AU2003266858B2

AU2003266858B2 - Classes of compounds that interact with GPCRs

Info

Publication number: AU2003266858B2
Application number: AU2003266858A
Authority: AU
Inventors: Giovanni Abbenante; Judy Halliday; Giang Le Thanh; Wim Meutermans; Gerald Tometzki; Johannes Zeugg
Original assignee: Vast Bioscience Pty Ltd
Current assignee: Vast Bioscience Pty Ltd
Priority date: 2002-10-11
Filing date: 2003-10-10
Publication date: 2006-09-14
Anticipated expiration: 2023-10-10
Also published as: AU2003266858A1

Description

WO 2004/032940 PCT/AU2003/001347 CLASSES OF COMPOUNDS THAT INTERACT WITH GPCRs FIELD OF THE INVENTION The invention provides classes of biologically active compounds that interact in a pharmaceutically significant manner with G-Protein Coupled Receptors (GPCRs), pharmaceutical compositions containing such compounds and methods of treatment of humans suffering from a disorder which can be at least partially overcome by the compounds or compositions.

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 will lead to vast numbers of targets for therapeutic intervention.

GPCRs represent the most important collection of therapeutic targets available.

GPCRs are proteins that tranduce signals across a cell membrane. They consist of a single polypeptide chain that threads back and forth seven times across the phospholipid bilayer that forms the cell membrane. The polypeptide chain has a portion inside the cell which form a G-protein coupling domain, and a receptor portion outside or in the cell wall. A signal molecule interacts with the receptor which sends the signal through the membrane wall and the signal causes the G-protein coupling domain to interact with a G protein.

Over 50% of marketed drugs target GPCRs. Whilst the druggable extent of GPCRs numbers some 450 receptors only some 200 GPCRs have been matched with their ligands. Orphan receptors suitable for drug targeting may therefore number in excess of 200 receptors. These are receptors with less than approximately 45% sequence identity to known GPCRs for which ligands have not been identified.

The targets of current GPCR drugs include, pain and inflammation, cancer, metabolic and gastrointestinal, cardiovascular and central nervous system disorders.

There is a continuing demand for new therapeutics, especially as our understanding of biological processes expands from the genomics revolution. The aforementioned GPCRs are suitable targets for therapeutic intervention due to their roles in such disorders as cancers, obesity and erectile dysfunction.

Considering the rate of generation and nature of the targets currently WO 2004/032940 PCT/AU2003/001347 2 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 GPCRs.

From a drug discovery perspective, carbohydrate pyranose and furanose rings and their derivatives are well suited as templates. Each sugar represents a threedimensional 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.

Employing a related methodology, Hirschmann et al (Hirschmann, R., et. al., J. Am. Chem. Soc., 1992, 114, 9217-9218, US 5,552,534, WO 97/28172, WO 95/11686) synthesised several compounds designed as somatostatin analogues and integrin binders. The methodology employed by Hirschmann relied on protracted, linear, non-combinatorial syntheses, employed exclusively non-aminated pyranoses, and did not exploit any epimerisation chemistry to allow greater access to structural diversity. Consequently, these compounds and methods are manifestly distinct from this present invention.

We have developed a 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.

Using the axioms of this drug discovery methodology, we synthesised several novel classes of chemotypes in an effort to develop drug candidates against GPCR targets.

WO 2004/032940 PCT/AU2003/001347 3 SUMMARY OF THE INVENTION It is a general object of the invention to provide compounds that interact with GPCRs in a biologically significant manner, 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.

In one aspect the invention provides for compounds of general formula I, that interact with GPCRs in a biologically significant manner,

R

7

R

6 0

ZR

1

R

5

X

R

4 X XR 2

XR

3 General Formula I Wherein the ring may be of any configuration; Z is sulphur, oxygen, CH 2 C(O)HNRA, NH, NR A or hydrogen, in the case where Z is hydrogen then R 1 is not present, R A is selected from the set defined for R 1 to R 5 X is oxygen or nitrogen providing that at least one X of General Formula I is nitrogen, X may also combine independently with one of R 1 to R 5 to form an azide, RI to Rs are independently selected from the following definition which includes but is not limited to H or an alkyl, acyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl substituent of 1 to 20 atoms, which is. optionally substituted, and can be branched or linear. Typical substituents include but are not limited to 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, WO 2004/032940 PCT/AU2003/001347 4 heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted, and

R

6 and R 7 are hydrogen, or may combine to form a carbonyl function.

In one embodiment the invention provides for compounds of general formula II that interact with GPCRs in a biologically significant manner, S ZR 1

R

5

X

HO y '""R2

XR

3 General Formula II Wherein R 1

R

2

R

3 Rs, Z and X are defined as in General Formula I.

In a second embodiment the invention provides for compounds of general formula III that interact with GPCRs in a biologically significant manner, o A

R

5

X

R

4 X XR 2

XR

3 General Formula III Wherein A is defined as hydrogen, SRI, or OR, where R 1 is defined as in General Formula I, and X and R 2 to R 5 are defined as in General Formula I.

In a preferred embodiment the invention provides for compounds of General Formula IV that interact with GPCRs in a biologically significant manner, WO 2004/032940 PCT/AU2003/001347 MeO 0 OR 1 HO" NHR 2

OR

3 General Formula IV Wherein Ri-R 3 are defined as in General Formula I.

In a second preferred embodiment the invention provides for compounds of General Formula V that interact with GPCRs in a biologically significant manner, 0 OR 1 HO.'

"NHR

2 OMe General Formula V Where in R 1

R

2 and R 5 are defined as in General Formula I.

In a third preferred embodiment the invention provides for compounds of General Formula VI that interact with GPCRs in a biologically significant manner,

NH

ROO 50

NH

2 V '/'N(RA)R2

OR

3 General Formula VI Wherein R A is H or combines with R 2 to form an azide, and

R

3

R

3 and R 5 are defined as in General Formula I.

WO 2004/032940 PCT/AU2003/001347 6 In a fourth preferred embodiment the invention provides for compounds General Formula VII that interact with GPCRs in a biologically significant manner of,

R

s O 0 SMe HO "'NHR 2

OR

3 General Formula VII Wherein, R 2

R

3 and R 5 are defined as in General Formula I.

In a fifth preferred embodiment the invention provides for compounds of General Formula VIII that interact with GPCRs in a biologically significant manner, MeO O OR 1 HO' NHR 2

OR

3 General Formula VIII Wherein R, to R 3 are defined as in General Formula I.

In a sixth preferred embodiment the invention provides for compounds of General Formula IX that interact with GPCRs in a biologically significant manner, WO 2004/032940 PCT/AU2003/001347 7 General Formula IX Wherein R 2 and R 5 are defined as in General Formula I.

