AU2006299733A1 - Method of drug design - Google Patents

Description

WO 2007/038829 PCT/AU2006/001431 Method of Drug Design Field of the invention The invention relates to a method of identifying biologically active compounds, 5 libraries of compounds. Background Small molecules involved in molecular interactions with a therapeutic target, be it enzyme or receptor, are often described in terms of binding elements or 10 pharmacophoric groups which directly interact with the target, and non-binding components which form the framework of the bioactive molecule. In the case of peptide ligands or substrates for instance, usually a number of amino acid side chains form direct interactions with their receptor or enzyme, whereas specific folds of the peptide backbone (and other amino acid residues) provide the 15 structure or scaffold that controls the relative positioning of these side chains. In other words, the three dimensional structure of the peptide serves to present specific side chains in the required fashion suitable for binding to a therapeutic target. The problem is that such models do not allow for rapid identification of drug candidates owing to the necessity to synthesize an enormous amount of 20 compounds to identify potential active compounds. A pharmacophoric group in the context of these libraries is an appended group or substituent, or part thereof, which imparts pharmacological activity to the molecule. 25 Molecular diversity could be considered as consisting of diversity in pharmacophoric group combinations (diversity in substituents) and diversity in the way these pharmacophoric groups are presented (diversity in shape). Libraries of compounds in which either diversity of substituents, or diversity of shape, or both 30 of these parameters are varied systematically are said to scan molecular diversity.

WO 2007/038829 PCT/AU2006/001431 2 Carbohydrate scaffolds provide a unique opportunity to create libraries of structurally diverse molecules, by varying the pharmacophoric groups, the scaffold and the positions of attachment of the pharmacophoric groups in a systematic manner. Such diversity libraries allow the rapid identification of minimal 5 components or fragments containing at least two pharmacophoric groups required for an interaction with a biological target. These fragments can be further optimized to provide potent molecules for drug design. Therefore these types of carbohydrate libraries provide an excellent basis for scanning molecular diversity. 10 In previous applications (W02004014929 and W02003082846) we demonstrated that arrays of novel compounds could be synthesized in a combinatorial manner. The libraries of molecules described in these inventions were synthesized in a manner such that the position, orientation and .chemical characteristics of pharmacophoric groups around a range of chemical scaffolds, could be modified 15 and/or controlled. These applications demonstrate the synthesis and biological activity of a number of new chemical entities. Many drug discovery strategies fail owing to lack of knowledge of the bioactive conformation of, or the inability to successfully mimic the bioactive conformation of 20 the natural ligand for a receptor. Libraries of compounds of the present invention allow for the systematic "scanning" of conformational space to identify the bioactive conformation of the target. Typically in the prior art, libraries based on molecular diversity are generated in a 25 random rather than a systematic manner. This type of random approach requires large number of compounds to be included in the library to scan for molecular diversity. Further, this approach may also result in gaps in the model because of not effectively accessing all available molecular space. 30 Therefore, one of the problems in the prior art is the necessity to synthesize an enormous amount of compounds to identify potential active compounds. Attempts WO 2007/038829 PCT/AU2006/001431 3 have been made to develop peptidomimetics using sugar scaffolds by Sofia et al. (Bioorganic & Medicinal Chemistry Letters (2003) 13, 2185-2189). Sofia describes the synthesis of monosaccharide scaffolds, specifically containing a carboxylic acid group, a masked amino group (N 3 ) and a hydroxyl group as substitution 5 points on the scaffold, with the two remaining hydroxyl groups being converted to their methyl ethers. Sofia teaches a specific subset of scaffolds not encompassed by the present invention and does not contemplate methods to simplify the optimization of pharmacophoric groups. 10 Therefore there remains a need to provide a method of effectively scanning libraries designed from compounds with a wider range of different pharmacophoric groups. The present invention is directed to a method of drug design utilizing iterative 15 scanning libraries, resulting in surprisingly efficient identification of drug candidates, starting from a selected number of pharmacophores (e.g., two) in the first library and designing subsequent libraries with additional pharmacophores based on SAR information from the first library. 20 The invention can provide a new method for the rapid identification of active molecules. In an embodiment, and to demonstrate the versatility of our invention, one of the G-protein coupled receptors (GPCR's) was chosen as a target: the somatostatin 25 receptor (SST receptor). The tetradecapeptide somatostatin is widely distributed in the endocrine and exocrine system, where it has an essential role in regulating hormone secretion [1-3]. Five different subtypes have been identified to date (SST1-5), which are expressed in varying ratios throughout different tissues in the body. Somatostatin receptors are also expressed in tumours and peptide 30 analogues of somatostatin affecting mainly SST5, such as octreotide, lanreotide, vapreotide and seglitide [4-7] have antiproliferative effects. They are used WO 2007/038829 PCT/AU2006/001431 4 clinically for the treatment of hormone-producing pituitary, pancreatic, and intestinal tumours. SST5 is also implicated in angiogenesis, opening up the possibility of developing anti-angiogenic drugs that act on the SST5 receptor, for example for the use in oncology. The "core sequence" in somatostatin responsible 5 for its biological activity is Phe-Trp-Lys (FWK), representing a motif of two aromatic groups and a positive charge, which is found in almost all SST receptor active compounds. It will be clearly understood that, if a prior art publication is referred to herein, this 10 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. Summary of the invention In one form, the invention provides a method of identifying biologically active 15 compounds comprising: (a) designing a first library of compounds of formula 1 to scan molecular diversity wherein each compound of the library has at least two pharmacophoric groups R1 to R5 as defined below and wherein compound of the library has same number of pharmacophoric groups; 20 (b) assaying the first library of compounds in one or more biological assay(s); and (c) designing a second library wherein each compound of the second library contains one or more additional pharmacophoric group with respect to the first library; 25 such that the/each component of the first and second library is a compound of formula 1: R5X 0

ZR

1

R

4 X XR 2

XR

3 Formula I WO 2007/038829 PCT/AU2006/001431 5 wherein the ring may be of any configuration; Z is sulphur, oxygen, CH 2 , C(0), C(O)NRA, NH, NRA or hydrogen, in the case where Z is hydrogen then R 1 is not present, RA is selected from the set defined for 5 R 1 to R 5 , or wherein Z and R1 together form a heterocycle, X is oxygen or nitrogen providing that at least one X of Formula I is nitrogen, X may also combine independently with one of R 1 to R 5 to form an azide, 10 R 1 to R 5 are independently selected from the following non-pharmacophoric groups H, methyl and acetyl, and pharmacophoric groups, R 1 to R 5 are independently selected from the group which includes but is not limited to C2 to C20 alkyl or acyl excluding acetyl; C2 to C20 alkenyl, alkynyl, heteroalkyl; C 5 to C20 aryl, heteroaryl, arylalkyl or heteroarylalkyl, which is optionally substituted, and 15 can be branched or linear, or wherein X and the corresponding R moiety, R 2 to R 5 respectively, combine to form a heterocycle. 20 In another form, the invention comprises biologically active compounds when identified by the method described above. In a preferred embodiment, the invention relates to said method wherein in the first library, three of the substituents R 1

