CZ20004498A3 - Oxazolidinone derivatives, process of their preparation and pharmaceutical preparations in which they are comprised - Google Patents

Abstract

The compound of formula (I) is not pharmaceutically acceptable an acceptable salt or an in-vivo hydrolysable ester thereof, wherein X is -O- or -S-, HET is optionally substituted C-linked 5- a membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S; Q is selected, for example, from groups Q1 and Q2; R2 and R3 are independently hydrogen or a fluorine atom; T is selected from the group range, for example, Unbound 5-membered heteroaryl ring system or a group of formula TC5 wherein R 6 is, for example, R 13 CO-, R13SO2 or R13CS- wherein R13 is, for example, optionally substituted alkyl having 1 to 10 carbon atoms or R 14 C (O) O (C 1 -C 6 alkyl) wherein R 14 is optionally substituted alkyl of 1 to 10 atoms carbon; said compounds are useful as antibacterial reagents. The present invention also relates to a process for preparing said compounds and the pharmaceutical compositions containing them.

Description

Technical field

The present invention relates to antibiotic compounds, in particular antibiotic compounds containing a substituted oxazolidinone ring. The invention further relates to a process for their preparation, intermediates useful for their preparation, their use and therapeutic agents and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION

The International Microbiological Society has consistently expressed serious concern that developments in antibiotic resistance could lead to strains against which currently available antibacterial agents are ineffective. In general, bacterial pathogens can be classified as either Gram positive or Gram negative pathogens. Antibiotic compounds that are effective against both Gram positive and Gram negative pathogens are generally considered to have a broad spectrum of activity. The compounds of the present invention are believed primarily to be effective against Gram-positive pathogens due to their particularly good activity against such pathogens.

Gram-positive pathogens such as staphylococci, enterococci, streptococci and mycobacteria are particularly important as the development of resistant strains is both difficult to treat and difficult to remove from the hospital environment. Examples of such strains are methicillin resistant staphylococcal (MRSA), methicillin resistant staphylococcal coagulase-negative (MRCNS), penicillin-resistant streptococcal pneumonia, and multiple-resistant enterococcus faecium.

The major clinically effective antibiotic for the treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with nephrotoxicity and ototoxicity. Further, and most importantly, antibacterial resistance to vancomycin and other glycopeptides occurs. This resistance increases with constant speed making these agents less and less effective in the treatment of Gram positive pathogens.

Certain antibacterial compounds containing an oxazolidinone ring have been described in the art (for example, Walter A. Gregory et al. In J. Med. Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al. In J. Med. Chem. 1992, 35, 1156-1165). Such 5-methylacetamide side chain antibacterial oxazolidinone compounds may be metabolised by a mammalian peptidase. Further, bacterial resistance to known antibacterial agents may be developed, for example (i) by developing active binding sites in the bacterium, rendering previously active pharmacophores less effective or excess, and / or (ii) developing means for chemically inactivating said pharmacophore. Therefore, there remains a continuing need to find new antibacterial agents having a favorable pharmacological profile, particularly of compounds containing new pharmacophores.

We have discovered a class of antibiotic compounds containing a new class of substituted oxazilidinone ring, which have useful activity against Gram-positive pathogens, including MRSA and MRCNS, and in particular against various strains showing vancomycin resistance and E. faecium strains resistant to both aminoglycosides and clinically used β-lactamum.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or an in-vivo hydrolysable ester thereof,

O

(AND)

wherein X is -O-, -S-, -SO- or -SO ₂ -;

HET is a C-linked 5-membered heteroaryl ring containing 2-4 heteroatoms independently selected from N, O and S, wherein the ring is optionally substituted on the available carbon atom with 1 or 2 substituents independently selected from the group consisting of C 1-4 alkyl carbon atoms, amino, (C 1 -C 4) alkylamino, (C 1 -C 4) alkoxy and halogen and / or on the available nitrogen atom (with the nitrogen not being quaternized) of (C 1 -C 4) alkyl;

Q is selected from Q1 to Q9:

wherein R ² and R ³ are independently hydrogen or fluoro;

wherein A 1 is a carbon atom or a nitrogen atom; Bi is O or S (or, only in Q 9 is NH);

X _q is O, S or NR ¹ (wherein R ¹ is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 hydroxyalkyl); and wherein in Q7, A 1 is always independently selected from carbon or nitrogen, with a maximum of 2 nitrogen heteroatoms in the 6-membered ring, and Q 7 binds to T through any of Ai (when A 1 is carbon) and in the 5-membered ring binds via a specific carbon atom or via A 1 when A 1 is a carbon atom; Q8 binds to T through any specific carbon atom in the 5-membered ring and binds in the benzene ring via any of the two specific atoms on either side of the shown bond; and Q 9 binds through any of the 2 specific atoms on either side of said bond;

wherein T is selected from (TA) to (TD) below (wherein AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are as defined below);

(TA) T is selected from the following groups: (TAa) AR 1, AR 1 -alkyl- having 1 to 4 carbon atoms in the alkyl moiety, AR 2 (bonded via carbon), AR 3;

(TAb) AR 1 -CH (OH) -, AR 2 -CH (OH) -, AR 3 -CH (OH) -;

(TAc) AR 1 -CO-, AR 2 -CO-, AR 3 -CO-, AR 4 -CO-;

(TAd) AR1-O-, AR2-O-, AR3-O-;

(TAe) AR 1 -S (O) _q -, AR 2 -S (O) _q -, AR 3 -S (O) _q - (q is 0, 1 or 2);

(TAf) an optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms;

(TAg) carbon-bonded tropol-3-one or tropol-4-one, optionally substituted at a position not adjacent to the linker position; or (TB) T is selected from the following groups: (TBa) halogen or C 1 -C 4 alkyl (optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy), (C až-Can) alkanoyl, cyano, halogen, trifluoromethyl, (C až-C alko) alkoxycarbonyl, -NRvRw, (C až-C alk) alkanoylamino, (C až-C alko) alkoxycarbonylamino alkoxy moieties, N-alkyl-Nalkanoylamino having 1 to 4 carbon atoms in the alkyl moiety and 1 to 6 carbon atoms in the alkanoylamino moiety, alkylS (O) _q - having 1 to 4 carbon atoms (q is 0, 1 or 2) , CY1, CY2 or AR1};

(TBb) -NR ¹ R w ¹ ;

(TBc) ethenyl, 2-C 1 -C 4 alkyllethenyl, 2-cyanoethenyl, 2-C 1 -C 4 alkyllethenyl, 2-nitroethenyl, 2- C 1 -C 4 nitro-2-alkylethenyl, C 1 -C 4 alkyl-2-alkylaminocarbonylethenyl, C 1 -C 4 2-alkoxycarbonylethenyl

Carbon atoms in the alkoxy moiety, 2- (AR1) ethenyl group, 2- (AR2) ethenyl group ;

(TBd) R ¹⁰ CO-, R ¹⁰ S (O) _q - (q is 0, 1 or 2) or R ¹⁰ CSwhere R ¹⁰ is selected from the following groups: (TBda) CY1 or CY2;

(TBdb) a hydrogen atom, a (C1-C4) alkoxycarbonyl group, a trifluoromethyl group, -NRvRw, an ethenyl group, a (C1-C4) alkylethenyl group, a 2-cyanoethenyl group, a 2-cyano-2- (C 1 -C 4) alkylethenyl, 2-nitroethenyl, 2-nitro-2-C 1 -C 4 -alkyl, 2-alkylaminocarbonylethenyl (C 1 -C 4) alkyl, 2-alkoxycarbonylethenyl C 1 -C 4 alkoxy, 2- (AR 1) ethenyl or 2- (AR 2) ethenyl; or (C 1 -C 4) alkyl (C 1 -C 4) alkyl optionally substituted as mentioned in (TBa) above or C ( _C 1 -C 4) alkylS (O) _p NH- or C (C) alkyl ( _S ) O- 1-4 carbon atoms in the alkyl moieties (p is 1 or 4;

2)};

wherein Rv is hydrogen or C1-C4alkyl; R w is hydrogen or C 1 -C 4 alkyl; R ¹¹ is hydrogen, C 1 -C 4 alkyl or C 3 -C 8 cycloalkyl; Rw ¹ is hydrogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkylCO- or C 1 -C 4 alkylS (O) _q - (q is 1 or 2); or (TC) T is selected from the following groups: (TCa) an optionally substituted, fully saturated 4-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidized) and bonded via a ring nitrogen atom or an sp ³ atom carbon;

(TC b) an optionally substituted 5-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidized) and bonded via a ring nitrogen atom or via a ring sp ³ or sp ² carbon atom, wherein the monocyclic ring is fully saturated, with with the exception (where appropriate) of a sp ² carbon bonding atom;

(TCc) optionally substituted 6- or 7-membered monocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S (optionally oxidized) and bonded via a ring nitrogen atom or via a ring sp ³ or sp ² carbon atom, wherein the monocyclic the ring is fully saturated, with the exception of (where appropriate) the linking carbon atom sp ² ; or (TD) T is selected from the following groups: (TDa) a bicyclic spirocyclic system containing 0, 1 or 2 nitrogen atoms as the only ring heteroatoms, wherein the structure comprises a 5- or 6-membered ring system (bonded via a ring nitrogen atom or a ring sp ³ or sp ² carbon atom) substituted (not adjacent to the linking position) by a 3-, 4- or 5-membered spiro via a carbon-linked ring; wherein the bicyclic ring system is (i) fully saturated with the exception of (where appropriate) the bonding carbon atom sp ² ;

(ii) it contains one -N (Rc) - in the ring system (at least two carbon atoms distant from the bonding position if the bond is through a nitrogen or sp ² carbon atom) or one -N (Rc) - in the optional substituent ( (iii) optionally further substituted on a suitable ring carbon atom; or a (TDb) 7-, 8- or 9-membered bicyclic ring system (bonded via a ring nitrogen atom or a ring sp ³ or sp ² carbon atom) containing 0, 1 or 2 nitrogen atoms (and optionally another O or S atom as a ring) heteroatom), wherein the structure comprises a bridge of 1, 2 or 3 carbon atoms; wherein the bicyclic ring system is (i) fully saturated with the exception of (where appropriate) the bonding carbon atom sp ² ;

(ii) contains one O or S as a heteroatom or one - N (Rc) group in the ring system (at least two carbon atoms distant from the bonding position if the bond is through a nitrogen or sp ² carbon atom) or one N (Rc) - in an optional substituent (not adjacent the linking position) and is (iii) optionally further substituted on a suitable ring carbon atom;

wherein R c is selected from (R c1) to (R c5); (R c1) a C 1-6 alkyl group (optionally substituted with one or more C 1 -C 4 alkanoyl groups (including geminal disubstitution) and / or optionally monosubstituted with cyano group C 1 -C 4 alkoxy, trifluoromethyl, C 1 -C 4 alkoxycarbonyl, phenyl (optionally substituted as indicated for AR 1 above), C 1 -C 4 alkylS (O) _q - (q is 0, 1 or 2); or on any one, except the first carbon atom of the C 1-6 alkyl chain, optionally substituted with one or more groups (including geminal disubstitution) independently selected from the group consisting of hydroxy and fluorine and / or optionally monosubstituted with oxo, -NRvRw [wherein R v is hydrogen or C 1 -C 4 alkyl; Rw is hydrogen or (C1-C4) -alkyl], C1-C6-alkanoylamino, C1-C4-alkoxycarbonylamino, N-alkyl-N-C1-C4-alkanoylamino alkyl moiety having 1 to 6 carbon atoms in the alkanoyl moiety, or alkylS (O) _p NH- having 1 to 4 carbon atoms or alkylS (O) _p alkylIN- having 1 to 4 carbon atoms in the alkyl moieties (p is 1 or 2)};

(Rc2) R ¹³ CO-, R ¹³ SO ₂ - or R ¹³ CSwhere R ¹³ is selected from (Rc2a) to (Rc2e) :( Rc2a) AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a , CY1, CY2;

(R c2b) hydrogen, C 1 -C 4 alkoxycarbonyl, trifluoromethyl, -NR v R w [wherein R v is hydrogen or C 1 -C 4 alkyl; R w is hydrogen or C 1 -C 4 alkyl], ethenyl, C 2 -C 4 alkyl-ethenyl. carbon in the alkyl moiety, 2-cyanoethenyl, 2-cyano-2-alkylethenyl of 1 to 4 carbon atoms in the alkyl moiety, 2-nitroethenyl, 2-nitro-2alkylethenyl of 1 to 4 carbon atoms in the alkyl moiety, 2alkylaminocarbonylethenyl (C 1 -C 4) alkyl, 2 (C 1 -C 4) alkoxy, 2 (AR 1) ethenyl, 2- (AR 2) ethenyl, or 2- (AR 2a) ethenyl;

(R c2c) C 1 -C 10 alkyl (optionally substituted by one or more groups (including geminal disubstitution), each independently selected from hydroxy, C 1 -C 10 alkoxy, C 1 -C 4 alkoxyalkoxy each alkoxy moiety, C 1 -C 4 alkoxyalkoxyalkoxy;

4 alkoxy moieties, C 1 -C 4 alkanoyl, phosphoryl [-OP (O) (OH) 2 and its mono- and di-C 1 -C 4 alkoxy derivatives in each alkoxy moieties], a phosphiryl group [the -OP (OH) _{2 group} and its mono- and dialkoxy derivatives of 1 to 4 carbon atoms], and an amino group; and / or optionally substituted by one group selected from the group consisting of a phosphonate group [a phosphone group, a -P (O) (OH) _{2 group} , and mono- and di-alkoxy derivatives thereof having 1 to 4 carbon atoms in each alkoxy moiety] , the phosphinate group [P (OH) ₂ and its mono- and di-alkoxy derivatives of 1 to 4 carbon atoms], cyano, halogen, trifluoromethyl, alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety, alkoxyalkoxycarbonyl of 1 C 1 -C 4 alkoxy, C 1 -C 4 alkoxyalkoxy, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 6 alkanoylamino, alkoxycarbonylamino having 1 to 4 carbon atoms in the alkoxy moiety, an N-alkyl-N-alkanoylamino group having 1 to 4 carbon atoms in the alkyl moiety and 1 to 6 carbon atoms in the alk moiety anoylamino moieties, (C 1 -C 4) alkylaminocarbonyl, (C 1 -C 4) dialkylaminocarbonyl (C 1 -C 4) alkyl, S (O) _p -alkylN- (C 1 -C 4) alkyl group, (C1-C4) fluoroalkylS (O) _p NH-, (C1-C4) fluoroalkylS (O) _p alkyl (1-4C) alkyl, (C1-C4) alkyl (S) (O) _q ; AR1, CY2, AR1, AR2, AR3, AR1-0-, AR2-0-, AR3-0-, AR1-S (O) _q , AR2S-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 further AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3};

(Rc2d) R group ^at C (O) Oalky! C 1 -C 6 alkyl wherein R ¹⁴ is AR 1, AR 2, C 1 -C 4 alkylamino, C 1 -C 4 benzyloxyalkyl or C 1 -C 10 alkyl {optionally substituted as defined for (Rc2c)};

(R c2e) R ¹⁵ O-, wherein R ¹⁵ is a benzyl group, an alkyl group having 1 to 6 carbon atoms {optionally substituted as defined for (RC2c)}, CY1, CY2 or AR2b; (Rc3) hydrogen, cyano, 2-cyanoethenyl, 2-cyano-2alkylethenyl of 1 to 4 carbon atoms in the alkyl moiety, 2-nitroethenyl, 2-nitro-2-alkylethenyl of 1 to 4 carbon atoms in the alkyl moiety a (C1-C4) alkylaminocarbonylethenyl group, a (C1-C4) alkoxycarbonylethenyl group, a 2 (AR1) ethenyl group, a 2- (AR2) ethenyl group or a group of formula (Rc3a); );

Ν X ⁰⁰ _R 1 S ( _R c 3a) wherein X ⁰⁰ is -OR ¹⁷ , -SR ¹⁷ , -NHR ¹⁷ and -N (R ¹⁷ ) ₂ ;

wherein R ¹⁷ is hydrogen (where X ⁰⁰ is -NHR ¹⁷ and -N (R ¹⁷ ) ₂ ) and R ¹⁷ is C 1-4 alkyl, phenyl or AR 2 (wherein X ⁰⁰ is -OR ¹⁷ , - SR ¹⁷ and -NHR ¹⁷ ); and R ¹⁶ is cyano, nitro, C 1 -C 4 alkylsulfonyl, C 4 -C 7 cycloalkylsulfonyl, phenylsulfonyl, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl;

(R c4) trityl, AR 1, AR 2, AR 2a, AR 2b, AR 3, AR 3a, AR 3b;

(Rc5) of the group RdOC (Re) = CH (C = O) -, RfC (= O) C (= O) -, RgN = C (Rh) C (= O) -or RiNHC (Rj) = CHC (= O) -, wherein R d is C 1 -C 6 alkyl; R e is hydrogen or C 1 -C 6 alkyl or R d and R e together form an C 3 -C 4 alkylene chain; R f is hydrogen, alkyl of 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon atoms, alkoxyalkyl of 1 to 6 carbon atoms in the alkoxy moiety and 1 to 6 carbon atoms in the alkyl moiety, -NRvRw [wherein Rv is a hydrogen atom or a (C 1 -C 4) alkyl group; R w is hydrogen or (C 1 -C 4) -alkyl], (C 1 -C 6) -alkoxy, C 1 -C 6 -alkoxyalkoxy, C 2 -C 6 -alkoxyalkoxy, (C 1 -C 6) alkylaminoalkoxy 4 carbon atoms in the alkyl moiety having 2 to 6 carbon atoms in the alkoxy moiety, a di-alkylaminoalkoxy group having 1 to 4 carbon atoms in the alkyl moiety and 2 to 6 carbon atoms in the alkoxy moiety; R 8 is C 1 -C 6 alkyl, hydroxy or C 1 -C 6 alkoxy; Rh is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, AR 1, AR 2, AR 2a, AR 2b and R 1 is hydrogen or alkyl of 1 to 6 carbon atoms;

where

AR 1 is optionally substituted phenyl or optionally substituted naphthyl;

AR 2 is an optionally substituted 5- or 6-membered, fully unsaturated (ie, with a maximum degree of unsaturation) monocyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N and S (but containing no 0-0, 0-S or SS bonds) ) and bound via a ring carbon atom or a ring nitrogen atom, unless quaternized;

AR2a is a partially hydrogenated version of AR2 (i.e., AR2 systems having a certain but not full degree of unsaturation) bonded via a ring carbon atom or ring nitrogen atom, unless quaternized;

AR 2b is a fully hydrogenated version of AR 2 (ie, AR 2 systems having no unsaturation) bonded via a ring carbon atom or ring nitrogen atom; AR 3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (ie, maximum degree of unsaturation) bicyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N and S (but containing no 0-0, 0- bonds) S or SS) and bonded via a carbon atom in any of the rings including the bicyclic system;

AR3a is a partially hydrogenated version of the group AR3 (i.e., systems of AR3 having a certain but not full degree of unsaturation) bonded via a ring carbon atom or a ring nitrogen atom, unless quaternized, in any of the rings including the bicyclic system;

AR3b is a fully hydrogenated version of the group AR3 (i.e., systems of AR3 having no unsaturation) bonded via a ring carbon atom or a ring nitrogen atom in any of the rings including the bicyclic system;

AR 4 is an optionally substituted 13- or 14-membered, fully unsaturated (ie, with a maximum degree of unsaturation) tricyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N and S (but containing no 0-0, 0-S or SS bonds) ) and bonded via a carbon atom in any of the rings comprising the tricyclic system;

AR4a is a partially hydrogenated version of AR4 (i.e., AR4 systems having a certain but not full degree of unsaturation) bonded via a ring carbon atom or a ring nitrogen atom, unless quaternized, in any of the rings including the tricyclic system;

CY 1 is an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl ring;

CY 2 is an optionally substituted cyclopentenyl or cyclohexenyl ring;

In the present specification, where the ring may be bonded through the sp ² carbon atom, the ring is fully saturated, with the exception of the sp ^2- bonding carbon atom, if present, the ring is believed to be bonded through the double binding

C = C.

In another embodiment, (R c1) is as defined above except for an optionally phenyl substituent on an alkyl group of 1 to 6 carbon atoms, optionally substituted as for AR 1 as defined below; and (R c2c) is as defined above and further includes a carboxyl group as an optional substituent on R ¹³ as C 1 -C 10 alkyl.

(TAf) When T is an optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms, it is preferably selected from the group consisting of (TAf 1) to (TAf 6) below (especially (TAf 1), (TAf2), (TAf4) and (TAf5), and in particular (TAf1) and / or (TAf2)). The above values (TAf) are particularly preferred when they are in Q1 or Q2, especially Q1 and wherein X is -O-.

R ⁵

R ⁶

R ⁵ R ⁵ (TA 3)

R ⁴ (TAf ⁴ )

R ⁵ (TAf ⁵ ) (TAf 6) where:

R ⁶ is selected (independently, where appropriate) from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkanoyl, carbamoyl and cyano;

R ⁴ and R ⁵ are independently selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, C 1 -C 4 alkoxy, C 1 -C 4 alkylS (O) _q (q is 0 , 1 or 2), (C1-C4) alkanoyl, (C1-C4) alkoxycarbonyl, (C2-C4) alkanoyloxyalkyl and (C1-C4) alkyl, benzoxyalkyl C 1 -C 4 alkyl, C 2 -C 4 alkanoylamino, -CONR v R w, -NR v R w, and C 1 -C 4 alkyl (optionally substituted by hydroxy, trifluoromethyl, cyano, nitro, C 1 -C 4 alkoxy) carbon atoms, alkylS (O) _q - of 1 to 4 carbon atoms (q is 0,1 or 2), alkoxycarbonyl of 1 to 4 carbon atoms, alkanoylamino of 1 to 4 carbon atoms, -CONRvRw, - NRvRw; wherein R v R w is hydrogen or C 1 -C 4 alkyl; Rw is hydrogen or (C1-C4) alkyl};

or R ⁴ is selected from one of (TAfa) to (TAfc) below, or (where appropriate) one of R ⁴ and R ⁵ is selected from the above list of values for R ⁴ and R ⁵ and the other is selected from (TAfa) to (TAfc) below: (TAfa) a group of formula TAfal

X «(TAphal) wherein Z 0 is hydrogen or C 1 -C 4 alkyl;

X 0 and Y 0 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, halogen, cyano, nitro, alkylS (O) _q - having one to four carbon atoms (q is 0, 1 or 2), RvRwNSO ₂ -, trifluoromethyl, • · pentafluoroethyl group, an alkanoyl group having 1-4 carbon atoms and CONRvRw [wherein Rv is hydrogen or alkyl of 1 up to 4 carbon atoms; R w is hydrogen or C 1 -C 4 alkyl]; or one of X ° and Y ° is independently selected from the above values for X ° and Y ° and the remaining is selected from phenyl, phenylcarbonyl, -S (O) _q -phenyl (q is 0, 1 or 2), N- (phenyl) carbamoyl, phenylaminosulfonyl, AR 2, (AR 2) -CO-, (AR 2) -S (O) _q - (q is 0, 1 or 2), N- (AR 2) a carbamoyl group and an (AR2) aminosulfonyl group; wherein any phenyl group in (TAfa) may be optionally substituted with up to three substituents independently selected from the group consisting of C 1 -C 4 alkyl, cyano, trifluoromethyl, nitro, halogen and C 1 -C 4 alkylsulfonyl;

(TAfb) an acetylene group of the formula --H or --C-- alkyl of 1 to 4 carbon atoms;

(TAfc) -X ¹ -Y ¹ -AR 2, -X ¹ -Y ¹ -AR 2a, -X ¹ -Y ¹ -AR 2b, -X ¹ -Y ¹ -AR 3, -X ¹ -Y ¹ -AR 3a or-X ¹ -Y ¹ AR 3b;

wherein X ¹ is a direct bond or -CH (OH) - a

Y ¹ is - (CH ₂ ) _m - (CH ₂ ) n -NH- (CH ₂ ) _m - -CO- (CH ₂ ) _m -, -CONH- (CH ₂ ) _m -, -C (= S ) NH (CH _{2) m} - or -C (= O) O- _{(CH2) m} -;

or wherein X ¹ is - (CH ₂ ) _n - or -CH (Me) - (CH ₂ ) _m - and

Y ¹ is - (CH ₂ ) _m -NH- (CH ₂ ) _m -, -CO- (CH ₂ ) _m -, -CONH- (CH ₂ ) _m -, -C (= S) NH- (CH ₂₎ ) _m -C (= O) O- (CH ₂ ) _m - or -S (O) _q - (CH ₂ ) _m -;

or wherein X ¹ is -CH 2 O-, -CH 2 NH- or -CH 2 -Nalkyl- with 1 to 4 carbon atoms and Y ¹ is -CO- (CH 2) _m -, -CONH- (CH ₂ ) _m -, -C (= S ) -NH- (CH _{2) m} -; and further Y ¹ is -SO 2 - when X ¹ is -CH ₂ NH - or -CH ₂ N -alkyl- with 1 to 4 carbon atoms in the alkyl moiety and Y ¹ is - (CH 2) m when X ¹ is -CH 2 O- or -CH ₂ Nalkyl - having 1 to 4 carbon atoms in the alkyl moiety; where n is

1,2 or 3; m is 0, 1, 2 or 3 and q is 0, 1 or 2; and wherein Y ¹ is - (CH ₂ ) _m -NH- (CH ₂ ) _m -, wherein each m is independently selected from 0, 1, 2 or 3.

It is to be understood that when the value for -X ¹ -is a diatomic bond and is, for example, written as -CH ₂ NH-, then the portion on the left side (here -CH ₂ -) is bound to the group of formula (TAf1) to ( TAf6) and the right part (-NH- here), is bonded to -Y ¹ - in the definition TAfc. Similarly, when -Y ¹ -is a diatomic bond and is, for example, written as -CONH-, then the left-hand portion is -Y ¹ - (here -CO-) that is bound to •

the right portion -X ¹ - and the left-hand portion -Y ¹ - (here -NH-), is bound to the AR2, AR2a, AR2b, AR3, AR3a or AR3b portion in the definition (TAfc).

R ⁶ is preferably hydrogen or C 1 -C 4 alkyl, and R ⁴ and R ⁵ are independently selected from hydrogen or C 1 -C 4 alkyl or one of R ⁴ and R ⁵ is selected from ( TAfa). Other preferred substituents on (TAf1) to (TAF6) are set forth in the Examples which form part of the invention.

(TAg) When T is a tropol-3-one or tropol-4-one bonded via a carbon atom, optionally substituted at a position that is not adjacent to the linker, (TAg) is preferably selected from the group of formula (TAg1), (TAg2) or (TAg3). The above values (TAg) are particularly preferred when they are present in Q1 or Q2, especially when X is -O-.

(TAg1) (TAg2) (TAg3) wherein R 'is selected from (TAga) hydrogen, C1-C4 alkyl (optionally substituted with one or two substituents (excluding geminal substitution) independently selected from fluoro , hydroxy, C1-C4 alkoxy and -NRvRw}; or (TagB) ^R -O-, R ⁸ -S-, ^{R 8} -NH- or R ⁸ R -N-;

wherein R ⁸ is selected (independently where appropriate) from the group consisting of hydrogen, C 1 -C 4 alkyl or C 3 -C 8 cycloalkyl (both optionally substituted with one or two substituents (excluding geminal substitution) independently selected from the group consisting of hydroxy, C1-C4 alkoxy and -NRvRw}; a C 2 -C 4 alkenyl group (optionally substituted with one or two -NR v R w) substituents, a C 1 -C 4 alkanoyl group (optionally substituted with one or two substituents selected from the group consisting of -NR V R w and a hydroxyl group), phenylalkyl a C 1 -C 4 alkyl group or a C 1 -C 4 pyridylalkyl group {wherein the phenyl and pyridyl (preferably 4-pyridyl) ring is optionally substituted with one or two -NR v R w 'substituents; or (TAgC) morpholino, thiomorpholino, pyrrolidino (optionally independently substituted at the 3α / or 4-position by C 1 -C 4 alkyl), piperidino substituted at the 4-position R ⁹ -, R ⁹ -O-, R ⁹ - S-, R ⁹ -NH- or R ⁹ R ⁹ -N-; wherein R ⁹ is selected (independently where appropriate) from the group consisting of hydrogen, C 1 -C 4 alkyl (optionally substituted with one or two substituents (excluding geminal substitution) selected from the group consisting of hydroxy, alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl or -NRv R w} and piperazino {optionally substituted in 4 position with C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, alkanoyl C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl or C 1 -C 4 alkylsulfonyl and optionally substituted in the 3 and / or 5 position by C 1 -C 4 alkyl}; wherein Rv is hydrogen or alkyl of 1 to carbon atoms; R w is hydrogen or C 1 -C 4 alkyl.

(TC) Preferred values for optional substituents and groups defined in (TCa) to (TCc) are given in formulas (TC1) to (TC4):

Rp

G — B, L_! A3 \ ; IN G— B 3 <t o ^ r n, () _ / G ^Z A- \ / ³ () o ^B 3 (TC1) (TC2) (TC3) (TC4)

where in (TC1):> A ₃ -B ₃ - is> C (Rq) -CH (Rr) - and G is -O-, -S-, -SO-, -SO ₂ - or> N (Rc) ; wherein at (TC 2): m 1 is 0, 1 or 2; > A ₃ -B ₃ - is> C = C (Rr) - or> C (Rq) -CH (Rr) - and G is O-, -S-, -SO-, -SO ₂ - or> N ( Rc);

wherein v (TC3); m 1 is 0, 1 or 2; > A ₃ -B ₃ -is> C (Rq) -CH (Rr) - (when Rq and Rr are not both hydrogen) and G is -O-, -S-, -SO-, -SO ₂ - or> N (R c);

• p

wherein v (TC 4): n 1 is 1 or 2; o1 is 1 or 2an1 + o1 = 2 or 3; > A ₃ -B ₃ -is> C = C (Rr) - or> C (Rq) -CH (Rr) - or> N-CH ₂ - and G is -O-, -S-, -SO-, -SO ₂ - or> N (R c); R _p is hydrogen, C 1 -C 4 alkyl (in the case where such substitution is not defined by> A ₃ -B ₃ -), hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkanoyloxy; wherein at (TC1), (TC2), and (TC4); m1, n1 and o1 have the meanings given above:

> A ₃ -B ₃ -is> N-CH ₂ - and G is> C (R ¹¹ ) (R ¹² ),>00,>C-OH,> C 1 -C 4 alkoxy in the alkoxy moiety, > C = N-OH,> C = N-C 1 -C 4 alkoxy,> C = N-NH-C 1 -C 4 alkyl,> C = NN- (alkyl) C 1 -C 4 alkyl) ₂ (which latter two alkyl groups having 1 to 4 carbon atoms in G being optionally substituted by hydroxy) or> oN-N-CO-alkoxy having 1 to 4 carbon atoms in the alkoxy moiety); where> represents two single bonds;

Rq is hydrogen, hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkanoyloxy;

R 1 is (independently, where appropriate) hydrogen or C 1 -C 4 alkyl;

R ¹¹ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkylthioalkyl in each alkyl moiety or C 1 -C 4 hydroxyalkyl and R ¹² is - [C (Rr) (Rr)] _{m 2} N (R c) (R c) wherein m 2 is 0, 1 or 2;

in cases where the substitution on the ring is not defined by G,> A ₃ -B ₃ - and R p, each ring system may be optionally substituted on a carbon atom not adjacent to a> A ₃ - bond by up to two substituents independently selected from the group consisting of (C 1 -C 4) alkyl, (C 1 -C 4) fluoroalkyl (including trifluoromethyl), (C 1 -C 4) alkylthioalkyl, (C 1 -C 4) hydroxyalkyl, amino, (C 1 -C 4) aminoalkyl (C 1 -C 4), (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoylaminoalkyl (C 1 -C 4) alkyl, carboxy, (C 1 -C 4) alkoxycarbonyl (C 1 -C 4) alkoxy, AR-oxymethyl, ARthiomethyl, oxo (= 0) (in cases other than when G is> N-Rc and Rc is a group (Rc2) defined by sh or a)) or independently selected from R c; as well as the hydroxy group and the halogen atom (the last two optional substituents are present only when G is -O- or -S-); wherein AR is as defined in formula (IP) above; R c is selected from (R c1) to (R c5) as defined above.

For the avoidance of doubt, () mi, () and () oi indicate (-CH ₂ -) mi, (-CH ₂ -) _n 1, and (-CH ₂ -) o 1 (optionally substituted as above).

In the above definitions (TC1) to (TC4) and other optional substituents, AR is preferably AR2 and the other optional substituents are preferably not selected from the values given for Rc. A preferred value for G is> N (Rc) or> C ^{(R11) (R12).}

Particularly preferred values for optional substituents and groups defined in (TCa) to (TCc) and (TC1) to (TC4) are included in the following definitions (TC5) to (TC11): Rc-N (TC5)

Rc-N

RC (TC6) (TC7)

Rc-HN

N '<7

Rc

Rc-HN (TCS) (TC9) (TC10) (TC11) wherein Rc has any of the meanings given above or below.

Particularly preferred are (TC5), (TC6), (TC7) and (TC9), most preferred is (TC5), wherein R c has any of the meanings given above or below (especially R ¹³ CO- with preferred values for R ¹³ below). R c in (TC 5) is preferably selected from (R c 2), in particular R ¹³ CO- with preferred values for R ¹³ mentioned above.

R c in (TC 7) is preferably selected from (R c 3) or (R c 4).

The above values for (TCa) to (TCc) are particularly preferred if they are present in Q1 or Q2, especially Q1, and when X is -O- (especially when HET is isoxazole).

(TDa) When T is a bicyclic spirocyclic system as defined in (TDa), it is preferably selected from the group of formulas (TDa1) to (TDa9). The above preferred values for • (TDa) are particularly preferred when present in Q1 or Q2, especially Q1 and when X is -O-.

(TDa1)

(TDa8)

(TDa5)

(TDa6)

wherein (i) the linking group / ¼ is a nitrogen atom or a sp ³ or sp ² carbon atom (with a double bond, where appropriate, oriented in a straight line); and (ii) one of the ring carbon atoms at the positions marked with * and is replaced by one of the following groups -NR c -,> CH-NHR c,> CH-NR c-alkyl of 1 to 4 carbon atoms in the alkyl moiety,> CH -CH ₂ NHR c,> CH-CH ₂ -NR c-C 1 -C 4 alkyl in the alkyl moiety [wherein the central -CH ₂ - chain bond is optionally mono- or disubstituted with C 1 -C 4 alkyl]; with the proviso that the positions marked 'are not replaced by -NH- in the ring containing the A4 bond when A4 is a nitrogen or carbon atom sp ² and the positions marked are not replaced by -NH- in the three-membered ring in (TDa1), (TDa4) and (TDa5) ;

and (iii) the ring system is optionally (further) substituted on the available carbon atom with up to two substituents independently selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl (including trifluoromethyl), alkylthioalkyl (C 1 -C 4) alkyl, (C 1 -C 4) hydroxyalkyl, (C 1 -C 4) aminoalkyl, (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoylamino (C 1 -C 4) alkyl group and 1 to 4 carbon atoms in the alkyl moiety, carboxy, C 1 -C 4 alkoxycarbonyl, AR 2 -oxymethyl, AR 2 -thiomethyl, oxo (= O) (in other cases than when the ring contains> N- Rc and Rc are (Rc2)) as well as hydroxy or halogen;

wherein R c has any of the meanings given above or hereinafter.

(TDb) When T is a 7-, 8- or 9-membered bicyclic ring system containing a 1, 2 or 3 carbon bridge as defined in (TDb), it is preferably selected from the group defined by the scaffolds shown in formulas (TDb1). to (TDb14): 7-membered ring skeletons

K.1,0] (TDt> 1)

[3.2.0] (TDb2) [3.1.1] (TDb3) [2.2.1] (TDb4)

8-member circular skeletons [3,3.0] (TDb5)

[4.2.0]

(TDb8) [3.2.1] (TDb8)

[2.2.2]

9-membered circular skeletons [4,3,0] (TDb10) [5.2,0] (TDb11) [4,2.1] (TDb12) [3.3,1] (TDb13) [3.2,2] (TDb14) • · • · ♦ • »»

wherein (i) the ring system contains 0, 1, or 2 ring nitrogen atoms (and optionally other ring heteroatoms O or S), and if a ring nitrogen atom is present, the O or S heteroatoms are in any position other than Part 3 -member ring at (TDb1);

(ii) the ring system is bonded through a ring nitrogen atom or ring carbon atom sp ³ or a carbon atom sp ² (with a double bond, if appropriate, oriented in any direction) from any position in any ring [other than the end position of the bridge or from a carbon atom ² in a 4-membered ring at (TDb2), (TDb6) and (TDb11) j;

(iii) one of the ring carbon atoms in the position not adjacent to the linking position is replaced (in cases other than when the ring contains O or S as a heteroatom) by one of the following -NRc- [not at the bridge end position],> CHN (H) R,> C (H) -NRc-C 1 -C 4 alkyl,> C (H) -CH2NHRc,> C (H) -CH ₂ -NR c C 1 -C 4 alkyl in the alkyl moiety [wherein the hydrogen atom in parentheses is not present when the substitution is made at the terminal position of the bridge and wherein the central -CH ₂ - chain bond is optionally mono- or disubstituted with C 1 -C 4 alkyl]; with the proviso that when the ring system is bonded via a nitrogen atom or a carbon atom of sp ² , any replacement of the ring carbon atom by an -NR c -, O or S group is at least two carbon atoms distant from the bonding position; and (iv) the ring system is optionally (further) substituted on an available ring carbon atom as described for (bpa) for the bicyclic spirocyclic system; wherein R c has any of the meanings given above or hereinafter.

It should be understood that anti-Bredt compounds are not contemplated in this definition (ie compounds with structures (TDb3), (TDb4), (TDb7), (TDb8), (TDb9), (TdB12), (TDb13) and (TDB14) in which the carbon atom sp ^{2 is} directly attached to the end position of the bridge).

Particularly preferred values (TDb) are the following structures of formulas (TDb4), (TDb8) and / or (TDb9); wherein R c has any of the meanings given above or hereinafter. The above-mentioned preferred values for (TDb) are particularly preferred when they are present in Q1 or Q2, especially Q1, and when X is -O-.