In a seventh preferred embodiment the invention provides for compounds of General Formula X that interact with GPCRs in a biologically significant manner, HO* "NHR 2 0

NH

2 General Formula X Wherein R 2 and Rs are defined as in General Formula I.

In an eighth preferred embodiment the invention provides for compounds of General Formula XI that interact with GPCRs in a biologically significant manner, SMe

NHR

NH2

NH

2 OR 3 General Formula XI Wherein R 2 and R 3 are defined as in General Formula I.

In a ninth preferred embodiment the invention provides for compounds of General Formula XII that interact with GPCRs in a biologically significant manner, WO 2004/032940 PCT/AU2003/001347 8 a 0 SMe HO~ N HR 2

NH

2 OR 3 General Formula XII Wherein R 2 and R 3 are defined as in General Formula I.

The compounds of the invention may be mixed with a pharmaceutical 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.

WO 2004/032940 WO 204102940PCTIAIJ2003/001347 Examples of the Invention Substituents per Example Libraries 1- 14 Pi 0 H H0H -f NH f r, N ,NH "CNH GI rN.H 2 0 G2 NH 2 G3 NH 0 yl_-NH 2 Al

NH

2 0A2 P3 ci P5 P6 P2 P4 0 A -NH 2 A3

A-CH

3 P7 0 E2 E30- 0 0 El N

H

0 N ES H 0 E6 N

H

NNH

2 N4

VI'CH

3 V N

H

3

NH

2 H

NH

2 0 EB oE9 HN NNH,

N

AIEl 0

NH

H

El16

NH

0 NH 2 EllI WO 2004/032940 PCT/AU2003/001347 Assay Conditions GPCR radioligand binding (RLB) assays Recombinant human receptors expressed in HEK 293 cells were used for all experiments. Receptor membrane preparations were purchased from Perkin Elmer BioSignal. The labelled ligand used in somatostatin GPCR RLB assays was 125 I]SST-14 and in melanocortin assays was [1"I]NDP-aMSH. All assays were done in a 96-well plate format using either glass fiber filter mats or filter plates. All reagents purchased were of the highest quality.

Specific assay buffer, incubation and washing conditions were optimized for each receptor however they all followed the same general format. The procedures for both filter mat and filter plate formats are based on the receptor manufacturers recommendations or those described extensively in the literature. The procedures are briefly outlined below.

In assays where filter mats are used we incubate receptor membranes, assay buffer and [1251] labelled ligand in 96 well microplates. Add compounds to incubation mixture and continue incubation for optimized period. Presoak Filter mat GF/B in 0.5 PEI for -2 hr at 4 0 C. On completion of assay mixture incubation add additional 100 L/well of assay buffer immediately prior to filtration. Filter the assay mixture onto the GF/B filter mat using a cell harvester. Dry the filter mats prior to sealing them into a scintillation counting bag with scintillant. Radioactivity in each well is detected by liquid scintillation counting.

In assays where filter plates are used Multiscreen glass fiber filter plates (Millipore, Cat No MAFCNOB10) are precoated with 0.5 PEI for -2hr at 4 0 C. All wells are then washed with 200 Ol/well assay buffer and filtered using the Multiscreen Separation System. Subsequently receptor membranes, assay buffer and labelled ligands are added to the wells and equilibrated. Compounds for testing are then added to the mixture and incubation is continued for an optimized time. Plates are then put into the Multiscreen Separation System and the assay mixture is filtered through the plate under vacuum. Each well is then washed several times with assay buffer. Plates are then dried prior to putting sealing tape onto the bottom of the plate.

Scintillant is added to each well and radioactivity measured by liquid scintillation counting.

WO 2004/032940 PCT/AU2003/001347 11 Comparison of assay conditionsfor 2 different assays MC4 Receptor membranes 2( d of labelled ligand (-80000 cpm) unlabelled ligand mQH 2 0 Compounds assay buffer Total volume (UL) S(1 ilut st( 10 Volume OL :40 40 (1:40 ion dilution of )ck) stock) 10 10 50 100 200 Data analysis Raw data was analysed according to standard methods using either GraphPad Prism software or IDDBS ActivityBase software.

