (M+H)+=636 321 Rt=5.97 min (M+H)+=622 6.48min (M+H)+=650 (48%) 322 Rt= 5.74min (M+H)+=592 Rt=6.27min (M+H)+=620 (57%) 323 Rt= 5.15mmn (M+H)'=569 Rt= 5.98min 597(860/) 324 Rt= 5.63min (M+H) t =603 Rt= 6.62min 631(52%) 325 Rt= 5.34mmn (M+H)'=599 Rt= 6.20min (M+H)+=627 (77%) 326 Rt= 5.51 min (M+H)'=583 Rt= 6.38min (M+H)+=611 (62%) 327 Rt= 5.58min (M+H)'=603 6.46min (M+H)+=631 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 328 Rt= 6.54min (M+H)+=625 Rt= 7.41 min (M+H)V=653 329 Rt= 5.77mn (M+H)+=647 (31 Rt= 6.66min 330 Rt= 5.59min (M+H)*=612 Rt=6.20 min (M+H)+=640 (61 331 Rt= 5.51min (M+H)-=583 6.31 min 1 (78%) 332 Rt= 6.57min (M+H)+=661 Rt= 7.50min (M+H) 4 =689 (58%) 333 Rt= 6.75min (M+H)+=675 Rt=7.62 min (M+H 4 =703 334 Rt=6.56min (M+H)"=645 Rt= 7.38min (M+H) 4 '=673 (44%) 335 Rt= 5.03min (M+H)"=535 Rt= 5.77min (M+H)+=563 (82%) 335 Rt= 5.58min (M+H)+=569 Rt= 6.35mmn (M+H)=597 (87%) 336 Rt= 5.26mmn (M+H)+=565 Rt= 6.0min (M+H)+=593 (84%) 337 Rt= 5.33min Rt= 6.04mmn (M+H) 4 '=577 (88%) 338 Rt= 5.41min (M+H)"=569 Rt= 6.27min (M-iH)+=597 339 Rt= 6.44min (M+H)+=591 Rt= 7.29min 619(64%) 340 Rt= 5.67 (M+H)+=615 Rt= 6.46mmn (79%) 341 Rt=651 min (M+H)+=591 342 Rt= 5.37mmn (M+H)+=549 Rt= 6.20min (M+H) 4 =577 343 Rt= 6.54mmn (M+H)+=627 Rt= 7.40min (M+H)+=655 (81 344 Rt= 6.64min (M+H)'=641 Rt= 7.52mmn (M+H)+=669 (69%) 345 Rt=6.41 min 1 min (M+H) 4 =639 (42%) WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 0 (a) H0a

N'

N

NR

H

20-1l 0 O3-N

-R

N CI 20-1 UrD

NH

2

H

20-111 0 0 (e) N" N (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.

Analysis of some typical example compounds: 718 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 proton NMVR (400MHz,d 6 -DMSO): 5: 8.37 1 8.24 1IH); 7.57 21-, J=8.8Hz); 7.35 2H-, J=7.2Hz); 7.30 2H, J=7.6Hz); 7.21 21-, J=7.2Hz), 6.77 2H, J=8.8Hz), 5.81 I H, J=4.4Hz); 4.71 -4.63(m, 3H), 4.64 1 H, J=4.8Hz); 4.46-4.38 (in, 2H); 4.33-4.30 (in, 1 3.76 31-).

0 SHe' 726 Beta isomer: proton NMVR (400MHz,d 6 -DMSO): 6: 8.27 1 7.88 1 7.55-7.41 (in, 6H); 7.28 (dd, 2H, J=1.2, 7.6H-z); 6.84 2H, J=8.8Hz); 5.31 I H, J21-14; 4.66 I H, J=11.2Hz); 4.51 I 4.41 -4.32 (mn, 3H); 3.97-3.88 (mn, 3H-); 2.98 3H); 1.73-1.66 (in, 2H); 1.39-1.26 (in, 12H); 0.87-0.84 (in, 3H-).

Alpha isomer: proton NMR (400MHz,de-DMSO): 8: 8.25 1H), 7.82 31-, J=8.4Hz); 7.51- 7.46 (mn, 7.11 2H-, J=8.8Hz); 5.43 1IH, J=4.4Hz); 4.91 IH); 4.37 1IH); 4.23 1IH, J=5.6, 8.Hz); 4.06 2H, J=6.4Hz); 3.79 1.77- 1.70 (mn, 2H); 1.44-1.26 (in, 12H); 0.87-0.84 (mn, 3H).

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 56 Examp~le 21:

OCH

3

N

O- CHI 0 NHBz PL-FMP resin 21-1 Nc 0H~ NIH 0N/SN 2 N,,i M/ NH 2 NH 21Il 21-11 (de) Nil SN.N/ Ni I N N 00 H R1, Ob H N,,;N 21-TV 21-V (21 General Method 12, (21 General Method 6, (21 General Method 7, (21-d) General Method I or 22, (21-G) General Method 9, (21-f) General Method 3-b then General Method 3a.

Analysis of some typical example compounds: C1 NH 2 N 0 ON

N

OH OH

OCH

3 920 proton (400MHz, d 6 -DMSO): 8.36 I H, 8.25 1IH, 7.88 2H, ArCH), 7.62 2H, J= 8.8Hz, ArCH), 6.84 2H, J=8.8Hz, ArCH), 5.85 (d, IH, J= 3.6Hz, 4.73 (dd, IH, J=3.5, 15.8Hz, OH), 4.57-4.64 (in, 2H,

OH

2 4.36 1 H, J= 5.6 Hz, CH), 4.22 (mn, I H, 3.80 3H, OCH 3 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 22:

OH

0 .,o.kKNH2 H R, 22-1 A(2.5 eq) 22-11 NHBz I ,H H N 1 N N2

W

2 0 H6O 02-0 (b) NHBz 0 0 HR NN JN ~yN N oHL.

22-Ill (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: 741 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 58 Isomeri: proton NMR (400MHz,d 6 -DMSO): 8: 8.48 I 8.17 I 7.39-7.22 (in, 6H); 7.11 2H, J=7.6Hz); 6.86 2H, J=6.8Hz); 5.93 I H, J=4.8Hz);, 4.67 1IH, J=4.8Hz); 4.59 I H, J=3.6Hz); 4.34 1IH, J=5.2Hz); 4.22 I H, J=4.8, 10OHz); 4.00 (dd, I1H, J=6.8, 15.2Hz); 3.76 (dd, 1 H, J=7.6, 14.8Hz); 3.26 (dd, 1 H, J=4.4, 14Hz); 3.05 (dd, 1IH, J=3.6, 14.4Hz).

