Title of Invention	FLAVONE DERIVATIVES AS INHIBITORS OF CYCLIN-DEPENDENT KINASES
Abstract	The present invention relates to novel compounds for the inhibition of cyclin-dependent kinases, and more particularly, to chromenone derivatives of formula (Ia), wherein R₁, R₂, R₃, R4, R5, R6, R7 and A have the meanings indicated in the claims. The invention also relates to processes for the preparation of such compounds, methods of inhibiting cyclin-dependent kinases and of inhibiting cell proliferation, use of such compounds in the treatment and prophylaxis of diseases, and to the use of the compounds in the preparation of medicaments to be applied in such diseases. The invention further relates to compositions containing such compounds either alone or in combination with another active agent, in admixture or otherwise in association with an inert carrier, in particular pharmaceutical compositions containing such compounds of either alone or in combination with another active agent, together with pharmaceutically acceptable carrier substances and auxiliary substances.

Title of Invention

FLAVONE DERIVATIVES AS INHIBITORS OF CYCLIN-DEPENDENT KINASES

Abstract

The present invention relates to novel compounds for the inhibition of cyclin-dependent kinases, and more particularly, to chromenone derivatives of formula (Ia), wherein R₁, R₂, R₃, R4, R5, R6, R7 and A have the meanings indicated in the claims. The invention also relates to processes for the preparation of such compounds, methods of inhibiting cyclin-dependent kinases and of inhibiting cell proliferation, use of such compounds in the treatment and prophylaxis of diseases, and to the use of the compounds in the preparation of medicaments to be applied in such diseases. The invention further relates to compositions containing such compounds either alone or in combination with another active agent, in admixture or otherwise in association with an inert carrier, in particular pharmaceutical compositions containing such compounds of either alone or in combination with another active agent, together with pharmaceutically acceptable carrier substances and auxiliary substances.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10; rule 13) 1. Title of the invention. - FLAVONE DERIVATIVES AS INHIBITORS OF CYCLIN-DEPENDENT KINASES 2. Applicant(s) (a) NAME: NICHOLAS PIRAMAL INDIA LIMITED (b) NATIONALITY : An Indian Company (c) ADDRESS : 100 Centre Point, Dr. Ambedkar Road, Parel, Mumbai 400 012, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed : FIELD OF THE INVENTION The present invention relates to novel inhibitiors of cyclin-dependent kinases (CDKs), to processes for the their preparation their use as active ingredients in pharmaceuticals, in particular for the treatment of proliferative discorders, and to pharmaceutical preparations comprising them. BACKGROUND OF THE INVENTION The ability of eukaryotic cells to proliferate in response to a growth signal is tighty controlled by a complex bnetwork of orderd biochemical events collectively known as the cell cycle, Mitogenic signals commit cells to entry into a series of regulated steps of the cycle. The synthesis of DNA (S phase), and separation of two daughter cells (M phase ) are the main features of cell ccycle progression. The GI phase separtes the M and S phases and prepares the cell for DNA duplication upon receiving mitogenic signals. The period between the S and M phases is known as the G2 phase during which cells repair entors that occurred during DNA duplication. RegLilatots of the cell cycle have gained wisepsead importance in profflerathe afescs. QdrrKfependent kinasss (CDKs)areaian% of enzyme subunit (the actual cydirHlep^ (CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8,eto)arri 15 different types of different din A,Bl,B2,Dl,D£re,Eefc)Bdislepcfthecd trars^(0)K2/c\dm^ Cancer Inst 2000> 3763871, S phase (OTGfcydin AX G2 phase (CDKl/cvdin A), G2M transition phase (CDKl/c>din3B> CDKsarearfetorAospharylatenBnypttf such as the retircdastama gene product Rb. The Rb is invdved in the Gl/S transition of the cell cvde and its phosphorylation by CDKs results in its inactivation (USA-5 723 313X which in turn leads to the release of the trarecripdc lactorE2Fand1te A wide variety of diseases are characterized by unccntroMoeflprolifer^^ pathways in the cell cyde [eg. cKerexpresaoicffcydirECT The overexpression of cycKnDl leads to the deregulation of CDK4D1 kinase activity and thereby contributes to urraitrdled cell ricfiferatm WilhlarfwledgscflreirieofGDKsmc^ approximately 90% of all neoplasBS are assodated with CDK hypeiactivation leading to the inactivation of the Rb pethway,CDKsareattractivetargets£»^ The first potent molecule to be devdoped as an effective CDK inhibitor was a flavone compound [c^2^ Havqiridol is known to inhibit diflerertCDKsaixIftedTib^ hin^ncaricercelkFurtlierieseaichon ttierapy. As are result, analogs offlavcpria^ chromone analog as inhibilois cf CDKCvdin complexes. USA-5 849 733 discloses 2-thb and 2-oxo analog of flavcpridd as protein kinase inhibitors for the treatment of proliferative diseases. WO 01/83469 discloses 3- hydtox)dironien4 flavoioidcanpcunasrflvir^ 4-one derivatives fer the control of tumoral diseases. US-A4 900 727 discloses benzopyran^-one derivatives antnntlarnrnafcxya^Tts. ArfHnflamnHtetybenzcpyran^ hyR-GNaiketalmTetrahedron, 1988,44(7^2081-2086. ThepranrenticteofCDK/cydinkinasea ceflproliferaticnand their der agents. 2 There is a clear need, however, for CDK specific manner. A focused analogs possessing structural features not envisaged in the prior art, as eflective inhibitors of CDKs. Moreover, the compounds of the inrerta M& CDK se under dintcal trials (Cur Pharm Bliarm Etaecra^ 107-116) and also show axnraativdy low cytotoxicity agair&varkxEcSfliererrt Ihetreatmentofvarious ceflrKfilaaricnielatedc&ordas SUMMARY OF IHE INVETION The present invention generally relates to oarrrpounds of the general farnula (la), prodrugs, tautomeric foms, sSereosorners, optical isomers, tiBrmaceiitk^ axepdte sah^ thereof wherein ^ isarytheterccyck^NR^iftOR!! orSRii; I^isfydiDgpn, aIkyl,aryU^^ R^RiandRsareeaiiirKkpendentrysdede^ hydrogen, alkyl, halogen, QRu, srfohjfy, efaft&bontfaxy, alkDxyarbcnylcBy, aryfcafcnyiaxy, carboxy, cyano, nitro, NR^Ria SRn, arylalkyfthio, -SQzdk>i SO?atyl, SQ2M^ftar>iardheterccyde; 1^ is hydrogen alkyl, acyl,h^^ SR^or^O)^; R7ishydroger\alleyl,alkylcar^^ Rsisl^drogsn, aO^aryicarrxKamid^ fyandRioareeadimderKn&ntrys^^ heterocycle, alkcpgorbcii^allqicarbor^ aryfcarbcnyl, hdao^ttarixiTyicaitxKamkfeaii^ I^andRiQtcgetewirhthenirrogenatcm fiitherhetercarcmsefectedfa aromatic; Ruish)drog2nJaIl^acyl,ar)icraI^^ Roish>drogen,teLbgeri,aIkyi,a^ Zisanox)g2natrjrn,asurrkaton%cr^^ is other than OR norSRn; nisaninteger of 1 or 2; 3 A is a 5-to 7- mernbaedring baein: (t) \\toAisa54nen±adringitBsaturatBdcriflTsa^ repreaentedbyanycneoflhe gaTeralsftuctLires ®to«5 \\foeremX1ardX2 are eaii independent atDm,asiilfcratoni,S(0)kanto^ andwhaemlhe nfep^atDmisatleastmcn^ubstitulfidty %\\hereinRj3 is Reeled fi3ral^dn^n,allQd,kMer alkali at)4 h)dioxyl,aikDxy,aIk34e^^ I^sh)drogMtfasub6tituentasde£n^ Rwishjdrogen, a!k)ihydroxyl,M^fthalog3i, ^-S^B^-S^hetocc^ttaryl; R^RgandRioateasdefindabovs; pisanmtegeroflor2; mJsaiintegaoroto^ wilhferiovisosfhat: (a) mcaseofgjenoalstrirlunsQto^ aIkano)ioraryl,andXi isacatbcnatcni,thenl^isctetah^^ sek^itehjdroxy^CK^^^ (b) mg3ladstructe(h'),^^toZisanc^^ cratyl andX>isacarbcnatenT,1rmI^isoteta iitah)drc^CK^dk5doxy,C\|^^ (c) \\taeitherXiCTX2isahe(aoa!^ A is unsaturated, tee is no douUe bcndbehwairingmemiasatpoaticns 1 and2orl and5;or (d) hca9eofgai^stoxl]je(v),vvta (H) \MmAisa64rexiberednn&ft^ wteon X3 is an oxygen atom, a sulfur atom, S(0^ or a rritrp^i atom, wherein ihe nitrogen atom is at least monosubstituted by R^ vrfieran Ro is selected fiom: fydrogen, alkyl, lower aBsnyl, aryl, hjdroxyl, alkoxy, alkjicatbci^cjanoi.-^Rioa^ R6ish)drrjgmcrasubstitiKntasdefinedarx^eon men±eratarycfpostkxE2,3,5or6; withfeprovisolhatvvhen ZisanoxygenatomaTid X315NR13 \\faerehRoish)drog^aIkyi,Ci^ thenR^isotherthan fydrogenorasutetituentatp^^ alkykp^Q^^dkylax^^^ R^RftRiftRj^pandmareasdefinedabovc; 4 (JS) vto Aisa7-rnmibadnngitisasatLiralBdring ofthe ^naalsttuctuie(vii)5 vtain X3 is an oxygai atom, a surfiir atom, S(0)^ cr a nitrogai atom, wherein Ihe nitrogen atom is at least marsitetituted by Rq, wherein Ro is selected fionx hydrogen, alkyl, lower alkali aryl, hjdroxyl, alkoxy, aIk>te^iQm>"SO^Ri03nd-CCHClQ11-^i.1; R^ishjdrogsncrasubstiruerilasdei^^ provisotewhenZisancK>^atDmandX3is>^ ctethmrr)dro@sncrasuter^^ CrsDqtogtaibci^aiyk^arriNRgRi^ R?,Rft Rift Ri4,pandm are asdefinedabov^L The present tmation further relates to a sub-group of ocmpounds of formula (lb), podri^s, tautomeric fams, stasoisameiSs optical isomers, pli^^ thereof wfaaein Ri isaryi,telaocycie,NR9RiftORii orSRn; R2isriydrog^aIk)iar>ihet^^ R3, R4 and R5 are each independent selected fionx hydrogen, alkyl, halogen, ORn, arylalkoxy, aIk>fcaitxxiyIcKy, afloKjcarbcqjflcKy, arylcarteflylcKy, caboxy, c^ano, nitro, NRsRto> SRn, arylalkyJthio, -SQ^Dgi SQ?«yl, S0^k^ftar>4andhede; Re ishydrogen, alkyl, acyl,hyircD^>^ O S _H _ll_ C-R12^ c-Ri2>SR]^0>R2; RTishjdioger^allQialkjtorbc^ Rgisri>drogen,aIkyl,aryl, carTXKanid^sur&mmkl^M^RjocrORii; R9arriRjo ate each indqxrrier%sefected arykarba^tetercc}dc^ 5 R$ arid RIQ together with tfeniti^^ which can teive at least ere fuite unsatLHatedo-aiaTiatic; Riiish>dR^i,all^ac5i,ar)4CTaIk3j^carba^i; Zisana?Q^natem,asulfurateni, orNR^ nisanintegroflcr^ AisasattflatedSmemteiediin^^ whaehXj and X2 are each mfeperrienllyse^ sdectBdfioir ancE^^dor^ asutfLr atomatda ardvvhoehttenitro^atmi aIker^aiyI,h)diox)taIkaxy,aI^^ -SO^Rioand{CHiWRi4; I^h>dro^ttasutetituentascto R^Rci and Rioaie as defined abow; Rwishydrogen,alkyi,hy^^ Mere embctfaient, the presento insectCDK,planlCDKandGffLin^ theldnassactivitycrfOK/cy^c^^ ccmplexes. As described mnxiecMbekiw, the pn^i^^ foimula (la) cr (lb) use of the compounds as active ingredients in phatmamiticaK and pharmaceutical preparations ccnipasinglheraTliephaiinaQ n^nirraliancdl, an insect cd^aplaitoeliaTd^ Ite present comipcirrxlscanbeus^ un^ntdpdi&atimcfendosaiajstissue. BRlEFDESamTlONOFIHEDRAWINGSOFTHElP^VENnON Figures ltD6iepesentsdiemesofprei^^ invention. TWTAU MlDESCMFnONOFTHEINVENTION The present compounds ate inhibkis of CDKs, particularly CDK/cyck\ complexes and find use in aniiptrfiiaative tterapiesfcraTseasescharactaM cfeoders, peooasB, Afcfaimer's disease, immundogjcal dtsotdas involving unwanted potifeialjcci of leukocytes, iestenosisandotherproliiaativesTi^^ Listed below ate definitions of^rious tonsil to described ccmpounds apply to Ihe terms as they are used throu^rut the specification (urfess they are cidienv^ 6 aIkyilhio,thk)ester,surft^ oflhealkylgjrjupmaybeinlemiplBdty afl^is are hydropQarieflTyi, hvdraxjdhyi, 2fydrox>elhyi, aminoelhyi cr rrcqiiolinoethyL Examples of substituted c^doall^gioupsarecjdoalkylgi^^ different acidic alkyl groups, fir example acidic (Q-C^Ikyl groups like methyl groups. Examples of substituted cyctoalk5igTDUpsare4fl^ ftwiflbeurcjastDodbythoseskM substituted if appropriate ^ fcnns of amino, imino, amida, suKbnyl (inducting sulfonate and sulfanamide), as vsefl as ether, aJkjithh carbonyl (irxiudingketones}akyTYd^ alkyl, alken)ialkaxyl,alky^ The terms '^dkoxyT or "afkoxy5* as used herein lefots 1o an alkyl groups as defined abo\e, having an ox}^n radical attach tfeietQ.Repesmrameal Tte term'^ralkyT as used haemiefesto (dsfoedbelovv) Exemplary aralkyl groups indufebsnzyl, ^Cr^^fyridyl, efc ThetanB'ykenyTarri'y^^ alkjfeoesoibedatov^btflhatcorA ancVatripfebond^proviotatlHtfe aromatic system results. Examples of alkenyl groups include vinyl, 1-popenyi, 2-propenyL 2-butenyL, 2-nethyl-l- properiylcr3fliethyl-24xil^ grojpscanalsobeiinsatura^\vh^^ Fiirthemxie, unless otherwise staled as vvdl as alkenyl ardalkynylgKxip^ goups mentioned above for alkyl, lor example, arninoalkenyi aminoalkynyl, amktoalkenyl, amidoall^nyi imiroalkenyl,imirrialkyn^ Urriesstherurirjerofcaib^ hasupto 10caibciiatrjn^mcierjK&^ 'loweralkenyr' iiiearE an aBo^ group asdffaedab^ Thetenri'^'asi^teranrefastorrnxx^ 14 ririg carbon atoms mvvhkhatleastciTecartocydicrir^ E\amriesof(Q-Ci4)^rylresidiies arephenyl,nariilhyl,bipher^iLa^ stated othervwse, and inespactive ofan^ the compounds of fbrmula (la) or (IbX aiyl residues, for example phenyl, naphfhyl or fluorenyl, can in general be irabstrfutdorsubstta dhenvise,substteits^(^bspKsenthsubstit^ arykxy, amines cyarArritio,th^ alderr>0£), sulfri>di>isil>i elher, trioc^^ rrienxydo group \vhich is saturated, partially urcatLiatedcrarom^ position, and in substituted aryl residues the substituenis can be located in any desired position. For example, in mcnaubstiMedriEnylresto pcslkn\viM]e2iHstkiibe^ 2,4irsitioi%2£posi!k^2^ 8 eiibar individually or as part of a larger group. They sraMrrtterrterpretedmthelM defimtaandaie rdev^criy ib^ The terms "flavcne", "chromQne"and Ixnzrjp^Taxn^'crtrfirarBlogsrrKa^ theibltowingbasbsbirtuie: wheremZrnayiepreserrtanGxygm As U9ed herein the tean'alkyTrdeis to ^ brarxheckharaalkylgioiip^cjdcal^ alkyl groups FMiemicte,iinless slated c^ gtoi^whkharesubstibJtedfcycnecr^^ crmalkyl IK 30 cr fewer carbonated nxierxeieiably20crfewa:.Iikew nxtepre&ab[yha\e5,6cr7c3irjCfB^ BcamplescfalkylreskiiESCCiTlarr^ atems are: metr^etliyl, propyl, b^ odadecyl and dcc^ the rHsomets of all tee reskties, isojKip^ i9cbut>l kretojlhityt, isopenlyl, ne^ drnetrrylhjlypinelhyi^^ Examples of cjdcdkyl residues ccr^^ qdoheod or c>doheptyl which can also be afatiluted. The tarn alkyl as used herein also comprises cydoalkyl- substituted alkyl grcqs arri alkyte^ cydcpcpylmeth)d-,(^^ l , l 2dopentyieft^-, 2 c>dopertylriopyK 3doaIkyl group as weQ as a^dk; group cai be substitUBd Of course, a cjdic alkjd group has to certain at least tiiee carbon atoms. Thus, a group like (G-Q)6flgi is to be inderstood as ccnipisrrg among c^ cjdoalk^i-all^ groups lite (C^ 4 to & Similarly, a group tike (Q-Q)alkyl is to be urrierstood as comprising anxi^ alky^CK^^oaB^c^ckipop^ Unless staled ctfierwise,tr]e1erm'fc^ to 6carbcnatctnsard whichembe linearabr^^ rnpartkxilartkm3tD6ririgcar^ reskbeslikemethji ethyl, iipror^ Unless stated otherwise, and inespectKe of any specific subsrituerte b^ defiritionofthecanrx^ mare, fir example 1,2,3,4 or 5 identical or client substituenK Any lord tf residues can be pesertmarryefesnedrxstapovkied A substitatedalkyl relets toanall^re^ withsubstitiier^ibrexamri^hak^ 7 ThetemisiKteroQdefW'heteflx^ hetenx^cfc ring system ccnlain^ diflererthetarjafcr^ groq3rr^fa©cffnp^ha\e 1 a2o>^^ or 2 phosphorus atoms in the ring. In monocyclic groups teterocycfo preferably is a 34iiembered, 4nimibaed) 5- membeie46mernberedcr74iien±e^ Exampksaf such heterocycb groups are piper^^ Inpcty3dfcgrciups,hetaD9d^ ringsmvshkiitvvoCTmcieca^^ ncn^acentatcrnslnpolyc}^ menTbaedcr6memberedhetenx)^ Exemr^ ticjdic arri trk^dk; b^ isciirrJt^riieriQxaai^rje^^ Therirgheterrafi^ resulting lielaDQdbsysto is kri^ heterocycb groups having 1 or 2 identical or diffirertteteioatamsiian sulfur. Examples ctf such teteroqd^ isothiazDtjj triazDtyi, pyrazctyJ, j^ridinyi pyrazinyi, pyridazinyi, pyrirradinyl, azepnyi tetratydrothkjprEn-yl, tebahydrofuranyl,nrjr^^ The heterocycb grc^n^ be bcrde^ rmgriitiogmata Thus, fir exam^ canbe lfynoMnyi(=pync^^ l-inikia2Dry1,2-4midaa^yl,4- iniicterj^crSimkJazrjlyL fathe group-NR^afyandl^ornay,tDg^ laving ere crrraeheteroalcrnsSui^ tovvhkhtheyareattache4areprs^ substituted asirdfcatedbetow. Heteioc^cfo ccmriises satiira^ wdl asnxno-unsatuiatedandpc^ 4cr5,cbubtebari&vviliihtte^ aroniatia Aion^tic heteiocycb gtcqs definitkirEandexplarciiiciEab^ tfoless stated cterwise, and in^^ definition of the compounds of formula (la) cr (D)), tfe tetenx^ group can be ira^ carbon atom v^ ere CT nrie, fir exampte 1, ^ 3,4 a atom in a heterocycb group can independer%cfeach other re substituted Examines of substituents fir the ring carben and ring nitrogen atoms arer(Q alkyljakKyleloge^bjdrc^ hydroxjethyl, alkerryl, alkynyl, (T^aryk^ famate, carbamide, an ester, tone or aldehyde^ siryi ether, thiocarbonyl (such as thioesteis, a triacetate or a thfofcunae), sutfcn>i arninoaad ester, heterocycio, aryl or the te The subsdruents can be present st one or more pcatiorB provided thatastabferro The term 'heteroatem" as used herein means an atom of any dement other than carbon or hydrogai Referred hetercatcrnsatenitroger^axyg^s^ Hak^isfi\x)rine,chksiri^ 9 ft will be understood mat 'substitution" or 'kitetituted with" includes me impbat proviso mat sudi substitution is in accaa^raEwithperrrM v^khdcesncitreadilyunde^ ft stouH berried mat any hetercata valences. "Specific ttribitoi^' or "specific mtiljlm,,irnptiesthes QK^dmcornpfcx. Ce^m cctnpourds of me ptesert invoitm asyrnmetrytoarepreserithmeca^^ cRocdiguiatmTfc{re^ fcnnairirrrixtiirescftwoCTririres Thus, cornpounds accading to the present invaiim\\hicharaexistasenar^ piiefcm^rxfoaslevcrotato^ tv\oeiwilxynefimaQratks.hth^ both ttecistbmiard the tram fbnri as\\dlasnTixturescfthesefbmBmaflr^^ separata ofa mixture by custom suchasfiactiadcrystallizat^ synmesMmtrecriicallyrji^ particularerHntiornerof a compound of the present invention may be prepared by deriwdcatm win a c^ cSasterecmeric mixture is sq^aratedarrife \\foere trie compound ccriaire^ diastereanerksatearefcmiedbyreac^ The diastereaneric salts musfbm^ the art and the pure erariorners are suteequenllyiscJated tram Ire cSas^ stereriscmas can be carried cut at tte during me syntheas. The present insertion alsoindudbafltautonTeKfixrffi A&iitiar^asymrnetrc mixriiestherec^areinteride^ Incasetrecctnpoindsaccariir^ cmiprisestecarespciidm^ urUizaUesaltSL Cbmrfluncfccffcn^ present and can be used accordingtD the invention m me fomi ofthar addition sa^ arick Examples of suitable inorganic acids inducfe bcric arid, percr^ sulfuric arid, sutfemic arid, phcephcocacki, nitric arid ardcte^ Exarr^cfsuilaMeoq^ibacklsincte n^ari4tartaricarid,citricacid,a^ ad^benzok: arid, salic>ik: acid, sulla^ arifletrBnecSsurfcnfcacflaxa^ cte or^roc aricfe lorjw^ to me pesrjn skiM groq^c^ be used according to the imtrit^ metal salts Hke Ca Mg salts, as aluminium salts, as salts of organic bases such as lysine, argjnine, guankfine, d1etrm)lamir^ch^trcmeta Trephatmaceuticaliyaccepta^ invasion can be synthescBd ficm the subject cctrpxmd v^i cataire a base 10 crmiicalnTelrxxkGerealrytresa^ an excess of die desired salt-forming inorganic or organic add or base in a suitable solvent or ctispfirsant or by anion exchange crcsfaexcrar^vvilhcte THF,olaxarEcrrnixturesofthese sdverfe The present invention furthermore irriufaafl solvates ctfccmpoiin^ adduds with alcohols and also derivatives and prodii^ctftrcccnirxiun&ofiQr^ pftyaobgkallytDlera^ Various pcJvrrcrphs of compounds of general fcrmula (la) or (Jb) fixming part of this invention may be prepared by crystallizalkaiofcomrjcu^ usd solvents or their mixtures fir a>staDizaticR% a>stalli^liari at diQbsit teTtpoatures; vanbus modes of ooding ranging from very fast to very staw cooling during aystallizaticns. Balvm^^ melting the ccrrrpound followed ty gradual T fast cooling. The presence of rr^Tnorphs may be ctemined by IR spectroscopy, solid probe NMR spectoHxxjy,difIeier^ techniques. Refined compounds aretaehwrrkhoreamciectfthegr^^ vvithaUtheoomfrrBixxBofr^ preferred compounds of formula (la) or (lb) te preserl imoilkn also inducts afl trfieofmafliaticeardtheirriiarrra^ are a subject of trepesertinventafofe estersandarnides. h a fetptelened errirxxlimerit, tiie present films, stereoisomers, optical isomers, rtemiaceutically acceptable sails, rtariaceutically acceptable solvates or pciyrnarrTBiereof wherein Ri isarvl, unsutetitLitedasubstitulBd Vy at least cmesutetftiientsefededfiom alkenyi, CyQaH^nyl, QCralkanoyl, nitrp, N&RIQ, SRH, triflLocmethyl, hydroxyl, cyano, carbaxy, Q-Cr alkc«ycairxi^arri iderikd or o5flerent heteroat^ imsubstituted or substituted by at least one substitL^sdectedfitohatoge^ C^alkynylCzCrfllkar^ ^i^^lMa^dn^NRgRitiCKita SRu; R2 is hydros; Q-Qfllkyl; aryl, imsutetitutedcr substituted r^ aBc>lC\| carbaxy, Q raving I,2,3a4iobitk^cro5ffireitre(eroafi3m urafaiituid cr substituted by at least ore su^ 11 £i-Qdl9tai])drcKyl;0^ R3, R4 and R5aie eadi independent selected fern hydrogen; Q-Qdkjt habgai; ORu;aryl Q-Crdkoxy; Q-Q- aJkykabanyiaxy; CK^dtossjcarbcnykKy^ SQK4-CraIk$S0?^SC)^ identical ordflerentheteroal^ Reis-Ci-QallQtaaiii; Rgis hydrog^C\|-CfflIkyl;aiyl; carbaxamide;suIfcramkfciNR^o;(xOR]i; R9 and Rio are each independently selected from: hydrogen; Q-Qfllkyl; ar>4; Q-Qdkanqyl; heterocyde, which certains l,2,3a4he(eroatQmssdec^ Q^^Ilo^iaroortytCi-Q- alkykarbonyl; atykarbonyl; h£ferotydccarbcn>i,\shaemfe fi^ nitrogen, CK>gi^ sulfur and r^^ heteroc^cfo-aro either imibstitutedCT substituted by at 1^ alko^', C^c-alken^ CyQ-alkynyl, C2-Ci-aIkano3l, nitro,NRgRj& SR\| i, trifaomelhyi hydroxy!, cyano, carboxy, Q- QflIkDX)carbci$andCrdky^^ fyandR^togetewthlrenilro^ further teteroatom selected fi^ heterocjdicringbeing either iins^ Crdkaxy, CzQfllkenyi, QQdtynyl, C2QaIkanoyl, nitro,NRRift SRn, trifluacmrihyl, hydroxy], cyano, carboxy, £i R11 is hydrogen; Q-Q-alkji; Q-Cfdkanpyl; arjt urfiutelirutedcrsiistitulBdbyatlea^ hak^QA^QQdl^ rrjdroxyl,cyanq,cartxKy,C\| Zisanc«ygmafcm;asulfuratom;ttNR$ AisaS-, 6-or7-raen±)eiedring \herein: (D tte5rOTTberedririgissatifla^^ iepesentedbyanyoieaffhe ^noalstnxtures(i)t)(v); v^heieh X\| and X2 ate each independently selected aion%asulikata,S(0)^arriari^^ heteroatom, andwheremtiienitic^iatmisatleastnxnceub RqVNheiefoRo is selectedfiOT hydros Q-alkyl, unsubstituted or substituted by at least cnesubstiiuert selected from: ha^ amiraniti^C1-CfAithk^sulflT>^ selected from halogen, hydroxy!, cabaxyi, Q-Qalkoxy, amino, nirro, CiQdkyftiki, surfh)dr)i and surfcnyt aryl, unsubstituted or substituted by at kast one suteliluertsefectedfronxhalo^ CyC^II^i^C2Crdkanpyinitro,NR^ftS^ ^i^ltalkylenehydrc^hjdie^ cyano; -SQ^oJ^-CCXG^hrRw; Reisasubstituertasctefindatovematlea^ Ryisr^dro^Q^ValkyliCK^dkyk^^ 12 RM is fybogai; CrCfdkjt hyiraxji; NR^IQ habgen; -SH; -SCi-Cr^t -Say!; aryi; vfoaan the aryl is ureutetitufi^crsubstitu^ CK^fllkynyl,C2CraIkanc^ £i-QaIk)fenetydiax$ahet^^ aDotCK^flikax^CzQata^ carboy CK^dtoxycanxnjiand^ pisanintegsrof 1 a 2 ;and misanintega'Qf0to6; (D) lhe64iiaTTbaEdiingisasaIuratedring ofthe gmeralstructurefa): whadn X3 is an cpcygai atem, a sulfur atom, S(0^ or a niticgpi atom, wharin the nitrogen atem is at feast nrno6ubstilutidbyR&\\n^^ R6is asubslituertas defined abovematfeastane^ Q (ID) te7-manbaBdring isasaturaledring cflhe ^neralslrucluie(vfiX whadn X3 is an axygpi atom, a sulfur atom, S(0]^ or a nitrogn atom, wherein tie niirogan atom is at least nxnoaibstitLiEdbyRo,vtednRoisasdefin^ R6is asubslituertas defined aboueoi at kastcne ring nTemberatanyofpostkxB^3,4)6CT7;arriR7ish>dnjaa^Ci- Qd^Qfcaibc^ foa9eocndpre£nedanbocfimertGte ZarriA,indqHideriiyficmeachothei;ha^ Rjisph^\\hidiisurEubstitutedasd CraIk)iCi CralkyfenetydnKylcris aheteroqcle,\\hkfcisasatuialed, iden&d (T cfin%ot heteroafcms sefedd fi^ imfotituled a substituted by ^ alkcKy, nitro, NR^m SR^ trifluoromethyl, hjdraxyi, cjanq, caibcKy, C\|-Q«lkcp^aibcf^4 and -Q-Cr alkylenehjdrcKyl; R2 is h^drogpn; CrQdtyfc phenyl, v^idi >S iJTEL±sdtulBd or s^edtutod by 1,2,073 kiaiticalordiffiiEntsubBtituaits sdededfrontetogen,CKVaIkylQ afa>carbanyland£i R3, R4 and R5 are each irxlependentiy sefeded fiom: hjdrogn, Q-Qalkyl, halogen, OR11, C\-C42tikfcaftxjnfosxy, NRgRiQSCbNR^qcatbc^c^nDatdnk^ Z is an CE^tsno-sulfur atom; Aisa5-CT&mernbaediir]g\\haek htheSmenitetedsatuialedttunsatu^^ general structures® to (v),Xi arri X2 are each nxlependeniry select suttur, and riitrogen, providedthat in structures (ft(iii)and(iv) at leastoneofXiandXzisahetaoatnm, and \\haeh the nitrogen aloiiisatl^manceubstrtutedty R^\\haemRo is select fiom hjdrog^ure substituted by halogen, hjdroxyl a carbaxyl; CzQalkenyl; h)drox)d; O-QdkERy; Q mliE6HTimibaed saturated ring oflhe general structure(vi), XsisancE^^ak^asutturaton^oranitto^i atan^vvherehtteritrog^atam QAdk$aCi^flItysubstitutdty alkykarbcnyttohKnesuHo^ least cnesutetituent selected ficm nrlrD,NR^ftSl^i,triflLK^^ Q9nD,caibcpty, Q I^and RJO ace eadi iriderxndaiiV sefectd fionx alkykatxiiyicarbcKarnicfe 1^ and RiQteg^te with the nitro^atalD\^^ \\hkh canteve at least cneturtehe^ unsaturated or aromatic, and other urBubstitu^orsubsrilutedbyatleastorK alk^QAfltoK^CzQolk^ carboxy,CK>dkDx>carbc^ Ri4ish)diDgmCiaIk>lh)^^ Inathiriprefbnedemlrxx^^ n^iepresentedby anyoneofftie general strudures(i)to(iv); \vh^X[ iseilhff acaibcnato sulfur, and rnrrog^ except thai in structure (iv)XiiseiieracarbmatanGrar]^ a6m3iibered saturated ring repesentedbylhe ^Taalstructure(vi): \^eanR6andR^3 areas definedabove faaiburtherribcdimerto^^ 3 idmMcr different substi^ tydrDX$c\aic^carbaxy,Ci^^ partially unsaturated or aromatic ring oatfainirg6ringatamsof\\Ji^ selected fonxrritrc^CDQ^ari ordifle^substituafcseled^ cyano, carboxy, Q^rflftoxycairxiiyiarri^^ ; R2arriRiareh\drog3i;and R3 andRsareeachindependentry selected ficmr^ In afirst alternative erribcdirn^ isms, stereoisomers, optical isomers, pharrnaceuticalry acceptable salts, phatn^ceutkalry acceptable solvates or polymorphs theeof wherein Ri isarvi, utxd^stitutedasubEtituted t^atl^ aBffinvi, CjQall^nvi, C2CtaIkanovi nitrp, NReRi SRn, trifliarjmethyl, hydroxyl, cyano, carboxy, -Q-Q- aIkox)carfci^arri identical or dflerent heteroatoms selected irom: nirrc^ c«yg^ su% unsubstituted or substituted by at feast one sutetituerf selected fiarirralc^ C3 arri<:i sru> R2 is rodrogen; Q-Qalkyl; aryl, unsubstituted asubstrtuted by at feast alkvl CK^iillaajcy, C2Q^ carboy, ^rQslkoxycarbanvi and ^^ffllkylerdivdroxyl; saturated, partialry unsaturated or aromatic heterocjde having 1, Z 3 or 4 identical ordrrfeertheteroatorrBsefectedfiarrtr^ urad^stituted a substituted by at least ctie sub^ 15 CyCtffllkynji C^Qdkanp^ rntip, NRSRIQ, SRii, trifluoramedtyi, hydRB^d, cjano, catbaxy, -Ci-CrA»QcaAx^d Ri Ri and R5 ae eadi indepaidenfy sefected ficnr l^^^ aflgtaibonjicKy; Ci^tflBoqcarbcnykKy; a^icaibonykHy; caiboxy; cyanc^ nitic^NI^ctSRii;ar54C\|ClrdlQlhio5 SO^K^oll^SOt^SQjb^^ idedkdcro^en^hetenHtams R6 is hydrogen, Q-Qalkyl, CiCjsBtecofl, hydroxy!, Q-QalkcKji ^K^alkoxjcaibonyl, -Ci-QaDQ^nBORn, -Q- Qaflgtatelo, ^i-QalMerkslR^ft ^i-Qall^reQPPRft itenaxy, -NR9R10 SRc, Sp^-QO)^ or- RgBh>drog^Ci-C^Ik)d,ar)^^ R^andRjoareeadi independent sdeo^ 3 cr4teteroataE selected from nitrogen, c^ arykatbonyl; heteroc>dccadxi^\\b^1heheteroc^^ afe and phosphoiits; carboxarmfe, and aiHbnamide; >\tain the aryl and heterocyde or hdoocycb- at? either unsutetitutedastixtit^ CjQdkjr^ QCraflanc^ nit^ and ^i^V^tatydraxyl; or R9 and R^ together with the nitrogen atom to which ihey are bended, fixm a heterocjdic ring vshkh can haw at least ere satut^ partial^ ixcatuiated a ataiiatic, substituent selected from halogen, CrQdlgi Q-Qdkoxy, C2Qfllk£nyl, CyQflBwl CzQalkanoyl, ratio, N^ftSRii,tnljciaT]ethyl,h>dt^ R11 is h>dic^n; Qdkarr(vi; hdogn, Ci-Cf^ Q hjdrc^cjanOjCartxp^, Crdkax5carbci^arri£i Re is h>drogen;halDgi^Ci QAaik^CrQdkD^ c^ano,cacbo^, subetitutdbyatleastonesditituert Ctfdkanoyi, nitro, NR$Rj& SRH, trifluorarnethyl, hvdrox)!, cyano, caroaxy, Q-Cfehxtysfaxyi and -Q-Cr alkyleneh}droxyl; ZisancKygenatDm;asulfuratam;CTN^ AisaSmembaedsstoiatedccunsatura^ general sttuctuies(i)to(v); vvkn^XiandX^areeadiindepoTcWysdec^ aten^asdfurafi^Sp^andanitrogenat^ andwhereinlhe nitrogen atom is at least nxnosubsliluted by RiaVvhoenR43is3eiectidtimih>dro^ substituted by at feast one substituent selected fern: habgai, h)droxyl, canbeugd, Q-CHtikmy, amino, nitro, Q-Gr alkytlhio, sulftT>dr>i and suifcnyl; CzCtffllkenyl, unsubstituted or afotitifed by at feast one substituent selected from halogai, hydroxy!, cartxKvt, Q-CrfllkDxy, amino, nitio, C\|-Cfdk>iIhiQ, sulfhydryl and sutronyi; aryl, unsubstituted or 16 suhstitutedby at leastcse subsdtuent sdecfied ficm: habgen, Ci-CraD^» Ci-Q-olkcp^ CrCValkenyi, Ca-C^aDgmyi Gr Crdkanpyi, ni&q, NR^ SRu, triftocmahyl, tydrcpgi cyanq, catboxy, Qcaibonyl and -Ci-Q-alkjflenefydicKyl; hydrcKyl; Ci-Cf«Ikaxy; Ci-CraQgteibG^l; I^asutetiti^asdeiMabcwma pisaninlegeroflor2; misanintE^rofOlD^and nisanintEg3TQflor2 foaseccrelerrixxlimentcfc^ 1,2, or 3 identical or difiaent substiluents selected front habgai, Ci-Q^Qi Q-CralkcKy, ratio, NRfta SR11, tritacciElhyl,hy^^ isasatarate^ partially uisatui^ tetoitoms selected from: nfaogan, oxygen, sulfur and ph^mE, and where the heteroc^de is unsiibstitiited or substitutedby 1,2, or3 ida^ordfartsubsli^^ SRii,triitoiornelh)thyc^ 1^ is l^drogen; Q alkyi,Q alkylerfhjdrc^QRii; telega cjano; nfoojNRsRioorSRu; R3, R» and R5arc each independently selected from hjdrogpn, Q-Qalkyi, halo^n, ORu, Q-CjallQteiba^iceQ', NR^RiqSOiNReEiiQcabaj^ c>anoandnita^ AisaSinenTbaBdsaturatadringKp^ \\heirinX\|aTidX2aieeadiiri&penden^ sdfii; andnitrogaT, provided lhat at least oneofXi and X2 is a heteroatem, arri \\tedn the nitro^n atom is a least rrmHiBtitutedby R£\\heranRoissdectedforah)di^ halogen, hjriogi, or carboxyi; CjQdkenyl; hydroxyl; CrQaDsKy; Q^^M^01^ tohjenesuMbnyl; cjano; selected fiom halog^Q^W^CK^dka^ aflacK>rabcnylarri RgarriRioaEeachhoependertlyselectedfte QAalkoxjcarbanyl, Q-Q. aIk>fcadxn>lcaiboxam^ RgandR^lDgfewifotherriirogmata \\hich can have at least one further heta^^ unsatutaled or aramaic and either aIkyi,Ci carbc«y, Riiisr5dK3^^Cicart»nyl; 17 R12ish>drD^n,hak)^n,Ci RwistydcgenQ^Irflll^hydro^ ZisanGxygenatomaasulikatam. InallMeniboalmentofccfi]^^ kfentk^cr different sub^^ hjdraxyl, o/sno, carbaxy, ^{^dkoxjcaibonyl and -Ci^^^aB^ienehyarcKyl; or can be a heterocjde, whkii is a saturated, partially unsaturated or aromatic ring conlainirig 6 ring atoms c)f uhich 1,2 cr 3 are kientkal (T dfail hetaoatomssdectidficiniTitrc^ l,2,or 3identk^ac5iie^sub5litiJ^sete^ h)draxyl,C)anc^carrxKy,C\| R2andR4canbe hydrogen; and RsandRscanbeeachirtJepericfentiyseb^fera InalburthernhxiinientcfcaiipcuT^ \\heemXiisertheracHbcnata and (iv) X] is eite a catbcn atom a anitrc^ atcn^ aQsyl; a Q-Qdkyl substituted by habgai, hjdroxyl, or catboxyi; QQalkenyl; hvdroxyi; Q-QdkoQr, Q-Q- alkylcaba^taluenesulfor^ or 3 identical or difiaent substituerts selected fiom: halogen, O-Qfllkyl, Q-QfllkDxy, ratio, NRsRi& SR^ trifluorcmethyI,h)diaxyl,c^^ h a furte anbcdirnent the present rh^^ riienyl (r pyricSnyl, subsdtuted by 1,2 v^ rodrog^R3andR5areh>draxyi,Aisasatiiia^ (y\ whetein Xi, X& R^ and R13 are as defined Mae particulady, X\| is carbon, X2 is nitrogn, Re is -Q-Q- alkyleneh)drc^RGisCi In alternative oonTixxmdsoflheiamiula(fe)G^ orheterocyie, irideperxleniiyficmeachdr^ RjandAandZcanhaNethepefenedcrparlkd^ Rj can be selected fiamaryi and teiei^^ Q triflicraiKlhyl, amino, Q irisatuiated5CT6iTTembaedring above. In another embodiment Ri can be selected fiom: unsubstituled phenyl; phenyl mono- or po^substituted by halogen, Q-Qfllkyi CrQdkoxy, hydroxy!, carboxyl, OOWkji CONih CONBdkyi OON(aflq% nitro, triftuonxnelfyiamiri^ p^riaymanD-crpol>suh6tirLtedbythe 18 subsdtuenls irdicalBd above fcrjiia^i M >et ancdior en^xdirrieril, R^ canbe selsctBd ficm: fher^4 chksc\|iia^ dkiiloophenyi, chhofkircphenyl, dkiihoflLnnFtenyi, dtei^dra?