Title of Invention

"A 3,5 SUBSTITUTED OXAZOLIDINONE COMPOUND OF THE FORMULA (I)"

Abstract A compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, wherein C is selected from (D) and (E), R<sub>2</sub>a, R<sub>6</sub>a, and R<sub>3</sub>a are independently selected from for example H, CF<sub>3</sub>, Me and Et; R<sub>2</sub>b and R6b are independently selected from for example H, F, CF<sub>3</sub>, Me and Et; R<sub>1</sub>b is for example optionally substituted diazolyl, triazolyl or tetrazolyl; R<sub>4</sub> is for example an optionally substituted 5- or 6-membered heterocyclic ring system. Methods for making compounds of the formula (I), compositions containing them and their use as antibacterial agents are also described.
Full Text The present invention relates to a 3,5 substituted oxazohdinone compound the formula (I)
The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing substituted oxazohdinone rings This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing thenx
The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity The compounds of the present invention are legarded as effective against both Gram-positive and certain Gram-negative pathogens
Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established Examples of such strains are methicihin resistant staphylococcus (MRSA), metmcilhn resistant coagulase negative staphylococci (MRCNS), pemcilhn resistant Streptococcus pneirmoniae and multiply resistant Enterococcus faeciurn.
The major clinically effective antibiotic for treatment of such resistant Grain-positive pathogens is vancomycin Vancomycin is a glycopeptide and is associated with various toxicities including nephrotoxicity Furthermore, and most importantly, antibactenal resistance to vancomycin and other glycopeptides is also appearing This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as ß-lactams, quinolones and macrohdes used foi the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including H influenzae and M catanhahs
Certain antibacterial compounds containing an oxazohdinone ring have been described in the ait (foi example, Walter A Gregory et al in J Med Chern. 1990, 33,2569-2578 and 1,989, 32(8), 1673-81, Chung-Ho Park et al in J Med Chem 1992, 35, 1156-1165) Bacterial resistance to known antibacterial agents may develop, for example, by (I) the evolution of active binding sites in the bacteria rendering a previously active pharmacophore less effective
or ledundant, and/or (n) the evolution of means to chemically deactivate a given pharmacophore, and/or (111) the evolution of efflux pathways Therefore, there lemains an ongoing need to find new antibacterial agents with a favourable pharmacological piofile, in particular for compounds containing new, moie potent, pharmacophores
Accoidrngly the present invention provides a compound of the formula (I), or a pharmaceutically-acceptable salt, or an rn-vivo-hydrolysable ester thereof,
(Formula Removed)
wherein group C is selected from groups D and E,
(Formula Removed)
wherein in D and E the phenyl rrng is attached to the oxazohdrnone rn (I), R1b is HET1 or HET2, wherein
I) HET1 is an N-linked 5-membered, fully or partially unsaturated heterocyclic ring, containing either (1) 1 to 3 further nitrogen heteioatoms or (u) a furthei heteroatom selected horn O and S together with an optional furthei nitrogen heteroatom, which rrng is optionally substituted on a C atom, other than a C atom adjacent to the unking N atom, by an oxo or thioxo group, and/oi winch rrng is optionally substituted on any available C atom, other than a C atom adjacent to the linking N atom, by a substituent selected from RT as heieinafter defined and/or on an available nitrogen atom, other than a N atom adjacent to the linking N atom, (provided that the ring is not thereby quatemised) by (l-4C)alkyl,
II) HET2 is an N-hriked 6-membered di-hydro-heteroaryl irng containing up to three nitrogen he tero atoms m total (including the linking heteio atom), which ling is substituted on a suitable C atom, other than a C atom adjacent to the linking N atom, by oxo or thioxo and/oi which ring is optionally substituted on any available C atom, othei than a C atom adjacent to the linking N atom, by one or two substituents independently selected from RT as hereinafter
defined and/or on an available nitrogen atom, other than a N atom adjacent to the linking N
atom, (provided that the ring is not theieby quaternised) by (i-4C)alkyl,
RT is selected from a substituent from the gioup
(RTal) hydrogen, halogen, (l-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkenyl,
(2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, (l-4C)alkylthio, amino, azido, cyano
and mtro, 01
(RTa2) (l-4C)a]kylarnino, di-(l-4C)alkylamino, and (2-4C)alkenylairiino,
or RT is selected from the group
(RTbl) (l-4C)alkyl group which is optionally substituted by one substituent selected
from hydroxy, (l-4C)alkoxy, (l-4C)alkylthio, cyano and azido, or
(RTb2) (l-4C)alkyl group which is optionally substituted by one substituent selected
from(2-4C)alkenyloxy, (3-6C)cycloa]kyl,and (3-6C)cycloalkenyl,
or RT is selected from the group
(RTc) a fully saturated 4-membered monocyclic ring containing 1 or 2 heteroatoms
independently selected from O, N and S (optionally oxidised), and linked via a ring mtrogen
or carbon atom,
and wherein at each occunence of an RT substituent containing an alkyl, alkenyl, alkynyl,
cycloalkyl or cycloalkenyl moiety in (RTal) or (RTa2), (RTbl) or (RTb2), or (RTc) each
such moiety is optionally substituted on an available carbon atom with one, two, three or more
substituents independently selected fromF, CI, Bi, OH and CN,
R2a and R^a are independently selected from H, CF3, OMe, SMe, Me and Jit,
R2b and R6b are independently selected from H, F CI, CF3, OMe, SMe, Me and Et,
R3a is selected fromH, (l-4C)alkyl, cyano, Br, F, CI, OH, (l-4C)alkoxy, -S(0)n(l-4C)alkyl
(wherein n = 0, 1, or 2), amnio, (l-4C)alkylcarbonylarmno, mtro, -CHO, -CO(l-4C)alkyl,
-CONH2 and -CONH(l-4C)alkyl;
R4 is selected fioml^a and R4b wbeiem
T -(CHa)k-R}, AR1, AR2, (l-4C)alkanoyl, -CS(l-4C)aIkyl, -C(=W)NRvRw [wherein W is O or
S, Rv and Rw are independently H, or (l-4C)alkyll, -(C=0;i-R -C=OARl, -C=OAR2, -COOAR1, S(0)n(l-4C)alkyl (wherein n = 1 or 2), -S(0)pARl,
-S(0)pAR2 and
-C(=S)0(l-4C)alky], wherein any (l-4C)aIkyl charn may be optionally substituted by
(l-4C)alkyl, cyano, hydroxy or halo, p = 0,1 01 2,
R4b is selected fromHET-3;
R6 is selected fromhydiogen, (l-4C)alkoxy, amino. (l-4C)alkylaxorao and
hydroxy(l ~4C)alkylarmno,
k is 1 oi 2,
lis 1 or 2,
R.7 and R8 aie nidependently selected fromH and (l-4C)alkyl, oi wherein R7 and R6 taken
together with the nitrogen to which they are attached can form a 5-7 membered ring
optionally with an additional heteroatom selected from N O, S(0)n (wherein n = 1 01 2) in
place of 1 carbon atom of the so formed ring, wherein the ling may be optionally substituted
by one or two groups independently selected from (l-4C)alkyl, (3-6C)cycloalkyl, (1-
4C)alkanoyl, -C00(l-4C)alkyl, -S(0)n(l-4C)alkyl (wherein n = 1 or 2), AR1, AR2,,
-O0AR1, -C=0AR2, -C00AR1, -CS(l-4C)alkyl, -C(=S)0(l-4C)alkyl, -C(=W)NRvRw
[wherein W is O 01 S, Rv and Rw aie nidependently H, or (l-4C)alkyl], -S(0)pARl and
-S(0)pAR2, wherein any (l-4C)alkyl, (3-6C)cycloalkyl or (l-4C)alkanoyl group may be
optionally substituted (except on a carbon atom adjacent to a heteioatom) by one or two
substituents selected from (1-4C)alky 1, cyano, hydroxy, halo, ammo, (l-4C)alkylamrno and
di(l-4C)alkylammo, p = 0,1 01 2,
R6 is independently selected fromR6a to R9d below
R9a AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2,
R6b cyano, carboxy, (l-4C)alkoxycaibonyi, -C(=W)NRvRw [wherein W is O 01 S, Rv and
Rw are nidependently H, 01 (l-4C)a!kyl and wherein Rv and Rw taken together with the
amide or thio amide nitrogen to which they are attached can form a 5-7 membered ring
optionally with an additional heteroatom selected from N, O, S(0)n m place of 1 carbon atom
of the so formed ring, wheiern when said ring is a piperazine ring, the ring may be optionally
substituted on the additional nitrogen by a gioup selected from (l-4Cjalkyl (3-6C)cycloalkyl,
(l-4C)alkanoyl, -COO(l-4C)alkyl, -S(0)n(l-4C)alkyl (wherein n = 1 or 2), -COOAR1,
-CS(l-4C)alkyl and -C(=S)0(l~4C)alkyl, wherein any (l-4C)alkyl, (3-6C)cycloalkyl or (1 -
4C)alkanoyl group may itself optionally be substituted by cyano hydroxy 01 halo)], ethenyl,
2-(l-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-mtroethenyl, 2-
mtro-2-((l-4C)a!kyl)ethenyI, 2-((l-4C;alkylaiirmocarbonyl)ethenyl,
2-((l-4C)alkoxycaibonyl)ethenyl, 2-(ARl)ethenyl 2-(AR2)ethen>l, 2-(AR2a)ethenyl,
R9c (l-6C)alkyl
{optionally substituted by one or more groups (including gerrmial disubstitution) each
independently selected fiomhydroxy, (l-10C)alkoxy, (l-4Cjalkox;y-(l-4C)alkoxy (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxy, (l-4C)alkylcarbonvl, phosphoiyl [-0-P(0)(OH)2. and mono- and di-(l-4C)alkoxy denvatives thereof], phosphnyl [-0-P(OH)2 and mono- and di-(l-4C)aIkoxy derivatives thereof], and ammo, and/or optionally substituted by one group selected fiom carboxy, phosphonate [phosphono, -P(0)(OH)2. and mono- and di-(l-4C)alkoxy derivatives thereof], phosphrnate [-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], cyano, halo, trrfluoromethyl, (l-4C)alkoxycafbonyl, (l-4C)a!koxy-(l-4C)alkoxycarbonyl, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxycarbonyl, (l-4C)alkylarruno, di((l~4C)akyl) amino, (l-6C)alkanoylammo-, (l-4C)a]koxycarbonylamino-, N-(l-4C)alkyl-N-(l-6C)alkanoylamino-, -C(=W)NRvRw [wheiein W is O 01 S, Rv and Rw are as hereinbefore defined], (=NORv) wherein Rv is as hereinbefore defined, (l-4C)a!kylS(0)pNH, (l-4C)alkylS(0)p-((l-4C)alkyl)N-, fluoro(l-4C)alkylS(0)pNH-,
fluoro(l-4C)alkylS(0)p((l-4C)alkyl)N-, (l-4C)alkylS(0)q-, CY1, CY2, AR1, AR2, AR3, AR1-0-, AR2-0-, AR3-0-, AR1-S(0)q-, AR2-S(0)q-, AR3-S(0)q-, AR1-NH-, AR2-NH-, . AR3-NH- (p is 1 01 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups}, wheiein any (l-4C)alkvl present in any substituent on R9C may itself be substituted by one or two groups independently selected fiom cyano, hydroxy, halo, ammo, (l-4C)alkylarnrno and di(l-4C)alkylamino, provided that such a substituent is not on a carbon adjacent to a heteroatom atom if present,
R9d Ri4C(0)0(l-6C)alkyl- wherein R14 is AR1, AR2, (l-4C)alkvlamrno, benzyloxy-(l-4C)alkyl or (l-10C)alkyl {optionally substituted as defined for (R9c)}, Rio is selected fi-omhydiogen, R9C (as heiembefore defined), (l-4C)acyl and (l-4C)alkylsulfonyl, HET-3 is selected from
a) a 5-membered heterocyclic ring contrmng at least one nitiogen and/or oxygen in which any carbon atom is a C=0 , C=N, or C=S group, wheiern said ring is of the formula HET3-A to HET3-E below
(Formula Removed)

b) a carbon-linked 5- or 6-rnembered heteroaromatic ring containing 1, 2, 3, oi 4 heteroatoms independently selected from N, O and S selected from HET3-F to HET3-Y below
(Formula Removed)
c) a nitrogen-linked 5- or 6-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected fromN, O and S selected fiomHET3-Z to HET3-AH below
(Formula Removed)
wherein m HET-3, R1a is a substituent on caibon, R1a is rndependently selected from R1al to R1aS below