I somer2: proton NMVR (400MHz,d 6 -DMSO): 8: 8.59 1 8.31 I 7.38-7.23 (in, io 5H); 7.11-7.06 (in, 3H); 6.88 2H, J=6.8Hz); 5.97 I H, J=6Hz); 4.84 (t, I H, J=4.8Hz); 4.50 1IH, J=3.6Hz); 4.25-4.22 (in, 2H); 4.14 (dd, 1IH, J=3.6, 14.8Hz); 3.23 (dd, 1IH, J=5.2, 14.4Hz); 3.00 (dd, 1 H, J=2.8, 14Hz).

NH

2 I I N NN N 0,0 HO bH 935 Isomer 1: proton NMR (400MHz,dr 6 -DMSO): 6: 10.94 1IH); 8.59 1 8.26 1IH); 7.48 1IH, J=8Hz); 7.32-7.26 (in, 4H); 7. 10 1IH); 7.06 1IH, J=7.6Hz); 6.93 1 H, J=7.6Hz); 6.69-6.67 (in, 2H); 5.95 1 H, J=5.2Hz); 4.66 1 H, J=5.6Hz); 4.54 1IH, J=3.2Hz); 4.33 1IH, J=4.8Hz); 4.25 I H, J=5.2, 10.8Hz); 4.00 (dd, I H, J=f6.4, 15.2Hz); 3.76 (dd, 1H, J=4, 14.8Hz); 3.37-3.25 (mn, 2H).

Isomer 2: proton NMVR (400MHz,d 6 -DMSO): 6: 10.95 I 8.68 I 7.43 1IH, J=8Hz); 7.32 2H, J8BHz); 7.27-7.25 (mn, 2H); 7.09 1 7.06 1 H, J-8Hz); 6.92 1 H, J=8Hz); 6.70 (dd, 2H, J=3.6, 7.6Hz); 5.99 1 H, WO 2004/022572 WO 204/02572PCT/AU2003/001 146 59 J=5.6Hz); 4.81 1 H, J=5.2 Hz); 4.47 1 H, J=3.2Hz); 4.29-4.22 (in, 2H); 4.12 (dd, 1IH, J=4.4, 14.8Hz); 3.68 (dd, 1IH, J=8.4, 14.8Hz); 3.36 (dd, 1 H, J=5.2, 15.2Hz); 3.24 (dd, I H, J=2.4, 15.2Hz).

NH

2 0NIN N N N N 0 0

H

948 Isomer 1: proton NMVR (400MHz,d 6 -DMSO): 6: 8.96 1 8.49 I 8.03 1IH); 7.73 2H, J=10.8Hz); 7.67 2H, J=7.2Hz); 7.49 2H, J7.6Hz); 7.40- 7.35 (in, 2H); 7.34 2H, J=8.4Hz); 5.95 I H, J=5.6Hz); 4.70 1IH, J=5.2Hz); 4.65 1 H, J=4.4Hz); 4.31 1 H, J=4.8Hz); 4.27-4.23 (in, 1 H); 3.95 (dd, 1 H, J=7.6, 15.2Hz); 3.77 (dd, 1H, J=4, 14.8Hz); 3.26-3.24 (mn, 2H).

Isomer 2: proton NMVR (400MHz,d 6 -DMSO): 5: 8.97 1IH); 8.51 I 7.82 I H); 7.73 2H, J=8.8Hz); 7.67 2H, J=7.2Hz); 7.49 2H, J=7.2Hz); 7.40-7.35 (in, 2H); 7.25 2H, i8.4Hz); 5.95 1IH, J=5.6Hz); 4.79 1IH, J=4.8Hz); 4.62 1 H, J=5.6Hz); 4.27-4.22 (in, 2H); 4.16 (dd, I H, J=4, 14.8Hz); 3.33- 3.21 (mn, 2H).

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 23: Part A N :N FmoHN Y rf/ 00 2

H

(a) FmocHN Zy 23-11 (C)0 Y< 23-111 (e) (f) R2- I-n 11N 0 N6/ 0 ONH-< NHBn 2-i (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 (23-f) General Method 12. (23-g) General Method 9. (23-h) General Method 3a.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 G1.

Part B

R

Ph 23-V

NH

2 N-fN 0 Ph 23-VIII 23-IX (23-ii) General Method 22, (23-j) General Method 3-a Part-C

RI-

(k) N02 H Ph K 23-IV N -eCONH 2 4 (in) Ph NHO OH NJ 23-XII

NH

2 H Ph NH H 23-X N>JN

NH-Q

0- Ph 00 R2 (23-k) General Method 7, (23-1) General Method 17, followed by treatment of 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-mn) WO 2004/022572 WO 204/02572PCT/AU2003/001 146 62 General Method 3-a.

Analysis of a typical example compounds: N oH NHBn 968 proton (400 MHz: d 6 DMSO) 3.79 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, 1 H, H5a), 4.91 J 14.8 Hz, 1H, H5b), 5.35 1H, HiI), 6.64 J 8.8 Hz, 2H, ArH), 6.98 J 8.8 Hz, 2H, ArH), 7.19 J 8.8 Hz, 2H, ArH), 7.22-7.36 (in, 5H, ArH, NHa), 7.42- 7.56 (mn, 5H, ArH), 7.71 J 7.6 Hz, 2H, ArH), 7.82 (bs, I H, NHb).

r/CONH 2 P h NJHCOPh proton (400 MHz: d 6 DMSO) 4.24-4.31 (mn, 1IH, H4), 4.38 (dd, J 7.4, 5.0 Hz, I H, H3), 4.47 (dd, J 4.4, 1.6 Hz, 1IH, H2), 4.50 (dd, J 15.6, 7.6 Hz, I H, 4.76 (dd, J 15.6, 2.8 Hz, 1IH, H5b), 5.33 J 1.2 Hz, I H, HI), 7.29 (dd, J 7.8, 1.4 Hz, 2H, ArH), 7.40-7.62 (in, 8H, ArH, ArCONHa), 7.68 J 8.4 Hz, 2H, ArH), 7.83 I1H, ArCONHb), 7.88 J 8.8 Hz, 2H, ArH), 7.91-7.99 (in, 3H, ArH), 10.46 I H, ArNHCOPh).

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 63 Example 24: 0 0 ()NHFmoc

()NH

2 R1

R,

(d) NH N- H 24-1 0 NY N~o K- 24-11 +0 N R ~N

NH

2 0 24-IHl -d Nb (24-a) General Method 1, (24-b) General Method 4, (24-c) General Method 12, (24-d) General Method 13, (24-el General Method 3-b.

