AU2005229153A1 - Antiviral agents - Google Patents

Description

WO 2005/095376 PCT/AU2005/000453 ANTIVIRAL AGENTS Field of the Invention 5 The present invention relates to the use of naphthopyrans as agents in the treatment and/or prophylaxis of hepatitis B, pharmaceutical compositions for use in such therapy and novel naphthopyrans, Background of the Invention 10 Infection with human hepatitis B virus is a major public health problem because of the ability of the virus to cause acute and chronic infections. Chronic hepatitis B virus infection (hereinafter referred to as "[IBV") causes serious liver disease in humans and frequently results in cirrhosis and hepatoccllular carcinoma. Currently there is no 15 completely effective therapy for the successful management of chronic HBV infections. The >250 million chronic HBV carriers throughout the world are unable to benefit from the commercial vaccine presently available. Currently available therapies for HBV are only partially effective and may be accompanied 20 by deleterious side effects, In addition, many patients develop antiviral resistance resulting in the loss of efficacy. Accordingly, a need exists for new effective treatments for -BV. It has now been discovered that compounds of Formula (1) are active agents against hepatitis B virus. 25 Summary of the Invention According to one aspect of the present invention there is provided a method of treatment or prophylaxis of hepatitis B virus in a subject comprising administering to said subject an 30 effective amount of a compound oF Formula (I): WO 2005/095376 PCT/AU2005/000453 R2 R4 R R3 . 1 R5 30R -04 5 R6 7 x R7 wherein X is OH, OR or halo; R and Ri are independently selected from H, C 1

.

6 alkyl, C 2 4 ,alkenyl, C2.

6 alkynyl, C.v-cycloalkyl, aryl, or together with the carbon atont to which they are attached fonn a 5 saturated or unsaturated C 2 6 carbocyclic ring;

R

2 and Ri are independently selected from H, C-al-kyl, C 2 -salkcnyl, C2-alkynyl,

C

3 .ecycloalkyl or together with the bond between th-e carbon atoms to which they are attached form a double bond4

R

4 and Rs arc independently seleced from H, Clualkyl, C;.

0 alkenyl, C2.salkynyl, 10 Ci.6cycloalkyl, OH, OR 9 , halo or NRiORio or together with the bond between he carbon atoms to which they are attached form a double bond; R5 and R7 are independently selected from H, Ci.6alkyl, C 2 ualkenyl, C 2 .alkynyl, C3.cycloalkyl, OH or ORy; R is independently selected from H, C 1

.

6 alkyl, C 2 .6mlkenyl, C2.ealkynyl, Ct.cycloalkyl, 15 OH, OR9 or halo; Ro is Ci.alkyl, Cz.alkenyl, C 2 0 alkynyl, C-ocycloalkyl; aryl, C(=O)R 1 or S(O)2Rr or OR 9 is an amino acid residuc; each R 1o is independently selected from H and Calky]; RI, is C 1

.

21 alkyl, C2.alkenyl, Czajkynyl, C 3 .cycloaLkyl, CiucycloalkylC.

6 alkyI, aryl or 20 arylCj-alkyl; and

R

1 2 is CI.6alkyl, CZcalkenyl, C 2 .alkynyl or aryL WO 2005/095376 PCT/AU2005/000453 -3 According to a further aspect of the present invention there is provided a use of a compound of Formula (1) in the manufacture of a medicarnent for the treatment or prophylaxis of hepatitis B virus. 5 According to yet a further aspect of the present invention there is provided a method of treatment or prophylaxis of hepatitis B virus comprising administering an effective amount of a compound of Formula (1) and a second therapeutic agent. According to another aspect of the invention there is provided a compound of Formula (1) 10 with the proviso that when R and R 1 arc both methyl and R 4 is OH or OR, R. is not selected From OH, OR, or NHRI. According to another aspect of the present invention there is provided a pharmaceutical composition comprising a compound of Formula (1)and a pharmaceutically acceptable 15 carrier, excipient or adjuvant, with the proviso that in the compound of Formula (1) when R and R i are both methyl and R 4 is OH or ORq, Rs is not selected from OH, OR 9 or

NHR

0 . According to the present invention the compounds of Formula (1) may be presented in the 20 form of a pharmaceutically acceptable derivative, salt or prodrug. Detailed Description Throughout this specification and the claims which follow, unless the context requires 25 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. The reference to any prior art in this specification is not, aiid should not be taken as, an 30 acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

WO 2005/095376 PCT/AU2005/000453 -4 As used herein, the term "halo" or "halogen" refers to fluorine (fluoro), cixIorine (chloro), bromine (bromo) or iodirie (iodo). As used herein, the term "alkyl" either used alone or in compound terms such as NH(alkyl) 5 or N(alkyl) 2 , refers to monovalent straight chain or branched hydrocarbon groups, having 1 to 3, 1 to 6, 1 to 10 or I to 21 carbon atoms as appropriate. For example, suitable alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-methylbutyl, 3-methylbutyl. n-hexLyl, 2-, 3- or -4-methylpentyl, 2-ethylbutyl, n-hexyl or 2-, 3-, 4- or 5-niethylpentyl. 10 As used herein, the term "alkenyl" refers to straight chain or branched hydrocarbon groups having one or more double bonds between carbon atoms, Suitable alkenyl groups include, but are not limited to ethenyl, propenyl, isopropenyl, butCnyl, pentenyl and hexonyl. 15 The term "alkynyl" as used herein, refers to straight chain or branched hydrocarbon groups containing one or more triple bonds. Suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexenyl. The term "cycloalkyl" as used herein, refers to cyclic hydrocarbon groups. Suitable 20 cycloalkyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "aryl" as used herein, refers to C*-Cj, aromatic hydrocarbon group, for example phenyl or naphthyL.

25 The erm "heterocyclyl" when used alone or in compound words inch des monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C.

6 ,whc-rein one or more carbon atoms (and where appropriate, hydrogen atoms aLached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue. Suitable heteroatorrs include, 0, N 30 and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatorns. Suitable examples of hctcrocyclic groups WO 2005/095376 PCT/AU2005/000453 -5 may include pyrrolidinyl, pyrrolinyl, piperidclyl, piperazinyl, rnorpholino, indolinyl, iniazolidinyl, pyrazolidinyl, thiomorpholino, dioxanyl, tetrabydrofaranyl, tetrahydropyranyl, tetrahydropyrrolyl etc. 5 Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclyl group may be optionally substituted with Cyjsalkyl, OH, C- 3 alkyl, halo, CN, NO 2 , CD 2 H, CO 2 C>;alkyl, CONH 2 , CONB(Cr.alkyl), CON(C.3alkyl)2, trifluoromethyl, NH 2 , NE(alkyl) or N(alkyl) 2 . For example, an optionally substituted aryl group may be a 4-methylphenyl or 4 hydroxyphenyl group, and an optionally substituted alkyl gro-np may be 2-hydroxyethyl, 10 trifluoromethyl or difluoromethyl. As used herein, the term "amino acid residue" refers to an c-ak-ino acid or a 5-amino acid which is attached to the naphthopyrandione structure, preferably through the carboxylic acid group of the amino acid. The amino acid may be a L- or D- isomer and may have a 35 naturally occurring side chain or a non-naturally occurring side chain. The amino acid may also be further substituted in the ot-position or the pf-posiion with a group selected from -C-Calkyl, -C2-Csalkenyl, -C2-Csalkynyl -(CH2).CORa -(CH2)nRh, -P0311, -(CH2),heterocyclyl or -(CH-I2)aaryl where RI is -OH, -NHz, -NHCi.Cqalkyl, -OCm-C.alkyl or -C-C 3 alkyl and Rb is -OH, -SH, -SCI-Calkyl, -OCz-C3alkyl, -C-Cocycloalkyl, 20 -C,-C 6 cycloalkenyl, -NH 2 , -NHCi-C 3 alkyl or -N1JC(C4NH)N 1-12, n is 0 or an integer from 1 to 6 and where each alkyl, alkenyl, alkynyl, cycloolkyl, cycloalkenyl. aryl or heterocyclyl group may be substituted with one or more groups selected from -OH, -NH 2 , -NHCi-C 3 aikyl, -OCj-Cpalky, -SH, -SCI-C 3 alkyl, -CO2H, -CO2CI-C3alkyl, -CONIt or -CONHC-Cjalkyl, 25 The tern "a-amino acid" as used herein, refers to a compound having an amino group and a carboxyl group in which the amino group and the carboryl group arc separated by a single carbon atom, the ot-carbon atom. An a-amino acid includes naturally occurring and non-naturally occurring L-amino acids and their D-isomers arid derivatives thereof such as 30 salts or derivatives where functional groups are protected b-y suitable protecting groups. The cc-amino acid mray also be further substituted in the ct-pcsition with a group selected WO 2005/095376 PCT/AU2005/000453 -6 from -Ci-COoalkyl, -C2-Cjcalkenyl, -C-CLOalkynyl, -(CH 2

)

1 COR,, -(CH2),R, -P03H, -(CHz)heterocyclyl or -(CH 2 ),aryl where R, is -OH, -NH 2 , -NHCr-C-alkyl, -0C-C 3 alkyl or Cr-C 3 alkyI and R- is -01, -SH, -SCe-C 3 alkyl, -OCe-C3alkyl, -C-Ci2cycloalkyl,

-C

3 -Cncycloalkenyl, -NH 2 , -NHCj-Cjalkyl or -NHC(C=NH)NH 2 , n is 0 or an integer from 5 1 to 10 and where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl group may be substituted with one or more groups selected from -OH, -N- 2 , -NHCj-Cjalkyl, -OCrC3alkyl, -SR, -SCI-Calky), -C0 2 1, -CO2C.{-Caalkyl, -CONH 2 or

-CONHC[-C

3 alkyl. 10 As used herein, the term "p-amino acid" refers to an amino acid that differs from an a-amino acid in that there are two (2) carbon atoms separating the carboxyf terminus and the amino terminus, As such, P-amino acids with a specific side chairs can exist as thc R or S enantiomers at either of the a (C2) carbon or the P (C3) carbon, resulting in a total of 4 possible isomers for any g iven side chain. The side chains may be the same as those of 15 naturally occurring a-amino acids or may be the side chains of non-naturally occurring amino acids, 3 3 2NCO 2 H 2HC 2 H

H

2 N H 0 N RR RR C0 2 H 700 2 H

H

2 N 3 H 2 N C 20 Furthermore, the P-amino acids may have mono-, di-, tri- or tetra-substitution at the C2 and C3 carbon atoms. Mono-substitution may be at the C2 or C3 carbon atom. Di-substitution includes two substituCts at the C2 carbon atom, twc. substituents at the C3 carbon atom or one substituent at each of the C2 and C3 carbon a.toms. Tri-substitution includes two substituents at the C2 carbon atom and one substituent at the C3 carbon atom WO 2005/095376 PCT/AU2005/000453 or two substituents at the C3 carbon atom and one substituent at the C2 carbon atom. Tetra-substitution provides for two substituents at the C2 carbon atom and two substituents at the C3 carbon atom. Suitable substituents include -Ci-Cealkyl, -C 2 -Ccalkenyl,

-C

2 -Calkynyl, -(CH 2 ).CORa, -(Cl 12)fRh, -PO1H, -(CH 2 )nheterocyclyl or -(CH2)Iaryl where 5 R, is -OH, -NH, -NHC 1 -Clalkyl, -OCI-C 3 alkyl or -C[-C.alkyl and R is -OH, -SH, -SCi-C 3 alkyl, -OC-C 3 alkyl, -C 3 -Cccycloalkyl, -C 3 -C6cycloa1keny1, -NH 2 , -NHCL-C 3 alkyl or -NHC(C=NH)NH 2 , n is 0 or an integer from 1 to 6 and where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclyl group may be substituted with one or more groups selected from -OH, -NH 2 , -NHC 1 -Caalkyl, -OC-C 3 aLkyl, -SH, 10 -SCi-C 3 alkyl, -CO 2 H, -CO 2

C

1

-C

3 alkyl, -CONH 2 or -CON HCI-Cgalkyl. The term "non-naturally occurring amino acid" as used herein, refers to amino acids having a side chain that does not occur in the naturally occurring L-a-anino acids. Examples of nou-natural amino acids and derivatives include, but are not limited to, use of norleucine, 15 4-amino butyric acid, 4-aminn-3-hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6 methylheptanoic acid, 2-thienyl alanine and/or D-isomers of amino acids. It will also be recognised that the compounds of formula (1) may possess asymmetric 20 centres and are therefore capable of existing in more than one tereisomeric form. The invention thus also relates to compounds in substantially pure isomneric form at one or more asymmetric centres eg., greater than about 90% cc, 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, 25 or by chiral resolution. The term "pharmiaceutically acceptable derivative" may include any pharmaceutically acceptable salt, hydrate or prodrug, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a compound of formula (1) or'an 30 antivirally active metabolite or residue thereof.