[3.2.1] [2.2.2] (TDb8) (TDb9)

In another embodiment, the invention provides a compound of formula I, which is defined by formula (IP) below, or a pharmaceutically acceptable salt thereof, or an in-vivo hydrolysable ester thereof, wherein:

X is -O-, -S-, -SO- or -SO ₂ -;

Het is a C-linked 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from N, O and S (with the proviso that no O-O, O-S or SS bonds are present), wherein the ring is optionally substituted on any one available carbon atom (with the proviso that when the N atom is adjacent to the X-bond, then no carbon atom adjacent to that N atom is substituted) with one or two substituents independently selected from the group consisting of an alkyl group of 1 to 2 C 4 -C 4 alkyl, C 1 -C 4 alkylamino, C 1 -C 4 alkoxy and halogen and / or on the available N atom (provided the ring is not quaternized), C 1 -C 4 alkyl;

wherein: R ² and R ³ are independently selected from hydrogen or chlorine;

R p is hydrogen, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy or C 2 -C 4 alkanoyloxy:

AB-is a group of formulas> C = C (Rr)------------------- ) -,> CHCHR 1 -,> C (OH) CHR 1 - or> N-CH ₂ - (> means two single bonds), wherein R 1 is hydrogen or C 1 -C 4 alkyl;

D is -O-, -S-, -SO-, -SO ₂ - or> NR cp;

Rp1 and Rp2 are independently selected from oxo (= O) [but not when Rcp is (PC) below], (C1-C4) alkyl, (C1-C4) alkanoylaminoalkyl, and C 1 -C 4 alkyl, C 1 -C 4 hydroxyalkyl, carboxy, C 1 -C 4 alkoxycarbonyl, AR-oxymethyl, AR-thiomethyl (where AR is as defined below) or independently as defined for Rcp below, with the proviso that Rp1 and Rp2 are not phenyl, benzyl, AR (as defined below), a tetrazole ring system, cyclopentyl or cyclohexyl; and when D is -O or -S-, R p1 and R p2 are further independently hydroxy or bromo; wherein R cp is selected from (PA) to (PE) below: (PA) a hydrogen atom, a cyano group, a 2-alkoxycarbonylethenyl group having 1 to carbon atoms in the alkoxy moiety, a 2-cyanoethenyl group, a 2-cyano-2-alkylethenyl group having 1 up to 4 carbon atoms in the alkyl portion, a 2-alkylaminocarbonylethenyl group having 1 to 4 carbon atoms in the alkyl portion;

(PB) phenyl, benzyl, AR (as defined below) or a tetrazole ring system [optionally monosubstituted at the 1- or 2- position of the tetrazole ring with a C1-C4 alkyl group, a C2-C4 alkenyl group, an alkynyl group (C 2 -C 4 or C 1 -C 4 alkanoyl group) wherein the tetrazole ring system is bonded to a nitrogen atom in the> NR cp ring carbon atom;

( ^PCa ) R ^13p CO-, R ^13p SO ₂ or R ^13p CS- wherein R ^13p is selected from (PCa) to (PCf) :( PCa) AR (as defined below);

(PCb) cyclopentyl or cyclohexyl, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl or 1,4-dioxan-2-yl [optionally mono- or disubstituted with substituents independently selected from the group consisting of alkyl 1-4 carbon atoms (including geminal disubstitution), hydroxy (but excluding 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl or 1,4-dioxan-2-yl substituted by hydroxy), alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkylthio, acetamido, C 1 -C 4 alkanoyl, cyano and trifluoromethyl];

(PCc) hydrogen, C1 -C4 alkoxycarbonyl, trifluoromethyl, amino, C1 -C4 alkylamino, C1 -C4 dialkylamino in each alkyl moiety, 2- (5- or 6-membered heteroaryl) ethenyl a 2- (5- or 6-membered (partially) hydrogenated heteroaryl) ethenyl group, a 2-phenylethenyl group [wherein the heteroaryl or phenyl substituent is optionally substituted on a suitable carbon atom by up to three substituents independently selected from the group consisting of 1 alkoxy up to 4 carbon atoms, halogen, cyano and (for phenyl substituent only) alkylsulfonyl of 1 to 4 carbon atoms];

(C 1 -C 10) alkyl group (optionally substituted by one or more groups (including geminal disubstitution), each independently selected from hydroxy and amino or optionally monosubstituted by cyano, halogen, C 1 -C 10 alkoxy , trifluoromethyl, C 1 -C 4 alkoxyalkoxy, C 1 -C 4 alkoxyalkoxyalkoxy, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl, alkylamino (C 1 -C 4) -alkyl, (C 1 -C 4) dialkylamino, (C 1 -C 6) alkanoylamino, (C 1 -C 4) alkoxycarbonyl, (N-alkyl-Nalkanoylamino); up to 4 carbon atoms in the alkyl moiety and 2 to 6 carbon atoms in the alkanoyl moiety, an alkylS (O) _p NH- group having 1 to 4 carbon atoms, an alkylS (O) _p alkylN- group having 1 to 4 carbon atoms in each alkyl moiety, a fluoroalkylS (O) _p NH- group having 1 to 4 carbon atoms carbon atoms, fluoroalkylS (O) _p alkylN- ₍ 1-4C) alkyl in each alkyl moiety, phosphonium, (C1-C4) alkoxyhydroxyphosphoryl, (C1 -C4) alkoxyphosphoryl (C1-4 alkyl) (O) _q - having 1 to 4 carbon atoms, phenyl, naphthyl, phenoxy, naphthoxy, phenylamino, naphthylamino, phenylS (O) _q -, naphthylS (O) _q - [wherein said phenyl and naphthyl groups are optionally substituted with up to three substituents independently selected from C 1 -C 4 alkoxy, halogen and cyano] or CY (as defined below), wherein p is 1 or 2 and q is 0, 1 or 2];

(PCE) R ^14p C (O) C 1 -C 6 alkyl in the alkyl moiety, wherein R ^14p is optionally substituted 5- or 6-membered heteroaryl, optionally substituted phenyl, C 1 -C 4 alkylamino, C 1 -C 4 benzyloxyalkylamino 4 carbon atoms in the alkyl moiety or an optionally substituted alkyl group having 1 to 10 carbon atoms;

(PCf) R ^15p O-, wherein R ^15p is a benzyl group or an optionally substituted alkyl group having 1 to 6 carbon atoms;

(PD) RdOC (Re) = CH (C = O) -, R f C (= O) C (= O) -, R g N = C (Rh) C (= O) - or

R 1 NHC (R 1) = CHC (= O) -, wherein R d is C 1 -C 6 alkyl; R e is hydrogen or C 1 -C 6 alkyl or R d and R e together form an C 3 -C 4 alkylene chain; Rf is hydrogen, (C1-C6) alkyl, (C1-C6) hydroxyalkyl, (C1-C6) alkoxyalkyl and (C1-C6) alkyl, amino, (C1-C6) alkylamino; 4 carbon atoms, C 1 -C 4 alkylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkoxy in each alkyl moiety, C 2 -C 6 hydroxyalkoxy, alkylaminoalkoxy C 1 -C 4 alkyl and C 2 -C 6 alkoxy, C 1 -C 4 dialkylaminoalkoxy and C 2 -C 6 alkoxy; R 8 is C 1 -C 6 alkyl, hydroxy or C 1 -C 6 alkoxy; Rh is hydrogen or (C 1 -C 6) alkyl; R 1 is hydrogen, C 1 -C 6 alkyl, optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl [and (partially) hydrogenated versions thereof] and R 1 is hydrogen or C 1 -C 6 alkyl carbon];

(PE) R ^15p CH (R ^17p ) (CH ₂ ) mp-, wherein mp is 0 or 1; R ^17p is fluorine, cyano, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkoxycarbonyl or hydroxy (provided that when mp is 0, R ^17p is not fluorine or hydroxy) and R ( ^1p) is hydrogen or (C 1 -C 4) alkyl;

Wherein AR is optionally substituted C 1 -C 4 phenylalkyl, optionally substituted naphthyl, optionally substituted

A 5- or 6-membered heteroaryl group; wherein AR is also an optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system in which bicyclic heteroaryl ring systems may be bonded through any of the rings containing the bicyclic system and wherein both mono- and bicyclic heteroaryl ring systems are bonded via a ring carbon atom and may be (partially) hydrogenated; wherein CY is selected from: (i) a cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl ring;

(ii) 5- or 6-membered heteroaryl groups, 5- or 6-membered heteroaryloxy groups,

5- or 6-membered heteroaryl-S (O) _q - groups, 5- or 6-membered heteroarylamino groups [and their (partially) hydrogenated versions], and (iii) 5/6 or 6/6 bicyclic heteroaryl groups, 5 / 6 or 6/6 bicyclic heteroaryloxy groups, 5/6 or 6/6 bicyclic heteroaryl-S (O) _q - groups, 5/6 or 6/6 bicyclic heteroarylamino groups [and their (partially) hydrogenated versions]; wherein q is 0, 1 or 2 and any of the above ring systems in CY may be optionally substituted with up to three substituents independently selected from halogen, C 1 -C 4 alkyl [including geminal disubstitution when CY is a cycloalkyl or cycloalkenyl ring in (i)], an acyl group, an oxo group and a nitroalkyl group having 1 to 4 carbon atoms.

For the avoidance of doubt, the phosphone group is -P (O) (OH) ₂ ; (C 1 -C 4) alkoxy (hydroxy) phosphoryl is a monoalkoxy derivative of -OP (O) (OH) 2 (C 1 -C 4); and the di-alkoxyphosphoryl group having 1 to 4 carbon atoms in each alkyl moiety is the di-alkoxy derivative -OP (O) (OH) ₂ with 1 to 4 carbon atoms in each alkoxy moiety.

In this embodiment of Formula (IP), "5- or 6-membered heteroaryl" and "heteroaryl (monocyclic) ring" mean a 5- or 6-membered aryl ring wherein, unless otherwise specified, 1, 2, or 3 ring atoms are selected nitrogen, oxygen and sulfur. Unless otherwise stated, such rings are fully aromatic. Special examples

The 5- or 6-membered heteroaryl ring systems are furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole and thiophene.

• ·

Particular examples of 5-membered heteroaryl rings containing 2 or 3 heteroatoms independently selected from N, O and S (with the proviso that no OO, O-S or SS bonds are present; and alternatively also no NS bonds) are pyrazole, imidazole 1,2,3-triazole, oxazole, isoxazole, thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole and also in an alternative isothiazole , 1,2,5-thiadiazole, 1,2,4-thiadiazole or 1,2,3-thiadiazole.

In this embodiment of formula (IP), "5/6 or 6/6 bicyclic heteroaryl ring system" and "heteroaryl (bicyclic) ring" mean an aromatic bicyclic ring system comprising a 6-membered ring fused to either a 5-membered ring or to another 6-membered ring wherein the bicyclic ring system contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise stated, these rings are fully aromatic. Particular examples of 5/6 and 6/6 bicyclic ring systems include indole, benzofuran, benzimidazole, benzothiophene, benzisothiazole, benzoxazole, benzisoxazole, pyridoimidazole, pyrimidoimidazole, quinoline, quinoxaline, phthalazine, cinnoline and naphthyridine.

Particularly optional substituents for alkyl groups, phenyl (and phenyl containing moieties) and naphthyl groups and ring carbon atoms in heteroaryl (mono or bicyclic) rings in R ^14p , R ^15p , R 1 and AR include a halogen atom, a C 1 -C 4 alkyl group carbon, hydroxy, nitro, carbamoyl, C 1 -C 4 alkylcarbamoyl, C 1 -C 4 alkylcarbamoyl, cyano, trifluoromethyl, trifluoromethoxy, amino, C 1 -C 4 alkylamino, (C 1 -C 4) alkylamino, alkylS (O) _q - (q is 0, 1 or 2), carboxy, (C 1 -C 4) alkoxycarbonyl, (C 2 -C 4) alkenyl C 4 -C 4 alkynyl, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxy, alkylS (O) 2 amino C 1 -C 4 alkanoylamino, C 1 -C 4 alkanoylamino, benzoylamino, benzoyl, phenyl (optionally substituted with up to three substituents selected from halogen, C 1 -C 4 alkoxy or cyano), furan, pyrrole, pyrazole , imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, C 1 -C 4 hydroxyiminoalkyl, C 1 -C 4 alkoxyiminoalkyl and C 1 -C 4 alkyl, hydroxyalkyl (C 1 -C 4) group;

(C 1 -C 4) haloalkyl, (C 1 -C 4) nitroalkyl, (C 1 -C 4) aminoalkyl, (C 1 -C 4) cyanoalkyl, (C 1 -C 4) alkanesulfonamide, aminosulfonyl, alkylaminosulfonyl a C 1 -C 4 -alkyl group, a C 1 -C 4 -alkylaminosulfonyl group in each alkyl moiety. The phenyl and naphthyl groups and heteroaryl (mono- or bicyclic) rings in R ^14p , R 1 and AR can be mono- or disubstituted on ring carbon atoms with substituents independently selected from the above list of optional, optional substituents.

In this specification, the term "alkyl" or "alkyl" includes straight-chain or branched structures. For example, an alkyl group having 1 to 6 carbon atoms includes propyl, isopropyl and tert-butyl. However, references to individual alkyl groups such as "propyl" are specific for the direct version only, and references to individual branched alkyl groups such as "isopropyl" are specific for the branched version only. Similar conventions apply to other groups, for example, a C 1 -C 4 haloalkyl group includes 1-bromoethyl and 2-bromoethyl.

The following are particular and preferred certain values for substituents and groups that relate to the present disclosure. These values may be used, where appropriate, with any of the definitions and embodiments described above or below.

Examples of the alkyl group having 1 to 4 carbon atoms and the alkyl group having 1 to 5 carbon atoms include methyl, ethyl and propyl and isopropyl; examples of the C 1 -C 6 alkyl group include methyl, ethyl, propyl, isopropyl, pentyl and hexyl; examples of the C 1 -C 10 alkyl group include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of the alkanoylaminoalkyl group having 1 to 4 carbon atoms in the alkanoyl moiety and 1 to 4 carbon atoms in the alkyl moiety include formamidomethyl, acetamidomethyl and acetamidoethyl; Examples of C 1 -C 4 hydroxyalkyl and C 1 -C 6 hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of C 1 -C 4 alkoxycarbonyl in the alkoxy moiety include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of the C 1 -C 4 alkoxycarbonylethenyl group include

2- (methoxycarbonyl) ethenyl and 2- (ethoxycarbonyl) ethenyl; examples of the 2-cyano-2alkylethenyl group having 1 to 4 carbon atoms in the alkyl moiety include 2-cyano-2-carboxylic acid.

methylethenyl and 2-cyano -2-ethylethenyl; examples of the 2-nitro-2-alkylethenyl group having 1 to 4 carbon atoms in the alkyl moiety include 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of the C 1 -C 4 -alkylaminocarbonylethenyl group include 2- (methylaminocarbonyl) ethenyl and 2 (ethylaminocarbonyl) ethenyl; examples of the C 2 -C 4 alkenyl group include allyl and vinyl; examples of the C 2 -C 4 alkynyl group include ethynyl and 2-propynyl; examples of the C 1 -C 4 alkanoyl group include forms I, acetyl and propionyl; examples of C 1 -C 4 alkoxy include methoxy, ethoxy and propoxy; examples of C 1 -C 6 alkoxy and C 1 -C 10 alkoxy include methoxy, ethoxy, propoxy and pentoxy; examples of C 1 -C 4 alkylthio include methylthio and ethylthio; examples of C 1 -C 4 alkylamino include methylamino, ethylamino and propylamino; examples of C 1 -C 4 -alkylamino include dmethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino and dipropylamino; examples of halogen groups include fluorine, chlorine and bromine; examples of C 1 -C 4 alkylsulfonyl include methylsulfonyl and ethylsulfonyl; examples of C 1 -C 4 alkoxyalkoxy in each alkoxy moiety of C 1 -C 6 alkoxyalkoxy in each alkoxy moiety include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; examples of C 1 -C 4 alkoxyalkoxyalkoxy in each alkoxy moiety include 2 (methoxymethoxy) ethoxy, 2- (2-methoxyethoxy) ethoxy; 3- (2-methoxyethoxy) propoxy and 2- (2-etnoxyethoxy) ethoxy; examples of C 1 -C 4 alkylS (O) 2 amino include methylsulfonylamino and ethylsulfonylamino; examples of C 1 -C 4 alkanoylamino and C 1 -C 6 alkanoylamino include formamido, acetamido and propionyl amido; examples of C 1 -C 4 alkoxycarbonylamino include methoxycarbonylamino and ethoxycarbonylamino; examples of the N-alkyl-N-alkanoylamino group having 1 to 4 carbon atoms in the alkyl portion and 1 to 6 carbon atoms in the alkanoyl portion include N-methylacetamido, N-ethylacetamido and N-methylpropionamido; examples of the alkylS (O) _p NH- group having 1 to 4 carbon atoms wherein p is 1 or 2 include methylsulfinylamino, methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examples of the alkylS (O) _p alkylN- group having 1 to 4 carbon atoms in each alkyl moiety wherein p is 1 or 2 include methylsulfinylmethylamino, methylsulfonylmethylamino, 2- (ethylsulfinyl) ethylamino and 2- (ethylsulfonyl) ethylamino; examples of fluoroalkylS (O) _p NH- group having 1 to 4 carbon atoms, wherein p is 1 or 2 include trifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examples of fluoroalkylS (O) _p alkyl of 1 to 4 carbon atoms in each alkyl moiety wherein p is 1 or 2 include trifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examples of the C 1 -C 4 alkoxy (hydroxy) phosphoryl group in the alkoxy moiety include methoxy (hydroxy) phosphoryl and ethoxy (hydroxy) phosphoryl; examples of the di-alkoxyphosphoryl group having 1 to 4 carbon atoms in each alkoxy moiety include di-methoxyphosphoryl, di-ethoxyphosphoryl and ethoxy (methoxy) phosphoryl; examples of the alkylS (O) _q - group having 1 to 4 carbon atoms wherein q is 0, 1 or 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of phenylS (O) _q and naphthylS (O) _q - groups wherein q is 0, 1 or 2 are phenylthio, phenylsulfinyl, phenylsulfonyl and naphthylthio, naphthylsulfinyl and naphthylsulfonyl; examples of the benzyloxyalkyl group having 1 to 4 carbon atoms in the alkyl moiety include benzyloxymethyl and benzyloxyethyl; examples of the C 3 -C 4 alkylene chain include trimethylene and tetramethylene; examples of the alkoxyalkyl group having 1 to 6 carbon atoms in the alkoxy moiety and 1 to 6 carbon atoms in the alkyl moiety include methoxymethyl, ethoxymethyl and 2-methoxyethyl; examples of the C 2 -C 6 hydroxyalkoxy group include 2-hydroxyethoxy and 3-hydroxypropoxy; examples of alkylaminoalkoxy having 1 to 4 carbon atoms in the alkyl moiety and 2 to 6 carbon atoms in the alkoxy moiety include 2-methylaminoethoxy and 2-ethylaminoethoxy; examples of the di-alkylaminoalkoxy group having 1 to 4 carbon atoms in each alkyl moiety and 2 to 6 carbon atoms in the alkoxy moiety include 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples of the phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety include benzyl and phenethyl; examples of C 1 -C 4 alkylcarbamoyl include methylcarbamoyl; and ethylcarbamoyl; examples of the di-alkylcarbamoyl group having 1 to 4 carbon atoms in each alkyl moiety include di (methyl) carbamoyl and di (ethyl) carbamoyl; examples of the C1 -C4 hydroxyiminoalkyl group include hydroxyiminoethyl, 2 (hydroxyimino) ethyl and 1- (hydroxyimino) ethyl; examples of the C 1 -C 4 alkoxyiminoalkyl group and the C 1 -C 4 alkyl group include methoxyiminomethyl, ethoxyiminomethyl, 1- (methoxyimino) ethyl and 2 (methoxyimino) ethyl; examples of the haloalkyl group having 1 to 4 carbon atoms include halomethyl, 1-haloethyl, 2-haloethyl and 3-halopropyl; examples of the C 1 -C 4 nitroalkyl group include nitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; examples of C 1 -C 4 aminoalkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl; examples of C 1 -C 4 cyanoalkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of the C 1 -C 4 alkanesulfonamide group include methanesulfonylamido and ethanesulfonylamido; examples of C 1 -C 4 alkylaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl; and examples of the C 1 -C 4 -alkylaminosulfonyl group in each alkyl moiety include dimethylaminosulfonyl, diethylaminosulfonyl and N-methyl-Nethylaminosulfonyl; examples of the C1 -C4 alkanesulfonyloxy group include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy; examples of C 1 -C 4 alkanoyloxy include acetoxy; examples of C 1 -C 4 alkylaminocarbonyl include methylaminocarbonyl and ethylaminocarbonyl; examples of the C 1 -C 4 -alkylaminocarbonyl group in each alkyl moiety include dimethylaminocarbonyl and diethylaminocarbonyl; examples of the C 3 -C 8 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of the C 4 -C 7 cycloalkyl group include cyclobutyl, cyclopentyl and cyclohexyl; examples of the di (N-alkyl) aminomethylimino group having 1 to 4 carbon atoms in the alkyl moiety include dimethylaminomethylimino and diethylaminomethylimino.

Particular values for AR2 include, for example, those wherein AR2 contains one heteroatom such as furan, pyrrole, thiophene; those wherein AR2 contains one to four nitrogen atoms such as pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1,2,3 and 1,2,4 triazole; and tetrazole; those wherein AR 2 contains one N atom and one O atom such as oxazole, isoxazole and oxazine; those wherein AR 2 contains one N atom and one S atom, such as thiazole and isothiazole; those wherein AR 2 contains two N atoms and one S atom, such as 1,2,4- and 1,3,4-thiadiazole.

Particular examples of AR2a include, for example, dihydropyrrole (especially 2,5-dihydropyrrol-4-yl) and tetrahydropyridine (especially 1,2,5,6-tetrahydropyrid-4-yl).

Particular examples of AR2b include, for example, tetrahydrofuran, pyrrolidine, morpholine (preferably morpholino), thiomorpholine (preferably thiomorpholino), piperazine (preferably piperazino), imidazoline and piperidine, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl.

Particular values for AR 3 include, for example, bicyclic benzo-fused systems containing a 5- or 6-membered heteroaryl ring containing one nitrogen atom and optionally 1 to 3 additional heteroatoms selected from oxygen, sulfur and nitrogen. Specific examples of such rings include, for example, indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline, quinoxaline, phthalazine and cinnolin.

Other particular examples of AR 3 include 5/5, 5/6 and 6/6 bicyclic ring systems containing heteroatoms in both rings. Specific examples of such ring systems include, for example, purine and naphthyridine.

Other particular examples of AR 3 include bicyclic heteroaryl ring systems, with at least one nitrogen atom as the terminal atom of the bridge and optionally additional 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen. Specific examples of such ring systems include, for example, 3H-pyrrolo [1,2-a] pyrrole, pyrrolo [2,1-b] thiazole, 1H-imidazo [1,2-a] pyrrole, 1H-imidazo [1,2-a] imidazole, 1H, 3H-pyrrolo [1,2-c] oxazole, 1Himidazo [1,5-ajpyrrole, pyrrolo [1,2-bisoxazole, imidazo [5,1-b] thiazole, imidazo [2,1-b] thiazole, indolizine, imidazo [ 1,2-a] pyridine, imidazo [1,5-a] pyridine, pyrazolo [1,5a] pyridine, pyrrolo [1,2-b] pyridazine, pyrrolo [1,2-c] pyrimidine, pyrrolo [1,2-ajpyrazine, pyrrolo [ 1,2-a] pyrimidine, pyrido [2,1-c] -s-triazole, s-triazolo [1,5-a] pyridine, imidazo [1,2-a] pyrimidine, imidazo [1,2-ajpyrazine, imidazo [1] , 2-a] pyrimidine, imidazo [1,5-ajpyrazine, imidazo [1,5-ajpyrimidine, imidazo [1,2-b] pyridazine, s-triazolo [4,3-a] pyrimidine, imidazo [5,1] -oxoxazole and imidazo [2,1-boxoxazole. Other specific examples of such ring systems include, for example, [1H] -pyrrolo [2,1-c] oxazine, [3H] -oxazolo [3,4-a] pyridine, [6H] -pyrrolo [2,1-c] oxazine, and pyrido [2, 1-c] [1,4] oxazine. Other specific examples of 5/5-bicyclic ring systems are imidazooxazole or imidazothiazole, particularly imidazo [5,1-b] thiazole, imidazo [2,1-b] thiazole, imidazo [5,1-boxoxazole or imidazo [2,1-b] oxazole.

Particular examples of AR3a and AR3b include, for example, indoline, 1,3,4,6,9,9ahexahydropyrido [2,1-cj [1,4] oxazin-8-yl, 1,2,3,5,8,8a-hexahydroimidazo [1]. 5-a] pyridin-7-yl, 1 ₍ 5,8,8a-tetrahydrooxazolo [3,4-a] pyridin-7-yl, 1,5,6,7,8,8-hexahydrooxazolo [3,4-a] pyridin-7-yl) (7aS) [3H, 5H] -1,7a-dihydropyrrolo [1,2-c] oxazol-6-yl, (7aS) [5H] -1,2,3,7a-tetrahydropyrrolo [1,2c] imidazo-6-yl, (7aR) [3H, 5H] -1,7a dihydropyrrolo [1,2-c] oxazol-6-yl, [3H, 5H] pyrrolo [1,2- c] oxazol-6-yl, [5 H] -2,3-dihydropyrrolo [1,2- c] imidazol-6-yl, [3 H, 5 H] -pyrrolo [1,2- c] thiazol-6-yl, [3 H] , 5H] -1,7-dihydropyrrolo [1,2-c] thiazol-6-yl, [5H] -pyrrolo [1,2-c] imidazol-6-yl, [1 H] -3,4,8,8-tetrahydropyrrolo [2,1-c] oxazin-7-yl, [3H] -1,5,8,8a-tetrahydrooxazolo [3,4-a] pyrid-7-yl, [3H] -5,8-dihydrooxazolo [3, 4-ajpyrid-7-yl; and 5,8-dihydroimidazo [1,5-a] pyrid-7-yl.

Particular values for AR4 include, for example, pyrrolo [a] quinoline, 2,3pyrroloisoquinoline, pyrrolo [a] isoquinoline, 1H-pyrrolo [1,2-a] benzimidazole, 9Himidazo [1,2-a] indole, 5H-imidazo [2]. , 1-a] isoindole, 1H-imidazo [3,4-a] indole, imidazo [1,2-quinoline, imidazo [2,1-ajisoquinoline, imidazo [1,5-a] isoquinoline.

The nomenclature is used in the description and is disclosed, for example, in "Heterocyclic Compounds (Systems with Bridgehead Nitrogen), W. L. Mosby (Interscience Publisher Inc., New York), 1961, Parts 1 and 2.

Where optional substituents are mentioned, such substitution is not preferred, unless otherwise specified, geminal disubstitution. Unless elsewhere appropriate suitable substituents are identified for a particular group, those intended for similar groups are contemplated.

Suitable substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are (on available carbon atom) up to three substituents independently selected from the group consisting of alkyl of up to 4 carbon atoms { optionally substituted with (preferably one) substituents independently selected from the group consisting of hydroxy, trifluoromethyl, alkylS (O) _q - (q is 0, 1 or 2) (with the last substituent preferably being only on AR 1), alkoxy of 1 to 2 C 4 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxy, cyano, nitro, C 1 -C 4 alkanoylamino, -CONR v R w}, trifluoromethyl, hydroxy, halogen, nitro, cyano, thiol, alkoxy C 1 -C 4 alkanoyloxy, C 1 -C 4 alkanoyloxy, dimethylaminomethyleneaminocarbonyl, C 1 -C 4 di (N-alkyl) aminomethylimino u in each alkyl moiety, carboxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkanoyl, C 1 -C 4 alkylSO ₂ , C 2 -C 4 alkenyl (optionally substituted with carboxy) or a (C 1 -C 4) alkoxycarbonyl group

C 2 -C 4 alkynyl, C 1 -C 4 alkanoylamino, oxo (= O), thio (= S), C 1 -C 4 alkanoylamino {alkanoyl optionally substituted hydroxy}, alkylS (O) _q - (q is 0, 1 or 2) {C1-C4 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of cyano, hydroxy and alkoxy of up to 4 carbon atoms}, -CONRvRw or -NRvRw [wherein Rv is hydrogen or alkyl of 1 to 6 carbon atoms; R w is hydrogen or C 1 -C 4 alkyl].

Further, suitable substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b,

AR4, AR4a, CY1 and CY2 (on available carbon atoms) as well as alkyl groups (unless otherwise specified) are up to three substituents independently selected from trifluoromethoxy, benzoylamino, benzoyl, phenyl (optionally substituted with up to three substituents) independently selected from the group consisting of halogen, C1 -C4 alkoxy or cyano}, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyiminoalkyl group C 1 -C 4, C 1 -C 4 alkoxyiminoalkyl, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkanesulfonamide, SO ₂ NR v R w [wherein R 7 is hydrogen or C 1 -C 4 alkyl; R w is a hydrogen atom or a C 1 -C 4 alkyl group]

Preferred optional substituents on Ar 2b such as 1,3-dioxolan-4-yl, 1,3-dioxa, n-4-yl,

1,3-dioxan-5-yl, or 1,4-dioxan-2-yl are mono- or disubstituted by substituents independently selected from the group consisting of (C 1 -C 4) alkyl (including geminal disubstitution), (C 1 -C 4) alkoxy C 1 -C 4 alkylthio, C 1 -C 4 alkylthio, acetamido, C 1 -C 4 alkanoyl, cyano, trifluoromethyl and phenyl.

Preferred optional substituents on CY 1 & CY 2 are mono- or disubstituted substituents independently selected from the group consisting of C 1 -C 4 alkyl (including geminal disubstitution), hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio carbon, acetamido, and, e. C 1 -C 4 alkanoyl, cyano and trifluoromethyl.

Preferred 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) a C1-C4 alkyl group, a C1-C4 alkanoyl group { wherein the C 1 -C 4 alkyl and C 1 -C 4 alkanoyl group is optionally substituted with (preferably one) substituents independently selected from the group consisting of cyano, hydroxy, nitro, trifluoromethyl, alkylS (O) _q - s 1-4 carbon atoms (q is 0, 1 or

2), (C1-C4) alkoxy, (C1-C4) alkoxycarbonyl, (C1-C4) alkanoylamino, -CONRvRw or -NRvRw [where Rv is hydrogen or (C1-C4) alkyl] carbon; Rw is hydrogen or (C1-C4) -alkyl]}, C2-C4-alkenyl-alkenyl, C2-C4-alkynyl, C1-C4alkoxycarbonyl or oxo (to form N-oxide).

Suitable pharmaceutically acceptable salts include acid addition salts such as methanesulfonate, fumarate, chloride, citrate, malate, tartrate and (less preferably) bromide. Also preferred are salts with phosphoric acid and sulfuric acid. In another aspect, basic salt salts such as alkali metal salts such as sodium, alkaline earth metal salts such as calcium or magnesium, or organic amine salts such as triethylamine, morpholine, N-methylpiperidine, Nethylpiperidine, procaine, dibenzylamine are preferred. , Ν, Ν-dibenzylethylamine, tris- (2-hydroxyethyl) amine, N-methyl d-glucamine, and amino acids such as lysine. Depending on the charge of functions and the valency of the cations and anions, more cations and anions may be present. A preferred pharmaceutically acceptable salt is the sodium salt.

However, to speed up the isolation of the salt during preparation, it may be advantageous to select a salt that is less soluble in the selected solvent, regardless of whether it is pharmaceutically acceptable or not.

The compounds of formula I may be administered in the form of a prodrug that is converted into a compound of formula in the human or animal body

I. A prodrug may be used to alter or improve the physical and / or pharmacokinetic profile of a parent compound and may arise when the parent compound contains a suitable group or substituent, which may be:

derivatized into a prodrug form. Examples of the prodrug include hydrolyzable esters of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

Various forms of drug precursors are known in the art. for example:

a) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985) and Methods in Enzymology, vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, published by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, "Design of Application of Prodrugs", H. Bundgaard p. 113191 (1991);

c) H. Bundgaard, Advanced Drug Reviews, 8, 1-38 (1992);

d) H. Bundgaard, et al. Journal of Pharmaceutical Sciences 77: 285 (1988); and

e) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984).

For example, an in-vivo hydrolysable ester of a compound of Formula I or a pharmaceutically acceptable salt thereof containing a carboxy or hydroxy group is a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to the starting acid or alcohol. Suitable pharmaceutically acceptable carboxy esters include alkoxymethyl esters of 1 to 6 carbon atoms in the alkoxy moiety, for example methoxymethyl, alkanoyloxymethyl esters of 1 to 6 carbon atoms in the alkanoyl moiety, for example pivaloyloxymethyl, esters of phthalic acid, cycloalkoxycarbonyloxyalkyl esters of 3 to 8 1 to 6 carbon atoms in the alkyl moiety, for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters, for example 5-methyl-1,3-dioxolan-2-ylmethyl; and alkoxycarbonyloxyethyl esters of 1 to 6 carbon atoms in the alkoxy moiety, for example

1-methoxycarbonyloxyethyl and can be prepared at any of the claryl groups in the compounds of the invention.

The in-vivo hydrolysable ester of a compound of Formula I, or a pharmaceutically acceptable salt thereof, containing hydroxy group (s) includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which result in in vivo hydrolysis the starting hydroxy group (s). Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. The choice of in-vivo hydrolysable ester forming group for the hydroxy group includes an alkanoyl group having 1 to 10 carbon atoms, a benzoyl group, a phenylacetyl group, and a substituted benzoyl and phenylacetyl group, a (C 1 -C 10) alkoxycarbonyl group (to form alkyl carbonate esters), a (C 1 -C 4) di-alkylarbamoyl group and a C (C 1 -C 4) alkylaminoethyl-N-alkylcarbamoyl group and C 1 -C 4 alkylcarbamoyl (to form carbamates), C 1 -C 4 dialkylaminoacetyl, and carboxyacetyl Examples of benzoyl substituents include chloromethyl or aminomethyl, C 1 -C 4 alkylaminomethyl. alkyl moiety and a (C 1 -C 4) dialkylaminomethyl group; to in each alkyl part, and morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4- position of the benzoyl ring.

Certain suitable in-vivo hydrolysable esters of a compound of Formula I are described within the definitions set forth herein, for example, esters described by definition (R c2d) and certain groups within (R c2c). Suitable in-vivo hydrolysable esters of the compound of formula I are described as follows. For example

The 1,2-diol can be cyclized to form a cyclic ester of formula (PD1) or pyrophosphate of formula (PD2):

(PD2) (PD2)

Of particular interest are those cyclic prodrugs where the 1,2-diol is on a C 1 -C 4 alkyl chain which is bonded to a carbonyl group in a substituent of formula Rc carried by a nitrogen atom in (TC4). Esters of compounds of formula I wherein the OH functions in (PD1) and (PD2) are protected with a C1-C4 alkyl group, a phenyl group, a benzyl group are useful intermediates for the preparation of such prodrugs.

··

Other in-vivo hydrolysable esters include phosphoramide esters as well as compounds of formula I wherein any free hydroxy group independently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0) ester of formula (PD3);

(O) _npd

HO / O HO (PD2)

Useful intermediates for the preparation of such esters include a compound containing a group (s) of formula (PD3) wherein either one or both of the hydroxy groups in (PD3) are independently protected with a C1-C4 alkyl group (such compounds are also interesting compounds per se) , phenyl or phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety (such as phenyl groups optionally substituted with 1 or 2 groups independently selected from the group consisting of C 1 -C 4 alkyl, nitro, halogen and C 1 -C 4 alkoxy 4 carbon atoms.

Drug precursors containing groups such as (PD1), (PD2) and (PD3) can be prepared by reacting a compound of formula I containing suitable hydroxy groups (hydroxy) with a suitably protected phosphorylating agent (e.g. containing a chlorine or dilakylamine leaving group) and then oxidizing ( if necessary) and removing the protecting group.

If a compound of the formula contains a number of free hydroxy groups, those groups that are not converted to the prodrug functional groups can be protected (for example using a tert-dimethylsilyl group) and later the protected group can be removed therefrom. Enzymatic methods can also be used to phosphorylate and dephosphorylate alcoholo functional groups.

Other interesting in-vivo hydrolysable esters include, for example, those in which R c is defined as, for example, R ¹⁴ C (O) O-C 1 -C 6 -alkyl-CO- in the alkyl moiety (where R ¹⁴ is, for example, benzyloxyalkyl of 1 to 6 carbon atoms) 4 carbon atoms in the alkyl moiety or phenyl group). Suitable substituents on the phenyl group in such esters include, for example, 4-alkylpiperazinoalkyl groups having 1 to 4 carbon atoms in the alkyl moieties, piperazinoalkyl groups having 1 to 4 carbon atoms in the alkyl moiety and morpholinoalkyl groups having 1 to 4 carbon atoms in the alkyl moiety.

β · · • · · · · · 38 • · · • · · · • · · • · · · · · • · · · · • · · · · · · · · · · · ·

Pharmaceutically acceptable salts of the in-vivo hydrolysable ester can be prepared by conventional techniques. For example, compounds containing a group of formula (PD1), (PD2) and / or (PD3) can be ionized (partially or completely) to form salts with a suitable number of counterions. For example, if an in-vivo hydrolysable prodrug ester of a compound of formula I contains two (PD3) groups, then the 4 HO-P- functional groups are present throughout the molecule, each of which may form a particular salt (e.g. for example, to form a mono-, di-, trine or tetrasodium salt).

The compounds of the present invention have a chiral center at the C-5 position of the oxazolidinone ring. The pharmaceutically active enantiomer has the general formula (IA):

O

The present invention includes the pure enantiomer depicted above or a mixture of the 5R and 5S enantiomers, for example a racemic mixture. When a mixture of enantiomers is used, greater amounts of this mixture (depending on the ratio of enantiomers) are used to achieve the same effect as the pharmaceutically active enantiomers. For the avoidance of doubt, the enantiomer shown above is the 5R enantiomer.

Further, some compounds of Formula I may have other chiral centers. It is to be understood that the invention encompasses all such diastereoisomers and racemic mixtures which exhibit antibacterial effects. It is well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, chiral syntheses, enzymatic cleavage, biotransformation or chromatographic separation) and how to determine antibacterial activity as described below.

The invention also encompasses all tautomeric forms of the compounds of formula I that exhibit antibacterial activity.

It will be appreciated that certain compounds of Formula I may exist in solvated and unsolvated forms such as hydrated forms. It is to be understood that the invention encompasses all such solvated forms which exhibit antibacterial activity.

It will also be appreciated that certain compounds of Formula I may exhibit polymorphism and that the invention encompasses all such forms which exhibit antibacterial activity.

As noted above, we have found compounds that have good activity against a wide range of Gram-positive pathogens, including organisms known to be resistant to most commonly used antibiotics. Important features are physical and pharmacokinetic properties, such as increased stability to mammalian peptidase metabolism and a favorable toxicological profile. The following compounds which exhibit particularly favorable physical and / or pharmacokinetic properties are preferred.

Particularly preferred compounds of the invention include a compound of Formula I or Formula (IP) or a pharmaceutically acceptable salt or involyzable hydrolyzable ester thereof, wherein the substituents Q, X, HET, T and the other substituents listed above have the meanings given above or any of the following meanings ( which may be used where appropriate with any of the definitions and examples described above or below):

Preferably Q is selected from Q1, Q2, Q4, Q6 and Q9; in particular Q1, Q2 and Q9; more preferably Q1 and Q2; and most preferably Q is Q1.

Preferably, T is selected from (TAf), (TDb) or (TC); in particular (TCb) and (TCc) groups; more preferably (TC2), (TC3) and (TC4); most preferably (TC5), (TC7) or (TC9) and even more preferably (TC5). Particularly preferred are cases where T is in Q1 and Q2, particularly in Q1.

Preferred meanings for the other substituents (which may be used where appropriate from any of the definitions and embodiments described above or below) are: (a) Preferably X is -O-;

(a1) In another aspect, X is -S-;

(b) Preferably HET is pyrazole, imidazole, oxazole, isoxazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, isothiazole or 1,2,5-thiadiazole. More preferably, HET is pyrazol-3-yl, imidazol-2-yl, oxazol-2-yl, isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, 1,3,4-oxadiazol-2-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl;

(b1) Particularly preferably, HET is isoxazole (optionally substituted as described above), especially isoxazol-3-yl;

• ·

(b2) In another embodiment, HET is as defined above or below, but excluding thiazole and thiadiazole; and in another embodiment, HET is as defined above or below, but excluding isothiazole and thiadiazole;

(b3) Preferably, HET is unsubstituted.

(c) Preferably Rp is hydrogen;

(d) Preferably, Rp1 and Rp2 are independently selected from hydrogen, C1-C4alkyl, carboxy, C1-C4alkoxycarbonyl in the alkoxy moiety, hydroxymethyl, C1-C4alkoxymethyl in the alkoxy moiety or a carbamoyl group;

(e) More preferably, Rp1 and Rp2 are hydrogen;

(f) Preferably one of R ² and R ³ is hydrogen and the other is fluorine;

(g) In another aspect, R ² and R ³ are both fluorine;

(h) Preferably,> AB- is a group of formula> C = CH- (i.e. Rr is preferably hydrogen) or a group> N-CH ₂ -;

(i) Preferably D is -O- or> NR cp;

(i) Preferably R cp is AR, R ^13p CO-R ^13p SO ₂ -, R ^13p CS-;

(k) More preferably, R cp is AR (most preferably benzyl, pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl) or R ^13p CO- (especially R ^13p CO-);

(1) Preferably AR is a 5- or 6-membered heteroaryl; more preferably AR is a 6-membered heteroaryl such as pyridinyl;

(m) Preferred substituents for phenyl and carbon atoms in heteroaryl (mono- and bicyclic) ring systems in AR, ^R14p and R1 include halogen, C1-C4alkyl, hydroxy, nitro, amino, cyano, alkylS; (O) _p - C 1 -C 4 and alkoxy C 1 -C 4;

(n) preferably, optionally substituted ring systems in AR, R ^14p and R 1 are unsubstituted;

(n1) In another embodiment of the definition of R ^13p in (PC) embodiment (IP), 1,3-dioxolan-4-yl and

1,4-dioxan-2-yl eliminated.

