CA2561896A1 - Antiviral agents - Google Patents

Abstract

The present invention provides a method of treatment or prophylaxis of hepatitis B virus in a subject comprising administering an effective amount of a compound of formula (1) or a pharmaceutically acceptable derivative, salt or prodrug thereof. In addition, there is provided compounds of formula (1) and pharmaceutical compositions thereof. Further, methods of preparing compounds of formula (1) are disclosed.

Description

_1_ ANTIYIRAT. AGENT
Field of the Invention The present invention relates to the use of naphthapyrans as agents in the treatment md/or prophylaxis of hepatitis B, gharmaceutical compositions for use in such therapy and novel naphthopyrans, Background of the Invention Infection with human hepatitis B virus is a major public health problem because of the ahilit.y of the virus to cause acute and chronic itltcctians. Cbrotuc hepatitis B vi.ivs infection (hereinafter refewed to as "t~BV") causes serious liver disease in humans and frequexitly rasults izi cirrhosis and hcpataccllular carcinoma. Currently there is do completely effective therapy for the successful management of chronic HBV
infections.
The >250 million chronic HBV carriers throughout the wand are un~~bla to beneru from the commercial vaccine presently available.
Currcnt.ly available therapies far HBV are only partially effective and may be accompanied 2Q by deletericaua side effects. In addition, many patients develcap antiviral resistance resulting in tha loss of efficacy. Accordingly, a nu;d exists for new cffcctiva treatrnants for HBV.
It has now boon discovered that compounds caf Fc>rmuia (1) are active agents against hepatitis B virus.
Summ;~ry of the Inventitm According to one aspect of the present invention there is provided a method of treatment or praphytaxis of hepatitis; B virus in a subject comprising administering to said subject an 3p effective amount UL's compound of Formula (1 ):

R
Ra X
t1) whcrain X is OH, ORS or halo;
R and R1 are uidependently sclcctcd from H, C~.nalkyl, Cz~salkenyl, C~.~,alkynyl, C~.~oycloalkyl, aryl, ur together with the carhon atom to v~hich they are attached form a saturated or unsaturated C3_ticarbocyclic ring;
R? and R;~ are independently selected from Vii, Ct~a11cy1, C2.6alhcnyl, C~.~alkynyl, C3.6cyc1oa1kyl or togcdtcr with the bond between th.~ carbon atcams to v~i~ich they are attached form tt double hand;
R.t and RS arc indcp~;ndcntly selected from H, C, fialkyl, G~.oalkenyl, C~.balkynyl, C~.~cyclualkyl, OH, Ot~v, halo or NRloRlo or together with the bottd between the carbon atoms to which they arc attached farm a double hnnd;
R~ and Et~ are independently selected from H, Ci~;alkyl, Cz.c,alkenyl, C~.,~alkynyl, C~.~;oyclo~tll:yl, OH ur ORu;
Rs is iudepeuctently scls:eted from H, C~.~;alkyl, CzfiaElkenyl, C~.~alkynyl, t:~.6cycloalkyl, OH, ORv or halo;
R~ is C,.E;alkyl, CZ.fi~tlkenyl, Cz.halkynyl, C~-ocycloalkyla aryl, C(=O)R~~
or S(t~)~R~~ or ORy is an amino acid rcsiduc;
each 12,~ is independently selected from H and Ci.~;alh.y3;
R" is C~.~ralkyl, CZ.~,:~Ikenyl, C~ ztaJkynyl, C3.ficycloalk.yl, C3~cyclaaIkylC,.~alkyl, aryl or arylCr.~alkyl; and R~2 is Ci.dalkyl, Czfialkenyl, C~.~alkynyl c>r aryl.

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 medicament for the treatment or prophylaxis of hepatitis B virus.
According to yet a further aspect of the prevent invention there is provided a method of treatment or prophylaxis of hepatitis B virus comprisuig administering au effective amount of a compound of Formula (1) and a :second therapeutic agent.
According, tc7 anc7ther aspect c7f the invention there is provided a compoutld of rormula (1) with the proviso that when R and Rt are both methyl and R:~ is OH or ORu, R5 is not selected Frcym OH, ORy arNHRi{~.
According tc7 another aspect <7f the present invention tl~e1'e is provided a phartnaecutieal composition comprising a compound of Formula (l)and a pharmaceutically aceeptahle l5 cal-ier, excipient c7r adjLlvant, with the proviso that in the compound of Formula (1) when R and Rt are both methyl and R4 is OH or OR.>, R5 is not selected from OH, p129 or NFil~~a.
According to the present invention the compounds of rorrzlula (1) may be presented in the form of a pllu'tnaccutically acceptable derivative, ;;alt car prcldrug.
1)4txtilCd Tleryc;rigtion Throughout this specification and the elainl5 which follow, tmless the context requires otherwl:;e, the we?rd "compriae", and variat10n4 StlCh a5 ~~cotnpriscs~~ aLld ~~COITlprislll~~', Wlll be understood to imply the inclusion of a stated integer car step or group of integers or steps but. not the exclusion of any other integer or step or group of iritea~rs car steps.
The reference to any prior art in thin specification is not, aitd should not be takon as, an acknowlcd,gtncnt or any form of suggestion that that prior art forms part of the common general knowledge in Australia.

_q._ f1s used herein, the tcrtn "halo" or "halogen" refers tea tluoriuc (fluoro), clL1ari31e (chloro), bromine (brarno) Or ipdin~ (i0ila).
As used herein, the term "alkyl" either used alone or in compound terms such as NH(alkyl) or N(alkyl)2, refers tea manavalcnt straight chain ar branched hydrocarbon groups, having 1 to 3, 1 to 6, 1 to 10 or 1 to 21 carbon atoms as appropriate. For example, suitable alkyl groups include, but are not iinutcd to methyl, ethyl, propyl, isvprc>pyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-tnethylhutyl, 3-mcthylbutyl, n-hexyl, 2-, 3- or ~-methylpcntyl, 2-ethylbutyl, xt-beryl or 2-, 3-, 4-- ar 5-methylpentyl.
As used herein, the term "alkenyl" refet~s to straight chain or branched hy~i~acarbon groups haviry one or mare double bonds between carbon atoms, Suitable aLkenyl groups include, but are nco limited to ethenyl, propcnyl, isopropenyl, bycnyl, penfenyl and hexcnyl.
The term "alkytiyl" as used herein, refers to straight chain or branched hydrcacarbon groups cc>ntainirtg one car mare triple bands. Suitable alkynyl group:, inc:ludc, bud are not limited to ethynyl, grapynyl, but,ynyl, pentynyl and he~enyl.
Tlte term "cyclaal>;yl" as used herein, refers to cyclic hydrocarbon grvup5.
Suitable 2U c:ycloalkyl groups include, but are. not limited to cycloprapyl, cyclcabutyl, cyclopentyl and cyclohexyl.
T'he term "aryl" as u.~;ed hereist, refers to C~-Cm aromatic hydrocarbon group, far example phony! yr naphthyl.
The term "heteroc;yelyl" when used alone or in compound wards inclu dcs monvcyclic, polycyclic, fused ar conjugated hydrocarbon residues, preferably C~.b,wha:reiu one or more carbon atoms (and where apprc}priatc, liydrogen atomwttached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue. Suitable heteroatvr~s include, O, N
3C1 and S. Where two or mare carbon atoms are replaced, this may he by tyro ar mare of the same heteroatom ar by different heteroatcarw. Suitable examples of hctcrocyclic groups may iitc.lude pyrrolidinyl, pyrrolinyl, piperidy~1, piperaainyl, moyhc~lino, indolinyl, imiazolidinyl, , pyrazc~lidinyl, thiomtarpholino, dioxa.nyf, tatrahydrofuranyl, tetrahydropyranyl, tctrahydrc~pyrrolyl etc.
Each alkyl, alkenyl, alkynyl, cyeloalkyl, aryl or heterocyclyi group play he optionally substituted with Ct-aalkyl, OH, C)C~-3alkyl, halo, CN, NO~, CpaH, GOzC~_.~alkyl, CONH2, CONH(Cr_:#alkyly, CON(Cl.saikyl)2, trifluorcamethyl, NHS,, NH(alkyl) or N(alkyl)~. For example, an optionally substituted aryl group may be a 4-.methylphenyl or 4 hydroxyphenyl group, and all optionally substituted alkyl ~ro.up may be 2-hydroxyethyl, trifluoromethyl hr difluoromethyl.
As used herein, the term "amino acid residua" refers to an a-a:n~ino acid or a ~3-amino acid wl5ich is att<~tched to the naphthopyrandione etrttcture, pretcrably throw the carboxylic acid group of the amitxo acid. The amino acid may be a L- or D- isomer and may have a l5 naturally occurring side chain or a halt-naturally occurring side chain.
The amino acid may also be further substituted in the a-position hr the [~-position with a group selected, froth -C1-C6alky~!, -C2,-G~alhenyl, -C.2-C~alk,ynyl, -(CH~)aCUIt3, -(CHZjc,lt," -F031~1, -(CH~~,hetercx;yclyl or -(~H~)naryl where R;, is -nH, -NHS, -t~tHCt-C~alkyl, -OCt-Caafkyl or -Cy-C3alkyl and Rb is -CaH, -,SH, -SCE-C3alkyl. -OCt-Caalkyl, -C3-C~cyeloalkyl, -C;~-C~,cyclaalkenyl, -NHS, -NHC1-C~alkyl ur -NHC(C=NH)N kl~, n is 0 or an integer from 1 to 6 and where each alkyl, a1lcenyl, alkynyt, cyclaalkyl, cycloaLlLenyl, aryl or heterocyclyl group may tie substituted with ono car more groups selected froth -OH, -NH,, -NHCI-C3alkyl, -OCt-C~alkyl, -~1~1, -SCi-C3alkyl, -COSH, -CO?Ct-C~alkyl, -CONl~f2 or -CONHC,-C,~all~yl, Tho ierrn "cx-amino acid" as used herein, refers to a ccampound having an amino group and a carboxyl group in which the amino group and the cart-ax'yl group arc separated by a single carbon atom, the a-carhop atoiu. An a-amino acid includes naturally occurring and non-naturally nccurriltg ~.-amino acids and their D-isatners and derivatives thereof such as 3U salts or derivatives where functional groups are protected h~ suitable protecting groups.
The c~-atninu acid may also be funher substituted in the a-pe~sition with a group selected -from -C~-Ctoalkyl, -Cz-Cloalkenyl, -Cz-Cloalkynyl, -(CHz)"Cc'aR;,, -(CFi2)ul~h, -PQsH, -(CHz)peterooyclyl or -(CHz)naryl where Ra is -UH, -NHz, -NFiCt-C3alkyl, -OC1-C;~alkyl car C1~-C;alkyl anti Rb is -Oli, -SH, -SCE-~,".;~alkyl, -OCt-G;~alkylr -C;~-CtzcYGloalkyl, -C3-C72CyG1oalkCIlyI, -NHz, -NF-iC~-C3alkyl or -NHC(C=NH)NHy, n i,a 0 ur an integer frc>m S to 1t) and where each alkyl, alkenyl, alhynyl, cycloalkyl, aycloalkenyl, aryl or hctercx;yclyl group may be substituted with one or more groups selected From -OH, -NHz, -hiHC~-C~alkyl, -OCt-C3alkyl, -,S H, -SCE-C:~alhyl, -COzH', -CChCvCaalkyl, -CONHz or -CO1V HC ~-C3alkyl.
As used herein, the term "~-amine acid" refers to an amino acid that diffexs from an oe-amino acid in that there arc two (?) carbon atoms separating the c~rbaxy!
terminus and the amino termitms. As such, (3-anvnca acids with a speciFic side chain can exist as the R ar ,S enantiomcrs at either c~f the tx (C2) carbon or the. p (C3) carbon, resulting in a total of 4 pcassible isomem for any given side chain. The side chains rnay be the sumo as those of 1S naturally occurring a,-amine kids or may be the side chailis of non-naturally occurril~g ~unina acids, ca~H . 3 i GO2N
H2N ~ Ha_N
R R
R R
CC32H ~t72H
H:N 3 H2N
Furthermore, the ~i-amino acids may have mono-, di-, tri- or tetra-substit.utican at the C2 and C3 carbon atoms. Mono-substitution ntay he at the C2 or C3 carbon atom.
Di-substitution includes two sub,stitucuts at the C2 carbon atom, twcv substituents at the C3 carbon atom or one suhstituent at each c~F the C2 and C3 carbon a"t.oms. 'f ri-substitution includes two substituents at the C2 carbon atom and onP ,substituent at the C3 carbon atom -or two suh;,tituents at the C3 carbon atom, and one suhstituent at the C2 carbon atom, Tetra-substiri~tion provides fcyr twc~ aubstituents at the C2 e~3rbon atom and two substituenta at the C:3 carhcm atom. Suitable substituents include -C~-C~alkyl, -C~-Chalkcnyl, -C~-C~alhynyl, -(CH2)aGORa, -(Cllz)nRh, -pO~H, -(CHn)"hete;rocyclyl or -(CHL),~aryl where R~ is -OH, -NI-t~, -NHC~-C~alkyl, -OCy-C3alkyl or -Ct-Caall'yl and l~h is -OH, -SH, -SCE-C3alkyl, -OC1-C3ah;.yl, -C3-(:~cycloallcyl, -Cs-C~,cycloalkenyl, -NH2, -i~lHCt-C3alkyl or -NHC(C=NH)NHz, n is 0 car an irite~er Crow 1 to 6 and where each alkyl, alkenyl, alkynyl, cyele~alkyl, eyeloalkenyl, aryl or heterocyclyl a coup rn~y be substitutc;d with one or rnarc groups selected from -OH, -NHS, -NHC1-C3alh-yl, -OCS-C~aikyl. -SH, 1U -SGt-C~alkyl, -COSH, -CO~Ct-Csahyl, -CONH~ or -CON1~CC,-Csalkyl.
The term "non-naturally occurring amino acid" as used herein, refera tea amino acids havutg a aide chain that does not occur in the nahiral 1y occurring Lra-alzlitto acids. Ehatnples of non-natural amino acids and dcrivative.s include, but are not limited to, use of norleucinc, 4~atr~ino butyric acid, 4-amine-3-hydroxy-5-phenylpcntanoic acid, 6-anlinohexanoic acid, t-butylglyeine, norvalinc, phenylelycine, ornithine, aareosine, 4-amino-3-hydroxy-6-methyllicptanoic acid; 2-thienyl alanine andkar D-isomers of amino acids.
It' will also be recognised that the ecnngounds of formal (1} may possess asymmetric centres and are therefore capable of existing in more than one ,atereoisnmeric form. The invention thus also relates to c.ompounda in auhatantiaily pure isomeric farm at one or .more asymmetric centre:, e~., ~,~aater than aboLtt 90°'o cc, such as about 95~'n or 97°lo ee or greater than 99~n ee, as well as mixtures, including racemic mixtures, thereat. Such reamers may be prepared by asymmetric synthesis, For example using chiral intermediates, ~5 or by chiral resolution.
The term "phartttaeeutieally acceptable derivative" may include any pharntaeeutieally acceptable salt, hydrate or prcxirug, or any criher c;c~mpuund which upon adminstmtion to a subject, is capable of providing (direc;tly or indirectly) a compound of formula (1 ) or'an 3U antivirally active metabolite or rc~iduc tltcrcof, _g_ suitable pharmaceutically acceptable salts include, hut are not limited to, salts of pharmaceutioally acceptable inorganic acids such as hydrochloric, sulphuric, phospliori~:., nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, prapionic, butyric, tarcario, malefic, hydrerxymaleic, futnaric, malic; citric, lactic, mucic, gluconac, benzoic, succinic, oxalic, phcnylacetio, methartcsulphonic, toluenesulphonic, bcnzenesulphonic, salicylic, sulphanilic, aspattic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantvthertic, tannic, ascorbic and valer~c acids.
Ha~se cats i.ttclude, but are not limited tu, those fcarmod with pharmaceutically acceptabf 1e catioits, such as sodium, potassium, lithium, calcium, magnesium, zinc, anuttoniurn, allcylamntoniurn such as salts formed front triethyiamine, alkcaxyamn~onium such as tho-~e fcac-mcd with ethanolamine itrtd salts formed frcsnt ctltylenediwttine.
cholitte or amino ac.ict:;
such as arg,itiille, lysiuc or histidine.
,g.'jSiG nilC0~~11-containitlg groups may he quartemised with sucdt agents as lower alkyl halide, such as methyl, ethyl, prc~pyl, and butyl chlorides, bromides <utd iodides; diall~yl sulfates like dimethyl and diethyl sulfate; and others.
2C1 Tlte term "prodrug" is used in its breadewt sense and encarnpasses those derivatives that ire converted in viva to the compounds of the invention. Such derivatives wcndd readily ocour to those skilled in the art, and include, for example, compounds in which a free hydrc~xy group is converted into a group, such a.~ an ester, carbonate or carbarnate, which is capable of hein~ converted in v~vn back to a hydroxy grcaup. A prodrug may include modifications of OclC of metre of the functional groups of, a compound of formula (1). Far example.
similar to tltc apprc7ach described in US 5,672,607, antiviral naphthopyran prodrugs haYZn;
enhanced water-solubility (c.g., which are better for parenterally administ~cd ccampositions) may be prepared by chemical reduction of the quirtone functionaiities to the ecyrrcsponding quinals, hollowed by reacticm with phc~aphorous oxyeltloride to dive the 3U corresponding phosphoric acid esters. Elftcr in viz~u administration of a camposit=tan eoutaining such a solubifiz~i alttiviral naphtopyrart prodrub, the prodrua will be readily _g.
hydrolysed to the corresponding quinnl, which thereafter will oxidize to re-form in v8vn the active parent antiviral naphthopyrandione. Likewise, other kinds of derivatives may be prepared frcym the reduced quinal derivatives of the antiviral naphthopyrandione; these can also serVG a~s prcxirugs fc~r use in therapeutic campoaitians. For example, other types of eaterification (e.g.. acetylation) may be used to prcxluce antiviral naphthopyran prodrugs, such as far example 7,$,10-tri3cetoxy-'~,3-dimethy!-3H'-naptha12,1-b~pyran.
Again, after in viva adn~ini5tration the prodrug would be readily hydrolysed and oxidized t.o its parent active antiviral naphthopyran compound.
1U In a brat aspect, there is provided a method of treatment or prophylaxis of hepatitis D virus in a subject camprisuig administering to said :subject an effective amount of a compound of Formula (1);
Rg X
('1 ) wherein ~ is OH, OR9 or halo;
1~ and Rt arc independently selected from ) 1, Cy.~aikyl, C~.Eaikenyl, CZ
~,alhynyl, C3~cycloall~;yl, aryl, or toaethcr with the carbon atom to which they arc attached form a saturated or unaawrated C3.ticarbQCyclic ring;
R2 and kz are independently selected Pram H, Ci.~alkyl, C2_~alkenyl, C~.~alkynyl, C~.~oyclcaalkyl or to~cther with the hc3nd between the carhop atori~s to which they are 2O attached form a Bauble hand;