WO 2005/095376 PCT/AU2005/000453 -8 Suitable pharmaceutically acceptable salts include, but are not limited to, salts caf 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, tarraric, maleic, hydroxymaleic:, 5 fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phonylacetic, nethancsulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic. edetic, stearic, palmitic, olcic, lauric, pantothenic, tannic, ascorbic and valerie acids. 10 Base sats include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, amnmoniurn, alkylammoniurn such as salts formed from triethylamine, alkoxyamnimonium such as those forn-med with elhanolamine and salts formed from ethylenediamine, choline or amino a ciis such as argialne, lysine or histidine. 15 Basic nitrogen-containing groups may be quarternised with such agents as lower allcyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. 20 The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds in which a free hydrcxy group is converted into a group, such as an ester, carbonate or carbamate, which is capable of being converted in vivo back to a hydroxy group. A prodrug may include modifications 25 of one or more of the functional groups of, a compound of formula (1). For example, similar to the approach described in US 5,672,607, antiviral naphthopyran prodrugs having enhanced water-solubility (e.g., which are better for parenterally administered compositions) may be prepared by chemical reduction of the quinone functionalities to the corresponding quinols, followed by reaction with phosphorous oxychloride to give the 30 corresponding phosphoric acid esters. Alter in vivo administration of a composition containing such a solubilized antiviral naphtopyran prodrug, the prodrug will be readily WO 2005/095376 PCT/AU2005/000453 hydrolysed to the corresponding quinol, which thereafter will oxidize to re-form in vivo the active parent antiviral naphthopyrandione. Likewise, other kinds of derivatives may be prepared from the reduced quinal derivatives of the antiviral naphthopyrandione; these can also serve as prodrugs for use in therapeutic compositions. For example, other types of 5 esterification (e.g., acetylation) may be used to produce antiviral naphthopyran prodrugs, such as for example 7,8,10-triacetoxy-3,3-dimethyl-3H-napthoL2,1-blpyran. Again, after in vivo administration the prodrug would be readily hydrolysed and oxidized to its parent active antiviral nnphthopyran compound. 10 In a first aspect, there is provided a method of treatment or prophylaxis of hepatitis B viruS in a subject comprising administering to said subject an effective amount of a compound of Formula (1): R2 R4 R R3 2x R1 3' 1 04 1 as 10 0 7 X H7 0 (1) wherein X is OH, OR 9 or halo; 15 R and RI are independently selected from II, Ca6aikyl, C 26 aikenyl, C 2 6 alkynyl,

C

3 ucycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated Cc 3 .darbocyclic ring;

R

2 and R: 3 are independently selected from H, Ci-alkyl, C 2 6 alkenyl, C 23 alkynyl,

C.

3 eycloalkyl or together with the bond between the carbon atoms to which they are 20 attached form a double bond; WO 2005/095376 PCT/AU2005/000453 - 10 R4 and Rs are independently selected from H, Clalkyl, C 2 .6alkenyl, C 2 6 alkynyl, C>.cycloalkyl, OH, OR , halo or NR:oRm or together with the bond between the carbon atoms to which they arc attached form a double bond; R6 and R7 are independently selected from 1I, Cp.alkyl, C2ualkenyl, C 2 6 alkynyl, 5 Ccycloalkyl, 011 or OR9; Rg is independently selected from H, C 1 6 alkyl, C 2 .c,alkenyl, C2ualkynyl, Ca-cycloalkyl, OR, OR or halo; R9 is C 1 alkyl, C 2 u5alkenyl, C2Aalkynyl, Csecycloalkyl, aryl, C(=O)R 1 or S(O)2Riz or OR 9 is an amino acid residue; 10 each R 1 m is independently selected from H and Cialkyl; Ru is CrtIaLkyl, C 2

-

2 alkenyl, Cuzialkynyl, Cecycloalkyl, CsacycloalkylCb6aLkyl, aryl or arylCpalkyl; and R1 2 is Cz-alkyl, Ca 6 ajkenyI, C 2 6 alkynyl or aryl, 15 In another aspect there is provided a compound of Formula (I), with the proviso that when R and R, are both methyl and R is OR or OR 9 . R9 is not selected from 01-1, OR4 or NH R In a preferred embodiment one or rore of the following definitions apply: X is OH, OC 1 &ulkyl or halo; 20 R and RI are independently selected from H or C vaLkyl or together with the carbon atom to which they are attached form a saturated or unsaturated C3carbocyclic ring;

R

2 and R 3 are each hydrogen; R4 and R. are independently selected from H, OH, OR 9 , or halo or together with the bond between the carbon atoms to which they are attached form a double bond; 25 Rc, and R 7 are independently selected from H, OH, C,.alkyl, Cvsalkoxy; RA is H, OH, OR 9 , C 1 6 alkyi or halo:

R

9 is C(=±O)R I or S(O)2R12; Ru is C [.alkyl; R 1 is Cjgalkyl, phenyl or tosyl. 30 Preferred compounds of the invention include those of formula (2): WO 2005/095376 PCT/AU2005/000453 - 11 R2 R4 R R a OH (2) wherein R, RI, R 2 , R 3 , R4 and R5 are defined as for formula (1). Preferred compounds of the inVention included 5 8-hydroxy-3,3-dimethyl-3H-naphthol2,1-b]pyran-7,10-dione, 8-hydroxy-3,3-dirmethyl-1,2-dibydro-3H-naphthol2,1 -b]pyran-7,10-diono, 9-broio-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H--naphthc[2,1-bjpyran-7,10-dione, 9-bromo-8-hydroxy-3,3-dinietliyl-3 H-naphtho{2,1-bjpyran-7,10-dione, 9-bronio-3,3-dinethyl-8-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-naphtho2,1-blpy I0 ran-7,10-dione, 9-bromno-3,3-dimethyl-8-(4-nethylbcazenesulfonyloxy)-3H-naphtho[2,1-bjpyran-7, 10 dione, 8-acctoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyrnt-7,10-dione, 2,9-dibroino-1,8-dihydroxy-3,3-dinethyl-1,2-dihydro-3 H-naphtho(2,1-b]pyran-7, 10-dione, 15 8,9-dichloro-3,3-dimcthyl-1,2-dihydro-3H-naphtho(2,1-b lpyran-7,10-dione, 7,8,10-triacotoxy-3,3-dimethyl-3H-naphtho[2,1-bjpyran, 9-Bromo-8-hydroxy-3,3-dimnethyl-3H-naphtho(2,1-bjpyran-7, 10-dione. 9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]p yran-7, 10-dione. 9-Bromo-3,3 -dimethyl-8-(4-methylben:enesulfonyloxy)- ,2-dihydro-3-naphthoL2, 1 20 bpyran-7,10-dione, 9-Brcmxo-3,3-diinethyl-8-(4-methyjbenzenesulfonyloxy)-3H-naphthlo2,1-bipyran-7,10 dione, WO 2005/095376 PCT/AU2005/000453 - 12 8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-3H-naphthof2,1 -blpyran-7, 10 dione, 8-Bromo-3,3-dirnetLhyl-9-(4-metliylbenzcnesulfonyloxy)-1,2-dihydro-311-naphtho[2, 1 bjpyran-7, 10-dione, 5 8,9-Dichloro-3,3-dimethyl -1,2-dihydro-31-naphtho[2, 1 -b]pyran-7, 10-dione, Sodium 3,3-dirnethyl-7.10-dioxo-7,10-dihydro-3H-benzolflchrornen-8-olate; Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3H-benzolfjchromen-10-olate 8-Hydroxy-3-methy1-3-phenyl-3--benzo[f]chronie-7,10-dione, and 8-Hydroxy-3,3-diphenyl-3H-benzofichronene-7,] 0-dione, 10 Preferably the compound of Formula (1) is: 8-hydroxy-3,3-dimethyl-3H-naphthu[2,I-b}pyran-7,10-dione (compound (1)), 8-hydroxy-3,3-diniethyl-1,2-dihydro-3H-naphthol2,1-blpyTan-7,10-dione (compound (2)). 15 In another embodiment the cOmponLds of the invention include those of Cormula (3): RR R4 R R18 Re R R7 O (3) 20 wherein R, RI, R 2 , R3, R 5 , R 6 , R 7 , RS, and X are as defined for formula (1) and R, is selected from H, C 1 salkyl, C 2 .6alkenyi, C 2

.

6 alkynyl, Cj.

6 cycloalkyl, halo or NRaoR 1 o or togeier with R5 and the bond between the carbon atoms to which R 4 and R 5 are attached, forni a double bond.

WO 2005/095376 PCT/AU2005/000453 - 13 Compounds of Formula (1) may be prepared using the methods depicted or described herein or known in the art. It will be understood that minor modifications to methods described herein or known in the art may be required to synthesize particular compounds 5 of Formula (1). General synthetic procedures applicable to the synthesis of compounds iay be found in standard references such as Comprehensive Organic Transfonnations, R. C, Larock, 1989, VCH Publishers and Advanced Organic Chemistry, J. March, 4th Edition (1992), Wiley InterScience, and references therein. It will also be recognised that certain reactive groups may require protection and deprotection during the synthetic process. 10 Suitable protecting and deprotecting methods for reactive functional groups are known in the art for example in Protective Groups in Organic Synthesis, T. W. Greene & P. Wutz, John Wiloy & Son, 3' Edition, 1999. The compounds of the present invention may be prepared according to the general 15 procedure of Scheme 1.

WO 2005/095376 PCT/AU20051000453 - 14 Scheme I F2 CH R, O OH FRROH 7 OH FR ( 0 Re 8 Re~" OH83 87 V R7 (7)) WO 2005/095376 PCT/AU2005/000453 -15 An appropriately substituted 2,6-dihydroxynaphthalene (3) is reacted with an appropriately substituted enal or enone (4) in the presence of a suitable baso to effect cyclisation and provide a naphthopyranoi (5). The naphthopyranol is then oxidised by a suitable oxidant to the corresponding intermediate orthcquinone (6), before being reduced by a suitable 5 reducing agent and further oxidised by a suitable oxidant to the desired naphthopyrandione (7). Further modification of the substituents on the naphthopyrandione may be effected using chemical approaches known to those skilled in the art for the generation of the desired substituent or substituents. Those skilled in the art may utilise conventional approaches to protect and deprotect certain functional groups during the reaction sequence. 10 Such mcthoads are well known in the art and include for example those described by Greene and Wutz (supra), The reaction sequence described in Examples 1 and 2 exemplify the preparation of compounds (1) and (2) and provide an example of how the reaction sequence of Scheme 1 is utilised. Those skilled in the art will appreciate that a wide variety of reaction conditions, including solvents, bases, oxidising agents, reducing agents, 15 temperature and time of the reaction, may be utilised to effect the desired transformation. A substituted none such as (4) may, dependent upon the exact nature of the reagents and conditions used, add to the substituted 2,6-dihydroxynaphthalene (3) in the opposite orientation to that shown in Scheme I and still provide a naphthopyran product. Such a 20 reaction is shown in Scheme 2, and provides naphthopyranol (8). Naphchopyranol (8) may be isomerised to provide a naphthopyranol effectively of general formula (5), which may then be subject to further reaction in accordance with the general procedures of Scheme 1 to provide compounds of Formula (1).