(o) Preferably R ^13p is C 1 -C 4 alkoxycarbonyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkyl (optionally substituted with one or two hydroxy or alkanoyl groups)

• e · ·······

(C 1 -C 4 alkyl), C 1 -C 4 alkylamino, C 1 -C 4 dimethylaminoalkyl, C 1 -C 4 alkoxymethyl, C 1 -C 4 alkanoylmethyl in alkanoyl, C1 -C4 alkanoyloxyalkyl and C1 -C4 alkyl, C1 -C5 alkoxy or 2-cyanoethyl;

(p) More preferably, R ^13p is 1,2-dihydroxyethyl, 1,3-dihydroxyprop-2-yl, 1,2,3-trihydroxyprop-1-yl, methoxycarbonyl, hydroxymethyl, methyl, methylamino, dimethylaminomethyl, methoxymethyl, acetoxymethyl, methoxy, methylthio, naphthyl, tert-butoxy or 2-cyanoethyl;

(p1) Even more preferably R ^13p is 1,2-dihydroxyethyl, 1,3-dihydroxyprop-2-yl or 1,2,3-trihydroxyprop-1-yl;

(q) Preferred optional substituents for the C 1 -C 10 alkyl group in R ^14p are hydroxy, cyano, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl moiety, alkylS (O) _p - (wherein p is 1 or 2) carboxy, (C 1 -C 4) alkoxycarbonyl, (C 1 -C 4) alkoxy, piperazine or morpholine;

(r) Preferred optional substituents for the C 1-6 alkyl group in R ^15p are hydroxy, C 1 -C 4 alkoxy, cyano, amino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each; alkyl moieties, alkylS (O) _p - (wherein p is 1 or 2);

(s) Preferably, the 5- or 6-membered heteroaryl in R ^14p is pyridinyl or imidazol-1-yl;

(t) Preferably, R ^15p is an alkyl group having 1 to 6 carbon atoms; most preferably R ^15p is tert-butyl or methyl;

(u) Preferably R ^17p is cyano or fluoro;

(v) Preferably ^R16p is hydrogen;

(w) Preferably, CY is naphthoxy, especially naphth-1-oxy or naphth-2-oxy.

Where preferred values for substituents in compound (IP) are preferred, the corresponding substituents in the compound of formula I have the same preferred values (for example, R ¹³ and R c in formula I correspond to R ^cp and R ^{13 p} in formula (IP), and similarly for groups D and G). For compounds of formula I, preferred values for Rc are those listed in (Rc2). Preferred values for R ^13p listed above for compounds of formula (IP) are also preferred values for ^R13 in compounds of formula I. In the definition of (Rc2c) the AR2a, AR2b, R3a and AR3b versions of AR2 and AR3 groups excluded.

In another aspect, HET is a C-linked 5-membered heteroaryl ring containing 2 or 3 heteroatoms independently selected from N, O, and S (provided there are no OO, O-S, SS, or NS bonds), wherein the ring is optionally substituted on any available carbon atom (provided that when N is adjacent to the X-bond, then no carbon atom adjacent to that N atom is substituted) with 1 or 2 substituents independently selected from the group consisting of an alkyl group C 1 -C 4 alkyl, amino, C 1 -C 4 alkylamino, C 1 -C 4 alkoxy and halogen and / or on the available N atom (provided that the ring is not quaternized), an alkyl group of 5 1 up to 4 carbon atoms.

In another aspect, HET is selected from formulas (HET1) to (HET3) below;

ON,

N-B,

U V \ -A.

(HET1) (HET2) (HET3) wherein A ₂ is a carbon or nitrogen atom and B ₂ is O, S or N (with a maximum of 3 ring heteroatoms), wherein the ring carbon and nitrogen atoms are optionally substituted as described for HET from above (preferably with no substitution at any carbon atom adjacent to a specific nitrogen atom).

In another embodiment, HET has the meaning as defined herein and is also optionally substituted on the available C atom with a C 1 -C 4 alkoxycarbonyl group in the alkoxy moiety.

The above definitions of HET are particularly preferred in embodiment (IP) and with a preferred value (n1) of the group R ^13p .

Particularly preferred compounds of the invention are compounds of formula (IB):

• ·

Rp1

R2 η

R

(IB) wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R ² and R ³ are independently hydrogen or fluorine; and R p1 and R p2 are independently hydrogen, hydroxy, bromine, C 1 -C 4 alkyl, carboxy, C 1 -C 4 alkoxycarbonyl, hydroxymethyl, C 1 -C 4 alkoxymethyl parts or a carbamoyl group; or a pharmaceutically acceptable salt thereof.

Other particularly preferred compounds of the invention are those compounds of formula (IB) wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5thiadiazol-3-yl; R ² and R ³ are independently hydrogen or fluorine; and Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, C 1 -C 4 phenylalkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine , isoxazole, oxazole, isothiazole, tniazole or thiophene); or a pharmaceutically acceptable salt thereof.

Among the especially preferred compounds of the formula (IB) above, those particularly preferred are those wherein Rp1 and Rp2 are hydrogen.

Further, particularly preferred compounds of the invention are compounds of formula (IC):

Rcp - row

F

HET

R 1 (IC) wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3yl; R ² and R ³ are independently hydrogen or fluorine; Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), (C1-C4) alkyl, carboxy, (C1-C4) alkoxycarbonyl, hydroxymethyl, (C1-C4) alkoxymethyl or carbamoyl and Rcp is cyano, pyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-alkylethenyl of 1 to 4 carbon atoms in the alkyl moiety or Rcp is R ^13p CO-, R ^13p SC> 2 or R ^13p CS- (wherein R ^13p is hydrogen, C 1 -C 5 alkyl [optionally substituted with one or more groups selected independently from hydroxy and amino, or optionally monosubstituted alkoxy) C 1 -C 4 -alkyl, C 1 -C 4 -alkylS (O) _q -, C 1 -C 4 -alkylamino, C 1 -C 4 -alkanoyl, naphthoxy, C 2 -C 6 -alkanoylamino or C 1 -C 4 -alkanoylamino; alkylS (O) _p NH- having 1 to 4 carbon atoms, wherein p is 1 or 2 and q is 0 or 2], imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, pyridoimidazole, pyrimidoimidazole, quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine or R ^13p is a group of the formula R ^14p (C (O) C 1 -C 6 alkyl in the alkyl moiety, where R ^14p is an alkyl group of 1 to 6 carbon atoms) or Rcp is the formula R f C (= O) C (= O) wherein R f is C 1 -C 6 alkoxy; or a pharmaceutically acceptable salt thereof.

Among the above-mentioned particularly preferred compounds of the invention of formula (IC), those wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5- thiadiazol-3-yl; R ² and R ³ are independently hydrogen or fluorine; Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or ARthiomethyl (wherein AR is phenyl, C 1 -C 4 phenylalkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), (C1 -C4) alkyl, carboxy, (C1 -C4) alkoxycarbonyl, hydroxymethyl, (C1 -C4) alkoxymethyl or carbamoyl and Rcp is cyano, pyrimidin-2-yl,.

2-cyanoethenyl, 2-cyano-2-alkylethenyl of 1 to 4 carbon atoms in the alkyl moiety or Rcp is a group of formula R ^13p CO-, R ^13p SO 2 or R ^13p CS- (wherein R ^13p is hydrogen, alkyl C 1 -C 5 alkyl [optionally substituted with one or more groups selected independently from hydroxy and amino, or optionally monosubstituted with C 1 -C 4 alkoxy, C 1 -C 4 alkyl, (C 1 -C 4) alkyl, C 1 -C 4 alkylamino C 1 -C 4 alkanoyl, C 1 -C 4 alkanoyl, C 2 -C 6 alkanoylamino or alkylS (O) _p NHC 1 -C 4, wherein p is 1 or 2 and q is 0, 1 or 2] , pyridine or R ^13p is a group of formula R ^14p C (O) C 1 -C 6 alkyl in the alkyl portion, wherein R ^14p is a C 1 -C 6 alkyl group) or R cp is a group of the formula R f C (= O) C ( = O), wherein R f is C 1 -C 6 alkoxy; or a pharmaceutically acceptable salt thereof.

Of the aforementioned particularly preferred compounds of the invention of formula (IC), particularly preferred are compounds wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazole -3-yl; R ² and R ³ are independently hydrogen or fluorine; Rp1 and Rp2 are hydrogen, and Rcp is pyridin-2-yl (optionally substituted with cyano) or Rcp is a group of formula ^R13p CO- (wherein ^R13p is hydrogen, 1,3-dioxolan-4-yl (optionally disubstituted) with (C 1 -C 4) alkyl or (C 1 -C 5) alkyl (optionally substituted with one or more hydroxy) or R ^13p is a group of formula R ^14p C (O) C 1-6 alkyl in the alkyl moiety where R ^14p (C1-C6 alkyl) or a pharmaceutically acceptable salt thereof.

Of the above-mentioned particularly preferred compounds of formula (IC) above, those particularly preferred are those wherein R ^cp is a group of formula R ^13p CO-, where R ^13p is hydrogen, 1,3-dioxolan-4-yl (optionally disubstituted with alkyl having (C 1 -C 4 -alkyl) or C 1 -C 5 -alkyl [substituted with two hydroxy groups] or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, all compounds of formula (IB) or (IC) described above are further preferred when HET is isoxazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl.

In yet another aspect, the invention relates to all compounds of formula (IB) or (IC) described above wherein HET is isoxazol-3-yl or 1,2,4-oxadiazol-3-yl.

• ·

In yet another aspect, the invention relates to all compounds of formula (IB) or (IC) described above wherein HET is isoxazol-3-yl.

In another aspect, the invention provides preferred compounds of formula (IP) wherein -X-HET is isoxazol-3-yloxy, 1,2,4-oxadiazol-3-yloxy, isothiazol-3-yloxy,

1,2,5-thiadiazol-3-yloxy; > AB- is> N-CH 2 - and D is NR cp, wherein R cp is a 6-membered aryl ring containing 1, 2 or 3 ring nitrogen atoms as the only ring heteroatoms attached through the ring carbon atom and optionally substituted on the ring carbon atom by one, two or three substituents independently selected from the group consisting of alkyl having 1 to 4 carbon atoms, halogen, trifluoromethyl, alkyl s (O) _q C 1 -C 4 alkyl (where q is 0, 1 or 2) (C1-C4) -alkyl (S) (O) 2 amino, (C1-C4) alkanoylamino, carboxy, hydroxy, amino, (C1-C4) alkylamino, (C1-C4) dialkylamino, (C1-C4) alkoxycarbonyl carbon atoms in the alkoxy moiety, carbamoyl, N-alkylcarbamoyl of 1 to 4 carbon atoms in the alkyl moiety, di-N-alkylcarbamoyl of 1 to 4 carbon atoms in the alkyl moiety, alkoxy of 1 to 4 carbon atoms, k yano or nitro; or a pharmaceutically acceptable salt thereof.

In all of the above aspects and preferred compounds of formula (IB) and (IC), in-vivo hydrolysable esters, especially phosphoryl esters (as defined by formula (PD3) with npd 1), are preferred.

In all of the above definitions, preferred compounds are shown in Formula (IA), i.e., the pharmaceutically active (5 (R)) enantiomer).

Particular compounds of the present invention include the following compounds (and individual isomers where a mixture of isomers is possible) 5 (R) -1soxazol-3-yloxymethyl-3- (3-fluoro-4- (3,6-dihydro- (2H)) (pyran-4-yl) phenyl) oxazolidin-2-one;

5 (R) - (5-Methyl-oxazol-3-yloxymethyl) -3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2-one;

5 (R) -1Soxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolane-4 (R, S) -ylcarbonyl) 5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one; 5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl -oxazolidin-2-one;

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1-formyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one;

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one;

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one;

5 (R) -1-Oxoxazol-3-yloxymethyl-3- (4- (4- (5-cyanopyrid-2-yl) piperazin-1-yl) -3-fluorophenyl) oxazolidin-2-one;

5 (R) -lsothiazol-3-yloxymethyl-3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2-one;

5 (R) - (1,2,5-Thiadiazol-3-yloxymethyl) -3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2-one ; or a pharmaceutically acceptable salt thereof.

Of the above compounds, particular preference is given to (and its individual isomers): 5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S), 3-dihydroxypropanoyl)) -1,2, 5,6-Tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one; or a pharmaceutically acceptable salt thereof, or an in-vivo hydrolysable ester thereof.

Also preferred are the 3-fluorophenylanogues of the particular 3,5-difluoro compounds mentioned above.

Other preferred compounds, unless specifically indicated, are those set forth in Examples 1, 2, 7, 14, 48, 148, 151, and 23.

Also preferred is compound (and its individual isomers): 5 (R) -lsothiazol-3-yloxymethyl-3- (4- (1- (2 (R, S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyridine) -4-yl) -3-fluorophenyl) oxazolidin-2-one; or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.

Most preferred compounds are those set forth in Examples 12, 18, 19, 20, 21 and 22, or pharmaceutically acceptable salts. Preferred are the in-vivo hydrolysable esters of Examples 12 and 18, especially phosphoryl esters.

Thus, preferred compounds or pharmaceutically acceptable salts thereof: 5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-diphosphoryl-propanoyl)) -1,2,5,6-tetrahydropyridine- 4-yl) -3-fluorophenyl) oxazolidin-2-one;

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-diphosphoryl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl Oxazolidin-2-one.

Also preferred are compounds or pharmaceutically acceptable salts thereof;

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphoryl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one;

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphoryl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5) (difluorophenyl) oxazolidin-2-one.

Also preferred are compounds or pharmaceutically acceptable salts thereof: 5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (3-hydroxy-2 (S) -phosphoryl-propanoyl)) -1,2,5, 6-Tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one;

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (3-hydroxy-2 (S) -phosphoryl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5) (difluorophenyl) oxazolidin-2-one.

Suitable pharmaceutically acceptable salts of the latter two compounds and those of Examples 19, 20, 21 and 22 are mono- and di-salts of monophosphoryl ester compounds and mono-, di-, tri- and tetra-salts of di-phosphoryl ester compounds ( Examples 19 and 21). Particularly preferred salts are sodium salts.

Preparation procedures:

In another aspect, the present invention provides a process for preparing a compound of Formula I, or a pharmaceutically acceptable salt thereof, or an in-vivo hydrolysable ester thereof. It will be appreciated that during certain of the following procedures, certain substituents will need to be protected to prevent an undesired reaction. One skilled in the art will recognize where such protection is desirable and how such protecting groups are to be introduced and later removed.

Examples of protecting groups are given in a number of publications, for example, "Protective Groups in Organic Synthesis, Theodora Green" (edited by John Wiley &amp; Sons). The protecting groups may be removed in a conventional manner as described in the literature or as known to the skilled person. The methods selected should be such that the protecting group is effectively removed with minimal disruption to groups located elsewhere in the molecule.

Thus, if the reactants include, for example, groups such as amino, carboxy or hydroxy, it may be appropriate to protect these groups in some of the reactions mentioned herein.

A suitable protecting group for an amino group or an alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl, arylmethoxycarbonyl, for example benzyloxycarbonyl; A benzoyl group, for example a benzoyl group. The deprotection conditions for the above protecting groups vary depending on the choice of protecting group. 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 lithium hydroxide or sodium hydroxide. Alternatively, an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed by hydrogenation on a catalyst such as palladium on carbon or by treatment with a Lewis acid such as boron tris (trifluoroacetate). A suitable alternative protecting group for the primary amino group is, for example, a phthaloyl group which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine or hydrazine.

A suitable protecting group for a hydroxyl group is, for example, an acyl group, for example an alkanoyl group, such as acetyl, an aroyl group, for example benzoyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups vary depending on the choice of protecting group. For example, an acyl group such as an alkanoyl or aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium hydroxide or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation on a catalyst such as palladium on carbon.

A suitable protecting group for a carboxy group is, for example, an esterification group such as a methyl or ethyl group which can be removed, for example, by hydrolysis with a base such as sodium hydroxide or a tert-butyl group can be removed for example by treatment with an acid such as an organic acid such as trifluoroacetic acid or a benzyl group which may be removed, for example, by hydrogenation on a catalyst such as palladium on carbon.

Examples of the use of resins as protecting groups are given in Examples 135 and 136.

The above protecting groups can be removed by any conventional method known in the art.

The compound of formula (I), or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof, can be prepared by any known method used to prepare chemically related compounds. Such procedures when used to prepare a compound of Formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof are a further feature of the present invention and are illustrated by the following representative examples. Necessary starting materials can be obtained by standard organic chemistry procedures (see, for example, Advanced Organic Chemistry (Wiley-Interscience) Jerry March). The preparation of such starting materials is described in the accompanying, non-limiting examples. Alternatively, the necessary starting materials are obtained by analogous procedures known to those skilled in the art of organic chemistry. Information on the preparation of essential starting materials or related compounds (which can be converted to essential starting materials) can also be found in the following patent publications, incorporated herein by reference;

WO 99/02525; WO 98/54161; WO 97/37980; WO 97/30981 (& US 5,736,545); WO 97/21708 (& US 5,719,154); WO 97/10223; WO 97/09328; WO 96/35691; WO 96/23788; WO 96/15130; WO 96/13502; WO 95/25106 (& US 5,668,286); WO 95/14684 (& US 5,652,238); WO 95/07271 (& US 5,688,792); WO 94/13649; WO 94/01110; WO 93/23384 (& US 5,547,950 & US 5,700,799); WO 93/09103 (& US 5,565,571, US 5,654,428, US 5,654,435, US 5,756,732 & US 5,801,246); U.S. 5,231,188; US 5,247,090; 5,523,403; WO 97/27188; WO 97/30995; WO 97/31917; WO 98/01447; WO 98/01446; WO 99/10342; WO 99/10343; WO 99/11642; European Patent Applications Nos. 0 359 418 and 0 609 905; 0693,491 A1 (& AU 24985/95); 0 694 544 A1 (& CA 2,154,024); 0 697 412 A1 (& US 5,529,998); 0 738,726 A1 (& AU 50735/96); 0 785 201 A1 (& AU 10123/97); German Patent Application Nos. 195 14 313 A1 (& US 5,529,998); DE 196 01 264 A1 (& AU 10098/97); DE 196 01 265 A1 (& AU 10097/97); DE 196 04 223 A1 (& AU 12516/97); DE 196 49 095 A1 (& AU 12517/97).

The following patent publications may also provide useful information, and the contents of the relevant process sections are incorporated herein by reference;

FR 2458547; FR2500450 (& GB 2094299, GB 2141716 & US 4,476,136); DE 2923295 (& GB 2028306, GB 2054575, US 4,287,351, US 4,348,393, US 4,413,001, US 4,435,415 & US 4,526,786), DE 3017499 (& GB 2053196, US 4,346,102 '& US 4

372,967); 4,705,799; European Patent Applications No. 0 312 000; 0,127,902; 0 352,781; 0 316 594

A person skilled in organic chemistry will be able to use the information contained in the above references to obtain the necessary starting materials.

Thus, according to the present invention, the compounds of formula I and their pharmaceutically acceptable salts and in vivo hydrolysable esters can also be prepared by processes (a) to (i) below (wherein the individual variables are as defined above unless otherwise indicated):

(a) modifying a substituent in a compound of Formula I or introducing a substituent into another compound of Formula I;

(b) reacting a compound of formula II

O

AND

Q— N O

(II) wherein Yp is a hydroxy group with a compound of formula (b1) HET-OH or (b2) HET-Lg, wherein Lg is a suitable leaving group;

(c) reacting a compound of formula II wherein Yp is a leaving group, for example, a halogen atom, mesylate or tosylate, with a metal alkoxide of HET-OM, wherein M is an alkali metal or other metal such as silver known to be promotes alkylation;

(d) reacting a compound of formula Q-Zp, wherein Zp is an isocyanate or amino group with an epoxide of formula CH ₂ (O) CH-CH ₂ O-HET;

(e) when X is -S-, by a process analogous to (c) using (e1) a metal thioxide compound of the formula HET-SM, wherein M is an alkali metal or other metal, such as silver, known as a compound that promotes S-alkylation; or (e2) alternatively by a method analogous to (c) using HET-SH and a compound of formula II, wherein Y p is a suitable leaving group;

(f) when X is -SO- or -SO ₂ - by oxidizing a compound wherein X is -S-;

(g) conversion to a non-quaternary compound of a compound of formula I wherein HET carries a quaternary nitrogen atom;

(h) when HET is an isoxazole ring, by reacting a compound of formula II wherein Yp is O-CH = N-OH with acetylene;

(i) reacting a urethane compound of formula III with a compound of formula IV-n OR ²¹

O (III) (IV) wherein R ²¹ is C 1 -C 6 alkyl or benzyl; and then, if necessary;

(i) removing any protecting group; (ii) forming a pharmaceutically acceptable salt;

(iii) forming an in vivo hydrolysable ester.

General information on reagents and reagents can be obtained in Advanced Organic Chemistry, 4th Edition, Jerry March (J. Wiley & Sons), 1992. Necessary starting materials are obtained by standard organic chemistry procedures as described in this section. according to a method of preparation, examples or analogous procedures known to those skilled in the art of organic chemistry. Certain references also provide (see above) the preparation of certain starting materials; for example, International Patent Application No. WO 97/37980, the contents of which are incorporated herein by reference. Procedures analogous to those in these references can be used by a normal organic chemist to obtain the necessary starting materials.

(a) Methods for converting substituents to other substituents are known in the art. For example, an alkylthio group may be oxidized to an alkylsulfinyl or alkylsulfonyl group, a cyano group may be reduced to an amino group, a nitro group may be reduced to an amino group, a hydroxy group may be alkylated to a methoxy group, a hydroxy group may be thiomethylated to an arylthiomethyl or heteroarylthiomethyl group. , 585 (1972)), a carbonyl group can be converted to a thiocarbonyl group (for example using Lawsson's reagent) a bromo group can be converted to an alkylthio group. it is also possible to convert one RC group to another RC group as the final step in the preparation of the compound of formula I.

One compound of formula (I) may be converted to another compound of formula (I) by reacting a compound of formula (I) wherein T is a halogen atom with a suitable compound to form a compound with a different meaning of T. For example, T as a halogen atom may be displaced by suitable vinyl, aromatic, tropolone and nitrogen bonded systems such as T by reaction using Pd (0) coupling techniques.

Further examples of converting substituents to other substituents are provided in the accompanying, non-limiting examples.

(b1) If HET-OH is used, reaction (b1) is performed using

Mitsunobu conditions, for example in the presence of tri-n-butylphosphine and diethyl azodicarboxylate (DEAD) in an organic solvent such as THF and at a temperature in the range of ⁰ to 60 ° C, but preferably at ambient temperature. Details of the Mitsunobu reaction are contained in Tet. Letts., 31, 699 (1990); The Mitsunobu Reaction, DL Hughes, Organic Reactions, 1992, Vol. 42, 355-656, and Progress in the Mitsunobu Reaction, DL Hughes, Organic Preparations and Procedures International, 1996, Vol. 28, 127-164.

(b2) If HET-Lg is used, reaction (b2) is performed using a suitably reactive HET under basic conditions (using a base such as 1,8-diazabicyclo [5,4,0] undec-7-ene) which are sufficiently mild to prevent damage to the oxazolidinone ring structure. One skilled in the art will recognize which suitable leaving group Lg (such as chlorine or bromine) and which reaction conditions are to be used.

Compounds of formula II wherein Yp is hydroxy may be obtained by reacting a compound of formula III with a compound of formula V:

O

O (ΠΙ) (V) wherein R ²¹ is C 1 -C 6 alkyl or benzyl and R ²² is C 1 -C 4 alkyl or -S (O) _q alkyl of 1 to 4 carbon atoms, wherein q is 0, 1 or 2. Preferably, R ^{22 is} alkyl of 1 to 4 carbon atoms.

The compounds of formulas II, III and V may be prepared by one skilled in the art, for example as described in International Patent Applications No. WO 95/07271,

WO 97/27188, WO 97/30995, WO 98/01446 and WO 98/01446, the contents of which are incorporated herein by reference and by analogous procedures.

When not commercially available, compounds of formula HET-OH and HET-Lg can be prepared by procedures selected from standard chemical procedures, procedures analogous to the preparation of known, structurally similar compounds, or procedures analogous to those described in the Examples. For example, standard chemical procedures are described in Houben Weyl, Methoden der Organische Chemie, E8a, Pt.1 (1993), 45-225, B.J. Wakefield (for isoxazoles) and E8c,

Pt.l (1994), 409-525, U. Kraatz (for 1,2,4-oxadiazoles). Also, for example, 3-hydroxyisoxazole can be prepared by cyclization of CH = C-CO-NHOH (prepared from CHeCCO-O- (C 1 -C 4 alkyl) as described in Chem. Pharm. Bull. Japan, 14, (1966)).

(c) & (e) Reactions (c) and (e) are carried out conventionally at a temperature in the range of 25 to 60 ° C in a solvent such as NMP or DMF.

A compound of formula II wherein Yp is fluoro can be prepared by reacting a compound of formula II wherein Yp is hydroxy (s) with a fluorinating agent such as diethylaminosulfurtrioxide in an organic solvent such as dichloromethane in a temperature range of 0 ° C to ambient temperature.

When Yp is a chlorine atom, a compound of formula II can be prepared by reacting a hydroxy compound with a chlorinating agent. For example, by reacting the hydroxyl compound with thionyl chloride, at a temperature ranging from ambient to reflux, optionally in a chlorinated solvent such as dichloromethane, or by reacting the hydroxy compound with a mixture of carbon tetrachloride / triphenylphosphine in dichloromethane in a temperature range of 0 ° C to ambient temperature. A compound of formula II wherein Yp is a chlorine or iodine atom may also be prepared from a compound of formula II wherein Yp is a mesylate or tosylate by reacting the latter compound with lithium chloride or lithium iodide and crown ether in a suitable organic

9 9 9 9 9 9 9 9 9 99 99 9999

999 999 9999 99 99 solvent, such as THF, in a temperature range from ambient to reflux.

When Yp is C 1 -C 4 alkanesulfonyloxy or tosylate, the compound of formula II can be prepared by reacting a hydroxy compound with C 1 -C 4 alkanesulfonyl chloride or tosyl chloride in the presence of a weak base such as triethylamine or pyridine.

The compounds of formula HET-OM and HET-SM can be prepared by one skilled in the art from the corresponding compounds of formula HET-OH or HET-SH using a suitable base such as sodium hydride, silver carbonate, carbonate or sodium alkoxide.

When X is -S-, a method analogous to (c) is used but using HET-SH and a compound of formula II wherein Yp is a suitable leaving group, wherein a suitable leaving group is, for example, mesylate and a suitable base for The reaction is a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (see, for example, Example 153).

(d) Reaction (d) is carried out using conditions analogous to those described in the following references, which describe how suitable and analogous starting materials can be obtained.

Compounds of formula Q-Zp wherein Zp is an isocyanate group can be prepared by one skilled in the art, for example, by methods analogous to those described by Walter A. Gregory et al. in J. Med. Chem. 1990, 33, 2569-2578 and Chung-Ho Park et al. in J. Med. Chem. 1992, 35, 1156-1165. Compounds of formula QZp wherein Zp is urethane (see process (i)) can be prepared by one skilled in the art, for example, by procedures analogous to those described in International Patent Application Nos. WO 97/30995 and WO 97/37980.

A similar reaction to reaction (d) may be carried out in which Q-Zp, where Zp is an amine group, reacts with the epoxide (preferably in the presence of an organic base) and reacts the product with, for example, phosgene to form an oxazolidinone ring. Such reactions and the preparation of starting materials can be determined by one of ordinary skill in the art having regard to the foregoing documents describing analogous reactions and preparations.

Epoxides of the formula _CH2 (O) _CH-CH2 O-HET may be prepared from corresponding compounds of formula _CH2 = _CH-CH2 -O-Het. Certain such epoxy and alkane intermediates are novel and are provided by methods that form a further feature of the present invention. For example, when HET is isoxazol-3-yl, 3- (2,3), (-) - - - - - - - - - - - 4-Oxiranpropyloxy) isoxazole can be prepared from 3-allyloxyisoxazole. Asymmetric epoxidation can be used to obtain the desired optical isomer.

(f) When X is -SO- or -SO2-, oxidation of the compound wherein X is -S- may be accomplished by standard reagents known in the art for oxidizing a thio group to a sulfinyl or sulfonyl group. For example, a thio group can be oxidized to a sulfinyl group by a peracid such as m-chloroperoxybenzoic acid and oxidizing agents such as potassium permanganate can be used to convert the thio group to a sulfonyl group.

(g) Conversion to a non-quaternary compound of a compound of formula I wherein the HET ring carries a quaternary nitrogen atom may be performed under thermal conditions suitable to eliminate the quaternary group (for example, a methyl group will be eliminated as a methyl halide).

A compound of formula I in which HET carries a quaternary nitrogen atom may be prepared in a manner similar to that described in reaction (c), but using a suitably quaternized HET compound substituted at the alpha position next to the nitrogen atom with a leaving group (such as a halogen atom) and a compound of formula (II) wherein Yp is -OH or -SH is used. Such starting materials are readily prepared by one skilled in the art.

A compound of formula I in which the HET ring carries a quaternary nitrogen atom can also be prepared in a similar manner as described in Chem. Pharm. Bull.

Japan, 27, 2415-2423, (1979) by reacting an N-alkylated HET-OH or HET-SH compound in a ketoform (with a keto group (oxo or thioxo) in the alpha position next to the nitrogen atom) with a compound of formula II wherein Yp is a leaving a group such as mesylate.

(h) If the HET ring is isoxazole, it may be prepared as a final step from a compound of formula II wherein Yp is -O-CH = N-OH by reaction under standard conditions with acetylene (see for example Acta Chem. Scand 47, 1004) , 1993).

(i) The compound of formula III is reacted with a compound of formula IV using conditions similar to those for the reaction of a compound of formula III with a compound of formula V described above. If not commercially available, suitable starting materials of formulas III and VI are prepared as described above or using analogous procedures.

Removal of any protecting group, formation of a pharmaceutically acceptable salt, and / or formation of an in vivo hydrolysable ester are procedures known to those skilled in the art. · ······

C7 ··· ·· · / · / ············· Details of these steps, for example the preparation of an in vivo hydrolysable ester prodrug, are given in the section relating to such esters or in certain non-limiting examples.

If an active form of a compound of formula I is desired, it can be obtained by one of the above methods using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step) or by resolution of the racemic form of the compound or intermediate using standard procedures or by chromatographic separation of stereoisomers arose). Enzymatic techniques can also be used to prepare optically active compounds / or intermediates.

Similarly, if a pure regioisomer of a compound of Formula I is desired, it can be obtained by performing one of the above procedures using the pure regioisomer as starting material or by resolving a mixture of regioisomers or intermediates using standard procedures.

In another aspect, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof, for use in a method of treatment of the human or animal body by therapy.

In another aspect, the present invention provides a method of obtaining an antibacterial effect in a warm-blooded animal such as a human in need of such treatment comprising administering to said animal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof.

The invention also provides a compound of Formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for use as a medicament; and the use of a compound of formula (I) of the invention or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof in the preparation of a medicament for obtaining an antibacterial effect in a warm-blooded animal such as a human.

For use, a compound of Formula I, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, including a pharmaceutically acceptable in vivo hydrolysable ester salt (above in this section relating to the pharmaceutical composition "compound of the invention" or "compound of the present invention" ') For therapeutic (including prophylactic) treatment of mammals, including humans, in particular for the treatment of infections, is formulated according to standard pharmaceutical practice as a pharmaceutical composition.

• · t · cp. · · · · · · · · · · · · · · · · · · · · · · 9 · 9 9 9 9 9 9 9 · ·

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, an in vivo hydrolysable ester or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable in vivo hydrolysable ester, and a pharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions of the present invention may be administered by standard methods for the disease state to be treated, for example, orally, rectally or parenterally. For this purpose, the compounds of the invention may be formulated in known manner into tablets, capsules, aqueous or oily solutions or suspensions of (lipid) emulsions, dispersible powders, suppositories, ointments, creams, aerosols (or sprays), drops and sterile injectable aqueous or oily solutions or suspensions.

In addition to the compounds of the present invention, the pharmaceutical composition of the invention may also contain, or be administered (simultaneously, sequentially or separately) one or more drugs selected from other clinically used antibacterial agents (e.g. β-lactams or aminoglycosides) and / or other drugs. anti-infective agents such as antifungal triazole or amphotericin). Carbapenems such as meropenem or imipenem may be included to extend the therapeutic effect. The compounds of the invention may also contain or be administered with bactericidal / permeabilt enhancing protein (BPI) products or effluent pump inhibitors to improve efficacy against gram-negative bacteria and bacteria resistant to antimicrobial agents.

A suitable pharmaceutical composition of the present invention is a composition suitable for oral administration in unit dosage form, such as a tablet or capsule, containing between 1 mg and 1 g of a compound of the invention, preferably between 100 mg and 1 g of a compound. Especially preferred is a tablet or capsule containing between 50 mg and 800 mg of a compound of the invention, in particular in the range 100 mg to 500 mg.

In another aspect, the pharmaceutical composition of the invention is suitable for intravenous, subcutaneous or intramuscular injection, for example an injection that contains between 0.1% w / v and 50% w / v (between 1 mg / ml and 500 mg / ml). ) of a compound of the invention.

For example, each patient may receive a daily dose of 0.5 mgkg ^-1 to 20 mgkg ^{-1 of the} compound of the invention intravenously, subcutaneously or intarmuscularly, wherein the composition is administered 1 to 4 times daily. In another embodiment, a daily dose of 5 mgkg ^-1 to 20 mgkg ^{-1 of a} compound of the invention may be administered daily. An intravenous, subcutaneous or intramuscular dose may be given as a bolus injection. Alternatively, the intravenous dose may be administered over a period of time as a continuous infusion.

Alternatively, each patient may receive an oral dose daily, which may be approximately equivalent to a daily parenteral dose, wherein the composition is administered 1 to 4 times daily.

The pharmaceutical composition to be dosed intravenously may advantageously contain (for example, in order to increase stability) suitable bactericides, antioxidants or reducing agents or masking agents.

In addition to the aforementioned pharmaceutical composition, process, method, use and preparation of a medicament, alternative and preferred embodiments of the compounds of the invention may be used.

Antibacterial efficacy

The pharmaceutically acceptable compounds of the present invention are useful antibacterial agents having a good spectrum of in vitro activity against standard gram positive organisms that are used against pathogenic bacteria. In particular, the pharmaceutically acceptable compounds of the invention are active against enterococci, pneumococci and methicillin-resistant S. aureus strains and coagulase-negative staphylococci. The antibacterial spectrum and potency of particular compounds can be determined by a standard assay system.

The (antibacterial) properties of the compounds of the invention can be demonstrated and investigated in vivo by conventional assays, for example, by oral and / or intravenous dosing of the compound to warm-blooded mammals, using standard techniques.

The following results were obtained using a standard in vitro test system. The activity is described in terms of the minimum inhibitory concentration (MIC) determined by the 10 ⁴ CFU / spot inoculum agar dilution technique. Typically, the compounds are active in the range of 0.01 to 0.26 pg / ml.

Staphylococci were tested on agar using a 10 ⁴ / spot stain and incubation temperature of 37 ° C for 24 hours - standard test conditions for expressing resistance to methicillin.

Streptococci and enterococci were tested on agar supplemented with 5% defibrinated horse blood using a 10 ⁴ CFU / spot inoculum and an incubation temperature of 37 ° C in a 5% carbon dioxide atmosphere. 48 hours - blood is required for growth of some test organisms.

Organism_____MIC (u / ml)

Example 4 Example 12 Example 18 Example 151

Staphylococcus aureus:

Oxford 0.25 0.25 0.25 0.13 Novb. res. 0.50 0.5 0.25 0.25 MRQR 0.50 0.5 0.5 0.25 Coagulase-negative staphylococcus MS 0.13 0.13 0.13 0.13 MR 0.50 0.5 0.5 0.25 Streptococcus pyogenes C203 0.50 0.5 0.25 0.25 Enterokokus faceaiis 1.00 1.00 0.5 0.25 Bacillus subtilis 0.25 0.25 0.25 0.13

Nov. Res = Novobiocin resistant

MRQR = methicillin resistant quinolone resistant MR = methicillin resistant

MS = methicillin sensitive

The compounds described in certain Reference Examples (e.g., Reference Examples 9, 10, 11, 30, 38 and 39) may also show useful activity.

The invention is now illustrated by the following examples, which are illustrative only and in no way limit the scope of the invention. Unless otherwise stated, the following examples apply:

(i) evaporation is carried out on a rotary evaporator under vacuum and treatment is carried out after removal of residual solids by filtration;

(ii) the operations are carried out at ambient temperature, i.e. typically in the range of 18 to 26 ° C and in air, unless otherwise indicated or when the person skilled in the art is operating in an inert atmosphere;

(iii) column chromatography (flash) is used to purify the compounds and, unless otherwise stated, is carried out on Merck Kieselgel (Art.

9385);

(iv) yields are given for illustration only and are not necessarily as high as possible;

(v) the structure of the final products of formula I was generally confirmed by NMR and mass spectral techniques [proton magnetic resonance spectra were generally determined in DMS0-D6 unless otherwise specified using a Varian Gemini 2000 fixed-field spectrometer 300 MHz or a Bruker AM250 spectrometer operating 250 MHz fixed field; chemical shifts are reported in parts per million downfield from tetramethylsilane as the internal standard (δ scale) and peak multiplicities are reported as follows: s, singlet; d, doublet; AB or dd, doublet of doublets; t, triplet; m, multiplet; fast atom bombardment (FAB) spectra were obtained using a Platform Spectrometer (supplied by Micromass) operating in electron sputtering and, if appropriate, positive ion data or negative ion data were collected];

(vi) intermediates are generally not fully characterized and purity is generally determined by thin layer chromatography, infrared spectroscopy (IR), mass spectral (MS), or NMR analysis; and (vii) the following abbreviations may be used:

® is a trademark; DMF is Ν, Ν-dimethylformamide; DMA is N, N-dimethylacetamide; TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; DMSO is dimethylsulfoxide; CDCl 3 is deuterated chloroform; MS is mass spectroscopy; ESP is electron spraying; THF is tetrahydrofuran; TFA is trifluoroacetic acid; NMP is N-methylpyrrolidone; HOBT is 1-hydroxybenzotriazole; EtOAc is ethyl acetate; MeOH is methanol; phosphoryl is (HO) 2 -P (O) -O-; phosphiryl is (HO) 2P-O-; EDC is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (hydrochloride); PTSA is p-toluenesulfonic acid.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

5 (R) -1xoxazol-3-yloxymethyl-3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2-one

248 mg (1.22 mmol) of diisopropyl azodicarboxylate are added dropwise at ambient temperature to a stirred solution of 300 mg (1.02 mmol) of 5 (R) -hydroxymethyl-3- (3-fluoro-4- (3,6-dihydro- (2H) (pyran-4-yl) phenyl) oxazolidin-2-one (International Patent Application No. WO 97/09328), 104 mg (1.22 mmol) of 3-hydroxyisoxazole and 340 mg (1.30 mmol) of triphenylphosphine in 8 1.0 ml THF. The resulting solution was stirred at ambient temperature for 30 minutes and the solvent was evaporated to give an oil which was purified by flash chromatography (Merck silica gel 9385, eluent EtOAc / isohexane (7: 3)) to give 219 mg (59%) of the title compound. as a crystalline solid.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.45-2.55 (m, 2H), 3.88-4.00 (m, 3H), 4.17 (t, 1H),

4.33 (m, 2H), 4.50 (dd, 1H), 4.58 (dd, 1H), 5.04 (m, 1H), 6.01 (d, 1H), 6.06 (m 1 H, 7.22-7.32 (m, 2H), 7.42 (d, 1H), 8.15 (d, 1H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 361.

