AU2012203083A1 - Substituted benzofurans, benzothiophenes, benzoselenophenes and indoles and their use as tubulin polymerisation inhibitors - Google Patents

Abstract

C:\NRPorbPDCC\ACG351%96. DOC-25/5/202 The present invention relates generally to substituted benzofurans, benzothiophenes, and indoles and their use as tubulin polymerisation inhibitors.

Description

A ustraliani Patents Act 1 990 - Regulatioi 3.2A ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title "Substituted benzofurans, benzothiophenes, benzoselenophenes and indoles and their use as tubulin polymerisation inhibitors" The following statement is a full description of this invention, including the best method of performing it known to us: C:WRPortblDCCACG\4351%6 DOC-25105/2012 CHEMICAL COMPOUNDS AND PROCESSES Field of the Invention 5 The present invention relates generally to chemical compounds and methods for their use and preparation. In particular, the invention relates to chemical compounds which may possess useful therapeutic activity, use of these compounds in methods of therapy and the manufacture of medicaments as well as compositions containing these compounds. 10 Background of the Invention Tubulin is an important target in controlling disease states associated with cell proliferation such as cancer and inflammation (eg, psoriasis). Tubulin is composed of a heterodimer of two related proteins called a and P tubulin. Tubulin polymerises to form structures called 15 microtubules. Compounds that inhibit tubulin's ability to polymerise to form microtubules interrupt cell division which is dependent on the formation of microtubules to form mitotic spindles. Examples of such compounds include the Vinca alkaloids such as vincristine and vinblastine. 20 Furthermore, compounds that inhibit the depolymerisation of microtubules can also prevent cell division since they often disrupt the proper formation of mitotic spindles which must also disassemble in order for cell division to be completed. Interruption of the mitotic process in this manner often induces cell death by an apoptotic mechanism. Examples of compounds which act in this manner include the taxoids such as paclitaxel. 25 For these antimitotic agents, selectivity for diseased versus non-diseased tissue is based on relative rates of proliferation, where the diseased tissue more rapidly proliferates. Accordingly, diseased tissue is generally more sensitive to the effect of these agents because it is more likely to be in a state of mitosis which is the stage of a cell's life cycle 30 affected by agents that target tubulin. Unfortunately however, a number of normal, healthy tissues also have quite high rates of proliferation (for example hair follicles and the lining C:\NRPotNDCC\ACG35196_I DOC-25 l/212 -2 of the gastro-intestinal tract) and accordingly, these tissues can be damaged during chemotherapy with these agents. Tubulin is also a target for treating disease states that are dependent or result from the 5 abnormal formation of blood vessels (neovascularisation) such as in cancerous tumours and in ocular myopathy. In these cases the cytoskeleton of the vascular endothelial cells are disrupted through depolymerisation of microtubles, which results from inhibiting the polymerisation of tubulin to form microtubules. Microtubule length is dependent on the rate of depolymerisation versus polymerisation. Depolymerising microtubles through 10 inhibition of polymerisation leads to a change in endothelial cell morphology, which then causes a blockage or shutdown in blood flow. In the case of cancerous tumours, blood flow to the diseased tissue is stopped, depriving the tumour of oxygen and nutrients leading to necrotic cell death. Neovascular systems are more sensitive to these agents because they are more dependent on microtubule cytoskeletons than normal, healthy, 15 vascular endothelial cells which are also supported by actin based cytoskeletal structures. For a number of tubulin polymerisation inhibitors (TPIs) that target the colchicine binding site of tubulin, the vascular targeting modality can be achieved at a lower in vivo concentration than the antiproliferative modality. In theory though, agents that target the colchicine binding domain of tubulin are potentially dual mode agents (ie. antimitotic and 20 antivascular). One of the most potent inhibitors of tubulin polymerisation that binds to the colchicine binding domain of tubulin is the cis-stilbene, combretastatin A4 (CA4) (1). Due to its insolubility CA4 is administered as its prodrug equivalent combretastatin A4 disodium 25 phosphate (CA4P) (2), where the phosphate is rapidly cleaved in vivo. CA4P is currently undergoing phase I and I clinical trials and is the most advanced vascular targeting agent being trialed. In view of some of the draw-backs associated with CA4P, such as, instability (can isomerise to the inactive trans-stilbene), toxicity and rapid clearance, a number of synthetic groups have sought to prepare more stable analogues that could be 30 designed to exhibit an improved therapeutic index and exhibit improved pharmacokinetics. Recently, a number of TPIs have been identified that contain the benzofuran, indole or C:\NRPrltbI\DCC\ACG\3 51%6 1 DOC-2S05/202 -3 benzothiophene ring systems (see for example, WO 1998/39323, WO 2001/19794 and WO 2001/68654) or chromene and dihydronapthalene ring systems (see for example, WO 2005/113532, and WO 1998/39323). Such ring systems are quite stable and should over come the stability issues associated with CA4P. Unfortunately, such compounds only 5 exhibit moderate tubulin binding and anti-mitotic activity. Accordingly, there exists a need to identify other compounds which are more stable than CA4 and exhibit satisfactory pharmacological properties and/or activity. OMe OMe OMe OR OMe (1) CA4: R = H (2) CA4P: R = -P(O)O 2 Na 2 10 Summary of the Invention The present invention provides compounds of formula (I) and salts thereof;

R

2 D R 2 C

R

2 E / R 2 B RIA L R 2 A RIB | Q RIC X RID 15 wherein; X represents 0, S, SO, So 2 , Se, SeO, SeO 2 or NR where R is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted 20 heterocyclyl, and optionally substituted sulfonyl; C WRPonNDCC\ACG351%6_L.DOC-25/05/2012 -4 RIA and RIB each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, 5 optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally 10 substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted 15 oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted 20 thioacyl, optionally substituted thioacylamino, or R IA and RIB together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; 25 Ric represents C1.

3 alkoxy, C 1

.

3 alkylthio, C 1

.

3 alkylamino, or C 1

.

3 dialkylamino; RID represents hydroxy or amino; L represents C=O, 0, S, SO, SO 2 , Se, SeO, SeO 2 , C=NZ', or NR' where Z' is H, 30 optionally substituted alkyl, optionally substituted aryl or optionally substituted amino; and where R' is selected from H, 0, optionally substituted acyl, optionally C : PonbI\DCC'ACG\4351%6_1 DOC-25/05/2012 -5 substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted sulfonyl; 5 R 2A-R2E each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylnamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, 10 optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally 15 substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted 20 oxyacylimino, optionally substituted oxyacyloxy, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted 25 thioacyl, optionally substituted thioacylamino, or optionally substituted thioacyloxy; or any of R 2 ^ and R 2 B, R 2 B and R 2 c, R 2 c and Rm, and Rm and R 2 E, together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; and 30 Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally C:\NRPortbl\DCC\ACG\4351%6_ DOC-25/05/2012 -6 substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally 5 substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acyl and optionally substituted oxyacyl, or NR.'NR"', where each R.' independently represents H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl. 10 The present invention also provides a method for treating a disease state by inhibiting tubulin polymerisation including the step of administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof;

R

2 D R 2 C

R

2 E R2B RIA L R 2 A RIB | Q RIC x 15 RID wherein; X represents 0, S, SO, SO 2 , Se, SeO, Se0 2 or NR where R is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally 20 substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl; RIA and RIB each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, 25 sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, C:RPorbl\DCC\ACG\435i%6_1 DOC-25/05/2012 -7 optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, 5 optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally 10 substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally 15 substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, optionally substituted thioacylamino, or R IA and RIB together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; 20 Ric represents CI.

3 alkoxy, CI.

3 alkylthio, C 1

.

3 alkylamino, or CI.

3 dialkylamino; RID represents hydroxy or amino; 25 L represents C=0, 0, S, SO, SO 2 , Se, SeO, SeO2, C=NZ', or NR' where Z' is H, optionally substituted alkyl, optionally substituted aryl or optionally substituted amino; and where R' is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally 30 substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted sulfonyl; C:\NRPonb CC\ACGW351%6_I DOC-255/V2012 -8 R 2A-R2E each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, 5 optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally 10 substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted 15 oxyacylimino, optionally substituted oxyacyloxy, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylanino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted 20 thioacyl, optionally substituted thioacylamino, or optionally substituted thioacyloxy; or any of R 2 A and R 2B, R2B and R 2 C, R 2 C and R 2 D, and R 2 D and R 2 E, together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; and 25 Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR"R", where each R" independently 30 represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, C DCCG 56 OC-25MS/OI2 -9 optionally substituted heteroaryl, optionally substituted acyl and optionally substituted oxyacyl, or NR"'NR'", where each R.' independently represents H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl. 5 The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof:

R

2 1 ) R 2 C

R

2 E /0\ R 2 B RIA L R 2 A RIB I Q R") 10 wherein; X represents 0, S, SO, SO 2 , Se, SeO, SeO 2 or NR where R is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted 1 5 heterocyclyl, or optionally substituted sulfonyl; RIA and RIB each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally 20 substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, 25 optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally C \NRPotbIDCCACG4351966I DOC-25/5/20l2 -10 substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted 5 oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted 10 thioacyl, optionally substituted thioacylamino, or R IA and RB together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; 15 RIc represents Ci 3 alkoxy, CI 3 alkylthio, CI.

3 alkylamino, or CI.

3 dialkylamino; RID represents hydroxy or amino; L represents C=0, 0, S, SO, SO 2 , Se, SeO, SeO 2 , C=NZ', or NR' where Z' is H, 20 optionally substituted alkyl, optionally substituted aryl or optionally substituted amino; or NR' where R' is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, or optionally 25 substituted sulfonyl; R 2A-R2E each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally 30 substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally C:\NRPodbI\DCC\ACG\4351%6_1.DOC-25/5/20L2 -11 substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally 5 substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted 10 oxyacylimino, optionally substituted oxyacyloxy, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted 15 thioacyl, optionally substituted thioacylamino, or optionally substituted thioacyloxy; or any of R 2 A and R 2 ", R 2 B and R 2 C, R 2 C and R 2 D, and R 2 D and R 2 E, together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; and 20 Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR"R", where each R" independently 25 represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acyl and optionally substituted oxyacyl, or NR"'NR"', where each R.' independently represents H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted 30 alkynyl, optionally substituted aryl and optionally substituted heteroaryl; C:\NRPortbl\DCC\ACG\4351%6_1 DOC-25/05/OI2 - 12 in the manufacture of a medicament for the treatment of a disease state by inhibiting tubulin polymerisation. Brief Description of the Figures 5 Figure 1 depicts a graph of cell viability/proliferation relative to control against concentration of CA4(1)(nM) in relation to proliferating and quiescent endothelial cells. Figure 2 depicts a graph of cell viability/proliferation relative to control against 10 concentration of compound example 11 (nM) against proliferating and quiescent endothelial cells. Figure 3 depicts a graph of fluorescence against time (mins) in relation to inhibition of tubulin polymerisation by CA4 (1), compound example 11, and a buffer solution. 15 Figure 4 depicts a graph of % perfusion control against an amount of compound (mg/kg) in relation to comparative levels of vascular shutdown (reduction in tumour perfusion) between CA4P (2) and compound example 29 of the present invention. 20 Figure 5 depicts a graph of Tumor Volume ratio (Day*/Day 1) against time (Days) in relation to tumor growth inhibition of compound example 29 in Balb/c nu/nu mice bearing MDA-MB-231 orthotopic breast solid tumors. Description of the Preferred Embodiments 25 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. 30 C:\NRPorbI\DCC\ACG4351%6_1 DOC-25/05/2012 - 13 The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of 5 endeavour to which this specification relates. "Alkyl" refers to monovalent alkyl groups which may be straight chained or branched and preferably have from I to 10 carbon atoms or more preferably I to 6 carbon atoms, and even more preferably I to 3 carbon atoms. Examples of such alkyl groups include methyl, 10 ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like. "Alkylene" refers to divalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms, and even more preferably 1 to 3 carbon atoms. Examples of such alkylene groups include methylene (-CH 2 -), ethylene (-CH 2

CH

2 -), and 15 the propylene isomers (e.g., -CH 2

CH

2

CH

2 - and -CH(CH 3

)CH

2 -), and the like. "Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (eg., phenyl) or multiple condensed rings (eg., naphthyl or anthryl), preferably having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like. 20 "Arylene" refers to a divalent aryl group wherein the aryl group is as described above. "Aryloxy" refers to the group aryl-O- wherein the aryl group is as described above. 25 "Arylalkyl" refers to -alkylene-aryl groups preferably having from I to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such arylalkyl groups are exemplified by benzyl, phenethyl and the like. "Arylalkoxy" refers to the group arylalkyl-O- wherein the arylalkyl group are as described 30 above. Such arylalkoxy groups are exemplified by benzyloxy and the like.

C:WRPortbI\DCC\ACO351%6_L DOC-25/05/2012 -14 "Alkoxy" refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. 5 "Alkenyl" refers to a monovalent alkenyl group which may be straight chained or branched and preferably have from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and have at least 1 and preferably from 1-2, carbon to carbon, double bonds. Examples include ethenyl (-CH=CH 2 ), n-propenyl (-CH 2

CH=CH

2 ), iso-propenyl (-C(CH 3

)=CH

2 ), but-2-enyl (-CH 2

CH=CHCH

3 ), and the like. 10 "Alkenyloxy" refers to the group alkenyl-O- wherein the alkenyl group is as described above. "Alkenylene" refers to divalent alkenyl groups preferably having from 2 to 8 carbon atoms 15 and more preferably 2 to 6 carbon atoms. Examples include ethenylene (-CH=CH-), and the propenylene isomers (e.g., -CH 2 CH=CH- and -C(CH 3 )=CH-), and the like. "Alkynyl" refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more 20 preferably 2 to 6 carbon atoms and having at least 1, and preferably from 1-2, carbon to carbon, triple bonds. Examples of alkynyl groups include ethynyl (-CE CH), propargyl

(-CH

2 C= CH), pent-2-ynyl (-CH 2

CECCH

2

-CH

3 ), and the like. "Alkynyloxy" refers to the group alkynyl-O- wherein the alkynyl groups is as described 25 above. "Alkynylene" refers to the divalent alkynyl groups preferably having from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms. Examples include ethynylene (-CE C-), propynylene (-CH 2 -CE C-), and the like. 30 "Acyl" refers to groups H-C(O)-, alkyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl- C \NRPortbI\DCCACG435196_ I DOC-25105/2012 - 15 C(O)- and heterocyclyl-C(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Oxyacyl" refers to groups HOC(O)-, alkyl-OC(O)-, cycloalkyl-OC(O)-, aryl-OC(O)-, 5 heteroaryl-OC(O)-, and heterocyclyl-OC(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Amino" refers to the group -NR*R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, 10 heteroaryl and heterocyclyl is as described herein. "Aminoacyl" refers to the group -C(O)NR*R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. 15 "Aminoacylamino" refers to the group -NR*C(O)NR*R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. 20 "Acylamino" refers to the group -NR*C(O)R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. "Acyloxy" refers to the groups -OC(O)-alkyl, -OC(O)-aryl, -C(O)O-heteroaryl, and 25 -C(O)O-heterocyclyl where alkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Aminoacyloxy" refers to the groups -OC(O)NR*-alkyl, -OC(O)NR*-aryl, -OC(O)NR*-heteroaryl, and -OC(O)NR*-heterocyclyl where R* is independently 30 hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

C :\RPortbl\DCC\ACG\43519%6 .DOC-25105/2012 - 16 "Oxyacylamino" refers to the groups -NR*C(O)O-alkyl, -NR*C(O)O-aryl, -NR*C(O)O-heteroaryl, and NR*C(O)O-heterocyclyl where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, 5 cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. "Oxyacyloxy" refers to the groups -OC(O)O-alkyl, -O-C(0)O-aryl, -OC(0)O heteroaryl, and -OC(O)O-heterocyclyl where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. 10 "Acylimino" refers to the groups -C(NR*)-R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. 15 "Acyliminoxy" refers to the groups -O-C(NR*)-R* where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. "Oxyacylimino" refers to the groups -C(NR*)-OR* where each R* is independently 20 hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. "Cycloalkyl" refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 8 carbon atoms. Such cycloalkyl groups 25 include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like. "Cycloalkenyl" refers to cyclic alkenyl groups having a single cyclic ring and at least 30 one point of internal unsaturation, preferably incorporating 4 to 8 carbon atoms.

C:NRPotblDCCACG\4351%6_1 DOC-25/05/2012 - 17 Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclohex-4-enyl, cyclooct-3-enyl and the like. "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo. 5 "Heteroaryl" refers to a monovalent aromatic heterocyclic group which fulfils the Hfckel criteria for aromaticity (ie. contains 4n + 2 a electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen). Such 10 heteroaryl groups can have a single ring (eg., pyridyl, pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (eg., indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl). "Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single 15 ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from I to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen. Examples of heterocyclyl and heteroaryl groups include, but are not limited to, 20 oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, 25 piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7 tetrahydrobenzo[b]thiophene, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, triazole, and the like. 30 "Heteroarylene" refers to a divalent heteroaryl group wherein the heteroaryl group is as described above.

C:\NRPonbPDCCACG4351%6_ LDOC-25aJ052012 -18 "Heterocyclylene" refers to a divalent heterocyclyl group wherein the heterocyclyl group is as described above. 5 "Thio" refers to groups H-S-, alkyl-S-, cycloalkyl-S-, aryl-S-, heteroaryl-S-, and heterocyclyl-S-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Thioacyl" refers to groups H-C(S)-, alkyl-C(S)-, cycloalkyl-C(S)-, aryl-C(S)-, 10 heteroaryl-C(S)-, and heterocyclyl-C(S)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. "Oxythioacyl" refers to groups HO-C(S)-, alkylO-C(S)-, cycloalkylO-C(S)-, arylO C(S)-, heteroarylO-C(S)-, and heterocyclylO-C(S)-, where alkyl, cycloalkyl, aryl, 15 heteroaryl and heterocyclyl are as described herein. "Oxythioacyloxy" refers to groups HO-C(S)-O-, alkylO-C(S)-O-, cycloalkylO-C(S)-O-, arylO-C(S)-O-, heteroarylO-C(S)-O-, and heterocyclylO-C(S)-O-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. 20 "Phosphorylamino" refers to the groups -NR*-P(O)(R**)(OR***) where R* represents H, alkyl, cycloalkyl, alkenyl, or aryl, R** represents OR*** or is hydroxy or amino and R*** is alkyl, cycloalkyl, aryl or arylalkyl, where alkyl, amino, alkenyl, aryl, cycloalkyl, and arylalkyl are as described herein. 25 "Thioacyloxy" refers to groups H-C(S)-O-, alkyl-C(S)-O-, cycloalkyl-C(S)-O-, aryl C(S)-O-, heteroaryl-C(S)-O-, and heterocyclyl-C(S)-O-, where alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl are as described herein. "Sulfinyl" refers to groups H-S(O)-, alkyl-S(O)-, cycloalkyl-S(O)-, aryl-S(O)-, 30 heteroaryl-S(O)-, and heterocyclyl-S(O)-, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein.

C:\NRPortbt\DCC\ACG4351966_1 DOC-25M5/2012 -19 "Sulfonyl" refers to groups H-S(O) 2 -, alkyl-S(O) 2 -, cycloalkyl-S(O) 2 -, aryl-S(O) 2 -, heteroaryl-S(O) 2 -, and heterocyclyl-S(O) 2 -, where alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are as described herein. 5 "Sulfinylamino" refers to groups H-S(O)-NR*-, alkyl-S(O)-NR*-, cycloalkyl-S(O) NR*-, aryl-S(O)-NR*-, heteroaryl-S(O)-NR*-, and heterocyclyl-S(O)-NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described 10 herein. "Sulfonylamino" refers to groups H-S(0) 2 -NR*-, alkyl-S(O) 2 -NR*-, cycloalkyl-S(O) 2 NR*-, aryi-S(O) 2 -NR*-, heteroaryl-S(O) 2 -NR*-, and heterocyclyl-S(O) 2 -NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and 15 where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. "Oxysulfinylamino" refers to groups HO-S(O)-NR*-, alkylO-S(O)-NR*-, cycloalkylO S(O)-NR*-, arylO-S(O)-NR*-, heteroarylO-S(O)-NR*-, and heterocyclylO-S(O)-NR*-, 20 where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. "Oxysulfonylamino" refers to groups HO-S(O) 2 -NR*-, alkylO-S(O) 2 -NR*-, 25 cycloalkylO-S(0) 2 -NR*-, arylO-S(O) 2 -NR*-, heteroarylO-S(O) 2 -NR*-, and heterocyclylO-S(O) 2 -NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein.

C WRPorIlDCC\ACGw351%6_1 DOC-25/05/2012 - 20 "Aminothioacyl" refers to groups R*R*N-C(S)-, where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. 5 "Thioacylamino" refers to groups H-C(S)-NR*-, alkyl-C(S)-NR*-, cycloalkyl-C(S) NR*-, aryl-C(S)-NR*-, heteroaryl-C(S)-NR*-, and heterocyclyl-C(S)-NR*-, where R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. 10 "Aminosulfinyl" refers to groups R*R*N-S(O)-, where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. 15 "Aminosulfonyl" refers to groups R*R*N-S(O) 2 -, where each R* is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is as described herein. In this specification "optionally substituted" is taken to mean that a group may or may not 20 be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxy, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, acylamino, cyano, halogen, nitro, sulfo, phosphono, phosphorylamino, phosphinyl, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, 25 -NHC(NH)NH 2 , oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and di-alkylamino, mono-and di (substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di-substituted amines having 30 different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and the C :NRPonbr\DCC\ACGu351%6 1.DOC-25/05/2012 - 21 like, and may also include a bond to a solid support material, (for example, substituted onto a polymer resin). An optionally substituted amino group may also include amino acid and peptide residues. 5 In some embodiments R A-R B and R 2

A-R

2 E are independently selected from the following groups: alkyl group, preferably methyl and ethyl; 10 substituted alkyl group, preferably 1-hydroxyethyl, 1-thioethyl, methoxyiminomethyl, ethoxyiminomethyl, 1 -(hydroxyimino)ethyl, I -(hydroxyimino)propyl, 1 hydrazinoethyl, I-hydrazinopropyl, hydroxyiminomethyl, 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 3-oxopentyl, nitromethyl, 1-nitromethyl, and 2-nitroethyl; 15 acyl group, preferably formyl acetyl, propionyl, benzoyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethyl or cyano); alkoxy group, preferably methoxy and ethoxy; 20 oxyacyl group, preferably methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl; acyloxy group, preferably acetoxy and propioxy; 25 substituted arylalkyl group, preferably 1-hydroxybenzyl, and 1-thiobenzyl; sulfinyl group, preferably methylsulfinyl, ethylsulfinyl, benzene sulfinyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano), 30 methoxysulfinyl, ethoxysulfinyl; C WRortN\DCACGU3516_ I _DOC-25/05/2OI2 - 22 sulfonyl group, preferably methylsulfonyl, ethylsulfonyl, benzenesulfonyl (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano), methoxycarbo, trifluoromethane; 5 oxyacylamino group, preferably methoxycarbonylamido, and ethoxycarbonyl amido; oxythioacyl group, preferably methoxythiocarbonyl and ethoxythiocarbonyl; thioacyloxy group, preferably thionoacetoxy and thionopropionoxy; 10 sulphinylamino group, preferably methylsulfinylamino, ethylsulfinylamino, and benzenesulfinylamino (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano); 15 amino group; substituted amino groups, preferably residues of L-valine, D-valine, L-alanine, D-alanine, aspartic acid, and alanylserine, N-methylamino, and N,N'-dimethylamino; 20 sulphonylamino group, preferably methylsulfonylamino, ethylsulfonylamino and benzene sulfonylamino (optionally substituted with methyl, methoxy, halogen, nitro, trifluoromethane or cyano); oxysulfinylamino group, preferably methoxysulfinylamino and ethoxysulfinylamino; 25 oxysulfonylamino group, preferably methoxysulfonylamino and ethoxysulfonylamino; optionally substituted alkenyl group, preferably, 1 -propenyl, vinyl, nitrovinyl, cyano vinyl, or trifluorovinyl and styryl (optionally substituted with methyl, methoxy, halogen, 30 nitro, trifluoromethane or cyano); C:\NRPonbl\DCC\CG\4351%6_1.DOC-25/05/2012 - 23 alkynyl group, preferably I -propynyl, ethynyl or trimethylsilylethynyl. In one embodiment R 2 D, R 2 c, and R 2 B are methoxy and L is a carbonyl group (C=0). 5 Accordingly, in this embodiment the compounds of the present invention are represented by formula (Ia)

OCH

3

CH

3 0

OCH

3

R

2 E R 2 A RIABO (Ia) RIC X Q RID wherein; X represents 0, S, SO, S02, Se, SeO, SeO 2 or NR where R is selected from H, 0, 10 optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl; 15 R A and RIB each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally 20 substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally 25 substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, C:WRPorblDCCO ACG\4351966_ DOC-25/05/2012 - 24 optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted 5 oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, optionally substituted thioacylamino, or RIA and RIB together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally 10 substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; Ric represents Ci 3 alkoxy, CI.

3 alkylthio, CI.

3 alkylamino, or CI.