^iiatyl, crfaocarboxyphenyl, cWoonilicphenyl, amiixxiilorciphenyl, N^ijdiaxjcaibcKjdTlaq^^ cjancchkxophenyl, homophenyl, dbromophenyl, bmrcflira^jiienyl, branx^drcfxyyia^i brcxnocaibcK^phenyi, OKmritrophenyl, arninoliamophenyi, N4^drox5caiba?^ticnrfte^i brcmx^anophenyl flira]phenyi, difiuaqte^i c5btomcpyricfyl,lianc&^ flinicpyriaVidifluciop^^ b&tofluaarieJh>iptBTji R2canbe selected iromhydrc^Q^ R3,R4andR5canbe selected ficnxhjdrog^Q^^ Q-Crdkaxyl; h^dicsxyi; carboxji; nitic^ amino; and -OacyL In one embodiment, Rgand Rsaie h)draxyl or Q-Q alkytetrbc^'toxy, and R^hjdrogen. Recan be selected irorrrh)drqgen;h)K^^ carbaxy; Q-QalkDxyl; CK^dkoxjcarbonyl; aryfoxy; amino; CK^fllkylaniino; cfi Q-Qalkylamino; and -Ci-Q- alkylen&OCi-CralkjA Recanbe^^^ftylene^H, andBpreieiabty-C^OH R?canbeh)ikj^gnafom. Zcanbeanoxygenatom. tnfonrajla{la)or(Ic),Acanbeas^[i^edcrixisaura^ leastoneheJeroatomselectedir^ni^^ R6 The unsaturated 5membaed ririg can have onetttwoctaurte bends intei^ (lg),Acanhpartkiilarbsasaairated5^ien^ saturated 6membaed nng containing 1 nitrogen atom, wherein in both cases 1he ring is unsubstituted or at least nxnosubstitutedbyRfi When A B a 5«iembered ririg of ^neral structii^ aekxldikin nitrogen, (a) Acanbeunsatoratedas\^enceands^bOilymaypetm^ (b) Xj can only be the heteroatom mitogen in the general stnxflires(fi)and(v)and}^canbeanyoneofflie hderoatomsinc&atedabov^ (c) Recanbeallachedtothecarbmringmember^^ (d) Recanbeaflachedtolhecarbcnn^nrerrte (e) Recanbeattachedtotecarbciiiingmenibff (f) RecanbeatladidtDthecarbanringnx^^ (g> I^canbeattachdtotecaibcnrirignien±ff faancteembocfin]ert,oompoin^ ring X2 is NRo, where R13 is h>dro@2n, Q-Q -aflqyi or acyl, Xi is a carixn atom, Re is selected fcm: hydrogen, unsutetiiufedQ^i^ M>^ancteemrxidimen1,ocnitxMiCB areccnipoundshwhichABa6iiem^^ where RD is hjdrogen, Q-Qfllkyl or acyl, Re is selected fiom: hjdro^n, unsubstitiied Q-Qdkyl, Q-Qalkyl substitLitedbyhalc^n,h)di)o^crcarbc^ 19 faafiateemlxxibienl,ca^^ Roishjdtog^CK^^CTac^Reissefe^ halq^hjdrci^acadiBQiandRzisl^dogaa Recatibe-Ci-Cr^D^en&OH Ri3canbe-Ot In)^aiiirteennbodiment,cc^^ c>aixNR^ft^haeniR^ardR\|oareasddiii^abo\^aOR\|^^ indqmientiysefectedficmihjdi^ CK)^aton^asuIfLratam,CT]^ cattx3xamide,NR9RioCTORii,wteieinR9and Rio ate eadi independatly selected fern: hydrogen, alkyl, acyL heSerocyde, alkKMSibonvi carboxamicle and ailfonamide, and Ru is selected from: hydrogen, alkj'l and ac^i Inasfflftnteenfaiimatcom^ isai>ia-aheteroc>de;R2is hjdK^p^ at least (lie of R3 and R5 is ORib v^fcadn Rii is h>dro^ alkox^iridhylcTalkyicarba^'ic^ Examples of pieced oompojndsaocadirigto (^-)to^2^ftayI}^^^ (4)^t^2^fh3TyI^ (f>>m9-2^-G]]atoiiTe^ (-)to^2^ Q^r^2^ (+)tan^244-Baii>fhsQiHK2^^ (f>#i^2{4£taT]oii]aiyi}$^^ (4)#t^2^4J£aTX>jiien)^57^^ (+)to^2{!KlloB>fi]en5fl}^ (+)#i^2 (+)^ft^2^4Tuon>fi]enyI)^24^ (+)tfi^2^Tuctoften5^57 (+)^t)?^2- (+)ta^2- (+)to^2-{2j&DifluQio^^ (4/-)tarc?4{iM2-H} fr)1nm4-{^2}fykKytt& ^)4nm4-{5JiyktydKxy^2^^ (^-)tft^57-Dih)dro^ (+)ftm&{2Hy&axymefafc\ (+)to^5J74)ih)draxy^4i>^^ 20 hgpnnitrile; benanitnle; (V-)a^242-B»3mo-5fliefli3J^te^ -3->fl- S74- one; (4/-}>r^2^ftomD-5me^^ one; (+)^tara-242-Bnm>-54^^ -3->C[- 574- one; (f>toro-2^-BOT]0-5Tietfx^ one; (^-)4t^2^&amo-51i)dro^ one; (+}t^2^-BraTio-51i)dn^ one; dlCmeD-4-One; (4/-)#t^2{(3,5J3fctaflirai^^ 4-ane; (4)>t^2^1JaK>5Hiidliy^^ (+)tft^2^0Tkw>54Tieth)i^^ (+)>t^2^3rano-5iiitiD^^ (^-)#t^2^-Bm]o-5flitofiie^^ (^-)^iw^2^-2pyikfc>3-^ (^-)h^2^43romD-5rita^ta (+)4i^2^-20iboi7yridh-^^ (V->^>CTis^4^dicpcymefl^ (^-)to^57-Bih) (+y-)tfi^2^4-Aii]ii]oph^^ (+)awsL34{^4^diD^^ baizcnitrile; (+)iOT^30ilcn>4{57dr^ beroonitrik; (+}4nw2^BKnto2ftBj^^ (+}#r^2{4-Bramc-2 (^-)^a^2^ diramen4aTe; (^>«w^2^ melhyH4nelhy4)yn^^ (4/-)to^2^4 one; 21 (V-)#t^2^ ere; (^-}>tm2{2 (4/-)to^2^3ik)n>5medx^^ one; one; (V-)#t^2^ (4/-}to?^-Azkfcmeh)4-lHn^^ (^-)>t»»^-Amincii]e^ (^-}ta^-3-{2^ph^ (4/-)#i^3{2^ (4/-)iOT^2^!likxofrenyt^-flien2^^ (V-)>r^2^ (^-)4im2^!Maqi]enyl^^ ty-}tivns-A£dac add 3^^ften)d>5J pynctth2-ylme%l esla; (4y~)to»2^2^ one; (4/-)£iJ2^2^Gikxo\|]hen^ one; (-t/-)tfi2ra-Acetic aad3^^fiienyfl^^^ ester, (4y-)to^2^i±en)^57^ (V-)to^2^4dtioji^ (^-)#i^2^43tai»4dto^^ arid; (4y-)£t^34&cnx>4{5jHiih)^^ acid; (4/-)to^2^4-flucio^^ (^-)to^2^4-AminQ-2 (^-)r»w40iloiD-3^57 acid; acid; hjdoQ^aizamkfe; (V-)£tOT4Chlc!o-3{5jH^^ h>dttKytei2aiiide; (4y-)^>tOT3^Ihkx^>4^5J h>drDx>--benramide; 22 hyckK)4sizamide; (4)£m$'-2^-Etaic^3-fta (+)to^2^-Btaric^fcjoi^^ (+}&tw2QBKjmfr5-fac^^ (+}1nw2QikBnffi (+)#Hrc-2^CHato-5Hcd>fhe^ (fyn^-2Q}tocm>$^^ (+)£i^2^-B[ci»$ (4)>t^2^-Btamc>4ritiD^^ (fynB&2QJ&amc>4iL8t^^ (+)to^2^4-Aniir]o-24xino^^ (^}imns-2^4-Aniro2hxx}^t^ (+)>i^2^-BtanTD-4-metn^ one one; (+)to^2^-B[omc44iyd^^ one; (+}ftarB -Acetic acid ^-ojeteK^niedTyl-l^netf^ 7->iesia; (+)tw-2H2,4C)ichlaD-5-flLno^ rr&fajynicMi&yfySJ-^^ one; and (+)£r^2^4I)Kiibc-5^^^ one; mdidirigphanraceuticaflyacc^^ \haein Ri, R& R3, R R5 and Z have the meaning defined above andPisafiinctki^gjoi^v^accnpcundcf fcnnula(llft 23 Tte present invention also idates to pn^^ phamiaceutically acceptable saliste \\teranAissub6titutedtyI^arriI^ e maribo^nngGfttegei^sIn^ saturatriaurBataated carta feiespedhecaibonatemstovvn^ i) uhercQisbourdtoanunsaliJaldcarixrigfc^ cr inorganic base and an orj^nic a inor^nic solved, arrifoflo\\edtytreatmatw ckxilie bad between members at p^^ and6cs" 1 arri2of6iraifaxlffiTgAaixlbc^^ 1 aid2cr 1 and7of 7-nianbacdiingA toa angjebondand fi) vvhoeQisboixidtoasatuK^carbmcian^c^ a leaving group, and,ifapprqnate,convatir^ salt h arete pocessftr the pqsralbi ofconpDun^ orphanratxxilicaflyacceptabtesahs N^TadnRtR^RiR^RsandZhawtemeaningde&da^ offcmuilapA), teeo£aboia^rarirEoffomTLib(ir): \\foeiemX2arriI^ halite meaning deiM anagancCTinoQ^sriv^toi^ which P is attached ard the nitrog^ cf^ cortpamdoffoimula (la),(Ib),(Ic)OT(lg)iniDarii^^ Atemathd^acampcurioffi^^ 24 reatirgaccnipouiidoffoimula(XA): cracnTipoundofftimula(XM): vtaein in each case RfeRaR^fyRs^RjarriAaieasdeiinedabcM^ an arid to the reactim mixture cap^ base and, if atpopriate, ccrMitmglheresulIantca^^ CbmpcmMfcmTula(XM^ l^tieatrnrtwlhanappropnalec^^ RiOTXwhoanXisahalqgEna-vvithanaclKatBdestersuhas anarf^dndemtepEsorecf abase suhas>^ina 9dv^suchasr^lFsTHForl,4 h the processAcanteseJected from: 25 Rii canbehjdro^nand'orRocanhenTdh)! Aprooessfathepqaiamcfacc^^ 26 \\iiadnRJ,I^R3,R»R5,RDandZaieasd^ndabc^ainpasffi wtenmRkRaRiR^Rs.RoandZaieasdetfW on the ptperidino ring by a good leaving groups m the presence of an ag^ suitable aganic base in the presence of a suitable oq^nc sohort to efe ccntin^ c apprcpria^ociiYQtinglheiesu^ Apocessfalheprepaiatmofacan^^ whasnR,Ra,RxR4 RsandZaieasa^inedabc^oarnaisesie^^ v^haehRi^RiR^Rs andZaie as defined above, vvfo an^ifapproprial^caiveriing AprocessferthepKpacatkxiofacompciundo^ vtaanRkRiR&R^Rg andZaieasdefined, ocmpn^ieactiiigaccinpciurricff^^ 27 \\teanRi,R2,R3,Ri,R5 andZaie as defined alx^^ -QOpH m the imkJaaa^ ring into Iheg^ icmiula (XXXVII) into aphami^^ teaciingaanqxxindofimiLilapOOCV): vvboenR^RiRiR^Rs aidZaieascfcfined,\vi!hanisoc>iai]i&m1he sohent The psert inwnlm also relates to a ptooess fo {i^maca]tk^aocq]y3bsaIt4i£ieof whercin R3, R+R5, R6and A are as defined, vvhkiipnxess comprises reacting the ia^ (VIM) with a diial auxOiay in the presence of a scfcnt aystaQiang out the xeqimed cBasdaecmeric salt and subsequentiyteatingwithbass toobtainthedesinriemrilmieraf^ 28 Gsnirxjiirids of general fanA sdiemes outlindbetow and iDifidated h Figures andRoaEeasdefinedhrespectof^naalfonnula (k)^(Jfo)Xlc)cr(I$above. Scheme l(Egure-l) The compounds ofdie present invention are famed m scheme 1 by ametalca^^ knownmtieartMieccflipcaricfi^^ triflateapAxiDberEerESul^^ 7^nembeied ring as defined atove. In fe memberedringofgeneral structure (vi), and tie 74nembered rirg of general structure (vifX Q is attachedto an unsaturated bond at position Q of ring A and is a halogai or a iunctkiia%suilal& using a^nometaDic catalysts. IfQtstriflaietaPissektedrrom such as paBadarrn comriexes, for example, Pd(OAcX RXZ^hCN^ and PdfhjP)* may be used for coupling .Caip^iscamedaitmTTOsencecfbBSK solvents such as DMF. The ckxiHebc^ hvdrcbcaticnorcatat)fc Where Q is attached to carbcn 4 bearirg a s^ organostannane (\\herein Q may represent tie stannate part) and Hgnd/catal>st such as 13- suhasarylp&ncbenzenesulra^ 6323) Where AisaSinembeiedringhaving the geiie^ be coupled directy with the compound of fctmula (D) using a suhabte catalyst such as FdpAcfe, RJClapO^ Ri^F^and CXi Ccq£ng is carried out m p^ ardpyinMrieusingscdvaitssuchasDMF. Scheme2(Figure-2) Alternatively, Ite (separation of^^ (Xffi)) WiereinZ is O, A is a 5membered ring oanespanclr^ to general sttuctiires®,® NR^I^ishvdroxjalkylarriRjish^^ becamedctffoacoardancevvithfes^ facompcuncfecf1heibnnute(VI)to ispeieiablyall^Asoufnedin Scheme 2, the preparation steps up to conp3undscffamula(V15 starting fontte aredescril^hUSA4900727,vvhkhisin^^ In tie conversion of the compound of ibnnijla(VTQto1rHtofibnnijla(OT gpcd leaving group such as tosyi mesvi triflate or haBde by treatmett with appropriate reagnts like p- toliHTesulibrrylchkxkfe; iric^ric base HE trietl^amine, t^^ acetatoinasoKentsuchasisopropandl^ asdepk^m Scheme2 cr itmay becbieafehiildff^ fcmii]]a(VIIl)mayberesolvedbyieac^ camrta-lOoiljii^ ete,etfyiace£^OTdrhdi^ asNaH(X)kNa£X)3ttK£Cbtooblainte The compound of famiia(VllI)nwthenbetnatedvvith^ac>to any activatedfcmicfanacH inthep^ ocoe^xno^acyla^caiTrxxirri 29 compound offcnnula(X) by treating ilvihareagentlikeanaridchlcikfeoflhel^ (I^OO)A^^ofttetypeR\|OT can also be bKHgjhtabctf by treating a Conveson of the compound of fcmula (K) to the oarapound of fimula (X) can also be brou^it about by a ccmbinateQfRi(X)QHandpo^^ iormula(XI) by standari ester hjddyss using bas^ abcMofibmu]la(XI)rnaytecaiv^^ aid ester sudi as RiCOOM^RjCC^^ activated ester suhasmanh>drife^ The ^diketae oflbmTijh(XI^ may finafy basesuchasNaHiblkMedbyc^diza^ rrriklbasesuchasNa£X]^ flavor of fomxib (XE) by trcatmcnl with a base such as NaH followed by cjdization using a strong add like ccrcertiatedHafcnc^ Analterrtftivemetfiodfrxrjrepari^ conpourriofgsnaalfanifo^ Scheme3(Figuie-3) Scheme3outimestterieparatm converted to a compound of fcmmla (XXII) by fcflcwng strik" poces ccnvaMcftheoarnpcuTdcffbmiuh(V^ prejBied herein is a ccmpciund of general fbmiuh cccesrmfingtogneial structure (&® AsciutlinedmschenTe3,tte(xi^^ P3V) The coiipoindof£mTLih(XIV) is fistoan^ caidensatkmrfthecompourrictf^ Mkfcdreactkxioftheresi^^ oxTTpourid of famula (XVD). The Mkhad reaction in die presence ofachiial base such as prcfefeadstochiral compound of farnula (XVII). Allemativdy, the compound cf^ aHeh>de(XIV)ir]to1reniliDsr}ienecta Michadieaction,i^baseasctecrib^ The resultirg compound offanuila(XVII)B nitro gp^ by kriown mefceds such as trea^ rectactimto)MfeccnTpciundcffa Ahemativ^,iedu^cjdizatmofte (XVH)usirgacalal>tfliteRar]eynM converted to Ihe compound of formula (XXH) as described msdrenc 3. ftocess steps fi^ (XVin)tothecompourrioffbrm^ conpomdoffamuh(XIII)hsdTerne2 Scheme4(Figute-4) Anoternethcdcfcblairiingac^ is O, A is a5nerribered ring represented b^ represertsp4duenesutfc^(Ts)^ R6 isateW^ grc^ inscheme4. 30 As outfined m sdieme 4, Itie compcuid cffcnr^ The oampound of firmula (XXDT) is converted using a Wittig reaction to fa coKSponding styrene compound of lbmTLila(3O(l\0vvhichmtum^ N 2709-2711) The compound (tffamula (XXV) is fan ccnvatd into fa compel of fimi^ compcm[lscffimiLte(}0(\^ c&mukpOCDQalsoleadstofaco^ Scheme5(Figure-5) PrepaiatkiicffapreiMc^^ \\tenanAisa54neni)eredringaxiespc^ andfasubstitiJtionReonAis-CH^^ As afed in scheme 5, fie compound of ibrmufo (XXXVI) is rsqmed s&rting fem fa compound of formula (XXXH) TteconipoundcfiQnnuh(XXXI^ ledidicn g^ fa conespending amir» com 200Q10,835). Conrasbiof amino flavons of famula (XXXIV)tofaconpx^ eflkiBdby treatment wilhetri^ of famula (XXXVI) may be brou$i about by empic^ fa method cfesaibedm fa 5453) fcr fa transformation of a-ariilincKx-dkroQ^cetates to imidazDles using tos>tahyiiscc}anide (TosMQ in presence of a base such as Na£Cb or K^CC^ in a sotvalsuchasethanolCTmetha^ (XXXVI) rnaythenbeccnvertedtofareq^ fikeMnuniaiiiminiumhydi^ Scheme 6(Figur&6) Asstatedhadnabc^iniesp3ctcfschenie2,fakey of formula (XXXXIH) in Figured, may be prepared by fa alternative process steps iDLBtrated h compound offcrmulapOCXXin) maybe ixeriredstartingfiDmfachirdc^ tomispretBredmaoccia^nre^ cfibmTu&(XXXVTn)mieading\^ resuMr^ ketone of iomubt^^ ocnpciindcffinriula(XXXXi) Rin^ base such as sodium hyckiekads to bond in the S^rmibend ring ty a ccrr\eta (XXXXffl)(occe5pandrngtotecc^ compcurxlcffcmTi]la(Xn^^ same process steps as described in scheme 2 fir fa conversm of fa compound c fismulaXHl Intermediates of this invention may also be peparedbyaptooessdisckmlmfaprkrartCT procedi^cfe9cnhedmUSA4900727,^^ TheccnpouridsaMcdingtofagaTaalfcinTuk^ dqsrt^ kinases arxl are hdi^pharn^ pesertinvenlk^treatmeriti^^ facrEenibodirnentfacompoun&^ faprcsert invention arecapableofinr^ anexeessrvecrabnonnalceflgcwth 31 There are a wide variety of pathological auditions with excessive or abncsmal cdl proliferatm against which the ccmpoundscftteinvato avarioEcaxasandleuten^ L carcinoma, including that of Madden, beast, colon, kidney, Iroa; lung ovary, pancreas stomach, cervix, %rcsd,fi06(ate, andskin; i henHtorxiieticturrKisci^^ BuiketfslynTrirnia; in. liematopoiefc tijnxirc prom^ekx^leukernia; iv. tLffrnsofmesenchyn^ v. otiierturrnsiriiudirgrr^^ hdierrfltteiapy-arrifr^ c damatology (pscdasisX d bone diseases, einflanrnationarilaTthritis; ffibropuiifiaalive disorders such as those involving connective tissues, atharjsderosis and cfoar smooth musde prolileiativediscrie^asv^ascr^^ gcaKfov^xJardTCCTHlities(ies^ hrtprm^tog^'i^Tenih-EiMis); i^arasilrio^iiikjdrula^ j. neurofogy(Akhemi^sc5sease,st^ k vidinlaiorE(cytari^^ L ni>o^K infections foaddirkmtotiolfeitive result fion% £r exarnrie, de o^gerfiativedisadersiridi^ as suggested by the finding that CDK5 is involved in Ihe fhcBfiaykfcncftM 749), fakinson's disease. Hurtmgon's chorea, amyotrophic lateral sclerosis and the like, as wefl as spinccetebellar degeroations Other dfleraii^^ tfreeteniay occur oYe to de^tifle^^ cbdiffiientiaton of eniaMal tissue glardiiarcdlsaridrerialoorioftiore baddfoiontotherapeuticaH^^ iteprcseriirivertacanbeiBedasace^ v^andcanafeotei^fcrec^tissuegen^ tbrimiianlaticnsuchasdesct^ Dffiereritialsaeeriirg assays km\\nh specificity fir nonfcuman CDK engines. Thus, ccmpcundswhkhartspeci^^ fir^l or antiparasitic agnts, can be selected fiom the subject ocmpcwncbcf^neral£irnLila(^ mrnritDE are uaetulh patted Ijniriiarra^a^etesrrdlD^ WhensdedBdfirartkr^cc&usestefcD^^ c^dirKfeperdentkinase complex ctfthehijrmpatlrigenwithm^ 32 inhibitmofalMraic^^ Jess. foasimikmanrierjCertafocflhep GX's relative to the maninialia^ inventionimdusemitBecti^^ The present invention thaefiie also dates to the compounds of the fcnnula (la), (fo\ (b) or ((g) anaVor their prmiaKiitical^ acoqptabte sahs anto (Drnparndsoffefomiula {k^(to)(fc)or(I$anaytttteff prodLictkxictfriiamTaceutic^ mentioned above, tbrexampfe icr tte production cfrismraKiit^ iriflanimaticnandarlr^ cfease, dr., and to methods of teatirent aiming at such p^ The present invention iMiermore relates to jiiarmaceuticalocnipositkre oonpoundofttiefismula OaX(lb),(Ic)tt(l$and/ori&ri^^ custornatypteornaoeutk^aocepl^ bringing at feast one compound of fixmula (Ta^ (jb), (fc) or Cfe) into a suitable administration torn using a (itmia&Jticallysuitab^ additives a aiMiiaiies.Tteprmi^ (la).(]b),(lc)CT(^)inari amount atfeqtifc to inhibripTttaJQ^ CanMidtocan AspergillusjwBg^Rhkpw Ttepre^ invention also relates to a m^^ discicfersassodatedwMi excessive eeflprc^^ (L^([b^Ic)a(lg)isu^asttephamiaceiiMfy Thephanriacaak^canbeadrriiraaEi^ crdixiis Administration, iccexariTr&iritiavenousiy,ini^^ topcally,ibrexamrieinthei^ ornasal sprays. The jiBmraosutkd preparation accadi^ skiQedhtealHMrnaceutk^acoeptabfeine^ totheccrnpound(s)cftelbirnula (kX(fo^(fc)cr(J©ancVcrits(t^ prodti^ Fa 1he ptxldkn cfp^ tabfet^ coaled lactose, ccmstairiicr derivatives suprxstxies ate^ for examrie, ^ vvax, na^ examrJe injection solutions, or of ernidskiB a syrups are^ibrexam^ akxh^ £r examiie, ethanol, ptopand a ^ycao^ mixtuKofftevarioussohatevviiidihawb^ The tiiamriaoaitk^ pEfHalkiB nom^ atoutl0toabotf30%fcyvt«^offeca^ ^^^)a©antofteirrliyskA^icaIiy tolerarie sails aridte their r^^ (b),(lb\(lc)or(Ig)ail/orils riiysiobgjcaliytoleral&sa^ The dose of fie compounds of this invention, which is to be administered, can cover a wide ranga The dose to be admiriisteied daily is to be sdected to suit tte paikr! [f raquiral h^ 33 eflbctive to achfeve the desired the^^ vvithout bong toxic to IhepaQenL ThesefededaV]6ag2le\dwiflckperriur^ present irrantmempk^ ate rate of excretion ofthe particular compound bemgemriqjed,^ /orrratdalsi^incoiribirEtionvvithl^ andpriorrnedk^MslDrydliepate Madditkxito foe active ingredienlscffe (k)^(Ibi(fc)or(l$andfatt prcdnjgpardtocaniersubGtaes,fe antbxidants, dspetsarCs, emula^ oontamftwormoieccnTpoii^ rjodrug^Furtterrno^mad^ (^(^(^ocQ^i^cs^T^adkj^csSfy tabafcte sate andbr its prodrug the liemacaitk^ preparation can pioph>1a3k^;actKeingiafiaTls, The ccmpcaicfecftTepresetlinvEntm part cf combined ftaapiea Fcr iffilance^ knc^nantkancer,c>1c6(aftc,ard^ ocmpcuidk cf the present iriventa^ withinilsapproveddos^erange. Forexami^theCDiCiiiii^ krxMnc>1ctoxicag^mindudngapcp^ (Ia),(lbX(fc) CT (1$ n^ be used sequentially wfa fornulationis inappropriate. ftisuxtaoodthatmcdifcalio^ areindudedvvilhhflTeima^ondisdc^ limittherxesert invention. Note: l)BemenlalarBrt\^ThevaluemtBrenlh^ Exampfel: l-MahvW^/^rimd (CompoundNa 1) ltfrrm30roglaciala^ackl(60Om^^ ffl(450mL)v^addedcK«20rrmThe1en^ 35ifiv^aQcM€dtoccxito40^txxiredc^CTCiudiedkE(4^ trimerhoxy benzoic was fittered off The filtrate \^basifiea\ at betowlO^toriT 11-12 usi^ 3oh.ttmTl£off\vrnte30^1)obtainedw^1ilta^ rdd:580gpp/o> 1^:117-119^ Rcm1:160a280a 20(s,lH)i MS:mfe2630Vt> 34 ExampteZ (CbmpoundNa2) Bcxontrifluoridediiaate(3(X)i^ ofoomr»iirxl(l)(300g 1.14x1^^ 1heieactioninixturewasslewlyiai3adto^ was sbwly added followed fcy addrfication with caxertratBdHQ (375 inL) The 5a55^.Itwasccc 225 mL)wasaddedover0.51i Theieadmmixiiins\\assta water adaW to dssohelrieprecipii^ TOAc{2x lL)7teai^ extracts woe oM was treated vvrfo4NHG(lX)ardextra^ Wo aqueous NO! sohition and extracted u^ ocncoiteitedtogjvetepDirtP) Vidd:210g(65.6%) Raril:350a 'HNMR(CDq3):86Ll5fe2H^4.4(m, lHk37(twos^9rft24(s,3H^33(m, tfft255(t,2Fft235(s, 1H20 MS: mb281(M,i 263 (M-H£>) Example3: (^taraMcetic acid l-mefliyl-3^4j(>iimel^^ ester(CcirirjoiirriNo3) DistiMlrielty amine (W^ mmcC»indryaW2(25 L)TofereactimmixtLrem 171.1 g, 1.49x lfrmmol) was added with stining at (K^imder an atrn^^ slinedirjm at 0^ ft was poured oersatura^ washed with brine, dried (anhy. Na£Gj) and corcenlia^tocfaaWtheCknes^ dtstiQdi9opop^akiM(15L),anh>diDtB iefliKedfrxlhftwascoctedtorocmlem^^ was concentrated to obtain the tide compound (3)k\vhkh was purified tang a sflka gel column and 60% Yield:241g(60%> 1H^Ml( Examfte4: (4/-)>r^l-MeJhyl-3^^ (CcnipoundNo. 4) A10%a3imisNaOHsolutm(59t^ methanol (596 mL) The reaction mixture was stirred at 5TCicr45rnhftwasconcentraledtD WurrmrithenpouredintokE^ (arfy.Na2S04)toob(amtte^ Ydd:198g(9%> ,HNMR(CIX^)86.15(s,2H^ tfft26(m, Uft242&3Hfc2jO(fr 2H)i 35 MS:mfe281^249(M-31> Exampte5: (-}#t^l-Meth)i3^4£4riineto (CbmpoundNa5) (^mKl^VfethykM£4£4^^ (Compound Na 4) (273 g, 97.1 mmo!), was dissolved in methanol (100 mL) aril heated to 70G To tiishtgoIulicn\^ added (+)DBTA (3631 & 1015 mnioI)arritheIieatrngwasort methanol (45mL) and isopropanol (31SmL). Httation and an isopropanol wash with subsequent drying afforded the aystaflinetartarate salt (13.14^^ (10mL)arriisopoim)l(40niL)^ The fe base \vasobtaWfiori this poiu as foQtMs Tte srft (9$ w^suspartel methyl ace^ addedandthemixture was stirred fir 30 minutes The 03^ ponin was separated and the aqueous pa extracted using ethyl acetate (2 x 50 mL) The organic portions woe combined and concentrated to obtain tic title compound(5) Yield: 3.6g(263%) [ab25=-17jff,(c=l.lfmetooft ™MR(OX^>6dl5(s, 2^352(^1^3^(1^3^ lHXZ6(m, lH)£42(s,3Hi20(m,2H). MS:nve281 (M),249 Bampfeo": (■)ftan$-A£dac add 3 Na6) BFj^therate (325 mU 250 mmol) was added dropwise, with stirring at (K^iiider>tatrTr6\|tee to a s^ poduct(5) (14.4 g, 51 mmol) in acetic anhydride (26 mL 250 mmol) The reaction mixture was stirred at room temperature fa2h It was poue^ extracted usingBOAc (3 x200niL) Theciganbext^ togettitkcompound(6). Yid±lUg(tS%) 'HNMR^CDCfe^S 142(s, Uft556fe Uft4.1 (d,2H), 352-3.75 (m,7Hk325(m, lH),2&(ni,2Hfc265(s,3H)>25 (s,31ft21(m,5H)i [ab^-7.Q2^c^).7,methanol> Example 7: (^-)tfr^l^l)drox)^3 No. 7) Toasciilkiicfccnirxiiid(6)(llg31mrix)0rnm aqueaBNaCH(25n^62rrimo0soiutm was cooled to room tenpoature, acidified using concenter HQ using a saturated aqueous. Na^COj sohlmThepBciptatedtfe dried Yield: 8J5&(87%> 1HNMR(OX^>855(s, 11^358 (ni, llft35(twsit^ets,^ 26(s,3H),258(m, lH),24k31ft20(m,2H). MS: mfe309 36 Example 8: (CompoundNaS) Scdiiim hydride (Wc^ 217 g 453 mm$ DMF(30mL)at(K;iiteniir^ mmol) was added The reactairaxtiro 2(KZiblkMedby,ackfitimofc^ (^mL)andpassag5cfastrangstieamcfffi mixture was poured c^cochd re (TO $a^ was extracted using CHCb {3 x 200 mL) The oiganic extract was waied with water; dried (anhy. NaaSO^ and caicertiated to obtain the tide compound (8) which was purified using a silica gd column and a mixture of 2% melIraTQlH%liquararmKi& Ydd:2.5g(64.6%). mp:95#7tC Rem4:340^1660. IHNMR(OXi):57.7(dd, lJft755(m,Hft7.45(m,2Ffte;45fe lHfc655 3^4.05fe3H^3j65(dd,ltft337(d4 tfft3.15(m, Uft277(d, Uft25 (m,Uft23fe3H)^205(m,2H> MS:nVe430^398(M-31> AraryskCsHs^^ Bampfe9: (^-)to^2^fiien)4>5J^ (CcmpoundNo.9) Amixlijrecfcompound®(0>25g0fmn^ 15hThereadicnmixturewascccledtDi^^ >^CX)j soLitm It was extracted usm^ Na^SGj) and ccoxrtraled Traces cfo^^ slkagdooIurmandaniixtiiecfS0/^^ Yidd:ai33g(5^/o> mp:22&-230C 'HhM^CDCycS 12J6(S, lHfc73(m,4Hi6i45fe Uft63(s, ltft4T5(m,lH),39(m,2Fft329(m,2H)i292(n% lHfc278(s,3H)£48(m, lift 1.98(m, 1H> MS:me402(]VW))384CVH8X370^1-31> Ran^StUlSaieSO. Example 10: (+)to^2^2 (CompoundNall) Ccn^ound(5) was conwated into (-)^ft^H241vdrc^-3^^ cfoieJhoxyFhenyi]4-etharKi^cc^ &24mmcft was reacted wilhmeth^ (5(%0582gl29mnicftusmg1teprD^ Yield: 0.G7g(&%) mpt9S^C iRcm^s^ieeo. 37 1HNMR(CDQ3)87.7(dd) 1^755(^1^7.45(^2^645(5,1^6^5(^1^4^7(1^1^405(3,3^395^ 3HX3£5(ddlUftl37(dcllI^3.1S (^1I^277(4U%25(^1^23(^3^2O50XI>2IQ. MS:nvfe430(Mf))398^1-31> Examptell: (CompcundNal2) Confound(ll) (0.4 g 0.9 mmd) subjected to cfereihylatian using pyridine h>drochloride (4.1 g 35.4 mmoT) as desaMhe>cxnple9,affb^ Yiekl:02g(56%) mp:22&-230fC lHNM^CDa^M26(sJH),75(rMH^^ Ilft278(s,31ft248(m, lift 1.98(m, lift MS:m/e4Q20VB-l),384(l^lg))37O(M-31> IRcm4:335Q318(U680. [ab^=+12120(c=ai32)meterxAaKfe,4ft^ Example 12 (-)to^2^-Gilciofhen$^ (CbmpoundNal4) (f>#m^l42fl)dn^-3^i^^ (ccmpound 13), was prepared fiom (+)to^l-NM^3^4£iimeli^ using the procedures cfescribedmecan3ples6&7.CcnTp^ ninioOin^DMF (15 mL)htte presence tf^^ exan^8toa&dtetitbocmpcund(14) YKU:025g(26%> mpc9$97C IRcni1^ 166a lHNMR(OX^)67.7(di) 1^755(^1^745(1^^645(3,^ 3Jft365(dd) lHX337(dd, 1HJ.3.15 (m, Uft277(d, l!ft25(nUtft23(s,3Ift2G5(m,2tft MS:nVe430(M^398(M-31> Example 13: (-)^>l^2 (QmipoundNoil5) Qinpound(14) (02 g 0.46 rnmol) subjected to deme%latkii using pyck£ne h>drodTkiide (2 g 173 mmoft as desoibadfoexanii&^aflaiddfe Yield:aig(Wo) mp:22&23tfC 1e lEftZ78(s,3ElXZ48(m, lift 1.98(m, lift MS:mfe4Q20VWi384flVW^37O^I-31> K.ari1:335Q,318Q,168a Ar^C2iIxPsKW)Q5945(^ [a^=-1228°(c=0aHnTetbaKia^40^0> 38 Bamptel4: (CbmpoindNal6) Ctxtipound(10) (07g 226 mrrwO in dry DMF 0 pesencecrf>ffl(W^051g,113niniotyascfe^^ Yidd:0.4g lHNMR(OXfe):877(d, lJft7£5ft Itft7.4(m,21ftd45(s, tfft6.4(s, lift 4.15 (m, tfft 3.9 (fcw arrets, 3jfi5(dd, 11^,338(41HX3J08011, lH)t2j68(dL U%Z4S2[{)L MS:nVe474(N^442(M31). Example 15: (ConpoundNalT) Cbmpciund(16) (036g 0.76 mmol) subjected to cbnelhylaticii using pyridine hydrochloride (3.6 g, 31.6 mmol) as de3cribedmexamifc9,ailbniedlhetilie Ydd0.182g(58%) njp:235237C 'HNMRCOX^^S 1275 (S, ltft7.86(d, lFft7.74(d, lift 7i6(m,2fft 644 (s, llftdl2(s, lift 3.78 (m, Hft3^- 3.12(m,3Fft29(m, tfft285(n% lift 24(s>3Ift 215 (m, lift L8(m, lift nW:345Q 1660. MS:nVe447(IVf>428 An^C2ftS^G5S53(56^ Example 16: (CompoundNal8) Cccnpciund(lty(0.83g2dnir^ inthepresenceGflsMl(5(%0j^ Yieki:057g(78%> 'HNMR(CDCy:573(d,^ 335(111,2^275(1^2^245(^3^215(111,2^ MS:nVe474(rVf),4C(M-32> Ban^fel7: (+)fc^2^44iomofhei^549do^^ (GnpoundNo.19) and (CbmpourdNa20) Ccmpour]d(18) (0.61 & 129 nimoD described in example 9, afforded me two title compounds(19) and (20) which were separated using column chraratography. Compounds Yield: 02g(36%> 39 1x^:163-165^ IRan4:342a297tU680. 'HNMRpMSOd^m llft275 (m, llft245 (s,3Jft2Q5(m,2H). MS: mfe461 Ana^C22IfcB^O^^Q5455(5524iH4j66(5.Q5);N)339(293X&,1668(ld70) Oampound2ft Ydd021g(38%> IRan1:34iai7ia 'HNMRODMSOc^SlZKC^ lift &09(d,2Ift 7^(^2^695(^1^615(^1^4.0(111,1^35-325(111,2^ 32(s, lH2#(m,2Ift25(s,3tft225(m, lift 1.97(m, lift MS:mfe446(Mfi428(M-ia414(M-33> AK^C2,IfeBiNO^Q5^^^ Example 18: (4)#t^2fte^^ (CompoundNa21) CompoureTO(lg324mrri30m^ ptesenoeofNaH(Oi776g 1616mmo0asdescribedme(am\|ie8,a^ Yidd:035g 1HNMR(CDQ3>8a08(d, tfft7S(d, 1^7.45(^2^665(5, Uftd45(s, ltft4.4(m, lH)^4.0(twodoi±fels,6Fft 3.75(dd, lift 335(m,2HX275(m,2HX245(s»3HX21 (m,2F5: MS: nVe430 Exampfel9: (CompouidNa22) and (+)to^2{3jitt^ (CompcuTdNa23) Cbmpcuid(21)(025g(X58nimoO desaibedhexaai^9,afW^^ Ccnqwund(22): Ydd0.035g(17%) mp:146-147C IRcm4:330CU650. 'HNMRpviSOd^ 13.1 (s, lift 827 (s, tfft&l (d, lift 7£5(m,2H),7.15(s) Uft665felIft44(bUIft3S5fe 3Ift3j6-33(m,2Fft3.12(m,lIft2^26(m,2H)^245(^3Ift2iQ5(m,2Eft NK:mfe416^3840Vt-32). CampouriCZft Ydd:0.085g(41%> mp:215-217C IRan4:340ai660. 40 'HNMR(DMS0d^8128& Uft82(s, lift 8.08(d, lift 7j65(m,2Ift 7.0 (s, Uft&18(s, ltft4.0(m, Uft36-3.1 (1^2^3.0(^3^245(^3^225(01,1^158(111,1^ MS:nVe4G2(M^384 Arc^Cal&O^l/ZI^ Bamffe20: (4)to3B^24fydraxymeft^ (CampouiiNa24) Canpcm](10)(0.45&146mn^ pesaixof^(035gWo>729nim^ YEktO29g(40%> !HNMR(CDq3)87.98(d, lHX75(m,2HX73(s; lHX645(s, llft635(s, ltft4,15(m, lift 4.0 (few sir#s,&ft 37(dUH),3.55(cUHp25(!nlH)J(^ MS:mfe522^Vifli490{M-32> Exampte21: (fyn^5J-Bkty&axyJ^^ (Compcxiid Na25) Compour^4) (029 g 0588 irimoDs^^ descnWinGiaTipfe9,afabltetilfecampomJ(^ Yidd:ai45g(58.7%> n?):23>235cC. ^01^:3400,1660. 'HNMRpv®0d6):8128(s, Uft82(s, lift 8 (m,2H^3.0(m,3Ift245fe3H^225(m, Uftl58(m, lift MS:mfe494{M^368(Ntl27)L Ai^C2iI^^O^^Q495(4933XH4.05(433);H=284(273); 1,24.48(2451) [ab -+1.92°(c=02(£ l:lNfeCHCHCb> Exampfe22: (+)iw^2^fluccc>fiia^ft^4i>dia!Qi^^ (CbmpoundNa26) CtaipcuiJ(10)Pg25ninr$matyI^ preseraeQfNaH(0^2s50PA 123mii»9asdesa^ Yidd:0.68g(65%) 1HNMR(CDOi):87.98(d, lift 75(m,21ft73fellft645fellft 635fe lift 4,15(m, lift 4.0(ftwan^ffft 37(dd,lHX355(dJlHX325(m,1^3.Q5(m,lIft257(niJlHXZ4(^3Hi215(^ M&mfe414(Mfli382(M-32> Example23: (+)taw^2^4:luQn>iiKr^^ (CcmpamiMx27) Compound (26) (0.07 g 0.169 mmd) subjected to demeft^latkii wMi pyndine l^dtocHcdde (1 g, 8.65 mmot) as describedinexample9,afa^ Ydd:a017g(26%> mp:206-208c1G 41 ttW:340Q1660. iHNMR(DMSO<8128> (dd, Uft3.7(m, tfft358(m, llft348(m, lHX33(m, lift 285 (s,3H),235 (m,2H)i MS:m/e386(MH> Ana^C2\|IfeFNO^Q^ Examp!e24: (CompourilNoi28) Omixxiri(10)(0.83g2®nTri^ tepresenoeof>Ml(OMg5(%1333n^ Ydd:a73g(68%> 1HNJMR(CDa3): 5 8.05 (1,2Ift7.65 (dd, lift 7.45 (m, lift 7.12 (s> 1H); 6.6(!