CA2218088A1 - Spirocyclic and bicyclic diazinyl and carbazinyl oxazolidinones - Google Patents

Abstract

A compound of structural Formula (I or II) useful for treating microbial infections in humans or other warm-blooded animals, or pharmaceutically acceptable salts thereof as defined herein.

Description

WO 96/35691 ~ JUS96JI)521)2 SPIROCYCLIC AND BICYCLIC DIAZ~YL
AND C~R~ YL OXAZOLIDINONES

Rc ~l, ~. v~ of ~e Inv~ntiol-The subject invention ~icrlnee~s new and useful oYA7nlirlinnnes having a spirocyclic or bicyclic diazinyl or carbazinyl moiety. The compounds are useful flntimirrobial agents e~ive AgAin~t a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as mlllt;rly-re~i~t~nt staphylococci, ~Ll~toco~,~,i and entelucoc~;i as well as anerobic org~niRmR such as Bacteroides spp.
and Clostridia spp. species, and acid-fast orgAniAmR such as Mycobacterium tuberculosis and other mycobacterial species.
Tnfnrmslffnrl T'l;crlo.cllre The present compounds are related by their phenylny~7~liAinon~ ring structure to those ~liRcloserl in the pllhlicAtinnc below except that the subject compounds have a ~ u~;lic or bicyclic diazinyl or carba_inyl moiety. The in~t~ntcompounds have usefill Antih~ct~rial activity.
PCT/US94/08904 applir~tinn ~i~clnse8 nYA7nliAinon~ Antih~cteri~l compounds having either a morrhnlin~ or thinmo~rholine sllhstitll~nt PCT/US93/03570 applir~t,ion AiRrln~es nY~nliAinon~s sQnt~ininF a 8llh;~ A
diazine moiety and their uses as Antimirrobials.
PCT/US92/08267 applicAtion AiRrlnc~ sllh~l:l .le-l aryl and helelua~ phenyl-nY~7nli~1innnes useful as AntihA~teriAl agents.
PCT/US89/03548 applirAtinn ~liRrloseR- 5'indolinyl-5B-Ami-lnm~hylnY~7oli~in-ones, 3-(fused-ring snhcL~ e~)phenyl-5~-Ami-lomPthyloY~7nli~linon~s~ and 3-(nitrogen snhsL;~-.Ie~)phenyl-5B-Ami~omPthylnY~7nli~1inon~s which are useful as ~ntihArterial agents.
Other references ~liRcloRing various oYA7nlillinonpR inrln~le US Patent 4,801,600, 4,921,869, Gregory W. A., et al., J. ~ Ch~m~ 32, 1673-81 (1989);
C.-~u-~ W. A., et al., J. Med. Ch.qm 33, 2569-78 (1990); Wang C., et al., TetrAh~-lror~ 45, 1323-26 (1989); and Rritt~lli, et al., J. ~P~7 ChPm . 35, 1156 (1992).
Eu~vuea~l Patent Pllh!irAtinn 352,781 rliRrloRes phenyl and pyridyl sllh~l ;l ~. le~l phenyl nYA7nlirlinnnP~
European Patent pllhlirAt;.~n 316,594 ~1iRrlos~R 3-sllhEL;I .i~cl styryl nY~7~ inl~nPR.
Eu,upea~ Patent pllhlir~t;on 312,000 tliRrlosç~ phenylmethyl and pyridinylmethyl sllhs~ phenyl nYA7nli~1innn~R

~nmm~rV of ~e Inv~ntioIl In one aspect the subject invention is a compound of structural Formula I:

6 / 2 nR2 (CH~ R3 (CH2)o--N~ O

R3J~N O
\~ H O

HN~R4 Formula I
In another aspect the subject invention is composed of structural Formula II:

Rl (CH2)n (CH2)m I R3 (CH2)p--N~ o H O
~NJ~R4 Formula 11 or pharmaceutically acceptable salts thereof wherein:
R1 is (a) NR5 (b) CR6R7;
R2 is indepen~1Pntly H or CH3;
30 R3 is indep~n~ently H, F, Cl or mPt.h~Yy;
R4 is (a) hy-Lo~
(b) Cl-C8 alkyl (optionally ~llh~ l with one or more of the following:
F, Cl, hydroxy, Cl-C8 alkoxy, Cl-C8 acyloxy), (c) C3-C6 cycloal~yrl, 36 (d) amino, (e) Cl-C8 alkyl~mino,

-2-WO 96135691 PCI-IUS3. ~ 02 (fl Cl-C8 diaLkylamino, (g) Cl-C8 alkoxy;
R~ i8 (a) H, (b) Cl 6 a~yl (optionally subsliLuLed with one or more of the following:Cl, F, CN, OH, Cl 4 aLkoxy, amino, hy.l.u~yl~mino alkoxyl~min-~, C14 acyloxy, Cl 4 allcylsulfenyl, C14 alkylsulfinyl, C14 alkylsulfonyl, aminosulfonyl, Cl 4 alkyl~mino~ulfonyl, Cl 4 diaLkyl~minoRulfonyl, 4-morpholinylsulfonyl, phenyl (optionally sllhst;tll~e~l with one or more of F, Cl, CN, OH, Cl-C4aLkoxy), 5 iRnY~7.olyl, ethenyloxy, e~.yllyl)~
10(c) Cl 6 acyl (optionally substituted with one or more of the following: Cl, F, OH, SH, Cl 4 aLkoxy, n~rhth~lAnnYy and phenoxy (optionally 8llh~1 ;1 .ie-l with one or more of the following: Cl, F, OH, C1-C4aLkoxy, amino, Cl-C4acylamino, Cl-C4alkyl), amino, C1-C4acyl~mino, hyLv~yl~mino, alkoxyl~minn, Cl 4 acyloxy, phenyl, Cl-C4alkylcarbonyl, Cl-c4alkyl~mino~ Cl-c4dia~
cl-c4hydlo~y~cyloxy~ Cl-C4alkylsulfenyl, rhth~limirl~, ms~l~imi~jo~
8llc ~ inimi~lo)~
(d) Cl 6 aikyisuifonyi (optionaiiy sllh~i;i i"P~i wi~n one or more of ihe following: Cl, F, OH, Cl 4 aLt~oxy, amino, hydru,.ylf-min~, alkoxyl~mino, Cl 4 acyloxy, phenyl), (e) arylsulfonyl (optionally sllh~ 3rl with one or more of the following:
F, Cl, OCH3, OH or Cl 4 alkyl), (fl Cl 6 aLkoxycarbonyl (optionally substituted with one or more of the 2~ following: Cl, F, OH, Cl 4 alkoxy, Cl 4 acyloxy, phenyl), (g) ~min~rbonyl, Cl 6 aLkyl~minoc~Lu~yl or Cl 6 diaLkyl~minoc~rbonyl (where the alkyl groups are opt,ionally sllh~' :l .,IP~ with one or more of the following: Cl, F, OH, Cl 4 alkoYy, phenyl), (h) five- and six-membered heteroc~. les, eRpe~ ly 2-oxazolyl, 2-thia_olyl,

3 ;RQY~7.01Y1, 3-isot~i~7~ 1yl and dihydro de~;v~Lves of these ring systems (all optionally sllhEl:l ~le~ with one or more of the following:
Cl, F, OH, amino, Cl 4acyl~min-, Cl 4 alkylsulfonyklmin~, Cl 4 alku~y~;~Lonyl~mino~ Cl 4 alkoxy, Cl 4 acyloxy, Cl 4alkyl which can be sllh~ with F, OH or Cl 4 alkoxy, 3a(i) C3-C6 cycloaLkylc~u~yl (optionally sllhEI l ~4~cl with one or more of the following: F, Cl, OH, Cl-C4alkoxy, CN), WO 96/3!j691 PCT/US96/OS202 (j) benzoyl (optionally sllhs~itllt~-l with one or more of the following: F, Cl, OH, Cl-C4alkoxy, Cl-C4alkyl, amino, Cl-C4acylamino), (k) pyrrolylcarbonyl (optionally sl7hstit~lte~l with one or more of Cl-C4alkyl), (1) C1-C2 acyloxyacetyl (acyl optionally substituted with the following:
amino, C1-C4alkylPmino~ C1-C4dialkylamino, 4-morpholino,

4-Pminophenyl~ 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl);

R is (a) H, (b) OH, (c) C1 6 alkoxy, (d) amino, Cl 6 alkyl~mino, Cl 6 dialkylamino, hyd~u~ylamino, or Cl 2 alkoxylamino (all of which can be optionally sllhsl l l,e-l on the nitrogen with: C1 6 acyl optionally substituted with one-two of Cl or OH, C1 6 alkylsulfonyl optionally substituted with one-two of Cl or OH, Cl 6 aLk)~ .~l,onyl), (e) Cl or F;
R7 is (a) H, (b) Cl 6 alkyl (optionally sllhsl ;1 .le~l with one or more of the following:
Cl, F, CN, OH, C1 4 alkoxy, C1 4 acyloxy, amino), (c) CN, (d) phenyl (optionally sllhstitllte~l with one or more of the following: Cl, F, OH, C1 4 alkoxy); or R6 and R7 taken together are (a) carbonyl or thiocarbonyl group, (b) ethylene ketal (-OCH2CH2O-), propylene ketal (-OCH2CH2CH2O-), ethylene thiok~t-sl (-SCH2CH2S-), propylene thir~k~t-sl (-SCH2CH2CH2S-), dimethyl ketal, diethyl ketal, dimethyl thi~kl~t-sl and diethyl thi~k~t9l, (c) oxime (optionally sllhstitllte~l with H, Cl 6 alkyl (optionally sllhstitllt~l with Cl, F or Cl 4 alkoxy), Cl 6 acyl (optionally sllhsl;l,-~e-l with one or more of the following: Cl, F, OH, Cl 4 alkoxy, Cl 4 acyloxy), (d) hyLazolle (optionally sllh~ ecl with H, Cl 6 alkyl (optionally ~llh~t.itllt,e~ with one or more Cl, F, OH, Cl 4 alkoxy, Cl 4 acyloxy, phenyl, Cl 6 acyl (optionally sllh~ l~~ with one or more of Cl, F, OH Cl 4 alkoxy, Cl 4 acyloxy, phenyl), Cl 6 alkuA~ I,ony (optionally sllh~ l with one or more of the following: Cl, F, OH, WO 96t3S691 PCT/US96~052l~2 C1 4 alkoxy, Cl 4 acyloxy, phenyl), Cl 6 alkylsulfonyl, (e) imine (optionally sl~hstit~llte~l with H or a Cl 6 aLkyl (optionally subsliluled with Cl, F, OH, Cl 4 alkoxy, Cl 4 acyloxy, phenyl), (f) carbon-carbon double bond (optionally subhLi~u~ed with H, Cl 4 alkuAyc~ . Lonyl, Cl 4 aLkyl (optionally substiuted with Cl, F, OH, Cl 4 aLkoxy, phenyl);
m is 0-2;
n is 1-3;
o is 0-3; and 10 p is 1-3.
In another aspect, the subject invention is directed toward a method for treating microbial infecti.~,nR in humans or other warm-bloo~l~cl ~nim~lR by ~~lminiRt~ring to a patient in need thereof an e~l ~;ve amount of a ~;o~lpound of Formula I or II as described above. The compound can be ,~lmini~tered in a 15 pharm rellti.~ l composition either orally, p~e~te~lly or topically. Preferably the compound is ~r1mini~tered orally or parenterally in an amount of from about 0.1 to about 100 mg/kg of body weight/day, more preferably, from about 3.0 to about 50 m~/kg of body weightJday.