3 dialkylamino; 15 RID represents hydroxy or amino; R 2A and R 2 E independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally 20 substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, 25 optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally 30 substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted C :NRPofbl\DCCACG\4351%6_ DOC-25/05/2012 - 25 oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted 5 thioacyl, optionally substituted thioacylamino, or optionally substituted thioacyloxy; and Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, 10 optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acyl and optionally 15 substituted oxyacyl, or NR"'.NR'", where each R"' independently represents H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl. In another embodiment, R'^, RIB, R 2 A and R 2 E represent H and Ric represents Ci.

3 alkoxy. 20 Accordingly, in this embodiment the compounds of the present invention are represented by formula (Ib)

OCH

3

CH

3 0

OCH

3 H H H H 0 (Ib) I I RIC X Q RID wherein; 25 X represents 0, S, SO, SO 2 , Se, SeO, Se0 2 or NR where R is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted C \NRPonbl\DCC\ACG4351966_1 DOC-2505/2012 -26 alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl; 5 RIc represents C 1

.

3 alkoxy; R' D represents hydroxy or amino; Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally 10 substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, 15 optionally substituted acyl and optionally substituted oxyacyl, or NR"'NR"', where each R.' independently represents H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl. 20 In a preferred embodiment RIc represents methoxy. For the compounds represented by formulae I, Ia and Ib, X is preferably selected from 0, S and NR. More preferably X is 0 or NR and most preferably X is 0. 25 Accordingly, in another embodiment the present invention provides novel benzofurans and pharmaceutically acceptable salts thereof of formula II: C \NRPotbl\DCC\ACGA351%6I DOC-25/05/2012 -27

R

2 D R 2 C

R

2 E / \ R 2 B RIA L R 2 A R IB I Q RIC 0 RID wherein; R A and RIB each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, 5 sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally 10 substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, 15 optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, 20 optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, optionally substituted thioacylamino, or RIA and RIB together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted 25 cycloalkenyl; C \NRPortb\DCACG\4351%6_1.DOC.25d5/21O2 -28 Ric represents CI.

3 alkoxy, C 1

.

3 alkylthio, CI.

3 alkylamino, or CI.

3 dialkylamino; RID represents hydroxy or amino; 5 L represents C=O, 0, S, SO, SO 2 , Se, SeO, Se0 2 , C=NZ', or NR' where Z' is H, optionally substituted alkyl, optionally substituted aryl or optionally substituted amino; and where R' is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally 10 substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted sulfonyl; R 2A-R2E each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, 15 trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally 20 substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, 25 optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacylimino, optionally substituted oxyacyloxy, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, 30 optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted C:\VRPortbl\DCCACG351%6_ LDOC-25/05/2012 -29 thioacyl, optionally substituted thioacylamino, or optionally substituted thioacyloxy; or any of R 2 A and R 2B, R2B and R 2 c, R 2 C and R 2 D, and R 2 D and R 2 E, together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally 5 substituted cycloalkenyl; and Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally 10 substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl and optionally substituted oxyacyl, or NR"'NR"', where each R"' independently represents H, 15 optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl. In this embodiment it is preferred that L is a carbonyl group (C=O). Also, preferably at least one of R 2 D, R 2 C or R 2 B represents a hydroxy or C 1

.

3 alkoxy group. More preferably 2D 2C 2B 20 when X=O, L is a carbonyl group an R , R and R represent methoxy. Even more preferably when X=O, L is a carbonyl group, R , R 2c, and R 2 B represent methoxy and RA, RIB, R 2 A, R 2 E are H. Furthermore, for the compounds of formula (I), (1a), (Ib) and (II) it is preferred that Q 25 represents H, CN, optionally substituted C2A alkynyl, optionally substituted C 2

-

6 alkenyl, optionally substituted C1A alkyl, hydroxy, optionally substituted oxyacyl, NR"R", SR" (where each R" is independently H, optionally substituted Cz4alkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl), NR"'NR"' (where each R"' is independently H, C 1

.

3 alkyl), optionally substituted acylamino, or halogen. 30 In some embodiments Q is independently selected from the following groups: C:\NRPonbDCC\ACG\4351%6_1 DOC-25/05/2012 - 30 H; CN; halogen, preferably Br or Cl; alkyl group, preferably methyl, ethyl, propyl, butyl; 5 substituted alkyl group, preferably amino, oxyacylaminoalkyl and oxysulphonylaminoalkyl; optionally substituted alkenyl, preferably ethenyl, 2-alkylethenyl, 2 oxyacylethenyl, 2-aminoacylethenyl; optionally substituted alkynyl, preferably ethynyl, 2-alkylethynyl; 10 optionally substituted oxyacyl; OR", preferably hydroxy, methoxy, ethoxy; NR"R", preferably NH 2 , alkylamino, dialkylamino, heteroarylamino, aminoalkylamino, hydroxyalkylamino, alkoxyalkylamino, oxyacylalkylamino, oxyacylaminoalkylamino, guanidinoalkylamino; 15 SR", preferably alkylthio, aminoalkylthio, heteroarylthio, aminoalkylthio, hydroxyalkylthio, alkoxyalkylthio, oxyacylalkylthio, oxyacylaminoalkylthio, guanidinoalkylthio; hydrazine. 20 The compounds of the present invention can be prepared by the multicomponent reaction system which has been described in PCT/AU02/00099 (WO 02/060872), the entire contents of which is incorporated herein by reference. In particular the compounds of the present invention can be prepared by the reaction sequence depicted in Scheme I below: C :RPorb\DCC\ACG433J%6_ I DOC-25NO2012 -31 Scheme 1 RIA RIA Q RIB Halogen or H RIB Ric XPorXM RIC XP or XMI RID RID R 2 D R 2 C (1) (2)

R

2 E R 2 B / CO(g) Halogen R 2 A RIA R 2 D R 2 C R 2 D R 2 C Q

R

2 EM

AR

2 B

R

2 E R2R 2 B RID M 2

R

2 A RlB O (3) R 2 D R 2 C Q Ric' X

R

2 E / R 2 B R ID Halogen O R2A

R

2 D R 2 C R 2 E R2B RIA L

R

2 A RID (5) where Q is for example optionally substituted alkyl, optionally substituted alkenyl, 5 optionally substituted alkynyl, OR", SR", NR"R" or NR"'NR"'; X is S, NR, 0 or Se, and L is 0, S, Se, or NR'. As shown above in Scheme 1, the compounds of formula I in which X is NR or 0 can be 10 derived from reacting together a phenol or protected amine and terminal alkyne respectively. The starting phenol or aniline and terminal alkyne can be coupled together C :WRPonb\DCC\ACCM351%6_1.DOC-25//2012 - 32 under conditions which allow for heteroannulation to spontaneously occur so as to form the target benzo[b]furan or indole in a "one-pot" synthetic strategy. Thus, the metal based compound required to form (2) (when XMi) should be such that the phenol or protected amine is deprotonated to form the group -OMI or NHMI. 5 Suitable M, are based on Li, Na, K, Mg, Cs and Ba as well as species formed therefrom, for example from Grignard reagents Cialkyl MgHal (Hal = I, Cl or Br). Suitable metal species include MgCl, MgBr or MgI. Formation of (1) can be effected by treating the corresponding phenol or protected amine with, for example, Li 2

CO

3 , Na 2

CO

3 , K 2

CO

3 , 10 MgCO 3 , Cs 2

CO

3 , BaCO 3 , MeMgCl, EtMgCl, MeMgBr, EtMgBr, MeMgI and EtMgI. M2 can be a hydrogen atom or metal species used in any palladium or nickel cross coupling protocols known in the art, for example, Stille, Sonogashira, Suzuki or Negishi cross-coupling reactions using stannanes (eg, aryl or alkylstannanes, boronic acids/esters 15 or zinc based compounds eg. ZnCl, ZnI 2 , ZnBr 2 , ZnOTf 2 ) for example based on Mg, Zn, Cu, B, Si, Mn, Sn, Ge or Al. Particularly suitable M 2 include ZnCl, (alkyl) 3 Sn, (aryl) 3 Sn,

B(OR)

2 (R is, eg, H alkyl, alkenyl or alkynyl), MgBr, MgCI and MgI. Preferably the palladium catalysed coupling reactions may also include a co-catalyst, for instance, Cul, in the presence of a suitable base such as a trialkyl amine base. 20 In a particularly preferred form of this aspect of the invention both M, and M 2 are derived from a Grignard reagent such as an alkyl magnesium halide eg. CialkylMgBr, (Cl) or (I). Suitable MI and M 2 thus include MgCl, MgBr and MgI. 25 Where X is NR, the nitrogen atom of the starting aniline is suitably protected by a nitrogen protecting group or as an imine. Suitable nitrogen protecting groups are known to those skilled in the art of organic synthesis and include acyl groups (eg acetyl, trifluoroacetyl), phenyl, benzyl and benzoyl. Other suitable nitrogen protecting groups may be found in Protective Groups in Organic Synthesis, T. W. Greene and P. Wutz, John Wiley & Son, 3 'd 30 Edition.

C 'NRPonblDCC\ACG4351%6_.DOC-25/05i2O[2 -33 The coupling agent used in this first step to form (2) is preferably a nickel or palladium based coupling agent. Suitable coupling agents are known in the art and include Pd(PPh 3

)

2 Cl2, Pd(PPh 3

)

4 , Pd(dibenzylideneacetone) 3 and PdCl 2

(CH

3

CN)

2 . 5 Such coupling reactions are generally performed at temperatures below room temperature, most preferably at 0"C and below. It is also preferred that such reactions are carried out under an inert atmosphere of either nitrogen or argon. Suitable solvents include ether solvents such as THF and diethyl ether. 10 The metallated (2) can be reacted, in situ, with Halogen-R 2 in the presence of a palladium catalyst in an atmosphere of CO to form (4). This may be accomplished by evacuating the inert reaction gas present in the initial coupling step and replacing said gases with CO. In this system it is also preferred that the initial reaction solvent is replaced with a more polar solvent such as, for instance, DMSO. Removal of the initial reaction solvent may be 15 achieved in vacuo. The preparation of benzo[b]thiophenes and benzo[b]selenophenes of formule (I), (la) or (Tb) are constructed using a variation of the methods described for the benzo[b]furans and indoles. In particular, the sulfur or selenium atom, X, must be protected by a suitable 20 protecting group (P) to circumvent competitive coupling of a thiolate or selenoate to the aryl halide to afford xanthones or selenones. Suitable sulfur and selenium protecting groups are those which are capable of sustaining a positive charge. Examples include benzyl, allyl, and alkyl. This method can also be used as an alternative method for the formation of benzo[b]furans and indoles where X = 0 or NR and P = benzyl, allyl, and 25 alkyl or where XP is an imine. As used herein a Hal+ producing agent is an agent which can effectively act as a Hal+ source. Examples of Hal+ producing agents include I2, Br 2 , Cl 2 , IBr, ICI, chloroacetamide, iodoacetamide, N-chlorosuccinamide, N-bromosuccinamide and N-iodosuccinamide. 30 Preferably, as shown in Scheme 1, the Hal+ producing agent is 12. Cyclisation of (2) can be effected by treating (2) with Hal+ to afford (3). Such reactions may be carried out in a C \NRPortbl\DCC\ACG\4351%6_.DOC-25/0/2lO2 - 34 variety of solvents including ionic liquids. The coupling of (3) with the moiety M'-aryl or R 2 -C(O)-Hal to produce (4) can be carried out via palladium-mediated coupling and/or metallation techniques as known in the art. 5 For example, lithiation of (3) (eg using nBuLi) allows for coupling with

R

2 D R 2 C

R

2 E R 2 B Hal-(O)C R 2 A (Hal is I, Br or Cl, preferably Cl). In another embodiment, a carbonylation reaction can be 10 carried out to access (4) by reacting (3) and

R

2 D R 2 C

R

2 E R 2 B

M

2

R

2 A with a palladium catalyst in the presence of CO. 15 Compounds (5) can be prepared by reacting (3) with a phenolate, phenothiolate or phenoselenoate anions or with an appropriately activated aniline in the presence of a base and palladium or copper catalyst. SO, SO 2 , SeO and Se0 2 derivatives can be prepared by controlled oxidation of the corresponding sulphides (ie, where L = S) and selenides (ie. 20 where L = Se), respectively. Scheme 2 represents an alternative approach to the compounds of the present invention.

C:W RPonbhDCC\ACGW351%6_ 1 DOC-25103/2012 -35 Scheme 2

R'

4 SiO RIA RIA R IB Halogen or H RIB 1 I SiR' 3 RIc XP RIC X RID RID (6) (8) + RIA H OSiR' 3 RIB (7) RIC SiR' 3 RID (9)

R

2 D R 2 C

R

2 E R 2 B M R 2 A

R

2 D R 2 C R 2 D R 2 C R 2 D R 2 C R 2E R 2 B R 2E R 2 B R 2 E R 2 B RIA R 2 A RIA R 2 A R IA R 2 A R0B O RIB 0 RIB 0 Q Halogen or H | SiR' 3 RIC X : RIC X RIC x RID Q-M 2 RID RID (12) (11) (10) 5 where Q is for example H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynl, OR", SR", NR"R" or NR"'NR'", and X is S, NR', O or Se. The compounds of the present invention represented by (12) can alternatively be prepared 10 by palladium coupling compounds (6) with an alkyne (7) to form (8) under the conditions described by Bishop, B.C., et al, Synthesis, 1997, 1315. The reaction sequence involves C:WRPonNlCC\ACGW351%6_ DOC-25/I5/20l2 -36 the desilylation and oxidation of the C-3 silyl ether to afford a formyl group. Desilylation can be carried out with the use of either an aqueous acid (for eg. hydrochloric acid) or by using a fluoride source. Oxidation can be carried out using Cr0 3 , MnO 2 , dichlorodicyanoquinone (DDQ) or under Swern conditions. Addition of 5

R

2 D R 2 C

R

2 E R 2 B Mi R 2 A to (9) can be carried out under standard 1,2-addition conditions (for example where MI=Li or Mg) followed by oxidation of the tertiary alcohol to ketone (10). Suitable oxidants 10 include Cr0 3 , MnO 2 , dichorodicyanoquinone (DDQ) or under Swern conditions. Conversion of the C-2 silyl group of (10) to a group suitable for Q addition can be carried out with ICI, IBr or Br (for when (11) bears a halogen which is I or Br) or TBAF (for when (11) is H). 15 If the C-2 position bears a suitable halogen, (11) can be reacted with Q-M 2 by either Suzuki coupling conditions (eg M 2 =B(0H 2 )), Negishi coupling conditions (eg M 2 =Zn), Stille coupling conditions (eg M 2 = Sn(alkyl) 3 ), or other palladium mediated couplings where M 2 = Cu, Zr, Al. These reactions provide for connection of Q to the C-2 position of (12) through a C-C bond. Connection of Q to the C-2 position of (12) through a C-N bond 20 is also possible by direct nucleophilic substitution of a deprotonated amine or by reaction of an amine with (11) in the presence of a base (eg. trialkylamine, pyridine, Na 2

CO

3 ,

K

2

CO

3 , etc). Scheme 3 represents a further approach to the compounds of the present invention. 25 C :\RPortbl\DC CAG351%6_.DOC.25/O5/Ol2 -37 Scheme 3 (6) (10)

R

2 E R 2 D SiR' 3 R 2C 0R 2 A R 2 B (13) (12) (11) where Q is for example H, for example optionally substituted alkyl, optionally 5 substituted alkenyl, optionally substituted alkynl, OR", SR", NR"R", CN, or NR"'NR.'; and X is S, NR', 0 or Se. Compound (10) can be prepared by palladium coupling compounds (6) with an alkyne (13) under the conditions discussed previously in relation to the analogous reaction depicted in 10 Scheme 2. Conversion of the C-2 silyl group of (10) to a halogen substituent (11) can be carried out with ICI, IBr, or Br 2 . Subsequent coupling of (11) with a Q group may be carried out by reacting (11) with nucleophilic CN, NR"R", SR" or OR" anions. For both schemes 2 and 3 compounds where Q = H can be prepared by protodesilylation of 15 either compound (9) or (10). An important aspect of the present invention relates to compounds which possess tubulin binding activity, as well as possessing selectivity and/or better solubility. In particular it has been found that the introduction of acyclic groups into the C2-position of benzofuran, 20 indole, benzothiophene or benzoselenophene based TPIs, can give rise to improved anticancer properties over the same compounds which bear aryl groups at C-2. Furthermore, it has been shown that the potency of such compounds can be further increased by the introduction of a polar heteroatom in the C-7 position (RID) where an electron donating group exists at C-6 (RIC) C \NRPonbl\DCCACGW351966 DOC-25/05/2012 -38 TPI compounds are important in the treatment of cancers primarily as a result of their capacity to selectively shut down blood flow through a tumour. Compounds that inhibit tumour blood flow are generally referred to as vascular disrupting agents (VDAs) (Tozer, 5 G. M.; Kanthou, C.; Baguley, B. C. Nature Rev., Vol. 5, 2005, 423). TPIs are VDAs because they inhibit a certain cell signalling pathway associated with microtubules, leading to interference in the regulation of the cytoskeleton of the endothelial cells that line the blood vessels of the tumour. As a result, these usually flat cells become more rounded, ultimately occluding blood flow through the vessels. The selectivity associated with these 10 agents results from the fact that tumour vasculature is weaker and more prone to collapse than normal vasculature. Nonetheless, a number of the dose limiting toxicities associated with VDAs are due to a reduction in blood flow in healthy tissues. An important aspect of the present invention is the combination of the specific RID and RiC groups together with the Q-group confers greater potency and selectivity upon TPI compounds (see Table 1). In 15 these preferred compounds selectivity is not simply reliant on the predisposition of tumour vasculature towards collapse when challenged with a VDA but on a capacity of the VDA to distinguish between tumour endothelial cells and normal endothelial cells. Normal endothelial cells, found in healthy tissues, are in a "quiescent" state and tumour endothelial cells are in an "activated" state. Most VDAs do not distinguish between these two states, 20 for example CA4 (1) is equally potent against quiescent and activated endothelial cells (see Figure 1). However, it has been discovered that certain acyclic Q-groups in conjunction with specific RID and RIC groups may confer selectivity upon the compounds of the formulae I, Ia, lb and II (see Figure 2). These compounds (see, for instance, compound examples 9, 11 and 15 in Table 1) show higher potency towards tumour endothelial cells 25 (activated) over normal endothelial cells (quiescent). Compound examples 11 and 29 demonstrated significantly greater potency than CA4 (1) in inhibiting tubulin polymerisation and at shutting-down tumour vasculature (see Figures 3 and 4). 30 In another beneficial aspect the invention allows for the capacity to introduce an acyclic Q C :NRPorbNDCC\ACGW351%6_ I DOC-25/05/2012 -39 group in compounds of formulae I, Ia, lb and II to affect the solubility and ADMET (absorption, distribution, metabolism excretion and toxicity) properties of the TPI compound. These pharmacokinetic properties of the drug are also important in attaining the maximum therapeutic index for a VDA. It has been reported that a low volume of 5 distribution (concentration of the drug in the vasculature) and short half-life are desirable for a VDA (Rustin, J et al. J. Clin. Oncol. 2003, 21, 2815; Davies P. D. et al. Cancer Res. 2002, 62, 7247). A low volume of distribution maximises drug exposure to the target tissue, vasculature endothelium, and minimises exposure to other tissues (outside the vasculature) that may be adversely affected by TPIs. Also, tumour vasculature shuts down 10 very quickly upon exposure to a VDA, so that ongoing exposure systemically is undesirable as it will not further affect the tumour and may lead to side-effects. A low volume of distribution can be achieved by increasing the hydrophilicity of a compound (introduction of polar, acidic and/or basic groups). Short-half life can be achieved by a high rate of clearance (hepatic or renal clearance), which in turn can be achieved by 15 incorporating readily metabolised groups and/or in the introduction of very polar groups (polar compounds are more readily cleared through the kidneys). Compounds of formulae I, Ia, lb and II are able to tolerate large variations in the acyclic nature of Q whilst retaining considerable potency (see Table 1). These compounds include systems that contain polar functionalities (carboxylates, amine and amides etc) and that contain metabolically labile 20 groups (eg OH and NH groups that can be glucuronidated. As mentioned previously, the preferred compounds of the invention having increased tubulin binding activity or anti-tumour vasculature activity, can be useful in methods of therapy. In particular these compounds may be used for treating tumours. As used herein 25 the term "tumour" is used to define any malignant cancerous growth, and may include leukemias, melanomas, colon, lung, ovarian, skin, breast, prostate, CNS, and renal cancers, as well as other cancers. The compounds of the invention having tubulin binding activity may also be used in the 30 treatment of solid tumours, eg. breast cancer.

C \NRPotibIDCCACG1A35 1966- I DOC-2512 -40 The invention also provides for the use of a compound of formulae (I), (Ia), (Ib), or (II) in the manufacture of a medicament for treating tumours. There is also provided a method of treatment of solid tumours comprising the 5 administration of an effective amount of a compound of formula (I), (1a), (Ib) or (II) to a subject in need thereof. However, it will be understood that the compounds of the invention can be used in the treatment of any disease state for which tubulin polymerisation plays a crucial role. 10 In particular, the present compounds can be used in treating inflammation. Such inflammatory conditions may include acute and chronic inflammatory conditions such as rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, psoriasis, and the like. 15 Compounds of the invention which possess bioactivity, such as tubulin binding activity, can be formulated as a composition, particularly a pharmaceutical composition, together with a pharmaceutically acceptable additive. The compounds of the invention are administered to the subject in a treatment effective 20 amount. As used herein, a treatment effective amount is intended to include at least partially attaining the desired effect, or delaying the onset of, or inhibiting the progression of, or halting or reversing altogether the onset or progression of the particular disease of condition being treated. 25 As used herein, the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. A typical 30 dosage is in the range of 1 pg to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to I g per kg of body weight per dosage. In one embodiment, the dosage C:\NRPotb1DCC\ACG4351%6 LDOC-25/0512012 -41 may be in the range of I mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of I mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage. 5 Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition as well as the general age, health and weight of the subject. 10 The active ingredient may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition. The formulation of such compositions is well known to those skilled in the art. The composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion 15 media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents. 20 The carrier must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parental (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form and 25 may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. 30 C :\ Ponbl\DCC\ACGI4351%6_1.DOC-25/05l/2 -42 Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil 5 liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine 10 the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The 15 tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach. 20 Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable 25 liquid carrier. Compositions suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like. Suitable carriers include mineral oil, propylene 30 glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and C ANRPornbIDCC(XACGJ351966 I DOC-25/05/2012 -43 water. Transdermal patches may also be used to administer the compounds of the invention. Compositions for rectal administration may be presented as a suppository with a suitable 5 base comprising, for example, cocoa butter, glycerin, gelatine or polyethylene glycol. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. 10 Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents 15 and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried lyophilisedd) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind 20 previously described. Preferred unit dosage compositions are those containing a daily dose or unit, daily sub dose, as herein above described, or an appropriate fraction thereof, of the active ingredient. 25 It should be understood that in addition to the active ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or 30 time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include cornstarch, methylcellulose, CNRonb\DCC\ACG351966_1 OC-255/2012 - 44 polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable 5 preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate. 10 The novel bioactive compounds of the invention can be administered to a subject as a pharmaceutically acceptable salt thereof. It will be appreciated however that non pharmaceutically acceptable salts also fall within the scope of the present invention since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts include, but are not limited to salts of 15 pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, 20 glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and 25 alkylammonium. In particular, the present invention includes within its scope cationic salts eg sodium or potassium salts, or alkyl esters (eg methyl, ethyl) of the phosphate group. Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl 30 halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

C \NRPortblDCC\ACG435966_.DOC-25/05/2012 -45 It will be appreciated that any compound that is a prodrug of a compound of formule (I) or (II) is also within the scope and spirit of the invention. The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the 5 compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group (for instance at the C-7 position or R ) is converted into an ester, such as an acetate or phosphate ester, or where a free amino group (for instance at the C-7 position or R ) is converted into an amide (eg a-aminoacid amide). Procedures for esterifying, eg. acylating, the compounds 10 of the invention are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base. A particularly preferred prodrug is a disodium phosphate ester. The disodium phosphate ester of novel compounds of the invention may be useful in increasing the solubility of the compounds. This would, for instance, allow for delivery of the compound 15 in a benign vehicle like saline. The disodium phosphate ester may be prepared in accordance with the methodology described in Pettit, G. R., et al, Anticancer Drug Des., 1995, 10, 299. Alternatively, the choice of an appropriate hydrophilic group as Q may also provide the 20 compound with better solubility properties. This may not only serve to avoid the need to prepare prodrugs (to increase solubility) but may also lead to an increase in targeting tumor vasculature pharmacokinetically. Examples of solubilizing groups which may be present as Q include substituted amino, amino acids, tetrazoles, sulphonamides, and so on. 25 The compounds of the invention may be in crystalline form either as the free compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art. It will also be recognised that compounds of the invention may possess asymmetric centres 30 and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more C:NRPtb\DCC\ACGW351%96_1 DOC.25/05/2012 - 46 asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or mixtures may be resolved by conventional methods, eg., chromatography, or use of a resolving 5 agent. Furthermore, depending on the substitution pattern the compounds of the present invention may be capable of undergoing tautomerism. Accordingly, all possible tautomers of a compound of the present invention fall within the scope and spirit of the invention. 10 The mode of proliferative diseases, such as solid tumors, is multi-factorial. In the treatment of such diseases drugs with different mechanisms may be combined (ie combination therapies). The compounds of the invention may be particularly useful in combination therapy, eg. combining the treatment with other chemotherapeutic or radiation 15 treatments. For instance in order to potentiate anti-tumor treatments using the compounds of the present invention one or more other cytotoxic compounds including 5-FU, oxaliplatin, paclitaxel, gemcitabine, docetaxel, cisplatin, and doxorubicin may also be administered. 20 The combination therapy may also include the addition of an angiogensis inhibitor (eg., Avastin) or another agent or therapy (eg., radiotherapy). Compounds that are vascularly active may be preferably administered in combination with antihypertensive (eg sublingual glyceryl trinitrite) or antihypotensive agents. 25 The combination partners in such therapies may be administered together, one after the other, separately in one combined unit dosage or in separate unit dosage forms. The synthetic methods and processes described herein to prepare the compounds of the 30 present invention are amenable to solid phase synthetic techniques and/or combinatorial chemistry to produce individual compounds or libraries of compounds.