Key for Assay Results Libraries 1-14 Indicates inhibition greater than... Indicates inhibition less than...50 WO 2004/032940 WO 204/02940PCTAU2003/001347 Example Library I CR4 o CR1 NHR2 CR3 Compound RI 112 R3 114 MC4 Number inhibition at inhibition at micromolar micromolar 1 PI GI Pt P7 *2 P1 G2 P2 P7 3 P1 A3 P3 P7 4 P2 A3 P3 P7 P3 Gi P1 P7 6 P3 G2 PI P7 +I 7 P3 A3 P1 P7 8 P3 G3 P1 P7 9 P3 A3 P3 P7 P3 G2 P4 P7 11 P3 A3 P4 P7 12 P3 G3 P4 P7 13 P4 G2 P1 P7 14 P4 G2 IP2 P7 P4 G3 JP2 P7 16 P4 A3 JP3 P7 17 P4 G2 JP4 P7 18 P4 G3 JP4 P7 19 P5 GI IP1 P7 P5 G2 IPt P7 21 P6 G2 P1 P7 22 P1 A3 P6 P7 23 P2 A3 P6 P7 24 P2 G3 P6 P7 P3 A3 P6 P7 26 P4 A3 P6 P7 27 P5 A3 P6 P7 28 PI A3 Pt P7 29 P1 G3 P1 P7 Pt G3 P2 P7 WO 2004/032940 WO 204/02940PCT/AU2003/001347 31 P1 JG2 P3 JP7 I 32 P1 G2 P4 P7 33 P1 A3 P4 P7 34 P1 G3 P4 P7 P2 GI P1 P7 36 P2 G2 P1 P7 +I 37 P2 A3 Pl P7 38 P2 G2 P2 P7 .39 P2 A3 P2 P7++ P2 G3 P2 P7 41 P2 G3 P3 P7 42 P2 A3 P4 P7 43 P2 G3 P4 P7 44 P4 A3 P1 P7 P4 G3 P1 P7 +4 46 P4 A3 P2 P7 47 P4 G3 P3 P7 48 P5 A3 PI P7 49 P5 G3 P1 P7 P5 A3 P2 P7 51 P5 A3 P4 P7 52 P5 G3 I4 P7 I 53 P1 A3 IP1 P7 54 P3 A3 JP2 P7 P4 A3 I4 P7 WO 2004/032940 WO 204102940PCTiAU2003!001347 Example Library 2 0R4 o ORI HU "NHR2 0R3 Compound RI R2 R3 R4 MC4 Number Inhibition at Inhibition at micromolar micromolar 56 P1 G1 P7 P1 57 P1 G2 P7 PI 58 PI G3 P7 P1 59 P1 GI P7 P2 P1 G2 P7 P2 I 61 PI A3 P7 P2 62 P1 G3 P7 P2 63 P1 G1 P7 P4 64 P1 G2 P7 P4 P1 A3 P7 P4 66 P1 G3 P7 P4 67 P2 GI P7 P1 68 P2 G2 P7 Pt 69 P2 A3 P7 P1 P2 G3 P7 P1 71 P2 Gl P7 P2 72 P2 G2 P7 P2 73 P2 A3 P7 P2 74 P2 G3 P7 P2 IP2 G1 IP7 P4 I 76 P2 G2 P7 P4 77 P2 A3 P7 P4 78 P2 G3 P7 P4 79 P3 G3 P7 P1 P3 GI P7 IP2 81 IP3 A3 P7 IP4 82 P3 -G3 P7 IP4 83 P4 Gl P7 IP1 84 P4 G2 P7 JP1 P4 A3 P7 P1 86 P4 G3 P7 P1 87 P4 GI P7 P2 WO 2004/032940 WO 204/02940PCT/AU2003/001347 89 P4 A3 P7 P2 P4 G3 P7 P2 91 P4 A3 P7 P3 92 P4 G1 P7 P4 93 P4 G2 P7 P4 94 P4 A3 P7 P4 P4 G3 P7 P4 96 P5 G1 P7 P1 97 P5 G2 P7 P1 98 P5 A3 P7 P1 99 P5 G3 P7 PI 100 P5 Gi P7 P2 101 P5 G2 P7 P2 102 P5 A3 P7 JP2 103 P5 G3 P7 P2 104 P5 GI P7 P4 105 P5 G2 P7 P4 106 P5 A3 P7 P4 107 P5 G3 P7 P4 108 P1 GI JP7 jP6 109 P2 A3 P7 P6 110 P4 G2 P7 P6 111 P4 A3 P7 P6 112 P6 GI P7 P1 113 P6 G2 P7 P1 114 P6 A3 P7 P1 115 P6 G3 P7 P2 116 P6 G2 P7 P2 117 P6 G3 P7 P2+- 118 P6 A3 P7 P4-+ WO 2004/032940 WO 204/02940PCT/AU2003/001347 Example Library 3 CR4 C SM e HOV' "NHR2 &R3 ComnpoundR2 R3 R4 MC4 Number inhibition at inhibition at micromolar 10 micromolar 119 Al P3 P3 120 G1 P3 P3 121 A2 P3 P3 122 G2 P3 P3 123 A3 P3 P3 124 G3 P3 P3 125 Al P3 P4 126 GI P3 P4 127 A2 P3 P4 128 G2 P3 P4 129 A3 P3 P4 130 G3 P3 P4 131 Al P3 P1 132 GI P3 P1 133 A2 P3 P1 134 G2 P3 P1 135 A3 P3 P1 136 G3 P3 P1 137 Al P3 P2 138 G1 P3 P2 139 A2 P3 P2 140 G2 P3 P2 141 A3 P3 P2 142 G3 P3 P2 143 Al P4 P3 144 GI P4 P3 +I 145 A2 P4 P3 146 G2 P4 P3 147 A3 P4 IP3 148 G3 P4 P3 149 Al P4 P4 150 GI P4 P4 151 A2 P4 P4 WO 2004/032940 WO 204/02940PCT!AU2003/001347 152 G2 P4 P4 153 A3 P4 P4 154 G3 P4 P4 155 Al P4 PI 156 GI P4 P1 157 A2__P4 P1 158 G2 P4 PI 159 A3 P4 PI 160 G3 P4 PI 161 Al P4 P2 162 GL P4 P2 163 A2 P4 P2 164 G2 P4 P2 165 A3 P4 P2 166 G3 P4 IP2 167 Al P1 P3 168 GI P1 P3 169 A2 P1 P3 170 G2 P1 P3 171 A3 P1 P3 172 G3 P1 P3 173 Al P1 P4 174 GI P1 P4 175 A2 PI P4 176 G2 P1 P4 177 A3 P1 P4 178 G3 PI P4 179 Al P1 JP1 180 Gi P1 P1 181 A2 PI P1 182 G2 PI PI 183 A3 P1 PI 184 G3 P1 P1 185 Al P1 P2 186 GI P1 P2 187 A2 P1 P2 188 G2 PI P2 189 A3 P1 P2 190 G3 P1 P2 191 Al P2 P3 192 Gi P2 P3 193 A2 P2 P3 194 G2 P2 P3 195 A3 P2 P3 196 G3 P2 P3 197 Al P2 P4 WO 2004/032940 WO 204/02940PCT/AU2003/001347 198 GI P2 I4 I 199 A2 P2 P4 200 G2 P2 P4 201 A3 P2 P4 202 G3 P2 P4 203 Al P2 P1 204 GI P2 PI 205 A2 P2 P1 206 G2 P2 P1 207 A3 P2 Pl 208 G3 P2 P1 209 Al P2 P2 210 GI P2 P2 211 A2 P2 P2 212 G2 P2 P2 Example Librar 4 OMe o R1 HO~~ "NHR2 6R3 Compound Ri R2 R3 MC4 inhibition Number at 10 inhibition at micromolar micromolar 213 P3 Al P3 214 P3 Gi P3 215 P3 A2 P3 216 P3 G2 P3 217 P3 A3 P3 218 P3 G3 P3 +4 219 P3 Al P4 220 P3 Gl P4 221 P3 A2 P4 222 P3 G2 P4 223 P3 A3 P4 224 P3 G3 P4 225 P3 Al P1 226 P3 GI PI WO 2004/032940 WO 204/02940PCT/AU2003/001347 227 P3 IA2 IN 228 P3 G2 P1 229 P3 A3 P1 230 P3 G3 PI 231 P3 Al P2 232 P3 GI IP2 I 233 P3 A2 P2 234 P3 G2 P2 235 P3 A3 P2 236 P3 C3 P2 237 P4 GI P3 238 P4 A2 P3 239 P4 G2 P3 240 P4 A3 P3 241 P4 G3 P3 +I 242 P4 Al P4 243 P4 Gi P4 244 P4 A2 N4 +I 245 P4 G2 P4 246 P4 A3 P4 247 P4 G3 P4 248 P4 Al