20 ne~ n~:e_,~VL or~ of the Inv~n1;nr The present invention ~li.crlosPs novel 2i~uil'O~ ,liC and fused bicyclic diazinyl and carbazinyl nY~7nli~1inonP5 of structural Formula I and II as ~le~r~rihecl above.
The compounds are useful ~ntimirrobial agents, e~ ~ive ~ nct a number of human and veterinary pathogens, particularly aerobic ~ram-positive bacteria, 25 in.~~ in~ m~ltirly-reRi~t~nt staphylococci, streptococci and e~.ucoc.;i, as well as anaerobic or~niRm~ such as bacteroides and rlnstri~i~ species, and acid-fast bacteria such as as Mycob~ ul~ tuberculosis and other mycob~rteri l spe-~iPff The R groups are as set forth ab-~v-. A R uRed here~n ~h.e te~ Gn m i8 inclusive such that a co.,.~uuud of Cl 8 would inrll~ P compounds of one to 8 carbons 30 and their iRnmPrir forms. The various carbon m-~:eti~~ are defined as follows: Alkyl - refers to an ~lirh~ti.~ hyd~.a~bon radical and inrlll~es branched or unbranched forms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, i-hexyl, n-heptyl, i-heptyl and n-octyl. Acyl refers to those having one to six carbon atoms such as formyl, acetyl, propionyl, etc.
35 and their isomeric forms.
The R3 sllhstitllPntR are preferably both flll-~,rine and, more preferably,

-5-CA 02218088 1997- lo- lo WO 96135691 PCT/USg6/05202 fluorine and hydrogen.
The R4 sllhstit~l~nt is preferably hy(Lo~ , methyl, difluoromethyl, dichloromethyl, hydlul~yl~ethyl or methoxy. More preferably R4 is m~thQYy, difluoromethyl, dichloromethyl or methyl. It is most ~refe~l~ d that R4 is methyl.
The R5 sllhstitll~nt is preferably hylllv~Lyacetyl.
The ~ ~ r~l . ed ~hSolllt~ configuration at C-5 of the oY~7Q~ inone ring of compounds rl~im~cl in this invention is as re,ulearnte~l in the structures of Formula I
and II. This ~hsolllte configuration is called (S) under the Cahn-Ingold-Prelog nom~nrlQtnre system. It is this (s)-en~ntinmer which is ph~rm~colngi- ~lly active.
The racemic lll~l/Ult~ iS useful in the same way and for the same purpose as thepure (S)-~n~ntiom~r; the dirrere~lce is that twice as much racemic material must be used to produce the same ~ntih~ct~rial effect. It will be apparent to one skilled in the art that when a chiral center is present in the diazinyl or carbazinyl fr~gmPnt of compounds of structural Formula I and II, then diastereomers are possible. Thesedia~ele:u-~ers, in racemic and en~ntif~m~rically enriched forms, are also within the scope of the compounds of Formula I and II of the invention.
Both organic and inorganic acids can be employed to form non-toxic pharmaceutically acceptable acid ~ it;on salts of the compounds of this invention, where applif~hl~. Illu~Lla~ive acids are sulfuric, nitric, rhoRphoric, hydlùcllloric, citric, acetic, lactic, tartaric, p~moi~, et.hsln~.rliRulfonic, slllfSImi~., S~ inir, cycloheYyl~lllf~mi~ film~ric, maleic, and benzoic acid. These salts are readily prepared by metho~R known in the art.
Pharm~relltic~l cnmroRitioT~R of this invention may be prepared by comhining the compounds of Formula I or II with a solid or liquid pharmaceutically acceptable carrier and, optionally, with pharmaceutically acceptable adjuvants and excipients employing standard and cullv~ n~l techniques. Such pharmaceutical comro~itionR can then be used in treating microbial infecti. nR in hl~m~nR or other warm-blooded ~nim~lR (p~ti~ntR) by various routes of ~lminiRtration in an e~i~ive amount or therapeutically erre.livt, amount. Typical amounts can be from about 0.1 to about 100 mglkg of body weight/day, more preferably, from about 3.0 to about 50 mg~kg of body weight/day.
Solid form c- ~oY;I :nn~ inrlll~e powders, t~hlets, dispersible granules, capsules, c~h~tR and ~u~posilu~;es. A solid carrier can be at least one sllhst~n~e which may also filn~ion as a ~iln~nt, flavoring agent, s~ lhili7~r, lubricant, sllRp~n-ling agent, binder, tablet ~liRinte~. dti~g agent, and ~nc~rslll~ting agent.
Inert solid carriers inClll~e m~gn~qillm carbon~te, m~En.sRillm ~lealale, talc, sugar,

-6-WO 96135691 PCT~US96~ 02 1A~ to~Q~ pectin, ~la~trin~ starch, gelatin, ca~ lo~ic m~teriAl~ low malting wax, cocoa butter, and the like. Liquid form compo~it;nn~ include solutions, suspPn~ion~ and amlllRion~ For P~Am~le, there may be provided solllt;on.~ of the compounds of this invention dissolved in water and water-propylene glycol and water-polyethylene 5 glycol systems, optionally cont~ininE suitable conventior~1 coloring agents, flavoring agents, st~hili~ers and t~i~kanjnF agents.
Preferably, the phArm~eutical composition is provided employing co~v~ nnAl techniques in unit dosage form co.lt~ F eC~ctive or a~u~uLo~ul;ate Pmounts of the active component, that is, the compound of Formula I according to10 this invention.
The quantity of active component, that is the compound of Formula I or II
acco~ g to this invention, in the phArmAr~ellti~Al composition and unit dosage for_ thereof may be varied or adjusted widely depending upon the particular appli~t;nthe potency of the particular co~ uuu~d, the desired conl~antration. Generally, the 15 quantity of active component will range between û.5% to 9û% by weight of the composition.
In therApellt;r use for treating, or comhAttinF~ bacterial infact;nn~ in warm-blno-ia~ ~nimAl~, the compounds or pharmaceutical compo~ition~ thereof will be A~lminictered orally and/or parenterally at a dosage to obtain and mAint~in a 20 concentration, that is, an amount, or blood-level of active component in the animal undergoing treAtmant which will be AntihArteriAlly e~tive. Generally, such AnffhAI~riAlly e~.~ive amount of dosage of active component will be in the range of about 0.1 to about lOû, more preferably about 3.0 to about 50 mg/kg of body weight/day. It is to be understood that the dosages may vary ~apan~linF upon the25 re.luil~lllents of the pAtiant the severity of the bacterial infac~;on being treated, and the particular compound being used. Also, it is to be understood that the initial dosage ~rlminiFtered may be increased beyond the above upper level in order to rapidly achieve the desired blood-level or the initial dosage may be ~mAller than the U~LilllUlll and the daily dosage may be plo~;las~ively increased during the course of 30 treAtm~nt. depending on the particular ~it,llAt;~n If desired, the daily dose may also be divided into mlllt;rle doses for A~miniF~ration, e.g., two to four times per day.
The cu ,,uc,ullds of Formula I or II accoL ling to this invention are ~mini~tered parenterally, i.e., by injection, for aY~mrla, by hlLldve:llous injection or by other p~l:llte1dl routes of A~lminiPtration. ph~rmA~ellti~Al cc~ o~; I ;nn~ for 35 p~e~ dl ~lminiPtration will generally cnntsin a pharmArellticAlly acc-:,utable ....t of the ui ,,uou~d accc,ldillg to Formula I or II as a soluble salt (acid

-7-WO 96/35691 PCT/U~,5~'~3202 addition salt or base salt) dissolved in a pharmaceutically acceptable liquid carrier such as, for PY~mrle, water-for-injection and a buffer to provide a suitably buffered isotonic solllt;~)nJ for example, having a pH of about 3-7. Suitable burrt~ g agents inrln-le, for PYslmrlç, trisodium orthorhosph~te~ sodium bicarbonate, sodium citrate, N-methylFhlr~mine, L(+)-lysine and L(+)-arginine to name but a few ~ e~lt~tive b~ F agents. The compound according to Formula I or II generally will be dissolved in the carrier in an amount sllffiriçnt to provide a pharmaceutically acGPptable inJectable con~entration in the rc~ ;v of about 1 ,,.~'~Al to zbout 400 mg/ml of solution. The resulting liquid ph~rm~--entir~l composition will be 10 ~imini~t~red so as to obtain the above-mpntionari ~ntih~terially effective amount of dosage.
A method of preparation of r~y~7oli~lin~nas of Formula I and II in Pns3ntiolnPrically pure form is ~lepicte~ in Charts I-VI.
As shown in Chart I, fused bicyclic ~ inas and carb~inPR of structure 1 are 1~ known in t-h-e lile~ e. EP 0 350 733 A2. Dave, P. R.; Forohar, F.; Axenrod, T.;
Qi, L.; Watnick, C.; y~7(lakhsl~ti~ H. Tetrahedron Lett. 1994, 35, 8965. Jacquet, J.-P.; Bouzard, D.; KierhPl, J.-R.; Remll~on, P. Tetrahedron Lett. 1991, 32, 1565. JP
8956 673. Chem. Abstr. 1989, 111, 153779w. Loftus, P.; et al. J. H~ ,o~cl. Chem.1~83, 20, 321. Gobeaux, B.; ~ThosP~ L. H~l~,o~rcles 1989, 28, 29. Xu, W.; Zhang,20 X.-M.; Mariano, P. S. J. Am. Chem. Soc. 1991, 113, 8863. In fl(~(1ition~ ~Lu~;y~,lic in~R and cd~ as of structure 2 are also known sllhst~n~es. Culbertson, T. P.;
~;:slnrhP~, J. p.; (~ mhino, L.; Sesnie, J. A. J. Med. Chem. 1990, 33, 2270. Dom~g~
J. M.; et al. U.S. Patent 4 638 067, 1987. Xu, W.; Zhang, X.-M.; Mariano, P. S. J.
Am. Chem. Soc. 1991,113, 8863.
Charts II-VI outline the synthesis of cY~7oli~inonP ~ntih~--tPrial agents of structural Formula I and II from t~ in~s or carb~inP~ 1 and 2.
As shown in Chart II, diazine or carbazine 1 is reacted with a filnctirn~ e nitrobenzene 3 (X = halogen or trifluoromPth~nPslllfrn~) in the presence of a suitable base/solvent comhin~t;on, for PY~mrlP dibasic pot~illm pho~rh~te in 30 dimethyl slllfr~Yi-le or N,N-diis~l ylethylPmine in ~ret~itrilp or THF, and at a sl~it~hlP te~e~ , typically ~mh;ent tempe.d~ to 70~C, to afford the adduct 4.
It will be apparent to one skilled in the art that the Rl residue of co~,uu~ d 1 _ight le4u~l~: the presence of a suitable protecting group. For QYample, in the diazine case, where R1 is nitrogen, the benzyl ,ul~e~ g group was found to be e~.~ivt, at 35 blr~rlring this po~it;~-n Alternatively, in the case of ca,L&z e variants (R1 =