WO 2005/095376 PCT/AU2005/000453 - 16 Scheme Z

R

2 Ri ~ R3 RI 1 R HO f, eHF OH 8 OH (3) RI R3 H Rs SOH 7 (5) WO 2005/095376 PCT/AU2005/000453 -17 Alternative synthetic procedures which provide compounds of Formula (1) are shown in Schemes 3 and 4. In Scheme (3) an appropriately substituted butyie (9) is reacted with an appropriately substituted hydroxy tetralone (10). The group L is any suitable leaving group and includes groups such as a bromo, chloro, and bydroxyl. Reaction between the 5 tetralone and the butyne may be acid or base catalysed to provide naphthopyran (12). In some cases the reaction may be conducted in one pot however an intermediate (11) may be isolated. Intermediate (11) may conveniently be cyclised for example by heating in the presence of a suitable base, such as diethylaniline. The cyclised product (12) is then oxidized to afford the quinone (13) which may then be further modified to provide other 10 compounds of Formula (1). Scheme (4) outlines a similar reaction sequence to that of Scheme (3) which would start with an appropriately substituted bydroxy naphthalcnc. This is based upon work reported by Bigi et al., J. Org. Chem,, 62, 7024-7027 (1997). The cyclised naphthopyran (15) could 15 be treated as per compound (5) of Scheme (1) to provide compounds of the invention. Many other methods of preparing benzopyrans have been reported in the chemical literature and those skilled in the art may adapt these methods to provide compounds of the present invention, sex for example, Ishino et al., Syn. Comm., 31, 439-448 (2001), WO 2005/095376 PCT/AU20051000453 Scheme 3 HO R 8 RB 0 R, OH R7

R

7 R2i2)R R I "E13) R73 WO 2005/095376 PCT/AU2005/000453 -19 Scheme 4 Ra RA R> HO i R R3 R6- A 6 H PR Ry ($) (14) R R3 RI (15

A

6 OH Further modification may include. derivatisation of double bonds, For example, when R 4 5 and R 5 together with the bond between the carbon atoms to which they are attached form a double bond, the double bond may he derivatised by addition, oxidation or reduction reactions. An example of possible derivatisation of such a double bond is given in Scheme 5. Following reductive acetylationi to protect the quinone portion of the compound, epoxidation of the pyran double bond, subsequent ring opening of the epoxide with an 10 amine, and deprotection and oxidation to regenerate the quinone may be effected. Those skilled in the art could readily determine appropriate reagents and conditions to effect such transformations.

WO 2005/095376 PCT/AU2005/000453 - 20 Scheme 5 0 F9 a O AC 0 C1 rQductive acetyrbon OAC eppxcation 0 A OH OAC R." GAR H OAC OA C 0 ACC OAC oxidat on R OH R OH O hydrdysis QAO CN H o A person skilled in the art would be able to modify such a reaction scheme by using 5 different reaents to open the epoxide, using asymmetric epoxidation catalysts and varying the nature of the substitLicats. As used herein, the term "effective amount" relates to an amount of compound which, WO 2005/095376 PCT/AU2005/000453 - 21 when administered according to a desired dosing regimen, provides the desired hepatitis B viius treatment or therapeutic activity, or disease prevention. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods, A therapeutic, or treatment, effective amount is an amount of the compound 5 which, when administered according to a desired dosing regimen, is sufficient to at least partially attain the desired therapeutic effect, or delay the onset of, or inhibit the progression of or halt or partially or fully reverse the onset or progression of hepatitis B virus. A prevention effective amount is an amount of compound which when administered according to the desired dosing regimen is sufficient to at least partially prevent or delay 10 the onset of a particular disease or condition. Yet another aspect of the present invention provides a use of a compound of Formula (1) in the preparation of a medicament for treating or preventing hepatitis B virus. 15 Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to I g per kg of body weight per dosage. The dosage is preferably in the range of I pLg to I g per kg of body weight per dosage, such as is in the range of 1 rg to 1 g per kg of body weight per dosage. In one embodiment, the dosage is in the range of I mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage is in the range of 1 mg to 250 rmg 20 per kg of body weight per dosage. In yet another preferred embodiment, the dosage is in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1pg to tmg per kg of body weight per dosage. 25 Suitable dosage amounts and dosing regimerns can be determined by the attending physician and may depend on the severity of the condition as well as the general age, health and weight of the subject. The active ingredient may be administered in a single dose or a series of doses. While it is 30 possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical cormposition.

WO 2005/095376 PCT/AU2005/000453 - 22 According to a further embodiment there is provided a method of treatment or prophylaxis of hepatitis B virus comprising administering an effective amount of a compound of Formula (1) and a second therapeutic agent. 5 When administered as a combination, the compound of Formula (1) and the second therapeutic agent may be administered simultancously, separately or sequentially. The second therapeutic agent may be a known antiviral or antiretroviral agent or another 10 pharmaceutical used in the treatment of viral infections. Representative examples of suitable second therapeutic agents include inununornodulators, inmunuostimulants and antibiotics, Exemplary antiviral agents include acyclovir, val-acyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, ribavirin, interferon-alpha. PEG-interferon-alpha, lanivudine, adefovir, thymosin alpha 1, entecavir, telbivudine, emtricitabine, elvucitabine, 15 MCC-478, hepavir 5, MIV-210, valtorcitabine, HoIpeX-B, Zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir, emtricitabine, saquinavir, indinavir, nelfinavir, amprenavir, ritonavir, azatanavir, nevirapirie, delavirdine, efavirenz, enfurvitide, trizivi, combivir, kalctra, MIV310, mozenavir, SPD754, SPD746, T1249, TMC125, TMC114, VX-175, tipranavir other non-nucleoside reverse transcriptase inhibitors and 20 protease inhibitors, Exemplary immunornodulators and immunostimulants include interferon alpha, PEG-interferon, thymosin alpha 1, HopeX-B, IlBV immunoglobulin, HBV monoclonal antibodies, and vaccines such as EngerixB, Havrix, H-B-Vax II, infanrix hcp B, twinrix. Preferably the second therapeutic agent is an agent suitable for the treatment or prophylaxis of hepatitis B virus in a subject. Such therapeutic agents include, 25 but are not limited to interferon-alpha, PEG-interferon-alpha, lamivudine, adefovir, thymosin alpha 1, entecavir, tclbivudine, emtricitabine, elvucitabine, MCC-478, hepavir B, MIV-210, valtoreitabine, and HepeX-B. Still another aspect of the present invention relates to a pharmaceutical composition 30 comprising a compound of Formula (1) and a pharmaceutically acceptable carrier, dilacat or excipient.

WO 2005/095376 PCT/AU2005/000453 -23 The formulation of such compositions is well known to those skilled in the art. The composition may contain pharmaceutically acceptable additives such as carriers, diluents or excipierits. These include, where appropriate, all conventional solvents, dispersion 5 agents, fillcrs, solid carriers, coating agents, 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. 10 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, inhalational, nasal, transdermal, topical (including buccal art] sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intraspinal, intravenous and intraderma)) administration. The compositions may 1. conveniently be presented in unit dosage form and 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, 20 and then if necessary shaping the product. Depending on the disease or condition to be treated, it may or may not be desirable for a compound of Formula (1) to cross the blood/brain barrier, Thus the compositions for use in the present invention may be formulated to be water or lipid soluble. 25 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 30 liquid crnulsion. The active ingredient may also be presented as a bolus, electuary or paste.

WO 2005/095376 PCT/AU2005/000453 -24 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 the active ingredient in a free-flowing form such as a powder or granules, optionally mixed 5 with a binder (eg inert diluent, preservative, disiutegrant (eg. sodium starch glycolate, cross-inked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose)) surface-active or dispersing agent. Moulded tablets may be rnade by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to 10 provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellkdose 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, 15 Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gurn; pastilles comprising [te active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier, 20 The compounds of Fornula (1) may also be administered intranasally or via inhalation, for example by atomiser, aerosol or nebulizer means. Compositions suitable for topical administration to the skin may comprise the compounds 25 dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointrnonts and the like. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, ectearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Transdermial devices, such as patches, may also be used to administer the 30 compounds of the invention.

WO 2005/095376 PCT/AU2005/000453 - 25 Compositions for rectal administration may be presented as a suppository with a suitable carrier base comprising, for example, cocoa butter, gelatin, glycerin or polyethylene glycol. 5 Compositions suitable for vagirml 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. Compositions suitable for parenteral administration include aqueous and non-aqueous 10 isotonic sterile injection solutic>ns which may contain anti-oxidants, buffers, bactericides and so lutes which render the coxoposition isotonic with the blood of the intcndecJ recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or rnulti-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried 15 lyophilisedd) condition requiritag 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 previously described, 20 Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as herein above de-scribed, or an appropriate fraction thereof, of the active ingredient. It should be understood that in addition to the active ingredients particularly mentioned 25 above, the compositions of thiLs 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 tine delay agents. Suitable sweeteners include sucrose, lactose, glucose, a.spartarne or 30 saccharine, Suitable disintegrating agents include corn starch, methylcellulose, polvviylpyrrolidone, xanthan gum, bentonite, algiric acid or agar, SuitablC flavoring WO 2005/095376 PCT/AU2005/000453 -26 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, zcin, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl 5 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. Those skilled in the art will appreciate that the invention described herein is susceptible toa 10 variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modiaications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in ihis specification, individually or collectively, and any and all combinations of any two or more of said steps or features. 15 The invention wil now be described with reference to the following examples which are included for the purpose of illustration only and are not intended to limit the generality cpf the invention hercinbefore described. 20 EXAMPLES Example 1 Compound 1:9-Ilydroxy-3,3-dimetlzyl-3H-naphtho[2,1-bjpyran-7,10-dione Step 1: 3,3-Dimetliyl-3ff-naphtho[2,1-b]pyran-8.ol 25 A mixture of 2,6-dihydroxynaphthalene (50.0 g, 0,312 mol), 3-methyl-2-butenal (30 mL, 26.24 g, 0.312 mol) and pyridine (38 mL, 37.02 g. 0.468 mol) were heated under reflux for 3.5 h. The mixture was cooled to room temperature, diluted with dichloromethane (500 mL), filtered through a sintered glass funnel (porosity 3) then washed with aquecors hydrochloric acid solution (1 M, 2 x 250 rnL) and water (I x 250 mL). The organic layer 30 was extracted with a solution of aqueous sodium hydroxide (2 M, 1 x 250 nL and 1 x 1 25 mL) and the combined aqueous extracts cooled in an ice-salt bath, acidified (with stirring) WO 2005/095376 PCT/AU2005/000453 -27 with aqueous hydrochloric acid solution (5 M) until a creamy-white precipitate formed (pH ~ 2). The solid was stirred for an additional 10 min with cooling, collected by filtration, washed with water and dried under high vacuLzm at 40 0 C to afford the desired crude product as a fluffy white-grey solid (43.9 g, 62 .%). The crude product was used in the 5 subsequent reaction without further purification. Recrystallised from diethyl ether/hexane m.p. 120-1234. S ('f-T) (300 MHz, CDC) 1.47, s; 2 x CH 3 ; 4.77, s, 014; 5.71, d, J 10.2 Hz, H2; 69'7, d, 1 10.2 Hz, Hi; 7.02, d, J 8.7 Iz, H5; 7.08, s, H7; 7.10. dd, J 8.7, 2.7 Hz, H9; 7.48, d, J 8.7 Hz, H6; 7.85, d, J 8.7 11z, H10. n/ 10 (ES*, 100 V) 471 (2M+H+H 2 0, 100%), 245 (M+-H+1, 2 0, 62), 227 (M+H, 63). Step 2: 3,3-Dimethyl-31H-naphthol2,1-bpyrana-,8-dione To an oxygen saturated solution of 3,3-dinietIy]-31-naphto[2,1-bjpyran-B-o (3.0 g, 13 mmol) in acetonitrile (70 mL) vras added catalytic amounts of 15 N.!N-Bis(salicylidene)ethylenecliamineocobalt(I) hydrate, ([Co(f1)(Salen)2]) (300 mg, 0.91 mmol, 7 molE). and oxygen was bubbled through the nixtIure until the reaction was deemed completed (generally 4.5 h) by TLC Chexane-ethyl acetate 4:1) or HPLC. The orange/brown reaction mixture was diluted wi%th ethyl acetate and the entire mixture filtered through a plug of flash silica (11 x 7 c:m) to remove the catalyst. The plug was 20 washed with ethyl acetate until the eluent was acarly colorless, The solvent concentrated in vacuo and the residue dried under high vacuum to afford the desired crude product s an orange solid (2.73 g, 86%). The crude product was used in the subsequent reaction without further purification. 25 The product was recrystalliscd from ethyl acetate/hexanes to afford red needles; m.p. 189-193" S ( t H) (3(0) MHz, CDC 3 ) 1.50, s, 2 x CH 3 ; 5.92, d, J 10.4 H2, H2; 6.43, d, J 10.4 Hz, Hi; 6.71, d, J 10.5 Hz, 119; 6.84, d, J 8.6 1-1z, H5; 7.72, d, J 10.5 Hz., H10; 7.97, d, J 8.6 Hz, H6. nVz (ES 4 , 30 V) 263 (M+Na, 9%), 242 (M+R+1, 19), 241 (M+H, 100). 30 Step 3: 9-Hydroxy-3,3-dinethyl-3H-n aphtho [2,1-bJpyran -7,10-dione A solution of 3,3-dimethyl-3H-naphtho[2,1-bIpyran-7,8-dione (4.59 g, 19.1 nmol) in WO 2005/095376 PCT/AU2005/000453 -28 toluene (340 mL) was washed twice with a solution of sodim dithionite (24.9 g, 0.143 mol) in water (250 mL). The yellow organic layer was there added in one portion to a oxygen saturated solution of potassium tert-butoxide ( 1 2.