-R

5 are non-pharmacophoric groups and 25 are selected from hydrogen or methyl or acetyl. In a preferred embodiment, the invention relates to said first method wherein in the first library, two of the substituents Rj-R 5 are non-pharmacophoric groups and are selected from hydrogen or methyl or acetyl. 30 WO 2007/038829 PCT/AU2006/001431 6 In a preferred embodiment, the invention relates to said first method wherein Z is sulphur or oxygen; In a preferred embodiment, the invention relates to said first method wherein at 5 least one of the pharmacophoric groups is selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl or acyl In a preferred embodiment, the invention relates to a library of compounds selected from compounds of formula I wherein in the first library, three of the non 10 pharmacophoric groups R 1

-R

5 are hydrogen or methyl or acetyl when used according to said first method. In a preferred embodiment, the invention relates to a library of compounds selected from compounds of formula 1 wherein in the second library, two of the 15 non-pharmacophoric groups R.-R 5 are hydrogen or methyl or acetyl when used according to said first method. In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or 20 formula 3 or formula 4 o ZR 1 0 ZR 1 0 ZR1

R

5 0 ""R 5 0 R 5 HN

R

4 HN NHR 2

R

4 0 NHR 2

R

4 0 NHR 2

OR

3 OR 3 OR 3 Formula 2 Formula 3 Formula 4 25 In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the gluco- or galacto or allo- configuration.

WO 2007/038829 PCT/AU2006/001431 7 In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 wherein the/each compound is of the galacto configuration. 5 In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the gluco configuration. 10 In a preferred embodiment, the invention relates to said first method wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4 and wherein the/each compound is of the allo configuration. 15 In a preferred embodiment, the invention relates to said first method wherein designing the library comprises molecular modeling to assess molecular diversity. In a preferred embodiment, the invention relates to said first method wherein R 1 to 20 R 5 optional substituents include 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, 25 hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted. The term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine. 30 The term "alkyl" used either alone or in compound words such as "optionally WO 2007/038829 PCT/AU2006/001431 8 substituted alkyl", "optionally substituted cycloalkyl", "arylalkyl" or "heteroarylalkyl", denotes straight chain, branched or cyclic alkyl, preferably C1-20 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2 5 dimethylpropyl,1, 1-dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2 methylpentyl, 3-methylpentyl, 1, 1-dimethylbutyl, 2,2-dimethylbutyl, 3,3 dimethylbutyl, 1, 2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2trimethylpropyl,1, 1,2 trimethylpropyl, heptyl, 5-methylbexyl, 1-methylhexyl, 2,2-dimethypentyl, 3,3 dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4 10 dimethylpentyl, 1,2,3trimethylbutyl,1, 1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3tetramethylbutyl, nonyl,1-, 2-, 3-, 4-, 5-, 6 or 7methyloctyl,1-, 2-, 3-, 4-or 5-ethylheptyl, 1-, 2-or 3propylhexyl, decyl,1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnonyl,1-, 2-, 3-, 4-, 5-or 6-ethyloctyl, 1-, 2-, 3or 4 propylheptyl, undecyll-, 2-, 3-, 4-, 5-, 6-, 7-, 8or 9-methyldecyl,1-, 2-, 3-, 4-, 5-, 6 15 or 7-ethylnonyl,1-, 2-, 3-, 4-or 5-propyloctyl,1-, 2-or 3-butylheptyl,1-pentylhexyl, dodecyl,1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl,1-, 2-, 3-, 4-, 5-, 6-, 7-or 8- ethyldecyl,1-, 2-, 3-, 4-, 5-or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2 pentylheptyl and the like. Examples of cyclic alkyl include mono-or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 20 cyclooctyl, cyclononyl, cyclodecyl and the like. The term "alkylene" used either alone or in compound words such as "optionally substituted alkylene" denotes the same groups as "alkyl" defined above except that an additional hydrogen has been removed to form a divalent radical. It will be 25 understood that the optional substituent may be attached to or form part of the alkylene chain. The term "alkenyl" used either alone or in compound words such as "optionally substituted alkenyl" denotes groups formed from straight chain, branched or cyclic 30 alkenes including ethylenically mono-, di-or polyunsaturated alkyl or cycloalkyl groups as defined above, preferably C2-6 alkenyl. Examples of alkenyl include WO 2007/038829 PCT/AU2006/001431 9 vinyl, allyl,1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl,1 heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl,1 decenyl, 3-decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3 cyclopentadienyl, 1,3 5 hexadienyl, 1,4-hexadienyl, 1,3cyclohexadienyl, 1,4-cyclohexadienyl, 1,3 cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. The term "alkynyl" used either alone or in compound words, such as "optionally substituted alkynyl" denotes groups formed from straight chain, branched, or 10 mono-or poly-or cyclic alkynes, preferably C 2-6 alkynyl. Examples of alkynyl include ethynyl,1-propynyl, 1-and 2butynyl, 2-methyl-2 propynyl, 2-pentynyl, 3-pentynyl, 4pentynyl, 2-hexynyl, 3-hexylnyl, 4-hexynyl, 5 hexynyl, 1 0-undecynyl,4-ethyl-l-octyn-3-y, 7-dodecynyl, 9-dodecynyl, 10 15 dodecynyl,3-methyl-1-dodecyn-3-yl, 2-tridecynyl, 11tridecynyl, 3-tetradecynyl, 7 hexadecynyl, 3-octadecynyl and the like. The term "alkoxy" used either alone or in compound words such as "optionally substituted alkoxy" denotes straight chain or branched alkoxy, preferably C1-7 20 alkoxy. Examples of alkoxy include methoxy, ethoxy, npropyloxy, isopropyloxy and the different butoxy isomers. The term "aryloxy" used either alone or in compound words such as "optionally substituted aryloxy" denotes aromatic, heteroaromatic, arylalkoxy or heteroaryl 25 alkoxy, preferably C6-13 aryloxy. Examples of aryloxy include phenoxy, benzyloxy,1-napthyloxy, and 2-napthyloxy. The term "acyl" used either alone or in compound words such as "optionally substituted acy I "or "heteroarylacyl" denotes carbamoyl, aliphatic acyl group and 30 acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl. Examples of acyl WO 2007/038829 PCT/AU2006/001431 10 include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, 5 octadecanoyl, nonadecanoyl, and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and 10 ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoy; aralkanoyl such as phenylalkanoyl (e. g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e. g. naphthylacetyl, naphthlpropanoyl and naphthylbutanoyl); aralkenoyl such as phenylalkenoyl (e. g. phenylpropenoyl, phenylbutenoyl, phenylmethacrylyl, 15 phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e. g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e. g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and naphthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; 20 arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienyihexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as 25 heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienyglyoxyloyl. The term "aryl" used either alone or in compound words such as "optionally 30 substituted aryl", "arylalkyl" or "heteroaryl" denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring WO 2007/038829 PCT/AU2006/001431 11 systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, 5 pyrrolyl, furanyl, imadazolyl, pyrrolydinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. Preferably, the aromatic heterocyclic ring system contains 1 to 4 heteroatoms independently selected from N, 0 and S and 10 containing up to 9 carbon atoms in the ring. The term "heterocycle" used either alone or in compound words as "optionally substituted heterocycle" denotes monocyclic or polycyclic heterocyclyl groups containing at least one heteroatom atom selected from nitrogen, sulphur and 15 oxygen. Suitable heterocyclyl groups include N-containing heterocyclic groups, such as, unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; saturated to 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, 20 pyrrolidinyl, imidazolidinyl, piperidin or piperazinyl ; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolizinyl, benzimidazoyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl or tetrazolopyridazinyl; unsaturated 3 to 6-membered heteromonocyclic group containing an oxygen atom, such as, pyranyl or furyl; unsaturated 3 to 6 25 membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl; unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, isoxazoyl or oxadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; unsaturated 30 condensed heterocyclic group containing I to 2 oxygen atoms and I to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; unsaturated 3 to 6-membered WO 2007/038829 PCT/AU2006/001431 12 heteromonocyclic group containing I to 2 sulphur atoms and I to 3 nitrogen atoms, such as, thiazolyl or thiadiazolyl; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl; and unsaturated condensed heterocyclic group 5 containing I to 2 sulphur atoms and I to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl. In a preferred embodiment, the invention relates to said first method wherein the compounds are synthesized. 10 In a preferred embodiment, the invention relates to said first method wherein the biological assays are selected from peptide ligand class of GPCRs. In another aspect the invention provides a compound according to formula 1 in 15 which at least one X is nitrogen, and said X is combined with the corresponding