Example 2

5 (R) - (5-Methylisoxazol-3-yloxymethyl) -3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2-one

300 mg (1.02 mmol) of 5 (R) -hydroxymethyl-3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2-one, 120 mg ( 1.21 mmol) of 3-hydroxy-5-methylisoxazole, 270 mg (1.03 mmol) of triphenylphosphine and 204 mg (1.01 mmol) of diisopropylazodicarboxylate were reacted in 8.0 mL of THF using the general method of Example 1. The resulting product Purification by flash chromatography (Merck silica gel 9385, eluent EtOAc / isohexane (7: 3)) afforded 176 mg (46%) of the title compound as a crystalline solid. ¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.34 (s, 3H), 2.45-2.55 (m, 2H), 3.86-4.00 (m, 3H),

4.14 (t, 1H), 4.32 (m, 2H), 4.46 (dd, 1H), 4.54 (dd, 1H), 5.02 (m, 1H), 5.65 (s) 1 H, 6.05 (m, 1 H), 7.20-7.32 (m, 2 H), 7.42 (d, 1 H).

· · · * * * * * * * * *

MS: ESP + (M + H) ⁺ = 375.

Reference Example 1

3,5-Difluoro-4- (1-benzyl-4-hydroxyhexahydropyrid-4-yl) aniline

350 ml (1.32 M in hexanes, 0.462 mol) of nBuLi are added dropwise over 20 minutes at -70 ° C under argon to a solution of 108.4 g (0.40 mol, J. Org. Chem. 60, 52555261 (1995) N, N- (1,2-bis (dimethylsilyl) ethane) -3,5-difluoroaniline in 800 mL dry THF. The mixture was stirred at -70 ° C for 4 hours, and 87.8 g (0.46 mol) of N-benzyl-4-piperidone in 270 mL of dry THF was added dropwise over the course of 40 minutes, and the mixture was stirred at ambient temperature. overnight. The solvent was removed in vacuo and the resulting product was treated with ice and concentrated HCl and extracted with ether. The aqueous acidic phase is then treated with 40% NaOH with cooling, extracted with ether (and further treated with water, brine and dried with anhydrous desiccant such as magnesium sulfate or sodium sulfate and evaporated - hereinafter referred to as &quot; usual work up) and 144.7 g of sludge are obtained. TLC analysis using 10% MeOH / dichloromethane on silica gel showed that the desired alcohol was obtained as an approximately 90% product and the crude product was used without further purification.

MS: ESP <+> (M + H) = 319.

Reference Example 2

3,5-Difluoro-4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) aniline

144.7 g of the crude product from Reference Example 1 was suspended in 400 ml of concentrated HCl and heated under reflux for 18 hours. TLC analysis showed that all the starting material had reacted and, after cooling with ice, the pH of the reaction mixture was adjusted to 11 with concentrated NH ₃ (aq) and extracted three times with dichloromethane. The usual work-up gives 119.5 g of a viscous oil.

TLC analysis showed 80% purity of the product which was used without further purification. MS: ESP <+> (M + H) = 301.

• ·

Reference Example 3

N-Benzyloxycarbonyl-3,5-difluoro-4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) aniline

3.2 g (10.7 mmol) of crude aniline from Reference Example 2 in 10 ml of acetone was added in one portion to a stirred solution of 3.0 g of sodium dihydrogen phosphate in 30 ml of water. The resulting mixture was cooled to 5-10 ° C and a solution was added dropwise

2.18 g (1.8 mL, 12.8 mmol) of benzyl chloroformate in 10 mL of acetone. The mixture was stirred for an additional hour at an ice bath temperature and then at ambient temperature for 2 hours. The mixture was diluted with 80 mL of water, basified with concentrated NH 3 (aq) and extracted with EtOAc. Conventional work-up gave a viscous oil which was purified by flash chromatography (Merck silica gel 9385, EtOAc / isohexane (3: 7) eluant) and triturated with isohexane to give

1.53 g (33%) of a solid.

MS; ESP + (M + H) = 434.

Reference Example 4

5 (R) -Hydroxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

5.54 g (12.76 mmol) of benzylurethane from Reference Example 3 are dissolved in 50 ml of dry THF, cooled to -70 ° C under nitrogen and treated dropwise at the same temperature with 8.80 ml of 1.6 M nBuLi in hexanes (14, 08 mmol). After 20 minutes, a solution of (R) -glycidyl butyrate (2.00 g, 13.88 mmol) in THF (5 mL) was added dropwise at the same temperature, and the mixture was stirred at -70 ° C for 30 minutes and then at room temperature overnight. After cooling with 100 ml of 10% ammonium chloride, the mixture was extracted with EtOAc and the usual work-up gave an oily solid which was purified by flash chromatography (Merck silica gel 060, eluent 5% MeOH / dichloromethane) to give 4.40 g (86%). crystalline solids.

MS; ESP @ + (M + H) = 401.

¹ H-NMR (250MHz, DMSO-d _s); δ = 2.32 (m, 2H), 2.63 (t, 2H), 3.05 (m, 2H), 3.50 3.72 (m, 4H), 3.82 (dd, 1H), 4.06 (t, 1 H), 4.73 (m, 1 H), 5.18 (t, 1 H), 5.78 (m, 1 H).

Reference Example 5

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

2.6 g (6.5 mmol) of the compound of Reference Example 4, 0.60 g (7.06 mmol) g of 3-hydroxyisoxazole, 1.96 g (7.48 mmol) of triphenylphosphine and 1.44 g (7.13 mmol) The diisopropyl azodicarboxylate in 40 ml of THF was reacted using the general method of Example 1. The resulting product was purified by flash chromatography (Merck silica gel 9385, eluent EtOAc / isohexane (3: 2) immediately, then repeated using tert-butyl ether as eluent) and 2.6 g (86%) of the title product are obtained as a gum.

MS: ESP + (M + H) + = 468.

Reference Example 6

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

2.6 g (5.57 mmol) of the compound of Reference Example 5 in 40 ml of dichloromethane was cooled under nitrogen in an ice bath and then 0.80 g (5.59 mmol) of 1-chloroethyl chloroformate was added dropwise via syringe. The resulting solution was stirred at ice temperature for 1 hour, and then the intermediate (carbamate) was isolated by flash chromatography (Merck silica gel 9385, eluent EtOAc / isohexane (1: 1). The resulting gum was transferred to 40 mL MeOH and heated to reflux. After 1 hour evaporation of the solvent, 1.46 g (64%) of the title compound was obtained as a crystalline solid.

¹ H-NMR (300MHz, DMSO-d _s): δ = 2.54 (m, 2H), 3.27 (m, 2H), 3.72 (m, 2H), 3.92 (dd, 1H) 4.20 (t, 1H), 4.38-4.52 (m, 2H), 5.10 (m, 1H), 5.88 (m, 1H), 6.38 (d, 1H), 7.37 (m, 2H), 8.68 (d, 1H), 9.39 (s (broad), 2H).

MS: ESP + (M + H) + = 378.

Example 3 «· · · ·············

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolane-4 (R, S) -ylcarbonyl) 1,2,5,6-tetrahydropyridine) -4-yl) -3,5-difluorophenyl) oxazolidin-2-one

160 mg (0.84 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added dropwise at ambient temperature to a stirred mixture of 300 mg (0.72 mmol) of the compound of Reference Example 6, 122 mg (0.84 mmol). mmol) of (R / S) -2,3-O-isopropylidene glyceric acid and 73 mg (0.72 mmol) of triethylamine in 6 ml of dichloromethane. The resulting mixture was stirred for 3 hours and then allowed to stand overnight and washed with water.

The dichloromethane solution was purified by flash chromatography (Merck silica gel 9385, eluent EtOAc / isohexane (3: 1)) to give 143 mg (39%) of the title compound as a crystalline solid.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 506.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 1.41 (s, 6H), 2.35-2.65 (m, 2H), 3.65-3.80 (m, 1H),

3.92-4.00 (m, 2H), 4.10-4.22 (m, 3H), 4.22-4.45 (m, 1H), 4.45-4.62 (m, 3H) ), 4.75 (t, 1H), 5.05 (m, 1H), 5.80-5.91 (m, 1H), 6.01 (d, 1H), 7.18 (m, 2H) 8.16 (d, IH).

Example 4

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2- (R, S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5- difluorophenyl) oxazolidin-2-one

194 mg (0.38 mmol) of the compound of Example 3 in a mixture of 3 mL of THF and 1 mL of 1N hydrochloric acid was allowed to stand at ambient temperature for 4 days. Then the solvent was evaporated to give an oil which was purified by flash chromatography (Merck silica gel 9385, eluent 10% MeOH / dichloromethane) to give 144 mg (80%) of the title compound as a crystalline solid.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 466.

@ ¹ H-NMR (300 MHz, DMSO-d6): _.delta . = 2.20-2.46 (m, 2H), 3.40-3.63 (m, 2H), 3.63 3.85 (m, 2H), 3.92 (dd, IH), 4.10 (m, IH), 4.18 (t, IH), 4.26-4.52 (m, IH), 4.68 (m, IH) ), 4.96 (m, 1H), 5.10 (m, 1H), 5.86 (m, 1H), 6.37 (d, 1H), 7.34 (m, 2H), 8.68 (d,

2H).

Example 5 • ·

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1-formyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

300 mg (0.72 mmol) of the compound of Reference Example 6 and 102 mg (1.01 mmol) of triethylamine in 10 ml of ethyl formate were stirred for 12 hours and then the mixture was evaporated to give an oil which was purified by flash chromatography (Merck 9385 silica gel). eluent 4% MeOH / dichloromethane) to give 261 mg (89%) of the title compound as a crystalline solid.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.18 & 2.37 (2s, 2H), 3.20-3.40 (m (partially unclear), 2H), 3.57-3.66 (m, 2H), 3.92 (m, 1H), 4.05 & 4.10 (2m, 2H), 4.20 (t, 1H), 4.38-4.54 (m, 2H), 5.10 (m, 1H), 5.86 & 5.90 (2m, 1H), 6.37 (d, 1H), 7.32 (m, 2H), 8.10 & 8.18 (2s, 1H), 8.68 (d, 1H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 406.

Example 6

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

400 mg (0.97 mmol) of the compound of Reference Example 6, 205 mg (2.03 mmol) of triethylamine and 30 mg of 4- (dimethylamino) pyridine in 10 ml of dichloromethane were cooled in an ice-water bath and then added after drops of syringe 145 mg (1.06 mmol) of acetoxyacetyl chloride. The mixture was stirred at ice temperature for 2 hours and then purified by flash chromatography (Merck silica gel 9385, eluent 2.5% MeOH / dichloromethane) to give 430 mg (93%) of the title compound as a crystalline solid.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.20 (s, 3H), 2.40-2.56 (m, 2H), 3.59 (t, 1H), 3.82 (t, 1H), 3.95 (dd, 1H), 4.08 & 4.25 (2m, 2H), 4.12 (t, 1H), 4.50 (dd, 1H), 4.58 (dd, 1H) ), 4.74 & 4.78 (2s, 2H), 5.05 (m, 1H), 5.80 & 5.88 (2m, 1H), 6.00 (d, 1H), 7.19 ( m, 2H), 8.17 (d, IH).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 478.

Example 7 • 0 0

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

280 mg (0.59 mmol) of the compound of Example 6 and 150 mg (1.09 mmol) of potassium carbonate in 6 mL of MeOH were stirred at ambient temperature for 4 hours. Add 30 mL of water to give a crystalline solid, which is filtered, washed with water and dried to give 215 mg (84%) of the title compound.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 436.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.22-2.42 (m, 2H), 3.52 (m, 1H), 3.68 (m, 1H),

3.92 (dd, 1H); 4.00-4.24 (m, 5H); 4.40-4.52 (m, 2H); 4.52-4.76 (m, 1H); 10 (m, 1H), 5.86 (m, 1H), 6.36 (d, 1H), 7.35 (m, 2H), 8.68 (d, 2H).

Reference Example 7

5 (R) -Hydroxymethyl-3- (4- (4- (5-cyanopyrid-2-yl) piperazin-1-yl) -3-fluorophenyl) oxazolidin-2-one

43.1 g (0.11 M) of 5 (R) -hydroxymethyl-3- (3-fluoro-4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl) oxazolidin-2-one (international patent application WO 93/23384 ) was suspended by stirring in 1000 ml of ethanol under nitrogen. 400 ml (3.8 M) of ethanolic hydrogen chloride solution are then added slowly and the mixture is stirred at ambient temperature for 18 hours. The resulting precipitate was filtered, washed with diethyl ether (3 x 250 mL) and dried to give 5 (R) -hydroxymethyl-3- (3-fluoro-4- (piperazin-1-yl) phenyl) oxazolidin-2- hydrochloride. onu. A further portion was obtained by evaporation of the mother liquors to give a total of 38.7 g.

¹ H-NMR (300MHz, DMSO-d ₆ ) δ: 3.17 (m, 8H); 3.53 (dd, IH); 3.64 (dd, IH); 3.79 (dd, IH); 4.03 (t, IH); 4.66 (m, IH); 7.10 (t, 1 H); 7.21 (dd, IH); 7.52 (dd, IH); 9.39 (brs, 2H).

MS: ESP + (M + H) &lt; + & gt ^; = 296.

g (75.4 mmol) of 5 (R) -hydroxymethyl-3- (3-fluoro-4- (piperazin-1-yl) phenyl) oxazolidin-2-one hydrochloride was suspended by stirring in 700 ml of acetonitrile under nitrogen.

and 16.8 g (166 mmol) of triethylamine are added. The mixture was stirred for 10 minutes, then 10.3 g (75.4 mmol) of 2-chloro-5-cyanopyridine was added and the mixture was heated under reflux for 18 hours. After cooling, the resulting solid was filtered, washed with water (3 x 500 mL) and diethyl ether to give 5 (R) -hydroxymethyl-3- (4- (4- (5-cyanopyrid-2-yl) piperazin-1-yl)) -3-fluorophenyl) oxazolidin-2-one. A further portion of the product was obtained by evaporation of the mother liquors to give a total of 23.2 g of product.

MS: ESP + (M + H) &lt; + & gt ^; = 398.

¹ H-NMR (300MHz, DMSO-d ₆ ) δ: 3.03 (t, 4H); 3.54 (m, IH); 3.63 (m, IH); 3.78 (t overlapping, 5H); 4.03 (t, IH); 4.66 (m, IH); 5.18 (t, 1 H); 6.97 (d, IH); 7.07 (t, 1 H); 7.20 (dd, IH); 7.53 (dd, IH); 7.85 (dd, IH); 8.49 (d, IH).

Example 8

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (4- (5-cyanopyrid-2-yl) piperazin-1-yl) -3-fluorophenyl) oxazolidin-2-one

397 mg (1 mmol) of the compound of Reference Example 7, 85 mg (1.1 mmol) of 3-hydroxyisoxazole and 416 mg of polymer-bound triphenylphosphine (3 mmol / g, 1.25 mmol) were suspended in 10 ml of dry THF under stirring. 242 mg (1.2 mmol) of diisopropyl azodicarboxylate was added dropwise via syringe and the mixture was stirred at ambient temperature for 1 hour. The mixture was filtered, evaporated to dryness and dissolved in EtOAc and purified by chromatography (on 10 g silica gel, Mega Bond Elut® column, eluting with a gradient of increasing polarity from 80 to 100% EtOAc in isohexane) to give 93 mg the title compounds.

MS: ESP +: (M + H) &lt; + & gt ^; = 465.

¹ H-NMR (300MHz, DMSO-d ₆ ) δ: 3.06 (t, 4H); 3.80 (t, 4 H); 3.87 (dd, IH); 4.16 (t, IH); 4.42 (dd, IH); 4.48 (dd, IH); 5.04 (m, IH); 6.37 (d, IH); 6.97 (d, IH); 7.08 (t, 1 H);

7.20 (dd, IH); 7.51 (dd, IH); 7.86 (dd, IH); 8.49 (d, IH); 8.67 (d, IH).

Example 9

5 (R) -lsothiazol-3-yloxymethyl-3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2-one

227 mg (1.12 mmol) of diisopropyl azodicarboxylate was added dropwise at ambient temperature to a stirred solution of 300 mg (1.02 mmol; see Example 1) of 5 (R) -hydroxymethyl-3- (3-fluoro-4- (3,6- dihydro- (2H) -pyran-4-yl) phenyl] oxazolidin-2-one, 114 mg (1.13 mmol) of 3-hydroxyisothiazole and 304 mg (1.16 mmol) of triphenylphosphine in 8 mL of THF, and the resulting solution was stirred at room temperature for 30 min. This oil was purified by flash chromatography (Merck silica gel 9385, eluent EtOAc / isohexane (7: 3)) to give 257 mg (67%) of the title compound as a colorless crystalline solid. substance.

MS: ESP + (M + H) + = 377.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.45-2.55 (m, 2H), 3.94 (t, 2H), 3.98 (dd, 1H), 4.14 (t, 1H), 4.32 (m, 2H), 4.61 -4.72 (m, 2H), 5.04 (m, 1H), 6.07 (m, 1H), 6.62 (d, 1H) 7.22 - 7.30 (m, 2H), 7.42 (dd, 1H), 8.48 (d, 1H).

Example 10

5 (R) - (1,2,5-Thiadiazol-3-yloxymethyl) -3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2-one

Solution 0.275 g (0.93 mmol; see Example 1) 5 (R) -Hydroxymethyl-3- (3-fluoro-4- (3,6-dihydro- (2H) -pyran-4-yl) phenyl) oxazolidin-2- one, 0.112 g (1.1 mmol) of 3-hydroxy-1,2,5-thiadiazole (Weinstock et al., J. Org. Chem. 32, 2823 (1967)) and 0.288 g (1.1 mmol) of triphenylphosphine are stirred at room temperature in dry THF and then 0.22 g (1.1 mmol) of diisopropyl azodicarboxylate in 1.0 ml dry THF are added dropwise over 10 minutes. After 1.5 hours, TLC (70% EtOAc / isohexane) showed essentially complete reaction. The reaction mixture was evaporated in vacuo and purified by chromatography (Merck silica gel 9385, eluent 50% EtOAc / isohexane) to give 256 mg (73%) of the title compound as a colorless solid, mp 46-48 ° C.

¹ H-NMR (300MHz, DMSO-d _s): δ = 2.40 (m, 1H), 3.78 (m, 3H), 3.96 (dd, 1H), 4.20 (m, 3H) 4.64 (m, 2H); 5.10 (m, 1H); 6.08 (s, 1H); 7.35 (m, 2H); 7.50 (d, 1H); s, 1H). MS: ESP + (M + H) + = 377.

Reference Example 8

5 (R) - (1,2,5-Thiadiazol-3-yloxymethyl) -3-phenyloxazolidin-2-one

4.45 g (22 mmol) of diisopropyl azodicarboxylate was added dropwise to a stirred solution of 4.25 g (22 mmol) of 5 (R) -hydroxymethyl-3-phenyloxazolidin-2-one (Gregory et al., J. Med. Chem. 32, 1673 (1989), 5.76 g (22 mmol) triphenylphosphine and 2.04 g (20 mmol) 3-hydroxy-1,2,5-thiadiazole (Weinstocka et al., J. Org. Chem., 32 , 2823 (1967)) in 30 ml THF, in an ice bath, stirred at ambient temperature for two hours and then evaporated in vacuo and the resulting oil purified by chromatography (Merck silica gel 9385). Further purification by silica gel flash chromatography using 1% MeOH / dichloromethane required to remove diisopropylcarboxyhydrazine residues yielded 4.7 g (83%) of the title compound as a white crystalline product.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 278.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 4.0 (dd, 1H), 4.21 (t, 1H), 4.6-4.77 (m, 2H), 5.04 (m, 1H), 7.17 (t, 1H), 7.39 (m, 2H), 7.56 (d, 2H), 8.0 (s, 1H).

Reference Example 9

5 (R) - (1,2,5-Thiadiazol-3-yloxymethyl) -3- (4-iodophenyl) oxazolidin-2-one

Silver trifluoroacetate (0.727 g, 3.29 mmol) was added to a stirred solution of Reference Example 8 (0.70 g, 2.53 mmol) in chloroform / acetonitrile (6 mL / 4 mL) at ambient temperature. 0.67 g (2.64 mmol) of iodine is then added in portions. The resulting brown mixture was stirred in the dark for 65 hours. The yellow solid was filtered off and washed with chloroform. The filtrate was washed and evaporated in vacuo, the residue redissolved in EtOAc and washed with dilute ammonium hydroxide, water and brine. After drying over sodium sulfate and evaporation in vacuo, a pale yellow solid was obtained on standing. Trituration with ether gave 0.749 g (73%) of the title compound as an off-white product.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 3.95 (dd, 1H), 4.19 (t, 1H), 4.67 (m, 2H), 5.1 (m, 1H) 7.37 (d, 2H); 7.69 (d, 2H); 8.4 (s, 1H).

MS: ESP + (M + H) &lt; + & gt ^; = 404.

Reference Example 10

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

Prepared according to the general method of Example 1, starting from 4.0 g (10.5 mmol) of 5 (R) -hydroxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyridine-4-one)). yl) -3-fluorophenyl) oxazolidin-2-one (WO 97/30995), 1.0 g (11.8 mmol)

3-hydroxyisoxazole, 3.24 g (12.4 mmol) of triphenylphosphine and 2.36 g (11.7 mmol) of diisopropyl azodicarboxylate in 60 ml of tetrahydrofuran. Purification by flash chromatography (Merck silica gel 9385; tert-butyl methyl ether / EtOAc / MeOH (70: 30: 0.5) eluent) afforded 3.0 g (64%) of the product as a colorless crystalline solid. MS: ESP ⁺ (M + H) &lt; + & gt ^; = 450.

Reference Example 11

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

Prepared according to the general method of Reference Example 6, using 7.09 g (15.8 mmol) of the compound of Reference Example 10 and 2.26 g (15.8 mmol) of 1-chloroethyl chloroformate in 120 ml of dichloromethane. This afforded 3.71 g (59%) of the product as a pale yellow crystalline solid.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 360.

¹ H-NMR (300MHz, DMSO-d ₆ ): d = 2.64 (m, 2H), 3.22-3.30 (m, 2H), 3.72 (m, 2H),

3.92 (dd, 1 H), 4.21 (t, 1 H), 4.40-4.55 (m, 2 H), 5.10 (m, 1 H), 6.02 (m, 1 H), 6 , 38 (d,

1H), 7.32-7.44 (m, 2H), 7.52 (d, 1H), 8.68 (d, 1H), 9.30 (s (br), 2H).

Example 11

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolan-4 (S) -ylcarbonyl) 1,2,5,6-tetrahydropyrid-4) -yl) -3-fluorophenyl) oxazolidin-2-one

550 mg (2.67 mmol) of 1,3-dicyclohexylcarbodiimide is added in one portion at room temperature to a stirred solution of 390 mg (2.67 mmol) of (S) -2,3-isopropylidene glyceric acid and 410 mg (2.58 mmol) of 1. -hydroxybenzotriazole in 10 ml of dichloromethane. The resulting suspension was stirred for 1 hour and then an additional 10 mL of dichloromethane was added followed by 1.0 g (2.53 mmol) of the compound of Reference Example 11 and 326 mg (2.53 mmol) of N, N-diisopropylethylamine. The reaction mixture was stirred at ambient temperature for 18 hours and filtered. The filtrate was washed with water (2x) and brine and purified by flash chromatography (Merck silica gel 9385; eluent 2% MeOH in dichloromethane) to give 754 mg (61%) of the product as a colorless crystalline solid.

MS: ESP + (M + H) + = 488.

¹ H-NMR (300MHz, CDCl ₃ ): d = 1.44 (s, 6H), 2.45-2.72 (m, 2H), 3.62-3.76 (m, 1H), 3, 89-4.05 (m, 2H), 4.10-4.20 (m, 3H), 4.24-4.38 (m, 1H), 4.44-4.62 (m, 3H),

4.75 (m, 1 H), 5.04 (m, 1 H), 5.97 (m, 1 H), 6.00 (d, 1 H), 7.25 (m, 2 H), 7.45 (d) (1H),

8.15 (d, IH).

Example 12

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidine -2-on

Prepared according to the general method of example 4, using 754 mg (1.55 mmol) of the compound of Example 11 in a mixture of 15 mL of THF and 5 mL of 1N hydrochloric acid. Purification by flash chromatography (Merck 9385 silica; eluent of 10% MeOH in dichloromethane) gave 486 mg (70%) of product as a colorless crystalline solid, m.p. 140-143 ° C ¹ H-NMR (300MHz, DMSO-d _s): d = 2.42 (m, 2H), 3.40-3.60 (m, 2H), 3.62-3.85 (m, 2H), 3.92 (dd, 1H), 4.10- 4.30 (m, 3H), 4.30-4.56 (m, 3H), 4.79 (m, 1H), 4.94 (m, 1H), 5.09 (m, 1H), 6 00 (m, 1H), 6.37 (d, 1H), 7.28-7.44 (m, 2H), 7.50 (d, 1H), 8.66 (d, 1H).

MS: ESP + (M + H) + = 448.

HPLC: Chiralpak AD (250 mm x 4.6 mm, ID), eluent 100% MeOH, flow rate 1 mL / min, retention time = 42.5 min.

Example 13

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolane-4 (R) -ylcarbonyl) 1,2,5,6-tetrahydropyrid-4) Prepared according to the general method of Example 11, using 390 mg (2.67 mmol) of (R) -2,3-O-isopropylidene glyceric acid, 410 mg (2-chloro-3-fluoro-phenyl) -oxazolidin-2-one. 58 mmol) of 1-hydroxybenzotriazole, 550 mg (2.67 mmol) of dicyclohexylcarbodiimide, 1.0 g (2.53 mmol) of the compound of Reference Example 11a and 326 mg (2.53 mmol) of diisopropylethylamine in 20 ml of dichloromethane. Purification by flash chromatography (Merck silica gel 9385; eluent 2% MeOH in dichloromethane) afforded 682 mg (55%) of the product as a colorless crystalline solid.

MS; ESP * (M + H) &lt; + &gt; = 488.

¹ H-NMR (300MHz, CDCl ₃ ): d = 1.44 (s, 6H), 2.45-2.72 (m, 2H), 3.62-3.76 (m, 1H), 3, 89-4.05 (m, 2H), 4.10-4.20 (m, 3H), 4.24-4.38 (m, 1H), 4.44-4.62 (m, 3H),

4.75 (m, 1 H), 5.04 (m, 1 H), 5.97 (m, 1 H), 6.00 (d, 1 H), 7.25 (m, 2 H), 7.45 (d) (1H),

8.15 (d, IH).

Example 14

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidine -2-on

Prepared according to the general method of example 12, using 682 mg (1.40 mmol) of the compound of Example 13 in a mixture of 15 mL of THF and 5 mL of 1N hydrochloric acid. Purification by flash chromatography (Merck 9385 silica gel; 10% MeOH in dichloromethane eluent) afforded 466 mg (74%) of the product as a colorless crystalline solid; mp 136-140 ° C.

¹ H-NMR (300MHz, DMSO-d ₆ ): d = 2.42 (m, 2H), 3.40-3.60 (m, 2H), 3.62-3.85 (m, 2H), 3.92 (dd, 1H), 4.10-4.30 (m, 3H), 4.30-4.56 (m, 3H), 4.79 (m, 1H), 4.94 (m,

1H), 5.09 (m, 1H), 6.00 (m, 1H), 6.37 (d, 1H), 7.28-7.44 (m, 2H), 7.50 (d, 1H) 8.66 (d, 1 H).

MS: ESP + (M + H) + = 448.

ΦΦ φ φ Φ * * * φ φ »» »» »φ φ φ · · · · φ · · * * * * φ φ · φ φ

HPLC: Chiralpak AD (250 mm x 4.6 mm, ID), eluent 100% MeOH, flow rate 1 mL / min, retention time = 18.5 min.

Example 15

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolan-4 (R) -ylcarbonyl) 1,2,5,6-tetrahydropyridine) -4-yl) -3,5-difluorophenyl) oxazolidin-2-one

315 mg (1.53 mmol) of 1,3-dicyclohexylcarbodiimide is added in one portion at ambient temperature to a stirred mixture of 660 mg (1.45 mmol) of the compound of Reference Example 6, 240 mg (1.64 mmol) of (R) -2, Of 3-O-isopropylidene glyceric acid and 115 mg (1.45 mmol) of pyridine in 15 mL of dichloromethane. The resulting mixture was stirred at ambient temperature for 18 hours and then purified by flash chromatography (Merck silica gel 9385; EtOAc / isohexane (3: 1) eluent) to give 315 mg (43%) of the product as a colorless crystalline solid.

Example 16

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (R), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin -2-on

Prepared according to the general method of example 14, using 315 mg (0.62 mmol) of the compound of Example 15 in a mixture of 6 mL of THF and 2 mL of 1N hydrochloric acid. Purification by flash chromatography (Merck silica gel 9385; eluent 10% MeOH in dichloromethane) afforded 208 mg (72%) of the product as a colorless crystalline solid; mp 128-134 ° C.

¹ H-NMR (300MHz, _DMSO-d): d 2.20 to 2.46 (m, 2H), 3.40 to 3.63 (m, 2H), 3.63 3.85 (m, 2H ), 3.92 (dd, 1H), 4.10 (m, 1H), 4.18 (t, 1H), 4.26-4.52 (m, 1H), 4.68 (m, 1H) 4.96 (m, 1 H), 5.10 (m, 1 H), 5.86 (m, 1 H), 6.37 (d, 1 H), 7.34 (m, 2 H), 8.68 ( d,

2H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 466.

HPLC: Chiralpak AD (250 mm x 4.6 mm, ID), eluent 100% MeOH, flow rate 1 mL / min, retention time = 11.2 min.

• · ···················

Example 17

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolane-4 (S) -ylcarbonyl) 1,2,5,6-tetrahydropyrid-4) -yl) -3,5-difluorophenyl) oxazolidin-2-one

Prepared according to the general method of example 15, using 315 mg (1.53 mmol) of 1,3-dicyclohexylcarbodiimide, 660 mg (1.45 mmol) of the compound of Reference Example 6, 240 mg (1.64 mmol) of (S). -2,3-O-isopropylidene glyceric acid and 115 mg (1.45 mmol) of pyridine in 15 mL of dichloromethane. Purification by flash chromatography (Merck 9385 silica gel; EtOAc / isohexane (3: 1) eluent) afforded 282 mg (38%) of the product as a colorless crystalline solid.

MS: ESP + (M + H) + = 506.

¹ H-NMR (300MHz, DMSO-d _s): δ = 1.32 (s, 3H), 1.34 (s, 3H), 2.25 to 2.50 (m, 2H);

3.63 - 3.87 (m, 2H), 3.95 (dd, 1H), 4.02 - 4.32 (m, 4H), 4.43 - 4.55 (m, 2H), 4, 92 (m 1H), 5.12 (m, 1H), 5.89 (m, 1H), 6.37 (d, 1H), 7.35 (d, 2H), 8.68 (d, 1H) .

Example 18

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidine -2-on

Prepared according to the general method of example 16, using 282 mg (0.56 mmol) of the compound of Example 17 in a mixture of 6 mL of THF and 2 mL of 1N hydrochloric acid. Purification by flash chromatography (Merck silica gel 9385; eluent 10% MeOH in dichloromethane) afforded 183 mg (70%) of the product as a colorless crystalline solid; m.p. 136-142 ° C ¹ H-NMR (300MHz, DMSO-d 6): d 2.20-2.46 (m, 2H), 3.40-3.63 (m, 2H), 3.63 3 85 (m, 2H); 3.92 (dd, 1H); 4.10 (m, 1H); 4.18 (t, 1H); 4.26-4.52 (m, 1H); 68 (m, 1H), 4.96 (m, 1H), 5.10 (m, 1H), (m, 1H), 6.37 (d, 1H), 7.34 (m, 2H), 8.68 (d, 2 H).

MS: ESP + (M + H) + = 466.

HPLC: Chiralpak AD (250 mm x 4.6 mm, ID), eluent 100% MeOH, flow rate 1 mL / min, retention time = 38.4 min.

Reference Example 12

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-di- (tert-butoxyphosphoryl) propanoyl) -1,2,5,6 tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

1.67 g (6.24 mmol) of di-tert-butyl Ν, Ν-diethylphosphoramidite was added dropwise at room temperature under a nitrogen atmosphere to a stirred suspension of 1.0 g (2.24 mmol) of the compound of Examples 12 and 1, 4 g (20.0 mmol) of 1H-tetrazole in 40 ml of tetrahydrofuran. The resulting mixture was stirred for 2 hours, then cooled to -40 ° C and added portionwise

1.9 g (60%, 6.6 mmol) of 3-chloroperoxybenzoic acid. The reaction mixture was stirred at 40 ° C to 20 ° C for 1 hour and then diluted with 150 mL EtOAc, washed successively with 10% aqueous sodium bisulfite solution, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to give colorless oil. Purification by flash chromatography (Merck silica gel 9385, 2030% acetonitrile / EtOAc) gave 625 mg (34%) of the product as a colorless foam. ¹ H-NMR (300MHz, CDCl 3): δ = 1.48 (m, 36H), 2.45-2.70 (m, 2H), 3.58-3.71 & 3.73-3.86 ( m, 1H), 3.92-4.10 (m, 2H), 4.10-4.38 (m, 5H), 4.47-4.62 (m, 2H), 4.97-5, 08 (m, 1H), 5.22-5.32 (m, 1H), 5.88 (m, 1H), 6.02 (d, 1H), 7.18-7.28 (m, 2H) 7.43 (d, 1H); 8.16 (d, 1H).

MS: ESP + (M + H) + = 832.

Example 19

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-diphosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2 -he

mL of 4M HCl in dioxane was added at room temperature to a stirred solution of 600 mg (0.72 mmol) of the compound of Reference Example 12 in 6 mL of dioxane. The resulting yellow mixture was stirred for 1 hour and then concentrated under reduced pressure. Trituration with ether gave a yellow solid, which was filtered, washed with ether, dried and then dissolved in water and lyophilized to give 435 mg of a yellow solid. ¹ H-NMR (300MHz, DSMO-d ₆ + CD ₃ COOD): δ = 2.35-2.50 (m, 2H), 3.52-3.68 &

3.70 - 3.85 (m, 2H), 3.90 (dd, 1H), 4.05 - 4.35 (m, 5H), 4.35 - 4.53 (m, 2H), 5, 05 (m 1H), 5.10-5.25 (m, 1H), 5.98 (m, 1H), 6.25 (d, 1H), 7.25-7.40 (m, 2H), 7.45 (dd, 1 H), 8.54 (d, 1 H).

MS: ESP + (M + H) ⁺ = 608.

Reference Example 13

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3- (di-tert-butoxyphosphoryl) propanoyl)) -1,2,5,6-tetrahydropyrid-4-yl (3-Fluorophenyl) oxazolidin-2-one

To a stirred solution of 600 mg (1.34 mmol) of the starting material of Example 12 and 310 mg (4.43 mmol) of 1H-tetrazole in 30 mL of THF was added under nitrogen over 5 minutes 368 mg (1.48 mmol) of di-tert. butyl N, N diethylphosphoramidite. After stirring for 90 minutes, the solution was cooled to -40 ° C and 425 mg (60%, 1.48 mmol) was added portionwise.

3-chloroperoxybenzoic acid. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes. EtOAc was added, the solution was washed with sodium metabisulfite, sodium bicarbonate, brine solution, the organic phase was dried over anhydrous magnesium sulfate and evaporated in vacuo. The crude product was purified by flash chromatography (Merck silica gel 9385, 10-20% acetonitrile / EtOAc) to give 165 mg of the title compound (19%) as a colorless gum.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 1.48 (s, 9H), 1.50 (s, 9H), 2.45-2.80 (m, 2H), 3.61 3.86 (m, 2H), 3.96 (dd, 1H), 4.02-4.12 (m, 3H), 4.16 (t, 1H), 4.22-4.30 (m, 2H),

4.47-4.61 (m, 2H), 4.64-4.77 (m, 1H), 5.03 (m, 1H), 6.00 (m, 1H), 6.03 (d, 1H), 7.20-7.30 (m, 2H), 7.46 (d, 1H), 8.16 (d, 1H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 640.

Example 20 · · · · · * · ·······

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidine -2-on

mL of TFA was added dropwise at room temperature to a stirred solution of 165 mg (0.26 mmol) of the compound of Reference Example 13 in 8 mL of dichloromethane. The resulting yellow solution was stirred for 30 minutes, then evaporated under reduced pressure to give a yellow foam. Trituration with diethyl ether gave 120 g of the title compound as a yellow solid.

¹ H-NMR (300MHz, DSMO-d _with + CD ₃ COOD): δ = 2.30-2.50 (m, 2H), 3.50-3.65 & 3.65-3.82 (m, 2H), 3.92 (dd, 1H), 3.97-4.40 (m, 5H), 4.40-4.62 (m, 3H), 5.05 (m, 1H), 6.00 (m, 1H), 6.28 (d, 1H), 7.25-7.34 (m, 2H), 7.48 (d, 1H), 7.57 (d, 1H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 528.

Reference Example 14

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-di-tert-butylphosphoryl) propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3 (5-difluorophenyl) oxazolidin-2-one

The title compound was prepared, with only non-critical variations, according to the procedure of Reference Example 12 at a 4.3 mM scale using the starting material shown in Example 18.

Yield 1.6 g (51%).

NMR (300MHz, _DMSO-d): δ 1.42 (s, 36H), 2.5 (m, partially obscured), 3.3 to 3.9 (m, 4H), 3.94 (dd, 1H ), 4.1 (s, 2H), 4.21 (t, 1H), 4.48 (m, 2H), 5.14 (m, 2H), 5.90 (s, 1H),

6.38 (s, 1H); 7.37 (d, 2H); 8.70 (s, 1H).

MS: ESP <+> (M + H) = 850.

Example 21 • ·

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-diphosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin -2-on o

The title compound was prepared, with only non-critical variations, according to the procedure of Example 19 at a 1.4 mM scale using the starting material shown in Reference Example 14.

Yield: 735 mg (98%).

NMR (300MHz, DMSO-d _s): δ = 2.5 (m, partially obscured), 3.57 & 3.77 (2m, 2H), 3.91 (dd, 1H), 4,0-4. 4 (m, 4H), 4.18 (t, 1H), 4.58 (m, 2H), 5.1 (m, 2H), 5.85 (s, 1H), 6.36 (s, 1H) 7.35 (d, 2H), 8.78 (s, 1H).

MS: ESP <+> (M + H) = 626.

Reference Example 15

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3- (di-tert-butylphosphoryl) propanoyl)) 1,2,5,6-tetrahydropyrid-4- yl) -3,5-difluorophenyl) oxazolidin-2-one

To a stirred solution of 1.02 g (2.2 mmol) of the starting material of Example 18 and 462 mg (6.6 mmol) of tetrazole in 30 mL of THF was added over about 2 minutes at room temperature under nitrogen under 575 mg (2.31 mmol). ) butyl N, N diethylphosphoramidite. After stirring for 90 minutes, the solution was cooled to -40 ° C and 480 mg (2.5 mmol, 90%) of m-chloroperbenzoic acid was added in portions. The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. EtOAc was added and the mixture was washed with aqueous sodium metabisulfite, saturated sodium bicarbonate, and brine. The organic phase was dried over anhydrous MgSO ₄ and evaporated under reduced pressure. The title compound was isolated by MPLC (EtOAc) as 406 mg (28%) of crisp glass.

MS: ESP <+> (M + H) = 658; ESP - (M-H) = 656.

··· ·· · · · · · · · · ·

NMR (300MHz, _DMSO-d): δ 1.42 (s, 18H), 2.5 (m, partially obscured) 3.55 - 3.95 (m, 4H), 3.95 (dd, 1H ), 4.0-4.15 (m, 2H), 4.25 (t, 1H), 4.50 (m, 2H), 4.63 (m, 1H),

5.14 (m, 1H), 5.54 (d, 1H), 5.91 (s, 1H), 6.40 (s, 1H), 7.37 (d, 2H), 8.70 (1H) , s).

Example 22

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxyphosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2 -he

To a stirred solution of 100 mg (0.15 mmol) of the starting material of Reference Example 15 in 1 mL of dioxane was added 3 mL of 4M HCl / dioxane. The solution was stirred at ambient temperature for 30 minutes and then evaporated. The residue was triturated with ether to give the title compound as 80 mg (96%) of a white powder.

