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;
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)[email protected]^^
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>[email protected], 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\[email protected]^
    ^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^

  • Documents:

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    15-mumnp-2005-abstract.doc

    15-mumnp-2005-abstract.pdf

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    15-MUMNP-2005-CORRESPONDENCE(26-12-2008).pdf

    15-MUMNP-2005-CORRESPONDENCE(3-10-2012).pdf

    15-MUMNP-2005-CORRESPONDENCE(3-4-2012).pdf

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    15-MUMNP-2005-DRAWING(GRANTED)-(16-3-2012).pdf

    15-mumnp-2005-drawings.pdf

    15-MUMNP-2005-FORM 1(28-2-2005).pdf

    15-MUMNP-2005-FORM 16(3-10-2012).pdf

    15-MUMNP-2005-FORM 2(GRANTED)-(16-3-2012).pdf

    15-MUMNP-2005-FORM 2(TITLE PAGE)-(10-1-2005).pdf

    15-MUMNP-2005-FORM 2(TITLE PAGE)-(GRANTED)-(16-3-2012).pdf

    15-MUMNP-2005-FORM 3(10-1-2005).pdf

    15-MUMNP-2005-FORM 5(10-1-2005).pdf

    15-mumnp-2005-form 6(12-3-2010).pdf

    15-mumnp-2005-form-1.pdf

    15-mumnp-2005-form-18.pdf

    15-mumnp-2005-form-2.pdf

    15-mumnp-2005-form-26.pdf

    15-mumnp-2005-form-3.pdf

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    15-mumnp-2005-pct-search report.pdf

    15-MUMNP-2005-REPLY TO EXAMINATION REPORT(9-3-2010).pdf

    15-MUMNP-2005-WO INTERNATIONAL PUBLICATION REPORT(10-1-2005).pdf

    abstract1.jpg


    Patent Number 251454
    Indian Patent Application Number 15/MUMNP/2005
    PG Journal Number 12/2012
    Publication Date 23-Mar-2012
    Grant Date 16-Mar-2012
    Date of Filing 10-Jan-2005
    Name of Patentee NICHOLAS PIRAMAL INDIA LIMITED
    Applicant Address 100 Centre Point, Dr. Ambedkar Road, Parel,
    Inventors:
    # Inventor's Name Inventor's Address
    1 LAL BANSI 30, Advani Apartment, Near Deep Mandir Theatre, Mulund (W), 400080
    2 JOSHI KALPANA SANJAY A-4, 103-104, Neetu Apts., Raj Park, Kalwa, Thane 400605
    3 KULKARNI SANJEEV ANANT K 32, Hoechst quarters, Amar Nagar, Dargah Road, Mulund (W), Mumbai 400082
    4 MASCARENHAS MALCOLM B-11, Nirmal, Plot No. 26, J.P Road, Andheri (W), Mumbai 400058
    5 KAMBLE SHRIKANT GANGADHAR M-3, Hoechst quarters, Amar Nagar, Dargah Road, Mulund (W), Mumbai 400082
    6 RATHOS MAGGIE JOYCE 201/A, Nirmal Co-op Hsg Soc., Luiswadi, Umed Nagar, Green Road, Thane (W) 400604
    7 JOSHI RAJENDRAKUMAR DINANATH K-14, Hoechst Quarters, Amar nagar, Dargah Road, Mulund (W), Mumbai 400082
    PCT International Classification Number C07D 311/30
    PCT International Application Number PCT/IN2003/00234
    PCT International Filing date 2003-07-07
    PCT Conventions:
    # PCT Application Number Date of Convention Priority Country
    1 616/MUM/2002 2002-07-08 India