19 g, 115 mnmol) in tert-butanol (110 rL) and the resulting mixture was stirred at room temperature with oxygen bubbling 5 for an additional 30 mn (NOTE: longer periods appears to result in reduced yield). The resultant dark red oludion was acidified with aqueous hydrocbloric acid solution (initially 2 M then 5 M) until the colour turns yellow/orange (pH - 1>. then water (- 40 mL) was added to dissolve the fonned salt, and the layers separated. The organic phase was washed with water (I x 85 mL), and then extracted with a saturated aqueous sodium hydrogen 10 carbonate solution (5 x 85 mL). The combined aqueous extracts were transferred back into the separating funnel and allowed to settle fur I h (to separate further amounts of toluene) and the layers separated again. The combined base extracts were cooled in an ice-salt bath, carefully acidified (aqueous hydrochloric acid, SM, - 80 ml) dropwise over 30 min with stirring until the colour turns pale yellowish (pH - 1-2). The resultant precipitate was 15 further cooled in the icc-salt bath with stirring, the solid collected, washed with water (-100 mL) to remove coloured impurities, and the orange/brown solid was recrystallised (absolute ethanol) to afford the desired product as orange coloured crystals (1.04 g, 21%), nip. 208" 6 (') (300 ME-z, CDC1 3 ) 1.48, s, 2 x CH 3 ; 5.94, c, j 10.5 Hz, F12; 6.23, s, H9; 7.03, d, .J 8.4 Hz, 115; 7.83, d, J 10.5 Hz, H1; 7.99, d, J 8.4 Hz, 16, m/z (ES", 100 V) 279 20 (M+Na, 100%), 257 (M+H, 46), 159 (46), 137 (49), 86 (44), 59 (50). Example 2 Compound 2: 8-Hydroxy.3,3-dimethyl-1,2-dih/ydro-3H-naphtho[2 1-bJpyran-7.10-dimue A mixture of 8-hydroxy-3,3-diniothyl-3H-naphtho[2,1-b]pyran-7,10-dione (132 mg, 0,52 25 rnmol) and platinum (IV) oxide (15 mg) in ethyl acetate C 15 mL) was stin-ed under an atmosphere of hydrogen for 7 h. The resulting mixture was stirred in air for 1 h then was filtered through a pad of diatomaccous earth, The pad was vvashed with ethyl acetate then the filtrate and washings were combined and cocnetrated ii-i vacuo to give a green solid (128 mg, 96%). Recrystallisation from ethyl acetate/hcxanes using activated charcoal gave 30 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho(2,1-blpyrar-7,10-iione m.p. 183.5-187". 6 ('H) (300 MHz, CDCI) 1,37, s, 2 x C143; 1.85, t, 16.8 Hli, 2 x H2; 3.30, t, J 6.8 HL, 2 x WO 2005/095376 PCT/AU2005/000453 - 29 H1; 6,20, s, H9; 7.03, d, J 8.6 Hz, 145; 7.98, d, J 8.6 Hz, H6. .mVz (ES*, 30 V) 259 (M+H, 77%), 174 (8B), 159 (100). Example 3 5 Compound 3: 8-Acetoxy-3,3-dimnethyl-3H-naphtlzo(2,1-b 4 pyran-7,1 0-dione Concentrated ulphuric acid (I drop) was added to a stired orange suspension of 8-hydroxy-3,3-dimethyl-3H-naphthoL2,1-blpyran-7,10-dioae (855 mg, 3.34 mmol) in acetic anhydride (10 miL) and the mixture was placed in an ail bath (oil bath temperature 1009 C). The mixture immediately became homogeneous red-black. After 10 mini the 10 mixture was cooled (ice/water bath) and water (50 mL) added. Products were extracted with ethyl acetate (150 mL), the organic phase separated, dried (Na 2

SO

4 ) and filtered .through a silica plug, washing the plug with ethyl acetate until no further colour eluted. The filtrate was concentrated in vacuo and the residue was cried ovemight under vacuum to afford the title compound as a red solid (965 mg, 97%), '1H NMR (300 MHz, CDC3) 5 15 1,48 (61H, s, 2 x CH 3 ), 2.37 (31, s, COCH,), 5.94 (iH, d, J 10.5 Hz, 1H2), 6.34 (I H, s, H9), 7.07 (1-, d, J8,4 Hz, H5), 7.73 (1H, d, J 10.5 Hz, Hi), 7.97, (1-1, d, J 8.4 Hz, 116). Example 4 Compound 4: 7,8,10-tiacetoxy-3,3-dinethyl-3 H-naphtho[,,1-b/pyran 20 A stirred solution of 8-Ihydroxy-3,3-dimethyl-3H-naphthol2,1-blpyran-7,10-dione (110 mg, 0.93 imol) in acetic anhydride (3 mL) and pyridhie (4 mL) was heated in an oil bath at 60*C fbr 15 min, Zinc powder (530 mg) was added in one portion and the mixture became pale yellow, After 15 min beating, the mixture was cooled to room temperature and filtered throuIgh a sinter (porosity 4), with ethyl acetate washings. The filtrate was 25 poured onto ice/water (20 mL) and acidified with aqueous Thydrochloric acid solution(2.0 M). The organic phase was separated and the aqueOus phase washed with ethyl acetate (3 x 50 mL). The combined organic phases were dried (Na 2

SC

4 ), filtered and concentrated in vacuo. The resulting solid was recrystalised from ethanol Lo afford the title compound as a colourless solid (96 rmg, 58%). IH NMR (300 MHz, CDCl 3 ) S 1.46 (6H, s, 2 x CH 3 ), 30 2.31 (3H, s, COCH3), 2.37 (3H, s, COCH3), 2.43 (3H, s, COCH3), 5.64 (1 H, d, J 10.1 Hz, -2), 7.11 (1 H, s, 119), 7.12 (11-, d, f 9.0 Hz, H6), 7.23 (11 , , 10.2 Hz, HI1), 7.67 (1 H, d, 1 9.0 Hz, H5).

WO 2005/095376 PCT/AU2005/000453 - 30 Example 5 Compound 5: 9-Brono-8hydroxy -3,3.dimethyl-3f.naphtho[2,1-blpy ran-T, 1 0-dione 0 OH OH Br 0 0 5 A solution of bromine (354 mg, 2.21 minol) in dry dichloromethane (4 nL) was added dropwise to a cooled (0' C) sohition of 8-hydroxy-3,3-dimiethyl-1,2-dihydro-3H naphtho[2,1-b]pyran-7,10-dione (506 mg, 1.96 nmol) in dry dichloromethanc (4 mL) containing 3 drops of glacial acetic acid. The cooling bath was removed and the mixture was stirred at room temperature for 20 min then concentrated in vacuo to alfcrd 9-brono 10 8-hydroxy-3,3-.diinethyl- 1,2-dihydro-3H-naphtho[2, 1 -bjpyran-7, 10-dione as a bright orange powder (635 mg, 96%): m.p. 213-216* C (Found: C, 53.5; H, 4.0, C, 5

H

3 BrO 4 requires C, 53.4: H, 3.9 %). vmx 3 316m, 1660s, 1642s, 1364s, 1286s, 12,62s, 1174m, I 114s, 1048s cn- 1 . 'H NMR (300 Mz, CDCl) 5 1.38 (6H, s, 2 x CH3), 137 (2H, t, J = 6.8 Hz, H2), 3,32 (2H, t, J= 6.8 1rz, H1), 7.06 (11H, d, J - 8.6 Hz, H5), 8.00 (L k1, d, J= 8.6 15 Hz, H6). m/z (FSI*) 339 (M[ 8 1 BrJ+H), 337 (Mf7Brj+H). Example 6 Compound 6; 9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[I2.b]pyran-7,20-dione Canpound 7: 2,9-dibromo-1,8-dlydroxy-3,3-dimethvl.1,2-dihzydro-3H-opFztho[2,1 20 bJpyran-7,10-dtone WO 2005/095376 PCT/AU2005/000453 -31 0 0 OH OH 0 Br Sodium hydride (42 mg, 80% dispersion in oil, 1.40 mmol) was washed with dry hexane then the supernatant was removed. The residual solid was dried Lnder a stream of 5 nitrogen. A solution of 8-hydroxy-3,3-dimethyl-3H-naphthoZ, 1-hjpyran-7,10-dione (327 mg, 1.28 mnol) in tetrahydrofuran (5 mlL) was added and the resulting solution was stirred at room temperature for 10 mmn. This was cooled to 0* C and a solution of bromine (265 mg, 1.66 mmol) in dry dichloroinethane (3 mL) was added. The mixture was allowed to warm to room temperature and tired for 20 min, after which the solvents were 10 concentrated in vacuo to afford a brown residue. Flash chromatography (20-50% ethyl acetate/hexane with 1% glacial acetic acid) afforded 9-bromu-S-hydroxy-3,3-dimethyl-3H naphtho2,1-h]pyran-7,10-dionc as an orange-brown solid (43 ng, 10%). (Found: M+H, 334,9909, 336.9887, CisH1- 2 BrO 4 * requires 334.9919, 336.9920). 'H NMR (300 MHz, CDCh) 6 1.49 (6B, s, 2 x CH3), 5.99 (1H, d, J= 10.2 Hz, -I2). 7.05 (11, d, J= 8.4 Hz, 15 H5), 7.75 (1 H, bs, OH), 7.82 (1h, d, J = 10.2 Hz, Hi), 8.01 (1 H, d, J = 8.4 Hz, H6). mh (ESl*) 337 (M[ 5 Br]+H), 335 (M."Brl+1). Also recovered from the flash chromatography column was crude compound 6 contaminated with a product of pyran ring bromination compoundd 7). This was subjected 20 to preparative HPLC (isocratic 60%A, 40%B) and gave a conpound suspected of being 2,9.dibromo-1, 8-dihydroxy-3,3.-dimnethyl-1,2-dihydro-3H-napAtho[2,1 -b]pyran-7,10-dione (3 mg, 0.5%), m.p. 202.5-205' (Found: M+H, 412.9011, 414.898]. 416.8961. ICisHu Br20s - H20 t* requires 412.9024, 414.9005, 416.8987'). v : 3475w, 1664m, 1582m, 1370n, 1284s, 1262s, 11 84m, 1122nm, 1016m em-. S ('H) (300 MHz, CDCI 3

)

WO 2005/095376 PCT/AU2005/000453 - 32 1.59, s, CH3: 1.66, s, CH 3 ; 4.42, d, J 3.8 Hz, H2; 4.73, bs, OH; 5.50, d, J 3.8 Hz, H I; 7.22, d, J 8.7 Hz, R5; 8.13, d, J 8.7 Hz, 116. rn/z (ES*, 70 V) 457 (MIl"Br][ EBrj+iNa, 13%), 455