NMR (300MHz, DMSO-d6): 2.43 (m, partially unclear), 3.6-4.35 (m, 8H), 4.35 4.60 (m, 3H), 5.09 (m, 1H), 5.85 (s, 1H), 6.30 (s, 1H), 7.31 (d, 2H), 8.60 (s, 1H).

MS: ESP <+> (M + H) = 546.

Example 23

5 (R) -1'-Oxazol-3-yloxymethyl-3- (4- (1- (cyclo-2 (S), 3-diphosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5) (difluorophenyl) oxazolidin-2-one

To a stirred partial solution of 100 mg (0.16 mmol) of the starting material of Example 21 in 8 mL of THF was added 40 mg (0.195 mmol) of dicyclohexylcarbodiimide. 4 mL of DMF was added to give a clear solution. The mixture was stirred at room temperature for 18 hours and an additional 40 mg (0.195 mmol) of DCCI was added. After a further 3 hours the reaction was complete by HPLC (Partisil SAX 10μ column, 0.0M to 0.3M, pH 6.5, phosphate buffer gradient). The solvent was evaporated and the residue was taken up in water and filtered. The filtrate was chromatographed by MPLC (0-25% acetonitrile / water gradient on Mitsubishi HP20SS polystyrene resin) and the compound was freeze-dried after partial evaporation to remove acetonitrile. Yield = 49 mg (50%).

MS: ESP (M-H) = 506;

NMR (300MHz, DMSO-d _6): δ = 2.4 (m, partially unknown), 3.7-4.0 (m, 3H), 4.18 (m, 4H), 4.48 (m, 3H), 5.05 (m, 1H), 5.19 & 5.30 (2m, 1H), 5.85 (s, 1H), 6.30 (s, 1H),

7.30 (d, 2H); 8.59 (s, 1H).

Example 24

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (4-hydroxybutanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

To a stirred solution of 0.223 g (0.54 mmol) of the compound of Reference Example 6, 0.082 g (0.65 mmol) of 4-hydroxybutanoic acid sodium salt and 0.087 g (0.65 mmol) of HOBT in 5 mL of DMF was added 0.124 g ( 0.65 mmol) EDC. The mixture was stirred for 4 days and then evaporated. The residue was purified by MPLC [5% MeOH / CH ₂ Cl ₂ as eluent] and after trituration with diethyl ether, 0.141 g of product (56%) was obtained as a white solid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 1.63 (m, 2H), 2.29 (m, 1H), 2.38 (m, 2H), 3.25 (d, 1H) 3.40 (m, 2H), 3.62 (m, 2H), 3.91 (dd, 1H), 4.10 (d, 1H), 4.19 (t, 2H), 4.44 ( m,

3H), 5.09 (m, 1H), 5.84 (s, 1H), 6.38 (d, 1H), 7.36 (d, 2H) and 8.70 (d, 1H).

MS: ESP ⁺ (M + H) + = 464.

Example 25

5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (4-methoxybutanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

To a stirred solution of 0.285 g (0.69 mmol) of the compound of Reference Example 6,

0.111 g (0.83 mmol) of 2- (2-methoxyethoxy) acetic acid, 0.070 g (0.096 mL, 0.69 mmol) of triethylamine and 0.112 g (0.83 mmol) of HOBT in 5 mL of dichloroethane are added 0.159 g (0 , 83 mmol) of EDC. The mixture was stirred for 17 hours and the solution was washed with 10 ml of water, dried and evaporated. The residue was purified by MPLC [3% MeOH / CH ₂ Cl ₂ as eluent] to give 0.201 g (61%) as a colorless oil.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.36 (d, 2H), 3.25 (s, 3H), 3.45 (m, 2H), 3.59 (m, 4H) 3.92 (dd, 1 H), 4.09 (m, 2 H), 4.18 (m, 3 H), 4.45 (m, 2 H), 5.09 (m, 1 H), 5.86 ( s, 1H), 6.38 (d, 1H), 7.35 (d, 2H) and 8.69 (d, 1H).

Reference Example 16

6-Hydroxymethyl-2-phenyl-1,3-dioxane

To 5.0 g (37 mmol) of (DL) -malic acid in 25 ml of dry THF under nitrogen was added dropwise at 0 ° C 12.5 ml of trimethyl borate and 60 ml (120 mmol) of borane dimethyl sulfide (2.0 M in THF). ). After the addition was complete, stirring was continued at 0 ° C for 5 minutes. During this time a white precipitate began to form. Remove the ice bath and continue stirring overnight. After 17 hours, the solution was slowly treated with 30 mL of MeOH and then evaporated. The residue was purified by MPLC [10% MeOH / CH ₂ Cl ₂ as eluent] to give 3.57 g of the triol. This product was dissolved in 150 ml of benzaldehyde containing 0.64 g (3.37 mmol) of p-toluenesulfonic acid and the mixture was stirred for 60 hours and then evaporated. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, dried and evaporated. The residue was purified by MPLC [20 → 45% EtOAc / hexanes as eluent] to give 1.47 g (22%) of the product as an oil.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 195.

¹ H-NMR (300MHz, _DMS0-d): δ = 1.50 (d, 1H), 1.62 (ddd, 1H), 3.38 (dd, 1H), 3.48 (dd, 1H) 3.90 (m, 2H), 4.14 (dd, 1H), 4.70 (t, 1H), 5.49 (s, 1H) and 7.38 (m, 5H).

Reference Example 17

6-Carboxy-2-phenyl-1,3-dioxane

To a stirred solution of 1.47 g (7.60 mmol) of the alcohol from Reference Example 16 in 0.304 g (30 mL, 7.60 mmol) of sodium hydroxide was added portionwise at 0 ° C 1.80 g (11.4 mmol) in portions. ) of potassium permanganate. After 3.5 h the mixture was filtered and acidified to pH 2. The aqueous solution was saturated with sodium chloride and extracted with EtOAc (4 x 50 mL), dried and evaporated to a residue. The white solid was dissolved in dichloromethane and extracted with ammonium hydroxide (2 x 15 mL). The basic extracts were acidified at 0 ° C to pH 2 with hydrochloric acid and the acidic mixture was extracted with dichloromethane (2 x 50 mL). The organics were dried and evaporated to give 0.15 g (10%) of the acid as a gum.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 209.

¹ H-NMR (300MHz, DMSO-d _s): δ = 1.82 (m, 2H), 3.96 (m, 1H), 4.18 (dd, 1H), 4.50 (dd, 1H) 5.58 (s, 1H), 7.40 (m, 5H) and 12.82 (s, 1H).

Example 26

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -phenyl) 1,3-dioxan-4 (R, S) -ylcarbonyl) 1,2,5), 6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

To a stirred solution of 0.220 g (0.53 mmol) of Reference Example 6, 0.133 g (0.64 mmol) of Example 17, 0.054 g (0.074 mL, 0.53 mmol) of triethylamine and 0.086 g (0.64 mmol). HOBT in 6 mL of dichloromethane was added 0.123 g (0.64 mmol) of EDO. The mixture was stirred for 60 hours and the solution was then washed with 10 mL of 2N HCl, 10 mL of brine, dried and evaporated. The residue was purified by MPLC [4% MeOH / CH ₂ Cl ₂ as eluent] to give 0.246 g (82%) of the product as an oil.

MS: ESP ⁺ (M + H + = 568).

¹ H-NMR (300MHz, DMSO-d _s): δ = 1.59 (d, 1H), 2.10 (m, 1H), 2.33 (m, 2H), 3.55 (m, 1H) 3.78 (m, 1H), 3.90 (dd, 1H), 4.07 (m, 2H), 4.15 (m, 3H), 4.45 (m, 2H), 4.90 (m, 1H), 5.10 (m, 1H), 5.71 (d, 1H), 5.88 (s, 1H), 6.38 (d, 1H), 7.38 (m, 7H) and 8.70 (d, 1H).

Reference Example 18

5 (R) -1soxazol-3-yloxamethyl-3- (4- (1- (3-tert-butoxycarbonylamino-2 (R, S) hydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) - 3,5-difluorophenyl) oxazolidin-2-one

To a stirred solution of 0.091 g (0.22 mmol) of the compound of Reference Example 6, 0.054 g (0.27 mmol) of (D, L) -N-BOC-isoserine, 0.022 g (0.031 mL, 0.22 mmol) of triethylamine and 0.036 g (0.27 mmol) of HOBT in 3 mL of dichloromethane was added 0.052 g (0.27 mmol) of EDC. The mixture was stirred for 18 hours and the solution was then washed with 10 mL of 2N HCl, 10 mL of brine, dried and evaporated. The residue was purified by MPLC [3% MeOH / CH ₂ Cl ₂ as eluent] to give 0.047 g (38%) of the product as a light brown solid.

MS: ESP + (M + H) + = 565.

Example 27

5 (R) -1soxazol-3-yloxamethyl-3- (4- (1- (3-amino-2 (R, S) -hydroxy-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3) (5-difluorophenyl) oxazolidin-2-one

0.047 g (0.083 mmol) of the compound of Reference Example 18 was dissolved in 3 mL of EtOAc saturated with hydrogen chloride and the mixture was stirred for 18 hours. The solution was evaporated and triturated with EtOAc to give 0.034 g (88%) of the product as an off-white solid.

¹ H-NMR (300MHz, DMSO-d _s): δ = 2.30 (d, 2H), 3.70 (m, 2H), 3.90 (dd, 1H), 45.19 (m, 4H) 4.44 (m, 2H); 4.60 (m, 1H); 5.10 (m, 1H); 5.90 (s, 1H); 6.37 (d, 1H); 7.30 ( s, 1H), 7.38 (s, 1H), 7.89 (s, 3H) and 8.69 (d, 1H).

MS: ESP + (M + H) + = 465.

Example 28

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -phenyl) 1,3-dioxan-5 (R, S) -ylcarbonyl) 1,2,5), 6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

To a stirred solution of 0.344 g (0.83 mmol) of the compound of Reference Example 6, 0.208 g (1.00 mmol) of 5-carboxy-2-phenyl-1,3-dioxane (JOC, 1997, 62, 4029), 0.084 g (0.116 mL, 0.83 mmol) of triethylamine and 0.135 g (1.00 mmol) of HOBT in 10 mL of dichloromethane were added 0.192 g (1.00 mmol) of EDC. The mixture was stirred for 24 hours and the solution was then washed with 10 mL of 2N HCl, 10 mL of brine, dried and evaporated. The residue was purified by MPLC [2% MeOH / CH ₂ Cl ₂ as eluent] to give 0.357 g (76%) of the product as an oil.

@ ¹ H-NMR (300 MHz, DMSO-d6): .delta. = 2.38 (d, 2H), 2.99 (s, 1H) 13.70 '(d', * 2H), 3,904.55 (m, 10H), 5.10 (m, 1H), 5.55 (s, 1H), 5.90 (s, 1H), 6.37 (d, 1H); 7.40 (m, 7H);

8.68 (d, IH).

MS: ESP + (M + H) + = 568.

Example 29

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (3-hydroxy-2-hydroxymethyl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

0.155 g (0.27 mmol) of the compound of Example 28 in 4 mL of dichloromethane was treated at 0 ° C for 4.5 hours with 0.40 mL (0.81 mmol) of boron trifluoride dimethyl sulfide (2.0 M in CH 2 Cl 2). ). Then 1 ml of MeOH is added until all solids have dissolved. The solution was evaporated and the residue was purified by MPLC [6% MeOH / CH ₂ Cl ₂ as eluent] and after trituration with diethyl ether, 0.025 g (19%) of the product was obtained as a white solid. MS: ESP + (M + H) + = 480.

¹ H-NMR (300MHz, DMSO-d 6): δ = 2.40 (d, 2H), 3.15 (m, 1H), 3.40 (m, 6H), 3.79 (d, 2H), 3.98 (dd, 1 H), 4.19 (s, 1 H), 4.26 (dd, 1 H), 4.34 (s, 1 H), 4.51 (m, 2 H), 5.15 (m) 1 H, 5.93 (m, 1 H), 6.43 (d, 1 H), 7.40 (s, 1 H), 7.44 (s, 1 H) and 8.74 (d, 1 H).

Example 30

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2,3-propenoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2- he

Acryloyl chloride (0.747 g, 0.67 ml, 8.25 mmol) in dichloromethane (5 ml) was treated at 0 ° C with 0.682 g (1.65 mmol) of the compound of Reference Example 6 in 5 ml of dichloromethane containing 0.201 g (1.65 mmol). DMAP and 0.333 g (0.46 mL, 3.39 mmol) of triethylamine. The solution was stirred for 1.5 hours. The solution was washed with 10 mL of 2N HCl, 10 mL of saturated aqueous sodium bicarbonate, 10 mL of brine, dried and evaporated. The residue was purified by MPLC [2% MeOH / CH ₂ Cl ₂ as eluent] to give 0.471 g (66%) of the product as a white solid.

MS: ESP + (M + H) + = 432.

· ¹ H-NMR (300MHz) · 1 · ¹ H-NMR (300MHz) DMSO-d _6): δ = 2.40 (d, 2H), 3.80 (d, 2H), 3.99 (dd, 1H), 4.25 (m, 3H), 4.54 (m 2H, 5.16 (m, 1H), 5.75 (d, 1H), 5.93 (s, 1H), 6.20 (d, 1H), 6.45 (s, 1H),

6.88 (m, 1H), 7.42 (s, 1H), 7.48 (s, 1H) and 8.75 (d, 1H).

Reference Example 19

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2,3 (R, S) -epoxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl Oxazolidin-2-one

0.65 ml (1.04 mmol) of n-butyllithium is added at -78 ° C to a solution of 0.26 ml (1.43 mmol) of tert-butyl hydroperoxide (5.5M in decane) in 5 ml of THF. The mixture was stirred for 5 minutes. A solution of acrylamide, 0.408 g (0.95 mmol) of the compound of Example 30 in 2 mL of dry THF was added and stirring was continued with the ice bath removed until the temperature reached about 0 ° C, after which the ice bath returned to its place. Solid sodium sulfite (0.080 g, 0.30 mmol) was added and stirring was continued for 15 minutes. 10 ml of dichloromethane are added and the mixture is filtered through Celite and then evaporated. The residue was purified by MPLC [2% MeOH / CH ₂ Cl ₂ as eluent] to give 0.378 g (89%) of the product as a gum.

1 H-NMR (300MHz, DMSO-d ₆ ): δ = 2.46 (d, 2H), 2.87 (m, 1H), 3.00 (m, 1H), 3.67 4.04 (m 4H), 4.17 (s, 1 H), 4.27 (t, 1 H), 4.40 (d, 1 H), 4.52 (m, 2 H), 5.16 (m, 1 H), 5 95 (s, 1H), 6.43 (s, 1H), 7.40 (s, 1H), 7.45 (s, 1H) and 8.76 (d, 1H).

MS: ESP + (M + H) + = 488.

Example 31

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -hydroxy-3-morpholinopropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3), 5-difluorophenyl) oxazolidin-2-one

0.073 g (0.16 mmol) of the compound of Reference Example 19 and 0.014 g (0.014 mL, 0.16 mmol) of morpholine were refluxed with 1 mL of isopropanol for 1 hour and then at 50 ° C for 2 hours. The solution was allowed to cool to room temperature overnight and then evaporated. The residue was purified by MPLC [4% MeOH / CH ₂ Cl ₂ as eluent] to give 0.056 g (66%) of the product as a white foam.

. *.,.:.:. ·· .. · *.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.41 (d, 2H) · H · NMR (300MHz, DMSO-d6): δ = 2.41 (d, 2H) 2.60 (m, 6H), 3.60 (d, 4H), 3.78 (m,

2H), 4.00 (dd, 1H), 4.17 (s, 1H), 4.26 (dd, 1H), 4.34 (s, 1H), 4.56 (m, 3H), 5, 04 (dd, 1 H), 5.15 (m, 1 H), 5.94 (s, 1 H), 6.43 (d, 1 H), 7.40 (s, 1 H), 7.44 (s, 1 H) ) and 8.74 (s, 1H). MS: ESP + (M + H) + = 535.

Reference Example 20

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -hydroxy-3- (2-tert-butyldimethylsilyloxypyrrolidin-1-yl)) -1,2,5,6-tetrahydropyridine) -4-yl) -3,5-difluorophenyl) oxazolidin-2-one

0.149 g (0.333 mmol) of the compound of Reference Example 19 and 0.067 g (0.333 mmol) of 2-tert-butyldimethylsilyloxypyrrolidine in 3 ml of isopropanol were heated to 60 ° C until TLC indicated complete reaction. The solution was evaporated and the residue was purified by MPLC [3-> 10% MeOH / CH ₂ Cl ₂ as eluent] to give 0.173 g (80%) of a colorless gum.

MS: ESP + (M + H) + = 649.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 0.00 (s, 6H), 0.82 (s, 9H), 1.50 (m, 1H), 1.98 (m,

1H), 2.23-2.95 (m, 8H), 3.71 (s, 2H), 3.90 (dd, 1H), 4.08 (s, 1H), 4.17 (t, 1H) 4.30 (s, 2H), 4.45 (m, 3H), 5.03 (m, 2H), 5.83 (s, 1H), 6.33 (d, 1H), 7.30 (s, 1H), 7.34 (s, 1H) and 8.64 (s, 1H).

Example 32

5 (R): - Isoxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -hydroxy-3- (2-hydroxypyrrolidino) propanoyl)) -1,2,5,6-tetrahydropyrid-4- yl) -3,5 (difluorophenyl) oxazolin-2-one

0.169 g (0.26 mmol) of the silyl ether of Reference Example 20 in 5 ml of dry THF was treated at 0 ° C with 0.52 ml (0.52 mmol) (1.0 M in THF) of tetrabutylammonium fluoride and the mixture was then stirred 5 hours. The solution was evaporated and the residue was purified by MPLC [3-> 6% MeOH / CH ₂ Cl ₂ as eluent] to give 0.104 g (75%) of a white solid.

* @ ¹ H-NMR (300 MHz, DMSO-d6): .delta. = 1.54 (s, 1H), 1, 92 (m, 1H), 2.30 (m, 3H), 2.50 2.88 (m, 5H), 3.63 (m, 2H), 3.89 (dd, 1H), 4.13 ( m, 4H), 4.45 (m, 3H), 4.65 (s, 1H), 5.05 (m, 2H), 5.86 (s, 1H), 6.35 (d, 1H), 7.34 (s, 1H), 7.38 (s, 1H) and 8.68 (d, 1H).

MS: ESP + (M + H) + = 535.

Reference Example 21

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -phenyl) -1,3-dioxan-5 (R, S) -ylcarbonyl) 1,2,5), 6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

To a stirred solution of 0.368 g (0.93 mmol) of the compound of Reference Example 11, 0.232 g (1.12 mmol) of 5-carboxy-2-phenyl-1,3-dioxane (JOC, 1997, 62, 4029), 0.094 g (0.129 mL, 0.93 mmol) of triethylamine and 0.151 g (1.12 mmol) of HOBT in 11 mL of dichloromethane were added 0.215 g (1.12 mmol) of EDC. The mixture was stirred for 20 hours and the solution was then washed with 10 mL of 2N HCl, 10 mL of brine, dried and evaporated. The residue was purified by MPLC [2% MeOH / CH ₂ Cl ₂ as eluent] to give 0.475 g (93%) of the product as an oil. ¹ H-NMR (300MHz, DMSO-d _s): δ = 2.62 (m, 2H), 3.48 (m, 1H), 3.70 (m, 1H), 3.82 (m, 1H) 3.93-4.60 (m, 10H), 5.14 (m, 1H), 5.60 (s, 1H), 6.08 (s, 1H), 6.42 (d, 1H), 7.46 (m, 8H) and 8.76 (d, 1H).

MS: ESP + (M + H) + = 550.

Example 33

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (3-hydroxy-2-hydroxymethyl-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

0.475 g (0.87 mmol) of the compound of Reference Example 21 was stirred in 10 mL of 80% acetic acid in water for 24 hours. The precipitate slowly dissolves. The solution was evaporated and purified by MPLC [5% MeOH / CH ₂ Cl ₂ as eluent] to give, after trituration with diethyl ether, 0.284 g (71%) of a white powder.

MS: ESP + (M + H) + = 462.

¹ H-NMR (300MHz, DMSO-d _s): δ = 2.51 (d, 2H), 3.15 (m, 1H), 3.58 (m, 4H), 3.78 (m, 2H) 3.99 (dd, 1 H), 4.26 (d, 2 H), 4.28 (t, 1 H), 4.54 (m, 2 H), 4.65 (m, 2 H), 5.15 ( m,

1H), 6.06 (s, 1H), 6.43 (d, 1H), 7.35-7.63 (m, 3H) and 8.76 (d, 1H).

Reference Example 22

5 (R, S) -carboxymethyl-2,2-dimethyl-4-oxo-1,3-dioxolane

12.41 g (92.6 mmol) of malic acid (DL) and 2.32 g (9.26 mmol) of PTSA are stirred in 35 ml of 2,2-dimethoxypropane for 5 days. The solution was evaporated and the residue was purified by MPLC [25% EtOAc / isohexane as eluent] to give 11.48 g (71%) of a colorless gum. ¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 1.58 (s, 3H), 1.60 (s, 3H), 2.82 (m, 2H), 4.85 (t, 1H) and 12.64 (s, 1H).

Example 34

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-4-oxo-1,3-dioxolane-5 (R, S) yl) acetyl) -1,2 (5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

To a stirred solution of 0.384 g (0.93 mmol) of the compound of Reference Example 11, 0.203 g (1.17 mmol) of the acid of Reference Example 22, 0.098 g (0.135 mL, 0.97 mmol) of triethylamine and 0.158 g (1.17 mmol). mmol) of HOBT in 11 mL of dichloromethane was added 0.225 g (1.17 mmol) of EDC. The mixture was stirred for 60 hours and the solution was dried and evaporated. The residue was purified by MPLC [3% MeOH / CH ₂ Cl ₂ ; ₂ as eluent] to give 0.356 g (71%) of the product as an oil.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 516.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 1.57 (s, 3H), 1.60 (s, 3H), 2.53 (d, 2H), 3.02 (m, 2H) 3.70 (m, 2H); 4.00 (dd, 1H); 4.19 (d, 2H); 4.25 (t, 1H); 4.52 (m, 2H); t, 1H)

5.15 (m, 1H), 6.05 (s, 1H), 6.44 (d, 1H), 7.36-7.63 (m, 3H) and 8.75 (d, 1H).

Example 35

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (3-carboxy-3 (R, S) -hydroxypropanoyl) -1 ', 2', 4'-tetrahydropyrid-4-yl) -3) (fluorophenyl) oxazolidin-2-one

0.345 g (0.67 mmol) of the compound of Example 34 was stirred in 5 mL of 80% acetic acid in water for 20 hours. The acetone is slowly dissolved and then the product slowly precipitates. Diethyl ether (10 mL) was added and the solid was collected by filtration to give 0.300 g (94%) of a white solid.

MS: ESP + (M-H) + = 474.

¹ H-NMR (300MHz, DMSO-d _s): δ = 2.52 (d, 2H), 2.80 (m, 2H), 3.71 (s, 2H), 4.00 (dd, 1H) 4.20 (d, 2H), 4.28 (t, 1H), 4.41 (t, 1H), 4.55 (m, 2H), 5.15 (m, 1H), 6.08 ( s, 1H)

6.46 (d, 1H), 7.35-7.62 (m, 3H) and 8.77 (d, 1H).

Reference Example 23

5 (R, S) -Methylaminocarbonylmethyl-2,2-dimethyl-4-oxo-1,3-dioxolane

2.84 g (16.32 mmol) of the acid of Reference Example 22 was heated to reflux in 25 ml of thionyl chloride under nitrogen for 1.25 hours. The solution was evaporated and azeotroped twice with toluene. A portion of the crude acid chloride (5.44 mmol) was dissolved in 5 mL of dichloromethane, treated with 5.44 mL (10.88 mmol) of methylamine (2.0 M in THF) and stirred for 1.5 h. The resulting suspension was diluted, washed with 10 mL of 2N HCl, 10 mL of brine, dried and evaporated. The residue was purified by MPLC [5% MeOH / CH ₂ Cl ₂ as eluent] to give 0.393 g (39%) of a light brown solid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 1.56 (s, 6H), 2.66 (m, 2H), 2.68 (s, 3H), 4.82 (t,

1H) and 7.95 (s, 1H).

MS: ESP + (M + H) + = 188.

Reference Example 24

2 (R, S) -Hydroxy-3-methylaminocarbonylpropanoic acid

0.392 g (2.10 mmol) of the amide from Reference Example 23 is stirred in 4 mL of MeOH containing 0.053 g (0.21 mmol) of PTSA for 5 days. The solution was evaporated and the residue was purified by MPLC [5% MeOH / CH ₂ Cl ₂ as eluent] to give 0.284 g. methyl ester. This product was dissolved in 4 mL of MeOH / water (3: 1), treated with 0.370 g (0.82 mmol) of lithium hydroxide and stirred for 15 minutes. The mixture was then diluted with 20 mL of water, treated with Dowex 50W-X8 (H), stirred for 5 minutes, filtered and evaporated in vacuo to give 0.216 g (83%) of a gum.

¹ H-NMR (300MHz, DMSO-d _s): δ = 2.38 (dd, 1H), 2.49 (dd, 1H), 2.64 (s, 3H), 3.54 (br s, 1H ), 4.34 (m, 1H), 7.87 (m, 1H) and 12.53 (br s, 1H).

MS: ESP (MH) ^&lt; ^{+ &gt}; = 146.

Example 36

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -hydroxy-3-methylaminocarbonylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl ) oxazolidin-2-one

To a stirred solution of 0.175 g (0.144 mmol) of the compound of Reference Example 11, 0.078 g (0.53 mmol) of the acid of Reference Example 24, 0.044 g (0.061 mL, 0.44 mmol) of triethylamine and 0.072 g (0.53 mmol) of HOBT 0.102 g (0.53 mmol) of EDC was added in 6 ml of dichloromethane. The mixture was stirred for 16 hours. TLC indicated incomplete reaction and an additional 0.138 g (0.94 mmol) of acid, 0.127 g (0.94 mmol) of HOBT and 0.180 g (0.94 mmol) of EDC were added. After 5 hours the solution was evaporated. The residue was purified by MPLC [5 → 15% MeOH / CH ₂ Cl ₂ as eluent] to give 0.070 g (33%) of an oil.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 489.

¹ H-NMR (300MHz, DMSO-d _s): δ = 2.44 (m, 4H), 2.63 (d, 3H), 3.66 (m, 1H), 3.77 (s, 1H) 4.00 (dd, 1 H), 4.22 (m, 3 H), 4.54 (m, 2 H), 4.79 (m, 1 H), 5.15 (m, 1 H), 5.38 ( d, 1H), 6.10 (s, 1H), 6.48 (d, 1H), 7.35-7.64 (m, 3H), 7.88 (s, 1H) and 8.79 (d) , 1H).

Example 37

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (3 (R, S) -hydroxy-3-methylaminocarbonylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl ) oxazolidin-2 *

To a stirred solution of 0.070 g (0.15 mmol) of the compound of Example 35 and 0.020 g (0.15 mmol) of HOBT in 4 mL of dichloromethane was added 0.028 g of EDC (0.15 mmol) and 0.23 mL (0.45 mmol). of methylamine (2.0M in THF). The mixture was stirred for 22 hours and then purified by MPLC [5% MeOH / CH ₂ Cl ₂ as eluent] and trituration with diethyl ether gave 0.01 g (14%) of a white solid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.48 (d, 2H), 2.65 (d, 3H), 2.69 (m, 2H), 3.69 (m, 2H) 3.94 (dd, 1 H), 4.17 (m, 2 H), 4.20 (t, 1 H), 4.30 (m, 1 H), 4.48 (m, 2 H), 5.08 ( m, 1H), 5.61 (m, 1H), 6.00 (s, 1H), 6.39 (d, 1H), 7.38 (m, 2H), 7.50 (d, 1H), 7.78 (m, 1H) and 8.70 (d, 1H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 489.

Reference Example 25

5 (R, S) - (2- (2-Methoxyethoxy) ethoxy) carbonylmethyl-2,2-dimethyl-4-oxo-1,3-dioxolane

2.75 g (15.80 mmol) of the acid of Reference Example 22 in 15 mL of dichloromethane at 0 ° C was treated with 2.99 g (2.1 mL, 23.71 mmol) of oxalyl chloride and stirred with a drop of DMF for for 2 hours. The solution was evaporated. A portion of the crude acid chloride (1.90 g, 9.84 mmol) in 20 mL of dichloromethane containing 1.20 g (9.84 mmol) of 4-DMAP was treated with 4.72 g (4.70 mL) at 0 ° C, 2- (2-methoxyethoxyethanol) (39.36 mmol) and stirred overnight. The solution was washed with 2N HCl (2 x 15 mL), 10 mL brine, dried and evaporated. The residue was purified by MPLC [3% MeOH / CH 2 Cl as eluent] to give 0.785 g (29%) of an oil.

¹ H-NMR (300MHz, DMSO-d _s): δ = 1.54 (s, 6H), 2.89 (t, 2H), 3.27 (s, 3H), 3.43 (m, 2H) 3.53 (m, 2H), 3.60 (m, 2H), 4.19 (m, 2H) and 4.84 (t, 1H).

Reference Example 26

2 (R, S) -Hydroxy-3- (2- (2-methoxyethoxy) ethoxy) carbonylpropanoic acid

0.785 g (2.84 mmol) of the compound of Reference Example was stirred in 5 mL of 80% acetic acid in water for 5 days. The solution was evaporated to give 0.60 g (89%) of an orange oil.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.54 (dd, 1H), 2.72 (dd, 1H), 3.26 (s, 3H), 3.42 (m, 2H) 3.52 (m, 2H), 3.59 (m, 2H), 4.13 (m, 2H), 4.30 (m, 1H), 5.49 (s, 1H) and 12.58 ( s, 1H).

MS: ESP + (M-H) + = 235.

Example 38

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S)) -hydroxy-3- (2- (2-methoxyethoxy) ethoxy) carbonylpropanoyl) -1,2,5,6- tetrahydropyrid-4-yl) -3-fluorophenyloxazolidin-2-one

To a stirred solution of 0.329 g (0.79 mmol) of the compound of Reference Example 11, 0.225 g (0.95 mmol) of the acid of Reference Example 26, 0.079 g (0.110 mL, 0.79 mmol) of triethylamine and 0.129 g (0.95 mmol). mmol) HOBT in 10 mL dichloromethane was added 0.183 g (0.95 mmol) EDC. The mixture was stirred for 48 hours and then the solution was dried and evaporated. The residue was purified by MPLC [5% MeOH / CH ₂ Cl ₂ as eluent] to give 0.283 g (62%) of a white solid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.52 (d, 2H), 2.60 (dd, 1H), 2.85 (dd, 1H), 3.31 (s, 3H) 3.50 (m, 2H), 3.60 (m, 2H), 3.68 (m, 2H), 3.80 (m, 2H), 4.00 (dd, 1H), 4.10 4 40 (m, 5H), 4.54 (m, 2H), 4.76 (m, 1H), 5.15 (m, 1H), 5.64 (m, 1H), 6.09 (s, 1H),

6.43 (d, 1H), 7.43 (m, 2H), 7.58 (d, 1H) and 8.75 (d, 1H).

MS: ESP + (M + H) + = 578.

Example 39

5 (R) -1Soxazol-3-yloxymethyl-3- (4-morpholino-3-fluorophenyl) oxazolidin-2-one

Prepared according to the general method of Example 1, starting from 300 mg (1.01 mmol) of 5 (R) -hydroxymethyl-3- (4-morpholino-3-fluorophenyl) oxazolidin-2-one (WO 95/07271), 95 mg (1.12 mmol) of 3-hydroxyisoxazole, 225 mg (1.11 mmol) of diisopropyl azodicarboxylate and 305 mg (1.16 mmol) of triphenylphosphine in 5 mL of THF. Purification by flash chromatography (Merck silica gel 9385) ··· ···················

EtOAc / isohexane (7: 3)) gave 254 mg (69%) of the title compound as a colorless solid.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 3.05 (m, 4H), 3.88 (m, 4H), 3.94 (dd, 1H), 4.14 (t, 1H), 4 47-4.62 (m, 2H); 5.01 (m, 1H); 6.00 (d, 1H); 6.94 (t, 1H); 7.15 (dd, 1H); 46 (d, 1 H), 8.15 (d, 1 H).

MS: ESP + (M + H) + = 364.

Reference Example 27

5 (R) -Hydroxymethyl-3- (4-iodophenyl) oxazolidin-2-one

3.0 g (15.5 mmol) of 3-phenyloxazolidin-2-one (U.S. Pat. No. 4,705,799), 4.5 g (20.4 mmol) of silver trifluoroacetate and 4.7 g (18.5 mmol) of iodine in of a mixture of 30 ml of acetonitrile and 30 ml of chloroform is stirred at room temperature for 72 hours and then a further 1 g of silver trifluoroacetate and 1 g of iodine are added and stirring is continued for 18 hours. The mixture was then filtered, the filtrate was evaporated to give an orange oil which was purified by flash chromatography (Merck silica gel 9385, 5% MEOH / dichloromethane) followed by recrystallization from EtOAc / isohexane to give 1.85 g (38%) of the compound. title compound as a colorless solid.

MS: ESP + (M + H) + = 320.

¹ H-NMR (300MHz, DMSO-d _s): δ = 3.53 (m, 1H), 3.47 (m, 1H), 3.78 (dd, 1H), 4.05 (t, 1H) 4.69 (m, 1H), 5.18 (t, 1H), 7.38 (d, 2H), 7.69 (d, 2H).

Reference Example 28

5 (R) -1xoxazol-3-yloxymethyl-3- (4-iodophenyl) oxazolidin-2-one

Prepared according to the general method of Example 1, using 1.85 g (5.80 mmol), 0.55 g (6.47 mmol) of 3-hydroxyisoxazole, 1.29 g (6.39 mmol) of diisopropylazodicarboxylate and 1. 75 g (6.68 mmol) of triphenylphosphine in 30 mL of THF. Purification by flash chromatography (Merck 9385 silica gel, EtOAc / isohexane (1/1)) afforded 1.45 g (64%) of the title compound as a colorless solid.

MS: ESP + (M + H) + = 387.

¹ H-NMR (300MHz, CDCl 3): δ = 3.94 (dd, 1H), 4.13 (t, 1H), 4.46-4.61 (m, 2H), 5.03 (m, 1H) 6.00 (d, 1H), 7.34 (d, 2H), 7.69 (d, 2H), 8.15 (d, 1H).

Reference Example 29

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) phenyl) oxazolidin-2-one

1.0 g (23.6 mmol) of lithium chloride, 0.95 g (3.10 mmol) of triphenylarsine and 0.7 g (0.76 mmol) of tris (dibenzylideneaetone) dipalladium (0) are added at room temperature under an atmosphere. nitrogen to a stirred solution of 3.0 g (7.77 mmol) of Reference Example 28 in 50 mL DMF (degassed). The resulting mixture was stirred for 15 minutes and then 3.0 g (8.67 mmol) of N-tert-butoxycarbonyl-4-trimethylstannyl-1,2,5,6-tetrahydropyridine (prepared from N-tert-butoxycarbonyl-4-triflate) was added in one portion. -1,2,5,6-tetrahydropyridine (WO 97/30995) by reaction with hexamethyltin and Pd (O) catalyst) in 10 ml DMF. The reaction mixture was stirred and heated at 50-55 ° C for 3 hours, then cooled to room temperature and treated with 8 mL of 2N aqueous potassium fluoride solution. The mixture was stirred for 30 minutes, the solvent was evaporated (50 ° C, high vacuum) and the residue was partitioned between dichloromethane and water, filtered and the dichloromethane layer separated. Then the mixture was washed with water (x2) and saturated brine, dried over magnesium sulfate and evaporated to a viscous oil. Purification by flash chromatography (Merck silica gel 9385, EtOAc / isohexane (3/2)) gave the title compound as a pale yellow solid.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 442.

Reference Example 30

5 (R) -1-Oxazol-3-yloxymethyl-3- (4- (1,2,5,6-tetrahydropyrid-4-yl) -phenyl) -oxazolidin-2-one

2.1 g (4.76 mmol) of the compound of Reference Example 29 in 30 mL of MeOH (partial solution) was treated at room temperature with approximately 4M HCl in ethanol and the resulting mixture was stirred for 4 hours and allowed to stand for 16 hours. Add 50 ml ·· 00 0 0 0 0 0 0 0 0

Of diethyl ether and the resulting pale yellow solid was filtered, washed with ether and dried. This gave 1.71 g (95%) of the title compound as the chloride salt.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.66 (m, 2H), 3.30 (m, partially unclear DMSO, 2H), 3.73 (m, 2H), 3.92 ( dd, 1H), 4.20 (t, 1H), 4.41-4.53 (m, 2H), 5.08 (m, 1H), 6.16 (m, 1H), 6.35 (d) 1H, 7.49 (d, 2H), 7.57 (d, 2H), 8.68 (d, 1H), 9.30 (s (br), 2H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 342.

The free base isolated by treatment with aqueous sodium hydroxide solution and extraction with dichloromethane affords the title compound as a yellow solid.

Reference Example 31

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolane-4 (R) -ylcarbonyl) 1,2,5,6-tetrahydropyrid-4) -yl) phenyl) oxazolidin-2-one

298 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide is added in one portion at room temperature to a stirred solution of 235 mg of (R) -2,3-O-isopropylidene glyceric acid (1.40 mmol, 87% purity) and 218 mg ( 1.42 mmol) of 1-hydroxybenzotriazole in 15 ml of dichloromethane. The resulting suspension was stirred for 1 hour, then another 5 mL of dichloromethane was added followed by 500 mg (1.47 mmol) of the compound of Reference Example 30, the mixture was stirred for 16 hours, filtered, the filtrate washed with water and saturated brine. Purification by flash chromatography (Merck silica gel 9385, 2.5% MeOH / dichloromethane) afforded 395 mg (57%) of the title compound as a colorless solid.

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 470.

Reference Example 32

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolan-4 (S) -ylcarbonyl) 1,2,5,6-tetrahydropyrid-4) -yl) phenyl) oxazolidin-2-one

Prepared according to the general method of Reference Example 31 using 500 mg (1.47 mmol) of the compound of Reference Example 30, 298 mg (1.45 mmol) of 1,3-dicyclohexylcarbodiimide, 235 mg (1.40 mmol, 87% purity). (S) -2,3-Oisopropylidene glyceric acid and 218 mg (1.42 mmol) of 1-hydroxybenzotriazole in 15 mL of dichloromethane. Purification by flash chromatography (Merck silica gel 9385, 2.5% MeOH / dichloromethane) afforded 408 mg (59%) of the title compound as a colorless solid.

MS: ESP + (M + H) + = 470.

Example 40

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (R), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) phenyl) oxazolidin-2-one

Prepared according to the general method of Example 4, using 395 mg (0.84 mmol) of the compound of Reference Example 31 in 3 mL of 1N hydrochloric acid and 9 mL of THF. Purification by flash chromatography (Merck silica gel 9385, 8%)

MeOH / dichloromethane) gave 203 mg (56%) of the title compound as a colorless solid, mp 138-144 ° C.

@ ¹ H-NMR (300 MHz, DMSO-d6): _.delta . = 2.40-2.56 (m, partially unclear DMSO, 2H), 3.40-3.63 and 3.63-3.88 (m, 4H), 3.92 (dd, 1H), 4.11 (m, 2H), 4.20 (t, 1H), 4,304.54 (m, 3H), 4.68 (m, 1H), 4, 92 (m, 1H), 5.07 (m, 1H), 6.15 (m, 1H), 6.37 (d, 1H),

7.46 (d, 2H), 7.53 (d, 2H), 8.68 (d, TH).

MS: ESP + (M + H) + = 430.

Example 41

5 (R) -Isoxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) phenyl) oxazolidin-2-one

Prepared according to the general method of Example 4, using 408 mg (0.87 mmol) of the compound of Reference Example 32 in 3 mL of 1N hydrochloric acid and 9 mL of THF. Purification by flash chromatography (Merck silica gel 9385, 8%)

MeOH / dichloromethane) gave 124 mg (33%) of the title compound as a colorless solid, mp 200-202 ° C (dec.).