WO 96135691 PCTrlJSg6105202 filnc~ nS~li7e~l carbon) sensitive groups such as a 11YVLV~Y1 group can be ~rote.;Led as their te7t-butyl-limPthylsilyl ethers. In t,he case where Rl is a carbonyl, prior cvLIvt:~dion to a ketal ~loLe~ this filnrt;ons~l group from sub8equent rhPmi~
~,ullv~L~ions. It will be apparent to thûse skilled in the art that these protecting 5 groups are merely represPnt~tive and that ~lt~rn~tive protecting groups, such as those ~Ps~r~he~l in Greene, T. W.; Wuts, P. G. M. "Protective Groups in Organic SynthPRiR", 2nd ed.; John Wiley & Sons: New York, 1991, can be employed. The nitro group of 4 is then reduced by catalytic hydLv~ t;nn in the presence of a suitable catalyst, such as 10% p~ rlillm/carbon or W-2 Raney nickel, and in an 10 a~Lv~L;ate solvent, for e~ample THF/H20. When this latter solvent system is lltili7e-l, the reaction ~ lule is first filtered to r~uv~: the catalyst and the filtrate cu--~;-.ing the intermP~i~te aniline is then treated with, for PY~mple, sodium bicarbonate and benzyl or methyl chlolorullllate to give the corresponding benzyl (R
= CH2Ph) or methyl (R = CH3) urethane derivatives 5. When Rl is a benzylamino 15 residue, the benzyl group is lost under the hyd~v~ tin~ contlitionR and is repl~se-l, for PY~mrl~, with a Cbz group during the subsequent urethane forming rezl-~t;on The ureth~n~ ~ are then dt:~.vl~ t,etl with a suitable base such as n-butyllit~ m (n-BuLi), lithillm diiso~uiopylamide (LDA) or lil~.i-.... bis(t~imPt1lylsilyl)amide, in a sllit~hlP solvent such as tetrahyvlvrul~ (1'~') and at a suitable tempe~tu~e such 20 as -78 to -60~C to give a lithi~t~-l interm~ te which is then treated with ccmm~rcially available (-)-(R)-glycidyl bu~y.ate. Warming to ~mhi~nt tempela~u ethen directly affords the 5-(hy-llv~yll~ethyl)nY~7oli~innnPs 6 in çn~nti~m~ric~lly ~nrif~h~-i form.
As shown in Chart III, compound 6 is then cv~lv~l~ed to the corresponding 26 mesylate 7 (R = methyl) or aryl slllfol ~t~ 7 (R = ArS02, for eY~mplP p-tolll~nPRulfonyl) by the action of, for eY~mp]e, mPth~nF!,slllfnnyl chloride/pyridine or mPt.ll~ne,Rulfonyl chloride/triethylamine/dichloromptll~np- orp-tolllpnp-R~lr(Jllyl chloride/pyridine. The rÇsnlt~nt slllfnn~te de.;vlltive 7 is then reacted with an azide source such as so~ lm or pot~RRillm azide in an aprotic solvent such as N,N-30 dimelLylL~ mi~e (DMF) or l-methyl-2-pyrroli~innne optionally in the presence of a catalyst such as 18-crown-6 at a temp~ ul~ of 50-90 ~C to afford the azide 8.
The azide is then reduced by hyLv~ t;nn with p~ illm on carbon or a pls~t;nllm catalyst in an applu,ul;ate solvent 8UCh as ethyl ~setstQ or mPth~nol to give the Cv~ uollding amine 9. ~lt~rn~t;vely, the azide 8 can be reduced by tre~t~nPnt with 36 a trivalent phosI?horus cu~,uuulld such as ~ iphPnylrhosrhinp in a suitable solvent 8UCh as tetraLyLuruldll followed by the ~ t;on of water. The int~rmPrli~tQ ~mine g WO 96/3~691 P~ JJ5~ ,!il.02 9 may also be prepared by tre~tmAnt of the pht~ imi~l~ del;vdlive 10 (obtained by reacting slllfnn~te 7 with potassium phth~limi-la in a suitable solvent, for example, ~-~etonitrile at relux tempeldtula) with methylamine in eth~nnl/H20 at reflux te~ dture. Alternatively, the amine 9 may be prepared dire~ ~ly from the 5 mesylate 7 by ~mmonolysis in a solvent system conRiRtinF of H20fispropanol/THF in a sealed reaction vessel immersed in a 70-9~ ~C oil bath. The amine 9 is then acylated by re~cti~ nR known to those skilled in the art to give ~ Yf~7.nli~ino~ Of structure 11. For example, the amine can be reacted with an acid chloride or anhydride in a basic solvent such as pyridine at a tempeldl,ula ranging from -30 to 10 30 ~C to provide the acylated compound 11 (R4 = optionally sllhstitlltP~ alkyl). It will be apparent to one skilled in the art that other carbonyl groups within the scope of this invention can be readily appended to the amine 9 by st~n-l~rd acylation techniques, for ~y~mple those hiFhliFhte(l in March, J. "Advanced Organic ChamiRtry", 3rd ed.; John Wiley & Sons: New York, 1985; p 370-375, to give 15 ~ ition~l eY~mpleR of 11. The oY~7oli~inonas 11 are ~Y~mple,s of structural Formula I, which are the subject of this invention.
As shown in Charts IV and V, s.slect~ Y~mplR~ of the fused bicyclic diazine and carba_ine cont~ining o~701i-linorlas 11, thamRçlves ~nffhA~tari~l agents of structural Formula I, can be further elaboldted to ~ ition~l compounds of Formula 20 I.
Co ,~ d 12 (see Chart IV), affi-~iRntly obtained by catalytic hyLvgenolysis of the cvll~E~ ling Cbz ~lvLec~ed der;v~Live 11 (Rl = CbzN), can be N-alkylated by procedures known to one skilled in the art, in~ ling tre~t~nRnt of 12 with alkylh~li.leS or togylates in the presence of a suitable base, to furnish cu.ll~vullds 13.
25 Alternatively, s~hRct~R~ alkyl groups can be appended on the nitrogen of 12 by a reductive alkylation procedure as described in March, J. "Advanced Organic Chami~try", 4th ed.; John Wiley & Sons: New York, 1992; p 898-900. Co~llpuulld 12 can also be c.,~vt:l~ed to various acylated d~l;vtltives 14 by trR~trnant of 12 with various carbonyl d~:l;v~lLves, such as acid chlorides, anhydrides and the like, in the 30 presence of ap~lvl,l;ate bases, and in suitable solvents known to one skilled in the art. .~imil~rly, slllfon~mi~a dc.;v~Lives 15 are prepared by reacting 12 with alkyl-and arylsulfonyl chlorides in the presence of ~ tohle ~mine bases and in a~plvpr;ate solvents known to one skilled in the art. Urethanes 16 are prepared from cvmpoulld 12 through the action of chlolvro~ ts~ and the like in the presence 35 of a~ l;ate bases and in suitable solvent systems known to one skilled in the art.

WO 96135691 PCT/~3S9.''~02 The above rli~cll~c~ion should be con~i~ered merely re}~S~se~t~tive in nature, since other de- ;v~Lives of 12 are possible, for example the reaction of 12 with an isocyanate to give ureas 14 (R = NHY, where Y is an optionally substitllte~l alkyl or phenyl group). Co~puu~lds 12-16 are fused bicyclic diazine PY~mr les of structural 6 Formula I, which are the subject of this invention.
Compound 17 (see Chart V), readily obtained from ketal 11 [R1 =
C(OCH2CH20)] by acidic hydrolysis, for PY~mplP with p-toluenesulfonic acid in ~cetone~water, can be further elaborated to ~ liti~n~l eY~mple.q of structural Formula I. For PY~mrle, various hydrazone del;v~liv~s 18 can be prepared by 10 reacting 17 with hydrazines, as described in Greene, T. W.; Wuts, P. G. M.
"Protective Groups in Organic SynthP~i~", 2nd ed.; John Wiley & Sons: New York, 1991, p 212-213 and March, J. "Advanced Organic ChPmi~try", 4t~s ed.; John Wiley& Sons: New York, 1992; p 904-905. Oximes 19 are readily prepared by reacting 17with, for PY~mple, hyds~-ylamine hy~ro. hl~ ri~e or mPthr~yylamine hydr~clsloride in 15 the presence of a suitable base, such as pyridine, and in an applo~;ate solvent, for in~ n~e mf~th~nnl, at ambient tempelal ~lre. Imines 20 are synth~Ri7~l by treating 17 with primary ~min~,s, as ~le.scrihe-l in March, J. "Advanced Organic Ch~mi~tryll~
4th ed.; John Wiley & Sons: New York, 1992; p 896-897. Olefinic de~;va~ives 21 are p~ d by reacting 17 with various ol~fin~ting reagents, such as ph~ sph- rus ylides 20 and the like, which are known to one skilled in the art. Re~ s .~ts~l v~ PY~mples are described in March, J. "Advanced Organic Ch~Tni~try", 4th ed.; John Wiley &
Sons: New York, 1992; p 956-963. The ketone moiety of 17 is ~m~n~hl~ to further mo-lifir~t;orl Re~-~tion of 17 with Lawesson's reagent or ~lt,ern~tive reagents, as described in March, J. "Advanced Organic Chemictry", 4th ed.; John Wiley & Sons:2~ New York, 1992; p 893-894, provides the c.,~ .J..~ing thi-k~tone 22. It will be apparent to one skilled in the art that further tr~n~form~tion~ of 17-22 are po~sihl~
For eY~m~l~, catalytic hydrv ~.lnt;~n con-liti~ nc or borane-based re-ln.~ti-~n m~tho~lA
selectively reduce the k~ne, oY~ne and olefin ml~i~t;?3, respectively, of 17, 1~ and 21 to give the corresponding hy~llv~y, amino and alkyl dL.;v~tivt~s, respectively.
30 Compound 17 can Pl80 be cu~v~:lLed to corresponding cyclic and acyclic ketals and dithio ketPls by reacting 17 with diols, ~ithiolR, l~lcnholl~ or thiols under con~itinn~
for eY~mrl~, described in Greene, T. W.; Wuts, P. G. M. "r}vL~ . Liv~: Groups inOrganic Synthesis", 2nd ed.; John Wiley & Sons: New York, 1991, p 177-207.
Compounds 17-22 and the above ~R~rihe~ de.;v~Lives ~:pres_-lt ~Y~mrleR of fused 3~ bicyclic carbazine n~Y~ inon~ ~ntih~-~ri~l agents, which are the subject of this invention.
It will be apparent to those skilled in the art that the described synthetic procedures for m~king fused bicyclic diazinyl and carbazinyl ~-Y~7o~ in~ e slntih~rt9ri~l agentg are merely laplasç~t~tive in nature and that alternative 5 synthetic ~lvces~es are known, for PY~mrlP some of those described in the cited references. It will also be apparent to those skilled in the art that the outlined synthetic plucess, with non-PR~ntiAl vari~ti~-nR, is readily adaptable to the preparation of ~iru~clic diazinyl and carbazinyl ~Y~7oli~inon~ antih~rtsrial agents of structural Formula II, which are also the subject of this invention (see Chart VI).

EXA~LE 1: (~o-N-rr3-r4-rcis-3-(carbobenzylt)y~y)-3.7-~ 37s~hicyclor3.3~olort~n-7-yll-3 flllt~rol?h~T~yll-?.-nY--5-r~Ys~7.~ in,yllm~th~yllacet~mi~e Step 1: cis-3-bPn7,yl-7-(2-fluoro-4-~itroph~T~vl)-3.7-~i~7~hicvclor3.3.01Octane To a solution of cis-3-benzyl-3,7-~i~7~hiryclo[3.3.0]octane (0.35 g, 1.73 mmol) in ~retonitrilP (10 mL) is added 3,4-difluoronitrobenzene (0.19 mL, 1.73 mmol) and pot~RRillm carbonate (0.60 g, 4.33 mmol) under a nitrogen ~tTnl sphPre at ambient tempelaLurt:. The reaction is stirred 15 hours, concentrated in vacuo, and diluted with ethyl acetate (100 mT-). The organic phase is washed with water (3Y20 mL) 20 and saline (20 mL), dried over sodium sulfate, conce..l~ ed in vacuo, and chrom~ lo~. aphed on silica gel (230-400 mesh, 100 mL), eluting with chlo~vfo~ /mpth~nol (99/1). The ~,uprop~iate fractions are comhinPf~ 0.49, TLC, chlo~vfu~ /mpth~nolJ 96/5) and conr~ntrated in vacuo to give the title compound,NMR (CDCl3) 7.94, 7.88, 7.29, 6.62, 3.73, 3.64, 3.44, 2.97, 2.75, 2.55.
Step 2: cis-3-(r~rbobPn7~yln~y)-7-r4-r(r~rbobpn7~y~ min~1-2-fluorophPrlyll-3.7-~i~7s~hicyclor3.3,010r~S~np cis-3-Benzyl-7-(2-fluoro-4-nitrophenyl)-3,7-~ hicyclo[3.3.o]octane (9.11 g, 26.71 mmol), THF (100 mL), and m~th~nol (50 mL) are comhin~-i with 10%
30 palladium on carbon (6.67 g) and nmmonillm formate (16.83 g, 266.90 mmol) under v~en~ heated to reflux for 2.5 hours, cooled to ~mhiPnt tellluela~ a~ stirred 15hours, filtered through celite and concentrated in vacuo to give crude cis-3-(4-aII~ino-2-fluorophenyl]-3,7-~ hiryclo[3.3.0]octsnP. cis-3-(4-Amino-2-fluorophenyl]-3,7-7~hicyclo[3.3.0]oct~nP, water (100 mT ), ~ceton~ (100 _L), and pot~RRillm 35 carbonate (7.75 g, 56.07 m~nol) are cc~mhinP~, cooled to 0~C, and benzylChlOrvrO~ ate i8 added 810wly. The reaction i8 warmed to slmhi~nt ~ PeL~

WO 96135691 PCT/US9G~ C2 stirred 15 hours, con-antrated in vacuo, and diluted with ethyl ~et~te The organic phase is washed with water (2x150 mL) and sPline (150 mL), dried over sodium suLfate, corlcel.t-dted in vacuo, and chrom~t~ a~hed on silica gel (230-400 mesh, 100 mL), eluting with hf-Y~na/ethyl ~cet~ (80/20). The a~Lvpl;ate fractions are 5 comhina-l (Rf~ 0.41, TLC, hPY~nPIethyl acetate, 50/50) and cont~e~nl~dted in vacuo to give the title ~u~ uul-d, mp 121-122~C.

Step 3: (R)-r3-r4-rcis-3-(-qrbob~n7,yl--~v)-3.7-~ q7~qhicvclor3.3.0lo~t-qn-7-yll-3-flllr~ro~h~ -5-oy~7~ yllmpt~h~n~l To a flame dried flask cooled to -78~C and equipped with a nitrogen inlet is uduced cis-3-(carbobenzyloxy)-7-[4-Kcarbobenzyloxy)amino]-2-fluorophenyl]-3,7-~i~q7~hi~yclo[3.3.o]octane (7.25 g, 14.81 mmol), THF (100 mL), and 1.6 M butyl 1;l1.;.. (9.72 mL, 15.55 mmol). The reaction is stirred at -78~C for 1 hour before (R)-(-)-glycidyl bu~yldte (2.26 mL, 15.99 mmol) is added slowly and stirred for 2 16 hours at -78~C and 15 hours at S~mhiant tempeldLu~e. Saturated ~mmnninm chloride (50 mT.) is added and the aqueous phase is extracted wit-h- ethyl qcet~t~
(2x50 mL). The extracts are combined, washed with saline (50 mL), dried over so~ lm sulfate, cQnce~t ated in vacuo, and chrom~t,o~.dphed on silica gel (230-400 mesh, 100 mL), eluting with chlolur~ /mPthqnol (99/1). The applù~. ;ate fractions 20 are comhine~ 0.13, TLC, chloro~J/math~nnl~ 95/5) and conc~l d~ed in vacuo to give the title compound, mp 168-171~C.