=slPft435(m,lH),3.95(t>wdaiH^ 6HX3j^325(m,«[X3.05(m,lHX2^5(ms Uft235fe3Iftl37(m,2Fft MS:mfe414(MH)382 B (4)tfi^2-fhen)^5,7A (CompoudNa29) Compound (28) (051 g 123nmxiDdenTelhylatriusir^ g 44.15 mmof) as described in examrje9, ^vt the title ccrnpound(29) Trek 025 g(42%) mp:21822ffC IlW:3390,1660. 'HNM^DMSOd^S1285 (s, lift 80 (m, 2HX7^5(m, llft7.45(m, llft7.G5(s, lift 6\18(s,llft4.a5(m, lift 37-32(^2^295(111,3^23^3^225(01,1^1^(1^114)1 MS:mfe386(MH), 368 (VH8X 354(M32) AnalyskC2ityM^l/2^Q6325(63^H5^(53^H357p5^ Examp!e26: (CompoundN3i30) Caiipcml(10)(1.5g4.85rnm^ g64mni30a5T;mfeptes^ Tte reaction mixbie was diluted w^ wasted with water; dried (anhy. Na^SOO and concenteted Tire semisobd lesdue thus obtained was treated with concentrated HQ (50 mL) and stined at room tempoaiure for 2h Rite pin^^ aicfddthetitteccmpcuid(30> Yidd:0.09g(5%) 1HNMR(OX%):875(m) lift 7.1 (t,2Ift642(twosi#as,2tft4.11 (n% lift 357 (two arrets, 6ift 3^6 (dd,lH), 3.52(d, Uft325(m, llft295(m, Uft265(m, lIft245(s,3Ift20(m)2H): MS:mte432(M+l),400(M-32)i Exampfe27: (CampoundNo.31) 42 Ccmpound (30) (O09g 0208 mmol) subjected to demdhyialion uang pyridine h>itexh!cdde (1 & 8J66 mmoft as describdhexampte9,aflcded1te^ Yidd:0.Q32g(38%) mp:242-244(C IRari1:3300,1660. lHNMRpvEOd6):6 lZ65(s, lHfc7.75(ro, 1^7.4(^66(5, ltftdl5(s, lHX3.7(m, 1H^3.6-3.1 (m,2H^3.88 (m3^245(s,3fft215(m, 1H), L85(m, IHL MS:nVe4MflVW),386(M-18i372(M.32> Ana^C2iHi^NaH^C;6043(59^5);H456(5jQ2);N)3.96(332> Example 28: (V-)£tw^^-H)draxyn^^ (Compound No. 32) Ccmpcud(7)(15g4^mm^mdiyDMF(15mL)ieac^ thepe9eneeofNaH(12g50%25mmcfy^ Yield: 0£5g(48%) mp:214-2ie^C IRari1:3400,2210,1640. WlR(aXi)o&15(d, 2^78(42^675^ lH),33(m,3Ift278(ms 1^,26(41^242(^3^208(111,2^ MS: me421(Mf 1^378(^42) AnaljasCM^NA L2^Q67.Q5(67.12);H5.78(5.63);N,6.1 (6i5> Examp!e29: (V-)taHS^5^)dia^^ batEmilnTe(CtriipoundNa 33) and (4/-)ira4{5J43ih>drcf^ (Cbmpou«lNa34) Compound (32) (030 g 0.71 mmol) \\asieacledwilh pyridine h>d^^ afibtddthetittecxsTpcuxH(33)and(34). Cbmpound(33): rddO.Q33g(10P/o> mp: dBocmpcatoV>25CPC IRari,:332Q,221(U#a lH>JMR(CDCb):51298(s) lift 835 (d,2H), 8.08 (d, 2H), 72(s, 1H), 665(s, lift 338 (m, lift 335 (s, 31^3532 (m,2HX3.1(m,2I^2^5(m,lfftZ4(s>3H),2j0(m,2H)L MS:mfe:40f7 AiB^C2fe^l£WQ63^ Campoundp^: Ydd:0.1g(36%> 1^:273-275=0 IRari1:350Q2220,166a 1H^MtpVlSOc&512£(s,llft826& 295(m,3H),255(s,3H^225(m, lH)£0(m, 1H). 43 MS:mfe393(MH)376(NM8> AraljssCaFfeNA l^OQ6&59(6657fcH526(52XNJ6.63(7.05X Example 30. (+}4tra4{i^241)diaxynT£^ (CompoundNa35) Gxnpaurri(10)(098g3T7mi^ 1hepre9enceGfNaH(50%0762gl5J£ Yield: 056g(43%). IRari1:340a221Q,16tt). ]HNMR(DMSOc&8828(d,2^ (m,2H)325-3.15(m,2H)265(m, lH),24&3H)£0(m,2H)i MS:m/e4210^-1)^378^4-42). Bampfe31: (+}totfB4{5Jl)dia^ bmaxiMfe(CbnEX)iiTdNa36) and (CompoundNa37) Compound (35) (03) gU9mmo0n^^ anadedtetilieocnipounds06)and(37): Compound(36): Yritaig(20P/o> mp: 117-119C IRan1:342a2250,166a 1HNMR (m,3HX3.08(m, lH)tZ6(m, 1H\|^235 (s^3H^ 158(m,2H). MS:n^407(MH),375 Aralyss:CBFfet^.l^^OQ61.44(6139XH5.11 (5.6);H 631(653) Compound(37)= Yidd:ai9g(40P/o> mp:245-24^X: IRan-4:340a224ai660. 'HNMR(DMSOc&5a8& lH)828(d,2H)&G5(d,2Fft7.1 (s> lH)615(s, lH)4.0(m, lH),3:34(m,2H)3.0 (m>3^2i(s^3H))225(mP 1H) 158(m, 11^. M&me393 (MH)376(IVH8) Ana^kCijH^Qs. 1/^OQ©38(63J(%H,522(552);N, 664(667) Bample32: (^-)#mf^ifydn3(ynieli^ (OompoundNo.38) Ccmpcund(7)(15g4#n]nxOindiyI^ 16fl2nTmoOinfhepre^^ Ytt 44 mp: 114-1150 IRcni1:345410OL ■HNMlCCDqjXSantt^XTSCi^dySCs, Uft6.48& llft438(m, Uft4J0(twsa^ffft3.7(d4 lift 338(41^328^275(^1^265(^1^244(^3^208(01,2^ MS:mfe464(^l),421(M42) Aral>as:C2iHsiF3NO^^OQ59.13(59^H551 (5.44)N,234(29) Exampfe33: (4/-)tft^5,74)ih)dioxy^^ (CcnsmxiNa39) Compound (38) (Oig 1.08 mmol) was demelhylalBdi^pyrk^ exan^9,tochainthetifeccfnpoundC39). YiekJ:028o(59%). np:23ffC Ran1:3350,166a 'HNMRiDMSOc&S127 (s, lift 833(d,2Ift 7.98 (d, lHX7.08(s^ lP^6.18(s, lIft4.Q5(m, lift 3.6-3.4 (m,2Ift 3 MS:mfe434(]VtU4m(M-31> Ari^CsBfeFsNOs Q6034(6a69);H4.48(4.63);N,289p.42)L Exan^te34: (Ccn?x]uadNa40) Compound(10)(0%26nm)9md^ mmotymthepresenoeof^^ Ydd:1.0g(87%> mp: 114-115^ 1HNMR(OXlj>8&15(d,2Fft7.78(d,2Fft675(^ ltft648fe lfft4.48(m, llft4.0(1wo an$£> fift 3.8 (d, lift 3.46(m,2tft288(m,2Eft255fe3H^218(m,2H). MS:iite4Gl(MH)432(M-31) Bampte35: (+)^>rw^5J4}ih>dra^^ (CcnipourriNa41) Compourri(40)(a7&L51miii!$ evaripfe9,tDot^theliIfeoarrpouiid(41) Yidd:028g(42%) mp:235237€ IRan1:340ai66a 1HNMR(OVlSOd6):81282(£s ltft 835(d,2fft 7.95(d, 2^7.08(^1^617(5,11^4.05(111,1^3^6(111,2^ 298(m,3tft25(s,3H),225(m, lift 1.98(m, lift MS:mM36(MH)4M(M-32) Ara^Cz^N^IRp Q55.79(56M);H453(5.1)sN,291 Examp!e36: (-)>tw^4l3draxyri^^ (OmpoundNo.42) 45 Gmpourri(13)(l g324ira^ mmoOhttepresenoeofNaH(0.77^^ YKW:a6g(40%) ,HNMR(OXl})5ai5(d)2tft 7.78(d,2Ift6i72(Ss Uftd45(Ss llft442(m, 1H4.Q5 (two a^&ft 3.75 (($ lHX335(m,2HX278(m,2HXZ45(s^3H^21(m,2H). lVB:m/e4#(lVMi432(M31) Example 37: (CbmpoundNa43) Cbn^xxmd (^) (03,1.08 mnx^ \\as demefl^te exan^9,tDobtahtetifeocmpciurid(43) Yidd:0.195g(42%). mp:234-236:C IRcm,:338G,1660. 'HNMRpvlSOd^S 128fe lift &32(d,2Ift 795(d, 21ft 7.1 (s> lift 615(s, lift 4.05 (m,llft338(m,21ft3.0 (m,3Ift23&3Ift222(JUIftl.95felIft MS: nVe436(MH),4(W(M-32) Ai^CzftHftJ/afcO Q57.08(57.15^H431(5.0^N,3.0p.Q2> Exampfe38: Can^xxiri(10)(lg323mmcftm(ty presenoeQfNaH(50%,0.77g 16(Hmi^asdescribedmexan^(8)to Yield:0.49g083%> 1HNMR(CDqJ)8a00(m,2Ift73(m,3Ift668fe lift 6A5& lift 4.4 (rnjlft 4.0 (tvwan^6tft 3.72 (dd, lHX3.45(d,lHX335(m,l!ft282(m,2FIX248(s;3HX21(m,2H)L MS:nVe395(Mf) Bcampfe39 (f)ton^5,7-Bfy CbmpcuTd(44)(03gl27mmctyvvffi1^^ e Yidd:03g(6t%> 11^:212-215^ IRcm:342ai6e0. 'HNMR(DMSOcy: 8129fe lift ai (d,2tft7j62(m,3Ift6.95 fe Ilft6.18fellft4.05(m,llft335(m,21ft3.0 (m, 3Ift252(s>3Ift 225 (m, lift 195 (m, lift MS:me368(MHi363(N«2) Anal>SB:C2iItiNO^.b2I^O Q 6695 (670);H, 5.81 (5^N,3J67(3.72> Exanpb4a (+)4nm^ifydmytt£fo^ (Cbmpouid Na46) CbmpcuTd(l(9 (0.95 g 3,07 m^ (225g 14.42 mmd) inlte presence of NaH (0.741g SCP/a, 15.43 mmo0asde3aib^mQamFfe8)tDgpttetite oompsmd^ 46 Tidd O5g(40P/o) lHNMR(aX33):8758(d1 ttft7.55(d, ltft 7.18ft Uft655fc lfft645 (s, ltft438(m, 1HJ.4J0 (hwsir#^6Hfc 375(dd,ltft3A5(i^2H)^252(m)2Fft258(s,3Ift22(in2H). MS:mfe402^-U369^-31> Example41: (4}W5J4)ih)diDxy^4T^^ (Compound Na47) CbnTpcund(46)(029g0.72nrf aso£saib0dmQ Ydd:ai49g(55%> mp:21&-22(Kl IF. cm4:?^, 1650. 'HNMR^MSOd^S 129(s, lH),&08(d, ltft&0(d, ltft 732ft lH^fe lH),62(s, llft3.95(m, 11^3.58 (m, 2H^252(m,3Ift2j65fe3H))225(m,lIftZ15(m,l^ MS:m>e374(M^342(M31) AnalysisiCKH^JO^lil^O Q57.11(5d96);H,5.03(5i);H3.44(3.4^ Exampfe42 (+}4w4{& banEOiitrii£(Cbn^)oundNa48) CampouriK10)(1.0g324nim^ rnrrx^intepresanoeofNaH(50)/^0.776g l&16mmotyasd£saibedmexar^ Ydd:05g(S7%> lHhJMR(CDq3):87.76(a; 1^765(^2^648(5, lHfc635(s, lfft42(m, lH^4.0(tswsir^e(s,^3.74 (d, lift 3.4(d, lfft335(m, Uft286(d, lJft275(m, Itft25(1\wsin^aft208(m,2^. MS:nVe435flVfrl),403(M-32> Bampfe43: bera3nitril£((jcn^Miiid>Ia49) Cbmpouod (48) (06 &138 mmoO vvas 0£me^^ eaTTpte9tootoahlhstiliecan^^ YdcL035g((S%> mp:145-147C IRan'4:340a225Q)1670. 'HNMRpvlSO c$51252(s, lH)J55(n%3Hk625(ftwsin^2H^ (m,2H)AG5(m,lH)a65(s,3H),255(nUH^ MS:roH07(Mfip75(M32) Analyas:C2H2NA-2^0 C,6235(6243);H,5.06(5J0);N,&1 (663) Exampte44: (^-)to^2^3tamo-5TKlho^^ one(CampaiidNa 50) 47 CcmpoundC7)(15g4&mm^ 1269 nrnoDhtepraenoe compound(50) Yri±L8g(ZiflB/o) lHNMR pXljE 5 755 (d, lift 7.12 (d, lift 69 (dU, lift 6.4 (fcw ar^2Fft 4.15 (m,ltft 4.0 (two st^eFft 355 (s,3Ift3.65(dd, lHfc3.4ft ltft3.15(m, Hft275(d, llft25(m, Uft234(s,3Ift2G5(m,2Ift MS:nVe5(>1flVlt))472^31X3^(M-lll> Exampfe45: (4/-}«^2^4i(xi]D-5tt^^ one.(CbmpoundNa51) and (^-}fo^2^-ftano-54i}d^ one (CorrpaindNo. 52) Cempcuxl(50)(G97g, 1.92mmo0\^demethyia^i6ing^ 12987 mmcQasdescribed in exan^9tocteinthetitfeoampcu^ Compouid(51) Yield: 02g(21.8%) HNMRPV1S0 Conpound(52): Yield: 0.14g(15.7%) mp:2552Src !HNMR(EMS0(y:8128(s, lift 7.6(d, lift 7.1 (4 lift 6L^(dd, lift 6.4(s, lift 6.15(ssHft35(m,Uft3J65-32 (m,2tft3.0-28(ni,31ft25fe31ft22(m)llftl55(m,llft MS:nVe463(NH-l)430(M-32> Exampk46: (+)£i^2^iomc-5m2lhc^^ -3-yI>- 5J-o5methoxy4- one(CompciundNd 53) CampoiM](l(9 (1.9 & 6il2 mm^ 1755miiM0inltepresenDeofN^ Ydd2Og(60J/o> lH^JMR(CDq3):8758(d, lift 733 (d, llft&92(dd, Uft638(s, llftd48(s, lift 4.15 (m, lift 4 3Ift3.85fe3Ift3.62(dd, llft335(bd, llftll (t, llft270(d, llft25(m, Uft228(s,3Ift 1.9(m,2Ift M&mfeSOKM) Exampfe47: (+)#i^2^Iiorno-5medr^^ one. (CampouridNo.54) and (+)fo^2^Btaiio-54T>d[0^^ pync&fin -3->ft5J ane, (CampoundNa 55) 48 Compound (53) (1.7 g 337mmd) was demethylatedi^i^ridte example9toctoahthetitlecaTTpc^^ Gompcwnd(54): YKkfc0.4g mp:233235(€ 1H^MRpfflO(ft(512«(% lHfc78(d, lift 735ft Uft7.1 (m, Uftd4& ttft62& lift 3.8 (s^ 3H), 3 A-32 (m, 3IftZ85(m,3IftZ5(s;3HX22(m,lK>)1^5(m,lHX MS:me476(MH) Cbmpoutd(55): Ydd:023g(15%> mp: 256258^ !HNMl(DMSOt^512.8(sJ^ 2r^3.1(m,2^2^(m,lHX248(s,3HX222(m,lHX19(m,lHX M&mfe460(M-l) Example 48: (^-}>t^24(3>Bis-trifta 4 Campcurri(7)(126g359mm^ chfcikfe(lg3j62 mmoI)in1tepe9enceofNaH(W^072gl5n^ compcxind(56)i Yiekfc0.85g 33(m,2H),29-2J6(n%2Fft245(si3Hi21(m,2H> MS:nve532(MH) Bcample49: (4/-)to^24(3,5J3is43flia^ 4 C&npcuri(5$(071gl34mmo0 mmol) as described in exan^(^tDob(amtetiflecciripciuncK57)L Yrid:a4g(59%> Ran4:340ai650. 'H>Ml(DMSOc&612£(^^ (m,3tft25( MS:nvfe5W(MHi486(\H8) Affl^CaHrfvNft,G54.1 (54^H,4.13(35);N,282(278> Exampie50: (CompomdNa58) Caqpound(10)(l g32mrrx^mdiyDMFC30mL)\\asi^^ mnr)0in1hepresaiEofNaH(5^ Yieki0.537g(374%) 49 'HNMR(OX^):8758(sJtft74(d,l^ 3j65(dd, U%3.4(41^X1801], HftZ75 (4111^2550^ lI^24Qhwsii^Bfc^fflX2jQ60xi>2H)L MS:nVe444^^f) ExamjJe51: (CbmpounlNa59) Cbmpcurri(58i(048gl.lnm)I)\vasreac^ 433mmDOasaescribedinexampfe (9)toob(aintetitfeoompou«i(59): Ydd:031g(68%> mpc206-20t?C ltNMR(CDq3)51259& lift 735 (1,21ft 7.18 (d, Uft635(s, lift 62(SslHi4.Q5(d,lHX3.72(m,2HX3.15(m, 2H)>2.9(CllH^26(S)3Hi235fe4H))1.9(m,lH). Rem4:320CX1735 N&mfe415(MHX384(M31) E\ampfe52: (+)£i^2^3taii[>-5ritoiiE^^ (CompoundNa61) 243tano-54iitroben^adti{^ I$riaine(25mLi\\iIhstiningu^ and (he reaction mixture stirred fir 15h at O-S'C ft was tan pcued o^CTcmd^Bdio^trealBd\^sal^IatBdaqu^ou5 Na^OOjsohjtion and exbacted with ditafbm (3x200 mL)Tte Na^QO and oonoentralBd. Traces of pyridine wae remold uncb-h^i vacuum to obtam(+)iOT^2-BKniD-5dta> benaic acid 2^-«jetaxymethvi4-melh\i^^ ester (compound No. 60) (Iffigo^nirnoOavkxjusolv^foic^ l,4 Yri±ai3g(4%> 1HhMt(aX3£o^(cUIft822^ (d41Ift335((UIft3.15(nUIft272(nUIft25^ MS:mfe519(M'> Example53: (+)ta^2^43ftin>5riliDiii2^^ pynokfin -3-}d>57drcDQKlionien4 (CbmpcundNa62) Cbmpcuri(61)(0.12g0t23mmo9wascb^ eKan^9toob!ahtetideocnipcund(62) YddG.07g(61%) IRari1^ 166a ,HNMR0^SOcyr8124(s, lHX&45(d, lift 82 (dd, lift 7.62 (d, ttft&48fe Uft62(s, lHX4.02(m,lHX3.7 (m,2Ift3.429(n%2Ift26(s,3Ift232(m, lift 1.9(m,2Ift MS:nVe491 Bcampte54: (+)to^2^ (CompoundNaM) 50 Compound(6)(42g ll^mmoOvvasieadBdwifa^^ ofypyikfcie(^mL)ar]dFOCb(4.4mU^ Q±iDrioofe aad2^-ax(D!^niEd^ ester (63) obtained in stuwasccnw^tothetilteoampo^^ inBampfe26. Ydd0.63g(12%) ,HNMR(CDCl3)):8 852(4 lHfc 825(4 lHfc7.42(m,Hftd45fc lPftdl2(s,lHX6.18(s^ lH\4.G5(tvwsingels, 6^3^(41^335(^1^3.18^1^2^25(01,2^23(3,31^2:08(111,^ MS:nVe431 (MH),399(M-32) Example 55: (4}t»^2^pyikfc3-}^5,7^ (Compound No. 65) Compcuid(64)(058g 135rnmc^v^d^^ exan^9,lDctohtetit]eoan^xuid(65) Yidd:aig(18%> mp: 125-127^C IRan4:338(\ 1660 "HNM^OXIj+DMSOa^S^^ (s,lHX4.1 (m, l!ft37(ni,2HX325(ms3H))265(s>3HX235(n\llft20(m,lH). MS:nVe403(MH)L Ar^Czflii^^HO^ Bcample56: (4/-)#t^2^4 (OnspjcrdNo.66) (4/-)tfw&-Aoetic acid 3^3^cetyl-24i>dia^£di^^ ester (1.65 g 4.7 mmG9\\asreacted\Mlh2 arriFOCh&lniL, 23.43 rrmic^us^^ acetaymetr^l-me%43yneM^ ester. This was comertad in situ to the tide oampcurid(66)i£ing>ffl(12^ Yrid:038g(19%) 1HNMR(CDa)>8855(d,lHi822(411^745 (n%ltft&7(s,lH)>6.48 (s>ltft425 (rn,lH),4X)2(tv\osin^e1s, 6Hi3.7(dd, ltft3.4(4 llft324(s, Hft29-26(m,2Fft245(s,3H),215(m,2H> MS:nVe431 (MH)399(M32) Example 57: (^-)«^2^pyriclin-3-^ pyndkfin -3-yI) -diomen-4 (CtxnpcuidNa 67} Compound (66) (03 g 0.69 mmoT) was otmeftylatBdusmg pyridine h^^ exan^9tocbamtretilJecornpcuid(67). rdd:0.O72g(25%). 1HhMipV1SOa^8127(s,lH))a68(41Hil825(n%lH^7.65(i^ (s,lH),355-32 (m, 3Ift3.0-27(m,3Fft25(s,3Hi22(m,lHX1^5(n%lH)i MS:me4Q3(^ffl)1385(VH8X371 flVt32> Aralysis:C2oH^aNA.BfeO Q5729(57.17);H,5.1(5.01);N,636(666)5a,8^(8.44> 51 Bample58: (GmpoundNa 69) Compound® (5.19 g 14.79 mnlo0^^^^eactd\vilh4-nitloto mmotyialhe presence of diy pyridine (35 mL)airiKX^ (55 m^ 23.43 nmity benzoic acid 2^-«riox)md^l4n£^ ester (Compound No. 68) This vrasconwatedin situ to ihe tMecompoiiiaX69)i^NaH(5()%3.41&71.(W mnioI)hl,4 described inexample 26 Ydd:1.9g(30%> 1HNMR(aX^+DMSOa^883(d,2Fft&18(a\2Fftd7^1Ift6.4(s)ltft432 (m,lH)338 (twoar^ets,6H) 3.68(oUlHfc33(m,2H)285-25 (n%2H)245 (^3^208(1^21^ MS:m/e441(IVH-l),^3^[-1^411(N4-31). Example 59: (+)4rw-5743ih}drcKy-^^^ pynolidin 3-yT>- 2^4^iitn>fteiyl)d]ranien^ (CompoundNa70) Compcund(69)(1.9g432rnino0v^ 1645mmDtyasde3cribedin exampk9to(]bdni£titleconpciioid(70) Vdd:12g(75%). mp:275-277C lRcm^:350ai66ai54a 'HNMRtDMSOcJP127(s, 1H) 835&4H) 7.1 (s, lH)6.15(s, 1H) 4.15 (m, lH)3.6(m,2Hpj(>5 (m,3H)255 (s,3H)225(m,lH)20(nUH) MS:nVe413(MH)381(\«l)365l^M$ Ara^C2iiy^07,Q61.48(61.16feH,4^8(4^H6^1 (6.79) Exampfe60: (CompouodNot 71) Ct3tnpcuid(70)(lg243mmoO\\^alssd\edhn^ qK%0jG5$asaca1a^fbr2hR^ was purified uangasflkagdcolumnand 5%methand+l%liqirramn^ ccmpound(71) Yield:a72g(77%) mp:\72-m°C IRan-4:334Q,1660. 'HNMRtDMSOc^mfe^ (twosingets,2H)4.0 (m,lH)3j6- 33 (m,2H)3.1-285 (m,3H)25 (s,3H)22 (m,lH)lS8(m,lH) MS:n^383(Nfrl)365 Am^C2lH^2^^1/2^^,Q63^(6♦.4XH5^(55^N,7.12(7.15) Examfte61: 2-Btomc^5ritobenzDicadd(CbniD^^ 72) 24xom3benzDk;ackl(10g49J5mmoI)\^sadklm 25niLarri69%HNOU2nTLn#Ttainingtte 52 fcrlhbekw5^ftwaspoiiedintok£wata^ withwateranddried Ydd7ig(6^/o> !HNMR(CDCb):5 a68(d^H),&15(dti,lIft7.85(a;tfft MS:nVe246(M). Example 62 5-Arnmo-24rcm>hen^aridm 73) Glacial acetic add (75 mL) was added dropwise with stimng,2t4(V50^toamixliieofoompoundC72)(15g57^2 mmol) and iron di£t (15 g, 0267 mol) in water (120 mL) The reaction mixture was stirred vigorously at room temperature for lhftwaspcunri into w with I^Ac(3x 250 mL) The ciganc extract carrpourxi(73) Yidd:12g^0%> NMR(CDq3):5738(d, lift 7.14ft Uft665(m, l!ft339(s,3H) MS:mfe231^ 199(M-32) 150 Bampfe63: 2-Btomc^5hydraxy4Denzoic 74) Compound (73) (12 g 521 mmol) was added to 10% aqueous sdto add (110 mL) at 0^ An aqueous sohiiori (4CtaiI)ofNaNOi(43g6232inri]Dl)w^ iranandthenitwasaddedtoaniceookiaqueo^ g 4755 nTmol) The resuftartrnix^ (3 x 500 mL) The agariic extract was washed v^ gelcohmarii2%EOAchpetrofeumete^ Yidd:65g(53%) NMR(CDqj)875(d, lift 735(o\ lH)685(m, lift 535 MS:mfe231(M^198(M-32) Example 64: 2-BronTC^5iietrrKy4)en™ Compound (74) (65 g 28.1 mmol) wascfissohedin dry l^cfic«arie(50mL)underdry>kata ]W(5(%337g 7020 mmol) was added mpartkiEatiocmtempeiatureTte at room temperature. Dimethyl sulfite (4 mL, 53 lg 40.48 nirnoO was added and the reactmn^^ 50^ & lh It waspcuted into ioe wate^ ackfified usirg exbactwas washed with wa^ dried (aiihy.Na230^o^ mp£eM60$0^aseliiiitoobtain^ Ydd3.9g(57%> NMR(CD03):67i5(a; lift 732 (d, lift 69 (mllft335 (s^Hp^tft MS:mfe2460VB-l),215(M-31> Example 65: 25-nitiD4HBacadd(CbmD^^ 76) 2-ChJarobenzDic acid (2 g 127 mmol) was added with stining at room temperature to a nitrating mixture (20 mL) prepared fiom 1:1 HNOj (70%) and 1^^4(98%) ft was stinedfomardpou^ (76) obtained was fiteredanddried 53 Yrid:20g(95%) NMR(CDqj>886fc lift 82(4 lH)J.6(d, 1H) MS:mfe200.9(M-l) Bampte66: 2 25ritrobenzrc was added slowly and Ihe reaction mixture heated to reflux for 4iTlTemixtLievv^ocn3enlratBdandttEiEadue\\as allowed to cod to room temperature; ft was poured over crushed ice The 03^ pota was extract elher (2 x 200 rnL^Tlieagarik; extract wa^ ociicediatedtogettetiileccnipound(77). Yiektl2g(100%> NN'tR(CDCb>58.6(s,lT-ft82(d) 1HX7.6 (d, IF!), 3.9 (s, 3H). MS:mfe214.9^1> Exampfe67: 5-Aniino-2 CcmixmJ(77)(12g55j6mrra^ (4:1) (50 mL) and subjected to h>drog\|snatbius^Rl£a^^ Yddt 10.1 g(?5%)i NMR(OX^)[87.1(d,lIft7.05(d,lIft68(dd)l}ft35(sJ3H). MS:nVel85.03(Mt)i Example 6& 234huo4)enzDbackln^ 79) Asolutionc£^^C)2pJ69g534^m^ 2 rrixturewasstinedibrfaurimitffi^ cfdaa^iimi fiuciolxiate salt separated whk^ ten carried out at 140C fir 15-20 mia The residue was purified usingasilkagelccJurm and 1(% ete(6(>«0^asanduerttofum&^ Yidd:28g(30P/o) NMR(aX^>53^fe3H^7.15(m,lHi74(n%lIft755(dcllH)L MS:nVel8959(Mfl> Example 69: 2 Oonipcuri(78)(?g485mrnoI) wassubjectBdtofedizaticni^NaN^ (4ig48^nmxJ)inwsto-(50mL)and H£Q\|(10% 100mL)as described inexanirfe(61)ExcessnitroiEacidwa^ waspouredntoasuspMsburfOS^^ (KlTliereactkiimixliiewassliiredfbrl5nm G^sanic extract was washed, drid(anhy.N^ petroleum etM60^^ Yiekt4g(44%) 54 NMR(CIX^)835(s>3Ift6^(ddlIft725(a;iHi173(t,lHL M5fcmfel87S3 BampteTft 2£hlo^5flieft]oxy4Den^ac^^ 81) As described in example 64, oompound(80) (4 g 21.4 mnioty was subjected to meihylata l,4 E0Achpetiofei]melher(tf>^^ (81> YiekM.lg^/o) 1Hl%lR(aXl)837(s)3H)(3.9(^3Iftd9(dd,ltft725(d,lIft73(UH). Bcampte71: 2 Ccmpcurd (7Q (4 g 195 mmoO fiom exampfe 65 v^ metl^atingoonita^ Ydd:4g(95%> 1HNMR(aX^>83.0(^6Tft3.9(^3Ift69(d)l}ft73ftlH)^735(41H)i M&nVe213(IVf)i Bample72: 2 24rilrobaia&^ 15nC)accadirigtDtteprooedtfedra Bcampfe73: 4-Ammo-2taaacaddnie^ Cbnipcuil(83)(50g232mmo5w^ Ydd:40gp3%> 1HNMR(aX33):83.7fe3H^6L5(dd) 1HX6L7(S, Uft78(d, 1H). M&nVelS&OetM1) Example 74: 244T)dcK)4)en^ackln^ 85) Compourri(^(79g425nra0 suspend mmd in35 mLv^ter) asdesoibedmexan^ G^(55g3&4nimo0inwater(800mQ^ Yield: 25g(31%) 1HNMR(CDq3):839^3Hip6L75(dp Hft695fe tfft7£9(d,1H> BamfteTS: 2 Toasdutmofconpxixl(^(^15m^ DMS(3.78g, 30 mmoft ft was stined at 6065^ fcr lh ft was poured irto ioe water and extracted with BOAc 55 (100mLx2) .The oniric extract was washed wilh brines dried (anhy. N^SQt) and amcentrated to obtain tie title conpouid(86> Yield: 25g(83%) >M^(CIXi):57^5(41Ift6.95felH\6L75(d,lIft35(^3^3^5fe3H); MS:nVe2Q295(MH) Example 76: 2 4-AmmcH2 sotutiori was cooled to (fC A solulion of NaNQ2 (11.15 g ld88 mmol) in water (50 mL) was added dropwise rriaintaininglrE tempera^ as^atcdaqixousNallCDjScJufo^ (13.87gl55mrHi)andKCN(10.07gl55rrm^^ iocmtemperatije.ItwasstW Excess satiiratedFeCb solution was then added to Ihe reaction rnixrure. It was extracted usir£EtOAc(^niLx 3) Ttecj^^ water; c^ (anhy. Na2S&t),ocsra^ (l:l)asek^toob^dietitieconipound(S7)L Yield: 12 g(84%> lH>JMR(CDal):540fe3H^7^(a\ ltft7.75(s, lH),79(d, 1H). MS:me:19fS88(M+-l) Exampfe77: 443romo-2 Ccmpound^)(10g54mmol)v^subjec^ HBr(48>A16mL, water 150mL) andNaNQi (4.1 g 594 mnxi m 20 mL waler) as cfescribd in exa^ 80Q solution cfCuBr(425 g 29^ mmc^ hH&(4^ room temperature fir 15 nm It was extracted using didh^ete {3 x 100 n^ processed ar^ exampte74toohahtrEtitleomTpouTd(88). Yield: aOg(59%> 1HNMR(aX33)5355^3Ift 7.45(0^11^765(5,1^7.75(0; 1H)L MS:nVe2495(Ml> Dample78: 4ftonTc^2 Gompound(78X10gMnimoOwasa1a2DtBBd uanglhe procedure arriquantiliescfreag^ 76to^tetitfeccmpcuid^9) Ydd:&0g(59%> 1HNMR(OXiX53S5(s,3Ift735(m, lFft7.7(d, lH)JS5(d, 1H). MS:itve249.88(Ml) Bamfte79: (+/-)#i2ra^-llydo9m^ (CompoundNa90) Cenirxml(7)(0.7g22rntrri)indryDMF^ 68mmc^hthepesenceGfl^(^ 56 Yd40.4g(41%> 'HNMR(CDq3>821 (m,2tft265(s,3Ift285(m,2Ift3.4(m, lift 164(4 lift 367 (djlft 3.95 (two sheets, 9Ift425(m, llft595(s, llft645(s, lift 7.0(4 1HX7.1 ft lift 7.45ft Uft&0(d, lift . MS:nVe42606(MH) ExampteSO: (^-)tft^5J-Qh)draxy4^24i)dn^^ (CompoundNa91) Ccmpcuidro(0.4g05nmxi)v^ (6 g 520 mmol) as described in ffiampfe9toob^ the tide ocrnpound(91) Yri±aig(22%) np:212-213 IRari1:3400,1650. M£fcmfe:»U5(M-l) Aml^Q5932(58^H535(5^N,174p^ Example 81: (+)ta»B^3-Gi]cK>4{^4^ benzmitrile. (CompoundNa 92) Ccmpound(10)(0.7g22irm)Om^ 4imnr)0ra1hepresencecOW(50%G2^ Yidd:031g(31%) 'HNMR(CDa>521 (n%2Ift265(s,3Ift285(m,2tftl4(m, llft364(d lift 367 (4 lift 3.95 (ftwsn^s, Q§425(mi llft6.45(s, lIft7.Q5(s, llft725(s, Ilft74(dllft83(4 lift MS:m/e455.12(MH) Example 82 (+)#iw30ilcio4{57 )flben2cnitrife(CcnTpc«rd>fe Compound (92) (03g 06 mmol) was cfemelhylated using pyridine hydrochloride (3g 260 mmol) as described in exampfe9tocfctamthetitle(xnipciu^^ Ydd 0.12g(4^/o> mp:237-239f€. lRari1:345a22iai650 1HNMRff)MSOcy:813X)(sJ lift &05(d,Hft725(m,2Ift72(s, lH),62(s lHX4.M(m, lPft2j65(s,3H),Zl (m, 21ft MS:m/e42686(JVW) Example 83: (+)#i^2^44l3fcnx£ (CompoundNa^) Ginpcu]d(10X07g22nTmc9m^ g 45 mmol) in the presence of NaH (50% 0271 g 113 mmol) as described in example 8, to obtain the tifle compound^). Yiekt03g(27%> 57 'HNMR (CDCfe) 8 7.95 (d, lift 7:68 (4 lift 755 (d, lift 655 (s, lift 6.45 (s lift 4.15 (ni^tft 4.05 (1\\o sr#as, ftft3.7(m, llft3.4(t 1HX325 (m, Ilft27(m,2tft24(s,3tft21 (m,2Ift M&mfe 50955 (MH) Example 84: (4)^>t^2^4-Blar]Q-2 (CbmpoundNo.95) Compcimd (94) (03g 059 imid) w^ cfemetf^a^ exampfe9toobtamthetilfecorr]p^ Yrid0.1g mp: 155-156^ Ran1:340ai660. 3^23 (m,2fft25(s,3Ift22(m, lift 15(m, lift MS:irve4829(MH). Arc^C2iHi Exampte85: (V-)#t^2^ Gxiipourri(7)(0£&25^ inmepresenoeof]^H(50PA031& 129mnxiI)asde3aibedfoexample8,tDct^ Yidd:ai50g(12%> 'HNMRfCDCb^SZeSCd, llft675(d, lift 666 (m, llft64(s, ltftdOfe Itft37(m,2tft3.0(s,&ft29(m,2tft 265(s,3Ift22(m,2H) M3:mH7lj08(Ntl). Example86: (^-}tfi^2K2 Compound (96) (025g, 053 mmd) was osmrihylatedu^pyiiiire exampk9tDcttammetWeocnipciiiTd(97)i Ydd0.O4g(17%) MP:20821OC 'HNMRpv1SO^)c81275(s, lift 7.4(d, llft&6(d, lift 65 (d, lift 638(s, !Ift62(s,ltft3-8(m,2HX33(m, 2Ift3.0(m,2Ift28(d,3Ift26(s,3Ift235(m, lift 20 (m, lift MS:me431.42 Ana^CzHaO^^Ift) Q54^3(54.49);H558(602);N,533(5.77). Example 87: (^-)#t^2^ Compound (7) (l%32nral)fodryIW(£niL)v^ g 64 mmd) in me presence of NaH (50%, 0388 g 16 mmol) as desaibed in example 8, to chain me tide oompound(98) Yiekl028g(19%> 58 'HbJMR(OXl3):87.7(d,lfft702(ssltft69(d, 1HX655 (s, Hftd45(s, lHX42(m, 1^4.Q5(twosff^eb,Sft 3.86(s,3tft3.7(dd, lift 3.45(4 llft32(m, lH>,28(d, llft27(4 Ilft24(s,31ft21 (n%2Ift MS:mH6023(MH) Example 88: coa (CcmpotiidNa 99) Cbmpoiiri(98)(025g0itai^ eKan^9tDobabtetit]eaiiipciund(99). Yield 0.1 g(44%) mp:>300f€ IRcm,:340ai6eO. 'H!^^(DMSOd£S127(:UIft7.4^ 3^(^1^,34(111,2^32(1^1^27(3,3^22(1X1,2^ M&mb41622(M-l> Example 89: (CompoundNalOO) Compaaid(7)(l%32mmQ0in^ pESCT£GfN^(50%0^ Yiekia9g(63%> 1HNMR(OX^)87i5(m, lift 7.46(m, lift 7.15 (m, ltft66(s, lift 645 (s lift 425 (nUH), 405 (too si#& flft37(41Ift3.4(4 llft33(m, llft28(4 llft26(m, Ilft25(s,31ft21 (m,2tft MS:mfe44821(MH) Example 89: (^)isff2^5-flioi>f4^ (QmpourriNalOO) Campaiid(7)(l.(k32mn^ presenoeotNaH(50%,0388gl6mmDO as desert Yidd:09g(fi3%> HNMR(CDCat6755ta llft7.46(m lift 7.15 (pi, lift 66 fe lift 6.45 (s lift 425 (m, lift 4.05 (two arrets 6Jft3.7(4 Uft34(4 llft33(m, Uft28(d, Ilft26\|follft25 IV&rTve44&21(MH) Example 9ft (+/-)to^2^fh^^ (CanpourriNalOl) Compound! 100)(05g, 1.78mmoI)\\ffideme%iatediE^ €xani^9lDciblahte1ideooriqxiund(101) Yidd:045g(60%) mp:253-254c<:> IRari:3450>1665. 'HNMRpMSO^a 12.7& lift 7^m,2tft755(m, lift 655(s, llft615(s, Uft35(m,llft36(m,31ft29(m, 2Eft25&3Eft22ta lift ISfollft MS:m/e43031(MH) 59 Analysis: CaH^dFNQs Q602(60.08);H,4^3(4i6);H3.86(334);a,8.17(&44> Exanpfe91: (4y-)#t^2^ one(CompoundNal02) Cbmpound(7)(1.0g32nTnioI)in^ afN^(5[%a776g, ldOmrnoOasdesaMmean^S^ Yfckl:0.8g(54%)i ,HNMR(CDqJ>67.4(d, 1H), 7.18^1^655 (m, llft6.46(s, lHfc642(s, lH),42(m, lH),4.Q5(t\wsir$e(sffli 3.85(s,3H),3.6(4 1^3.45(4 1HX32 (m, 1HX3.0& !Hfc28(4 tfft26(m,3Hfc21 (m,2H)i MS:nVe46036(M+l) Banffe92: (^-}^^-2^54Tyd^ cne.(CompoundNa 103) and (+/-)#t^2^ oe(GiiipoundNal(M) CcmpaunoXl(E:)(0L75gl^ ean^9lDcbfcrinfeilfeoo^^ Cbmpourii(lG3) Ydd:a05g(7%) mp 220-221^ IRcm4:345ai6S5. 'HNMR(OXl3):5126(s, lift 7.4(4 lift 7.1 (4 lift 7.0 (m, ltft6.45(s, lHfc63(s, Uft42(m, lift 185 fc3Hfc 3.4(m, lHfc33(m, lHfc32(m, Uft27(s, 31^265 (m, ffl),24(m, 1HX2.1 (m, IHL M&mfe430.19(]VH> Ccnipoiiri(lW): Ydd:03g(44%> mp:26&267qC IRan^SOQjeeO. 'HNMRfDMSO (&8127&lHfc 7.47(4 tfft 7.12 feltft 7.0 (m, Uft 6i45(s, 11^625 (s, lift 335 (m,lHfc3.5 (m,3Ift3.0(n%2tft25fe3tft22(^ lift 15(m 1H> MS:nVe416(lVH) Exampfe93: (4/-)>t^l^41)dK^3^3-n^^ (Compound Na 105) CcmpciiMi(9(15g53.4mrn^ (37.9g267miTd)arocmtapaal^ sAN^OOjSohimllw^exti^^ Na^O&andconceniiate^ teairiwilh,Be\\^(l(X)mLXac^acy pB3ductwasocmpteHtralionanaddte Ydd:9g(545%> 60 1HNMR (CDOj) 8 558 (s, lift 4.45 (m, lift 350 (d, 6fft 325 (dd, lift 3.1(t, lift 295 (d,llft26(s>3tft235(s, 3Ift21(UIft 155(1, lift 158(m,2Ift MS:me310(MH) Exampb9fc (4/-)>i^2- 106) . Can^xxixi(lQ5(?g29mn^ presenceofNaH(50%699g, 161.6nm^as(fescribedfoexampte81too^^ Yidd:75g(60P/o) 1H>Mt(CDq!):87£5(d, 1^755-74(^3^64(42^455(111, lIft355(^61ft345ftlIft335-32(m)2H)) 295(d, Uft24(i>3Ift 20(m, lift l£(d,2Ift MS:m/e429.05(N4-l). Bampfe95: (4/-)#aw?^-Azidcmelh^ (CompourilNal07) E^(a7Q5g7mnt)D\asaddritoaso^ al((>5^ibIkMedbyadropwiseaddta thenstinedfcr30miamanic^^ asatura^aqiEousNaH(X^sdulicn,daed(arh^ (25 mL) treated \wth NaN (057 g, &7 mmoO and stined fcr 2i at 6(>70^ The ieadm mixture vas poured orto aushedk^extradduangCHCk(iro ocnoenbated to obah tie tide conipoun^ sfcagdandEOAc:petether(l:l)aseluant. yrid:0.6g IRcm^^ieai^O. 1HhJMR(CDqJ>87^(4 lift 73675 (m,3Ift 6.46 (d,2Ift 4.05 (hum& lift 4.05(ds^ft3.45(twodouHets) lift 33-3.1 lHX2j0(m, lift MS:nVe455.09(Ntl> Bcampfe96 (+/-)#ia7#^-Amincme^ (OmpoundNo.108) CcmpouriJ(ia^^ mL)Theresultantsdita^ ctanatDgraphyijangsfa Yidd:a45g(81%) 1HNMR(CDQi)§7.6-7.45(m,€ft 645(s, 2tft4j0(d,6H),395(m, Uft3 (m, ltft235(m, lPft225(s^3HX2j0(m,2H)L MS:me429j03flVH> Bfflmple97: (4/-)rff»^^mitrrneft^ (CompciundNal09) 61 Ccmpcxi]d(108)(045 Qian^9tD(MnttietWe(xii^ound(109). Vdd:025g(62%) mp:21&-219fC ^0^:34511660 'H>Ml(DlVro tfft22(s,3Fft205(m, lift 13(m,2H). MS:nvfe400S5(^l> Aral^C2i^aClv^Q6252(62^^H528(528iH724(6:9^a8il (854) Bample98: (+/■}^fe^3^2 (GnqxxiriNo.110) EfeN (0352 & 15 mmol) was added to a solution of compound^ (1.0 g 23 mm^ storing at (0-5^ followed by a drop wise addition of melhans suHbr^ dik^ mixtiiewasthenstnidJbr30m^ NaHX)j9oh \\di KCN (0925 g 142 mmdji The rea^ion m^ destroy excess K.CN. It was baafed with aa^eoush^pDiediactdwifoEtOAcO dnd(ai%.N^SO^andoamentiatBdT^ IktamrrrniamCTCbasandueritoota Yddt05g(495%) HNMR(!CI)CB)87J^ (m,2H)235(s,3Hfc218(m, tfft20(m, lfft 1.8(m, 1H> MS:mfe4373(\«) Exampfe99: (Con?wurrlNalll) Cbmpciid(ll(5(045gl.0mmc0waso£^^ exan^9tocfc^tetit]econpoii]d(l 11) Yrid:035g(85%) nplOWWC lRori,:340ft230aifiSO "HNMRPMSOO^S 127(s, lH),7.75(d, lHfc7.6-7.4(m,3tft65(s, tfft63(s, lHJ,4.15(d, HftlSSft Uft335ft ltft28-24(m,4H)^26(s,3H^2j0(m, 1H) MS:nVe411(Mfl) Ai^C2ftO^Q622^ Example 100: (^-)to^2^pr]i^ (CompouiriNall2) Canpound(l()6k(a7gl.6im^ wife methane suMbnjicMcride (028 g 24 n^ wiftiimida2de(044 g, 65 mmoI)tDgpttetilfecnmpound(l 12) Yield: 035g(46%) 62 1HNMR(CD03):8754-73(m,5H))6L77fe lift 667 (s, lHX6.4(d,2tft 4.0 two sii#£6H 3.9 (m, lift 3.8 (m, llftll (m,2Ift24(m> Ilft225(s,31ft21 (m, lift lS(m,2tft MS:irVe48a(W(Mfl> Example 101: (V->^wsH2^ (GompouriNain) AirrixtureafoonTpoundfl^ mmd) was heated as (fescribdinexampfe9to^1hetifeair5X]iind(ll3) Yidd:0.15g(53%) mp:249-25(K: IRan1:3500,1670 'HNMR (DMS04) 512.7 ($, lift 7.67 (s, lift 7.6-7.4 (m, 4Fft 6.97 (s, lift 6.87 (s, lift 6.4563 (d, 2H), 425 (n% lIft4.Q5(m, llft3.88(m, llft3,45(m, Hft255(m,2Ift25(s,3Ift228(ms llft20(m, lift MS:nvb45156 Anafcss: Cattfl^Q63S7(©:^ Example 102 (4/-)#t^2-[2j^^ (CbmpourxlNall4)i G3mpaixK10$(1.0&23n^ wifti methane suHmyl chloride (031% 28 mmoI)ascfesaitedme wilhthk)uira(07g92nTnxtytogaihette Ydd:0.6g(5&5%) 'iMV^CDCfa^^to^^ . (n%3Ift23^3Ift20(mJ2Ift MS:nVe444flVH> Example 103: (^y-)^!^w^2^ (OxnpcundNallS). Ccmpcmj(114)(0.^13mm^ (60 g 520 nmxfl as described in exar^9tDobtamtiietitfeoompound(115). Yield: 0.15g 115x205-206^0 IRari^: 340(^1650 lHNMR(OXfe):5127(s) lift 7j6(m, lift 75(m,2tft735(m, Uft66fe Itft6i5(s, Uft42(m,2Ift3.7(1, lift 16ft llft3.4(d, llft33 (m, llft3.1 (m, Hft29(m, Hft25 (s,31ft23 (m,2Ift MS;mfe41&Q5(MH) BamptelOfc l-Ben^l4iieftyMfsperidinta 116) Toasohitionof l^Tied^4fipetidinoDe(15 g) in dry acetone (100mL)wasaddad l-bramomefl^benzene(249g) dropwise. lwasstinediicr3hTlietidecanpcu]d(l 16) sejmitedwhidiwas filtered, wasbedwithdryaaelciieanddried Yrid:35g3%) 63 Example 105: 1^4-Methaxyiiis^}^^ 117) Ai%. K^CXDj v^adddto asohiticn additioncfasolLitkii^^^ firlhftvvasaIlo\\edtocodtoiQcmte^^ 3)The«\|^extiact\^\ashedwil^ VidktU8g(79%) ■HNMR(a)C^56&(d,^ MS:mfe205(\l^ Exampte 106: l^^ (CompoundNa 118) Ccmpourri(117)(19flg92mn^ acetic acid (50 mL) at rocm temperature. HQ gas was bubbled throu^ the reactm tempaatineip to 90^ Acetic arid \\asi^^ cariidkE(3Wg)illie resulting sc^^ \\asil£n^\\ashed\s^\\ateraiTdcbJ^ tfe^toiernowtracesctftrim^^ Yfckt30g 2H). M3:nVe355(]V«) Example 107: H4Melhc^henyi>4^ (CcrapoiniNall9) Compound(118)(15 g42mnri)\\assutjectedtotyd^^ 8itfnmr^mTlff (50 rnL) Excess diba^ adddarriiheiea^ mixture was stM made bask (rtt 12-14) usir^ an aqjmB 50%^^ was stirred at 50-55X! for lKThe reaction mixture was processed as desaibed in example 2 to obtain the title compound(119). Ydd:95g(602%) 27(m, lH),26(m2H) \JSfa2H). MS:me374(MH) BcamptelOS: (^-)£rm-Acetic acid 4-(3-ace(5424i)dttKy4^ ester (QinpoundNcxl20) Ccmpajrl(119H03&13n^ arih)dikfe(0.68g67rnmotyacaH^ Yidd:ai5g(25%> 1H^Mt(a)a)57.1(c^2H)69(^ 27(s,3H), 1.75 (m,2H), 13(s,3H) MS:mfe443^1> 64 Example 109: (QmpourelNal21) CenTpound(120X025&05nm)0w^ g\|\cnheKamFfe7,toob^thetitfeoariipcuiid(121) Yidd:02g(88%> H>Ml(CDCb)86&(42Hi68ft (4 llft32(m, Uft27(m, lift 265 (s,3H),255(m, lift 1.7(m,2Ift MS:mfe401(Ml) BamplellO: (4/-)#r^2^ aie(CanpGnndNo. 