C \NRPonbl\DCC\ACGM4351%6_.DOC-2O5/5202 -47 Traditionally, drug candidates have been synthesised individually, this being a time consuming and laborious process if the synthetic sequence contains even just a few steps and large numbers of compounds are to be evaluated for their biological activity. 5 Combinatorial synthesis is an emerging technique for effecting the generation of large libraries of molecules and has been successfully exploited in the synthesis and evaluation of small organic libraries. These libraries and their starting substrates may exist as molecules in free solution or preferably, linked to a solid support, for example, beads, pins, microtitre plates (wells) or microchips which can be polymeric, glass, silica or other 10 suitable substrate. Chemical diversity can be achieved by either parallel or split (split and mix) syntheses wherein each step has the potential to afford a multitude of compounds. Solution phase libraries may be prepared via parallel syntheses wherein different compounds are synthesised in separate reaction vessels in parallel, often in an automated fashion. Alternatively, attachment of the individual components employed in a synthetic 15 sequence to an appropriate solid phase support allows for the further creation of chemical diversity by utilising not only parallel synthesis but also split synthesis wherein the solid support containing the compounds prepared in the prior step can be split into a number of batches, treated with the appropriate reagent and recombined. 20 The substrates can be attached to a solid support surface by any linkers known in the art. The linkers may be any component capable of being cleaved to release the substrate or final compound from the support. Preferably, the solid support is a polymer support. Examples of polymeric supports 25 currently used in solid phase synthesis include: alkenyl resins: eg. REM resins; BHA resins: eg. benzhydrylamine (polymer-bound hydrochloride, 2% crosslinked), benzhydryl chloride (polymer bound); Br- functionalised resins: eg. brominated PPOA resin, brominated Wang resin; Chloromethyl resins: eg. 4-methoxybenzhydryl chloride (polymer bound); CHO-functionalised resins: eg. indole resin, formylpolystyrene; CI-functionalised 30 resins: eg. Merrifield's resin, chloroacetyl (polymer bound); CO 2 H-functionalised resins: eg. carboxypolystyrene; I-functionalised resins: eg. 4-iodophenol (polymer bound); Janda C:\NRPorbl\DCC\ACGW 351%6_1,DOC-2505/2012 -48 JelsTM; MBHA resins: eg. 4-methylbenzhydrylamine hydrochloride (polymer bound), 4 hydroxymethylbenzoic acid-4-methyl benzhydrylamine (polymer bound); Amine functionalised resins: eg. (aminomethyl)polystyrene, PAL resin, Sieber aide resin; Nitrophenyl carbonate resins: eg. 4-nitrophenyl carbonate (polymer bound); OH 5 functionalised resins: eg. 4-benzyloxybenzyl alcohol (polymer bound); Hydroxy methyl resins: eg. benzyl alcohol (polymer bound); HMBA resin; Oxime resins; Rink acid resin; Triazine-based resin; Trityl amine resins; Trityl resins: eg. trityl-chloride (polymer bound), 2-chlorotrityl alcohol, 1,3-diaminepropane trityl. 10 Thus, individual compounds or libraries of compounds can be synthesised by initially attaching the first compound substrate to a solid support surface which can be performed by providing a plurality of solid support surfaces, suitably derivatising each of the surfaces with groups capable of reacting with either the compound substrate or a linker moiety attached thereto. The various support surfaces with the attached first compound substrate 15 can then be subjected to various reaction conditions and second compound substrates to provide a library of attached compounds, which may, if necessary, be reacted further with third and subsequent compound substrates or varying reactions conditions. Attachment and detachment of substrates and products can be performed under conditions similar to those as described in Johnson, M.G., et al., Tetrahedron, 1999, 55, 11641; Han Y., et aL. 20 Tetrahedron 1999, 55, 11669; and Collini, M.D., et al., Tetrahedron Lett., 1997, 58, 7963. Those skilled in the art will appreciate that the invention described herein in susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit 25 and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features. Certain embodiments of the invention will now be described with reference to the 30 following examples which are intended for the purpose of illustration only and are not intended to limit the scope of the generality hereinbefore described.

C:\RPortb\DCC\ACG\A351%61. DOC-25/05/2012 - 49 Examples Biological data 5 (i) In Vitro Studies Table 1: In Vitro Data for Compounds: These are the results for growth inhibition studies of compounds using the Sulforhodamine B (SRB) or Systmex cell counting (CC) assays. IC 50 is the concentration required to inhibit net cell growth by 50%. Entries 1-4, 10 13, 36, 39, and 45 provided for comparison, all other entries are compounds of the invention. Entry Example/ Structure Cancer HUVECs' Comparator cell Tum: ICso, nM line: Norm: ICs 0 ,

IC

50 , nM nM 1. Comparator OMe 5 Turn: 1-10 A OMe Norm: 1-10 OMe OH OMe 2. Comparator OMe 5 Turn: 1-10 B OMe Norm: 1-10 OMe ONa O-- 1ONa 0 OMe C:\NRPonblDCC\ACG4351%6 .DOC-25/ Y2012 -50 Entry Example/ Structure Cancer HUVECs' Comparator cell Tum: IC 50 , nM line: Norm:

IC

50 , ICso, nM nM 3. Comparator MeO OMe 55 Tum: 10-100 C Norm: 10-100 Example 5 MeO \ / 0 MeO 0 4. Comparator MeO OMe 500 Tum: 100-1000 D - Norm: 100-1000 Example 3 MeO \ / 0 Br MeO O 5. Example 6 MeO OMe 45 Tum: 10-100 Norm: 10-100 MeO 0 MeO O OH 6. Example 52 OMe 35 Tum: 100-1000 - Norm: 100-1000 MeO 0 MeO O

OH

C XNRfonblflCC\ACG143319661 LDOC-Z5IuOfl0lZ -51 Entry Example/ Structure Cancer HUVECs' Comparator cell Tum: IC 50 , nM line": Norm: IC 50 ,

IC

50 , nM nM 7. Example 53 F F 800 Tum: >1000 Norm: >1000 F F FO MeO OH 0 8. Example 18 Meo OMe 3.5 Tur: 1-10 Norm: 0. 1-1 MeO 0 NHMe MeO O OH 9. Example 9 OMe 1.2 Tum: 0.1-1 MeO Norm: 1-10 MeO\ 0 SMe MeO 0 OH 10. Example 8 MeO OMe 3.3 Tum: 1-10 Norm: 1-10 MeO \| 0 MeO 0

OH

CWRPortbhDCCACG351%61 DOC-25/05/2012 -52 Entry Example/ Structure Cancer HUVECs' Comparator cell Tum: IC 5 0 , nM line: Norm: IC 50 , ICso, nM nM 11. Example 10 MeO OMe 35 Tum: 1-10 Norm: 10-100 MeO 0 ,NH2 NH MeO 0 OH 12. Example 11 MeO OMe 2.0 Tum: 0.1-1 -- Norm: 10-100 MeO 0 Me MeO 0 OH 13. Comparator MeO OMe 575 Tum: 100-1000 E - Norm: 100-1000 Example 30 MeO \ / 0 S OH MeO 0 14. Example 23 OMe 260 Tum: 100-1000 Norm: 100-1000 MeO 0 NH 0 MeO 0 OH OH C :NPortbl\DCC\ACG4351966 _.DOC-2305/2012 -53 Entry Example/ Structure Cancer HUVECsc Comparator cell Tum: IC 50 , nM line': Norm:

IC

50 ,

IC

50 , nM nM 15. Example 14 MeO OMe 2.0 Tum: 0.1-1 Norm: 1-10 MeO 0 MeO O OH OMe 16. Example 13 MeO OMe 8.0 Tum: 1-10 Norm: 1-10 MeO 0 MeO O OH 17. Example 2 OMe O-H0 Tum: 1-10 MeO Norm: 1-10 MeO 0 H MeO 0

NH

2 18. Example 15 MO OMe 1-10 Tum: 1-10 Norm: 1-10 MeO 0 \O MeO 0 OH NH 2 C \NRPonbI\DCCACGW33%6_ .DOC-25M05/lOI2 - 54 Entry Example/ Structure Cancer HUVECs* Comparator cell Tum: IC 50 , nM line: Norm: IC 50 , ICso, nM nM 19. Example 21 OMe 10-106 Tum: 10-100 Norm: 10-100 MeO 0 NH MeO O 0 OH N 20. Example 20 MeO OMe 1-07 Tum: 1-10 Norm: 1-10 MeO 0 NH MeO 0 OH OH 21. Example 16 MeO OMe 0.1-1F Tum: 1-10 Norm: 1-10 MeO\ 0 CN MeO O OH 22. Example 17 MO OMe -0 Tum: 1-10 Norm: 1-10 MeO 11 00 MeO 0 OMe

OH

C \NRorN\DCCOACG\435 19661 DOC.25/15T012 -55 Entry Example/ Structure Cancer HUVECs' Comparator cell Tum: IC 50 , nM line': Norm: IC 50 , ICso, nM nM 23. Example 19 MeO OMe 0.I_-I Tum: 1-10 Norm: 1-10 MeO 0

NH

2 MeO 0 OH 24. Example 24 MeO Oe1-10 Tum: 1-10 Norm: 1-10 MeO 0 NH 0 MeO 0 ______OH OMe 25. Example 25 MeO OMe T-10 Tum: 1-10 .. Norm: 1-10 MeO\ 0 NH 26. Example 22 MO OMe mTum: 1-10 Norm: 1-10 MeO\ 0 NMe 2 MeO 0

OH

C:NRPortbI\DCOACG4351966_. DOC.25105/2012 -56 Entry Example/ Structure Cancer HUVECs' Comparator cell Tum: IC 50 , nM line: Norm: IC 50 ,

IC

50 , nM nM 27. Example 26 OMe Tum: 1-10 MeO ONorm: 1-10 MeO 0 O HN -/ O NH tBu MeO 0 OH 28. Example 27- OMe Tum: 100-1000 HCI Me Norm:100-1000 MeO O

NH

2 HCI NH MeO O OH 29. Example 28 MeO OMe Tum: 100-1000 - Norn:10- 100 MeO NH O HN

NH

2 .HCI I\NH MeO O OH 30. Example 31 OMe Tum: 1-10 Norn:1-10 MeO 0 MeO 0

OH

C :WRPortb\DCC\ACG151%6_1. DOC-2505/212 - 57 Entry Example/ Structure Cancer HUVECsc Comparator cell Tum: IC 50 , nM line': Norm: IC 50 ,

IC

50 , nM nM 31. Example 32 MO OMe Tum: 0.1-1.0 Norm:0.1-1.0 MeO 0 MeO 0 OH 32. Example 34 MeO OMe Tum: 1-10 Norm:1-10 MeO 0 MeO 0 N OH 33. Example 35 MeO OMe Tum: 1-10 Norm:1-10 MeO 0 MeO O N OH 34. Example 36 MeO OMe Tum: 1-10 Norm:1-10 MeO 0 MeO 0 N-N OH N, N NH2 C:W\RPorlb\DCC\ACGW35I%6 I DOC-25//21O 2 -58 Entry Example/ Structure Cancer HUVECs Comparator cell Tum: IC 5 0 , nM lines: Norm: ICso,

IC

50 , nM nM 35. Example 37 MeO OMe Tum: 10-100 Norn:10-100 MeO 0 MeO 0 N OH N 36. Comparator eO OMe Tum: 0.1-1 F ... Norm: 0.1-1 Example 50 MeO 0 MeO N H 37. Example 39 MeO OMe Tum: 0.01-0.1 Norm: 0.1-1 MeO 0 MeO N OH 38. Example 40 OMe Tum: 1-10 HO Norm: 10-100 MeO 0 MeO N H

OH

C WRPortbFlDCC\ACG\4351%6_I.DOC-25/5/lO2 -59 Entry Example/ Structure Cancer HUVECs' Comparator cell Tum: IC 50 , nM line': Norm: IC 50 ,

IC

50 , nM nM 39. Comparator OMe Tum: 1-10 G MeO Norm: 1-10 Example 51 MeO' 0 MeO S 40. Example 42 MeO OMe Tum: 0.1-1 Norm: 1-10 MeO 0 MeO S OH 41. Example 43 MeO OMe Tum: 1-10 Norm: 1-10 MeO 0 MeO 0 N OH MeO 42. Example 44 OMe Tum: 10-100 MeO Norm: 10-100 MeO 0 MeO O 0 N OHO

HO

C:\NRPonbI\DCC\ACGM351%6_1 DOC-252O12 - 60 Entry Example/ Structure Cancer HUVECs* Comparator cell Tum: IC 50 , nM line: Norm: IC 5 0 ,

IC

50 , nM nM 43. Example 45 OMe Tum: 1-10 MeO Norm: 1-10 MeO 0 NH MeO O0 0 OH , 0 NH 2 44. Example 46 OMe Tum: 10-100 HO Norm: 100-1000 MeO 0 MeO 0 OH 45. Comparator OMe Tum: 1-10 H Norm: 1-10 MeO 0 MeO N a Unless otherwise stated the cancer cell line is MCF-7. b The cancer cell line is MDA-MB-23 1. C Human umbilical vein endothelial cells (HUVECs) tumour type activated 5 endothelial cells (Tum) and normal quiescent type endothelial cells (Norm). General Description of Biological Experiments: Tubulin Polymerisation Assay: Tubulin polymerisation inhibition assays were 10 performed using a fluorescent-based detection kit (#BKO 11, Cytoskeleton) according to the instructions of the manufacturer. The test compound was added to a 2mg/ml tubulin C:\NRPorb1\DCC\ACGIA351%6_1 DOC.25/052012 -61 solution containing 20% glycerol and ImM GTP in lx Buffer I (Buffer 1: 80mM Piperazine-N,N'-bis[2-ethanesulfonic acid] sequisodium salt; 2mM magnesium chloride; 0.5mM Ethylene glycol-bis(b-amino-ethyl ether)N,N,N',N'-tetra-acetic acid, pH 6.9, I OuM fluorescent reporter). Fluorescence was measured over a period of 42 minutes at 1 5 minute intervals. Increased fluorescence indicates increase in tubulin polymerisation. There is a ten-fold increase in the affinity of the fluorescent reporter for polymerised tubulin compared to monomeric tubulin subunits. The result is a fluorescence signal that closely follows tubulin polymerisation. 10 Proliferation Assay - quiescent endothelium: Human umbilical vein endothelial cells (CC-2519, Clonetics) were plated at 15000 cells/well in EBM2 (CC-3156, Clonetics) + 0.5%FBS (CC-4101A, Clonetics) + GA-1000 (CC-4381A, Clonetics) in a 96 well plate in triplicate. Cells were cultured overnight at 37*C 5% CO 2 . Medium was subsequently replaced with fresh medium including the compound or negative control. Cells were 15 cultured for a period of 48hrs. An MTT assay was performed to measure changes in cell numbers. Briefly, 20pl of MTT reagent was added to cells containing 100Al of EBM2 + 0.5%FBS and incubated at 37*C for 2 hours. Absorbance was measured at 492nm. Proliferation Assay - activated endothelium: Human umbilical vein endothelial cells 20 (CC-2519, Clonetics) were plated at 2500 cells/well in EGM2 (CC-3162, Clonetics) in a 96 well plate in triplicate. Cells were cultured overnight at 37*C 5% CO 2 . Medium was subsequently replaced with fresh medium including the compound or negative control. Cells were cultured for a period of 48hrs. An MTT assay was performed to measure changes in cell numbers. Briefly, 20pl of MTT reagent was added to cells containing 25 100pl of EGM2 and incubated at 37*C for 2 hours. Absorbance was measured at 492nm. (ii) In Vivo Studies Vascular Disruption Assay: Female athymic BALB/c-nu/nu mice (nude mice) were used 30 for this study. Mice were between 6-8 weeks old and were purchased from the Animal Resource Centre, Perth, Western Australia and allowed to acclimatize for a couple of days.

C:NRPonbIDCC\ACGU35J96_ .DOC-25/05/2012 -62 All the animals were housed under pathogen-free conditions and cared for in accordance with Flinders University of South Australia and NH&MRC guidelines and the Australian Code of Practice for the care and use of animals for scientific purposes. The human breast cancer MDA MB 231 was grown as orthotopic xenografts in the mammary fat pad of nude 5 mice. Each mouse was injected with 2 x 106 cells in 50 l Dulbecco's PBS subcutaneously just above the mammary fat pad, below the right forward limb. Tumors were selected for treatment when they reached a diameter of 100-150 mm 3 (3 weeks after implantation). The test compound (Example 29) was dissolved in saline solution and injected intravenously at concentrations ranging from 150 mg/kg - lmg/kg in a total volume of 400ul. Tumor 10 bearing animals were injected intravenously with 10mg/kg Hoechst 33342, 24 hours after the injection of the test compound. Animals were euthanised 1 minute after the Hoechst 33342 injection. Tumors were recovered for histochemical analysis. Tumor perfusion analysis was performed by assessing the amount of Hoechst 33342 staining across an entire tumor cross-section. 10 micron sections of frozen tumor biopsies were viewed under an 15 ultraviolet light filter. Using a 4x objective lens, 8-bit monochromatic images were captured in succession, representing the total area of the tumor section. Composite images of the total tumor section were generated by overlaying common areas of the monochromatic images. Hematoxylin and Eosin-Y staining of the same tumor section was performed to identify non-tumor regions. Non-tumor regions were mapped on Hoechst 20 33342 composite images and excluded from the quantitation analysis. Quantitation was performed by measuring the pixel area of Hoechst 33342 staining and the total pixel area of the tumor region. Perfusion was expressed as a percentage of Hoechst 33342 stained area to total tumor area (see Figure 4). 25 Tumor Growth Inhibition: Balb/c nu/nu mice bearing MDA-MB-231 solid orthotopic tumors were treated with compound Example 29 at 40mg/kg. Animals were i.v. dosed with a total of two cycles of Example 29 treatment. Each cycle was dosing on days and 8 followed by a three week no-dosing period. Tumor growth represented as a ratio to initial tumor volume is shown over a total of 72-days. 30 C VRPOnbIhDCCACG43 51966 1. DOC-25/O5/2U12 - 63 Tumor growth as well as animal health were monitored for up to 72 days post-day I of treatment. The results seen in this experiment (see Figure 5) clearly show tumor growth inhibition in animals treated with two cycles of Example 29. Significant differences in tumor growth between Example 29 treated (n=64) and vehicle treated (n=20) animals were 5 observed as early as day 4 (p<0.001; unpaired t-test; Prism@ analysis) through to Day 70. Synthetic Protocols Example 1 10 Preparation of (6-Methoxy-7-nitrobenzofuran-3-yI)(3,4,5-trimethoxyphenyl)methanone: MeO OMe MeO 0 MeO 0

NO

2 Step 1: 2-Nitro-3-methoxyphenol 15 To a mixture of 2.01 g (1.3 mmol) of 2-nitroresorcinol in 15 ml of dry pyridine 0.28 ml (1.36 mmol) of acetic anhydride was added dropwise at 0 0 C. The resulting mixture was allowed to warm to room temperature. After 1 h of stirring at room temperature the solvent was removed by evaporation in vacuo and the residue diluted to 10 ml with anhydrous acetonitrile. To this 2 g of anhydrous potassium carbonate was added followed by the 20 addition of 1.5 ml of methyl iodide. The resulting suspension was stirred overnight at room temperature, filtered off and filtrate evaporated to dryness under reduced pressure to give 2.63 g of crude 3-methoxy-2-nitrophenyl acetate. This was dissolved in 15 ml of acetonitrile and 2 ml of concentrated ammonium hydroxide was added. The resulting mixture was allowed to stand for 30 minutes at room temperature and evaporated to 25 dryness under reduced pressure. The residue was purified by flash column chromatography to give 1.36 g (62% yield) of pure title compound as red crystals; 'H C:\PoblDCC CGW35196_ LDOC-2,5M2012 - 64 NMR (CDCl 3 ) 3.92 (s, 3H, OMe); 6.51 (d, 1H, CH, J= 8.5 Hz); 6.68 (d, IH, CH, J= 8.5 Hz); 7.35 (m, I H, CH); 10.18 (s, I H, OH). Step 2: 6-Iodo-3-methoxy-2-nitrophenol 5 A mixture of 1.36 g (8 mmol) of the product of Step 1 and 0.68 g (8 mmol) of sodium bicarbonate was sonicated at room temperature until it become homogenous. The resulting mixture was cooled to 0"C and 2.04 g (8 mmol) of iodine was added. After stirring for 1 h at room temperature the precipitate formed was filtered off, dried and recrystallized from ethyl ether to give 2.28 g (96% yield of pure title compound as an orange crystals; 'H 10 NMR (CDCl 3 ) 3.92 (s, 3H, OMe); 6.41 (d, 1 H, CH J= 9Hz); 7.82 (d, I H, J=9Hz); 10.37 (s, IH, OH). Step 3: 3-Methoxy-2-nitro-6-((trimethylsilyl)ethynyl)phenol A modified procedure of Gottardo and Aquirre, Tetrahedron Letter, 2002(43), 7091 - 7094 15 was used. A mixture of 0.0982 g (0.33 mmol) of the product of Step 2, 8.7 mg of copper iodide, 13.8 mg of palladium dichlorobis(triphenyl)phosphine and 0.5 ml of anhydrous triethylamine in 1.5 ml of anhydrous acetonitrile was degassed under reduced pressure and saturated with 20 anhydrous nitrogen at 0*C. After stirring for about 10 minutes at 0 0 C, 0.07 ml (0.495 mmol) of trimethylsilylacetylene was added dropwise over 10 minutes. The resulting mixture was stirred overnight at room temperature and filtered through Celite. The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography (silica gel; methylene chloride:ethyl acetate 1:1) to give 0.05 g (57% yield 25 of pure title product as a yellowish crystals; 'H NMR (CDCI 3 ) 0.25 (s, 9H, SiMe); 3.9 (s, 3H, OMe); 6.5 (d, I H, CH, J = 8.8 Hz); 7.46 (d, 1 H, CH, J = 8.8 Hz); 8.81 (s, 1 H, OH). Step 4: (6-Methoxy-7-nitrobenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone A modified procedure of Hu et al, J.Org. Chem. 2002, 67, 2365 - 2368 was used. 30 C:W4RPonblDCCACC\4351%61 .DOC-25105/2012 - 65 A mixture of 0.04 g (0.151 mmol) of the title compound of Step 3 and 0.089 g (0.301 mmol) of 3,4,5,-trimethoxyiodobenzene, 0.1 g (0.73 mmol) of anhydrous potassium carbonate and 13.1 mg (0.Olmmol) of palladium tetrakis(triphenylphosphine) in 5 ml of anhydrous acetonitrile was degassed under reduced pressure and stirred for 24 hours at 5 80 0 C under carbon monoxide balloon. The resulting mixture was cooled to room temperature, filtered through a pad of Celite and washed with 20 ml of methylene chloride. The combined filtrates were evaporated to dryness and the residue was purified by flash column chromatography to give 0.0295 g (50% yield) of pure title compound as a colorless solid. 10 H NMR (CDCl 3 ) 3.9 (s, 6H, OMe); 3.94 (s, 3H, OMe); 4.04 (s, 3H, OMe); 7.14 (s, 2H, CH aromatic); 7.15 (d, IH, CH aromatic J= 9 Hz); 8.1 (s, 11H, CH furan); 8.3 (d, 1H, J= 9Hz). 15 Example 2 Preparation of (7-Amino-6-methoxybenzofuran-3-yI)(3,4,5-trimethoxyphenyl)methanone MeO OMe MeO 0 MeO O NH2 A mixture of 0.022 g (0.057 mmol) of (6-methoxy-7-nitrobenzofuran-3-yl)(3,4,5 20 trimethoxyphenyl)methanone, 0.1 g of ammonium formate and 0.1 g of 10% palladium on carbon in 5 ml of a mixture of 1,2-dimethoxyethane and methanol (4:1) was refluxed for 30 minutes (TLC controlled reaction). After cooling to room temperature the mixture was filtered through a pad of Celite and washed with methylene chloride. The filtrates were evaporated to dryness under reduced pressure and the residue was purified by flash column 25 chromatography to give 0.011 g (55% yield) of pure title compound as a colorless solid; 'H NMR (CDCl 3 ) 8 3.89 (s, 6H, OMe); 3.92 (s, 6H, OMe); 4.01 (broad s, 2H, NH 2 ); 6.95 (d, C:\NPonb\CC\ACG4351%6_ IDOC-25/05/2012 - 66 1 H, CH aromatic, J = 8.54 Hz); 7.14 (s, 2H, CH aromatic); 7.46 (d, I H, CH aromatic, J 8.54 Hz); 8.0 (s, IH, CH furan). Example 3 (Comparator D) 5 Preparation of 2-Bromo-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofu ran MeO OMe MeO \/ 0 Br MeO ' Step 1: tert-Butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6 methoxybenzofuran (Larock coupling) 10 A suspension of 2-iodo-5-methoxyphenol (1.1 g, 4.41 mmol), 1-(Iert-butyldimethylsilyl) 3-(tert-butyldimethylsilyloxy)propyne (1.5 g, 5.28 mmol), lithium chloride (189 mg, 4.45 mmol) and sodium carbonate (2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100 0 C was deoxygenated 4 times by evacuation and backfilling with nitrogen. Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vessel was degassed twice with 15 nitrogen. The reaction mixture was then stirred at this temperature for 4 hours (monitored by tic) and the solvent was removed by distillation under vacuum. The residue was dissolved in ethyl acetate (75 mL), stirred well, filtered and treated with triethylamine (5 mL). The solution was concentrated onto silica gel (10 g) and purified by flash chromatography (silica gel, eluent = hexane/diethyl ether/triethylamine; 95:5:1%) to give 20 the title compound as a yellow oil (1.09 g, 87 %); 'H NMR (300 MHz, CDCl 3 ) 6 7.52(d, 1H, J= 8.57 Hz), 6.97(d, 1H, J= 2.15 Hz), 6.83(dd, 1H, J= 8.54, 2.18 Hz), 4.81(s, 2H,