Analysis of some typical example compounds: 0 CI w NH 2 N N 0 N C1 0 He I- z

OH

954 proton (d 6 -DMSO, 400MHz): 8.51 1H, 8.31 1H, 7.60- 7.05 (in, 8H, ArCH), 5.86 1H, J=5.6,Hz, 4.67 1H, J=5.5Hz, H'- 4.64 1H, JAB=16.lHz, 4.39 1H, JAB=16.lHz, 4.34 (t, I H, J=5.1Hz, 4.09 I1H, J=4.2Hz, 3.99 (mn, 1 H, 3.67 (dd, 1IH, 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, 3.02 (dd, I H, J=4.6, 14.4Hz, WO 2004/022572 WO 204/02572PCT/AU2003/001 146

NH

'NP

/NH

N'N

960 proton (d 6 -DMSO, 400MHz); 8.48 I1H, 8.29 1 H, 7.57- 7.00 (in, 8H, ArCH), 5.88 1 H, J=5.8Hz, 4.68 J=5.2Hz, 4.60 1IH, JAB=1 6.1 Hz, 4.38 I H, JAB=I6.1 Hz, 4.34 1IH, J=5.1 Hz, H- 4.07 I H, J=4.6Hz, 4.01 (in, I1H, 3.64 2H, AB system, 3.12 (dd, 1IH, J=5.2, 14.6Hz, 3.01 (dd, I1H, J=4.4, 14.6H-z, HB-).

Exemnplary compounds of the Invention: 0 The substructures A-H listed below are substituents in the field RI in the libraries of compounds that follow.

NH

2

A

NH Bz N N

B

0 N

NH

2

D

OMe

E

Others substiuents referred to in the following libraries may be subsequently found in the text at the end of examples.

WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example R2HN"% R1 R1 R2 R (on Comp. ISOMER arm) 1 A ha-I Land D H 2 A Ib-I Land D H 3 A lc-I L and D H 4 A lid-I Land D H A lie-I L

H

6 A lie-I D H 7 A lf-I L and D H 8 A 119-I Land D H 9 A Hh- L and D H A L- Land D H 11 A I1j0 L and D H 12 A Ilk-I L and D H 13 A 111-1 L and D H 14 A Ito-1 L H A lb0-1 D H 16 B lha-I L and D methyl 17 B bib-I L and D methyl 18 B iic-I L and D -methyl 19 B Ild-I L and D -methyl B lie-I L and D H 21 B hif-I L and D H 22 B Ilh-I L and D methyl 23 EB L- Land D ethyl 24 B Lh- Land D ethyl B ilk-I L and D methyl 26 B Ih- L and D methyl 27 B llI Land D methyl 28 B i10-1 L and D methyl 29 B lip-I- L and D methyl 1B IIq-I L and D methyl WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 26: R2HN'%' 0 RI R (on Comp. RI R2 Isomer arm) 31 C lla-I Land D H 32 C Jib-I L and D H 33 D ilb-I L and D H 34 C tiC-I Land D H C iid-I L and D H 36 D Id-I Land D H 37 D lie-I L and D H 38 C ile-1 L and D H 39 D lhf-I Land D H C hlf-I Land D H 41 D l1L Land D H 42 C llh-I L and D H 43 D lih-1 Land D H 44 C h- L H D luI L H 46 C I L H 47 DB IA!LL L H 48 C Ilk-I Land D H 49 D ilk-I Land D H c ilr-1 L H 51 D lir-I L H 52 C l- L H 53 D luI L H 54 C lini-1 L H D lun-I L H 56 C 110-I L H 57 D ilo-1 L H 58 C JiphL L H 59 D JipfL L H C L H 61 D j.!q L H 62 C lib-1 L H 63 D ilb-1 L H 64 C iie-1 L H JIG-1 L I H WO 2004/022572 WO 204/02572PCT/AU2003/001 146 0 H0

RO

and 0 OH lIb-1 OH 0 O OR hlf-i and 0 hlg-I

N

RO

and 0 0H 0 RO and 0"N lIh-1

'~OH

ld-1 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 H 0 and II II o 0 Y H 0 R0,T,,-N o 0 llj-1 and 0 H 0

RO

and 0 Ilk-I N 0

H

0 H 0

N

RO

and 0 0

NH

F- "p-i WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 27: H R2.-

R

3 A1 N /j Rl 0R4'- OH& 0H Comp. RI R2 R3 R4 66 A a4 v2 z 67 A A~7 v2 Yi 68 A [36 v2 2:1 69 A X 5 Y2 Zl A ic4 v2 zl 71 A at4 v2 a4 72 A [37 v2 a4 73 A [36 v2 a4 74 A X5 v2 a4 A K(4 v2 a4 76 A aL4 ali 71 77 A P37 al zl 78 A P36 al 11 79 A al zl A K4 al 11 81 A a4 al al 82 A P37 al al 83 A P36 al atl 84 A al al A x4 al al Example 28: Comp. RI R2 86 A p 87 A 7 -88 A P2 89 A 82 A 91 A Ki WO 2004/022572 WO 204/02572PCT/AU2003/001 146 92 A I 93 A (01 94 A A al1 96 A 0 97 A y2 98 A y3 99 A 8 100 A 0 101 A 0c 102 A 7r2__ 103 A c4___ 104 A J04 105 A y4 106 A 107 A +1 108 A 7 109 A +2 110 A V1 ill A v2 112 A v3 113 A A4 114 A 21%1 115 A 116 A v6 117 A s 118 A s 119 A v7 120 A 7jj1 Example 29: 0

RI

H& bH~ Comp. RI R2 121 C al WO 2004/022572 WO 204/02572PCT/AU2003/001 146 122 C J01 123 C 7 124 C J2 125 C 81 126 C 8 127 C K 128 C 7C1 129 C Oi~1 130 C P,2 131 C (7i 132 C 0 133 C y2~ 134 C y3 135 C 82 137 C s3___ 137 C x 138 C it2 139 C s4 140 C P4~ 141 C yl4 142 C 143 C 1l 144 C T 145 C 02 146 C v 1 147 C v2 148 C 03 149 C v4 150 C 1 151 C 152 C v6 153 C ~p 154 C 155 C 156 C p2 157 C v7 158 C ZI 159 D atl WO 2004/022572 WO 204/02572PCT/AU2003/001 146 161 162

D

D

163 D 81 164 D 6i 165 D iKi 166 D 7di 167 D CAl 168 D c2 169 D cr1 170 D P 171 D y 172 D 73 173 D 82 174 D s3 175 D 1C2 176 D 7c 177 D 178 D 04 179 D y 180 D 181 D jl 182 D 763 183 D 02 184 D V1 185 D v2 186 D 03 187 D v4 188 D Xi 189 D 190 D v6 191 D P1 192 D 193 D 194 D0 p 195 D 07 196 D Z WO 2004/022572 PCT/AU2003/001146 Example Comp.