PI 249 P4 Gi Pt 250 P4 A2 PI 251 P4 G2 P1 252 P4 A3 P1 253 IN 4 G3 P1 254 P4 Al P2 255 P4 Gl P2 256 P4 A2 P2 257 P4 G2 P2 258 P4 A3 P2 259 P4 G3 P2 260 P5 Al P3 261 P5 Gl P3 262 P5 A2 IP3 263 P5 G2 P3 264 P5 A3 P3 4 265 P5 G3 P3 266 P5 Al P4 267 P5 Gl P4 268 P5 A2 P4 269 P5 G2 P4 270 P5 A3 P4 271 P5 G3 P4 272 P5 Al P1 WO 2004/032940 WO 204/02940PCT/AU2003/001347 273 P5 Gi P1 274 P5 A2 P1 +I 275 P5 G2 Pl 276 P5 A3 P1 277 P5 G3 P1 278 P5 Al P2 +I 279 P5 GI P2 280 P5 A2 P2 281 P5 G2 P2 282 P5 A3 P2 283 P5 G3 P2 284 P2 Al P3 285 P2 GI P3 286 P2 A2 P3 287 P2 G2 P3 288 P2 A3 P3 289 P2 G3 P3 290 P2 Al P4 291 P2 Gi P4 292 P2 A2 P4 293 P2 G2 P4 294 P2 A3 P4 295 P2 G3 P4 296 P2 Al P1 297 P2 GI P1 298 P2 A2 I1 299 P2 G2 P1 300 P2 A3 P1 301 P2 G3 P1 302 P2 Al P2 303 P2 Gi P2 304 P2 A2 P2 305 P2 G2 P2 306 P2 A3 P2 307 P2 G3 P2 Example Library CR3 C SM e HONU. .'/NHR1 OR2 WO 2004/032940 PCTIAU2003/001347 Compound RI R2 R13 MC4 inhibition Number at 10 microinolar inhibition at micromolar 308 P3 N4 E2 309 P3 N4 E4 310 P3 N4 E5 311 P3 N4 E6 312 P4 N4 El 313 P4 N4 E2 314 P4 N4 E4 315 P4 N4 E5 WO 2004/032940 WO 204102940PCTiAU2003!001347 Example Library 6 CR3 o SMe H"N HRI CR2 Compound Ri R2 R3 MC4 inhibition Number at 10 inhibition at micromular 10 micromolar 316 -El N4 P3 317 E2 N4 JP3 I 318 E4 N4 P3 319 E5 N4 P3 320 E6 N4 P3 321 El N4 P4 322 E2 N4 P4 323 E4 N4 P4 324 ES N4 P4 325 E6 N4 P4 Exaniple Library 7 CR3 o SMe H "NHR1 OR2 Compound RI R2 R3 MC4 Number inhibition at inhibition at micromolar micromola r 326 EltP3 N4 327 E2 P3 N4 328 E4 P3 N4 329 ES P3 N4 330 JE6 JP3 N4 I 331 JEl P4 N4 I WO 2004/032940 WO 204/02940PCT/AU2003/001347 332 1E6 IP4 1N4 I I I Example Library 8 CR3 0 SMe H0~~ 'NHRI Compound RI R2 R3 MC4 Number inhibition at inhibition at _______micromolar micromolar 333 El P3 N4 334 E2 P3 N4 335 E3 P3 N4 336 E5 P3 N4 337 E6 P3 N4 338 El P4 N4 339 E2 P4 N4 340 E3 P4 N4 341 JE5 P4 N4 Example Library 9 CR3 0 R 1 &me Compound RI R2 R3 MC4 Number Inhibition at Micromolar 342 P4 E8 P2 343 P4 E9 P2 344 P4 ElO P2 WO 2004/032940 WO 204/02940PCTIAUI2003/001347 345 P4 GI P2 I 346 P4 E8 P2 347 P4 E9 P2 348 P4 Ell P2 349 IP4 GI P2 Example Library 0R4 o ORI H "NHR2 0R3 Compound RI R2 R3 R4 MC4 Number Inhibition at Micromolar 350 P2 A2 P4 P2 351 P2 A2 P4 -P2 352 P2 A2 P4 P3 353 P2 A2 P4 P3 354 P2 A2 P4 P4 355 P2 A2 P4 P4 356 P2 A2 P2 P2 357 P2 A2 P2 P2 358 P2 A2 P2 P3 359 P2 A2 P2 P4 360 P2 A2 P2 P4 361 P2 A2 P3 P2 362 P2 A2 P3 IP3 363 P2 A2 P3 JP3 I 364 P2 A2 P3 IP4 365 P2 A3 P4 P2 366 P2 A3 P4 P2 367 P2 A3 P4 P4 368 P2 A3 P4 P4 369 P2 A3 P2 P2 370 P2 A3 P2 P4 371 P2 A3 P2 P4 372 P2 A3 P3 P2 373 P2 A3 P3 P2 WO 2004/032940 WO 204/02940PCT/A1J2003!001347 374 P2 IA3 IP3 375 P2 A3 P3 P4 376 P4 A2 P4 P3 377 P4 A2 P4 P4 378 P4 A2 P2 P2 379 P4 A2 P2 P3 380 P4 A2 P2 P3 381 P4 A2 P2 P4 382 P4 A2 P2 P4 383 P4 A2 P3 P2 384 P4 A2 P3 P3 385 P4 A2 P3 P4 386 P4 A3 IP4 P2 387 P4 A3 P4 P3 388 P4 A3 P4 P4 389 P4 A3 P2 P2 390 P4 A3 P2 P2 391 P4 A3 P2 P3 392 P4 A3 P2 P3 393 P4 A3 JP2 P4 34 P4 A3 P2 P4+ P4 A3 P3 P2 36 P4 A3 P3 P4 Example Library I11 0R4 5R3 Compound Ri R2 R3 R4 MC4 Number Inhibition at Micromolar 397 P3 A2 P4 P2 398 P3 A2 P4 P3 399 P3 A2 P4 P4 400 P3 A2 P2 P2 401 P3 A2 P2 P3 402 P3 IA2 JP2 IP4 I WO 2004/032940 WO 204/02940PCT/AU2003/001347 403 P3 A2 JP3 jP2 404 P3 A2 JP3 jP3 405 P3 A2 P3 IP4 406 P3 A3 P4 P2 407 P3 A3 P4 P4 408 P3 A3 P2 P2 409 P3 A3 P2 P3 410 P3 A3 P2 P4 411 P3 A3 P3 P2 412 P3 A3 P3 P4 413 P2 A2 P4 P2 414 P2 A2 P4 P3 415 P2 A2 P4 P4 416 P2 A2 P2 P2 417 P2 A-2 P2 P3 418 P2 A2 P2 P4 419 P2 A2 P3 P2 420 P2 A2 P3 P3 421 P2 A2 P3 P4 422 P2 A3 P4 P2 423 P2 A3 P4 P3 424 P2 A3 P4 P4 425 P2 A3 P2 P2 426 P2 A3 P2 P3 427 P2 A3 (P2 P4 428 P2 A3 JP3 P2 429 P2 P3 IP3 430 P2 A3 IP3 JP4 Example Library 12 0R4 o ORI "NHR2 0R3 Compound RI R2 R3 R4 MC4 Number Inhibition at Micromo lar 431 P3 G IP4 P2 WO 2004/032940 WO 204/02940PCT/AU2003/001347 432 P3 GI IP4 IP2 433 P3 GI IP4 IP3 434 P3 GL P4 P3 435 P3 GI P4 P4 436 P3 GI P2 P2 437 P3 Gi P2 P2 438 P3 Gi P2 P3 439 P3 GI P2 P4 440 P3 Gd P2 P4 441 P3 GI P1 P2 442 P3 GI PI P3 443 P3 GI P1 P3 444 P3 GL P1 P4 445 P3 GL P1 P4 446 P3 G2 P4 P2 447 P3 G2 P4 P2 448 P3 G2 P4 P3 449 P3 G2 P4 P3 450 P3 G2 P4P4 451 P3 G2 P4 P4 452 P3 G2 P2 P2 453 P3 G2 P2 P3 454 P3 G2 P2 P3 455 P3 G2 P2 P4 456 P3 G2 P2 P4 457 P3 G2 P1 P2+ 458 P3 G2 P1 -P2+ 459 P3 G2 P1 P3 460 P3 G2 PI P4 461 IP3 IG2 1P1 P4 462 IP3 IG2 P1' P5 Example Librar 13 0R4 o OR