122) Campound(121)(20g5X)mm^ 1hepresenceQfNaH(W{n9g£ YiekH.8g(69%) 1HNMR(OXl}>87^(m,^ft76(d, ltft745(n% llft69(m, lift 68(4 lift 646(s lift 64(s, llft4.6(m, lift 4.0(s,&ft3.85(m, lift 3.75 (s,3Ift 355 (m, Uft3.4(m, Uft275(m, llft255(m, ltft 1.75(m,2Ift MS:mfe5210VH> Exarffelll: (-+/-)taw-Acelic acid ${!Qdtiaoikenfy5y- pynolidin-2-)%neth)ie3&^ 123) Compciund(122) (1.7 g 32 mmcJ) was afojected to ring ccn&adian as described mexan^ di]onfe(0.448g03mU39mmol)1^ fiimishlhetiflecaT]pouTd(123)L Yield: 12g(60>/o) 'HNMR((X)q3):.575(cl lift 7.4(4 lift 73ft lift 7.1 ft lH),d8(d,2HX 665 (42tft655(s> llft635(s, Uft435 (m, llft428(m, llft42(m, Ilft4.12(s,31ft3.95(m, Ilft3.78(s,31ft3.7(s,31ft35(m, llft335(m, llft225(m, 2HU75(s,3fft Example 112 (^-)>r^2^ Compamd(123)(l.lgl.94nim^ ccnpcuid(124> Ttewxkipproc^ Yield: 0.7g (69%) ,HNMR(CDCfe):87J6(m, lift 7.4(4 llft73(m, Uft7.Q5(m, 1^68(42^665(^2^66(^64(5,1^ 44(m, Uft4.0(s,&ft4.15(m, llft355(m, lift 3.75 (s,3Ift 365 (m, llft35(m, llft3.4ft llft24-21 (m,2Ift MS:mfe52Z53(MH). Example 113: one (CompoundNa 125) 65 (imix3Uiid(124)(ft7g,13mri^ mmd) as described in exan^9tocdamflTetife(xii^X]und(125). Yidd:0.03g(5%) mp:212-213X: H>JMR(CDq3)57.6(m, lIft7.45-7^5(m,3Bft6i77(42Fft6;7(d,2^6.42(^ lHfc635(s,lHfc46(m, 1HX3^5 ft lH^3.45(d) ltft32(m, 1H), 26-23 (m,2H), L65ft lH^(m, 1H). MS:nVe480.17(MH) Example 114: (+/-ytmrB-Aotic arid 4^^fiienyI}5,7 (CompoundNo.126) Toasditactfcanpounc^^ mmo!) at nxm tenp^rntiin? u#» stirring, followed by the addition ofdimdhjtairK? j^Tidire (0.033 g 1% \\Av). The mbdurewasstiiiedfbrOSiftwaspxie^ extractedi^CHI^(100iTiLx3)TlBOig^ extras Tlie oil obtained waspurifiedisngasilka^ oampound(126)i Yiekfc333g(89.7%) ■HNMR(CDCb)c87^8(dd, lfft7£(dd, lH^7.42(t,2Eft6^(^Uft638(s,Uft5i(n%lH))4.0(s,Sft3^(m,ltft 322ft lH),295(m, lIftZ55(m, lFftZ4(s,3H)^208(ms2Fft 1.7(s,3H) MS:nVe472(M^412(M60) Exanpfell5: (4/-}to-Acetk; acid 4^^ (CompoundNal27) To oompound(126) (29 g, 0615 mrnol) in diy CHCb (40 mL) at 0^^^asaiMc>anc^nhtaTlide (2.1 & 1.979 nnmo^TheieactmnTixturewass^ QlCb (100 mL x 3) llie ctganic exbact \\as \\ashed \^ iesidiieobtairiedwaspurifiediHngaalka tidecompound(127). Viekt2218gC73%) ^0^:3400,2220; 1740,1640 1HNMR(CEXi>57^(m,^645(t\MDdciuble^2fft Z5S(n\lHX1.7(s)3H>. MS:nVe4833^H-U423(M60> Example 116. (4/-)iw^2^ Ocmpoittl(12^(&0414mmoOv^ room temperature and pouted onto ice (-100 g). ft was made basic using a safumftrl aqueous Na^OOj solution and extracted withBOAc(3x 150mL)Tteo^nicextia^vvaswa5hdwiftiwatei; dried (anhy.Na^O^atdccixenlrated. The enriectoined was purified using a sto flmai the tide oompound(128> Yield: 0£7g(50.5%) 'HNMR(CDa+DM^^ 32(nUHfc23(nUH^235(m,2H)aG5(iiUH MS:me416^ip97^vH8X380^36)i 66 Example 117: ty-}frcm2Q 129X Amixtiire of compare^) (0.^ (1.15 g 0833 mmd) indiy DMF(20mL) wasstinedaioomteniperaturefer2h.There^^ water and extracted withBOAc (2 x 100 mL) The organic extract ^^^\^ad^edwim.v^ dried (anhy.Na2SO^) and concentrated The cnjdecteinedw^ ffl(laseluarttogettetifeconTpoiiKi(129> Ydd:0i3g(57.4%) 'HNMUOX^STffi&l^ 2ft3j05(%lIft25&3Fa21to3[ftljffi(42fftQ92ft3H)i MS:m/e458.4(M+1),440(N'f-1g))428(M-29). Bamp!ell8: ty-yfrans-Axtic add 3^2 ester(Canpound>kxl31) Methane suffixed chloride (0.178 g) was added to amixtureGfccnTpciuncKl^ CHQ(10mL),\\Tlhstimrio^ aqueous sohiimofN^OOi The aganfcl^ mL) The combined agric extracts woe washed with water, dried (anhy. N^SOt) and concentrated to obtain compound (^-y^nm^/i^axsMxk sod 442^ P5x^3-)4esler030)It^ 25h at 80-900 The mixture was aflowedto attainicomtemperatireandpoured into ire i^asataqNa£Q solution It was extract dried (anhy. Na^SGi) and concentrated The ofty residue was purified using a silica gel column and 1%IPA +1% aninxniamCHChaseh^toobtainfe Ydd:02g{335%) MS:nVe5(M(MH)440.0 Exampbll9: (C6mpoundNal32) Can^x)und(131)(02&Oj04mmoO was subjected to tyMyas using a 1% methanofc NaOH solution (10 mL) accorolngtotheprccedLiremexani^ Yidd:0.17g(918%) 'HNMR(aXJ,):S7.7(dd, lift 7.48 (m,3Iftd48 (two sir#i,2H),42(ra lHfc4.0(twosin^&ft3.66(dd, lift 3.4(m,2H),3.1 (bs, Hft28(m, Uft2£2(m, Uft215fa3fft 1.6(m,2Jft0S>&3H). MS:mfe45&4(Mfl)4&4(M-32) Example 120: (CbmpouriNal33) Following me procedure in example 9, compound(132) (0.155g 0.033 mmd) was demethylated using pyixfine fydrcdikridet^toctothetitfecom^^ 67 YKtt IRari1:3000,1650 tHNMR(CDCIi):97j61 (del l!ft7.45(m)3tftd45fe3H))6L3(^lIft4.15(m, \H)>ffifa2ify3AfaZ§29fa 3H^245(n% llft208(m, lift l:68(m,2Ift095(t,3H)i Nficmfe4305(MflX4124ff4-l^ B (+)^taw^2^^^ (CbmpoutdNal34) Compound^ (09 g 29 imi^m 23-fluaDbaizDate(0£56g 3.48 mmol) in the presaioe of 50% NaH (0j696g, 14.5 mmol) as delated in eampb 8> to obtain Ihe title compound(134). Yidd:29% lH>JMR(CDaj)r87^8(d) lift 735 (m,2Ift 655 (s, llft645(s, 115,42(111,1^4.08(^3^358(5,3^3.68(04 lHX34(m,lI^32(b,lH^275(^lHX26(m,lIft235(Ss3^2Q5(iTi,2^ MS:nVe448{M-l),416(M-32) Example 122: (+)to^2^fta)^ (CompoutdNal35) CanjMii]d(134)(031g0.74mnxiD\^ de3cribedhexampfe9,toobtam^ Yrici:41.8% mp:221-223cC Ran-1:340^165^1200 'HNMR(DMSOa$8123(MHe^^ (m,2Ift275(m, Ilft242(s,3tft21 (m, lift 1.7(m, lift ]VB:nVe420(MHi387(M32) Anatyas C2,HriCIFNOfeQ5a77(58^7)5H4j61 (4£7);H327 B (CompoiniNal36) Compound®(l.l&3j6nmiQDmdiyDN^ 24iomo-3-fluorobaEDate (&858 mmoOintiieptesareof50%NaH(0^54g, 17.79nTn^aso&Mhexan^8,toobla^^ Yrid:285)/a lHNMR(OX^)5775(m, lift 7.4 (m,2Eft&46(s, ltft642(s, llft4.15(m, Uft4j02(s^3HX358(^3HX3^5(m, llft335(m, llftll (m, llft27(m, lHX245(m, lift 228 (s,3Ift 202 (m,2H> MS:nVe4915^1X462(M-32)i Exampfel24: (+}ta«^2^43nm>3-fluc^^ (GmpoundNo.137) Comixjurri(13$(a45g 0914m asdesaibedinecarT^9,toob(ainteti^oQmpcuxl(137)L 68 Yidd:49i% mp:237-239C Ron1:3400,1650 'HNMRCCDqrflFA^S 125fe XHedan&akh76fa lift 7.4 (m,2tft&85(s, lift 6.65fe lHX4.06(m,5HX 35(m, 1HX3.1 fe3Ift25(m, lH),Z4(m, lift MS:mk465(MH>433(M31) Araljss CaH1^fNOfeQ53.47(5329);H,3-53 (42);N,251 (295),Br, 1645(1&88) Example 125: (Gn?x)U«iNal3g) Ccn^ound(6)(% 19.42 mmc^mdiyDMF(60mL)\vasiea^\^n^^ 24acm&5-flLaoben2Date (6Jg2875 mrml) hfepnserceof50%NaH(3.88g, 80.8 mrr^ Ydd-471% 'HNMRCCDCfe) 67mm, llft7.45(m, lift 7.1 (m,Uft6.48k llft64(s, llft4.15(m, lift 4.02 fe 31ft 3.92 (s, 3HX3j64(m,lIft335(d,lHX3.1(r^lPft2^(in,lFft245(m,lIft23(^3HX20(^ MS:mfe493(Mfli461(M-32) Exampte 126: (+)4r^25-fluoK>^^ (Cat5XjurdNal39) CbmpcuTd(138)P% desaWine Yidd:48S% mp: 145-147^ Rem-4:345{\ 174QGW lHNMR(CDC^-TFA):8124(s^ lH,eflto^bfei7i5(m, llft728(m, Ilft7j0(m, 1HX631 (s, Uft628(s, lift 358(m, 1^3^(111,2^35(111,2^3.15(111,111X25(^3^23(111, lHX208(m, lHt MS:m/e465(MH) An^Metasifcr^ 459(554). Exanptel27: (4^yj^2^5ixbfiTQi^ (CompoudN3Ll40) Ocmpound(6)(aeg l^rmi^mdiyI^F(10mL)\^iEaadvsiflimed^4 2-000-5-iodobenzcate (126&424 mm)0mtepresmceofmNaH(a46^ Yidd:27^/a 'HNMR (OX3J) 8 8.08(d, lift 7.75 (m, 21ft 658 (s, lift 6.42 (s, lift 42 (m, lift 4.02 (s^3Ift 358 fe3Ift 3.7 (m, llft338(ro, Uft32(m, llft27(m, llft255(m, lift 232 &3Ift2Q5(m, lift MS: mfe556^H-l), 524(M32) Exampbl28: (+>t^2jiie^ (Ccn?wurdNal41) Cbmpcuid(140)(0.1g0.18nm^ desaibedhe 69 Yidd:52^/o IRan1:3450,172a6W lHNMR(OXlj):8 UA(% lHexdw^2fcte),7.9(s, lHfc7.8(d, 1HX7.1 (d, llft62(s, ltftdl (s, 1HX 3.98 (m, 1H), 3.8(m,2H),3.1 (m,2tft27(m, l!ft25(s;3HX22(m, 1H), 13(m, IHL MS:me528(MH) Bcamplel29: (Con^oundNal42) Oxnpcuxi®(lg323mm$h^ 2-aar»-5-dte)benzDate (1.5% 625 mniDOintfiepresenoeof50%NaH(0.76^ tfrntnoIJasde&iklmexampbS^ctah Yiekt8% lPINMR(CDQi): 5 7.7(m, 1H),7.4 (m, lift 6.96 (d, lift 6.48 (s, 21ft 42 (m, lift 3.98 (s, 3T-ft 3.95 fe3Tft 3.7 (m, llft3.4(m, lHX32(m, l!ft275(m,2Hfc235(s,3Ift2G2(m,2H). MS:mfe510?VH-U478(M-32> Exampfel30: (+)#i^2^I£aiic-5 (Qir9wurdNal43) Gxnpound(14:9(0.11g0216m^ describedm©tanT{&9,tQobta^^ Yidd:48% mp:233-235(C Ran4:3400,1640 'lM^R(CDq3]^lSO):5 124felHexda^able),7.48(d, 1HX73(s, 1^7.12(d,ltft &12fellft 5.98(s, lift 3.85 (m, lift 35(m,7H),29^(m>\H),275(mi\H),145(si3U)>23\ (m, lHXZ15(m, 1HX l-7(m, ll^i MS:nVe481 (MHi449(M31) Analysis: C2iH19aa>q5)Q5127(5153^H426(4.1^H3.07(2^6)i Example 131: (4/-}ta^3^2ChhDfh^ (CorapaundNal44) Dimethyl sulfoxide (15 ml, 253 mmd) in methylene chloride (20 mtyu^a^ (840 uJ, 9.84 inmotyindiymefylenech]^^ hour. Compound (20&4^ra resulting mediae was finther stined for cneaixIhatfhaixTrie^amire mixtue was ten vanned to room temperature and baafiedvvith>MKX^9Qlutm eta thetifbccrnpound(144) Yidd:0950g(47.7%) 'HNMR (CDCIJ) 8 7.4-7J6 (m, #ft 65 (s, lift 6.4 (s. lift 42 (m, lift 3S5& 31ft 3-85(5, 31ft 3.18(m,llft 3.1(m,lH>,245(ni,lHX23fe3HX2X)5(m,2H) MS:mfe(M+l)42&,^30)39a Example 132 (^ft^3^^fiien}^^^ ackl(CompoundNoLl45) 70 55% nxhkxo patent arid (2193g0.^^ soktactfccmpour^^ lxusandcaicertiatedtoGblamasc^ \\ashd\#i\\toarridriedin\3aiLin^ Yidd:07g(653%) lH^M^aXV^DMSO)5732(d^^ (5,3^3^31^33(111,2^3.05^3^22(111,2^ Examptel33: (4/-)rwv3^^4Ihkxc>ia^ acid (Can^oundNal46) 10%Pd€(3(h^\\^addedlDa9Dta mixiiie\\ash)drogpia^atl^ waterand methandinttE ratio 7525 ^anduarltoofcdnltetilteocrripound(146) Yidd:02J0g(59^/o) 'HNMR(pyq):87.75(dd, lHX7.4-7j6(m,3HX625(s, lift 65(s, lift 4.12(m, lfta82fc3HpSfe3Hfc352 2Jft3.15(m, lHX278(s,3HX21 (m, 1H) MS:nVe444(M+l),410(M35) ExamftelM: (4/-}to^3-P^3ikxDji]^ acid (CorapoundNal47) Campcuid(146)(025g05ffi^ Mierheatedat 180flCfor2h. Mwatff\\asacUdaflerocniple^ HP-20cotarinu^asdiel^^ v^^htetal»7030tocfctaintetidecampound(147) Yidd:0.1Q%(43jff/o) mpc29S-297C 'HNMR(OX33+D(vBO+TTA):8752(dd, lift 7.0-7.4(m,3Ift6jQ5(sJ lift 6.1(s, lift 4.1(m, llft33(m, lift 3.46fa llft3.1(m, Uft265&3Ift2G5(m,2H) MS:mH16(M+l),382(M35) Arc^CaHifP^l/^ (834) Example 135: (GxnpaundNal48) Campcuid(147)(aigl0249m^ N^Bnd(3C^wasaddedtodssc^teieacticnm^^ solkl mixtu^ basifid withsatua^ wilhvvatffanddiidmvacuintoob^thette Yidi:0.a35g(33.4%) 1H>]MR(axa3+TFA+DMSO)87.4-755(m)^ft6.4fe lift 6.47 (s, lIft42(m,2tft3.96(m,2H, Hft3^5fe 3Ift358(m, llft221 (m, lHX252(m,lI^ MS:mfe(M+l)416 71 Example 136: 2-Bra«>4ritorfiie(0cn^^ 149) >^Efcmosuccinin^ diyDMFmpcitraBiiita stirring^ au^icesfoufyunda-vTg^^ Ydd:30gm(95%) 'HNMR(OX33):58.4(^ lHfc&l (d, lfft&75(d, lH),4,85(bs2H). MS:nVe218(MH) Bamplel37: 2£taio4ritobenzDni^ 150) Cariipound(149(^g AsdutmGfNaNQ2(7j64gll^ 5^ Tternixtiie\\as stirred fbrlOniin^ex^ Thereaiting mixture wasthen added to a preoodd((>-5X!)susperHciicfCuCN (9.46 g 105 mmd) and NaCN (520£l06nimo0h\vater(^mL).lt\ass^ 05h and iinaDy heated cri a sEari bath for Oih. ExoesssaturatedFeC^solita\\asthenadc^^ VMS extracted using BOAc (200 mL x 3) The organic extract was washed with water, dried (anhy. NajSO^ concerfliaedarripurifidu^aali^ compound(150> Ydd:3j^n(17%) 'HNMR(CDqj):8 858(s, lH),83(d, lfft7Sft IHL MS:nVe228(Mi-l) IRcm^l0Q,2233,160ai35O. Example 138: 2Ttaro4dtro4xnzc^ 151) 2-Brcm>4^iitK>tena3rritrife (05 gn^ lis After oonii&imcfreacticn ethyl acetate. Aqueous laja: was separated, acidified wife 1:1 HQ and extract \^efl^aceae.Ccn±n^(i^nic lajavvasliienccnjentiatedtoob^^ Ydd:300mg(55.0P/o) mpc 164-1600 'HhMl(aS4SO):8&4(s»lH^ai(41Ift7^5(o;itft555(s,l^ MS:me248(MH) Ran-' :31(XU70Q 1534,135a Example 139 (+)frans- 2^J&cni>4flitiCii«nyi}^ (QmpoundNal53) 2Brcmo-4-nilrd3enzok;addp^^ mL)using POQ3(7gP%45£mmc^asdtscriD^ aoelcKjnKtfyW^relhji^^ 152)(34gm,5.9mmd)a viscous o3,whkh\^cai\ertedtolhetitiec^^ (lOOmL) asdesadbed inB 72 Yddll% Ran4:3400,166a 1525,1350 'HNMR(OX3,)88.6& lift 832(4 lift 755(4lift d6(s, Uft644(s, lift 42 (^1^4.02(5,311), 3.98 (s,3Ift 3.65(d4 llft32(m, 1^275(4 llft26(4 Ilft245(s,31ft21 (m,2Ift JVS:mfe521 ^W),489^t-32> Examftel40: (C0mpoundNal54) CaiTpouriJ(153) (03g, 0.6 mmol) \vas cfcmed^ g, 26 mmd) as described in exam^9tD(i^tetMecxxnpound(154)i Yri±54% mp: 186^C IRon1:340(U65G,1525,.1350 1HNMR(CDCM^1SOd6):5122(s> lH®dH^abfe>8i(s,lH&25(41Ift7.75(41Ift635(s)lIft6Ll5fe Hft355(m,ltft3.65(m, Ilft325(m,21ft3.1 (m,2Ift26(s,3Ift 225 (m, lift 2Q2(m,lIft MS:nYe493 (CcmpoutidNal55) Cbnnpoimd(153)(30(^0j6intno9\Kti^^ (12mL)asdesaibdmExanipfe62toofc Yidd:88% 'HNMRtOXy^ 7.45(4 lift 695 (s, lift 67 (4 llft648(s, llft624(s, lift 4.15 (m, lift 4.05 (s,3Ift 355 (s, 3Ift3^(d4 llft35(m, llft3.15(m, lift 2^(m, lift 258(m, lift 235(s,3tft201(m,2tft MS:nVe491 (Mf l),459{M-32> Examptel42: (4)tft^2{4-Arnino-2-taa^^ (CompoundNal56) Oanpouid(155)(150ing03mn^\\^ eatTpfe9tDob(am the title orr5xxixl(156> Ydd70mg(50%) np:208qC IRcmt:34(XU65Q,1575,.1380 •HNMR (OXMJMSO 4J: 51228 (s, 1H e?dH^atte),6L85(41Ift6L5(silIft62(41Ift5^(^lIft5j65(s, lift 3.54(m, Hft32(42tft264(m,3Ift215fe3Ift lJ8(m, lift L4(m, lift M3:mfe462(MH), Example 143: 2-Sanc>4medxr^tenzi^add (CbmpoundNa 157) 243ftm>4rilroben2DicackI Q (250 ml) at 80C Afoainpleikmfieactara w^dhjiaoe^GganKlajo-viasta Yiekt81% 73 MS:nve232(MH) Example 144: one(ConTpourdNal59) GDrnpaund(157){2i^l21m^^ FOGj (7gm, 455 mmd) as described in Exampfe 52 to obtain (4)#i^243iDmo-44nethoxy benzoic acid 2- acetoxymethyMHTiethylfy^^ viscous c4 vdiich was converted to the tide ocmpoundflSS^msituusn^ dioxare(1 OOmL) as described in Example 26. Ydd 19% 'H>JMR(CDq3):8 7j6(d, Uft72(s, Uft7.02(d, ltft6£(s, llft645(s, llft42(m, lift 4.08 (s>3Ift 4.01 (s,3Ift 3.8fe3Ift3j65(m, llft3.4(m, lift 3.5 (m, lift 2.8(m, Ilft2j6(m, Uft245(s,3tft212(m,2H) MSfcmfe5D4(MHX4Z3 (M-32) Example 145: (+)to^2^-Bramc>4fl]elhaxy^^ aE(Conp)iidNal60) Cbmpound(159)(155mg!03nTn^ exarnpfe9toobtahthatilfeoonpound(160). Yrid:70mg(49%) ■HNMR (OXJJ+OMSO) : 8 12J6(S, 1H excte^s), 7.4(d,lH^7.1felJftd8(d,lfft625(SslH^615(Ss lift 4.01 (m, 1^3.75(3,3^25(^2^05 (m,3tft 265(s,3Ift 22(m, lift 138(m, lift Example 146: (+)to^2^ftonic44T)dn2 (C6mpcuriNc,161) CtonTpcud(160)(150n^025mirBO^ mexampte9tochahtetitteconTpJund(161) YKU42% (n% Uft3^2(m, Hft3.45(m,2Fft3.15(m, lift 295 (m, lift 27(s,3Ift245(m, lH)22(m, lift MS:mfe462(MH> Exampbl47: tfyrans -Acetic acid 8^■a^etoxyme^hyH^ne%^Jy^DM 7-^eslenPiiipcundNa 162) To a sdutmof c 03mmol)and dimethylaminopyttline (3 n^ mixture vvas ten adsabed on 05 gm abca, concentrated and vvaspuifedus^ silica gel chon^oga^ MeQHinchlcidbnn+l%liq^ 74 Yrid:20ng ]H>Mt(aX^)S125felHexd^ 34(m,2^25(m,lHX27fe3Ift 245(ni,2Hi215(s,3Ift2G5(s,3Ift Kfimfe494# Example 148: (+)to^2^4Dfciik)H>5-fli^^ nhy4)yncMi>3-)ft5,7^^ cne(CcmpciundNa 163) Oampouii®(0£g2i8mn^ was thai reac^\\^2,4I)id]ioro^^ tifecccnpcurri(163) Ydd:0i4gn(40%) lHNMR(OXi)67.75(d) Uft7j6(d,lHi66fc ltft645(s, lHfc42(n%lHi4jO(d,6Tft37(m, lift 335 (d, lift 32(m, lift 265(^2^235(^3^21(111,2^ MS:irve481Sl(MH) Bcampiel49: (+)iOT^2^44Dkiik»>54riofh^ (CbmpaniNalGt) Ctompoiiid(163)(053gJ.lni^ cksciibedinexarnri29,toctoah1hetife Ydd029(55%) ,HNMR(OXlrtaV1SO):574(m)2Ift63(^ lift 605 fe Hft35(d,lIft3^(m,2Ift3.0(m,2Ift28(qlH),25 (s,3tft245(s,lIft225(m,lJft M&mfe454(MH) TIE efficacy of Ihepre3er4ccmpci]& nuTiteofptomiaa)fogj^ aLBkxtemBiqi^IteCcfm]^ can be proteins isolated from mammalian cells, or altemativdy, they can be prolans produced raxrnbinartly. The ewmpfifiedphammitogjcdassajs^ irw^nlm and their salts. CDK4CjdinDl Kinase AssayandCDK2A^dmEKina9e Assay Theassajsnxasurephcejiuylatmc^^ 9dm£iespecti\dy,lhiQugfa^ Materials: CIK4crCDK2\^cx»q3res9ed\Mfa cefls. Fcrthis,lxl07Sf9cdls\\recoinfected graandafo72houlscdls^^rel>^m5(X)Dlofa OTT,5 Dgml ofaprotinin,5 pgfaloflei2eptin,ai rnM^^mMphenyirretf^ls^^ socfiumcdiovanadate) C&ilriL^b^^^PU1^^3^-36^^ PurityofteptJteinsvvaschecked 75 G^-etincblastama(Rb) (aa 776528) fuskriprotanisexriesdmthete affinity chrcrnatDgaji^ Readout Quantitation was by sdntiDatkridetectiori of ^> counta(Rria4USA) Rooedure The C[K4crCDK 2 enzyme assay was iunm 96^ Allassay stepstockpbxmasmgfefiter^ Thefitoatkii\\dk\\aepe-\\etv^ (l(X)QlfadI)andtescttn\^ta arrifevaaiurnon 5001ofGCT4tobourdtoGSHSefh^ added to each v\efl and vacuum was applied to removed the buffer. A further 25 D! of a reaction mix containing ATP (odd+hot) arrijAosphalase inhibte (fluted mkiraseb^ ccmpaiirri(4XiMoonce^^ Dlwlume. Finally 50 Ql (100n$ofhiiianCDK4DlCTCDK-^ reacticiiwasirxirjatedfir30mmatW washed\\ilh1hewashbuflia-(I>W ]iafeToeachwdl,30DlRackariMkjc^ The plate v^ccuntEdh a M^Tcp Court Mita-rnaQthee^erirrEnK Tteccncentiaticnofoanii^^ arriG)K2-c)dinEwas inhibited (IQo) was cahte 1. Tabtel: NO COMPOUND NO KfiM RaiocflGo aX4€YOJNDl CDK2 1 31 028 &75 312 2 % 008 6C0 750 3 Ftocpodol 004 018 45 Tte results irrficate that thscon^ Dl a^(MC2/c>dmE\vifc@eatersefect^ ^v^cdprotiferatknardc>lDtoxk% BqxiErtially growing culti^cffto 460 Lung MDA-MB-231 Breast, MCK7 Breast, MaGavix, Cc4o-205Ccto\I©LyiT?ram(rCdlsil^^ HistiocytcLyraiiiMXiB^^ riDfeJkii(NCI,USAFrctocd)ar^ i^teandMISassay,respectiw(y ^a^Th>rnic&Bi5]lakE:CdlKctes', AlibaateiyHanolxxk, 1998, Vol 1 Eld Mo E Cefis, and For MIS assay: Ptamegi PtotaxJ, USA, 2(X)0)i fa te ^T^rMre uplake assay, ceils ^WIe har\fl^afler72hoursa)GFB plates waecourtedcnal^d^Tc^ 50%ofprofiieiati\£activity ocnipoundsdeacribedmtreBcan^^ 76 Tabte2: NO COMPOUND NO IQdpM) Covix MCF-7 Breast PG3 Predate MDAMB-231 Eteast B460 Lung U937 (monocytes) 1 12 Q1-Q5 05-1 05-1 05-1 50-10 01-1 ++ NT -H- NT NT + 2 17 Ql-1 05-1 IJO-IO 01 >10 Ql-1 + + NT NT NT + 3 Ravcpridol ai-05 05 00501 01 005 Ql +++ + ++ -H- + ++ NA: nctactive NT: retteKK + : 3a50P/otKic ++ : 5O-70P/ofcpcic -t+h cws70%fcKb 77 WECLABM: 1. Accmpciundcfgai^fibmTuk acceptabtesalt,phainroeulicallyac^^ wherein Rjisaiyl,unsubstitutedcrsuta#^ aJkenyi, OjQdkynyl, CjCrdkanp)^ nitto, NRRIQ, SRH, ttfhncmethyl, hydrce^l, cyano, caiboxy, Q-Q- aIkox)cartxiT>iand^i-Cf^imdT>dn^ts^^ kfcntkdcr afferent lieteroatcnBato iiEtf^stibJri a substituted by at te CjQdk)T^C2CrflIkaii^i^ R2 is hydrogen; Q-Qfllkyi; atyl, imiriitutda substituted by at least ere aIkyi,CiCIraIkoxy,C2Q^ carbcocy, C]-QaIkcK>caibcnyl and ^i^lrfllkytenehjdroxyl; saturated, partially unsaturated or aromatic heterocyde teving 1,2,3 a4 idertical ordflbertheteroatD^ unsubstitiM a substituted by at leag CjQaIkynyl,C2Ctfllkatr^ Ra, R4 and R5 are each independent selected ficm h>diogen; Q-Qalkyi; halogen; ORi ± aylQ-QfllkEKy; Q-Q- aD^fcataiyio^ Q 4kientkalcfdiflereitfheten]^^ Reis-Ci-QaflgtaJCKii; R«ish>drog^Ci-CraIkyi;ai>1; caibcamide;sulfbnamkk^N^ R9 and Rio are each independently selected ficm: hydrogen; Q-Q-alkyi; aryl; Q-Cfdkanoyl; heterocyde, which cailainsl,^3or4lieteroatDmssekctedficnrn^ Q-Ctdkaxycaftxxifi, Q-Cr alkykHbanyl; a^caixnyl; hetatQdocaibcnyl, whenm ficm nitrogen, oxygen, sulfur and phosphorus; caibcxamkle; aid suHbnam^ heterocjdo- are either ii^jbedtutedcr substituted by a least a^ aIkDxy,C2Q-dk£nyl,CjQdky^ CrfllkDxjcaibcqyi arri I^andRiQtogetewlhlherntrogm^ fuiteheteroatam selected ficm: tiitroge^ heterocyjJcringbemgeiteiiRfeft Crdkcpcy, C2QaIken}i CjQdkynyl, CjCfdkanpyl, ntocsNRcRift SRi; tn^uaromefl^, hydroxy!, cyano, caiboxy, £i£4dk$ycaAxxy\ anddiCK>i; 78 Rii is t^drogfr^ Q-C^IlQi; Ci-Ctelkanp>d; aiyl, utBubstitu^crsdbstiluted hy at feastca^ substituent sefected fiom: Zisanax)^atom;asulfuratem;aNR$ Aisa5 memberedring ^^tenan: (heSflienTbenriringissatLiatedOT^ general anxtuies® to (v); \vho^X\|and)Qaeeadiindq3endt^3dectedfiaTtac^^ atcm,asulfiratcn\S(0^ardanitro^ateinpw heteroatom, aidwhaanlhenilicgenatDm^ RQ\\teonRuissdectedfionxh5di^^ QdkjiursijstitLitricr substituted amiri^nitiOjCi^^alkjrth^ selected for halogen, hydragi carbaxyl, Ct-CraIkcKy, amino, nitro, Q-Qfllkyithio, sutflTycfr>4 and suHbnyl; aryl, unsub6titutedasubsti!i4e^ QK^aIk}i^QC\|^Ikano^^ d^ R^isasubstilLel as defined ahcaemakast ere caibma^ RjJshjdrogj^Q^ZfalkjiCK!^^ RM is hydrogen; Q-Qalkyl; h>diax$ NR^IQ halogen; -SH; -SCrQdkyl; -Sa>t ayt vsterein Ihe a>l is unsubstituted or substituted by at kast one sUbstituertsefededficm CjQaB^T^CjCralkanpyl,!^ CraIkylendi>diox)i;aheteta^ phosphc^ the hetasx^ being iraM aIkyl,Cifl]kDxy,C;K^aIke^ carfcoxy, Q Z Acampcundctfthefaniu^ R]isphan>iv^khisunsubstitulBdasubG&^ Qdkyierehjdro^CTisatetenxjde,^ atcmscfv\hkiU,2CT3arekbitkdCTC^ \\baetheheteroc>deisiiEU^^ Qdk)1,Ci Q^lydkybiehydrcKyl; R2 is hjdrogen; Q-Qalkyl; phenyl, which is unsubstittfed a substituted by 1,2, a 3 kl^^ selected fiomhak^CrCr«l^Ci altoraycaibci^and^Kilralk^^ 79 R.3, R4 and Rgaie each independenliy selected from: hydrogen, Q-Qaflgd, halogen, ORn, CK^alkykHbanykKy, NR^QSOfeNR^QCaiba^c>anDandnitK^ Zisanco^genorsLdfiratom; Aisa5 memberedring wherein; ^tteSinmiberedsatuiHtedtf usati^^ g£n^stnxtures®to(v)asdaimediri damLXiandX^aieeachiridepento sutfis; atiinitio^n, provided tiatmsbulLires (ft alamisatleastnxrosubstitutedby RQwhednRoissdectedfronrhyctog^ substituted by halogen, hydroxy! or caboxyl; CjQdkenyl; hjdroxyl; Q-Cffalkaxy; Q tc&msutibnyl; cyano; SQ2R40; -CXXCHjlhiRH and phenyl which is unsubstituted cr substituted by at least one substituent selected from: halogen, Q-Qfllkyl, Q cabc«y,Ci R9 and Rio are each inoependentfy selected ficxix h>d^ al^karbon}'!, catboxarnideand sulfonamide or fyandRjQ together with ttenita^ whkiicanhawatleastcrefuiteheteiD^^ unsaturated or aromatic, and either unsiitetitLi^OT substituted b alkyl,Ci caiboxy, CiQ^myaabc^ard^iQeto^ Riiishyck^i;Ci-Ct€^C[ Rwishydrog2nCiaIkyl,h)^^ 3. AcniTrxjundcftrefarr^ unsatuiatedm^iepesentedby anyone ofilTe^radstiuctiKs(i)to(ivX \vhoemX\|iseitheracaibonatamcrahetero^ suffix, ardnitrog^occqtthamstnxture(iv) XjiseilheracarocnatomCTanitrogenate^ 4. A compcaid of the ionuila (fc) as claimed h any ere unsubstituted or substituted by 1,2, or 3 klertk^crdifflaentsubstituente alkoxy, nitro, NRgRio, SRn, trifluacmelhyi, hydroxy!, cjano, caiboxy, Q a!k>feneh>diD\yi,CTisalttaDc>de,\\hich wrnchl,2cr3aieklerMttc5naenthete^^ is unsubstituted or substituted by 1,2, or 3 identk^OTcfinaertsubstiluenlsse! alkoxy, nitro, NR^Q, SRJI, Irihjatomelhyi, hydroxy!, cyano, caiboxy, Qcabonyl and -Q-Cr alkyfenehydroxyl; ^andRjare hydrogen; and R3 andRsareeaiiirrlerjerdenliy select from: n^^ 80 5. Accmpourdofttefcmiula(^)asdaimedhanya£ pyridine subsdlutBd by 1,2 cr 3 identical or different substituenls selected ficm: habgai and nkx R2 and R4 ate h>dic^R3aiiiR5aieh)drc^ (vi^^teteitlXl,^R6andRl3 areas defined. 6 Accmpourriasdaimedm Ci-CraDQlandZisanaQ^nalDm 7, AoompouridofgaTadfom^ (fyn^2Q{XteR>{bEr^5y-^^ (-)iTO^2^-Otaofha^5jKfihjdicp^ (+)#i^2^43iaT»fhen)i>^ (f>#t^2^Bmioiii2n)^5,7 (f}0xjn^2-{^!crno^ba^ (+)to^2{4ftixnoii]e^^ (+)^>tiw^2-{3 (+)£t^25J (4}>ttf#^4l5dinxjme^ (4^c?^2^1iion>tiienyI>^4iydrc^^ (+)#t^2^4TLnDiiien)^5J«fi^^ (+)tw^2-{3^1iac>fiien>^57^^ (+}i>tws-2-^57 (+)to^2{2£QfiLat>ftoen)d)^ (+)i>i^2 (fyzm4{5,7-Btoydmy-^tyikx^^ (-}taw&{2fl>draxyme1h^ (-)tfr^5J4)ih)drcKy^4])^^ (+)#iws^-H)diDxymeth^ (4)#tOT^5J4)ih>draxy^4^^ benaxiilrile; benzanitrile; 81 one; (^-)#t^2^-Btaiio-5nel^^ one; (+)tosL2^-feni>5into one; (+)CTis^2^-Bicmo-5flieftio^f^ one; (4/-}iK^2^-ftonio-54i)d^ one; one; (V-)tfi^24(3,543&tiifli^^ 4-one; (^-)#ry^24p^Bfet[iflucraT^^ 4-ane; (+)#i^2^-QTkiD$medTylf^ (+)ta^2^1ibi>5iiTelh}4i]e^ (4}#t^2^-B[cn^5iTitiD^ta^^ (^-)to^2^-Bronx>$riln>ji^^ (4/-)to^2^ (4/-)#t^2^EyiK^ (^-)tfi^2^BraniD-54Tilion^^ (+)aw^2^0iloB>pyikJin-3->^5,^ benanitrile; (4) benaanitrife; (+)£r^2^4-Btanp-2j^^ (+)#i^2^Btamo-2Hiifao^^ (4/-)^)T2m2^ diomen-4-one; (^-)to^2^4nTedT)^^ medijW-nieihyiftnol^ (4/-)#tM^2^ one; (V-)tOT^2^ one; (^-)to^2^ (^-)^T»^2^ (4/-)tfu?^2^ one; (^-)i»^2^ one; 82 cue; (4/-)tfrws^H2-AminGmed^^ (^-)4m?^-Amincmeli^l4rie^^ (^-)H^3^[2^3T^ (V-)rOT9-2^iiia^^^ (^-)#t^2^ (^-)#tyff-2^fi]e^^ (+/-}&CBW- Acetic add 3^^H±hD}ii3^5;7tathyl ester, one; (+A)£m^2K2 one; (^y-)>t^AceticacioV3^^^ ester, (^-)#t^2^fheny^ (+/-)£t^2^fhen)^^^ (^-)to^2^ (^-)0t^2^3tonio4riln>fi^^ arid; (V-)#t^34fexnc^5J ait (V-)CTa^2^ (V-)to^2{4-Aniino-2 (^-)£t^2^43ramo44iuciof^^ (^-)tJ7^2^4^mino-2-bBDmD^te (V-}#itfs40]kM>3^57-^ chn3iH>2->l}teBdc add; acid; hjdrax>4)emamide; (V-)tftws4Q]lc^^ hydrcp^teramide; (^-)#i^:Kl]ton>4{5J- hjdraxytazamide; ImkKy-bmzaiTJde; (4y-)to^2^4I)iflLion>fiiei^ (4)#tOT^23^^^ ; (4)to^2^-&cmo3-fluQ^^ (+)iTO^2 (+)ta^2^-ftcnx>5-flLiQ^^ 83 (+}£r^2^fi]eny^ (+}frcw2QBKrK>$ (fymns-2^-&cm>44ito^^ (fyn^2Q&amc>4ti^^ (+)ia^^4-Amino-24xcni>phe^ (fynD&2^Arrko2JxaDx>^^ one; (+)rffs-2^-Btario4medre^ one; (+}Vwro-2^-Bromo44^^ one; (fynms -Acetic acid ^-aretoxymethjWirKlhy^^ 7-ylester, (+)>t^2^4I)ki]]oio-5^u^^ methy43>irolife^)^5J^ one; or (4)tw^2^4Cklilctc-5^iac^te^ one. & The ire ctf a compound of geneMita acceptabfesafttherecijftrlten^ 9. Iheusecfacon5XXidofgme^fixmula(fc)accadn^ acceptable saftthoeo£ibr1hemanuiactLre^ 10. Theuseofaccnipourriofgene^fixm^ axsptabtesaft thereof fcr the nranuia^^ deKfiflaentiaticncfadfiaa^ 11. The use ofa compound of gsnoalfcm^ 1 to7,aaphamiaceufcally acceptabfesaltlhaec^ibrliTeman^^ 12 Theirecfaccnipourricfga]^ acceptabte salt thaec^ fir the maoria^^ mja&infectasvi^ 13. Theirecrfaoompouriiofgraalta agricultLial applications 14. AphamraceUkdccmpositkiicci^^ fcnrnjh(fc)accax£ngtDariy(yieofdaiiTBl to acceptabJecamtr. 15. AphanraoeuticalocnTpostmccnq^^ gpnaatlbnTii&(Ic) acceding to an^ furiherphamraixutk^a^ccmp^ 84 Id The ire of a compound cfgnealfam^ 1 to^crapteimaQeutically acoep^saltlhen^fcrltenmfo^ e^eessKeceflpdifeatic^ phamaoeutx^activeoanpMid 17. Aproessfcrtheprgmtacfaan^^ phamraceuik^acceplabbsattll]^^ \\haOTRj,RiR3,R4,R5atdZ have lit meaning tifined ltD6,andPisafunctianalgrouft\^a compoundoffbmiula(IIIX (a) ffiactingabaiaopyiananeoffcmiiiajl): wh^ABsutetitutedbyRearriR&an^ Aiscte11ma5]Tmrt)a^ringGf^ urEaOiiatBdcaibcnatominteAnngand 1) wioeQ is bound to an uraaturafid carbon a^ o^roccrha^nr baseandana^TKaincig^so^ famed betvseenthere^ectivecarbmatcms^^ redre any aVdfe band betw^ member tofcmia ccmpcuTdoffctmula(Ic^aTd ii) \hoeQisboundtoasAia!edcabaiaton^ cata^standa lea\irig group, vvteii^ \\heronRi,Ra>R3,RfeR5aiiZha\e1hemeaiii^^ ccnipctiidoffcnTiLila(IIIA), 85 to\\foidiPaidQarebciundtofamacaTipc^ ifaflprcpriate,ccn\«tir£lheies^ (b) reactingabaTzcpyrancreofftirriuk(II> wherehXjandl^rHielhemearaTga^ inorganic base and an agonic or inorganic sohal, to fctm a nitrogeiKarban coupling between the carbon of the ccmpc«indoffcmiiia(II)to\\hichPisaaadTedan^ ctiivatirigtiTeiesullartcaiTr^^ intoafinmaceutk^acoeplaUesatt 18. A process fir the preporaQcnofaconTpound of g0iad phamiaaetfically accept s^^ de£nedinat^Gt£ofckims 1 to 6, \\hichpnxess comprises iea^ CTaoarnixurioffbmuda(XIIA): wherein ineadi case RfeR&RiR^RsjI^Rjaid A are as defined, wilhanaganiccrirxs^nk: base, subsequatiy addriganackitolheieactimrnixtiiec^ adding an organic cr inorganic base, and, if appropriate, cciwatinglte 19. Aprooessaooardingtoctol£^\faerem^I]ea (XnA)ts obtained by reactingacompciundofi^^ 86 \\teremR1,R2,R3,Ri,R5,R6R7and A areas defined above vvilhacarbcKylic aid ester, an ackihalide, (reactivated estermtheprcsenxofana^nicarincsganicbase inano^niccrinaganicsctot 20. ApocessaccoKlingtodaiml8CT^ wheran.Rn andRaateasdefined 21. Apnxessacconir]g©cto2Q,\vhe^ 22 AproessfcrlhepepaalicnGfa^ 87 \\ba^Ri,RiR3,Ri.R5,Ro^ZareasddM fcmmla(\i\) \teranRi,R2,R3jR\|)Rg,Ri3andZaieasddMfo the^Hgapcnttepipmdiroringbyalea^ addrngasuitabfeag^basem^ appropriate, cometinglheres^^ 23. ApccessiolhepreparatiQnctfac^^ phamiatxiJdc^aocqMiiesatttesf uheranR],R2,R3,R4iR5 atriZaeasdefinedmanycneGfdaims 1 to6,wfaidipKx^ccii]prisesi^^ offcrnndapOOCVI):' 88 \\teremRi, Ra Rj Rt, R5 arri Z are as cfefin^ ester gjoup -0(0)1®: on Are imidazc^d ring to Ihe group -CH£)H, and,ifappn^xiaIe,ocnvertingteresullart ccmpcuTdoffbmiula(XXXVII)ir^ 24. ApK»essacooriingtockm23,\\h^ (XXXVI)ispqHidbyieactingaoGrnixxidof&mda(XX^ \tereinRi,RaR3,R4,R.5 arriZansasckfinedmarycneofdairTBlto^wfa inciganicbasehanaganicsoKait 25. Anocesibrlheprcrjaratianofao^ wherein Ri, Rj, R3, Rj, R5 and R13 arc as defined in any one of daims 1 to 6, ocn^ais^ieaclingaiaoembaiqxxindofte famula(Vin): 89 vdramR^RtRs and R^are as dsfinedin anyone ofclaims 1 to^uithachiralau^lia^-mThepKsmceofasoKalto fcnn a dastaxiuic salt of fhs compound of formula Qflfl), ty&Sfiang out fir required diastacamic salt and subsequently treating wiih a base to obtein Ihe desired enantiomer of the oompound of formula (VEft treating the cnnpoiiriGffcmiula(VIQ)with to(^theacylatedconTpourriof^^ \^iaeinRaR3,R4R5 andRcareasdefinedmanycneofclaims 1 to6, tieatinglheoompcundoficm^ (a) anactfchkikleofthetypeRiCOQ^ v,haeR4tsasdtfcd, (b) anaridoftiTenpeRiCOOHvYtaR^as sca\«]££rtDcbtainanackidiki& (c) aoombirBtaofR\|CCOH\*i]ereRiisasd v\heranR\|,RiR3,R4,R5 andRnareasdefiriedhanyorieofdairrisl to6, 90 toiamteccnpouridoffixmulaPQ treating IhecxiTipc^ctffcn^^ subsequently with a mild base to fcmi the subject ccmpcurioffcniuila(Xnft coripoundintoaiAamiace^^ attonali\dy,subjecting1te amethandtofcimacanpc^ wb^RaRiR^RsandRoaeasdefinedm tieatingthecanixxindo^^ abase inasahatftofamaccniixiundtf^ \^TeranRi)Ra,R3,RbR5 andRoareasdefindmanyaTecfdaims 1 to6, arri treating the coiipajritf^ andsubsequentiytreatingwifa^^ sut^canrxajTriirtoatiBrn^^ Dated ttDs/daycf^iuary2005 91 S.MAJUMDAR GfS.MAJUMDAR&CO. Applicants'Agert ABSIKACT FLAVONE DERIVATIVES AS INHIBITORS OF CYC LIN-DEPENDENT KINASES Tfepre^imaTtimidaiKtDno\d dicmatnTedadv^v«offixniula(Ia) tcr Ihepq^naQcnofsudi compound^ mdho^ usectfsuchccmpourilsmtte^ madkanmlstDbeapp^insLriicfaeas^ dteataTeormocnibm£icmvfa partkxilariiHmaoetfk^a^ ag^togtev^jiHinBKUtic^