CH

2 ), 3.83(s, 3H, OMe), 0.93(s, 9H), 0.91(s, 9H), 0.34(s, 6H), 0.11 (s, 6H). Step 2: 2-t-Butyldimethylsilyl-3-formyl-6-methoxybenzofuran 25 To a solution of 2-t-butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy benzofuran (1.09 g, 2.69 mmol) in methanol (100 mL) was added concentrated hydrochloric acid (200 iL) and the reaction was stirred for 30 minutes (monitored by tic), C:\NRPortbr\DCC\ACG'435 19661 DOC-25)05/2012 - 67 quenched with triethylamine (2 mL) and the solvent removed by distillation under vacuum. The residue was dissolved in dichloromethane (20 mL), washed with water (10 mL), dried over magnesium sulfate, concentrated under vacuum and co-distilled with toluene (20 mL); 'H NMR (300 MHz, CDCl 3 ) 8 7.57(d, lH, J= 8.57 Hz), 7.00(d, I H, J = 2.17 Hz), 5 6.86(dd, I H, J= 8.55, 2.22 Hz), 4.81(s, 2H, CH 2 ), 3.84(s, 3H, OMe), 0.94(s, 9H), 0.37(s, 6H). The crude yellow paste (-985 mg) was dissolved in dry dichloromethane (4 mL) and added to a stirred solution of Collin's reagent (chromium trioxide (1.01 g), pyridine(I.65 mL) in dry dichloromethane (30 mL)). The suspension was stirred for 10 minutes, filtered and the residue washed with diethyl ether (20 mL). The filtrate was concentrated onto 10 silica (10 g) and purified by flash chromatography (silica gel, eluent = hexane/diethyl ether/triethylamine (90:9:1) to afford the title compound as a light yellow oil which crystallized on standing (485 mg, 68 %); 'H NMR (300 MHz, CDC 3 ) 6 10.25(s, IH, CHO), 8.06(d, I H, J= 8.61 Hz), 7.03(d, I H, J= 2.16 Hz), 6.95(dd, I H, J= 8.60, 2.19 Hz), 3.84(s, 31-, OMe), 0.97(s, 9H), 0.46(s, 6H); "C NMR (75 MHz, CDCl 3 ) 6 186.91(CHO), 15 174.18, 159.19, 159.17, 132.82, 122.77, 117.34, 113.56, 95.36, 55.60, 27.04, 17.09, -5.24. Step 3: 2-t-Butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofu ran To a stirred solution of 3,4,5-trimethoxyiodobenzene (377 mg, 1.27 mmol) in dry tetrahydrofuran (1 mL) at -78'C under nitrogen was added n-butyllithium (795 LL, 1.59 20 mmol, 2M solution in cyclohexane) and the reaction mixture was stirred at this temperature for 40 minutes. After this time a solution of 2-t-butyldimethylsilyl-3-formyl 6-methoxybenzofuran (310 mg, 1.07 mmol) in dry tetrahydrofuran (1 mL) was added to the reaction dropwise via syringe pipette. The reaction mixture was stirred at -60 C for 20 minutes and then allowed to warm to 0 C, stirred for 10 minutes, quenched with saturated 25 ammonium chloride solution (2 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water (10 mL), dried over magnesium sulfate and the solvent was removed under vacuum to give a residue that was co-distilled with toluene. The crude product (908 mg) was dissolved in dry tetrahydrofuran (10 mL) and treated with 2,3 dichloro-5,6-dicyano-1,4-benzoquinone (900 mg, 1.59 mmol) was added. The reaction 30 mixture was stirred at room temperature for 16 hours (monitored by tic) and then loaded onto silica (10 g) and purified by flash chromatography (silica gel, eluent = hexane/diethyl C NRPortbl\DCC\ACG351%6_1 DOC-25M05/2012 - 68 ether/triethylamine, 90:9:1) to afford the title compound as a light yellow paste that crystallised on standing (232 mg, 48 %); 'H NMR (300 MHz, CDC1 3 ) 8 7.14(s, 2H, benzoyl Hs), 7.05(d, I H, J = 2.45 Hz), 6.77(dd, I H, J = 8.76, 2.17 Hz), 6.56(d, I H, J = 8.38 Hz), 3.94(s, 3H, OMe), 3.85(s, 6H, 2 x OMe), 3.78(s, 3H, OMe), 1.00(s, 9H), 0.28(s, 5 6H); 1 3 C NMR (75 MHz, CDCl 3 ) 8 190.51(CO), 164.77, 158.23, 158.12, 152.64, 142.35, 133.19, 131.37, 123.19, 121.04, 119.63, 112.26, 107.03, 104.96, 95.00, 60.47, 55.81, 55.60, 55.13, 26.43, 17.29, -6.09. Step 4: 2-Bromo-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran 10 To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6 methoxybenzofuran (200 mg, 0.44 mmol) in 1,2-dichloroethane (2 mL) at 0 "C under nitrogen was added bromine (23 pl, 0.44 mmol) dropwise and the reaction mixture was stirred for 10 minutes. After this time the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (20 mL), dried over magnesium sulfate 15 and the solvent removed by distillation under vacuum. The crude product was re crystallised from acetonitrile to afford the title compound as a colourless crystalline solid (69 mg, 37%); 'H NMR (300 MHz, CDCl 3 ) 6 7.45(d, 1H, J = 8.78 Hz), 7.15(s, 2H, benzoyl-Hs), 7.01 (d, I H, J= 2.18 Hz), 6.90(dd, I H, J= 8.74, 2.27 Hz), 3.94(s, 3H, OMe), 3.85(s, 9H, 3 x OMe); 1 3 C NMR (75 MHz, CDCl 3 ) 6 188.21(CO), 158.29, 155.80, 152.72, 20 142.55, 131.99, 130.69, 120.98, 119.97, 119.67, 112.90, 107.00, 95.30, 60.67, 55.94, 55.43. Example 4 25 Preparation of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran. MeO OMe MeO 0 Br MeO 0 OAc C NRPortbDCC\ACGW351%6_ .DOC-25/5/2012 - 69 Step 1: 2-t-Butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy-7 isopropoxybenzofuran (Larock coupling). A suspension of 2-isopropoxy-3-methoxy-5-iodophenol (4.41 mmol), I -(tert butyldimethylsilyl)-3-(tert-butyldimethylsilyloxy)propyne (1.5 g, 5.28 mmol), lithium 5 chloride (189 mg, 4.45 mmol) and sodium carbonate (2.34 g, 22.08 mmol) in dry dimethylformamide (5 mL) at 100 0 C was deoxygenated 4 times by evacuation and backfilling with nitrogen. Palladium acetate (135 mg, 0.60 mmol) was added and the reaction vessel was degassed twice with nitrogen. The reaction mixture was then stirred at this temperature for 4 hours (tlc) and the solvent was removed by distillation under 10 vacuum. The residue was dissolved in ethyl acetate (75 mL), stirred well, filtered and treated with triethylamine (5 mL). The solution was concentrated onto silica gel (10 g) and purified by flash chromatography (silica gel, eluent = hexane/diethyl ether/triethylamine; 95:5:1%) to afforded the title compound as a yellow oil (1.45 g, 96 %); 'H NMR (300 MHz, CDCl 3 ) 8 7.24(d, IH, J = 8.45 Hz), 6.88(d, I H, J = 8.47 Hz), 4.80(s, 2H, CH 2 ), 15 4.73(m, I H), 3.88(s, 3H, OMe), 1.36(d, 6H, J= 6.17 Hz), 0.94(s, 9H), 0.92(s, 9H), 0.35(s, 6H), 0.12(s, 6H). Step 2: 2-t-Butyldimethylsilyl-3-formyl-6-methoxy-7-isopropoxybenzofuran To a solution of 2-t-butyldimethylsilyl-3-(t-butyldimethylsilyloxymethylene)-6-methoxy 20 7-isopropoxybenzofuran (2.69 mmol) in methanol (100 mL) was added concentrated hydrochloric acid (200 gL) and the reaction was stirred for 30 minutes (monitored by tlc), quenched with triethylamine (2 mL) and the solvent removed by distillation under vacuum. The residue was dissolved in dichloromethane (20 mL), washed with water (10 mL), dried over magnesium sulfate, concentrated under vacuum and co-distilled with toluene (20 mL). 25 The crude product was dissolved in dry dichloromethane (4 mL) and added to a stirred solution of Collin's reagent (chromium trioxide (1.01 g), pyridine (1.65 mL) in dry dichloromethane (30 mL)). The suspension was stirred for 10 minutes, filtered and the residue washed with diethyl ether (20 mL). The filtrate was concentrated onto silica (10 g) and purified by flash chromatography (silica gel, eluent = hexane/diethyl 30 ether/triethylamine (90:9:1) to afford the title compound as a light yellow oil (503 mg, 48%); 'H NMR (300 MHz, CDCl 3 ) 6 10.25(s, IH, CHO), 7.79(d, IH, J= 8.45 Hz), 6.98(d, C WRPorbhDCC\ACG\4351966_I.DOC-25052012 - 70 1 H, J= 8.46 Hz), 4.65(m, I H), 3.89(s, 3H, OMe), 1.35(d, 6H, J= 6.17 Hz), 0.97(s, 9H), 0.45(s, 6H). Step 3: 2-t-Butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7 5 isopropoxybenzofuran To a stirred solution of 3,4,5-trimethoxyiodobenzene (377 mg, 1.27 mmol) in dry tetrahydrofuran (1 mL) at -78 C under nitrogen was added n-butyllithium (795 IL, 1.59 mmol, 2M solution in cyclohexane) and the reaction mixture was stirred at this temperature for 40 minutes. After this time a solution of 2-t-butyldimethylsilyl-3-formyl-6 10 methoxy-7-isoproxybenzofuran (1.07 mmol) in dry tetrahydrofuran (1 mL) was added to the reaction dropwise via syringe pipette. The reaction mixture was stirred at -60 C for 20 minutes and then allowed to warm to 0 0 C, stirred for 10 minutes, quenched with saturated ammonium chloride solution (2 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water (10 mL), dried over magnesium sulfate and the solvent was 15 removed under vacuum to give a residue that was co-distilled with toluene. The crude product (908 mg) was dissolved in dry tetrahydrofuran (10 mL) and treated with 2,3 dichloro-5,6-dicyano-1,4-benzoquinone (900 mg, 1.59 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours (monitored by tic) and then loaded onto silica (10 g) and purified by flash chromatography (silica gel, eluent = hexane/diethyl 20 ether/triethylamine, 90:9:1) to afford the title compound as a light yellow oil (498 mg, 69%); 'H NMR (300 MHz, CDCl 3 ) 8 7.14(s, 2H, benzoyl Hs), 6.81(d, IH, J = 8.64 Hz), 6.77(d, I H, J= 8.64 Hz) 4.74(m, I H), 3.93(s, 3H, OMe), 3.86(s, 3H, OMe), 3.78(s, 6H, 2 x OMe), 1.39(d, 6H, J= 6.14 Hz), 1.01(s, 9H), 0.26(s, 6H). 25 Step 4: 2-(tert-butyldimethylsilyloxy)-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6 methoxybenzofuran To a stirred solution of 2-(t-butyldimethylsilyloxy)-7-isopropoxy-3-(3,4,5 trimethoxybenzoyl)-6-methoxy-benzofuran (160 mg, 0.31 mmol) in dry DCM (2 mL) at room temperature under nitrogen was added solid aluminium trichloride (83 mg, 0.62 30 mmol) and the reaction mixture was stirred for 15 minutes (monitored by tlc). The reaction was quenched with a saturated solution of ammonium chloride, extracted with C \NRPontbCC\ACG4351%6IDOC-25//2012 -71 dichloromethane and dried over magnesium sulfate. The solvent was removed by distillation and residue was dried by azeotropic removal of water with toluene. The crude product was dissolved in pyridine (2 mL), acetic anhydride (1 mL) was added and reaction mixture was stirred for 2 hours at room temperature. The solvent was distilled under 5 vacuum and the residue was loaded onto silica gel (1 g) and purified by column chromatography (silica gel, eluent, hexane:diethyl-ether; 80:20) (134 mg, 84%); 'H NMR (300 MHz, CDCl 3 ) 6 7.14(s, 2H, benzoyl Hs), 6.98(d, I H, J= 8.72 Hz), 6.85(d, 1H, J= 8.72 Hz), 3.93(s, 3H, OMe), 3.86(s, 3H, OMe), 3.80(s, 6H, 2 x OMe), 2.41(s, 3H), 0.99(s, 9H), 0.25(s, 6H). 10 Step 5: 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran To a stirred solution of 2-t-butyldimethylsilyl-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6 methoxybenzofuran (120 mg, 0.44 mmol) in 1,2-dichloroethane (1 mL) at room temperature under nitrogen was added bromine (12 VI, 0.44 mmol) dropwise and the 15 reaction mixture was stirred at this temperature for 10 minutes. After this time the reaction was quenched with saturated sodium thiosulfate solution, extracted with ethyl acetate (20 mL), dried over magnesium sulfate and the solvent removed by distillation under vacuum. The crude product was purified by silica gel column chromatography (eluent = Hexane:diethyl ether; 8:2 - 7:3) to afford the title compound as a colourless crystalline 20 solid (91 mg, 81%); ' H NMR (300 MHz, CDCl 3 ) 6 7.40(d, I H, J= 8.70 Hz), 7.14(s, 2H, benzoyl-Hs), 6.98(d, 1 H, J= 8.75 Hz), 3.94(s, 3H, OMe), 3.89(s, 3H, OMe), 3.86(s, 6H, 2 x OMe), 2.43(s, 3H); 1 3 C NMR (75 MHz, CDCl 3 ) 8 187.95(CO), 167.71, 152.75, 149.54, 147.49, 142.59, 131.92, 131.80, 123.91, 121.84, 119.89, 117.72, 109.89, 106.92, 60.69, 56.61, 56.00, 20.09. 25 Example 5 (Comparator C) Preparation of 3-(3,4,5-Trimethoxy benzoyl)-6-methoxy-benzofuran C \NPotbl\DCCACGW351%6_ .DOC-25/05J2012 -72 MeO OMe MeO 0 MeO 0 To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy benzofuran (30 mg, 0.066 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammoniumfluoride (76.5 VL, 0.076 mmol, 1 M solution in tetrahydrofuran). The 5 reaction mixture was stirred at room temperature for 20 minutes (monitored by tic), diluted with ethyl acetate (1OmL) and washed with 1M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The crude product was purified by flash chromatography (silica gel, eluent = hexane/diethyl ether; 7:3) to afford the title product as a cream crystalline solid (19.3 mg, 86%); 'H NMR 10 (300 MHz, CDCl 3 ) 6 8.02(d, lH, J= 8.97 Hz), 8.01(s, lH, C 2 H), 7.14(s, 2H, benzoyl Hs), 7.05(d, IH, J= 2.11 Hz), 7.00(dd, IH, J= 8.63, 2.11Hz), 3.93(s, 3H, OMe), 3.90(s, 6H, 2 x OMe), 3.87(s, 3H, OMe); 1 3 C NMR (75 MHz, CDCl 3 ) 8 188.71(CO), 158.64, 156.31, 152.82, 150.22, 141.72, 133.97, 122.58, 120.87, 118.12, 113.11, 106.07, 95.53, 60.63, 55.99, 55.40. 15 Example 6 Preparation of 3-(3,4,5-Trimethoxybenzoyl)-6-methoxy-7-hydroxybenzofuran MeO OMe MeO 0 MeO 0 OH 20 Step 1: 3-(3,4,5-Trimethoxy benzoyl)-6-methoxy-7-isopropoxy benzofuran To a stirred solution of 2-t-butyldimethylsilyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-7 isopropoxy-benzofuran (0.066 mmol) in tetrahydrofuran (1 mL) was added I MKFPftJ\UtALU\4 I%6_LUUU-2,/U,/20I2 - 73 tetrabutylammoniumfluoride (76.5 iL, 0.076 mmol, IM solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 20 minutes (monitored by tic), diluted with ethyl acetate (1 OmL) and washed with I M hydrochloric acid (5 mL). The organic layer was dried over magnesium sulfate and the solvent was removed under vacuum. The 5 crude product was purified by flash chromatography (silica gel, eluent = hexane/diethyl ether; 7:3) to afford the title compound as a light yellow paste (23 mg) that was used directly in the next step; 'H NMR (300 MHz, CDCl 3 ) 8 8.00(s, IH, C 2 H), 7.78(d, IH, J = 8.60 Hz), 7.15(s, 2H, benzoyl Hs), 7.04(d, IH, J = 8.61 Hz), 4.73(m, IH), 3.93(s, 3H, OMe), 3.92(s, 3H, OMe), 3.90(s, 6H, 2 x OMe), 1.37(d, 6H, J= 6.14 Hz). 10 Step 2: 3-(3,4,5-Trimethoxybenzoyl)-6-methoxy-7-hydroxybenzofuran A solution of 3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxybenzofuran (23 mg, 0.058 mmol, co-distilled with toluene before use) in dry dichloromethane (I mL) was treated with solid aluminum chloride (16 mg, 0.116 mmol). The reaction mixture was 15 stirred for 20 minutes at room temperature (monitored by tic) then quenched with saturated ammonium chloride solution and extracted with ethyl acetate (10 mL). The organic layer was washed with water (5 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (silica gel, eluent = hexane/diethyl ether/ethyl acetate; 80:19:1) to afford the title compound as a creamy white 20 crystalline solid (18 mg, 86%); 1H NMR (300 MHz, CDC 3 ) 8 8.04(s, 1H, C 2 H), 7.63(d, IH, J = 8.53 Hz), 7.14(s, 2H, benzoyl Hs), 7.02(d, IH, J = 8.38 Hz), 3.97(s, 3H, OMe), 3.93(s, 3H, OMe), 3.89(s, 6H, 2 x OMe); 1 3 C NMR (75 MHz, CDCI 3 ) 6 188.73(CO), 152.82, 151.24, 144.54, 143.30, 141.76, 133.97, 130.87, 120.92, 120.62, 112.43, 109.16, 106.06, 60.62, 56.85, 55.97. 25 Example 7 Alternative synthesis of 2-t-Butyldimethylsilyl-3-(3,4,5-trimethoxybenzoyl)-6 methoxy-7-isopropoxy-benzofuran 30 Step 1: 3-(tert-Butyldimethylsilyl)-1-(3,4,5-trimethoxyphenyl)propynone C :\RPotbl\DCC\ACG4351966_ .DOC-2505/2012 - 74 N-Butyl-lithium (1.7 M in THF, 8.12 mL, 13.8 mmol) was added dropwise to a stirred solution of t-butyl-dimethyl-silyl-acetylene (2.5 mL, 13.39 mmol) in dry THF (10 mL) at 78 *C under nitrogen and the reaction mixture was stirred at between -78 to -60 *C for I hour. Solution of 3,4,5-trimethoxy-benzaldehyde (2.7 g, 13.8 mmol) in dry THF (5 mL) 5 was added to the above stirred solution dropwise and stirring was continued for 20 minutes. The reaction was warmed to room temperature and stirred for one hour (monitored by tic), quenched with saturated ammonium chloride solution and diluted with ethylacetate (100 mL). The organic layer was separated, dried over magnesium sulfate and the solvent was distilled and co-distilled with toluene to afford the crude product as creamy 10 paste (4.47 g). The above product was dissolved in dry dichloromethane (200 mL), MnO 2 (2.5 g, 28.75 mmol) was added and the suspension was stirred for overnight (monitored by tlc). Reaction was filtered through celite, washed with dichloromethane (50 mL) and solvent was distilled to afford the crude product as creamy paste (4.16 g, 93%); IH NMR (300 MHz, CDCl 3 ) S 7.41(s, 2H, benzoyl Hs), 3.89(s, 3H, OMe), 3.87(s, 6H, 2 x OMe), 15 0.99(s, 9H), 0.21(s, 6H). Step 2: 2-t-Butyldimethylsilanyl-3(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy benzofuran: Procedure similar to Larock coupling described above; (3.96 g, 60%), see above in Example 6 for spectral data. 20 Example 8 Preparation of 2-Ethynyl-7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl) benzofuran MeO OMe MeO 0 MeO 0 25 OH C WRPorDCACGu351%6_1.DOC.25/05/2012 -75 To a stirred solution of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6 methoxybenzofuran (50 mg, 0.10 mmol) in dichloromethane (1 ml) and triethylamine (0.5 ml) was added Pd(Ph 3

P)