R.r and RS are independently selected from H, C, fiallsyl, C2.6alkenyl, C2.Galkynyl, Ca_ccycloalkyl, OH, ORS, halo or NRlaft~" or together with the band he.tween the carbon atoms to which they arc attached form a douhJe bond;
R6 and R~ are independently selected Crom Ft, C~.~alhyl, C2~salJ;enyl, C.
~alkynyl, C3_c,CyClOalkyl., OH cyr OR9;
Rs is independently selected from H, Ci alkyl, Cz.c,ulkcnyl, Cz.~alkynyi, C3.~cyclcyalkyl, QH, ORS or halo;
R~ is C,_nalkyl. C~_5allrenyi, C2.~alkynyl, C3_~cyc.loalkyf, aryl, C(=O)R,1 or S(O~R~2 or ORS
is an amino acid residue;
1U each R,n is indenenrlcntly selected from H and Cl.~a11~y1;
R~i iv C1_~ialkyl., C~.~~alkenyl, Cz_~yalkynyl, C~.bcycfc~akyl, G;c.ncycloalkylCl.sall:yl, aryl or arylCj.~alk.yl; and Rig is Ci.salkyl, C~.6alkenyl, C~.balkynyl or aryl.
1 S Ln another aspect there i;; pravlded a eomPcnuid of Formula (.1 ), with the proviso that when R and R, arc both methyl and R is CJC-1' or ORq, R5 is not selected from OH, Qfty or NHRy.
In a preferrc,d etnh«dffment ono or more of the following definitions apply;
X is OH, Of:,~.,~alkyl or halo;
20 lZ and R~ are indegendcndy selected from H or C~_aalkyl or tc~~cther with the carbon atom to which they are attached form a saturated or unsahtrated C~_ecarhncyclie ring;
Rz and R~ are each hydrofieu;
R4 and 1~5 arc independently ae1ceted from H, OH, OR9, or halo or tcyethcr with tltc bond between the carbon atoms to which they are attached form a douhle bond;
25 Rc, ~d R7 are >zidenendently selected from H, OH, C~.~alkyl, Ci.tyalloxy;
Rs is H, OH, ORy, C,.balhyl or halo;
R9 is C(=O)Rt1 car S(O)~:R~z;
R,~ isC~.~lalkyl;
R,z is Cj.c,alkyl, phenyl or tosyl.

Preferred compounds of the. inventican include those of formula (Z):

(Z) wherein I~, R~, Rz, R;3, R4 and R5 are dcflned as for formula {1).
Preferred compounds of the invcntican include:
8-hydroxy-3,3-dimcthyl-3H-naphtha[2,l-h]pyran-7,10-dionc;, 8-hydroxy-3,3,dimethyl-1,2-dihydrca-3H-naphtho~ 2,1-h]pyran-7,10-dicanc, ~-6romQ-8-hydroxy-3,3-dirnethyi-1,2-di hydra-3 H-naphthc>[2,1-~]lryran-7,10-dione, 9-bromo-8-hydroxy-3,3-dime.tlyl-3Fi-naphthea[2,1-tx]pyran-7,10-dione, 9-brama-3,3-dimethyl-8-(4-nzethylbcnzsnesulfonyloxy)-1,2-dihydra-311-nsphtho~2,1-b]py can-7,10-dinne, 9-brain.o-3,3-dimethyl-8-(4-rnethylbcnzenestMfanylaCy)-3H naphtha[?,1-6]lryran-7,10-dione, S-ac;ctoxy-3,3-dimethyl-;1H naphtha[2,1-b]pyran-7, y 0-dione.
2,9-dihrorna- l ,8-dihydroxy-:i,3-diznethyl-1,2-dihydra-~ H-naphtha[2,1-b]pa~ratt-7,10-dione, t3,~-dichloro-3,3-dimcthyl-1,2-dihydra-3l'~-naphtha(2,1-b~pyrazi-7,10-diane, 7,8,1 U-tri srctnxy-3,3-dimethyl-3H-naphtha[2,1-b]pyran, 9~Bromo-8-hydroay-3,3-dimethyl-3H-naphtha[2,1-b[Pyran-7,10-diane.
9-~rmna-8-hydroxy-3,3-dimethyl-3H-naphtha [2,1-b]p y~ran-'1,10-thane.
9-Bromc~-3,3 ndimethyl-8-(4.methylbena,enesulfonylaxy)-1,2-dihydrc5-.3H-naphtha~?,1-2U h]pyran-7,1U-dionc.
9-Brarrto-3,;~-dimethyl-8-(4-methylhenzcnesulfanylaxy)-3H-naphtha[2,1-b[py~ an-7,1U-diane, -12.
8-l3rorno-3,3-di methyl-9-(4-methylhenzenesulfnnylax y)-3l~-naphtholz,1-h]pyran-7, 7 0-diane., $-Br«mo-3,3-dimethyl-9-(4-methylhenzenesulfanyloxy)-1,2-dihydrn-3fi-naphtha[2,1-blpyran-7,10-dione, $,9-Dicltloro-3,3-dimethyl-1,2-dilaydra-3N-naphtha'2,1-h]pyran-7,tC?-dione, radium 3,3-dimethyl-'~,1C)-dioro-7,10-dihydro-3H-benzo[f]chromen-8-alate;
Sadium 3,3-dirnethyl-7,$-dioao-7,8-dihydro-3H~benzo[f]chromen-1U-date 8-Hydroxy-3-methyl-3-phenyl-3H-henzv[f]cluamene-7,10-dione, and 8-Hydrcaxy-3,3-Biphenyl-3H-benco[~]chromene-7,J 0-dione, 1 () I~referably the. wmpaund of Formula ( 1 ) is:
$-hydraxy-3,3-dirrtethyl-3N-nnphthu[2,1-h]pyran-7,1U-dione (compound (1)), 8-hyd~~c~xy-3,3-dimethyl-1,2-dihydro-;3H naphthop~.,1-b]pyran-'~,10-dione (campound (2)).
In anather embodimeilt the compounds of the invention include those of formula (3):
R
Rg X
(-1) wherein R, fti, R2, R;t, Rs, R~, R7, Rs, and ~C are as defined far formula ( 1 ) and t~~ is selected frcam H, C~_~alkyl, C2.~alkenyl, C~.Galkynyl, C3.~cycloalkyl, halca or hlR~aRuo or together with RS axed the bond between the carbon atoms to which R4 and R; arc attached, farm a double hand.

~:ompounda of Formula (1) may be prepwed using the methods dcpicteri or described herein or known in the a.crt. It will he understood that minor trLOditications to methods described herein or known in the art may be required to synfheaise particular compounds of Formula (1). General synthetic procedures applicable to the synthesis of compounds rmay be found in standard references such as Cvrnprerhcatsive C)rganic 7ra~~,efnrrnatian,s, R.
C. Larock, 1 g89, VCH Publishers and Advanced Urgc~oir, Chemistry, J. March, 4th Edition (1992), Wiley W terScience, rznd references therein. It will also be recognised that certain reactive groups may require protection and deprotection during the synthetic process.
f0 Suitable pmtccting and deprotecting methcxis for reactive functional groups are known in the art. for example in Protective Grutcps in C)rb~arcic Syntla~si~s, '1'. W.
Greene ~ P. Wutz, John Yvilcy & Son, 3'~ Edition, 19<~~.
The cor~~pounds of the present inventicm may be pre;parcd according to the general procedure of scheme 1.