(M[

1 BrIi! " t 'Br]+Na. 31), 453 (M[Brj["'Brl+Na, 22), 435 (M["Br][blBrj+*-H, 7), 433 (M[BrI I 9 Br)+H, 18), 431 (M[7Br][7'Brl+H, 12), 417 (M[ 1 "Brj[E"Brl-FtO+H, 16), 415 5 (M[ 8 1 BrIt "Brl-H 2 0+H, 36), 413 (M[ 9 BrUf 7 18r-H 2 O+H, 20), 336 (M-l "]Er +H 2 o]+H, 100), 334 (M-[ "Br +1120 ]+H, 100). Example 7 Compound 8 9-Bromo-3,3-dimethyl-8.(4-methylbenzenesulfonylorxy)-.1,2-dihydro-3H 10 nap htio[2,l-blpyran-7,10-dione Compound .9: 9-Bromo-3,3-dimethyl-8-(4-methylbenzenesulfonylaxy)-3H-naphtho[2,1 b]pyran-7,10-dione 15 o 0 OH- . . o O O I Br & Br + 0 Br o 0 0 Pyridine (0.40 mL 4.95 mmol) was added to a cooled (0Q C), stirred solution of 9-bromo-8 20 hydroxy-3,3-dinethyl- 1,2-dihydro-3H-naphtho[2,1-b Ipyran-7, 10-dione (550 mg, 1.63 mrnmol) in dry dichloromnethane (10 nL) under nitrogen. A. solution of 4 niethylbenzenesulfonyl chloride (350 mg, 1.84 mmol) in dry dichloraithane (8 nIL) was added dropwise, then stirring was continued for 1.5 h at 0' C. Diisoprerylethylamine (2.5 mL, 14.4 mmol) was added and stirring was continued for a further 3 h when aqueous WO 2005/095376 PCT/AU2005/000453 -33 hydrochloric acid solution (2.0 M) was added. Products were extracted Wih dichloromethane and ethyl acetate, and the combined extracts dried, filtered and concentrated in vacuo to afford a brown solid (798 mg). Trituration of this with ethydl acetate/hexane gave a yellow solid (610 mg) which by 1 H NM spectroscopy contained 5 -10% of the unsaturated pyran (compound 9). A sample of the above yellow solid (560 mg) was dissolved in ethyl acetate (30 mL) aitd platinum (IV) oxide (25 mng) was added. The resulting mixture was stirred under itn atmosphere of hydrogen for 8.5 h after which it was filtered through a pad of Celite* aud 10 the filtrate was stirred in air at room temperature overnight Concentration in vacuo gave a b-rown solid which contained -5% of the unsaturated pyran (compound 9) by 'H NMR spectroscopy. The above hydrogenation was repeated on this solid using platinum (1v) oxide (69 mg) in ethyl acetate (35 ml.) under hydrogen at room temperature overnight, The mixture was fihered through a pad of Colite" and the filtrate concentrated in vacuo to 15 afford a brown residue (580 mg). Th is was dissolved in acetonitrile (45 rnL) and a solution of ceric ammoniuni nitrate (617 mg) in water (20 m-L) was added dropwise. The resuhirg mixture was stirred at room temperature for 2 h and water (35 niL) was added, 2The resulting precipitate was collected by filtration, washed with water, hexane and dried under vacuum for 2 h at 400 C to give 9-bromo-3,3-dimethy1-8-(4-methylbenzenesulfonyloxy) 20 1,2-dihvdro-3H-naphthot2,1-h]pyran-7,10-dione as a brown solid (300 mg, 41%): rrxp. 109-115' C (Found: C, 53,6; H, 4.1. C22HsBrOOS requires C, 53.8; H, 3.9 %), vm 1672s, 158im, 1370s, 1302s, 1288s, 1222m, 1202m, 1174s, 994s, 718s cm. H NMR (300 MHz, CDC1q) 4 1.37 (6H, s, 2 x CH), 1.87 (2H, t, J = 63 Hz, H2), 2.50 (3R. s, ArCH 3 ), 3.27 (2H, t, J= 6.3 Hz, H1), 7.11 (1H, d, J= 8.4 Hz, H5), 7.41 (211, d, J= 7.8 -. , 25 13'), 7.98 (3H, app d, J 8. 1 HIz, 2 x H2' and H6),. m/z (ESI) 493 (M["Brf+H, 491 (ME 9 Br]+H), WO 2005/095376 PCT/AU2005/000453 - 34 Example 8 Compound 9: 9.Bromo-3,3-dimethyl-8-(4-neItylbenzene.sulfonyloxy)-3H-naphthao(2,1 b]pyran-7,10-4ione 00 OH OH O ~ O O Br 0 r 0 0 5 Pyridine (0.15 mL 1.85 mmol) was added to a cooled (QO C), stirred solution of 9-bromo-8 liydroxy-3,3.dimethyl-311-naphtho[2,1-b pyran-7,10-dione (235 mg, 0.70 mmol) in dry dichloromethane (5 mL) under nitrogen. A solution of 4-methylbenzenesulfonyl chloride 10 (0.148 ng, 0.78 mmol) in dry dichloromethane (4 mL) was added dropwise, and stirring was continued for 1 h at 0' C. Diisopropylethylanine (1.0 mL, 5,74 mmol) was added and stirring was continued for a further 3 h when aqueous hydrochloric acid solution (1.0 M) was added. Products were extracted with dichloromethane and ethyl acetate, and the combined extracts dried, filtered and concentrated in vacuo to afford a brown solid. Flash 15 chromatography (ethyl aectate/hexane 3:7) afforded 9-bromo-3,3-dimethyl-8-(4 methylbenzenesulfonyloxy)-3H-naphtho[2,1-bIpyran-7,10-dione as a brown soLid (97 mg, 28%): m.p. 167-168' C (Found: M+l, 490.998, 488.999. CnaHisBrO6S requires 490.999, 489.001). vat 1672s, J388, 1288s, 121 Sm, 1172s, 1 112m, 1018m, 1004mu, 732s, 706mn, 688 cm'. 'H4 NMR (300 MHz, CDC13) U.1.49 (6H, s, 2 x CH 3 ), 2.50 (3H, s, ArCH 3 ), 6.00 20 (1 R, d, J = 10,5 Hz, H2), 7,10 (111, d, J R.4 lz, HS). 7.41 (2H, d, J = 8.1 Hz, ~3'), 7.69 (1it, d, J 10.5 Hz, H1), 7.98 (2H, d, J = 8.1 Hz, H2), 8.00 (1H, d, J= 8.4 Hz, H6). n/z (EST) 491 (MIX Br]+H), 490 (M[Bzr]+H+I) WO 2005/095376 PCT/AU2005/000453 - 35 Example 9: Compound 10: 8-Bromo-3,3-dimethyl-9-(4-nethylbenizenesrfonyloxy)-3H.naphtho[2,1 bipyran-7,10-dione 5 Step I 3,3-Dimethyl-3H-naphtho[2,1-blpyran-9-ol HoN OH ' HOO , =OO - 0 0 OH 10 A mixture of 2,7-dihydroxynaphthalene (33.2 g, 207 mmol), 3-methyl-2-butenal (20.0 rnL, 207 mmol) and pyridine (17.0 rnL) was heated at 110' C for 20 h under nitrogen. The mixture was cooled to room temperature and diluted with diethyl ether (150 mL). The organic phase was separated and washed successively with aqucous sulphuric acid solution 15 (5%, 150 ml), water (150 niL), aqueous sodium hydrocn carbonate solution (5%, 150 mL) and water (150 muL). The organic phase was dried, filtered and concentrated in vacuao to afford 3,3-dimothyl-3H-naphtho[2,1-b]pyran-9-ol as a buff coloured solid (43.1 g, 92%): 'H NMR (300 MHz, CDCb) 5 1.48 (6H, s, 2 x CH3), 4.99 (I, br s, OH), 5.67 (1H, d, J= 10 Hz, H2), 6.84-6.93 (31H, m, H1, -1, H8), 7.23 (1 Rf, d, J 2.3 = Hz, H10), 7.55 (1H, 20 d, J 8.8 Hz, H6), 7.63 (111, d, J = 8.8 Hz, R7). n/z (FAB, 3NBA/MeOH) 227 (M+H, 68%). Step 2 25 3,3-Dimethyl-3H-naphtho[2,1-bIpyran-9, 10-dione WO 2005/095376 PCT/AU2005/000453 -36 N OH O N, N'-Bis(salicylidene)ethylenediamninocobalt(II) hydrate (4.5 g, 14 mmoml) was added to a stirred solution of 3,3-dimethyl-3H-naphthot2,1-blpyran-9-ol (43.2 g, 190 nmol) in 5 pcetonitrile (1.0 L) and oxygen bubbled through the mixture with reaction progress monitored by HPLC. Further portions of the catalyst (4.1g, 3.4 g and 2.7 g) were added after 18.5 h, 24.5 h and 44.5 h respectively. After 112 h in total, 1PLC showed no starting naphthol and the mixture was filtered though a silica pad (5 x 12 cm), washing the pad with ethyl acetate until no further red colour eluded. The filtrate was concentrated in vacuo 10 and the resulting residue recrystallised from ethyl acetate/hexane to afford 3,3-dimethyl 3H-naphtho[2,1-b]pyran-9,10-dione as maroon needles (14.5 g, 32%): imp. 109-1104 C. 'H NMR (300 MHz, CDCI 3 ) 6 1.46 (6H, s, 2 x CH 3 ), 6,00 (1P, d, J= 10.3 Hz, H2), 6.27 (I H, d, J= 10 Hz, HB), 6.98 (1 H, d, J = 8.2 Hz, H5), 7.09 (1H, d, J= 8.2 Hz, 16), 7,32 (1H, d, J= 10.3 Hz, H11). m/z (FA B, 3NBA/MeOH) 242 (M+H+1, 52%), 15 Step 3 9-Hydroxy-3,3-dinethyl-3H-naphtho[2,1-bJpyran-7,10-dione N o N-0 0 ~ Q o~ OH 20 A solution of 3,3-dimethyl-3H-naphthu[2,1-b]pyran-9,10-dione (14,5 g, 60.3 nial) in toluene (850 aL) was washed twice with a solution of sodium dithionite (84 g) in water (850 mL). The resulting pale yellow solution was then added to a solution of potassium 25 ter-butoxide (37.0 g, 330 nanol) in wert-butanil (370 mL) saturated with oxygen. Thc.

WO 2005/095376 PCT/AU2005/000453 -37 resulting mixture was stirred at ambient temperature for 30 min. after which aqueous hydrochloric acid solution (1.0 M, 250 nL) was added. The organic phase was separated and extracted with saturated aqueous sodium hydrogen carbonate (3 x 250 mL). The combined aqueous extracts wore cooled (ice/water bath) and acidified with concentrated 5 hydrochloric acid. The resulting precipitate was collected by filtration and washed with water (1.0 L) and dried under vacuum for 2 h at 40* C to afford 9-hydroxy-3.3-dimethyl 3H-naphtho[2,1-b]pyran-7,10-dione as an orange solid (7.10 g, 46%): 'H NMR (300 MHz, CDCl3) 8 1.47 (6H, s, 2 x CH 3 ), 5.99 (iH, d, J = 10.4 Hz, H2), 6.25 (1H, s, HS), 7.11 (1H, dd, J = 8.4, 0,6 Hz, HS), 7.47 (1H, s, OH), 7.76 (dd, J= 10.4, 0.6 Hz, HIl), 7.97 (IH, d, J 10 8.5 Hz, H6. tn/z (FAD, 3NBA/MeOH) 258 (M+H+1. 50%), 257 (M+H, 100). Step 4 8-Bromo-3,3-dimethyl-9-(4-methylbenzcnesulfonyloxy)-3 H-naphtho[2,1-]pyran-7,10 15 dione 00 o ,OH OH Br Br 0 0 Sodium hydride (12 mg, 80% dispersion in oil, 0.40 mmol) was added to a solution of 9. hydroxy-3,3-dimcthyl-3H-naphthc[2,1-b]pyran-7,10-dione (100 mg, 0.39 mmol) in 20 tetrahydrofuran (2 mL) and the mixture was stirred at room temperature for 10 min, The suspension was cooled to 04 C, and a solution of bromine (70 mg, 0,44 mnol) in dichloromethane (1 ni) was added. The orange solution was allowed to warni to room temperature then stirred for 20 min. Aqueous hydrochloric acid solution (1.0 M) was added and the product was extracted with dichloromethane and ethyl acetate, The 25 combined organic phases were dried, filtered and concentrated in vacuo to give a brown residue (129 mg, 99%).