Step 4~ )-N-rr3-r4-rcis-3-(CqrbobPn7~yloxy)-3.7-~i~7~hicvclor3.3.0ln~n-7-vll-3-flll- ropher~ Y ~-6-oY,q7~ inyllmat.hvll,q~.al q...i~
To a flame dried flask equipped with a nitrogen inlet is introduced (R)-[3-[4-[cis-3-(carbobenzyloxy)-3,7-~i~7~hi~yclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-~Ys~7nli~inyl]mp~hz~n~l (1.75 g, 3.84 mmol) and methylene chlori~la- (100 mL) cooled to 0~C. Triethylamine (0.80 mT., 5.76 mmol) and mPth~npslllfr~nyl ~-hl~ri~a are added, stirred at 0~C for 2 hours, and warmed to ~mhiant te~elal,u~ for 1 hour. The renrt;on is washed with water (30 mL), sa~ ted so~inm bicarbonate (30 ~), and ~ saline (30 mT-), dried over so~linm sulfate, and cQnre~l rdted in vacuo to give the crude (R)-[[3-[4-[cis-3-(c~bobenzyloxy)-3~7-~in7~hi~yclo[3.3.o]octan-7-yl]-3-- fluorophenyU-2-oxo-5--~Y~7~ inyl]methyUm~t~na8lllf ~n~te. (R)-[[3-[4-[cis-3-(Ca~l,obe~zyloxy)-3,7-~i~7~hicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oy~7~ inyl]methyl]mpths~naBlllfnn~te i8 c-mhin~d in a rese~l~hle tube with THF (5 _L), isopropanol (5 mL), and ccncc...l~ated ~mmr~nillm hyd~u~ide (10 _L) and WO 9613S691 PCTIUS~ 02 heated to 95~C for 10 hours. The reaction is diluted with methylene chloride (50mL) and washed with saline (30 mT-), dried over sodium sulfate, concPntrated in vacuo to give (S)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-~ 7~hi-.yclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oY~7oli~inyl]methyl]amine. The crude (S)-[[3-[4-[cis-3-5 (carbobenzyloxy)-3,7-~i~7~h;cyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-ny~7oli~linyl]methyl]amine (1.67 g, 3.67 mmol) is dissolved in methylene chloride (20 mL), cooled to 0~C under nitrogen, pyridine (0.89 mT., 11.02 mmol) and acetic anhydride (0.43 _L, 4.59 mmol) are added, and the reaction is stirred 15 hours at slmhiPnt temperature. The reaction is diluted with methylene chloride (50 mL), 10 washed with lN HCl (25 mT.), ~atu clted so~ m bicarbonate (25 mL), saline (25mI ), dried over sodium sulfate, col cPntrated in vacuo, and chrom~tographed on silica gel (230-400 mesh, 200 mL), eluting with chlolvÇul~/mPth~nol (98/2). The aAu,uio~.;ate fractions are comhinçd (Rf~ 0.15, TLC, chlorofoLI~/methAnol~ 95/5) and concentrated in uacuo to give the title compound, mp 165-168~C.
EXAMPLE 2: (S)-N-rr3-r3-fluoro-4-rcis-3-(ban7~yl--Y,yacetyl)-3.7-7slhi~yclor3.3~olor~n-7-yll~hp-n~ll-2-~yn-s-ny~7nli~ yllmpth~yllacets~mi~p (S)-N-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-rli~7~hiryclo[3.3.0]octan-7-yl]-3-fluorophenyll-2-oxo-5-nY~7oli-1inyl]methyl]~r~et~mi-la (150 mg, 0.30 mmol), methylene 20 ~~hlnri~le (5 mL), and mP~h~nol (10 mL) are comhinP~ with 10% palladil~m on carbon (30 mg) and placed under a hyd.v~ tmo~phPre (balloon) for 15 hours. The reaction is filtered through celite and con~entrated in vacuo to give crude (S)-N-[[3-[4-[cis-3,7-~i~7~hicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-0~s~7nli~inyl]methyl]fl~et~mirle. The crude amine is taken up in methylene chloride 25 (15 mL), cooled to 0~C, and triethylamine (0.09 mL, 0.67 mmol) and benzyloxyacetyl chloride (0.06 mL, 0.40 mmol) are added. The reaction i8 warmed to ~mhiPnt tempelr ~u~ a, stirred 15 hours, and diluted with methylene chloride (100 mL). The organic phase is washed with water (2x50 mL) and saline (150 mL), dried over sodium sulfate, conrç..l-dted in vacuo, and chrom~t,o~ ,uhed on silica gel (230400 30 mesh, 100 mL), eluting with chlorvru..l./mPth~nol (95/5). The a~u~uro~u~;ate fractions are comhinP~ 0.41, TLC, chlo.vru.~/mPt~nnol, 90/10) and COI~C~lt~dted in vacuo to give the title cvlLlpuuLLd, mp 138-140~C.

F~AMPLE 3: (,O-N-rr3-r3-fluoro-4-rcis-3-(l~y.l . . .~cetyl)-3.7-~i~7nhi~yclor3.3.olort~n 35 7-yll;~hPr~yll-~ y~-5-t~y~7nlit~ yllmpt~yll~r~ts~ a The (s)-N-[[3-[3-fluoro~-[cis-3-(benzyloxyacetyl)-3~7-~ 7~hicyclo[3.3.o]octan-7 WO 96135691 PCT~US!76~ 202 yl]phenyl~-2-oxo-6-.~,Y~7~ inyl]methyl]~cet~mi-1e (110 mg, 0.22 mmol), methanol(25mT ) and 10% p~ll~ lm on carbon (100 mg) are combined and placed under 40 p.8 i. of hydlv~ and Rh~k~n for 5 days. The reaction i8 filtered through celite,conr.~ aled in vacuo, and chrom~t~Agraphed on silica gel (230-400 mesh, 100 mL),5 eluting with chlol~,rul.~l/m~tl~nol (95/5). The ~p~ liate fractiong are comhin~
(Rf~ 0.20, TLC, chlolofol..Jm~t~ nol, 90/10) and c.~nt~e-.L.dted in vacuo to give the title ~ o-.~pound, mp 167-168~C.

lPLE 4~ N-rr3-r3-flllnro-4-rcis-3-(5-i~ny~7Alin~yl)-3.7 10 (~ hicvclor3.3.olortAn-7-yll~hRrl,y~ -n~ -5-~ 7~ irl,yllmRt~vllflr~t:Amirlr (S)-N-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-~ 7~hic.yclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5--~Y~7oli-linyl]methyl]acetamide (150 mg, 0.30 mmol), methylene .~hl~~ri~e (5 mL), and m~th~n.~l (10 mT.) are comhinecl with 10% palladium on carbon (30 mg) and placed under a hy~;lrù~n ~tmoRph~re (balloon) for 15 hours. The 15 reaction is filtered through celite and con- e~ al ed in vacuo to give crude (S)-N-[[3-[4-[cis-3,7-~ hi-~yclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-nYA7nli~1inyl]methyl]~ret-mifl~. To the crude (S)-N-[[3-[4-[cis-3,7-~li~7shicyclo[3.3.0]octan 7-yl]-3 fluorophenyl]-2-oxo-5-oY~7nli~1inyl]methyl]~cet~mi~1 (115 mg, 0.30 mmol) dissolved in pyridine (5 mL) at 0~C is added 1-(3-20 dimethylaminopropyl)-3-ethylcarbo~iimi~ hydlucllloride (70 mg, 0.35 mmol), 4-dimethyl~minopyridine (5 mg, 0.05 mmol), and iR.~,Y~7.~,le 5-carboxylic acid (40 mg, 0.35 mmol). The reaction is warmed to ~mhient tempelf~Lu~e, stirred 15 hours, diluted with methylene ~~hl-~Jri~le (30 mL). The organic phase is washed with lN HCl (20 mL) and saline (20 mL), dried over sodium sulfate, cvnrentrated in vacuo, and 25 chrom~t{~graphed on silica gel (230-400 mesh, 100 mL), eluting with chlul~ru~/m~th~nnl (97/3). The ap~rù~;ate fractions are comhinerl (Rfc 0.16, TLC, chlolofoL~/m~t~nnl, 95/5) and cnnce..~ ted in uacuo to give the title ccmpou,.d, mp 172-175~C.

30 Ii'XAlVrPLE 5~ -N-rr3-r3-flllnro~-rcis-3-(~-intl~~lyl~Arb~ yl)-3.7-tliA7Ahicvclor3.3.olvt~t~n-7 yl~har~ ~,Yn-5-nys~ yllmathvllA~Aat.~ a Following the general ~cedul~ of P~AMpLE 4 and m~ kin~ noncritical v~ri tion~ but ~lh~l:l~.l ;--e indole-2-carboYylic acid (60 mg, 0.35 mmol) for i~nY~~~ole 5 c~l,u..ylic acid, the title co~ûulld i8 obtained, mp 211~C.
rPLE 6 (lO-N-rr3-r3-fluoro~-rcis-3-(~~~rb~~mathny~y)-3.7-t~ hi~ r3.3.oln~ n WO 96/35691 PCT/U~,~''(J5:~02 7-yl~h~rl,yll-2-- Yo-5-oyz~ yllm~t~,yllacet~slm~
Following the general procedure of EXAMPLE 2 and m~king noncritical v~ri~t;on~ but sllh~ .,l ;.,g methyl chlorofo.illate (80 mg, 0.80 mmol) for benzyloxyacetyl chloride, so~lillm bicarbonate (240 mg, 2.80 mmol) for triethyl~mine, 5 and using ~(etone (5 mL) and water (5 mL) as solvent, the title compound iB
obtained, mp 128-132~C.

EXAMPLE 7: (S)-N-rr3-r3-fluoro-4-rcis-3-(formyl)-3.7-~ 7~hicvclor3.3 0loct~n-7-yll,Dh~r~,yll-~--Yn-5-oxsl7olit~ ,yllm~t~,yllacetslmide Following the general procedure of EXAMPLE 4 and m~kinF noncritical variations but sllhstitnting formic acid (40 mg, 0.60 mmol) for i~nY~7ole-5-carbo~y-ylic acid, the title compound is obtained, HRMS calcd for ClgH23N4F04 390.1703.
Found: 390.1709.

EXAMPLE 8: (S)-N-rr3-r3-fluoro4-rcis-3-(~tyl)-3.7-~ 7~hicyclor3.3.0loGt~n-7-yll}?h~r~yll-2-nyn-5-l Y~7~ yllm~th~yllacet~mide Following the general procedure of EXAMPLE 2 and m~king noncritical v~ri~ti~n~ but ~llh5~ g acetyl chloride (80 mg, 1.05 mmol) for benzyloxyacetyl chloride, the title compound is obt~ine~ mp 168-170~C.
F'XAl\~PLE 9: (~)-N-rr3-r4-rcis-3-(~rbob~n7~y~ y)-3.7-~i~7~hicyclor3.3.oloGt~n-7yll;c h~r~yll-~ rn-5-n~r~7~ invllm~thyllacetslmifl~
Step 1: czs-3-benzyl-7-(4-nitrophenyl)-3,7-diazabicyclo[3.3.0]octane Following the general procedure of EXAMPLE 1, Step 1 and m~king noncritical variations but substituting 4-fluoronitroberl7en~ (8.16 g, 57.80 mmol) for 3,4-difluoronitrobenzen~, the interm.s~i~tQ title cv~pou~d is obtained, mp 121-123~C.
Step 2: cis-3-(carbobenzyloxy)-7-[4-[(carbobenzyloxy)amino]phenyl]-3,7-rlin7~hicyclo[3.3.o]octane Following the general procedure of EXAMPLE 1, Step 2 and m~king noncritical variations but sllhEt;tllt;nF cis-3-benzyl-7-(4-nitrophenyl)-3,7-7ohicyclo[3.3.o]octane (1.00 g, 3.10 mmol) for cis-3-benzyl-7-(2-fluoro-4-nitrophenyl)-3,7--lio7~hicyclo[3.3.0]oct-on~, the interme~i~t~ title compound isobtoin~l, mp 145-146~C.
Step 3: (R)-[3-[4-[cis-3-(carbobenzyloxy)-3,7--lio7-ohir~yclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-cY-o.7nli~inyl]m~tl1onnl wo 96/35691 PCT~IJS96/OS2D2 Following the general procedure of EXAMPLE 1, Step 3 and m~king noncritical variations but sl~h~L;~ F cis-3-(carbobenzyloxy)-7-[4-Kcarbobenzyloxy)amuno]phenyl]-3,7-~ 7~hi.yclo[3.3.0]octane (575 mg, 1.22 mmol) for cis-3-(carbobenzyloxy)-7-[4-[(carbobenzyloxy)amino]-3-fluorophenyl]-3,7-5 ~ 7~hil.yclo[3.3.0]octane, the inte~nP~ te title compound is obtained, mp 163- 164~C.
Step 4: (S)-N-[[3-[4-[cis-3-(carbobenzyloxy)-3,7~ 7~hir.yclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-- Y~7oli~1inyl]methyl]acetamide Following the general ~-wedu- e of ~Al\/rpLE 1, Step 4 and m~king 10 noncritical variatiûns but snh~ ;g (R)-[3-[4-[cis-3-(carbobenzyloxy)-3,7-7~hiryclo[3.3.0]octan-7-yl]phenyl]-2-oxo-6-Q~7~ inyl]methanol (280 mg, 0.65 mmol) for (R)-[[3-[4-[cis-3-(carbobenzyloxy)-3~7-~i~7~hi~yclo[3.3.o]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oY~7oli-linyl]m-oth~nnl, the title compound i9 obtained, mp 136-140~C.
EXAMPLE 10: (~)-N-rr3-r3-fluoro-4-rcis-2-(r~rboban7vloxv)-~ 8-~i~7~hicvclor4~3.oln~m~n-8-yll~hf~Tlyll-~2-n~ -6-o~fl7nlitliT~vllm~t~l,yllacets1~nitlf~
Step 1:
(, )-cis-2,8-~ 7~hi-yclo[4.3.0]non~ne (24.6 mmol) was dissolved into 30 mL of dry DMSO. The solllti- ~ was treated with K2HP04 (8.6 g, 49.2 mmol) followed by 3,4-difluoronitrobenzene (3.9 g, 24.6 mmol). The ~lu~2 became a bright orange color. The ~lu~ was stirred for 20 hours at ~mhi~nt temperature under N2.
After this time the ~ LuLe was poured into a sepa ato~.~ funnel along with CHC13.
The solllti~n was washed with H20 and brine. The organic phase was separated and dried over anhydrous Na2SO4. The solution was filtered and concentrated to give an orange oil that was purified by chrcTn~ ;.d~hy on silica gel eluting with a gradient of 1-5~o MeOH/CHC13. This gave 4.2 g of product as an orange waxy solid.
MP: 77-79~C.
Step 2:
The nitro aromatic product obtained in Stepl (1.5 g, 5.6~ mmol) was - dissolved into 50 mT- of THF. The solllti~n was treated with the catalyst 10~o Pd/C
under a stre~m of N2. The ~ixlule was rle~Rqe~l by ev~r~ 9ti~n and flllqhine with N2 (3 times), followed by eV~cll~ti~n and flush with H2 (3 times). The ~i~ was m~int~in~r~ at 35 psi of H2 and was qh~k~n on the parr. After 4 hours of re~-~t;~ n time TLC showed starting m~tATi~l was c~ nqllmP~ This solllff~n was diluted with50 mL of 1:1 ~ eton~H2O and the ~i~ e was cooled to 0~C. The reaction ~i~ e CA 022l8088 l997- lO- lO