~chenae 1 Rz .r~'~ R3 F
R
.~'~ "~ Rg Ry O

(4) die ~ ~'~'. 'O H
Rr v ,. r F
R
(6) R
R~
Rs Rs ---OH
(7) -1.5-An appropriately substituted 2,6-dihydroxynaphthalene (3) is reactt;d with an apprcapriately substituted enal or enone (4) in the gresenee of a suitable base to efCu;t cyclisation and provide. a naphthopyranai (5). The naphthopyranol is then oxidised by a suitable oxidant to the corresponding intermediate orthc~quinone (f), before being reduced by a suitable reducing agent and further oxidised by a suitable oxidant to the desired uaphthopyrandicane (7). Further modification of the substikuents on the naphthopyrandione may be effected using chemical approaches 1'nown to those skilled in the art for the gcneratian of the desired suhstilucnt or aubstituenta. Those skilled in the art may utilise Conventional approaches to protect and deprotcct certain Functional groups during the reaction sequence.
Such ntctho~cis arc well known in the art and include Cor example those described by Grc;cne a,nd Wutz (supra), The re:~ction seyucnce described in Ex~tnplea 1 and 2 exemplify the preparation of compounds (1) and (2) and provide att example of how the reaction sequence oC Scheme 1 is utilised. These skilled in the art will appreciate that a wide variety of reaction conditions, including solvent,, bases, oxidising agents, reducing agents, temperature and time of the reaction, may be utilised to effect the desired transformation.
A substituted c.none auc;h as (4) may, dependant upon the exacrt nature of the reagents and conditions used, add to the substituted 2,f~-dihydroxynaplithalene (3) in the opposite orientation to that shown in Scheme '1 and still provide a naphthopyran product, Such a ~.Q reaction is shown in Scheme 2, and provides naphthopyranol (8).
Naphthopyranol (8) may be isomerised to provide a naphthopyranol efCtetively c~C general formula (5), which may then be subject tc~ Cmther reaction in t~ccordmce with the general prcxedures of Scheme 1 to prc>vidc cscmpounds of Formula (l).

- ltd -S~;hem~ 2~

z P1~ R3 Rt r/ R3 "o"
HO ~,,. ...,' Rs '4a) H /' ~"~ Re r.
p ~ V R6 ~ v (3) ($?

(5) _17_ Alternative synthetic procedures which provide compounds of Fornmla (1) are ahawn in Schemes 3 and ~~. In Scheme (3) an appropriately substituted butye (9) is reacted with an appropriately substitute.il hydroxy tctralone (10), ~'he group L is a.ny suitable leavinb group and includes groups ouch as a promo, chloro, and hydroxyl. Ideaction hetwcen the tetralone and the butyne may be acid or base catalysed to provide naphthopyran {17). In some cases the reaction may be conducted in one pot however an intermediate (1 1) rttay be isolated, Intermediate (11) may ccynvcn.iently be cycliaed far example by heating in the presence c~f a suitable base, such as diethylaniline. The cyclised product (1?) is then oxidised to afford the quinonc (13) which may then be further modified to provide other 1U compounds of Formula (1).
Scheme (4) outline a similar reaction seduence to that of Scheme (3) which would start with an appropriately substituted hydroxy naphthalene. This is based upon work reported by Bigi et al., J. Clrg. Chem., ~2, 7024-7027 (1997). The cyclised naphthapyran (:15) could be treatad as per compound (5) of Scheme (1) to provide compounds of the inventiUn.
Many other methods of preparing hanzopyrana have been reported itt the chemical literature and those skilled in the art may adopt these methods to provide compounds of the present invention, sec for ex~urlplc, lshino ec al., Syn. Comm., 31, 439-44g (200'1).

Scheme 3 L R
R R3 Ri HO ~ Rs Ri ~g~ !. R0 Rd A~ p (10) R
I~~) (~2) r R~

_ yg ~4heme 4 Ra R~
Hd Re R Ra R
~'"'', R, (9, ,,.~ ~ -,~,, s R~ ~'. !' off R \ ~ off a (74) (i 5) Further mudifrcatian may include derivatisation of double bonds. For example, when R~
and R$ together v~~ith He bond between the carhc~n atoms to which they are attached form a douhle. bond, tire double bond may he derivatise~i by addition, oxidation or reduction reactions. r1n example of possible de=rivatisation of such ~ douhle bond is given in ~chcrne 5. Follr~wing xcductive acetylaticati to protect the quinone portion of the compound, epo~idation of the pyran doable bond, subseriuent ring opening of floe epoxide with an 1U amine, and dcprnteotion and axidati~n to regenerate the quiuane may he effected. Those skilh;d in tire art could readily deterr~iine appropriate reagents <urd conditions to effect such transformations.

_ ~Cl Scheme S
a R
Y~duciiva acetylatlOn ;r-epoxida!ion a' p~'1' t~J'"r f~~
H
hydrdysis ---A person skilled in tl~te art would be able to modify such a reaction scheme by using different re~gcnts to open tY;.e epoxide, using asymmetric ePoxidation catalysts and varying the nature of the substituants.
As used herein, the tcnxt "effective smaunt" relates to an amount of compound which, oxidation p;~

when administered according to a desired dosing regimen, pruvidew tha desired hepatitis B
virus treatment or therapeutic activity, or disease prevention. Dosing may occur at iy.~ais of minutes, hours, days, wee);s, months oar years or cotitiuuously cover any one of these periods. A therapeutic, or treatment, effective mount is an amount of the compound which, when administered according to a desired dosing regimen, is sufficient tea at least partially attain the desired therapeutic effect, or delay the crnsct of, or uihihit the pxagression ~C 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 ac~carding to the de:;ired dasina regimen is :;ufticient to at lcaat pairtially prevr;nt, or delay IU the onset caC a particular disease or condition.
Yet another aspect of the preaent invention provides a use of a compound oC
Formula ( 1 ) in the preparation of a mcdicame.nt far treating car preventing hepatitis I3 virus.
Suitable dosages may lie within the range of about (1.l ng par kg c>C bcxiy weight to 1 g per kg of body weight per dosage. The dosage is preferably in the range of ! p.g to 1 g per kg tat body weight per dosage, such as is in the range c~C 1 tog t.o J g per kg of body weight per daaage. In one embodiment, the dosage is in thr: range of 1 mg to SOU mg per kg of body weight per dcasage. W another embodiment, the dcasage i;; in the range of 1 mg to 250 mg 2f1 per ~g of body weight per dosage. In yet another preferred e.mbadiment, the dosage is in the range of 1 rng to 10U mg per kg of body weight pt~r dosa6e, ;,ooh a,5 up to 5U tzig per kg of heady weight per doaage. In yet another e.tnbadirue.nt, the dosage is in the range of l~tg to img per kg of body weight per dosage.
Suitable dosage amounts and da;;ing, regimema can be determined by the attending physician and may dap~nd on the. severity of the eotiditic~n as vvcll as the general age.
health and weiyt of the subject.
The active ingredient may be administered in a jingle Base or a series of doses. While it is possible for the active ingredient to be administered alone, it is preCerahle to present it as a eurnpasition, preferably as a pharniaceutieal ccympoaition.

Accardinb to a further embodiment there is provided a xnethad of treatment or prophylaxis of hepatitis 1~ virus c,~ompri:~ing administering an effective amount csf a compound of Formula (1 ) and a second therapeutic agent.
When adrwinistered as a combination, the compound of Formula {1) and the second therapeutic agent may be administered simultanwusly, separately or sequentially.
The second therapeutic agent may be a known antiviral ar aintiretrovirai agent car another '1U pharmaceutical used in the treatment «f viral infections. Representative examples of Suitable aecand tlcraPeutic. agents include imtnunornodutators, inmiunostimulcuzts and autihiotics. Exemplary untiviral agents include acyclovir, val-acyclovir, pcncicluvir, famciclovir, ganciclavir, foaewnet, ribavirin, interferon-alpha. F'EC~-interferon-alpha, latnivudine, adcfovir, thymosul alpha 1, entccavir, tclbivudine, emtricitabine, elvucitabine, MCC-478, hepavir B, hilV-210, valtorcitabine, Hcpe?C-B, 7idavudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir. emtricitabine, saduinavir, indinavir, nelfinavir, amprenavir, ritonavir, azatanavir, nevirapine, delavirdine>
ofaviren~, enfurvitide, trizivir, combivir, kalctra, MIV310, nu»cnavir, 5PD754, ~PD'746, T1249, TMC125, TMC114, VX-175, tipranavir other non~nuGleoside reverse transcriptase iiihibitnrs and proteaae inhibitors, Exemplary imn~unomodulat4rs and imnlunwtimulants include ulterfcron alpha, 1'EG-interferon, thymosin alpha I, Hcpe31-B, )'IBV
immunoglcabulin, HBV monoclonal antibodies, and vaccines suCl1 as Eng,erixB, Havrix, H-B-Vax II, it~fanrix hcp ~, twinrix. !h-eferably the second therapeutic agent is an agent suitable far the treatment car prophylaxis of hepatitis L1 virus in a subject. Such therapeutic agents include, but are not limited to interferon-alpha, IyEG-interferon-alpha, lamivudine, ade.fovir, thymosin alpha 1, entccavir, tclbivudule, emtricitabime, elvucitahine, MCC-47A, hcpavir B, MrV-21d, valtoraitabine, and HepeX-fi.
Mill another aspect of the present invention relates t« a pharmaceutical composition 3(~ comprising a compcaund of Formula (1) and a Pharmaceutically acceptable carrier, dilucnt or excipient.

The formulation of such compositions is well known to those skilled in the art. The ~on2pOSil10i1 m:.ty contain phaxmaccutiGally acccptahle additives such a.~;
carriers, dilucnts or excipier,<is. These include, where appropriate, all canve'ntlonal solvents, dispersion agents, fillers, solid carriers, coating agents, antifungal and antihucterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like.
it will he understood that the compositions of the invention may also include other supplementary physicalogically active agents.
1Q The carrier must he pharmaeeutic;ally acceptable in the sense of Ding compatible with the other ingredient;, of the composition and not injurious to the subject.
Compositions include those suitable far oral, rcet.al, inhalutionai, nasal, traaasdermai, topical (including buecal and sublingual), vaginal ur parentcral (includin g subcutaneous, ititramuscuiar, intraspinal~, intravenous and iutradermal) administratinn_ The curnposi.tions may 1~ conveniently be presented in unit dosage form and may be prepared by any rnethcxis well known iw the art of pharmacy. Such methods include the ;;tc:p of bringing into assoc.-iation the active ingredient with the carrier which constitutes unc or more ac;e;cssury ingredients.
In Qeneral, the compositions are. prepared by uniformL.y and: iriticnately hringi.ng into association the active inGredient with liquid earrier~; or finely divided wlid couriers or bath, '~0 and then if rtec:~SSAry shaping the. product.
J~~pcuding an the di.;ease or condition to be treated, it rnay or may not he desir~.bla fur a compaurid of Formula ( 1 ) to crass the bloodlbrain harrier, Thus the compositions for use in the present invention rrlay he formulated to be water or lipid soluble.
'~ S
Cort~positions of the present invention suitable for oral administration may be presented as discrete units such as capsulea, sachets or tablc;ts each containing a predete.rmuied amount of the active ingredient; as a powder car granules; as a solution i~r a stcspensicsn i.n an aqueous or nun-aqueous liquid; or as an oi!-in-water liduid emulsion ur a water-in-oil 30 liquid emulsion. The active ingredient may also he pre~;ented as a bolus, eleetuary or paate.

A tablet may be made by compression or moulding, optionally with one or mcare accessory ingredients. Compressed tablets nnay bc. prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or ~Tranules, optionally mixed with a binder (eg ine.rt dituent, preservative, disihte~aitt (eg. sodium starch glycolate, cross-linked polyvinyl pyrralidone, cross-linked sodium curhoxymethyl cellulose)) surface-active or dispersing agent. MUUlded tablets may he made by moulding in a suitable machine a mixture of the powdered compound moiste:nod with an inert liquid diluent. The tablets may optionally be coated or scored and may be Cormulated so as to 1L1 provide slaw or contrcyllcd release of the active ingredient therein usinY, far example, hydrnxypropylrnethyl celfidose in varying prcapartions to provide the desired release praFile. Tablets may optionally be provided with an cnt.eric coating, to provide =elcase in parts of the gut other than the stomach.
Compositions suitable for topical administration in the mouth include lc~;~enges campriying the active ingredient in a flavoured base, usually sucrose ~~trd acacia or tragacanth gurrl;
pastilles comprising the active inb edient in an inert basis such ;as gelatin and Glycerin, or sucrose and acacia gum; and mouthwashes eomprving the active ingredient in a suitable liquid carrier, Tlc compounds of >~ortnula. (I} may also he administered intranasally or via inhalation, for csample by atomiser, aercasol or nebulizer means.
ComPc~sitions suitable for topical administration tc~ the skin ma.~ cotnprisa the compounds dissolved or suspended in any suitable carrier or base and may be in the form of Inti:ons, gel, creams, pastes, ointments and the like. Suitable carriers include mineral ail, propylene glycol, polycaxyethylene, pcalyoiypropylene, emulsifying wax, sorbitan nnonostearatc, polysarbate 60, cetyl eskers v~ax, cetearyl alcohol, 2-octyldadecanal, henzyl alcohol and water. 'fransderntal devices, such as patches, may also be used to adrtzini;;tar the ccmpaunds of thr; invention.