2 Cl 2 (3.5 mg, 5 mol%) and the reaction vessel was evacuated and backfilled with nitrogen three times. Trimethylsilylacetylene (30 mg, 0.30 mmol) and 5 copper (I) iodide (3 mg, 15 mol%) were added sequentially and the resulting dark mixture was stirred for two hours at room temperature. After this time the reaction was concentrated under vacuum and treated with methanol (1 ml) and potassium hydroxide (30 mg, excess). Stirring was continued for 0.5 hours then the crude mixture was concentrated onto silica and chromatographed (silica gel, gradient elution - 2:1 hexanes : ethyl acetate, 10 1:1 hexanes : ethyl acetate) to afford the product as a tan solid (10 mg, 26%); 'H NMR (CDCl 3 ) 8 7.26 (d, J = 8.6 Hz, 1H), 7.20 (s, 2H), 6.98 (d, J = 8.6 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 3.87 (s, 6H), 3.51 (s, I H); LRMS (ESI) m/z = 383 (M + H*). Example 9 15 Preparation of 7-Hydroxy-6-methoxy-2-methylsulfanyl-3-(3,4,5 trimethoxybenzoyl)benzofuran MeO OMe MeO 0 SMe MeO 0 OH To a suspension of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran 20 (22 mg, 0.046 mmol) in methanol (1 ml) in a screw cap vial was added sodium thiomethoxide (16 mg, 0.23 mmol) and the resulting orange solution was shaken for 20 minutes during which time the reaction became homogeneous. The crude reaction mixture was concentrated onto silica and chromatographed (silica gel, eluent = 2:1 hexanes : ethyl acetate) to give the product as a resin (10 mg, 54%) that could be crystallised by standing 25 in hexanes in the freezer overnight; 'H NMR (CDCl 3 ) 8 7.08 (s, 2H), 6.92 (d, J = 8.3 Hz, C:\NPorN\DCACGM351%6_ .DOC-25/05/2012 - 76 1H), 6.82 (d, J= 8.3 Hz, I H), 5.73 (br s, 1 H), 3.93 (s, 3H), 3.92 (s, 3H), 3.84 (s, 6H), 2.66 (s, 3H). Example 10 5 Preparation of 2-Hydrazino-7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl) benzofuran MeO OMe MeO 0 NH MeO 0 NH 2 OH To a solution of the 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran 10 (30 mg, 0.062 mmol) in tetrahydrofuran (0.5 ml) was added hydrazine monohydrate (15piL, 0.3 mmol). A yellow precipitate immediately formed and the heterogeneous mixture was heated to 60 0 C for 1 hour during which time more solid separated from the reaction. After cooling, the solid product was collected by filtration, washed with ether and dried under vacuum (6 mg, 25%); 'H NMR (d'-DMSO) 6 9.70 (br s, 1H), 9.27 (br s, 15 1 H), 6.85 (s, 2H), 6.68 (d, J= 8.5 Hz, 1 H), 6.21 (d, J= 8.5 Hz, I H), 5.00 (br s, 2H), 3.73 (s, 6H), 3.71 (s, 31H), 3.70 (s, 3H). LRMS (ESI) m/z = 389 (M + H), 372 (M + H* - NH 3 ). Example 11 20 Preparation of 2-Methyl-7-hyd roxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran C:\NRPonbI\DCC\ACGW5196_1 DOC-25M05/2012 -77 MeO OMe MeO 0 MeO 0 OH To a stirred solution of 2-Bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6 methoxybenzofuran (20 mg, 0.042 mmol), methyl-boronic acid (40 mg, 0.67 mmol), in 1,4 dioxane (2 mL) at 90 C was added tetrakis-triphenylphosphine palladium (II mg, 0.01 5 mmol) followed by the addition of a solution of sodium bicarbonate (40 mg, 0.48 mmol) in distilled water (0.5 mL). The reaction mixture turned red after 5 minutes. After 2 hours (tic) the reaction mixture was brought to room temperature and was added saturated ammonium chloride (2 mL) and diluted with dichloromethane (20 mL). The organic layer was separated and washed with water, dried over magnesium sulfate and the solvent was 10 removed by distillation under vacuum. The residue was purified by PTLC (eluent = Dichloromethane/Methanol, 1:1) to give the title compound (actate cleaved during rection) as a fluffy white solid; (3 mg, 19%). Example 12 15 Alternative Method for preparing 2-Methyl-7-hydroxy-3-(3,4,5-trimethoxybenzoyl) 6-methoxybenzofuran (Negishi Coupling) To a stirred solution of zinc-bromide (592 mg, 2.63 mmol) in dry THF(1.5 mL) at 0*C was 20 added the solution of methyl lithium (1.6 M solution in diethyl-ether, 2.6 mL, 4.15 mmol) and the reaction mixture was stirred for 2 hours. Solid 2-bromo-7-acetoxy-3-(3,4,5 trimethoxybenzoyl)-6-methoxy-benzofuran (300 mg, 0.63 mmol) (compound of example 4) was added and the ether was removed under vacuum and to the rest suspension was added dichlorobis(triphenylphosphine)palladium catalyst (21 mg) and catalytic amount of 25 copper (I) iodide. The reaction mixture was stirred at room temperature for 36 hours (monitored by tlc), quenched with saturated ammonium chloride solution and extracted C .RPonbl\DlCC\ACG435%6_LDOC-25/05/2012 - 78 with dichloromethane (10 mL), dried over magnesium sulfate and solvent distilled under vacuum and the product was purified by silica gel column (eluent = hexane/ethyl acetate; 8:2). The product was crystallized in methanol (106 mg, 46%); 'H NMR (300 MHz, CDCl 3 ) 6 7.09(s, 2H, benzoyl Hs), 6.93(d, I H, J = 8.54 Hz), 6.83(d, 1H, J = 8.56 Hz), 5 5.70(bs, IH, OH), 3.93(s, 3H, OMe), 3.92(s, 3H, OMe), 3.83(s, 6H, 2 x OMe), 2.54(s, 3H, 2-Me) Example 13 10 Preparation of 17-Hydroxy-6-methoxy-2-{(E)-pent-1-enyl)benzofuran-3-yl]-3,4,5 trimethoxy-phenyl) methanone MeO OMe MeO 0 MeO 0 OH As for the Suzuki reaction above (see Example 11), except the methylboronic acid was replaced with trans-4,4,5,5-tetramethyl-2-pent-1-enyl-1,3,2-dioxaborolane the identical 15 procedure afforded the title compound as light creamy solid (24 mg, 27%); 'H NMR (300 MHz, CDCl 3 ) 6 7.12(s, 2H, benzoyl Hs), 6.97(d, IH, J= 8.55 Hz), 6.83(d, IH, J = 8.61 Hz), 6.87-6.78(m, I H), 6.45 (and 1H, J= 14.44 Hz), 5.68(b, IH, OH), 3.93(s, 6H, 2 x OMe), 3.83(s, 6H, 2 x OMe), 2.2 - 2.15(m, 2H), 1.50 - 1.41(m, 2H), 0.92(t, 3H, J= 7.41 Hz). 20 Example 14 Preparation of (E)-3-17-Hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl) benzofuran-2-yl]-acrylic acid methyl ester C:\NRPort6DCC\ACGWA351%6_ LOC-25/05/20l2 -79 MeO OMe MeO 0 MeO O OH OMe Mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50 mg, 0.10 mmol) and methylacrylate(0.5 mL, excess) in a mixture of acetonitrile: TEA; I mL:0.5 mL was degassed with nitrogen and palladium acetate (10 mg) was added to it. 5 Reaction mixture was stirred for one hour under nitrogen at reflux, more palladium acetate (15 mg) was added and the refluxing was continued for 7 hours (monitored by tic). Methanol (1 mL) was added followed by the addition of potassium carbonate (70 mg, 0.51 mmol) and stirring was continued for 1 hour. Solvent was distilled and the crude material was purified over silica gel column (eluent Hexane:diethylether; 1:1) to afford the title 10 compound as yellow crystalline solid (17 mg, 37%); 'H NMR (300 MHz, CDCl 3 ) 6 7.61(d, I H, J= 15.76 Hz), 7.14(s, 2H, benzoyl Hs), 6.98(d, 1 H, J= 8.64 Hz), 6.89(d, 1H, J= 8.69 Hz), 6.81(d, IH, J = 15.78 Hz), 3.96(s, 3H, OMe), 3.95(s, 3H, OMe), 3.81(s, 6H, 2 x OMe), 3.77(bs, 3H, OMe). 15 Example 15 Preparation of (E)-3-17-Hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)benzofuran 2-yll-acrylamide MeO OMe MeO 0 MeO O OH

NH

2 20 As for Example 14 above except methyl acrylate was substituted with acrylamide, gave the title compound as light yellow solid (5 mg, 17%); 'H NMR (300 MHz, CD 3 0D) 6: 7.48(d, IH, J= 15.5 Hz), 7.18(s, 2H, benzoyl Hs), 7.00(d, IH, J= 8.65 Hz), 6.94(d, 1H, J= 15.52 C\NRPonbI\DCC\ACG\4351966_ .DOC-25/05/2012 - 80 Hz), 6.88(d, 1H, J= 8.62 Hz), 4.55(b, 2H, NH 2 ), 3.91(s, 3H, OMe), 3.87(s, 3H, OMe), 3.79(s, 6H, 2 x OMe). Example 16 5 Preparation of 2-cyano-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran MeO OMe MeO 0 MeO 0 OH A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran (25 mg, 0.05 mmol) and sodium cyanide (15 mg, 0.38 mmol) in dry DMSO (1 mL) under 10 nitrogen at room temperature was stirred for 3.5 hours (monitored by tic), quenched with saturated ammonium chloride solution and diluted with ethylacetate (20 mL). The organic layer was separated, dried over magnesium sulfate and the solvent distilled to afford the crude material which was purified over silica gel column (eluent - Hexane: diethyl-ether 1:1 to 0:100) to afford the desired product as pale cream solid (13 mg, 65%); 'H NMR 15 (300 MHz, CDCl 3 ) 8: 7.29(d, 1 H, J= 8.71 Hz), 7.19(s, 2H, benzoyl Hs), 6.06(d, 1H, J= 8.77 Hz), 5.82(b, IH, OH), 3.99(s, 3H, OMe), 3.96(s, 3H, OMe), 3.88(s, 6H, 2 x OMe). Example 17 20 Preparation of 7-Hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2 methylcarboxylate MeO OMe MeO 0 0 MeO 0 OMe

OH

C \NRPortbhDCC\ACG4351965_L DOC-2505/2012 -81 To a solution of 2-cyano-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (20 mg, 0.05 mmol) in a mixture of methanol:acetonitrile; 2 mL: I mL was added potassium carbonate (50 mg, 0.36 mmol) and the reaction mixture was stirred for 16 hours at room temperature (monitored by tic). Solvent was distilled and to the residue was added 5 saturated ammonium chloride solution (2 mL) and ethyl acetate (15 mL) and the crude mixture was stirred for 15 minutes. The organic layer was separated and dried over magnesium sulfate. The crude material was purified over silica gel column (eluent - neat diethyl-ether to diethyl-ether: ethyl-acetate 80:20) to afford the title compound as pale cream solid (9 mg, 42%); 'H NMR (300 MHz, CDCl 3 ) 8: 7.12(s, 2H, benzoyl Hs), 6.99(d, 10 1 H, J= 8.57 Hz), 6.93(d, 1H, J= 8.72 Hz), 5.28(b, I H, OH), 3.96(s, 3H, OMe), 3.93(s, 3H, OMe), 3.81(s, 6H, 2 x OMe), 3.68(bs, 3H, OMe). Example 18 15 Preparation of 2-(N-Methylamino)-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6 methoxy-benzofuran MeO OMe MeO 0 NH MeO 0 OH To a stirred solution of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy benzofuran (20 mg, 0.066 mmol) in acetonitrile (3 mL) was added the solution of 20 methyamine (I mL, excess as reactant and base), and the reaction mixture was stirred at room temperature for 1 hour when the precipitates appeared. The solvent was distilled under vacuo and the crude was dissolved in tetrahydrofuran (2 mL), I M hydrochloric acid (1 mL) was added and the reaction mixture was stirred for 1 hour then diluted with dichloromethane (10 mL) and washed with water. The organic layer was dried over 25 magnesium sulfate and solvent was distilled under vacuo. The crude was purified by PTLC (eluent = Hexane:ethylacetate:triethylamine; 2:8:1%) to gave the title compound as C RPQnb\DCC\ACG435 1%6_1 DOC-25/05/2012 - 82 a yellow-green solid (5 mg, 29%); 'H NMR (300 MHz, CDCl 3 ) 6 8.91(broad, IH, NH), 6.93(s, 2H, benzoyl Hs), 6.59(d, I H, J= 8.56 Hz), 6.46(d, 1H, J= 8.51 Hz), 5.61(bs, I H, OH), 3.91(s, 3H, OMe), 3.86(s, 3H, OMe), 3.84(s, 6H, 2 x OMe), 3.28(d, 3H, J = 5.28 Hz). 5 Example 19 Preparation of (2-Amino-7-hydroxy-6-methoxy-benzofuran-3-yl)-(3,4,5 trimethoxyphenyl)-methanone MeO OMe MeO 0

NH

2 MeO 0 10 OH Step 1: (2-Benzylamino-7-hydroxy-6-methoxy-benzofuran-3-yI)-(3,4,5-trimethoxy phenyl)-methanone: 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (140 mg, 0.29 mmol) was dissolved in dry pyridine (2 mL) and benzylamine (500 pL, excess) was added 15 to it and the reaction mixture was stirred at 80 C for 1 hour. Solvent was distilled and the crude product was purified over silica gel column to afford the title compound as light yellow solid (112 mg, 83%); 'H NMR (300 MHz, CDCl 3 ) 8: 9.27(b, IH, NH), 7.39 7.32(m, 5Hs, Ar Hs), 6.96(s, 2H, benzoyl Hs), 6.61(d, 1H, J = 8.47 Hz), 6.50(d, 1H, J= 8.10 Hz), 4.83(d, 2H, J = 4.95 Hz, Benzyl Hs), 3.91(s, 3H, OMe), 3.85(s, 3H, OMe), 20 3.84(s, 6H, 2 x OMe). Step 2: (2-Amino-7-hydroxy-6-methoxy-benzofuran-3-yI)-(3,4,5-trimethoxy phenyl)methanone: A mixtuer of 2-benzylamino-7-hydroxy-6-methoxy-benzofuran-3-yl)-(3,4,5-trimethoxy 25 phenyl)-methanone (105 mg, 0.23 mmol) and Pd/C (10%, 100 mg) in a mixture of solvents ethylacetate/THF/water/HCl (3mL:2mL: I mL) 2 drops was stirred at room temperature for C:\NRPorb\DCC'ACG\4351%66_IOC.25/5/2012 - 83 2.5 hours under the atmosphere of hydrogen (monitored by tic). The mixture was filtered through celite, washed with dichloromethane (5 mL x 3) and solvent was distilled to afford the product as green yellow solid which was purified by flash column to gave the crystalline yellow green solid (79 mg, 93%); 'H NMR (300 MHz, CDCl 3 ) 6: 6.98(s, 2H, 5 benzoyl Hs), 6.93(bs, 2H, NH2), 6.63(d, IH, J = 8.18 Hz), 6.52(d, IH, J= 8.41 Hz), 5.65(bs, 1H, OH), 3.92(s, 3H, OMe), 3.86(s, 3H, OMe), 3.84(s, 6H, 2 x OMe). Example 20 10 Preparation of [7-Hydroxy-2-(2-hydroxy-ethylamino)-6-methoxy-benzofuran-3-ylI (3,4,5-trimethoxy-phenyl)methanone MeO OMe MeO \/ 0 NH MeO 0 OH OH When benzylamine was substituted with ethanolamine as in Example 19 (see step 1) the same procedure gave the title compound as greenish yellow solid (29 mg, 67%); 'H NMR 15 (300 MHz, CDCl 3 ) 8: 9.13(b, I H, NH), 6.94(s, 2H, benzoyl Hs), 6.60(d, 1 H, J = 8.54 Hz), 6.47(d, I H, .J= 8.55 Hz), 3.94 - 3.89(m, 4H), 3.91(s, 3H, OMe), 3.85(s, 3H, OMe), 3.83(s, 6H, 2 x OMe). Example 21 20 Preparation of [2-(2-Dimethylamino-ethylamino)-7-hydroxy-6-methoxy-benzofuran 3-yl-(3,4,5-trimethoxy-phenyl)methanone C:WRPortbl\DCC\ACGM4351%6 L.DOC-25/05/2012 -84 MeO OMe MeO 0 NH MeO 0 OH N When benzylamine was substituted with N,N'-dimethylethylenediamine as in Example 20 (see step 1) the same procedure gave the title compound as greenish yellow solid (25 mg, 54%); 'H NMR (300 MHz, CDCl 3 ) 8 9.1(b, I H, NH), 6.95(s, 2H, benzoyl Hs), 6.60(d, I H, 5 J= 8.44 Hz), 6.48(d, 1 H, J= 8.48 Hz), 3.90(s, 3H, OMe), 3.84(s, 3H, OMe), 3.83(s, 6H, 2 x OMe), 3.82 - 3.83(m, 2H), 2.65(t, 2H, J = 5.63 Hz), 2.34(s, 6H). Example 22 10 Preparation of (2-N,N'-Dimethylamino-7-hydroxy-6-methoxy-benzofuran-3-yI) (3,4,5-trimethoxy-phenyl)-methanone MeO OMe MeO 0 NMe 2 MeO O OH The 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (40 mg, 0.084 mmol) was dissolved in THF (1 mL) and solution of N,N'-dimethyl-amine (2M 15 solution in THF, 0.5 mL) was added to it. The reaction mixture was stirred for overnight. Solvent was distilled and the crude was purified over silica gel plate to afford the title compound as yellow solid (18 mg, 54%); 'H NMR (300 MHz, CDCl 3 ) 8 7.11(s, 2H, benzoyl Hs), 6.61(d, I H, J= 8.55 Hz), 6.44(d, IH, J= 8.51 Hz), 3.91(s, 3H, OMe), 3.86(s, 3H, OMe), 3.84(s, 6H, 2 x OMe). 20 C:\NRPorb\DCC\ACG4351%6_I DOC-25M5/2012 - 85 Example 23 Preparation of [7-hydroxy-6-methoxy-3(3,4,5-trimethoxy-benzoyl)-benzofuran-2 ylamino]-acetic acid MeO OMe MeO 0 NH OH MeO O 0 5OH 0 A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran(50 mg, 0.10 mmol), glycine (18 mg, 0.29 mmol) and potassium carbonate (29 mg, 0.21 mmol) in a mixture of MeCN/water 80:20 (5 mL) was refluxed for six hours. Solvent was distilled and the residue was taken in water:dichloromethane 1:2 (30 mL) and stirred for 20 10 minutes. Aqueous layer was separated, washed with dichloromethane (20 mL) and acidified with 2 drops of concentrated HCI and was diluted with dichloromethane (50 mL) and was stirred for 30 minutes. The organic layer was separated and dried over magnesium sulfate and solvent was distilled to afford the title compound as yellow powder (23 mg, 51%); 'H NMR (300 MHz, Acetone d6) 8 9.09(b, 1H, NH), 6.97(s, 2H, benzoyl 15 Hs), 6.74(d, 1H, J= 8.53 Hz), 6.45(d, I H, J= 8.48 Hz), 4.48(d, 2H, J= 4.28 Hz), 3.82(s, 6H, 2 x OMe), 3.79(s, 3H, OMe), 3.78(s, 3H, OMe). Example 24 20 Preparation of [7-Hydroxy-6-methoxy-3-(3,4,5-trimethoxy-benzoyl)-benzofuran-2 ylamino]-acetic acid methyl ester MeO OMe MeO 0 NH OMe MeO O 0 OH 0 C:\NRPrb\DCC\ACG351%6_ 1 DOC-2/05/2012 - 86 [7-hydroxy-6-methoxy-3 -(3,4,5 -trimethoxy-benzoyl)-benzofuran-2-ylamino]acetic acid (30 mg, 0.07 mmol) was dissolved in dry methanol (5 mL) and trimethylsilyl chloride (100 pL) was added to it. The reaction was stirred at room temperature for 6 hours (monitored by tic). Solvent was distilled under vacuum and the crude was purified over silica gel plate 5 to afford the title compound as yellow solid (23 mg, 79%); 'H NMR (300 MHz, CDCl 3 ) 8 9.11 (b, I H, NH), 6.97(s, 2H, benzoyl Hs), 6.62(d, 1 H, J = 8.56 Hz), 6.51 (d, I H, J = 8.49 Hz), 4.42(d, 1H, J= 6.09 Hz), 3.91(s, 3H, OMe), 3.86(s, 3H, OMe), 3.84(s, 6H, 2 x OMe), 3.81(s, 3H, OMe). 10 Example 25 Preparation of 17-Hydroxy-6-methoxy-2-(pyridin-3-ylamino)-benzofuran-3-yll-(3,4,5 trimethoxy-phenyl)-methanone MeO OMe MeO 0 NH MeO O OH N 15 A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzofuran (50 mg, 0.10 mmol) and 3-amino-pyridine (30 mg, 0.30 mmol) in a mixture of solvent acetonitrile:water (8:2, 5 mL) was refluxed with stirring for 6 hours. The solvent was distilled under vacuum and the residue was purified over silica gel column to afford the title compound as yellow solid (11 mg, 23%); 'H NMR (300 MHz, CDCl 3 ) 8 11.22(s, IH), 20 8.77(b, I H), 8.42(b, 1 H), 8.01(bd, I H), 7.28(b, 1 H), 7.03(s, 2H, benzoyl Hs), 6.71(d, IH, J = 8.82 Hz), 6.63(d, I H, J= 8.37 Hz), 3.94(s, 3H, OMe), 3.90(s, 3H, OMe), 3.86(s, 6H, 2 x OMe). 25 CANRPorbl\DCC\ACG4351%6_ .DOC-25/05/012 -87 Example 26 Preparation of tert-Butyl-2-(7-hydroxy-6-methoxy-3-(3,4,5 trimethoxybenzoyl)benzofuran-2-ylamino)ethyl carbamate MeO OMe MeO 0 H N N O MeO 0 H 5 OH A mixture of 0.05 g (0.1 mmol) of 2-bromo-6-methoxy-3-(3,4,5-trimethoxybenzoyl) benzofuran-7-yl acetate and 0.057 g (0.35mmol) of tert-butyl 2-aminoethylcarbamate (Fontand & Pignatti J. Label. Compd. Radiopharm., 2002, 45, 899 - 909) in 0.5 ml of anhydrous pyridine was stirred overnight at room temperature under nitrogen atmosphere. 10 After evaporation of solvent in vacuo, the residue was diluted to 10 ml with ethyl acetate and washed with saturated ammonium chloride, water and dried over anhydrous magnesium sulfate. Filtration and evaporation of solvent gave 0.054 g of residue, which was purified by flash column chromatography to give the title compound as a creamy solid (0.031 g, 59%); 'H NMR (CDCl 3 ) 8 1.42 (s, 9H, Me BOC); 3.45 (m, 2H, CH 2 ); 3.75(m, 15 2H, CH 2 ); 3.84 (s, 6H, OMe); 3.86 (s, 3H, OMe); 3.91 (s, 3H, OMe); 4.86 (broad s, 1H, NH); 5.76 (broad s, 1H, OH); 6.47 (d, IH, CH aromatic, J = 8.52 Hz); 6.6 (d, I H,CH aromatic, J = 8.52 Hz); 6.94 (s, 2H, CH aromatic); 9.04 (m, 1 H, NH). Example 27 20 Preparation of [2-(2-aminoethylamino)-7-hydroxy-6-methoxybenzofuran-3-yI](3,4,5 trimethoxyphenyl)methanone Trifluoroacetate Salt C RPorftbID CG 5 1%66_I DOC-25/ol2 -88 MeO OMe MeO 0 N

-

NH2HOOCF3 MeO 0 H OH 0.026 g (0.05 mmol) of [2-(2-aminoethylamino)-7-hydroxy-6-methoxybenzofuran-3 yl](3,4,5-trimethoxyphenyl)methanone was dissolved in 1 ml of anhydrous trifluoroacetic acid. After stirring for 1 h at room temperature the solvent was removed under reduced 5 pressure and the residue was suspended in 2 ml of anhydrous methylene chloride and evaporated under reduced pressure. The residue was washed with 2 ml of anhydrous methylene chloride to give the title compound as a yellowish solid (0.011g, 42%); 'H NMR (CD 3 0D) 8 3.31 (tr, 2H, CH 2 , J= %.84 Hz); 3.8 (s, 9H, OMe); 3.83 (s, 3H, OMe); 3.92 (tr, 2H, CH, J = 5.84 Hz); 6.33 (d, I H CH aromatic,.J = 8.52 Hz); 6.69 (d, I H, CH 10 aromatic, J= 8.52 Hz); 6.95 (s, 2H, CH aromatic). Example 28 Preparation of 1-[2-(7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)benzofuran-2 15 ylamino)ethyljguanidine MeO OMe MeO 0 N NH MeO O NH OH HNS