R

2

-R

5 to form a heterocycle. The synthesis of the heterocyclic components of the present invention is disclosed in WO 2004/022572. In a preferred embodiment, the invention provides a compound according to 20 formula 1 wherein X and R 2 combine to form a heterocycle. In a preferred embodiment, the invention provides a compound according to formula 1 wherein the heterocycle is heteroaryl, including triazoles, benzimidazoles, benzimidazolone, benzimidazolothione, imidazole, hydantoine, 25 thiohydantoine and purine. Detailed Description of the invention The embodiments of the invention will be described with reference to the following examples. Where appropriate, the following abbreviations are used. 30 Ac Acetyl WO 2007/038829 PCT/AU2006/001431 13 DTPM 5-Acyl-1, 3-dimethylbarbiturate Ph Phenyl TBDMS t-Butyldimethylsilyl TBDPS t-Butyldiphenylsilyl 5 Bn benzyl Bz benzoyl Me methyl DCE 1,2-dichloroethane DCM dichloromethane, methylene chloride 10 Tf trifluoromethanesulfonyl Ts 4-methylphenylsulfonyl, p-toluenesulfonyl DMF N,N-dimethylformamide DMAP N,N-dimethylaminopyridine c,a-DMT a,a-dimethoxytoluene, benzaldehyde dimethyl acetal 15 DMSO dimethylsulfoxide DTT dithiothreitol DMTST Dimethyl(methylthio)sulphoniumtrifluoro- methanesulphonate TBAF tetra-n-butylammonium fluoride 20 Part A: Preparation of building blocks: In order to fully enable the invention, there is described below methods for the preparation of certain building blocks used in the preparation of the compounds of the invention. The building blocks described are suitable for both solution and solid phase synthesis of the compounds of the invention.

WO 2007/038829 PCT/AU2006/001431 14 Example A: Synthesis of a 2,4 dinitrogen containing Galactopyranoside Building Block OH Ph Ph O SMe -0.0 H0S~ SMe zo SMe NHDTPM NHDTPM A-1 A-2 A-3 (iii) N3 OTBDPS OTBDPS OH Bz ~ (v) 0zS (iv) E ~ BzO 0S~ O V O)e0- NHDTPM NHDTPM NHDTPM A-6 A-5 A-4 5 Conditions: (i) a,a-dimethoxytoluene (a,a-DMT), p-toluenesulphonic acid (TsOH), acetonitrile (MeCN), 760C, 85%; (ii) Benzoylchloride (BzCI), triethylamine; DCM, 99%; (iii) methanol (MeOH)/MeCN/water, TsOH, 750C, 98%; (iv) t butyldiphenylsilylchloride (TBDPS-CI), imidazole, pyridine, 1200C, 99% ; (v) Tf 2 O, pyridine, DCM, O 0 0C, 100%;(b) NaN 3 , DMF, 16hr, RT, 99%.

WO 2007/038829 PCT/AU2006/001431 15 Example B: Synthesis of a 3-nitrogen containing Gulopyranoside Building Block Ph Ph 0 0 0OH OH HO SMe 4 SMe i) "SMe OBzCI N 3 OBzCI 3 OBzCl B-1 B-2 B-3 ,~(iii) 0 0 -~-OTBDPS SMe

N

3 OBzCI B-4 5 Conditions: (i) (a) trifluoromethanesulfonic anhydride (Tf 2 O), pyridine, -200C, dichloromethane (DCM), 1 hour, 100%, (b) sodium azide (NaN 3 ), NN dimethylformamide (DMF), 500C, 5 hours, quantitative; (ii) TsOH, MeCN/ MeOH/water (12:3:1), 900C, 6 hours, 88%(iii) TBDPSCI, DMAP, pyridine, 1200C, 10 12 hours, 93% WO 2007/038829 PCT/AU2006/001431 16 Example C: Synthesis of a 2,6-dinitrogen substituted Glucopyranoside Building Block OH

N

3 .0 ( O zO ..-- SMe zOSMe NHDTPM NHDTPM A-4 C-1 5 Conditions: (i) (a) Tosylchlodride, pyridine, RT, 24 hours, 33%(b) NaN 3 , DMF, RT, 168 hours. Example D: Synthesis of a 2-nitrogen containing Tallopyranoside Building Block Ph OPh OPOO HO SMe (i) TBD SMe TBDPSOSe OBz OBz OH B-1 D-1 D-2 (iii) OBzO OH Ph- O '.30 (iv) 3 TBDPSO u SMe TBDPSO 0 SMe TBDPSO SMe 10 D-5 D-4 D-3 Conditions: (i) TBDPSCI, imidazole, 1,2-DCE, reflux; (ii) NaOMe/MeOH; (iii) (a) Tf 2 O, pyridine, -200C, DCM, 1 hour, (b) NaN 3 , DMF, 500C, 5 hours; (iv) TsOH, MeCN/MeOH/water; (v) benzoylchloride, DMAP, 1,2-DCE, -20 0

C.