Compositions for rectal administration rnay be presented as a suppository with a suit4~ble carriex base comprising, for example, cocoa butter, gelatin, glycerin ar polyethylene glyccal.
S Compcfsitions suitable for vaginal administration may be presented as pcssaries, tampons, creams, gels, pastes, foams or spray formulations containing in addltiUI1 to the active ingredient such carriers as arc known in the ~u~t to be appropriate.
Compasitiar~s suitable for par~nteral administration include aqucau;; and non-aqueous isotonic sterile injection solutions which rnay corltaill ants-oxidants, buffers, bactericides and salutes which render the composition i:;otaruc with the blcaod of the intended recipient;
and aqueauw and non-aqueous sterile suspen ,sicans which may include suapendi.ng agents and tllsCkeIllIIg agents. The compositions may he presented in unit-dose Qr -multi-dose sealed containers, far exau~ple~ ampoules and vials, and may be ;;torcd in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, irtymediately prior to use. Extemparancous injection aalutiaw and ;;uspensinns may be prepared from sterile powders, gn"anule:; and tablets pf the kind previously described.
Preferred unit dosage eompca~itio~ are those containing a daily dose or unit, daily sub-dose, as heroin above described, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the active ingredients pat~ticularly' mentioned above, the compositions c>f this invention may include other agents canvention~al in tile art havin4 regard to the type of corzlpaslttUn 11 question, far example, those suitable far oral administration may include such further agents as bircdeus, sweeteners, thickeners, flavouring agents, disintegrating agents, coating agents, preservatives, lularicants andJar tint delay agents. Suitable sweeteners include sucrose, lactose, glucose, a.~;partanle or saccharine. Suitahle disintegrating agents include corn starch, methyleellulose, pcalyvisiylpyrrolidone, xantharx gum, bcntanite, alginic acid or agar.
Suitable flavouring . 26, _ agents include peppermint oil, ail of wintergreen, cherry, orange or raspberry ilavauring, Suitable coating agents include polymers or copolymers of acrylic acid andlur methacrylic acid srtdlor their esters, waxes, fatty alcohols, zein, shellac ar gluten.
5uitahle preservatives include sodium benzoate, vit<~min E, alpha-toeophe.rol, aveorbic acid, methyl paraben, propyl parahen ar sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium Qleatc, sodium chloride or talc, Suitable tune delay agents include glyce.ryl rnanostearate or glyceryl distearate.
'those skilled in the art will appreciate that the invention described herein is auseeptiblc t~
variations and rnodiCieatiow other th,~n those specifically described. It is to be tmelerstocxi that the invention iu.cludes all xuch variations and modiL"rcations which fall within the spirit and scope. The invention also include,; all of the steps, featmcs, compositions and compounds referred to ur indicated in this specifieatican, individually or collectively, and airy and all combinations of any two or n~nre of said steps ur features, The invention will now be described with reference to the following examples which ale included far the purpose of illustration only and are not intended to limit the generality of the invention hcreinbctore deserihed.
EXANO'Lt:B
Example 1 Compound y:9-l~ydroxy-3,3-~Iimetlayr-3H-ncr,~h~"ft.vj2,1-b,jpyra~t-?',ro-dione Step 1: 3,9-pimethyl-31'-I-~tuphthujZ,l-bJPyr'an-$~ol ' A mixture of 2,6-dihydraxynaphthaient (50.0 g, 0.312 moi), 3.methyl-2-butenal (:10 xn_L, 26.24 g, 0.312 mol) and pyridine (38 mL, 37,02 g; 0.468 mal) were heated under retlux fbr 3.5 h. 'the mixture was cooled to room temperature, diluted with dichlaromethane (500 mL), filtered through a sintered glass funnel (porosity 3) then washed with aqueous hydrc~hlouc acid solution (1 hi, 2 x 25U mL) and water (1 x 25U mL). The organic layer u~as eatlvcter3 with a solution of aqueous sodium hydroxide (2 M, 1 x 250 mL
and 1 x 125 mL) and the combined aqueous extracts eooied in an ice~salt hath, acidilied (mith stirring) with aqueous hydrochloric acid ;;elution (5'v~ mL~i1 a creamy-white precipitate formed (pH
2). The saiid wits stirred Cor an additional 1l) mur with ccaoling, collected by filtration, washed with water and dried under high vacum at 4i7 °C to affnrd the desired crude product as a t~luffy white-grey solid (43.9 g, fit .°~o). The crude product was used in the.
S subsequent reactian withcaut further purification.
Rccrystallised from diethyl etherlheRane m.p. 12~-123°. S ('f~ (300 MHz, CI~Cf3) 1.47, s;
2xCH3;4.77,s,01'-1;5.71,d,J10.2Hz,H2;6.9t?,d,J10.2Hz,H1;7.U~,,d,J8.7Ha:,HS;

7.U$, s, H7; 7.10, dd, J $.7, 2.7 Hz, H9; 7.4$, d, J 8.7 H~, H6; 7.85, d, J

8.7 flz, H10. m/z (F.S+, 1Ut) V) 471 (2M+H+H?CJ, 100rra), 24S (M+-H+1 (z0, 62), 227 (M+H, ~3).
Step 2: 3,3-Taimethy6-~H'-r:aphthoj2,l-bJpy~rar~-T,S-dio~ee To an oxygen saturated xolutian of 3,3-dimethyl-3JI-naphta[2,1-bJpyran-8-al (3.0 g, 1:i mmol) in acetonitrilc (70 mL) was uddcd catalytic amounts of N.N-Bis(salicylidenc)ethylenediamineocobalt(11~ hydrate, ([Co(II)(Salen~]) (3U0 mg, 0.91 mmol, 7 mal~t~), a.nd oxygen was bubbled tltraugh the mixture until the reaction was deemed completed (generally 4.5 h) by TLC Chexanc-ethyl acetate 4:1) or HPLC.
The carangelbrcawn reaction mixture was diluted with ethyl acetate and the entire mixture filtered tltraugh a plug of flash silica (11 x 7 cm) to remave,thc catalyst.
The plug was 2U washed with ethyl acetate until the eluent was zicarly cc~lrrurlcss. The solvent concentrated ire uacun and the residue dried under high vaeumm tea afford the desired crude product ais an ornn,~a solid (2.73 g, 8fi~'o). The crude pruc3uct was used in the subsequent rcactian wiillout further purification.
The product was reerystalliscd from etliyl acJetatclhexanes to afford red needles; m.p.
189-193° 6 (tH) (3U() MHz, CDCI3) 1.5U, s, 2 x CHs; 5.92, d, J 1U.4 H2, H2, 6.43, d, J 10.4 Hz, H1; 6.71, d, J I0.5 Hlz, H9; 6.84, d, J f3.G 3iz, H5; 7.72, d, J 1U.S Hz, H1U; 7,97, d, J
8.6 Hz. H6. nr/z (ES+, 30 V) 263 (M+Na, 9TH), 242 (M+1-1+1, 19), 241 (M+H, 100).
Step 3: 9-Flydrory-3,3~dimethyl-3H-naphthuj~,l-bJPyran-7,1U-diano A solution of 3,3-dimethyl-3H-naphtha[2,1-b ~pyraii-7,8-dicme {4.59 g, 19.1 nu-nol) in _~g_ toluene (340 mL) wa.5 washed twice with a solution of sodimn dithionitc (24.9 ~, 0,143 'mol) in water (250 ntL,). The yellow organic layer was theLZ added ui one portion to a oxygen saturated solution csf potassium fir!-butaxide (12.19 g, 11S mmol) in tert-hutanol (110 mL) and the resulting mixture was stirred at room tempc~ature with oxygen bubbling . for an additional 30 min (MOTE: longer periods appears to result in reduced yield). Tltc resultant dark red solution was acidified with aqueous hy~irr~c~loric acid solution (ittitially 2 M then 5 M) until the colour turns yellowlorange (pH -- 1), then water (~ 40 n1L) was added to dissolve the fc~rmcd salt, and the layer, separated. Tl~.e organic phase was washed with water (1 x $5 mL), and then extracted with a ;,atmated aqueous radium hydrogen carbonate solution (5 x 85 mL). The combined aqueous extract;; were transferred hack isito the separating funnel and allowed to settle fur 1 h (to ;;eparat~ further axnaunts e~f toluene) and the layers acparated main. The combined hale extracts were cooled in an ice-salt bath, carefu!!y acidified (aducous hydrochloric acid, 5~.4, ~ 80 ntLy drapwisc Over 30 min with stirring until the colour turns pale yellowish (pH ~ I-2)- The resultant precipitate was further cuolcd in the ice-salt hath with stirring, the aolid collected, washed with water 0100 mL) tea remove coloured impurities, and the arangelhrow solid was rccrystalli.scd (absolute ethanol) to afford the desired product as orange coloured crystals (1.U4 g, ~l~la), m.p. 208° c~ ('H) (300 MHz, CDC13) 1.48, s, 2 x CH;~; 5.94, d, J 10.5 Hz, H2; 6.23, s, H9;
7.U3, d, .T 8.4 Hz, H5; 7.83, d, J 10,5 Elz, H1; 7.99, d, J 8.4 Hz, lib, m~,z (ES+, 100 V) 27~
2U (M+Na, ) 00~'Io), 257 (M+H, 45), l 59 (46), 137 (49), S6 (44), 59 (SO).
LYample 2 Conapaasnd 2: SY-HydrOxy-3,3-dBmetlryl-1,2-ddhydra-3H-naphthrrj2,l-b,JPyran-7,1U-diu~le A mixture of R-hydroxy-3,3-dintcthyl-3H-napht1ta12,1-h]pysan-7,y0-clione (132 mg, U,52 mmc.~l) and platinum (I V) pride ( 1 S mg) in ethyl acetate ~ 15 mL) was stirred under an ~it~nosphere of hydrcagen for 7 h, The resulting mixture was stirred in air for 1 h then was filtered through a pad of diatomaceous earth. The pad was cwasUed with ethyl acetate then the filtrate. and washings were combined and cocnetratcd irz yac~uu to give a green solid (128 mg, 9670). Reciystallisation from ethyl acetatelhexane~ using activated e;harcaal gave 3U 8-hydroxy-3,3-dimethyl-1,2-dihydra-3H-naphtho[2,l,blpyra~~7,1U-thane rn,p.
'183.5-187°.
S (~H) (;300 MHz, C;f~CI.;) 1.37, a, 2 r CND; 1.85, t, J 6.$ Hc, 2 x H2; 3.30, t, J 6.S E-Iz, 2 x _2~_ H1; 6.20, s, 1i9; 7.U3, d, J 8.6 Hz, 115; 7.98, d, J 8.6 Hz, H6. xrtl4 (ES+, 30 V) 259 (M+H, 77°!0), 174 (88), 1,'.59 {1U0).
Cx~rttple 3 Cr~rrspaurrd 3: 8-rlcetaxy~3,3-dirrret):yl-3H rraphtho(2,f-bJpyran~7,10-rlione CQncentratcd acclphuric acid (1 drop) was added tcf a stirred arangc suspension of i~-hydrc~xy-3,3-dimetl~yl-3F1-naphthoi2,1-b~pyran-7,1()-dione (855 mg, 3.34 nrrno!) in acetic anhydride (1() mL) and the mixture was placed in an oil bath (oil bath ternnerautre 100° C). The rtvxture immediately heca.me han~ogeneous red~blaclC.
After 10 min the 1U mixture was cooled (icelwater bath) and, water (5U mL) addsd. Prc~duct~~
were eztracted with ethyl acetate (1S0 mL), the organic phase seg~~rated, dried (NazSC~,~) aizd filtered .
.through a silica laJug, washing the plug with ethyl acetate until ncs Cmther ~e~lour eluted.
The filtrate was concentrated irt vercua and the residue wav cried overnight under vacuum to uCJ:ard the title. compound as a reel solid (965 mg, 97'/0), ~H NMR. (3(X.1 MHz, C:DCI~) c5 1.48 (tiH, s, 2 x CH;;). 2.37 (3H, s, COCH,~), 5.94 (1H, d, J 10.5 H(z, H2), 6.34 ( 1 H; s, H9), 7.07 (11-1, d, J &.4 Hz, H5), 7.73 (1H, d. J 10.5 Hz, Hl), 7.97, f 1k1, d, J
~.4 Hz, H6).
Ex~mplc 4 C'nmpaund4: 7,S,lD-triacetoxy-;i,3-din:etltyx-3H-naphtf:of ,1-bJpyratt A stirred solution of $~hydruxy-:1,3-dirncthyl-3H-naphtho ] 2.,1-b~pyTan-7,1(1-dione (110 mg, U.93 n~rnol) in acetic at~lzydride (3 mL) and pyridine (4 inL) was heated in an ail batli at 6U°C for 15 mug. 2iric powder (530 mg) was added inE one portion and the mixture became pale yellow. After 15 mixl heatiztg, the rni~ture was cooled to room temperature and filtered thrayh a sinter (porosity 4), with ethyl acetate washings. The filtrate was poured onto icelwater (20 tol.) and acidiCicd with aqueous hydrochloric acid sc~lution(2.0 tv>). The organic phase was scp,.~ratcd and the aqueous phase washed with ethyl acetate (3 x SO mL). The ec~rrtbined organic phases were dried (NazSQ~), filtered and concentrated in vatrcsu. 'fhe resulting solid was reu~rystaali,sed from echanal ~o afford the title compound a.s a culourJeas solid (96 mg, Sf~°la). 1H NMR. (3UU MHz, ~:C~C13) & 1.46 (6H, s, 2 x CH3), 3t? 2.:11 (3H, a, COC,H3), 2.~7 (3H, s, COCH3), 2.43 (3H, s, C~7CH3), 5.64 (11-1, d, J 10.1 Hz, H2), 7.11 (1H, s, 1:19), 7.'12 (1H, d, d 9.0 Hz, H6), 7.23 (1H, d, 3 1U.2 ~Iz, Ei.l), 7.b7 (1H, d, J 9.0 Hz, H5).