NH

2 .HCI To a mixture of 0.02 g (0.046 mmol) of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6 methoxybenzofuran and 0.02 g (0.11 mmol) of N-(2-aminoethyl)guanidine dihydrochloride (prepared by Fontand & Pignatti, J. Label. Compd Radiopharm., 2002, 45, 899 - 909) in 20 0.5 ml of anhydrous dimethylacetamide 0.032 ml (0.184mmol) of N,N diisopropylethylamine was added at room temperature under nitrogen atmosphere. The C.NRPotbrDCoACGW35J%6_1. DOC-25/05/2012 - 89 resulting mixture was stirred for 30 h at room temperature, then evaporated to dryness in vacuo. The residue was purified by flash column chromatography (silica gel, acetonitrile/water 9 : 1) to give the title compound as a yellowish solid (0.006g, 28%); 'H NMR (CD 3 0D) 8 3.55 (tr, 2H, CH 2 , J = 6 Hz); 3.7 - 3.86 (in, 14H, OMe x 4, CH 2 ); 4.82 5 (s, H 2 0); 6.32 (d, I H, CH aromatic, J = 8.47 Hz); 6.69 (d, I H, CH aromatic, J = 8.47 Hz); 6.94 (s, 2H, CH aromatic). MS (m/z) 458.9; 459.9, 460.9. Example 29 10 Preparation of Disodium 6-methoxy-2-methyl-3-(3,4,5 trimethoxybenzoyl)benzofuran-7-yI phosphate MeO OMe MeO 0 MeO 0 O, ONa // ONa 0 Step 1: Dibenzyl 6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzofuran-7-yI phosphate: 15 To a mixture of 0.081 g (0.22 mmol) of (7-hydroxy-6-methoxy-2-methylbenzofuran-3 yl)(3,4,5-trimethoxyphenyl)methanone, 0.086 g (0.261 mmol) of carbon tetrabromide and 0.063 ml (0.283 mmol) of dibenzylphosphite in 2.5 ml of anhydrous acetonitrile 0.046 ml of anhydrous triethylamine was added dropwise at 0 0 C under nitrogen atmosphere. The resulting mixture was stirred for 2h at room temperature, then diluted to 20 ml with ethyl 20 acetate, washed with water brine, dried over anhydrous magnesium sulfate, filtered off and evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/ ethyl acetate, 9:1) to give the title compound as a colorless foam (0.13g, 94%); 'H NMR (CDCl 3 ) 6 2.42 (s, 3H, Me-2); 3.83 (s, I1H, OMe); 3.93 (s, 3H, OMe); 5.33 (in, 4H, CH 2 Ph); 6.89 (d, CH aromatic, J= 8.7 Hz); 7.21 (dd, I H, C:\NRPorbI\DCC\ACGW351%6. LDOC-25M5/2012 - 90 CH aromatic, J= 8.72 Hz; J= 1.2 Hz); 7.08 (s, 2H, CH aromatic); 7.29 - 7.43 (m, 10 H, CH aromatic). Step 2: Disodium 6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzofuran-7-yl 5 phosphate: To a stirred solution of 0.122 g (0.193 mmol) of the product from Step 1 in I ml of anhydrous acetonitrile 0.075 ml (0.58 mmol) of bromotrimethylsilane was added at -5OC under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0 0 C, then evaporated to dryness in vacuo. The residue was diluted to 5 ml with anhydrous methanol 10 and pH of the solution was brought up about 10 by the addition of sodium methoxide. After evaporation of the resulting mixture under reduced pressure the solid residue was washed with anhydrous isopropanol (4 x 1.5 ml) and anhydrous ethanol (3 x 1.5 ml) and dried under vacuum to give 0.062 g (65 % yield) of title compound as an colorless solid; H NMR (D 2 0) 6 2.37 (s, 3H, Me-2); 3.76 (s, 6H, OMe); 3.79 (s, 3H, OMe); 3.82 (s, 3H, 15 OMe); 4.66 (s, H 2 0); 6,93 (d, IH, CH aromatic, J= 8.6 Hz); 7.04 (d, IH, CH aromatic, J = 8.6 Hz); 7.10 (s, 2H, CH aromatic). Example 30 20 Preparation of (2-Hydroxy-6-methoxybenzofuran-3-yl)(3,4,5 trimethoxyphenyl)methanone MeO OMe MeO 0 OH MeO 0 Step 1: 3-Oxo-3-(3,4,5-trimethoxyphenyl)propionic acid 10 ml of 2M solution of n-butyllithium in cyclohexane was added dropwise over 10 25 minutes to a stirred solution of 5.08g (20 mmol) of bis(trimethylsilyl)malonate in 40 ml of anhydrous ether under nitrogen atmosphere at -60 "C. The mixture was then allowed to warm to O 0 Cand the solution of 2.3 g (10 mmol) of 3,4,5-trimethoxybenzoyl chloride in 20 C:NRPorbl\DCC\ACG\4351%6_l.DOC-25/05/2012 -91 ml of anhydrous ethyl ether was added in one portion. The resulting mixture was stirred for 10 min. at 0C then shaken with 100 ml of 5% aqueous sodium bicarbonate for 5 minutes. The aqueous phase was acidified to pH = -1 with cold 4N sulfuric acid and extracted with ethyl ether (3 x 100 ml). The combined extracts were dried over anhydrous 5 magnesium sulfate, filtered off and evaporated to dryness to give the title compound as a creamy crystals (1.82g, 71.6%); 'H NMR (CDCl 3 ) 8 3.8 - 3.92 (in, 9H, OMe); 4.03 (s, 1.8 H, CH 2 ); 5.62 (s, 0.2 H, CH enol); 7.2 (s, 2H, CH aromatic). Step 2: 3-Methoxyphenyl 3-oxo-3-(3,4,5-trimethoxyphenyl)propanoate 10 To a mixture of 0.27 g (1.06 mmol) of the product of Step 1 and 0.13 g (1.06 mmol) of 3 methoxyphenol in 2 ml of anhydrous methylenechloride 0.16 ml (1.06 mmol) of diisopropylcarbondiimide was added at room temperature. The resulting mixture was stirred for 24 hours at room temperature and filtered off. The filtrate was evaporated to dryness and purified by flash column chromaytography (silica gel; methylene chloride) to 15 give the title compound as a colorless crystals (0.185g, 49%); 'H NMR (CDCl 3 ) 6 3.77 (s, 3H, OMe); 3.91 (s, 6H, OMe); 4.17 (s, 3H, OMe); 4.173 (s, 2H, CH 2 ); 6.6 - 6.8 (m, 3H, CH aromatic); 7.2 - 7.3(m, 3H, CH aromatic). Step 3: (2-Hydroxy-6-methoxybenzofuran-3-yI)(3,4,5-trimethoxyphenyl)methanone 20 The procedure of Baumm et al, Synthetic Communication 1987, 17(14), 1709 - 1716, was used. To a stirred solution of 0.0561 g (0.156 mmol) of the product of Step 2 and 0.041 g (0.171 mmol) of 4-acetamidobenzenesulfonyl azide in 2 ml of anhydrous acetonitrile 0.065 ml (0.47 mmol) of triethylamine was added at 0*C. After stirring for 3 hours at room temperature the solvent was evaporated to dryness under reduced pressure and the residue 25 was purified by flash column chromatography (silica gel, methylene chloride) to give 0.059 g (98% yield) of 3-methoxyphenyl 2-diazo-3-oxo-3-(3,4,5 trimethoxyphenyl)propanoate. This was dissolved in 2 ml of anhydrous methylene chloride and 3.5 mg (7.9 ptmol) of rhodium (III) acetate was added at room temperature under nitrogen atmosphere. The resulting mixture turned deep green after I h of stirring at 30 room temperature. After filtration through Celite and washing with fresh methylene chloride, the filtrate was evaporated to dryness under reduced pressure to give the title C :URPotbtIDCC\ACG\4351%6_ L DOC-2555212 -92 compound as an deep yellow crystals (0.049g, 91%); 'H NMR (CDC 3 ) 8 3.8 (s, 3H, OMe); 3.9 (s, 6H, OMe); 3.94 (s, 3H, OMe); 6.58 (dd, 1H, CH aromatic, J = 2.4 Hz; 8.6 Hz); 6.76 (d, IH CH aromatic; J = 2.4 Hz); 7.04 (s, 2H, CH aromatic); 7.25 (d, 1H, CH aromatic, J= 8.6 Hz). 5 Example 31 Preparation of 2-Butyl-3-(3,4,5-trimethoxyphenyl)-7-hydroxy-6-methoxy benzolblfuran: MeO OMe MeO \ 0 MeO O 10 OH This compound was prepared according to the procedure described for Example 12, except that butyllithium was used in place of methyllithium. 'H NMR (300 MHz, CDCl 3 ) 8- 7.10 (s, 2H, benzoyl Hs), 6.87 (d, J= 8.61 Hz, I H), 6.82 (d, J= 8.58 Hz, I H), 5.71 (s, 1H, OH), 3.94 (s, 3H, OMe), 3.93 (s, 3H, OMe), 3.82 (s, 6H, 15 2 x OMe), 2.87 (t, 2H, J= 7.54 Hz), 1.81 - 1.71 (m, 2H), 1.38 - 1.70 (m, 2H), 0.87 (t, 3H, J= 7.37 Hz). Example 32 20 Preparation of 2-Ethyl-3-(3,4,5-trimethoxyphenyl)-7-hydroxy-6-methoxy benzolblfuran: C:\NRPorbl\DCC\ACGM351%6_L DOC-255O22 -93 MeO OMe MeO 0 MeO 0 OH This compound was prepared according to the procedure described for Example 12, except that ethyllithium was used in place of methyllithium. 5 'H NMR (300 MHz, CDCl 3 ) 8- 7.11 (s, 2H, benzoyl Hs), 6.91 (d, J= 8.61 Hz, 1H), 6.83 (d, J= 8.58 Hz, I H), 3.93 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.82 (s, 6H, 2 x OMe), 2.88 (q, 2H,.J= 15.00, 7.52 Hz), 1.33 (t, 3H, J= 7.49 Hz). Example 33 10 Preparation of 2-Bromomethyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7- acetoxy benzo[bifuran: MeO OMe MeO 0 MeO 0 Br OAc To a stirred solution of 2-methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy 15 benzo[b]furan (Example 11) (985 mg, 2.65 mmol) in dry pyridine (10 mL) under nitrogen was added acetic anhydride (540 pL, 5.71 mmol) and after 0.5 hours more of acetic anhydride (540 pL, 5.71 mmol) was added and the solution was stirred for 1.5 hours. The solvent was distilled and the residue was taken in dichloromethane (20 mL), washed with I M HCl. The organic layer was separated and dried over magnesium sulphate and solvent 20 was distilled to gave the crude product which was purified over silica gel column to afford the title compound as a creamy solid (1.09 gm, 99%). 'H NMR (300 MHz, CDCl 3 ) 6 7.28 C:\NRPonbl\DCCACM3 51%6_L DOC-25/05/2012 - 94 (d, J = 8.74 Hz, I H), 7.09 (s, 2H, benzoyl Hs), 6.90 (d, J = 8.69 Hz, IH), 3.93 (s, 3H, OMe), 3.87 (s, 6H, 2 x OMe), 3.84 (s, 3H, OMe), 2.51 (s, 3H), 2.43 (s, 3H). The 2-methyl 3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-0-acyl-benzo[b] furan (390 mg, 0.94 mmol, as obtained above) was dissolved in dry carbon tetrachloride (10 mL) and catalytic amount of 5 benzoyl peroxide was added to it followed by the addition of N-bromosuccinamide (167 mg, 0.94 mmol). The mixture was stirred at reflux for 3 hours and the solvent was distilled under vacuum. The residue was dissolved in DCM (20 mL) and was washed with 10% sodium bicarbonate solution and water. The organic layer was separated, dried over magnesium sulphate and the solvent was distilled under vacuum to gave the title 10 compound as creamy white solid (461 mg, 99%). 'H NMR (300 MHz, CDCl 3 ) 6 7.28 (d, J = 8.76 Hz, 1H), 7.14 (s, 2H, benzoyl Hs), 6.95 (d, J= 8.75 Hz, 1 H), 4.6 (s, 2H), 3.94 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.86 (s, 6H, 2 x OMe), 2.43 (s, 3H). Example 34 15 Preparation of 2-Dimethylaminomethylene-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy 7-hydroxy-benzolb]furan: MeO OMe MeO MeO 0 MeO O N OH To a stirred solution of 2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7 20 acetoxy-benzo[blfuran (Example 33) (25 mg, 0.051 mmol) in dry THF (0.5 mL) was added solution of dimethylamine (0.5 mL, excess, 2M solution in THF) and the mixture was stirred for 6 hours at room temperature (tlc). The solvent was distilled and the crude was purified over silica gel to afford the title compound as a light yellow solid (15 mg, 71%). 'H NMR (300 MHz, CDCl 3 ) 8- 7.14(s, 2H, benzoyl Hs), 6.85(s, 2H, Ar-Hs), 3.93(s, 25 3H, OMe), 3.92(s, 3H, OMe), 3.81(s, 6H, 2 x OMe), 3.75(s, 2H), 2.31(s, 6H).

C:\NRfPotDCC\ACG\4351%6_ 1.DOC-25/05/2012 -95 Example 35 Preparation of 2-(1H-Imidazol-1-yl)methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7 hydroxy-benzoIbifuran: MeO OMe MeO 0 MeO O N 5 OH \N To a stirred suspension of 2-bromomethyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7 acetoxy-benzo[b]furan (Example 33) (35 mg, 0.071 mmol) and potassium carbonate (20 mg, 0.15 mmol) in dry acetonitrile (1.5 mL) was added imidazole (19 mg, 0.28 mmol) and the reaction mixture was stirred for overnight (tic). The solvent was distilled inder vacuum 10 and the crude was taken in ethyl acetate, filleted and purified over silica gel plate to afford the title compound as a light yellow solid (6 mg, 19%). 'H NMR (300 MHz, CDCI 3 ) 6 7.66(s, IH), 7.19(s, IH), 7.09(s, 2H, benzoyl Hs), 7.07(s, I H), 6.85(d, J = 8.63 Hz, 1H), 6.74(d, J= 8.63 Hz, 1 H), 5.37(s, 2H), 4.00(s, 3H, OMe), 3.95(s, 3H, OMe), 3.79(s, 6H, 2 x OMe). 15 Example 36 Preparation of 2-(5-amino-2H-tetrazol-2-yl)-methyl-3-(3,4,5-tri-methoxy-benzoyl)-6 methoxy-7-hydroxy-benzo [b] furan: MeO OMe MeO\ 0 MeO 0 N-N OH N 20 NH2 C:RNPonb\DCC\ACG\435 1%6_1 DOC-25052012 - 96 When imidazole was replaced with aminotetrazole as in the above example the identical procedure afforded the title compound as a light yellow solid (2 mg, 9%). 'H NMR (300 MHz, CDCl 3 ) 7.20(s, 2H, benzoyl Hs), 6.86(d, J = 8.71 Hz, 1 H), 6.72(d, J = 8.48 Hz, 1 H), 6.01(s, 2H), 5.61(s, 2H), 3.98(s, 3H, OMe), 3.92(s, 3H, OMe), 3.81(s, 6H, 2 x OMe). 5 Example 37 Preparation of 2-(4-Methylpiperazin-1-yl)methyl-3-(3,4,5-tri-methoxy-benzoyl)-6 methoxy-7-hydroxy-benzo b fu ran: MeO OMe MeO 0 MeO 0 N OH N 10 To a stirred solution of 2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7 acetoxybenzo[b]furan (Example 33) (50 mg, 0.10 mmol) in dry THF (2 mL) at room temperature was added N-methylpiprazine (24 pLL, 0.22 mmol) and the mixture was stirred for 2 hours and then added solution of dimethylamine (0.2 mL, 2M solution in THF, 15 excess) and stirred for 4 hours. The solvent was distilled and the crude was purified over silica gel column and the product was crystallized from acetonitrile to afford the title compound as a light yellow crystalline solid (22 mg, 46%). 'H NMR (300 MHz, CDCl 3 ) 6 7.12 (s, 2H, benzoyl Hs), 6.89 (d, J= 8.58 Hz, 1 H), 6.85 (d, J= 8.58 Hz, 1 H), 3.93 (s, 6H, 2 x OMe), 3.82 (s, 6H, 2 x OMe), 2.57 (b, 4H), 2.39 (b, 4H), 2.23(s, 3H, NMe). 20 Example 38 Preparation of 7-isopropoxy-6- Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1H indole C:W4RPonbl\DCC\ACGC351%6 1 DOC-25/05/2012 -97 MeO OMe MeO 0 MeO H OiPr Step A: 2-isopropoxy-3-methoxyaniline: To a solution of 2-nitroguaiacol (Thompson, M.J.; Zeegerers, P.J. Tetrahedron, 1990, 46, 2661; 0.5062g; 3 mmol) in anhydrous DMF (5 ml) K 2

CO

3 (0.41g; 3 mmol) was added and resulting mixture was stirred for 15 min under 5 reduced pressure and saturated with N 2 . To it, 2-bromopropane (1 ml; 10.6 mmol) was added and the reaction flask was sealed with septum and stirred overnight at 55 C. After evaporation of DMF under reduced pressure the residue was partitioned between diethyl ether (20 ml) and water (10 ml). The organic phase was washed with 2% aq. KOH (5 ml), brine, dried over anhydrous MgSO 4 . filtered off and filtrate evaporated to dryness. The 10 residue was dissolved in small volume of CH 2

CI

2 and filtered through short column with SiO 2 , which was eluded with fresh CH 2

CI

2 . The combined filtrates were evaporated to dryness under reduced pressure to give 2-isopropoxy-3-methoxynitrobenzene (0.62g; 98% yield) as creamy syrup. 'H-NMR(CDCl 3 ) 1.26 (d, 6H, J = 6.17 Hz); 3.87 (s, 3H); 4.61 (m, 1H, J = 6.17 Hz); 7.06 (m, 2H); 7.26 (m, IH). This was dissolved in ethanol (30 ml) and 15 the resulting mixture was degassed under reduced pressure. To it 10% Pd on carbon (0.22g) was added and the mixture was saturated with H 2 and stirred for 5h under the balloon pressure of H 2 . The catalyst was removed by filtration through Celite. The filtrate was evaporated to dryness to give the title compound (0.702g; 92.5% yield) as colourless oil. 'H-NMR(CDCl 3 ) 1.28 (d, 6H, J = 6.19 Hz); 3.7 broad s, 2H); 3.79 (s, 3H); 4.45 (m, 20 1 H, J = 6.19 Hz); 6.2 - 6.78 (m, 2H); 6.8(m, I H). Step B: 6-iodo-2-isopropoxy-3-methoxy-N-trifluoroacetylaniline: To a suspension of

CF

3

CO

2 Ag and the product of Step A (0.702g; 3.88 mmol) in CH 2

CI

2 (30 ml) 12 (0.99g: 3.88 mmol) was added at 0 0 C. After stirring for 30 min at 0C the reaction mixture was 25 filtered through Celite and filtrate washed with 5%aq Na 2

S

2 0 5 solution (2 x 15 ml), dried over anhydrous MgSO 4 , filtered off and filtrate evaporated to dryness to give the crude 2- C:NRPrnbJ\DCCACG4351%6_ DOC-25/05/2012 -98 iodo-2-isopropoxy-3-methoxyaniline, which was used without further purification. This (0.84g; 2.7 mmol) was dissolved in dry pyridine (5 ml) and to it trifluoroacetic anhydride (0.41 ml; 2.9 mmol) was added at room temperature. The resulting mixture was stirred for 2 h at room temperature and evaporated to dryness under reduced pressure. The residue 5 was purified by flash column chromatography (SiO 2 , hexane/ethyl acetate, 8:2) to give the title compound (0.675g; 61% yield) as a colourless crystals. 'H-NMR(CDCl 3 ) 1.21 (d, 6H, J = 6.16 Hz); 3.83 (s, 3H); 4.51(m, 1H, J = 6.16Hz); 6.69 (d, 1H, J = 8.86Hz); 7.51(d, 1 H, d, I H, J = 8.86 Hz); 7.67 (broad s, I H). 10 Step C: 2-isopropoxy-3-methoxy-6-(prop-1-ynyl)-N-trifluoroacetylaniline: A mixture of the product of Step B (0.275 g; 0.681 mmol), C1 2 Pd(PPh 3

)

2 (0.058 g; 0.083 mmol); CuI (0.025 g; 0.131mmol), anhydrous N,N-diisopropyl ethylamine (1 ml) in anhydrous DMF (5 ml) was cooled to -40"C, degassed under reduced pressure and saturated with dry N 2 . To it, propyne gas (0.5 g; 12.4 mmol) was added at -40'C. The reaction flask was sealed 15 with septum and allowed to warm up to room temperature and stirred overnight at room temperature than evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , hexane /ethyl acetate, 8:2) to give the title compound (0.171g; 79% yield) as creamy solid. 'H-NMR(CDCl 3 ) 1.21 (d, 6H, J = 6.16 Hz); 2.00 (s, 3H); 3.86 (s, 3H); 4.43 (in, 1 H, J = 6.16 Hz); 6.79 (d, I H, J = 8.67 Hz); 7.14 20 (d, I H, J = 8.67 Hz); 7.72 (broad s, 1 H). Step D: 7-isopropoxy-6- methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1H-indole: A mixture of the product of Step C (0.171 g; 0.54 mmol), 3,4,5-trimethoxyphenyl iodide (0.191 g; 0.65 mmol), CI 2 Pd(PPh 3

)

2 (0.044 g; 0.063 mmol); dry K 2

CO

3 (0.23 g; 1.62 25 mmol in anhydrous DMF (5 ml) was degassed under reduced pressure and saturated with CO gas. The resulting mixture was vigorously stirred overnight at room temperature under CO balloon, then diluted to 50 ml with ethyl acetate and washed with water (3 x 15 ml), brine and dried over anhydrous MgSO 4 , filtered off and filtrate evaporated to dryness. The residue was purified by flash column chromatography (SiO 2

CH

2

CI

2 /ethyl acetate, 9:1) to 30 give the title compound (0.143 g; 64 % yield) as a yellow solid. 'H-NMR(CDCl 3 ) 1.27 (d, 6H, J = 6.14 Hz); 2.51 (s, 3H); 3.79 (s, 6H); 3.85 (s, 3H); 3.90 (s, 3H); 4.69 (m, 1 H, J = C:RPonb\DCC\ACGW351966 1. DOC-2505/20I2 - 99 6.14 Hz): 6.76 (d, I H, J = 8.75 Hz); 7.04 (s, 2H); 7.11 (d, 1 H, J = 8.75 Hz); 8.83 (broad m, I H). Example 39 5 Preparation of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1H indole: MeO OMe MeO \ 0 MeO N H OH To a solution of the product of Step D of above Example 38 (0.055 g; 0.133 mmol) in 10 anhydrous CH 2 Cl 2 , TiC 4 (0.04 ml; 0.36 mmol) was added at 0"C. The resulting mixture was stirred for I h and quenched by addition of H 2 0 (3 ml). The two-phase mixture was diluted to 15 ml with CH 2 Cl 2 and organic phase separated, dried over anhydrous MgSO 4 , filtered off and filtrate evaporated to dryness. The residue was purified by flash column chromatography (SiO 2 ; CH 2 Cl 2 /ethyl acetate, 9:1) to give the title compound (0.0365 g; 74 15 % yield) as a yellow solid. 'H-NMR(CDCl 3 ) 2.54 (s, 3H); 3.81 (s, 6H); 3.88 (s, 3H); 3.92 (s, 3H), 5.65 (s, I H); 6.77 (d, I H, J = 8.71 Hz); 6.96 (d, I H, J = 8.71 Hz); 7.05 (s, 2H); 8.48 (s, 1 H). Example 40 20 Preparation of 3-(3,5-Dimethoxy-4-hydroxybenzoyl)- 7-hydroxy-6- methoxy-2 methyl-1H-indole: C\NRPrblDCC\ACG\4351%6_1 DOC-2505/OI2 -100 HO OMe MeO 0 MeO N H OH The title compound (0.003 g; 6.3% yield) was obtained as a by-product from the purification of Example 39, as a creamy solid. 'H-NMR (CDC 3 ) 2.58 (s, 3H); 3.85 (s, 6H); 3.9 (s, 3H); 5.67 (s, I H); 5.86 (s, I H) 6.75 (d, I H, J = 8.7 Hz); 6.94 (d, I H, J = 8.71 Hz); 5 7.12 (s, 2H); 8.47 (s, 1 H). Example 41 Preparation of 6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-7-tosyloxy 10 benzolblthiophene. MeO OMe MeO 0 MeO S OTs Step A: Benzyl 2-iodo-6-isopropoxy-5-methoxyphenyl sulfide: A mixture of the product of Step B, Example 37 (0.4 g; 1.16 mmol) in 20% solution of hydrazine in iPrOH (10 ml) was refluxed for 4 h under N 2 and evaporated to dryness under reduced pressure. The 15 residue was diluted to 30 ml with diethyl ether, washed with H 2 0 (2 x 5 ml), brine (10 ml), dried over anhydrous MgSO 4 , filtered and filtrate evaporated to dryness under reduced pressure to give 2-amino-3-isopropoxy-4-methoxy-iodobenzene (0.256 g; 71%) which was used without further purification. This was stirred with the mixture of H 2 0 (1.2 ml) and 48%HBF 4 (0.8 ml) for 15 min at room temperature. The resulting mixture was cooled to 20 0 0 C and NaNO 2 (0.069g; 1 mmol) in H 2 0 (0.5 ml) was added to it drop wise at 0 0 C during 10 min with stirring. This was allowed to warm up to room temperature and the precipitate C:NRPortblDCC\ACGU351966_I DOC-25/05/2012 - 101 filtered off, washed with H 2 0 (1 ml), diethyl ether (1 ml) and dried in vacuo to give relevant diazonium intermediate (0.23g; 69%). This was added portionwise to a solution of EtOC(S)SK (0.lg; 0.62 mmol) in acetone (1.5 ml) at 0*C during 10 min. After stirring for 30 min at 0 0 C, the stirring was continued for 45 min at room temperature and the mixture 5 was evaporated to dryness under reduced pressure. The residue was diluted to 15 ml with diethyl ether, washed with H 2 0 (10 ml), 2%KOH (2 ml), brine, dried over anhydrous MgSO 4 , filtered and filtrate evaporated to dryness under reduced pressure. The residue was dissolved in MeOH (2 ml) and KOH (0.3 g; 5.3 mmol) was added. After stirring for 1 h at room temperature the mixture was evaporated to dryness under reduced pressure and the 10 residue partitioned between CH 2 Cl 2 (2 ml) and H 2 0 (1 ml). Benzyl bromide (0.14 ml; 0.96 mmol) and n-Bu 4

NHSO

4 (0.05g; ) was added to it, and the resulting mixture was vigorously stirred for 1 h, diluted to 15 ml with CH 2 CI2. The organic phase was dried over anhydrous MgSO 4 , filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO 2 ; hexane/ethyl acetate 9.5: 0.5) 15 to give pure title compound (0.123g; 52%) as colourless syrup. 'H-NMR(CDCl 3 ) 1.33 (d, 6H, J = 6.18 Hz); 3.8 (s, 3H); 4.12 (s, 2H); 4.62 (m, 1H, J = 6.18 Hz); 6.58 (d, I H, J = 8.71 Hz); 7.14 -7.32 (m, 5 H); 7.5 (d, I H, J = 8.71 Hz). Step B: Benzyl 6-isopropoxy- 5-methoxy-2-(prop-1-ynyl)phenyl sulfide: A mixture of 20 the product of Step A (0.123 g; 0.296 mmol), CI 2 Pd(PPh 3

)

2 (0.040 g; 0.057 mmol), Cul (0.014 g; 0.073 mmol) in anhydrous triethylamine (3 ml) was cooled to -40'C, degassed under reduced pressure and saturated with dry N 2 . The propyne gas (0.45 g; 11.2 mmol) was added to it at -40'C. The reaction flask was sealed with septum and allowed to warm up to room temperature and stirred for 3h at room temperature and diluted to 20 ml with 25 diethyl ether and solid precipitated, filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue, purified by flash column chromatography (SiO 2 , hexane, hexane /ethyl acetate, 9:1) to give the title compound (0.065g; 67% yield) as colourless syrup. 'H-NMR(CDCl 3 ) 1.26 (d, 6H, J = 6.17 Hz); 2.09 (s, 3H); 3.79 (s, 3H); 4.2 (s, 2H); 4.44 (m, IH, J = 6.17 Hz); 6.73 (d, 1 H, J = 8.53 Hz); 7.12 (d, I H, J = 8.53 Hz); 30 7.15 - 7.4 (m, 5H).