WO 2007/038829 PCT/AU2006/001431 17 Example E: Synthesis of two 3-nitrogen containing Altropyranoside Building Block HO OH a _0O HO~~ (n) 0 ~ 0 iimn~~ HlO SMe-O SMe SMe E-1 E-2 E-3 PhOMe O OBn-OMe HO OBn-OMe -O 00O OBn-OMe HO SMe Seiv)SMe HO

N

3 E-6 E-5 E-4 (vi) (vii) TBDPSH Bn-OMe OBz TBDPSO OBz HO SMe HO SMe ii HO SMe N3N 3

N

3 E-7 E-8 E-9 5 Conditions: (i) cyclohexanone dimethylacetal, TsOH, MeCN; (ii) p methoxybenzaldehyde dimethylacetal, TsOH, MeCN; (iii) DIBAL, -780C, diethyl ether; (iv) (a) Tf 2 O, pyridine, -200C, DCM, 1 hour, (b) NaN 3 , DMF, 500C, 5 hours; (v) TsOH, MeCN/MeOH/water; (vi) TBDPSCI, DMAP, 1,2-DCE; (vii) (a) CAN, (b) 10 BzCl, DMAP, 1,2-DCE, (c) TsOH, MeCN/MeOH/water; (viii) TBDPSCI, DMAP, 1,2-DCE.

WO 2007/038829 PCT/AU2006/001431 18 Example F: Synthesis of a 2-nitrogen containing Glucopyranoside Building Block Ph Ph HO 0 ~ 0; HO 0~- 0) O"-R(ii) AI-o HO SMe-Ph- O SMe O SMe

N

3 N 3 N 3 F-1 F-2 F-3 TBDPSO HO HO : (iv)0 BzO SMe H --- HO SMe N3 F-4 N 3 F-5 Conditions: (i) a,a-DMT, TsOH, MeCN; (ii) 1,2-DCE, BzCI, DMAP; (iii) TsOH, 5 MeOH/MeCN; (iv) TBDPS-Cl, DMAP, 1,2-DCE. HO 0TBDPSO HO~~ 0)i O SMeHO pSMe F-1 NF6 N 3 TBDPSO TBDPSOS BzO~ ~ + HO HOBzO-- -~--- SMe

N

3

N

3 F-7 F-5 Conditions: (i) TBDPSCI, DMAP, pyridine, 1200C, 0.5 hours, 81%; (ii) a. (Bu)2SnO, MeOH; b. Benzoylchloride, RT, 24 hour; WO 2007/038829 PCT/AU2006/001431 19 Example G: Synthesis of a 2-nitrogen containing Allopyranoside Building Block Ph Ph Ph 0 0 S O il!Ae MS3 -S e 0 ~

HON

3 NI ON 3 0 , S l F-2 G-1 OBz 3 G-2 TBDPSO HO 0 (v) HO HO S e :eHO 0 SMe I N 3 j-~ OBz 3 G-4 G-3 5 Conditions: (i) DCM/pyridine, MsCl, DMAP, OC; (ii) sodium benzoate, dimethylsulphoxide (DMSO), 140 0 C; (iii) TsOH, MeOH/MeCN/water; (iv) TBDPS Cl, imidazole, DCM, 1 hour, reflux. The Solid Phase Library Synthesis of Sugars is illustrated in Scheme 1. 10 The reaction conditions are as follows: (A) 2P compound synthesis: R 1

=R

2 =OMe; i) 2-naphthalene methanol, DMTST, DCM; ii) TCA-Wang resin, BF 3 -Et 2 O, DCM; iii) 15 NaOMe, methanol; iv) a. KOtBu, DMF; b. Mel, DMF; v) HF'proton sponge', AcOH, DMF, 650C; vi) a. KOtBu, DMF; b. Mel, DMF; vii) 1,4-dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-@-Ala-OH, DIPEA, DMF; ix) piperidine/DMF (1/4); x) TFA, Et 3 SiH, DCM (B) 3P compound synthesis: R1=methyl-2-naphthyl, R 2 =OMe; WO 2007/038829 PCT/AU2006/001431 20 i) 2-naphthalene methanol, DMTST, DCM; ii) TCA-Wang resin, BF 3 'Et 2 O, DCM; iii) NaOMe, methanol; iv) a. KOtBu, DMF; b. 2-bromomethyl-naphthalene, DMF; v) HF''proton sponge', AcOH, DMF, 65 0 C; vi) a. KOtBu, DMF; b. Mel, DMF; vii) 1,4 dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-@-Ala-OH, DIPEA, DMF; ix) 5 piperidine/DMF (1/4); x) TFA, Et 3 SiH, DCM (C) 4P compound synthesis: R 1 =methyl-2-naphthyl, R 2 =4-chlorobenzyl i) 2-naphthalene methanol, DMTST, DCM; ii) TCA-Wang resin, BF 3 'Et 2 O, DCM; iii) NaOMe, methanol; iv) a. KOtBu, DMF; b. 2-bromomethyl-naphthalene, DMF; v) HF''proton sponge', AcOH, DMF, 65 0 C; vi) a. KOtBu, DMF; b. 4 10 chlorobenzylbromide, DMF; vii) 1,4-dithio-DL-threitol, KOtBu, DMF; viii) HBTU, Fmoc-P-Ala-OH, DIPEA, DMF; ix) piperidine/DMF (1/4); x) TFA, Et 3 SiH, DCM WO 2007/038829 PCT/AU2006/001431 21 OTBDPS OTBDPS OTBDPS HO O Lfl 03 0 HBO\ SMe HB~z0 Z

N

3 N 3 O N3 Q\ OTBDPS OTBDPS OA O v N3HO N O ROO

N

3

O/N

3 O O ORi O vii VI - Vi NH, - 0 1 NH 0 - / NHFmoc OR2 OR 2 R. HO R NH 0 \- R O NH O 0 0/

NH

2

NH

2 Scheme I Solid Phase library Synthesis of sugars WO 2007/038829 PCT/AU2006/001431 22 OH HO 0 SMe -i MO hSeSMeM h O NPhth MeO O NPhth 0 ~0 PMB SiD SMe MeO ,, TfO Nehth MeO - z h h OOBz NPhth O H OMS PMBO 0 V PMBO 0 e vi PMOSMe HO SMe NPhth NPhth OBz OBz NT