Example 5 Cvrrapound 5: ~-Rromo-$~hydroxy-3,3:dimethy!-3H~nnphtbu[2,1-h]gyran-7,10-dione O
OH ~ ' ' , OH
~ ' 8r A solution of hramine (354 mg, 2.21 moral) ll1 dry dichlnramcthane (4 ml~~ was added dropwisa to a cooled (0° C) solution of A-hydra~y-3,3-dimethyl-1,2-dilydro-3H-naphtho[2,1-h]pyrW -7,10-thane (506 mg, 1.~6 rnrnol) in dry dichlarometh~c (4 mL) containing 3 drops of glacial acetic acid. 'The cooling bath was removed and flee mixture Gvaa stirred at roam temperature far 20 ruin then aaneentratc:d iir vacuo to afCo~rd ~-hramo-1Q 3-hydrary-3,3-dimethyl-1,2-dihydra-3H-naghtho[2,I-hjpyrau-?,1f)-dune as a t~right aratygc powder (C:iS rng, 96%): m.p. 213-216° C (Found; C, 53.5; H, 4,0, ClSHoBrU~s reduires C, 53,4; H, 3.~ ~~o). V~,~x 3316m, 1660x, 1642x, l3fi~4.;, I?.~bs, 12fi2s, 1174m, 1114x, 1(?-~8s cm~l. ~H NMR. (3Uta MHz, C:DCl_~) 5 1.38 (6H, a, 2 x C113), 1.5:? (2H, t, J =
6.8 Hz, ~I2), 3,32 (2H, t. J = 6.S 1 fz, Hl), 7.06 (1H., d, J- $.fi i-lz, H5), 8.00 (Lff, d, J= ~.C
Fee, Hfi). »zlz (FSI~ 33~ (M[s~Br]+H), 3;i7 (M(~'~Br]+.H).
Fxamplc b' Co»rporcnrl 6; 4-Bramo-$-)rydroxy-3,3-dinrethyl-3H.naphthoE2,1-b)pyran-7,~(l~dione Cnrrtporsnd ~'; 2,,p~dibromo-l,8-dihydroxy-3',3-dirnetlawl-1,2.dit~ydro-3H~nap~tho(2,1-bJpyrrxn-?,Yt7-diorre ' a a OH
p ',~,' ~ ~,' ' Br 0 . -r' a, podium hydride (42 rng, 80% dispersion in ail, 1.40 ~unol) was washed with dry hexane then the supernatant was removed. The residual solid was dried mtdcr a stream of nitrogen. A solution of 8-hydroxy-3,3-dimerhyl-3H-uaphtho[2,1-h]pyran-7,1U-dione (327 mg, 1.28 moral) in tetrahydrofuran (S mL) was added arid the resulting solution was stirred at room temperature for 10 min. This was cooled to c)° C and a~
solut.ion of bromine (265 mg, 1.66 moral) in dry dichloromc;thane (3 ml.) was added. The. mixture was allowed to warm to room temperature and stiwed for 2U min, after which t he solvents were ccane~entratcd in vcacuo to afford a brown residue.. Flash chromatography (20-50~k~ ethyl aeet<~tolhexane with 1 ~lo glacial acetic acid) afforded 9-bromo-~3-hydrax.y-3,3'-dimethyl-:1i~I-naphthca[2,1-b]pyran-7,10-dionc as an orange-broE~~n solid (43 mg, 10°l°). {Found. M+I-t, 334.9909, 336.9857. C151i1zBr0~+T~qllires 334.9919, 33b.99C~t?). 1H NMR (30i) MHz, CDC:l3) b 1.49 (6H, s, 2 x CHs), 5.99 (11-1, d, J= 10.2 Hz, H2), 7.05 {1H, d, J= 8.4 Hz, H5), 7.75 ( t H, bs, OH), 7.82 (1H, d, J = 1 Q.2 Hz, Hl), 8.(~1 (133, d, J =
8.4 Hz, 1i6). rrrlz (ESl*) 337 (M~snr~+H), 33S (ML79Br1+f~f).
Also recovered from the flasli chromatography coltunn was crude cowpcaimd 6 contaminated with a product of py~ran ring bromination (compound 7). This was subjected 2U to preparative HPh.C (isocratic 60%A, 40r"oB) and gave a co~n.pound sus~ctcd of being 2, ~-dihrumo-l , 8-dijrydrc~.xy-3, 3-dimeihyl-.1, 2-di~tydrrr-3H-nrrp~t.t~to(2,1-b)~yrutt-7, I Q-c~inne (3 mg, 0.5°ln), m.p. 202.5-ZOS° (Found: M+Ei, 412.9011, 414.5981. 416.8)61.
LC~SHt~~r~05 - HBO i~ reduires 412.9024, 414.9005, 416.8y87]. v~,;"~ 3475w, 1664m, 1582m, 1370rn, 12S4s, 1262s, 1184m, 11.22m, lOlfim cni'. ~ (tH) (300 MHz, CDC13) . 3~, _ 1.69, s, CHs; 1.66, s, CH3; 4.42, d, ,l 3.8 Hz, H2; 4.73, ba, OH; 5.6Q, d, J
3.f3 Hz, i 11; 7.22, d, ,l 8.7 Hz, H5; 8.13, d, J 8.7 Hc, H6. m/~ (ES*, ?0 V) 457 (MI'~~ sr][
s~Br)'~'Na, 13'%'0), 455 (M[slBr~J'''Br]+Na, 31), 453 (M[~eBrJ[~qBrl+Na, 22), 435 (M(a'Br][B,BrJ~-H, 7), 433 (M[siBrJ~'~Br]+H, 18), 431 (M[~QBr)[~~Br1+f(, 12), 417 (IvI(s~l3r][siBr]-Ii~O+H, 16), 415 (!1Z[siBrJ[ 7gBr]-H=Q+H, 36), 413 (M[~sBr]1''ol3r]-H20+H, 2U), ;i36 (M-L "Br +H~Oj+H, 1 (X1), 334 (M-( s~ Br +H20 J+H, 10U).
Examgle 7 Compound ~'; 9-Brom~r3,3-rlimethyl-b'~(.~-rrcethylbenze~eculJ'onyln.~yrl,2-dihydro-~H-1(? napftthaj2,1-b]pyrat:-x,10-dipue Carnpor'nd ~: 9-D'romp-3,3-dimethy!-F.(4-m.ethylben~e~aesr~lfonyloxy)-3H~nupletf~u[2,1-BJpyran-?,yrJ~diune O p a n ~ + ~ ~. ~ 0 tJ ~ Br ~O '~ 6r0 I ,~' ~ 6r O O ~ O
Pyridine (0.4U mL 4.95 nlmol) «~as ~ddcd to a cooled. (0° C), stirred saluticm of >-bromo-8-2U hydroxy-3,3-dimethyl-1,2-dihydro-3f1-napiltho[2,1-bJpyran-7,10-thane (550 mg, 1.63 mmol) in dry dichloromethane (10 mL") under nitrogen. A solution e~f 4-methylbenzenesulfonyl chloride (3SU mg, 1.84 mmul) in dry dichlorconothane (8 nn:) was added dropwise, then stirring was continued for 1.5 h at U° C:.
Diisopru~~ylcthylamiue (2.5 mL, 14.4 rnmol) was added and stirring was continued far a further 3 h when aqueaas hydrochloric acid solution (2,0 M) was added. Products were extracted with diehlcaromethane and ethyl acetate, and the combined extracts dried, filtered and concentrated in vucwo to afford a brown solid (798 mg). 'frituration of this with ethyl acetatelhcxane gave, a yellow solid (fil0 mg) which by'H Nlv~ speotrc~scopy contained ~l()~'o of the unsaturated pyran (compound 9).
A sample of the above yellow solid (560 mg) was dissolved in ethyl acetate (3U
mL) atLd platinum (JV) oxide (25 mg) was added, The resulting mixture was stirred under am atmosphere of hydrogen Cor S.5 h after which it was filtered through a pad of ~:elite~~' arid lU the filtrate was stirred in air at rocam temperature overnight.
Concentration ir: ~~acua gave a brown scatid which ec~ntaixied ~5% of the unsaturated gyran (camgound a) by 1H
NM R
spectroscopy. The about hydrngt~nation was repeated on this solid using nlatuiuu~ (l~) oxide (69 mg) in ethyl acetate (35 mi.) under hydrca~en at roe?m ternperah.ire overnight.
The mirturc was filtered through a pad caC Celite~' and tire filtrate concentrated in t~acun to afford a brown residue (5S0 m~;). Thi;; wan dissolved in acetonitrile; (45 mL) and a solution of eerie annnonium nitrate (617 mg) in water (2(? mL) was added dropwise. The resulting mixture was atirred at roam temperature for ~ h and water (35 mL,) was added.
Tic resulting precipitate was collected by filtration; washed with watar, hexane and dried under vacuum for '~ h at 4U° C to give 9-hromo-3,3-dim~thyl~S-(4-methylhemenesulfonyloxy)-2U 1,2-dihr~dra-3N-nnphtJ~oi~,1-h]pyran-7,1U-dione as a brown solid (3UU m~, 41°fn): rc~.p.
lUy-115° C (Found: C, 5~,fi; H, 4.1. C2~HlgBr(36a reduires C, 53.8; fa, 3.9 °l<r). v="~
1fi72s, 1580m, 1:~70s, 13U'2a, 1288s, 1222m, 1202m, 1174s, 994x, 718s cm-t. 1H
NMR
(30U MHz, CD(:l~) S 1.37 (6H, s, 2 x (:H~), l,li7 ('~H, t, J = 6.3 Hz, H2), 2.5U (3I-f~ s, ArCH3), ;i.27 (2H, t, J = fi.3 Hz. H 1), 7.11 ( 1 H, d, J = 8.4 Hz, H~), 7.41 (2H, d, J = 7.8 )F lx:, 113'), 7.95 (3H, app d, J - 8, 1 J lx, 2 x H~' and H6), , rr:J: (ESI~) 493 (M~'''13r~+H), 491 (~,l C~9$r)+H), _g.4-Example 8 rC'~nmpoccnd 9: 9~Brvmo-3,~-dimethyl-8-(~meti:yltrenzcnesrclfvnyloxy)-3H
naphtJro(2,1-hjpyrn~-7,1 ~-df one O O
aH ~. -.a ~ ~ ~ ~, o ~' Br ~' 0 ~ ~r°
o ~ o Pyridine (0.15 mI~ 1.85 rnmol) wa:; addcci to a cooled (0° C), stirred solution caf 9-b.~omo-8-llydroxy-3,3-dimethyl-3F1-naphtha[2,1-bJpyran-7,10-dione (23S mg, U.70 rrnnol]
in dry dichlororucthane (5 mF.,) under nitrogen. A solution of .~-methylbcnzenesulfonyl chloride (0.148 mg" t).78 mmol) in dry dichloromethane (4 mL) war added dropwise, and stirring was continued for 1 h at 0° C. Diisopropylethylatnine ( 1.0 mL, 5.74 mmcal) was aided and stirring was cx>ntit~ued for a further 3 h when aqueous hydrochloric acid solution (1.0 M) was added. Products were extracted with dichloromethanc and ethyl acetate, and the combined extracts dried, filtered and concentrated ira vac~~o to afford a brown sold. Fla'~11 chromatography (ethyl aectatelhexane 3:7) afforded 9-bromo-3,3-dimet=hyl-8-(4-metliylbenzene>.sulfouyloxy)-3H-naphthca[2,1-bJpyran-7,10-dione a,s a brawn solid. (97 mg, 28°,%): m.p. 167-168° C (Found: M+I C, 490.998, 468.99~J.
C~HtsBrO~,St requires 490.999, 4&9.001). v~,3=1672s, a3$8m, 1288s, 1218rn, 1172s, 1112m, 1018m, 1(?174tti, 732x, 706m.
fi88 crn t. 'Ii NMR (300 MHO, CI7Cia) ~ 1.49 (6H, s, 2 x CH;x), 2.5U (3H, s, ArCH~), b.00 ( 1 H, d, J = 10.5 Hz, H2), 7.10 (1H, d, J = 8.4 Hz, H5), 7.41 (2H, d. J = $.1 Fi2, I-i3'), 7.69 (lII, d, J 1U.5 = H~, Hl), 7.9$ (2H, d, J = $,1 H~, H2'), $.00 (1H, d, J= $.4 H~, Hfi). >rrlz ~LS1*) 491 (MiXlllr]-~H), 4~9U (ML~9Br]+H+1) _~j.
Fxamglc 9:
iG'nrnpnr~nd 10: 8-.f~rn»to-3,3~dintethyl-9-(4-methylbenzenesrslfortylox,)-3H-napht~arr[2,1-hJgyrrYn-T,10-thane Step 1 3,3-Dimethyl-3h-naphtho(2,1-b jpyran-y-of HO ~ .' C7H ''~
--'----~- O ,~ ,' O H
A u~izturc of 2,7-dihydraxynaghthalene (33.2 ~, 207 n~rnul), 3-methyl-2-butenal (20.U mL, 2()7 Lnmol) and pyridine (17.0 mL) was heated at 110° C Cor 2(.) h tinder nitrogen. 'I'he mixture was caalcd to room temperature and diluted with diethyl ether (150 mL). 'fhc organic phase was aeparateJ and wahhed suc;ccssively with aducoua sulphuric acid aolution (5°~u, 150 1n1~), water (150 rtlL), aqueous sodium hydrtycn carhanate solution (5~I>, 150 mL) and water (150 ntL). The organic phase was dried, filtered and concentrated n vucuo to afford 3,3-dir~ncthyl-3H-.naphtha[2,1-b]pyran-9-of as a buff coloured solid (43.1 g, 92c~o): ~H lVIvIR (300 MHz, CDCI:a) h 1.48 {6H, s, 2 x CH3), 4.99 (111, br s, ~JH), 5.57 (1H, d, .l = '10 Hz, H2), 6.84-6.93 (3H, m, H'1, H5, H8), 7.23 ( 1 f-C, d, J 2.3 =
Hz, H10), 7.55 ('lFi, 2U d, J = 8.8 Hz, H6), 7.63 (1F1, d, J = 8.8 Hz, H7). rn/z (FAB, 3NBAlMeOH) 227 (IvtfH, 6.S~o), Step 2 '25 3,3-Dimethyh3fl-naphtho[2,1-hipyran-9,10-dione 0 .,,~ ,,,~ OH O ."" 0 ..- ~ .r' N, N'-Bis(salicylidene)ethylenediaminacol~alt(II) hydrate (4,5 g, 14 mnal) was added to a stirred solution of 3,3-dimetlay!-3H-naphthoi2,1-b~pyr.~n-9-of (43.2 g, 1~)0 mmol) in acetonitrilc (1.0 L) and oxygen buhbled throu4h the mixture with reaction progress monitored by HPL,C. Further portions of the catalyst (4.1g, 3.4 ~ and 2.7 g) were added.
after 18,5 h, 24.5 h and 44.5 h respectively. After 112 h in total, H !LC
shc~wt;d no starting naphthal and the mixture was filtered though a silicon pad (S x 12 cm), washing the pad with ethyl a4etate until na further red valour eluted. Thc. filtrate was concentrated in aacun 1() and the resulting re:,idue recryst~afliacd from ethyl acetatelhexane to afford 3,3-dimethyl-3H-naphtha[2,1-b]pyran-9,1U-dione as maroon needlas (14.5 g, :i2~'o): m.p. 1U9-11U° C:.
1H NMR (30Q MHO,, CDC1;~) S 1.46 (6H, s, 2 x CH3), 6.(70 (1H, d, J -_ 10.3 Hz, H2), 6.27 ( 1 H, d, J = 1U Hc, H8), 6.98 (1 H, d, J = 8.2 Hz, 1iS), 7.U9 (1H, d, J = 8:?
Hz, lrifi), 7.32 (1H, d, J= 1t).3 Hz, H1), rru''; (FAS, 3NBAIMcOt-1) 242 (M+H+l, 52~Yo), Step 3 9-Hydroxy,3,3-dixnethyl-3H-naphtha[2,1-h]pyran-7,10-dione O ''~' fi o ..o o ~, off -~a 0~ d A wlution of 3,3-dimethyl-3H-naphtha[2,1-b]pyn-9,10-dione (14.5 g, 6(,1.3 xztnu~l) in toluene (850 mL) was washed twice with a salation of sodium dithionite (84 g) in water (8S0 mL). The rcsuiting pale yellow solution was LhGll added to a solution of poOassium 2 r tort-hutaxide (37.U g, 33U nunol) in ~c~rt-butanol (37U mL) saturated with oxygen. The resulting mixture was stirred at ambient temperature fc~r 30 min, after which aqueous hydrochloric acid solution (1.U M, 2SCl mL) was added. The organic phase was separated and extracted with saturated aqueous sodium hydrogen carhcmate (3 x 250 ml,).
'flhe combined aqueouw extracts were cooled (icelwater bath) and acidified with concentrated hydrochloric acid. The resulting precipitate was collected by filtration and washed with water (1.U L) and dried under vacuum for 2 h at 40° C to afford 9-hydroxy-3.3-dimethyl-3H-naphtha[2,1-b]pyran-7,1U-dione as an orange solid (7.10 g, 46%): ~H NMR
{300 MHz, CI7Cls) S 1.47 (6k-f, s, 2 x CH3), 5.99 (1H, d. J = 1. d.4 Hz, H2), 6.25 (1H, s, Hb), 7.1 1 {1H, dd, J = $.4, 0.6 H~, HS), 7.47 (1H, s, Uk l), 7.7f~ (dd, .l = 10.4. 0.6 Hz, H1), 7.97 (1H, d, J
1 (T 8.5 HE, H6. m/z (FAk3, ;~t~lB.4/MeQH) 258 (M+H+1, 5(,)c'ln), 257 (MPH, 100).
Stop 4 8-Brorno-~3,3-dimethyl-9-{4-methylbenzcncsulfonyloxy)-3 H-naphtha['2,1-h]pyran-7,1 U-dione o ', o w. a ,S'o aH -~-~ o ,.. off -~.- Q
'''' I ~r Br 0 o a Sodium hydride {12 mg, 8Uro dispersion in oil, 0.40 moral) was added to a solution of 9-hydrc~xy-3,3-dimcthyl-3H-naphthca[2,1-b]pyran-7,10-dione (1U0 mg, 0.3.9 rnruol) in tetrahydrofuran (2 mL) and the mixture wa's stirred at room temperature for 10 min. The suspension wa;; cooled to 0° C, and a solution i~f bromino (70 tog, U,44 mmcal) in dichlc~romethane (1 mL,) was added. The orange solution was allowed to warn t Co rOOil1 temperature then stirred far 20 rzlin. Aqueous hydrochloric acid solutiurt (1.0 Ivl) was added and the product was extracted with dichl<>rcamethane and ethyl acetate.
The conihined organic phases were dried, filtered and concentrated in vacuo to give a brown t~eaidue (129 rng, 99°ln).