C:WRPOnblDCC\ACGM35L%6_ LDOC-25/05/2012 - 102 Step C: 3-Iodo-7-isopropoxy-6-methoxy-2-methylbenzo[blthiophene: When the product of Step B was substituted for benzyl 5-methoxy-2-(prop-1-ynyl)phenyl sulfide in Step B of Comparator D, the identical process provided the title compound in 67 % yield, as a heavy colourless syrup. 'H-NMR(CDC 3 ) 1.32 (d, 6H, J = 6.14 Hz); 2.53 (s, 3H); 3.9 5 (s, 3H); 4.69 (m, IH, J = 6.14 Hz); 7.07 (d, I H, J = 8.66 Hz); 7.28 (d, I H, J = 8.66 Hz). Step D: 7-Isopropoxy-6-methoxy-2-methylbenzo[bjthiophene: When 3-iodo-7 isopropoxy-6-methoxy-2-methylbenzo[b]thiophene was substituted for 3-iodo-6-methoxy 2-methylbenzo[b]thiophene in Step C of Comparator D, the identical process provided the 10 title compound in 67 % yield, as a heavy colourless syrup. . 'H-NMR(CDCl 3 ) 1.33 (d, 6H, J = 6.14 Hz); 2.51 (s, 3H); 3.88 (s, 3H); 4.69 (m, 1H, J = 6.14 Hz); 6.84(, 1H); 6.96 (d, I H, J = 8.51 Hz); 7.27 (d, I H, J = 8.51 Hz). Step E: 6-methoxy-2-methyl-7-tosyloxy-benzolblthiophene: To a mixture of the product 15 of Step D (0.033g; 0.0941 mmol) in CH 2 Cl 2 ( ml) TiCl4 (0.02 ml; 0.182 mmol) was added at room temperature under N 2 . After stirring for 10 min at room temperature, the mixture was diluted tol5 ml with CH 2

CI

2 and quenched with H 2 0 (5 ml) and the organic phase was dried over anhydrous MgSO 4 , filtered and filtrate evaporated to dryness under reduced pressure to give 7-hydroxy-6-methoxy-2-methyl-benzo [b]thiophene (0.0256g; 20 100%). This was diluted to 1.ml with CH 2 Cl 2 and tosyl chloride (0.03g; 0.158 mmol), followed by triethylamine 0.022 ml; 0.158 mmol) of were added to it. The resulting mixture was stirred for I h at room temperature, washed with H 2 0, dried over anhydrous MgSO 4 , filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by crystallization from hexane/ethyl acetate mixture (9.5:0.5) to give the title 25 compound (0.035g; 68%), as creamy crystals. 'H-NMR (CDCl 3 ) 2.45 (s, 3H); 2.48 (s, 3H); 3.63 (s, 3H); 6.83 (s, 1H); 7.32 (d, 2H, J = 8.27 Hz); 7.43 (d, 1H, J = 8.62 Hz), 7.87 (d, 2H, J = 8.62 Hz). Step F: 6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-7-tosyloxy 30 benzo bithiophene: When 6-methoxy-2-methyl-7-tosyloxy-benzo[b]thiophene was substituted for 6-methoxy-2-methylbenzo[b]thiophene in Step D of Comparator C, the C :\NPonbl\DCC\ACG\4351%6_L.DOC-2I5/0O 2 - 103 identical process provided the title compound in 68 % yield, as a heavy colourless syrup. 'H-NMR(CDCl 3 ) 2.42 (s, 3H); 2.46 (s, 3H); 3.61 (s, 3H); 3.82 (s, 6H); 3.93 (s, 3H): 6.91 (d, IH, J = 8.87 Hz); 7.09 (s, 2H); 7.34 (d, 2H, J = 8.19 Hz), 7.43 (d, 1H, J = 8.87 Hz); 7.88 (d, 2H, J = 8.19 Hz). 5 Example 42 Preparation of 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5 trimethoxybenzoyl)benzo[b Ithiophene. MeO OMe MeO 0 MeO S 10 OH A mixture of the product of Example 41 (0.035g; 0.00645mmol) in THF (0.5 ml) and 1%NaOH in MeOH (0.52 ml; 0.0129 mmol) was stirred overnight at 30 0 C under N 2 and acidified with the drop of CF 3

CO

2 H. This was evaporated to dryness and diluted to 15 ml with diethyl ether, washed with 0.1 M HCl (2 ml), 5%NaHCO 3 (2 ml), brine, dried over 15 anhydrous MgSO 4 , filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO 2 , CH 2 Cl 2 ) to give pure title compound ( 0.007g; 28%), as a colourless crystals. 'H-NMR(CDCl 3 ) 2.47 (s, 3H); 3.83 (s, 6H); 3.92 (s, 6H); 5.94 (s, I H); 6.93 (d, I H, J = 8.69 Hz); 7.05 (d, I H, J = 8.69 Hz); 7.1 (s, 2H). 20 Example 43 Preparation of 2-[(N-Methyl-2-amino-aceticacid methyl ester)-methenyl)-3-(3,4,5 trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzoIb]furan: C:WRPortbl\DCC\ACG\4351%6_1 DOC-2505/2O2 -104 MeO OMe MeO 0 MeO O 0 N OH MeO A mixture of 2-bromomethyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-acetoxy benzo[b]furan Example 33 (185 mg, 0.38 mmol) and sarcosine-methyl-ester hydrochloride(156 mg, 1.11 mmol) in a mixture of dry DMF: DIEA (3 mL: 0.5 mL) was 5 stirred at room temperature for overnight (tlc). The solvent was distilled and the crude residue was dissolved in THF (1 mL) and dimethylamine (0.5 mL, excess) was added to it and stirred for 2 hours at room temperature. The solvent was distilled and the crude product was purified over silica gel column to gave the product as a light yellow paste (132 mg, 75%). 'H NMR (300 MHz, CDCl 3 ) 6- 7.13(s, 2H, benzoyl Hs), 6.85(s, 2H, Ar-Hs), 10 4.02 (s, 2H), 3.93 (s, 6H, 2 x OMe), 3.81 (s, 6H, 2 x OMe), 3.64 (s, 3H, OMe), 3.88 (s, 2H), 2.45 (s, 3H, NMe). Example 44 15 Preparation of 2-[(N-Methyl-2-amino-aceticacid)-methenyl)-3-(3,4,5 trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo [b] furan: MeO OMe MeO 0 MeO O 0 N OHO HO The ester Example 43 above (120 mg, 0.25 mmol) was dissolved in THF:water (3 mL; 2:1), solution of LiOH (12 mg, 0.5 mmol in 0.25 mL of water) was added to it and the 20 mixture was stirred for 3 hours at room temperature. The solvent was distilled to I mL and diluted with dichloromethane (10 mL). Tri-fluro acetic acid (40 pL, 0.52 mmol) was added C WRPortbl\DCC\CGM 351%6_ I DOC-25/5202 - 105 when the compound went into dichloromethane making the solution yellow colored. The organic layer was separated, dried over magnesium sulphate and solvent was distilled to gave the product as light yellow solid which was crystalized from hexane/DCM to gave the dirty colored solid (66 mg, 57%). 'H NMR (300 MHz, CDCl 3 ) 6- 7.10(s, 2H, benzoyl Hs), 5 7.07(d, J= 8.62 Hz, I H), 6.63(d, J= 8.58 Hz, I H), 4.69(s, 2H), 4.00(s, 2H), 3.92(s, 3H, OMe), 3.82(s, 3H, OMe), 3.76(s, 6H, 2 x OMe), 2.96(s, 3H, NMe). Example 45 10 Preparation of 2-N-(Aminoethanesulphonamide)-3-(3,4,5-trimethoxybenzoyl)-6 methoxy-7-hydroxy-benzo [b] furan: MeO OMe MeO 0 | ' NH MeO 0 0 OH 0 "

NH

2 When benzyl-amine was substituted with aminoethane sulphonamide. HCl as in Example 19 step I the identical procedure afforded the title compound as a yellow solid (25 mg, 15 25%) along with 2-amino-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-hydroxy benzo[b]furan (Example 19 27 mg, 35%). 'H NMR (300 MHz, CDCl 3 ) 6- 9.21(bs, IH, NH), 6.94(s, 2H, benzoyl Hs), 6.62(d, J= 8.61 Hz, I H), 6.5 1(d, J= 8.47 Hz, I H), 5.1(b, 2H), 4.15(q, 2H, J= 12.32, 6.38 Hz), 3.91(s, 3H, OMe), 3.86(s, 3H, OMe), 3.83(s, 6H, 2 x OMe), 3.54(t, 2H, J= 6.18 Hz). 20 Example 46 Preparation of 3-(4-Hydroxy-3,5-di-methoxy-benzoyl)-7-hydroxy-6-methoxy-2 Methyl-benzo[b]furan: C:Pobl\CC \ACG4351%6_.DOC-2/05/2012 - 106 HO OMe MeO 0 MeO O OH 2-Methyl-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6-methoxy-benzo[b]furan Example 11 (100 mg, 0.27 mmol) was dissolved in dry dichloromethane (5 mL) and solid aluminium trichloride (72 mg, 0.54 mmol) was added to it. The mixture was stirred for 2 hours when 5 additional amount of aluminium trichloride (72 mg, 0.54 mmol) was added and the stirring was continued for 2 more hours (tlc). The reaction was quenched with saturated solution of ammonium chloride and diluted with DCM (20 mL) the organic layer was separated and washed with water, dried over magnesium sulphate and solvent was distilled to gave the crude product which was purified over silica gel column. The compound was crystallized 10 from methanol to gave the product as white solid. (42 mg, 44%). 'H NMR (300 MHz, CDCl 3 ) 6 7.16 (s, 2H, benzoyl Hs), 6.91 (d, J= 8.58 Hz, I H), 6.83 (d, J= 8.58 Hz, I H), 5.94 (s, 1 H, OH), 5.68 (s, I H, OH), 3.91 (s, 3H, OMe), 3.87 (s, 6H, 2 x OMe), 2.54 (s, 3H, Me). 15 Example 47 Further Alternative Method for the Preparation of 2-Methyl-3-(3,4,5 trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo [b] furan by Multi-component Coupling: 20 Step 1: 2 -Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy benzolbifuran: To a stirred solution of 2-isopropoxy-3-methoxy-6-iodophenol (308 mg, 1.00 mmol) in dry tetrahydrofuran (2 mL) was added dropwise a solution of 1-propynyl magnesium bromide 25 (5, 6 mL, 3 mmol, 0.5 M solution in THF) at 0 0 C under nitrogen. Dichloro-bis triphenylphosphine palladium catalyst (40 mg, 0.06 mmol) was added and the reaction C :NRPorbnDCC\ACG4351%6_.DOC-25W5/2012 - 107 mixture was heated to 70 0 C for 3 hours (tic). The solvent was removed under vacuum and the residue was dried under vacuum. Dry dimethylsulfoxide (8 mL) was added and the nitrogen atmosphere was replaced with carbon monoxide. 3,4,5-Trimethoxyiodobenzene 6 (310 mg 1.05 mmol) was added and the reaction mixture was stirred at 90 C for 17 hours 5 and then quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2 x 25 mL). The organic layer was washed with water and dried over magnesium sulphate. The crude product was purified by flash chromatography (silica gel, eluent = hexane/diethyl ether; 8:2-7:3) to afford the title compound as a creamy white solid. The product was crystallized from methanol. Yield - 290 mg, 70%; 'H NMR (300 MHz, 10 CDCl 3 ) 6- 7.10(s, 2H, benzoyl Hs), 7.07(d, IH), 6.85(d, I H, J= 8.57), 4.74 - 4.68(m, IH), 3.93(s, 3H, OMe), 3.87(s, 3H, OMe), 3.83(s, 6H, 2 x OMe), 2.52(s, 3H, Me), 1.37(d, 6H, J= 6.18 Hz). Step 2: 2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[b] furan: 15 To a stirred solution of 2-methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-isopropoxy benzo[b]furan (30 mg, 0.073 mmol) at 0 "C in dry dichloromethane (I mL) was added boron trichloride solution (IM solution in DCM, 73 pL, 0.073 mmol) and reaction mixture was warmed to room temperature and the stirring was continued for 2 hours (tlc). The reaction mixture was quenched with saturated ammonium chloride solution and diluted 20 with dichloromethane (5 mL). the organic layer was separated and dried over magnesium sulphate. The solvent was distilled to gave the crude product as off white colored crystalline solid which was re-crystallized from methanol to gave the product as white crystalline material. Yield - 25 mg, 93% (Note 1). 1H NMR (300 MHz, CDCl 3 ) 6- 7.09(s, 2H, benzoyl Hs), 6.93(d, IH, J= 8.54 Hz), 6.83(d, IH, J= 8.56 Hz), 5.70(bs, IH, OH), 25 3.93(s, 3H, OMe), 3.92(s, 3H, OMe), 3.83(s, 6H, 2 x OMe), 2.54(s, 3H, 2-Me). Note: A similar reaction when scaled-up with 2-methyl-3-(3,4,5-trimethoxybenzoyl)-6 methoxy-7-isopropoxy-benzo[b]furan (1.25 gm) and boron trichloride solution (IM solution in DCM, 3.1 mL) gave the title compound (930 mg, 83%). 30 C:NRPortbl\DCCWCG\4351%6_ I.DOC-25S//2012 - 108 Example 48 Further Alternative Method for the Preparation of 2-Methyl-3-(3,4,5 trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[bJfuran by Friedel-Crafts 5 Acylation: Step 1: 2-Methyl-7-hydroxy-6-methoxy-benzo [b] furan: The solution of 3-iodo-6-methoxy-1,2-phenylene diacetate [(prepared by the iodination of diacetylglucinol with I2 and CF 3

CO

2 Ag (1 gm, 2.86 mmol) 'H NMR (300 MHz, CDCl3) 10 8- 7.59(d, IH, J = 8.88 Hz), 6.66(d, IH, J = 8.94 Hz), 3.81(s, 3H, OMe), 2.34(s, 3H), 2.27(s, 3H)] in a mixture of DMF/diisopropylethylamine (12 mL: 1.5 mL) was degassed with nitrogen gas and the solution was cooled to -40 *C. Propyne gas (app wt. 3 gm, excess) was passed through this stirred solution over a period of 30 minutes. To this mixture was added Pd(PPh) 2 Cl 2 (120 mg) followed by the addition of the copper (I) 15 iodide (40 mg) and the mixture was allowed to come to room temperature and stirred for additional 40 hours (tic). To this solution was added di-methyl-amine (4 mL, IM solution in THF) and the mixture was stirred for another 18 hours at room temperature. The solvent was distilled in vacuum and the residue was taken in ethyl-acetate (50 mL). The organic layer was washed with water, dried over magnesium sulphate and the solvent was distilled 20 to give the crude compound which was characterized as such by NMR. 'H NMR (300 MHz, CDC1 3 : D 2 0 exchange) 8- 6.82(d, I H, J = 8.58 Hz), 6.39(d, I H, J = 8.60 Hz), 3.85(s, 3H, OMe), 2.08(s, 3H, Me). The above crude product was dissolved in dry THF (6 mL) and TBAF (1 mL, 1 M solution 25 in THF) was added to it and the mixture was stirred with refluxing for 8 hours. Solvent was distilled in vacuum and the residue was dissolved in DCM (20 mL) and washed with I M HCl solution. The organic layer was separated, dried over magnesium sulphate and the crude was purified over silica gel column (eluent = Hexane: di-ethyl-ether; 100:0 to 60:40) to give the pure product (17) as light cream paste (390 mg, 77%). 'H NMR (300 MHz, 30 CDCl 3 : D 2 0 exchange) 6- 6.89(d, 1 H, J = 8.37 Hz), 6.39(d, I H, J = 8.38 Hz), 6.26 (s, 1H, 3H), 5.61(bs, I H, OH), 3.91(s, 3H, OMe), 2.42(s, 3H, Me).

C WRPorbnDCC\ACCW 351%6_ DOC-2$05/2012 -109 Step 2: 2-Methyl-6-methoxy-7-(4-toluylsulphonate)-benzo [b] furan: 2-Methyl-7-hydroxy-6-methoxy-benzo[b]furan, from Step I above, (180 mg, 1 mmol) was dissolved in dry pyridine (2 mL) and p-toulene-sulphonyl-chloride (228 mg, 1.2 mmol) 5 and the mixture was stirred at 80 *C for 6 hours. Solvent was distilled and the crude was taken in ethyl-acetate (15 mL) and washed with water. The organic layer was dried over the magnesium sulphate and solvent was distilled to gave the crude which was purified over silica gel column (eluent = Hexane:ethyl-acetate:dieth-ylether; 80:0:20 to 70:10:20) to gave the compound (3, 128 mg, 39% + starting material) as light yellow paste solidify on 10 standing at room temperature. 'H NMR (300 MHz, CDC1 3 : D 2 0 exchange) 8- 7.84(d, 2H, J= 7.71 Hz), 7.29(d, 2H, J = 8.05 Hz), 7.21(d, 1H, J = 8.49 Hz), 6.78(d, IH, J = 8.47 Hz), 6.22(s, 1 H, 3H), 3.69(s, 3H, OMe), 2.42(s, 3H, Me), 2.25(s, 3H, Me). Step 3: 2-Methyl-3(3,4,5-trimethoxybenzoyl)-6-methoxy-7-(4-methyl-benzene 15 sulphonate)-benzolblfuran: 2-Methyl-6-methoxy-7-(4-methylbenzenesulphonate)-benzo[b]furan, from Step 2 above (65 mg, 0.2 mmol) was dissolved in dry dichloromethane (2 mL) and 3,4,5-trimethoxy benzoyl-chloride (55 mg, 0.24 mmol) followed by the addition of tin(II) chloride (28 IL, 0.24 mmol) and the mixture was stirred at reflux for 8 hours, more acid chloride (20 mg) 20 and reaction was continued for another 6 hours (tlc). Reaction was diluted with dichloromethane (15 mL) and organic layer was washed with sodium bicarbonate solution. The organic layer was separated, dried over the magnesium sulphate and solvent was distilled to gave the crude which was purified over silica gel column (eluent = Hexane:diethyl ether; 80:0 to 70:30) to gave the product (70 mg, 68%) as light yellow 25 solid. 'H NMR (300 MHz, CDCl 3 : D 2 0 exchange) 8 7.86 (d, 2H, J= 8.31 Hz), 7.34-7.22 (overlapping doublets, 3H), 7.06 (s, 2H, benzoyl H), 6.83 (d, 1H, J = 8.73 Hz), 3.93 (s, 3H, OMe), 3.84 (s, 6H, 2 x OMe), 3.68(s, 3H, OMe), 2.46 (s, 3H, Me), 2.39 (s, 3H, Me). Note: The same reaction was run by using 240 mg of starting benzofuran, acid chloride 254 mg, tin (IV) chloride 101 uL. (Yield = 297 mg, 78%). 30 C \NRPorbI\DCC\ACG\4351%6_l.DOC-2$/05/20 12 -110 Step 4: 2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-hydroxy-benzo[bifuran (Example 11): 2-Methyl-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7-(4-methyl-benzene-sulphonate) benzo[b]furan, from Step 3 above, was dissolved in a mixture of solvent (THF/MeOH; 4 5 mL: 10 mL) and sodium hydroxide (32 mg) was added to it and the mixture was stirred with refluxing for 6 hours. The solvent was distilled and the crude was taken in dichloromethane (20 mL) and washed with water (20 mL x 2). The organic layer was separated and dried over magnesium sulphate and the solvent was distilled. The crude product was purified over silica gel column to give the product (150 mg, 76%). 10 Example 49 Alternative Method for the Preparation of Example 29 using POC1 3 : 15 To a solution of freshly distilled POC1 3 (0.125 ml; 1.34 mmol) in anhydrous CH 2 Cl 2 (1 ml) a mixture of Example 11 (0.2 g; 0.54 mmol) and triethylamine ( 0.12 ml; 0.86 mmol) in anhydrous CH 2 Cl 2 (I ml) was added dropwise at -5 to 0C under N 2 with stirring. After stirring for 10 minutes at 0*C, the mixture was evaporated to dryness under reduced pressure. The residue was suspended in anhydrous toluene (2 ml), stirred for 5 minutes at 20 room temperature and evaporated to dryness under reduced pressure. The residue was kept in vacuo for 30 minutes and then resuspended in acetonitrile (2 ml). This was added at once to 0.5 M aqueous NaOH (5 ml). The resulting mixture was evaporated to dryness under reduced pressure and the residue was suspended in water (2.ml). After adjusting the pH of the solution to -10 with 0.5 M NaOH, the resulting solution was filtered through 25 Whatman glass microfibre filter to remove any traces of solid material. The filtrate was concentrated to about 0.5 ml and acidified to pH - 1 with concentrated HCl. To facilitate the removal of water and the excess of HCI the mixture was repeatedly diluted to 5 ml with acetonitrile and evaporated to dryness (x 3), followed by dilution with CH 2 Cl 2 and evaporation. The residue formed, was kept in vacuo for 30 minutes and suspended in 30 methanol /CH 2 Cl 2 mixture (5 : 95; 10 ml) (NOTE 2) and insoluble NaCl was filtered off. The filtrate was evaporated to dryness and the crystalline residue was washed with CANRPonb\DCCACOU35%6_1 DOC-25/02012 - 111 hexane/CH 2 Cl 2 mixture (1:1; 10 ml) and dried to give free acid as a slightly creamy solid (0.209g; 87%). 'HNMR (CDCl 3

/CD

3 0D 1:1) 2.5 (s, 3H); 3.29 (m, CD 3 0D); 3.8 1(s, 6H); 3.87(s, 3H); 3.88(s, 3H); 4.6(s, HDO); 6.91(d, 1H, J = 8.7 Hz); 7.08(s, 2H); 7.12(d, IH, J = 8.7Hz); 7.55(s, CDC 3 ); LC, retention time = 1.19 min (+99%); MS 452.8 (MH 2 +1). The 5 free acid was suspended in methanol (2 ml) and the pH of the resulting suspension was adjusted to -10 by addition of 0.5 M NaOH. During this process the mixture gradually become homogenous. This was concentrated to about I ml and the product was precipitated by the addition of acetonitrile (10 ml). The solid was washed with fresh acetonitrile, anhydrous ethyl ether and dried in vacuo until constant mass to give 0.215 g of 10 pure title compound (94% yield) as a creamy solid. 'HNMR (D 2 0) O 7.09 (s, 2H), 7.02 (d, 1H, J= 8.68 Hz), 6.91 (d, I H, J= 8.68 Hz), 4.66 (HDO), 3.8 (s, 3H), 3.79 (s, 3H), 3.75 (s, 6H), 2.36 (s, 3H). LC, retention time = 1.19 (+99%). MS 452.8 (MH 2 -2Na + 1). Anal. Calculated for C 20

H

19 Na 2 OIOP x 0.5 H 2 0: Na 9.10%; P 6.13%; Found Na 9.09%; P 9.26%. 15 Example 50 (Comparator F) Preparation of 6- Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)-1H-indole: MeO OMe MeO MeO \N 20 A mixture of 2-iodo-5-methoxy-N-trifloroacetylaniline (Flynn et al, J.Med.Chem., 2002, 45(12), 2670; 0.508 g; 1.5 mmol), CI 2 Pd(PPh 3

)

2 (0.102 g; 0.145 mmol); Cul (0.016 g; 0.085mmol), anhydrous N,N-diisopropyl ethylamine (1 ml) in anhydrous DMF (10 ml) was cooled to -40'C, degassed under reduced pressure and saturated with dry N 2 . The propyne gas (0.53g; 13.3 mmol) was added to it at -40 0 C. The reaction flask was sealed 25 with septum and allowed to warm up to room temperature and stirred for 3 h. After removal of excess of propyne under reduced pressure 3,4,5-trimethoxyphenyl iodide (0.5 g; 1.7 mmol) was added to it, followed by dry K 2

CO

3 (0.621g; 4.5 mmol). The resulting C RPortb\CC\ACG\43596I DOC-2505/202 -112 mixture was degassed in vacuo and saturated with CO gas and stirred for 3 h under CO balloon pressure. The mixture was diluted to 50 ml with diethyl ether, washed with H 2 0 (2 x 15 ml), brine (10 ml), dried over anhydrous MgSO 4 , filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography 5 (SiO 2 ; CH 2 Cl 2 ) to give pure title compound ( 0.295g; 55%) as a yellow crystals: 'H-NMR(CDCl 3 ) 2.52 (s, 3H,); 3.8 (m, 9H); 3.91 (s, 3H); 6.73 (dd, 1 H, J = 2,22, 8.75 Hz); 6.79 (d, 1H, J = 2.22 Hz); 7.06 (s, 2H); 7.35 (d, I H, J = 8.75 Hz); 8.6 (broad s, I H, NH). Example 51 (Comparator G) 10 Preparation of 6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzolblthiophene: OMe MeO MeO\/ 0 MeO S Step A: Benzyl 5-methoxy-2-(prop-1-ynyl)phenyl sulfide: 15 When benzyl 2-iodo-5-methoxyphenyl sulfide (Flynn et al, Org. Lett. 2001, 3(5), 651) was substituted for 6-iodo-2-isopropoxy-3-methoxy-N-trifluoroacetylaniline in Step C of Example 38 and reaction time was extended to 72 h, the similar process provided the title compound in 69% yield as a creamy solid. 'H-NMR (CDC 3 ) 2.1 (s, 2H); 3.7 (s, 3H); 4.17 (s, 2H); 6.61 (dd, IH, J = 2.53, 8.5 Hz); 6.72 (d, I H, J = 2.53 Hz); 7.2 - 7.33 (m, 5H); 7.38 20 (d, I H, J = 8.5 Hz). Step B: 3-Iodo-6-methoxy-2-methylbenzoIbithiophene: To a solution of the product of Step A (0.156 g; 0.58 mmol) in CH 2