R1al AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2 Rja2 cyano, carboxy, (l-4C)allcoxycaibony], -C(=W)NRvKw [wherein W is O 01 S, Rv and Rw are independently H, or (l-4C)alkyl and wherein Rv and Rw taken together with the amide 01 thioamide rntiogen to which they aie attached can fonn a 5-7 rnembered ring optionally with an additional heteroatom selected from N, O, S(0)n in place of 1 caibon atom of the so formed ring, wherein when said ring is a piperazine ring, the ring may be optionally substituted on the additional mtiogen by a group selected from (l-4C)al]cyl, (3-6C)cycloalkyl, (l-4C)alkanoyl, -COO(l-4C)alkyl -S(0)n(l-4C)alkyl (wheiein n = 1 oi 2), -COOAR1, ~CS(l-4C)arkyl) and -C(=S)0(l-4C)alkyl, whereni any (l-4C)alkyl, (l-4C)alkanoyl and (3-4C)cycloalkyl substituent may itself be substituted by cyano, hydroxy or halo, provided that, such a substituent is not on a carbon adjacent to a mtiogen atom of the piperazine ring], efhenyl, 2-(l-4C)alkylethenyL 2-cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl, 2-rhtioethenyl, 2-mtro-2-((l-4C)alkyl)ethenyl, 2-((l-4C)arkylanirnocarbonylJethenyl, 2-((l-4C)a]koxycaibonyl)ethenyl, 2-(ARl)ethenyl, 2-(AR2)ethenyl, 2-(AR2a)ethenyl, R1a3 (1-IOC) alky 1
{optionally substituted by one or more gioups (including gemrnal disubstitution) each independently selected from hydroxy, (l-lOC)afkoxy, (l-4C)alkoxy-(l-4C)alkoxy, (l-4C)alkoxy-(l-4C)allcoxy-(l-4C)alkoxy, (l-4C)alkylcaibonyl, phosphoryl [-0-P(0)(OH)2, and mono- and di-(l-4C)alkoxy derivatives thereof], phospiuryi f-0-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], and amino, and/oi optionahy substituted by one group selected from carboxy, phosphonate [phosphono, -P(OXOH)2, and mono- and di-(l-4C)alkoxy derivatives thereof], phosphrnate [-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], cyano, halo, tirfluoromethyl, (l-4Cjalkoxycarbonyl, (l-4C)alkoxy-(l-4C)alkoxycai-bonyl, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxyearbonyL (l-4C)alkylamrno, di((l-4C)allcyl)amino, (l-6C)alkanoylainmo-, (l-4Cjalkoxycarbonylamrno-, N-(l-4C)alkyl-N-(l-6C)alkanoylamrno-, -C(=W)NRvRw [wheiein W is O or S, Rv and Rw are independently H, or (l-4C)alkyl and wherern Rv and Rw taken together with the amide or thioarmde nitrogen to which they are attached can form a 5-7 membeied ling optionally with an additional heteroatom selected from N, O, S(0)n in place of 1 carbon atom of the so formed ling, wherein when said ring is a piperazine irng, the ring may be optionally substituted on the additional nitrogen by a gioup selected fiom (l-4C)al3cyl, (3-6C)cyeloalkyl, (l-4C)alkaiioyL -COO(l-4C)afkyl, -S(0)n(l-4C)alkyl (wherein n= 1 or 2), -COOAR1,
-CS(l-4C)alkyl and -C(=S)0(l-4C)alkyl], (=NORv) wherein Rv is as hereinbefore defined, (l-4C)alkylS(0)pNH-, (l-4C)a]kylS(0)p-((l-4C)alkyl)N-,fluoro(l-4C)alkylS(0)pNH-; fluoro(l-4C)alkylS(0)p((l-4C)alkyl)N-, (l-4C)alkylS(0)q-, CY1, CY2, AR1, AR2, AR3, AR1-0-, AR2-0-, AR3-0-, AR1-S(0)q-, AR2-S(0)q-, AR3-S(0)q-, AR1-NH-, AR2-NH-, AR3-NH- (p is 1 or 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups}, wheiein any (l-4C)alkyl, (l-4C)alkanoyl and (3-6C)cycloalkyl present rn any substituent on Rja3 may itself be substituted by one or two groups independently selected fromcyano, hydroxy, halo, amino, (1-4C) alky 1 amino and di(l-4C)alkylaimno , provided that such a substituent is not on a carbon adjacent to a heteroatom atom if present,
Rja4 Ri4C(0)0(l-6C)alkyl- whereinR14is AR1, AR2, AR2a, AR2b, (l-4C)alkylarmno, benzyloxy-(l-4C)alkyl or (l-10C)alkyl {optionally substituted as defined for (R1a3)}, R1a5 F, CI, hydroxy, mercapto, (l~4C)alkylS(0)p- (p = 0,1 oi 2), -NR7R8 (whereinR7 and Rg are as hereinbefore defined*) or -OR10 (where Rio is as hereinbefore defined), mis 0, 1 01 2,
R21 is selected from hydrogen, methyl [optionally substituted with cyano, tnfluoromethyl, -C=WNRvRw (where W, Rv and Rw are as heiernbefore defined for R1a3), (l-4C)alkoxycarbonyl, (l-4C)alkoxy-(l-4C)alkoxycarbonyl, (l-4C)alkoxy-(l-4C)allcoxy-(l-4C)alkoxycarbonyl, CY1, CY2, AR1, AR2, AR2a, AR2b (not linked through nitrogen) or AR3J, (2-10C)a]kyl [optionally substituted other than on a carbon attached to the HET-3 ring nitrogen with one or two groups independently selected from the optional subsituents defined for R1a3] and Ri4C(0)0(2-6C)alkyl- .wherein R3.4 is as defined heiernbefore foi Raa4 and wherein Ri4C(0)0 group is attached to a carbon other than the carbon attached to the HET-3 ring nitrogen,
R22 is cyano, -COR12, -COOR12, -CONHR12, -CON(Ri2)(Ri3), -SO2R12 (provided that R12 is not hydrogen), -SO2NHR12, -S02N(Rn)(Ri3) or N02, wherein R12 and R13 are as defined herernbelow,
R12 and R13 are rndependently selected from hydrogen, phenyl (optionally substituted with one or more substituents selected from halogen, (l-4C)alkyl and (l-4C)alkyl substituted with one, two, three 01 more halogen atoms) and (l-4C)alkyl (optionally substituted with one, two, thiee or more halogen atoms), 01 for any N(Ri2)(Ri3) gioup, R12 and R13 may be taken together with the mtiogen to which they are attached to form a 5-7 membered ring optionally with an additional heteroatom selected from N, O, S(0)n rn place of 1 carbon atom of the so
formed lmg, -wherein the nag may be optionally substituted by one 01 two groups
independently selected fiom (l-4C)alkyl (optionally substituted on a carbon not adjacent to
the mtiogen by cyano, hydroxy 01 halo), (3-6C)cycloalkyl, (1 -4Qa]kanoyl, -COO(l-4C)a]kyl,
-S(0)n(l-4C)alkyl (wherein n - 1 or 2), AR1, AR2, , -C=OARl, -C=OAR2, -COOAR1,
-CS(l-4C)aHcyl, -C(=S)OQ-4C)alkyl, -C(=W)NRvRw [wheiern W is O or S, Rv and Rw are
independently H, or (l-4C)alkyl ], -S(0)pARl and -S(0)pAR2, wherein any (l-4C)afkyl
chain may be optionally substituted by (l-4C)alkyl, cyano, hydroxy oi halo, p = 0,1 or 2,
AR1 is an optionally substituted phenyl or optionally substituted naphthyl,
AR2 is an optionally substituted 5- or 6-membered, fully unsaturated (I e with the maximum
degree of unsaturation) monocyclic heteroarylrmg containing up to foui heteroatoms
independently selected from O, N and S (but not containing any O-O, O-S or S-S bonds), and
linked via a rmg carbon atom, or a ring nitrogen atom if the ring is not thereby quatermsed,
AR2a is a partially hydrogenated version of AR2 (i e AR2 systems retaining some, but not
the full, degree of unsaturation), linked via a ring carbon atom oi linked via a ring nitrogen
atom if the rmg is not thereby quatermsed,
AR2b is a fully hydrogenated version of AR2 (i e AR2 systems having no unsaturation),
linked via a rmg carbon atom or linked via a ring nitrogen atom,
AR3 is an optionally substituted 8-, 9- or 10-meixibered, fully unsaturated (I e with the
maximum degree of unsaturation) bicychc heteroaryl ring containing up to four heteioatoms
independently selected from O, N and S (hut not containing any O-O, O-S or S-S bonds), and
linked via a rmg carbon atom in either of the rings compnsing the bicychc system,
AR3a is a partially hydiogenated veision of AR3 (l e AR3 systems retaining some, but not
the fall, degree of unsaturation), linked via a rmg carbon atom, or linked via a rmg nitrogen
atom if the rmg is not theieby quatermsed, m either of the rings comprising the bicychc
system,
AR3b is a fully hydiogenated veision of AR3 (I e AR3 systems having no unsaturation),
linked via a rmg carbon atom, or linked via a rmg mtiogen atom, in either of the rings
comprising the bicychc system,
4R4 is an optionally substituted 13- or 14-membered, fully unsatuiated (i e with the
naxrmum degree of unsaturation) tricyclic heteioaryl rmg containing up to four hetero atoms
ndependently selected from O, N and S (but not containing any O-O, O-S oi S-S bonds), and
inked via a rmg carbon atom in any of the rings comprising the tricyclic system,
^.R4a is a partially hydrogenated version of AR4 (l e AR4 systems letainrng some, but not
the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not theieby quatermsed, in any of the rings comprising the tricyclic system, CY1 is an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl lrng, CY2 is an optionally substituted cyclopentenyl or cyclohexenyl iing, ; wherein, optional substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are (on an available carbon atom) up to thiee substituents independently selected fiom (l-4C)alkyl {optionally substituted by substituents selected independently fiom hydroxy, tnfluoromethyl, (l-4C)alkylS(0)q- (q is 0, 1 or 2), (l-4C)alkoxy, "(l-4C)alkoxycarbonyl, cyano, mtro, (l-4C)alkanoylamino, -CONRvRw or -NRvRw}, tnfluoromethyl, hydroxy, halo, mtro, cyano, thiol, (l-4C)alkoxy, (,l-4C)alkanoyloxy, dnriethylanirnomethyleneaminocai-bonyl, di(N-(l -4C)alkyl)ammomemylnnrno, carboxy, (l-4C)a]koxycarbonyl, (l-4C)alkanoyl, (l-4C)alkylS02amrno, (2-4C)alkenyl {optionally substituted by carboxy or (l-4C)alkoxycarbonyl}, (2-4Q)alkynyl, (l-4C)alkanoylamrno, oxo (-0), thioxo (=S), (l-4C)alkanoylamrno {the (l-4C)alkanoyl gioup being optionally substituted by hydroxy}, (l-4C)alkyl S(0)q- (q is 0, 1 oi 2) {the (l~4C)alkyl group being optionally substituted by one or more groups independently selected from cyano, hydroxy and (l-4C)alkoxy}, -CONRvRw or -NRvRw J wherein Rv is hydrogen or (l-4C)alkyl, Rw is hydrogen or (l-4C)alkylJ,
and further optional substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 (on an available carbon atom), and also on aflcyl gioups (unless indicated otherwise) are up to three substituents independently selected from trifluoromethoxy, benzoylamino, benzoyl, phenyl {optionally substituted by up to three substituents independently selected from halo, (l-4C)a]koxy oi cyano}, furan, pyrrole, pyrazole, nmdazole, triazole, pyrrmidme, pyndazrne, pyridine, isoxazole, oxazolc, lsothiazole, thiazole, thiophene, hydroxyimrno(l-4C)alkyl) (l-4C)alkoxynmno(l-4C)alkyl, halo-(l-4C)alkyl, (l-4C)alkanesulfonamido, ~S02NRvRw [wheieni Rv is hydrogen oi (l-4C)alkyl, Rw is hydrogen or (l-4C)alkyl], and
optional substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4a are (on an available nitiogen atom, wheie such substitution does not lesult in quatemrzation) (l-4C)alkyl, (l-4C)alkylcarbonyl {wherem the (l-4C)aIkyl and (l-4C)a]kylcarbonyl groups are optionally substituted by (pieferably one) substituents independently selected fiom cyano hydioxy, mtro, tnfluorometliyl, (l-4C)alkyl S(0)q- (q is 0, 1 or 2), (l-4C)alkoxy
(l-4Q)alkoxycarbonyl, (l-4C)a]kaaoylamino, -CONRvRw or-NRvRw [wherein Rv is hydrogen or (l-4C)alkyl, Rw is hydiogen or (l-4C)aIkylJ}, (2-4C)a]kenyl (2~4C)alkynyl, (l-4C)alkoxycarbonyl or oxo (to form an N-oxide)
In another aspect, the invention relates to compounds of formula (1) as hereinabove defined 01 to a pharmaceutically acceptable salt
In another aspect, the invention 1 elates to compounds of formula (1) as hereinabove defined or to a pro-drug thereof Suitable examples of pro-drugs of compounds of formula (1) are in-vivo hydrolysable esters of compounds of formula (1) Theiefoie in another aspect, the invention relates to compounds of formula (1) as hereinabove defined oi to an in-vivo hydro lysable ester thereof
In another aspect, theie is provided a compound of the formula (I) as hereinbefore defined, wherein HET3 is selected from " a) HET3-A to HET3-E,
b) HET3-F to HET3-Y, and
c) HET3-Z to HBT3-AE
Where optional substituents are chosen from "0, 1, 2 or 3" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups An analogous convention applies to substituents chose from "0, 1 or 2" groups and "1 or 2" groups
In tins specification the term 'alkyl' includes straight chained and branched structures For example, (l-4C)alkyl includes propyl and isopiopyl However, references to individual allcyl groups such as "propyl" are specific for the straight chained veision only, and references to individual branched chain alkyl groups such as "isopropyl" are specific for the branched chain version only In tins specification, the terms 'alkenyl' and 'cycloalkenyl' include all positional and geometrical isomeis In tins specification, the term 'arvl' is an unsubstituted carbocychc aromatic group, in particular phenyl, 1- and 2-naphthyl
For the avoidance of doubt, refeience to a caibon atom in HET1 oi HBT2 being substituted by an oxo or thioxo gioup means leplacement of a CfL by C=0 or C=S respectively
Within this specification composite terms aie used to descube gioups comprising more that one functionality such as (l-4C)alkoxy-(l-4Qalkoxy (l-4C)alkyl Such terms are to be interpreted in accordance with the meaning which is understood by a peison skilled in
the art foi each, component part For example (l-4C)alkoxy(l-4C)alkoxy-(l-4C)aIkyl includes mefhoxymethoxymethyl, ethoxymethoxypropyl and propxycthoxymethyl
It will be undeistood that where a group is defined such that is optionally substituted by more than one substituent, then substitution is such that chemically stable compounds are formed For example, a trrfluoromethyl group may be allowed but not a triliydroxymethyl gioup This convention is applied wherevei optional substituents aie defined
There follow particular and suitable values for certain substituents and groups referred to in this specification These values may be used wheie appropriate with any of the definitions and embodiments disclosed hereinbefoie, or hereinafter For the avoidance of doubt each stated species represents a particular and independent aspect of this invention
Examples of (l-4C)aJDkyl and (l-5C)aIkyl include methyl, ethyl, propyl, isopropyl and t-butyl, examples of (l-6C)alkyl include methyl, ethyl, propyl, isopropyl, t-butyL pentyl and hexyl, examples of (l-lOC)alkyl include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl andnonyl, examples of (l-4C)alkanoylaxrino-(l-4C)alkyl include formamidomethyl, acetamidomethyl and acetamidoethyl, examples of hydbroxy(l-4QaIkyi and hydroxy(l-6C)alkyl include hydioxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl, examples of (l-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and piopoxycarbonyl, examples of (l-4C)alkoxy-(l-4C)alkoxycarbonyl mclude methoxymethoxycarbonyl methoxyethoxycarbonyl and propoxymethoxycarbonyl, examples of (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxycarbonyl include methoxymethoxymethoxycarbonyl, rnethoxyethoxymethoxycarbonyl and propoxyethoxymefhoxycaibonyl, examples of 2-((l-4C)aIkoxycarbonyl)ethenyl include 2-(methoxycaibonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl, examples of 2-cyano-2-((l-4C)alkyl)ethenyl include 2-cyano 2-methylethenyl and 2-cyano-2-ethylethenyl, examples of 2-nitro-2-((l-4C)alkyl)ethenyl mclude 2-mtro-2-methylethenyl and 2-tutro-2-ethylethenyl, examples of 2-((l-4C)aIkylairunocarbonyl)etheiiyl include 2-(methylamrnocarbonyl)ethenyl and 2-(ethylaimnocarbonyl)ethenyl, examples of (2-4C)alkenyl include allyl and vinyl, examples of (2-4C)alkenyloxy mclude allyloxy and vrnyloxy, examples of (2-4C)alkkynyl include ethynyl and 2-propynyl, examples of (2-4C)alkynyloxy mclude ethynyloxy and 2-propynyloxy, examples of (l-4C)alkanoyT include fonnyl, acetyl and piopionyl, examples of (1-4C)alleylcarbonyl include acetyl and propionyl, examples of (l~4C)alkoxy mclude methoxy, ethoxy and propoxy, examples of (l-6C)alkoxy and (l-lOC)alkoxy mclude methoxy, ethoxy, propoxy and pentox}, examples of (1-
Rg4C)alkylthio include methylthio and ethylthio, examples of (l-4C)alkylamino include methylamino, ethylamino andpiopylamino, examples of (2-4C)alkenylamino include vinylamino and aUylarnino, examples of hydroxy(l-4C)allkylamiao include 2-hydroxyethylarnino, 2-hydioxypiopylamino and 3-hydioxypropylamxao, examples of di-((l-4C)aIkyl)ainino include dimefhylainino, N-ethyl-N-methylammo, diethylamtao, N-methyl-N-piopylamino and dipropylamino, examples of halo groups include fluoro, chloio and bromo, examples of (l-4C)alkyIsulfonyl include methylsulfonyl and ethylsulfonyl, examples of (l-4C)alkoxy-(l-4C)alkoxy and (l-6C)alkoxy-(l-6C)aIkoxy include methoxyrnethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy, examples of (l-4C)alkoxy-(l-4C)aIkoxy-(l-4C)alkoxy include 2-(methoxymethoxy)ethoxy; 2-(2-methoxyethoxy)ethoxy, 3-(2-methoxyethoxy)propoxy and 2-(2-ethoxyethoxy)ethoxy, examples of (l-4C)alkylS(0)2amino include methylsulfonylamino and ethylsulfonylamino, examples of (l-4C)alkanoylarumo and (l-6C)alkanoylamino include formamido, acetamido and propionylamino, examples of (l-4C)alkoxycarbonylamino include methoxycarbonylamino and ethoxycaibonylamino, examples ofN-(l-4C)alkyl-N-(l-6C)alkanoyIamino include N-methylacetamido, N-etliylacetamido and N-methylpiopionamido, examples of (l-4C)alky)S(0)pNH- wherein p is 1 or 2 include methylsulfinylamino, methylsulfonylamino, ethylsulfinylarmno and ethylsulfonylamino, examples of (l-4C)alkylS(0)p((l-4C)alkyl)N- wherein p is 1 or 2 mclude methyls ulfmylmethylamino, methylsulfonyhnethylamino, 2-(ethylsulfinyl)ethylaraino and 2-(ethylsulfonyl)ethylamino, examples of fluoro(l-4C)alkylS(0)pNH- wherein p is 1 or 2 include trrfluorometliylsulfmylamino and tnfluoromethylsulfonylamino, examples of fluoro(l-4C)alkylS(0)p((l-4C)alkyl)NH- wherein p is 1 or 2 include
trifluoromethylsulfmylmemylarmno and trifluoromethylsulfonylmethylarruno examples of (l-4C)alkoxy(hydroxy)pliosp]ioryl include methoxy(hydroxy)phospfioryl and ethoxy(hydroxy)phosphoryl, examples of di-(l-4C)alkoxyphosphoryl include di-metiioxypbosphoryl, di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl,examples of (l-4C)aIkylS(0)q- wherein q is 0, 1 or 2, and -S(0)n(l-4C)alkyl (wheiein n = 1 or 2), include methylthio, ethylthio, methylsulfmyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl, examples of plienylS(0)q and naphthylS(0)q- wherein q is 0, 1 or 2 are phenylthio, phenylsulfrnyl, phenylsulfonyl and naphthylthio, naphthylsulfinyl and naphthylsulfonyl respectively, examples of benzyloxy-(l-4C)alkyl include benzyloxymethyl and benzyloxyethyl, examples of a (3-4C)alkylene chain are tnmethylene or tetramethylene,
examples of (l-6C)aLkoxy-(l-6C)alkyl include methoxymetrryl, ethoxyraethyl and 2-methoxyethyl, examples of hydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy, examples of (l-4C)alkylamino-(2-6C)aIkoxy include 2-methylaimnoethoxy and 2-ethylammoethoxy, examples of di-(l-4C)alkylauxixio-(2-6C)alkoxy include 2-dimethylaminoetfa.oxy and 2-diethylammoethoxy,examples of phenyl(l-4C)alkyl include benzyl and phenethyl, examples of (l-4C)a[kylcarbam.oyl include methylcarbamoyl and ethylcarbamoyl, examples of di((l-4C)alkyl)carbainoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl, examples of hydroxyimino(l-4C)aIkyl include hydroxyimmomethyl, 2-(hydioxymnno)ethyl and l-(hydroxymuno)ethyl, examples of (l-4C)alkoxyimino-(l-4C)aIkyl include methoxyuxanometliyl, ethoxyumnomethyl, l-(methoxyimino)ethyl and 2-(methoxymnno)ethyl, examples of halo(l-4C)alkyl include, halomethyl, 1-haloethyl, 2-haloethyl, and 3-halopropyl, examples of nitro(l-4C)alkyl include nitromethyl, 1-mtroethyl, 2-nitroethyl and 3-nitropropyl, examples of amino(l-4C)aIkyl include aminomethyl, 1-amnio ethyl, 2-ammoethyl and 3-ammopropyl, examples of cyano(l-4C)a]kyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopiopyl, examples of (l-4C)alkanesulfonaniido include methanesulfonamido and ethanesulfonamido, examples of (l-4C)alkylammosiilfoiiyl mclude metliylaminosulfonyl and ethylaminosulfonyl, examples of di-(l-4C)alkylaimnosulf Particulai values foi AR2 mclude, for example, for those AR2 containing one heteioatom, furan, pyrrole, thiophene, foi those AR2 containmg one to four N atoms, pyiazole, mndazole, pyridine, pyirrnidme, pyiazme, pyndazine 1,2,3- & 1,2,4-tnazole and tetrazole, for those^AR2 contarmng one N and one O atom, oxazole, isoxazole and oxazme,
for those AR2 containing one N and one S atom, thiazole and iso thiazole,
for those AR2 containing two N atoms and one S atom, 1,2,4- and 1,3,4-thiadiazole
Particular examples of AR2a include, foi example, dihydropyn ole (especially 2,5-dihydropyrrol-4-yl) and tetrahydropyridrne (especially l,2,5,6-tetrahydropyrid-4-yl)
Paiticular examples of AR2b include, for example, tetrahydrofuran, pyn-ohdrne, morpholine (preferably morpholino), thiomorpholine (preferably thiomoiphohno), prperazrne (preferably piperazrno), nmdazoline and piperidrne, l,3-dioxolan-4-yl, l,3-dioxan-4-yl, l,3-dioxan-5-yl and 1,4-dioxan-2-yl
Particular values for AR3 include, for example, bicychc benzo-fused systems containing a 5- or 6-meinbeied heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen Specific examples of such ring systems include, for example, indole, benzofuran, benzothiophene, benzrmidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, qurnolrne, qurnoxalrne, qurnazohne, phthalazine and crrmohne
Other particular examples of AR3 include 5/5-, 5/6 and 6/6 bicychc ring systems containing heteroatoms in both of the rings Specific examples of such ring systems include, for example, purine and naphthyndrne
Further particular examples of AR3 include bicychc heteroaryl ring systems with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen horn oxygen, sulfur and nitrogen Specific examples of such ring systems include, for example, 3H-pyrrolo[l,2-a]pyrrole, pyrrolo[2,l-b]thiazole, lH-imidazo[l,2-a]pyrrole, lH-imidazo[l,2-a]nnidazole, lH,3H-pyrrolo[l,2-cjoxazole, lH-irmdazo[l,5-a]pyrrole, pyrrolo[l,2-b]isoxazole, nmdazo[5,l-b]thiazole, imidazo [2,1-b] thiazole, indohzine, imidazo[l,2-a]pyndine, nxridazo[l,5-a]pyiidine, pyiazolo[l,5-a]pyndme, pyrrolo[ 1,2-b]pyndazrne, pyrrolo[ 1,2-c]pyrnnidme, pynolo[ 1,2-a]pyrazrne, pyrrolo[l,2-a]pyrimidnie, pyndo[2,l-c]-s-triazole, s-triazole[l,5-a]pyndrne, nnidazo[l,2-c]pyrrmidine, nmdazo[l,2-a]pyrazine, imidazo[l,2-a]pyrrmidine, rmidazo[l,5-aJpyrazrne, imidazo[l,5-a]pyrirmdme, rmidazo[l,2-b]-pyndazrne, s-tiiazolo[4,3-a]pyrnnidine, nmdazo[5,l-b]oxazole and nnidazo[2,l-bjoxazole Other specific examples of suchirng systems include, for example, [lH]-pyrrolo[2,l-c]oxazrne, [3H]-oxazolo[3,4-a]pyridrne, [6H]-pynolo[2,l-c]oxazine andpyudo[2,l-c][l,4]oxazrne Other specific examples of 5/5- bicychc ring systems ai e rmidazooxazole or rmidazothiazole, in
particular rxrudazo[5,l-b]thiazole, rrnidazo[2,l-b]thiazole, rmidazoi5,l-b]oxazole or rxnidazo[2.1 bjoxazole
Particular examples of AR3a and AR3b include, for example, indoline, l,3,4,6,9,9a-hexaliydiopyiido[2flc][l,4]oxazni-8-yl, 1,2,3,5,8,8a-hexahydioimidazo[l ,5a]pyndrn-7-yl, 1,5,8,8 a-teti ahydi ooxazolo [ 3,4a]pyndin-7-yl, l,5,6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl, (7aS)[3H,5H]-l,7a-dihydropyrrolo[l,2c]oxazol-6-yl, (7aS)[5HT|-l,23,7a-tetiahydropyrrolo[l,2c]imidazol-6-yl, (7aR)[3H,5H]-l,7a-diliydropyn-olo[l,2c]oxazol-6-yl, [3H,5H]~pyrrolo[l,2-c]oxazol-6-yL [5H]-2,3-dihydiopyn-olo[l,2-c]imidazol-6-yl, [3H,5H]-pyn'olo[1.2-cJtkazol 6-yL, [3H,5H]-l,7a-dmydropyirolo[l,2-c]thiazol-6-yl, [5H]-pyrrolo[l,2-c]umdazol-6-yl, [lH]-3,4,8,8a-tetrahydropyiTolo[2,l-c]oxazin-7-yl, [3H]-1,5,8,8a-tetrahydrooxazolo-[3,4-a]pynd-7-yl, [3H]-5,8-dihydroxazolo[3,4-a]pyrid-7-yl and 5,8-dihydrormidazo-[l,5-a]pyrid-7-yl
Particular values for AR4 include, for example, pynolo[a]qmnohne, 2,3-pyrroloisoquxaoline, pynr>lo[a]isoqurnohne, lH-pyiTolo[l,2-a]benzrmidazole, 9H-imidazo[l,2-a]indole, 5H-imidazo[2,l-a]isorndole, lH-imidazo[3,4-a]uidole, rmidazo[l,2-a]qurnokne, rrrndazo[2,l-a]isoqurnohne, rmidazo[l,5-a]quinolme and rmidazo [5,1-ajisoqurnolme
The nomenclature used is that found in, for example, "Heteiocyclic Compounds (Systems with bridgehead nitrogen), W L Mosby (Baterscience Publishers lac , New York), 1961, Parts 1 and 2
Where optional substituents are listed such substitution is preferably not germnal disubstitution unless stated otherwise If not stated elsewheie, suitable optional substituents foi a particular group are those as stated for similar groups herein
Preferable optional substituents on Ar2b as l,3-dioxolan-4-yl, l,3-dioxan-4-yl, l,3-dioxan-5-yl or 1,4-dioxan-2-yl are mono- or disubstitution by substituents independently selected from (l-4C)aIkyl (including gemrnal disubstitution), (i-4C)alLoxy, (1-4C) alky Ithio, acetamido, (l-4C)alkanoyl, cyano, trrfluoiomethyl and phenyl]
Preferable optional substituents on CY1 & CY2 aie mono- or disubstitution by substituents independently selected from (l-4C)alkyl (mcluding gemrnal disubstitution), hydroX}, (l-4C)alkoxy, (l-4C)alkylthio, acetamido, (l-4C)alkanoyl, cyano, and trifluoromethyl
Suitable pharmaceutically-acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, citiate, male ate, tamate and (less preferably)
ydrobromide Also suitable are salts formed with phosphoric and sulfuric acid In another aspect suitable salts aie base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium 01 magnesium, an oiganic amine salt for example triethylarrnne, morphohne, N-inethylpipendine, N-efhylpipendme, piocame, dibenzylamine, N,N-dibenzylethylamrne, tris-(2-hydroxyethyi)amrne; N-methyl d-glucamrne and amino acids such as lysine There may be more than one cation or anion depending on the number of charged functions and the valency of the cations 01 anions A preferred pharmaceutically-acceptable salt is the sodium salt
However, to facilitate isolation of the salt during preparation, salts winch are less soluble in the chosen solvent may be preferred whethei pharmaceutically-acceptable or not
The compounds of tire invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the invention A prodrug may be used to alter or improve the physical and/or pharmacokinetic piofile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodrug Examples of pio-drugs include in-vivo hydrolysable esteis of a compound of the invention or a phaimdceutioally-acceptable salt thereof
Various forms of piodrugs are known in the art, foi examples see
a) Design of Prodrugs, edited by H Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol 42, p 309-396, edited by K Widdei, et al (Academic Press, 1985),
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and
H Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H Bundgaardp 113-191 (1991),
c) H Bundgaard, Advanced Drug Delivery Reviews, d) H Bundgaard, et al, Journal of Pharmaceutical Sciences, 77, 285 (1988), and
e) N Kakeya, et al, Chern Pharm Bull, 32, 692 (1984)
Suitable pro-drugs for pyridine or tuazole denvatives include acyloxymethyl pyridinium oi tnazohum salts eg hahdes, for example a pro-drug such as
(Formula Removed)
(Ref T Yamazaki et al 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 2002, Abstract F820)
Suitable pro-drugs of hydroxy 1 groups are acyl esters of acetal-carbonate esters of formula RCOOC(R,R')OCO-, where R is (l-4C)alkyl and R' is (l-4C)alkyl or H Furthei suitable prodrugs are carbonate and carabamate esters RCOO- and RNHCOO-
An in-vivo hydrolysable ester of a compound of the invention oi a pharmaceutically-acceptable salt thereof containing a carboxy oi hydioxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human oi animal body to produce the parent alcohol
Suitable pharmaceutically-acceptable esters foi carboxy include (l-6C)alkoxymethyl esters for example methoxymethyl, (l-6C)alkanoyloxyrnefhyl esters for example pivaloyloxymethyl, phthahdyl esters, (3-8C)cycloalkoxycarbonyloxy(l-6C)aIkyl esters for example 1-cyclohexylcarbonyloxyetbyl, l,3~dioxolan-2-onyknethyl esters for example 5-methyl-l,3-dioxolan-2-yhnethyl, and (l-6C)alkoxycarbonyloxyethyl esters foi example 1-mefhoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds ol tins invention
An ni-vivo hydrolysable ester of a compound of the invention or a phaimaceutically-acceptable salt thereof containing a hydroxy gioup oi groups includes inorganic esters such as phosphate esters (rncludmg phosphoramidic cyclic esters) and a-acyloxyalkyl ethers and related compounds which as a result of the ni-vivo hydiolysis of the ester breakdown to give the patent hydroxy group/s Examples of a-acyloxyalkyl ethers include acetoxymethoxy and 2,2-drmethylpropionyloxymethoxy A selection of in-vivo hydrolysable ester forming groups for hydroxy include (l-lOC)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (l-iOC)alkoxycarbonyl (to give alkyl caibonate esteis),
di-(l~4C)alkylcarbamoyl and N-(di-(l-4C)alkylarnnioethyl)-N-(l-4C)alkylcarbamoyl (to give caibamates), di-(l-4C)aJkylaminoacetyl, carboxy(2-5C)alkylcarbonyl and carboxyacetyl Examples of ring substituents on phenylacetyl and benzoyl include cMoiomethyl or amrnomethyl, (l-4C)alkylamrnomethyl anddi-((l-4C)alkyl)ammomethyl, and morphohno or piperazrno linked from a ring nitrogen atom via a methylene hnlcing group to the 3- or 4-position of the benzoyl ring Other interesting rn-vivo hydrolysable esters include, foi example, RAC(OjO(l-6C)alkyi-CO- (wh erern RNs foi example, optionally substituted benzyloxy-(l-4C)alkyl, or optionally substituted phenyl, suitable substituents on a phenyl group in such esters include, for example, 4-(l-4C)piperazmo-(l-4C)alkyl, piperazmo-
(l-4C)a]kyl and morpholmo-Cl-4C)aIkyl
Suitable in-vivo hydiolysable esters of a compound of the formula (I) are described as follows For example, a 1,2-diol may be cyclised to form a cyclic ester of formula (PD1) or a pyrophosphate of formula (PD2), and a 1,3-diol may be cyclised to form a cyclic ester of the formula (PD3)
(Formula Removed)