I

HOV' NHR2 bR3 Compound Ri RI1 R3 R14 MC4 Inhibition Number at WO 2004/032940 WO 204/02940PCT/AU2003/001347 [licromolar 463 P1 GI P4 P2 464 P1 GI P4 P3 465 P1 GI P4 P4 466 PI GI P2 P3 467 P1 GI P2 P4 468 P1 Gl IP1 P3 469 P1 GI IP1 P4 470 P1 G2 P4 P2 471 P1 G2 P4 P3 472 P1 G2 P4 P4 473 P1 G2 P2 P2 474 P1 G2 P2 P3 475 P1 G2 P2 P4 476 P1 G2 P1 P2 477 P1 G2 P1 P3 478 P1 G2 IP1 P4 479 P4 GI P4 P2 480 P4 Gl P4 P3 481 P4 Gi P4 P4 482 P4 GI P2 P2 483 P4 Gi P2 P3 484 P4 GI P2 P4 485 P4 Gi IP1 P2 486 P4 Gl P1 P3 487 P4 Gi P1 P4 488 P4 G2' P4 P2 489 P4 G2 P4 P3 490 P4 G2 P4 P4 491 P4 G2 P2 P2 492 P4 G2 P2 IP3 493 P4 G2 P2 P4 494 P4 G2 P1 P2 495 P4 G2 P1 P3 496 P4 G2 P1 P4 497 P1 G3 P3 P3 WO 2004/032940 WO 204/02940PCTIAU2003/001347 Example Library 14 Compound RI R2 R3 MC4 Inhibit .ion Number at Micromolar 498 A2 G4 P3 499 A2 G4 P12 500 A2 G4 P13 501 A2 G4 PI 502 A2 El P3 503 A2 El P4 504 A2 El P12 505 1A2 El P13 506 JAl El 1P3 1 507 JAl E IP4I 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

1. A method of inhibiting or effecting the activity of a GPCR which comprises contacting a GPCR with a compound of general formula 1, or a pharmaceutically acceptable salt thereof RsX O ZR, R 4 X XR 2 XR 3 General Formula I Wherein the ring may be of any configuration; Z is selected from the group consisting of: sulphur, oxygen, or NR A wherein RA is selected from the set defined for R 1 to R 5 or Cl to C15 acyl, C4 to C15 arylacyl or C4 to C15 heteroarylacyl, with the proviso that both Ri and R A are not hydrogen, X is selected from the group consisting of: oxygen or NR A providing that at least one X of General Formula I is NRA, R, to R 5 are independently selected from the group consisting of: H, Cl to C12 alkyl, Cl to C12 alkenyl, Cl to C12 alkynyl, C1 to C12 heteroalkyl, C4 to C15 aryl, C4 to heteroaryl, C4 to C15 arylalkyl or C4 to C15 heteroarylalkyl substituent, wherein, when X is NRA, both RA and the corresponding R 1 to R 5 are not hydrogen.

2. The method of claim 1, wherein any one of R A or Ri to R 5 is substituted with a moiety 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, WO 2004/032940 PCT/AU2003/001347 31 hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl.

3. The method of claim 1, wherein the compound is RX HO '/XR2 XR 3 General Formula II

4. The method of claim 1, wherein the compound is o A R, 5 X HO R XR 2 XR 3 General Formula III Wherein A is selected from the group consisting of: N(RA)RI, SRI, or OR The method of claim 1, wherein the compound is MeO 0 OR, HO" ''NHR 2 OR 3 General Formula IV WO 2004/032940 PCT/AU2003/001347 32

6. The method of claim 1, wherein the compound is R 5 0 OR 1 HO" "'NHR 2 OMe General Formula V

7. The method of claim 1, wherein the compound is 0 R0 0 HN NH 2 HO' "'N(RA)R2 OR 3 General Formula VI

8. The method of claim 1, wherein the compound is RsO 5 O SMe H O' "'NHRZ OR 3 General Formula VII

9. The method of claim 1, wherein the compound is MeO 0 R, R HO2''G F 'N HR 2 OR 3 General Formula VIII WO 2004/032940 PCT/AU2003/001347 33 The method of claim 1, wherein the compound is RsO' SMe HO '"NHR2 0. NH 2 General Formula IX The method of claim 1, wherein the compound is R 5 0 0 Me T"'NHR 2 0. NH 2 General Formula X The method of claim 1, wherein the compound is 1 2 OR 3 General Formula XI WO 2004/032940 PCT/AU2003/001347 34

13. The method of claim 1, wherein the compound is 0 SMe Hc,' "'NHR 2 OR 3 General Formula XII 14 The method of claim 1, wherein the receptor is a somatostatin receptor. The method of claim 1, wherein the receptor is a melanocortin receptor.

16. The method of claim 14, wherein the compound is OR4 O ORI H '"NHR2 OR3 wherein RI, R2, R3 and R4 are selected from the group combinations of: R1 R2 R3 R4 P1 G1 P1 P7 P1 G2 P2 P7 PI A3 P3 P7 P2 A3 P3 P7 P3 G2 P1 P7 P3 A3 P1 P7 P3 G3 P1 P7 P3 A3 P3 P7 P3 G2 P4 P7 P3 A3 P4 P7 P3 G3 P4 P7 P4 G2 P1 P7 P4 G2 P2 P7 P4 G3 P2 P7 P4 A3 P3 P7 WO 2004/032940 WO 204/02940PCT/A1J2003!001347 P4 P4 P6 P1 P2 P2 P3- P4 P1 Pi P1 P1 Pi Pi P1 P2 P2 P2 P2 P2 P2 P2 P2 P2 P4 P4 P4 P4 P1 G2 G3 G2 A3 A3 G3 A3 A3 A3 A3 G3 G3 G2 G2 A3 G3 GI G2 A3 G2 A3 G3 G3 A3 G3 G3 A3 G3 A3 G3 A3 A3 G3 A3 A3 A3 P4 P4 P1 P6 P6 P6 P6 P6 P6 P1 P1 P2 P3 P4 P4 P4 P1 P1 P1 P2 P2 P2 P3 P4 P4 P1 P1 P2 P3 P1 P1 P2 P4 P4 P1 P2 P4 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 and wherein the groups A, P and G are as described in "Substituents per Example Libraries 1- 14" in the specification. WO 2004/032940 WO 204/02940PCTIAU20031001347 36