CI

2 I ml) 12 (0.147g: 0.58 mmol) was added and the mixture was stirred for I h at room temperature, then 25 washed with 5%aq Na 2

S

2 0 5 solution (2 x 5 ml), dried over anhydrous MgSO 4 , filtered off and filtrate evaporated to dryness to give the crude 2-iodo-2-isopropoxy-3-methoxyaniline, which was purified by flash column chromatography (SiO 2 , hexane, hexane/ethyl acetate 9.5 : 0.5) to give the title compound (0.0863 g; 47 %) as colourless syrup. 'H- CA WonbDCCXCG&3 51966_1 DOC.2 55t212 -113 NMR(CDCl 3 ) 2.58 (s, 3H); 3.85 (s, 3H); 6.99 (dd, IH, J = 2.33, 8.8 Hz); 7.19 (d, I H, J = 2.33 Hz); 7.51 (d, I H, J = 8.8 Hz). Step C: 6-Methoxy-2-methylbenzoIblthiophene: 5 t-BuLi (1.7 M in pentane; 0.32 ml; 0.54 mmol) was added to a solution of the 3-iodo-6 methoxy-2-methylbenzo[b]thiophene (0.0863 g; 0.27 mmol) in anhydrous THF (2.5 ml) at -78*C under N 2 . The mixture was allowed to warm up to 0 0 C and quenched by the addition of saturated NH 4 CI (1 ml). This was diluted to 15 ml with diethyl ether and washed with 5%NaHCO 3 (10 ml), dried over anhydrous MgSO 4 , filtered off and filtrate 10 evaporated to dryness. The residue was purified by flash column chromatography (SiO 2 , hexane, hexane/ethyl acetate 9.5 : 0.5) to give the title compound (0.024 g; 50 % yield) as colourless solid. 'H-NMR (CDCl 3 ) 2.53 (s, 3H); 3.84 (s, 3H); 6.86 (s, 1 H); 6.92 (dd, 1 H, J = 2.24, 8.87 Hz); 7.222 (d, I H, 1= 2.24 Hz); 7.51 (d, I H, J = 8.67 Hz). 15 Step D: 6-Methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzoIbithiophene: To a mixture of 6-methoxy-2-methylbenzo[b]thiophene (0.024 g; 0.132 mmol) and 3,4,5 trimethoxybenzoyl chloride (0.052 g; 0.225 mmol) in 1,2-dichloroethane (1 ml) SnCl 4 (0.023 ml) was added. The resulting mixture was stirred for I h at 40'C, quenched with

H

2 0 (1 ml), diluted to 15 ml with diethyl ether, washed with 5% NaHCO 3 (5 ml), brine (10 20 ml), dried over anhydrous MgSO 4 , filtered and filtrate evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO 2 ; hexane/ethyl acetate 9:1) to give pure title compound ( 0.020g; 41%) as a colourless crystals. 'H NMR(CDCl 3 ) 2.47 (s, 3H); 3.8 (s, 6H); 3.84 (s, 3H); 3.93 (s, 3H); 6.90 (dd, I H, J = 2.4, 8.89 Hz); 7.1 (s, 2H); 7.24 (d, I H, J = 2.4 Hz); 7.42 (d, 1H, J = 8.89 Hz). 25 Example 52 Preparation of 3-(3,5-Dimethoxybenzoyl)-7-hydroxy-6-methoxybenzo Ib] furan: C WnRPortbnDCACG A351%6_1.DOC-25S05/2Ol2 -114 OMe MeO 0 MeO 0 OH Step 1: 2 -t-Butyldimethylsilanyl-3-(3,5-dimethoxybenzoyl)-6-methoxy-7-isopropoxy benzolblfuran: When 3,4,5-trimethoxyiodobenzene was replaced by 3,5-di 5 methoxyiodobenzene as in Example 4 (step 3) the identical procedure afforded the title compound as a light yellow paste (102 mg, 49%). 'H NMR (300 MHz, CDC 3 ) 6 7.00 (d, J = 2.32 Hz, 2H), 6.81 (d, J= 8.30 Hz, 1 H), 6.71 (d, J= 8.61 Hz, 1H), 6.67 (t, J= 2.31 Hz, IH), 4.74 (m, IH), 3.86 (s, 3H, OMe), 3.78 (s, 6H, 2 x OMe), 1.38 (d, 6H, J= 6.16 Hz), 1.0 1(s, 9H), 0.27(s, 6H). 10 Step 2: 3-(3,5-Dimethoxybenzoyl)-6-methoxy-7-isopropoxy-benzo [bifuran: The procedure same as in Example 6 (Step 1) afforded the title compound (57 mg, 83%). 'H NMR (300 MHz, CDCl 3 ) 5 8.02 (s, 1 H, C 2 H), 7.82 (d, I H, J = 8.59 Hz), 7.04 (d, J = 8.63 Hz, 1H), 6.99 (d, J= 2.31 Hz, 2H), 6.67 (t, J= 2.30 Hz, IH), 4.71 (m, I H), 3.91 (s, 3H, 15 OMe), 3.83 (s, 6H, 2 x OMe), 1.36 (d, 6H, J = 6.15 Hz). Step 3: 3-(3,5-Dimethoxybenzoyl)-7-hydroxy-6-methoxybenzo Ib Ifuran: The procedure same as in Example 6 (Step 2) afforded the title compound as a creamy crystalline solid (21 mg, 49%). 'H NMR (300 MHz, CDC 3 ) 6 8.05 (s, I H, C 2 H), 7.69 (d, J= 8.56 Hz, I H), 20 7.02 (d, J= 8.59 Hz, 1H), 6.99 (d, J= 2.03 Hz, 2H), 6.67 (broad t, I H), 5.70 (broad s, 1 H, OH), 3.97 (s, 3H, OMe), 3.83 (s, 6H, 2 x OMe); 3 C NMR (75 MHz, CDCI3) S 189.48(CO), 160.50, 152.09, 144.56, 143.32, 140.79, 130.84, 120.87, 120.48, 112.53, 109.22, 106.27, 104.28, 56.84, 55.25. 25 C:\NRPortbhDCC\ACG\4351%6I DOC-25/05/2O12 - 115 Example 53 Preparation of 3-(Pentafluorobenzoyl)-6-methoxy-7-hydroxybenzo [b] furan: F F F F F O MeO 0 5 OH Step 1: 2 -t-Butyldimethylsilanyl-3-(pentafluorobenzoyl)-7-isopropoxy-6 methoxybenzolbifuran: When 3,4,5-trimethoxyiodobenzene was replaced by pentafluoroiodobenzene as in Example 4 (step 3) the identical procedure was used for 10 nucleophilic addition, however, the oxidation step was different and was as follow [180 mg of the crude material obtained was co-distilled with toluene and dissolved in dry dichloromethane (5 mL) and pyridine-dichromate (266 mg, 0.71 mmol) was added to in portions and the reaction mixture was stirred for overnight (tlc). The solution was diluted with dichloromethane, solvent was decanted and washed with water. The organic layer was 15 separated, dried over magnesium sulphate and the solvent was distilled to give the crude product, which was purified over silica gel column to afford the title compound as a light yellow paste (156 mg, 35%)] 'H NMR (300 MHz, CDCl 3 ) 6 6.82 (d, J = 8.67 Hz, IH), 6.31 (d, J= 8.64 Hz, IH), 4.71 (m, 1 H), 3.86 (s, 3H, OMe), 1.37 (d, 6H, J= 6.15 Hz), 1.03 (s, 9H), 0.42 (s, 6H). 20 Step 2: 3-(Pentafluorobenzoyl)-6-methoxy-7-isopropoxy-benzoIbIfuran: The procedure same as in Example 6 (Step 1) afforded the title compound as a light yellow paste (31 mg, 83%). 'H NMR (300 MHz, CDCl 3 ) 6 7.89 (s, I H, C 2 H), 7.83 (d, J= 8.58 Hz, 1 H), 7.07 (d, J= 8.61 Hz, 1 H), 4.69 (m, 1 H), 3.93 (s, 3H, OMe), 1.35 (d, 6H,J= 6.16 Hz). 25 C:\NRPOrbI\DCC\ACGN435196_I DOC-25/05/2012 -116 Step 3: 3-(Pentafluorobenzoyl)-6-methoxy-7-hydroxybenzoIbifuran: The procedure same as in Example 6 (step 2) afforded the title compound as a creamy crystalline solid (21 mg, 63%). 'H NMR (300 MHz, CDCl 3 ) 6 7.93 (s, 1H, C 2 H), 7.70 (d, J= 8.55 Hz, 1H), 7.05 (d, J= 8.56 Hz, 1H), 5.73 (bs, 1H, OH), 3.98 (s, 3H, OMe). 5

Claims (29)

1. A compound of formula (I) or a salt thereof; R 2 D R 2 C R 2 E / \ R 2 B RIA L R 2 A RIB Q RICK x 5 RID wherein; X represents 0, S, SO, SO 2 , Se, SeO, Se0 2 or NR where R is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally 10 substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl; R A and RIB each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, 15 sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally 20 substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, 25 optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted C :NPor1thDCCACG4351%6_1 DOC-255l2012 - 118 oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally 5 substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, optionally substituted thioacylamino, or R IA and RIB together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; 10 Ric represents CI. 3 alkoxy, CI. 3 alkylthio, CI. 3 alkylamino, or CI. 3 dialkylamino; R represents hydroxy or amino; 15 L represents C=0, 0, S, SO, S02, Se, SeO, Se0 2 , C=NZ', or NR' where Z' is H, optionally substituted alkyl, optionally substituted aryl or optionally substituted amino; and where R' is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally 20 substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted sulfonyl; R 2 A-R 2 E each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, 25 trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally 30 substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally C.V4RPo~bPflCCXACGX4 3 5966_ 1. DDC-23/Ot20 12 -119 substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally 5 substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacylimino, optionally substituted oxyacyloxy, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally 10 substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, optionally substituted thioacylamino, or optionally substituted 2A 2B B2C 2 21 thioacyloxy; or any of R and R , R2B and R 2 C, Rc and R2, and R2D and R 2 E, together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally 15 substituted cycloalkenyl; and Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally 20 substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acyl and optionally substituted oxyacyl, or NR"'NR"', where each R"' independently represents H, 25 optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl.

2. A compound of formula (Ia) or a salt thereof; C:\NRPonbDCCACG\435196_.DOC-2$M052012 -120 OCH3 CH30 OCH3 R 2 E R2A RIA RlBO (Ia) RID wherein; X represents 0, S, SO, S02. Se, SeO, SeO 2 or NR where R is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted 5 alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl; R A and R 1 B each independently represents H, carboxy, cyano, dihalomethoxy, 10 halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted 15 alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted 20 aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted 25 oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally C \NRPortbl\DCC\ACG\4351%6_1.DOC.25/05/2012 -121 substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, optionally substituted thioacylamino, or RIA and RIB together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted 5 cycloalkenyl; Ric represents CI. 3 alkoxy, CI. 3 alkylthio, C 1 . 3 alkylamino, or CI. 3 dialkylamino; R ID represents hydroxy or amino; 10 R 2A and R 2 E independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, 15 optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally 20 substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted 25 oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally substituted sulphonylamino, optionally substituted thio, optionally substituted 30 thioacyl, optionally substituted thioacylamino, or optionally substituted thioacyloxy; and C WPonbrDCC\ACGM351%6_l.DOC-2505/2012 - 122 Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally 5 substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acyl and optionally substituted oxyacyl, or NR.'NR"', where each R"' independently represents H, 10 optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl. A I B 2A 2

3. A compound of formula (Ia) according to claim 2 wherein R'^, RB, R and R 2 E represent H. 15

4. A compound of formula (Ib) or a salt thereof; OCH 3 CH 3 O OCH 3 H H H H 0 (Ib) RIC X Q RID wherein; X represents 0, S, SO, SO 2 , Se, SeO, SeO 2 or NR where R is selected from H, 0, 20 optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and optionally substituted sulfonyl; 25 RIC represents C 1 . 3 alkoxy; C \NRPortb\DCC\ACG351%6_ L, DOC-25/05/O212 - 123 RID represents hydroxy or amino; and Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, 5 optionally substituted oxyacyl, optionally substituted acylamino, optionally substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl and optionally substituted oxyacyl, or NR'NR"', where 10 each R"' independently represents H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl.

5. A compound of formula (II) or a salt thereof; 15 R 2 D R 2 C R 2 E /0\ R 2 B RIA L R 2 A RIB RIC o RID wherein; RIA and R' 8 each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, 20 sulfo, trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally 25 substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, optionally substituted amino, optionally substituted aminoacyl, optionally C:\NRPortb\DCC\ACGU351%661 DOC-25/5/2012 -124 substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally 5 substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacyloxy, optionally substituted oxyacylimino, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally 10 substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, optionally substituted thioacylamino, or RIA and RIB together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted cycloalkenyl; 15 RIc represents CI. 3 alkoxy, C 1 . 3 alkylthio, CI. 3 alkylamino, or CI. 3 dialkylamino; R D represents hydroxy or amino; 20 L represents C=O, 0, S, SO, S02, Se, SeO, SeO 2 , C=NZ', or NR' where Z' is H, optionally substituted alkyl, optionally substituted aryl or optionally substituted amino; and where R' is selected from H, 0, optionally substituted acyl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally 25 substituted heteroaryl, optionally substituted heterocyclyl, or optionally substituted sulfonyl; R 2A-R 2 E each independently represents H, carboxy, cyano, dihalomethoxy, halogen, hydroxy, nitro, pentahaloethyl, phosphorylamino, phosphono, phosphinyl, sulfo, 30 trihaloethenyl, trihalomethanethio, trihalomethoxy, trihalomethyl, optionally substituted acyl, optionally substituted acylamino, optionally substituted acylimino, C :NRPob\DCC\ACGW3$l%6_ I.DOC-2505/2012 - 125 optionally substituted acyliminoxy, optionally substituted acyloxy, optionally substituted arylalkyl, optionally substituted arylalkoxy, optionally substituted alkenyl, optionally substituted alkenyloxy, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkynyloxy, 5 optionally substituted amino, optionally substituted aminoacyl, optionally substituted aminoacyloxy, optionally substituted aminosulfonyl, optionally substituted aminothioacyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted cycloalkenyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally 10 substituted oxyacyl, optionally substituted oxyacylamino, optionally substituted oxyacylimino, optionally substituted oxyacyloxy, optionally substituted oxysulfinylamino, optionally substituted oxysulfonylamino, optionally substituted oxythioacyl, optionally substituted oxythioacyloxy, optionally substituted sulfinyl, optionally substituted sulfinylamino, optionally substituted sulfonyl, optionally 15 substituted sulphonylamino, optionally substituted thio, optionally substituted thioacyl, optionally substituted thioacylamino, or optionally substituted 2A 2B3 2B 2 2C 2D 2D 21 thioacyloxy; or any of R and R , R and R 2 c, R and R , and R and R2E together form an optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally 20 substituted cycloalkenyl; and Q represents H, CN, halogen, trialkylsilyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted oxyacyl, optionally substituted acylamino, optionally 25 substituted aminoacylamino, OR", SR" or NR"R", where each R" independently represents, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted acyl and optionally substituted oxyacyl, or NR"'NR"', where each R.' independently represents H, 30 optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl and optionally substituted heteroaryl. C WRPortblDCC\ACG4359%6I DOC-25/05/2012 - 126

6. A compound of formula (II) according to claim 5, wherein L is a carbonyl group (C=O), and at least one of R 2 D, R 2 C or R 2 B is a hydroxy or Ci. 3 alkoxy group. 5

7. A compound of formula (II) according to claim 5, wherein L is a carboxyl group (C=O), and R 2 D, R 2 C, and R 2 B are methoxy.

8. A compound of formula (11) according to claim 5, wherein L is a carbonyl group B C 2BI 2A 21 10 (C=O), R 2 D, R 2 c, and R 2 B are methoxy and RI^, R", R and R are H.

9. A compound of formula (II) according to claim 5, wherein L is a carbonyl group (C=0), R 2 D, R 2 C, and R 2 B are methoxy, RIA, RIB, R 2 A and R 2 E are H, and Ric is hydroxy. 15

10. A compound of formula (II) according to any one of claims 5 to 9 wherein Q represents H, CN, optionally substituted C24 alkynyl, optionally substituted C 2 - 6 alkenyl, optionally substituted CIA alkyl, hydroxy, optionally substituted oxyacyl, NR"R", SR" (where each R" is independently H, optionally substituted Ciaalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl), NR"'NR"' (where each R"' is 20 independently H, CI. 3 alkyl), optionally substituted acylamino, or halogen.

11. A compound of formula (I) according to claim 1 selected from: (7-Amino-6-methoxybenzofuran-3-yl) (3,4,5-trimethoxyphenyl)methanone; 2-Bromo-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran; 25 3-(3,4,5-Trimethoxybenzoyl)-6-methoxy-7-hydroxybenzofuran; 2-Ethynyl-7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-benzofuran; 7-Hydroxy-6-methoxy-2-methylsulfanyl-3-(3,4,5-trimethoxybenzoyl)benzofuran; 2-Hydrazino-7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)-benzofuran; 2-Methyl-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran; 30 [7-Hydroxy-6-methoxy-2-{(E)-pent-1-enyl)benzofuran-3-yl]-3,4,5-trimethoxy phenyl) methanone; C \NRWorlbI[fCC\ACG\435 I%66l DC.25A~nfl1 - 127 (E)-3 -17-Hydroxy-6-methoxy-3-(3 ,4,5-trimethoxy-benzoyl)-benzofiran-2-yl] acrylic acid methyl ester; (E)-3-[7-Hydroxy-6-methoxy-3-(3 ,4,5 -trimethoxy-benzoyl)benzofuran-2-yl] acrylamide; 5 7-Hydroxy-6-methoxy-3 -(3 ,4,5-trimethoxybenzoyl)-benzofuran-2 methylcarboxylate; 2-(N-Methylamino)-7-hydroxy-3 -(3,4,5 -trimethoxybenzoyl)-6-methoxy benzofuran; (2-Amino-7-hydroxy-6-rnethoxy-benzofuran-3-yl)-(3 ,4,5-trimethoxyphenyl) 10 methanone; [7-Hydroxy-2-(2-hydroxy-ethylamino)-6-methoxy-benzofuran-3 -yl] -(3,4,5 trimethoxy-phenyl)methanone; [2-(2-Dimethylamino-ethylamino)-7-hydroxy-6-methoxy-benzofuran-3-y-(3,4,5. trimethoxy-phenyl )methanone; 15 (2-N,N '-Dimethylamino-7-hydroxy-6-methoxy-benzofiiran-3-yl)-(3,4,5 trimethoxy-phenyl)-methanone; [7-hydroxy-6-methoxy-3 (3 ,4,5 -tri metboxy-benzoyl)-benzo furan-2 -ylam ino] -acetic acid; [7-Hydroxy-6-methoxy-3-(3 ,4,5 -trimethoxy-benzoyl )-benzofuran-2-ylamino] 20 acetic acid methyl ester; [7-Hydroxy-6-methoxy-2-(pyridin-3 -ylamino)-benzofuran-3 -yl]-(3 ,4,5-trimethoxy phenyl)-methanone; tert-Butyl-2-(7-hydroxy-6-methoxy-3-(3 ,4,5-trimethoxybenzoyl)benzofuran-2 ylamino)ethyl carbamnate; 25 [2-(2-aminoethylamino)-7-hydroxy-6-methoxybenzofuran-3 -yl ](3 ,4,5 trimethoxyphenyl)methanone; 1- [2-(7-hydroxy-6-methoxy-3 -(3 ,4,5-trimethoxybenzoyl)benzofuran-2 ylamino)ethyl]guanidine; 2-Butyl-3 -(3 ,4,5-trimethoxybenzoyl)-7-hydroxy-6-methoxy-benzo [b] furan; 30 2- Ethyl -3 -(3 ,4,5 -trimethoxybenzoyl)-7-hydroxy-6-methoxy-benzo [b] furan; C:NRPortbIDCC\ACG4351%'6_1 DOC-25/05/2012 - 128 2-Dimethylaminomethylene-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6-methoxy benzo[b]furan; 2-(1 H-Imidazol- I -yl)-methyl-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6-methoxy benzo[b]furan; 5 2-(5-amino-2H-tetrazol-2-yl)-methyl-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6 methoxy-benzo[b] furan; 2-(4-Methylpiperazin- I -yl)methyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-7 hydroxy-benzo[b]furan; 7-Hydroxy-6-methoxy-2-methyl-3 -(3,4,5-trimethoxybenzoyl)- I H-indole; 10 3-(3,5-Dimethoxy-4-hydroxybenzoyl)-7-hydroxy-6-methoxy-2-methyl- I H-indole; 7-Hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene; 2-[(N-Methyl-2-amino-aceticacid methyl ester)-methenyl)-3-(3,4,5 trimethoxybenzoyl-6-methoxy-7-hydroxy-benzo[b]furan; 2-[(N-Methyl-2-amino-aceticacid)-nethenyl)-3-(3,4,5-trimethoxybenzoyl-6 15 methoxy-7-hydroxy-benzo[b]furan; 2-N-(Aminoethanesulphoneamide)-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7 hydroxy-benzo[b] furan; 3-(4-Hydroxy-3,5-di-methoxy-benzoyl)-7-hydroxy-6-methoxy-2-methyl benzo[b]furan; 20 and salts thereof.

12. A compound of formula (I) according to claim I selected from: 2-Dimethylaminomethylene-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6-methoxy 25 benzo[b]furan; 2-(1 H-Imidazol- 1 -yl)-methyl-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6-methoxy benzo[b]furan; tert-Butyl-2-(7-hydroxy-6-methoxy-3-(3,4,5-trimethoxybenzoyl)benzofuran-2 ylamino)ethyl carbamate; 30 2-(5-amino-2H-tetrazol-2-yl)-methyl-3-(3,4,5-trimethoxybenzoyl)-7-hydroxy-6 methoxy-benzo[b]furan; C \N ortDCCC4351%6_LDOC-25/05/2012 - 129 2-(4-Methylpiperazin- I -yl)methyl-3-(3,4,5-trimethoxy-benzoyl)-6-methoxy-7 hydroxy-benzo[b]furan; 2-[(N-Methyl-2-amino-aceticacid)-methenyl)-3-(3,4,5-trimethoxybenzoyl-6 methoxy-7-hydroxy-benzo[b]furan; 5 2-N-(Aminoethanesulphoneamide)-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-7 hydroxy-benzo[b]furan; and salts thereof 10

13. A compound of formula (I) according to claim 1 which is 2-methyl-7-hydroxy-3 (3,4,5-trimethoxybenzoyl)-6-methoxybenzofuran or a salt thereof.

14. A compound of formula (I) according to claim I which is disodium 6-methoxy-2 methyl-3-(3,4,5-trimethoxybenzoyl)-benzofuran-7-yl phosphate. 15

15. A method of treating a disease state by inhibiting tubulin polymerisation including the step of administering to a patient in need thereof a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof. 20

16. A method of treating a disease state by inhibiting tubulin polymerisation including the step of administering to a patient in need thereof a compound of formula (Ia) as defined in claim 2 or a pharmaceutically acceptable salt thereof.

17. A method of treating a disease state by inhibiting tubulin polymerisation including 25 the step of administering to a patient in need thereof a compound of formula (Ib) as defined in claim 4 or a pharmaceutically acceptable salt thereof.

18. A method of treating a disease state by inhibiting tubulin polymerisation including the step of administering to a patient in need thereof a compound of formula (II) as defined 30 in claim 5 or a pharmaceutically acceptable salt thereof. C:\NRPonblDCC\ACG\4351%6_1 DOC-25052012 - 130

19. A method according to any one of claims 15 to 18 wherein the disease state is a solid tumor.

20. Use of a compound according to any one of claims 1 to 9 in the manufacture of a 5 medicament for the treatment of a disease state by inhibiting tubulin polymerisation.

21. The use according to claim 20 wherein the disease state is a solid tumor.

22. A method according to claim 15 further comprising the step of administering at 10 least one other cytotoxic compound in combination with the compound of formula (I).

23. A method according to claim 16 further comprising the step of administering at least one other cytotoxic compound in combination with the compound of formula (Ia). 15

24. A method according to claim 17 further comprising the step of administering at least one other cytotoxic compound in combination with the compound of formula (Ib).

25. A method according to claim 18 further comprising the step of administering at least one other cytotoxic compound in combination with the compound of formula (II). 20

26. A method according to claim 15 further comprising the step of administering a antihypertensive or antihypotensive agent in combination with the compound of formula (I). 25

27. A method according to claim 16 further comprising the step of administering a antihypertensive or antihypotensive agent in combination with the compound of formula (Ia).

28. A method according to claim 17 further comprising the step of administering a 30 antihypertensive or antihypotensive agent in combination with the compound of formula (Ib). C:\NRPonbl\CCACG435%66 I DOC-25/05/2012 - 131

29. A method according to claim 18 further comprising the step of administering a antihypertensive or antihypotensive agent in combination with the compound of formula (II). 5