Esters of compounds of formula (I) wheiern the HO- function/s rn (PD1), (PD2) and (PD3) are protected by (l-4C)alkyl, phenyl or benzyl are useful intermediates for the preparation of such pro-drugs
Further in-vivo hydiolysable esters include phosphoramidic esters, and also compounds of invention rn which any free hydroxy group independently forms a phosphoryl (npd is 1) or phosphrryl (npd is 0) ester of the formula (PD4)
(Formula Removed)
For the avoidance of doubt, phosphono is -P(0)(OH)2, (l-4C)alkoxy(hydroxy)-phosphoryl is a mono-(l-4C)alkoxy derivative of-0-P(0)(OH)2, and di-(l-4C)alkoxyphosphoryl is a di-(l-4C)alkoxy derivative of-0-P(0)(OH)2
Useful intermediates for the preparation of such esteis include compounds containing a group/s of formula (PD4) in which either or both of the -OH groups m (PD1) is independently protected by (l-4C)alkyl (such compounds also being interesting compounds rn then- own right), phenyl or phenyl-(l-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (l-4C)alkyl, nitro, halo and (l-4C)alkoxy)
Thus, piodrugs containing groups such as (PD1), (PD2) (PD3) and (PD4) may be prepared by reaction of a compound of invention containing suitable hydroxy group/s with a
suitably protected phosphoiylatrng agent (for example, containing a chloro or dialkylamrno leavrng group), followed by oxidation (if necessary) and deprotection
Other suitable prodrugs include phosphonooxymefhyl etheis and then salts for example a piodrug of R-OH such as
(Formula Removed)
When a compound of invention contains a number of free hydroxy group, those groups not being converted into a piodrug functionality may be protected (for example, using a t butyl-dnnethylsilyl gioup), and later deprotected Also, enzymatic methods may be used to selectively phosphorylate or dephosphorylate alcohol functionalities
Where pharmaceutically-acceptable salts of an in-vivo hydrolysable ester may be foimed tins is achieved by conventional techniques Thus, for example, compounds containing a group of formula (PD1), (PD2), (PD3)and/or (PD4) may ionise (partially or fully) to form salts with an appropriate numbei of counter-ions Thus, by wa> of example, if an in-vivo hydro lysable ester prodrug of a compound of invention contains two (PD4) groups, there are four HO-P- functionalities present in the overall molecule, each of which may form an appropriate salt (1 e the overall molecule may form, for example, a mono-, di-, to- or tetra-sodium salt)
The compounds of the present invention have a choral centre at the C-5 positions of the oxazolidrnone ring The pharmaceutically active diasteieomer is of the formula (la)
(Formula Removed)
which is generally the (5R) configuration, depending on the natuie ol R1b and C
The piesent invention includes pure diasteieomers or mixtures of diasteieomers, for example a racermc mixture If a mixture of enantiomei s is used, a larger amount (depending
"upon the ratio of the enantiomers) will be requued to achieve the same effect as the same weight of the pharmaceutic ally active enantiomer
Furthermore, some compounds of the invention may have othei chual centres, for example on substituents on gioup C It is to be understood that the invention encompasses all such optical and diasteieoisomers, and iactinic mixtures, that possess antibacterial activity It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form by recrystallisation techniques, by chnal synthesis, by enzymatic lesolution, by biotransformation or by chromatographic separation) and how to determine antibacterial activity as described herernaftei
The invention relates to all tautomeric forms of the compounds of the invention that possess antibacterial activity
It is also to be understood that certain compounds of the invention can exist in solvated as well as unsolvated forms such as, for example, hydrated forms It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity
It is also to be undei stood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms which possess antibacterial activity
As stated before, we have discoveied a range of compounds that have good activity against a broad range of Giam-positive pathogens including organisms known to be resistant to most commonly used antibiotics, together with activity against fastidious Gram negative pathogens such as H mflueuzae, M catarrhalis, Mycoplasma and Chlamydia strains The following compounds possess preferred pharmaceutical and/or physical and/oi pharmacokinetic properties
In one embodiment of the invention aie piovided compounds of foimula (I), in an alternative embodiment are piovided pharmaceutically-acceptable salts of compounds of formula (I), in a farther alternative embodnnent aie provided in-vivo hydrolysable esters of compounds of formula (I), and in a furthei alternative embodiment aie provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula (I)
hi one aspect, an in- vivo hydrolysable ester of a compound of the formula (I) is a phosphoryl ester (as defined by formula (PD4) with npd as 1)
Compounds of the formula (I), or a pharmaceutically-acceptable salt or an in-vivo hydiolysable ester thereof, wheiern C is selected from group D or group E lepresent separate
and independent aspects of the invention
Particularly preferred compounds of the invention comprise a compound of the
invention, or a pharmaceutically-acceptable salt or an in-vivo hydrolysable estei thereof,
wherein the substituents R1a, R1b, R2a, Rob, R3a, R6a and R6b and other substituents
mentioned above have values disclosed herernbefoie, or any of the following values (which
may be used where appropriate with any of the definitions and embodnxients disclosed
heiembefore orherernaftei)
In one embodiment are provided compounds of the foimula. (1) or pharmaceutically
acceptable salt or in-vivo hydrolysable ester thereof wherein gioup C is group D hi another embodiment are provided compounds of the formula (I) or
pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof wherein group C is
group E
In one aspect R2a and R6a are hydrogen
In one aspect one R?b and R6b is fluoro and the other is hydrogen In another aspect
both one R2b and R6b are fluoro In a fui ther aspect R2b is fluoro and R6b is selected fiorn CI,
CF3, Me, Et, OMe and SMe
In one aspect one of R2b and Reb is chloro and other hydrogen In another aspect one of R2b and R In one embodiment R1b is HET1 wherein HET1 is selected from the structures (Za) to (Zf) below
(Formula Removed)
wherein u and v are independently 0 or 1 and RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter
In one embodiment Rib is HET1 wherein HET1 is selected from 1,2,3-rnazole (especially 1,2,3-hiazol-l-yi (Zd)), 1,2,4-niazoie (especially 1,2,4-u.iazol-l-yi (Zc)) and tetrazole (preferably tetrazol-2-yl (Zf)) and wherein u and v are independently 0 oi 1 and RT is as defined in any of the embodiments or aspects defined hereinbefoie or hereinafter
In another embodiment Rib is HET1 wheiein HET1 is selected from 1,2,3-triazol-l-yl (Zd) and tetrazol-2-yl (Zf) and wherein u and v are independently 0 or 1 and RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter
In another embodiment Rib is HET1 wherein HET1 is 1,2,3-triazol-l-yl (Zd) and wherem u and v are independently 0 or 1 and RT is as defined in any of the embodiments or aspects defined hereinbefoie or hereinafter
In one embodiment Rib is HET2 wherein HET2 is a di-hydro version of pyrimidine, pyiidazine, pyrazine, 1,2,3-tnazine, 1,2,4-tiiazrne, 1,3,5-triazine and pyridine and wherein RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinaftei
In another embodiment Rib is HBT2 wheiein HET2 is selected frompyrrmidone, pyndazinone, pyrazinone, 1,2,3-tnazinone, 1,2,4-tnazinone, 1,3,5-tiiazinone andpyndone and wherein RT is as defined in any of the embodiments oi aspects defined hereinbefore or hereinaftei
In another embodiment Rxb is HET2 wherein HET2 is selected from thiopynrnidone, thiopyndazrnone, thiopyrazrnone, thio-l,2,3-triazinone, thio-l,2,4-tuazinone, thio-1,3,5-triazmone and thiopyndone and wherein RT is as defined in any of the embodiments oi aspects defined hereinbefoie or heieinafter
In one aspect RT is preferably selected flora a substituent from, the groups RTal to
RTb2, wherein
(RTal) hydrogen, halogen, (l-4C)alkoxy, (2-4C)alkenyloxy (2-4C)alkenyl,
(2-4C)alkynyJ, (3-6C)cycloalkyl, (3-6C)cycloalkenyL (l-4C)aTkylthio, ammo, azido, cyano ' andrutio,
(RTa2) (l-4C)atkylamrno, di-(l-4C)alkylamuio and (2-4C)alkeuylamrno,
(RTbl) a (l-4C)alkyl group which is optionally substituted by one substituent selected
fromhydioxy, (l-4C)alkoxy, (l-4C)aikylthio, cyano and azido,
(RTb2) a (l-4C)alkyl group which is optionally substituted by one substituent selected from (2-4C)alkenyloxy, (3-6C)cycloalkyl and (3-6C) cycloalkenyl,
and wheiein at each occunence of an RT substituent containing an alky 1, alkenyl, alkynyl, cycloallcyl or cycloalkenyl moiety rn (RTal) or (RTa2), or (RTbl) 01 (RTb2) each such moiety is optionally substituted on an available carbon atom with one, two, three or more substituents independently selected fiomF, CI, Br, OH and CN
In another aspect RT is piefeiably selected from a substituent from the groups RTal and RTbl, wherein
(RTal) hydrogen, halogen, (l-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyL (3-6C)cycloalkenyl, (l~4C)alkylthio, ammo, azido, cyano, andmtro,
(RTbl) a (l-4C)a]kyl group which is optionally substituted by one substituent selected from hydroxy, (l-4C)alkoxy, (l-4C)alkylthio, cyano and azido,
and wherein at each occurrence of an RT substituent containing an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety rn (RTal) or (RTbl) each such moiety is optionally substituted on an available carbon atom with one, two, three or more substituents independently selected fromF, CI, Bi, and CN In a further aspect RT is most prefeiably
(a) hydrogen oi
(b) halogen, in particular fluorine, chlorine, or bromine, or
(c) cyano, or
(d) (l-4C)alkyl, rn particular methyl, 01
(e) rnonosubstituted (1 4C)alkyl, m particular fluoromethyl, ehoromethyl, bromomethyl, cyanomethyl, azidomethyk hydi oxymethyl, or
(f) djsubstituted (l-4C)alkyl, foi example drfluoiomethyl, or
(g) trisubstituted (l-4C)alkyl, for example tixfiuoroinerhyl
la one aspect R4 is selected fromRta In another aspect R4 is selected fromR4D In one aspect R4a is selected fiom (l-4C)a]kyl, (3-6C)cycloalkyl, AR1, AR2, (l-4C)alkanoyl, -CS(l-4C)a%L -C(=W)NRvRw [wheiern W is 0 01 S, Rv andRw aie rndependently H, 01 (l-4C)alkyl], -COO(l-4C)alkyl, -C=OARl, -C=OAR2, -COOAR1, -S(0)n(l-4C)alkyl (wherem n = 1 or 2), -S(0)pARl, -S(0)pAR2 and -C(=S)0(l-4C)aIkyl, wherein any (l-4C)alkyl chain may be optionally substituted by (l-4C)alkyl, cyano, hydroxy or halo, p = 0,1 or 2)
hi a farther aspect R4a is selected from azido, -NR7Rg, -ORi0(l-4C)aIkoxy, -(CH2)m-R9 and -(C=0)rR6
In one aspect HET-3 is selected fromHET3-A, HET3-B, HET3-C, HET3-D and HET3-E
In another aspect HET-3 is selected fromHBT3-F, HET3-G, HET3-H and HET3-I In another aspect HET-3 is selected fromHET3-J, HET3-K, HET3-L, HET3-M, HET3-N, HET3-0, HET3-P, HET3-Q, HET3-R and HET3-S
In a furthei aspect HET-3 is selected from HET3-J, HET3-L, HET3-M, HET3-N, HET3-P, HET3-Q, HET3-R and HET3-S
In a further aspect HET-3 is selected from HET3-L and HET3-M In a further aspect HET-3 is selected from HET3-P and HET3-Q In a further aspect HET-3 is selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y
In a further aspect HET-3 is selected HET3-T, HET3-V, HET3-Y and HET-3-W. In a further aspect HET-3 is selected HET3-V, and HET3-Y In a further aspect HET-3 is selected fromHET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH.
When m = 1, in one aspect Rxa is selected from Rial, in another aspect Rxa is selected fromRia2, rn a further aspect Rxa is selected fromR, in a further aspect Rxa is selected from Ria4 and rn a further aspect Rja is selected from Rxa5
When m = 2, in one aspect both groups Ria aie independently selected from the same group Rial to Ria5 In a further aspect when m = 2, each Ria is independent!}' selected fiom different gioups Rtal to Ria5
Conveniently m is 1 01 2 In one aspect, piefeiably m is 1 In another aspect, preferably mis 2
Particular values ioi R1a when selected from Rjal ai"e AR1 and AR2, moie particularly AR2
Particular values for R1a when selected fiomRia2 are cyario and -C(=W)NRvRw
[wherein W is O or S, Rv and Rw are independently H, or (l-4C)alkyl and wherein Rv and
Rw taken together with the amide or thioarrnde nitrogen to which they aie attached can form a
5-7 membered ring optionaUy with an additional heteroatom selected ftom N, O, S(0)n in
place of 1 carbon atom of the so formed ring, wherein when said ling is a piperazrne ring, the
ring may be optionally substituted on the additional nitrogen by a group selected fiom
(l-4C)alkyl (optionally substituted on a carbon not adjacent to the nitrogen),
(3-6C)cycloalkyl, (l-4C)alkanoyL -COO(l-4C)alkyl, -S(0)n(l-4C)alkyl(whereinn= 1 or2,),
-COOAR1, -CS(l-4C)a]kyl and -C(=S)0(l-4C)alkyl, wherein any (l-4C)alkyl, (1-
4C)alkanoyl and (3-6C)cycloalkyl is optionally substituted by cyano, hydroxy or halo] More
particular values for Ria when selected fromRia2 are cyano, formyl, -COO(l-4C)alkyl,
-C(=0)NH2, -(C=0)piperazrne and -(C=0)morpholrne
Particular values for Ria when selected fromRia3 ate (l-lOC)alkyl (optionally
substituted by one or more groups (including gernrnal disubstitution) each independently selected from hydroxy, (l-10C)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)afkoxy, (l-4C)afkylcarbonyl, phosphoryl [-0-P(0)(OH)2, and mono- and di-(l-4C)alkoxy derivatives thereof], phosphnyl [-0-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], and amnio, and/oi optionally substituted by one group selected from carboxy, cyano, halo, trrfluoromethyl, (l-4C)alkoxycarbonyl, (l-4C)alkoxy-(l-4C)alkoxycarbonyl, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxycaibonyl, (l-4C)alkylamrno, di((l-4C)a]kyl)ammo, (l-6C)alkanoylamrno-, (l-4C)alkoxycaibonylamrno-, N-(l-4C)alkyl-N-(l-6C)alkanoylaimno-, -C(=W)NRvRw [wherein W is O, Rv and Rw are independently H, or (l-4C)alkyl and wherein Rv and Rw taken togethei with the amide nitiogen to which they are attached can form a morpholrne, pyrrolidine, pipendme oi piperazrne rrng, wherin when said rrng is a piperazrne ring, the ring may be optionally substituted on the additional nitrogen by a group selected from (l-4C)afkyl and (1 -4C)alkanoyl], (l-4C)afkylS(0)q-, (q is 0, 1 or 2), AR2, AR2-0-, AR2-NH-, and also AR2a, AR2b veisions of AR2 containing groups}, wherein any (l-4C)alkyl and (l-4C)acyl present m any substituent onR1a3 may itself be substituted by one or two groups independently selected from cyano hydroxy halo, ammo, (l-4C)alkylammo and di(l-4C)alkylamrno, provided that such a substituent is not on a carbon adjacent to a heteroatom atom if piesent,
More particular values foi Ria when selected fiomRia3 ate (l-10Cjalkyl {optionally substituted by one or more groups (including geirunal disubstitutiou) each, independently selected from hydroxy, (l-lOC)alkoxy, (l-4C)alkoxy-(l-4C)aIk:oxy, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxy, phosphoryl [ 0-P(0)(OH)2> and mono- anddi~(l-4C)alkoxy derivatives thereof], phosphrryl [-0-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], carboxy, amino, (l-4C)alkylammo, di(l-4C)alkylamrno, (l-4C)alkylS(0)q (preferably where q=2), AR2 and AR2b More particular values foi R^a when selected from Ria3 are (l-6C)alkyl substituted as hereinbefore described Even more particular values foi R^ when selected fromRia3 aie (l-4C)alkyl substituted as hereinbefore described
Particular values for substituents on a (1-lOQalkyl, (l-oC)alkyl 01 (l-4C)alkyl group comprising Ria3 are hydroxy, (l-10C)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy-(l~4C)alkoxy, phosphoryl [-0-P(0)(OH)2, and mono- and di-(l-4C)alkoxy derivatives thereof], phosphrryl [-0-P(OH)2 and mono- and di-(l-4C)aIkoxy derivatives thereof] and carboxy Preferably Ria3 is a (l-4C)alkyl group substituted with 1 or 2 hydroxy groups
Particulai values for Ria when selected fiom Ria4 are RwC(0)0(l-6C)a3kyl- wherein Rw is selected from AR1, AR2, AR2a,AR2b and (1-lOQalkyl (optionally substituted by one or more substituents independently selected fiom OH and di (l-4C)alkylainrno Moie particular vales for R14 aie AR2a, AR2b and (l-6C)alkyl substituted with hydroxy More particular values for Rw are AR2a, AR2b and (l-4C)alkyl substituted withhydroxy
Particular values for Rja when selected from Ria5 aie fluoro, chloro and hydroxy
Particular values foi other substituents (winch may be used wheie appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinaftei) are -
a) in one aspect R7 and Rg are independently H or (l-4C)alkyl
b) ma further aspect Rvand R8 taken togethei with the nitiogen to which they aie attached form a 5-7 membered ling, optionally substituted as defined hereinbefore or hereinafter
c) preferably R?and Rs taken together with the nitrogen to which they aie attached form a pyrrohdrnyl, pipendrnyl, pipeiazmyl or moiphoknyl rnig
d) preferable optional subsituents on R7 and R8 as a pyrrohdinyl, pipendrnyl, piperazrn\l or morphohnyl rrng are (l-4C)alkyl and (l-4C)alkanoyl, wherein the (l-4C)alkyl 01 (1-4C)alkanoyl gioup itself may be optionally substituted with one or two substituents selected from hydroxy, ammo, (l-4C)alkylainino and di(l-4C)alkylarmno
e) In one aspect R9 is selected from R9a, preferably selected from AR2, AR2a and AR2b
f) In another aspect Rg is selected frorxiR6b, preferably selected from-C(=W)NRvRw, wherein W is O, Rv and Rw are independently H, 01 (l-4C)alkyl and wherein Rv and Rw taken together with the amide mtiogen to which they a' e attached can form a morphohne, pyrrolidine, pipendrne or piperazrne ring, wherein when said ring is a piperazrne ring, the ring may be optionally substituted on the additional nitrogen by a gioup selected from (l-4C)alkyl and (l-4C)alkanoyl, and wherein any (l-4C)alkyl and (l-4C)alkanoyl may itself be substituted by one or two groups independently selected ftoni cyano, hydroxy, halo, amino. (l-4C)alkylarmno and di(l-4C)alkylamrno, provided that such a substituent is not on a caibon adjacent to a heteroatom atom rf present
g) In a further aspect R9 is selected frornR9c, wherein R9c is (l-6C)alkyl {optionally
substituted by one, two or three gioups (including gemrnal disubstitution) each independently
selected from hydroxy, (1-lOQalkoxy, (l-4C)alkoxy-(l-4C)alkoxy, (l-4C)alkoxy-
(l-4C)alkoxy-(l-4C)alkoxy, (l-4C)alkylcarbonyl, phosphoryl [-0-P(0)(OH)2, and mono- and
di-(l-4C)alkoxy derivatives thereof], phosphiryl [-0-P(0H)2 and mono- and di-(l-4C)alkoxy
derivatives thereof], and amino, and/or optionally substituted by one group selected from
carboxy, cyano, halo, tnfluoromethyl, (l-4C)a!koxycarbonyl, (l-4Cjalkoxy-
(l-4C)alkoxycarbonyl, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxycarbonyl, (l-4C)a]kylarmno,
di((l-4C)alky 1)amino, (l-6C)alkanoylamrno-, (l-4Qalkoxycarbonylamrno-, N-(l-4C)a]kyl-
N-(l-6C)alkanoylamrno-, -C(=W)NRvRw [wheiern W is O, Rv and Rw are independently H,
or (l-4C)alkyl and wherein Rv and Rw taken together with the amide nitrogen to which they
are attached can form a morphohne, pyrrolidine pipendrne or piperazrne ring, wherein when
said ring is a piperazrne ring, the ling may be optionally substituted on the additional nitrogen
by a group selected from (l-4C)alkyl and (l-4C)alkanoyl], (l-4C)alkylS(0)q- (q is 0, 1 or 2),
AR2, AR2-0-, AR2-NH-, and also AR2a, AR2b versions of AR2 containing groups},
wherein any (l-4C)alkyl and (l-4C)alkanoyl present in any substituent on R9c may itself be
substituted by one or two groups independently selected fiom cyano, hydroxy, halo, amino,
(l-4C)alkylamrno and di(l-4C)alkylamino, provided that such a substituent is not on a carbon
adjacent to a heteroatom atom if present
h) In a further aspect R9 is selected horn R9c, wheieni R9c is (l-6C)alkyl {optionally substituted by one, two or thiee groups (including gemrnal disubstitution) each independently selected from hydroxy, (l-10C)alkoxy, (l-4C)alkoxy-(l-4C)aIkoxy, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxy, phosphoryl [-0-P(0)(OH;2, and mono- and di-(l-4C)alkoxy