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. -
FLAVONE DERIVATIVES AS INHIBITORS OF CYCLIN-DEPENDENT
KINASES

2. Applicant(s)
(a) NAME: NICHOLAS PIRAMAL INDIA LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : 100 Centre Point, Dr. Ambedkar Road, Parel, Mumbai 400 012, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed :

FIELD OF THE INVENTION
The present invention relates to novel inhibitiors of cyclin-dependent kinases (CDKs), to processes for the their preparation their use as active ingredients in pharmaceuticals, in particular for the treatment of proliferative discorders, and to pharmaceutical preparations comprising them.
BACKGROUND OF THE INVENTION
The ability of eukaryotic cells to proliferate in response to a growth signal is tighty controlled by a complex bnetwork of orderd biochemical events collectively known as the cell cycle, Mitogenic signals commit cells to entry into a series of regulated steps of the cycle. The synthesis of DNA (S phase), and separation of two daughter cells (M phase ) are the main features of cell ccycle progression. The GI phase separtes the M and S phases and prepares the cell for DNA duplication upon receiving mitogenic signals. The period between the S and M phases is known as the G2 phase during which cells repair entors that occurred during DNA duplication.
RegLilatots of the cell cycle have gained wisepsead importance in profflerathe afescs. QdrrKfependent kinasss
(CDKs)areaian% of enzyme
subunit (the actual cydirHlep^
(CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8,eto)arri 15 different types of different din
A,Bl,B2,Dl,D£re,Eefc)Bdislepcfthecd
trars^(0)K2/c\dm^
Cancer Inst 2000> 3763871, S phase (OTGfcydin AX G2 phase (CDKl/cvdin A), G2M transition phase
(CDKl/c>din3B>
CDKsarearfetorAospharylatenBnypttf
such as the retircdastama gene product Rb. The Rb is invdved in the Gl/S transition of the cell cvde and its
phosphorylation by CDKs results in its inactivation (USA-5 723 313X which in turn leads to the release of the
trarecripdc lactorE2Fand1te
A wide variety of diseases are characterized by unccntroMoeflprolifer^^
pathways in the cell cyde [eg. cKerexpresaoicffcydirECT
The overexpression of cycKnDl leads to the deregulation of CDK4D1 kinase activity and thereby contributes to
urraitrdled cell ricfiferatm WilhlarfwledgscflreirieofGDKsmc^
approximately 90% of all neoplasBS are assodated with CDK hypeiactivation leading to the inactivation of the Rb
pethway,CDKsareattractivetargets£»^
The first potent molecule to be devdoped as an effective CDK inhibitor was a flavone compound
[c^2^ Havqiridol is known to inhibit diflerertCDKsaixIftedTib^
hin^ncaricercelkFurtlierieseaichon
ttierapy. As are result, analogs offlavcpria^
chromone analog as inhibilois cf CDKCvdin complexes. USA-5 849 733 discloses 2-thb and 2-oxo analog of
flavcpridd as protein kinase inhibitors for the treatment of proliferative diseases. WO 01/83469 discloses 3-
hydtox)dironien4 flavoioidcanpcunasrflvir^
4-one derivatives fer the control of tumoral diseases. US-A4 900 727 discloses benzopyran^-one derivatives
antnntlarnrnafcxya^Tts. ArfHnflamnHtetybenzcpyran^
hyR-GNaiketalmTetrahedron, 1988,44(7^2081-2086.
ThepranrenticteofCDK/cydinkinasea ceflproliferaticnand their der
agents.
2

There is a clear need, however, for CDK
specific manner. A focused
analogs possessing structural features not envisaged in the prior art, as eflective inhibitors of CDKs. Moreover, the
compounds of the inrerta M& CDK se
under dintcal trials (Cur Pharm Bliarm Etaecra^ 107-116) and also show axnraativdy low cytotoxicity
agair&varkxEcSfliererrt
Ihetreatmentofvarious ceflrKfilaaricnielatedc&ordas
SUMMARY OF IHE INVETION
The present invention generally relates to oarrrpounds of the general farnula (la), prodrugs, tautomeric foms,
sSereosorners, optical isomers, tiBrmaceiitk^ axepdte sah^
thereof

wherein
^ isarytheterccyck^NR^iftOR!! orSRii;
I^isfydiDgpn, aIkyl,aryU^^
R^RiandRsareeaiiirKkpendentrysdede^ hydrogen, alkyl, halogen, QRu, srfohjfy, efaft&bontfaxy,
alkDxyarbcnylcBy, aryfcafcnyiaxy, carboxy, cyano, nitro, NR^Ria SRn, arylalkyfthio, -SQzdk>i SO?atyl,
SQ2M^ftar>iardheterccyde;

1^ is hydrogen alkyl, acyl,h^^ SR^or^O)^;

R7ishydroger\alleyl,alkylcar^^
Rsisl^drogsn, aO^aryicarrxKamid^
fyandRioareeadimderKn&ntrys^^ heterocycle, alkcpgorbcii^allqicarbor^
aryfcarbcnyl, hdao^ttarixiTyicaitxKamkfeaii^
I^andRiQtcgetewirhthenirrogenatcm
fiitherhetercarcmsefectedfa
aromatic;
Ruish)drog2nJaIl^acyl,ar)icraI^^
Roish>drogen,teLbgeri,aIkyi,a^
Zisanox)g2natrjrn,asurrkaton%cr^^ is other than OR norSRn;
nisaninteger of 1 or 2;
3

A is a 5-to 7- mernbaedring baein:
(t) \\toAisa54nen±adringitBsaturatBdcriflTsa^ repreaentedbyanycneoflhe gaTeralsftuctLires
®to«5

\\foeremX1ardX2 are eaii independent
atDm,asiilfcratoni,S(0)kanto^ andwhaemlhe
nfep^atDmisatleastmcn^ubstitulfidty %\\hereinRj3 is Reeled fi3ral^dn^n,allQd,kMer alkali at)4
h)dioxyl,aikDxy,aIk34e^^
I^sh)drogMtfasub6tituentasde£n^
Rwishjdrogen, a!k)ihydroxyl,M^fthalog3i, ^-S^B^-S^hetocc^ttaryl;
R^RgandRioateasdefindabovs;
pisanmtegeroflor2;
mJsaiintega*oroto^
wilhferiovisosfhat:
(a) mcaseofgjenoalstrirlunsQto^
aIkano)ioraryl,andXi isacatbcnatcni,thenl^isctetah^^
sek^itehjdroxy^CK^^^
(b) mg3ladstructe(h'),^^toZisanc^^ cratyl andX>isacarbcnatenT,1rmI^isoteta iitah)drc^CK^dk5doxy,C|^^
(c) \\taeitherXiCTX2isahe(aoa!^ A is unsaturated, tee is no douUe bcndbehwairingmemiasatpoaticns 1 and2orl and5;or
(d) hca9eofgai^stoxl]je(v),vvta
(H) \MmAisa64rexiberednn&ft^

wteon X3 is an oxygen atom, a sulfur atom, S(0^ or a rritrp^i atom, wherein ihe nitrogen atom is at least
monosubstituted by R^ vrfieran Ro is selected fiom: fydrogen, alkyl, lower aBsnyl, aryl, hjdroxyl, alkoxy,
alkjicatbci^cjanoi.-^Rioa^ R6ish)drrjgmcrasubstitiKntasdefinedarx^eon
men±eratarycfpostkxE2,3,5or6;
withfeprovisolhatvvhen ZisanoxygenatomaTid X315NR13 \\faerehRoish)drog^aIkyi,Ci^
thenR^isotherthan fydrogenorasutetituentatp^^
alkykp^Q^^dkylax^^^
R^RftRiftRj^pandmareasdefinedabovc;
4

(JS) vto Aisa7-rnmibadnngitisasatLiralBdring ofthe ^naalsttuctuie(vii)5

vtain X3 is an oxygai atom, a surfiir atom, S(0)^ cr a nitrogai atom, wherein Ihe nitrogen atom is at least
marsitetituted by Rq, wherein Ro is selected fionx hydrogen, alkyl, lower alkali aryl, hjdroxyl, alkoxy,
aIk>te^iQm>"SO^Ri03nd-CCHClQ11-^i.1;
R^ishjdrogsncrasubstiruerilasdei^^
provisotewhenZisancK>^atDmandX3is>^
ctethmrr)dro@sncrasuter^^
CrsDqtogtaibci^aiyk^arriNRgRi^
R?,Rft Rift Ri4,pandm are asdefinedabov^L
The present tmation further relates to a sub-group of ocmpounds of formula (lb), podri^s, tautomeric fams,
stasoisameiSs optical isomers, pli^^
thereof

wfaaein
Ri isaryi,telaocycie,NR9RiftORii orSRn;
R2isriydrog^aIk)iar>ihet^^
R3, R4 and R5 are each independent selected fionx hydrogen, alkyl, halogen, ORn, arylalkoxy, aIk>fcaitxxiyIcKy,
afloKjcarbcqjflcKy, arylcarteflylcKy, caboxy, c^ano, nitro, NRsRto> SRn, arylalkyJthio, -SQ^Dgi SQ?«yl,
S0^k^ftar>4andhede;
Re ishydrogen, alkyl, acyl,hyircD^>^
O S
_H _ll_
C-R12^ c-Ri2>SR]^0>R2;
RTishjdioger^allQialkjtorbc^
Rgisri>drogen,aIkyl,aryl, carTXKanid^sur&mmkl^M^RjocrORii;
R9arriRjo ate each indqxrrier%sefected
arykarba^tetercc}dc^
5

R$ arid RIQ together with tfeniti^^ which can teive at least ere fuite unsatLHatedo-aiaTiatic; Riiish>dR^i,all^ac5i,ar)4CTaIk3j^carba^i;
Zisana?Q^natem,asulfurateni, orNR^
nisanintegroflcr^
AisasattflatedSmemteiediin^^

whaehXj and X2 are each mfeperrienllyse^
sdectBdfioir ancE^^dor^ asutfLr atomatda
ardvvhoehttenitro^atmi
aIker^aiyI,h)diox)taIkaxy,aI^^ -SO^Rioand{CHiWRi4;
I^h>dro^ttasutetituentascto
R^Rci and Rioaie as defined abow;
Rwishydrogen,alkyi,hy*^^
Mere embctfaient, the presento
insectCDK,planlCDKandGffLin^
theldnassactivitycrfOK/cy^c^^ ccmplexes.
As described mnxiecMbekiw, the pn^i^^
foimula (la) cr (lb) use of the compounds as active ingredients in phatmamiticaK and pharmaceutical preparations
ccnipasinglheraTliephaiinaQ
n^nirraliancdl, an insect cd^aplaitoeliaTd^
Ite present comipcirrxlscanbeus^
un^ntdpdi&atimcfendosaiajstissue.
BRlEFDESamTlONOFIHEDRAWINGSOFTHElP^VENnON
Figures ltD6iepesentsdiemesofprei^^ invention.
TWTAU MlDESCMFnONOFTHEINVENTION
The present compounds ate inhibkis of CDKs, particularly CDK/cyck\ complexes and find use in aniiptrfiiaative
tterapiesfcraTseasescharactaM
cfeoders, peooasB, Afcfaimer's disease, immundogjcal dtsotdas involving unwanted potifeialjcci of leukocytes,
iestenosisandotherproliiaativesTi^^
Listed below ate definitions of^rious tonsil to described ccmpounds
apply to Ihe terms as they are used throu^rut the specification (urfess they are cidienv^
6

aIkyilhio,thk)ester,surft^
oflhealkylgjrjupmaybeinlemiplBdty
afl^is are hydropQarieflTyi, hvdraxjdhyi, 2fydrox>elhyi, aminoelhyi cr rrcqiiolinoethyL Examples of substituted
c^doall^gioupsarecjdoalkylgi^^
different acidic alkyl groups, fir example acidic (Q-C^Ikyl groups like methyl groups. Examples of substituted
cyctoalk5igTDUpsare4fl^
ftwiflbeurcjastDodbythoseskM
substituted if appropriate ^
fcnns of amino, imino, amida, suKbnyl (inducting sulfonate and sulfanamide), as vsefl as ether, aJkjithh carbonyl
(irxiudingketones}akyTYd^
alkyl, alken)ialkaxyl,alky^
The terms '^dkoxyT or "afkoxy5* as used herein lefots 1o an alkyl groups as defined abo\e, having an ox}^n radical attach tfeietQ.Repesmrameal
Tte term'^ralkyT as used haemiefesto
(dsfoedbelovv) Exemplary aralkyl groups indufebsnzyl, ^Cr^^fyridyl, efc
ThetanB'ykenyTarri'y^^
alkjfeoesoibedatov^btflhatcorA
ancVatripfebond^proviotatlHtfe
aromatic system results. Examples of alkenyl groups include vinyl, 1-popenyi, 2-propenyL 2-butenyL, 2-*nethyl-l-
properiylcr3fliethyl-24xil^
grojpscanalsobeiinsatura^\vh^^
Fiirthemxie, unless otherwise staled
as vvdl as alkenyl ardalkynylgKxip^
goups mentioned above for alkyl, lor example, arninoalkenyi aminoalkynyl, amktoalkenyl, amidoall^nyi
imiroalkenyl,imirrialkyn^
Urriesstherurirjerofcaib^
hasupto 10caibciiatrjn^mcierjK&^ 'loweralkenyr'
iiiearE an aBo^ group asdffaedab^
Thetenri'^'asi^teranrefastorrnxx^ 14 ririg carbon atoms
mvvhkhatleastciTecartocydicrir^ E\amriesof(Q-Ci4)^rylresidiies
arephenyl,nariilhyl,bipher^iLa^
stated othervwse, and inespactive ofan^
the compounds of fbrmula (la) or (IbX aiyl residues, for example phenyl, naphfhyl or fluorenyl, can in general be
irabstrfutdorsubstta
dhenvise,substteits^(^bspKsenthsubstit^
arykxy, amines cyarArritio,th^
alderr>0£), sulfri>di>isil>i elher, trioc^^
rrienxydo group \vhich is saturated, partially urcatLiatedcrarom^
position, and in substituted aryl residues the substituenis can be located in any desired position. For example, in
mcnaubstiMedriEnylresto
pcslkn\viM]e2iHstkiibe^
2,4irsitioi%2£posi!k^2^
8

eiibar individually or as part of a larger group. They sraMrrtterrterpretedmthelM defimtaandaie rdev^criy ib^
The terms "flavcne", "chromQne"and Ixnzrjp^Taxn^'crtrfirarBlogsrrKa^ theibltowingbasbsbirtuie:

wheremZrnayiepreserrtanGxygm
As U9ed herein the tean'alkyTrdeis to ^
brarxheckharaalkylgioiip^cjdcal^
alkyl groups FMiemicte,iinless slated c^
gtoi^whkharesubstibJtedfcycnecr^^
crmalkyl IK 30 cr fewer carbonated
nxierxeieiably20crfewa:.Iikew
nxtepre&ab[yha\e5,6cr7c3irjCfB^ BcamplescfalkylreskiiESCCiTlarr^
atems are: metr^etliyl, propyl, b^
odadecyl and dcc^ the rHsomets of all tee reskties, isojKip^ i9cbut>l kretojlhityt, isopenlyl, ne^
drnetrrylhjlypinelhyi^^
Examples of cjdcdkyl residues ccr^^
qdoheod or c>doheptyl which can also be afatiluted. The tarn alkyl as used herein also comprises cydoalkyl-
substituted alkyl grcqs arri alkyte^
cydcpcpylmeth)d-,(^^ l , l 2dopentyieft^-, 2 c>dopertylriopyK 3doaIkyl group as weQ as
a^dk; group cai be substitUBd
Of course, a cjdic alkjd group has to certain at least tiiee carbon atoms. Thus, a group like (G-Q)6flgi is to be inderstood as ccnipisrrg among c^
cjdoalk^i-all^ groups lite (C^
4 to & Similarly, a group tike (Q-Q)alkyl is to be urrierstood as comprising anxi^
alky^CK^^oaB^c^ckipop^
Unless staled ctfierwise,tr]e1erm'fc^
to 6carbcnatctnsard whichembe linearabr^^
rnpartkxilartkm3tD6ririgcar^
reskbeslikemethji ethyl, iipror^
Unless stated otherwise, and inespectKe of any specific subsrituerte b^
defiritionofthecanrx*^
mare, fir example 1,2,3,4 or 5 identical or client substituenK Any lord tf
residues can be pesertmarryefesnedrxstapovkied A
substitatedalkyl relets toanall^re^
withsubstitiier^ibrexamri^hak^
7

ThetemisiKteroQdefW'heteflx^
hetenx^cfc ring system ccnlain^
diflererthetarjafcr^
groq3rr^fa©cffnp^ha\e 1 a2o>^^ or 2
phosphorus atoms in the ring. In monocyclic groups teterocycfo preferably is a 34iiembered, 4nimibaed) 5-
membeie46mernberedcr74iien±e^ Exampksaf
such heterocycb groups are piper^^ Inpcty3dfcgrciups,hetaD9d^
ringsmvshkiitvvoCTmcieca^^
ncn^acentatcrnslnpolyc}^
menTbaedcr6memberedhetenx)^
Exemr^ ticjdic arri trk^dk; b^
isciirrJt^riieriQxaai^rje^^
Therirgheterrafi^
resulting lielaDQdbsysto is kri^
heterocycb groups having 1 or 2 identical or diffirertteteioatamsiian
sulfur. Examples ctf such teteroqd^
isothiazDtjj triazDtyi, pyrazctyJ, j^ridinyi pyrazinyi, pyridazinyi, pyrirradinyl, azepnyi tetratydrothkjprEn-yl,
tebahydrofuranyl,nrjr^^
The heterocycb grc^n^ be bcrde^
rmgriitiogmata Thus, fir exam^
canbe lfynoMnyi(=pync^^ l-inikia2Dry1,2-4midaa^yl,4-
iniicterj^crSimkJazrjlyL
fathe group-NR^afyandl^ornay,tDg^ laving ere crrraeheteroalcrnsSui^ tovvhkhtheyareattache4areprs^ substituted asirdfcatedbetow. Heteioc^cfo ccmriises satiira^ wdl asnxno-unsatuiatedandpc^ 4cr5,cbubtebari&vviliihtte^ aroniatia Aion^tic heteiocycb gtcqs definitkirEandexplarciiiciEab^
tfoless stated cterwise, and in^^
definition of the compounds of formula (la) cr (D)), tfe tetenx^ group can be ira^
carbon atom v^ ere CT nrie, fir exampte 1, ^ 3,4 a
atom in a heterocycb group can independer%cfeach other re
substituted Examines of substituents fir the ring carben and ring nitrogen atoms arer(Q
alkyljakKyleloge^bjdrc^
hydroxjethyl, alkerryl, alkynyl, (T^aryk^
famate, carbamide, an ester, tone or aldehyde^ siryi ether, thiocarbonyl (such as thioesteis, a triacetate or a
thfofcunae), sutfcn>i arninoaad ester, heterocycio, aryl or the te The subsdruents can be present st one or more
pcatiorB provided thatastabferro
The term 'heteroatem" as used herein means an atom of any dement other than carbon or hydrogai Referred hetercatcrnsatenitroger^axyg^s^
Hak^isfi\x)rine,chksiri^
9

ft will be understood mat 'substitution" or 'kitetituted with" includes me impbat proviso mat sudi substitution is in
accaa^raEwithperrrM
v^khdcesncitreadilyunde^
ft stouH berried mat any hetercata valences.
"Specific ttribitoi^' or "specific mtiljlm,,irnptiesthes QK^dmcornpfcx.
Ce^m cctnpourds of me ptesert invoitm
asyrnmetrytoarepreserithmeca^^
c*RocdiguiatmTfc{re^
fcnnairirrrixtiirescftwoCTririres
Thus, cornpounds accading to the present invaiim\\hicharaexistasenar^
piiefcm^rxfoaslevcrotato^
tv\oeiwilxynefimaQratks.hth^ both ttecistbmiard the tram fbnri
as\\dlasnTixturescfthesefbmBmaflr^^
separata ofa mixture by custom
suchasfiactiadcrystallizat^
synmesMmtrecriicallyrji^ particularerHntiornerof
a compound of the present invention may be prepared by deriwdcatm win a c^
cSasterecmeric mixture is sq^aratedarrife
\\foere trie compound ccriaire^
diastereanerksatearefcmiedbyreac^
The diastereaneric salts musfbm^
the art and the pure erariorners are suteequenllyiscJated tram Ire cSas^
stereriscmas can be carried cut at tte
during me syntheas. The present insertion alsoindudbafltautonTeKfixrffi
A&iitiar^asymrnetrc
mixriiestherec^areinteride^
Incasetrecctnpoindsaccariir^
cmiprisestecarespciidm^
urUizaUesaltSL
Cbmrfluncfccffcn^
present and can be used accordingtD the invention m me fomi ofthar addition sa^
arick Examples of suitable inorganic acids inducfe bcric arid, percr^
sulfuric arid, sutfemic arid, phcephcocacki, nitric arid ardcte^
Exarr^cfsuilaMeoq^ibacklsincte
n^ari4tartaricarid,citricacid,a^
ad^benzok: arid, salic>ik: acid, sulla^
arifletrBnecSsurfcnfcacflaxa^
cte or^roc aricfe lorjw^ to me pesrjn skiM
groq^c^ be used according to the imtrit^
metal salts Hke Ca Mg salts, as aluminium salts, as salts of organic bases such as lysine, argjnine, guankfine,
d1etrm)lamir^ch^trcmeta Trephatmaceuticaliyaccepta^
invasion can be synthescBd ficm the subject cctrpxmd v^i cataire a base
10

crmiicalnTelrxxkGerealrytresa^
an excess of die desired salt-forming inorganic or organic add or base in a suitable solvent or ctispfirsant or by anion
exchange crcsfaexcrar^vvilhcte
THF,olaxarEcrrnixturesofthese sdverfe
The present invention furthermore irriufaafl solvates ctfccmpoiin^
adduds with alcohols and also derivatives and prodii^ctftrcccnirxiun&ofiQr^
pftyaobgkallytDlera^
Various pcJvrrcrphs of compounds of general fcrmula (la) or (Jb) fixming part of this invention may be prepared by
crystallizalkaiofcomrjcu^
usd solvents or their mixtures fir a>staDizaticR% a>stalli^liari at diQbsit teTtpoatures; vanbus modes of ooding
ranging from very fast to very staw cooling during aystallizaticns. Balvm^^
melting the ccrrrpound followed ty gradual T fast cooling. The presence of rr^Tnorphs may be ctemined by IR
spectroscopy, solid probe NMR spectoHxxjy,difIeier^
techniques.
Refined compounds aretaehwrrkhoreamciectfthegr^^
vvithaUtheoomfrrBixxBofr^
preferred compounds of formula (la) or (lb) te preserl imoilkn also inducts afl
trfieofmafliaticeardtheirriiarrra^
are a subject of trepesertinventafofe
estersandarnides.
h a fetptelened errirxxlimerit, tiie present
films, stereoisomers, optical isomers, rtemiaceutically acceptable sails, rtariaceutically acceptable solvates or
pciyrnarrTBiereof

wherein
Ri isarvl, unsutetitLitedasubstitulBd Vy at least cmesutetftiientsefededfiom
alkenyi, CyQaH^nyl, QCralkanoyl, nitrp, N&RIQ, SRH, triflLocmethyl, hydroxyl, cyano, carbaxy, Q-Cr
alkc«ycairxi^arri iderikd or o5flerent heteroat^
imsubstituted or substituted by at least one substitL^sdectedfitohatoge^
C^alkynylCzCrfllkar^
^i^^lMa^dn^NRgRitiCKita SRu;
R2 is hydros; Q-Qfllkyl; aryl, imsutetitutedcr substituted r^
aBc>lC| carbaxy, Q raving I,2,3a4iobitk^cro5ffireitre(eroafi3m
urafaiituid cr substituted by at least ore su^
11

£i-Qdl9tai])drcKyl;0^
R3, R4 and R5aie eadi independent selected fern hydrogen; Q-Qdkjt habgai; ORu;aryl Q-Crdkoxy; Q-Q-
aJkykabanyiaxy; CK^dtossjcarbcnykKy^
SQK4-CraIk$S0?^SC)^
identical ordflerentheteroal^
Reis-Ci-QallQtaaiii;
Rgis hydrog^C|-CfflIkyl;aiyl; carbaxamide;suIfcramkfciNR^o;(xOR]i;
R9 and Rio are each independently selected from: hydrogen; Q-Qfllkyl; ar>4; Q-Qdkanqyl; heterocyde, which
certains l,2,3a4he(eroatQmssdec^ Q^^Ilo^iaroortytCi-Q-
alkykarbonyl; atykarbonyl; h£ferotydccarbcn>i,\shaemfe
fi^ nitrogen, CK>gi^ sulfur and r^^
heteroc^cfo-aro either imibstitutedCT substituted by at 1^
alko^', C^c-alken^ CyQ-alkynyl, C2-Ci-aIkano3l, nitro,NRgRj& SR| i, trifaomelhyi hydroxy!, cyano, carboxy, Q-
QflIkDX)carbci$andCrdky^^
fyandR^togetewthlrenilro^
further teteroatom selected fi^
heterocjdicringbeing either iins^
Crdkaxy, CzQfllkenyi, QQdtynyl, C2QaIkanoyl, nitro,NRRift SRn, trifluacmrihyl, hydroxy], cyano, carboxy,
£i R11 is hydrogen; Q-Q-alkji; Q-Cfdkanpyl; arjt urfiutelirutedcrsiistitulBdbyatlea^
hak^QA^QQdl^
rrjdroxyl,cyanq,cartxKy,C| Zisanc«ygmafcm;asulfuratom;ttNR$
AisaS-, 6-or7-raen±)eiedring \*herein:
(D tte5*rOTTberedririgissatifla^^ iepesentedbyanyoieaffhe ^noalstnxtures(i)t)(v);

v^heieh X| and X2 ate each independently selected
aion%asulikata,S(0)^arriari^^
heteroatom, andwheremtiienitic^iatmisatleastnxnceub RqVNheiefoRo is selectedfiOT hydros
Q-alkyl, unsubstituted or substituted by at least cnesubstiiuert selected from: ha^
amiraniti^C1-CfAithk^sulflT>^
selected from halogen, hydroxy!, cabaxyi, Q-Qalkoxy, amino, nirro, CiQdkyftiki, surfh)dr)i and surfcnyt aryl,
unsubstituted or substituted by at kast one suteliluertsefectedfronxhalo^
CyC^II^i^C2Crdkanpyinitro,NR^ftS^
^i^ltalkylenehydrc^hjdie^ cyano; -SQ^oJ^-CCXG^hrRw;
Reisasubstituertasctefindatovematlea^
Ryisr^dro^Q^ValkyliCK^dkyk^^
12

RM is fybogai; CrCfdkjt hyiraxji; NR^IQ habgen; -SH; -SCi-Cr^t -Say!; aryi; vfoaan the aryl is
ureutetitufi^crsubstitu^
CK^fllkynyl,C2CraIkanc^
£i-QaIk)fenetydiax$ahet^^
aDotCK^flikax^CzQata^
carboy CK^dtoxycanxnjiand^
pisanintegsrof 1 a 2 ;and
misanintega'Qf0to6;
(D) lhe64iiaTTbaEdiingisasaIuratedring ofthe gmeralstructurefa):

whadn X3 is an cpcygai atem, a sulfur atom, S(0^ or a niticgpi atom, wharin the nitrogen atem is at feast
nrno6ubstilutidbyR&\\n^^
R6is asubslituertas defined abovematfeastane^
Q (ID) te7-manbaBdring isasaturaledring cflhe ^neralslrucluie(vfiX

whadn X3 is an axygpi atom, a sulfur atom, S(0]^ or a nitrogn atom, wherein tie niirogan atom is at least
nxnoaibstitLiEdbyRo,vtednRoisasdefin^
R6is asubslituertas defined aboueoi at kastcne ring nTemberatanyofpostkxB^3,4)6CT7;arriR7ish>dnjaa^Ci-
Qd^Qfcaibc^
foa9eocndpre£nedanbocfimertGte ZarriA,indqHideriiyficmeachothei;ha^
Rjisph^\\hidiisurEubstitutedasd
CraIk)iCi CralkyfenetydnKylcris
aheteroqcle,\\hkfcisasatuialed,
iden&d (T cfin%ot heteroafcms sefedd fi^
imfotituled a substituted by ^
alkcKy, nitro, NR^m SR^ trifluoromethyl, hjdraxyi, cjanq, caibcKy, C|-Q«lkcp^aibcf^4 and -Q-Cr
alkylenehjdrcKyl;

R2 is h^drogpn; CrQdtyfc phenyl, v^idi >S iJTEL±sdtulBd or s^edtutod by 1,2,073 kiaiticalordiffiiEntsubBtituaits
sdededfrontetogen,CKVaIkylQ
afa>carbanyland£i R3, R4 and R5 are each irxlependentiy sefeded fiom: hjdrogn, Q-Qalkyl, halogen, OR11, C\-C42tikfcaftxjnfosxy,
NRgRiQSCbNR^qcatbc^c^nDatdnk^ Z is an CE^tsno-sulfur atom;
Aisa5-CT&mernbaediir]g\\haek
htheSmenitetedsatuialedttunsatu^^ general structures® to (v),Xi
arri X2 are each nxlependeniry select suttur, and
riitrogen, providedthat in structures (ft(iii)and(iv) at leastoneofXiandXzisahetaoatnm, and \\haeh the nitrogen aloiiisatl^manceubstrtutedty R^\\haemRo is select fiom hjdrog^ure
substituted by halogen, hjdroxyl a carbaxyl; CzQalkenyl; h)drox)d; O-QdkERy; Q mliE6HTimibaed saturated ring oflhe general structure(vi), XsisancE^^ak^asutturaton^oranitto^i atan^vvherehtteritrog^atam QAdk$aCi^flItysubstitutdty alkykarbcnyttohKnesuHo^
least cnesutetituent selected ficm nrlrD,NR^ftSl^i,triflLK^^
Q9nD,caibcpty, Q I^and RJO ace eadi iriderxndaiiV sefectd fionx
alkykatxiiyicarbcKarnicfe
1^ and RiQteg^te with the nitro^atalD\^^
\\hkh canteve at least cneturtehe^
unsaturated or aromatic, and other urBubstitu^orsubsrilutedbyatleastorK
alk^QAfltoK^CzQolk^
carboxy,CK>dkDx>carbc^
Ri4ish)diDgmCiaIk>lh)^^
Inathiriprefbnedemlrxx^^
n^iepresentedby anyoneofftie general strudures(i)to(iv);

\vh^X[ iseilhff acaibcnato sulfur, and rnrrog^ except thai in structure
(iv)XiiseiieracarbmatanGrar]^ a6m3iibered saturated ring
repesentedbylhe ^Taalstructure(vi):

\^eanR6andR^3 areas definedabove
faaiburtherribcdimerto^^
3 idmMcr different substi^
tydrDX$c\aic^carbaxy,Ci^^
partially unsaturated or aromatic ring oatfainirg6ringatamsof\\Ji^
selected fonxrritrc^CDQ^ari
ordifle^substituafcseled^
cyano, carboxy, Q^rflftoxycairxiiyiarri^^ ;
R2arriRiareh\drog3i;and
R3 andRsareeachindependentry selected ficmr^
In afirst alternative erribcdirn^
isms, stereoisomers, optical isomers, pharrnaceuticalry acceptable salts, phatn^ceutkalry acceptable solvates or
polymorphs theeof

wherein
Ri isarvi, utxd^stitutedasubEtituted t^atl^
aBffinvi, CjQall^nvi, C2CtaIkanovi nitrp, NReRi* SRn, trifliarjmethyl, hydroxyl, cyano, carboxy, -Q-Q-
aIkox)carfci^arri identical or dflerent heteroatoms selected irom: nirrc^ c«yg^ su%
unsubstituted or substituted by at feast one sutetituerf selected fiarirralc^
C3 arri<:i sru> R2 is rodrogen; Q-Qalkyl; aryl, unsubstituted asubstrtuted by at feast
alkvl CK^iillaajcy, C2Q^
carboy, ^rQslkoxycarbanvi and ^^ffllkylerdivdroxyl; saturated, partialry unsaturated or aromatic heterocjde
having 1, Z 3 or 4 identical ordrrfeertheteroatorrBsefectedfiarrtr^
urad^stituted a substituted by at least ctie sub^
15

CyCtffllkynji C^Qdkanp^ rntip, NRSRIQ, SRii, trifluoramedtyi, hydRB^d, cjano, catbaxy, -Ci-CrA»QcaAx^d
Ri Ri and R5 ae eadi indepaidenfy sefected ficnr l^^^
aflgtaibonjicKy; Ci^tflBoqcarbcnykKy; a^icaibonykHy; caiboxy; cyanc^ nitic^NI^ctSRii;ar54C|ClrdlQlhio5
SO^K^oll^SOt^SQjb^^
idedkdcro^en^hetenHtams
R6 is hydrogen, Q-Qalkyl, CiCjsBtecofl, hydroxy!, Q-QalkcKji ^K^alkoxjcaibonyl, -Ci-QaDQ^nBORn, -Q-
Qaflgtatelo, ^i-QalMerkslR^ft ^i-Qall^reQPPRft itenaxy, -NR9R10 SRc, Sp^-QO)^ or-
RgBh>drog^Ci-C^Ik)d,ar)^^
R^andRjoareeadi independent sdeo^
3 cr4teteroataE selected from nitrogen, c^
arykatbonyl; heteroc>dccadxi^\\b^1heheteroc^^
afe and phosphoiits; carboxarmfe, and aiHbnamide; >\tain the aryl and heterocyde or hdoocycb- at? either
unsutetitutedastixtit^
CjQdkjr^ QCraflanc^ nit^
and ^i^V^tatydraxyl; or R9 and R^ together with the nitrogen atom to which ihey are bended, fixm a
heterocjdic ring vshkh can haw at least ere
satut^ partial^ ixcatuiated a ataiiatic,
substituent selected from halogen, CrQdlgi Q-Qdkoxy, C2Qfllk£nyl, CyQflBwl CzQalkanoyl, ratio,
N^ftSRii,tnljciaT]ethyl,h>dt^
R11 is h>dic^n; Qdkarr(vi;
hdogn, Ci-Cf^ Q hjdrc^cjanOjCartxp^, Crdkax5carbci^arri£i Re is h>drogen;halDgi^Ci QAaik^CrQdkD^
c^ano,cacbo^, subetitutdbyatleastonesditituert
Ctfdkanoyi, nitro, NR$Rj& SRH, trifluorarnethyl, hvdrox)!, cyano, caroaxy, Q-Cfehxtysfaxyi and -Q-Cr
alkyleneh}droxyl;
ZisancKygenatDm;asulfuratam;CTN^
AisaSmembaedsstoiatedccunsatura^ general sttuctuies(i)to(v);

vvkn^XiandX^areeadiindepoTcWysdec^
aten^asdfurafi^Sp^andanitrogenat^ andwhereinlhe
nitrogen atom is at least nxnosubsliluted by RiaVvhoenR43is3eiectidtimih>dro^
substituted by at feast one substituent selected fern: habgai, h)droxyl, canbeugd, Q-CHtikmy, amino, nitro, Q-Gr
alkytlhio, sulftT>dr>i and suifcnyl; CzCtffllkenyl, unsubstituted or afotitifed by at feast one substituent selected from
halogai, hydroxy!, cartxKvt, Q-CrfllkDxy, amino, nitio, C|-Cfdk>iIhiQ, sulfhydryl and sutronyi; aryl, unsubstituted or
16

suhstitutedby at leastcse subsdtuent sdecfied ficm: habgen, Ci-CraD^» Ci-Q-olkcp^ CrCValkenyi, Ca-C^aDgmyi Gr Crdkanpyi, ni&q, NR^ SRu, triftocmahyl, tydrcpgi cyanq, catboxy, Qcaibonyl and -Ci-Q-alkjflenefydicKyl; hydrcKyl; Ci-Cf«Ikaxy; Ci-CraQgteibG^l; I^asutetiti^asdeiMabcwma
pisaninlegeroflor2;
misanintE^rofOlD^and
nisanintEg3TQflor2
foaseccrelerrixxlimentcfc^ 1,2,
or 3 identical or difiaent substiluents selected front habgai, Ci-Q^Qi Q-CralkcKy, ratio, NRfta SR11,
tritacciElhyl,hy^^
isasatarate^ partially uisatui^
tetoitoms selected from: nfaogan, oxygen, sulfur and ph^mE, and where the heteroc^de is unsiibstitiited or
substitutedby 1,2, or3 ida^ordfartsubsli^^
SRii,triitoiornelh)thyc^
1^ is l^drogen; Q alkyi,Q alkylerfhjdrc^QRii; telega cjano; nfoojNRsRioorSRu;
R3, R» and R5arc each independently selected from hjdrogpn, Q-Qalkyi, halo^n, ORu, Q-CjallQteiba^iceQ',
NR^RiqSOiNReEiiQcabaj^ c>anoandnita^
AisaSinenTbaBdsaturatadringKp^

\\heirinX|aTidX2aieeadiiri&penden^ sdfii;
andnitrogaT, provided lhat at least oneofXi and X2 is a heteroatem, arri \\tedn the nitro^n atom is a least rrmHiBtitutedby R£\\heranRoissdectedforah)di^ halogen, hjriogi, or carboxyi; CjQdkenyl; hydroxyl; CrQaDsKy; Q^^M^*01^ tohjenesuMbnyl; cjano;
selected fiom halog^Q^W^CK^dka^
aflacK>rabcnylarri RgarriRioaEeachhoependertlyselectedfte QAalkoxjcarbanyl, Q-Q.
aIk>fcadxn>lcaiboxam^
RgandR^lDgfewifotherriirogmata
\\hich can have at least one further heta^^
unsatutaled or aramaic and either
aIkyi,Ci carbc«y, Riiisr5dK3^^Cicart»nyl;
17

R12ish>drD^n,hak)^n,Ci RwistydcgenQ^Irflll^hydro^
ZisanGxygenatomaasulikatam.
InallMeniboalmentofccfi]^^
kfentk^cr different sub^^
hjdraxyl, o/sno, carbaxy, ^{^dkoxjcaibonyl and -Ci^^^aB^ienehyarcKyl; or can be a heterocjde, whkii is a
saturated, partially unsaturated or aromatic ring conlainirig 6 ring atoms c)f uhich 1,2 cr 3 are kientkal (T dfail
hetaoatomssdectidficiniTitrc^ l,2,or
3identk^ac5iie^sub5litiJ^sete^
h)draxyl,C)anc^carrxKy,C| R2andR4canbe hydrogen; and
RsandRscanbeeachirtJepericfentiyseb^fera
InalburthernhxiinientcfcaiipcuT^

\\heemXiisertheracHbcnata
and (iv) X] is eite a catbcn atom a anitrc^ atcn^
aQsyl; a Q-Qdkyl substituted by habgai, hjdroxyl, or catboxyi; QQalkenyl; hvdroxyi; Q-QdkoQr, Q-Q-
alkylcaba^taluenesulfor^
or 3 identical or difiaent substituerts selected fiom: halogen, O-Qfllkyl, Q-QfllkDxy, ratio, NRsRi& SR^
trifluorcmethyI,h)diaxyl,c^^
h a furte anbcdirnent the present rh^^
riienyl (r pyricSnyl, subsdtuted by 1,2 v^
rodrog^R3andR5areh>draxyi,Aisasatiiia^
(y\ whetein Xi, X& R^ and R13 are as defined Mae particulady, X| is carbon, X2 is nitrogn, Re is -Q-Q-
alkyleneh)drc^RGisCi In alternative oonTixxmdsoflheiamiula(fe)G^ orheterocyie, irideperxleniiyficmeachdr^ RjandAandZcanhaNethepefenedcrparlkd^
Rj can be selected fiamaryi and teiei^^
Q triflicraiKlhyl, amino, Q irisatuiated5CT6iTTembaedring
above. In another embodiment Ri can be selected fiom: unsubstituled phenyl; phenyl mono- or po^substituted by
halogen, Q-Qfllkyi CrQdkoxy, hydroxy!, carboxyl, OOWkji CONih CONBdkyi OON(aflq% nitro,
triftuonxnelfyiamiri^ p^riaymanD-crpol>suh6tirLtedbythe
18

subsdtuenls irdicalBd above fcrjiia^i M >et ancdior en^xdirrieril, R^ canbe selsctBd ficm: fher^4 chksc|iia^
dkiiloophenyi, chhofkircphenyl, dkiihoflLnnFtenyi, dtei^dra?^iiatyl, crfaocarboxyphenyl, cWoonilicphenyl, amiixxiilorciphenyl, N^ijdiaxjcaibcKjdTlaq^^ cjancchkxophenyl, homophenyl, dbromophenyl, bmrcflira^jiienyl, branx^drcfxyyia^i brcxnocaibcK^phenyi, OKmritrophenyl, arninoliamophenyi, N4^drox5caiba?^ticnrfte^i brcmx^anophenyl flira]phenyi, difiuaqte^i
c5btomcpyricfyl,lianc&^ flinicpyriaVidifluciop^^
b&tofluaarieJh>iptBTji
R2canbe selected iromhydrc^Q^
R3,R4andR5canbe selected ficnxhjdrog^Q^^
Q-Crdkaxyl; h^dicsxyi; carboxji; nitic^ amino; and -OacyL In one embodiment, Rgand Rsaie h)draxyl or Q-Q
alkytetrbc^'toxy, and R^hjdrogen.
Recan be selected irorrrh)drqgen;h)K^^
carbaxy; Q-QalkDxyl; CK^dkoxjcarbonyl; aryfoxy; amino; CK^fllkylaniino; cfi Q-Qalkylamino; and -Ci-Q-
alkylen&OCi-CralkjA Recanbe^^^ftylene^H, andBpreieiabty-C^OH
R?canbeh)ikj^gnafom.
Zcanbeanoxygenatom.
tnfonrajla{la)or(Ic),Acanbeas^[i^edcrixisaura^
leastoneheJeroatomselectedir^ni^^
R6 The unsaturated 5membaed ririg can have onetttwoctaurte bends intei^
(lg),Acanhpartkiilarbsasaairated5^ien^
saturated 6membaed nng containing 1 nitrogen atom, wherein in both cases 1he ring is unsubstituted or at least
nxnosubstitutedbyRfi
When A B a 5«iembered ririg of ^neral structii^ aekxldikin nitrogen,
(a) Acanbeunsatoratedas\^enceands^bOilymaypetm^
(b) Xj can only be the heteroatom mitogen in the general stnxflires(fi)and(v)and}^canbeanyoneofflie hderoatomsinc&atedabov^
(c) Recanbeallachedtothecarbmringmember^^
(d) Recanbeaflachedtolhecarbcnn^nrerrte
(e) Recanbeattachedtotecarbciiiingmenibff
(f) RecanbeatladidtDthecarbanringnx^^
(g> I^canbeattachdtotecaibcnrirignien±ff
faancteembocfin]ert,oompoin^
ring X2 is NRo, where R13 is h>dro@2n, Q-Q -aflqyi or acyl, Xi is a carixn atom, Re is selected fcm: hydrogen,
unsutetiiufedQ^i^
M>^ancteemrxidimen1,ocnitxMiCB areccnipoundshwhichABa6*iiem^^
where RD is hjdrogen, Q-Qfllkyl or acyl, Re is selected fiom: hjdro^n, unsubstitiied Q-Qdkyl, Q-Qalkyl
substitLitedbyhalc^n,h)di)o^crcarbc^
19

faafiateemlxxibienl,ca^^
Roishjdtog^CK^^CTac^Reissefe^
halq^hjdrci^acadiBQiandRzisl^dogaa
Recatibe-Ci-Cr^D^en&OH
Ri3canbe-Ot
In)^aiiirteennbodiment,cc^^
c>aixNR^ft^haeniR^ardR|oareasddiii^abo\^aOR|^^
indqmientiysefectedficmihjdi^
CK)^aton^asuIfLratam,CT]^ cattx3xamide,NR9RioCTORii,wteieinR9and
Rio ate eadi independatly selected fern: hydrogen, alkyl, acyL heSerocyde, alkKMSibonvi carboxamicle and
ailfonamide, and Ru is selected from: hydrogen, alkj'l and ac^i
Inasfflftnteenfaiimatcom^ isai>ia-aheteroc>de;R2is
hjdK^p^ at least (lie of R3 and R5 is ORib v^fcadn Rii is h>dro^
alkox^iridhylcTalkyicarba^'ic^
Examples of pieced oompojndsaocadirigto
(^-)to^2^ftayI}^^^
(4)^t^2^fh3TyI^
(f>*>m9-2^-G]]atoiiTe^
(-)to^2^ Q^r^2^ (+)tan^244-Baii>fhsQiHK2^^
(f>#i^2{4£taT]oii]aiyi}$^^
(4)#t^2^4J£aTX>jiien)^57^^
(+)to^2{!KlloB>fi]en5fl}^
(+)#i^2 (+)^ft^2^4Tuon>fi]enyI)^24^
(+)tfi^2^Tuctoften5^57 (+)^t)?^2- (+)ta^2- (+)to^2-{2j&DifluQio^^
(4/-)tarc?4{iM2-H} fr)1nm4-{^2}fykKytt& ^)4nm4-{5JiyktydKxy^2^^
(^-)tft^57-Dih)dro^
(+)ftm&{2Hy&axymefafc\ (+)to^5J74)ih)draxy^4i>^^
20

hgpnnitrile;
benanitnle;
(V-)*a^242-B»3mo-5fliefli3J^te^ -3->fl- S74-
one;
(4/-}*>r^2^ftomD-5me^^
one;
(+)^tara-242-Bnm>-54^^ -3->C[- 574-
one;
(f>toro-2^-BOT]0-5*Tietfx^
one;
(^-)4t^2^&amo-51i)dro^
one;
(+}*t^2^-BraTio-51i)dn^
one;
dlCmeD-4-One;
(4/-)#t^2{(3,5J3fctaflirai^^
4-ane;
(4)*>t^2^1JaK>5Hiidliy^^
(+)tft^2^0Tkw>54Tieth)i^^
(+)*>t^2^3rano-5iiitiD^^
(^-)#t^2^-Bm]o-5flitofiie^^
(^-)^iw^2^-2pyikfc>3-^
(^-)*h^2^43romD-5rita^ta
(+)4i^2^-20iboi7yridh-^^
(V->^>CTis^4^dicpcymefl^
(^-)to^57-Bih) (+y-)tfi^2^4-Aii]ii]oph^^
(+)*awsL34{^4^diD^^
baizcnitrile;
(+)*iOT^30ilcn>4{57dr^
beroonitrik;
(+}4nw2^BKnto2ftBj^^
(+}#r^2{4-Bramc-2 (^-)^a^2^ diramen4aTe;
(^>«w^2^ melhyH4nelhy4)yn^^
(4/-)to^2^4 one;
21