-3g_ Pyridine (25 pL, 0.31 mmol) was added to a cooled (0° G), stirred solution of the above $-brnmo-9-hydroxy-3,3-dimethyl-;1H-naplttho~2,1-h]pyran-7,1U-diore (25 mg, 0.07 mrnol) in dry dichlorc~rnethane (1 mL), A solution caf 4-mcthylt}emenest~lfotlyl chloride (17 mg, U.09 mmol) in dry dichloromethane (1 mL) was added dropwise, then stirring was cc>ntinucd far 1 h at 0° C. L7iiaopropylethylamine (115 ltl.w O.fi6 mmol) was added and stirring was continued far a further :~ h when aqueous hydrochloric acid solution (1.0 M) was added and the mixture extracac;d with dichloromcthane and ethyl acetate.
The combined organic phases were dried, filtered and concentrated in vacaso to afford 8-bromo-3,3-dimctlyl-9-(4-methylbenz~nesutfonylo~y)-3H-naphtho(2,'1-b]pyran-7,10-dio~~e as a t'0 brown solid (35 mg, 95~'e): m.p. 151.5-184° C (Found: C, 54.0: H, 3.5. C~~HI~Bt~J~S
requires C, 54.U; lI, 3.5 'w). v,n;~~ 1678m, 1382x, 1294;;, l2SSS, 11&3m, 1128m, lUb2m, 98fim, 8Q6n, 6826. 564m crri t. 'H ~1MR (300 MHz, C.DCl3) b 1.49 (fih, a, 2 x CH3), 2.5f) (3H, s, AtCII;~), 5.98 (1H, d, ,! = 10.5 Hz, H2), '7.09 (1H, d. J _- 8.4 h~, H5), 7.41 (2H, d, J
= 8.3 1~I7, H3'), 7.70 (1I-i, d, .1=_ 1U.5 ~i~, H1), 7.95 (2H, d, J= S.3 Hz, N2'), 8.04 (1H, d, ,!
8.4 Hz, Hb), rrrlz (FAT') 491 (M[gtBr]+H), (My'a~r]+H) hxample y0 Compound 11; 8-l3romo-3,3~dimet~.yf-,~-(~-rraetjty~~enZenesulfunyloxy)-I,2-dil~ydra-31f-naphthnj~,l-b]pyrmr.~?,.IO-rlzane 2~l .,.. 0 ' '~ O ' /
o ,~~o o ,~~o f Br I .-Br Platinum (IV) oxide (25 mg) was added to a solution of 8-bromo-3,3-dimethyl-9-(4-methylhen~onesultoz~ylnxy)-3H~uaphthc~[2,1-h]pyran-7,Ip-dionc (19y mg, 0.41 mtnol) in ethyl acetate (S mL) and the resulting suspension alas stirred under an atmosphere of hydrogen fc~r 28 h. The reaction wa,s ftlter4d through a pad of C.elite'~ acid the filter cake was vVashcd with ethyl acetate and dic;hlorometlmne. The filtc-ata and washinøs~
were comhined, dried, filtered and concentrated ira vac~uu to afford a brown residue which was dissolved in acetonitrile (20 mL) and cooled to 0° ~'.. A
solution of eerie arninonium nitrate (2(H7 nag, 0.3fi mmol) in water (6 mI,) was then added and the mixture wus allowed to warm to roc?m temperature :end stirred far 2 h, after which it was diluted with water. Products were extracted with di.chlorornethane, a,nd the extract dried, filtered and concentrated in vcacuo t.o afford 5-h~~omu-3,3-dimethyl-9-(4-methylbanzcnesulfonyioxy)-1,?-dihydro-31i-naphtha[2,1-b~pyran-7,10-dione as an orange-brown solid (193 mg, 970); tn.p. 168-169.5° C (Found: C, 53.6;
H, 3.8.
C2:HI~WrCl6,S requires C, X3.8; H, 3.9 °o). vn,~x 1680x, lf~f$m, 1620th, 1S78w, 1566w, 1382x, 129Us crri j. 1H NMR (300 MHz, C:DC13) $ 1.37 {6H, :;, 2 x CHa). 1.87 (2H, t. J
_ 6.2 Hz. 1-12), 2.50 (3H, s, ArCH~), 3.27 (2H, t, J = 6.~ 1-Iz, Hl), 7.1U ( 1 H, d, J 8.6 =
H~, HS), 7.41 (2H, d, J = 7.7 Hz, H3'), 7.97 (2H, d, J = 7.7 Hz, H2'), R.03 (1H, d, J =
8.6 Hz, Flci). rm'z (BSI+) CMCs~Brl+H), 4~1 (IVI[~''arJ+li).
hxample 11 Cc~r~por«~d 12: ~',9-niehloro-3,3-ciin~ethyl' -r,2-dihydra-3F1-nalrhtho(2,1-bjpYrc~n-7,IU-tfiorae ,tap 1 9-Hydroxy-3,3-dimcthyl-1,2-dihydro-:3H-naphtha[2,1-bipyr~n-7,10-thane O Q
O f OH Q ~, OH
I ,~
a A mixture of 9-hydroxy-3,3-dimethyl-3H-naphtho~2,1-h]pyran-7,10-dione (1.20 g,, 4.6 tnn5p() and platinum(IV) oxide {125 mg) in ethyl acetate (30 mL) was stirred under hydrogen far 3.5 h. The dark nllxture was allowed to stir exposed to air for 3t) n,in before I"~ltration through a plug of Celite~'. Concentration of the filtrate in vf~crsn gave a yellow residue wluch was sub,~ect~d to~ flash elromatn~ aphy (ethyl acctatelhexanc 7;3 with l~ii~
glacial acetic acid) followed by recrywtallisation from ethyl acetatc;llmxune to give 9-hydroxy-3,3-dimethyl-l,2-dihydro-3H-naphtho[2,1-b~pyran-7,10-dione as yellow net;dles 1U {948 tng, 79°/u): na.p. 155° C (auhl.), x177° C (dec).
vtn~ 332$, 3148, 31c)$, 1656, 1628, 1566 cm-~, 'H NMR (3C~ MHO, CIaCI;~) ~ 1.38 (bH, s, 2 x C:H3), I.89 (2H, l, J-_ Ci.S Hz, H2), 3.'29 (2Ii, t, J = 6.:5 Hz, H3), C~.25 (1H, s, H8); 7.13 (1 H, d, J =
1i:5 Hz, H5), 7.47 (1H, .;, C7I~), 7.97 (1H, d, .T = b.5 H~, H6). Trr/z (FAB, 31'~1BAI1~2cC)1 () 26I
(M+}I+2,. 11%), 260 (M+Htl, 27%), 259 {M+H, 51).
Step 2 9-Ghlt~re-3,3-dimelhyl-'1,2-dihydra-3H-naphtho~ 2,1-h]pyratl-7,1 ~-dione O O
a ~.'. aH p ~ ~I
,,., I I ~ I I
2l7 a 9-Efydroxy-3,3-dimcthyl-1,2-dihydro-3N-naphtho[2,1-b]pyran-7,10-dione {1.1 g, 4.3 mmol) was dissolved in dichloromediane (2p niL,) arid thiotiyl chloride (15 mL). The reaction was stirred at room temperature. for 24 h and the volatiles were removed ira vucun.