was treated with solid NaHC03 (1.4 g, 17.0 mmol) followed by benzyl chlu~vru~ ate (2.0 g, 11.9 mmol). This llLi~L,Ul~ was left to stir overnight with warming to room tempel~tu.e. After 16 hours the reaction llli~Lure was diluted with CH2C12 and filtered through celite. The filtrate was poured into a separatory funnel along with 5 H20. The lllixlu~ was RhQk~n and the organic phase was separated, washed with brine followed by drying over anhydrous Na2SO4. The solntinn was filtered and concçntrated to give a solid that was purified by chromslt~.a~hy on silica gel eluting with 5:1 hPY~n~EtOAc. TRnlQt~-l 2.0 g of U-141248 as a yellow solid. This material was recystallyzed from 10% EtOAc/hexane to give a white solid. MP: 139-10 140~C.Step 3:
The product of Step 2 (505 mg, 1.00 mmol) was dissolved into 10 mL of dry THF and the solntion was cooled to -78~C. The solution was treated with n-BuLi (1.6 M soln. in hP~Qnes; Aldrich; 656 ,uL, 1.05 mmol) via syringe. After 10 minutes 15 (R)-glycidyl butyrate (151 mg, 1.05 mmol) was added and the l~lule was left to stir overnight with warming to room tempelatu.~. After 14 hours the l~lule was PY~min~ by TLC which showed the starting m~t~riQl was conRllmP-l The reaction was poured into a separatory funnel along with EtOAc. The lllil~lule was washed with sdl ulated aqueous NH4Cl and brine. The organic phase was separated and 20 dried over anhydrous Na2SO4. Filtered and conc~t dted to give a residue that was purified by radial chromQt~graphy eluting with a gradient of 1-3% MeOH/CHC13.
TRnlQt~l 294 mg of 5-(hydlvl~ylllethyl)oy~nlitlinone intermp~ q as a tan foam. MP:
71-73~C.
Step 4:
The alcohol obtained in Step3 (880 mg, 1.90 mmol) was dissolved into 15 mL
of dry CH2C12 and the sollltinn was cooled to 0~C. The solllt;~ n was treated with Et3N (336 mg, 3.32 mmol) and stirred for 5 minnt~R Next solid 3-nitrobqn~en~RlllfoTlyl chloride (NosylCl, 561 mg, 2.53 mmol) was added and the ~i~lule was stored in the freezer overnight. After 15 hours TLC showed the starting alcohol was conRllm~-l with the fr~rmQtion of a new higher Rf product. The reaction was poured into a s~at~l ,r funnel along with CH2C12. The solnt;~n was washed with 1.0 N aqueous HCl and sdl~u~d~ed sotlinm bicarbonate. The organic phase was separated and dried over anhydrous Na2S04. Filtered and concentrated to give 1.3 g of the nosylate as an orange foam. This mQtqriQl was used without pllrifics~ti~n wo s6r3s6sl PCT/US~>C,'~,Ji202 Step 6:
The crude nosylate (1.9 mmol) was dissolved into 10 mL of CH3CN and the ~ollltion was transfered to a rP,sP~l~hlP tube. The ~olnt;o~ was diluted with 5 mL of isopropanol and 10 mL of 28% aqueous NH40H. The tube was 6ealed and heated to 65~C. After 15 hours the sollltil n was cooled to ~mhi~nt temper~tula and TLC
showed that the nosylate was consumed. The reaction was poured into a sep~dlc~.
funnel along with CH2C12. The solllti- n was washed wit-h- saLu~ aLed aqueous NaHCO3 and brine. The organic phase was separated and dried over anhydrous Na2S04. Filtered and con~upntrated to give the crude amine as a foam. This 10 material was dissolved into 20 mL of dry CH2Cl2 and the ~olllti~n was cooled to 0~C.
The reaction was treated with 500 ~L of dry pyridine along with an excess of Ac2O
(200 IlL). This l~Lu~ was left to stir overnight with warming to room temperature. After 18 hours the reaction ~llixLu~e was poured into a separatory funnel along with CH2Cl2. The solution was washed with 1.0 N aqueous HCl and 15 saturated aqueous NaHC03. The organic phase was separated and dried over anhydrous Na2SO4. The sollltion was filtered and conre~ ated to give a tan foam that was purified on silica gel by radial chrnm~t~graphy eluting with 3%
MeOH/CHCl3. This provided 776 mg of the title compound as a tan foam (l~u~e of diastereomers). MP: 74-76~C. HRMS (EI) calcd for C27H31FN405 510.2278, 20 found 510.2278.

EXAMPLE 11: (S)-N-rr3-r3-fluoro-4-rcis-2-(~s~rbomPtho~y) 7.~hicyclor4.3.olnnn~n-8-yll~?harlyll-2-n~n-5-~ 7~ yllmf~t.l~yllacet~mi~la Step 1:
The starting material, ~Al\/rPLE 10, (850 mg, 1.7 mmol) was dissolved into 20 mL of MeOH. The solnti~ n was treated with the catalyst 10~o Pd/C (85 mg) under a stream of N2. The parr bottle was eV~r~ t~e~l and fln~h~ with N2 (3 times) followed by ev~ t;~ n and flll~h~cl with H2 (3 times). The ~ c was m~int~i at 35 psi of H2 ~I~E~ and was ~h~k~n on the parr. After 10 hours of reaction 30 time TLC showed starting m~t,~ri~l was con~llm~ The solnt;~n was filtered through celite and the filtrate was conr~ ed under reduced P~ to give 585 mg of a tan foam. This crude amine was used without purificS~t;~n Step 2:
The crude ~mine (380 mg, 1.01 mmol) was dissolved into 2:1 slreton~/H2O
35 and the solllt;~ was cooled to 0~C. Solid NaHC03 (170 mg, 2.02 mmol) was added WO 96/35691 P~~ 3~ 1J5202 along with methyl chlorofo,-,-ate (119 mg, 1.26 mmol). The mixture was left to stir overnight with warming to room tempelature. After 16 hours the reaction ~i~Ul~
was poured into a separatory funnel along with CH2C12. The ~ cLule was washed with H2O and brine. The organic phase was separated and dried over anhydrous 5 Na2SOg. The solllti~n was filtered and conce~.t-dted to give a white foam that was purified by radial chro~ hy eluting with 20% CH3CN/CHCl3. This gave 367 mg of the title co~ oulld as a white foam (mixture of diastereomers). MP: 83-85~C.
HRMS tEI) calcd for C2lH27FN405 434.1965, found 434.1971.

10 EXA~LE 12: (s)-N-rr3-r3-fluoro4-rcis-?-(~pt~ y~p-tvl)-2.8-hicyclor4.3.olnon~n-8-yllI~hpll~yll-2-o~ -5-n~ra7:oli~ yllmpt~yllacet~mitl~s Step 1:
The crude amine intermP~ te described in EXAMPLE 11, Step 1, (500 mg, 1.33 mmol) was dissolved into 10 mL of dry CH2Cl2. The solution was cooled to 0~C
15 and treated with 1.0 mL of dry pyridine followed by acetoxyacetyl chloride (218 mg, 1.59 mmol). This ~ lul~ was left to stir overnight with w~ g to room tempe,dture. After 18 hours TLC showed starting material was consumed. The reaction l~ lule was poured into a s~aldto,.~ funnel along with CH2C12. The golllt;~n was washed with 0.5 N aqueous HCl, saLu,dted aqueous NaHC03 and 20 brine. The organic phase was separated and dried over anhydrous Na2SO4.
Filtered and con-~e..~ Led to give a gum that was purified by radial chrom~ .d~hy eluting with 10% CH3CN/2~o MeOH/CHC13. This gave 426 mg of the title co~pound as a white foamy solid (l~ Lu~ of diastereomers). MP: 113-116~C.
HRMS (EI) calcd for C23H29FN4O6 476.2071, found 476.2065.
F'.~AlVIPLE 13: (~o-N-rr3-r3-fluoro-4-rcis-2-(~ cetyl)-~ 8-hi~yclor4.3.0ln~ n-8-yllI~hPrl,yll-~ o-5-~ yllm~t~h~ylla~t~mi( Step 1:
The starting material, EXAMPLE 12, (325 mg, 0.68 mmol) was dissolved into 30 6 mT- of MeOH. The solllt;on was cooled to 0~C under N2. The sohlt;on was treated with 3.0 mT- of 10% aqueous K2C03. The ~ Lule was ~tirred for 2 hours. After this time TLC showed U-141950 was cQn~llmP-l The reaction was qllPn~he~l with 1.0 N aqueous HCl to pH 6.5 (litmus). The reaction ~ Lul~ was poured into a se~a~dtc,,.~ funnel along with CH2Cl2. The solllt;~n was washed with H20 and 35 brine. The organic phase was se~alated and dried over anhydrous Na2S04.
Filtered and conc~-.t .lted to give 276 mg of the title CO~ d as a white foam WO 96/3~i691 PCT/USg6,'v~3~02 (lLUALU~ of diastereomers). ~: 102-110~C.
HRMS (EI) calcd for C2lH27FN405 434.1965, found 434.1976.
Following the general procedures outlined in the Charts and in view of the terhniques used in the ~l~mple~ 1-13, in particular to prepare (S)-N-[[3-[3-fluoro4-tcis-3-(carbobenzyloxy)-3,7-.li~hiryclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oy~nli~inyl]methyl]~cet~mi~le (F~Y~mrlP, 1), (S)-N-[[3-[3-fluoro4-[cis-3-(benzyloxyacetyl)-3,7-~i~7~hiryclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oY~oli~inyl]methyl]flcet~mi~le (Example 2); (S)-N-[[3-[3-fluoro-4-[cis-3-(hyL o~y~cetyl)-3,7-~ hicyclO[3.3.0]octan-7-yl]phenyl]-2-oxO-5-10 oY~ inyl]methyl]~cet~mi(le (Example 3); and (S)-N-[[3-[3-fluoro4-[cis-3-(5-iRrYs~olinr~yl)-3,7-~ 7~hiryclo[3.3.0]octan-7-yl]phenyl]-2-oxo-6-~-Y~7~ inyl]methyl]~etslmitle (~y~mple 4) the following sl~tlit;on~l compounds of Formula I can be prepared:
(S)-N-[[3-[3-fluoro4-[cis-3-(acetoxyacetyl)-3,7~ hi-yclo[3.3.0]octan-7-16 yl]phenyl]-2-oxo-5-oY~oli-linyl]methyl]~ret~mitle;