N

3

N

3 PMBO-- VII PMBO 0vi wh SMe -4 Ph~ SMe OBz NPhth OH NPhth

N

3 N 3 PMBO- ix 0M - X S~e 0-N -SMe HH N HDTPM

H

2 OH

N

3 N 3 PMBO 0i xi O SM - SMe OBz NHTMOBZ NHDTPM 5 Scheme 2 Synthesis of allose 2,6 building block, an example of synthesis of 2P, 3P and 4P type compound WO 2007/038829 PCT/AU2006/001431 23 The synthesis of the Allose 2,6N building block is illustrated in Scheme 2. The reaction conditions are as follows: 5 i) p-methoxybenzaldehyde dimethylacetal, camphorsulfonic acid, N,N dimethylformamide (DMF); ii) Tf 2 O, pyridine, dichloromethane (DCM); iii) tetrabutylammonium benzoate, DMF, 55 0 C; iv) BH 3 *THF, Bu 2 BOTf, DCM; v) methanesulfonylchloride, pyridine, DCM; vi) sodium azide, DMF, 85*C; vii) sodium methanolate (NaOMe), methanol; viii) n-butanol, ethylene diamine, reflux; ix) 10 DTPM reagent, methanol; x) benzoic anhydride, pyridine; xi) trifluoroacetic acid, triethylsilane, DCM Designing libraries: The design of the libraries is based on the presentation of a positive charge and a 15 varying number of aromatic substituents in different spatial arrangements on a monosaccharide scaffold. Starting with a positive charge and one aromatic displayed on the core scaffold, actives from this first library were elaborated on by further variation and addition of more aromatic substituents to quickly identify highly active molecules. 20 The first library of compounds comprises two pharmacophoric groups, known as a 2P library, in particular, one containing an aromatic and a positive charge. The library was designed such that each molecule presents two pharmacophoric groups in different relative orientation or presentation (e.g., distance, relative 25 angle, i.e. relative position in space is different). Actives from this library were identified and SAR information from this library was used to design subsequent library of compounds wherein each compound may include three pharmacophoric groups, known as a 3P library. Subsequent libraries with four pharmacophoric groups are called 4P library, etc. 30 WO 2007/038829 PCT/AU2006/001431 24 Members of significantly improved activity were identified out of the second library and were selected for further drug development. The method of the invention includes real and virtual libraries. 5 Thus, the molecules according to formula 1 are well suited for generating iterative scanning libraries, starting from a selected number of pharmacophores (eg, two) in the first library and designing subsequent libraries with additional pharmacophores based on SAR information from the first library, thereby assisting 10 in delineating pharmacophores. The 2P and 3P library of compounds were synthesized according to the building blocks as described in Examples A-G. 15 The 2P library (Table 1) was designed to scan molecular diversity for 2P molecules, comprising an aromatic and a positive charge. The 2P library was screened for biological activity and the results are given in Table 1. 20 Similarly, the 3P library was designed to scan molecular diversity for 3P molecules. Design of 3P library resulted from SAR obtained from 2P library in Table 1. The 3P library was screened for biological activity and the results are given in 25 Table 2. A visual analysis of the results according to Table 1 (2P library) and Table 2 (3P Library) indicates that: WO 2007/038829 PCT/AU2006/001431 25 1. 1, 2 allose substitution according to formula 3 (and Scaffold C/D) presents the most active arrangement of molecules in the library wherein Z is oxygen, R 1 is naphthyl and R 2 is propylamine or ethylamine. These compounds represent most actives at low nM range, and are suitable 5 candidates for further drug development. 2. R 1 as naphthyl is more active than the corresponding p-chlorobenzyl substituent. 3. 1, 2 allose according to formula 3 (Scaffold C/D) is more active than the corresponding 1, 2 glucose conformation (Scaffold A/B). 10 4. 1, 2 substitution according to formula 3 (Scaffold C/D) is more active than the corresponding 2, 6 substitution according to formula 4 (Scaffold G) 5. R 2 as propylamine and ethylamine are more active than methylamine wherein Z, R 1 and R 2 are as described above. 6. 2, 3 allose substitution according to formula 3 (Scaffold C/D) presents the more 15 actives wherein R 2 is ethylamine, and R 3 is p-chlorobenzyl compared to corresponding R 2 as propylamine and ethylamine wherein R3 is p-chlorobenzyl substituent, and also wherein R 2 is methylamine, ethylamine or propylamine and R3 is naphthyl. 7. 2, 3 glucose substitution according to formula 3 (scaffold A/B) presents the 20 more actives wherein R2 is propylamine and R 3 is naphthyl compared to corresponding R 2 as methylamine or ethylamine, and also wherein R 2 is methylamine, ethylamine or propyfamineand R 3 is p-chlorobenzyl. 8. 2, 4 and 3, 4 substitutions according to formula 3 (Scaffold G) present the least actives. 25 Part B: Biological assays Example H. In vitro screening of compounds aainst somatostatin subtypes SSTR-1 to SSTR-5 30 WO 2007/038829 PCT/AU2006/001431 26 General method Receptor membrane preparations containing the desired cloned receptor (for example cloned human somatostatin receptor subtype 5, SSTR5) and radio 5 labeled ligand were diluted at the concentration required for testing and according to the specific parameters associated with the selected receptor-ligand combination, including receptor Bmax, ligand Kd and any other parameters necessary to optimize the experimental conditions. When tested for competition activity to the reference ligand, "compound " was mixed with membrane 10 suspension and the radiolabeled reference ligand (with or without an excess of unlabeled ligand to the receptor for determination of non-specific binding) and incubated at the temperature required by internal standard operating procedures. Following incubation, the binding reaction was stopped by the addition of ice-cold washing buffer and filtered on appropriate filters, which are then counted. Data 15 analysis and curve-fitting was performed with XLfit (IDBS). Preparation of compounds 10mM solutions of test compounds in 100% DMSO were prepared. -160 pl was 20 used for each dilution (20 jil/well in triplicate). A 1.25 mM assay stock was prepared by making a 1:8 dilution of the 10 mM solution. To 30 pL of the 10 mM solution was added 210 pL milli-Q H 2 0. A 1:5 dilution series in milli-Q H 2 0 was then prepared. 25 Final concentration Final concentration in SST4 assay in SST5 assay A. 240 iL of 1.25 mM 0.25 mM 0.125 mM B. 48 pL A + 192 pL mQ 0.05 mM 0.025 mM C. 24 pL B + 192 L mQ 0.01 mM 0.005 mM 30 etc WO 2007/038829 PCT/AU2006/001431 27 Assays were performed in triplicate at each concentration within the 1:5 dilution series: 250pM, 50pM, 10pM, -mM, 0.4pM, 0.08pM, 0.016pM, 0.0032 pM, etc. (for SST4 assay) and 125pM, 10pM, 2pM, 1pM, 0.5. pM, etc (for SST5 assay). 5 Filter plate assay for SS T5 receptor Human SST5 somatostatin receptor was transfected into HEK-293 EBNA cells. Membranes were suspended in assay buffer (50 mM Tris-HCI, 1 mM EGTA, 5 mM MgC 2 , 10% sucrose, pH 7.5). The receptor concentration (Bmax) was 0.57 10 pmol/mg proteinKd for [ 1 2 5 ]SST-14 Binding 0.31 nM, volume 0.4 ml per vial (400 microassays/vial), and protein concentration 1.03 mg/ml. After thawing the frozen receptor preparation rapidly, receptors were diluted with binding buffer, homogenized, and kept on ice. 1. Use Multiscreen glass fiber filter plates (Millipore, Cat No MAFCNOB10) 15 precoated with o.5 % PEI for ~ 2hr at 40C. Before use add 200 pl/well assay buffer and filter using Multiscreen Separation System. 2. Incubate 5.5 pg of membranes (40 pl of a 1:40 dilution), buffer and