17. The method of claim 15, wherein the compound is 0R4 o ORI "NHR2 0R3 wherein RI, R2, R3 and R4 are selected from the group combinations of: RI R2 R3 R4 MC4 inhibition at micromolar P1 G1 P1 P7 P3 GI P1 P7 P3 G2 P1 P7 P4 G2 P1 P7 P4 G2 P2 P7 P4 G3 P2 P7 G1 P1 P7 G2 P1 P7 P1 A3 P1 P7 P1 G3 P1 P7± P1 G3 P2 P7 P1 G2 P4 P7 P1 A3 P4 P7 P1 G3 jP4 P7 P2 G1 P1 P7 P2 G2 P1 P7 P2 A3 PI P7 P2 G2 P2 P7 P2 A3 P2 P7+ P2 G3 P2 P7+ P2 G3 P4 P7 P4 G3 P1 P7 P4 A3 P2 P7 G3 P1 P7 P1 A3 P1 P7 and wherein the groups P, G and A are as described in "Substituents per Example Libraries 1-14" in the specification. WO 2004/032940 WO 204/02940PCTIAU2003/001347 The method of claim 15, wherein the compound is 0R3 wherein RI, R2, R3 and R4 are selected from the group combinations of: R1 ]R2 JR ]R4 P1 P1 P1 P1 PI Pt P1 PI P1 P1 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P3 P3 P3 P4 P4 P4 P4 P4 P4 P4 P4 P4 G1 G2 G3 G1 A3 G3 GI G2 A3 G3 Gi G2 A3 G3 G1 G2 A3 G3 GI A3 G3 G 3 GL d3 G1 G2 G3 GI G2 G3 G2 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 p7- P7 P1 P1 P1 P2 P2 P2 P4 P4 P4 P4 P1 P1 Pt Pt P2 P2 P2 P2 P4 P4 P4 P4 Pi P2 P4 P1 P1 Pt P2 P2 P2 P2 P4 P4 WO 2004/032940 WO 204/02940PCT/AU2003/001347 P4 P4 PS P1 P4 P6 P6 P6 P6 P6 P6 A3 G3 GI G2 A3 G3 GL G2 A3 G3 GI G2 A3 G3 GL G2 Gi G2 A3 G3 G2 G3 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P4 P4 Pi P1 P1 P1 P2 P2 P2 P2 P4 P4 P4 P4 P6 P6 P1 P1 Pt P2 P2 P2 and wherein the groups P, G and A are as described in "Substituents per Example Libraries 1-14" in the specification.

19. The method of claim 14, wherein the compound is CR4 0OCR1 v NHR2 CR3 wherein Ri, R2, R3 and R4 are selected from the group combinations of: RI IR2 IR3 ]R4 I P1 P1 P1 Pt P2 P2 P2 GL G2 G2 A3 A3 A3 A3 P7 P7 P7 P7 P7 P7 P7 P1 P1 P2 P2 P1 P2 P4 WO 2004/032940 WO 204/02940PCT!AU2003/001347 P3 P3 P4 P4 P4 P4 P4 P4 P4 P4 P4 P2 P4 P6 G1 A3 G2 A3 G3 G1 G2 A3 G3 A3 A3 A3 A3 G3 A3 A3 A3 A3 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P7 P2 P4 P1 P1 P1 P2 P2 P2 P2 P3 P4 PI P2 P2 P4 P6 P6 P4 and wherein the groups P, G and A are as described in "Substituents per Example Libraries 1- 14" in the specification.

20. The method of claim 15, wherein the compound is 0R4 L o SMe HCU'. NHR2 OR3 wherein R4, R2 and R3 are selected from the group combinations of: R2 R3 R4 G1 P3 P3 A2 P3 P3 G2 P3 P3 G3 P3 P3 GI P3 P4 G2 P3 P4 A3 P3 P4 G3 P3 P4 WO 2004/032940 WO 204/02940PCTIAU2003/001347 A2 P3 P1 G2 P3 P1 A3 P3 Pi G3 P3 P1 Al P3 P2 GI P3 P2 A2 P3 P2 G2 P3 P2 A3 P3 P2 G3 P3 P2 Gi P4 P3 A2 P4 P3 G2 P4 P3 G3 P4 P3 Gi P4 P4 A2 P4 P4 G2 P4 P4 G3 P4 P4 Al P4 P1 Gi P4 P1 A2 P4 P1 G2 P4 P1 A3 P4 Pi G3 P4 P1 Al P4 P2 GI P4 P2 A2 P4 P2 G2 P4 P2 A3 P4 P2 G3 P4 P2 Al P1 P3 GI P1 P3 A2 P1 P3 G2 P1 P3 A3 P1 P3 G3 P1 P3 Al P1 P4 Gi Pi P4 A2 P1 P4 G2 P1 P4 A3 P1 P4 G3 P1 P4 Al P1 Pi Gi p1 P1 A2 P1 P1 WO 2004/032940 WO 204/02940PCTIAU2003/001347 A3 P1 P1 Al PI P2 G1 P1 P2 A2 P1 P2 G2 P1 P2 A3 PI P2 G3 P1 P2 Al P2 P3 GI P2 P3 G2 P2 P3 A3 P2 P3 G3 P2 P3 Al P2 P4 GI P2 P4 A2 P2 P4 G2 P2 P4 A3 P2 P4 G3 P2 P4 Al P2 P1 GI P2 P1 A2 P2 P1 G2 P2 P1 A3 P2 P1 G3 P2 P1 Al P2 P2 Gi P2 P2 A2 P2 P2 G2 P2 P2 and wherein the groups P, G and A are as described in "Substituents per Example Librarics 1- 14" in the specification. 21 The method of claim 14, wherein the compound is 0R4 o SMe HDOV NHR2 6R3 wherein R4, R2 and R3 are selected from the group comnbinations of: R2 R3 R4 WO 2004/032940 WO 204/02940PCTIAU2003/001347 Al Gi A2 G2 A3 G3 Al Gl A2 G2 A3 G3 Al G I A2 G2 A3 G3 Al Gi A2 G2 A3 G3 Al Gi A2 G2 A3 G3 Al GI A2 G2 A3 G3 Al Gi A2 G2 A3 G3 Al G I A2 G2 P3 P3 P3 P3 P3 P3 FP3- P3 r P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P4 P3 P3 P3 P3 P3 P3 P4 P4 P4 P4 P4 P4 Pi P1 PI P1 P1 P1 P2 P2 P2 P2 P2 P2 P3 P3 P3 P3 P3 P3 P4 P4 P4 P4 P4 P4 Pi P1 Pi P1 P1 Pi P2 P2 P2 P2 WO 2004/032940 WO 204/02940PCT/AU2003/001347 A3 G3 Al GI A2 G2 A3 G3 Al Gi A2 G2 A3 G3 Al Gi A2 G2 A3 G3 Al Gi A2 G2 A3 G3 Al Gi A2 G2 A3 G3 Al GI A2 G2 A3 G3 Al GI A2 G2 A3 G3 Al Gi P4 P4 P1 P1 Pi P1 Pi P1 P1 P1 Pt pt P1 P1 Pi Pi P1 P1 P1 Pi Pi P1 P1 P1 P1 Pi P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P2 P3 P3 P3 P3 P3 P3 P4 P4 P4 P4 P4 P4 P1 P1 P1 P1 P1 P1 P2 P2 P2 P2 P2 P2 P3 P3 P3 P3 P3 P3 P4 P4 P4 P4 P4 P4 Pi P1 P1 P1 P1 Pi P2 P2 WO 2004/032940 WO 204/02940PCTIAUI2003/001347 44 A2 JP2 IP2 G2 P2 P2 and wherein the groups P, G and A are as described in "Substituents per Example Libraries 1-14" in the specification. The method of claim 15, wherein the compound is OMe C R 1 H*V"N HR2 CR3 wherein Ri, R2 and R3 are selected from the group combinations of. RI R12 R3, P3 G1 P3 P3 G2 P3 P3 G3 P3 P3 Al P4 P3 Gl P4 P3 A2 P4 P3 G2 P4 P3 A3 P4 P3 G3 P4 P3 Al P1 P3 GI P1 P3 A2 P1 P3 G2 P1 P3 A3 P1 P3 G3 P1 P3 GI P2 P3 A2 P2 P3 G2 P2 P3 A3 P2 P3 G3 P2 P4 G1 P3 P4 G2 P3 P4 G3 P3 WO 2004/032940 WO 204/02940PCTIAU2003/001347 P4 Gi P4 P4 A2 P4 P4 G2 P4 P4 A3 P4 P4 G3 P4 P4 Al P1 P4 GI Pi P4 A2 P1 P4 G2 Pt P4 A3 P1 P4 G3 Pi P4 Al P2 P4 GI P2 P4 A2 P2 P4 G2 P2 P4 A3 P2 P4 G3 P2 Gi P3 G2 P3 G3 P3 GI P4 A2 P4 G2 P4 A3 P4 G3 P4 Al Pi GI Pt A2 Pt G2 Pt A3 P1 PS G3 Pi Al P2 Gl P2 A2 P2 G2 P2 A3 P2 G3 P2 P2 GL P3 P2 A2 P3 P2 G2 P3 P2 Gl P4 P2 G2 P4 P2 A3 P4 P2 G3 P4 P2 Gl Pi WO 2004/032940 WO 204/02940PCTIAU20031001347 P2 G2 P1 P2 A3 P1 P2 G3 P1 P2 Al P2 P2 GI P2 P2 G2 P2 P2 G3 P2 and wherein the groups P, G and A are as described in "Substituents per Example Libraries 1- 14" in the specification.