197 198

RI

A

A

R2 7T4 Bi R3 wl1 199 A 200 A 201 A s2 u 202 A al IWl 203 A a2 Wl 204 A Jl Wl 205 A CI 206 A c2 207 A g2 gil 208 A s7 Wl 209 A g 13 14 IL 210 A y2 W 211 A y5 Wl 212 A 70 al 213 A pi al 214 A I al 215 A s5 al 216 A s2 cxl 217 A al al 218 A a2 al 219 A [11 al 220 A T1 al 221 A 2 cl 222 A 7 l 223 A j xal 224 A y2 al 225 A y5 al 226 C 7 I 227 C Wl 228 C lI 229 C s5 1l WO 2004/022572 PCT/AU2003/001146 230 C g 231 C tl 1 232 C c2 l 233 C g2 1l 234 C 67 1 235 C p 1 236 C y 237 C 7 238 C 1 al 239 C E5 al 240 C s2 al 241 C al al 242 C cL2 al 243 C al 244 C T1 al 245 C v2 al 246 C g2 a 247 C C al 248 C 3 ol 249 C y2 al 250 C Y al 251 D r4 al 252 D pi al 253 D c2__ 254 D al W Example 31: Comp. RI R2 255 A a2 256 A 3 257 A P 258 A 01 259 A 8 260 A X WO 2004/022572 PCT/AU2003/001146 261 262 A X3 A y.4 263 A v8 264 A P8 265 A 266 A 94 267 A 268 A r3 269 A a3 270 A 4 271 A a3 272 A 09 273 A 46 274 C 42 275 C 96 276 C (pl 277 C 01 278 C X2 279 C 3 280 C 74 281 C v8 282 C P8 283 C 284 C g4 285 C 286 C T3 287 C a3 288 C 4 289 C 03 290 C p9 291 C g6 292 D 02 293 D 42 294 D P6 295 D (p 296 D 61 297 D 88 298 D X2 299 D X3 300 D X4 301 D v8 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 303 D 304 D g4 305 D [t 306 D 'r3 307 D 0c 308 D T 309 D cr3 310 D 9 311 D 4 Example 32: R3 0 RI

H

2

N

Comp. RI R2 R3 312 A E A4 313 A E2 P6 314 A E2 7, 315 A 9 316 A 12 P~7 317 A 12 81 318 A xyl 1 02 319 A F, d1 320 A E2 Z6 321 A Wj X 322 A E2 aY3 323 C E2 a4 324 c E2 06 325 C 12 326 C Z2 C9 327 C Wl D 328 C Wl 610 329 C E2 02 330 C E2 43 WO 2004/022572 PCT/AU2003/001146 331 332 c 22 sll C E2 y,6 333 C E2 X4 334 C Wl o3 335 D ,2 a4 336 D -2 36 337 D Z2 338 D Z2 s9 339 D wl1 37 340 D 12 c1O 341 D 02 02 342 D 12 11 343 D Z2 X6 344 D 12 X4 345 D 1 Y3 Example 33: Comp. R1 R2 346 A 347 D 348 A s9 349 D e9 350 A 76 351 D X7 352 A al1 353 C al 354 D al 355 A 03 356 C 03 357 D 03 358 A y3 359 C y3 360 D 3 361 A 04 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 363 D 04 364 A YI 365 c yl 366 D y 367 A E 368 C E3___ 369 D 03 370 A Y' 371 C X1~ 372 D C 373 A 374 C 375 D 376 A 1i 377 C 378 D 1c 379 A 01 380 C 01 381 D 01 382 A -2 383 C rI2 384 D ic2 385 A 386 C 387 D 388 A 310 389 C 1310 390 D 1310 391 A y6I 392 C y6 393 D y6 394 A v2 395 C v2 396 D v2 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 34: Comp. RI R2 397 A 0 398 C 01 399 D 01 400 A a 401 A Ell 402 A X8 403 A E9___ 404 A 3 405 A (o2 406 A a 407 A g7 408 A j3 409 -A xr4 410 A cLV 411 A g8 412 A a 413 A 610 414 A K3 415 A M1 416 A y7 417 A y8 418 A 79 419 C a~4 420 C Ell 421 C X8 422 C C9 423 C 43 424 C o)2 425 C at6 426 C -7 427 C 3 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 429 C cL7 430 C g 431 C al 432 C 810 433 C 0 434 C c12 435 C y7 436 C 78 437 C 792 438 D aL4 439 D E11 440 D 7, 441 D E9 442 D 3 443 D o 444 D a6 445 D g7L 446 D L.

447 D cr4 448 D 07 449 D g8 450 D axl 451 D 810 451 D 03 453 D s12 454 0 y7f 455 D 8 456 D9 Exampjle WO 2004/022572 WO 204/02572PCT/AU2003/001 146

-COMP.

457 Comp. RI R 457 D 0 R2 01 458 D P 459 D X 461 D g Example 36: Camp. RI R2 462 D P-2 463 D ayl 464 D 6 465 D P4 466 D Ol Example 37.: R3 Compound No. RI R2 R3 467 E X3 E3_ 468 E g6 Z 469 E E I3 470 E X3 ly 471 E j0 W 472 473 a3 1V WO 2004/022572 PCT/AU2003/001146 474 E X2 l 475 C x3 I1 476 C g6 1l 477 C 03 V1 478 C X4 l 479 C X2 Il 480 A X3 Wl 481 A p6 W 1 482 A a3 Wl 483 A X4 1 484 A x2 1l Example 38: NH2 Compound No R1 R2 R3 485 A 75 T 1 486 A X9 W1 487 A X7 ul 488 A 710 Il 489 A 7 11 Il 490 A y12 1l 491 A X13 I1 492 A X1 4 Wl 493 A X15 1l 494 A %16 It/1 495 A X17 IL1 496 A X18 gl 497 A X1 9 l/1 498 A X23 l1 499 A 04 W1 500 A 720 Wl 501 A 4 yl 502 A il311 1 503 A X21 1 504 A X22 Il WO 2004/022572 PCT/AU2003/001146 505 C X5 1l 506 C X9 1l 507 C x7 Wl 508 C zcl0 Y 509 C 11i wl 510 C X 12 y w 511 C X 113 W l1 512 C X14 wl 513 C x,15 y l 514 C Z216 q 515 C x17 qf 1 516 C 18 T 1 517 C 19 y 1 518 C X x23 y 1v 519 C a4 1 1pl 520 D I0 521 C I 4 Y Iv 522 D 11 yl 523 C x21 Iyl 524 C X x22 I lv 525 D X15 wl 526 D X19 j 527 D X17 Wl 528 D zl8 Y 529 D I xll W ur 537 D X12 W 1 531 D X13 y 1 539 D X14 yl 533 D XIS w 534 D 16 Wl 535 D X 17 W ur 536 D X 18 xyl 537 D X x19 xyl 538 D X23 y 1r 539 D a4 W 540 D 120 W1 541 D 4 W 1I 542 D p pl TI~ 543 D x 2 1 yl 544 D X22 Wl 545 A X5 X1 83 WO 2004/022572 PCT/AU2003/001146 1 546 .9 X9-1 547 A 7 x7-1 548 A X10 X10-1 549 A x11 X11-1 550 A X12 X12-1 551 A 13 X13-1 552 A 14 X14-1 553 A 1 5 X15-1 554 A xl6 X16-1 555 A x17 x17-1 556 A x18 %18-1 557 A x19 X19-1 558 A x23 X23-1 559 A aG4 74-1 560 A 20 20-1 561 A 4 4-1 562 A P11 563 A X22 2-1 564 C 565 C X9 x9-1 566 C X7 7-1 567 C X1O X10-1 568 C %11 X11-1 569 C X12 X12-1 570 C X13 X13-1 571 C X14 X1 4 -1 572 C Xl5 X15-1 573 C X16 X1 6 -1 574 C X17 X1 7 -1 575 C X18 Xl 8 -l 576 C Y19 X19-1 577 C X 23 X23-1 578 C 74 a4-1 579 C x20 X20-1 580 C 4 4-1 581 C 11 P 582 C X22 X22-1 583 D X5 X 584 D x 9 1 585 D X7 X7-1 586 D XlO Xl0-1 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 587 'ri 1 yll-1 588 D -X1 2