[

12 1]SST-14 (4 nM, -80 000 cpm, 2000 Ci/mmol) in a total volume of 200 pl for 60 min at 250C. Calculate IC50 for SST-14 (a truncated version of the 20 natural ligand SST-28) (Auspep, Cat No 2076) and SST-28 (Auspep, Cat No 1638). Prepare serial dilutions (1:5) of compounds, as described above and instead of adding SST-14 in well, add 20 pl of compounds (Table 3). 3. Filter using Multiscreen Separation System with 5 x 0.2 ml ice-cold Assay buffer. 25 4. Remove the plastic underdrain and dry plate in oven for 1 hr at 400C. 5. Seal tape to the bottom of the plate. 6. Add 50 pl/well scintillant (Supermix, Wallac, Cat No 1200-439). 7. Seal and count in the BJET, program 2.

WO 2007/038829 PCT/AU2006/001431 28 Table 3 Volume (ul) TB NSB Compounds I, =testing Membranes (5.5 pg/well) 40 40 40 Radio-labeled label (~ 80000 40 40 40 cpm, ~ 4nM) Unlabeled ligand - 20 mQH 2 0 20 Compounds 20 Assay buffer 100 100 100 Total volume (P1) 2002020 TB: total binding NSB: non-specific binding 5 Part C: General Experimental Methods Example I: HPLC Method for compounds in Tables I and 2 10 The HPLC separation of compounds in Tables 1 and 2 was conducted under Method A or Method B as shown below. Method A Column: Agilent SB Zorbax C18 4.6x5Omm (5pm, 80 A) 15 LC mobile phase: 5% aqueous MeCN /1 min 100% MeCN/7 -12 min Method B Column: Agilent SB Zorbax C18 4.6x5Omm (5pm, 80 A) 20 WO 2007/038829 PCT/AU2006/001431 29 LC mobile phase: 5% aq MeCN/1min 30% aq MeCN/3min 40% aq MeCN/12 min 5 100% MeCN/13-15 min Key to Building Blocks for Tables I and 2 Table 1: * % SST5 radio- ligand binding displaced at conc (pM) for 2P library of 10 compounds Table 2: * % SST5 radio- ligand binding displaced at conc (pM) for 3P library of compounds; ; R 4 = X30; compounds 60-63, 119 and 156-159 are comparative compounds from 2P library 15 "+ +" : % SST5 radio- ligand binding displaced at conc (pM) >60% "+": % SST5 radio- ligand binding displaced at conc (pM) 60>+>40% % SST5 radio- ligand binding displaced at conc (pM) -<40% Blank: not determined 20 RT: retention time/minutes M+H: mass ion +1 WO 2007/038829 PCT/AU2006/001431 30 K~1) Q~ w wo - 0) (11 . W. K) m~C CO ( co (2 CLD x 0 (0 (0 co CO (D mO (D m CD C) m1 C w) N.0 CA A) C) C) C) C) CD) C) C)) C) C) C) C) CD) C) N)~~p N)N ) )<> Ch O CA) CA) w% ~ I) ~ O C 00 0) co N' 0) 1%o 0 , ~D co to.CD .~. % N~ -4 m~ CA) cn 0 co 0) co WO 2007/038829 PCT/AU2006/001431 31 o cc 00 -4 0) (A 4h- W -L 0 CO 00 -4 ) 01 44 -n -nuo U m m m m m w3 M > mr m n m ca co (D CA) NnM m cn C ) C) ) C) C N)) . N) N ) N )N )N) N) N) co N) N) -1 4 -1 .11 4 N) 411 N) Cl C CD C) C 0 C C) C C C) C C) C CD C) C C w)~ N) N) N) N) w< w>K< N) w N Jl -P, PC-A,)L 4~ 4 .~ + I + I + + I + I + + + + 4I CD o m1 -4t (p D a) 00 io 13066 -4 N3 p4 -4 -j (Ih (It . 0) 0) (0 wp (0 Wp (0 WO 2007/038829 PCT/AU2006/001431 32 %1 0) al 4h Wi N~ -A 0 c000o N 0) Cii 4 W~ N G) G) 0 -n -n -n 0 0 0) -n 0 0 0 0) -n C.0 4 Cn al c7n mu cn 0) C0 0D C 0 0(0 (0 O C O C >< X~ X ) C') X) X X XX X () - 0C' C') C) C) C) CD) C) C) C) C) C) C') C) 0 C) X>X >< >< X X> XXX C) CD) N) N) CN) >< ><h >41 >< I I + + I + I + + + I + I I I + ++ C, 0 W, -a WA C A A CA) CD CD co C) 00 N~ CD ~. C4 -4 c"01 - 0) 0) CA cc 1f. ( ~ 4 N~ WO 2007/038829 PCT/AU2006/001431 33 CO0 CO - 0)0 Cn 4 W P -L Q0 W 0o 0) -n n G G0 0 0 0 0G) 0) 0 0 0G G m I I I I I I I I I I -A. m~ OD N) 00 0.) N.) NJ r -ri NJ NJ jr. - 3 CA) co CA) - - - rN. N NJ) X N) N) N.) w3 w CA) CA) CA) w w w co 4 - 4. 