WO 2005/095376 PCT/AU2005/000453 - 38 Pyridine (25 iL, 0.31 mmol) was added to a cooled (QO C), stirred solution of the above 8 bromo-9-hydroxy-3,3-dimethyl-3H-naphthol 2,1 -bjpynmn-7, 10-dione (25 mg, 0.07 mmol) in dry dichloromethane (1 mL). A solution of 4-mcthylbenzenesulfonyl chloride (17 mg, 0.09 mmol) in dry dichloromethane (1 mL) was added dropwise, then stirring was S continued for I h at 00 C. Diisopropylethylamine (115 pl., 0.66 mmol) was added and stirring was continued for a further 3 h when aqueous hydrochloric acid solution (1.0 M) was added and the mixture extracted with dichloromethane and ethyl acetate. The combined organic phases were dried, filtered and concentrated in vacuo to afford 8-bromo 3,3-dimcthyl-9-(4-methylbenzeneulfonyloxy)-3H-naphthof2,1-bjpyran-7,1.0-dione as a 10 brown solid (35 mg, 95%): im.p. i8I5-1840 C (Found: C, 54.0; H, 3.5. CnHIBrOS requires C, 54.0; 11, 3.5 %). v,, 1678m, 1382s, 1294s, 1285s, ll83n, 112Sm, 1062m, 986m, 806s, 682s, 564m cm 1 . 'H NMR (300 MHz, CDC 1 ) 6 1.49 (6H, s, 2 x CH 3 ), 2.50 (3H, s, AiC), 5.98 (1H, d, J= 10.5 Hz. H2), 7.09 (1H, d. J 8.4 Hz, H5), 7,41 (2H, d, J = 8.3 H z, H3'), 7.70 (1 H, d, .= 10.5 Hz, ff1), 7.98 (2H, d, j= 8.3 Hz, 142'), 8.04 (11H, d, J 15 9A Hz, H6), m/z (ESl') 491 (M[ 8 BrI+H), (Mt"Br]+H) Exam ple 10 Compound 11: 8-Bromo-3,3.dimethyl-9-(4.methylbenzenesulfonyloxy)-1,2-dihydro-3L nzaphtha[2,1-b]pyran.7,10-dione 20 0 0 -0 0 Br Br 0o Platinum (IV) oxide (25 mg) was added to a solution of 8-bromo-3,3-dimethyl-9-(4 methylbenzcnosulfonyloxy)-3H.naphtho[2,1-b]pyran-7,10-diane (199 ng, 0.41 mmol) 25 in ethyl acetate (8 nL) and the resulting suspension was stirred under an atmosphere of WO 2005/095376 PCT/AU2005/000453 - 39 hydrogen for 28 h, The reaction was filtered through a pad of Celite.® and the filter cake was Washed with ethyl acetate and dichloromethane. The filtrate and washings were combined, dried, filtered and concentrated in vacuo to afford a brown residue which was dissolved in acetonitrile (20 mL) and cooled to O C. A solution of ceric 5 ammonium nitrate (200 mg, 0.36 mmol) in water (6 mL) was then added and the mixture was allowed to warm to room temperature and stirred for 2 h, after which it was diluted with water. Products were extracted with dichloromethane, and the extract dried, filtered and concentrated in vacuo to afford 8-brono-3,3-dinethyl-9-(4 methylbenzenesulfonyloxy)-1,2-dihydro-3H-naphtho[2,1-blpyran-7,10-dione as an 10 orange.-brown solid (193 mg, 97%): m.p. 168-169.54 C (Found: C, 53.6; H, 3.,

C

22

H

1 yBrO 6 S requires C, 53.8; H, 3.9 %). v, 1680s, 1668m, 1620m, 1578w, 1566w, 1382s, 1290s em-.. I NMR (300 MHz, CDCl 3 ) 6 1.37 (6H, s, 2 x CH 3 ), 1.87 (2H, t, J =-6,2 Hz, Ff2), 2.50 (3H, s, ArCH 3 ), 3.27 (2H, t, J= 6.2 Hz, HI), 7.10 (1 H, d, J 8.6 = Hz, H5), 7.41 (2H, d, J = 7.7 Hz, H3'), 7.97 (2H, d, J = 7.7 Hz, H2'), 8.03 (1H, d, J = 15 8.6 Hz, H16). n/z (ESI) (M[Br1+H), 491 (M["'BI'j+11). Exam ple 11 Compound 12: 8,9-Dichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho[2,1.bpyraiz-7,10 dione 20 Step 1 9-Hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-bjpyran-7,10-dione 25 WO 2005/095376 PCT/AU2005/000453 -40 0 OH 0 . OH 0 0 A mixture of 9-hydroxy-3,3-dimethyl-3H-naphthol2,1-b]pyran-7,10-dione (1.20 g, 4,6 mmol) and platinum(IV) oxide (125 rg) in ethyl acetate (30 mL) was stirred under 5 hydrogen for 3.5 h. The dark mixture was allowed to stir exposed to air for 30 min before filtration through a plug of Celite*. Concentration of the filtrate in vacuo gave a yellow residue which was subjected to flash chromatography (ethyl acetate/hexane 7:3 with 1% glacial acetic acid) followed by recrystallisation from ethyl ocetate/hexane to give 9 hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-blpyran-7,10-dione as yellow needles 10 (948 mg, 79%): m.p. 155' C (subL), >177' C (dec). vmax 3328, 3148, 3108, 1656, 1628, 1566 cm 1 . 'H NMR (300 Mz, CDC) 6 1.38 (6H, s, 2 x CH3), 1.89 (21-f, i, J= 6.5 Hz, 142), 3.29 (21, t, J = 6,5 Hz, 113), 6.25 (11, s, H8), 7.13 (1 H, d, J = 8.5 Hz, H5), 7.47 (1H, s, OH), 7.97 (11, d,. = 8.5 Hz, H6). rn/z (FAD, 3NBA/MeO 1) 261 (M+1+2, 11%), 260 (M+Hi+1, 27%), 259 (M+H, 51). 15 Step 2 9-Chloro-3,3-dimeLhyl-1,2-dihydro-3H-naphthol2,1-b]pyran-7,10-dione 0OH 20 20 00 9-]H[ydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-bpyran-7,10-dione (1.1 g, 4.3 mmol) was dissolved in dichloromethane (20 nL) and thionyl chloride (15 iL). The reaction was stirred at room temperature for 24 h and the volatiles were removed in vacuo, WO 2005/095376 PCT/AU2005/000453 - 41 The residue was dissolved in ethyl acetate (30 mL), washed with water (30 nL), dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/hexane 5:95) followed by recrystallisation from ethanol to give 9-chloro-3,3 dimeLhyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione as orange neodles (633 mg, 5 53%): m.p. 140-2' C (Found: C, 64.9; H,4.8. C 1 5

H

13 C10 3 requires C, 65.1; H, 4.7%). Amux (log e) 216, 268, 350 sh, 412 nm (4,35, 4.25, 3,23, 3.44). vma 3700-3300s br, 3070w, 3000w, 1680s, 1660s, 1620m, 1590m, 1580s cm' H NMR (300 MHz, CDCla) 8 1.38 (611, s, 2x CHI 3 ). 1.88 (2H, t, J = 7.0 -lz, H2), 3.29 (211, t, J = 7.0 Hz, H1), 7.12 (1H, d, J= 8.5 Hz, 115), 7.12 (, s, H18), 7.95 (1H, d, = 8.5 Hz, 116). n/z (FA B, 3NBA) 280 10 (M[ 37 ClJ+Ht+1, 14%), 279 (MfP 7 Cl]+H, 40), 278 (M1 35 Cl]+H+l, 49), 277 (M[ 35 CIJ+H, 100), 276 (44),233 (17). Step 3 15 8,9-D ichloro-3,3-dimethyl -1,2-dihydro-3H-naphthoL2,1-blpyian-7,10-dione 0 O CI CI 0 Chlorine gas was bubbled through a solution of 9-chloro-3,3-dimethyl-1,2-dihydro-3H 20 naphthol2,1-blpyran-7,10-dione (633 mg, 2.3 mmol) in glacial acetic acid (50 mL) containing concentrated hydrochloric acid (5 drops) at 70" C for 5 nn. The reaction was stirred for 55 min at 701 C, cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography (toluene/hexano 7:3) tO give 8,9- dichloro 3,3-dimethyl -1,2-dihydro-3H-naphtho[2,1-bjpyran-7,10-dione as an orange solid (508 mg, 25 71%). A sample of this material was recrystallised from ethanol to give orange micro crystals: m.p. 158-60* C (Found: C, 57.9; H, 3.7. CISH 12 C10 3 requires C; 57.9; H, 3.9%). Xm\ (log e) 220, 275, 290 sh, 350 sh, 412 nm (4.32, 4.19, 4,01, 3.29, 3.38). vmn WO 2005/095376 PCT/AU2005/000453 - 42 3700- 3330m br, 3050m. 2950m. 1700s, 1680m, 1600m, 1580s cm- 1 . 'H NMR (300 MHz, CDCl) 6 1.3B (6H, s, 2 x CH 3 ), 1.88 (2H, t, J = 7.0 Hz, 112), 3,27 (211, t, J = 7.0 H1 ), 7.12 (1, d, J = 8.5 Hz, 145), 8,04 (114, d, J = 8.5 Hz, H6). n/z (FAB, 3NBA) 315

(MP

7 Cl 2 }+H, 16%), 314 (M[ 37 C1 35 CIJ+H+1, 32), 313 (N4[ 37 Ci 35 CiI+H, 74), 312 5 (M[ 5 C1 2 ]+H+1, 64), 311 (M[ 35 Cl 2 J+H, 100), 310 (42), 309 (16). Example 12 Compound 13: Sodium 3,3.dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo[fchromenl-8 odate or Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3F-benzoftfchromen-10-olate 10 0 0 OH NaOH ONa I -or 0 O 0 ONa Aqueous sodium hydroxide (2.0 M, 3.38 mL, 6.75 mmo) was added drmpwise to a stirred 15 orange suspension of compound 1 (1,73 g, 6.75 mmol) in methanol (10 nL). The mixture became homogencous Ted. After 30 min volatiles were removed in VwCu and the resulting red residue dissolved in water (150 niL.), Filtered (porosity 4 sinter) and freeze dried for 48 h. Compound 13 was obtained as a red solid (1.80 g, 96%): 'H NMR (300 MHz,

D

6 DMSO) J 1.38 (6H. s, 2 x C1t), 5.26 (1H, s, H9), 5.82 (1W, d, J 10.2 1 (z, R2). 6.83 20 (1H, d, J = 8.4 Hz, 116), 7.64 ( K d, J = 8.4 Hzt, H5), 8.14 (I R, d, J= 10.2 Hz, 1-11). in/ (ESt 30 V) 257 (M-Na+H, 100%); HPLC 100%/ 4.74 min. The 1H NMR can also be run in D20, compound 13 is fully soluble in water at 10 mg/mL 25 HPLC Conditions WO 2005/095376 PCT/AU2005/000453 - 43 Performed on Water 2690 Alliance System, using a Waters C18 5 pmn Synmietry Column (Part # WAT046980) and a flow rato of 0.7 il.min. Column temperature of 30" C and measured at X=254 nM, Buffers: 5 Buffer A: 100% water Buffer B: 100% Buxffer C: 2 % aqueous formic acid Gradient (linear gradient clave "6") 10 min 5 min 45% A:50% B:5% C - 95% B:5% c -- 95% B:5% C j 1 min 45% A;50% 8:5% C 45% A:50% 8:5% C 10 Example 13 Compound 14: 8-Hydroxy-3-nethyl-3-phenyl-3H.benzo[fjchronene.7,10-dione Step 1 15 3-Methyl-3-phenyl-3H-benzolfchromen-8-ol N NOH H H HO A stired suspension of 2,6-dihydroxy naphthalene (7)6 mg, 4.47 mol) in toluene (200 20 mL) was heated to reflux (oil bath temperature 160 C). After I h, the mixture was homogeneous and p-toluenc sulphonic acid hydrate (54 mg, 0.40 mmol) was added followed by a solution of 2-phenyl-but-3-yn-2-ol (588 mg, 4.02 mmol) in toluene (50 niL) over 20 min while maintaining reflux. TLC (ethyl acetate/hexane 1:4) after 4 h showed WO 2005/095376 PCT/AU2005/000453 -44 very faint 2,6-dihydroxy naphthalene. After a further 2 h, the mixture was cooled to room temperature and washed with aqueous sodium hydroxide solution (10%, 400 ml). The organic phase was diluted with ethyl acetate (100 niL), dried (Na 2