X

1 2 -1 589 D 1 3 _X13-1 590 D 14 X1 4 -1 591 D 15 X15-1 592 D 16 X16-1 593 D X17 X17-1 594 D 18 x18-1 595 D 19 x19-1 596 D X2 23-1 597 D a4 cr4-1 598 D 4 4-1 599 D P11 P4 600 D X22 X22-1 Examplie 39: Compound No RI R2 R3 601 A al.

602 A a 603 A F2 al.

604 A cxl l 605 A -c2 xl 606 A jA axl 607 E -c2 axl 608 E g2 axl 609 E g3 cl 610 E a cl WO 2004/022572 PCT/AU2003/001146 Example Compound No RI R2 R3 R4 611 C X4 W 1 Jl 612 F X5 y1 Wl 613 D X 5 Wl xyl 614 C X5 Wl xyw 615 G Z 5 w Wl 616 H X5 MA Ni 617 F X5 Y,5 xyl 618 D X5 K5 1 619 C X5 K5 l 620 G X 5 K5 1 l 621 H X5 KS 622 F X5 I 623 D X5 624 C X5 wl 625 G X5 Vi 626 H X5 Wl 627 F X5 012 1P12 628 D X5 112 1312 629 C X5 -12 1P12 630 G X5 112 1312 631 H X5 112 1312 632 F X18 jl wl 633 D X18 XiV1 jjyj 634 C X18 XV1 wl 635 G X18 W I1 Wl 636 H X18 yI 1

W

637 F s18 r,5 xy 638 D Xl18 c5 TI 639 C X18 r5 W 640 G y, 18 Y,5 1 641 H X1 8 16 WS 642 F X18 wl TA IX gx E 1789 gA JW iX C7389 gA ~JITF -IX Ca 99 P1 IX18 ph 5- X H 089 ph g~ xE 6L9 i3W g- Ix r- 3 RL9 IX gx a LL9 phV gx I 9L9 7fh JA 1 IX H GL9 Ik ph' TX 9z E 1719 7Kh JA X gx 0 L9 JA fj1' -X a ZL9 zTid zidJ tX H 0L9 ZN~ Ztid E 699 zTVJ zidi X 0 899 zlif ~ilJ U L99 gA TA~ H 999 gA TAI E 9 1799 gA ojI CX 3 99 UW *1 c99 TA HN1 099 Tl T- b 699 JA 37 999 Il a c L99 I tx-- j 999 W t4 X H 999 Ti X 1799 NiK TX a =I z% g9 ZrU zi H m9 ix !D 099 ZiTi zidJ 3 6V79 Zi-V zEd aT qv 17 ZIF ZW 8-yJ L179 ph 81 H 9M7 gA uph 81 st'9 gA 3A 17179v 81 CV9 91'1 OO/fOOZT1V/13)d LUIOrOA ZLgZZO/VOOZ OA WO 2004/022572 PCT/AU2003/001146 W r I 'vi I E I 686 D X5 Xl j12 p312 687 C X X P12 1012 688 G X :5 xl P 12 D 12 689 H X5 Xl 112 P 12 690 F X18 X1 8 -1 'I V vW 691 C X18 X1 8 -1 x1 T 1 692 G X18 X18-1 xl VVI 693 H X18 X18-1 yl1 j 694 H X(18 X18-1 0 I 695 F X18 X(18-1_ yl 696 C X(18 x18-i1 Wl vS 697 D (18 9(18-1 xyl vS 698 G X18 X18-1 jr4 vS 699 H 18 lX1 8 -l1 y vS 700 F Z18 x 1 8 -1 112 1312 701 D _X18 X1 8 -1 112 1P12 702 c -Xl8 18-1 p312 1312 703 G 18 18-1 112 P12 704 H x(18 l,1 8 -1 p12 0312 705 F X4 X24 xjjl If1 706 C X,4 X24 wl1 N/I 707 G Y.4 X24 Wi IWl 708 H X4 X24 Mf 1 Wl 709 F x4 x24 710 D X4 X24 K5 1 711 C X4 X24 ic5 W 712 H X4 X24 713 D X4 X24 'V 1 vS 714 F X4 X24 112 1312 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 41: Compound No. RI R2 R3 715 A X5 al1 716 C X5 axl 717 A X3 al1 718 C X3 al 719 A ar3 al1 720 C ar3 al1 721 A X5 722 C X5 723 C X5 724 A Y- 725 C X3 726 C X3 727 A cr3 728 C cr3 729 c cY3 Example 42: R31* J

N

0 R2 H' b Compound No RI R2 -R3 730 A P2 al1 731 A E5 l 732 A P3 at 733 A X19 axl 734 A XIl cx 735 A ylO a 1 736 A 5 axl 737 A cr1 a 1 738 Z4-1 al WO 2004/022572 PCT/AU2003/001146 739 740 741 742 743 744 745 746 747 748 749 750