4 0 CD CD D CD C0 C 0 C + + + 1 00 0. -& -L~ CD~ 0 0a )hrCh c0 co ChI 00) .4 C) 0 I CO WO 2007/038829 PCT/AU2006/001431 34 -. (D 000) 0))D0) 0) 0) -Z o oco -i 0) ci 4h~ W) K Q 0D w 0 C) CD ) C) C) 0 0 C D D CD ) CD P. J0. 4-. 0 0 0 0 + + + + o2 o~~~ on 0 )000 CDI + + + + +x 0) + + + D + CD 0 +0 +o + ++ +n +o co +n M +o) C 4 0 WO 2007/038829 PCT/AU2006/001431 35 000000000000 co00 00 -4 1*4 1A -- ~-J - - -A -4 4~ 0) Cli 40 W N -1 W (00 -40) (ni -Ph W N -& >00 > > > Wo 0 0 C)0 C) C) C) oo 0 w) w w~l a) w) w) m w co CL 0L CL 0. 0. 0L D. 0. 0 0 0 0 0 0 0 0 xx x<> x x> xxxx ) N) C ' ) CD C ) CD N) CD N NDC) C) N)C) C) ) C) 00 0 ) 0 0 0 0 0 0 0 w 0 Xx XXXX X xx x x x x xx x + + + + I I+ co -4 (0 02 02 0 0 -- 4 0) m1 Cfl 01 -4 3 ( N) 0 0 0 2 30 0 P . ~ ( 0 0 02co) 4 0 02 N 2 - 4 - ~ 0 1 0 ~ (D WO 2007/038829 PCT/AU2006/001431 36 CD - 0 - (0 0 W0 to to W W W W W W wco co £)0 0 0 0) 0 0 0 0 0 L. .) C) () ~ C N) N) N) N) ") I ) " N) N) "I 0) (ni 4. CA) N) - ~C) C) C) C) C) C) CD CD CD CD C) N) N) N)N N) C) ,) Q I + I + + + ++ + + I + I + I I + I + I I I I I I + I I C) 0) N -- 4 CD CD 4b. 01 -4 co) w ~ -6 C, (0 (0 w, 01 IN W0 I01 -4 01 IQ --4 CO) C, W, CO) 01 -4 01 0) 01" 01 m) 01 01 01 01 01 01 01 01 4 01 01 01 01m (0 0) - n 01 01 01 w~ (A-4 C) , 0 4 C) C) ( (0 01 p :-4 (0 (0 01 01 p~0 C 1 0 ~) 0 -4 .-4 -4 3) 0) 0)0C)() 0)0C C) m10)0()0C001 c .41 -A -j4 0) -4 -A 01 01 (D w, (A) (0 01 (0 w, CA) (0 WO 2007/038829 PCT/AU2006/001431 37 - ~ ~ ~ ~ ~ ~ C 0(D0 C) 0)CiC)i ~000 ~ o) w o - )alA D co - D 00 C-11 0i (n or 0n CA on rh x + + +++ + + + + I+ + + + coI + + *- + CA -P 01 CA CA) 01 -1h~ 4. 41- 4 0) 01 0 CO 0~0) 0 (0 ~0 CO) -- 4 N 0) r) M1 01 m1 m1 01 01 01 M1 0 m1 al 0n 02 0) .n 0)1 w ~ w) al 01(0A ) A 1 4 -4- 0) 9~0 ~ ) N ) 0 P- 0 pC 0) m~ m) C) 0) 41 1 0C00D 4 C 0o co 4 1 01 02Ic Ic 4h, 0) w C,) co 1 -4 WO 2007/038829 PCT/AU2006/001431 38 W W W) m )K 00- 0 1 M. -& 0D 0. 00 -4 0) 0. 44h C4 M N) ) N N) N) ) ) N) N N ) ) N) N NJ ) N 02 01 0A 031 01 01 01 01 M1 0i 01 01 M1 al 0 01 0m w 0 4 -~ ~ 4 w) 02 N)N. ) ) N) + ~4 + + I"o+ + + + + +I + + + + + + K + + + + + + + + + + + + I I I + I I I II + 0)) w0 OD 00 -4 010 01C) 1 4~ 0 4J N) N) -1 0) OD 01 -4 -4 0) -4i 0) OD m1 m1 m 40 0) c WO 2007/038829 PCT/AU2006/001431 39 01 01 01 01 01 01 01 01 01 01 0 1 N4~ ~ C C 01 W1 N~C ) 0 (000 - 0) c 1n + I I I I I I I + + + + + + + I +++ + I + I + 0) CD 00 w o -4 -11 D w P. 4 01 0) N) 00 0) 01 4- 01 01 -- 4 .11 0)CD0 01 m1 01 m1 0) 0) 01h 01 0N 0 01 -4 p' -. 4 (0 -4 C0 0) CD 4. -4 -Ph 50 p -4 -4 Ki~ ~ P ~b) b) b) 6 C) -- 4 -j -4 m~0 0) 01 --4 0P 01 (0 0) 0) 01n 0) -4 CIO0 -- A -4 WO 2007/038829 PCT/AU2006/001431 40 K) -& C0 000 -40)0 (A 44 C4 ~ CO- 0( 0 -J 0) > > > > > > > 0 0 0 0 0 0 0 0 WM > o 0 0 0 0 w w) w w a) w w C3 u, co vi M 00 CA ~ ~ ~ ~ ~ ~ 0 &0C 3C3 C) ~ ( ~ & 3 03 0 3 0 3 0 co CD co (0 co P.. co 4 w3 (D C0 (0 C0 co C0 Co CD w3 0 co 00 ISJ w3 N) N No N (D c N) OD 03 0D Jr:. 4~. 4~. ~ 4. ~ ) N ~ ~ 4~ ~ - ~ -~ ~U4 0I 0 I C)I I WO 2007/038829 PCT/AU2006/001431 41 -4- 4 - -4 -,1 -4 w~ 0. 0. 00w co co C.0 CD C o CO CO N) 0 NJ N) N) 0) CC) C) OD -. p C~) C)D r 01c cn01 4 WO 2007/038829 PCT/AU2006/001431 42 Figure 1: Sidearms for Tables I and2 CI OH

NH

2

CH

3 X1 X2 X3 X4 X5 X6 X7 N NH 2 HH X8 X9 X1O X11 X12 X13 NH N NH N NH 2 _,N NH H N N NN X1 NH 2 NH2 NH2 X 21 X16 X17 2 X 25 5 K ONH 2 Z 2NH2