(S)-N-[[3-[3-fluoro4-[cis-3-(formyl)-3,7-~ hicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5---Y~olitlinyl]methyl]slret~mi.l~;

(S)-N-[[3-[3-fluoro4-[cis-3-(methylsulfonyl)-3,7--liQ7~hiryclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-cy~7oli~linyl]methyl]~

(S)-N-[[3-[3-fluoro4-[cis-3-(2-fluoroethyl)-3,7-~ hi~yclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-n~ nli-linyl]methyl]~cet~mi.lP;
(S)-N-[[3-[3-fluoro4-[cis-3-(2-hyLuAye~lyl)-3,7-~ hiryclo[3.3.o]octan-7 yl]phenyl]-2-oxo-5-~Y~7nli~inyl]methyl]~r~~ P;

(S)-N-[[3-[3-fluoro4-[cis-3-(2-mPth.~y~ yl)-3~7-~ hicyclo[3.3.o]octan-7 30 yl]phenyl]-2-oxo-5-oys~ inyl]methyl]s~cet~mi~lp;

(S)-N-[[3-[3-fluoro-4-[cis-3-(cys~n~mf~t~yl)-3,7-~ hiryclo[3.3.o]octan-7 yl]phellyl]-2-oxo-5-~ YS~7~ inyl]methyl]~~~ P;

(S)-N-[[3-[3-fluoro4-[cis-3-(carbnmPtht~yy)-3~7-~ hicyclo[3.3.o]octan-7 yl]phenyl]-2-oxo-5-oy~7~ inyl]methyl]~et~mirl~;

(S)-N-[[3-[3-fluoro-4-[(5,5)-2-(carbobenzyloxy)-2,8-~ hi( yclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-(~Y~7.oli-1inyl]methyl]ace+~mi~1a;

(S)-N-[[3-[3-fluoro-4-[(5,5)-2-(hy.lio~y~lcetyl)-2~8-~ 7~hiryclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-nYs3701i-1inyl]methyl]slr,etslmi~1a;

(S)-N-[[3-[3-fluoro4-[(S,S)-2-(acetoxyacetyl)-2,8-~i~7~hicyclo[4.3.0]non-8-yuphenyl]-2-oxo-5-ny~7~ inyl]methyl]~re+~mi~lp;

(S)-N-[[3-[3-fluoro4-[(S,S)-2-(formyl)-2,8-~ 7~hiryclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-nY~7oli~inyl]methyl]~r~et~mifle;

(S)-N-[[3-[3-fluoro4-[(5,5)-2-(methylsulfonyl)-2,8-~ 7~hicyclo[4.3.0]non-8-yl]phenyl]-2-oxo-5--)Y~701itlinyl]methyl]~r,et~mitle;
(S)-N-[[3-[3-fluoro4-[(5,5)-2-(2-fluoroelhyl)-2,8-~ 7~hir.yclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-ny~7Q~ inyl]methyl]~r~et~mi~lp;

(S)-N-[[3-[3-fluoro4-[(5,5)-2-(2-hy~liv,~y~Lhyl)-2~8-~ 7~hiryclo[4.3.o]non-8 20 yl]phenyl]-2-oxo-5-ny~7nli~inyl]met-h-yl]~re+slmi(~a-;

(S)-N-[[3-[3-fluoro4-[(5,5)-2-(2-mPth~Yy~ yl)-2,8-~ 7~hir.yclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-nY~7oli~inyl]methyl]s~retSImi~lP;

25 (S)-N-[[3-[3-fluoro4-[(5,5)-2-(cyslnnmP+hyl)-2,8-~ 7~hir.yclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-nYS~7Oli~inyl]methyl]&~rets~mi-l ~a;

(S)-N-[[3-[3-fluoro4-[(5,5)-2-(carbomPtl~nyy)-2~8-fli~7~hiryclo[4.3.o]non-8 yl]phenyl]-2-oxo-5-ny~7oli~linyl]methyl]~rets7mi~a;
(S)-N-[[3-[3-fluoro4-[(R,R)-2-(carbobenzyloxy)-2,8-tli~7~hiryclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-c~y~7~ inyl]methyl]~r~et~m (S)-N-[[3-[3-fluoro4-[(R,R)-2 (lly~lrvl~y~lcetyl)-2~8-~i~7~hiryclo[4.3.o]non-8 35 yl]phenyl]-2-oxo-5-nys~7~ inyl]methyus~r~ t~

WO 96135691 PCT~US~5.'J.5~a2 (S)-N-[[3-[3-fluoro-4-[(R,R)-2-(acetu~y~cetyl)-2,8-rli~7~hicyclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-~Y~7oliflinyl]methyl]s~.~.et~miclP;

(S)-N-[[3-[3-fluoro-4-[(R,R)-2-(formyl)-2,8-.li~7~hiryclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-nY~7n~ inyl]methyl]~- et~mi~le;

(S)-N-[[3-[3-fluoro-4-[(R,R)-2-(methylsulfonyl)-2,8-~ 7~hiryclo[4.3.0]non-8-yl]phenyu-2-oxo-5-~y~7~ inyl]methyl]~et~m~

(S)-N-[[3-[3-fluoro-4-[(R,R)-2-(2-fluolo~Lhyl)-2,8-~ 7~hicyclo[4.3.0]non-8-yuphenyl]-2-oxo-5-oy~7Qli~linyl]methyl]~et~mi~a (S)-N-[[3-[3-fluoro4-[(R,R)-2-(2-hy~ y~l~,yl)-2,8-tli~7~hicyclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-oY~7~ inyl]methyl]~et~mi~le;

(S)-N-[[3-[3-fluoro4-[(R,R)-2-(2-me~.hn~ryethyl)-2,8-~ 7~hicyclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-oy~7~ inyl]methyl]acet~mi~

(S)-N-[[3-[3-fluoro4-[(R,R)-2-(cy~nomPtl~yl)-2,8-~i~7~hit~.yclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-QY~7~ inyl]methyl]~l~et~mi~

(S)-N-[[3-[3-fluoro-4-[(R,R)-2-(carbom~th- Yy)-2,8-~ hicyclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-nY~7Qliflinyl]methyl]~cet~mi~

(S)-N-[[3-[3-fluoro-4-[cis-3-(carbobenzyloxy)-3,6-~ 7~hi~yclo[3.2.0]heptan-6-yl]phenyl]-2-oxo-5-ny~7~ inyl]methyl]~et~mitlp;

(S)-N-[[3-[3-fluoro4-[cis-3-(hy~ ,Ay~cetyl)-3,6-~i~7~hicyclo[3.2.0]heptan-6-yl]phenyl]-2-oxo-5-- Y~7~ inyl]methyl]iqcet~

(S)-N-[[3-[3-fluoro4-[cis-3-(ace~o~y~cetyl)-3~6-~ 7~hiryclo[3.2.o]heptan-6 yl]phenyl]-2-oxo-5-ny~7~ inyl]methyl]~l~et~mi~;

(S)-N-[[3-[3-fluoro4-[cis-3-(formyl)-3,6-~ 7~hicyclo[3.2.0]heptan-6-yl]phenyl]-3~i 2-oxo-5-nY~7~ inyl]methyl]~r~tç~

CA 02218088 1997- lo- lo (S)-N-[[3-[3-fluoro4-[cis-3-(met,hylsulfonyl)-3,6~hicyclo[3.2.0]heptan-6-yl]phenyl]-2-oxo-5-~Y~7:oli-linyl]methyl]~cet~mi~1e;

(S)-N-[[3-[3-fluoro-4-[cis-3-(2-fluo~vt l~lyl)-3,6-~ hicyclo[3.2.o]heptan-6 yl]phenyl]-2-oxo-5-nY~oli-linyl]methyl]S~-~et~mi-lP

(S)-N-[[3-[3-fluoro-4-[cis-3-(2-hydlu~y.3t~lyl)-3,6-diazabicyclo[3.2.0]heptan-6-yl]phenyl]-2-oxo-5-~y~oli~inyl]methyl]s~et~mi~lp;

(S)-N-[[3-[3-fluoro-4-[cis-3-(2-mPth- Yyethyl)-3,6-~ hi~yclo[3.2.o]heptan-6 yl]phenyl]-2-oxo-5-~y~:oli~inyl]methyl]~et~mi~

(S)-N-[[3-[3-fluoro-4-[cis-3-(cy~nomPthyl)-3,6-rli~ hicyclo[3.2.0]heptan-6-yl]phenyl]-2-oxo-5-1~Y~oliflinyl]methyl]~et~mille (S)-N-[[3-[3-fluoro-4-[cis-3-(carbomPthoYy)-3,6-~hi~.yclo[3.2.0]heptan-6-yl]phenyl]-2-oxo-5-c Y~olirlinyl]methyl]~cet~mi~p (S)-N-[[3-[3-fluoro-4-[cis-6-(carbobenzyloxy)-3,6-~ hicyclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-oy~7oli~linyl]methyl]~cet~mi~p;

(S)-N-[[3-[3-fluoro-4-[cis-6-(hyd~ v~y~cetyl)-3,6-~ hicyclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-- Y~oli~linyl]methyl]~et~mi~e (S)-N-[[3-[3-fluoro-4-[cis-6-(ace~ y2lcetyl)-3~6-~hi~yclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-r.Y~ inyl]met,hyl]~cet~mi-lP.

(S)-N-[[3-[3-fluoro4-[cis- 6-(formyl)-3,6-~ hicyclo[3.2.O]heptan-3-yl]phenyl]-2-oxo-5-r Y~lirlinyl]methyl]acetsmi~e;

(S)-N-[[3-[3-fluoro-4-[cis-6-(methylsulfonyl)-3,6-~ hi-~.yclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-- Y~ litlinyl]methyl]~et~mif~e (S)-N-[[3-[3-fluoro-4-[cis-6-(2-fluol~t Lhyl)-3,6-~hil~.yclo[3.2.0]heptan-3-36 yl]phenyl]-2-oxo-5-~Y~ inyl]methyl]~et~miflp;

WO 96135691 PCT)IJS96JI)5202 (S)--N--[r3-[3-fluoro4-[cis-6-(2-lly~l~v~y~t~lyl)-3~6-rliA~Ahicyclo[3.2~0]hept--n-3--yl]phenyl]-2-oxo-5-~yA7o~ inyl]methyl]~cet (S)-N-[[3-[3-fluoro-4-[cis-6-(2-met.h-.xy~lhyl)-3~6-rliA7Ahicyclo[3.2.o]heptan-3 yl]phenyl]-2-oxo-6-oYA7oli-1inyl]methyl]Acet~mi~;

(S)-N-[[3-[3-fluoro4-[cis-6-(cyAnomPt~yl)-3,6--liA7Ahicyclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-o~701irlinyl]methyl]acet~mi~e (S)-N-[[3-[3-fluoro-4-[cis-6-(carboInPthn~y)-3,6-~ 7.Ahicyclor3.2.0]heptan-3-yl]phenyl]-2-oxo-5-oYA7oli~inyl]methyl]A-~et~mitle;

(S)-N-[[3-[3-fluoro-4-[cis-3-aza-6-oxobicyclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-oYA7oli~inyl]methyl]Sl~etAmi~;

(S)-N-[[3-[3-fluoro-4-[cis-3-_za-6-(hyd~v~yi~ o)bicyclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-~YA7oli-linyl]methyl]A~etAmi~

(S)-N-[[3-[3-fluoro-4-[cis-3-aza-6-(mPt~.~Yyi~ o)bicyclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-nYA~ inyl]methyl]A~ets~m~

(S)-N-[[3-[3-fluoro-4-[cis-3-aza-6-oxobicyclo[3.2.0]heptan-3-yl]phenyl]-2-oxo-5-oYA~oli-linyl]methyl]Aset~mi~e ethylene ketal;

(S)-N-[[3-[3-fluoro4-[trans-3-aza-7-oxobicyclo[4.4.0]decan-3-yl]phenyl]-2-oxo-5-oY~olillinyl]methyl]~-~et~mi~;

(S)-N-[[3-[3-fluoro4-[trans-3-aza-7-(m~th,J Yy; . . . i~Lo)bicyclo[4.4.0]decan-3-yl]phenyl]-2-oxo-5--~YA7oli~inyl]methyl]~

(S)-N-[[3-[3-fluoro-4-[trans-3-aza-7-(hyd~ v~yi~ o)bicyclo[4.4.0]decan-3-yl]phenyl]-2-oxo-5-oYA7~ inyl]methyl]~ret~ le;

(S)-N-[[3-[3-fluoro4-[trans-3-aza-7-oxobicyclo[4.4.0]decan-3-yl]phenyl]-2-oxo-5-- Y~7oli~inyl]methyl],~/,~t~ . . .iti~ ethylene ketal;

CA 02218088 1997- lO- lO
WO 96/35691 PCT/U:,!)C,'0~i202 (S)-N-[[3-[3-fluoro~-[cis-3-[2-(ethylsulfenyl)ethyl]-3,7-tli~7 ~hi-yclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oYn7o~ inyl]methyl]nf~et~micla;