- 4'1 -The residue was dissolved in ethyl acetate (30 mfr), washed with water (30 mL), dried, filtered and concentrated in vaccco. The residue was purified by flash chrcamatography (ethyl acetatelhexanc 5:95} followed by recrystallisation from ethanol to giva 9-chloro-3,3-dimethyl-1,2-dihydz~o-3H-naphtho(2,1-f~]pyran-7,10-diode as orange noodle;
(633 mg, 53°fu): m.p, 14U-2° C (Found: C, 64.9; H,4.8. C~gHI,C103 requires C, 65.1; H, 4.7%).
~m;i" (lug e) 216, 268, 350 sh, 412 11m (:1.35, 4.25, 3.23, 3.44). Vm,~x 370U-3300s br, 3070w, 3000w, y 680s, l6fiDa, 1620rn, 1590m, 1580s cm-t. tH NMR (30U MHL, CDC.1;~) 1.38 (6H, s, 2x CH3), 1.88 (2>-!, t, J = 7,(? 'Hz, H2), 3.29 (21a, t, J = 7.0 HL, H1), 7.12 (11-f, d, J- 8.5 Ht, H5}, 7.12 (11-1, s, H8), 7.95 (1H, d, ,T- 8.5 Hz, H6}, rnlz (PAB, 3NEA1280 (M[3761]+H-i-1, 14'~l0), 279 (Mi3~C:l]+H, 4U), 278 (Ml;3~C1]+H+I, 49), 277 (i~i'35C:1]+H, lUU), 276 (4d), 233 (17).
~itep '3 1S 8,9-Uichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho(2,1-b]pyan-7,10-dione O
O ~ CI Q J CI
Ci Q
C:hlarine gas was hubblcd thrc>uglt a scalution of 9-chloro-3,3.dirrtethyl-1,2-dihydro-3H-nap)ltho[2,1-b]pyran-7,1U-dicme (633 mg, 2.3 mrttol) in ~lacia! aortic acid (50 mL) containing concentrated hydrochloric acid (5 drops) at 70° C for 5 min.
The reaction was stirred for :55 min at 70° C, cooled to rocam temperature and concentrated in vacuo. The re~,'tdue wss purified by flash chrornata~~raphy (tolucne/hexartc 7:3) to.give 8,9- dichJorU-3,3-dimethyl -1?-dihydro-3H-naphtho[2,1-bJpyran-7,10-dione as ;gin orange solid (508 mg, 71'0}. A sample of thin material was recrystallised from ethanol to give orange miero-crystals: m.p, 158-60° C (Found: C, i7.9; H, 3,7. Ci5HI201203 requires C;; 57.9; H, 3.910). ~I,m;ix Clog E) '220, 275, 290 sh, 350 sh, 412 nrtl (4.32, 4.19, 4,01, 3.29, 3.38). vmax . 42 _ 37t?U- 333(1m br, :~D50m. Z950m, 170Us, 168Um, l6UOm, 158(7s cmv. ~H NMR (30U
MHz, CDCI;~) F~ 1.38 {6H, s, 7 x GH3), 1.88 (2H, t, J = 7.0 Hz, l-12), 3.2'7 (2H, t, J = 7.0 Hz, H1), 7.12 (1H, d, ,l = 8.5 Hz, HS), ~3,(~. (1k1, d, J = 8.5 Hz, H6). ndz (FAIL, 3N~.4) 315 (M[~7C;lz]+H, 16%a), 314 (M[37C13~CiJ+H+l, 32}, 3I3 (R~f[3~CI~SC1~+H, 74), 31?
(M(=~sClz~+H+1, 64), 311 (M(3sCl~~+H, 1()U), 310 {42), :i09 (1~).
Example 12 Compound 1'3: Sadi.urn 3,3~rlimethyl-7,x0-d'ioxo-7,10-di3syc~ro-3H-herrzajfJchro»ten-8-aCate or' 5~odium 3,3-dimc~hyl'-T,8~diaxa~7,8-dihydra3l'I-ben;,u(~''Jchromen-r0~-plate 1 t) O O O
NaOH ' .," ~ l ON~a O r' pr ,.~ O ~ (J ,.f QNa Aqueous sodium hydroxide (2.0 M, 3.38 mL, 6.75 mmol) was added drnpwise tc~ a stirred 1:5 orange suspension of compound 1 (1.73 g, 6.75 rntnoi) in methanol (10 m!-). The mixture became homogeneous red. After 30 min valatiles were remuvcd iT~ vck«~n and the resulting red residue dissolved W water ( 150 ctrl.), C~ltcred (porosity 4 sint~;r} and freeze dxied for 4$
h. Compound 13 was obtained as a red solid (1.80 g, 96'0}: tH NlviR (3(?Q MHc, T3~'DMS(7} ~ 1.38 (bH, s, '~ x CHa), 5.26 (1H, s, H9), 5.82 (!F(, d, J = 10.2 1 f~:, H2), 6.83 2U (1H, d, J = 8.4 H~, H6), 7.64 ( 1 H, d, J = 8.4 H~, H5), 8.14 ( 1 H, d, J =
1U.2 Hz, H 1). n~lz (k,S~, 30 V) 257 (M-Na+H, 1()O~u); HPLC 1f70%f 4.74 min.
The 1H NMR can also be run in DZO, compound 13 is fully soluble in water at 1U
m« niL
2S H,p'LC' Canddtions Perforniccl on Water 2590 Alliance System, using a l~~uters CylB 5 utn Syrlimetry Column (Part # WAT04fi98U) and a flaw rate of 0.7 mL.lmin. Column temperature of 3U° C and measured at a, =254 nNl, f3yf~'ers:
Buffer A: l0U%n water Buffer Ii : 100 °b Buffer ~: 2 °r'c. aqueous formic acid Uradienl (ldraeur gradient Glcn~e "b") min ~ min 45% A:50% B:5% C:-~-~ 95% B:5% C--~- 9fi°o 8;59'o C
1 min 5 min 45go A:50% ~;5°!o C '"~ 450~o A:6Q9o '~;5% C
L~;rample 13 CarnporEnd 14: $-HydrQxy-3-methyl-3 phe~~,yl-3H-henzo(fJchrornerae~7,llJ-dune step 1 3..lVLethyl-3-phenyl-3tA-he~~,o~ fjchromen-8-of OH OH
HO
HO
A stirred suspension of 2,b-dihydroxy naphthalene (7l ~ rng, 4.47 mmol) in toluene (2UU
mL) waa heated to rcflux (oil bath temperumre l.fi0° C). After 1 h, the rnixturc ww homogeneous and p-toluene sulPhonic acid hydrate (54 mg, U.4c? mmol) was added (allowed by a. wlution c}L 2-phenyl-but-3-yn-2-of (583 mg, 4.02 mmc51) ilx toluene (50 mL,) over 2U min while maintaining rcflu:~. TLC (ethyl acetatt~/he~ane 1:4) after 4 h shcawed -very faint 2,5-dihydroxy naphthalene. After a further 2 h, the mixture was cooled to room temperature and washed with aqueous sodi~rm hydroxide soluticm (10~, 400 m1).
Tle organic Above was diluted with ethyl Acetate ( 100 mL,), dried (Na~SO~), filtered and concentrated ir: vacwc? to afford a black semi-solid (8U4 mg). Thiw was dissolved in ethyl acetatelhexaneldiehlorcamothanelmetlanol (1 n~L: 4 mL: 1 mL: 1 mL) and subjected to flask chrornatngraphy, eluting with ethyl acetatelhexane 1:4. 3-Methyl-3-phenyl-3H-bc.nTO[f~ohlnmen-8-of was obtained as a brown solid (230 mg, 18}: MS (E~Sh) m/z 287 (M-1}. HPIfi 99.3 %n/ 7.53 min ~tcp 2 3-Mcthy f-3-phenyl-3 H-benzo( f ]chromene-7, 8-cli one Co(SALEN)2, 02 ~0 0 Co(w~AL,EN)z (23 mg) wa:, added in one portion to a stirred homogenous yellow solution of 3-methyl-3-phenyl-~H-bcnza~cltxonten-8-oI (217 m~, 0.75 mmol) in acetonitrile (3 mL).
Oxygen vras bubbled through the mixture and after cJn min the mireure was filtered tlirouqh a silica plug, washing the plug with ethyl acetate until no further colour eluted.
V'olatiles were. removed irt vcrcuu to affcard 3-methyl-'3-phenyl-3H-benzo[~]chromene-7,8-dione as an orange solid (228 tng, 100~so}: ~H NMR (300 MHz, ~:DC13} cS x.86 (3H, s, C:H;~), 6.25 (iFi, d, J = 10.2 Ha;, H2}, 6.43 (1H, d, J= 10.5 Hz, H9), 6.$5 (1H, d, J = 10.2 HG, H1}, b.97 (1f{, d, J= 8.4 Hz, H6), 7.35 (51 f, m, Ari-1), 7.72 (1H, d, .l=
1U.5 Ht, H9), 7.99 ( 1 H, d, J = $.4 Hz, HS) M~ (EST"} rrtlz 30~ (M+1.).