CH

3 X19 X20NHH X21 X22 X23 X24 X25 0NH 2 HNNH ' NAOH

NH

2 O kN2 X26 X27 X28 X29 X30 5 WO 2007/038829 PCT/AU2006/001431 43

NH

2 HN NH X31 X33 X35

H

2 N N X32 X34 X36

NH

2 R

NH

2 H 55c N

NH

2 X37 X38 X39 N X40 X41 X42

H

2 N

NH

2 X43 X44 X45 WO 2007/038829 PCT/AU2006/001431 4-4 X46 X47 X48 N N X49 X50 X51 cci CCA X52 X53 X54 0 X5 -C' X55 WO 2007/038829 PCT/AU2006/001431 45 OR5 OR5 R40 0 R40 O OR1 R304 R30~ -R NH NH 0 Scaffold A 0 Scaffold B R2 R2 OR5 OR5 R40 0 R40 O R30 NH ORI R30 NH 0 : Scaffold C 0 Scaffold D R2 R2 0R5 0 R40 -) m R30 SMe R40 SMe R30 NH o Scaffold E 0 Scaffold F R2 R2 0 R4 NH ORS Scaffold G R30 NH 0= R2 WO 2007/038829 PCT/AU2006/001431 46 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. 5 Throughout the specification and claims (if present), unless the context requires otherwise, the term "substantially" or "about" will be understood to not be limited to the value for the range qualified by the terms. 10 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. References 15 [1] Patel, Y.C. (1999) Somatostatin and its receptor family. Front. Neuroendocr. 20,157-198 [2] Csaba, Z. and Dournaud, P. (2001) Cellular biology of somatostatin receptors. Neuropeptides 35, 1-23 [3] T Reisine, T. (1995) Somatostatin receptors; Am. J. Pysiol. (Gastrointest. Liver 20 Physiol. 32) 269, G813-G820 [4] Bauer, W. et al. (1982) SMS201-995: A very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 31, 1133-1140 [5] Lamberts, S.W.J. et al. (1996) Drug therapy: Octreotide. N. Eng. J. Med. 334, 246-254 25 [6] Robinson, C. and Castaner, J. (1994) Lanreotide acetate. Drugs Future 19, 992-999 [7] Reisine, T. and Bell. G.I. (1995) Molecular biology of somatostatin receptors. Endocr. Rev. 16, 427-442

Claims (20)

1. A method of identifying biologically active compounds comprising: (a)designing a first library of compounds of formula 1 to scan molecular diversity wherein each compound of the library has at least two 5 pharmacophoric groups R1 to R5 as defined below and wherein compound of the library has same number of pharmacophoric groups; (b)assaying the first library of compounds in one or more biological assay(s); and (c)designing a second library wherein- each compound of the second 10 library contains one or more additional pharmacophoric groups with respect to the first library such that the/each component of the first and second library is a compound of formula 1: 15 0 ZR 1 R 5 X R 4 X XR 2 XR 3 Formula I 20 wherein the ring may be of any configuration; Z is sulphur, oxygen, CH 2 , C(0), C(O)NRA, NH, NRA or hydrogen, in the case where Z is hydrogen then R 1 is not present, RA is selected from the set defined for R 1 to R 5 , or wherein Z and R1 together form a heterocycle, WO 2007/038829 PCT/AU2006/001431 48 X is oxygen or nitrogen providing that at least one X of Formula I is nitrogen, X may also combine independently with one of R 1 to R 5 to form an azide, R 1 to R 5 are independently selected from the following non-pharmacophoric groups H, methyl and acetyl, and pharmacophoric groups R 1 to R 5 are independently selected 5 from the group which includes but is not limited to C2 to C20 alkyl or acyl excluding acetyl; C2 to C20 alkenyl, alkynyl, heteroalkyl; C5 to C20 aryl, heteroaryl, arylalkyl or heteroarylalkyl, which is optionally substituted, and can be branched or linear, or wherein X and the corresponding R moiety, R 2 to R 5 respectively, combine to form a heterocycle. 10

2. A method according to claim I wherein in the first library, three of the substituents R 1 -R 5 are non-pharmacophoric groups and are selected from hydrogen or methyl or acetyl. 15

3. A method according to claim 1 wherein in the first library, two of the substituents R 1 -R 5 are non-pharmacophoric groups and are selected from hydrogen or methyl or acetyl.

4. A method according to claim 1 wherein Z is sulphur or oxygen. 20

5. A method according to any one of claims 1-4 wherein at least one of the pharmacophoric groups is selected from aryl, arylalkyl, heteroaryl, heteroarylalkyl or acyl. WO 2007/038829 PCT/AU2006/001431 49

6. A library of compounds selected from compounds of formula 1 when used according to claim 2.

7. A library of compounds selected from compounds of formula 1 when used 5 according to claim 3.

8. A method according to any of claims 1 to 5 wherein the/each component of the library is a compound selected from formula 2 or formula 3 or formula 4. 0 ZR 1 0 ZR 1 0 ZR 1 R 5 0O'VNR R 5 0 402 R 5 HN R 4 HN NHR 2 R 4 0 NHR 2 R 4 0 NHR 2 10 OR 3 OR 3 OR 3 Formula 2 Formula 3 Formula 4

9. A method according to claim 8 wherein the/each compound is of the gluco- or 15 galacto- or allo- configuration.

10. A method according to claim 9 wherein the/each compound is of the gluco configuration. 20

11. A method according to claim 9 wherein the/each compound is of the allo configuration. WO 2007/038829 PCT/AU2006/001431 50

12. A method according to claim 9 wherein the/each compound is of the galacto configuration.

13. A method according to claim 1 wherein designing the library comprises 5 molecular modeling to assess molecular diversity.

14. A method according to claim 1 wherein R 1 to R 5 optional substituents are selected from 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 10 amide, aryl, cycloalkyl, heteroalkyl, heteroaryl, aminoalkyl, aminodialkyl, aminotrialkyl, aminoacyl, carbonyl, substituted or unsubstituted imine, sulfate, sulfonamide, phosphate, phosphoramide, hydrazide, hydroxamate, hydroxamic acid, heteroaryloxy, aminoaryl, aminoheteroaryl, thioalkyl, thioaryl or thioheteroaryl, which may optionally be further substituted. 15

15. A method according to any of claims 1 to 5 wherein the compounds are synthesized.

16. A method according to claim 1 wherein the biological assays involve peptide 20 ligand class of GPCRs.

17. A compound according to formula I in which at least one X is nitrogen, and said X is combined with the corresponding R 2 -R 5 to form a heterocycle. WO 2007/038829 PCT/AU2006/001431 51

18. A compound according to claim 17 wherein X and R 2 combine to form a heterocycle.

19. A compound according to any one of claims 17 and 18 wherein the heterocycle 5 is heteroaryl.

20. A compound according to any one of claims 17-19 wherein the heteroaryl is selected from triazoles, benzimidazoles, benzimidazolone, benzimidazolothione, imidazole, hydantoine, thiohydantoine and purine. 10