A

A

A

A

A

A

A

A

A

A

A

A

p10 2 a4 a8 02 s5 P3 X19

XI

ylO al al al al 2a 02 P2 p2 P2 P2 P2 P2 751 A 24-1 p2 752 A p10 p2 753 A j2 02 754 A a4 32 755 A a8 p2 756 A 2 757 A s5 758 A 13 759 A X19 760 A Z1 l 761 A y10 762 A 5 763 A al 764 A 74-1 765 A u10 766 A 2 767 A a4 768 A a8 769 A P2 41 770 A g5 1 771 A P3 1 772 A yl £1 773 A 710 1 774 A l1 41 775 A X4-1 1 776 A I 777 A d2 1 778 A a4 I1 779 A a8 1 WO 2004/022572 PCT/AU2003/001146 780 A P2 1w 781 A P2 fl 782 A 65 W 783 A s5 784 A Pl3 l 785 A P3 786 A X 1yl 787 A Zl 788 A 7Y10 y 789 A Ylo 790 A 5 wl 791 A 792 A al -WI 793 A al U 794 A x4-1 jjV1 795 A p 10 wl 796 A AO 797 A A2 798 A 2 799 A a8 800 A a8 801 A Pl2 c 802 A s5 o1 803 A P 3 cM 804 A 19 o1 805 A Z 1 O1 806 A X19 W4 807 A Yl9 808 A 2 809 A pt10 f 810 A L2 1l 811 A a4 1Yf 812 A a8 71 813 A 02 r, 2 814 A s5 K2 815 A K3 r,2 816 A X19 K2 817 A I l 2 818 A YIO K2 819 A X5 K2 820 A ol Kc WO 2004/022572 PCT/AU2003/001146 821 A 7,4-1 K2 822 A j410 K2 823 A 2 K2 824 A a4 K2 825 A a8 r,2 826 A j 02 827 A 85 c2 828 A P3 c2 829 A X19 _2 830 A Z c2___ 831 A ylO -r2 832 A X5 T2 833 A al T2 834 A 24-1 r2 835 A g10 T2 836 A 02 T2 837 A a4 T2 838 A 8 v2 839 A P2 2 840 A s5 p2 841 A 03 p 842 A X19 p2 843 A X p 844 A ylO j 845 A X5 g 846 A jp 847 A X4-1 p2 848 A glO p2 849 A 2 g 850 A a4 g 851 A a8 g2 852 A 02 X 853 A s5 7,1 854 A 03 X 855 A X19 X1 856 A IXli Xl 857 A l10 Z 858 A X5 r 859 A al Xi 860 A 4-1 X1 861 A 2 X1 WO 2004/022572 PCT/AU2003/001146 862 A 'vi I 863 A a8 2 Jl 864 A 02 14 865 A s5 Z4 866 A P3 Z4 867 A X19 Z4 868 A X 4 869 A y 10 Z4 870 A X5 14 871 A al _4 872 A x4-1 Z4 873 A IglO Z4 874 A 0 _2 Z4_ 875 A a4 14 876 A a8 Z4 877 A al v1 878 A od v2 879 A al v9 880 A v4 al 881 A v4 y2 882 A v4 c2 883 A v4 'ri 884 A X1 v4 885 A rt7-1 al 886 A _7-1 y2 887 A g_7-1 c2 888 A I7-1 ul 889 A I7-1 XI 890 A ylO 61 891 A X5 ol 892 A l ol 893 A X4-1 Ol 894 A gt10 Oal 895 A a4 ol 896 A A 1l 897 A 02 1 898 A s5 71 899 A P3 11fl 900 A X19 4 901 A I l 902 A -ylO jyl WO 2004/022572 PCT/AU2003/001146 903 904

A

A al 71 905 A X4-1 I l 906 A P 1 X 907 A pll c2 908 A v4 g 909 A al al 910 A al 2 911 A ol Example 43: R3 R4 R2 H& bH Compound No RI R2 R3 R4 912 A x4 p1 2 p 913 A 7 5 1 4I il 914 A X18 1 I fl 915 A X5 l 916 A X1 8 IV1 917 A X 918 A X K5 1 919 A 7l 8 K5 1 920 A X5 012 112 921 A I 4 112 P 12 922 A X18 P1312 112 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 Example 44: Compound No RI R2 R3 923 A at a4 924 A ad P~6 925 A al 69 926 A at ic6 927 A ad cF3 928 A at X 929 A Wil a~4 930 A 1 P36 931 A Wl s 932 A W1 K6 933 A Vj a 934 A Wi X8__ 935 A 7-1 a4 936 A j7-1 J36 937 A gi7-1 69 938 A 4i~-i 939 A p71 ca3 940 A g71 941 A fit3 ax4 942 A 1113 P 943 A g13 E 944 A g 13 K6 945 A g1ji3 u~3 946 A g13 X 947 A at a 948 A al P 949 A 471 a4 950 A p01 P36 951 A p1-i1 a3 952 A p13 ar3 953 A p13 X8__ WO 2004/022572 PCT/AU2003/001146 Example Compound No RI R2 R3 954 A 4 al 955 A P2 al 956 A &3 al 957 A y2 al 958 A jl al 959 A P3 al 960 A P al 961 A 02 al 962 A 63 al 963 A y2 al 964 A Yj al 965 A P3 cl Example 46: Compound No RI R2 R3 R4 966 C ccl Wi 1 967 G ccl TI 1 968 H ccl XVi 1 969 C ccl ,5 Wl 970 G al K5 41 971 H ctl K5 Wl 972 C acl Wl 973 G al i1 974 H al 4i WO 2004/022572 WO 204/02572PCT/AU2003/001 146 975 C al 312 1312 976 G ccd P312 0312 977 h 13ctF 12 012_ Example 47: Compound No. RI R2 R3 978 A a~2 ca2-1 979 A 2 2-1 980 A 06 P 981 A 01 03 982 A c8 8 983 A P8 P 984 A 76__ 7C1 985 A r3 U 986 A ax3 03-1 987 A -v4 T 988 A a3 a 989 C X2 X2-1 990 C X3 3-1 991 C X4 X 4 1 992 C y8 VI 993 C 6 g5-1 994 C -6 T1 995 C r4 T 996 C L g6-1___ 997 D co2 a2-1 998 D 2-1 999 D 06 0 1000 D (Pl (p1-1

X

4 -1 Qx 24 1001 0 X4 1002 D V8 -VI 1003 D 'r4 r2 WO 2004/022572 PCT/AU2003/001146 1004 D 1005 D 09 @9-1 1006 D 6 6-1 1007 A X2 72-1 Example 48: o

H

2

N

N N R1 R31 R2 H4 tH Compound No. R1 R2 R3 1008 A a4 al 1009 A e11 s3 1010 A X8 X8-1 1011 A 89 1012 A 82 E1 1013 A a6 a6-1 1014 A J|3 j02 1015 A c4 1016 A a7 a7-1 1017 A al 1018 A 810 82 1019 A 3 K7 1020 A 812 s7 1021 A y7 y4 1022 A y8 78-1 1023 A y9 1024 C a4 al 1025 C 01 03 1026 C ell s3 1027 C X8 X8-1 1028 C s9 1029 C 83 81 1030 C a6 a6-1 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 1031 C 03 02 1032 C -r4 1033 C 0t a7-1 1034 C al 1035 C ElO 02 1036 C K3 0c 1037 C M1 s7__ 1038 C y7l y4 1039 C y8 78-1 1040 C Y9 y 1041 D a4 l 1042 D 01 03 1043 D 611 03 1044 D X8 X8-1_ 1045 D E9 1046 D Q E 1047 D at6 ac6-1 1048 D 3 02 1049 0 aL7 a7-1 1050 0 610 s2 1051 0 K3 0c 1052 D s12 0 1053 D j7 y4 1054 0 jy y8-1 1055 D Y9 Y WO 2004/022572 PCT/AU2003/001146 100 Example 49: Selected activity data tested at 25 micromolar except! tested at micromolar.