step 3 8-Hyciroxy-3-methyl-3-phenyl-3H-benzc>[ f]chramene-7,10-dionu 4 N Na~H
a HO
S
Aqueous sodium hydroxide solution (4 M, S mL) was added to stirred orange suspension of 3-methyl-3~phenyl-3H benzo[J~chromene-7,8-dione (32 mg, 0.1'1 mmol) iz~
ethanol {5 mL) arid the mixture became IIUIIIO~CIl00t1S hrowm. After 1 h, the mixture was c:aoled (icelwater bath) and acidified to pH-~ 2.0 (5.0 M aqueous hydrochloric acid ;solution). The resulting orange wepcnsion was stirred for LD min in the cooling bath then at i0 min at room temperature. The precipitate was cc~ilected by filtration acrd washed wish water (317 mL) then dried overnight under vacuum tea afford 8-hydroxy-3-methyl-3-phenyl-'t~nzo~,f]chrc>meno-7,1(>-dinne as an orange solid (27 mg, A2~?o): 'H NMR (300 MHO, GDCI~) S 1.84 (311, v, CH3), 6.~2 ( 1 H, s, H9), t7.26 ( 1 H, d, ,7 = 10. S
~~T, H2), 7.14 (.I l i, d, J
= 8.7 kl~, H5), 7,2U-7.4.5 (5H, m, ArH), 8.05 (2H, m, H5 and H1). M,8 (FSC) rn~<, 317 (tvt-I ). HPLC '1 UO ~~ol 7.12 min.
example 14 Cumpoe~nd ~'S: ~~Hydro~,y-3,~~diphetcyl-aft-hen~u(f]cl~romene-?,ff~dione Step 1 3,3-Taiphenyl-3H-ben~o[fJchromcit-S-of f \
"-. o H
.,. ~". a H
r ,i HQ
Ha A stirred ~uapenaion of 2,6-dihydroxy naphthalene (50?. mg, 3.13 mural) in toluene f2(lU
mL) wav heated to retlux {oil bath temperature 130" C). Aticr 1 li, the.
mixture o~as hamagenevus and p-toluene sulPhonlc acid hydrate (54 rug, 0.28 n>tnol) was added followed by a solution of 1,1-diphcnyi-pxop-2-yn-1-of (583 mg, 2.52 ntmol) in toluene (40 mL,) over 30 min while n~aintai.nin~ reflex. After 2 d, the mixture was cooled to room ~emparature and wawhcd with aqueous sodium hydra;cide solution (I0%, 4LlU
mT,). The uxganic phase was diluted with ethyl acetate (?0t) tnL.}, dried (IVazSO~), filtered and 1(.) conceittratcd in vucun to afford a black solid. This was dissolved uz ehlarofai~tn,/hexane (5 mL; 5 r_ttl~) and wbjected to Clash cluomatogr~tphy, eluting with chloroformlltexanc 1:1 then neat cliloroform. 3,3-biphenyl-3H ben~o[,fjchromen-8-of ryas obtained as a brown valid (213 rng, l9~ro): MS (F~f) nt/287 {M-1}. F3PLC BU.:i~7o! 8.89 min a 5 Step 2 ~,3~I7iphcnyl-3FI-henzoG,~]clrromene-7,8-dione cQ(sat.~N~2, a2 ~0 0 zo Co{SALEN)Z (22 mg) was added in one portion to a stirred hc~mcagenous yellow solution of 3,3-diphenyl-3H-bcnzo[J)chrome«-$-o! (2,13 mg, 0.61 tnmol) in acetonitrile (3 mL).
Oxygen was laubbled through the mixture ar'<d after 3 h the mixture was Ciltered through a silica plug, washing the plug with ethyl acetate until no further colour eluted. Volatiles were removed 'vz vacuo to afford brown solid which was dissolved in dichlcaromathane and the solution. subjected to flash chromatography, eluting with neat dichloromethane. 3,3-Diphenyl-3H-benzo[f'lchromene-7,i1-dime was obtained as an orange solid (3'2 mp, 14'0).
MS {ESI'~ rtt/z 365 (M+1).
1U step 3 8-Hydroxy-3,3-diphenyl-3H-t~en~o[ f ~ chrotnctte-7,'1 U-dione 4 N NaI~H
H (~
Aqueous sodium hydrcaxide solution (4 M, 3 n1L) was added to stirred orange suspension of ;i,3-diphenyl-3H-bettzo[J~cluamene-7,8-dicane (22 mg, 0.06 tntnal) in e.thanvl (3 mL) and the mixture became homogeneous brown. After 30 min, the mixture was cooled (iccJwat.er bath) and acidified to pH-- 2.U (5.0 lVl aqueous hydrc~chlot~ic acid solution). The resulting orange suspension was stirred for 20 min in the cooling bath then at 1U min at room temperature. The precipitate was collected by filtration and washed with water (15 ttiL,). This residua waa dissolved in ethyl acetate (S mL) and filtered though a silica plug, eluting the plug with crliyl acetate (150 mL) then ethyl acetatclacctic acid (3U;1), coLle.cting 3 x 15 ntL fractions. Fractions 1 and 2 were combined ;md concentrated in vacun to afford 8-hydroxy~'3,3-ciiphenyL-;i7-~-henzo[fJcl>zotnene-7,1U-dione as an grange solid ('6 mg, Z~.°w).
LH IVMR (300 MHO, CDCl3) 8 6.23 (1H, s, H~). G.45 (11-(, d, J = 10.4 Hz, H2), 7.20 (1H, d, -48~
J -- 8,4 Hz, H6), 7.40 (10H, III, ArH), 8.00 (1H, d, J = 8.4 Hz, H51. 8.16 (1H, d, J = 10,4 Hz, lily. MS (E~I'~ m/z 381 (M+1). HPLC 86.5°1018.81 min, Antiviral Activity Test; of antiviral activity were perCornied in 2.2,15 human hepatoma cells infected with hepatitis B according to the method of Korba and Gerin, Antiviral Research, 19, 55-70 (199?). Briefly, cells were seeded into} 96 well plates and cell media containing variaw concentrations of the compounds was added. Media was changed daily far 9 days and fresh media containing compound was added each day. On the 10'~ d:~y, viral DNA in the supernatant was measured and the reduction in the amount of virus izi the supernatant was calculated compared to cells incubated without drug. Six separate replic;atcs were performed for each dmg concentration. 'The cffe.etive concentration for 50°h and 90'0 irtliibition of the replication of the virus was deterntittcd from dose response curves.
Results fear ;;ome compounds of the invention arc shown in Tahle 1.
Table 1 Teat Compound >H:C50 ~tM EC;90 1M

Compound 1 0.6 3.4 Compound 2 1.1 Antiviral activity was also examined in HepG2 hepatoma cells infected with HZ~V
eontaiuing mutaticms associated with resistance to larnivudine (3TC). ~l'wo cell lines containing an I,1$OM mutation in the HBV DNA polymerar,e, and a double L180MfM204V mutation were used. Cells were plated out in six well plates and allowed to attach overnight, Next day, the culture medium was replaced with either medium alone or medium containing the desired concentration of antiviral compound. Media wsa chaitgcd for fresh medium with or without. antiviral compound an day 3. cJn day 5, supernatant and cell lysates wem analysed CUr lc;vcls of HBV core protein by non-denuturixy Western blot using an anti-HBV core antihady, z5 Results for same of the compounds a.re shown in 'fable 2 whore a SU~u reduction <>r more in measured level at' the viral core protein compared to contt'ols at a compound concentration of groater than 50 Ltmolar is designated +, 50~~'o care reduction at less than 50ymalar is designated ++ end 50°la c~rc redu4tion at Iess than l0unaolar compound concentration is designated +++.
Table 2

Claims (12)

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 a pharmaceutically acceptable derivative, salt or prodrug thereof:
wherein X is OH, OR9 or halo:
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6 cycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected froth H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond;
R4 and R5 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9, halo or NR10R10, or together with the bond between the carbon atoms to which they are attached form a double bond;
R6 and R7 are independently selected from H, C2-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH ar OR9;
R8 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9 or halo;

R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or S(O)2R12 or OR9 is an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl, aryl or arylC1-6alkyl; and R12 is C1-6alkyl, C2-6alkenyl, C1-6alkynyl or aryl.

2. A method according to claim 1 wherein the compound of formula (1) is a compound of formula (2):
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl. C2-6alkynyl, C3-6cycloalkyl or together with the bond between the carbon atoms to which they are attached farm a double bond;
R4 and R5 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9, halo or NR10R10 or together with the bond between the carbon atoms to which they are attached form a double bond;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or S(O)2R12 or OR9 is an amino acid residue;

each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl, aryl or arylC1-6alkyl; and R12 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or aryl.

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

8-hydroxy-3,3-dimethyl-3H naphtho[2,1-b]pyran-7,10-dione, 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione, 9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-6]pyran-7,10-dione, 9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione, 9-bromo-3,3-dimethyl-8-(4-methylbenzensulfonyloxy)-1,2-dihydro-3H-naphtho[2 ,1-b]pyran-7,10-dione, 9-bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-3H-naphtho[2,1-b]pyran-7 ,10-dione, 8-acetoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10)-dione, 2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,1 0-dione, 8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b[pyran-7,10-dione, 7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran, 9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione.
9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione, 9-Bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione, 9-Bromo-3,3-dimethyl-8-(4-methylbenzensulfonyloxy)-3H-naphtho[2,1-b]pyran-7,10-dione, 8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-3H-naphtho[2,1-b]pyran-7,10-dione, 8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,1o-dione, 8,9-Dichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione, Sodium 3,3-dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo[f]chromen-8-olate;
Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3H-benzo[f]chromen-10-olate 8-Hydroxy-3-methyl-3-phenyl-3H-benzo[f]chromene-7,10-dione, and 8-Hydroxy-3,3-Biphenyl-3H-benzo[f]chromene-7,10-dione.

4. A method according to claim 1 wherein the compound of formula (1) is selected from the group consisting of:

8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione, 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b)pyran-7,10-dione).

5. The method of claim 1 wherein the compound of formula (1) is a compound of formula (3);

wherein X is OH, OR9 or halo R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond;

R4 is selected from H, C1-6alknyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, halo or NR10R10 or together with R5 and the bond between the carbon atoms to which R4 and R5 are attached, form a double bond;

R5 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9, halo or NR10R10 or together with R4 and the bond between the carbon atoms to which R4 and R5 are attached, form a double bond;

R6 and R7 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH or OR9;

R8 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9 or halo;

R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or S(O)2R12 or OR9 is an amino acid residue;

each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl, aryl ar arylC1-6alkyl; and R12 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or aryl.

6. A method according to any one of claims 1 to 5 further comprising administering a second therapeutic agent.

7. A compound of Formula (1) or a pharmaceutically acceptable derivative, salt or prodrug thereof:

wherein X is OH, OR9 or halo;
R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl,~
C3-6cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond;
R4 and R5 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9, halo or NR10R10 or together with the bond between the carbon atoms to which they are attached form a double bond;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl. C(=O)R11 or S(O)2R12 or OR9 is an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl,~
aryl or arylC1-6alkyl; and R12 is C1-6alkyl, C2-6alkenyl, C23-6alkynyl or aryl;
with the proviso that when R and R1 are both methyl and R is OH or OR9, R5 is not selected from OH, OR9 or NHR9.

8. ~A compound according to claim 7 wherein the compound of Formula (1) is a compound of formula (2);

R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond;
R4 and R5 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9, halo or NR10R10 or together with the bond between the carbon atoms to which they are attached form a double bond;
R6 and R7 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH or OR9;
R8 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH. OR9 or halo;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or S(O)2R12 or OR9 it an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl, aryl or arylC1-6alkyl; and R12 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or aryl,

9. ~A compound according to claim 7 wherein the compound of formula (1) is selected from the group consisting of:
8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione, 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione, 9-bromo-8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione, 9-bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione, 9-bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-naphtho[2 ,1-b]pyran-7,10-dione, 9-bromo-3,3-dimethyl-8-(4-methylbenenesulfonyloxy)-3H-naphtho[2,1-h]pyran-7 ,10-dione, 8-acetoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione, 2,9-dibromo-1,8-dihydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,1 0-dione,~
8,9-dichloro-3,3-dimethyl-1,2-dihydro-3H-naphtho(2,1-b]pyran-7,10)-thione, 7,8,10-triacetoxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran, 9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione.
9-Bromo-8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione, 9-Bromo-3,3-dimethyl-8-(4-methylhenzenesulfonyloxy)-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10)-dione.
9-Bromo-3,3-dimethyl-8-(4-methylbenzenesulfonyloxy)-3H-naphtho[2,1-b]pyran-7,10-dione,~~
8-Bromo-3,3-dimethyl-9-{4-methylbenzenesulfonyloxy)3H-naphtho[2,1-b]pyran-7,10-dione, 8-Bromo-3,3-dimethyl-9-(4-methylbenzenesulfonyloxy)-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione, 8,9-Dichloro-3,3-dimethyl -1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10)-dione, Sodium 3,3-dimethyl-7,10-dioxo-7,10-dihydro-3H-benzo[f]chromen-8-olate;
Sodium 3,3-dimethyl-7,8-dioxo-7,8-dihydro-3H-benzo[f]chromen-10-olate;
8-Hydroxy-3-methyl-3-phenyl-3H-benzo[f]chromene-7,10-dione, and 8-Hydroxy-3,3-diphenyl-3H-benzo[f]chromene-7,10-dione.

10. ~A compound according to claim 7 wherein the compound of formula (1) is selected from the group consisting of:
8-hydroxy-3,3-dimethyl-3H-naphtho[2,1-b]pyran-7,10-dione, 8-hydroxy-3,3-dimethyl-1,2-dihydro-3H-naphtho[2,1-b]pyran-7,10-dione).

11. ~The compound of claim 7 wherein the compound of formula (1) is a compound of formula (3):
~
wherein X is OH, OR9 or halo R and R1 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, or together with the carbon atom to which they are attached form a saturated or unsaturated C3-6carbocyclic ring;
R2 and R3 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl or together with the bond between the carbon atoms to which they are attached form a double bond;
R4 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, halo or NR10R10 or together with R5 and the bond between the carbon atoms to which R4 and R5 are attached, form a double bond;

R5 is selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9, halo or NR10R10 or together with R4 and the bond between the carbon atoms to which R4 and R5 are attached, form a double bond;
R6 and R7 are independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C2-6cycloalkyl, OH or OR9;
R8 is independently selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, OH, OR9 or halo;
R9 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, aryl, C(=O)R11 or S(O)2R12 or OR9 is an amino acid residue;
each R10 is independently selected from H and C1-6alkyl;
R11 is C1-21alkyl, C2-21alkenyl, C2-21alkynyl, C3-6cycloalkyl, C3-6cycloalkylC1-6alkyl, aryl or arylC1-6alkyl; and R12 is C1-6alkyl, C2-6alkenyl, C2-6alkynyl or aryl,

12. A pharmaceutical composition comprising a compound according to any one of claims 7 to 11 and a pharmaceutically acceptable carrier, diluent or excipient.