denvatives thereof], phosphnyl [-0-P(OH)2 and mono- and di-(l-4C)a!koxy derivatives
thereof], caiboxy, ammo, (l-4C)a]kylarmno, di(l-4C)aIkylarmno, (l-4C)alkylS(0)q
(pieferably wheie q=2), ARJ2 and AR2b A more particular value foi R9c is (l-4C)alkyl,
optionally substituted as heieinbefoie described
i) In a farther aspect R9 is selected frornRpd wherein R9d is R14C(0)0(l-6C)alkyl- and
Rw is selected from AR1, AR2, AR2a,AR2b and (1-lOQalkyl (optionally substituted by one
or two substituents independently selected from OH and di (l-4C)alkylamino) Particular
vales for R14 are AR2a, AR2b and (l-6C)alkyl substituted with hydroxy More particular
values for R14 are AR2a, AR2b and (l-4C)alkyl substituted with hydroxy
j) Particular- values foi R21 are Ri4C(0)0(2-6C)alkyl-, wherein RH is pieferably selected
from AR1, AR2, AR2a,AR2b and (l-lOC)alkyl (optionally substituted by one or two
substituents independently selected from OH and di (l-4C)alkylarnino
k) Further particular values foi R21 are (2-IOC) alky 1, optionally substituted other than
ona carbon attached to the HET-3 rrng nitrogen with one or two gioups independently seleted
from the optional substituents defined hereinbefore or heieniafter for Ria3, further particular
values for R21 are optionally substituted (2-6C)alkyl, moie paiticularly optionally substituted
(2-4C)alkyl
1) Particular substituents for a (2-6C)alkyl or (2-4C)alkyl gioup comprising R21 are 1 or
2 substituents independently selected from hydroxy, (l-lOC)alkoxy, (l-4C)alkoxy-
(l-4C)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxy, phosphoryl [-0-P(0)(OH)2, and
mono- and di-(l-4C)a]koxy derivatives thereof], phosphrryl [-0-P(OH)2 and mono- and di-
(l-4C)alkoxy derivatives theieof], carboxy, amino, (l-4C)alkylamino, di(l-4C)alkylamino,
(l-4C)alkylS(0)q (preferably where q=2), AR2 and AR2b
m) Fuither particular values for substituents on a (2-6C)alkyl or (2-4C)alkyl group
comprising R2i are 1 or 2 substituents rndependently selected from hydroxy, (l-lOC)alkoxy,
(l-4C)alkoxy-(l-4C)alkoxy (l-4C)a]koxy-(l-4C)arkoxy-(l-4C)alkoxy, phosphoryl [-0-
P(0)(OH)2, and mono- and di-(l-4C)alkoxy derivatives thereof], phosphrryl [-0-P(OH)2 and
mono- and di-(l-4C)alkoxy derivatives theieof] and caiboxy Pieferably substituents on a (2-
6C)alkyl or (2-4C)alkyl group comprising R21 are 1 or 2 hydroxy groups
n) Preferably R22 is cyano
0) Particularly preferred values foi AR2, AR2a and AR2b groups are those containing a
basic nitiogen, foi example pyridine, pyrrolidine, pipeiazme and piperidrne, optionally
substituted as hereinbefore defined
In one embodiment is provided a compound of the formula (la) or a pharmaceutic ally-acceptable salt or an in-vivo hydrolysable estei thereof,
(Formula Removed)
(la) wherein group C is group D, R2a and Rea are both hydrogen, R2b and R6b are independently hydrogen 01 fluorine, and R4 is selected fromHET-3
In another embodiment is provided a compound of the formula (la) 01 a phaimaceutically-acceptable salt or an in-vivo hydrolysable estei theieof, wherein group C is group D, R2a and R6a aie both hydiogen, R2b and R6b aie independently hydrogen or fluorine, and R4 is selected fromHET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y
In another embodiment is provided a compound of the formula (la) or a phaimaceutically-acceptable salt or an in-vivo hydiolysable ester theieof, wherein group C is group D, R2a and R6a are both hydrogen, R2b and R6b ai e independently hydrogen or fluorine, andR, is selected fromHET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and BET3-AH
In another embodiment is provided a compound of the formula (la) or a pharmaceutically-acceptable salt or an in-vivo hydiolysable ester thereof, wherein group C is group D, R2a and R6a are both hydrogen, R2b and R6b are independently hydrogen or fluorine, R4 is selected fromHET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, m=l and Ria is selected fiomRia3
In another embodiment is provided a compound of the formula (la) 01 a pharmaceutically-acceptable salt 01 an in-vivo hydrolysable ester theieof, wherein group C is gioup E, R2a and R6a aie both hydrogen R2b and R6b are mdependently hydrogen or fluorine, and R4 is selected fromHET3-T, HE13-U, HET3-V, HET3-W, HET3-X and HBT3-Y
In another embodiment is provided a compound of the formula (la) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein gioup C is
group E, R2a and R6a are both hydrogen, R2b and R6b axe nidependently hydrogen 01 fluorine, and R4 is selected nomHET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH
hi another embodrraent is provided a compound of the formula (la) or a pharrnaceutically-acceptable salt or an in-vivo hydiolysable ester theieof, wherein group C is group E, R2a and R6a are both hydrogen, R2b and R6b are independently hydrogen or fluorine, R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, m=l and Rja is is selected fromRia3
In another embodiment is provided a compound of the formula (la) or a pharrnaceutically-acceptable salt 01 an in-vivo hydiolysable ester theieof, wherein group C is group D, R2a and R6a are both hydrogen, R2b and R6b are independently hydrogen or fluorine, R4 is selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y, Rib is selected fiom Zd and Zi, u and v are nidependently 0 or 1 and RT is selected from hydiogen, halogen, cyano, methyl, fluoromethyl, choromethyl, bromomethyl, cyanomethyl, azidomefhyl, hydioxymethyl, drfluoromethyl, and trrfluoromethyl
In another embodiment is provided a compound of the formula (la) or a pharrnaceutically-acceptable salt or an in-vivo hydrolysable estei thereof, wherein group C is group D, R2a and R6a are both hydrogen, R2b and R6b are independently hydrogen or fluorine, and R4 is selected HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, Rib is selected from Zd and Zf, u and v are nidependently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, choromethyl, biomomethyl, cyanomethyl, azidomefhyl, hydroxymethyl, drfluoromethyl, and tiifluoromethyl
In another embodmoent is provided a compound of the formula (la) or a pharrnaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein group C is group D, R2a and R6a are both hydrogen, R2b and R6b are nidependently hydrogen or fluorine, R4 is selected fromRET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, m=l, Ria is selected fiomRia3, Rib is selected from Zd and Zf, u and v are independently 0 ot 1 and RT is selected from hydiogen, halogen, cyano, methyl, fluoromethyl, choromethyl, biomomethyl, cyanomethyl, azidomefhyl, hydroxymethyl, drfluoromethyl, and trifluoromethyl
In anothei embodiment is provided a compound of the formula (la) or a pharrnaceutically-acceptable salt or an m-vivo hydrolysable ester thereof, wheieni group C is
group E, R2a and R6a are "both hydrogen, R2b and R6b are independently hydrogen or fluorine, and R4 is selected fromHET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y, Rib is selected frornZd and Zf, u and v are rndependently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoiomethyl, choiometbyl, bromomethyl, cyanomethyl, azidomethyl, liydroxymethyl, difluoromethyl, and trifluoromethyl
In another embodiment is provided a compound of the formula (la) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable estei theieof, wherein group C is group E, R2a and R6a are both hydrogen; R2b and Reb aie independently hydrogen or fluorine, andR4 is selected fromHET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, R2b is selected frornZd and Zf, u and v are independently 0 or 1 and RT is selected horn hydrogen, halogen, cyano, methyl, fluoromethyl, choromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl, and trifluoromethyl
In another embodiment is provided a compound of the formula (la) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, whereni group C is group E, R2a and Rga are both hydrogen, R2b and R6b are independently hydrogen or fluorine, R4 is selected fromHET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, m=l, Ria is selected fiomRia3, Rib is selected from Zd and Zf, u and v are rndependently 0 or 1 and RT is selected from hydrogen, halogen, 1 cyano, methyl, fluoromethyl, choromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl, and trifluoromethyl
In another embodiment is piovided a compound of the formula (la) or a pharmaceutically-acceptable salt 01 an in-vivo hydiolysable ester thereof, wherein group C is group E, R2a and Rga are both hydiogen; R2b and R6b aie independently hydrogen or fluorine, and R4 is HET3-Y, Rib is selected from Zd and Zf, u and v are rndependently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoiomethyl, choromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, drfluoiomethyl, and trifluoromethyl In another embodnnent is provided a compound of the formula (la) 01 a pharmaceutically-acceptable salt or an rn-vivo hydrolysable ester thereof, wheiern group C is group B, R2a and R6a are both hydrogen, R2b and R6b aie rndependently hydrogen or fluorine, R4 is HET3-V, Rib is Zd or Zf, u and v aie rndependently 0 01 1, R21 is methyl or (2-4QaIkyl (optionally substituted with 1 or 2 substrtuents independently selected from hydroxy, (l-lOC)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy, (l-4C)alkoxy-(l-4C)aIkoxy-(l-4C)alkuxy,
phosphoryl [-0-P(0)(OH)2, and mono- and di-(l-4C)alkoxy derivatives theieof], phosphnyl [~0-P(OH)2 and mono- and di-(l-4C)alkoxy deuvatives thereof] and caiboxy), and RT is selected horn hydrogen, halogen, cyano, methyl, fluororuethyl, choromethyl, bromorriethyl, cyanomethyl, azidomethyl, hydioxymethyl, diiluoromethyl, and tnfluoromethyl In another embodiment is provided a compound of the formula (la) 01 a pharmaceutically-acceptable salt or an rn-vivo hydrolysable ester thereof, wherein group C is group E, R2a and Rga are both hydrogen, R.2b and R6b are rndependently hydiogen or fluorine, R4 is HET3-V, Rib is Zd, n and v are independently 0 01 1, R2i is methyl or (2-4C)alkyl (optionally substituted with 1 or 2 hydroxy), and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, choromethyl, biomomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluorornethyl, and trrfluoromethyl
In another embodiment is provided a compound of the formula (la) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable estei thereof, wherein group C is group E, R2a and R6a are both hydiogen, R2b and R6b are independently hydrogen or fluorine, R4 is HET3-V, Rib is Zd, u and v are independently 0 or 1, R21 is methyl or (2-4C)alkyi (optionally substituted with 1 or 2 hydroxy), and RT is selected from hydiogen, halogen, methyl, fluoromethyl, choromethyl, bromomethyl, difluorornethyl, and tnfluoromethyl
In another embodiment is provided a compound of the formula (la) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein gioup C is group E, R2a and Rga are both hydrogen, R2b and R6b aie independently hydrogen or fluorine, R4 is HET3-V, Rib is Zd, u and v are independently 0 or 1, R2i is methyl or (2-4C)alkyl (optionally substituted with 1 or 2 hydioxy), and RT is selected from hydrogen, fluoro, chloro, methyl, fluoromethyl, choromethyl, difluorornethyl, and tnfluoromethyl
In another embodiment is provided a compound of the fonnula (la) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein group C is group E, R2a and Rga are both hydrogen, R2b and R6b are independently hydiogen or fluorine, R4 is HET3-V, Rib is Zd, u and v are rndependently 0 or 1, R2i is methyl 01 (2-4C)alkyl (optionally substituted with 1 or 2 hydioxy), and RT is selected from hydrogen, chloro, fluoiomethyl and difluorornethyl
In all of the above definitions the preferred compounds are as shown in formula (la)
Particular compounds of the present invention include each individual compound descnbed in the Examples, each of which provides an independent aspect of the invention A more particular compound is Example 1
Piocess section
In a furfhei aspect the present invention provides a process for prepairng a compound of invention or a pharmaceutically-acceptable salt 01 an in-vivo hydrolysable ester thereof It will be appreciated that during certain of the foho wing processes certain substituents may require piotection to prevent their undesired leaction The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed
For examples of protecting groups see one of the many geneial texts on the subject, for example, 'Protective Groups in Organic Synthesis' by Theodora Green (publisher lohn Wiley & Sons) Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule
Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the leactions mentioned herein
A suitable protecting group foi an amino or alkylamnio gioup is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, foi example a mefhoxycarbonyl, ethoxycarbonyl or r-butoxycarbonyl gioup, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, foi example benzoyl. The deprotection conditions for the above protecting groups necessarily vaiy with the choice of protecting group Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example hthmm or sodium hydroxide Alternatively an acyl group such as a /-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid ashydiochloiic, sulfuric 01 phosphonc acid or trrfiuoroacetic acid and an aiylmefhoxycarbonyl group such as a benzyloxycaibonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-caihon, 01 by treatment with a Lewis acid for example boron tris(tnfluoroacetate) A suitable alternative protecting group for a pirmary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamrne, for example dnnethylaixunopropylamme, 01 withhydiazine
A suitable protecting group for a hydroxy gioup is, for example, an acyl gioup, for example an alkanoyl group such as acetyl, an arojl group, foi example benzoyl, or an arylmethyl gioup, foi example benzyl The deprotection conditions for the above piotecting
groups will necessarily vary with the choice of protecting group Thus, for example, an acyl group such as an alkanoyl or an aioyl group may be removed, foi example, by hydrolysis with a suitable base such as an alkali metal hydioxide, for example hthium or sodium hydroxide Alternatively an arylmethyl group such as a benzyl group may be lemoved, for example, by hydrogenation over a catalyst such as palladium-on-carbon
A suitable protecting group for a carboxy group is, for example, an esterrfying gioup, for example a methyl or an ethyl gioup which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a r-butyl group which may be removed, foi example, by treatment with an acid, for example an organic acid such as tnfluoro acetic acid, or for example a benzyl gioup which may be removed, foi example, by hydrogenation over a catalyst such as paUadium-on-carbon Resins may also be used as a piotectrng group. The protecting groups may be removed at any convenient stage rn the synthesis using conventional techniques well known rn the chemical art
A compound of the invention, or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester thereof, may be prepaied by any process known to be applicable to the preparation of chemically-related compounds Such processes, when used to piepare a compound of the invention, 01 a pharmaceutically-acceptable salt 01 an in vivo hydrolysable ester thereof, aie provided as a further feature of the invention and are illustrated by the following repiesentative examples Necessaiy starting materials may be obtained by standard procedures of organic chemistry (see, for example, Advanced Organic Chemistry (Wiley-Interscience), Jerry Match or Houben-Weyl, Methoden der Organischen Chemie) The preparation of such starting materials is described within the accompanying non-lrrmting Examples Alternatively, necessary starting materials aie obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist Information on the preparation of necessary starting matenals or related compounds (which may be adapted to form necessary starting materials) may also be found m the certain Patent Application Publications, the contents of the relevant piocess sections of which aie hereby incorporated herein by reference, for example WO 94/13649, WO 98/54161, WO 99/64416, WO 99/64417, WO 00/21960, WO 01/40222
In paiticular we refer to our PCT patent applications WO 99/64417 and WO 00/21960 wherein detailed guidance is given on convenient methods for preparing oxazolidinone compounds
The skilled organic chemist will be able to use and adapt the information contained and refeienced within the above refeiences, and accompanying Examples therein and also the Examples herein, to obtain necessary stalling materials, and pioducts For example, the skilled chemist will be able to apply the teaching herein foi compounds of formula (I) in which a pyrimidyl-phenyl group is present (that is when group" C is group D) to prepare compounds in which a pyridyl-phenyl group is present (that is when group C is group E) as heereinbefore defined and vice versa
Thus, the present invention also provides that the compounds of the invention and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by a process (a) to (j), and thereafter if necessary 1) lernovmg any protecting groups,
n) forming a pio-drug (for example an in-vivo hydrolysable ester), and/or m) foraung a pharmaceutically-acceptable salt,
wherein said processes (a) to 0) ^^ as follows (wherein the variables are as defined above unless otherwise stated)
a) by modifying a substituent in, or introducing a substituent into another compound of
the invention by using standard chermstiy, (see for example, Comprehensive Organic Functional Group Transformations (Pergamon), Katritzky, Meth-Cohn & Rees or Advanced Organic Chemistry (Wiley-Interscience), Jerry March or Houben-Weyl, Methoden der Orgamschen Chemie), foi example
an acylamuio group may be converted into a thioacylammo gioup, an acylamino group or thioacylammo gioup may be converted into another acylamino or thioacylamino, heterocyclyl for instance tetrazolyl or thiazolyl, orheterocyclylarmno group (optionally substituted or protected on the amino-nitrogen atom), an acyloxy group may be converted into a hydroxy group or into the groups that may be obtamed from a hydioxy group (either du-ectly 01 through the rntermediacy of a hydroxy group),
an alkyl hahde such as alkylbromide 01 alkyhodide may be converted into an alkyl fluoride or mtrile;
an alkyl sulfonate such as alkyl methanesulfonate may be converted into an alkyl fluoride or nitiile,
an alkylthio group such as methylthio may be converted mto amethanesulfm}! ormethanesulfonyl gioup,
an arylthio group such as phentlthio may be converted into a benzenesulfrnyl or
benzenesulfonyl group,
an armdrno or guanidrno group may be converted into a lange of 2-substituted 1,3-diazoles
and 1,3-diazrnes,
an amnio group may be converted for instance into acyJamrno or thioacylamrno for instance
an acetamide (optionally substituted), alkyl- or dialkyl-amino and thence into a further lange
of N-alkyl-amrae derivatives, sulfonylamnio, sulfinylaimno, amidrno, guanidino, arylamrno,
heteroarylamrno, N-knked heteiocychc for instance an optionally 4-substituted 1,2,3-triazol-
1-ylgroup,
an aryl- 01 heteroary-halide group such as an aryl- 01 hetero-aiyl chloride or bromide or iodide
may be converted by transition metal mediated coupling, especially Pd(0) mediated coupling
into a range of aryl-, heteroaryl, alkenyl, alkynyl, acyl, alkylthio, or alkyl- 01 dialkyl-ammo
substituted aryl or heteroaiyl groups,
an aryl- or heteroaiy-sulfonate group such as an aryl- or hetero-aryl trrfluorometlianesulfonate
may be converted by transition metal mediated coupling, especially Pd(0) mediated coupling
into a range of aryl-, heteroaryl, alkenyl, alkynyl, acyl, alkylthio, or alkyl- or dialkyl-amino
substituted aryl or heteroaryl groups,
an aryl- or heteroary-halide group such as an aryl- or hetero-aryl chlonde or bromide or iodide
may be converted by transition metal mediated coupling, especially Pd(0) mediated coupling
into a range of tnalkyltin, dialkylboronate, trialkoxysilyl, substituted aryl or heteroaiyl groups
useful as intermediates for the synthesis of compounds of the invention,
an azido group may be converted for instance into a 1,2,3-triazolyl or amine and thence by
methods that are well known in the art into any of the range common amine denvatives such
as acylammo for instance acetamido gioup,
a carboxyhc acid group may be converted into trrfloiomethyl, hydroxymethyl,
alkoxycaibonyl, aimnocarbonyl optionally substituted on nitrogen, formyl, or acyl gioups,
a cyano group may be converted into a tetrazole, or an rmidate, an amidine, an amidrazone, an
N-hydroxyamidrazone, an amide, a thioamide, an ester, or an acid and thence by methods that
are well known in the ait into any of the range of heterocycles derived from such nitrile
derivatives,
a hydroxy gioup may be converted for instance into an alkoxy, cyano, azido, alkylthio, keto
and oxnmno, fluoro, bromo, chloro, lodo, alkyl- or aryl-sulfonyloxy for instance
trrfluoromethanesulfonate, methanesulfonate or tosylsulfonate, sifyloxy , acylamrno or
thioacylamino , for instance an acetamide (optionally substituted 01 protected on the airudo-
nitrogen atom), acyloxy, for instance an acetoxy, phosphono-oxy, heterocyclylarnrno
(optionally substituted oi piotected on the amino-nitiogen atom), foi instance an isoxazol-3-
ylarmno 01 a l,2,5-thiadiazol-3-ylarmno, heterocyclyl linked through nitrogen (optionally
substituted on a carbon other than a carbon atom adjacent to the linking nitrogen iing atom),
for instance an optionally 4-substituted 1 2,3-triazol-l-yl, 01 amidino, for rnstance an
l-(N-cyanoirnrno)ethylarruno group, such conversions of the hydioxy group taknig place
directly (for rnstance by acylation or Mitsunobu reaction) or thi ough the intermediacy of one
or more denvatives (foi instance a mesylate 01 an azide),
a silyloxy gioup may be converted into a hydioxy gioup or into the groups, that may be
obtained from a hydroxy group (eithei directly or through the intermediacy of a hydroxy
group),
a keto group may be converted into a hydroxy, fhiocarbonyl, oxrmino, or drfluoro group,
a mtro-group may be converted into an amino group and thence by methods that are well
known in the art into any of the range common amine derivatives such as acylamino for
rnstance acetarmdo group,
a 2-, 4-, or 6-pyridyl or 2-, 4-, or 6-pyiimidyl hahde such as chloride or sulfonate such as
mesylate substituent may be converted into alkoxy, alkythio, amrno, alkylamrno,
dialkylamino, oi N-hnked heterocyclic substituents,
moreover, an optionally substituted heteroaromatic ring D or E may be converted into another
heteroaromatic ring D or E by introduction of a new substituent (R2a, R3a, or R6a) or by
refunctionahsation of an existing substituent (R2a, R3a, or R6a)
a heterocyclylamrno group (optionally substituted or protected on the amnio-nitrogen atom)
may be converted into another heterocyclyl amino group (optionally substituted or piotected
on the ammo-nitrogen atom) by refunctionahsation, for rnstance by protection or depiotection,
of the amino-nitrogen atom, by introduction of a new ring substituent, or by
lefunctionahsation of an existing ring substituent,
a heterocyclyl group linked through nitrogen (optionally substituted on a carbon other than a
caibon atom adjacent to the linking nitiogen ring atom) may be conveited into anothei
heteiocyclyl group linked through nitrogen (optionally substituted un a carbon other than a
carbon atom adjacent to the linking nitrogen ring atom) by introduction of a new ring
substituent oi by refunctionahsation of an existing iing substituent, for rnstance by modifying
the 4-substituent of a 4-substituted 1,2,3-triazol-l-yl group,
for rnstance, examples diawn from the methods for conversion of a hydroxy group rnto an optionally substituted tiiazole group ea e illustrated by the scheme
(Scheme Removed)
examples drawn from the range of regioselective methods that proceed under very mild conditions aie illustrated by processes (h), (1), and (j),
b) by reaction of a molecule of a compound of formula (Ha) [wherein X is a leaving group useful rn palladium coupling (for example chloride, bromide, iodide, trifluoiomethylsulfonyloxy, tnmethylstannyl, trialkoxysilyl, or aboronic acid residue) and rn this instance A is either N or C-R3a] with a molecules of a compound of formula (lib) (wherein X' is a leaving group useful rn palladium coupling, for example chloride, bromide, iodide, tirfluoromethylsulfonyloxy, tmnethylstannyl, trialkoxysilyl, 01 a boromc acid residue) wherein X and X' are chosen such that an aryl-ar)l, heteioaiyl-aiyl, 01 heteioaryl-heteroaryl bond replaces the aryl-X (or heteroaryl-X) and aryl-X' (01 heteroaryl-X') bonds Such
rnethods are now well known, see for instance J K Stiile, Angew Chem Int Ed. Eng , 1986, 25, 509-524, N Miyaura and A Suzuki, Chem Rev , 1995, 95, 2457-2483, D Baxanano, G Mann, and J F Hartwig, Current Org Chem , 1997,1, 287-305, S P Stanforth, Tetmhedron, 541998,263-303, and PR Pany, C Wang, AS Batsanov,MR Bryce, andB Taibit, / Org Chem, 2002, 67, 7541-7543,
(Formula Removed)
the leaving groups X and X' are chosen to be different and to lead to the desired cross-coupling products of formula (I), for example
(Formula Removed)
the pyridines, pyrirnidrnes, and aryl oxazohdrnones required as reagents for process b) or as intermediates for the preparation of leagents for pi o cess b) may be piepared by standard organic methods, for instance by methods analogous to those set out in process sections (c) to (]) Methods for the introduction and rnteiconversion of Groups X and X' are well known in the art
c) by reaction of a heterobiaiyl derivative (HI) carbamate with an appiopnately
substituted oxirane to form an oxazohdrnone ring,
(Formula Removed)
variations on tins process in which the carbamate is replaced by an isocyanate or by an amine or/and m which the oxirane is replaced by an equivalent reagent X-CH2CH(0-optionally protected)CH2Rib where X is a displaceable gioup ate also well known rn the art For example,
(Formula Removed)
(d) by reaction of a compound of formula (VI) .
(Formula Removed)
wheie X is a replaceable substituent - such as chloride, bromide, iodide, trifluoromethylsulfonyloxy, tnmethylstannyl, tnalkoxysilyl, or a boronic acid residue with a compound of the formula (VII)
(Formula Removed)
(VII) wherein T-X' is HET3 as herein above defined and X' is a replaceable C-knked substituent -such as chloride, bromide, iodide, trifluoiomethylsulfonyloxy, trrmethylstannyl, tnalkoxysilyl,