¹ H-NMR (300MHz, DMSO-d 6): δ = 2.38-2.56 (2H), 3.20-3.40 (m, partially unclear DMSO, 2H), 3.54 (m, 1H) 3.64 - 3.85 (m, 1 H), 3.92 (dd, 1 H), 4.12 (m, 2 H), · · · · · · · ···· ·· ·>

4.20 (t, 1H), 4.30-4.55 (m, 3H), 5.07 (m, 1H), 6.15 (m, 1H), 6.37 (d, 1H), 7 46 (d, 2H); 7.53 (d, 2H); 8.66 (d, 1H).

MS: ESP + (M + H) + = 430.

Example 42

5 (R) -1xoxazol-3-yloxymethyl-3- (4-methylthiophenyl) oxazolidin-2-one

Prepared according to the general method of Example 1, using 650 mg (2.72 mmol) of 5 (R) -hydroxymethyl-3- (4-methylthiophenyl) oxazolidin-2-one (prepared by reaction of 4-methylthioaniline and (R) -glycidyl butyrate), 243 mg (2.86 mmol) of 3-hydroxyisoxazole, 577 mg (2.86 mmol) of diisopropyl azodicarboxylate and 770 mg (2.94 mmol) of triphenylphosphine in 10 mL of THF. Purification by flash chromatography (Merck silica gel 9385,

EtOAc / isohexane (1/1)) gave 507 mg (61%) of the title compound as a colorless solid.

MS: ESP + (M + H) + = 307.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.47 (s, 3H), 3.97 (dd, 1H), 4.15 (t, 1H), 4.47-4.62 (m, 2H), 5.02 (m, 1H), 6.00 (d, 1H), 7.30 (d, 2H), 7.49 (d, 2H), 8.14 (d, 1H).

Example 43

5 (R) -1soxazol-3-yloxymethyl-3- (4-methylsulfinylphenyl) oxazolidin-2-one;

Example 44

5 (R) -1xoxazol-3-yloxymethyl-3- (4-methylsulfonylphenyl) oxazolidin-2-one

282 mg (70%, 1.14 mmol) of 3-chloroperoxybenzoic acid was added at -40 ° C to a solution of 340 mg (1.11 mmol) of Example 42 in 10 mL of dichloromethane. The reaction mixture is stirred at -30 ° C to -40 ° C for 3 hours, then diluted with 10 ml of dichloromethane, washed with aqueous sodium bisulfite solution, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to give a yellow solid. A colorless oil is obtained. High-speed cleaning

100 :::. ::

Chromatography (Merck 9385 silica gel, 5% MeOH / dichloromethane) afforded 275 mg (77%) of Example 43 and 31. mg of the compound of Example 44, both compounds as a colorless solid.

Example 43: MS: ESP + (M + H) + = 323.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.73 (s, 3H), 4.06 (dd, 1H), 4.22 (t, 1H), 4.50-4.65 (m, 2H), 5.08 (m, 1H), 6.00 (d, 1H), 7.69 (d, 2H), 7.77 (d, 2H), 8.15 (d, 1H).

Example 44: MS: ESP + (M + H) + = 339.

¹ H-NMR (300MHz, DMSO-d 6): δ = 3.14 (s, 3H), 3.98 (dd, 1H), 4.26 (t, 1H), 4.43 4.54 (m, 2H), 5.10 (m, 1H), 6.34 (d, 1H), 7.80 (d, 2H), 7.92 (d, 2H), 8.66 (d, 1H).

Example 45

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -hydroxy-3- (1-imidazoyl) propanoyl)) 1,2,5,6-tetrahydropyrid-4 -yl) -3,5-difluorophenyl) -oxazolidin-2-one

200 mg (0.45 mmol) of the compound of Reference Example 19 and 34 mg (0.50 mmol) of 1H-imidazole in 2 ml of 2-propanol were refluxed for 8 hours and the resulting solution was cooled to room temperature and purified by flash chromatography ( Merck silica gel 9385, 10% MeOH / dichloromethane) gave 83 mg (36%) of the title compound as a colorless solid.

¹ H-NMR (300MHz, DMSO-d _6): δ = 2.25 to 2.50 (m, 2H), 3.55 to 3.83 (m, 2H), 3.95 (dd, 1H) 4.00-4.40 (m, 5H), 4.44-4.56 (m, 2H), 4.56-4.68 (m, 1H), 5.11 (m, 1H), 5, 65 (d) and 5.75 (d) (1H), 5.87 (m, 1H), 6.37 (d, 1H), 6.85 (m, 1H), 7.15 (m, 1H) ), 7.36 (d,

2H), 7.58 (m, 1H), 8.68 (d, 1H).

MS: ESP + (M + H) + = 516.

Example 46

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (R, S) -hydroxy-3- (1,2,4-triazol-1-yl) propanoyl)) 1,2, 5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

Prepared according to the general method of Example 45 using 200 mg (0.45 mmol) of the compound of Reference Example 19 and 35 mg (0.50 mmol) of 1H-1,2,4-triazole in 2 ml.

101 ··· ·· · · · · * ··· ··········

Of 2-propanol. Purification by flash chromatography (Merck silica gel 9385, 10% MeOH / dichloromethane) afforded 84 mg (36%) of the title compound as a colorless solid.

MS: ESP + (M + H) + = 517.

1 H-NMR (300MHz, DMSO-d ₆ ): δ = 2.25-2.50 (m, 2H), 3.55-3.85 (m, 2H), 3.95 (dd, 1H), 4.00 - 4.40 (m, 5H), 4.40 - 4.55 (m, 2H), 4.68 - 4.82 (m, 1H), 5.12 (m, 1H), 5, 77 (d) and 5.81 (d) (1H), 5.90 (m, 1H), 6.77 (d, 1H), 7.35 (d, 2H), 7.95 (s, 1H) 8.44 (s, 1H).

8.68 (d, IH).

Example 47

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -acetoxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

126 mg (0.84 mmol) of (S) -2-acetoxypropionyl chloride was added dropwise at room temperature to a stirred suspension of 300 mg (0.76 mmol) of the compound of Reference Example 11 and 210 mg (1.63 mmol) Ν, Ν of diisopropylethylamine in 10 ml of dichloromethane. The reaction mixture was stirred at room temperature and purified by flash chromatography (Merck silica gel 9385, 2.5% MeOH / dichloromethane) to give 322 mg (90%) of the title compound as a colorless solid.

MS: ESP + (M + H) + = 474.

1 H-NMR (300MHz, CDCl ₃ ): δ = 1.48 (s) and 1.51 (s) (3H), 2.14 (s, 3H), 2.50-2.74 (m, 2H) ), 3.68 (m) and 3.96 (m) (3H), 4.05 - 4.36 (m, 3H), 4.47 - 4.62 (m, 2H), 5.04 (m) 1 H, 5.35-5.55 (m, 1 H), 5.97 (m, 1 H), 6.00 (d, 1 H), 7.20-7.30 (m, 2 H), 7, 45 (d, 1 H),

8.15 (d, IH).

Example 48

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

200 mg (0.42 mmol) of the compound of Example 47 in 10 ml of a saturated solution of ammonia in MeOH was stirred at room temperature for 18 hours and then cooled in ice water and

102. .:.:. ··.

··· · ························

9 9 9 9 9 9 9 9 9 9 9 9 »· 9 9 The colorless solid is filtered off. Washing with ice-cold methanol and diethyl ether and drying gave 156 mg (86%) of the title compound. MS: ESP + (M + H) + = 432.

¹ H-NMR (300MHz, DMSO-d _s): δ = 1.23 (s) and 1.25 (s) (3H), 2.33 to 2.50 (m, 2H), 3.52 3, 85 (m, 2H), 3.93 (dd, 1H), 4.02-4.38 (m, 3H), 4.40-4.60 (m, 2H), 4.85-5.00 ( m, 1H), 5.11 (m, 1H), 6.03 (m, 1H), 6.38 (d, 1H), 7.33 (dd, 1H), 7.41 (t, 1H), 7.52 (dd, 1 H), 8.68 (d, 1 H).

Example 49

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

Prepared according to the general method of Example 6 using 300 mg (0.76 mmol) of Reference Example 11, 114 mg (0.83 mmol) of acetoxyacetyl chloride, 88 mg (0.87 mmol) of triethylamine and 25 mg of 4- (dimethylamino) pyridine in 10 ml of dichloromethane. Purification by flash chromatography (silica gel Bond elut, 10 g, 1-2% MeOH / dichloromethane) afforded 230 mg (66%) of the title compound as a colorless solid.

MS: ESP + (M + H) + = 460.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.20 (s, 3H), 2.50-2.66 (m, 2H), 3.60 (t), and 3.83 (t) (2H 3.96 (dd, 1H), 4.10 (m) and 4.24 (m) (2H), 4.15 (t, 1H), 4.50-4.64 (m, 2H), 4.77 (s) and 4.81 (s) (2H), 5.04 (m, 1H), 5.90-6.00 (m, 1H), 6.00 (d, 1H), 7, 21-7.30 (m, 2H), 7.45 (d, 1H), 8.15 (d, 1H).

Example 50

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

Prepared according to the general method of Example 48 using 170 mg (0.37 mmol) of the compound of Example 49 in 10 mL of a saturated solution of ammonia in MeOH to give 121 mg (79%) of the title compound as a colorless solid.

MS: ESP + (M + H) + = 418.

103 ¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.52-2.62 (m, 2H), 3.48 (t) and 3.65 (t) (2H), 3.87 (t) and

3.95 (m) (3H), 4.16 (t, 1H), 4.22 (dd, 1H), 4.30 (m, 1H), 4.48-4.62 (m, 2H), 5.04 (m,

1H), 5.92 (m) and 6.00 (m) (1H), 6.00 (d, 1H), 7.20-7.30 (m, 2H), 7.43 (d, 1H) 8.15 (d, 1 H).

Example 51

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3- (3-pyridin-1-methylmethylbenzoyloxy) propanoyl)) -1,2,5,6-tetrahydropyrid-4 (yl) -3-fluorophenyl) oxazolidin-2-one chloride

0.40 g (0.89 mmol) of the compound of Example 12 is suspended in 20 ml of dichloromethane and 0.07 g (0.89 mmol) of pyridine and 0.2 g of 4-dimethylaminopyridine are added. 3-Chlorobenzoyl chloride was then added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The resulting solution was washed with water, dried over MgSO ₄ and purified by flash chromatography (Merck silica gel 9385, 5-10% MeOH in CH 2 Cl 2) to give, after trituration with diethyl ether, 0.30 g (42%) of the title compound as a light. yellow solid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.43 (partially unclear DMSO, 2H), 3.64-4.52 (m, 10H), 4.74 (m, 1H), 08 (m, 1H), 5.98 (m, 3H), 6.37 (m, 1H), 7.35 (m, 2H), 7.467.63 (m, 2H), 7.81 (m, 1H) ), 8.00 (m, 1H), 8.16 (m, 2H), 8.54 - 8.65 (m, 2H), 8.68 (m, 1H), 9.26 (m, 2H) .

MS: ESP ⁺ (M) ⁺ = 643.

Example 52

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3- (3-chloromethylbenzoyloxy) propanoyl)) -1,2,5,6-tetrahydropyrid-4-yl (3-Fluorophenyl) oxazolidin-2-one

0.50 g (1.12 M) of the compound of Example 12 was suspended in 20 mL of dichloromethane and 0.11 g (0.16 mmol) of triethylamine was added. 3-Chlorobenzoyl chloride was then added dropwise and the reaction mixture was stirred at room temperature for 2 hours. The resulting solution was washed with water, dried over MgSO ₄ and purified by flash chromatography (Merck silica gel 9385, 4-5% MeOH in CH 2 Cl 2) and after trituration with diethyl ether and c.

104 ^In isohexane, 0 is obtained by isohexane. 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 · 0 46 g (69%) of the title compound as a pale yellow solid containing some disubstituted derivative.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.45 (partially unclear DMSO, 2H), 3.65-3.98 (m, 3H), 3.98-4.25 (m, 2H) 4.31-4.55 (m, 4H), 4.70-4.87 (m, 4H), 5.07 (m, 1H),

5.71 (m, 1 H), 6.04 (m, 1 H), 6.41 (m, 1 H), 7.28-7.46 (m, 2 H), 7.46-7.59 (m, 2 H) ,

7.71 (m, 1H); 7.87-8.12 (m, 2H); 8.72 (m, 1H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 600.

Example 53

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3- (3-morpholinomethylbenzoyloxy) propanoyl)) -1,2,5,6-tetrahydropyrid-4-yl (3-Fluorophenyl) oxazolidin-2-one

0.10 g (0.17 mmol) of the compound of Example 52 is stirred in 3 ml of DMF and ca 10 mg of sodium iodide and 0.07 g (0.67 mmol) of morpholine are added and the reaction mixture is heated to 50 ° C for for 5 hours. The DMF was removed by evaporation and the residue was taken up in dichloromethane, washed with water, dried (MgSO ₄ ) and purified by chromatography (Merck silica gel 9385, 5-10% MeOH in CH 2 Cl 2) to yield 65 mg after trituration with diethyl ether and isohexane. (6%) of the title compound as an off-white solid.

¹ H-NMR (300MHz, DMSO-d 6): δ = 2.27 (m, 4H), 2.41 (partially unclear by the presence of DMSO, 2H), 3.40-3.59 (m, 6H), 3, 63-3.98 (m, 3H), 3.98-4.57 (m, 7H), 4.74 (m, 1H), 5.08 (m, 1H), 5.67 (m, 1H) 6.04 (m, 1H); 6.39 (m, 1H); 7.28-7.64 (m, 5H); 7.88 (m, 2H); 8.72 (m, 1H).

MS: ESP ⁺ (M + H) &lt; + & gt ^; = 651.

Example 54

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3- (3- (4-methylpiperazinomethyl) benzoyloxy) propanoyl)) -1,2,5,6-tetrahydropyridine) -4-yl) -3-fluorophenyl) oxazolidin-2-one •

Prepared according to the general method of example 53 using 0.10 g (0.17 mmol) of the compound of Example 52, about 10 mg of sodium iodide and 0.07 g (0.67 mmol) of Nmethylpiperazine. Purification by chromatography (Merck silica gel 9385, 5-10% MeOH in CH 2 Cl 2 - 10% MeOH + 1% ammonia in CH ₂ Cl ₂ ) gave 55 mg (50%) of the title compound as a white solid after trituration with isohexane.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.44 (partially unclear by the presence of DMSO, 5H), 2.62 (m, 4H), 3.21-3.35 (partially unclear by water, 4H) 3.55 (m, 2H), 3.65-3.84 (m, 2H), 3.92 (dd, 1H), 4.08-4.25 (m, 2H), 4.34 (m 1H, 4.45 (m, 4H), 4.75 (m, 1H), 5.08 (m, 1H), 5.62 (m, 1H), 6.02 (broad s, 1H), 6.36 (m, 1H); 7.38-7.60 (m, 5H);

7.88 (m, 2H); 8.68 (m, 1H).

MS: ESP + (M + H) + = 664.

Example 55

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3- (3-di-butylaminomethylbenzoyloxy) propanoyl)) -1,2,5,6-tetrahydropyrid-4 -yl) -3-fluorophenyl) oxazolidin-2-one

Prepared according to the general method of example 53 using 0.10 g (0.17 mmol) of the compound of Example 52, about 10 mg of sodium iodide and 0.07 g (0.67 mmol) of di-N-butylamine. Purification by chromatography (Merck silica gel 9385, 5-10% MeOH in CH 2 Cl 2, 10% MeOH + 1% ammonia in CH 2 Cl 2) gave 54 mg (47%) of the title compound as a white solid after trituration with isohexane.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 0.71 -0.89 (m, 6H), 1.13-1.43 (m, 8H), 2.31 (partially unclear DMSO, 6H) ), 3.33 (partially unclear with water, 2H), 3.42-3.59 (m, 2H), 3.67-3.97 (m, 3H), 3.97-4.56 (m, 5H) 4.74 (m, 1H); 5.08 (m, 1H); 5.67 (m, 1H);

1H), 6.03 (broad s, 1H), 6.38 (m, 1H), 7.28-7.63 (m, 5H), 7.87 (m, 2H), 8.69 (m, 1H).

MS: ESP + (M + H) + = 693.

Example 56

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-n-propyl-1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

106

500 mg (1.26 mmol) of the compound of Reference Example 11 is stirred in 10 ml of MeOH and about 0.5 ml of glacial acetic acid is added to adjust the pH to 4. 80.7 mg (1.39 mmol) is then added dropwise. of propanal) and the reaction mixture was stirred for 40 minutes.

Sodium cyanoborohydride (83.4 mg, 1.33 mmol) was added portionwise to the stirred solution. The reaction mixture was stirred an additional 30 minutes at room temperature. Then the reaction was cooled with 10% NaOAc and extracted with dichloromethane and the combined organic phases were dried over MgSO 4 and evaporated under reduced pressure. The resulting brown oil was triturated with ether to give 300.6 mg (59%) of the title compound as an orange oil.

MS: ESP + (M + H) + = 402.

¹ H-NMR (300MHz, DMSO-d _s): δ = 0.85 (t, 3H), 1.46 (m, 2H), 2.32 (t, 1H), 2.40 (br s, 2H 2.57 (t, 2H), 3.04 (d, 2H), 3.93 (dd, 1H), 4.19 (t, 1H), 4.48 (m, 2H), 5.08 (m,

1H), 5.97 (broad s, 1H), 6.37 (d, 1H), 7.29-7.40 (m, 2H), 7.49 (dd, 1H), 8.70 (d, 1H) 1H).

Example 57

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2-hydroxyethyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

To a stirred partial solution of 318 mg (0.80 mmol) of the compound of Reference Example 11 and 169 mg (2.01 mmol) of NaHCCH in 5 mL of ethanol was added dropwise 151 mg (1.21 mmol) of 2-bromoethanol under nitrogen. The reaction mixture was then heated at reflux for 20 hours. Add 200 ml water and the mixture was extracted with EtOAc and the combined organic phases were washed with saturated NaCl and dried over MgSO ₄ and evaporated under reduced pressure. The resulting yellow oil was triturated with ether to give 163 mg (50%) of the title compound as a yellow solid.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.40 (broad s, 2H), 2.49 (unclear DMSO, 2H), 2.63 (t, 2H), 3.09 (d 2H, 3.52 (m, 2H), 3.91 (dd, 1H), 4.19 (t, 1H), 4.39 (m, 1H), 4.45 (m, 2H), 5 05 (m, 1H), 5.96 (broad s, 1H), 6.37 (d, 2H), 7.25-7.38 (m, 2H), 7.47 (dd, 1H), 8 68 (d, 2H).

MS: ESP + (M + H) + = 404.

107

Example 58

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2-acetoxyethyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

To a stirred solution of 103 mg (0.26 mmol) of the compound of Example 57 and 77.4 mg (0.77 mmol) of triethylamine in 10 mL of dichloromethane was added dropwise 60.2 mg (0, 0 ° C) at 0 ° C under nitrogen. 77 mmol) of acetyl chloride. The reaction mixture was then allowed to warm to room temperature and stirred for 1 hour. Water is added, the organic phase is separated and washed with saturated NaCl, dried over MgSO4 and evaporated under reduced pressure. This afforded 110 mg (97%) of the title compound as a clear orange oil.

MS: ESP + (M + H) &lt; + & gt ^; = 446.

@ ¹ H-NMR (300 MHz, DMSCL3d): .delta. = 2.09 (s, 3H), 2.50 (broad s, 2H), 2.74 (m, 4H), 3.20 (broad s, 2H), 3.99 (m, 1H), 4.19-4.29 (m, 3H), 4.53 (m, 2H), 5.14 (m, 1H), 6.04 (broad s, 1H), 6.46 (d, 1H), 7.34-7.49 (m, 2H), 7.55 (dd, 1H), 8.75 (d, 1H).

Example 59

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxan-5-yl) -1,2,5,6-tetrahydropyrid-4-yl) - 3-fluorophenyl) oxazolidin-2-one

To a stirred partial solution of 600 mg (1.52 mmol) of the compound of Reference Example 11 in 15 mL MeOH was added dropwise 218 mg (1.67 mmol) at 0 ° C.

2,2-dimethyl-1,3-dioxan-5-one. The reaction mixture was allowed to warm to room temperature and stirred for 40 minutes. Sodium cyanoborohydride (100.4 mg, 1.60 mmol) was then added portionwise and the reaction stirred for an additional 48 hours. The reaction was cooled with 10% NaOAc and extracted with dichloromethane and the combined organic phases were dried over MgSO 4 and evaporated under reduced pressure. The reaction mixture was purified by MPLC (Merck silica gel 9385, 5% MeOH in dichloromethane). The solvent was removed to give an orange oil which was triturated with ether to give 295 mg (41%) of the title compound as an orange solid,

MS: ESP + (M + H) &lt; + & gt ^; = 474.

108

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 1.29 (s, 3H), 1.35 (s, 3H), 2.39 (broad s, 2H), 2.58 (m, 1H) ), 2.74 (m, 2H), 3.22 (d, 2H), 3.78 (m, 2H), 3.92 (m, 3H), 4.20 (t, 1H), 4.45 (m, 2H), 5.05 (m, 1H), 5.95 (broad s, 1H), 6.38 (d, 1H), 7.29-7.40 (m, 2H), 7.48 (dd, 1 H), 8.69 (d, 1 H).

Example 6

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (1- (hydroxymethyl) -2-hydroxyethyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidine- 2-on

To a stirred solution of Example 59 (203 mg, 0.43 mmol) in THF (15 mL) was added 1N HCl (10 mL). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was basified with ammonia solution until pH12 was reached. The reaction mixture was extracted with EtOAc and the combined organic phases were washed with saturated NaCl and then dried over MgSO ₄ and evaporated under reduced pressure. The resulting yellow oil was triturated with ether to give 167 mg (90%) of the title compound as a pale yellow solid.

MS: ESP + (M + H) &lt; + & gt ^; = 434.

@ ¹ H-NMR (300 MHz, DMSO-d6): .delta. = 2.39 (broad s, 2H), 2.59 (m, 1H), 2.84 (m, 2H),

3.38 (d, 2H), 3.51 (m, 4H), 3.91 (dd, 1H), 4.20 (t, 1H), 4.30 (broad s, 2H), 4.48 ( m, 2H), 5.08 (m, 1H), 5.96 (broad s, 1H), 6.37 (d, 1H), 7.27-7.38 (m, 2H), 7.48 (m, 2H) dd,

1H), 8.69 (d, 1H).

Reference Example 33

3,5-Difluoro-4- (1-methyl-4-hydroxyhexahydropyrid-4-yl) aniline

To a stirred solution of 3,5-difluoroaniline (7.0 g, 54 mmol) in THF (250 mL) was added dropwise under nitrogen and cooled to -74 ° C over 10 minutes.

78.6 mL of ⁿ BuLi (1.45M in hexanes, 0.114 mol). The reaction mixture was stirred at -74 ° C for 30 minutes. 12.4 g (0.114 mol) of chlorotrimethylsilane in 100 ml of anhydrous THF are then added dropwise over 10 minutes. The solution was allowed to warm to room temperature and then stirred for 40 minutes. The reaction mixture was recooled to -74 ° C and 43.0 mL (1.45M in hexanes, 62.4 mmol) of nBuLi was added dropwise over 10 minutes.

• ·

109 ································

Stir for an additional 3.5 hours at -74 ° C and dropwise over 10 minutes and add 7.90 g (70.5 mmol) of N-methyl-4-piperidone in 50 mL of anhydrous THF over 10 minutes. The reaction mixture was allowed to warm to ambient temperature over the weekend. The reaction mixture was acidified to pH < 1 and extracted with diethyl ether. The aqueous phase was separated and treated with 40% NaOH to pH 12 and then extracted with diethyl ether, and the combined organic phases were washed with saturated NaCl and dried over MgSO 4 and evaporated under reduced pressure. The resulting brown oil was triturated with cyclohexane to give 9.30 g (71%) of the title compound as a pale yellow solid.

¹ H-NMR (300MHz, DMSO-d _s): δ = 1.87 to 2.05 (m, 4H), 2.10 (s, 3H), 2.25 to 2.42 (m, 4H), 4.70 (s, 1H), 5.54 (s, 2H), 6.07 (dd, 2H).

MS: ESP + (M + H) &lt; + & gt ^; = 243; ESP - (M + H) - = 241.

Reference Example 34

3,5-Difluoro-4- (1-methyl-1,2,5,6-tetrahydropyrid-4-yl) aniline

Prepared according to the general method of Reference Example 2, using 9.0 g (37 mmol) of the compound of Reference Example 33 and 35 mL of concentrated sulfuric acid. Yield 8.20 g, 98%.

MS: ESP + (M + H) &lt; + & gt ^; = 225.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.25 (s, 5H), 2.50 (partially unclear with DMSO, 2H), 2.93 (m, 2H), 5.60 (broad) s, 1H), 5.66 (s, 2H), 6.15 (dd, 2H).

Reference Example 35

N-Benzyloxycarbonyl-3,5-difluoro-4- (1-methyl-1,2,5,6-tetrahydropyrid-4-yl) aniline To a stirred solution of 8.20 g (35.7 mmol) of Reference Example 34 in 250 ml of dichloromethane and 4.00 ml (49.4 mmol) of pyridine are added under a nitrogen atmosphere at -10 ° C and dropwise 7.49 g (43.9 mmol) of benzyl chloroformate in dichloromethane. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Water and ice are added and the organic phase is separated, washed with saturated NaCl, dried over MgSO4 and evaporated under reduced pressure. The resulting brown oil was purified by MPLC (Merck silica gel, 4-8% MeOH in dichloromethane). The solvent is removed and recovered.

110, a yellow oil was triturated with cyclohexane to give 7.60 g (58%) of the title compound as a pale yellow solid.

MS: ESP + (M + H) + = 359.

¹ H-NMR (300MHz, DMSO-d _s): δ = 2.29 (m, 5H), 2.54 (partly obscured by DMSO, 2H), 2.90 (m, 2H), 5.15 (s 2H, 5.73 (broad s, 1H), 7.15 (dd, 2H), 7.31-7.44 (m, 5H), 10.18 (s, 1H).

Reference Example 35A

5 (R) -Hydroxymethyl-3- (4- (1-methyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

To a stirred solution of 7.25 g (20.3 mmol) of the compound of Reference Example 35 in 100 mL of anhydrous THF was added dropwise 14.9 mL of ⁿ BuLi (1.45M) dropwise over 10 minutes under nitrogen and cooled to -74 ° C. in hexanes, 21.7 mmol). The reaction mixture was stirred at -74 ° C for 30 minutes. 3.18 g (22.1 mmol) of R-glycidyl butyrate are then added in one portion and the reaction mixture is allowed to warm to room temperature and stirred overnight. MeOH (10 mL) was added and the reaction stirred for 10 min. 150 ml of water and the mixture was extracted with EtOAc and the combined organic phases were washed with NaCl and dried over MgSO ₄ and evaporated under reduced pressure. The resulting oil was triturated with ether to give 4.51 g (69%) of the title compound as a pale yellow solid.

¹ H-NMR (300MHz, DMSO-d 6): δ = 2.25 (s, 3H), 2.31 (broad s, 2H), 2.53 (partially unclear with DMSO, 2H), 2.98 (m (2H), 3.55 (m, 1H), 3.67 (m, 1H), 3.82 (dd, 1H), 4.06 (t, 1H), 4.71 (m, 1H), 5 21 (m, 1H), 5.78 (broad s, 1H), 7.32 (dd, 2H).

MS: ESP + (M + H) + = 325.

There is no example 61

Example 62

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1-methyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one

• · · • · · · · · · · 111 • · · • · · · · · • · · • · · · · • · · · · ·

1.0 g (3.10 mmol) of Reference Example 35A, 0.39 g (4.59 mmol) of 3-hydroxyisoxazole, 1.21 g (4.63 mmol) of triphenylphosphine and 1.17 g (4.64 mmol) of diisopropyl azodicarboxylate in 60 mL of anhydrous THF was reacted using the general method of Example 1. The resulting product was purified by MPLC (Merck silica gel, 5% MeOH in dichloroethane). The solvent was removed to give 0.93 g (77%) of a clear orange glass.

MS: ESP + (M + H) + = 392.

¹ H-NMR (300MHz, DMSO-d ₆ ): δ = 2.25 (s, 3H), 2.30 (broad s, 2H), 2.54 (partially obscured by the presence of DMSO, 2H), 2.97 ( m, 2H), 3.90 (dd, 1H), 4.19 (t, 1H), 4.46 (m, 2H), 5.09 (m, 1H), 5.78 (broad s, 1H) 6.37 (d, 1H); 7.31 (dd, 2H); 8.68 (d, 1H).

Example 63

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-acetamidopropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin -2-on

To a solution of 500 mg (1.25 mmol) of the compound of Reference Example 11 in 25 mL of anhydrous DMF stirred at room temperature was sequentially added: 220 μΙ (2.0 mmol) of N-methylmorpholine, 220 mg (1.5 mmol) of N- acetyl-L-isoserine, 213 mg (1.5 mmol) of 1-hydroxybenzotriazole and 287 mg (1.5 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were added and the mixture was stirred for 18 hours. DMF was removed by high vacuum rotary evaporation and the residue was purified by MPLC (Merck silica gel 9385, eluting with 5% MeOH / CH ₂ Cl ₂ ) and triturated with diethyl ether to afford 430 mg (70%) of the title compound as a white solid.

MS: ES +. (M + H) + = 489.

NMR (300MHz, DMSO-d ₆₎ δ / ppm: 1.78 (s, 3H), 2.21 (m, 2H), 3.10 (m, 1H), 3.30 (m, 1H), 3, 70 (m, 2H), 3.92 (dd, 1H), 4.08 (dd, 2H), 4.21 (m, 2H), 4.43 (m, 2H), 5.08 (m, 1H) 5.18 (t, 1H), 6.00 (br s, 1H), 6.38 (d, 1H), 7.28-7.41 (m, 2H), 7.50 (dd, 1H) )

7.92 (m, 1H); 8.65 (d, 1H).

Reference Example 36

112

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -tert-butoxycarbonylamino-3-hydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl Oxazolidin-2-one

Prepared using the method described in Example 63 using the following amount of reagents: 1.00 g (2.5 mmol) of the compound of Reference Example 11; 50 ml DMF; 440 μΙ (4.0 mmol) of N-methylmorpholine; 616 mg (3.0 mmol) of N-BOC-Lserine; 425 mg (3.0 mmol) of 1-hydroxybenzotriazole; 575 mg (3.0 mmol) of hydrochloride

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. 1.2 g (96%) of the title compound are obtained as a white foam.

NMR (300MHz, DMSO-d ₆₎ δ / ppm: NMR (300MHz, _DMSO-d6)? / Ppm:

1.37 (s, 9H), 2.40 (m, partially unclear, 2H), 3.46 (m, 1H), 3.57 (m, 1H), 3.70 (m, 2H), 3, 93 (dd, 1H), 4.06 (s, 1H), 4.20 (m, 2H), 4.46 (m, 3H), 4.81 (t, 1H), 5.08 (m,

1H), 6.02 (brs, 1H), 6.38 (d, 1H), 6.86 (dd, 1H), 7.35 (m, 2H), 7.50 (d, 1H), 8, 69 (d, 1 H).

MS: ES ^&lt; ^{+ &gt};. (M + H) &lt; + & gt ^; = 547.

Reference Example 37

5 (R) -1xoxazol-3-yloxymylethyl-3- (4- (1- (2 (S) -amino-3-hydroxy-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) ) Oxazolidin-2-one ml of TFA was added to 250 mg (0.46 mmol) of the compound of Reference Example 36 with gas evolution and the mixture was stirred at room temperature for 5 minutes to give a yellow solution. Excess TFA was removed by rotary evaporation and trituration with diethyl ether gave 230 mg (89%) of the title compound as a yellow solid.

MS: ES ^&lt; ^{+ &gt};. (M + H) &lt; + & gt ^; = 447.

Example 64

5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S) -acetamido-3-hydroxy-propanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl Oxazolidin-2-one

113

To a stirred solution of 168 mg (0.3 mmol) of the compound of Reference Example 37 and 202 mg (2.4 mmol) of sodium bicarbonate in 10 mL of a 1: 1 mixture of acetone and water cooled to 0 ° C was added dropwise under nitrogen. 70.6 mg (0.90 mmol) of acetyl chloride in 1.0 mL of acetone and stirred for 5 h. Acetone was removed by rotary evaporation, water and 1N HCl were added to pH 5, and the mixture was extracted with CH ₂ Cl ₂ (3x), the organic phase separated to give 30 mg (20%) of the title compound as a white solid. . MPLC was then performed (Merck 9385, eluting with 10% MeOH / CH ₂ Cl ₂ ) and triturated with diethyl ether.

MS: (M + H) &lt; + & gt ^; = 489.

NMR (400MHz, _DMSO-d) δ / ppm: (300MHz DMSO-d ₆₎ δ / ppm: 1.84 (s, 3H), 2.47 (d, partially unclear, 2H), 3.46 (m, 1H), 3.62 (m, 1H), 3.73 (m, 2H), 3.96 (t, 1H), 4.10 -

4.30 (m, 3H), 4.50 (m, 2H), 4.88 (m, 2H), 5.11 (m, 1H), 6.03 (br s, 1H), 6.40 (m, 2H) d, 1H),

7.35 (dd, 1 H), 7.41 (m, 1 H), 7.52 (dd, 1 H), 8.07 (t, 1 H), 8.70 (d, 1 H).

Example 65

3- (4- (3-Hydroxy-1-azetidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

230 mg (0.5 mmol) of 3- (4- (3-tert-butyldimethylsilyloxy-1-azetidinyl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidine are dissolved in 10 ml of tetrahydrofuran and the mixture was cooled to 0 ° C under nitrogen. A solution of 1 ml of a solution of tetra-butylammonium fluoride (1M, 1 mmol) was then added and the mixture was cooled to room temperature. 2 ml of water are added and the mixture is evaporated to dryness. The residue was purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity of 0 to 2.5% MeOH in dichloromethane. The relevant fractions were combined and evaporated and redissolved in EtOAc and 96 mg of the desired product precipitated by addition of isohexane.

MS (ESP): 350 (MH ⁺ ) for C ₁₆ H ₁₅ FN ₃ O ₅

NMR (DMSO-d 6) δ: 3.52 (t, 2H); 3.83 (dd, IH); 4.09 (overlap m, 3H); 4.45 (m, 2 H);

4.51 (quintet, 1H); 5.00 (m, IH); 5.53 (d, IH); 6.37 (d, IH); 6.56 (t, IH); 7.11 (dd, IH);

7.37 (dd, IH); 8.66 (d, IH).

114 ··· ·· ···············

The intermediate for this compound was prepared as follows:

3- (4- (3-tert-Butyldimethylsilyloxy-1-azetidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

2.47 g (6.25 mmol) of 3- (4- (3-tert-butyldimethylsilyloxy-1-azetidinyl) -3-fluorophenyl-5 (R) hydroxymethyloxyoxazolidin-2-one (WO 96/13502), 580 mg ( 6.86 mmol) of 3-hydroxyisoxazole and 1.58 g (7.8 mmol) of tributylphosphine were dissolved in 100 ml of dry tetrahydrofuran by stirring under nitrogen and the mixture was cooled in an ice bath and 1.96 g (7 ml) was added dropwise over 10 minutes. The solution was stirred for 18 hours and the temperature was allowed to rise to ambient temperature. Silica gel, eluting with a gradient of 50 to 75% EtOAc in isohexane, combined the relevant fractions and evaporated to give 1.31 g of an oil.

NMR (DMSO-d ₆ ) δ: 0.00 (s, 6H); 0.79 (s, 9H); 3.47 (t, 2 H); 3.77 (dd, IH); 4.07 (t, IH);

4.11 (t, 2 H); 4.39 (m, 2 H); 4.65 (quintet, 1H); 4.95 (m, IH); 6.30 (d, IH); 6.53 (t, IH); 7.06 (dd, IH); 7.33 (dd, IH); 8.61 (d, IH).

Example 66

3- (4- (3-Oxo-1-azetidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

349 mg (1 mmol) of 3- (4- (3-hydroxy-1-azetidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one is dissolved in 5 ml of nitrogen after nitrogen of dry DMSO and treated with 502 mg (3.15 mmol) of pyridine-sulfur trioxide complex in 5 mL of dry DMSO for 10 minutes. The solution was stirred for 3 hours, poured into 100 mL of water and extracted with EtOAc (3 x 50 mL). The organic extracts were washed with water (3 x 50 mL), saturated brine (50 mL) and dried (magnesium sulfate). The residue was purified by chromatography on a 10 g Mega Bond Elut® silica gel column eluting with a gradient of increasing polarity from 0 to 5% MeOH in dichloromethane. The relevant fractions were combined, evaporated and the residue triturated with diethyl ether to give 227 mg of the desired product.

MS (ESP): 348 (MH ⁺ ) for C 16 H 14 FN 3 O 5; 380 (MH ⁺ + MeOH) for C ₁₇ H ₁₈ FN ₃ O ₆ ;

NMR (DMSO-d ₆ ) δ: 3.89 (dd, 1H); 4.16 (t, IH); 4.47 (m, 2 H); 4.76 (s, 4H); 5.04 (m, IH); 6.38 (d, IH); 6.77 (d, IH); 7.21 (dd, IH); 7.49 (dd, IH); 8.67 (d, IH).

Example 67

3- (4- (4-tert-Butoxycarbonylpiperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one g (25.3 mmol) 3- (4- (4-tert-butoxycarbonylpiperazin-1-yl) -3-fluorophenyl) -5 (R) hydroxymethyl-oxazolidin-2-one (WO 93/23384), 2.58 g (30 mmol) of 3-hydroxyisoxazole and 9.95 g (37, 8 mmol) of triphenylphosphine was dissolved in 300 ml of anhydrous tetrahydrofuran and the mixture was cooled to 4 ° C under nitrogen. 6.04 g (30 mmol) of diisopropyl azodicarboxylate are then added dropwise over 10 minutes and stirring is continued at the same temperature for 2 hours. The mixture was evaporated to dryness and the residue was purified by silica gel flash chromatography eluting with 50% EtOAc in isohexane. The relevant fractions were combined and evaporated to give 10.2 g of the desired product.

MS (ESP): 463 (MH ⁺ ) for C ₂₂ H ₂₇ FN ₄ O ₆

NMR (DMSO-d 6) δ: 1.39 (s, 9H); 2.91 (t, 4H); 3.45 (t, 4 H); 3.87 (dd, IH); 4.14 (t, 1 H);

4.44 (m, 2 H); 5.03 (m, IH); 6.35 (d, IH); 7.06 (t, 1 H); 7.18 (dd, IH); 7.36 (dd, IH);

8.66 (d, IH).

Example 68

3- (4- (Piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) -oxazolidin-2-one dihydrochloride

10.24 g (22 mmol) of 3- (4- (4'-tert-butoxycarbonylpiperazin-1-yl) -3-fluorophenyl-5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one is suspended in 150 ml. A solution of hydrogen chloride (5M) in 75 ml of ethanol was added at 0 [deg.] C. The resulting solution was left to stand at ambient temperature for 18 hours and the product was precipitated, after diluting with 200 ml of diethyl ether. .

Microanalysis: Found: C, 46.9, H, 4.8, N, 12.2%; C17H19FN4O4, 2HCl requires C, 46.9; H, 4.6; N, 12.9%.

116

MS (ESP): 363 (MH +) for C 24 H 25 FN 4 O 2

NMR (DMSO-d 6) δ: 3.19 (s, 8H); 3.87 (dd, IH); 4.16 (t, IH); 4.45 (m, 2 H); 5.03 (m, 1H) 6.36 (d, 1H); 7.11 (t, 1 H); 7.22 (dd, 1H) 7.51 (dd, 1H); 8.68 (d, IH); 9.47 (br. 2H).