SO

4 ), filtered and concentrated in vacuo to afford a black semi-solid (804 mg). This was dissolved in ethyl 5 acetaLe/hexane/dichloromothane/methanol (1 niL: 4 mL: 1 niL: 1 mL) and subjected to flask chromatography, eluting with ethyl acetate/hexane 1:4. 3-Methyl-3-phcnyl-JH benzomchromen-S-ol was obtained as a brown solid (230 Mg. 18): MS (E$T) m/z 287 (M 1). HPLC 99.3 %/ 7.58 min 10 Step2 3-Methyl -3-phenyl-3 H-benzo[flehromene-7,8di one Co(SALEN) 2 , 02 0 15 Co(SALEN) 2 (23 mg) was added in one portion to a stirred homogenous yellow solution of 3-mothyl-3-phenyl-3H-benzo[fehronen-s-ol (217 mg, 0.75 mmol) in acebonitrile (3 mL). Oxygen was bubbled through the mixture and after 90 min the mixture was filtered through a silica plug, washing the plug with ethyl acetate until no further colour eluted. 20 Volatiles were removed in vacuo to afford 3-methyl-3-phenyl-3H-benzo[flchromene-7,8 dione as an orange solid (228 ing, 100%): 'R NMR (300 MHz, CDCl 2 ) 8 1.86 (3H, s, CH1) 6.25 (1H, d, J = 10.2 Hz, H2), 6.43 (1H, d, J= 10.5 147, H9), 6.85 (1 H, d, J = 10.2 Hz, HI), 6.97 (1, d, J= 8.4 Hz, H6), 7.35 (514, m, Ar-), 7.72 (1H, d, -T 10,5 Hz, H9), 7.99 (1 H, d, J = 8.4 Hz, 15) MS (EST) n/z 303 (M+i). 25 WO 2005/095376 PCT/AU2005/000453 - 45 Step 3 8-Hydroxy-3-mcthyl-3-phenyl.3H-benzcflchronmene-7,10-diono 4 N NaOH 5 0 Aqueous sodium hydroxide solution (4 M, 5 mL) was added to stirred orange suspension of 3-methyl-3-phenyIl-3H-benzolffchromene-7,8-dione (32 mg, 0.11 mrnmol) in ethanol (5 mL) and the mixture became homogeneous brown. After I h, the nuxture was cooled 10 (ice/water bath) and acidified to pH- 2.0 (5.0 M aqueous hydrochloric acid solution), The resulting orange suspension was stirred for 20 min in the cooling bath then at 10 min at room temperature. The precipitate was collected by filtration and washed with water (30 mL) then dried overnight under vacuum to afford 8-hydroxy-3-nethyl-3-phenyl-3H 'bcnzoflchromenc-7,10-dcrne as an orange solid (27 mg, 82%): 1H NMR (300 MHz, 15 CDCI) 8 1.84 (311, s, CH 3 ), 6.22 (11H, s,119), 6,26 (IH, d,J= 10.5 1z, H2), 7.14 (lI1, d,J = 8.7 lHz, H6), 7.20-7.45 (51-1, mn, ArH)l 8.05 (2H, m, 15 and H1). MS (ESI-) mIz 317 (Mvf J). HPLC 100 %/7.12 min. Example 14 20 Compound 15; 8-Hydroxy-3,3-diphenyl-3fl-benzooy]hromene-7,1.(tdione Step 1 3,3-Diphenyl-3H-benzof]]chromcn-8-ol WO 2005/095376 PCT/AU2005/000453 -46 OH -~ Ho HO A stirred suspension of 2,6-dihydroxy naphthalene (502 mg, 3.13 mmol) in toluene (200 mL) was heated to reflux (oil bath temperature 130' C). After 1. h, the mixture was 5 homogeneous and p-toluene sulphonic acid hydrate (54 nmg, 0.28 mmol) was added followed by a solution of 1,1-diphcnyl-prop-2-yn-1-ol (588 mg, 2.82 nmiol) in toluene (40 mL) over 30 min while maintaining reflux. After 2 d, the mixture was cooled to room .emperature and washed with aqueous sodium hydroxide solution (10%, 400 nL), The organic phase was diluted with ethyl acetate (200 mnL), dried (Na2SO4), filtered and 10 concentrated in vacuo to afford a black solid. This was dissolved in ehloroform/hexane (5 mL: 5 mL) and subjected to flash chromatography, eludng with chloroforn/iexane 1:1 then neat chloroform. 3,3-Diphenyl-3H-benzoflchronen-8-ol was obtained as a brown solid (213 mg, 19%): MS (FSM) ttV 287 (M-1). HPLC 80,3%/ 8.89 ni 15 Step2 3,.3-Diphcnyl-311-benzolfjchromene-7,8-dione

CO(SALEN)

2 , 02 0 N) Hoo HO20 200 WO 2005/095376 PCT/AU2005/000453 - 47 Co(SALEN) 2 (22 mg) was added in one portion to a stirred homogenous yellow solution of 3,3-diphenyl-3H-benzoUlchromen-8-oI (213 mg, 0.61 mmol) in acetonitrile (3 ML). Oxygen was bubbled through the mixture and after 3 h the mixture was filtered through a silica plug, washing the plug with ethyl acetate until no further colour eluted, Volatiles 5 were removed in vacuo to afford brown solid which was dissolved in dichloromethane and the solution subjected to flash chromatography, eluting with neat dichloroniethane, 3,3 Diphenyl-3H-benzoflchromene-7,8-dione was obtained as an orange solid (32 mg, 14%). MS (ESI) tn/z 365 (M+1). 10 Step 3 - 8-Hydroxy-3,3-diphcnyl-3H-benzo[fclehromone-7,10-dione 4 N NaOH 0N 0N I 0 HO o 0 15 Aqueous sodium hydroxide solution (4 M, 3 niL) was added to stirred orange suspension of 3,3-diphenyl-3H-bonz6[flchromene-7,8-dione (22 img, 0,06 imnol) in ethanol (3 mL) and the mixture became homogeneous brown. After 30 min, the mixture was cooled (icc/water bath) and acidified to pH- 2.0 (5.0 M aqueous hydrochloric acid solution). The resulting orange suspension was stirred for 20 min in the cooling bath then at 10 min at 20 room temperature. The precipitate was collected by filtration and washed with water (15 mnL). This residue was dissolved in ethyl acetate (5 mL) and filtered though a silica plug, eluting the plug with ethyl acetate (150 mL) then ethyl acetate/acetic acid (30:1), coLlecting 3 x 15 niL fractions. Fractions I and 2 were combined and concentrated in vacuo to afford 8-hydroxy-3,3-diphenyl-3H-benzo[f]choiene-7,10-dione as an orange solid (6 mg, 24%). 25 'H NMR (300 MHz, CDC) 3 6.23 (1H, s, H9), 6.45 (1 H, d, J = 10.4 Hz, H2), 7.20 (1H, d, WO 2005/095376 PCT/AU2005/000453 - 48 J - 8.4 lz, H6), 7.40 (10H, m, ArH), 8.00 (1 H, d, J 8.4 Hz, H5), 8.16 (1H, d, J= 10.4 Hz, Ii1). MS (ESF) m/z 381 (M+I). HPLC 86.5%/8.81 min.

WO 2005/095376 PCT/AU2005/000453 - 49 Antiviral Activity Tests of antiviral activity were performed in 2.2.15 human hepatorna cols infected with hepatitis B according to the method of Korba and Gerin, Antiviral Research, 19, 55-70 (1992). -Briefly, cells were seeded into 96 well plates and cell media containing various 5 concentrations of the compounds was added. Media was changed daily for 9 days and fresh media containing compound was added each day. On the I 06 day, viral DNA in the supernatant was measured and the reduction in the amount of virus in the supernatant was calculated compared to cells incubated without drug. Six separate replicates were performed for each drug concentration. The effective concenLration for 50% and 90% 10 inhibition of the replication of the virus was determined from dose response curves. Results for some compounds of the invention arc shown in Table 1. Table 1 Test Compound ECS PM EC90 pM Compound 1 0.6 3.4 Compound 2 1.1 13 15 Antiviral activity was also examined in HepG2 hepatoma cells infected with HBV containing mutations associated with resistance to lamivudine (3TC). rwo cell lines containing an L180iM mutation in tie HBV DNA polymerase, and a double L18OM/M204V mutation were used. Cells were plated out in six well plates and allowed 20 to attach overnight. Next day, the culture medium was replaced with either medium alone or medium containing the desired concentration of anti-viral compound. Media was changed for fresh medium with or without antiviral compound on day 3, On day 5, supernatant and cell lysates were analysed Fur levels of HBV core protein by non-denaturing Western blot using an anti-HBV core antibody, 25 Results for some of the compounds are shown in Table 2 where a 50% reduction or more in measured level of the viral core protein compared to controls at a compound concentration of greater than 50 pmolar is designated +. 50% core reduction at less than WO 2005/095376 PCT/AU20051000453 - 0 50lpmolar is designated + amd 50% core reduction at les.i than 10pinolar compound concentration is designated -i-+. Tabfle 2 Compound 1I+ Compound 5 + Compound 6 + CompoLund 13 +~

Claims (6)

1. A method of treatment or prophylaxis of hepatitis B virus in a subject comprising administering to said subject an effective amount of a compound of Formula (1) or 5 a pharmaceutically acceptable derivative, salt or prodrug thereof: R2 RI4 R Rn. R1 3 1 R5 04 10 R8 6 X R 7 D (1) wherein X is OH, OR 9 or halo: R and Rj are independently selected from H, Csalkyl, CZsalkenyl, C 2 6 alkynyl, 10 C 3 .6cycloalkyl, aryl, or together with the carbon atom to which they arc attached form a saturated or unsaturated C 3 carbocyclic ring; R 2 and R 3 are independently selected from 1-1, Cisealkyl, C 2 -alkenyl, Cualkynyl, C 3 6 cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond; 15 R4 and R5 are independently selected from H, C, 0 alkyl, C 2 ,alkenyl, Czsalkynyl, C 3 ucycloalkyl, OH, OR9, halo or NRimRim or together with the bond between the carbon atoms to which they are attached form a double bond; RG and R 7 are independently selected from I, Ci(alkyl, C 2 ualkenyl, C2.dalkynyl, C. 3 -cycloalkyl, OH or OR9; 20 Rs is independently selected from H, Cs 6 alkyl, C 2 ualkenyl, C 2 6 alkynyl, C3.scycloalkyl, OH,OR, or halo; WO 2005/095376 PCT/AU2005/000453 - 52 R, is CI.alkyl, C2. 6 alkenyl, C2.salkynyl, C3ucycloalkyl, aryl, C(=O)R 1 Or S(O)2R or OR 9 is an amino acid residue: each RIo is independently selected from H and C t1alkyl; Ru is Cim. 2 aLkyl, C 2 .. 1 alkenyl, C 2 . 21 alkynyl, C 3 -6cycloalky, CecycloalkylC alkyl, 5 aryl or arylC,.6alkyl; and Ra is Coalkyl, C2.6alkenyl, Cualkynyl or aryl.

2. A method according to claim 1 wherein the compound of formula (1) is a compound of formula (2): 10 R2 R4 R1 R5 0 OH (2) R and R 1 are independently selected from H, Cj. 6 alkyl, Calkenyl, C 2 ualkynyl, C 3 . 6 cycloalkyl, aryl, or together with the carbon atom to which they are attached 15 form a saturated or unsaturated Cycarbocyclic sing; R 2 and R 3 are independently selected frorn H, C1. 6 alkyl, C 2 . 6 alkenyl. C 2 . 6 alkynyl, Csccycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond; R 4 and R 5 are independently selected from H, Ci.oalkyl, C 2 . 6 alkenyl, C 2 ualkynyl, 20 C 3 gcycloalkyl, OH, OR 9 , halo or NRioRio or together with the bond between the carbon atoms to which they are attached form a double bond; R 9 is C,-alkyl, C 2 -alkenyl, Casalkynyl, C3.eycloalkyl, aryl, C(=O)R 1 , or S(O) 2 Ri 2 or OR 9 is an amino acid residue; WO 2005/095376 PCT/AU2005/000453 - 53 each Rw is independently selected from H end C±alkyl; Ril is C 12 1 alkyl, C2.n alkenyl, C 221 alkynyl, C 3 -cycloalkyl, CncycloalkylC., alkyi, aryl or arylCj 6 alkyl; and R 1 2 is Ci. 6 alkyl, Cu.5alkenyl, C2.dalkynyl or aryl. 5

3. The method of claim i wherein the compound of formula (1) is selected from the group consisting of:

8-hydroxy-3,3-dimcthyl-3H-naphtho[2,1-bjpyran-7,10-dione, 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-bIpyran-7,10-diane, 10 9-brono-8-hydroxy-3,3-dimethyl- 1,2-dihydro-3H-naphthol2, 1 -b]pyran-7, 10-dione,