compound number EGF-R c-Kit VEGF ABL MET PDGFalpha CDK2 Tie2 PKC P38 100 69 52 58 109 88 106 70 42 146 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 0 246 15 6 81 30 27 28 26 -1 13 279 66 17 31 6 72 85 20 12 345 58 40 54 74 87 82 67 41 456 96 92 96 107 103 113 28 91 104 466 84 55 72 110 102 104 114 88 87 4861 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 9 659! 17 63 8 94 668! 16 1 669! 11 34 1 97 670! 9 23 1 718! 7 8 1 725! 6 912 88 38 44 96 88 96 119 72 96 Blank not determined.

The following lists examples of compound numbers that demonstrate activity s 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: 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, is 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, 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 668,669,670,100,198,205,207, 221,222,223,224,225,227,233, 273,279,291,345,370,371,379, 209,211,212,214,215,216,218,220, 235,238,244,246,252,254,256,271, 403,466: 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, 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: CDK2 inhibitors at25 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 912, inhibitors at 25 micromlar: 470, 471, 472, 474, 478, 480, 604, 605, 611, 508,528,534,535,604,605,606,607,608,609,610,654,657,658, 659,660,667,668,669,670, 108,109,113,114,127,131, 152,153,154,155,160,168, 212,217,214,215,216,218, 235,238,240,241,244,246, 333,334,345,376,379,446, 71,91,92,99,100,101,103,104,106,107, 135,136,138,139,143,144,145,146,151, 177,178,183,192,198,205,207,209,211, 220,221,222,223,224,225,227,231,233, 248,250,252,254,256,271,273,279,291, 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, 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: WO 2004/022572 WO 204/02572PCT/AU2003/001 146 102 Tables of Substituents: "Nz N N cd 31F CI CN CH 3 3 I ci3 N H 3 N Z c 5;F I

NZ

N0 2

CF

3

N

1(2 Z1

H

3 C N H 3 CI N

H

3 C O H 3 02

OH

3 :2 14 4 0 2 763 O; H 3 ,y 3 1 6 52 Fj F

H

3

O,,

v2

H

3 0 03 HC CH 3

H

3

OH

3 E6

H

3

CA

V5 p2

H

3 07 H3C->-, v6

OCH

3

HO--

p 1

CF

3 704 HOyf 0 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 103 NO, 7t4 HC' 'CH, a2 J~L1

HC

CF

3

F

,y 0 0

HA-'

N'

1

N

N

Kl.

P36 Br 01

CH

3 o

(CH)

7 O H 3

H

3 C H, 3 C1 270, Cv C'N 0 2 N P738 715 H N C'

I

N'N

C

r3 a3

T

FC&

K6 p 1 0

XCF,

K6 1312 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 104 ci 0

HC&

0 H3CN 1) Z2 X0 H3C,,NC) N 4 0-K aL4

H

3

C

HCOH

3 610 Br'C 02 ell y,6 03 Br04 CH3

ZN

NC'

010

HN-J

p 1 7 ax6

CCF

3 0c

'N

'N 3 a7

OH

3 'N NH ,r4 g±8

F

K8

F

3 C

F)

7 9 N 'N JL9 c12 y WO 2004/022572 WO 204/02572PCT/AU2003/001 146 105 Y,9-

(CHA)

X

1 0- 1 Y IOCH 3

H-

OCH

3 Xll-1

H

3 CO 'NC

C

X15-1

CM

3 X12-1 HO CH, X16-1 I H 3 CO

H

3 CO OCH 3

H

3 CO) OCH 3 X13-1 X14-1

H

3 CO

'N

OCH,

X17-1

HO"

X18-1

H

3 CO

M

3

CO

X19-1 X. 20-1

OH-

H

3

CO

X

2 1-1

X

2 4 (X4-1) 'N

HO

X22-1

X

2 3 1 Kl: C i C o ca4-1 H 44-1 OMe

X

7 -1 WO 2004/022572 WO 204/02572PCT/AU2003/001 146 106 y,13-1 Y,10-1

H

3 00

N

HCO OCH, S14-1 'N H 2 O H 3 H 3

OCH

3 2 11 -1 HC0 00LOH, X 15-1 ,co

OCH,

H

X

16 1 H ,0 0

'N

X1 7-1

OH

X

2 1-1 'N H 3 00 HO'I H 3 00 X18-1X 19 1 Z22-1X 2 3 -1 'r

X

2 0 -1 pCl 0N

X

24 Qx 4 cY4-l H 4l1O~

Z

7 -1 WO 2004/022572 PCT/AU2003/001146 107 42-1 a3-1

X

2 -1 a2-1 x 3 C)-i H, X3-1

OCH

3 X8-1 p.5-1 p.6-i (p1-1 p9-1 (:r a6-1 k'5 yF y 8 -1 ,710

H

3

C

NN

g.13 a7-i

CF

3 K7 p12 Throughout the specification and the claims (if present), unless the context requires otherwise, the term "comprise", or variations such as "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 and scope of the invention

Claims (47)

1- F 0 A R, R R N '315 110 c R6 is selected from the group consisting of: H, C1 to C7 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, (C3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, optionally R7 and R8 combine to form a cyclic 0s 5 structure; optionally R6 and one of R7 or R8 combine to form a cyclic N structure; with the proviso that R6, R7 and R8 are not all H, SR9 is selected from H, or -(CO)-R6, t'n R7, R8, R11, R12, R14, are independently selected from the 0group consisting of: H, C1 to C7 alkyl, C2 to C7 alkenyl, C2 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, optionally R11 and R12 combine to form a cyclic structure; R13 is selected from the group consisting of :unsubstituted phenyl unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C2 to C7 alkenyl, C2 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, and the groups R1 to R14 are optionally substituted; 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, 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.

2. The method of claim 1, wherein R1 is substituted, cyclic or acyclic, branched and/or linear.

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 form a cyclic structure.