Example 69

3- (4- (4- (2 (R), 3-Dihydroxypropanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

A solution of 162 mg (1.1 mmol) of 2,2-dimethyl-1,3-dioxolane-4 (R) -carboxylic acid in 20 ml of dichloromethane was cooled to 4 ° C with stirring and gradually treated with 227 mg (1 1 mmol) of dicyclohexylcarbodiimide and 147 mg (1.1 mmol) of 1-hydroxybenzotriazole and the mixture was stirred at the same temperature for 1 hour. 129 mg (1 mmol) of Ν, Ν-diisopropylethylamine are then added followed by 399 mg (0.92 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazole) dihydrochloride. 3-yloxymethyl) oxazolidin-2-one. The mixture was stirred for 2 hours and the temperature was allowed to rise to room temperature. The solid was filtered off and the organic solution was washed with water (2 x 20 ml), dried over magnesium sulphate and evaporated to dryness. The residue was purified by chromatography on a 10 g Mega Bond Elut® silica gel column eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane. The relevant fractions were combined, evaporated to give 82 mg of the desired product.

MS (ESP): 451 (MH ⁺ ) for C 20 H 23 FN 4 O 7

NMR (DMSO-d _s) δ: 2.93 (br m, 4H); 3.49 (m, 2 H); 3.66 (br m, 4H); 3.88 (dd, IH);

4.14 (t, 1 H); 4.34 (m, IH); 4.43 (m, 2 H); 4.37 (m, IH); 4.92 (d, IH); 5.04 (m, IH); 6.36 (d, IH); 7.06 (t, 1 H); 7.20 (dd, IH); 7.51 (dd, IH); 8.67 (d, IH).

Example 70

3- (4- (4- (2 (S), 3-Dihydroxypropanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

Using the same procedure and scale as in Example 69, but starting from 2,2-dimethyl-1,3-dioxolane-4 (S) -carboxylic acid, 75 mg of the title compound is obtained.

MS (ESP): 451 (MH ⁺ ) for C 20 H 23 FN 4 O 7

NMR (DMSO-d 6) δ: 2.93 (br m, 4H); 3.45 (m, IH); 3.53 (m, IH); 3.65 (br m, 4H); 3.87 (dd, IH); 4.16 (t, IH); 4.34 (dd, IH); 4.45 (m, 2 H); 4.67 (t, IH); 4.92 (d, IH); 5.04 (m, IH); 6.37 (d, IH); 7.07 (t, 1 H); 7.20 (dd, IH); 7.51 (dd, IH); 8.67 (d, IH).

Example 71

3- (4- (4- (2- (2-Methoxyethoxy) ethoxy) acetylpiperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

To a solution of 399 mg (0.92 mmol) of 3- (4-piperazin-1-yl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) -oxazolidin-2-one dihydrochloride in 10 ml of pyridine was added 0.31 ml (2.2 mmol) of triethylamine and 197 mg (1 mmol) of 2- (2- (2-methoxyethoxy) ethoxy) acetyl chloride. The mixture was stirred for 18 hours, evaporated to dryness, and the residue dissolved by chromatography on a 10 g Mega Bond Elut® silica gel column eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane. The relevant fractions were combined, evaporated to give 95 mg of the desired product.

MS (ESP): 523 (MH ⁺ ) for C ₂₄ H ₁₃ FN ₄ O ₈

NMR (DMSO-d ₆ ) δ: 2.93 (br m, 4H); 3.21 (s, 3H); 3.41 (t, IH); 3.47 (t, 2 H); 3.54 (overlap m, 8H); 3.87 (dd, IH); 4.14 (t, 1 H); 4.16 (s, 2 H); 4.45 (m, 2 H); 5.03 (m, IH);

6.36 (d, IH); 7.06 (t, 1 H); 7.20 (dd, IH); 7.51 (dd, IH); 8.67 (d, IH).

Example 72

3- (4- (4- (3-Hydroxy-2-hydroxymethylpropanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one

450 mg (0.82 mmol) of 3- (4- (4- (2-phenyl-1,3-dioxan-5-ylcarbonyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazole-3) -yloxymethyl) oxazolidin-2-one was dissolved in 10 mL of 4: 1 acetic acid and water and stirred at ambient temperature for 18 hours. After evaporation to • ·

118 dry residue was azeotroped with 15 ml and the residual gum was purified by chromatography on a 20 g Mega Bond Elut® silica gel column eluting with gradient with increasing polarity from 5 to 10% MeOH in dichloromethane. The relevant fractions were combined, evaporated to give 237 mg of the desired product.

MS (ESP): 465 (MH ⁺ ) for C 21 H 25 FN 4 O 7

NMR (DMSO-d 6) δ: 2.94 (br d, 4H); 3.05 (quintet, 1H); 3.47 (m, 4H); 3.65 (br d, 4H);

3.87 (dd, IH); 4.15 (t, 1 H); 4.46 (m, 2 H); 4.56 (t, 2 H); 5.03 (m, IH); 6.34 (d, IH); 7.06 (t, 1 H); 7.19 (dd, IH); 7.50 (dd, IH); 8.67 (d, IH).

The intermediate for this compound was prepared as follows:

3- (4- (4- (2-Phenyl-1,3-dioxan-5-ylcarbonyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

To a stirred solution of 2-phenyl-1,3-dioxan-5-ylcarboxylic acid (478 mg, 2.3 mmol) and N-hydroxysuccinimide (291 mg, 2.5 mmol) in anhydrous dichloromethane (25 mL) was added 522 mg at 0 ° C. (2.5 mmol) of dicyclohexylcarbodiimide. The mixture was stirred at 0 ° C for 1 hour. 623 mg (4.8 mmol) of Ν, Ν-diisopropyiethylamine were added followed by 1 g (2.3 mmol) of 3- (4- (piperazine-1-) - dihydrochloride over 5 minutes. yl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one The temperature was allowed to rise to ambient temperature and stirring was continued for 3 hours The solid was filtered off, washed with 2 x 20 mL dichloromethane The combined organic phases were evaporated to dryness, and the residue was purified by chromatography on a 20 g Mega Bond Elut® silica gel column eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane The relevant fractions were combined and evaporated to give 890 mg. of the desired intermediate as a mixture of cis and trans isomers.

MS (ESP): 553 (MH ⁺ ) for C 28 H 29 FN 4 O 7

NMR (DMSO-d 6) δ: 2.93 (br d, 4H); 3.58 (br. 4H); 3.78 (dd, IH); 3.96-4.30 (overlap m, 6H); 4.45 (m, 2 H); 5.03 (m, IH); 5.53 (2.times.s, 1H); 6.36 (d, IH); 7.06 (t, 1 H); 7.21 (dd, 1H); 7.34 (m, 5H); 7.51 (dd, IH); 8.66 (d, IH).

Example 73 ··

119 · · · t t t t • • • • • • • • • • • • • • • •

3- (4- (4-Acetoxyacetylpiperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

1.29 g (3 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol) -3yloxymethyl) oxazolidin-2-one dihydrochloride was suspended under nitrogen at ambient temperature. in 25 ml of dichloromethane. 1.06 g (10.5 mmol) of triethylamine is added and after 15 minutes a solution is obtained. The mixture was cooled to 4 ° C and acetoxyacetyl chloride (410 mg, 3 mmol) was added dropwise. The mixture was stirred at ambient temperature for 18 hours, washed with 2 x 20 mL water, 20 mL saturated brine, and dried over magnesium sulfate. The residue was purified by chromatography on a 20 g Mega Bond Elut® silica gel column eluting with a gradient of increasing polarity from 0 to 5% MeOH in dichloromethane. The relevant fractions were combined, evaporated to give 1.16 g of the desired product.

MS (ESP): 463 (MH ⁺ ) for ^C 21 H 23 FN 4 O 7

NMR (DMSO-d 6) δ: 2.07 (s, 3H); 2.94 (br. 4H); 3.53 (brd, 4H); 3.87 (dd, IH); 4.16 (t, IH); 4.45 (m, 2 H); 4.78 (s, 2 H); 5.03 (m, IH); 6.36 (d, IH); 7.08 (t, 1 H); 7.21 (dd, IH);

7.48 (dd, IH); 8.66 (d, IH).

Example 74

3- (4- (4-Hydroxyacetylpiperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

0.93 g (2 mmol) of 3- (4- (4-acetoxyacetyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one and 417 mg ( 3 mmol) of potassium carbonate was stirred at ambient temperature under nitrogen in 20 ml of MeOH for 4 hours. The mixture is evaporated to dryness, dissolved with 80 ml of dichloromethane, washed with 2 x 30 ml of water, 30 ml of saturated brine and dried over magnesium sulfate. Filtration and evaporation gave 0.59 g of the desired product.

MS (ESP) 421 (MH ⁺ ) for C ₁₉ H ₂₁ FN ₄ O _S

NMR (DMSO-d ₆ ) δ: 2.93 (br, 4H); 3.48 (brs, 2H); 3.60 (brs, 2H); 3.86 (dd, IH); 4.11 (d, 2 H); 4.15 (t, 1 H); 4.45 (m, 2 H); 4.58 (d, IH); 5.04 (m, IH); 6.37 (d, IH); 7.06 (t,

1H); 7.21 (dd, IH); 7.51 (dd, IH); 8.66 (d, IH).

120 *.: ·: ·: ::

• · ··· ····· · · ··· · · ·

Example 75

3- (4- (4-Acetylpiperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

The title compound was prepared using essentially the method described in Example 73, starting from 0.59 g (1.35 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - dihydrochloride. (isoxazol-3-yloxymethyl) oxazolidin-2-one and acetyl chloride. Purification by chromatography eluting with increasing gradient polarity from 0 to 2.5% MeOH in dichloromethane gave 142 mg of the desired product.

MS (ESP): 405 (MH ^&lt; ^{+ &gt;} ) for C19H21FN3O4

NMR (DMSO-d 6) δ: 2.02 (s, 3H); 2.93 (br d, 4H); 3.55 (br. 4H); 3.87 (dd, IH); 4.16 (t, IH); 4.45 (m, 2 H); 5.04 (m, IH); 6.36 (d, IH); 7.06 (t, 1 H); 7.20 (dd, IH); 7.51 (dd,

1H); 8.66 (d, IH).

Example 76

3- (4- (4 - ((3R) -3-Hydroxy-4-trimethylammonobutanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one chloride 200 mg (0.33 mmol) of 3- (4- (4 - ((3 R) -3-acetoxy-4-trimethylammonobutanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - ( isoxazol-3yloxymethyl) oxazolidin-2-one and 67 mg (0.49 mmol) of potassium carbonate were stirred at ambient temperature under nitrogen in 20 mL of MeOH for 5 hours. The mixture was evaporated to dryness, the solid was triturated with water, filtered and washed with 20 mL of water to give 137 mg of the desired product.

MS (ESP): 506 (M ⁺ ) for C 24 H 33 FN 5 OS

NMR (DMSO-d ₆ ) δ: 2.51 (dd, 1H); 2.65 (dd, IH); 2.93 (br d, 4H); 3.14 (s, 9H); 3.61 (brs, 4H); 3.87 (dd, IH); 4.17 (t, IH); 4.47 (m, 3H); 5.05 (m, IH); 5.74 (br. 1H); 6.38 (d, IH); 7.07 (t, 1 H); 7.23 (dd, IH); 7.52 (dd, IH); 8.69 (d, IH).

The intermediate for this compound was prepared as follows:

• ·

121 • · · ··············

3- (4- (4 - ((3R) -3-Acetoxy-4-trimethylammonobutanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one- chloride

527 mg (2.2 mmol) of 3 (R) -3-acetoxy-4-trimethylammoniumbutanoic acid (see J. Org. Chem., 1967, 32, 3989) is stirred in 3 ml of thionyl chloride at ambient temperature for 3 hours to obtain a solution. The excess thionyl chloride was evaporated and the residue azeotroped with toluene and then dissolved in 10 ml of anhydrous dichloromethane. This solution was added dropwise at 4 ° C to a solution of 0.87 g (2 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidine dihydrochloride -2-one and 404 mg (4 mmol) of triethylamine in 10 mL of anhydrous dichloromethane. The mixture was stirred at ambient temperature for 18 hours and then evaporated to dryness. The residue was dissolved in 20 ml of brine and purified by chromatography on an HP20SS resin column eluting with increasing gradient polarity from 0 to 10% acetonitrile in water. The relevant fractions were combined, evaporated to dryness, dissolved in 50 ml of deionized water and freeze-dried to give 0.39 g of the desired product.

MS (ESP): 548 (M ⁺ ) for C 26 H 35 FN 5 O 7

NMR (DMSO-d 6) δ: 2.05 (s, 3H); 2.82 (d, 2 H); 2.94 (br m, 4H); 3.12 (s, 9H); 3.55 (br m, 4H); 3.58-3.78 (overlap, 2H); 3.87 (dd, IH); 4.17 (t, IH); 4.46 (m, 2 H); 5.04 (m, IH); 5.49 (m, IH); 6.38 (d, IH); 7.06 (t, 1 H); 7.21 (dd, IH); 7.51 (dd, IH); 8.68 (d, IH).

Example 77:

3- (4- (4-Methoxycarbonylpiperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

866 mg (2 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one dihydrochloride was suspended under nitrogen at ambient temperature at 40 ° C. ml of dichloromethane. 707 mg (7 mmol) of triethylamine are added followed by 190 mg (2 mmol) of methyl chloroformate. The mixture was stirred at ambient temperature for 2 hours, washed with 2 x 50 mL water, 50 mL saturated brine, and dried over magnesium sulfate. After filtration and evaporation, the residue was triturated with diethyl ether to give 689 mg of the desired product. MS (ESP): 421 (MH ⁺ ) for C ₁₉ H ₂₁ FN ₄ O ₆ · ·

122 • · # ·· ··· ·····················

NMR (DMSO-d ₆ ) δ: 2.93 (t, 4H); 3.52 (td, 4H); 3.62 (s, 3H); 3.89 (dd, IH); 4.16 (t,

1H); 4.46 (m, 2 H); 5.04 (m, IH); 6.37 (d, IH); 7.08 (t, 1 H); 7.20 (dd, IH); 7.52 (dd,

1H); 8.67 (d, IH).

Example 78

3- (4- (4- (3- (4-Imidazolyl) acryloyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

690 mg (5 mmol) of 3- (4-imidazole) acrylic acid are suspended under nitrogen in 5 ml of dichloromethane and 10 ml of thionyl chloride and one drop of DMF are added. The mixture was stirred at ambient temperature for 18 hours, the excess thionyl chloride was evaporated and the residue was azeotroped with 2 x 50 mL dichloromethane. The acid chloride was suspended in 30 mL of dichloromethane, cooled to 4 ° C and a solution of 866 mg (2 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - dihydrochloride was added dropwise. (isoxazol-3-yloxymethyl) oxazolidin-2-one and 2.02 g (20 mmol) of triethylamine in 25 mL of anhydrous dichloromethane. The mixture was stirred at ambient temperature for 18 hours and the insoluble material was filtered off. The organic layer was treated with water (50 mL), further insoluble materials were removed, washed with brine, and dried over magnesium sulfate. After evaporation to dryness, the residue is dissolved in 5 ml of ethanol and treated with excess ethanol saturated with hydrogen chloride, and 122 mg of the desired product precipitates in the form of the chloride salt. Microanalysis: Found: C, 48.2, H, 5.0, N, 14.4%; C23H23FN6O5.2HCl.H2O requires C, 48.1; H, 4.7; N, 14.4%.

MS (ESP): 483 (MH ⁺ ) for C 23 H 23 FN 6 O 5

NMR (DMSO-d 6) δ: 3.01 (br, 4H); 3.86 (complex, covered with H ₂ O, ca. 5H); 4.16 (t, IH);

4.45 (m, 2 H); 5.04 (m, IH); 6.36 (d, IH); 7.08 (t, 1 H); 7.21 (dd, 1H); .42 (d, 1H); 7.51 (dd, IH); 7.71 (d, IH); 7.97 (s, 1 H); 8.66 (d, IH); 9.20 (s, 1 H).

Example 79

3- (4- (4- (4-Imidazolylacetyl) -piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

123

Using the procedure of Example 78, but starting from 810 mg (5 mmol) of 4-imidazolylacetic acid hydrochloride salt, the acid chloride was prepared and reacted with piperazine. After 18 hours, the mixture was diluted with 20 mL of saturated sodium carbonate solution. The organic layer was washed with water (2 x 50 mL), then brine (30 mL) and dried over magnesium sulfate. The residue was purified by chromatography on a 40 g Mega Bond Elut® silica gel column eluting with 10% MeOH in dichloromethane. The relevant fractions were combined and evaporated, the residue was dissolved in 5 ml of ethanol and treated with excess ethanol saturated with hydrogen chloride, then an excess of diethyl ether was added to precipitate 124 mg of the desired product as the hydrochloride salt.

Microanalysis: Found: C, 47.3, H, 5.1, N, 14.8%; C22H23FN6O5.2HCl.H2O requires C, 47.0, H, 4.8, N, 15.0%.

MS (ESP): 471 (MH ⁺ ) for C ₂₂ H ₂₃ FN ₅ O ₅

NMR (DMSO-d ₆ ) δ: 2.95 (br m, 2H); 3.03 (br m, 2H); 3.63 (br m, 2H); 3.68 (br m,

2H); 3.95 (s + m, H ₂ O superimposed, ca. 3H); 4.17 (t, IH); 4.45 (m, 2 H); 5.04 (m, IH); 6.36 (d, IH); 7.08 (t, 1 H); 7.22 (dd, IH); 7.44 (s, 1 H); 7.52 (dd, IH); 8.67 (d, IH); 9.01 (s,

1H); 14.38 (br, 2H).

Example 80: 3- (4- (4- (3- (4-Imidazolyl) propanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2- he

460 mg (0.63 mmol) of 3- (4- (4- (3- (1-triphenylmethyl-4-imidazolyl) propanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazole-3- yloxymethyl) oxazolidin-2-one was dissolved in a mixture of 20 mL of ethanol and 10 mL of MeOH, cooled to 0 ° C and treated with a 5 mL (3.8 M) solution of hydrogen chloride in ethanol. The mixture was stirred at ambient temperature for 48 hours, adjusted to pH 8 with triethylamine and evaporated to dryness. The residue was purified by chromatography on a 10 g Mega Bond Elut® silica gel column eluting with a gradient of 0 to 20% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 60 mg of the desired product.

MS (ESP): 485 (MH ⁺ ) for C 23 H 25 FN 5 O 5

NMR (DMSO-d ₆ ) δ: 2.59 (t, 2H); 2.74 (t, 2 H); 2.92 (br. 4H); 3.60 (br. 4H); 3.90 (dd,

1H); 4.16 (t, IH); 4.46 (m, 2 H); 5.06 (m, IH); 6.38 (d, IH); 6.76 (s, 1 H); 7.06 (t, 1 H);

7.22 (dd, IH); 7.59 (s, 1 H); 7.63 (dd, IH); 8.67 (d, IH); 11.72 (br. 1H).

Intermediates for this compound are prepared as follows:

• ·

124

3- (4- (4- (3- (1-Triphenylmethyl-4-imidazolyl) propanoyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2 -he

420 mg (1.1 mmol) of 3- (1-triphenylmethyl-4-imidazolyl) propionic acid are suspended in 10 ml of dichloromethane under nitrogen and treated sequentially with 227 mg (1.1 mmol) of dicyclohexylcarbodiimide and 149 mg (1.1 mmol). mmol) of 1-hydroxybenzotriazole and the mixture is then stirred at ambient temperature for 30 minutes. To this was added a solution of 435 mg (1 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one dihydrochloride and 258 mg (2 mmol) of Ν, Ν-diisopropylethylamine in 5 ml of dichloromethane. The mixture was stirred at the same temperature for 18 hours, the solids were filtered off and the organic phase was purified by chromatography on a 20 g Mega Bond Elut® silica gel column eluting with a gradient of increasing polarity from 0 to 15% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 460 mg of the desired product.

MS (ESP): 727 (MH ⁺⁾ for C ₄₂ H ₆ O ₃ 9FN ₅

NMR (DMSO-d ₆ ) δ: 2.61 (t, 2H); 2.70 (t, 2 H); 2.87 (br. 4H); 3.54 (br. 4H); 3.88 (dd,

1H); 4.17 (t, IH); 4.45 (m, 2 H); 5.06 (m, IH); 6.37 (d, IH); 6.66 (d, IH); 7.03 (t, 1 H); 7.06 (d, 6H); 7.21 (dd, IH); 7.25 (s, 1 H); 7.36 (m, 9H); 7.52 (dd, IH); 8.67 (d, IH).

3- (1- (Triphenylmethyl-4-imidazolyl) propionic acid)

1.0 g (7.1 mmol) of 3- (4-imidazolyl) propionic acid is suspended in a mixture of 5 ml of dichloromethane and 25 ml of dichloromethane. acetonitrile. 781 mg (7.2 mmol) of trimethylsilyl chloride was added and the mixture was heated under reflux for 4 hours. 1 ml of triethylamine is added and refluxing is continued for 15 minutes. The mixture was cooled, 1 ml of triethylamine was added, followed by 1.99 g (7.1 mmol) of chlorotrifenylmethane in 10 ml of dichloromethane, and the mixture was stirred at ambient temperature for 2 hours. MeOH (20 mL) was added, the mixture was stirred for 30 min

125 and evaporated to dryness. 50 ml of water are added to the residue and the pH of the mixture is adjusted to 8-8.5 with triethylamine. The precipitate was filtered off, washed with diethyl ether and dried to give 2.25 g of the desired product.

MS (ESP): 383 (MH ⁺ ) for C 25 H 22 N 2 O 2

NMD (DMSO-d ₆ ) δ: 2.48 (t, 2H); 2.77 (t, 2 H); 6.65 (s, 1 H); 7.08 (d, 6H); 7.08 (d, 6H);

7.29 (s, 1 H); 7.36 (m, 9H); 12.10 (br. 1H).

Example 81

3- (4- (4-Methanesulfonyl-piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) -oxazolidin-2-one

433 mg (1 mmol) of 3- (4-piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one dihydrochloride in 15 ml of pyridine and 15 ml of dichloromethane are treated with 353 mg (3.5 mmol) of triethylamine and the mixture was stirred at ambient temperature for 30 minutes. 138 mg (1.2 mmol) of methanesulfonyl chloride are added and the mixture is stirred for 18 hours. The mixture was diluted with 50 mL of dichloromethane, washed with 2 x 25 mL of water, 25 mL of saturated brine, and dried over magnesium sulfate. After evaporation to dryness and azeotropic distillation with 10 ml of toluene, the residue is triturated with diethyl ether to give 365 mg of the desired product.

MS (ESP): 441 (MH ⁺⁾ for C ₄ O ₈ H2iFN _S

NMR (DMSO-d 6) δ: 2.91 (s, 3H); 3.05 (br m, 4H); 3.26 (br m, 4H); 3.87 (dd, IH); 4.15 (t, 1 H); 4.42 (dd, IH); 4.48 (dd, IH); 5.05 (m, IH); 6.36 (d, IH); 7.10 (t, 1 H); 7.21 (dd, IH); 7.48 (dd, IH); 8.66 (d, IH).

Example 82 (3- (4- (4-Chloroacetyl-piperazin-1-yl) -3-fluoro-phenyl) -5 (R) - (isoxazol-3-yloxymethyl) -oxazolidin-2-one

114 mg (1 mmol) of chloroacetyl chloride are added at ambient temperature to a stirred solution of 435 mg (1 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) dihydrochloride of oxazolidin-2-one and 302 mg (3 mmol) of triethylamine in 10 ml of dichloromethane. After 10 minutes, the reaction mixture was purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with dichloromethane. The relevant fractions were combined and evaporated to give 390 mg of the desired product.

and

126 ··· · · · · · ··········

MS (ESP): 439 (MH ⁺⁾ for C ₁₉ H ₃ 0 _{5 4} oCIFN

NMR (DMSO-d 6) δ: 2.93 (br m, 1H); 2.99 (br m, 2H); 3.59 (br m, 4H); 3.87 (dd, IH);

4.16 (t, IH); 4.40 (s, 2 H); 4.46 (m, 2 H); 5.04 (m, IH); 6.36 (d, IH); 7.07 (t, 1 H); 7.21 (dd, IH); 7.51 (dd, IH); 8.66 (d, IH).

Example 83

3- (4- (4-Morpholinoacetyl-piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) -oxazolidin-2-one

The preparation of Example 82 is repeated until the chloroacetamide formation step. The mixture was then cooled to 0 ° C and treated with 0.262 mg (3 mmol) of morpholine and then stirred for 48 hours and allowed to warm to ambient temperature. The reaction mixture was evaporated to dryness and purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of 0 to 10% MeOH in dichloromethane. The relevant fractions were combined and evaporated after trituration with diethyl ether to give 420 mg of the desired product.

MS (ESP): 490 (MHO for C ₂₃ H _2S FN ₅ O ₆

NMR (CDCl ₃ ) δ: 2.52 (br m, 4H); 3.03 (m, 4 H); 3.23 (s, 2 H); 3.71 (m, 4H); 3.77 (m,

4H); 3.93 (dd, IH); 4.14 (t, 1 H); 4.50 (dd, IH); 4.57 (dd, IH); 5.01 (m, IH); 6.00 (d,

1H); 6.92 (t, IH); 7.26 (dd, IH); 7.47 (dd, IH); 8.16 (d, IH).

Example 84

3- (4- (4 - ((2S, 4R) -1-Acetyl-4-hydroxy-2-pyrrolidinylcarbonyl) -piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yl) -benzamide; oxymethyl) oxazolidin-2-one

A suspension of (2S, 4R) -1-acetyl-4-hydroxy-2-pyrrolidinecarboxylic acid (173 mg, 1 mmol) in dichloromethane (10 ml) and DMF (2 ml) was treated successively with dicyclohexylcarbodiimide (227 mg, 1.1 mmol) and 149 mg ( 1.1 mmol) of 1-hydroxybenzotriazole and the mixture is then stirred at ambient temperature for 1 hour. Then a solution of 435 mg (1 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one dihydrochloride and 258 mg (2 mmol) is added. Ν, Ν-diisopropylethylamine in 5 ml

127 of dichloromethane and stirred for 18 hours. The solids are filtered off, the organic solution is evaporated to dryness and the residue is purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 15% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 210 mg of the desired product after trituration with diethyl ether.

MS (ESP): 518 (MH ⁺ ) for C ₂₄ H ₂₈ FN ₅ O ₇

NMR (CDCl 3) δ: 2.08 (s, 3H); 2.16 (m, 3H); 2.45 (m, IH); 3.05 (m, 3 H); 3.19 (m, IH); 3.62 (overlap m, 2H); 3.91 (dd overlap m, 4H); 4.13 (t, IH); 4.49 (dd, IH); 4.56 (dd,

1H); 4.66 (m, IH); 5.01 (overlap m, 2H); 5.99 (d, IH); 6.92 (t, IH); 7.27 (dd, IH); 7.48 (dd, IH); 8.15 (d, IH).

Example 85

3- (4- (4 - ((2S, 4R) -1-Methyl-4-hydroxy-2-pyrrolidinylcarbonyl) -piperazin-1-yl) -3-fluoro-phenyl) -5 (R) - (isoxazol-3-yloxymethyl) -oxazolidine- 2-on

A solution of 435 mg (1 mmol) of 3- (4- (piperazin-1-yl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one dihydrochloride and 258 mg (2 mmol) of Ν, Νdiisopropylethylamine in 2 ml of DMF is added under stirring at room temperature to a stirred solution of 145 mg (1 mmol) of (2S, 4R) -1-methyl-4-hydroxy-2-pyrroloidinecarboxylic acid (see Angewandte Chemie, 1995, 9, 1095) and 380 mg (1 mmol) of O- (7-azobenzonitrile-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate in 5 mL of DMF. 387 mg (3 mmol) of Ν, Ν-diisopropylethylamine was added and the mixture was stirred at ambient temperature for 18 hours. After evaporation to dryness, the residue is partitioned between 5 ml of water and 10 ml of dichloromethane. The separated organic layer was evaporated and the residue purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 256 mg of the desired product.

MS (ESP): 490 (MH ⁺ ) for C 14 H 15 FN 5 O 5

NMR (CDCl 3) δ: 1.96 (m, 1H); 2.07 (m, IH); 2.36 (m, IH); 2.38 (d, 3H); 3.02 (m, 4H);

3.33 (dd, IH); 3.71 (overlap m, 5H); 3.89 (dd, IH); 4.18 (t, IH); 4.30 (m, IH); 4.46 (m, IH); 4.53 (dd, IH); 4.59 (m, IH); 5.03 (m, IH); 6.28 (d, IH); 7.08 (t, 1 H); 7.20 (dd, IH); 7.46 (dd, IH); 8.57 (d, IH).

128

Example 86

3- (4 - ((3R) -3-Amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

108 mg (0.23 mmol) of 3- (4 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one was Dissolve under nitrogen in 7 mL of dichloromethane and treat with 3 mL of TFA at ambient temperature. The mixture was stirred for 48 hours, evaporated to dryness and azeotroped with 2 x 10 mL toluene. The resulting gum was transferred to 5 mL of ethanol and a 2 mL (3.8 M) solution of hydrogen chloride in ethanol was added. Excess ethyl ether was added and 80 mg of the title compound precipitated as the hydrochloride.

MS (ESP): 363 (MH ⁺ ) for C ₁₇ H ₁₉ FN ₄ ^O ₄

NMR (DMSO-d 6) δ: 1.99 (m, 1H); 2.23 (m, IH); 3.25 (m, IH); 3.41 (m, IH); 3.52 (m, 2 H); 3.84 (dd, IH); 4.14 (t, 1 H); 4.42 (m overlap H ₂ O ca. ₃ H); 5.02 (m, IH); 6.37 (d, IH); 6.79 (t, IH); 7.15 (dd, IH); 7.44 (dd, IH); 8.34 (br. 2H); 8.68 (d, IH).

Intermediates for this compound are prepared as follows:

3-Fluoro-4 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) nitrobenzene

Dissolve 16.03 g (0.101M) of 3,4-difluoronitrobenzene in 300 ml of acetonitrile and treat with 32.63 g (0.253 M) of Ν, di-diisopropylethylamine and 20.65 g (0.111 M) of 3 (R) 3. -tert-butoxycarbonylaminopyrrolidine. The mixture was stirred and refluxed for 18 hours. The solvent was evaporated and the residue was treated with 300 mL EtOAc and 200 mL water. The organic weight was washed with 150 mL of water, 10% citric acid in water (2 x 50 mL) and dried over magnesium sulfate. Evaporation gave 32.7 g of the desired product as a yellow solid of sufficient quality for further use without purification.

MS (ESP): 326 (MH ⁺ ) for C ₁₅ H ₂₀ FN ₃ O ₄

NMR (CDCl 3) δ: 1.43 (s, 9H); 1.85 (m, IH); 2.25 (m, IH); 3.44 (dt, IH); 3.65 (overlap m, 2H); 3.84 (dm, IH); 4.34 (br m, IH); 4.69 (br. 1H); 6.53 (t, IH); 7.87 (dd, IH); 7.92 (dd, IH).

129

5-Amino-2 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) fluorobenzene

32.7 g (0.101 M) of 3-fluoro-4 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidine) nitrobenzene are dissolved in 500 ml of EtOAc and hydrogenated on a palladium catalyst (10% on carbon, 7.5 g). ) at atmospheric pressure to the theoretical gas consumption. After filtration through celite and evaporation, 29.85 g of the desired product is obtained in the form of a red gum of sufficient quality and used without further purification.

MS (ESP): 296 (MH ⁺ ) for C ₁₅ H ₂₂ FN ₃ O 2

NMR (CDCl ₃ ) δ: 1.44 (s, 9H); 1.82 (m, IH); 2.27 (m, IH); 3.11 (m, 2 H); 3.37 (m, 2 H);

3.43 (br. 2H); 4.27 (br m, IH); 4.82 (br. 1H); 6.38 (dd, IH); 6.44 (dd, IH); 6.57 (t, 1 H).

5-Ethoxycarbonylamino-2 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) fluorobenzene

27.33 g (0.093 M) of 5-amino-2 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) fluorobenzene are dissolved in 150 ml of dry pyridine and cooled to 0 ° C under nitrogen with stirring. Ethyl chloroformate (11.01 g, 0.102 M) was added dropwise and the mixture was stirred at the same temperature for 30 minutes. 250 ml of ice water are added and stirring is continued for 1 hour. The precipitate formed is cooled, washed thoroughly with water and dried to give 33.6 g of a product of sufficient quality for use without purification.

MS (ESP): 368 (MH ⁺ ) for C ₁₈ H ₂₆ FN ₃ O ₄

NMR (DMSO-d ₆ ) δ: 1.21 (t, 3H); 1.36 (s, 9H); 1.90 (m, IH); 2.05 (m, IH); 3.04 (m,

1H); 3.20 (m, IH); 3.32 (m, IH); 3.40 (m, IH); 4.02 (br. 1H); 4.05 (q, 2 H); 6.62 (t, IH); 7.02 (d, IH); 7.08 (d, IH); 7.22 (d, IH); 9.38 (br. 1H).

3- (3-Fluoro-4 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) phenyl) -5 (R) hydroxymethyl-oxazolidin-2-one

33.6 g (0.092 M) of 5-ethoxycarbonylamino-2 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) fluorobenzene are dissolved in 300 ml of dry tetrahydrofuran under nitrogen, cooled to -70 ° C and added dropwise 100.7 ml over 30 minutes

130 of lithium tert-butoxide solution (1 M in tetrahydrofuran) while maintaining the temperature below -65 ° C. The mixture was stirred for 5 minutes, 14.52 g (0.101 M) of (R) -glycidyl butyrate was added and stirring was continued at -65 ° C for 1 hour and the temperature was raised to ambient temperature over 16 hours. The mixture was treated with 50 mL of MeOH, stirred at ambient temperature for 1 hour, and the precipitate was collected and washed well with tetrahydrofuran to give 21.8 g of the desired product.

MS (ESP): 396 (MH ⁺ ) for C ₁₉ H ₂₆ FN ₃ O ₅

NMR (DMSO-d ₆ ) δ: 1.36 (s, 9H); 1.80 (m, IH); 2.07 (m, IH); 3.09 (m, IH); 3.26 (t,

1H); 3.35 (m, IH); 3.49 (m, 2 H); 3.62 (m, IH); 3.73 (dd, IH); 3.98 (t, IH); 4.04 (m,

1H); 4.63 (m, IH); 5.15 (t, 1 H); 6.70 (t, IH); 7.09 (dd overlapping br, 2H); 7.39 (dd, IH).

3- (4 - ((3R) -3-tert-Butoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one g (12.7 mmol) 3- (3-fluoro-4 - ((3R) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) phenyl) 5 (R) -hydroxymethyloxazolidin-2-one, 2.15 g (25.3 mmol) of 3-hydroxyisoxazole and 6.39 g (25.3 mmol) of 1,1 '- (azodicarbonyl) dipepiridine was suspended by stirring in 100 ml of dry tetrahydrofuran under nitrogen and cooled in an ice bath to 5 ° C. (3 mmol) of tributylphosphine and the solution was stirred for 18 hours and allowed to warm to room temperature The reduced compound was evaporated to dryness and the residue triturated with ether and purified by chromatography on a 90 g Biotage silica gel column, eluting with increasing polarity gradient 50-75% EtOAc in isohexane The relevant fractions were combined and evaporated to give 3.92 g of the desired product.

MS (ESP): 463 (MH ⁺ ) for C 22 H 27 FN 4 O 6

NMR (DMSO-d 6) δ: 1.38 (s, 9H); 1.81 (m, IH); 2.08 (m, IH); 3.10 (m, IH); 3.25 (t,

1H); 3.36 (m, IH); 3.48 (m, IH); 3.84 (dd, IH); 4.05 (m, IH); 4.12 (t, IH); 4.44 (m,

2H); 5.02 (m, 1 H), 6.36 (d, 1 H); 6.71 (t, 1 H); 7.11 (dd overlapping br, 2H); 7.38 (dd, IH);

8.66 (d, IH).

Example 87

131

3- (4- (1,4-Dioxa-8-azaspiro [4.5] decan-8-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

3.52 g (10 mmol) of 3- (4- (1,4-dioxa-8-azaspiro [4.5] decan-8-yl) -3-fluorophenyl) -5 (R) hydroxymethyl-oxazolidin-2-one, 893 mg (10.05 mmol) of 3-hydroxyisoxazole and 3.03 g (12 mmol) of triphenylphosphine are dissolved by stirring in 75 ml of tetrahydrofuran under a nitrogen atmosphere. The mixture was cooled in an ice bath and 2.33 g (12 mmol) of diisopropyl azodicarboxylate was added dropwise over 10 minutes. The solution was stirred for 18 hours and allowed to warm to ambient temperature. Dilute the mixture with 750 mL EtOAc, wash the organic layer with 3 x 500 mL water, dry over magnesium sulfate and evaporate. The residue was purified by MPLC on silica gel eluting with a gradient between 0.25% and 1% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 3.58 g of product. MS (ESP): 420 (MH ⁺ ) for C ₂₀ H ₂₂ FN ₃ O _s

NMR (DMSO-d _s) δ: 1.73 (t, 4H); 3.03 (t, 4 H); 3.86 (dd, IH); 3.90 (s, 4H); 4.14 (t, 1 H);

4.42 (dd, 1H) 4.47 (dd, 1H); 5.03 (m, 1 H), 6.35 (d, 1 H); 7.08 (t, 1 H); 7.17 (dd, IH);

7.47 (dd, IH); 8.65 (d, IH).

Intermediates for this compound are prepared as follows:

4- (1,4-Dioxa-8-azaspirol [4,5] decan-8-yl) -3-fluoronitrobenzene

15.53 g (0.098 M) of 3,4-difluoronitrobenzene are dissolved in 150 ml of acetonitrile and then treated with 31.5 g (0.244 M) of Ν, di-diisopropyiethylamine and 15.36 g (0.107 M) of 1,4-dioxa. -8azaspiro [4,5] decane. The mixture was stirred and refluxed for 18 hours. After cooling, the product precipitated as a yellow and a solid and was filtered to give 16.1 g of product; an additional 8.43 g of product can be further obtained by concentrating the residues.

MS (ESP): 283 (MH ⁺ ) for C ₁₃ H ₁₅ FN ₂ O ₄

NMR (CDCl ₃ ) δ: 1.86 (t, 4H); 3.41 (t, IH); 4.00 (s, 4H); 6.91 (t, 1 H); 7.89 (dd, IH);

7.96 (dd, IH).

5-Amino-2- (1,4-dioxa-8-azaspirol [4,5] decan-8-yl) fluorobenzene

132 · β · 9 · 9 9 9 · · · «« «« «« «« «« «« «« «9 9 9 9 · ·· ··

Starting from 24.48 g (0.087 M) of 4- (1,4-dioxa-8-azaspiro [4,5] decan-8-yl) -3-fluoronitrobenzene, the title compound is prepared in an amount of 19.3 g essentially in the same manner as the corresponding intermediate of Example 86,

MS (ESP): 253 (MH ⁺ ) for C ₁₃ H ₁₇ FN ₂ O ₂

NMR (DMSO-d ₆ ) δ: 1.69 (t, 4H); 2.84 (t, IH); 3.86 (s, 4H); 4.91 (s, 2 H); 6.28 (m, 2 H);

6.75 (t, 1 H).

5-Ethoxycarbonylamino-2- (1,4-dioxa-8-azaspirol [4,5] decan-8-yl) fluorobenzene

Starting from 19.26 g (0.076 M) of 5-amino-2- (1,4-dioxa-8-azaspiro [4.5] decane-8-fluorobenzene), the title compound is prepared in an amount of 20.5 g in substantially the same manner. according to the corresponding intermediate of Example 86.

MS (ESP): 325 (MH ⁺ ) for C ₁₆ H ₂₁ FN ₂ O ₄

NMR (DMSO-d _s) δ: 1.21 (t, 3H); 1.71 (t, 4 H); 2.96 (t, 4H); 3.88 (s, 4H); 4.09 (q, 2 H);

6.95 (t, IH); 7.09 (dd, IH); 7.27 (dd, IH); 9.54 (s, 1 H).

3- (4- (1,4-Dioxa-8-azaspirol [4,5-decan-8-yl) -3-fluorophenyl) -5 (R) hydroxymethyl-oxazolidin-2-one

Starting from 22.9 g (0.071 M) of 5-ethoxycarbonylamino-2- (1,4-dioxa-8azaspiro [4,5] decan-8-yl) fluorobenzene, the title compound is prepared in an amount of 17.8 g in substantially the same manner as the corresponding intermediate of Example 86.