(V-)#t^2^ ere;
(^-}*>tm2{2 (4/-)to^2^3ik)n>5medx^^ one;
one;
(V-)#t^2^ (4/-}to?^-Azkfcme*h)4-lHn^^ (^-)*>t»»^-Amincii]e^
(^-}ta^-3-{2^ph^ (4/-)#i^3{2^ (4/-)*iOT^2^!likxofrenyt^-flien2^^
(V-)*>r^2^ (^-)4im2^!Maqi]enyl^^
ty-}tivns-A£dac add 3^^ften)d>5J pynctth2-ylme%l esla;
(4y~)to»2^2^

one;
(4/-)£iJ2^2^Gikxo|]hen^
one;
(-t/-)tfi2ra-Acetic aad3^^fiienyfl^^^
ester,
(4y-)to^2^i±en)^57^ (V-)to^2^4dtioji^ (^-)#i^2^43tai»4dto^^
arid;
(4y-)£t^34&cnx>4{5jHiih)^^
acid;
(4/-)to^2^4-flucio^^
(^-)to^2^4-AminQ-2 (^-)*r»w40iloiD-3^57 acid;
acid;
hjdoQ^aizamkfe;
(V-)£tOT*4Chlc!o-3{5jH^^
h>dttKytei2aiiide;
(4y-)^>tOT*3^Ihkx^>4^5J h>drDx>--benramide;
22

hyckK)4sizamide;
(4)£m$'-2^-Etaic^3-fta
(+)to^2^-Btaric^fcjoi^^
(+}&tw2QBKjmfr5-fac^^
(+}1nw2QikBnffi
(+)#Hrc-2^CHato-5Hcd>fhe^
(fyn^-2Q}tocm>$^^
(+)£i^2^-B[c*i»$ (4)*>t^2^-Btamc>4ritiD^^
(fynB&2QJ&amc>4iL8t^^
(+)to^2^4-Aniir]o-24xino^^
(^}imns-2^4-Aniro2hxx}^t^
(+)*>i^2^-BtanTD-4-metn^
one*
one;
(+)to^2^-B[omc*44iyd^^
one;
(+}ftarB -Acetic acid ^-ojeteK^niedTyl-l^netf^
7->iesia;
(+)*tw-2H2,4C)ichlaD-5-flLno^ rr&fajynicMi&yfySJ-^^
one; and
(+)£r^2^4I)Kiibc-5^^^
one;
mdidirigphanraceuticaflyacc^^
\*haein Ri, R& R3, R* R5 and Z have the meaning defined above andPisafiinctki^gjoi^v^accnpcundcf fcnnula(llft
23
Tte present invention also idates to pn^^ phamiaceutically acceptable saliste

\\teranAissub6titutedtyI^arriI^ e maribo^nngGfttegei^sIn^
saturatriaurBataated carta
feiespedhecaibonatemstovvn^
i) uhercQisbourdtoanunsaliJaldcarixrigfc^
cr inorganic base and an orj^nic a inor^nic solved, arrifoflo\\edtytreatmatw
ckxilie bad between members at p^^
and6cs" 1 arri2of6iraifaxlffiTgAaixlbc^^ 1 aid2cr 1 and7of 7-nianbacdiingA toa
angjebondand
fi) vvhoeQisboixidtoasatuK^carbmcian^c^ a leaving group,
and,ifapprqnate,convatir^
salt
h arete pocessftr the pqsralbi ofconpDun^ orphanratxxilicaflyacceptabtesahs

N^TadnRtR^RiR^RsandZhawtemeaningde&da^ offcmuilapA),

teeo£aboia^rarirEoffomTLib(ir):
\\foeiemX2arriI^ halite meaning deiM anagancCTinoQ^sriv^toi^ which P is attached ard the nitrog^ cf^ cortpamdoffoimula (la),(Ib),(Ic)OT(lg)iniDarii^^
Atemathd^acampcurioffi^^
24
reatirgaccnipouiidoffoimula(XA):

cracnTipoundofftimula(XM):

vtaein in each case RfeRaR^fyRs^RjarriAaieasdeiinedabcM^
an arid to the reactim mixture cap^ base and, if atpopriate,
ccrMitmglheresulIantca^^
CbmpcmMfcmTula(XM^

l^tieatrnrtwlhanappropnalec^^
RiOTXwhoanXisahalqgEna-vvithanaclKatBdestersuhas anarf^dndemtepEsorecf abase suhas>^ina
9dv^suchasr^lFsTHForl,4 h the processAcanteseJected from:
25

Rii canbehjdro^nand'orRocanhenTdh)! Aprooessfathepqaiamcfacc^^

26
\\iiadnRJ,I^R3,R»R5,RDandZaieasd^ndabc^ainpasffi

wtenmRkRaRiR^Rs.RoandZaieasdetfW
on the ptperidino ring by a good leaving groups m the presence of an ag^
suitable aganic base in the presence of a suitable oq^nc sohort to efe ccntin^ c
apprcpria^ociiYQtinglheiesu^
Apocessfalheprepaiatmofacan^^

whasnR,Ra,RxR4 RsandZaieasa^inedabc^oarnaisesie^^

v^haehRi^RiR^Rs andZaie as defined above, vvfo an^ifapproprial^caiveriing
AprocessferthepKpacatkxiofacompciundo^

vtaanRkRiR&R^Rg andZaieasdefined, ocmpn^ieactiiigaccinpciurricff^^
27

\\teanRi,R2,R3,Ri,R5 andZaie as defined alx^^ -QOpH m the imkJaaa^ ring into Iheg^ icmiula (XXXVII) into aphami^^
teaciingaanqxxindofimiLilapOOCV):

vvboenR^RiRiR^Rs aidZaieascfcfined,\vi!hanisoc>iai]i&m1he sohent
The psert inwnlm also relates to a ptooess fo {i^maca]tk^aocq]y3bsaIt4i£ieof

whercin R3, R+R5, R6and A are as defined, vvhkiipnxess comprises reacting the ia^
(VIM) with a diial auxOiay in the presence of a scfcnt aystaQiang out the xeqimed cBasdaecmeric salt and
subsequentiyteatingwithbass toobtainthedesinriemrilmieraf^
28

Gsnirxjiirids of general fanA
sdiemes outlindbetow and iDifidated h Figures
andRoaEeasdefinedhrespectof^naalfonnula (k)^(Jfo)Xlc)cr(I$above.
Scheme l(Egure-l)
The compounds ofdie present invention are famed m scheme 1 by ametalca^^
knownmtieartMieccflipcaricfi^^
triflateapAxiDberEerESul^^
7^nembeied ring as defined atove. In fe
memberedringofgeneral structure (vi), and tie 74nembered rirg of general structure (vifX Q is attachedto an unsaturated
bond at position Q of ring A and is a halogai or a iunctkiia%suilal&
using a^nometaDic catalysts. IfQtstriflaietaPissektedrrom
such as paBadarrn comriexes, for example, Pd(OAcX RXZ^hCN^ and PdfhjP)* may be used for coupling
.Caip^iscamedaitmTTOsencecfbBSK
solvents such as DMF. The ckxiHebc^
hvdrcbc*aticnorcatat)fc
Where Q is attached to carbcn 4 bearirg a s^
organostannane (\\herein Q may represent tie stannate part) and Hgnd/catal>st such as 13-
suhasarylp&ncbenzenesulra^ 6323)
Where AisaSinembeiedringhaving the geiie^
be coupled directy with the compound of fctmula (D) using a suhabte catalyst such as FdpAcfe, RJClapO^
Ri^F^and CXi Ccq£ng is carried out m p^
ardpyinMrieusingscdvaitssuchasDMF.
Scheme2(Figure-2)
Alternatively, Ite (separation of^^
(Xffi)) WiereinZ is O, A is a 5membered ring oanespanclr^ to general sttuctiires®,®
NR^I^ishvdroxjalkylarriRjish^^
becamedctffoacoardancevvithfes^
facompcuncfecf1heibnnute(VI)to ispeieiablyall^Asoufnedin
Scheme 2, the preparation steps up to conp3undscffamula(V15 starting fontte
aredescril^hUSA4900727,vvhkhisin^^ In tie conversion of the compound of
ibnnijla(VTQto1rHtofibnnijla(OT
gpcd leaving group such as tosyi mesvi triflate or haBde by treatmett with appropriate reagnts like p-
toliHTesulibrrylchkxkfe;
iric^ric base HE trietl^amine, t^^
acetatoinasoKentsuchasisopropandl^
asdepk^m Scheme2 cr itmay becbieafehiildff^
fcmii]]a(VIIl)mayberesolvedbyieac^
camrta-lOoiljii^
ete,etfyiace£^OTdrhdi^
asNaH(X)kNa£X)3ttK£Cbtooblainte The compound of
famiia(VllI)nwthenbetnatedvvith^ac>to
any activatedfcmicfanacH inthep^
ocoe^xno^acyla^caiTrxxirri
29

compound offcnnula(X) by treating ilvihareagentlikeanaridchlcikfeoflhel^
(I^OO)A^^ofttetypeR|OT
can also be bKHgjhtabctf by treating
a Conveson of the compound of fcmula (K) to the oarapound of fimula (X) can also be brou^it about by a
ccmbinateQfRi(X)QHandpo^^
iormula(XI) by standari ester hjddyss using bas^
abcMofibmu]la(XI)rnaytecaiv^^
aid ester sudi as RiCOOM^RjCC^^
activated ester suhasmanh>drife^
The ^diketae oflbmTijh(XI^ may finafy
basesuchasNaHiblkMedbyc^diza^
rrriklbasesuchasNa£X]^
flavor of fomxib (XE) by trcatmcnl with a base such as NaH followed by cjdization using a strong add like ccrcertiatedHafcnc^
Analterrtftivemetfiodfrxrjrepari^ conpourriofgsnaalfanifo^
Scheme3(Figuie-3)
Scheme3outimestterieparatm
converted to a compound of fcmmla (XXII) by fcflcwng strik" poces
ccnvaMcftheoarnpcuTdcffbmiuh(V^
prejBied herein is a ccmpciund of general fbmiuh
cccesrmfingtogneial structure (&®
AsciutlinedmschenTe3,tte(xi^^
P3V) The coiipoindof£mTLih(XIV) is fistoan^
caidensatkmrfthecompourrictf^
Mkfcdreactkxioftheresi^^
oxTTpourid of famula (XVD). The Mkhad reaction in die presence ofachiial base such as prcfefeadstochiral
compound of farnula (XVII). Allemativdy, the compound cf^
aHeh>de(XIV)ir]to1reniliDsr}ienecta
Michadieaction,i^baseasctecrib^
The resultirg compound offanuila(XVII)B
nitro gp^ by kriown mefceds such as trea^
rectactimto)MfeccnTpciundcffa Ahemativ^,iedu^cjdizatmofte
(XVH)usirgacalal>tfliteRar]eynM
converted to Ihe compound of formula (XXH) as described msdrenc 3. ftocess steps fi^
(XVin)tothecompourrioffbrm^
conpomdoffamuh(XIII)hsdTerne2
Scheme4(Figute-4)
Anoternethcdcfcblairiingac^
is O, A is a5*nerribered ring represented b^
represertsp4duenesutfc^(Ts)^ R6 isateW^ grc^
inscheme4.
30

As outfined m sdieme 4, Itie compcuid cffcnr^
The oampound of firmula (XXDT) is converted using a Wittig reaction to fa coKSponding styrene compound of
lbmTLila(3O(l\0vvhichmtum^
N 2709-2711) The compound (tffamula (XXV) is fan ccnvatd into fa compel of fimi^
compcm[lscffimiLte(}0(\^
c&mukpOCDQalsoleadstofaco^
Scheme5(Figure-5) PrepaiatkiicffapreiMc^^ \\tenanAisa54neni)eredringaxiespc^ andfasubstitiJtionReonAis-CH^^
As afed in scheme 5, fie compound of ibrmufo (XXXVI) is rsqmed s&rting fem fa compound of formula
(XXXH) TteconipoundcfiQnnuh(XXXI^
ledidicn g^ fa conespending amir» com
200Q10,835). Conrasbiof amino flavons of famula (XXXIV)tofaconpx^
eflkiBdby treatment wilhetri^
of famula (XXXVI) may be brou$i about by empic^ fa method cfesaibedm fa
5453) fcr fa transformation of a-ariilincKx-dkroQ^cetates to imidazDles using tos>tahyiiscc}anide (TosMQ in
presence of a base such as Na£Cb or K^CC^ in a sotvalsuchasethanolCTmetha^
(XXXVI) rnaythenbeccnvertedtofareq^
fikeMnuniaiiiminiumhydi^
Scheme 6(Figur&6)
Asstatedhadnabc^iniesp3ctcfschenie2,fakey
of formula (XXXXIH) in Figured, may be prepared by fa alternative process steps iDLBtrated h
compound offcrmulapOCXXin) maybe ixeriredstartingfiDmfachirdc^
tomispretBredmaoccia^nre^
cfibmTu&(XXXVTn)mieading\^
resuMr^ ketone of iomubt^^
ocnpciindcffinriula(XXXXi) Rin^
base such as sodium hyckiekads to
bond in the S^rmibend ring ty a ccrr\eta
(XXXXffl)(occe5pandrngtotecc^
compcurxlcffcmTi]la(Xn^^
same process steps as described in scheme 2 fir fa conversm of fa compound c
fismulaXHl
Intermediates of this invention may also be peparedbyaptooessdisckmlmfaprkrartCT
procedi^cfe9cnhedmUSA4900727,^^
TheccnpouridsaMcdingtofagaTaalfcinTuk^
dqsrt^ kinases arxl are hdi^pharn^
pesertinvenlk^treatmeriti^^
facrEenibodirnentfacompoun&^ faprcsert invention arecapableofinr^ anexeessrvecrabnonnalceflgcwth
31

There are a wide variety of pathological auditions with excessive or abncsmal cdl proliferatm against which the ccmpoundscftteinvato
avarioEcaxasandleuten^
L carcinoma, including that of Madden, beast, colon, kidney, Iroa; lung ovary, pancreas stomach, cervix,
%rcsd,fi06(ate, andskin; i henHtorxiieticturrKisci^^
BuiketfslynTrirnia; in. liematopoiefc tijnxirc
prom^ekx^leukernia; iv. tLffrnsofmesenchyn^ v. otiierturrnsiriiudirgrr^^
hdierrfltteiapy-arrifr^
c damatology (pscdasisX
d bone diseases,
einflanrnationarilaTthritis;
ffibropuiifiaalive disorders such as those involving connective tissues, atharjsderosis and cfoar smooth musde
prolileiativediscrie^asv^ascr^^
gcaKfov^xJardTCCTHlities(ies^
hrtprm^tog^'i^Tenih-EiMis);
i^arasilrio^iiikjdrula^
j. neurofogy(Akhemi^sc5sease,st^
k vidinla*iorE(cytari^^
L ni>o^K infections
foaddirkmtotiolfeitive
result fion% £r exarnrie, de o^gerfiativedisadersiridi^
as suggested by the finding that CDK5 is involved in Ihe fhcBfiaykfcncftM
749), fakinson's disease. Hurtmgon's chorea, amyotrophic lateral sclerosis and the like, as wefl as spinccetebellar
degeroations Other dfleraii^^
tfreeteniay occur oYe to de^tifle^^
cbdiffiientiaton of eniaMal tissue
glardiiarcdlsaridrerialoorioftiore
baddfoiontotherapeuticaH^^ iteprcseriirivertacanbeiBedasace^ v^andcanafeotei^fcrec^tissuegen^ tbrimiianlaticnsuchasdesct^
Dffiereritialsaeeriirg assays km\\nh
specificity fir nonfcuman CDK engines. Thus, ccmpcundswhkhartspeci^^
fir^l or antiparasitic agnts, can be selected fiom the subject ocmpcwncbcf^neral£irnLila(^
mrnritDE are uaetulh patted
Ijniriiarra^a^etesrrdlD^
WhensdedBdfirartkr^cc&usestefcD^^ c^dirKfeperdentkinase complex ctfthehijrmpatlrigenwithm^
32

inhibitmofalMraic^^ Jess.
foasimikmanrierjCertafocflhep GX's relative to the maninialia^ inventionimdusemitBecti^^
The present invention thaefiie also dates to the compounds of the fcnnula (la), (fo\ (b) or ((g) anaVor their
prmiaKiitical^ acoqptabte sahs anto
(Drnparndsoffefomiula {k^(to)(fc)or(I$anaytttteff
prodLictkxictfriiamTaceutic^
mentioned above, tbrexampfe icr tte production cfrismraKiit^
iriflanimaticnandarlr^
cfease, dr., and to methods of teatirent aiming at such p^
The present invention iMiermore relates to jiiarmaceuticalocnipositkre
oonpoundofttiefismula OaX(lb),(Ic)tt(l$and/ori&ri^^
custornatypteornaoeutk^aocepl^
bringing at feast one compound of fixmula (Ta^ (jb), (fc) or Cfe) into a suitable administration torn using a
(itmia&Jticallysuitab^
additives a aiMiiaiies.Tteprmi^ (la).(]b),(lc)CT(^)inari
amount atfeqtifc to inhibripTttaJQ^
CanMidtocan AspergillusjwBg^Rhkpw
Ttepre^ invention also relates to a m^^ discicfersassodatedwMi excessive eeflprc^^
(L^([b^Ic)a(lg)isu^asttephamiaceiiMfy
Thephanriacaak^canbeadrriiraaEi^ crdixiis Administration, iccexariTr&iritiavenousiy,ini^^ topcally,ibrexamrieinthei^ ornasal sprays.
The jiBmraosutkd preparation accadi^
skiQedhtealHMrnaceutk^acoeptabfeine^
totheccrnpound(s)cftelbirnula (kX(fo^(fc)cr(J©ancVcrits(t^
prodti^ Fa 1he ptxldkn cfp^ tabfet^ coaled
lactose, ccmstairiicr derivatives
suprxstxies ate^ for examrie, ^ vvax, na^
examrJe injection solutions, or of ernidskiB a syrups are^ibrexam^
akxh^ £r examiie, ethanol, ptopand a ^ycao^
mixtuKofftevarioussohatevviiidihawb^
The tiiamriaoaitk^ pEfHalkiB nom^
atoutl0toabotf30%fcyvt«^offeca^ ^^^)a©antofteirrliyskA^icaIiy
tolerarie sails aridte their r^^ (b),(lb\(lc)or(Ig)ail/orils
riiysiobgjcaliytoleral&sa^
The dose of fie compounds of this invention, which is to be administered, can cover a wide ranga The dose to be
admiriisteied daily is to be sdected to suit tte
paikr! [f raquiral h^
33

eflbctive to achfeve the desired the^^
vvithout bong toxic to IhepaQenL
ThesefededaV]6ag2le\dwiflckperriur^
present irrantmempk^ ate
rate of excretion ofthe particular compound bemgemriqjed,^
/orrratdalsi^incoiribirEtionvvithl^
andpriorrnedk^MslDrydliepate
Madditkxito foe active ingredienlscffe (k)^(Ibi(fc)or(l$andfatt
prcdnjgpardtocaniersubGtaes,fe
antbxidants, dspetsarCs, emula^
oontamftwormoieccnTpoii^
rjodrug^Furtterrno^mad^ (^(^(^ocQ^i^cs^T^adkj^csSfy
tabafcte sate andbr its prodrug the liemacaitk^ preparation can
pioph>1a3k^;actKeingiafiaTls,
The ccmpcaicfecftTepresetlinvEntm
part cf combined ftaapiea Fcr iffilance^
knc^nantkancer,c>1c6(aftc,ard^
ocmpcuidk cf the present iriventa^
withinilsapproveddos^erange. Forexami^theCDiCiiiii^
krxMnc>1ctoxicag^mindudngapcp^ (Ia),(lbX(fc)
CT (1$ n^ be used sequentially wfa
fornulationis inappropriate.
ftisuxtaoodthatmcdifcalio^ areindudedvvilhhflTeima^ondisdc^ limittherxesert invention.
Note: l)BemenlalarBrt\^ThevaluemtBrenlh^
Exampfel:
l-MahvW^/^rimd (CompoundNa 1)
ltfrrm30roglaciala^ackl(60Om^^
ffl(450mL)v^addedcK«20rrmThe1en^
35ifiv^aQcM€dtoccxito40^txxiredc^CTCiudiedkE(4^
trimerhoxy benzoic was fittered off The filtrate \*^basifiea\ at betowlO^toriT 11-12 usi^
3oh.ttmTl£off\vrnte30^1)obtainedw^1ilta^
rdd:580gpp/o>
1^:117-119^
Rcm1:160a280a
20(s,lH)i MS:mfe2630Vt>
34

ExampteZ
(CbmpoundNa2)
Bcxontrifluoridediiaate(3(X)i^
ofoomr»iirxl(l)(300g 1.14x1^^
1heieactioninixturewasslewlyiai3adto^
was sbwly added followed fcy addrfication with caxertratBdHQ (375 inL) The
5a55^.Itwasccc 225 mL)wasaddedover0.51i Theieadmmixiiins\\assta
water adaW to dssohelrieprecipii^
TOAc{2x lL)7teai^ extracts woe oM
was treated vvrfo4NHG(lX)ardextra^
Wo aqueous NO! sohition and extracted u^
ocncoiteitedtogjvetepDirtP)
Vidd:210g(65.6%)
Raril:350a
'HNMR(CDq3):86Ll5fe2H^4.4(m, lHk37(twos^9rft24(s,3H^33(m, tfft255(t,2Fft235(s, 1H*20
MS: mb281(M,i 263 (M-H£>)
Example3:
(^taraMcetic acid l-mefliyl-3^4j(>*iimel^^ ester(CcirirjoiirriNo3)
DistiMlrielty amine (W^
mmcC»indryaW2(25 L)TofereactimmixtLrem 171.1 g, 1.49x lfrmmol) was
added with stining at (K^imder an atrn^^
slinedirjm at 0^ ft was poured oersatura^
washed with brine, dried (anhy. Na£Gj) and corcenlia^tocfaaWtheCknes^
dtstiQdi9opop^akiM(15L),anh>diDtB
iefliKedfrxlhftwascoctedtorocmlem^^
was concentrated to obtain the tide compound (3)k\vhkh was purified tang a sflka gel column and 60%
Yield:241g(60%>
1H^Ml( Examfte4:
(4/-)*>r^l-MeJhyl-3^^ (CcnipoundNo. 4)
A10%a3imisNaOHsolutm(59t^
methanol (596 mL) The reaction mixture was stirred at 5TCicr45rnhftwasconcentraledtD
WurrmrithenpouredintokE^
(arfy.Na2S04)toob(amtte^
Ydd:198g(9*%>
,HNMR(CIX^)86.15(s,2H^
tfft26(m, Uft242&3Hfc2jO(fr 2H)i
35

MS:mfe281^249(M-31>
Exampte5:
(-}#t^l-Meth)i3^4£4riineto
(CbmpoundNa5)
(^mKl^VfethykM£4£4^^ (Compound Na 4) (273 g, 97.1 mmo!),
was dissolved in methanol (100 mL) aril heated to 70*G To tiishtgoIulicn\^ added (+)DBTA (3631 & 1015
mnioI)arritheIieatrngwasort
methanol (45mL) and isopropanol (31SmL). Httation and an isopropanol wash with subsequent drying afforded the
aystaflinetartarate salt (13.14^^
(10mL)arriisopoim)l(40niL)^
The fe base \vasobtaWfiori this poiu as foQtMs
Tte srft (9$ w^suspartel methyl ace^
addedandthemixture was stirred fir 30 minutes The 03^ ponin was separated and the aqueous pa
extracted using ethyl acetate (2 x 50 mL) The organic portions woe combined and concentrated to obtain tic title
compound(5)
Yield: 3.6g(263%)
[ab25=-17jff,(c=l.lfmetooft
™MR(OX^>6dl5(s, 2^352(^1^3^(1^3^
lHXZ6(m, lH)£42(s,3Hi20(m,2H).
MS:nve281 (M*),249 Bampfeo":
(■)ftan$-A£dac add 3 Na6)
BFj^therate (325 mU 250 mmol) was added dropwise, with stirring at (K^iiider>tatrTr6|tee to a s^
poduct(5) (14.4 g, 51 mmol) in acetic anhydride (26 mL 250 mmol) The reaction mixture was stirred at room
temperature fa2h It was poue^
extracted usingBOAc (3 x200niL) Theciganbext^
togettitkcompound(6).
Yid±lUg(tS*%)
'HNMR^CDCfe^S 142(s, Uft556fe Uft4.1 (d,2H), 352-3.75 (m,7Hk325(m, lH),2&(ni,2Hfc265(s,3H)>25
(s,31ft21(m,5H)i
[ab^-7.Q2^c^).7,methanol>
Example 7:
(^-)tfr^l^l)drox)^3 No. 7)
Toasciilkiicfccnirxiiid(6)(llg31mrix)0rnm
aqueaBNaCH(25n^62rrimo0soiutm
was cooled to room tenpoature, acidified using concenter HQ
using a saturated aqueous. Na^COj sohlmThepBciptatedtfe
dried
Yield: 8J5&(87%>
1HNMR(OX^>855(s, 11^358 (ni, llft35(twsit^ets,^
26(s,3H),258(m, lH),24k31ft20(m,2H).
MS: mfe309 36

Example 8:
(CompoundNaS)
Scdiiim hydride (Wc^ 217 g 453 mm$
DMF(30mL)at(K;iiteniir^
mmol) was added The reactairaxtiro
2(KZiblkMedby,ackfitimofc^ (^mL)andpassag5cfastrangstieamcfffi
mixture was poured c^cochd re (TO $a^
was extracted using CHCb {3 x 200 mL) The oiganic extract was waied with water; dried (anhy. NaaSO^ and
caicertiated to obtain the tide compound (8) which was purified using a silica gd column and a mixture of 2%
melIraTQlH%liquararmKi&
Ydd:2.5g(64.6%).
mp:95#7tC
Rem4:340^1660.
IHNMR(OXi):57.7(dd, lJft755(m,Hft7.45(m,2Ffte;45fe lHfc655 3^4.05fe3H^3j65(dd,ltft337(d4 tfft3.15(m, Uft277(d, Uft25 (m,Uft23fe3H)^205(m,2H>
MS:nVe430^398(M-31>
AraryskCsHs^^
Bampfe9:
(^-)to^2^fiien)4>5J^
(CcmpoundNo.9)
Amixlijrecfcompound®(0>25g0fmn^
15hThereadicnmixturewascccledtDi^^
>^CX)j soLitm It was extracted usm^
Na^SGj) and ccoxrtraled Traces cfo^^
slkagdooIurmandaniixtiiecfS0/*^^
Yidd:ai33g(5^/o>
mp:22&-230C
'HhM^CDCycS 12J6(S, lHfc73(m,4Hi6i45fe Uft63(s, ltft4T5(m,lH),39(m,2Fft329(m,2H)i292(n%
lHfc278(s,3H)£48(m, lift 1.98(m, 1H>
MS:me402(]VW))384CVH8X370^1-31>
Ran^StUlSaieSO.
Example 10: (+)to^2^2 (CompoundNall)
Ccn^ound(5) was conwated into (-)^ft^H241vdrc^-3^^
cfoieJhoxyFhenyi]4-etharKi^cc^
&24mmcft was reacted wilhmeth^
(5(%0582gl29mnicftusmg1teprD^
Yield: 0.G7g(&%)
mpt9S^C
iRcm^s^ieeo.
37

1HNMR(CDQ3)87.7(dd) 1^755(^1^7.45(^2^645(5,1^6^5(^1^4^7(1^1^405(3,3^395^ 3HX3£5(ddlUftl37(dcllI^3.1S (^1I^277(4U%25(^1^23(^3^2O50XI>2IQ.
MS:nvfe430(Mf))398^1-31>
Examptell:
(CompcundNal2)
Confound(ll) (0.4 g 0.9 mmd) subjected to cfereihylatian using pyridine h>drochloride (4.1 g 35.4 mmoT) as
desaMhe>cxnple9,affb^
Yiekl:02g(56%)
mp:22&-230fC
lHNM^CDa^M26(sJH),75(rMH^^
Ilft278(s,31ft248(m, lift 1.98(m, lift
MS:m/e4Q20VB-l),384(l^lg))37O(M-31>
IRcm4:335Q318(U680.
[ab^=+12120(c=ai32)meterxAaKfe,4ft^
Example 12
(-)to^2^-Gilciofhen$^
(CbmpoundNal4)
(f>#m^l42fl)dn^-3^i^^ (ccmpound
13), was prepared fiom (+)to^l-NM^3^4£*iimeli^ using the procedures
cfescribedmecan3ples6&7.CcnTp^
ninioOin^DMF (15 mL)htte presence tf^^
exan^8toa&dtetitbocmpcund(14)
YKU:025g(26%>
mpc9$97C
IRcni1^ 166a
lHNMR(OX^)67.7(di) 1^755(^1^745(1^^645(3,^
3Jft365(dd) lHX337(dd, 1HJ.3.15 (m, Uft277(d, l!ft25(nUtft23(s,3Ift2G5(m,2tft
MS:nVe430(M^398(M-31>
Example 13:
(-)^>l^2 (QmipoundNoil5)
Qinpound(14) (02 g 0.46 rnmol) subjected to deme%latkii using pyck£ne h>drodTkiide (2 g 173 mmoft as
desoibadfoexanii&^aflaiddfe
Yield:aig(Wo)
mp:22&23tfC
1e lEftZ78(s,3ElXZ48(m, lift 1.98(m, lift
MS:mfe4Q20VWi384flVW^37O^I-31>
K.ari1:335Q,318Q,168a
Ar^C2iI*xPsKW)Q5945(^
[a^=-1228°(c=0aHnTetbaKia^40^0>
38

Bamptel4:
(CbmpoindNal6)
Ctxtipound(10) (07g 226 mrrwO in dry DMF 0
pesencecrf>ffl(W^051g,113niniotyascfe^^
Yidd:0.4g
lHNMR(OXfe):877(d, lJft7£5ft Itft7.4(m,21ftd45(s, tfft6.4(s, lift 4.15 (m, tfft 3.9 (fcw arrets, 3jfi5(dd, 11^,338(41HX3J08011, lH)t2j68(dL U%Z4S2[{)L
MS:nVe474(N^442(M31).
Example 15:
(ConpoundNalT)
Cbmpciund(16) (036g 0.76 mmol) subjected to cbnelhylaticii using pyridine hydrochloride (3.6 g, 31.6 mmol) as
de3cribedmexamifc9,ailbniedlhetilie
Ydd0.182g(58%)
njp:235237C
'HNMRCOX^^S 1275 (S, ltft7.86(d, lFft7.74(d, lift 7i6(m,2fft 644 (s, llftdl2(s, lift 3.78 (m, Hft3^-
3.12(m,3Fft29(m, tfft285(n% lift 24(s>3Ift 215 (m, lift L8(m, lift
nW:345Q 1660.
MS:nVe447(IVf>428 An^C2ftS^G5S53(56^
Example 16:
(CompoundNal8)
Cccnpciund(lty(0.83g2dnir^
inthepresenceGflsMl(5(%0j^
Yieki:057g(78%>
'HNMR(CDCy:573(d,^
335(111,2^275(1^2^245(^3^215(111,2^
MS:nVe474(rVf),4C(M-32>
Ban^fel7:
(+)*fc^2^44iomofhei^549do^^
(GnpoundNo.19)
and
(CbmpourdNa20)
Ccmpour]d(18) (0.61 & 129 nimoD
described in example 9, afforded me two title compounds(19) and (20) which were separated using column
chraratography.
Compounds Yield: 02g(36%>
39

1x^:163-165^
IRan4:342a297tU680.
'HNMRpMSOd^m llft275 (m, llft245 (s,3Jft2Q5(m,2H).
MS: mfe461 Ana^C22IfcB^O^^Q5455(5524iH4j66(5.Q5);N)339(293X&,1668(ld70)
Oampound2ft Ydd021g(38%>
IRan1:34iai7ia
'HNMRODMSOc^SlZKC^ lift &09(d,2Ift 7^(^2^695(^1^615(^1^4.0(111,1^35-325(111,2^
32(s, lH*2#(m,2Ift25(s,3tft225(m, lift 1.97(m, lift
MS:mfe446(Mfi428(M-ia414(M-33> AK^C2,IfeBiNO^Q5^^^
Example 18:
(4)#t^2fte^^
(CompoundNa21)
CompoureTO(lg324mrri30m^
ptesenoeofNaH(Oi776g 1616mmo0asdescribedme(am|ie8,a^
Yidd:035g 1HNMR(CDQ3>8a08(d, tfft7S(d, 1^7.45(^2^665(5, Uftd45(s, ltft4.4(m, lH)^4.0(twodoi±fels,6Fft
3.75(dd, lift 335(m,2HX275(m,2HX245(s»3HX21 (m,2F5:
MS: nVe430
Exampfel9:
(CompouidNa22) and
(+)to^2{3jitt^ (CompcuTdNa23)
Cbmpcuid(21)(025g(X58nimoO desaibedhexaai^9,afW^^
Ccnqwund(22):
Ydd0.035g(17%)
mp:146-147C
IRcm4:330CU650.
'HNMRpviSOd^ 13.1 (s, lift 827 (s, tfft&l (d, lift 7£5(m,2H),7.15(s) Uft665felIft44(bUIft3S5fe
3Ift3j6-33(m,2Fft3.12(m,lIft2^26(m,2H)^245(^3Ift2iQ5(m,2Eft
NK:mfe416^3840Vt-32).
CampouriCZft Ydd:0.085g(41%> mp:215-217C IRan4:340ai660.
40

'HNMR(DMS0d^8128& Uft82(s, lift 8.08(d, lift 7j65(m,2Ift 7.0 (s, Uft&18(s, ltft4.0(m, Uft36-3.1
(1^2^3.0(^3^245(^3^225(01,1^158(111,1^
MS:nVe4G2(M^384 Arc^Cal&O^l/ZI^
Bamffe20: (4)to3B^24fydraxymeft^
(CampouiiNa24)
Canpcm](10)(0.45&146mn^
pesaixof^(035gWo>729nim^
YEktO29g(40%>
!HNMR(CDq3)87.98(d, lHX75(m,2HX73(s; lHX645(s, llft635(s, ltft4,15(m, lift 4.0 (few sir#*s,&ft
37(dUH),3.55(cUHp25(!nlH)J(^ MS:mfe522^Vifli490{M-32>
Exampte21:
(fyn^5J-Bkty&axyJ^^ (Compcxiid
Na25)
Compour^4) (029 g 0588 irimoDs^^
descnWinGiaTipfe9,afabltetilfecampomJ(^
Yidd:ai45g(58.7%>
n?):23>235cC.
^01^:3400,1660.
'HNMRpv®0d6):8128(s, Uft82(s, lift 8 (m,2H^3.0(m,3Ift245fe3H^225(m, Uftl58(m, lift
MS:mfe494{M^368(Ntl27)L
Ai^C2iI^^O^^Q495(4933XH4.05(433);H=284(273); 1,24.48(2451)
[ab -+1.92°(c=02(£ l:lNfeCHCHCb>
Exampfe22:
(+)*iw^2^fluccc>fiia^ft^4i>dia!Qi^^
(CbmpoundNa26)
CtaipcuiJ(10)Pg25ninr$matyI^
preseraeQfNaH(0^2s50PA 123mii»9asdesa^
Yidd:0.68g(65%)
1HNMR(CDOi):87.98(d, lift 75(m,21ft73fellft645fellft 635fe lift 4,15(m, lift 4.0(ftwan^ffft
37(dd,lHX355(dJlHX325(m,1^3.Q5(m,lIft257(niJlHXZ4(^3Hi215(^
M&mfe414(Mfli382(M-32>
Example23:
(+)*taw^2^4:luQn>iiKr^^
(CcmpamiMx27)
Compound (26) (0.07 g 0.169 mmd) subjected to demeft^latkii wMi pyndine l^dtocHcdde (1 g, 8.65 mmot) as
describedinexample9,afa^
Ydd:a017g(26%>
mp:206-208c1G
41

ttW:340Q1660.
iHNMR(DMSO<8128> (dd, Uft3.7(m, tfft358(m, llft348(m, lHX33(m, lift 285 (s,3H),235 (m,2H)i
MS:m/e386(MH>
Ana^C2|IfeFNO^Q^
Examp!e24:
(CompourilNoi28)
Omixxiri(10)(0.83g2®nTri^
tepresenoeof>Ml(OMg5(%1333n^
Ydd:a73g(68%>
1HNJMR(CDa3): 5 8.05 (1,2Ift7.65 (dd, lift 7.45 (m, lift 7.12 (s> 1H); 6.6(!=slPft435(m,lH),3.95(t>wdaiH^
6HX3j^325(m,«[X3.05(m,lHX2^5(ms Uft235fe3Iftl37(m,2Fft
MS:mfe414(MH)382 B (4)tfi^2-fhen)^5,7A
(CompoudNa29)
Compound (28) (051 g 123nmxiDdenTelhylatriusir^ g 44.15 mmof) as described in
examrje9, ^vt the title ccrnpound(29)
Trek* 025 g(42%)
mp:21822ffC
IlW:3390,1660.
'HNM^DMSOd^S1285 (s, lift 80 (m, 2HX7^5(m, llft7.45(m, llft7.G5(s, lift 6\18(s,llft4.a5(m, lift
37-32(^2^295(111,3^23^3^225(01,1^1^(1^114)1
MS:mfe386(MH), 368 (VH8X 354(M32)
AnalyskC2ityM^l/2^Q6325(63^H5^(53^H357p5^
Examp!e26:
(CompoundN3i30)
Caiipcml(10)(1.5g4.85rnm^ g64mni30a5T;mfeptes^
Tte reaction mixbie was diluted w^
wasted with water; dried (anhy. Na^SOO and concenteted Tire semisobd lesdue thus obtained was treated with
concentrated HQ (50 mL) and stined at room tempoaiure for 2h Rite pin^^
aicfddthetitteccmpcuid(30>
Yidd:0.09g(5%)
1HNMR(OX%):875(m) lift 7.1 (t,2Ift642(twosi#as,2tft4.11 (n% lift 357 (two arrets, 6ift 3^6 (dd,lH),
3.52(d, Uft325(m, llft295(m, Uft265(m, lIft245(s,3Ift20(m)2H):
MS:mte432(M+l),400(M-32)i
Exampfe27:
(CampoundNo.31)
42

Ccmpound (30) (O09g 0208 mmol) subjected to demdhyialion uang pyridine h>itexh!cdde (1 & 8J66 mmoft as
describdhexampte9,aflcded1te^
Yidd:0.Q32g(38%)
mp:242-244(C
IRari1:3300,1660.
lHNMRpvEOd6):6 lZ65(s, lHfc7.75(ro, 1^7.4(^66(5, ltftdl5(s, lHX3.7(m, 1H^3.6-3.1 (m,2H^3.88
(m3^245(s,3fft215(m, 1H), L85(m, IHL
MS:nVe4MflVW),386(M-18i372(M.32>
Ana^C2iHi^NaH^C;6043(59^5);H456(5jQ2);N)3.96(332>
Example 28: (V-)£tw^^-H)draxyn^^
(Compound No. 32)
Ccmpcud(7)(15g4^mm^mdiyDMF(15mL)ieac^
thepe9eneeofNaH(12g50%25mmcfy^
Yield: 0£5g(48%)
mp:214-2ie^C
IRari1:3400,2210,1640.
WlR(aXi)o&15(d, 2^78(42^675^
lH),33(m,3Ift278(ms 1^,26(41^242(^3^208(111,2^
MS: me421(Mf 1^378(^42)
AnaljasCM^NA L2^Q67.Q5(67.12);H5.78(5.63);N,6.1 (6i5>
Examp!e29:
(V-)taHS^5^)dia^^
batEmilnTe(CtriipoundNa 33)
and
(4/-)*ira4{5J43ih>drcf^
(Cbmpou«lNa34)
Compound (32) (030 g 0.71 mmol) \\asieacledwilh pyridine h>d^^ afibtddthetittecxsTpcuxH(33)and(34).
Cbmpound(33):
rddO.Q33g(10P/o>
mp: dBocmpcatoV>25CPC
IRari,:332Q,221(U#a
lH>JMR(CDCb):51298(s) lift 835 (d,2H), 8.08 (d, 2H), 72(s, 1H), 665(s, lift 338 (m, lift 335 (s, 31^3532
(m,2HX3.1(m,2I^2^5(m,lfftZ4(s>3H),2j0(m,2H)L
MS:mfe:40f7 AiB^C2*fe^l£WQ63^
Campoundp^:
Ydd:0.1g(36%>
1^:273-275=0
IRari1:350Q2220,166a
1H^MtpVlSOc&512£(s,llft826&
295(m,3H),255(s,3H^225(m, lH)£0(m, 1H).
43

MS:mfe393(MH)376(NM8>
AraljssCaFfeNA l^OQ6&59(6657fcH526(52XNJ6.63(7.05X
Example 30.
(+}4tra4{i^241)diaxynT£^
(CompoundNa35)
Gxnpaurri(10)(098g3T7mi^
1hepre9enceGfNaH(50%0762gl5J£
Yield: 056g(43%).
IRari1:340a221Q,16tt).
]HNMR(DMSOc&8828(d,2^
(m,2H)325-3.15(m,2H)265(m, lH),24&3H)£0(m,2H)i
MS:m/e4210^-1)^378^4-42).
Bampfe31:
(+}totfB4{5Jl)dia^ bmaxiMfe(CbnEX)iiTdNa36) and
(CompoundNa37)
Compound (35) (03) gU9mmo0n^^ anadedtetilieocnipounds06)and(37):
Compound(36):
Yritaig(20P/o>
mp: 117-119C
IRan1:342a2250,166a
1HNMR (m,3HX3.08(m, lH)tZ6(m, 1H|^235 (s^3H^ 158(m,2H).
MS:n^407(MH),375
Aralyss:CBFfet^.l^^OQ61.44(6139XH5.11 (5.6);H 631(653)
Compound(37)=
Yidd:ai9g(40P/o>
mp:245-24^X:
IRan-4:340a224ai660.
'HNMR(DMSOc&5a8& lH)828(d,2H)&G5(d,2Fft7.1 (s> lH)615(s, lH)4.0(m, lH),3:34(m,2H)3.0
(m>3^2i(s^3H))225(mP 1H) 158(m, 11^.
M&me393 (MH)376(IVH8)
Ana^kCijH^Qs. 1/^OQ©38(63J(%H,522(552);N, 664(667)
Bample32:
(^-)#mf^ifydn3(ynieli^
(OompoundNo.38)
Ccmpcund(7)(15g4#n]nxOindiyI^
16fl2nTmoOinfhepre^^
Y*tt
44

mp: 114-115*0
IRcni1:345410OL
■HNMlCCDqjXSantt^XTSCi^dySCs, Uft6.48& llft438(m, Uft4J0(twsa^ffft3.7(d4 lift
338(41^328^275(^1^265(^1^244(^3^208(01,2^
MS:mfe464(^l),421(M42) Aral>as:C2iHsiF3NO^^OQ59.13(59^H551 (5.44)N,234(29)
Exampfe33:
(4/-)tft^5,74)ih)dioxy^^
(CcnsmxiNa39)
Compound (38) (Oig 1.08 mmol) was demelhylalBdi^pyrk^
exan^9,tochainthetifeccfnpoundC39).
YiekJ:028o(59%).
np:23ffC
Ran1:3350,166a
'HNMRiDMSOc&S127 (s, lift 833(d,2Ift 7.98 (d, lHX7.08(s^ lP^6.18(s, lIft4.Q5(m, lift 3.6-3.4 (m,2Ift
3 MS:mfe434(]VtU4m(M-31>
Ari^CsBfeFsNOs Q6034(6a69);H4.48(4.63);N,289p.42)L
Exan^te34:
(Ccn?x]uadNa40)
Compound(10)(0%26nm)9md^
mmotymthepresenoeof^^
Ydd:1.0g(87%>
mp: 114-115^
1HNMR(OXlj>8&15(d,2Fft7.78(d,2Fft675(^ ltft648fe lfft4.48(m, llft4.0(1wo an$£> fift 3.8 (d, lift
3.46(m,2tft288(m,2Eft255fe3H^218(m,2H).
MS:iite4Gl(MH)432(M-31)
Bampte35:
(+)^>rw^5J4}ih>dra^^
(CcnipourriNa41)
Compourri(40)(a7&L51miii!$
evaripfe9,tDot^theliIfeoarrpouiid(41)
Yidd:028g(42%)
mp:235237€
IRan1:340ai66a
1HNMR(OVlSOd6):81282(£s ltft 835(d,2fft 7.95(d, 2^7.08(^1^617(5,11^4.05(111,1^3^6(111,2^
298(m,3tft25(s,3H),225(m, lift 1.98(m, lift
MS:mM36(MH)4M(M-32)
Ara^Cz^N^IRp Q55.79(56M);H453(5.1)sN,291 Examp!e36:
(-)*>tw*^4l3draxyri^^
(OmpoundNo.42)
45