5. The method of claim 1, wherein R11 and R12 combine to form a cyclic structure,

6. The method of claim 1, wherein X is selected from: OR1, N pN N R2 R3 or N. N' R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C1 to C7 112 u heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl Sand C3 to C14 heteroarylalkyl, C R4 is selected from the group consisting of: H, C1 to C7 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 N, heteroarylalkyl, is selected from the group consisting of: H, C1 to C7 alkyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, SC3 to C14 heteroaryl, C6 to C14 arylalkyl or C3 to C14 heteroarylalkyl, C1 to C7 acyl, C6 to C14 arylacyl, and C3 to C14 heteroarylacyl, optionally R7 and R8 combine to form a cyclic structure; optionally R6 and one of R7 or R8 combine to form a cyclic structure; optionally R11 and R12 combine to form a cyclic structure R2 is selected from the group consisting of: OR4, and -(C=O)-NH-R4, Y is selected from: WO 2004/022572 WO 204/02572PCT/AU2003/001 146 A B R 11 R, 9 N R 12 -N C R 1 4 R 13 D R 11 F N H r N\ N R, N NS G 7 The method of claim 6, wherein at least one of RI 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. The method of claim 6, wherein R11 and R12 combine to form a cyclic structure.

11. The method of claim 1 and claim 6 wherein at least one of R1 R14 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, CF3, CHF 2 CH 2 F, nitrile, alkoxy, aryloxy, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, alkyl, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted.

12. The method of claim 1 wherein the group X is N N -R2 R 3

13. The method of claim 1, wherein the group X is WO 2004/022572 PCT/AU2003/001146 The method of claim 1, wherein X is -OR1 The method of claim 12 wherein the group Y is R 6

16. The method of claim 13 wherein the group Y is R7 O R 8 R 6 0 A

17. The method of claim 12 wherein Y is R7 e- N R, 0 B

18. The method of claim 13, wherein Y is WO 2004/022572 WO 204/02572PCT/AU2003/001 146 116 R 8 0 R 7 R 6 0 B

19. The method of claim 12, wherein Y is R 1 RIO R 9 N R1 N C The method of claim 13 wherein Y is /I I R 9 N C

21. The method of claim 12, wherein Y is R 13 D

22. The method of claim 13, wherein Y is WO 2004/022572 PCT/AU2003/001146

23. The method of claim 12, wherein Y is E

24. The method of claim 13, wherein Y is The method of claim 12, wherein Y is 118 c R, RR12 R1N4 R 13 n F t 26. The method of claim 13, wherein Y is 0 R CR 12 R N N N 14 R 13 F

27. The method of claim 12, wherein Y is N H N R7 N N G

28. The method of claim 13, wherein Y is N H rN\ N, R 7 N Re^ N R G

29. The method of claim 1 wherein the protein kinase is a serine or threonine kinase. 119 The method of claim 1 wherein the protein kinase is a tyrosine 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 known 0s 5 as TEK, HPK-6, TIE-2, VMCM VMCM1.

33. The method of claim 1 wherein the protein kinase is c-Kit also known In as SCFR, CD117, PBT. n 34. The method of claim 1 wherein the protein kinase is VEGF-R2/KDR S also known as VEGFR2 VEGFR-2 VEGFR, Hs.KDR, Hs.12337, FLK1 FLK-1. 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, ABL1.

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 known as PDGFR1, PDGFR, PDGF-R-beta, JTK12, CD140B, PDGFRB. 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.

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

42. A compound of formula I which is a derivative of a furanose form of a monosaccharide of general formula I, formula I Wherein; n is 1, X is selected from: OR1, R 4 1R N N R1 and R3 are independently selected from the group consisting of: C1 to C7 alkyl, C2 to C7 alkenyl, C2 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, C2 to C7 alkenyl, C2 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to 121 N C14 heteroarylalkyl, R5 is selected from the group consisting of: H, C1 to C7 alkyl, Z C2 to C7 alkenyl, C2 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to 014 aryl, C3 to 014 heteroaryl, C6 to C14 arylalkyl or C3 to 014 heteroarylalkyl, C1 to C7 acyl, C6 to 014 arylacyl, and C3 to 014 heteroarylacyl, optionally R4 and R5 combine to form a ring structure; R2 is selected from optionally R2 and R3 combine to form a ring structure; Y is selected from the group consisting of: 0 1 R 8 R 7 R 0 0 A B R 1 R1 6R N R N ZR411 R 13 C D R 1 R 1 3 E F G R6 is selected from the group consisting of H, C1 to C7 alkyl, C2 Sto C7 alkenyl, C2 to C7 alkynyl, C1 to C7 heteroalkyl, C6 to C14 aryl, C3 to C14 heteroaryl, C6 to C14 arylalkyl and C3 to C14 heteroarylalkyl; optionally R7 and R8 combine to form a cyclic N structure; optionally R6 and one of R7 or R8 combine to form a cyclic Sstructure with the proviso that R6, R7 and R8 are not all H, SR9 is selected from H, or -(CO)-R6, R7, R8, R 11 R12, R14, are independently selected from the group consisting of: H, C1 to C7 alkyl, C2 to C7 alkenyl, C2 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, optionally R11 and R12 combine to form a cyclic structure; R13 is selected from the group consisting of: unsubstituted phenyl, unsubstituted benzyl, substituted phenyl, substituted benzyl, H, C1 to C7 alkyl, C2 to C7 alkenyl, C2 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, and the groups R1 to R14 are optionally substituted; 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, 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.

43. The compound of claim 42, wherein R7 and R8 combine to form a cyclic cstructure. 0s 5 44. The compound of claim 42, wherein R6 and one of R7 or R8 combine to Sform a cyclic structure. In The compound of claim 42, wherein R11 and R12 combine to form a 0cyclic structure.

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

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 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, amidine, guanidiniums, carboxylic acid, carboxylic acid ester, carboxylic acid amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoalkyl, alkyl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted, The compound of claim 42 in which the group X is WO 2004/022572 PCT/AU2003/001146 124 NN S R2 R3

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

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

53. The compound of claim 50 wherein Y is R7

54. The compound of claim 51 wherein Y is The compound of claim 50, wherein Y is WO 2004/022572 PCT/AU2003/001146 R 6 The compound of claim 51, wherein Y is

57. The compound of claim 50, wherein Y is RI Rio S/ R,-k- C The compound of claim 51, wherein Y is R R 9 S/ 1 R N

59. The compound claim 50, wherein Y is WO 2004/022572 PCT/AU2003/001146 R 14 D The compound claim 51, wherein Y is

61. The compound of claim 50, wherein Y is

62. The compound of claim 51, wherein Y is WO 2004/022572 PCT/AU2003/001146 127 R 1 N R14 E

63. The compound of claim 50, wherein Y is R11 R 12 f N R14" R 13 F

64. The compound of claim 51, wherein Y is R11 N N ,N R14 R13 F The compound claim 50, wherein Y is N H RN N

66. The compound claim 51, wherein Y is 2003257259 m 13 Jul 2007 C)