or a boromc acid residue, wherein the substituents X and X' are chosen to "be complementary parrs of substituents known in the ait to be suitable as complementaiy substrates for coupling leactions catalysed by transition metals such, as palladium(0), (d(i)) by reaction catalysed by transition metals such as palladmm(0) of a compound of
foi inula (VIII)
(Formula Removed)
wherein X is a replaceable substituent - such as chloride, bromide, iodide, trifluoromethylsulfonyloxy, tnmethylstaruayl, tnalkoxysilyl, or a boromc acid lesidue with a compound of the formula (IX) {Tetrahedron Letts , 2001, 42(22), 3681-3684),
(Formula Removed)
(d(ii)) by reaction of a compound of formula (X)
(Formula Removed)
X is a replaceable substituent - such as chlonde, bromide, iodide, trrtluoromethylsulfonyloxy -with a compound of the formula (XI)
(Formula Removed)
wherein T-H is an amine R7R8NH, an alcohol RioOH, or an azole with an available ruig-NH group to give compounds (Xlla), (XUb), or (XQc) wherein in this instance A is mtiogen oi C-R3a and A' is nitrogen or carbon optionall> substituted with one oi moie groups Rla,
(Formula Removed)
(Xltc) (e) by reaction of a compound of foimula (XIII)
(Formula Removed)
wherein Xi and X2 here ai'e independently optionally substituted heteroatoms drawn in combination from O, N, and S such that C(Xi)X2 constitutes a substituent that is a carboxyhc acid derivative substituent with a compound of the formula (XIV) and X3 and X4 are independently optionally substituted heteroatoms drawn in combination fromO, N, and S
(Formula Removed)
and wherein one of C(Xi)Xz and C(X3)X) constitutes an optionally substituted hydrazide, tbiohydrazide, or arrudrazone, hydroxrrrndate, or hydroxamidme and the other one of C(Xi)X2 and C(X3)X4 constitutes an optionally substituted acylating, tmoacylating, or rmidoylatrng agent such that C(Xi)X2 and C(X3)X4may be condensed together to form a 1,2,4-heteroatom 5-membeied heterocycle contarmng 3 heteroatoms drawn ni combination from O, N, and S, foi Distance thiadiazole, by methods well-known in the art, (e (i)) by leaction of a compound of formula (XV)
(Formula Removed)
wherein X2 is a displaceable group such as ethoxy or drphenylphosphonyloxy with a source of azide anion such as sodium azide to give a tetrazole (XVI)
(Formula Removed)
Alternatively mtriles of formula (XVII)
(Formula Removed)
may be reacted directly with azides such as ammonium azide or tnalkylstannylazides to give tetrazoles (XVI, Rla = H) that are subsequently alkylated with gioups Rla * H to give tetrazoles (XVilla) and (XVIIIb), (Formula Removed)
(f) by reaction of a compound of foimula (XIX)
(Formula Removed)
with a compound of the foimula (XX)
(Formula Removed)
wherein, one of C(Xs)X6 and C(X7)X8 constitutes an optionally substituted alpha- (leaving-group-substiruted)ketorie, wherein the leaving group is for example a halo-group or an (alkyl or aryl)-sulfonyloxy-group, and the other one of C(X5)XS and C(X7)Xs constitutes an optionally substituted amide, thioamide, 01 amidine, such that C(X5)X6 and C(X7)X8 are groups that may be condensed together to form a 1,3-heteioatom 5-niembered heterocycle contarmng 2 heteroatoms drawn in combination from O, N, and S, for instance thiazole, by methods well-known rn the art,
(g) for HET as optionally substituted 1,2,3-triazoles, compounds of the formula (I) may be made by cycloaddition via the azide (wheiern e g Y m (II) is azide) to acetylenes, or to acetylene equivalents such as optionally substituted cylcohexa-l,4-dienes or optionally substituted ethylenes bearing elxmrnatable substituents such as arylsulfonyl, (h.) for HET as 4-substituted 1,2,3-tnazole compounds of formula (1) may be made by reacting airmomethyloxazohdrnones with 1,1-dihaloketone sulfonylhydrazones (Sakai, Kunihazu, Hida, Nobuko, Kondo, Kryosi, Bull Chan Soc. Jpn , 59,1986, 179-183, Sakai, Kumkazu, Tsunemoto, Daiei, Kobori, Takeo, Kondo, Kryoshi, Hido, Noboko EP 103840 A2 19840328), (Formula Removed)

(i) for HET as 4-substituted 1,2,3-tnazole compounds of formula (I) may also be made by reacting azidomethyl oxazohdruones with terminal alkynes using Cu(I) catalysis meg aqueous alcoholic solution at ambient temperatuies to give 4-substituted 1,2,3-tnazoles (V V Rostovtsev, L G Green, V V Fokrn, and K B Sharpless Angew Chem hit Ed , 2002, 41, 2596-2599)
(Formula Removed)
(j) for HET as 4-halogenated 1,2,3-tnazole compounds of formula (1) may also be made by reacting azidomethyl oxazolidrnones with halo vmylsulfonyl chlorides at a temperature between 0 °C and 100 °C either neat oi in an inert diluent such as chlorobenzene, chloioform or droxan
(Formula Removed)
A similar cycloaddition leaction to that shown in (]) with an unrelated azide to give an unrelated tnazole has been disclosed in the literature for the case where the halogen rn the vmylsulfonylchlonde reagent shown above is bromine (C S Rondestvedt, Jr and P K Chang, / Amer. Chem. Boc , 77,1955, 6532-6540, piepaiation of l-bromo-l-ethenesulfonyl chloride by C S Rondestvedt, Jr , J Amei Chem Soc , 76,1954, 1926-1929) However, a reaction of vrnylsulfonyl chloride failed to stop at the desired product and gave instead an unwanted by-product Moreover, the factors that govern the formation of either the undesired tnazole by elimination of the elements of H-Halogen from the intermediate cycloadduct or the desired tnazole by elimination of the elements of HC1 and S02 from the intermediate cycloadduct are not set out in the literature
We have now surprisingly found that, when the halogen is chlorine, that is when the reagent is the compound 1-chloro-l-ethenesulfonyl chlonde
(Formula Removed)
the cycloaddition reaction is highly regioselective and gives a good yield of the desired product Fuithermore theieagent 1-cMoro-i-ethenesulfonyl chloride is novel Therefoie a further aspect of the invention comprises the compound 1-chloro-l-ethenesulfonyl chloride Another aspect of the invention comprises the use of 1-chloro-l-ethenesulfonyl chloride m a cycloaddition reaction with an azide to form a 4-chloi o-1,2,3-hiazole A fui ther aspect of the invention comprises use of 1-chloro-l-ethenesulfonyl chloride with an azide derivative in a process to form a compound of the formula (I) wherein Rib is 4-chloro-l,2,3-tnazole, or R4 is 4-chloro-HET3-AB
the cycloaddition reaction with 1-clnoio-l-ethenesulfonyl chloride with an azide derivative in a piocess to form a compound of the formula (I) wheiern Rxb is 4-chloro-l,2,3-tnazole and or R4 is 4-chloio-HET3-AB is caixied out at 0 °C and 100 °C , preferably at room tempeiatuie, either in an meit solvent, preferably chlorobenzene, chloroform, or dioxan, or moie preferably without a solvent
The removal of any protecting groups, the formation of a phairnaceuticaUy-acceptable salt and/01 the formation of an in-vivo hydrolysable estei are within the skill of an oidrnary organic chemist using standard techniques Furthemioie, details on the these steps, for example the preparation of in-vivo hydrolysable ester prodrugs has been provided, for example, rn the section above on such esters
When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using an optically active starting material (formed, for example, by asymmetric induction of a suitable reaction step), or by resolution of a racemic form of the compound or intermediate using a standard procedure, or by chromatographic separation of diastereoisomers (when produced) Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates
Similarly, when a pure regioisomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers 01 intermediates using a standaid procedure
According to a further feature of the invention there is provided a compound of the invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof for use rn a method of treatment of the human or arumal body by theiapy
Accoidrng to a further featuie of the piesent invention theie is provided a method foi producing an antibacterial effect in a warm blooded annual, such as man, rn need of such treatment, which compuses admmisteimg to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof
The invention also piovides a compound of the invention, or a pharmaceutically-acceptable salt, or in-vivo hydiolysable ester thereof, foi use as a medicament, and the use of a compound of the invention of the present invention, or a phaimaceutically-acceptable salt, or in-vivo hydrolysable estei theieof, m the manufacture of a medicament for use m the production of an antibacterial effect rn a warm blooded animal such as man
Ia order to use a compound of the invention, an in-vivo hydiolysable ester or a pharmaceutically-acceptable salt thereof including a pharmaceutically-acceptable salt of an. rn-vivo hydrolysable ester, (hereinafter rn this section ielating to pharmaceutical composition "a compound of this invention") for the therapeutic (including prophylactic) treatment of > mammals including humans, in particular in treating infection, it is normally formulated rn accordance with standard pharmaceutical practice as a pharmaceutical composition Therefore rn another aspect the present invention provides a pharmaceutical composition which comprises a compound of the invention, an nvvivo hydrolysable ester or a ' pharmaceutically-acceptable salt thereof, including a pharmaceutically-acceptable salt of an rn-vivo hydrolysable estei, and a phaimaceutically-acceptable diluent or carriei
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or ehxus), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration as eye-drops, for administration by inhalation (for example as a finely divided powder or a liquid aerosol), foi administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, sub-lingual, intramuscular or mtiamuscular dosing 01 as a suppository for lectal dosing)
In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also contain (le through co-formulationj 01 be co-administered (simultaneously, sequentially or separately) wrth one or more known drugs selected from other clinically useful antibacterial agents (for example, B-lactams, macrolides, qurnolones or aminoglycosides) and/or other auti-mfective agents (for example an antrfungal tnazole or amphotericin) These may include carbapenems, foi example meropenem or nxnpenem, to broaden the therapeutic effectiveness Compounds of tins invention may also be co-foimulated or co-administered with bactericidal/permeability-increasing protein (BPI) products or efflux pump rnhibitors to improve activity against gram negative bacteria and bacteria resistant to antrmiciobial agents Compounds of this invention may also be co-formulated or co-admrnistered with a vitamin, for example Vitamin B, such as Vitamin B2, Vitamin B6, Vitamin B12 and folic acid Compounds of the invention may also be formulated or co-admrnistered with cyclooxygenase (COX) rnhibitors, particularly COX-2 inhibitois
In one aspect of the invention, a compound of the invention is co-formulated with an antibacterial agent which, is active against gram-positive bactena
In another aspect of the invention, a compound of the invention is co-formulated with an antibacteiial agent which is active against grain-negative bactena
In another aspect of the invention, a compound of the invention is co-administei ed with an antibacterial agent which is active against gram-positive bactena
In another aspect of the invention, a compound of the invention is co-admimsteied with an antibacterial agent which is active against gram-negative bactena
The compositions of the invention may be obtained by conventional piocedures using conventional pharmaceutical excipients, well known in the ait Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents A pharmaceutical composition to be dosed intravenously may contain advantageously (for example to enhance stability) a suitable bactericide, antioxidant or reducing agent, or a suitable sequestering agent
Suitable pharmaceutically acceptable excipients for a tablet iormuJation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn staich or algenic acid, binding agents such as staich, lubricating agents such as magnesium stearate, stearic acid or talc, preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid Tablet formulations may be uncoated 01 coated either to modify their disintegiation and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appeal ance, in eithei case, using conventional coating agents and proceduies well known in the art
Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, c ale mm carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in winch the active nigiedient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil
Aqueous suspensions generally contain the active ingredient in finely powdered form togethei with one 01 moie suspending agents, such as sodium cdiboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrohdone, gum tragacanth and gum acacia, dispersing 01 wetting agents such as lecithin cr condensation pioducts of an alkylene oxide with fatty acids (for example polyoxethylene steal ate), or condensation pioducts of ethylene oxide with long chain aliphatic alcohols, for example
heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, 01 condensation products of ethylene oxide with partial esters derived fiom fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters denved from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate The aqueous suspensions may also contain one or moie preservatives (such as ethyl or propyl p-hydroxybenzoate, antioxidants (such as ascorbic acid), colouring agents, flavouiing agents, and/or sweetening agents (such as sucrose, sacchaime or aspartame)
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as hquid paraffin) The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives Suitable dispeismg 01 wetting agents and suspending agents are exemplified by those already mentioned above Additional excipients such as sweetening, flavouring and colouring agents, may also be present
The pharmaceutical compositions of the invention may also be m the form of oil-rn-water emulsions The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid pai affin or a mixture of any of these Suitable emulsifying agents may be, foi example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esteis derived from fatty acids and hexitol anhydrides (foi example sorbitan monooleate) and condensation products of the said partial esteis with ethylene oxide such as polyoxyethylene sorbitan monooleate The emulsions may also contain sweetening, flavouiing and preservative agents
Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent
The pharmaceutical compositions may also be in the form of a sterile injectable ' aqueous or oily suspension, which may be formulated according to known procedures using one or moie of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above A sterile injectable preparation may also be a sterile injectable solution or suspension m a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol Solubility enhancing agents, foi example cyclodextnns may be used
Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid dioplets Conventional aerosol propellants such as volatile fluomiated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a meteied quantity of active ingredient
For further information on formulation the reader is referred to Chapter 25 2 m Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansen, Chairman of Editorial Board), Pergamon Press 1990
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vaiy depending upon the host treated and the particular route of administration For example, a formulation intended foi oral administration to humans will generally contain, for example, from 50 mg to 5 g of active agent compounded with an appiopnate and convenient amount of excipients which may vaiy from about 5 to about 98 percent by weight of the total composition Dosage unit forms will generally contain about 200 mg to about 2 g of an active ingredient For furtiier information on Routes of Admmistiation and Dosage Regimes the reader is referred to Chapter 25 3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch, Chairman of Editorial Boaid), Peigamon Press 1990
A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet oi capsule which contains between lmg and Ig of a compound of this invention, preferably between lOOmg and Ig of a compound Especially preferred is a tablet or capsule which contains between 50mg and SOOmg of a compound of this invention, particularly in the range lOOmg to 500mg
In another aspect a pharmaceutical composition of the invention is one suitable foi mtiavenous, subcutaneous or intramuscular injection, for example an injection which contains between 0 1% w/v and 50% w/v (between lmg/ml and 500mg/rnl) of a compound of this invention
Each patient may receive, for example, a daily intravenous, subcutaneous or intramuscular dose of 0 5 mgkg"1 to 20 mgkg" of a compound of this invention, the composition being administered 1 to 4 times pei day In another embodiment a daily dose of 5 rngkg"1 to 20 mgkg"1of a compound of this invention is administered The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection Alternatively the intravenous dose ma> be given by continuous infusion ovei a period of tune Alternatively each patient may receive a daily oral dose which may be approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day
In the above other, pharmaceutical composition, process, method, use and medicament manufactuie features, the alternative and piefened embodiments of the compounds of the invention described herein also apply
Antibacterial Activity
The pharmaceuticalfy-acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of activity in vitro against standard Gram-positive organisms, which are used to screen for activity against pathogenic bacteria Notably, the pharmaceutically-acceptable compounds of the piesent invention show activity against enterococci, pneurnococci and mefhicillin resistant strains of S aureus and coagulase negative staphylococci, togethei with haemophflus and moraxella strains The antibacterial spectrum and potency of a particular compound may be determined in a standard test system.
The (antibacterial) pioperties of the compounds of the invention may also be demonstrated and assessed in-vivo in conventional tests, for example by oral and/or intravenous dosmg of a compound to a warm-blooded mammal using standard techniques
The following results weie obtained on a standard in-vitro test system. The activity is descubed in terms of the lrunimum inhibitory concenti ation (MIC) determined by the
agar-dilution technique with an inoculum size of lO4 CFU/spot Typically, compounds are active in the i ange 0 01 to 256 fig/uA
Staphylococci weie tested on agar, using an inoculum of 10^ CFU/spot and an
incubation temperatuie of 37°C for 24 hom s - standard test conditions foi the expression of methicillrn lesistance
Stieptococci and enterococci were tested on agar supplemented with 5%
defibiinated horse blood, an inoculum of Kr" CFU/spot and an incubation temperatuie of 37°C rn an atmosphere of 5% carbon dioxide for 48 hours - blood is required for the growth of some of the test organisms Fastidious Gram negative organisms weie tested m Mueller-Hrnton broth, supplemented withhemrn and NAD, grown aerobically for 24 hours at 37°C, and with an innoculum of 5xl04 CFU/well
For example, the following results were obtained for the compound of Example 1
Organism MIC (/xg/ml)
Staphylococcus aureus MSQS 0 25
MRQR 0 25
Streptococcus pn«. umon?ae Enterococcus faecium 0 25
Haemophilus influenzae 2
Moraxella catarrhahs 0 25
Lmezohd Resistant Streptococcus pneumoniae 0 5
MSQS = methicillrn sensitive and qurnolone sensitive MRQR = methicillrn resistant and qurnolone resistant
Certain intermediates and/or Reference Examples described hereinafter are within the scope of the invention and may also possess useful activity, and are piovided as a further feature of the invention
The invention is now illustrated but not limited by the following Examples in which unless otherwise stated -
(l) evaporations were carried out by lotary evaporation in-vacuo and work-up procedures weie earned out after removal of residual solids by filtration,
(n) operations were earned out at ambient tempeiature, that is typically in the range 18-26°C and without exclusion of an unless otherwise stated, oi unless the skilled person would otherwise work undet an rneit atmosphere, (in) column chromatography (by the flash procedure) was used to purify compounds and
was performed on Meick Kteselgel silica (Art 9385) unless otherwise stated, (IV) yields aie given for illustration only and are not necessarily the maximum attainable, (v) the structure of the end-products of the invention weie generally confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra weie generally determined rnDMSO-de unless otherwise stated using a Varian Gemini 2000 spectrometer operating at a field strength of 300 MHz, oi a Bruker AM250 spectrometer operating at a field strength of 250 MHz, chemical shifts are reported in parts pei million downfield from tetramethysilane as an. internal standard (S scale) and peak multiplicities are shown thus s. singlet, d, doublet, AB or dd, doublet of doublets, dt, doublet of triplets, dm, doublet of multiplets, t, triplet, m, multiplet, bi, broad, fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected], optical rotations weie determined at 589nm at 20°C for 0 1M solutions in methanol using a Perkin Elmer Polanmeter 341,
(vi) each inteimediate was purified to the standaid required for the subsequent stage and was characterised in sufficient detail to confirm that the assigned structuie was correct, purity was assessed by HPLC, TLC, oi NMR and identity was determined by infia-ied spectroscopy (IR), mass spectioscopy or NMR spectroscopy as appropriate, NOE is nuclear oveihauser effect, (vu) in which the following abbreviations may be used -
DMF is N,N-dimethylformamide, DMA is N,N-dimethylacetamide, TLC is thin layer chromatography, HPLC is high pressure liquid chromatography, MPLC is medium pressure liquid chiomatography, NMP is N-methylpyrrohdone, DMSO is dimethylsulfoxide, CDCl3 is deuterated chloioforrn, MS is mass spectroscopy, ESP is electrospray. EJ is election impact, CI is chemical lorusation, APCI is atmospheric pressure chemical lonisation, EtOAc is ethyl acetate, MeOH is methanol, phosphoryl is (HO)2-P(0)-0-, phosphnyl is (HO)2-P-0-, Bleach is "Clorox" 6 15% sodium hypochlonte, THF is tetrahydrofuran (vni) temperatures aie quoted as °C
Example l:(5R)-3-(3-Fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pvrid-3-yl)phenyl)-5-(lff-l,2,3-triazol-l-ylmethyl)-l,3-oxazolidm-2-oiie
(Formula Removed)
Amixture of (522)-3-(3-fluoio-4-iodophenyl)-5-(liy-l,23-triazol-l-ylmethyl>l,3-oxazolidm-i 2-one (370 mg, 0 95 mrnol), bis(pinacolato)diboron (605 ing, 2 4 mmol), and potassium acetate (326 mg, 3 3 mmol) in dunethylsulfoxtde (5 mL) was degassed, flushed with nitrogen and trated with dichloro[l,r]6zj(diphenylphosphnio)ferrocene]palladmm (II) dichloromethane adduct (69 mg, 10 mol %) The mixture was heated to 80 °C for 1 5 hours, cooled to room temperature, filtered through Cehte, and extracted with ethyl acetate The organic phase was washed with aqueous ammonium chloride solution, dried over magnesium sulfate, and evaporated to dryness. The involatile residue was purified by chromatography on silica-gel [elation withhexanes ethyl acetate (3 2)] to give arrnxtuie of (5R)-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboiolan-2-yl)phenyl)-5-( \H-1,2,3-triazol- 1-ylmethyl)-l,2-oxazohdin-2-one and the corresponding boronic acid (210 mg, ~0 54 mmol, 57%) that was used without further purification
A mixture of the mixture of boronate estei and boronic acid prepared above, 5-bromo-2-(2-methyl-2iJ-tetrazol-5-yl)pyndnie (160 mg, 0 67 mmol), and potassium carbonate (448 mg. 3 24 mmol) in AT, iV-dimethyl fomiamide and water (10 mL, 7 1) was degassed, flushed with nitrogen, and treated with tetrakis (tnphenylphosprne) palladium (0) (62 mg, 0 054 mmol) The reaction mixture was heated at 80 CC for 1.5 hours, cooled to room temperature, filtered thiough Cehte, extracted with ethyl acetate, dried over magnesium sulfate, and evaporated to dryness The involatile residue was purified by chromatography on silica-gel [elation with ethyl acetate hexanes (3 2)] to give the product as a colorless amorphous solid (140 mg, 61 %)
MS (ESP) 422 47 (MH+) for C19H16EN9O2
1H-NMR (DMSO-d6) δ 3 98 (dd, 1H), 4 31 (dd, 1H), 4 47 (s, 3H), 4 86 (m, 2H), 5 18 (m, 1H), 7 45 (m. 1H), 7 61 (m, 1H), 7 74 (m, 1H), 7 77 (brs, 1H), 8 12-8 27 (m, 3H), 8 93 (s, 1H)
The intermediates for Example 1 were prepared as follows
Acetic acid (5R)-3-f3-fluoiophenyl)-13-oxazoMm-2-oii-5-ylmettiyLester
(Formula Removed)
i-(5R)-3-(3~Fluoropbenyl)-5 hydroxymemyl-l,3-oxazohdrn-2-one (40 g, 0 189 M, see Upjohn WO 94-13649) was suspended by stirring in dry dicMoromethane (400 mL) under nitrogen Tnethylamme (21 g, 0 208 M) and 4-dimethylaminopyndine (0 6 g, 4 9 mM) were added, followed by dropwise addition of acetic anhydride (20 3 g, 0 199 M) over 30 minutes, and stirring continued at ambient temperature for 18 houis Saturated aqueous sodium bicarbonate (250 rnL) was added, the organic phase separated, washed with 2% sodium dihydiogen phosphate, dried (magnesium sulfate), filtered and evaporated to give the desned product (49 6 g) as an oil MS (ESP) 254 (MH+) for Ci2H12FN04
NMR (CDCl6) b 2 02 (s, 3ii), 3 84 (dd, 1H), 4 16 (t, 1H), 4 25 (dd, iH), 4 32 (dd, IK), 4.95 (m, IH), 6 95 (td, IH), 7 32 (d, IH), 7 43 (t, IH) , 7 51 (d, IH)
Acetic acid (5^)-3-(3-fluoro-4-iodo-phenyl)-13-oxazohdrn-2-one-5-yfmetliyl ester
(Formula Removed)
Acetic acid (5R)-3-(3-fluoro-phenyl)-l,3-oxazohdrn-2-one-5-yrmethyl ester (15 2 g, 60 mM) was dissolved in a mixture of chloroform (100 mL) and acetomtrile (100 mL) under nitrogen, and silvei tnfluoroacetate (16 96 g, 77 mM) added Iodine (18 07 g, 71 mM) was added in portions over 30 mmutes to the vigorously stirred solution, and stin ing continued at ambient temperature foi 18 hours As reaction was not complete, a further portion of silvei tirfluoroacetate (2 64 g, 12 mM) was added and stirring continued for 18 hours After filtration, the mixture was added to sodium thiosulfate solution (3%, 200 mL) and dichlorornethane (200 mL), and the organic phase separated, washed with sodium thio sulfate (200 mL), saturated aqueous sodiumbicaibonate (200 mL), biine (200 mL), dried (magnesium sulfate), filteied and evapoiated The crude product was suspended rn zwhexane (100 mL), and sufficient diethyl ether added to dissolve out the brown impurity while stirring
for 1 hour Filtration gave trie desired pioduct (24 3 g) as a ciearn solid
MS (ESF) 380 (MH+) foi C12H11HNO4
NMR (DMSO-d6) δ 2 03 (s, 3H), 3 82 (dd, 1H), 4 15 (t, 1H), 4 24 (dd, 1H), 4 30
(dd, 1H), 4 94 (m, 1H), 7 19 (dd, lPf), 7 55 (dd, 1H), 7 84 ft, 1H) (5R)-3-(3-Fluoro-4-iodoplienYl)-5-lwdioxvmethyl-l,3-oxazolidra-2-oue
(Formula Removed)
Acetic acid (5R)-3-(3-fluoro-4-iodophenyl)-l,3-oxazolidiii-2-orie-5-ylmethyl ester (30 g, 79
mM) was treated with potassium carbonate (16 4 g, 0 119 mM) rn a mixture of methanol (800
mL) and dichloromethane (240 rriL) at ambient temperature for 25 minutes, then immediately
neutralised by the addition of acetic acid (10 mL) and water (500 roL) The precipitate was
filtered, washed with water, and dissolved rn dichloromethane (1 2 L), the solution washed
with satuiated sodium bicarbonate, and dried (magnesium sulfate) Filtration and evaporation
gave the desned product (23 g)
MS (ESP) 338 (MH+) for CioH9FINO?
NMR (DMSO-d6) δ 3.53 (m, 1H), 3 67 (m, 1H), 3 82 (dd, 1H), 4 07 (t, 1H), 4 70
(m, 1H), 5 20 (t, 1H), 7 21 (dd, 1H), 7 57 (dd, 1H), 7 81 (t, 1H)
(5R)-5-Azidomethyl-3-(3-fluoro-4-iodophenyD-1,3-oxazohdin-2-one
(Formula Removed)
Methanesulfonyl chloride (17 9 mL) was added dropwise to a strned solution of (5JR)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-l,3-oxazohdm-2-one (55 8 g) and triethylamine (46 1 mL) rn dry dichloromethane (800 mL) under an atmospheie of dry nitrogen and maintained below room temperature by an ice-bath The stirred reaction mixture was allowed to warm to room temperature during 3 hours and then washed sequentially with water and brine and then dried (Na2S04) Solvent was removed under reduced pressure to give the intermediate mesylate as a yellow solid (68 g) that was used without further purification
A stirred solution in DMF (800 mL) of a mixture of the intermediate mesylate (68 g) and sodium azide (32 3 g) was heated at 75°C overnight The mixture was allowed to cool to room tempeiature, diluted with water, and extracted twice with ethyl acetate The combined extiacts weie washed sequentially with water and brine, and then dried (Na2S04) Solvent was lemoved under reduced pressure to give a yellow oil that was purified by column chromatography on silica-gel [elution with ethyl acetate hexanes (1 1)] to give the product azide as an off-white sohd (49 g) The product could be further purified by trituration with ethyl acetate/bexanes
JH-NMR (DMSO-d6) δ 3 57-3 64 (dd, 1H), 3 70-3 77 (dd, 1H), 3 81-3 87 (dd, 1H), 4 06 (t, 1H), 4 78-4 84 (m, 1H), 7 05-7 09 (ddd, 1JH), 7 45 (dd, 1H), 7 68-7 74 (dd, 1H)
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(lJff-l,2,3-triazol-l-yhnethyl)-l,3-oxazohdin-2-one
(Formula Removed)
A stirred solution in dioxan (300 mL) of a mixture of the (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-l,3-oxazohdrn-2-one (30 g) and bicyclo[2 2 ljheptadiene (30 mL) was heated under reflux overnight The mixtuie was allowed to cool to room temperature and then evaporated to dryness under reduced pressure to give a brown sohd The brown sohd was purified by column chromatography on sihca-gel [elution with a giadient from 9 8 2 to 95 5 methanol cMoroform] to give the product tnazole as a pale yellow sohd (20 g) The product could he further purified by trituration with dicHorornethane/hexanes (1 1) to give an off-white sohd
JH-NMR (DMSO-d6) δ 3 86-3 92 (dd, 1H), 4 23 (t, 1H), 4 83 (d, 2H), 5 11-5 19 (m, 1H), 7 12-7 16 (dd, 1H), 7 47-7.51 (dd, 1H), 7 76 (s, 1H), 7 79-7 85 (dd, 1H), 8 16 (s, 1H)
3-Bromo-6-cyano-pyridrne
(Formula Removed)
A stirred solution of 2,5-dibromopyridrue (39 465 g, 0 17 mol) m anhydrous NMP (100 niL) was treated with CuCN (14 &2 g, 0 17 mol) for 20 hours at 110°C undei nitrogen The reaction mixture was cooled to 40°C and tieated with aqueous sodium hydioxide (2M, 200