9-bromo-8-hydroxy-3.,3-dimnethyl-3H-naphthol 2,1 -b]pyran-7, 10-dione, 9-brono-3,3-dimethyl-8-(4-niehylhenzenesulfonyloxy)- 1,2-dihydro-3H-naphrbo[2 1-b]pyran-7,10-dione, 9-brono-3,3-dinethyl-8-(4-methylbenzenesulfonyloxy)-3H-naphtio[2, I -b]pyran-7 15 ,10-dione, 8-acetoxy-3,3-dimeihyl-3H-naphtho(2, 1-b )pyran-7, 10-dione, 2,9-dibromo- 1,8-dihydroxy-3,3-dimothyl-1,2-dihydro-3Hf-naphhoI 2,1 -bpyran-7,1 0-dione, 8,9-dichloro-3,3-dimethyl-1,2-di hydro-3H-naphtho(2,1-blpyran-7, 1 0-dione, 20 7,8,1 0-tiacetoxy-3 ,3-dinethyl-3H-naphtil 2,1 -b]pyran, 9-Bramo-8-hydroxy-3,3-diniothyl-3H-naphtho[2, 1 -b]pyran-7, 10-dione. 9-Bromo-8-hydroxy-3,3-dirnethyl-3H-naphtho[2, 1-b pyran-7,10-dione. 9-Bromo-3,3-dimethyl-8-(4-niethylbenzenesulfonyloxy)-1 ,2-dihydro-3H naphtho[2, 1-bipyran-7,10-dione, 25 9-Bromo-3,3-dimethyl-S-(4-methylbenzenesulfonyloxy)-3H-naphtho(2, 1-b Ipyran 7,10-dione, 8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-3H-naphtl2o2, I -b]pyran 7,10-dione, S-Brono-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)- 1,2-dihydro-3H 30 naphtho[2,1-blpyran-7,10-dione, 8,9-Dichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho[2, 1-b pyran-7,10-dione, WO 2005/095376 PCT/AU2005/000453 -54 Sodium 3,3-dimnethyl--7,10-dioxo-7,10-dihydro-3H-benzolfjchromen-8-olato; Sodium 3,3-dimethyl-7,8-dioxo--7,8-dihydro-3H-benz lchronen-10-clate 8-Hydroxy-3-methyl-3-phenyl-31f-benzoflchromcne-7,10-dionc, and 8-I-lydroxy-3,3-diphonyl-3H-benzoflchromene-7, 10-dione. 5 4. A method according to claim 1 wherein the compound of formula (1) is selected from the group consisting of: 8-hydroxy-3,3-dimrethyl-3H-naphihoL2,1-blpyran-7, 10-dione, 8-hydroxy-3,3-dimothyl-1,2-dihydro-3H-naphthol2,1-bjpyran-7,10-dione). .10 5. The method of claim 1 wherein the compound of formula (1) is a compound of formula (3): Az R4 R, ReX 15 A? O (3) wherein X is OH, OR 9 or halo R and R 1 are independently selected from H, Ci. 4 alkyl, C 2 .ralkenyl, C 2 Nlkynyl, C 3 6 cycloalkyl, aryl, or together with the carbon atom to which they are attached 20 form a saturated or unsaturated Cj. 6 carbocyclic ring; R 2 and R. are independently selected from H, C 1 .alkyl, C 2 .6alkenyl, C 2 . 6 alkynyi, C 3 1,cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond; WO 2005/095376 PCT/AU2005/000453 - 55 R4 is selected from H, C 1 alkyl, C 2 -6alkenyl, C 2 .alkynyl, C 3 . 6 cycloalkyl, halo or NRoRio or together with Rs and the bond between the carbon atoms to which R4 and R5 are attached, form a double bond; Rs is selected from H, Calkyl, C .alkenyL, C 2 ,alkynyl, C 3 . 6 cycloalkyl, OH, OR 9 , 5 halo or NROR 1 O or together with R 4 and the bond between the carbon aloms to which R 4 and Rs are attached, form a double bond; Rr and R 7 are independently selected from H, C.alkyl, Cz.alkenyl, Cz. 6 alkynyl, C3.6cycloalkyl, OH or ORg; R 8 is independently selected from H,- Cl6alkyl, C 2 . 6 alkcny. C2. 6 alkynyl, 10 C3. 6 cycloalkyl, O, OR 9 or halo; RQ is Cj alkyl, C2-6alkenyl, C. (alkynyl, C24Cycloalkyl, aryl, C(=O)R,, or S(O)Ru2 or OR is an amino acid residue; each Rio is independently selected from H and C1salkyl; R 11 is C-21alkyl, C 2 . 21 alkenyl, C2. 2 1 alkynyl, C3.scycloalkyi, C 3 - 6 cycloalkylC 1 4alkyl, 15 aryl or arylCj-alkyl; and R 12 is Cjealkyl, C2 oalkenyi, C 2 -alkynyl or aryl. 6. A method according to any one of claims I to 5 further comprising administering a second therapeutic agent. 20 7, A compound of Formula (1) or a pharmaccutically acceptable derivative, salt or prodrug thereof: WO 2005/095376 PCT/AU2005/000453 -56 R?, R4 R Ra 2 7 0 - R3 i R 5 04 10 Re 5 ReX R7 O (1) wherein X is OH, ORO or halo; R and R 1 are independently selected from H, CI-alkyl, C 2 ualkenyl, Cisalkynyl, C35cycloalkyl, aryl, or together with the carbon atom to which they are attached 5 form a saturated or unsaturated C 3 4 carbocyclic ring; R2 and R3 are independently selected from H, C 1 alkyl, C 2 -6alkenyl, C 2 alkynyl, C 3 6 cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond; .R4 and R 5 are independently selected from H. Ci.salkyl, C 2 . 6 alkenyl, C 2 .alkynyl, 10 C:)cycloalky , OH, OR,, halo or NRwcRIO or together with the bond between the carbon atoms to which they arc attached form a double bond; Rq is C 1 .,alkyl, Cz 6 alkenyl, C2.alkynyl, C3 6 cycloalkyl, aryl, C(=O)Rn 1 or S(O) 2 R 1 2 or ORg is an amino acid residue; each RLO is independently selected from H and C-,alkyl; 15 Ra is C. 1 2 alkyl, C 2 1 alkenyl, C 2 ..Ialkynyl, C.cycloalkyl, C 3 .6cycloalkylCealkyl, aryl or aryJCIe6alkyl; and R 12 is Cq 1 ,alkyl, Caalkenyl, CZtalkynyl or aryl; with the proviso that when R and R1 are both methyl and R is OH or OR 9 , R. is not selected from OH, OR 9 or NHR 9 . 20 S. A compound according to claim 7 wherein the compound of Formula (1) is a compound of formula (2): WO 2005/095376 PCT/AU2005/000453 -57 R2 R4 - R3 R1 R, O O OH (2) R and R are independently selected from H4, C 1 .6alkyl, C2.alkcnyl, C2.aalkynyl, 5 C3,cycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated C3j6carbocyciic ring; R 2 and R 3 are independently selected from H, C 1 6 alkyl, C 2 u 6 alkenyl, C 2 . 0 alkynyl, C1.cycloalkyl or together with the bond between the carbon atoms to which they ore attached form a dOuLble bond; 10 R 4 and R 5 are independently selected from 11, C 2 -alkyl, C 2 . 0 alkonyl, C 2 ualkynyl, C3cycloalkyl, OH, OR 9 , halo or NRIORIO or together with the bond between the carbon atoms to which they are attached form a double bond; R6 and RI are independently selected from R, C .alkyl, C 26 alkenyl, C.2ualkynyl, C 3 . 0 cycloalkyl, OH or ORg; 15 Rg is independently selected from H, Cualkyl, Ccualkcnyl, Ctualkynyl, C3Mcycloalkyl, OH, OR 0 or halo; R 9 is C 1 .ralkyl, C 2 .Oalkenyl, C2ealkynyl, C.cycloalkyl, aryl, C(=O)R 1 or S(O)2R, or ORp is an amino acid residue; each R 3 o is independently selected from H and C 1 . 6 alkyl; 20 Rn is CI.2alkyl, C2.Ialkenyl, C 2 . 2 1 alkynyl, C3ucycloalkyl, CjscycloalkylC.ealkyl, aryl or arylClvakyl; and R3 2 is C 1 4 alkyl, C 2 . 6 alkenyl, C 2 6 alkynyl or aryl WO 2005/095376 PCT/AU2005/000453 - 58 9. A compound according to claim 7 wherein the compound of formula (1) is selected from the group consisting of: 8-hydroxy-3,3-dimcthyl-3H-naphtho[2,1-b]pyran-7,10-dione, 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphthof2,1-b]pyran-7,10-dione, 5 9-bromo-8-hydroxy-3,3-dimethyl-1,2-diliydro-3H-naphtho[2,1-h]pyran-7,10-dioane, 9-bromo-8-hydroxy-3,3 -di methyl-3H-n aphtho[2, 1-bjpyran-7, 10-di one, 9-bromo-3,3-dinethyl-8-(4-methylbenzenesulfonyloxy)- 1,2-dihydro-3H-naphtho[2 1 -bipyran-7,10-dione, 9-bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-3 tnapbtho[2, I -bpyran-7 10 , I 0-dione, 8-acetoxy-3,3-dimethyl-3 H-naphthol2,1-blpyran-7,10-dione, 2,9-dibromo-1,8-dibydroxy-3,3-dimethyl-1,2-dihydro-3H-naphlhol2,1-blpyran-7,I 0-dione, 8,9-dic.bloro-3 ,3-dimethyl-1,2-dihydro-3Hi-naphtho[2,1 -hjpyran-7,10-dione, 15 7,8,10-iriacetoxy-3,3-dimethyl-3 H-naphtho(2, 1-blpyran, 9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphthol 2,1-blpyran-7,10-dione. 9-Bromo-8-hydroxy-3,3-dimethyl-31-naphtho[2, 1-b]pyran -7,10-dianc, 9-Bromo-3,3-dimethyl-8-(4-methylhenzenesulfonyloxy)-1,2-dihydro-3H naphtho[2,1-h]pyran-7,10-dione. 20 9-Brono-3,3-dimethyl-8-(4-methlylbenzenesulfonyloxy)-3H-naphthoL2,1-b Ipytan 7,10-diane, S-Bromo-3,3-dimethyl-9-(4-methylbenzcnesuLfonyioxy)-3H-naphthor2, 1-hipyran 7,10-dione, 8-Bromo-3,3-dinethyl-9-(4-methylbenzensulfonyloxy).1,2-dihydro-311 25 naphthoF2,1-blpyran-7,10-dione, 8,9-Dichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho2,1-h]pyran-7,10-dione, Sodium 3,3-dimcthyl-7,10-dioxc-7,10-dihydro-3H-ienzo[flchromen-8-olate; Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3H-benzoUlchromen-10-olate; 8-H ydroxy-3-methyl-3-phenyl-3H-benzolflchromene-7,10-dione, and 30 8-Hydroxy-3,3-dipbenyl-3H-benzo[fjchromene-7,10-dione. WO 2005/095376 PCT/AU2005/000453 - 59 10. A compound according to claim 7 wherein the compound of formula (1) is selected [rom the group consisting of: 8-hydroxy-3,3-dimethyl-3H.-naphthot2,1-b ipyran-7,10-dione, 8-hydroxy-3,3-dimothyl-1,2-dihydro-3H-naphtho{2,] -b]pyran-7,10-dione). 5

11. The compound of claim 7 wherein the compound of formula (1) is a compound of formula (3): R 2 R4 RR R1e Re x 10 7 (3) wherein X is OR, ORq or halo R and R, are independently selected from H, C-zalkyl, C 2 . 0 alltenyl, C 2 oalkynyl, C 3 . 6 cycloalkyl, aryl, or together with the carbon atom to which they are attached 15 form a saturated or unsaturated C>-carbocyclic ring; R 2 and R 3 are independently selected from H, Cjtalkyl, C 2 .6alkenyl, C 2 .ralkynyl, C 2 .cycloalkyl or together with the bond between the carbon atoms to which they are attached formi a double bond; R1 4 is selected from H, Ct-6alkyl, C 2 6 alkenyl, C 2 .6alkynyl, C 3 4 cycloalkyl, halo or 20 NRIORio or together with R5 and the bond between the carbon atoms to which R4 and Rs are attached, form a double bond;. WO 2005/095376 PCT/AU2005/000453 -60 R 5 is selected from H, Cisalkyl, C 2 -alkenyl, C 2 . 6 alkynyl, C.fcycloalkyi, OH, OR, halo or NRiOR,e or together with R 4 and Lie bond between the caarbon atoms to which R 4 and RS are attached, form a double bond; R 0 and R 7 arc independently selected from H, Cl6alkyl, Ctsalkenyl, C 2 .aalkynyl, 5 C e. 6 cycloalkyl, OH or ORp; R 8 is independently selected from H, Ci.ealkyl, C 2 .6alkenyl, C 2 -6alkynyl Cr-cycloailkyl, OH, OR 0 or halo; R 9 is C-aalkyl, C 2 6 alkenyl, C 2 . 6 alkynyl, C 3 4cycloalkyl, aryl, C(=O')R I or S(O)2Ru or OR 9 is an amino acid residue; 10 each RIo is independcutly selected from H and Cp-alkyl; R1 is C1-21alkyl, C.2- 2 1 alkenyl, C 2 -Lalkynyl, C.6cycloalkyl, C3- 6 cyC-loalkylC bcalkyl, arylor aryIC alkyll; and R 12 is C,-alkyl, Cu 2 alkenyl, C 2 _alkynyl or aryl. 15 12. A pharmaceutical composition comprising a compound according to any one of claims 7 to 11 and a pharmaceutically acceptable carrier, diluent or excipient.