(S)-N-[[3-[3-fluoro-4-[cis-3-[2-[(4-morpholinyl)sulfonyl]ethyl]-3,7-tlin7~hicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oY~7Q~ inyl]methyl]n~ et~mi~

(S)-N-[[3-[3-fluoro-4-[(5,5)-2-[2-(ethylsulfenyl)ethyl]-2,8-~i~7nhiryclo[4.3.0]non-

8-yl]phenyl]-2-oxo-5-~y~7Qlitlinyl]methyl]~et~mit~

(S)-N-[[3-[3-fluoro-4-[(S,S)-2-[2-[(4-morpholinyl)sulfonyl]ethyl]-2,8-~i~7nhicyclo[4.3.o]non-8-yl]phenyl]-2-oxo-5-nyn7(?li~inyl]methyl]acet~mitle;

(S)-N-[[3-[3-fluoro-4-[(R,R)-2-[(4-morpholinyl)sulfonyl]ethyl]-2,8-~lin7nhicyclo[4.3.o]non-8-yl]phenyl]-2-oxo-5-~y~7oliflinyl]methyl]~et~mi~e;

(S)-N-[[3-[3-fluoro-4-[(R,R)-2-[2-(ethylsulfenyl)ethyl]-2,8-~ 7~hi-~yclo [4.3.0]non-8-yl]phenyl]-2-oxo-5-oY~7~ inyl]methyl]~cet~micle;

(S)-N-[[3-[3-fluoro-4-[cis-3-(2-fluorobenzoyl)-3,7--lin7~hi~.yclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-- Y~7oli~linyl]methyl]ncet~mi~la;

(S)-N-[[3-[3-fluoro4-[cis-3-[(cyclopropyl)carbonyl]-3,7--lin7nhi(yclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-<~yn7oli~linyl]methyl]n~et~mitla;

(S)-N-[[3-[3-fluoro-4-[(5,5)-2-(2-fluorobenzoyl)-2,8-~ 7nhicyclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-oyn7~ inyl]methyl]ncet~mi-la;

(S)-N-[[3-[3-fluoro-4-[(5,5)-2-[(cyclopropyl)carbonyl]-2,8-~lin7~hicyclo[4.3.o]non 8-yl]phenyl]-2-oxo-5-nYn7.oli~inyl]methyUf-~etslmi~a;
(S)-N-[[3-[3-fluoro-4-[(R,R)-2-(2-fluorobenzoyl)-2,8-~ 7~hicyclo[4.3.o]non-8 yl]phenyl]-2-oxo-5-~yn7oli~linyl]methyl]nrel~ln~

(S)-N-[[3-[3-fluoro-4-[(R,R)-2-[(cyclo~ro~yl)carbonyl]-2,8-~in7~hi~yclo[4.3.0]non-3ff 8-yl]phenyl]-2-oxo-6-~yn7oli~inyl]methyu~cehm WO 96135691 PCT/lJS96~0!~202 (S)-N-[[3-[3-fluoro~-[cis-3-(m~+~l- Yyacetyl)-3,7-~i~7S~hicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-nY~701i~1inyl]methyl]~ret~mi~1P,;

(S)-N-[[3-[3-fluoro-4-[cis-3-(mPt~- Yyacetyl)-3,7-~ 7~hicyclo[3.3.0]octan-7'-6 yl]phenyl]-2-oxo-6--Y~7o~ inyl]methyl]sl~et~mitlp (S)-N-[[3-[3-fluoro-4-[(S,S)-2-(mPt~ Yyacetyl)-2,8-~ 7~hicyclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-~y~7~ 1inyl]methyl]~et~mi~

(S)-N-[[3-[3-fluoro4-[(5,5)-2-(m~th~ yacetyl)-2,8-~ 7~hicyclo[4.3.0]non-8-yl]phenyl]-2-oxo-5-oY~7nlitlinyl]methyl]~ret~mirl~;

(S)-N-[[3-[3-fluoro-4-[(R,R)-2-(methoYyacetyl)-2,8-~ 7~hir.yclo[4.3.0]non-8-yl]phenyl]-2-oxo-6-c.Y~7oli-1inyl]methyl]~et~mi~e;
(S)-N-[[3-[3-fluoro-4-[(R,R)-2-(mPthnYyacetyl)-2~8-~ 7~hicyclo[4.3.o]non-8 yl]phenyl]-2-oxo-5-oY~7o~ inyl]methyl]~cehmi~le-;

The following ~iition~l compounds of Formula II can be ,u.~ d using techniques 20 of Formula I and as rlPpirte~l in Chart VI:

(S)-N-[[3-[3-fluoro-4-[7-(hy~l-u~y-lcetyl)-2,7-~ 7~.cpiro[4.4]nonan-2-yl]phenyl]-2-oxo-6-~Y~7oli-iinyl]methyl]~cet~mi~le;

26 (s)-N-[[3-[3-fluoro-4-[7-(acetuAy2lcetyl)-2~7-~i~7s~RFiro[4.4]nonan-2-yl]phenyl]-2 oxo-5-nY~7~ iinyl]methyl]acet~mi.l~;

(S)-N-[[3-[3-fluoro-4-[7-(formyl)-2,7-~ 7~Rpiro[4.4~nonan-2-yl]phenyl]-2-oxo-5-~Y~7oli~1inyl]methyl]~cet~mitl~;
(S)-N-[[3-[3-fluoro-4-[7-(methylsulfonyl)-2,7-~i~74Rpiro[4.4]nonan-2-yl]phenyl]-2-oxo-5-f~Y~7nli~inyUmethyl]~et~mi~

(S)-N-[[3-[3-fluoro~-[7-(2-fluoluelllyl)-2,7-~ 7~Rpiro[4.4]nonan-2-yl]phenyl]-2 oxo-5--~Y~7~ inyl]methyl]~et~mitlp;

(S)-N-[[3-[3-fluoro-4-[7-(cy~nom.otllyl)-2,7-~ 7.~Rpiro[4.4]nonan-2-yl]phenyl]-2-oxo-5-nYS17nli-1inyl]methyl]~-~et~mi-1e;

(S)-N-[[3-[3-fluoro4-[7-(carbom~th-~Yy)-2,7-~ 7.~Rpiro[4.4]nonan-2-yl]phenyl]-2-oxo-5-oY~7oli(1inyl]methyl]:~etslmi~

(S)-N-[[3-[3-fluoro-4-[l-(hydruAy~cetyl)-1,7-tli~7~Rpiro[4.4]nonan-7-yl]phenyl]-2-oxo-5-- YP.7oli~linyl]methyl]~cet~mi~le;

10 (S)-N-[[3-[3-fluoro4-[l-(acetoxyacetyl)-1,7-~ 7~Rpiro[4.4]nonan-7-yl]phenyl]-2-oxo-5-oY~701i-~inyl]met,hyl]~.et~mi~

(S)-N-[[3-[3-fluoro-4-[l-(formyl)-1,7-~ 7~Rpiro[4.4]nonan-7-yl]phenyl]-2-oxo-5-r~y~7oli(linyl]methyl]acet~mitl~;

(S)-N-[[3-[3-fluoro4-[ l-(methylsulfonyl)- 1, 7-.1 i ~ 75~ Rpi ro[4 .4]nonan-7-yUphenyl]-2-oxo-5-~Y~7oli~inyl]methyl]~set~mi~1e;

(S)-N-[[3-[3-fluoro4-[1-(2-fluoroethyl)-1,7-~ 7~Rpiro[4.4]nonan-7-yl]phenyl]-2-20 oxo-5-oY~7oli~linyl]methyl]~cet~mi~

(S)-N-[[3-[3-fluoro-4-[l-(cy~nom~t~yl)-1,7-~ 7~Rpiro[4.4]nonan-7-yl]phenyl]-2-oxo-5--Y~7oli-1inyUmethyl]~et~mi~e;

(S)-N-[[3-[3-fluoro4-[l-(carbomPt~-Yy)-1,7-~ 7~Rpiro[4.4]nonan-7-yl]phenyl]-2-oxo-5-~Y~7.olitlinyl]methyl]~cet~mitle;

(S)-N-[[3-[3-fluoro4-[2-a_a-7-uAu~,uil û[4.5]decan-2-yl]phenyl]-2-oxo-5-l~y~7~ inyl]met~hyl]~et~mif~
~0 (S)-N-[[3-[3-fluoro4-[2-a_a-7-(m~th~ ~ Yyi~i~û)spiro[4.5]decan-2-yl]phenyl]-2-oxo-5-cy~7olitlinyl]methyl]~r~~

(S)-N-[[3-[3-fluoro4-[2-a_a-7-(h~.lruAyi~i~o)spiro[4.5]decan-2-yl]phenyl]-2-oxo-s-oys~7~lklinyl]methyu~set~mifle; and WC) 96135691 PC~/IJS96105202 (S)-N-[t3-[3-fluoro4-[2-aza-7-oxospiro[4.5]decan-2-yl]phenyl]-2-oxo-5-oli~inyl]methyl]~et~mitle ethylene ketal.

Ant~h~rt~ ,al A~il,ivily The l Y~7olitlinone ~ntih~t~rial agents of this invention have useful activity ~in.~t a variety of org~ni~m.~. The in vitro activil~y of compounds of this invention can be ~Ra~etl by standard testing procedures such as the detel~ tion of minimum inhihitc!~ con-~on~ration (MIC) by agar ~ tion as described in "Methods for Dilution ~n~imi~robial Susceptibility Tests for Bacteria That Grow Aerobically"
10 (MFT) p~7hli~he~ Jan. 1983 by the National Co~illee for Clinic~l Laboratory Standards, 771 East T,~n~ter Avenue, Villanova, Pennsylvania 19084, USA. The activity of s~l~cte~ compounds of this invention ~ n~:t Staphylococcus aureus and Streptococcus pneumoniae are shown in Table 1.

Table 1 M;n;n~llrn Tnhih;tory Con~ ~I;on (~glmL) T~ m~l~ No.S. aureus UC0 9213S. pneumoniae UC

3 4 <0.5 var~co,.. y.. i,l 1 0.5 SUBSTITUTE SHEET (RULE 26) WO 96/3S691 PCT/US9C~' ~!i202 Chart I

~CH2)n~
~N H t (CH2)m R2 (CH2)o ~CH2)n ~
R~ >~ NH
(CH2)m (CH2)p WO 96135691 PCT/~JS~v~202 CHART II

~CH2)n ~ R3 3 \(CH )~(C/ ) X~NO2 ~C H 2)n \ ~N ~2 (CH2)m (CH2)o R3 ~C H 2)n ~N ~N ~OR
(CH2)m (CH2)o R)=/ H
F

1. n-BuLi or LiN R2 2.~, o~

R\ 6~ H

WO 96/3S691 PCT/U~9'~S202 Chart m R2 R3 o )n ~ ~N O

(CH2)m (CH2)o R~ OH\
6 R2 R3 o )n ~ ~ NJ~O
(CH2)m (CH2)o R~J \~H

F~2 ~9 N O
(CH2)m (CH2)o 3 \~

~ \(c~ ~N O

R2 R3 o 10 N--)n ~ ~N O / o~3 (CH2)m (CH2)o R~ H

R2 R3 o )n ~ ~NJ~O

)m (CH2)o R'~ N~R~

WO 96/35691 PC~US96JI)52~2 Chart IV

~CH2)n N~N O
\(CH2)--(CH2)0 R3 \~H O

R2 R3 o (~ H2)m IC H,)~ . . ~ ~H O

)n - ~ N~o 14 H

(CH2)m (CH2)0 R3 \~H O

2)n ~N~O
\(CH2)~(CH2)~ R3 \~;NJ~R4 H

R2 R3 o 0~ ~CH2)n - ~ ~NJ~o R--O (cH2)m (CH2)o R>=~ ; NJJ~R4 WO 96/3S691 PCT/US9f (J5:202 Chart V

R2 R3 o RHN =<~CH2)n ~ ~NJ~O

(cH2)m (CH2)o R>=/ \~N~R~' R2 R3 o RO\ =~~H2~n __~ ~H O

1~ H

3 \--~H O

H

7 \ R =<5CH2)n ~ ~N O

(CH2)m(CH2)o J \~NJ~R~
R2 R3 o R~=<lCH2)n ~N O
(CH2)m (CH2)o R>=/ \~H O
21 H R~
R2RJ o ~CN2, (--6,~ \_~N O

WO 96135691 PCTt'US~rt'~5Z02 Chart VI

,~H2)n (C H 2)m (C H 2 \

2~ 3 N O
~C H 2)m (C H 2~ R 3 ~HN ~

Formula 11

Claims (18)

What is Claimed:

1. A compound of structural Formula I:

Formula I

or pharmaceutically acceptable salts thereof wherein:
R1 is (a) NR5, (b) CR6R7;
R2 is independently H or CH3;
R3 is independently H, F, Cl or methoxy;
R4 is (a) hydrogen, (b) C1-C8 alkyl optionally substituted with one or more of the following:
F, Cl, hydroxy, C1-C8 alkoxy, C1-C8 acyloxy, (c) C3-C6 cycloalkyl, (d) amino, (e) C1-C8 alkylamino, (f) C1-C8 dialkylamino, (g) C1-C8 alkoxy;
R5 is (a) H, (b) C1-6 alkyl optionally substituted with one or more of the following: C1, F, CN, OH, C1-4 alkoxy, amino, hydroxylamino, alkoxylamino, C1-4 acyloxy, C1-4 alkylsulfenyl, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylaminosulfonyl, C1-4 dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl (optionally substituted with one or more of F, Cl, CN, OH, C1-C4 alkoxy), 5-isoxazolyl, ethenyloxy, ethynyl, (c) C1-6 acyl optionally substituted with one or more of the following: C1, F, OH, SH, C1-4 alkoxy, naphthalenoxy and phenoxy (optionally substituted with one or more of the following: Cl, F, OH, C1-C4alkoxy, amino, C1-C4acylamino, C1-C4alkyl), amino, C1-C4acylamino, hydroxylamino, alkoxylamino, C1-4 acyloxy, phenyl, C1-C4alkylcarbonyl, C1-C4alkylamino, C1-C4dialkylamino, C1-C4hydroxyacyloxy, C1-C4allkylsulfenyl, phthalimido, maleimido, succinimido, (d) C1-6 alkylsulfonyl optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, amino, hydroxylamino.
alkoxylamino, C1-4 acyloxy, phenyl, (e) arylsulfonyl optionally substituted with one or more of the following:
F, Cl, OCH3, OH or C1-4 alkyl, (f) C1-6 alkoxycarbonyl optionally substituted with one or more of the following: Cl, F, OH, C1-4 aLkoxy, C1-4 acyloxy, phenyl, (g) aminocarbonyl, C1-6 alkylaminocarbonyl or C1-6 dialkylaminocarbonyl (where the alkyl groups are optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, phenyl), (h) five- and six-membered heterocycles optionally substituted with one or more of the following: Cl, F, OH, amino, C1-4acylamino, C1-4 alkylsulfonylamino, C1-4 alkoxycarbonylamino, C1-4 alkoxy, C1-4 acyloxy or C1-4alkyl which can be substituted with F, OH or C1-4 alkoxy, (i) C3-C6cycloalkylcarbonyl optionally substituted with one or more of the following: F, Cl, OH, C1-C4alkoxy, CN, (j) benzoyl optionally substitued with one or more of the following: F, Cl, OH, C1-C4alkoxy, C1-C4alkyl, amino, C1-C4acylamino, (k) pyrrolylcarbonyl optionally substituted with one or more of C1-C4alkyl, (l) C1-C2 acyloxyacetyl where the acyl is optionally substituted with the following:
amino, C1-C4alkylamino, C1-C4dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl;
R6 is (a) H, (b) OH, (c) C1-6 alkoxy, (d) amino, C1-6 alkylamino, C1-6 dialkylamino, hydroxylamino, or C1-2 alkoxylamino all of which can be optionally substituted on the nitrogen with: C1-6 acyl (optionally substituted with one or two of Cl or OH), C1-6 alkylsulfonyl optionally substituted with one or two of Cl or OH), or C1-6 alkoxycarbonyl, (e) Cl or F;
R7 is (a) H, (b) C1-6 alkyl optionally substituted with one or more of the following: Cl, F, CN, OH, C1-4 alkoxy, C1-4 acyloxy, amino, (c) CN, (d) phenyl optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy; or R6 and R7 taken together are (a) carbonyl or thiocarbonyl group, (b) ethylene ketal (-OCH2CH2O-), propylene ketal (-OCH2CH2CH2O-), ethylene thioketal (-SCH2CH2S-), propylene thioketal (-SCH2CH2CH2S-), dimethyl ketal, diethyl ketal, dimethyl thioketal or diethyl thioketal, (c) oxime optionally substituted with H, C1-6 alkyl (optionally substituted with Cl, F or C1-4 alkoxy), C1-6 acyl (optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy), (d) hydrazone optionally substituted with H, C1-6 alkyl (optionally substituted with one or more Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl, C1-6 acyl (optionally substituted with one or more of Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl), C1-6 alkoxycarbonyl (optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl), or C1-6 alkylsulfonyl, (e) imine optionally substituted with H or a C1-6 alkyl (optionally substituted with Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl), (f) carbon-carbon double bond optionally substituted with H, C1-4 alkoxycarbonyl, C1-4 alkyl (optionally substiuted with Cl, F, OH, C1-4 alkoxy, phenyl);
m is 0-2; n is 1-3; o is 0-3; and p is 1-3.

2. The compound of Claim 1 wherein one R3 is fluorine and the other is hydrogen.

3. The compound of Claim 1 wherein each R3 is fluorine.

4. The compound of Claim 1 wherein R4 is hydrogen, methyl, difluoromethyl, dichloromethyl, hydroxymethyl or methoxy.

6. The compound of Claim 4 wherein R4 is methyl, difluoromethyl, dichloromethyl or methoxy.

6. The compound of Claim 5 wherein R4 is methyl.

7. The compound of Claim 1 wherein R5 is hydroxyacetyl.

8. The compound of Claim 1 which is (a) (S)-N-[[3-[3-fluoro-4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 1), (b) (S)-N-[[3-[3-fluoro-4-[cis-3-(benzyloxyacetyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 2), or (c) (S)-N-[[3-[3-fluoro-4-[cis-3-(hydroxyacetyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-6-oxazolidinyl]methyl]acetamide (Example 3), (d) (S)-N-[[3-[3-fluoro-4-[cis-3-(5-isoxazolinoyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 4), (e) (S)-N-[[3-[3-fluoro-4-[cis-3-(2-indolylcarbonyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 5), (f) (S)-N-[[3-[3-fluoro-4-[cis-3-(carbomethoxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 6), (g) (S)-N-[[3-[3-fluoro-4-[cis-3-(formyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinil]methyl]acetamide (Example 7), (h) (S)-N-[[3-[3-fluoro-4-[cis-3-(acetyl)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 8), (i) (S)-N-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 9), (j) (S)-N-[[3-[3-fluoro-4-[cis-2-(carbobenzyloxy)-2,8-diazabicyclo[4.3.0]nonan-8-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 10), (k) (S)-N-[[3-[3-fluoro-4-[cis-2-(carbomethoxy)-2,8-diazabicyclo[4.3.0]nonan-8-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 11), (l) (S)-N-[[3-[3-fluoro-4-[cis-2-(acetoxyacetyl)-2,8-diazabicyclo[4.3.0]nonan-8-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Expample 12), or (m) (S)-N-[[3-[3-fluoro-4-[cis-2-(hydroxyacetyl)-2,8-diazabicylo[4.3.0]nonan-8-yl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 13).

9. A compound of structural Formula II:

Formula II

or pharmaceutically acceptable salts thereof wherein:
R1 is (a) NR5, (b) CR6R7;
R2 is independently H or CH3;
R3 is independently H, F, Cl or methoxy;
R4 is (a) hydrogen, (b) C1-C8 alkyl optionally substituted with one or more of the following:
F, Cl, hydroxy, C1-C8 alkoxy, C1-C8 acyloxy, (c) C3-C6 cycloalkyl, (d) amino, (e) C1-C8 alkylamino, (f) C1-C8 dialkyamino, (g) C1-C8 alkoxy;
R5 is (a) H, (b) C1-6 alkyl optionally substituted with one or more of the following: Cl, F, CN, OH, C1-4 alkoxy, amino, hydroxylamino, alkoxylamino, C1-4 acyloxy, C1-4 alkylsulfenyl, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, aminosulfonyl, C1-4 alkylaminosulfonyl, C1-4 dialkylaminosulfonyl, 4-morpholinylsulfonyl, phenyl (optionally substituted with one or more of F, Cl, CN, OH, C1-C4alkoxy), 5-isoxazolyl, ethenyloxy, ethynyl, (c) C1-6 acyl optionally substituted with one or more of the following: Cl, F, OH, SH, C1-4 alkoxy,naphthalenoxy and phenoxy (optionally substituted with one or more of the following: Cl, F, OH, C1-C4alkoxy, amino, C1-C4acylamino, C1-C4alkyl), amino, C1-C4acylamino, hydroxylamino, alkoxylamino, C1-4 acyloxy, phenyl, C1-C4alkylcarbonyl, C1-C4alkylamino, C1-C4dialkylamino, C1-C4hydroxyacyloxy, C1-C4alkylsulfenyl, phthalimido, maleimido, succinimido, (d) C1-6 alkylsulfonyl optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, amino, hydroxylamino, alkoxylamino, C1-4 acyloxy, phenyl, (e) arylsulfonyl optionally substituted with one or more of the following:
F, Cl, OCH3, OH or C1-4 alkyl, (f) C1-6 alkoxycarbonyl optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl, (g) aminocarbonyl, C1-6 alkylaminocarbonyl or C1-6 dialkylaminocarbonyl (where the alkyl groups are optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, phenyl), (h) five- and six-membered heterocycles optionally substituted with one or more of the following: Cl, F, OH, amino, C1-4acylamino, C1-4 alkylsulfonylamino, C1-4 alkoxycarbonylamino, C1-4 alkoxy, C1-4 acyloxy or C1-4alkyl which can be substituted with F, OH or C1-4 alkoxy, (i) C3-C6cycloalkylcarbonyl optionally substituted with one or more of the following: F, Cl, OH, C1-C4alkoxy, CN, (j) benzoyl optionally substituted with one or more of the following: F, Cl, OH, C1-C4alkoxy, C1-C4alkyl, amino, C1-C4acylamino, (k) pyrrolylcarbonyl optionally substituted with one or more of C1-C4alkyl, (l) C1-C2 acyloxyacetyl where the acyl is optionally substituted with the following:
amino, C1-C4alkylamino, C1-C4dialkylamino, 4-morpholino, 4-aminophenyl, 4-(dialkylamino)phenyl, 4-(glycylamino)phenyl;
R6 is (a) H, (b) OH, (c) C1-6 alkoxy, (d) amino, C1-6 alkylamino, C1-6 dialkylamino, hydroxylamino, or C1-2 alkoxylamino all of which can be optionally substituted on the nitrogen with: C1-6 acyl (optionally substituted with one or two of Cl or OH), C1-6 alkylsulfonyl optionally substituted with one or two of Cl or OH), or C1-6 alkoxycarbonyl, (e) Cl or F;
R7 is (a) H, (b) C1-6 alkyl optionally substituted with one or more of the following: Cl, F, CN, OH, C1-4 alkoxy, C1-4 acyloxy, amino, (c) CN, (d) phenyl optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy; or R6 and R7 taken together are (a) carbonyl or thiocarbonyl group, (b) ethylene ketal (-OCH2CH2O-), propylene ketal (-OCH2CH2CH2O-), ethylene thioketal (-SCH2CH2S-), propylene thioketal (-SCH2CH2CH2S-), dimethyl ketal, diethyl ketal, dimethyl thioketal or diethyl thioketal, (c) oxime optionally substituted with H, C1-6 alkyl (optionally substituted with Cl, F or C1-4 alkoxy), C1-6 acyl (optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy), (d) hydrazone optionally substituted with H, C1-6 alkyl (optionally substituted with one or more Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl, C1-6 acyl (optionally substituted with one or more of Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl), C1-6 alkoxycarbonyl (optionally substituted with one or more of the following: Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl), or C1-6 alkylsulfonyl, (e) imine optionally substituted with H or a C1-6 alkyl (optionally substituted with Cl, F, OH, C1-4 alkoxy, C1-4 acyloxy, phenyl), (f) carbon-carbon double bond optionally substituted with H, C1-4 alkoxycarbonyl, C1-4 alkyl (optionally substituted with Cl, F, OH, C1-4 alkoxy, phenyl);
m is 0-2; n is 1-3; o is 0-3; and p is 1-3.

10. The compound of Claim 9 wherein one R3 is fluorine and the other is hydrogen.

11. The compound of Claim 9 wherein each R3 is fluorine.

12. The compound of Claim 9 wherein R4 is hydrogen, methyl, difluoromethyl, dichloromethyl, hydroxymethyl or methoxy.

13. The compound of Claim 12 wherein R4 is methyl, difluoromethyl, dichloromethyl or methoxy.

14. The compound of Claim 13 wherein R4 is methyl.

15. The compound of Claim 9 wherein R5 is hydroxyacetyl.

16. A method for treating microbial infections in warm-blooded animals by administering to a patient in need thereof an effective amount of a compound of Formula I or II.

17. The method of Claim 16 wherein the compound of Formula I or II is administered in an effective amount of from about 0.1 to about 100 mg/kg of bodyweight/day.

18. The method of Claim 17 wherein the compound of Formula I or II is administered in an effective amount of from about 3.0 to about 50 mg/kg of body weight/day