mL) and then with ethyl acetate (200 mL) The mixtuie was stined foi 1 hour and then filteied thio agh Cehte to remove the resulting pi ecipitate The i etarned sohd was washed with aqueous sodium hydroxide (2M, 600 mL) and then with ethyl acetate (600 mL) The oiganic layers were combined and washed with aqueous ainmoiimm hydroxide (5M, 800 mL), dried over magnesium sulfate, and evaporated to dryness under reduced pressure The nivolatile residue was purified by chromatography on silica gel [elution gradient 1% to 7% of ethyl acetate nihexanes] to give the title compound (8 538 g, 28%), as a colorless amorphous sohd 1H-NMR (DMSO-d6) (300 MHz) δ 8 05 (d, 1H), 8 40 (dd, 1H), 8 95 (d, 1H)
5-Bromo-2-teh azol-5-ylpyndine
(Formula Removed)
A mixtuie oi 3-bi.ouio-6-eyaitO -pyiidine (2 g, 10 9 mmol), sodium azide (0.85 g , 13 muiul), and ammonium chloride (0 59 g, 11 mmol) in N,A^dimethylformamide (20 mL) was heated foi 1 h at 120 °C The reaction mixtuie was diluted with ethyl acetate (-100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous sohd winch was used in the next step without fuither purification
5-Bromo-2-(2-methyl-2H-tetrazol-5-vl)pyndine and 5-biomo-2-( 1-methyl-lif-tetrazo 1-5-yDpvndrne
(Formula Removed)
5-Bromo-2-(2-methyl-2F-tetiazol-5-yl)pyndineand5-biomo-2-(l-methyl-lfl-tetrazol-5-yl)pyridrue were prepared according to the proceduie described by Dong A Pharmaceuticals (WO 01/94342)
A mixtuie of 6 5 g unpurrfied 5-bromo-2-tetiazol-5-ylpyndrne [Dong A Pharmaceuticals (WO 01/94342)] (-28 mmol) and sodium hydi oxide (9 g 125 mmol) rn dry DMF was evaporated to dryness under reduced pressure A stirred solution of the involatile lesidue in dry DMF (50 rnL)was tieated dropwise at ice-bath temperature with lodomethane (3 0 mL, 48 mmol) The
stared reaction mixture was allowed to warm arid then maintained at room temperature for 2 hours The reaction mixture was partitioned between iced water and ethyl acetate The organic phase was washed with water, dned ovei magnesium sulfate, and tehn evapoiated under reduced pressure to give a residue that was purified by chromatography on silica gel [elution with dichloromethane ethyl acetate (60 1)1 to give.
1 5-biomo-2-(l-methyl-lJff-tetrazol-5-vl)pyridrne (1 397 g), a colorless solid, (TLC smca-gel. hexanes ethyl acetate (4 1), Rf 0 3), 1H- NMR (DMSO-dj) (300 MHz) δ 4 38 (s, 3H), 8 17 (d, ffi), 8 35 (dd, IK), 8 96 (d, 1H)
2 5-bromo-2-(2-methyh2H-tetrazol-5-yl)pyudme (1 07 g), a colorless solid, (TLC silica-gel, hexanes ethyl acetate (4 1), Rf 0 1) 1H-NMR (DMSO-d6) (300 MHz) δ 4 46 (s, 3H), 8 09 (d, 1H), 8 28 (dd, 1H), 8 88 (d, 1H)
Structure assignment based on nmr HMBC (Heteionuclear Multiple Bond Correlation) expenments, m which long range coupling of the protons of CH3 to the C5 of the tetrazole ring is observed m the l-niethyl-1H-i sorrier of Rf 0.3, but not in the 2-methyl-2rff-isomer of Rf 0 1) The compound referred to as 5-bromo-2-(l-methyl-li?-tetrazol-5-yl)pyndrne is thus the isomer of Rf 0 3 and the compound refened to a& 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridme is thus the isomer of Rf 0 1
Example 2: (5/?)-3-(3-Fluoro-4-(6-(2-rnethyl-2ff-tetrazol-5-yl)pvrid-3-vI)DJienyl)-5-(4-fluoroinethYl-lff-l,2,3-triazol-l-vImetliYl)-l,3-oxazoIidm-2-one
(Formula Removed)
A mixture of (5is!)-3-(3-fluoro-4-iodophenyl)-5-(4-fluoromethyl-li/-l,2,3-txiazol-l-ylmethyl)-l,3-oxazohdrn-2-one (1 5 g, 3 57 mmol), Z>/j(pinaeolato)diboron (2 26 g, 8 9 mmol), and potassium acetate (1 22 g, 12 5 mmol) in dmrethylsulfoxide (15 mL) was treated with dichloro[l,i']Z?w(diphenylphosplnno)ferrocene]palladium(n) dichloromethane adduct (261 mg, 10 rnol %) and allowed to react as described for Example 1 The reaction mixture was purified by chromatography on silica gel [elution with hexanes ethyl acetate (3 2)] to give a mixture of (5R)-3-(3-fluoro-4-(4,4,5,5-tehamethyl-l,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluoromethyl-li?-l,2,3-triazol-l-yhiiethylVl,3-oxazohdin-2-one with the conesponding boromc acid (562 mg, -37%) that was sufficiently pure for further use
A rnrxtuie of a portion of the mixture of boronate ester and boronic acid prepared above (337
mg, 0 8 mmol), 5-bromo-2-(2-methyl-2F-tetrazol-5-yl)pyridrne (175 mg, 0 73 mrnol), and
potassium carbonate (504 mg, 3 65 mmol) in N,N~dimethylfonnarmde water (10 IDL, 7 1) was
treated with teti-akis(ti-iphenylphospme) palladium (0; (84 rug, 10 mol %) and allowed to react
as described for Example 1 The reaction mixture was purified by chromatography on silica
gel [elution with ethyl acetate hexanes (1 2)] to give the product as a colorless amorphous
solid (180 mg, 49%)
MS (ESP) 454 45 (MFT) for C20H17F2N9O2
1H-NMR (DMSO-d6) δ 3 98 (dd, IH), 4 32 (dd, IH) 4 47 (s, 3H), 4 88 (in, 2H); 5 19 (m,
1H), 5 46 (d, 2H, JHp 48 Hz) 7.45 (m. 1H), 7 63 (m, 1H), 7 75 (m, 1H), 8 15-8 24 (m, 2H),
8 38 (d, 1H), 8 93 (s, 1H)
The intermediates foi Example 2 were prepared as follows
(5#)-3-(3-Fluoio-4-iodophenyl)-5-(4-hydroxymethyl- IH-1,2,3-tnazoI- l^lmethyl)-1,3-oxazohdin-2-one
(Formula Removed)
A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-azidomethyl-l,3-oxazoMin-2-one (10 g, 28
mmol) and propargyl alcohol (3 2 mL, 56 mmol) m acetomtrile (80 mL) was treated with Cul
(526 mg, 2 8 mmol) and then stirred overnight The solidified reaction mixture was extracted
with ethyl acetate acetomtrile, washed with water, and dried over magnesium sulfate, and then
evaporated under reduced pressure to give a crude product sufficiently puie for furthei use
(12 3 g, quantitative)
MS (ESP) 419 13 (MH+) for Ci3H12FIN403
1H-NMR (DMSO-d6) δ 3 88 (dd, IH), 4 23 (dd, IH), 4 51 (d, 2H), 4 80 (m, 2H), 5 14
(m, IH), 5 22 (dd, IH), 7 16 (no, IH), 7 51 (m, IH), 7 83 (m, IH), 8 01 (d, IH)
(5R)-3-(3-Huoro-4-iodophenyl)-5-(4-bromomethYl-]1H-l 2,3-triazol-l-vlmethyl)-l,3-oxazohdrn-2-one
(Formula Removed)
A stirred mixtme of(5R)-3-(3-fluoio-4-iodophenyl)-5'(4-hydioxymethyl-lHA,2,3~triazol-l -
ylmethyl)-l,3-oxazolidrn-2-one (14 7 g, 35 1 mmol) and carbon tetrabrornide (12 16 g, 36 7
romol) in dichloromethane (1 L) was heated at 0°C with triphenylphosphrne (12 34 g, 61 2
mmol) The reaction mixture was stirred for 30 minutes at 0°C and then at room temperature
overnight The reaction mixture was applied onto a silica-gel column and eluted with
hexanes ethyl acetate (1 1) and then with ethyl acetate methanol (95 5) to give a product that
was further purified by reciystallization from ethyl acetate to give the title compound as a
colorless solid (14 g)
MS (ESP) 482 69 (MH' for Br81) for d3Mi iBrHN4Oz
1H-NMR (DMSO-d6) δ 3 87 (dd, 1H), 4 23 (dd, 1H), 4 74 (s, 2H), 4 81 (m, 2H), 5 12
(m, 1H), 7 14 (m, 1H), 7.49 (m, 1H), 7 81 (rn, 1H), 8 22 (d, 1H)
(5i2V3-(3-fluoro-4-iodophenyl)-5-f(4-fluoromethyl-lflr-l,2,3-tiiazol-l-yl)methylloxazohdin-2-one
A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-bromomethyl-lflr-l,2,3-triazol-l-ylmethyl)-l,3-oxazohdrn-2-one (6.94 g, 14 4 mmol), potassium fluonde (4 19 g, 72 1 mmol), and l-butyl-3-methyhmidazohumtetrafiuoroboiate (18 4 mL) in acetonitiile (250 mL) and water (1 5 mL) was heated to 90 °C overnight The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and evaporated to diyness The mvolatile lesidue was purified by chromatography on sihca gel [elution with ethyl acetate] gave the title compound as an off-white amorphous solid (2 7 g, 45 %) MS (ESP) 421 34 (MH+) for C13H11F 2 I nOii
JH-NMR (DMSO-d6) δ 3 88 (dd, 1H), 4 23 (dd, 1H), 4 84 (m, 2H), 5 14 (m, 1H), 5 45 (d, 2H, JH^ 52 Hz), 7 14 (m, 1H), 7.49 (m, 1H), 7 81 (m, 1H), 8 34 (d, 1H)

Example3:(5R)-3-(3-Fluoro-4-(6-92-methyl-2if-tetrazol-5-vl)pYrid-3-vl)pliejivl)-5-(4-chloro-lJHr-l,2,3-triazoI-l-YlmetlLVl)-l,3-oxazolidiii-2-one
(Formula Removed)
A mixture of (5R)-3-(3-fluoio-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboiolan-2-yl)phenyl)-5-(4-chloro-liy-l,2,3-tiiazol-l-y]meth.yl)-l,3-oxazolidiii-2-one (300 mg, 0 71 mmol), 5-bromo-2-(2-methyl-2Hr-tetrazol-5-yl)pyndme (170 mg, 0 71 mmol), and sodium carbonate (226 mg, 2 13 mmol) in iV,7Y-dimethylformamide water (5 mL, 10 1) was degassed, flushed with nitrogen, and treated with tetraka"s(tnphenylphosphme)palladmm (0) (82 mg, 10 mol %) The reaction mixture was heated at 70 °C for 3 hours, cooled to room temperature, and evaporated to dryness under reduced pressure The rnvolatile residue was purified by chromatography on silica gel [elution with dichloiomethane iV,7Y-dniiethylformamide (25 1 to 20.1)] The product fraction was concentrated to a small volume (~3 mL) and treated with dichloromethane (5 mL) and hexanes (15 mL) to precipitate the product as a colorless amorphous solid (229 mg, 71 %)
MS (ESP) 456 27 (MH+) foi C19Hi5FN902
1H-NMR ODMSO-d6) δ 3 98 (dd, 1H), 4 32 (dd, 1H), 4 47 (s, 3H) 4 86 (m, 2H), 5 19 (m, 1H), 7 46 (m, 1H). 7 63 (m, 1H), 7 76 (m, 1H), 8 15-8 27 (m, 2H), 8 47 (s, 1H), 8 93 (s, 1H)
The intermediates for Example 3 were prepared as follows Ethenesulfonyl chloride
(Formula Removed)
A stirred solution of 2-chloroethanesulfonyl chloride (50 g, 0 307 mol) in dry ether (400 mL) was treated at -60 °C to -50 °C under an atmospheie of rutiogen with a solution of 2,6-lutidine (42 2 mL, 0 36 mol) in dry ether (60 mL) and then with a further portion of dry ether (200 mL) The stirred reaction mixture was allowed to warm to room temperatuie, cooled to 0 °C and then treated slowly with dilute aqueous sulfuric acid (1 %, 125 mL) The etheieal phase was separated, washed with dilute aqueous sulfuric acid (1%, 125 mL) and brine (2 x 120 mL), dried over magnesium sulfate, and concentiated undei reduced pressure
(500 mmHg) to give a crude oil that -was purified by distillation to give ethenesulfonyl
chloride (C S Rondestveldt, 7 Amer Chem Soc , 16, 1954, 1926) (24 6 g, 63%),
b p 27 2°C / 0 2mmHg
1H nmr (CDC13) δ 7 20 (dd, 7 = 16 2 and 9 4 Hz, 1H), 6 55 (dd, 7= 16 2 and 1 7 Hz, 1H), and
6 24 (dd, 7 = 9 4 and 1 7 Hz, 1H)
1,2-Dichloroethanesulfonyl chloride
(Formula Removed)
A stirred solution of chlorine in a solution of ethenesulfonyl chloride (32 g, 0 25 mol) in carbon tetrachloride was irradiated at about room tempei ature (200W light) for 5 h The reaction mixture was concentrated under reduced pressure (50 mmHg) and the involatile residue was fractionally distilled to give 1,2-dichloroethanesulfonyl chloride (Goldstein et al Zh Obshch Khun, 28,1958, 2107) (15,5 g, 31%), bp 75°C/0 7mmHg 1H-nmr (CDC13) δ 5 29 (dd, 7= 8.9 and 3 3 Hz, 1H), 4 40 (dd, 7= 12 4 and 3 3 Hz, 1H), and 3 97 (dd, 7= 12 4 and 8 9 Hz, 1H) 1-Chloro-l -ethenesulfonyl chloride
(Formula Removed)
A stirred solution of 1,2-dichloroethanesulfonyl chloride (14 54 g, 73 62 mrnol) in dry ether (140 mL) was treated at -60 °C to -50 °C under an atmosphere of nitrogen with2,6-lutidine (10 30 mL, 88 34 mmol) The stirred reaction mixture was allowed to warm to room temperature, cooled to 0 °C and then treated slowly with dilute aqueous sulfuric acid (1%, 50 mL) The ethereal phase was separated, washed with dilute aqueous sulfuric acid (1 %, 2 x 60 mL) and brine (3 x 60 mL), dried over magnesium sulfate, and concentiated under reduced pressme (60 rnrnHg) to give an oil that was puiified by distillation to give 1-chloro-l-ethenesulfonyl chloride (7 2 g, 61%), b p 26 °C / 2mmHg te-nmr (CDCI3) δ 6 70 (d, 7= 3 8 Hz, 1H) and 6 22 (d, J= 3 8 Hz 1H) (5^)-3-(3-Fluoro-4-iodophenYl)-5-(4-cMoro-17/-1.2,3-tnazoLl-vlmethyl)-l,3-oxazohdin-2-one
(Formula Removed)
A stirred mixture of (5R)-3-(3-fluoro-4-iodoplieiiyl)-5-azidomethyl-i,3-oxazoMrii-2-one (1 g, 28 mmol) and 1-cHoio-l-efhenesulfonyl chloride (1 g, 6 2 mmol) was heated in a piessure tube at 80 °C for one hour The reaction mixture was cooled to room temperature, diluted with chloroform (15 mL), and heated at 80 °C for an additional 4 houis The reaction mixture was cooled to room temperature and the precipitate was collected by filtration and washed with little dichloromethane to yield the title compound as a colorless amorphous solid (725 mg, 62%)
MS (ESP) 423 3 (MH+) for C12H9FIN4O2
^-NMR (DMSO-d6}5 3 89 (dd, 1H), 4 22 (dd, 1H), 4 82 (m, 2H), 5 15 (m, 1H), 7 15 (m, 1H), 7 49 (m, 1H), 7 82 (m, 1H), 8 44 (s, 1H)
(5R)-3-(3-Fluoro-4-(4,4,55-tetramethyl-13a-dioxaborolan-2-yl)phenyl-5-(4-chloro-lH-1,2,3-triazol-1 - vlmethyl)-1.3-oxazohdrn-2-one
(Formula Removed)
A mixture of (5R)-3-(3-fluoro-4-iodophenyl)-5-(4-chloro-1H-l ,2,3-triazol-1-ylmethyl)-l,3-oxazohdrn-2-one (725 mg, 1 7 mmol), bis(pinacolato)diboron (1 09 g, 4 3 mmol), and potassium acetate (590 mg, 6 mmol) m dune thy lsulfoxide (10 mL) was tieated with dichloro[l,r]bis(diphenylphosphrno)feiTocene]palladium(II) dichloromethane adduct (90 mg, 0 11 mmol) and allowed to leact as described for Example 1 After 45 minutes the reaction mixtuie was cooled to room temperature, diluted with ethyl acetate and washed with aqueous ammomum chloride solution The aqueous layei was extracted two times with ethyl acetate and the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness The rnvolatile lesidue was puirfied by cliromatography on silica gel [elution with withhexanes acetone (2 1)] and fuithei purified by pi ecipitation from dichloromethane withhexanes to give the product as a colorless amorphous solid (590 mg 81 %) that was sufficiently puie foi subsequent leactions MS (ESP) 423 (MH+) for Ci8H2iBFN404
1H-NMR (DMSO-d6) δ 1 28 (s, 12H), 3 92 (dd, 1H), 4 24 (dd, 1H), 4 83 (in, 2H) 5 16 (m, 1H), 7 30 (ro, 1H), 7.39 (m, 1H), 7 63 (m, 1H), 8 45 (s, 1H)
Example 4: (5R)-3-{3-Fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-l-oxidopyridin-3-yl]phenyl}-5-(1H-l,2,3-triazol-l-ylmethyI)-2,3-oxazolidin-2-one