23. The method of claim 14, wherein the compound is OMe O CR 1 "N'HR2 6R3 wherein RI, R2 and R3 are selected from the group combinations of- RI R2 R3 P3 Al P3 P3 G1 P3 P3 A2 P3 P3 G2 P3 P3 A3 P3 P3 G3 P3 P3 At P4 P3 GI P4 P3 A2 P4 P3 G2 P4 P3 A3 P4 P3 G3 P4 P3 Al P1 P3 G1 IN1 P3 A2 P1 P3 G2 1P1 WO 2004/032940 WO 204/02940PCTIAU2003/001347 P3 G3 P1 P3 Al P2 P3 GI P2 P3 A2 P2 P3 G2 P2 P3 A3 P2 P3 G3 P2 P4 Gi P3 P4 A2 P3 P4 G2 P3 P4 A3 P3 P4 G3 P3 P4 Al P4 P4 GI P4 P4 A2 P4 P4 G2 P4 P4 A3 P4 P4 G3 P4 P4 Al P1 P4 Gi P1 P4 A2 P1 P4 G2 P1 P4 A3 P1 P4 G3 P1 P4 Al P2 P4 Gl P2 P4 A2 P2 P4 G2 P2 P4 A3 P2 P4 G3 P2 Al P3 A2 P3 C2 P3 A3 P3 G3 P3 Al P4 GI P4 A2 P4 G2 P4 A3 P4 G3 P4 Al P1 GI P1 Al P1 G2 P1 WO 2004/032940 WO 204/02940PCTIAU2003/001347 G3 P1 Al P2 GI P2 A2 P2 G2 P2 A3 P2 G3 P2 P2 Al P3 P2 GI P3 P2 A2 P3 P2 G2 P3 P2 A3 P3 P2 G3 P3 P2 Al P4 P2 Gi P4 P2 A2 P4 P2 G2 P4 P2 A3 P4 P2 G3 P4 P2 Al P1 P2 Gi P1 P2 A2 P1 P2 G2 P1 P2 A3 P1 P2 G3 P1 P2 Al P2 P2 GI P2 P2 A2 P2 P2 G2 P2 P2 A3 P2 P2 G3 P2 and wherein the groups P, G and A are as described in "Substituents per Example Libraries 1-14" in the specification.

24. The method of claim 15, wherein the compound is CR3 0 SMe HOV'. "N HRI CR2 wherein Ri1, R2 and R3 are selected from the group combinations of: WO 2004/032940 PCT/AU2003/001347 R1 R2 R3 P3 N4 E2 P3 N4 E4 P3 N4 E6 P4 N4 E2 P4 N4 E4 and wherein the groups P, N and E are as described in "Substituents per Example Libraries 1-14" in the specification. The method of claim 14, wherein the compound is OR3 O SMe HO' 'NHR1 OR2 wherein R1, R2 and R3 are selected from the group combinations of: R1 R2 R3 P3 N4 P3 N4 E6 P4 N4 El P4 N4 E2 P4 N4 and wherein the groups P, N and E are as described in "Substituents per Example Libraries 1-14" in the specification. WO 2004/032940 PCT/AU2003/001347

26. The method of claim 15, wherein the compound is OR3 O0 SMe HO" '"NHR1 OR2 wherein R1, R2 and R3 are selected from the group combinations of: R1R2R3 E2 E4 E6 E4 E6 and wherein the groups P, N and E are as described in "Substituents per Example Libraries 1-14" in the specification.

27. The method of claim 14, wherein the compound is OR3 O SMe "/NHR1 OR2 wherein RI, R2 and R3 are selected from the group combinations of: R1 R2 IR3 El E6 El E2 P3 P3 P3 P4 P4 P4 and wherein the groups P, N and E are as described in "Substituents per Example WO 2004/032940 PCT/AU2003/001347 Libraries 1-14" in the specification.

28. The method of claim 15, wherein the compound is OR3 0 SMe 'NHR1 OR2 wherein RI, R2 and R3 are selected from the group combinations of: R1 R2 R3 E2 E4 E6 El E6 and wherein the groups E, P and N are as described in "Substituents per Example Libraries 1-14" in the specification. The method of claim 14, wherein the compound is HO"' OR2 wherein R1, R2 and R3 are selected from the group combinations of: R1 R2 El E2 E6 El R3 N4 N4 N4 N4 N4 WO 2004/032940 PCT/AU2003/001347 52 and wherein the groups E, P and N are as described in "Substituents per Example Libraries 1-14" in the specification. The method of claim 15, wherein the compound is OR3 O SMe HO 'NHR 1 OR2 wherein R1, R2 and R3 are selected from the group combinations of: R1 R2 R3 El P3 N4 E2 P3 N4 E3 P3 N4 P3 N4 El P4 N4 E2 P4 N4 E3 P4 N4 P4 N4 and wherein the groups E, P and N are as described in "Substituents per Example Libraries 1-14" in the specification.