Gmpourri(13)(l g324ira^
mmoOhttepresenoeofNaH(0.77^^
YKW:a6g(40%)
,HNMR(OXl})5ai5(d)2tft 7.78(d,2Ift6i72(Ss Uftd45(Ss llft442(m, 1H*4.Q5 (two a^&ft 3.75 (($
lHX335(m,2HX278(m,2HXZ45(s^3H^21(m,2H).
lVB:m/e4#(lVMi432(M31)
Example 37:
(CbmpoundNa43)
Cbn^xxmd (^) (03,1.08 mnx^ \\as demefl^te
exan^9,tDobtahtetifeocmpciurid(43)
Yidd:0.195g(42%).
mp:234-236:C
IRcm,:338G,1660.
'HNMRpvlSOd^S 128fe lift &32(d,2Ift 795(d, 21ft 7.1 (s> lift 615(s, lift 4.05 (m,llft338(m,21ft3.0
(m,3Ift23&3Ift222(JUIftl.95felIft
MS: nVe436(MH),4(W(M-32)
Ai^CzftHftJ/afcO Q57.08(57.15^H431(5.0^N,3.0p.Q2>
Exampfe38:
Can^xxiri(10)(lg323mmcftm(ty
presenoeQfNaH(50%,0.77g 16(Hmi^asdescribedmexan^(8)to
Yield:0.49g083%>
1HNMR(CDqJ)8a00(m,2Ift73(m,3Ift668fe lift 6A5& lift 4.4 (rnjlft 4.0 (tvwan^6tft 3.72 (dd,
lHX3.45(d,lHX335(m,l!ft282(m,2FIX248(s;3HX21(m,2H)L
MS:nVe395(Mf)
Bcampfe39
(f)ton^5,7-Bfy CbmpcuTd(44)(03gl27mmctyvvffi1^^
e
Yidd:03g(6t%>
11^:212-215^
IRcm*:342ai6e0.
'HNMR(DMSOcy: 8129fe lift ai (d,2tft7j62(m,3Ift6.95 fe Ilft6.18fellft4.05(m,llft335(m,21ft3.0
(m, 3Ift252(s>3Ift 225 (m, lift 195 (m, lift
MS:me368(MHi363(N«2)
Anal>SB:C2iItiNO^.b2I^O Q 6695 (670);H, 5.81 (5^N,3J67(3.72>
Exanpb4a
(+)4nm^ifydmytt£fo^ (Cbmpouid
Na46)
CbmpcuTd(l(9 (0.95 g 3,07 m^
(225g 14.42 mmd) inlte presence of NaH (0.741g SCP/a, 15.43 mmo0asde3aib^mQamFfe8)tDgpttetite
oompsmd^
46

Tidd O5g(40P/o)
lHNMR(aX33):8758(d1 ttft7.55(d, ltft 7.18ft Uft655fc lfft645 (s, ltft438(m, 1HJ.4J0 (hwsir#^6Hfc
375(dd,ltft3A5(i^2H)^252(m)2Fft258(s,3Ift22(in2H).
MS:mfe402^-U369^-31>
Example41:
(4}*W5J4)ih)diDxy^4T^^ (Compound
Na47)
CbnTpcund(46)(029g0.72nrf
aso£saib0dmQ Ydd:ai49g(55%>
mp:21&-22(Kl
IF. cm4:?^, 1650.
'HNMR^MSOd^S 129(s, lH),&08(d, ltft&0(d, ltft 732ft lH^fe lH),62(s, llft3.95(m, 11^3.58 (m,
2H^252(m,3Ift2j65fe3H))225(m,lIftZ15(m,l^
MS:m>e374(M^342(M31)
AnalysisiCKH^JO^lil^O Q57.11(5d96);H,5.03(5i);H3.44(3.4^
Exampfe42
(+}4w4{& banEOiitrii£(Cbn^)oundNa48)
CampouriK10)(1.0g324nim^
rnrrx^intepresanoeofNaH(50)/^0.776g l&16mmotyasd£saibedmexar^
Ydd:05g(S7%>
lHhJMR(CDq3):87.76(a; 1^765(^2^648(5, lHfc635(s, lfft42(m, lH^4.0(tswsir^e(s,^3.74 (d, lift
3.4(d, lfft335(m, Uft286(d, lJft275(m, Itft25(1\wsin^aft208(m,2^.
MS:nVe435flVfrl),403(M-32>
Bampfe43:
bera3nitril£((jcn^Miiid>Ia49)
Cbmpouod (48) (06 &138 mmoO vvas 0£me^^
eaTTpte9tootoahlhstiliecan^^
YdcL035g((S%>
mp:145-147C
IRan'4:340a225Q)1670.
'HNMRpvlSO c$51252(s, lH)J55(n%3Hk625(ftwsin^2H^
(m,2H)AG5(m,lH)a65(s,3H),255(nUH^
MS:roH07(Mfip75(M32)
Analyas:C2H2NA-2^0 C,6235(6243);H,5.06(5J0);N,&1 (663)
Exampte44:
(^-)to^2^3tamo-5*TKlho^^ one(CampaiidNa 50)
47

CcmpoundC7)(15g4&mm^
1269 nrnoDhtepraenoe compound(50)
Yri±L8g(ZiflB/o)
lHNMR pXljE 5 755 (d, lift 7.12 (d, lift 69 (dU, lift 6.4 (fcw ar^2Fft 4.15 (m,ltft 4.0 (two st^eFft
355 (s,3Ift3.65(dd, lHfc3.4ft ltft3.15(m, Hft275(d, llft25(m, Uft234(s,3Ift2G5(m,2Ift
MS:nVe5(>1flVlt))472^31X3^(M-lll>
Exampfe45:
(4/-}*«^2^4i(xi]D-5tt^^
one.(CbmpoundNa51)
and
(^-}fo^2^-ftano-54i}d^
one (CorrpaindNo. 52)
Cempcuxl(50)(G97g, 1.92mmo0\^demethyia^i6ing^ 12987 mmcQasdescribed in
exan^9tocteinthetitfeoampcu^
Compouid(51) Yield: 02g(21.8%)
*HNMRPV1S0 Conpound(52):
Yield: 0.14g(15.7%)
mp:2552Src
!HNMR(EMS0(y:8128(s, lift 7.6(d, lift 7.1 (4 lift 6L^(dd, lift 6.4(s, lift 6.15(ssHft35(m,Uft3J65-32
(m,2tft3.0-28(ni,31ft25fe31ft22(m)llftl55(m,llft
MS:nVe463(NH-l)430(M-32>
Exampk46:
(+)£i^2^iomc-5m2lhc^^ -3-yI>- 5J-o5methoxy4-
one(CompciundNd 53)
CampoiM](l(9 (1.9 & 6il2 mm^
1755miiM0inltepresenDeofN^
Ydd2Og(60J/o>
lH^JMR(CDq3):8758(d, lift 733 (d, llft&92(dd, Uft638(s, llftd48(s, lift 4.15 (m, lift 4 3Ift3.85fe3Ift3.62(dd, llft335(bd, llftll (t, llft270(d, llft25(m, Uft228(s,3Ift 1.9(m,2Ift
M&mfeSOKM*)
Exampfe47:
(+)#i^2^Iiorno-5medr^^
one. (CampouridNo.54)
and
(+)fo^2^Btaiio-54T>d[0^^ pync&fin -3->ft5J ane, (CampoundNa 55)
48

Compound (53) (1.7 g 337mmd) was demethylatedi^i^ridte example9toctoahthetitlecaTTpc^^
Gompcwnd(54):
YKkfc0.4g mp:233235(€
1H^MRpfflO(ft(512«(% lHfc78(d, lift 735ft Uft7.1 (m, Uftd4& ttft62& lift 3.8 (s^ 3H), 3 A-32 (m,
3IftZ85(m,3IftZ5(s;3HX22(m,lK>)1^5(m,lHX
MS:me476(MH)
Cbmpoutd(55):
Ydd:023g(15%>
mp: 256258^
!HNMl(DMSOt^512.8(sJ^
2r^3.1(m,2^2^(m,lHX248(s,3HX222(m,lHX19(m,lHX
M&mfe460(M-l)
Example 48:
(^-}*>t^24(3>Bis-trifta
4 Campcurri(7)(126g359mm^
chfcikfe(lg3j62 mmoI)in1tepe9enceofNaH(W^072gl5n^
compcxind(56)i
Yiekfc0.85g
33(m,2H),29-2J6(n%2Fft245(si3Hi21(m,2H> MS:nve532(MH)
Bcample49:
(4/-)to^24(3,5J3is43flia^
4 C&npcuri(5$(071gl34mmo0 mmol) as described in
exan^(^tDob(amtetiflecciripciuncK57)L
Yrid:a4g(59%>
Ran4:340ai650.
'H>Ml(DMSOc&612£(^^
(m,3tft25( MS:nvfe5W(MHi486(\H8)
Affl^CaHrfvNft,G54.1 (54^H,4.13(35);N,282(278>
Exampie50:
(CompomdNa58)
Caqpound(10)(l g32mrrx^mdiyDMFC30mL)\\asi^^
mnr)0in1hepresaiEofNaH(5^
Yieki0.537g(374%)
49

'HNMR(OX^):8758(sJtft74(d,l^
3j65(dd, U%3.4(41^X1801], HftZ75 (4111^2550^ lI^24Qhwsii^Bfc^fflX2jQ60xi>2H)L
MS:nVe444^^f)
ExamjJe51:
(CbmpounlNa59)
Cbmpcurri(58i(048gl.lnm)I)\vasreac^ 433mmDOasaescribedinexampfe
(9)toob(aintetitfeoompou«i(59):
Ydd:031g(68%>
mpc206-20t?C
ltNMR(CDq3)51259& lift 735 (1,21ft 7.18 (d, Uft635(s, lift 62(SslHi4.Q5(d,lHX3.72(m,2HX3.15(m,
2H)>2.9(CllH^26(S)3Hi235fe4H))1.9(m,lH).
Rem4:320CX1735
N&mfe415(MHX384(M31)
E\ampfe52:
(+)£i^2^3taii[>-5ritoiiE^^
(CompoundNa61)
243tano-54iitroben^adti{^
I$riaine(25mLi\\iIhstiningu^
and (he reaction mixture stirred fir 15h at O-S'C ft was tan pcued o^CTcmd^Bdio^trealBd\^sal^IatBdaqu^ou5
Na^OOjsohjtion and exbacted with ditafbm (3x200 mL)Tte
Na^QO and oonoentralBd. Traces of pyridine wae remold uncb-h^i vacuum to obtam(+)*iOT^2-BKniD-5dta>
benaic acid 2^-«jetaxymethvi4-melh\i^^ ester (compound No. 60)
(Iffigo^nirnoOavkxjusolv^foic^
l,4 Yri±ai3g(4%>
1HhMt(aX3£o^(cUIft822^
(d41Ift335((UIft3.15(nUIft272(nUIft25^
MS:mfe519(M'>
Example53:
(+)ta^2^43ftin>5riliDiii2^^ pynokfin -3-}d>57drcDQKlionien4 (CbmpcundNa62)
Cbmpcuri(61)(0.12g0t23mmo9wascb^
eKan^9toob!ahtetideocnipcund(62)
YddG.07g(61%)
IRari1^ 166a
,HNMR0^SOcyr8124(s, lHX&45(d, lift 82 (dd, lift 7.62 (d, ttft&48fe Uft62(s, lHX4.02(m,lHX3.7
(m,2Ift3.429(n%2Ift26(s,3Ift232(m, lift 1.9(m,2Ift
MS:nVe491
Bcampte54:
(+)to^2^ (CompoundNaM)
50

Compound(6)(42g ll^mmoOvvasieadBdwifa^^
ofypyikfcie(^mL)ar]dFOCb(4.4mU^
Q±iDrioofe aad2^-ax(D!^niEd^ ester (63) obtained in
stuwasccnw^tothetilteoampo^^
inBampfe26.
Ydd0.63g(12%)
,HNMR(CDCl3)):8 852(4 lHfc 825(4 lHfc7.42(m,Hftd45fc lPftdl2(s,lHX6.18(s^ lH\4.G5(tvwsingels,
6^3^(41^335(^1^3.18^1^2^25(01,2^23(3,31^2:08(111,^
MS:nVe431 (MH),399(M-32)
Example 55: (4}*t»^2^pyikfc3-}^5,7^
(Compound No. 65)
Compcuid(64)(058g 135rnmc^v^d^^
exan^9,lDctohtetit]eoan^xuid(65)
Yidd:aig(18%>
mp: 125-127^C
IRan4:338(\ 1660
"HNM^OXIj+DMSOa^S^^ (s,lHX4.1 (m,
l!ft37(ni,2HX325(ms3H))265(s>3HX235(n\llft20(m,lH).
MS:nVe403(MH)L
Ar^Czflii^^HO^
Bcample56:
(4/-)#t^2^4 (OnspjcrdNo.66)
(4/-)tfw&-Aoetic acid 3^3^cetyl-24i>dia^£di^^ ester (1.65 g 4.7
mmG9\\asreacted\Mlh2 arriFOCh&lniL, 23.43 rrmic^us^^
acetaymetr^l-me%43yneM^ ester. This was comertad in situ to the tide
oampcurid(66)i£ing>ffl(12^
Yrid:038g(19%)
1HNMR(CDa)>8855(d,lHi822(411^745 (n%ltft&7(s,lH)>6.48 (s>ltft425 (rn,lH),4X)2(tv\osin^e1s,
6Hi3.7(dd, ltft3.4(4 llft324(s, Hft29-26(m,2Fft245(s,3H),215(m,2H>
MS:nVe431 (MH)399(M32)
Example 57:
(^-)*«^2^pyriclin-3-^ pyndkfin -3-yI) -diomen-4 (CtxnpcuidNa 67}
Compound (66) (03 g 0.69 mmoT) was otmeftylatBdusmg pyridine h^^
exan^9tocbamtretilJecornpcuid(67).
rdd:0.O72g(25%).
1HhMipV1SOa^8127(s,lH))a68(41Hil825(n%lH^7.65(i^ (s,lH),355-32 (m,
3Ift3.0-27(m,3Fft25(s,3Hi22(m,lHX1^5(n%lH)i
MS:me4Q3(^ffl)1385(VH8X371 flVt32>
Aralysis:C2oH^aNA.BfeO Q5729(57.17);H,5.1(5.01);N,636(666)5a,8^(8.44>
51

Bample58:
(GmpoundNa 69)
Compound® (5.19 g 14.79 mnlo0^^^^eactd\vilh4-nitloto mmotyialhe presence of diy
pyridine (35 mL)airiKX^ (55 m^ 23.43 nmity
benzoic acid 2^-«riox)md^l4n£^ ester (Compound No. 68)
This vrasconwatedin situ to ihe tMecompoiiiaX69)i^NaH(5()%3.41&71.(W mnioI)hl,4 described inexample 26
Ydd:1.9g(30%>
1HNMR(aX^+DMSOa^883(d,2Fft&18(a\2Fftd7^1Ift6.4(s)ltft432 (m,lH)338 (twoar^ets,6H)
3.68(oUlHfc33(m,2H)285-25 (n%2H)245 (^3^208(1^21^
MS:m/e441(IVH-l),^3^[-1^411(N4-31).
Example 59:
(+)4rw-5743ih}drcKy-^^^ pynolidin 3-yT>- 2^4^iitn>fteiyl)d]ranien^
(CompoundNa70)
Compcund(69)(1.9g432rnino0v^ 1645mmDtyasde3cribedin
exampk9to(]bdni£titleconpciioid(70)
Vdd:12g(75%).
mp:275-277C
lRcm^:350ai66ai54a
'HNMRtDMSOcJP127(s, 1H) 835&4H) 7.1 (s, lH)6.15(s, 1H) 4.15 (m, lH)3.6(m,2Hpj(>5 (m,3H)255
(s,3H)225(m,lH)20(nUH)
MS:nVe413(MH)381(\«l)365l^M$
Ara^C2iiy^07,Q61.48(61.16feH,4^8(4^H6^1 (6.79)
Exampfe60:
(CompouodNot 71)
Ct3tnpcuid(70)(lg243mmoO\\^alssd\edhn^
qK%0jG5$asaca1a^fbr2hR^
was purified uangasflkagdcolumnand 5%methand+l%liqirramn^
ccmpound(71)
Yield:a72g(77%)
mp:\72-m°C
IRan-4:334Q,1660.
'HNMRtDMSOc^mfe^ (twosingets,2H)4.0 (m,lH)3j6-
33 (m,2H)3.1-285 (m,3H)25 (s,3H)22 (m,lH)lS8(m,lH)
MS:n^383(Nfrl)365 Am^C2lH^2^^1/2^^,Q63^(6♦.4XH5^(55^N,7.12(7.15)
Examfte61: 2-Btomc^5ritobenzDicadd(CbniD^^ 72)
24xom3benzDk;ackl(10g49J5mmoI)\^sadklm 25niLarri69%HNOU2nTLn#Ttainingtte
52

fcrlhbekw5^ftwaspoiiedintok£wata^
withwateranddried
Ydd7ig(6^/o>
!HNMR(CDCb):5 a68(d^H),&15(dti,lIft7.85(a;tfft
MS:nVe246(M*).
Example 62
5-Arnmo-24rcm>hen^aridm 73)
Glacial acetic add (75 mL) was added dropwise with stimng,2t4(V50^toamixliieofoompoundC72)(15g57^2 mmol) and iron di£t (15 g, 0267 mol) in water (120 mL) The reaction mixture was stirred vigorously at room temperature for lhftwaspcunri into w with I^Ac(3x 250 mL) The ciganc extract
carrpourxi(73)
Yidd:12g^0%>
NMR(CDq3):5738(d, lift 7.14ft Uft665(m, l!ft339(s,3H)
MS:mfe231^ 199(M-32) 150 Bampfe63:
2-Btomc^5hydraxy4Denzoic 74)
Compound (73) (12 g 521 mmol) was added to 10% aqueous sdto add (110 mL) at 0^ An aqueous sohiiori
(4CtaiI)ofNaNOi(43g6232inri]Dl)w^
iranandthenitwasaddedtoaniceookiaqueo^
g 4755 nTmol) The resuftartrnix^
(3 x 500 mL) The agariic extract was washed v^
gelcohmarii2%EOAchpetrofeumete^
Yidd:65g(53%)
NMR(CDqj)875(d, lift 735(o\ lH)685(m, lift 535 MS:mfe231(M^198(M-32)
Example 64: 2-BronTC^5*iietrrKy4)en™
Compound (74) (65 g 28.1 mmol) wascfissohedin dry l^cfic«arie(50mL)underdry>kata
]W(5(%337g 7020 mmol) was added mpartkiEatiocmtempeiatureTte
at room temperature. Dimethyl sulfite (4 mL, 53 lg 40.48 nirnoO was added and the reactmn^^
50^ & lh It waspcuted into ioe wate^ ackfified usirg
exbactwas washed with wa^ dried (aiihy.Na230^o^
mp£eM60$0^aseliiiitoobtain^
Ydd3.9g(57%>
NMR(CD03):67i5(a; lift 732 (d, lift 69 (mllft335 (s^Hp^tft
MS:mfe2460VB-l),215(M-31>
Example 65:
25-nitiD4HBacadd(CbmD^^ 76)
2-ChJarobenzDic acid (2 g 127 mmol) was added with stining at room temperature to a nitrating mixture (20 mL)
prepared fiom 1:1 HNOj (70%) and 1^^4(98%) ft was stinedfomardpou^
(76) obtained was fiteredanddried
53

Yrid:20g(95%)
NMR(CDqj>886fc lift 82(4 lH)J.6(d, 1H)
MS:mfe200.9(M-l)
Bampte66: 2 25ritrobenzrc
was added slowly and Ihe reaction mixture heated to reflux for 4iTlTemixtLievv^ocn3enlratBdandttEiEadue\\as
allowed to cod to room temperature; ft was poured over crushed ice The 03^ pota was extract
elher (2 x 200 rnL^Tlieagarik; extract wa^
ociicediatedtogettetiileccnipound(77).
Yiektl2g(100%>
NN'tR(CDCb>58.6(s,lT-ft82(d) 1HX7.6 (d, IF!), 3.9 (s, 3H).
MS:mfe214.9^1>
Exampfe67: 5-Aniino-2 CcmixmJ(77)(12g55j6mrra^ (4:1) (50 mL) and subjected to
h>drog|snatbius^Rl£a^^
Yddt 10.1 g(?5%)i
NMR(OX^)[87.1(d,lIft7.05(d,lIft68(dd)l}ft35(sJ3H).
MS:nVel85.03(Mt)i
Example 6&
234huo4)enzDbackln^ 79)
Asolutionc£^^C)2pJ69g534^m^
2 rrixturewasstinedibrfaurimitffi^
cfdaa^iimi fiuciolxiate salt separated whk^
ten carried out at 140C fir 15-20 mia The residue was purified usingasilkagelccJurm and 1(%
ete(6(>«0^asanduerttofum&^
Yidd:28g(30P/o)
NMR(aX^>53^fe3H^7.15(m,lHi74(n%lIft755(dcllH)L
MS:nVel8959(Mfl>
Example 69:
2 Oonipcuri(78)(?g485mrnoI) wassubjectBdtofedizaticni^NaN^ (4ig48^nmxJ)inwsto-(50mL)and
H£Q|(10% 100mL)as described inexanirfe(61)ExcessnitroiEacidwa^
waspouredntoasuspMsburfOS^^
(KlTliereactkiimixliiewassliiredfbrl5nm
G^sanic extract was washed, drid(anhy.N^
petroleum etM60^^ Yiekt4g(44%)
54

NMR(CIX^)835(s>3Ift6^(ddlIft725(a;iHi173(t,lHL M5fcmfel87S3 BampteTft
2£hlo^5flieft]oxy4Den^ac^^ 81)
As described in example 64, oompound(80) (4 g 21.4 mnioty was subjected to meihylata
l,4 E0Achpetiofei]melher(tf>^^ (81>
YiekM.lg^/o) 1Hl%lR(aXl)837(s)3H)(3.9(^3Iftd9(dd,ltft725(d,lIft73(UH).
Bcampte71:
2 Ccmpcurd (7Q (4 g 195 mmoO fiom exampfe 65 v^ metl^atingoonita^
Ydd:4g(95%> 1HNMR(aX^>83.0(^6Tft3.9(^3Ift69(d)l}ft73ftlH)^735(41H)i
M&nVe213(IVf)i
Bample72:
2 24rilrobaia&^ 15nC)accadirigtDtteprooedtfedra
Bcampfe73: 4-Ammo-2taaacaddnie^
Cbnipcuil(83)(50g232mmo5w^
Ydd:40gp3%>
1HNMR(aX33):83.7fe3H^6L5(dd) 1HX6L7(S, Uft78(d, 1H).
M&nVelS&OetM1)
Example 74:
244T)dcK)4)en^ackln^ 85)
Compourri(^(79g425nra0 suspend
mmd in35 mLv^ter) asdesoibedmexan^
G^(55g3&4nimo0inwater(800mQ^
Yield: 25g(31%)
1HNMR(CDq3):839^3Hip6L75(dp Hft695fe tfft7£9(d,1H>
BamfteTS:
2 Toasdutmofconpxixl(^(^15m^
DMS(3.78g, 30 mmoft ft was stined at 6065^ fcr lh ft was poured irto ioe water and extracted with BOAc
55

(100mLx2) .The oniric extract was washed wilh brines dried (anhy. N^SQt) and amcentrated to obtain tie title conpouid(86>
Yield: 25g(83%)
>M^(CIXi):57^5(41Ift6.95felH\6L75(d,lIft35(^3^3^5fe3H);
MS:nVe2Q295(MH)
Example 76:
2 4-AmmcH2 sotutiori was cooled to (fC A solulion of NaNQ2 (11.15 g ld88 mmol) in water (50 mL) was added dropwise
rriaintaininglrE tempera^
as^atcdaqixousNallCDjScJufo^
(13.87gl55mrHi)andKCN(10.07gl55rrm^^
iocmtemperatije.ItwasstW Excess satiiratedFeCb solution was
then added to Ihe reaction rnixrure. It was extracted usir£EtOAc(^niLx 3) Ttecj^^
water; c^ (anhy. Na2S&t),ocsra^
(l:l)asek^toob^dietitieconipound(S7)L
Yield: 12 g(84%>
lH>JMR(CDal):540fe3H^7^(a\ ltft7.75(s, lH),79(d, 1H).
MS:me:19fS88(M+-l)
Exampfe77: 443romo-2 Ccmpound^)(10g54mmol)v^subjec^ HBr(48>A16mL, water 150mL) andNaNQi
(4.1 g 594 mnxi m 20 mL waler) as cfescribd in exa^
80Q solution cfCuBr(425 g 29^ mmc^ hH&(4^
room temperature fir 15 nm It was extracted using didh^ete {3 x 100 n^ processed ar^
exampte74toohahtrEtitleomTpouTd(88).
Yield: aOg(59%>
1HNMR(aX33)5355^3Ift 7.45(0^11^765(5,1^7.75(0; 1H)L
MS:nVe2495(Ml>
Dample78:
4ftonTc^2 Gompound(78X10gMnimoOwasa1a2DtBBd uanglhe procedure arriquantiliescfreag^
76to^tetitfeccmpcuid^9)
Ydd:&0g(59%>
1HNMR(OXiX53S5(s,3Ift735(m, lFft7.7(d, lH)JS5(d, 1H).
MS:itve249.88(Ml)
Bamfte79:
(+/-)#i2ra^-llydo9m^
(CompoundNa90)
Cenirxml(7)(0.7g22rntrri)indryDMF^ 68mmc^hthepesenceGfl^(^
56

Yd40.4g(41%>
'HNMR(CDq3>821 (m,2tft265(s,3Ift285(m,2Ift3.4(m, lift 164(4 lift 367 (djlft 3.95 (two sheets, 9Ift425(m, llft595(s, llft645(s, lift 7.0(4 1HX7.1 ft lift 7.45ft Uft&0(d, lift . MS:nVe42606(MH)
ExampteSO:
(^-)tft^5J-Qh)draxy4^24i)dn^^
(CompoundNa91)
Ccmpcuidro(0.4g05nmxi)v^ (6 g 520 mmol) as described in
ffiampfe9toob^ the tide ocrnpound(91)
Yri±aig(22%)
np:212-213 IRari1:3400,1650.
M£fcmfe:»U5(M-l)
Aml^Q5932(58^H535(5^N,174p^
Example 81:
(+)ta»B^3-Gi]cK>4{^4^ benzmitrile. (CompoundNa 92)
Ccmpound(10)(0.7g22irm)Om^
4imnr)0ra1hepresencecOW(50%G2^
Yidd:031g(31%)
'HNMR(CDa>521 (n%2Ift265(s,3Ift285(m,2tftl4(m, llft364(d lift 367 (4 lift 3.95 (ftwsn^s,
Q§425(mi llft6.45(s, lIft7.Q5(s, llft725(s, Ilft74(dllft83(4 lift
MS:m/e455.12(MH)
Example 82
(+)#iw30ilcio4{57 )flben2cnitrife(CcnTpc«rd>fe
Compound (92) (03g 06 mmol) was cfemelhylated using pyridine hydrochloride (3g 260 mmol) as described in
exampfe9tocfctamthetitle(xnipciu^^
Ydd 0.12g(4^/o>
mp:237-239f€.
lRari1:345a22iai650
1HNMRff)MSOcy:813X)(sJ lift &05(d,Hft725(m,2Ift72(s, lH),62(s lHX4.M(m, lPft2j65(s,3H),Zl (m,
21ft
MS:m/e42686(JVW)
Example 83:
(+)#i^2^44l3fcnx£ (CompoundNa^)
Ginpcu]d(10X07g22nTmc9m^
g 45 mmol) in the presence of NaH (50% 0271 g 113 mmol) as described in example 8, to obtain the tifle
compound^).
Yiekt03g(27%>
57

'HNMR (CDCfe) 8 7.95 (d, lift 7:68 (4 lift 755 (d, lift 655 (s, lift 6.45 (s lift 4.15 (ni^tft 4.05 (1\\o sr#as, ftft3.7(m, llft3.4(t 1HX325 (m, Ilft27(m,2tft24(s,3tft21 (m,2Ift M&mfe 50955 (MH)
Example 84:
(4)^>t^2^4-Blar]Q-2 (CbmpoundNo.95)
Compcimd (94) (03g 059 imid) w^ cfemetf^a^
exampfe9toobtamthetilfecorr]p^
Yrid0.1g mp: 155-156^
Ran1:340ai660.
3^23 (m,2fft25(s,3Ift22(m, lift 15(m, lift
MS:irve4829(MH).
Arc^C2iHi Exampte85:
(V-)#t^2^ Gxiipourri(7)(0£&25^ inmepresenoeof]^H(50PA031&
129mnxiI)asde3aibedfoexample8,tDct^
Yidd:ai50g(12%>
'HNMRfCDCb^SZeSCd, llft675(d, lift 666 (m, llft64(s, ltftdOfe Itft37(m,2tft3.0(s,&ft29(m,2tft
265(s,3Ift22(m,2H)
M3:mH7lj08(Ntl).
Example86:
(^-}tfi^2K2 Compound (96) (025g, 053 mmd) was osmrihylatedu^pyiiiire
exampk9tDcttammetWeocnipciiiTd(97)i Ydd0.O4g(17%)
MP:20821OC
'HNMRpv1SO^)c81275(s, lift 7.4(d, llft&6(d, lift 65 (d, lift 638(s, !Ift62(s,ltft3-8(m,2HX33(m,
2Ift3.0(m,2Ift28(d,3Ift26(s,3Ift235(m, lift 20 (m, lift
MS:me431.42 Ana^CzHaO^^Ift) Q54^3(54.49);H558(602);N,533(5.77).
Example 87:
(^-)#t^2^ Compound (7) (l%32nral)fodryIW(£niL)v^
g 64 mmd) in me presence of NaH (50%, 0388 g 16 mmol) as desaibed in example 8, to chain me tide
oompound(98)
Yiekl028g(19%>
58

'HbJMR(OXl3):87.7(d,lfft702(ssltft69(d, 1HX655 (s, Hftd45(s, lHX42(m, 1^4.Q5(twosff^eb,Sft 3.86(s,3tft3.7(dd, lift 3.45(4 llft32(m, lH>,28(d, llft27(4 Ilft24(s,31ft21 (n%2Ift
MS:mH6023(MH)
Example 88:
coa (CcmpotiidNa 99)
Cbmpoiiri(98)(025g0itai^
eKan^9tDobabtetit]eaiiipciund(99).
Yield 0.1 g(44%)
mp:>300f€
IRcm,:340ai6eO.
'H!^^(DMSOd£S127(:UIft7.4^
3^(^1^,34(111,2^32(1^1^27(3,3^22(1X1,2^
M&mb41622(M-l>
Example 89:
(CompoundNalOO)
Compaaid(7)(l%32mmQ0in^
pESCT£GfN^(50%0^
Yiekia9g(63%>
1HNMR(OX^)87i5(m, lift 7.46(m, lift 7.15 (m, ltft66(s, lift 645 (s lift 425 (nUH), 405 (too si#&
flft37(41Ift3.4(4 llft33(m, llft28(4 llft26(m, Ilft25(s,31ft21 (m,2tft
MS:mfe44821(MH)
Example 89:
(^)isff2^5-flioi>f4^
(QmpourriNalOO)
Campaiid(7)(l.(k32mn^
presenoeotNaH(50%,0388gl6mmDO as desert
Yidd:09g(fi3%>
*HNMR(CDCat6755ta llft7.46(m lift 7.15 (pi, lift 66 fe lift 6.45 (s lift 425 (m, lift 4.05 (two arrets
6Jft3.7(4 Uft34(4 llft33(m, Uft28(d, Ilft26|follft25 IV&rTve44&21(MH)
Example 9ft
(+/-)to^2^fh^^
(CanpourriNalOl)
Compound! 100)(05g, 1.78mmoI)\\ffideme%iatediE^
€xani^9lDciblahte1ideooriqxiund(101)
Yidd:045g(60%)
mp:253-254c<:> IRari*:3450>1665.
'HNMRpMSO^a 12.7& lift 7^m,2tft755(m, lift 655(s, llft615(s, Uft35(m,llft36(m,31ft29(m,
2Eft25&3Eft22ta lift ISfollft
MS:m/e43031(MH)
59

Analysis: CaH^dFNQs Q602(60.08);H,4^3(4i6);H3.86(334);a,8.17(&44>
Exanpfe91:
(4y-)#t^2^ one(CompoundNal02)
Cbmpound(7)(1.0g32nTnioI)in^
afN^(5[%a776g, ldOmrnoOasdesaMmean^S^
Yfckl:0.8g(54%)i
,HNMR(CDqJ>67.4(d, 1H), 7.18^1^655 (m, llft6.46(s, lHfc642(s, lH),42(m, lH),4.Q5(t\wsir$e(sffli
3.85(s,3H),3.6(4 1^3.45(4 1HX32 (m, 1HX3.0& !Hfc28(4 tfft26(m,3Hfc21 (m,2H)i
MS:nVe46036(M+l)
Banffe92:
(^-}^^-2^54Tyd^
cne.(CompoundNa 103)
and
(+/-)#t^2^ oe(GiiipoundNal(M)
CcmpaunoXl(E:)(0L75gl^ e*an^9lDcbfcrinfeilfeoo^^
Cbmpourii(lG3)
Ydd:a05g(7%)
mp 220-221^
IRcm4:345ai6S5.
'HNMR(OXl3):5126(s, lift 7.4(4 lift 7.1 (4 lift 7.0 (m, ltft6.45(s, lHfc63(s, Uft42(m, lift 185 fc3Hfc
3.4(m, lHfc33(m, lHfc32(m, Uft27(s, 31^265 (m, ffl),24(m, 1HX2.1 (m, IHL
M&mfe430.19(]VH>
Ccnipoiiri(lW):
Ydd:03g(44%>
mp:26&267qC
IRan^SOQjeeO.
'HNMRfDMSO (&8127&lHfc 7.47(4 tfft 7.12 feltft 7.0 (m, Uft 6i45(s, 11^625 (s, lift 335 (m,lHfc3.5
(m,3Ift3.0(n%2tft25fe3tft22(^ lift 15(m 1H>
MS:nVe416(lVH)
Exampfe93:
(4/-)*>t^l^41)dK^3^3-n^^ (Compound Na
105)
CcmpciiMi(9(15g53.4mrn^
(37.9g267miTd)arocmtapaal^
sAN^OOjSohimllw^exti^^
Na^O&andconceniiate^
teairiwilh,Be\\^(l(X)mLXac^acy
pB3ductwasocmpteHtralionanaddte
Ydd:9g(545%>
60

1HNMR (CDOj) 8 558 (s, lift 4.45 (m, lift 350 (d, 6fft 325 (dd, lift 3.1(t, lift 295 (d,llft26(s>3tft235(s,
3Ift21(UIft 155(1, lift 158(m,2Ift
MS:me310(MH)
Exampb9fc
(4/-)*>i^2- 106) .
Can^xxixi(lQ5(?g29mn^
presenceofNaH(50%699g, 161.6nm^as(fescribedfoexampte81too^^
Yidd:75g(60P/o)
1H>Mt(CDq!):87£5(d, 1^755-74(^3^64(42^455(111, lIft355(^61ft345ftlIft335-32(m)2H))
295(d, Uft24(i>3Ift 20(m, lift l£(d,2Ift
MS:m/e429.05(N4-l).
Bampfe95:
(4/-)#aw?^-Azidcmelh^
(CompourilNal07)
E^(a7Q5g7mnt)D\*asaddritoaso^
al((>5^ibIkMedbyadropwiseaddta
thenstinedfcr30miamanic^^
asatura^aqiEousNaH(X^sdulicn,daed(arh^
(25 mL) treated \wth NaN* (057 g, &7 mmoO and stined fcr 2i at 6(>70^ The ieadm mixture vas poured orto
aushedk^extradduangCHCk(iro
ocnoenbated to obah tie tide conipoun^
sfcagdandEOAc:petether(l:l)aseluant.
yrid:0.6g IRcm^^ieai^O.
1HhJMR(CDqJ>87^(4 lift 73675 (m,3Ift 6.46 (d,2Ift 4.05 (hum& lift 4.05(ds^ft3.45(twodouHets) lift
33-3.1 lHX2j0(m, lift
MS:nVe455.09(Ntl>
Bcampfe96
(+/-)#ia7#^-Amincme^
(OmpoundNo.108)
CcmpouriJ(ia^^
mL)Theresultantsdita^
ctanatDgraphyijangsfa
Yidd:a45g(81%)
1HNMR(CDQi)§7.6-7.45(m,€ft 645(s, 2tft4j0(d,6H),395(m, Uft3 (m, ltft235(m, lPft225(s^3HX2j0(m,2H)L
MS:me429j03flVH>
Bfflmple97:
(4/-)*rff»^^mitrrneft^
(CompciundNal09)
61

Ccmpcxi]d(108)(045
Qian^9tD(MnttietWe(xii^ound(109).
Vdd:025g(62%)
mp:21&-219fC
^0^:34511660
'H>Ml(DlVro tfft22(s,3Fft205(m, lift 13(m,2H).
MS:nvfe400S5(^l>
Aral^C2i^aClv^Q6252(62^^H528(528iH724(6:9^a8il (854)
Bample98:
(+/■}^fe^3^2 (GnqxxiriNo.110)
EfeN (0352 & 15 mmol) was added to a solution of compound^ (1.0 g 23 mm^
storing at (0-5^ followed by a drop wise addition of melhans suHbr^ dik^
mixtiiewasthenstnidJbr30m^
NaHX)j9oh \\di KCN (0925 g 142 mmdji The rea^ion m^
destroy excess K.CN. It was baafed with aa^eoush^pDiediactdwifoEtOAcO
dnd(ai%.N^SO^andoamentiatBdT^
IktamrrrniamCTCbasandueritoota
Yddt05g(495%)
*HNMR(!CI)CB)87J^
(m,2H)235(s,3Hfc218(m, tfft20(m, lfft 1.8(m, 1H>
MS:mfe4373(\«)
Exampfe99:
(Con?wurrlNalll)
Cbmpc*iid(ll(5(045gl.0mmc0waso£^^
exan^9tocfc^tetit]econpoii]d(l 11)
Yrid:035g(85%)
nplOWWC
lRori,:340ft230aifiSO
"HNMRPMSOO^S 127(s, lH),7.75(d, lHfc7.6-7.4(m,3tft65(s, tfft63(s, lHJ,4.15(d, HftlSSft Uft335ft
ltft28-24(m,4H)^26(s,3H^2j0(m, 1H)
MS:nVe411(Mfl)
Ai^C2ftO^Q6*22^
Example 100: (^-)to^2^pr]i^
(CompouiriNall2)
Canpound(l()6k(a7gl.6im^ wife methane suMbnjicMcride (028 g 24 n^ wiftiimida2de(044 g, 65 mmoI)tDgpttetilfecnmpound(l 12) Yield: 035g(46%)
62

1HNMR(CD03):8754-73(m,5H))6L77fe lift 667 (s, lHX6.4(d,2tft 4.0 two sii#£6H 3.9 (m, lift 3.8 (m,
llftll (m,2Ift24(m> Ilft225(s,31ft21 (m, lift lS(m,2tft
MS:irVe48a(W(Mfl>
Example 101: (V->^wsH2^ (GompouriNain)
AirrixtureafoonTpoundfl^ mmd) was heated as
(fescribdinexampfe9to^1hetifeair5X]iind(ll3)
Yidd:0.15g(53%)
mp:249-25(K:
IRan1:3500,1670
'HNMR (DMS04) 512.7 ($, lift 7.67 (s, lift 7.6-7.4 (m, 4Fft 6.97 (s, lift 6.87 (s, lift 6.4563 (d, 2H), 425 (n%
lIft4.Q5(m, llft3.88(m, llft3,45(m, Hft255(m,2Ift25(s,3Ift228(ms llft20(m, lift
MS:nvb45156
Anafcss: Cattfl^Q63S7(©:^
Example 102
(4/-)#t^2-[2j^^
(CbmpourxlNall4)i
G3mpaixK10$(1.0&23n^
wifti methane suHmyl chloride (031% 28 mmoI)ascfesaitedme wilhthk)uira(07g92nTnxtytogaihette
Ydd:0.6g(5&5%)
'iMV^CDCfa^^to^^ .
(n%3Ift23^3Ift20(mJ2Ift
MS:nVe444flVH>
Example 103:
(^y-)^!^w^2^ (OxnpcundNallS).
Ccmpcmj(114)(0.^13mm^ (60 g 520 nmxfl as described in
exar^9tDobtamtiietitfeoompound(115).
Yield: 0.15g 115x205-206^0
IRari^: 340(^1650
lHNMR(OXfe):5127(s) lift 7j6(m, lift 75(m,2tft735(m, Uft66fe Itft6i5(s, Uft42(m,2Ift3.7(1, lift
16ft llft3.4(d, llft33 (m, llft3.1 (m, Hft29(m, Hft25 (s,31ft23 (m,2Ift
MS;mfe41&Q5(MH)
BamptelOfc
l-Ben^l4iieftyMfsperidinta 116)
Toasohitionof l^Tied^4fipetidinoDe(15 g) in dry acetone (100mL)wasaddad l-bramomefl^benzene(249g)
dropwise. lwasstinediicr3hTlietidecanpcu]d(l 16) sejmitedwhidiwas filtered, wasbedwithdryaaelciieanddried
Yrid:35g3%)
63

Example 105:
1^4-Methaxyiiis^}^^ 117)
Ai%. K^CXDj v^adddto asohiticn additioncfasolLitkii^^^
firlhftvvasaIlo\\edtocodtoiQcmte^^
3)The«|^extiact\^\*ashedwil^
VidktU8g(79%)
■HNMR(a)C^56&(d,^
MS:mfe205(\l^
Exampte 106:
l^^ (CompoundNa 118)
Ccmpourri(117)(19flg92mn^
acetic acid (50 mL) at rocm temperature. HQ gas was bubbled throu^ the reactm
tempaatineip to 90^ Acetic arid \\asi^^
cariidkE(3Wg)illie resulting sc^^
\\asil£n^\\ashed\s^\\ateraiTdcbJ^
tfe^toiernowtracesctftrim^^
Yfckt30g 2H). M3:nVe355(]V«)
Example 107:
H4Melhc^henyi>4^
(CcrapoiniNall9)
Compound(118)(15 g42mnri)\\assutjectedtotyd^^
8itfnmr^mTlff (50 rnL) Excess diba^
adddarriiheiea^ mixture was stM
made bask (rtt 12-14) usir^ an aqjmB 50%^^
was stirred at 50-55X! for lKThe reaction mixture was processed as desaibed in example 2 to obtain the title
compound(119).
Ydd:95g(602%)
27(m, lH),26(m2H) \JSfa2H).
MS:me374(MH)
BcamptelOS:
(^-)£rm-Acetic acid 4-(3-ace(5424i)dttKy4^ ester
(QinpoundNcxl20)
Ccmpajr*l(119H03&13n^
arih)dikfe(0.68g67rnmotyacaH^
Yidd:ai5g(25%>
1H^Mt(a)a)57.1(c^2H)69(^
27(s,3H), 1.75 (m,2H), 13(s,3H)
MS:mfe443^1>
64

Example 109:
(QmpourelNal21)
CenTpound(120X025&05nm)0w^
g|\cnheKamFfe7,toob^thetitfeoariipcuiid(121)
Yidd:02g(88%>
*H>Ml(CDCb)86&(42Hi68ft
(4 llft32(m, Uft27(m, lift 265 (s,3H),255(m, lift 1.7(m,2Ift
MS:mfe401(Ml)
BamplellO: (4/-)#r^2^ aie(CanpGnndNo. 122)
Campound(121)(20g5X)mm^
1hepresenceQfNaH(W{*n9g£
YiekH.8g(69%)
1HNMR(OXl}>87^(m,^ft76(d, ltft745(n% llft69(m, lift 68(4 lift 646(s lift 64(s, llft4.6(m, lift
4.0(s,&ft3.85(m, lift 3.75 (s,3Ift 355 (m, Uft3.4(m, Uft275(m, llft255(m, ltft 1.75(m,2Ift
MS:mfe5210VH>
Exarffelll:
(-+/-)taw*-Acelic acid ${!Qdtiaoikenfy5y- pynolidin-2-)%neth)ie3&^ 123)
Compciund(122) (1.7 g 32 mmcJ) was afojected to ring ccn&adian as described mexan^
di]onfe(0.448g03mU39mmol)1^
fiimishlhetiflecaT]pouTd(123)L
Yield: 12g(60>/o)
'HNMR((X)q3):.575(cl lift 7.4(4 lift 73ft lift 7.1 ft lH),d8(d,2HX 665 (42tft655(s> llft635(s, Uft435
(m, llft428(m, llft42(m, Ilft4.12(s,31ft3.95(m, Ilft3.78(s,31ft3.7(s,31ft35(m, llft335(m, llft225(m,
2HU75(s,3fft
Example 112
(^-)*>r^2^ Compamd(123)(l.lgl.94nim^
ccnpcuid(124> Ttewxkipproc^
Yield: 0.7g (69%)
,HNMR(CDCfe):87J6(m, lift 7.4(4 llft73(m, Uft7.Q5(m, 1^68(42^665(^2^66(^64(5,1^
44(m, Uft4.0(s,&ft4.15(m, llft355(m, lift 3.75 (s,3Ift 365 (m, llft35(m, llft3.4ft llft24-21 (m,2Ift
MS:mfe52Z53(MH).
Example 113:
one (CompoundNa 125)
65