(Formula Removed)
5-Bimno-2-(2-memyl-2H-tetrazol-5-yl)pyridine (175 tog, 0 73 mM) and
3-chloroperbenzoic acid (wet, 70% 0 50 g, 2 05 mM) were dissolved in 1,2-dichloroethane (5
ml) and heated at 80 °C for 1 5 hours The mixture was submitted directly to silica gel
chromatogiaphy, elating with 25% acetomtnle in dichloromethane 5-Bromo-2-(2-methyl-
2H-tetrazol-5-yl)pyndrne 1-oxide was thus obtained as a white solid (165 mg) This material
was homogeneous by tic analysis and was used in the subsequent step without further
characterization oi purification
The above sample of pyridine oxide was combined with (5R)-3-[3-fiuoio-4-(4,4,5,5-
tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-5-(lF-l,2,3-taazol-l-yrmethyl)-l,3-oxazolidrn-
2-one (335 mg, 0 86 mMol, prepared as in Bxamplel), potassium caibonate (400 mg, 2 9
mMol), and tetrakis(tnphenylphosplrko)palladium(0) (80 mg, 0 07 mMol) and suspended in
THF (10 ml) and water (1 ml) The mixture was heated at 75 °C for 2 hours, then diluted with
water The precipitated solids were collected on a filter, rinsed with water, ether and 1 1
methylene chloride hexane and dried in vacuo to give the puie product as an off-white solid,
134 mg
MS (electiosprav) 438 (M+l) for C19H16FN9O3
1H-NMR (300 MHz, DMSO-d6) δ 3 97 (dd, 1H), 4 30 (t, 1H), 4 49 (s, 3H), 4 86 (d, 2H)
5 19 (m, 1H), 7 43 (dd, 1H), 7 61 (dd, 1H), 7 68 (dd, 1H), 7 77 (t, 2H), 8 06 (d, 1H), 8 18 (s,
1H), 8 68 (s, 1H)

Example 5: (5R)-3-F3-Fluoro-4-[6-(2-(2-hydroxyethyl)-2H-l,2,3.4-tetrazol-S-yl)-3-pyridinyl]phenyl]-5-(1H-l,2,3-txiazol-l-ylmethyl)oxazolidn-2-one
(Formula Removed)
2-[5-(5-Biomopyndm-2-yl)-2H-tetrazoi-2 yljethanol (167 mg. 0 62 mmol), (5R)3-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboiolan-2-yl)phenyI]- [(1H ,2,3-triazol-1-yl)merhyrjoxazohdin-2-one (240 mg, 0 62 mmol) and sodium carbonate (262 mg, 2 47 mmol) were dissolved/ suspended in N,N-drmethyl formamide/ water (5 ml, 10 1) It was degassed, flushed with nitrogen and tetrakis (triphenylpho spine) palladium (0) (71 mg, 0 061 mmol) was added It was heated at 70 °C for 3 hours, cooled to loom temperature, and the solvent was evaporated Chromatography on silica gel with dichlorotnethane/ DMF (20 1) gave the requited product (198 mg, 71 %) as a colorless solid MS (ESP) 452 18 (MH+) for C20H18FN9O3
1H-NMR (DMSO-d6) δ 3 97 (no, 3H), 4 31 (dd, 1H), 4 70-4 90 (m, 4H), 5 05-5 25 (m, 2H), 7 40-7 80 (m, 4H), 8 15-8 30 (m, 3H), 8 93 (s, 1H)
The intermediates for Example 5 were piepared as follows
(5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl,-1,3,2-dioxaborolau-2-yl)phenyl]-[(1H-l,2,3-triazol-l-yl)methyl]oxazolidin-2-one
(Formula Removed)
(as rn Example 1) 2-[5-(5-Bromopyridin-2-yl)-2H-tetrazol-2-yl]ethanol
(Formula Removed)
5-Bromo-2-(2H-tetrazol-5-yi)pyridrne (WO 0194342 Al) (J 2 g, 5 3 mmol) was dissolved/ suspended in l-propanol (15 ml), a solution of potassium hydroxide (250 mg, 4 5 mmol) in 1-propanol (15 ml) was added and it was heated at 80 °C foi 1 houi 2-Bromoethanol (0 344 ml, 4 8 mmol) was added and it was xefluxed for one day Furthei potassium hydi oxide (270 mg) and 2-bromoethanol (0 35 ml) weie added and the mixture was heated foi another 4 hours at leflux Further potassium hydroxide and 2-bromoethanol were added once moie and the mixture was refluxed for 14 hours The reaction mixture was filtered through a 0 45 pM rnembiane and the filter cake was washed with ethanol and dichloromethane Chromatography on silica gel with hexanes/ ethyl acetate 1 1 to ethyl actetate gave 0 342 g of the title compound (24%), together with 0 225 g of the corresponding lH-tetrazole regioisomer
XH-NMR (DMSO-d6) δ 3 90-4 02 (dt. 2H), 4 78 (t, 2H), 5 09 (t, 1H), 8 10 (m, 1H), 8 27 (dd, 1H), 8 88 (d, 1H)
The assignment of structure for the regioisorners is based upon HMBC NMR experiments with the lH-tetrazole isomer
Example 6: (5R)-3-r3-Fluoro-4-r6-(l-(propane-l,3-diol-2-yl)-l-H-l,2,3,4-tetrazol-5-yl)-3-pyridtoyl}[phenyl]-5-[(4-fluoromethyl-1H-1,23-triazoI-l-tl)methyl]oxazolidin-2-
(Formula Removed)
2-[5-(5-Bromopyndm-2-yl)-lH-tetrazol-l-ylJpiopane-l,3-diol (170 mg, 0 57 mmol), (5i2)-3-[3-fluoro-4-(4,4,5;5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyn- [(1H-l,2,3-triazol-l-yl)methyi]oxazohdin-2-one (220 mg, 0 57 mmol) and sodium carbonate (240 mg, 2 27 mmol) were dissolved/ suspended in N,N-dnnethyl formamide/ water (5 mL, 10 1) It was degassed, flushed with nitrogen and tetrakis (tiiphenylphospme) palladium (0) (65 mg, 0 056 mmol) was added It was heated at 70 °C for 3 hours, cooled to room temperature, and the solvent was evapoiated Chromatography on silica gel with dichloro methane/ DMF (20 1) gave 189 rag product (69 %) as a colorless solid
MS (ESP) 482 17 (MH+) foi C2oHlsFN903
aH-NMR (DMSO-d6) S 3 85-4 00 (ID, 5H), 4 31 (dd, 1H), 4 86 (m, 2H), 5 03(dd, 2H), 5 19 (m, 1H), 5 84 (m, 1H), 7 46 (dd, 1H), 7 62 (dd, 1H), 7 73-7 82 (m, 2H), 8 19 (s, 1H), 8 22-8 35 (in, 2H); 8 98 (s, 1H)
The intermediate for Example 6 was piepaied as follows
2-r5-(5-BromopYridin-2-vl)-lH-tetrazol-l-yllpropane-l,3-diol
(Formula Removed)
5-Bromo-2-(2H-tetrazol-5-yl)pyndine 0 56 g (2 5 mmol) (WO 0194342 Al, the free acid was generated by dissolving the material obtained following the procedure in WO 0194342 Al (1 g) in hot water (70 mL, 90 °C), upon addition of HC1 (aqueous, 1M, 4 mL) and cooling to room temperature the free acid precipitated, was collected by filtration, washed with water and dried under high vacuum to give 0 56 g free acid), tiiphenyl phosphme (0 65 g, 2 5 mmol) and l,3-bis-(tert-butyl-dimethyl-silanyloxy)-propan-2~ol (0 79 g, 2 5 mmol) (D.P Curran and J -C Chao, Synth Commun 20, No 22, 1990, 3575-3584) were dissolved/ suspended in dry THF (25 mL) It was cooled to 0°C and dnsopropylazodieai boxy late (0 49 mL, 2 5 mmol) was added and the reaction was allowed to warm to room temp over night The solvent was evaporated under reduced pressure and the residue subjected to chromatography on silica gel with hexanes/ ethyl acetate (30 1) to give the bis-silyl ethei of the title compound as a mixture together with the corresponding 2H-tetrazole legioisomer (809 mg) This mixture was dissolved in dry THF (10 mL), cooled to 0°C and tetrabutylammonium fluoride (1M in THF, 5 mL, 5 mmol) was added drop wise After one hour solvent was evaporated and the residue subjected to chromatography on silica gel with dichloromethane/ acetone (3 1 to 2 1) to give 318 mg of the title compound and 69 mg of the corresponding regioisomeric 2H-substituted tetrazole The assignment of structure was based on NOE-NMR expermients with the title compound
'H-NMR (DMSO-d6) δ 3 80-3 95 (m, 4H), 5 01 (t, 2H), 5 69 (m, 1H), 8 14 (m, 1H), 8 35 (m, 1H), 8 94 (m, 1H)
Example7:(5J?)-5-{r4-(Difluoroiiiethvl)-lg-l,2,3-triazol-l-YllmethYl}-3-{3-fluoro-4-r6-(2-methyl-2i7-tetrazol-5-vl)pyridiii-3-Yl]pherivll-l,3-oxazolidin-2-one
(Formula Removed)
(5R)-5-{[4-(Difluoromethyl)-lJ9r-l,2,3-tiiazol-l-yl]methyl}-3-L3-fluoro-4-(4,4,5,5^ tetramethyl-1,3,2-dioxaborolan-2-yl)plienyl]-l,3-oxazolidiii-2-one (0 25 g, 0 586 mmol) were taken together with5-bromo-[2-(2-methyl-2H-l,2,3,4-tetrazol-5-yl)]pyridine (155 mg, 0 645 mmol) and potassium carbonate (404 mg, 2 93 mmol) and dissolved/ suspended in N,N-dimethyl forrnamide/ water (10 mL, 7 1) and reacted under catalysis with Tetrakis (tiiphenylphospine) palladium (0) (67 mg, 10 mol %) like described for example 1 1 Chromatogiaphy on silica gel with ethyl acetate/ hexanes (1 2) gave 200 mg product as a colorless amorphous solid
MS (ESP) 472 15 (MH+) for CaoHieftNgOz
^-NMR (DMSO-d6} 5 3 98 (dd, 1H), 4 32 (dd, 1H), 4 47 (s, 3H), 4 88 (d, 2H), 5 22 (m, 1H); 7 05-7 42 (t, br, 1H), 7 46 (m, 1H), 7 60 (m, 1H), 7 75 (m,lH), 8 15-8 24 (m, 2H), 8 65 (s, 1H), 8 93 (s, 1H).
The intermediates for Example 7 were prepared as follows
(5R)-5-{r4-(DifluoroinetIiyl)-lflr-l,2,3-triazol-l-YllmethyI}-3-r3-fluoro-4-(4,4,5,5-tetramethvl-l,3,2-dioxaborolan-2-yl)phenYll-l,3-oxazolidin-2-one
(Formula Removed)
(5R)-5- {[4-(Drfluoromethyl)- 1H-1,2,3-triazol- l-yl]methyl}-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidrn-2-one (2 56 g, 5 84 mmol), bis(prnacolato)diboron (3 71 g, 14 6 mmol), potassium acetate (2 0 g , 20 44 mmol), and l,r-[bis(diphenylphosphino)ienoceneJ dichloiopalladium(II) dichoiomethane complex (0 427 g, 0 584 mmol) weie suspended in DMSO (10 ml) The mixture was heated at 80 °C for 90 minutes to give a clear black
solution After cooliag down to room tempeiature, ethyl acetate (150 ml) was then added and the rnixtuie was filtered through celite, washed with saturated brine (2 x 100 ml), dried over sodium sulfate and concentrated to dryness The dark residue was dissolved in dicHoiomethane(20rnl), followed by slow addition of hexanes( 100ml), the resulting precipitate was filtered and washed with 5% dichloromethane in hexanes and collected as the desined product(l 73g) which was used directly as an intermediate without further purification
JH-NMR (DMSO-d6) δ 1 12 (s, 12H), 3 88 (dd, 1H), 4 23 (dd, 1H), 4 84 (m, 2H), 5 14 (m, 1H), 6 80-7 20 (t, hr, 1H), 7 14 (m, 1H), 7 28 (m, 1H), 7 51 (imlH), 8 45 (s, 111)
(5R)-5-{[4-(Difluoromethyl)-lH-l,2,3-triazol-l-yl]methyl}-3-(3-fluoro-4-iodophenyl)-l,3-oxazolidin-2-one
(Formula Removed)
1 - {[(5R)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazohdm-5-yl]methyl}- 1H-1,2,3-triazole-4-caibaldehyde (3 6 g, 8 65 rnmol) and [Bis(2-methoxyethyl)amnao]-sulfur trrfluonde (2 3 g, 10 38 mrnol) were mixed in dry dichloromethane(20ml), followed by the addition of ethanol(20ul), the reaction mixture was then refluxed for 14 hours, cooled down to room tempeiatuie, washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulphate The concentrated crude sample was then purified by column chiomatography eluted withhexanes/ethylacetate(l 5 1) to give the title compound(2 58 g)
MS (ESP) 439 02 (MH+) for C13H10F3INOo
1H-NMR (DMSO-d6) δ 4 02 (dd, 1H), 4 40 (dd, 1H), 5 03 (d, 2H), 5 30 (m, 1H), 7 15-7 53(t, br, 1H), 7 28 (dd, 1H), 7 6 (dd,lH), 7 95 (t, 1H), 8 70 (s, 1H)
l-{f(5R)-3-f3-Fluoro-4-iodophenyl)-2-oxo-l,3-oxazolidin-5-yl]methyl}-l,H-l,2,3-triazole-4-carbaldehyde
(Formula Removed)
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[(4-hydroxymethyl- 1H ,2,3-triazol-1 -yl)methyl]oxazolidin-2-one(5 Ig, 13 6 mmol) and manganese oxide(3 56g, 40 9mmol) were mixed and heated up to 100°C in dry l,4-d\oxane for 48 hours, then the mixture was cooled down to 70°C and filtered through cehte The filtrate was concentrated and dissolved in 5% methanol in dichloromethane, hexaneses was added and the formed precipitates were filtered and collected as the title compound(3,6g)
MS (ESP) 416 91 (MH+) foi C13H10FrN4O3
lH-NMR (DMSO-d6) δ 3 87 (in, 1H), 4 18 (dd, 1H), 4 85 (d, 2H), 5 15 (rn, 1H), 7 12 (d, 1H), 7 42 (d, 1H), 7 8 (dd,lH), 8 88 (s, 1H), 10 01 (s, 1H)
(5R)-3-(3-Fluoro-4-iodoplienyl)-5-[(4-bylroxyrnethyl-lH-l,2,3-triazol-1-yl)methy H oxazolidin- 2- one
(Formula Removed)
(5R)-3-(3-FIuoro-4-iodophenyl)-5-(azidornethyl)oxazohdin-2-one (10 g, 28 mmol) was dissolved rn acetomtnle (80 mL) Propaigyl alcohol (3 2 mL, 56 inmol) was added and then Cul (526 mg, 2 8 rnmol) and it was stirred overnight The sohdrfied reaction mixture was extracted with ethyl acetate/ acetorntiile, washed with water and dried ovei magnesium sulfate Evaporation of solvent under vacuum gave 12 3 g crude product (quantitative)
MS (ESP) 419 13 (MH+) for C13Hi2FIN403
1H-NMR (DMSO-d6) δ 3 88 (dd, IB), 4 23 (dd, 1H), 4 51 (d, 2H), 4 80 (m. 2H), 5 14 (m, 1H), 5 22 (dd, 1H), 7 16 (m, 1H), 7 51 (m, iH), 7 83 (m, 1H), 8 01 (d. 111)
Example 8: (5R)-3-{3-Fiuoro-4-r2-methyl-6-(4-methyl-lH-l,2,3-triazol-l-yl)pyrid-3-yl]phenyl}-5-(lH-l,2,3-triazol-l-ylmethyl)-1.3-oxazolidin-2-one
(Formula Removed)
3-Bromo-2-methyl-6-(4-methyl-lH-l,2,3-tuazol-l-yl)pyridine (196 mg, 0 773 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-l>3,2-dioxaborolan-2-yl)plienyl]-5-(lH-l,2,3-triazol-l-yhnethyl)-l,3-oxazohdin-2-one (300 mg, 0 773 mmol), potassium carbonate (320 mg, 2 31 mmol), and tetralas(triphenylphosphino) palladrum(O) (89 mg, 0 077 mmol) were combined and suspended in DMF (3 ml) and water (0 3 ml) The mixture was heated at 80 QC for 2 hours, then diluted with water to 7 ml The sohds were collected, rinsed with water and resuspended in warm DMSO (3 ml) The suspension was diluted with dichloromethane (5 ml) and ether (4 ml) The solid was collected, rinsed with ether and methanol, and dried in vacuo to give the pure product as a white solid, 110 mg MS (APCD 435 (M+l) for C21H19N802F
NMR (DMSO-d6) δ 2 36 (s, 3H), 2 41(s, 3H), 3 95 (dd, 1H): 4 31 (t, 1H), 4 88 (d, 2H), 5 15-5 24 (m, 1H), 7 44 (dd, 1H), 7 50 (t,lH), 7.62 (dd, 1H), 7 79 (d, 1H), 7 95 (q, 2H), 8 20 (d, 1H), 8 61 (d, 1H)
The intermediates for the above compound was made as follows 3-Bromo-2-methyl-6-(4-methyl-1-H-l,2,3-triazol-l-yl)pyrzdine
(Formula Removed)
To a solution of 6-amrno-3-biomo-2-methylpyridme (1 0 g, 5 3 mmol) in methanol (20 ml) was added dnsopropylefhylamrne (2 8 ml, 16 0 mmol) at room temperature The solution was stirred for 10 mrn , [(lJE)-2,2-dichloro-J-methylethyhdene]hydrazide-4-methyl-benzenesulfonic acid (2 0 g, 6 95 mmol) was added at 4°C and the reaction mixture was stirred over weekend at loom temperature The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel ejuting with 25% ethyl acetate in hexane to give the title compound (758 mg)
MS (APCD 254 (M+l) foi C9H9BrN+
1H-NMRCDMSO-d6) δ 2 34 (s, 311), 2 64 (s, 3H), 7 83 (d, 2B), 8 26 (d, YES), 8 56 (s,lH)
(5R)-3-[3-Fluoro-4-(4,4,5 5-tetramethyl-1,3 2-dioxaborolan-2~yl)phenyl]-5-{ lH,2,3-triazol-l-y]methyl)-1,3-oxazolidin-2-one see Example 1