31. The method of claim 14, wherein the compound is OR3 O SMe HO"' "NHRI OR2 wherein RI, R2 and R3 are selected from the group combinations of: R1 R2 R3 P3 N4 E6 P3 N4 El P4 N4 E2 P4 N4 P4 N4 WO 2004/032940 PCT/AU2003/001347 53 and wherein the groups E, P and N are as described in "Substituents per Example Libraries 1-14" in the specification.

32. The method of claim 15, wherein the compound is OR3 O0 OR1 HO'' NHR2 OMe wherein R1, R2 and R3 are selected from the group combinations of: R1 R2 R3 P4 E8 P2 P4 E9 P2 P4 E10 P2 P4 G1 P2 P4 E8 P2 P4 E9 P2 P4 Ell P2 P4 G1 P2 and wherein the groups P, G and E are as described in "Substituents per Example Libraries 1-14" in the specification.

33. The method of claim 15, wherein the compound is OR4 O ORI HO'" "NHR2 OR3 wherein RI, R2, R3 and R4 are selected from the group combinations of: R1 R2 R3 R4 P2 A2 P4 P2 P2 A2 P4 P2 P2 A2 P4 P3 P2 A2 P4 P3 P2 A2 P4 P4 WO 2004/032940 WO 204/02940PCTIAU2003/001347 P2 A2 P2~A P2 A2 P2 A2 P2 A2 P2 lAl P2 lAl P2 A2 P2 ;A2 P2 !Al P2 A3 P2 lA3 P2 'A3 P2 IA3 P2 A3 P2 A3 P2 A3 P2 A3 P2 A3 P2 A3 P2 A3 P4 Al P4 A2 P4 A2 P4 A2 P4 A2 P4 A2 P4 A2 P4 A2 P4 A2 P4 A2 P4 A3 P4 A3 P4 A3 P4 A3 P4 A3 P4 A3 P4 A3 P4 A3 P4 A3 P4 A3 P4 A3 and wherein the groups P, and A are as described in "Substituents per Example Libraries 1-14" in the specification. WO 2004/032940 PCT/AU2003/001347

34. The method of claim 15, wherein the compound is 0R4 o ORI HO"' NHR2 6R3 wherein RI, R2, R3 and R4 are selected from the group combinations of: RI R2 R3R4 P3 A2 P4 P2 P3 A2 P4 P3 P3 A2 P4 P4 P3 A2 P2 P2 P3 A2 P2 P3 P3 A2 P2 P4 P3 A2 P3 P2 P3 A2 P3 P3 P3 A2 P3 P4 P3 _A3 P4 P2 P3 A3 P4 P4 P3 A3 P2 P2 P3 A3 P2 P3 P3 A3 P2 P4 P3 A3 P3 P2 P3 A3 P3 P4 P2 A2 P4 P2 P2 A2 P4 P3 P2 A2 P4 P4 P2 A2 P2 P2 P2 A2 IP2 P3 P2 A2 P2 P4 P2 A2 P3 P2 P2 A2 P3 P3 P2 A2 P3 P4 P2 A3 P4 P2 P2 A3 P4 P3 P2 A3 P4 P4 P2 A3 P2 P2 P2 A3 JP2 JP3 P2 A3 P2 I4 P2 A3 P3 P2 P2 A3 P3 P3 P2 A3 P3 P4 WO 2004/032940 PCTIAU2003/001347 56 and wherein the groups P, and A are as described in "Substituents per Example Libraries 1- 14" in the specification. The method of claim 15, wherein the compound is CR4 0 CR1 H0~' "NHR2 CR3 wherein Ri, R2, R3 and R4 are selected from the group combinations of: RI R2 R3R4 P3 GI P4 P2 P3 G1 P4 P2 P3 G1INP P3 P3 G1 P4 P3 P3 GI PN P4 P3 G1 JP2 P2 P3 GI JP2 P2 P3 G1 JP2 P3 P3 Gi JP2 P4 P3 GI JP2 P4 P3 G1 I1 P2 P3 GI IN P3 P3 G1 I1 P3 P3 G1 IN P4 P3 GI P1 P4 P3 G2 IN P2 P3 G2 P4 P2 P3 G2 P4 P3 P3 G2 I4 P3 P3 G2 I4 P4 P3 G2 I4 P4 P3 G2 JP2 P2 P3 G2 JP2 P3 P3 G2 JP2 P3 P3 G2 JP2 P4 P3 G2 JP2 P4 P3 G2 IN P2 P3 G2 P1 P2 P3 G2 P1 P3 P3 G2 PI P4 P3 G2 P1 P4 WO 2004/032940 WO 204/02940PCT/A1J2003!001347 and wherein the groups P, and A are as described in "Substituents per Example Libraries 1- 14" in the specification. The method of claim 15, wvherein the compound is CR3 wherein RI, R2, R3 and R4 are selected from the group combinations of: RI ]RM IR3 [R41 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3 P3_ WO 2004/032940 PCTIAUI2003/001347 57 P3 JG2 IPt and wherein the groups P, and G are as described in "Substituents per Example Libraries 1-14" in the specification.

36. The method of claim 15, wherein the compound is 0R4 O O R I HOV" .NHR2 6R3 wherein RI, R2, R3 and R4 are selected from the group combinations of: RI R2R3W R4 P1 G1 P4 JP2 P1 Gi P4 JP3 PI GI P4 P4 P1 Gi P2 P3 Pt Gi P2 P4 P1 G1 P1 P3 P1 G1 P1P4 P1 G2 P4 P2 PI P4 P3 P1 G2P P4 I P1 G2 JP2 JP2 PI G2 P2 P3 PI G2 P2 P4 P1 G2 P1 P2 P1 G2 P1 P3 Pt G2 IPt P4 P4 Gl P4 P2 P4 Gl P4 P3 P4 -GI P4 P4 P4 GI P2 P2 P4 Gl P2 P3 P4 GI P2 P4 P4 GL Pt P2 P4 GI P1 P3 P4 GL Pt P4 P4 G2 P4 JP2 P4 G2 P4 JP3 P4 G2 P4 P4 P4 G2 P2 JP2 WO 2004/032940 PCT/AU2003/001347 P4 P4 P4 P4 P4 P1 and wherein the groups P, and G are as described in "Substituents per Example Libraries 1-14" in the specification.

37. The method of claim 15, wherein the compound is OH O NHR1 HO' NHR2 OR3 wherein R1, R2 and R3 are selected from the group combinations of: R1 R2 R3 A2 A2 A2 A2 A2 A2 A2 A2 Al Al and wherein the groups P, A and E are as described in "Substituents per Example Libraries 1-14" in the specification.

38. A pharmaceutical formulation comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.