(imix3Uiid(124)(ft7g,13mri^ mmd) as described in
exan^9tocdamflTetife(xii^X]und(125).
Yidd:0.03g(5%)
mp:212-213X:
*H>JMR(CDq3)57.6(m, lIft7.45-7^5(m,3Bft6i77(42Fft6;7(d,2^6.42(^ lHfc635(s,lHfc46(m, 1HX3^5
ft lH^3.45(d) ltft32(m, 1H), 26-23 (m,2H), L65ft lH^(m, 1H).
MS:nVe480.17(MH)
Example 114:
(+/-ytmrB-Aotic arid 4^^fiienyI}5,7 (CompoundNo.126)
Toasditactfcanpounc^^
mmo!) at nxm tenp^rntiin? u#» stirring, followed by the addition ofdimdhjtairK? j^Tidire (0.033 g 1% \\Av). The
mbdurewasstiiiedfbrOSiftwaspxie^
extractedi^CHI^(100iTiLx3)TlBOig^ extras
Tlie oil obtained waspurifiedisngasilka^
oampound(126)i
Yiekfc333g(89.7%)
■HNMR(CDCb)c87^8(dd, lfft7£(dd, lH^7.42(t,2Eft6^(^Uft638(s,Uft5i(n%lH))4.0(s,Sft3^(m,ltft
322ft lH),295(m, lIftZ55(m, lFftZ4(s,3H)^208(ms2Fft 1.7(s,3H)
MS:nVe472(M^412(M60)
Exanpfell5:
(4/-}to*-Acetk; acid 4^^ (CompoundNal27)
To oompound(126) (29 g, 0615 mrnol) in diy CHCb (40 mL) at 0^^^asaiMc>anc^nhtaTlide (2.1 & 1.979
nnmo^TheieactmnTixturewass^
QlCb (100 mL x 3) llie ctganic exbact \\as \\ashed \^
iesidiieobtairiedwaspurifiediHngaalka
tidecompound(127).
Viekt2218gC73%)
^0^:3400,2220; 1740,1640
1HNMR(CEXi>57^(m,^645(t\MDdciuble^2fft
Z5S(n\lHX1.7(s)3H>.
MS:nVe4833^H-U423(M60>
Example 116.
(4/-)*iw^2^ Ocmpoittl(12^(&0414mmoOv^
room temperature and pouted onto ice (-100 g). ft was made basic using a safumftrl aqueous Na^OOj solution and
extracted withBOAc(3x 150mL)Tteo^nicextia^vvaswa5hdwiftiwatei; dried (anhy.Na^O^atdccixenlrated.
The enriectoined was purified using a sto
flmai the tide oompound(128>
Yield: 0£7g(50.5%)
'HNMR(CDa+DM^^
32(nUHfc23(nUH^235(m,2H)aG5(iiUH* MS:me416^ip97^vH8X380^36)i
66

Example 117:
ty-}frcm2Q 129X
Amixtiire of compare^) (0.^
(1.15 g 0833 mmd) indiy DMF(20mL) wasstinedaioomteniperaturefer2h.There^^
water and extracted withBOAc (2 x 100 mL) The organic extract ^^^\^ad^edwim.v^ dried (anhy.Na2SO^) and
concentrated The cnjdecteinedw^
ffl(laseluarttogettetifeconTpoiiKi(129>
Ydd:0i3g(57.4%)
'HNMUOX^STffi&l^
2ft3j05(%lIft25&3Fa21to3[ftljffi(42fftQ92ft3H)i
MS:m/e458.4(M+1),440(N'f-1g))428(M-29).
Bamp!ell8:
ty-yfrans-Axtic add 3^2 ester(Canpound>kxl31)
Methane suffixed chloride (0.178 g) was added to amixtureGfccnTpciuncKl^
CHQ(10mL),\\Tlhstimrio^
aqueous sohiimofN^OOi The aganfcl^
mL) The combined agric extracts woe washed with water, dried (anhy. N^SOt) and concentrated to obtain
compound (^-y^nm^/i^axsMxk sod 442^ P5x^3-)4esler030)It^
25h at 80-90*0 The mixture was aflowedto attainicomtemperatireandpoured into ire
i^asataqNa£Q solution It was extract
dried (anhy. Na^SGi) and concentrated The ofty residue was purified using a silica gel column and 1%IPA +1%
aninxniamCHChaseh^toobtainfe
Ydd:02g{335%)
MS:nVe5(M(MH)440.0 Exampbll9:
(C6mpoundNal32)
Can^x)und(131)(02&Oj04mmoO was subjected to tyMyas using a 1% methanofc NaOH solution (10 mL)
accorolngtotheprccedLiremexani^
Yidd:0.17g(918%)
'HNMR(aXJ,):S7.7(dd, lift 7.48 (m,3Iftd48 (two sir#*i,2H),42(ra lHfc4.0(twosin^&ft3.66(dd, lift
3.4(m,2H),3.1 (bs, Hft28(m, Uft2£2(m, Uft215fa3fft 1.6(m,2Jft0S>&3H).
MS:mfe45&4(Mfl)4&4(M-32)
Example 120:
(CbmpouriNal33)
Following me procedure in example 9, compound(132) (0.155g 0.033 mmd) was demethylated using pyixfine fydrcdikridet^toctothetitfecom^^
67

YKtt IRari1:3000,1650
tHNMR(CDCIi):97j61 (del l!ft7.45(m)3tftd45fe3H))6L3(^lIft4.15(m, \H)>ffifa2ify3AfaZ§29fa
3H^245(n% llft208(m, lift l:68(m,2Ift095(t,3H)i
Nficmfe4305(MflX4124ff4-l^
B (+)^taw^2^^^
(CbmpoutdNal34)
Compound^ (09 g 29 imi^m 23-fluaDbaizDate(0£56g
3.48 mmol) in the presaioe of 50% NaH (0j696g, 14.5 mmol) as delated in eampb 8> to obtain Ihe title
compound(134).
Yidd:29%
lH>JMR(CDaj)r87^8(d) lift 735 (m,2Ift 655 (s, llft645(s, 115,42(111,1^4.08(^3^358(5,3^3.68(04
lHX34(m,lI^32(b,lH^275(^lHX26(m,lIft235(Ss3^2Q5(iTi,2^
MS:nVe448{M*-l),416(M-32)
Example 122:
(+)to^2^fta)^
(CompoutdNal35)
CanjMii]d(134)(031g0.74mnxiD\^
de3cribedhexampfe9,toobtam^
Yrici:41.8%
mp:221-223cC
Ran-1:340^165^1200
'HNMR(DMSOa$8123(MHe^^
(m,2Ift275(m, Ilft242(s,3tft21 (m, lift 1.7(m, lift
]VB:nVe420(MHi387(M32)
Anatyas C2,HriCIFNOfeQ5a77(58^7)5H4j61 (4£7);H327 B (CompoiniNal36)
Compound®(l.l&3j6nmiQDmdiyDN^ 24iomo-3-fluorobaEDate (&858
mmoOintiieptesareof50%NaH(0^54g, 17.79nTn^aso&Mhexan^8,toobla^^
Yrid:285)/a
lHNMR(OX^)5775(m, lift 7.4 (m,2Eft&46(s, ltft642(s, llft4.15(m, Uft4j02(s^3HX358(^3HX3^5(m,
llft335(m, llftll (m, llft27(m, lHX245(m, lift 228 (s,3Ift 202 (m,2H>
MS:nVe4915^1X462(M-32)i
Exampfel24:
(+}ta«^2^43nm>3-fluc^^
(GmpoundNo.137)
Comixjurri(13$(a45g 0914m asdesaibedinecarT^9,toob(ainteti^oQmpcuxl(137)L
68

Yidd:49i%
mp:237-239*C
Ron1:3400,1650
'HNMRCCDqrflFA^S 125fe XHedan&ak*h76fa lift 7.4 (m,2tft&85(s, lift 6.65fe lHX4.06(m,5HX
35(m, 1HX3.1 fe3Ift25(m, lH),Z4(m, lift
MS:mk465(MH>433(M31)
Araljss CaH1^fNOfeQ53.47(5329);H,3-53 (42);N,251 (295),Br, 1645(1&88)
Example 125:
(Gn?x)U«iNal3g)
Ccn^ound(6)(% 19.42 mmc^mdiyDMF(60mL)\vasiea^\^n^^ 24acm&5-flLaoben2Date (6Jg2875
mrml) hfepnserceof50%NaH(3.88g, 80.8 mrr^
Ydd-471%
'HNMRCCDCfe) 67mm, llft7.45(m, lift 7.1 (m,Uft6.48k llft64(s, llft4.15(m, lift 4.02 fe 31ft 3.92 (s,
3HX3j64(m,lIft335(d,lHX3.1(r^lPft2^(in,lFft245(m,lIft23(^3HX20(^
MS:mfe493(Mfli461(M-32)
Exampte 126:
(+)4r^25-fluoK>^^
(Cat5XjurdNal39)
CbmpcuTd(138)P%
desaWine Yidd:48S%
mp: 145-147^
Rem-4:345{\ 174QGW
lHNMR(CDC^-TFA):8124(s^ lH,eflto^bfei7i5(m, llft728(m, Ilft7j0(m, 1HX631 (s, Uft628(s, lift
358(m, 1^3^(111,2^35(111,2^3.15(111,111X25(^3^23(111, lHX208(m, lHt
MS:m/e465(MH)
An^Metasifcr^
459(554).
Exanptel27:
(4^yj^2^5ixbfiTQi^
(CompoudN3Ll40)
Ocmpound(6)(aeg l^rmi^mdiyI^F(10mL)\^iEaadvsiflimed^4 2-000-5-iodobenzcate (126&424
mm)0mtepresmceofmNaH(a46^
Yidd:27^/a
'HNMR (OX3J) 8 8.08(d, lift 7.75 (m, 21ft 658 (s, lift 6.42 (s, lift 42 (m, lift 4.02 (s^3Ift 358 fe3Ift 3.7 (m,
llft338(ro, Uft32(m, llft27(m, llft255(m, lift 232 &3Ift2Q5(m, lift
MS: mfe556^H-l), 524(M32)
Exampbl28:
(+>t^2jiie^
(Ccn?wurdNal41)
Cbmpcuid(140)(0.1g0.18nm^ desaibedhe 69

Yidd:52^/o
IRan1:3450,172a6W
lHNMR(OXlj):8 UA(% lHexdw^2fcte),7.9(s, lHfc7.8(d, 1HX7.1 (d, llft62(s, ltftdl (s, 1HX 3.98 (m, 1H),
3.8(m,2H),3.1 (m,2tft27(m, l!ft25(s;3HX22(m, 1H), 13(m, IHL
MS:me528(MH)
Bcamplel29:
(Con^oundNal42)
Oxnpcuxi®(lg323mm$h^ 2-aar»-5-dte)benzDate (1.5% 625
mniDOintfiepresenoeof50%NaH(0.76^ tfrntnoIJasde&iklmexampbS^ctah
Yiekt8%
lPINMR(CDQi): 5 7.7(m, 1H),7.4 (m, lift 6.96 (d, lift 6.48 (s, 21ft 42 (m, lift 3.98 (s, 3T-ft 3.95 fe3Tft 3.7 (m,
llft3.4(m, lHX32(m, l!ft275(m,2Hfc235(s,3Ift2G2(m,2H).
MS:mfe510?VH-U478(M-32>
Exampfel30:
(+)#i^2^I£aiic-5 (Qir9wurdNal43)
Gxnpound(14:9(0.11g0216m^
describedm©tanT{&9,tQobta^^
Yidd:48%
mp:233-235(C
Ran4:3400,1640
'lM^R(CDq3]^lSO):5 124felHexda^able),7.48(d, 1HX73(s, 1^7.12(d,ltft &12fellft 5.98(s,
lift 3.85 (m, lift 35(m,7H),29^(m>\H),275(mi\H),145(si3U)>23\ (m, lHXZ15(m, 1HX l-7(m, ll^i
MS:nVe481 (MHi449(M31)
Analysis: C2iH19aa>q5)Q5127(5153^H426(4.1^H3.07(2^6)i
Example 131:
(4/-}ta^3^2ChhDfh^
(CorapaundNal44)
Dimethyl sulfoxide (15 ml, 253 mmd) in methylene chloride (20 mtyu^a^
(840 uJ, 9.84 inmotyindiymefylenech]^^
hour. Compound (20&4^ra
resulting mediae was finther stined for cneaixIhatfhaixTrie^amire
mixtue was ten vanned to room temperature and baafiedvvith>MKX^9Qlutm
eta
thetifbccrnpound(144)
Yidd:0950g(47.7%)
'HNMR (CDCIJ) 8 7.4-7J6 (m, #ft 65 (s, lift 6.4 (s. lift 42 (m, lift 3S5& 31ft 3-85(5, 31ft 3.18(m,llft
3.1(m,lH>,245(ni,lHX23fe3HX2X)5(m,2H)
MS:mfe(M+l)42&,^30)39a
Example 132
(^ft^3^^fiien}^^^
ackl(CompoundNoLl45)
70

55% nxhkxo patent arid (2193g0.^^
soktactfccmpour^^
lxusandcaicertiatedtoGblamasc^
\\ashd\*#i\\toarridriedin\3aiLin^
Yidd:07g(653%)
lH^M^aXV^DMSO)5732(d^^
(5,3^3^31^33(111,2^3.05^3^22(111,2^
Examptel33:
(4/-)*rwv3^^4Ihkxc>i*a^ acid
(Can^oundNal46)
10%Pd€(3(h^\\^addedlDa9Dta
mixiiie\\ash)drogpia^atl^
waterand methandinttE ratio 7525 ^anduarltoofcdnltetilteocrripound(146)
Yidd:02J0g(59^/o)
'HNMR(pyq):87.75(dd, lHX7.4-7j6(m,3HX625(s, lift 65(s, lift 4.12(m, l*fta82fc3HpSfe3Hfc352 2Jft3.15(m, lHX278(s,3HX21 (m, 1H)
MS:nVe444(M+l),410(M35)
ExamftelM:
(4/-}to^3-P^3ikxDji]^ acid
(CorapoundNal47)
Campcuid(146)(025g05ffi^
Mierheatedat 180flCfor2h. Mwatff\\asacUdaflerocniple^
HP-20cotarinu^asdiel^^ v^^htetal»7030tocfctaintetidecampound(147)
Yidd:0.1Q%(43jff/o)
mpc29S-297C
'HNMR(OX33+D(vBO+TTA):8752(dd, lift 7.0-7.4(m,3Ift6jQ5(sJ lift 6.1(s, lift 4.1(m, llft33(m, lift
3.46fa llft3.1(m, Uft265&3Ift2G5(m,2H)
MS:mH16(M+l),382(M35)
Arc^CaHifP^l/^ (834)
Example 135:
(GxnpaundNal48)
Campcuid(147)(aigl0249m^
N^Bnd(3C^wasaddedtodssc^teieacticnm^^
solkl mixtu^ basifid withsatua^
wilhvvatffanddiidmvacuintoob^thette
Yidi:0.a35g(33.4%)
1H>]MR(axa3+TFA+DMSO)87.4-755(m)^ft6.4fe lift 6.47 (s, lIft42(m,2tft3.96(m,2H, Hft3^5fe
3Ift358(m, llft221 (m, lHX252(m,lI^
MS:mfe(M+l)416
71

Example 136: 2-Bra«>4ritorfiie(0cn^^ 149)
>^Efcmosuccinin^
diyDMFmpcitraBiiita stirring^
au^icesfoufyunda-vTg^^
Ydd:30gm(95%)
'HNMR(OX33):58.4(^ lHfc&l (d, lfft&75(d, lH),4,85(bs2H).
MS:nVe218(MH)
Bamplel37:
2£taio4ritobenzDni^ 150)
Cariipound(149(^g
AsdutmGfNaNQ2(7j64gll^
5^ Tternixtiie\\as stirred fbrlOniin^ex^
Thereaiting mixture wasthen added to a preoodd((>-5X!)susperHciicfCuCN (9.46 g 105 mmd) and NaCN
(520£l06nimo0h\vater(^mL).lt\*ass^
05h and iinaDy heated cri a sEari bath for Oih. ExoesssaturatedFeC^solita\\asthenadc^^
VMS extracted using BOAc (200 mL x 3) The organic extract was washed with water, dried (anhy. NajSO^
concerfliaedarripurifidu^aali^
compound(150>
Ydd:3j^n(17%)
'HNMR(CDqj):8 858(s, lH),83(d, lfft7Sft IHL
MS:nVe228(Mi-l)
IRcm^l0Q,2233,160ai35O.
Example 138:
2Ttaro4dtro4xnzc^ 151)
2-Brcm>4^iitK>tena3rritrife (05 gn^
lis After oonii&imcfreacticn
ethyl acetate. Aqueous laja: was separated, acidified wife 1:1 HQ and extract \^efl^aceae.Ccn±n^(i^nic
lajavvasliienccnjentiatedtoob^^
Ydd:300mg(55.0P/o)
mpc 164-160*0
'HhMl(aS4SO):8&4(s»lH^ai(41Ift7^5(o;itft555(s,l^
MS:me248(MH)
Ran-' :31(XU70Q 1534,135a
Example 139
(+)frans- 2^J&cni>4flitiCii«nyi}^
(QmpoundNal53)
2Brcmo-4-nilrd3enzok;addp^^
mL)using POQ3(7gP%45£mmc^asdtscriD^
aoelcKjnKtfyW^relhji^^ 152)(34gm,5.9mmd)a
viscous o3,whkh\^cai\ertedtolhetitiec^^
(lOOmL) asdesadbed inB 72

Yddll%
Ran4:3400,166a 1525,1350
'HNMR(OX3,)88.6& lift 832(4 lift 755(4lift d6(s, Uft644(s, lift 42 (^1^4.02(5,311), 3.98 (s,3Ift
3.65(d4 llft32(m, 1*^275(4 llft26(4 Ilft245(s,31ft21 (m,2Ift
JVS:mfe521 ^W),489^t-32>
Examftel40:
(C0mpoundNal54)
CaiTpouriJ(153) (03g, 0.6 mmol) \vas cfcmed^ g, 26 mmd) as described in
exam^9tD(i^tetMecxxnpound(154)i
Yri±54%
mp: 186^C
IRon1:340(U65G,1525,.1350
1HNMR(CDCM^1SOd6):5122(s> lH®dH^abfe>8i(s,lH&25(41Ift7.75(41Ift635(s)lIft6Ll5fe
Hft355(m,ltft3.65(m, Ilft325(m,21ft3.1 (m,2Ift26(s,3Ift 225 (m, lift 2Q2(m,lIft
MS:nYe493 (CcmpoutidNal55)
Cbnnpoimd(153)(30(^0j6intno9\*Kti^^
(12mL)asdesaibdmExanipfe62toofc Yidd:88%
'HNMRtOXy^ 7.45(4 lift 695 (s, lift 67 (4 llft648(s, llft624(s, lift 4.15 (m, lift 4.05 (s,3Ift 355 (s,
3Ift3^(d4 llft35(m, llft3.15(m, lift 2^(m, lift 258(m, lift 235(s,3tft201(m,2tft
MS:nVe491 (Mf l),459{M-32>
Examptel42:
(4)tft^2{4-Arnino-2-taa^^
(CompoundNal56)
Oanpouid(155)(150ing03mn^\\^
eatTpfe9tDob(am the title orr5xxixl(156>
Ydd70mg(50%)
np:208qC
IRcmt:34(XU65Q,1575,.1380
•HNMR (OXMJMSO 4J: 51228 (s, 1H e?dH^atte),6L85(41Ift6L5(silIft62(41Ift5^(^lIft5j65(s,
lift 3.54(m, Hft32(42tft264(m,3Ift215fe3Ift lJ8(m, lift L4(m, lift
M3:mfe462(MH),
Example 143:
2-Sanc>4medxr^tenzi^add (CbmpoundNa 157)
243ftm>4rilroben2DicackI Q
(250 ml) at 80C Afoainpleikmfieactara
w^dhjiaoe^GganKlajo-viasta
Yiekt81%
73

MS:nve232(MH)
Example 144:
one(ConTpourdNal59)
GDrnpaund(157){2i^l21m^^
FOGj (7gm, 455 mmd) as described in Exampfe 52 to obtain (4)#i^243iDmo-44nethoxy benzoic acid 2- acetoxymethyMHTiethylfy^^
viscous c4 vdiich was converted to the tide ocmpoundflSS^msituusn^
dioxare(1 OOmL) as described in Example 26. Ydd 19%
'H>JMR(CDq3):8 7j6(d, Uft72(s, Uft7.02(d, ltft6£(s, llft645(s, llft42(m, lift 4.08 (s>3Ift 4.01 (s,3Ift 3.8fe3Ift3j65(m, llft3.4(m, lift 3.5 (m, lift 2.8(m, Ilft2j6(m, Uft245(s,3tft212(m,2H) MSfcmfe5D4(MHX4Z3 (M-32)
Example 145:
(+)to^2^-Bramc>4fl]elhaxy^^
aE(Conp)iidNal60)
Cbmpound(159)(155mg!03nTn^
exarnpfe9toobtahthatilfeoonpound(160).
Yrid:70mg(49%)
■HNMR (OXJJ+OMSO) : 8 12J6(S, 1H excte^s), 7.4(d,lH^7.1felJftd8(d,lfft625(SslH^615(Ss lift 4.01
(m, 1^3.75(3,3^25(^2^05 (m,3tft 265(s,3Ift 22(m, lift 138(m, lift
Example 146:
(+)to^2^ftonic*44T)dn2 (C6mpcuriNc,161)
CtonTpcud(160)(150n^025mirBO*^
mexampte9tochahtetitteconTpJund(161)
YKU42%
(n% Uft3^2(m, Hft3.45(m,2Fft3.15(m, lift 295 (m, lift 27(s,3Ift245(m, lH)22(m, lift MS:mfe462(MH>
Exampbl47:
tfyrans -Acetic acid 8^■a^etoxyme^hyH^ne%^Jy^DM
7-^eslenPiiipcundNa 162)
To a sdutmof c 03mmol)and dimethylaminopyttline (3 n^
mixture vvas ten adsabed on 05 gm abca, concentrated and vvaspuifedus^ silica gel chon^oga^
MeQHinchlcidbnn+l%liq^
74

Yrid:20ng ]H>Mt(aX^)S125felHexd^
34(m,2^25(m,lHX27fe3Ift
245(ni,2Hi215(s,3Ift2G5(s,3Ift
Kfimfe494# Example 148:
(+)to^2^4Dfciik)H>5-fli^^ n**hy4)yncMi>3-)ft5,7^^
cne(CcmpciundNa 163)
Oampouii®(0£g2i8mn^ was thai reac^\\^2,4I)id]ioro^^ tifecccnpcurri(163)
Ydd:0i4gn(40%)
lHNMR(OXi)67.75(d) Uft7j6(d,lHi66fc ltft645(s, lHfc42(n%lHi4jO(d,6Tft37(m, lift 335 (d, lift
32(m, lift 265(^2^235(^3^21(111,2^
MS:irve481Sl(MH)
Bcampiel49:
(+)*iOT^2^44Dkiik»>54riofh^
(CbmpaniNalGt)
Ctompoiiid(163)(053gJ.lni^ cksciibedinexarnri29,toctoah1hetife
Ydd029(55%)
,HNMR(OXlrtaV1SO):574(m)2Ift63(^ lift 605 fe Hft35(d,lIft3^(m,2Ift3.0(m,2Ift28(qlH),25
(s,3tft245(s,lIft225(m,lJft
M&mfe454(MH)
TIE efficacy of Ihepre3er4ccmpc*i]&
nuTiteofptomiaa)fogj^
aLBkxtemBiqi^IteCcfm]^
can be proteins isolated from mammalian cells, or altemativdy, they can be prolans produced raxrnbinartly. The
ewmpfifiedphammitogjcdassajs^
irw^nlm and their salts.
CDK4CjdinDl Kinase AssayandCDK2A^dmEKina9e Assay
Theassajsnxasurephcejiuylatmc^^ 9dm£iespecti\dy,lhiQugfa^
Materials:
CIK4crCDK2\^cx»q3res9ed\Mfa
cefls. Fcrthis,lxl07Sf9cdls\\recoinfected
graandafo72houlscdls^^rel>^m5(X)Dlofa
OTT,5 Dgml ofaprotinin,5 pgfaloflei2eptin,ai rnM^^mMphenyirretf^ls^^
socfiumcdiovanadate) C&ilriL^b^^^PU1^^3*^-36^^ PurityofteptJteinsvvaschecked
75

G^-*etincblastama(Rb) (aa 776528) fuskriprotanisexriesdmthete affinity chrcrnatDgaji^
Readout
Quantitation was by sdntiDatkridetectiori of ^> counta(Rria4USA)
Rooedure
The C[K4crCDK 2 enzyme assay was iunm 96^ Allassay
stepstockpbxmasmgfefiter^ Thefitoatkii\\dk\\aepe-\\etv^
(l(X)QlfadI)andtescttn\^ta
arrifevaaiurnon 5001ofGCT4tobourdtoGSHSefh^
added to each v\efl and vacuum was applied to removed the buffer. A further 25 D! of a reaction mix containing ATP
(odd+hot) arrijAosphalase inhibte (fluted mkiraseb^
ccmpaiirri(4XiMoonce^^ Dlwlume. Finally 50 Ql
(100n$ofhiiianCDK4DlCTCDK-^
reacticiiwasirxirjatedfir30mmatW
washed\\ilh1hewashbuflia-(I>W
]iafeToeachwdl,30DlRackariMkjc^
The plate v^ccuntEdh a M^Tcp Court
Mita-rnaQthee^erirrEnK
Tteccncentiaticnofoanii^^ arriG)K2-c)dinEwas
inhibited (IQo) was cahte
1.
Tabtel:

NO COMPOUND NO KfiM RaiocflGo

aX4€YOJNDl CDK2 1 31 028 &75 312
2 % 008 6C0 750
3 Ftocpodol 004 018 45
Tte results irrficate that thscon^
Dl a^(MC2/c>dmE\vifc@eatersefect^
^v^cdprotiferatknardc>lDtoxk%
BqxiErtially growing culti^cffto
460 Lung MDA-MB-231 Breast, MCK7 Breast, MaGavix, Cc4o-205Ccto\I©LyiT?ram(rCdlsil^^
HistiocytcLyraiiiMXiB^^
riDfeJkii(NCI,USAFrctocd)ar^
i^teandMISassay,respectiw(y ^a^Th>rnic&Bi5]lakE:CdlKctes', AlibaateiyHanolxxk, 1998, Vol 1 Eld
Mo E Cefis, and For MIS assay: Ptamegi PtotaxJ, USA, 2(X)0)i fa te ^T^rMre uplake assay, ceils ^WIe
har\fl^afler72hoursa*)GFB
plates waecourtedcnal^d^Tc^
50%ofprofiieiati\£activity
ocnipoundsdeacribedmtreBcan^^
76

Tabte2:

NO COMPOUND NO IQdpM)

Covix MCF-7 Breast PG3
Predate MDAMB-231
Eteast B460 Lung U937 (monocytes)
1 12 Q1-Q5 05-1 05-1 05-1 50-10 01-1

++ NT -H- NT NT +
2 17 Ql-1 05-1 IJO-IO 01 >10 Ql-1

+ + NT NT NT +
3 Ravcpridol ai-05 05 00501 01 005 Ql

+++ + ++ -H- + ++
NA: nctactive NT: retteKK + : 3a50P/otKic
++ : 5O-70P/ofcpcic
-t+h *cws70%fcKb
77

WECLABM:
1. Accmpciundcfgai^fibmTuk acceptabtesalt,phainroeulicallyac^^

wherein
Rjisaiyl,unsubstitutedcrsuta#^
aJkenyi, OjQdkynyl, CjCrdkanp)^ nitto, NRRIQ, SRH, ttfhncmethyl, hydrce^l, cyano, caiboxy, Q-Q-
aIkox)cartxiT>iand^i-Cf^imdT>dn^ts^^
kfcntkdcr afferent lieteroatcnBato
iiEtf^stibJri a substituted by at te
CjQdk)T^C2CrflIkaii^i^
R2 is hydrogen; Q-Qfllkyi; atyl, imiriitutda substituted by at least ere
aIkyi,CiCIraIkoxy,C2Q^
carbcocy, C]-QaIkcK>caibcnyl and ^i^lrfllkytenehjdroxyl; saturated, partially unsaturated or aromatic heterocyde
teving 1,2,3 a4 idertical ordflbertheteroatD^
unsubstitiM a substituted by at leag
CjQaIkynyl,C2Ctfllkatr^
Ra, R4 and R5 are each independent selected ficm h>diogen; Q-Qalkyi; halogen; ORi ± aylQ-QfllkEKy; Q-Q-
aD^fcataiyio^ Q 4kientkalcfdiflereitfheten]^^
Reis-Ci-QaflgtaJCKii;
R«ish>drog^Ci-CraIkyi;ai>1; caibc*amide;sulfbnamkk^N^
R9 and Rio are each independently selected ficm: hydrogen; Q-Q-alkyi; aryl; Q-Cfdkanoyl; heterocyde, which
cailainsl,^3or4lieteroatDmssekctedficnrn^ Q-Ctdkaxycaftxxifi, Q-Cr
alkykHbanyl; a^caixnyl; hetatQdocaibcnyl, whenm
ficm nitrogen, oxygen, sulfur and phosphorus; caibcxamkle; aid suHbnam^
heterocjdo- are either ii^jbedtutedcr substituted by a least a^
aIkDxy,C2Q-dk£nyl,CjQdky^
CrfllkDxjcaibcqyi arri I^andRiQtogetewlhlherntrogm^
fuiteheteroatam selected ficm: tiitroge^
heterocyjJcringbemgeiteiiRfeft
Crdkcpcy, C2QaIken}i CjQdkynyl, CjCfdkanpyl, ntocsNRcRift SRi; tn^uaromefl^, hydroxy!, cyano, caiboxy,
£i£4dk$ycaAxxy\ anddiCK>i;
78

Rii is t^drogfr^ Q-C^IlQi; Ci-Ctelkanp>d; aiyl, utBubstitu^crsdbstiluted hy at feastca^ substituent sefected fiom:
Zisanax)^atom;asulfuratem;aNR$
Aisa5 memberedring ^^tenan:
(heSflienTbenriringissatLiatedOT^ general anxtuies® to (v);

\vho^X|and)Qaeeadiindq3endt^3dectedfiaTtac^^
atcm,asulfiratcn\S(0^ardanitro^ateinpw
heteroatom, aidwhaanlhenilicgenatDm^ RQ\\teonRuissdectedfionxh5di^^
QdkjiursijstitLitricr substituted
amiri^nitiOjCi^^alkjrth^
selected for halogen, hydragi carbaxyl, Ct-CraIkcKy, amino, nitro, Q-Qfllkyithio, sutflTycfr>4 and suHbnyl; aryl,
unsub6titutedasubsti!i4e^
QK^aIk}i^QC|^Ikano^^
d^
R^isasubstilLel as defined ahcaemakast ere caibma^
RjJshjdrogj^Q^ZfalkjiCK!*^^
RM is hydrogen; Q-Qalkyl; h>diax$ NR^IQ halogen; -SH; -SCrQdkyl; -Sa>t ayt vsterein Ihe a>l is
unsubstituted or substituted by at kast one sUbstituertsefededficm
CjQaB^T^CjCralkanpyl,!^
CraIkylendi>diox)i;aheteta^
phosphc^ the hetasx^ being iraM
aIkyl,Cifl]kDxy,C;K^aIke^ carfcoxy, Q Z Acampcundctfthefaniu^ R]isphan>iv^khisunsubstitulBdasubG&^
Qdkyierehjdro^CTisatetenxjde,^
atcmscfv\hkiU,2CT3arekbitkdCTC^
\\baetheheteroc>deisiiEU^^
Qdk)1,Ci Q^lydkybiehydrcKyl;
R2 is hjdrogen; Q-Qalkyl; phenyl, which is unsubstittfed a substituted by 1,2, a 3 kl^^
selected fiomhak^CrCr«l^Ci altoraycaibci^and^Kilralk^^
79

R.3, R4 and Rgaie each independenliy selected from: hydrogen, Q-Qaflgd, halogen, ORn, CK^alkykHbanykKy,
NR^QSOfeNR^QCaiba^c>anDandnitK^
Zisanco^genorsLdfiratom;
Aisa5 memberedring wherein;
^tteSinmiberedsatuiHtedtf usati^^ g£n^stnxtures®to(v)asdaimediri
damLXiandX^aieeachiridepento sutfis;
atiinitio^n, provided tiatmsbulLires (ft
alamisatleastnxrosubstitutedby RQwhednRoissdectedfronrhyctog^
substituted by halogen, hydroxy! or caboxyl; CjQdkenyl; hjdroxyl; Q-Cffalkaxy; Q tc&msutibnyl; cyano; SQ2R40; -CXXCHjlhiRH and phenyl which is unsubstituted cr substituted by at least one
substituent selected from: halogen, Q-Qfllkyl, Q cabc«y,Ci R9 and Rio are each inoependentfy selected ficxix h>d^
al^karbon}'!, catboxarnideand sulfonamide or
fyandRjQ together with ttenita^
whkiicanhawatleastcrefuiteheteiD^^
unsaturated or aromatic, and either unsiitetitLi^OT substituted b
alkyl,Ci caiboxy, CiQ^myaabc^ard^iQeto^
Riiishyck^i;Ci-Ct€^C[ Rwishydrog2nCiaIkyl,h)^^
3. AcniTrxjundcftrefarr^ unsatuiatedm^iepesentedby anyone ofilTe^radstiuctiKs(i)to(ivX

\vhoemX|iseitheracaibonatamcrahetero^ suffix, ardnitrog^occqtthamstnxture(iv)
XjiseilheracarocnatomCTanitrogenate^
4. A compcaid of the ionuila (fc) as claimed h any ere
unsubstituted or substituted by 1,2, or 3 klertk^crdifflaentsubstituente
alkoxy, nitro, NRgRio, SRn, trifluacmelhyi, hydroxy!, cjano, caiboxy, Q a!k>feneh>diD\yi,CTisalttaDc>de,\\hich
wrnchl,2cr3aieklerMttc5naenthete^^
is unsubstituted or substituted by 1,2, or 3 identk^OTcfinaertsubstiluenlsse!
alkoxy, nitro, NR^Q, SRJI, Irihjatomelhyi, hydroxy!, cyano, caiboxy, Qcabonyl and -Q-Cr
alkyfenehydroxyl;
^andRjare hydrogen; and
R3 andRsareeaiiirrlerjerdenliy select from: n^^
80

5. Accmpourdofttefcmiula(^)asdaimedhanya£
pyridine subsdlutBd by 1,2 cr 3 identical or different substituenls selected ficm: habgai and nkx R2 and R4 ate
h>dic^R3aiiiR5aieh)drc^
(vi^^teteitlXl,^R6andRl3 areas defined.
6 Accmpourriasdaimedm Ci-CraDQlandZisanaQ^nalDm
7, AoompouridofgaTadfom^
(fyn^2Q{XteR>{bEr^5y-^^
(-)*iTO^2^-Otaofha^5jKfihjdicp^
(+)#i^2^43iaT»fhen)i>^
(f>#t^2^Bmioiii2n)^5,7 (f}0xjn^2-{^!crno^ba^ (+)to^2{4ftixnoii]e^^
(+)^>tiw^2-{3 (+)£t^25J (4}*>ttf#^4l5dinxjme^
(4^c?^2^1iion>tiienyI>^4iydrc^^
(+)#t^2^4TLnDiiien)^5J«fi^^
(+)*tw^2-{3^1iac>fiien>^57^^
(+}i>tws-2-^57 (+)to^2{2£QfiLat>ftoen)d)^
(+)i>i^2 (fyzm4{5,7-Btoydmy-^tyikx^^
(-}taw*&{2fl>draxyme1h^
(-)tfr^5J4)ih)drcKy^4])^^
(+)#iws^-H)diDxymeth^
(4)#tOT^5J4)ih>draxy^4^^
benaxiilrile; benzanitrile;
81

one;
(^-)#t^2^-Btaiio-5*nel^^
one;
(+)tosL2^-feni>5into
one;
(+)*CTis^2^-Bicmo-5flieftio^f^
one;
(4/-}iK^2^-ftonio-54i)d^
one;
one;
(V-)tfi^24(3,543&tiifli^^
4-one;
(^-)#ry^24p^Bfet[iflucraT^^
4-ane;
(+)#i^2^-QTkiD$medTylf^
(+)ta^2^1ibi>5iiTelh}4i]e^
(4}#t^2^-B[cn^5iTitiD^ta^^
(^-)to^2^-Bronx>$riln>ji^^
(4/-)to^2^ (4/-)#t^2^EyiK^
(^-)tfi^2^BraniD-54Tilion^^
(+)*aw^2^0iloB>pyikJin-3->^5,^
benanitrile;
(4) benaanitrife;
(+)£r^2^4-Btanp-2j^^
(+)#i^2^Btamo-2Hiifao^^
(4/-)^)T2m2^ diomen-4-one;
(^-)to^2^4nTedT)^^
medijW-nieihyiftnol^
(4/-)#tM^2^ one;
(V-)*tOT^2^ one;
(^-)to^2^ (^-)^T»^2^ (4/-)tfu?^2^ one;
(^-)*i»^2^ one;

82

cue;
(4/-)tfrws^H2-AminGmed^^
(^-)4m?^-Amincmeli^l4rie^^
(^-)*H^3^[2^3T^
(V-)*rOT9-2^iiia^^^
(^-)#t^2^ (^-)#tyff-2^fi]e^^
(+/-}&CBW- Acetic add 3^^H±hD}ii3^5;7tathyl ester,
one;
(+A)£m^2K2 one;
(^y-)*>t^AceticacioV3^^^
ester,
(^-)#t^2^fheny^
(+/-)£t^2^fhen)^^^
(^-)to^2^ (^-)0t^2^3tonio4riln>fi^^
arid;
(V-)#t^34fexnc^5J ait
(V-)*CTa^2^ (V-)to^2{4-Aniino-2 (^-)£t^2^43ramo44iuciof^^
(^-)*tJ7^2^4^mino-2-bBDmD^te
(V-}#itfs40]kM>3^57-^ chn3iH>2->l}teBdc
add;
acid;
hjdrax>4)emamide;
(V-)tftws4Q]lc^^
hydrcp^teramide;
(^-)#i^:Kl]ton>4{5J- hjdraxytazamide;
ImkKy-bmzaiTJde; (4y-)to^2^4I)iflLion>fiiei^
(4)#tOT^23^^^ ;
(4)to^2^-&cmo3-fluQ^^
(+)*iTO^2 (+)ta^2^-ftcnx>5-flLiQ^^
83

(+}£r^2^fi]eny^
(+}frcw2QBKrK>$ (fymns-2^-&cm>44ito^^ (fyn^2Q&amc>4*ti^^ (+)*ia^^4-Amino-24xcni>phe^ (fynD&2^Arrko2JxaDx>^^
one;
(+)*rffs-2^-Btario4medre^
one;
(+}Vwro-2^-Bromo44^^
one;
(fynms -Acetic acid ^-aretoxymethjWirKlhy^^
7-ylester,
(+)*>t^2^4I)ki]]oio-5^u^^ methy43>irolife^)^5J^
one; or
(4)*tw^2^4Cklilctc-5^iac^te^
one.
& The ire ctf a compound of geneMita acceptabfesafttherecijftrlten^
9. Iheusecfacon5XXidofgme^fixmula(fc)accadn^ acceptable saftthoeo£ibr1hemanuiactLre^
10. Theuseofaccnipourriofgene^fixm^ axsptabtesaft thereof fcr the nranuia^^ deKfiflaentiaticncfadfiaa^
11. The use ofa compound of gsnoalfcm^ 1 to7,aaphamiaceufcally acceptabfesaltlhaec^ibrliTeman^^
12 Theirecfaccnipourricfga]^ acceptabte salt thaec^ fir the maoria^^ mja&infectasvi^
13. Theirecrfaoompouriiofgraalta
agricultLial applications
14. AphamraceUkdccmpositkiicci^^
fcnrnjh(fc)accax£ngtDariy(yieofdaiiTBl to
acceptabJecamtr.
15. AphanraoeuticalocnTpostmccnq^^
gpnaatlbnTii&(Ic) acceding to an^
furiherphamraixutk^a^ccmp^
84

Id The ire of a compound cfgnealfam^ 1 to^crapteimaQeutically
acoep^saltlhen^fcrltenmfo^
e^eessKeceflpdifeatic^
phamaoeutx^activeoanpMid
17. Aproessfcrtheprgmtacfaan^^ phamraceuik^acceplabbsattll]^^

\\haOTRj,RiR3,R4,R5atdZ have lit meaning tifined ltD6,andPisafunctianalgrouft\^a
compoundoffbmiula(IIIX

(a) ffiactingabaiaopyiananeoffcmiiiajl):
wh^ABsutetitutedbyRearriR&an^
Aiscte11ma5*]Tmrt)a^ringGf^
urEaOiiatBdcaibcnatominteAnngand
1) wioeQ is bound to an uraaturafid carbon a^
o^roccrha^nr baseandana^TKaincig^so^ famed
betvseenthere^ectivecarbmatcms^^
redre any aVdfe band betw^ member tofcmia
ccmpcuTdoffctmula(Ic^aTd ii) \*hoeQisboundtoasAia!edcabaiaton^
cata^standa lea\irig group, vvteii^

\\heronRi,Ra>R3,RfeR5aiiZha\e1hemeaiii^^ ccnipctiidoffcnTiLila(IIIA),
85
to\\foidiPaidQarebciundtofamacaTipc^ ifaflprcpriate,ccn\«tir£lheies^ (b) reactingabaTzcpyrancreofftirriuk(II>

wherehXjandl^rHielhemearaTga^
inorganic base and an agonic or inorganic sohal, to fctm a nitrogeiKarban coupling between the carbon of the
ccmpc«indoffcmiiia(II)to\\hichPisaaadTedan^
ctiivatirigtiTeiesullartcaiTr^^ intoafinmaceutk^acoeplaUesatt
18. A process fir the preporaQcnofaconTpound of g0iad
phamiaaetfically accept s^^
de£nedinat^Gt£ofckims 1 to 6, \\hichpnxess comprises iea^

CTaoarnixurioffbmuda(XIIA):

wherein ineadi case RfeR&RiR^RsjI^Rjaid A are as defined, wilhanaganiccrirxs^nk: base, subsequatiy
addriganackitolheieactimrnixtiiec^ adding an organic cr inorganic base, and, if
appropriate, cciwatinglte
19. Aprooessaooardingtoctol£^\faerem^I]ea (XnA)ts obtained by reactingacompciundofi^^
86

\\teremR1,R2,R3,Ri,R5,R6R7and A areas defined above vvilhacarbcKylic aid ester, an ackihalide, (reactivated estermtheprcsenxofana^nicarincsganicbase inano^niccrinaganicsctot
20. ApocessaccoKlingtodaiml8CT^

wheran.Rn andRaateasdefined
21. Apnxessacconir]g©cto2Q,\vhe^
22 AproessfcrlhepepaalicnGfa^

87

\\ba^Ri,RiR3,Ri.R5,Ro^ZareasddM fcmmla(\i\)

\*teranRi,R2,R3jR|)Rg,Ri3andZaieasddMfo the^Hgapcnttepipmdiroringbyalea^ addrngasuitabfeag^basem^ appropriate, cometinglheres^^
23. ApccessiolhepreparatiQnctfac^^ phamiatxiJdc^aocqMiiesatttesf

uheranR],R2,R3,R4iR5 atriZaeasdefinedmanycneGfdaims 1 to6,wfaidipKx^ccii]prisesi^^
offcrnndapOOCVI):'
88

\\teremRi, Ra Rj Rt, R5 arri Z are as cfefin^
ester gjoup -0(0)1®: on Are imidazc^d ring to Ihe group -CH£)H, and,ifappn^xiaIe,ocnvertingteresullart
ccmpcuTdoffbmiula(XXXVII)ir^
24. ApK»essacooriingtockm23,\\h^ (XXXVI)ispqHidbyieactingaoGrnixxidof&mda(XX^

\*tereinRi,RaR3,R4,R.5 arriZansasckfinedmarycneofdairTBlto^wfa inciganicbasehanaganicsoKait
25. Anocesibrlheprcrjaratianofao^

wherein
Ri, Rj, R3, Rj, R5 and R13 arc as defined in any one of daims 1 to 6, ocn^ais^ieaclingaiaoembaiqxxindofte
famula(Vin):
89

vdramR^RtRs and R^are as dsfinedin anyone ofclaims 1 to^uithachiralau^lia^-mThepKsmceofasoKalto fcnn a dastaxiuic salt of fhs compound of formula Qflfl), ty&Sfiang out fir required diastacamic salt and subsequently treating wiih a base to obtein Ihe desired enantiomer of the oompound of formula (VEft treating the cnnpoiiriGffcmiula(VIQ)with to(*^theacylatedconTpourriof^^

\^iaeinRaR3,R4R5 andRcareasdefinedmanycneofclaims 1 to6, tieatinglheoompcundoficm^
(a) anactfchkikleofthetypeRiCOQ^ v,haeR4tsasdtfcd,
(b) anaridoftiTenpeRiCOOHvYtaR^as sca\«]££rtDcbtainanackidiki&
(c) aoombirBtaofR|CCOH\*i]ereRiisasd
v\heranR|,RiR3,R4,R5 andRnareasdefiriedhanyorieofdairrisl to6,
90
toiamteccnpouridoffixmulaPQ

treating IhecxiTipc^ctffcn^^
subsequently with a mild base to fcmi the subject ccmpcurioffcniuila(Xnft
coripoundintoaiAamiace^^
attonali\dy,subjecting1te
amethandtofcimacanpc^
wb^RaRiR^RsandRoaeasdefinedm
tieatingthecanixxindo^^
abase inasahatftofamaccniixiundtf^
\^TeranRi)Ra,R3,RbR5 andRoareasdefindmanyaTecfdaims 1 to6, arri treating the coiipajritf^ andsubsequentiytreatingwifa^^ sut^canrxajTriirtoatiBrn^^
Dated ttDs/daycf^iuary2005
91

S.MAJUMDAR
GfS.MAJUMDAR&CO.
Applicants'Agert

ABSIKACT
FLAVONE DERIVATIVES AS INHIBITORS OF CYC LIN-DEPENDENT KINASES
Tfepre^imaTtimidaiKtDno\d dicmatnTedadv^v«offixniula(Ia)

tcr Ihepq^naQcnofsudi compound^ mdho^
usectfsuchccmpourilsmtte^
madkanmlstDbeapp^insLriicfaeas^
dteataTeormocnibm£icmvfa
partkxilariiHmaoetfk^a^
ag^togtev^jiHinBKUtic^

FLAVONE DERIVATIVES AS INHIBITORS OF CYCLIN-DEPENDENT KINASES

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