We Claims
1. A 3,5 substituted oxazolidinone compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester or pro drug thereof,
(Formula Removed)
wherein C is selected from D and E,
(Formula Removed)
wherein in D and E the phenyl ring is attached to the oxazolidinone in (I); Rib is HET1 or HET2, wherein
i) HET1 is an N-linked 5-membered, fully or partially unsaturated heterocyclic ring, containing either (i) 1 to 3 further nitrogen heteroatoms or (ii) a further heteroatom selected from O and S together with an optional further nitrogen heteroatom; which ring is optionally substituted on a C atom, other than a C atom adjacent to the linking N atom, by an oxo or thioxo group; and/or which ring is optionally substituted on any available C atom, other than a C atom adjacent to the linking N atom, by a substituent selected from RT as hereinafter defined and/or on an available nitrogen atom, other than a N atom adjacent to the linking N atom, (provided that the ring is not thereby quaternised) by (l-4C)alkyl;
ii) HET2 is an N-linked 6-membered di-hydro-heteroaryl ring containing up to three nitrogen heteroatoms in total (including the linking heteroatom), which
ring is substituted on a suitable C atom, other than a C atom adjacent to the linking N atom, by oxo or thioxo and/or which ring is optionally substituted on any available C atom, other than a C atom adjacent to the linking N atom, by one or two substituents independently selected from RT as hereinafter defined and/or on an available nitrogen atom, other than a N atom adjacent to the linking N atom, (provided that the ring is not thereby quaternised) by (1-4C)alkyl;
RT is selected from a substituent from the group:
(RTal) hydrogen, halogen, (l-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkenyl,
(2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, (l-4C)alkylthio, amino,
azido, cyano and nitro; or
(RTa2) (l-4C)alkylamino, di-(l-4C)alkylamino, and (2-4C)alkenylamino;
or RT is selected from the group
(RTbl) (l-4C)alkyl group which is optionally substituted by one
substituent selected from hydroxy, (l-4C)alkoxy, (l-4C)alkylthio, cyano and
azido; or
(RTb2) (l-4C)alkyl group which is optionally substituted by one
substituent selected from (2-4C)alkenyloxy, (3-6C)cycloalkyl,and (3-
6C)cycloalkenyl;
or RT is selected from the group
(RTc) a fully saturated 4-membered monocyclic ring containing 1 or 2
heteroatoms independently selected from O, N and S (optionally oxidised), and
linked via a ring nitrogen or carbon atom;
and wherein at each occurrence of an RT substituent containing an alkyl,
alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety in (RTal) or (RTa2), (RTbl) or
(RTb2), or (RTc) each such moiety is optionally substituted on an available
carbon atom with one, two, three or more substituents independently selected
from F, CI, Br, OH and CN;
R2a and R6a are independently selected from H, CF3, OMe, SMe, Me and Et;
R2b and R6b are independently selected from H, F, CI, CF3, OMe, SMe, Me and
Et;
Raa is selected from H, (l-4C)alkyl, cyano, Br, F, CI, OH, (1-4C)alkoxy, -S(O)n(l-
4C)alkyl (wherein n = 0, 1, or 2), amino, (l-4C)alkylcarbonylamino, nitro,
CHO, -CO(l-4C)alkyl, -CONH2 and -CONH(l-4C)alkyl;
R4 is selected from R4a and R4b wherein
R4a is selected from azido, -NR7R8, OR10, (l-4C)alkyl, (l-4C)alkoxy, (3-
6C)cycloalkyl,
-(CH2)k-R9, AR1, AR2, (l-4C)alkanoyl, -CS(l-4C)alkyl, -C(=W)NRvRw [wherein W
is O or S, Rv and Rw are independently H, or (l-4C)alkyl ], -(C-OJi-Re, -COO(l-
4C)alkyl, -C=OARl, -C=OAR2, -COOAR1, S(O)n(l-4C)alkyl (wherein n = 1 or 2),
-S(O)pARl, -S(O)pAR2 and
-C(=S)0(l-4C)alkyl; wherein any (l-4C)alkyl chain may be optionally
substituted by (l-4C)alkyl, cyano, hydroxy or halo; p = 0,1 or 2;
R4b is selected from HET-3;
R6 is selected from hydrogen, (l-4C)alkoxy, amino, (l-4C)alkylamino and hydroxy( 1 -4C)alkylamino; k is 1 or 2; 1 is 1 or 2;
R7 and Rs are independently selected from H and (l-4C)alkyl, or wherein R7 and Rs taken together with the nitrogen to which they are attached can form a 5-7 membered ring optionally with an additional heteroatom selected from N, O, S(O)n (wherein n = 1 or 2) in place of 1 carbon atom of the so formed ring; wherein the ring may be optionally substituted by one or two groups independently selected from (l-4C)alkyl, (3-6C)cycloalkyl, (l-4C)alkanoyl, -COO(l-4C)alkyl, -S(O)n(l-4C)alkyl (wherein n = 1 or 2), AR1, AR2, , -C=OARl, -C=OAR2, -COOAR1, -CS(l-4C)alkyl, -C(=S)0(l-4C)alkyl, -C(=W)NRvRw [wherein W is O or S, Rv and Rw are independently H, or (l-4C)alkyl], -S(O)pARl and -S(O)pAR2; wherein any (l-4C)alkyl, (3-6C)cycloalkyl or (l-4C)alkanoyl group may be optionally substituted (except on a carbon atom adjacent to a
heteroatom) by one or two substituents selected from (l-4C)alkyl, cyano,
hydroxy, halo, amino, (l-4C)alkylamino and di(l-4C)alkylamino; p = 0,1 or 2;
Rg is independently selected from R9a to R9d below:
Rga: AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;
R9b: cyano, carboxy, (l-4C)alkoxycarbonyl, -C(=W)NRvRw [wherein W is O or
S, Rv and Rw are independently H, or (l-4C)alkyl and wherein Rv and Rw
taken together with the amide or thioamide nitrogen to which they are attached
can form a 5-7 membered ring optionally with an additional heteroatom
selected from N, O, S(O)n in place of 1 carbon atom of the so formed ring;
wherein when said ring is a piperazine ring, the ring may be optionally
substituted on the additional nitrogen by a group selected from (l-4C)alkyl, (3-
6C)cycloalkyl, (l-4C)alkanoyl, -COO(l-4C)alkyl, -S(O)n(l-4C)alkyl (wherein n =
1 or 2), -COOAR1,
-CS(l-4C)alkyl and -C(=S)0(l-4C)alkyl; wherein any (l-4C)alkyl, (3-
6C)cycloalkyl or (l-4C)alkanoyl group may itself optionally be substituted by
cyano, hydroxy or halo)], ethenyl, 2-(l-4C)alkylethenyl, 2-cyanoethenyl, 2-
cyano-2-((l-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl, 2-((
1 -4C)alkylaminocarbonyl)ethenyl,
2-((l-4C)alkoxycarbonyl)ethenyl, 2-(AR1) ethenyl, 2-(AR2)ethenyl, 2-
(AR2a)ethenyl;
R9c: (l-6C)alkyl
{ optionally substituted by one or more groups (including geminal
disubstitution) each independently selected from hydroxy, (1-10C)alkoxy, (1-
4C)alkoxy-(l-4C)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxy, (1-
4C)alkylcarbonyl, phosphoryl [-O- P(O)(OH)2, and mono- and di-(l-4C)alkoxy derivatives thereof], phosphiryl [-O- P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], and amino; and/or optionally substituted by one group selected from carboxy, phosphonate [phosphono, -P(O)(OH)2, and mono- and
di-(l-4C)alkoxy derivatives thereof], phosphinate [-P(OH)2 and mono- and di-(l-
4C)alkoxy derivatives thereof], cyano, halo, trifluoromethyl, (1-
4C)alkoxycarbonyl, (l-4C)alkoxy-
(1 -4C)alkoxycarbonyl, (1 -4C)alkoxy-( 1 ~4C)alkoxy~ (1 4C)alkoxycarbonyl, (1
4C)alkylamino, di((l-4C)alkyl) amino, (l-6C)alkanoylamino-, (1-
4C)alkoxycarbonylamino-, N-( 1 -4C)alkyl-N-( 1 -6C)alkanoylamino, -C(=W)NRvRw
[wherein W is O or S, Rv and Rw are as hereinbefore defined], (NORv) wherein
Rv is as hereinbefore defined, (l-4C)alkylS(O)pNH, (l-4C)alkylS(O)p-((l-
4C)alkyl)N-, fluoro(l-4C)alkylS(O)pNH-,
fluoro(l-4C)alkylS(O)p((l-4C)alkyl)N-, (l-4C)alkylS(O)q-, CY1, CY2, AR1, AR2,
AR3, ARl-O-, AR2-0-, AR3-0-, AR1-S(O)q-, AR2-S(O)q-, AR3-S(O)q-, AR1- NH-,
AR2-NH-, AR3-NH- (p is 1 or 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a
and AR3b versions of AR2 and AR3 containing groups } ; wherein any (1-
4C)alkyl present in any substituent on R9c may itself be substituted by one or
two groups independently selected from cyano, hydroxy, halo, amino, (1-
4C)alkylamino and di(l-4C)alkylamino, provided that such a substituent is not
on a carbon adjacent to a heteroatom atom if present;
R9d: R14C(O)0(l-6C)alkyl- wherein R14 is AR1, AR2, (l-4C)alkylamino,
benzyloxy-
(l-4C)alkyl or (1-10C)alkyl { optionally substituted as defined for (R9c) } ;
R10 is selected from hydrogen, R9c (as hereinbefore defined), (l-4C)acyl and (1-
4C) alkylsulfonyl;
HET-3 is selected from:
a) a 5-membered heterocyclic ring confining at least one nitrogen and/or
oxygen in which any carbon atom is a C=0, C=N, or C=S group, wherein said
ring is of the formula HET3-A to HET3-E below:

(Formula Removed)
b) a carbon-linked 5- or 6-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O and S selected from HET3-F to HET3-Y below:
(Formula Removed)
c) a nitrogen-linked 5- or 6-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O and S selected from HET3-Z to HET3-AH below:
(Formula Removed)
wherein in HET-3, Ria is a substituent on carbon;
R1a is independently selected from Rial to Ria5 below:
R1al: AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;
R1a2: cyano, carboxy, (l-4C)alkoxycarbonyl, -C(=W)NRvRw [wherein W is O or
S, Rv and Rw are independently H, or (l-4C)alkyl and wherein Rv and Rw
taken together with the amide or thioamide nitrogen to which they are attached
can form a 5-7 membered ring optionally with an additional heteroatom
selected from N, O, S(O)n in place of 1 carbon atom of the so formed ring;
wherein when said ring is a piperazine ring, the ring may be optionally
substituted on the additional nitrogen by a group selected from (l-4C)alkyl, (3-
6C)cycloalkyl, (l-4C)alkanoyl, -COO(l-4C)alkyl, -S(O)n(l-4C)alkyl (wherein n =
1 or 2), -COOAR1,
-CS(l-4C)alkyl) and -C(=S)0(l-4C)alkyl; wherein any (l-4C)alkyl, (1-
4C)alkanoyl and
(3-4C)cycloalkyl substituent may itself be substituted by cyano, hydroxy or
halo, provided that, such a substituent is not on a carbon adjacent to a
nitrogen atom of the piperazine ring], ethenyl, 2-(l-4C)alkylethenyl, 2-
cyanoethenyl, 2-cyano-2-((l-4C)alkyl)ethenyl,
2-nitroethenyl, 2-nitro-2-((l-4C)alkyl)ethenyl, 2-((l-
4C)alkylaminocarbonyl)ethenyl, 2-((l-4C)alkoxycarbonyl)ethenyl, 2-(ARl
Jethenyl, 2-(AR2)ethenyl, 2-(AR2a)ethenyl;
Ria3: (1-10C)alkyl
{ optionally substituted by one or more groups (including geminal
disubstitution) each independently selected from hydroxy, (1-10C)alkoxy, (1-
4C)alkoxy-(l-4C)alkoxy, (l-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxy, (1-
4C)alkylcarbonyl, phosphoryl [-O- P(O)(OH)2, and mono- and di-(l-4C)alkoxy
derivatives thereof], phosphiryl [-O- P(OH)2 and mono- and di-(l-4C)alkoxy
derivatives thereof], and amino; and/or optionally substituted by one group
selected from carboxy, phosphonate [phosphono,
-P(O)(OH)2, and mono- and
di-(l-4C)alkoxy derivatives thereof], phosphinate [-P(OH)2 and mono- and di-(l-4C)alkoxy derivatives thereof], cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl, (l-4C)alkoxy-
(1 -4C)alkoxycarbonyl, (1 -4C)alkoxy~( 1 -4C)alkoxy- (1 - 4C)alkoxycarbonyl, (1
4C)alkylamino, di((l-4C)alkyl)amino, (l-6C)alkanoylamino-, (1-
4C)alkoxycarbonylamino-, N-(l-4C)alkyl-N-(l-6C)alkanoylamino-,
C(=W)NRvRw [wherein W is O or S, Rv and Rw are independently H, or (1-
4C)alkyl and wherein Rv and Rw taken together with the amide or thioamide
nitrogen to which they are attached can form a 5-7 membered ring optionally
with an additional heteroatom selected from N, O, S(O)n in place of 1 carbon
atom of the so formed ring; wherein when said ring is a piperazine ring, the
ring may be optionally substituted on the additional nitrogen by a group
selected from (l-4C)alkyl, (3-6C)cycloalkyl, (l-4C)alkanoyl, -COO(l-4C)alkyl, -
S(O)n(l-4C)alkyl (wherein n = 1 or 2), -COOAR1, -CS(l-4C)alkyl and -C(=S)0(1-
4C)alkyl], (=NORv) wherein Rv is as hereinbefore defined, (l-4C)alkylS(O)pNH-,
(l-4C)alkylS(O)p-((l-4C)alkyl)N-, fluoro(l-4C)alkylS(O)pNH-, fluoro(l-
4C)alkylS(O)p((l-4C)alkyl)N-, (l-4C)alkylS(O)q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-0-, AR3-0-, AR1-S(O)q-, AR2-S(O)q-, AR3-S(O)q- , AR1-NH-, AR2-NH-, AR3-NH- (p is 1 or 2 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups } ; wherein any (l-4C)alkyl, (1-4C)alkanoyl and (3-6C)cycloalkyl present in any substituent on Ria3 may itself be substituted by one or two groups independently selected from cyano, hydroxy, halo, amino, (l-4C)alkylamino and
di(l-4C)alkylamino , provided that such a substituent is not on a carbon adjacent to a heteroatom atom if present;
Ria4: Ri4C(O)0(l-6C)alkyl- wherein Ri4 is AR1, AR2, AR2a, AR2b, (1-4C)alkylamino, benzyloxy-(l-4C)alkyl or (1-10C)alkyl { optionally substituted as defined for (Ria3)} ;
Ria5: F, CI, hydroxy, mercapto, (l-4C)alkylS(O)p- (p = 0,1 or 2), -NRyRs (wherein R7 and Rs are as hereinbefore defined) or -OR10 (where Rio is as hereinbefore defined);

m is 0, 1 or 2;
R21 is selected from hydrogen, methyl [optionally substituted with cyano, trifluoromethyl, -C=WNRvRw (where W, Rv and Rw are as hereinbefore defined for Ria3), (l-4C)alkoxycarbonyl, (1 4C)alkoxy-(l-4C)alkoxycarbonyl, (1-4C)alkoxy-(l-4C)alkoxy-(l-4C)alkoxycarbonyl, CY1, CY2, AR1, AR2, AR2a, AR2b (not linked through nitrogen) or AR3], (2-10C)alkyl [optionally substituted other than on a carbon attached to the HET-3 ring nitrogen with one or two groups independently selected from the optional subsituents defined for Ria3] and Ri4C(0)0(2-6C)alkyl-, wherein R14 is as defined hereinbefore for Ria4 and wherein Ri4C(0)0 group is attached to a carbon other than the carbon attached to the HET-3 ring nitrogen; R22 is cyano, -COR12, -COOR12, -CONHR12, -CON(R12)(R13), -SO2R12 (provided that R12 is not hydrogen), -SO2NHR12, -SO2N(R12)(R13) or NO2, wherein R12 and R13 are as defined hereinbelow;
R12 and R13 are independently selected from hydrogen, phenyl (optionally substituted with one or more substituents selected from halogen, (l-4C)alkyl and (l-4C)alkyl substituted with one, two, three or more halogen atoms) and (1 -4C)alkyl (optionally substituted with one, two, three or more halogen atoms), or for any N(R12)(R13) group, R12 and R13 may be taken together with the nitrogen to which they are attached to form a 5-7 membered ring optionally with an additional heteroatom selected from N, O, S(0)n in place of 1 carbon atom of the so formed ring; wherein the ring may be optionally substituted by one or two groups independently selected from (l-4C)alkyl (optionally substituted on a carbon not adjacent to the nitrogen by cyano, hydroxy or halo), (3-6C)cycloalkyl, (l-4C)alkanoyl, -COO(l-4C)alkyl, -S(0)n(l-4C)alkyl (wherein n = 1 or 2), AR1, AR2, , -C=OARl, -C=OAR2, -COOAR1, -CS(1-4C)alkyl, -C(=S)0(l-4C)alkyl, -C(=W)NRvRw [wherein W is O or S, Rv and Rw are independently H, or (l-4C)alkyl], -S(0)pARl and -S(0)pAR2; wherein any (1- 4C)alkyl chain may be optionally substituted by (l-4C)alkyl, cyano, hydroxy or halo; p = 0,1 or 2;
AR1 is an optionally substituted phenyl or optionally substituted naphthyl;
AR2 is an optionally substituted 5- or 6-membered, fully unsaturated (i.e. with
the maximum degree of unsaturation) monocyclic heteroaryl ring containing up
to four heteroatoms independently selected from O, N and S (but not
containing any O-O, O- S or S-S bonds), and linked via a ring carbon atom, or
a ring nitrogen atom if the ring is not thereby quaternised;
AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems retaining
some, but not the full, degree of unsaturation), linked via a ring carbon atom or
linked via a ring nitrogen atom if the ring is not thereby quaternised;
AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having no
unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom;
AR3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (i.e.
with the maximum degree of unsaturation) bicyclic heteroaryl ring containing
up to four heteroatoms independently selected from O, N and S (but not
containing any O-O, O- S or S-S bonds), and linked via a ring carbon atom in
either of the rings comprising the bicyclic system;
AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems retaining
some, but not the full, degree of unsaturation), linked via a ring carbon atom,
or linked via a ring nitrogen atom if the ring is not thereby quaternised, in
either of the rings comprising the bicyclic system;
AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having no
unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen
atom, in either of the rings comprising the bicyclic system;
AR4 is an optionally substituted 13- or 14-membered, fully unsaturated (i.e.
with the maximum degree of unsaturation) tricyclic heteroaryl ring containing
up to four heteroatoms independently selected from O, N and S (but not
containing any O-O, O- S or S-S bonds), and linked via a ring carbon atom in
any of the rings comprising the tricyclic system;
AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems retaining
some, but not the full, degree of unsaturation), linked via a ring carbon atom,
or linked via a ring nitrogen atom if the ring is not thereby quaternised, in any of the rings comprising the tricyclic system;
CYl is an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl ring; CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring; wherein; optional substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CYl and CY2 are (on an available carbon atom) up to three substituents independently selected from (l-4C)alkyl { optionally substituted by substituents selected independently from hydroxy, trifluoromethyl, (1-4C)alkylS(0)q- (q is 0, 1 or 2), (l-4C)alkoxy,
(l-4C)alkoxycarbonyl, cyano, nitro, (l-4C)alkanoylamino, -CONRvRw or -
NRvRw}, trifluoromethyl, hydroxy, halo, nitro, cyano, thiol, (l-4C)alkoxy, (1-
4C)alkanoyloxy, dimethylaminomethyleneaminocarbonyl, di(N-(l-
4C)alkyl)aminomethylimino, carboxy,
(l-4C)alkoxycarbonyl, (l-4C)alkanoyl, (l-4C)alkylSO2amino, (2-4C)alkenyl { optionally substituted by carboxy or (l-4C)alkoxycarbonyl }, (2-4C)alkynyl, (1-4C)alkanoylamino, oxo (=0), thioxo (=S), (l-4C)alkanoylamino { the (1-4C)alkanoyl group being optionally substituted by hydroxyl}, (l-4C)alkyl S(0)q-(q is 0, 1 or 2) { the (l-4C)alkyl group being optionally substituted by one or more groups independently selected from cyano, hydroxy and (l-4C)alkoxy }, -CONRvRw or - NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl]; and further optional substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CYl and CY2 (on an available carbon atom), and also on alkyl groups (unless indicated otherwise) are up to three substituents independently selected from trifluoromethoxy, benzoylamino, benzoyl, phenyl { optionally substituted by up to three substituents independently selected from halo, (l-4C)alkoxy or cyano }, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino(l-4C)alkyl, (l-4C)alkoxyimino(l-4C)alkyl, halo-(l-4C)alkyl, (l-4C)alkanesulfonamido, -SO2NRvRw [wherein Rv is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl]; and
optional substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4a
are (on an available nitrogen atom, where such substitution does not result in
quaternization)
(l~4C)alkyl, (l-4C)alkylcarbonyl { wherein the (1 4C)alkyl and (1
4C)alkylcarbonyl groups are optionally substituted by (preferably one)
substituents independently selected from cyano, hydroxy, nitro,
trifluoromethyl, (l-4C)alkyl S(0)q- (q is 0, 1 or 2), (l-4C)alkoxy,
(l-4C)alkoxycarbonyl, (l-4C)alkanoylamino, -CONRvRw or -NRvRw [wherein Rv
is hydrogen or (l-4C)alkyl; Rw is hydrogen or (l-4C)alkyl]}, (2-4C)alkenyl, (2-
4C)alkynyl,
(l-4C)alkoxycarbonyl or oxo (to form an N-oxide).
2. A compound of the formula (I) as claimed in claim 1, or a pharmaceutically-acceptable salt, or an in-vivo hydroloysable ester thereof, wherein Rib is HET1 wherein HETI is selected from the structures (Za) to (Zf),
(Formula Removed)
wherein u and v are independently 0 or 1 and RT selected from:
(a) hydrogen;
(b) halogen;
(c) cyano;
(d) (l-4C)alkyl;
(e) monosubstituted (l-4C)alkyl;
(f) disubstituted (l-4C)alkyl, and
(g) trisubstituted (l-4C)alkyl.

3. A compound of the formula (I) as claimed in claim 1 or claim 2, or a pharmaceutically-acceptable salt, or an in-vivo hydroloysable ester thereof, wherein R4 is R4b.
4. A compound of the formula (I) as claimed in any preceding claim or a pharmaceutically-acceptable salt, or an in-vivo hydroloysable ester thereof, wherein HET-3 is selected from HET3-T, HET3-V, HET3-Y and HET-3-W.
5. A compound of the formula (I) as claimed in any preceding claim, or a pharmaceutically-acceptable salt, or an in-vivo hydroloysable ester thereof, wherein HET-3 is selected from HET3-V and HET3-Y.
6. A compound of the formula (I) as claimed in any preceding claim, or a pharmaceutically-acceptable salt, or an in-vivo hydroloysable ester thereof, wherein Ria is Ria3.
7. A compound of the formula (I) as claimed in any preceding claim, or a pharmaceutically-acceptable salt, or an in-vivo hydroloysable ester thereof, wherein group C is group D.
8. A compound of the formula (I) as claimed in any preceding claim, or a pharmaceutically-acceptable salt, or an in-vivo hydroloysable ester thereof, wherein group C is group E.
9. A compound of the formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydroly sable ester thereof, as claimed in claim 1, wherein group C is group E; R2a and R6a are both hydrogen; R2b and R6b are independently
hydrogen or fluorine; and R4 is HET3-V, Rib is selected from Zd and Zf, u and v are independently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, choromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl, and trifluoromethyl.
10. A pharmaceutical composition for oral administration which comprises a compound of the invention as claimed in any one of claims 1 to 9, or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, and a pharmaceutically-acceptable diluent or carrier.
11. A process for the preparation of a compound of formula (I) as claimed in claim 1 or pharmaceutically acceptable salts or in-vivo hydrolysable esters thereof where HET-1 is 4-halogenated 1,2,3-triazole, by reacting azidomethyl oxazolidinones with halovinylsulfonyl chlorides at a temperature between 0 °C and 100 °C either neat or in an inert diluent

Documents:

2093-delnp-2005-abstract.pdf

2093-delnp-2005-claims.pdf

2093-delnp-2005-complete specification (as files).pdf

2093-delnp-2005-complete specification (granted).pdf

2093-delnp-2005-correspondene-others.pdf

2093-delnp-2005-correspondene-po.pdf

2093-delnp-2005-description (complete).pdf

2093-delnp-2005-form-1.pdf

2093-delnp-2005-form-18.pdf

2093-delnp-2005-form-2.pdf

2093-delnp-2005-form-3.pdf

2093-delnp-2005-form-5.pdf

2093-delnp-2005-gpa.pdf

2093-delnp-2005-pct-210.pdf

2093-delnp-2005-pct-304.pdf

2093-delnp-2005-pct-409.pdf

2093-delnp-2005-pct-416.pdf

2093-delnp-2005-petition-137.pdf

abstract.jpg


Patent Number 245573
Indian Patent Application Number 2093/DELNP/2005
PG Journal Number 04/2011
Publication Date 28-Jan-2011
Grant Date 25-Jan-2011
Date of Filing 17-May-2005
Name of Patentee ASTRAZENECA AB
Applicant Address S-151 85 SODERTALJE, SWEDEN.
Inventors:
# Inventor's Name Inventor's Address
1 FOLKERT RECK ASTRAZENECA R&D BOSTON, 35 GATEHOUSE DRIVE, WALTHAM, MA 02451, USA.
2 FEI ZHOU ASTRAZENECA R&D BOSTON, 35 GATEHOUSE DRIVE, WALTHAM, MA 02451, USA.
3 MICHAEL BARRY GRAVESTOCK ASTRAZENECA R&D BOSTON, 35 GATEHOUSE DRIVE, WALTHAM, MA 02451, U.S.A.
4 NEIL JAMES HALES ASTRAZENECA R&D ALDERLEY, ALDERLEY PARK, MACCLESFIELD, CHESHIRE SK10 4TG, ENGLAND.
PCT International Classification Number C07D 413/14
PCT International Application Number PCT/GB2003/005091
PCT International Filing date 2003-11-24
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0310828.9 2003-05-10 U.K.
2 0227704.4 2002-11-28 U.K.