MS (ESP): 353 (MH ⁺ ) for C 17 H 21 FN 2 O 5

NMR (DMSO-d 6) δ: 1.83 (t, 4H); 3.09 (t, 4 H); 3.69 (dd, IH); 3.82 (dd, IH); 3.88 (dd,

1H); 3.96 (s, 4H); 4.07 (t, IH); 4.72 (m, IH); 4.92 (s, IH); 7.05 (t, 1 H); 7.15 (dd, IH);

7.46 (dd, IH).

Example 88

3- (4- (4-Oxopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

133 ·· · · ··· · · · · φ · · · · · · · · · · · • ·

ΦΦΦ φ ♦ · · φ φ φ

3.58 g (8.52 mmol) of 3- (4- (1,4-dioxa-8-azaspiro [4.5] decan-8-yl) -3-fluorophenyl) -5 (R) (isoxazole-3) -yloxymethyl) oxazolidin-2-one is dissolved in a mixture of 50 ml of glacial acetic acid and 50 ml of water and the mixture is heated at 50 ° C for 12 hours. The solvent was evaporated, the residue azeotroped with 50 ml of toluene, partitioned between 150 ml of EtOAc and 100 ml of water. The organic layer was washed with 2 x 100 mL saturated aqueous sodium bicarbonate, 100 mL water, dried over magnesium sulfate and evaporated. The residue was purified by chromatography on a 90 g Biotage silica gel column, eluting with a gradient of 5: 1 EtOAc to isohexane to EtOAc. The relevant fractions were combined to give 2.84 g of the desired product.

MS (ESP): 376 (MH ⁺⁾ for C ₁₈ Hi ₈ FN ₃ O ₅

NMR (CDCl ₃ ) δ: 2.61 (t, 4H); 3.37 (t, 4 H); 3.93 (dd, IH); 4.14 (t, 1H); 4.50 (dd, IH);

4.57 (dd, 1H) 5.02 (m, 1H); 6.00 (d, 1 H), 6.98 (t, 1 H); 7.14 (dd, IH); 7.49 (dd, IH);

8.15 (d, IH).

Example 89

3- (4- (4-Hydroxypiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

173 mg (0.46 mmol) of 3- (4- (4-oxopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one are dissolved in 5 ml of ethanol, The solution was treated with 18 mg (0.48 mmol) of sodium borohydride and heated at reflux for 1 hour. The solvent was evaporated, 5 ml of water was added to the residue, then the mixture was neutralized with 1N hydrochloric acid, extracted with 3 x 10 ml of dichloromethane and dried over magnesium sulfate. Evaporation gave 76 mg of the desired product.

MS (ESP): 376 (MH ⁺ ) for C ₁₈ H ₂₀ FN ₃ O ₅

NMR (CDCl 3) δ: 1.60 (br, ca. 1 H); 1.76 (m, 2 H); 2.05 (m, 2 H); 2.85 (m, 2 H); 3.32 (m,

2H); 3.85 (m, IH); 3.91 (dd, IH); 4.12 (t, IH); 4.48 (dd, IH); 4.55 (dd, IH); 4.98 (m,

1H); 6.00 (d, IH); 6.98 (br. 1H); 7.11 (dd, IH); 7.42 (dd, IH); 8.12 (d, IH).

Example 90 • ·

134 ··· ···················

3- (4- (4-Aminopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

375 mg (1 mmol) of 3- (4- (4-oxopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one is dissolved in 10 mL of MeOH, per solution The reaction mixture was treated with ammonium acetate (771 mg, 10 mmol) and sodium cyanoborohydride (440 mg, 7 mmol) and refluxed for 4 hours. The mixture was neutralized with 1 N hydrochloric acid, water (15 ml) was added, extracted with dichloromethane (3.times.15 ml), and the mixture was dried over magnesium sulfate. Evaporation gave 334 mg of the desired product.

MS (ESP): 377 (MH ⁺ ) for C ₁₈ H ₂₁ FN ₄ O ₄

NMR (CDCl ₃ ) δ: 1.53 (br, 4H); 1.94 (m, 2 H); 2.77 (overlap m, 3H); 3.38 (m, 2 H); 3.92 (dd, IH); 4.13 (t, IH); 4.47 (dd, IH); 4.55 (dd, IH); 4.99 (m, IH); 6.00 (d, IH); 6.94 (t, 1 H); 7.12 (dd, IH); 7.40 (dd, IH); 8.15 (d, IH).

Example 91

3- (4- (4-Hydroxyiminopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

125 mg (0.33 mmol) of 3- (4- (4-oxopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one are dissolved in 5 ml of MeOH and 5 ml of dichloromethane and stirred at ambient temperature under nitrogen. Thereafter, the mixture was treated with hydroxylamine hydrochloride (27 mg, 0.39 mmol) and sodium acetate (65 mg, 0.79 mmol) and stirring was continued for an additional 4 hours. The mixture was filtered, evaporated and the residue partitioned between 10 ml of water and 10 ml of dichloromethane. The organic layer was washed with 10 mL saturated sodium bicarbonate, 10 mL water, dried over magnesium sulfate and evaporated to dryness. The residue was purified by chromatography on a 5 g Mega Bond Elut® silica gel column, eluting with 1% MeOH in dichloromethane. The relevant fractions were combined to give 74 mg of the desired product.

MS (ESP): 391 (MH ⁺ ) for C ₁₈ H ₁₉ FN ₄ O ₅

• · · 9 9 99 99 135 • · · 9 9 9 9 9 • * · • · · · · 9 9 9 9 9

NMR (DMSO-d ₆ ) δ: 2.36 (t, 2H); 2.62 (t, 2 H); 3.02 (t, IH); 3.08 (t, 2 H); 3.87 (dd, IH);

4.16 (t, 1H) 4.42 (dd, 1H) 4.49 (dd, 1H); 5.04 (m, IH); 6.37 (d, 1H); 7.08 (t, 1H); 7.21 (dd, IH); 7.50 (dd, IH); 8.67 (d, IH); 10.38 (s, 1 H).

Example 92

3- (4- (4-Methoxycarbonylaminoiminopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

125 mg (0.33 mmol) of 3- (4- (4-oxopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one are dissolved in 5 ml of MeOH and 5 ml of dichloromethane and 34 mg (0.37 mmol) of methyl carbazate are added and the mixture is stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated and the residue was purified by chromatography on a 5 g Mega Bond Elut® silica gel column, eluting with a gradient of 0 to 1% MeOH in dichloromethane. The relevant fractions were combined to give 98 mg of the desired product.

MS (ESP): 448 (MH ⁺ ) for C ₂₀ H ₂₂ FN ₅ O ₆

NMR (CDCl 3) δ: 2.53 (t, 2H); 2.67 (t, 2 H); 3.18 (t, 2 H); 3.22 (t, 2 H); 3.83 (s, 3H); 3.92 (dd, IH); 4.14 (t, 1 H); 4.49 (dd, IH); 4.57 (dd, IH); 5.01 (m, IH); 6.01 (d, IH); 6.96 (t, IH); 7.13 (dd, IH); 7.47 (dd, IH); 7.79 (s, 1 H); 8.16 (d, IH).

Example 93

3- (4- (4- (2-Hydroxyethyl) aminoiminopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-3-one

125 mg (0.33 mmol) of 3- (4- (4-oxopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one are dissolved in 5 ml of MeOH and 5 ml of dichloromethane and 29 mg (0.37 mmol) of 2-hydroxyethylhydrazine were added and the mixture was stirred at ambient temperature under nitrogen for 18 hours. The mixture was evaporated and the residue was purified by chromatography on a 5 g Mega Bond Elut® silica gel column, eluting with a gradient of 0 to 1.5% MeOH in dichloromethane. The relevant fractions were combined to give 98 mg of the desired product.

MS (ESP): 434 (MH ⁺ ) for C ₂₀ H ₂₄ FN ₅ O ₅ · ·

136

NMR (DMSO-d 6) δ: 2.34 (t, 2H); 2.43 (t, 2 H); 3.04 (m, 4H); 3.47 (q, 2 H); 3.76 (q, IH);

3.87 (dd, IH); 4.16 (t, IH); 4.43 (overlap m, 4H); 5.04 (m, IH); 5.73 (br. 1H); 6.37 (d, IH); 7.07 (t, 1 H); 7.18 (dd, IH); 7.50 (dd, IH); 8.67 (d, IH).

Example 94

3- (4- (4-Methanesulfonaminopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-3-one

249 mg (0.66 mmol) of 3- (4- (4-aminopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one in 20 ml of dichloromethane are cooled in An ice bath was treated with 140 mg (1.4 mmol) of triethylamine and 160 mg (1.4 mmol) of methanesulfonyl chloride, and the mixture was stirred for 18 hours and the temperature was allowed to rise to ambient temperature. The solution was washed with 3 x 5 mL water and the residue was purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of 0 to 5% MeOH in dichloromethane. The relevant fractions were combined to give 38 mg of the desired product.

MS (ESP): 455 (MH ⁺ ) for C ₁₉ H ₂₃ FN ₄ O ₆ S

NMR (CDCl 3) δ: 1.74 (m, 2H); 2.12 (m. 2H); 2.78 (t, 2 H); 3.01 (s, 3H); 3.34 (d, 2 H);

3.47 (m, IH); 3.91 (dd, IH); 4.12 (t, IH); 4.34 (d, IH); 4.48 (dd, IH); 4.56 (dd, IH);

4.99 (m, IH); 5.99 (d, IH); 6.92 (t, IH); 7.11 (dd, IH); 7.43 (dd, IH); 8.14 (d, IH).

Example 95

3- (4- (4-Methoxycarbonylaminopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

Using essentially the technique of Example 94, starting from 249 mg (0.66 mmol) of 3- (4- (4-aminopiperidin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidine- Of 2-one and 70 mg (0.74 mmol) of methyl chloroformate in place of methanesulfonyl chloride and chromatography gave 125 mg of the desired product.

MS (ESP): 435 (MH ⁺⁾ for C ₂ oH _{2 4} 0 ₆ 3FN

137

NMR (CDCl 3) δ: 1.65 (m, 2H); 2.06 (m, 2 H); 2.78 (td, 2 H); 3.34 (dm, 2 H); 3.67 (d overlap with br, 4H); 3.92 (dd, IH); 4.11 (t, IH); 4.48 (dd, IH); 4.55 (dd, IH); 4.63 (m, IH);

4.99 (m, IH); 5.99 (d, IH); 6.93 (t, IH); 7.11 (dd, IH); 7.43 (dd, IH); 8.15 (d, IH).

Example 96

3- (4 - ((3R) -3-Methoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

Using essentially the procedure of Example 94, starting from 249 mg (0.62 mmol) of 3- (4 - ((3R) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazole) hydrochloride -3yloxymethyl) oxazolidin-2-one and 189 mg of the title compound are obtained without chromatography.

MS (ESP): 441 (MH ⁺⁾ for C ₈ H _{21 S} FN4O

NMR (CDCl 3) δ: 1.94 (m, 1H); 2.25 (m, IH); 3.02 (s, 3H); 3.27 (m, IH); 3.38 (t, IH);

3.45 (t, IH); 3.61 (m, IH); 3.92 (dd, IH); 4.05 (m, IH); 4.19 (t, IH); 4.48 (dd, IH);

4.54 (dd, IH); 5.08 (m, IH); 6.37 (d, IH); 6.83 (t, IH); 7.19 (dd, IH); 7.45, 7.48 (dd overlap br, 2H); 8.76 (d, IH).

Example 97

3- (4 - ((3R) -3-Methanesulfonamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

Using essentially the procedure of Example 94, starting from 232 mg (0.58 mmol) of 3- (4 - ((3R) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazole) hydrochloride 3-yloxymethyl) oxazolidin-2-one and 66 mg (0.7 mmol) of methyl chloroformate instead of methanesulfonyl chloride are obtained, without the need for chromatography, 182 mg of the title compound.

MS (ESP): 421 (MH ⁺ ) for C ₁₉ H ₂₁ FN ₄ O ₆

NMR (DMSO-d 6) δ: 1.89 (m, 1H); 2.18 (m, IH); 3.21 (m, IH); 3.36 (m, IH); 3.43 (m, IH); 3.56 (m, IH); 3.59 (s. 3H); 3.92 (dd, IH); 4.19 (t overlap m, 2H); 4.48 (dd, IH);

«·

4.55 (dd, IH); 5.08 (m, IH); 6.46 (d, IH); 6.80 (t, IH); 7.17 (dd, IH); 7.48 (dd, IH);

7.53 (d, IH); 8.77 (d, IH).

Example 98

3- (3-Fluoro-4- (imidazol-1-yl) phenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

280 mg (1 mmol) of 3- (3-fluoro-4- (imidazol-1-yl) phenyl-5 (R) -hydroxymethyloxazolidin-2-one (WO 96/23788), 94 mg (1.1 mmol) of 3-hydroxyisoxazole and 330 mg (1.25 mmol) of triphenylphosphine is suspended by stirring in 10 ml of tetrahydrofuran under nitrogen at ambient temperature, 308 mg (1.5 mmol) of diisopropyl azodicarboxylate are added dropwise over 10 minutes. Evaporate to dryness and purify the residue by chromatography on a 20 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 50 to 100% EtOAc in isohexane, to combine and evaporate the relevant fractions to give 206 mg of the desired product. .

MS (ESP): 345 (MH ⁺ ) for C ₁₆ H ₁₃ FN ₄ O ₄

NMR (DMSO-d ₆ ) δ: 3.97 (dd, 1H); 4.24 (dd, IH); 4.48 (m, 2 H); 5.11 (m, IH); 6.37 (d,

1H); 7.11 (d, IH); 7.47 (dd, IH); 7.52 (d, IH); 7.66 (t, 1 H); 7.74 (dd, IH); 7.99 (s, IH);

8.66 (d, IH).

Examples 99-103

The following compounds were prepared by multiple parallel synthesis using the conditions of the intermediate of Example 65, the same reaction conditions, the appropriate hydroxymethyl starting material, and purification as described above on a Mega Bond Elut® column.

139

Example Starting material Used moly Product Mass product Note 99 O νχ / Ή- F 03 / mmol 20 mg 1.6 100 ALIGN! i n — \ r —- N 5 > = / At F 0.7 mmol C F 70 mg 2.6 101 O W __H2-Cw 0.3 mmol 0 'O N - \ / - ⁱ ^ \ Lj ^Q 50 mg 3.7 102 C ýZ / O t 0.6 mmol jc-n-ix · - · y = / t 110 mg 4.8 103 O \\ ΛΛ 0/3 mmol -P-p-Cv-0 o * 70 mg 5.9

Comment:

1. MS (ESP): 346 (MH ⁺ ) for C ₁₅ H ₁₂ FN ₅ O ₄

2. MS (ESP): 346 (MH) for C ₁₈ H 12 FN ₅ O 4

NMR (DMSO-d ₆ ) δ: 3.97 (dd, 1H); 4.26 (dd, 1H) 4.48 (m, 2H); 5.11 (m, IH); 6.37 (d, IH); 7.53 (dd, IH); 7.74 (dd, IH); 7.83 (t, IH); 8.13 (s, 2 H); 8.69 (d, IH).

3. MS (ESP): 326 (MH ⁺⁾ for ₇ 0ι Η Ν ₁₅ Ο _{3 4}

NMR (DMSO-d ₆ ) δ: 3.93 (dd, 1H); 4.22 (t, IH); 4.47 (m, 2 H); 5.06 (m, IH); 6.22 (m, 2 H); 6.37 (d, IH); 7.31 (m, 2 H); 7.60 (dd, 4H); 8.68 (d, IH).

4. MS (ESP): 369 (MH ⁺ ) for C ₁₈ H ₁₃ FN ₄ O ₄

NMR (DMSO-d 6) δ: 3.96 (dd, 1H); 4.23 (t, IH); 4.47 (m, 2 H); 5.10 (m, IH); 6.37 (d, IH); 6.70 (m, IH); 7.28 (m, IH); 7.47 (dd, IH); 7.64 (t, 1 H); 7.74 (dd, IH); 7.99 (m, IH); 8.67 (d, IH).

5. MS (ESP): 405 (MH ⁺ ) for C 19 H ₂₁ FN ₄ O ₅

140 ··· ·· ········

NMR (DMSO-d ₆ ) δ: 1.04 (t, 3H); 3.35 (t + m, 6H); 3.59 (s, 2 H); 3.87 (dd, IH); 4.16 (t,

1H); 4.45 (m, 2 H); 5.03 (m, IH); 6.36 (d, IH); 7.05 (t, 1 H); 7.21 (dd, IH); 7.53 (dd,

1H); 8.68 (d, IH).

6. The starting material is described in WO 96/23788.

7. The intermediate for this compound is prepared as follows:

- (4-Ethoxycarbonylaminophenyl) pyrrole

0.38 ml of ethyl chloroformate was added dropwise to a stirred solution of 0.56 g (3.54 mmol) of 1 - (- aminophenyl) pyrrole 4 Corelli et al., Farmaco. Ed. Sci., 1983, 38, 219) in 5 ml of pyridine at 5-10 ° C and for 15 minutes. The cooling bath was removed and stirring continued for 1.5 hours. The mixture was evaporated and the residue purified by flash chromatography on silica gel eluting with a gradient of 1-4% MeOH in dichloromethane to give 0.43 of the title compound as a solid.

MS (ESP): (MH ⁺ ) 231 for C ₁₃ H ₄ N ₂ O ₂

NMR (CDCl ₃ ) δ: 1.33 (t, 3H); 4.25 (q, 2 H); 6.32 (t, 2 H); 6.60 (s, 1 H); 7.02 (t, 2 H); 7.32-7.42 (m, 4H).

(5S) -3- (4- (1-Pyrrolyl) phenyl) -5 (R) -hydroxymethyloxazolidin-2-one

To a solution of 0.45 g (2.14 mmol) of 1- (4-ethoxycarbonylaminophenyl) pyrrole in 30 mL dry tetrahydrofuran at -60 ° C was added dropwise 1.3 mL (1.6 M in isohexane) of n- butyllithia. The mixture was stirred for 20 minutes and 0.3 g (2.1 mmol) of (R) -glycidylburate in 2 ml of tetrahydrofuran was added dropwise. The mixture was allowed to warm to room temperature, stirred for 16 hours and partitioned between EtOAc and saturated ammonium chloride solution. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was recrystallized from ethanol to give 0.21 g of the title compound, mp 179-181 ° C.

MS (ESP): 259 (MH ⁺ ) for C ₁₁ H ₁₄ N ₂ O ₃

NMR (DMSO-d 6) δ: 3.5 - 3.75 (m, 2H); 3.87 (m, IH); 4.12 (t, IH); 4.70 (m, IH); 5.18 (t, 1 H); 6.24 (t, 2 H); 7.31 (t, 2 H); 7.5-7.7 (m, 4H).

C ₄ H ₁₄ N ₂ O 3 Calculated C: 65.1, H: 5.46, N: 10.8%; found: C: 64.5, H: 5.5, N: 10.6%.

• ·

141

8. The intermediate for this compound is prepared as follows:

3-Fluoro-4- (3-cyano-1-pyrrolyl) nitrobenzene

3.6 g (39.1 mmol) of 3-cyanopyrrole (CE Loader et al., Can. J. Chem., 1981, 59, 2673) and

6.5 g (40.9 mmol) of 3,4-difluoronitrobenzene are dissolved in DMF (50 mL) and the mixture is cooled in an ice bath. The mixture was stirred and 1.6 g (60% in oil, 40 mmol) of sodium hydride was added over 20 minutes. The mixture was allowed to warm to ambient temperature and then heated to 65 ° C for 1 hour. The solvent was evaporated and the residue was triturated with water and filtered. The crude solid was purified by silica gel flash chromatography eluting with dichloromethane. The relevant fractions were combined to give 3.75 g of the title compound, mp 117-119 ° C.

MS (ESP): 230 (MH +) for C 11 H 6 FN 3 O 2

NMR (CDCl 3) δ: 6.68 (s, 1H); 7.09 (m, IH); 7.61 (overlap m, 2H); 8.20 (overlap m, 2H).

5-Amino-2- (3-cyano-1-pyrrolyl) fluorobenzene

5.3 g (22.9 mmol) of 3-fluoro-4- (3-cyano-1-pyrrolyl) nitrobenzene are dissolved in 250 ml of hot MeOH and 700 mg of palladium catalyst (10% on carbon) are added under nitrogen. The mixture was cooled and hydrogenated at atmospheric pressure for a period of time

3.5 hours. After filtration through celite, the solution was evaporated to dryness to give 4.6 g of the title compound in sufficient purity for the next step.

MS (ESP): 202 (MH ⁺⁾ for C _with FN ₃

NMR (CDCl 3) δ: 3.93 (brs, 2H); 6.50 (m, 3H); 6.82 (s, 1 H); 7.10 (t, 1 H); 7.31 (s, 1 H).

5-Ethoxycarbonylamino-2- (3-cyano-1-pyrrolyl) fluorobenzene

4.6 g (22.9 mmol) of 5-amino-2- (3-cyano-1-pyrrolyl) fluorobenzene are stirred in 50 ml of dry pyridine at 0 ° C. 2.66 g (24.5 mmol) of ethyl chloroformate are added and stirring is continued at the same temperature for 20 minutes and then the temperature is raised to ambient temperature over 2 hours. The solvent was evaporated, 50 ml of water was added to the residue,

142 is filtered and dried. Crystallization of the crude product from 200 ml of ethanol yielded 4.9 g of the title compound, m.p. 188-190 ° C.

MS (ESP): 274 (MH ⁺ ) for C ₁₄ H ₁₂ FN ₃ O 2

NMR (DMSO-d ₆ ) δ: 1.26 (t, 3H); 4.16 (q, 2 H); 6.69 (m, IH); 7.23 (m, IH); 7.33 (dd,

1H); 7.53 (t, IH); 7.59 (dd, IH); 7.92 (m, IH); 10.04 (brs, 1H).

(5S) -3- (3-Fluoro-4- (3-cyano-1-pyrrolyl) phenyl) -5 (R) -hydroxymethyloxazolidin-2-one

4.8 g (17.6 mmol) of 5-ethoxycarbonylamino-2- (3-cyano-1-pyrrolyl) fluorobenzene are dissolved under nitrogen in 200 ml of tetrahydrofuran at -70 ° C and treated with 11.0 ml (1 (6 M in isohexane) n-butyllithium solution. The mixture was stirred at -70 ° C for 45 minutes and 2.8 g (19.4 mmol) of (R) -glycidyl butyrate dissolved in 5 ml of tetrahydrofuran was added at the same temperature. Stirring is continued for 18 hours and the temperature is raised to ambient temperature. 50 mL of saturated ammonium chloride solution was added and the mixture was extracted first with 250 mL and then with 2 x 100 mL of EtOAc. The combined extracts were washed with brine (60 ml), dried over magnesium sulfate and evaporated and the residue was purified by crystallization from ethanol to give 3.9 g of the desired product, m.p. 157-159 ° C.

MS (ESP): 302 (MH ⁺ ) for C ₁₅ H ₁₂ FN ₃ O ₃

NMR (DMSO-d 6) δ: 3.58 (dd, 1H); 3.71 (dd, IH); 3.88 (dd, IH); 4.14 (t, 1 H); 4.75 (m, IH); 5.21 (t, 1 H); 6.72 (m, IH); 7.28 (m, IH); 7.49 (dd, IH); 7.65 (t, 1 H); 7.76 (dd,

1H); 7.79 (m, IH).

9. The starting material described in WO 97/27188.

Example 104

3- (4- (4-Hydroxymethylimidazol-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

0.59 g (1.2 mmol) of 3- (4- (4-tert-butyldimethylsilyloxymethylimidazol-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one in 15 ml of anhydrous tetrahydrofuran was cooled to 0 ° C. 5 mL (1 M, 5 mmol) of tetra-n-butylammonium fluoride solution was added and the mixture was stirred for 3 hours when the temperature was raised to ambient temperature. The mixture was evaporated to

143 dry, redissolved in 50 ml of dichloromethane, washed with 3 x 25 ml of water and dried over magnesium sulfate. After filtration and evaporation, the residue is purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane. The relevant fractions were combined to give 245 mg of the desired product.

MS (ESP): 375 (MH ⁺ ) for C ₁₇ H ₁₅ FN ₄ O ₅

NMR (DMSO-d 6) δ: 3.96 (dd, 1H); 4.26 (t, IH); 4.40 (d, 2 H); 4.48 (m, 2 H); 4.99 (t,

1H); 5.11 (m, IH); 6.39 (d, IH); 7.35 (s, 1 H); 7.47 (dd, IH); 7.66 (t, 1 H); 7.75 (dd, IH) 7.93 (s, IH); 8.70 (d, IH).

The intermediate for this compound was prepared as follows.

1.57 g (3.72 mmol) of 3- (4- (4-tert-butyldimethylsilyloxymethylimidazol-1-yl) -3-fluorophenyl) -5 (R) -hydroxymethyl-oxazolidin-2-one (WO 99/10343), 350 mg ( 4.1 mmol) of 3-hydroxyisoxazole and 934 mg (4.6 mmol) of tributylphosphine are dissolved in 100 ml of dry tetrahydrofuran under nitrogen atmosphere with stirring. The mixture was cooled in an ice bath and 1.16 g (4.6 mmol) of 1,1 '(azodicarbonyl) dipiperidine was added dropwise over 10 minutes. The solution was stirred for 18 hours while allowing the temperature to rise to room temperature. The reduced azo compound was filtered off and the solution was evaporated to dryness and the residue triturated with ether. The ether layer was evaporated, dissolved in dichloromethane, purified by chromatography on a 40 g Mega Bond Elut® silica gel column, eluting with dichloromethane and then 1% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 0.59 g of (5S) -3- (4- (4-tert-butyldimethylsilyloxymethylimidazol-1-yl) -3-fluorophenyl-5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2- like oil.

MS (ESP): 489 (MH ⁺ ) for C 23 H 29 FN 4 O 5 Si

NMR (CDCl 3) δ: 0.00 (s, 6H); 0.79 (s, 9H); 3.90 (dd, IH); 4.07 (t, IH); 4.38 (dd, IH);

4.48 (dd, IH); 4.63 (s, 2 H); 4.92 (m, 2 H); 5.88 (d, IH); 6.98 (s, IH); 7.21 (dd, IH);

7.27 (t, IH); 7.57 (dd, IH); 7.61 (s, 1 H); 8.03 (d, IH).

Example 105 (3- (3-Fluoro-4- (2-methylimidazol-1-yl) phenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one)

144

Using essentially the same procedure as for Intermediate Example 65, but starting from 202 mg (0.69 mmol) of 3- (3-fluoro-4- (2-methylimidazol-1-yl) phenyl) -5 (R) hydroxymethyl-oxazolidine- 2-one and purification by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 2.5% MeOH in dichloromethane, gave 137 mg of the title compound.

MS (ESP): 359 (MH ⁺ ) for C ₁₇ H ₁₅ FN ₄ O ₄

NMR (DMSO-d ₆ ) δ: 2.16 (s, 3H); 4.00 (dd, IH); 4.27 (t, IH); 4.49 (m, 2 H); 5.12 (m,

1H); 6.40 (d, IH); 6.94 (d, IH); 7.23 (d, IH); 7.50 (dd, IH); 7.57 (t, 1 H); 7.77 (dd, IH);

8.71 (d, IH).

Intermediates for this compound are prepared as follows:

3-Fluoro-4- (2-methyl-imidazol-1-yl) nitrobenzene

9.02 g (0.11 M) of 2-methylimidazole and 32.2 g (0.25 M) of Ν, Ν-diisopropylethylamine are dissolved in 160 ml of acetonitrile and 15.9 g (0.1 M) 3 are added, 4-difluomitrobenzene. The mixture was stirred and refluxed under nitrogen for 24 hours. The solvent was evaporated and the residue was dissolved in 300 mL EtOAc, washed with 150 mL water, 150 mL brine, and dried over magnesium sulfate. The residue was recrystallized from 25 mL of EtOAc and 150 mL of cyclohexane with charcoal to give 11.5 g of the title compound, mp 106-107 ° C.

MS (ESP): 222 (MH ⁺ ) for Ο ₁₀ Η ₈ ΡΝ ₃ θ2

NMR (DMSO-d ₆ ) δ: 2.25 (s, 3H); 7.00 (d, IH); 7.35 (t, 1 H); 7.87 (t, IH); 8.23 (dd, IH);

8.43 (dd, IH).

5-Amino-2- (2-methylimidazol-1-yl) fluorobenzene (0.181 M) 3-fluoro-4- (2-methylimidazol-1-yl) nitrobenzene was dissolved in a mixture of 200 mL MeOH and 800 mL tetrahydrofuran, cooled at 0 ° C under a nitrogen atmosphere and treated with 57 g (0.905 M) of ammonium formate and then 2 g (10%).

145 palladium on activated carbon. The mixture was stirred at ambient temperature for 18 hours, filtered through Celite, washed with 100 mL of MeOH and the filtrate evaporated to dryness. The residue was partitioned between 800 mL EtOAc and 250 mL 10% aqueous sodium bicarbonate. The organic layer was separated, washed with 250 mL of brine, dried over magnesium sulfate and evaporated to give 34.6 g of the title compound.

MS (ESP): 192 (MH +) for C ₁₀ H ₁₀ FN 3

NMR (DMSO-d 6) δ: 2.08 (s, 3H); 5.68 (s, 2 H); 6.45 (overlap m, 2H); 6.84 (d, IH); 7.03 (overlap m, 2H).

5-Benzyloxycarbonylamino-2- (2-methylimidazol-1-yl) fluorobenzene

34.25 g (0.179 M) of 5-amino-2- (2-methylimidazol-1-yl) fluorobenzene are dissolved in 600 ml of dry dichloromethane under nitrogen and the mixture is cooled to -5 ° C. Pyridine (17.7 g, 0.224 M) was added followed by benzyl chloroformate (33.7 g, 0.197 M) over 20 minutes. The mixture was stirred for 16 hours when the temperature was raised to ambient temperature. 250 ml (5%) of aqueous sodium bicarbonate are then added, the organic layer is separated, the aqueous layer is extracted again with 2 x 300 ml of dichloromethane and the combined extracts are dried over magnesium sulfate. After filtration and evaporation, the residue is recrystallized from 400 ml of toluene to give 54.5 g of the title compound.

MS (ESP): 326 (MH +) for C 11 H 11 FNaCl 4

NMR (DMSO-d ₆ ) δ: 2.13 (s, 3H); 5.18 (s, 2 H); 6.89 (s, 1 H); 7.17 (s, 1 H); 7.41 (overlap m, 7H); 7.73 (dd, IH); 10.21 (br. 1H).

(5S) -3- (3-Fluoro-4- (2-methylimidazol-1-yl) phenyl) -5 (R) -hydroxymethyloxazolidin-2-one g (0.166 M) 5-benzyloxycarbonylamino-2- (2-methylimidazole -1-yl) fluorobenzene is dissolved under nitrogen in a mixture of 600 ml of tetrahydrofuran and 100 ml of 1,3-dimethyl-2,4,5,6-tetrahydro-2 (1H) -pyrimidinone cooled to -70 ° C and subjected to 30 minutes with 114 ml (1.6 M in isohexane) n-butyllithium solution. The mixture was stirred at -70 ° C for 30 minutes, and a solution of 26.35 g (0.183 M) of (R) glycidyl butyrate in 50 ml of dry tetrahydrofuran was added over 15 minutes. Stirring is continued for 16 hours when the temperature is raised to ambient temperature. The mixture was treated with 500 mL (5%) aqueous sodium bicarbonate and 800 mL EtOAc, organic was added

The 146 layer was separated and the aqueous layer was extracted with 3 x 750 mL EtOAc. The combined extracts were dried over magnesium sulfate, evaporated and the resulting oil triturated with diethyl ether. The resulting solid was recrystallized from isopropanol to give 21.5 g of the title compound.

MS (ESP): 292 (MH ⁺ ) for C ₁₄ H ₁₄ FN ₃ O ₃

NMR (DMSO-d ₆ ) δ: 2.16 (s, 3H); 3.56 (dt, IH); 3.69 (dt, IH); 3.88 (dd, IH); 4.15 (t,

1H); 4.74 (m, IH); 5.24 (t, 1 H); 6.92 (s, 1 H); 7.20 (s, 1 H); 7.48 (dd, IH); 7.53 (t, IH);

7.74 (dd, IH).

Example 106

3- (3-Fluoro-4- (4-methylimidazol-1-yl) phenyl-5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

Using essentially the same procedure as for Intermediate Example 65, but starting from 81 mg (0.29 mmol) of 3- (3-fluoro-4- (4-methylimidazol-1-yl) phenyl) -5 (R) hydroxymethyloxazolidine- 2-one (see Example 141) and purification by chromatography on a 5 g silica gel Mega Bond Elut® column, eluting with a gradient of increasing polarity from 0 to 2.5% MeOH in dichloromethane, afforded 80 mg of the title compound.

MS (ESP): 359 (MH ⁺ ) for C ₁₇ H ₁₅ FN ₄ O ₄

NMR (CDCl ₃ ) δ: 2.30 (s, 3H); 4.02 (dd, IH); 4.23 (t, IH); 4.52 (dd, IH); 4.60 (dd, IH); 5.07 (m, IH); 6.00 (d, IH); 6.94 (s, 1 H); 7.50 (overlap, 2H); 7.69 (dd, IH); 7.77 (s, 1 H); 8.16 (d, IH).

Example 107

3- (3-Fluoro-4- (4-cyanimidazol-1-yl) phenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

360 mg (0.93 mmol) of 3- (3-fluoro-4- (4-hydroximinomethylimidazol-1-yl) phenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one and 3 ml of acetic acid is refluxed under nitrogen for 2 hours. After cooling and pouring into ice, the mixture is extracted into 3 x 15 ml of dichloromethane, dried over magnesium sulphate and evaporated. The rest • •

147 chromatographs on a 10 mg Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 2.5 % MeOH in dichloromethane 135 mg of the title compound was prepared.

MS (ESP): 370 (MH ⁺ ) for C ₁₇ H ₁₂ FN ₅ O 4

NMR (DMSO-d 6) δ: 3.99 (dd, 1H); 4.27 (t, IH); 4.49 (m, IH); 5.12 (m, IH); 6.37 (d,

1H); 7.52 (dd, IH); 7.74 (t, 1 H); 7.82 (dd, IH); 8.29 (d, IH); 8.56 (t, IH); 8.69 (d, IH).

The intermediate for this compound was prepared as follows:

460 mg (1.24 mmol) of 3- (3-fluoro-4- (aldehydoimidazol-1-yl) phenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one (WO 99/10343) is dissolved in a mixture of 10 ml of ethanol and 2 ml of water and treated with 86 mg (1.24 mmol) of hydroxylamine hydrochloride and 176 mg (1.74 mmol) of triethylamine. The mixture was stirred at room temperature for 18 hours, the precipitated solid was filtered off and the residue was evaporated to dryness. The residue and the precipitate were combined, washed with 2 x 25 mL of water and dried at 70 ° C to give 361 mg of 3- (3-fluoro-4- (4-hydroxyiminomethylimidazol-1-yl) phenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one as a 3: 1 mixture of E and Z isomers.

MS (ESP): 388 (MH +) for C ₁₇ H ₁₄ FN ₅ O ₅

NMR (DMSO-d ₆ ) δ: 3.97 (dd, 1H); 4.26 (t, IH); 4.45 (dd, 2 H); 5.11 (m, 2H); 6.39 (d,

1H); 7.44 (s, 0.25H); 7.49 (dd, IH); 7.73 (t, 1 H); 7.77 (dd + s, 1.75H); 8.00 (s, 0.75H);

8.06 (s, 0.75H); 8.10 (s, 0.25H); 8.13 (s, 0.25H); 8.70 (d, IH); 10.91 (s, 0.75H); 11.60 (s, 0.25H).

Example 108

3- (4- (imidazol-1-yl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one

500 mg (1.8 mmol) of 3- (4- (imidazol-1-yl) -3-fluorophenyl) -5 (R) -hydroxymethyloxazolidin-2-one (WO 96/23788), 221 mg (2.17 mmol) 3 hydroxy-1,2,5-thiadiazole and 707 mg (2.7 mmol) of triphenylphosphine are suspended in 15 ml of dry tetrahydrofuran under nitrogen and with stirring. The mixture was cooled in an ice bath and diisopropyl azodicarboxylate (545 mg, 2.7 mmol) was added dropwise over 10 minutes. The solution is stirred for 18 hours when •

the temperature rises to ambient temperature. The mixture was diluted with 200 mL of dichloromethane and extracted with 200 mL of hydrochloric acid (1 M). The aqueous layer was washed with dichloromethane (2 x 100 mL) and the aqueous layer was basified with a minimum amount of concentrated ammonia solution. The organic material was extracted into 200 and then 100 mL of dichloromethane, dried over magnesium sulfate and purified by chromatography on a 20 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 520 mg of the title compound.

MS (ESP): 362 (MH ⁺ ) for C ₁₅ H ₁₂ FN ₅ O ₃ S

NMR (DMSO-d _s) δ: 4.02 (dd, 1H); 4.26 (t, IH); 4.66 (d, IH); 4.71 (d, IH); 5.15 (m, IH); 7.11 (t, 1H) 7.48 (dd, 1H); 7.52 (m, IH); 7.66 (t, 1 H); 7.74 (dd, IH); 7.98 (m,

1H); 8.43 (s, 1 H).

Example 109

3- (4 - ((3R) -3-Hydroxy-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

1.8 g (3.77 mmol) of 3- (4 - ((3R) -3-tert-butyldimethylsilyloxy-1-pyrrolidinyl) -3-fluorophenyl) 5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2 The mixture was stirred in 40 ml of a 3: 1: 1 mixture of acetic acid, water and tetrahydrofuran at 90 ° C for 4 hours. The solvent was evaporated and the residue was purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 420 mg of the desired product as a foam.

MS (ESP): 364 (MH ⁺ ) for C ₁₇ H ₁₈ FN ₃ O ₅

NMR (DMSO-d ₅ ) δ: 1.82 (m, 1H); 1.97 (m, IH); 3.10 (d, IH); 3.25 (t, IH); 3.40 (dd, IH); 3.84 (dd, IH); 4.12 (t, IH); 4.32 (br. 1H); 4.43 (m, 2 H); 4.87 (d, IH); 5.02 (m,

1H); 6.36 (d, IH); 6.70 (t, IH); 7.10 (dd, IH); 7.38 (dd, IH); 8.67 (d, IH).

Intermediates for this compound are prepared as follows:

3-Fluoro-4 - ((3R) -3-hydroxy-1-pyrrolidinyl) nitrobenzene

149

g (0.163 M) of (3R) -3-hydroxypyrrolidine hydrochloride was suspended by stirring in 200 ml of acetonitrile under nitrogen at 50 ° C, and then the mixture was treated with 52.5 g (0.41 M) of Ν, di-diisopropylethylamine and 25 ml. 0.9 g (0.153 M) of 3,4-difluoronitrobenzene. The mixture was heated at 90 ° C for 17 hours and then the solvent was evaporated. The residue was dissolved in 500 mL of dichloromethane and washed with 300 mL of 5% aqueous dihydrogen phosphate, causing partial precipitation. The precipitate was filtered, washed and the combined aqueous layers re-extracted with 200 mL of dichloromethane. The organic layers were evaporated and the residue combined with previously filtered material and azeotroped with toluene to give 35 g of the desired product of sufficient quality to be used without further purification.

MS (ESP): 227 (MH ⁺ ) for C 10 H 11 FN 2 O 3

NMR (CDCl ₃ ) δ: 1.89 (m, 1H); 1.97 (m, IH); 3.47 (d, IH); 3.61 (overlap m, 3H); 4.35 (br m, IH); 5.03 (d, IH); 6.73 (t, IH); 7.89 (overlap m, 2H).

3-Fluoro-4 - ((3R) -3-tert-butyldimethylsilyloxy-1-pyrrolidinyl) nitrobenzene

35.8 g (0.158 M) of 3-fluoro-4 - ((3R) -3-hydroxy-1-pyrrolidinyl) nitrobenzene are dissolved in 200 ml of DMF and treated with 21.6 g (0.318 M) of imidazole and 35, 7 g, (0.239 M) of tert-butyldimethylsilyl chloride were added and the mixture was stirred at room temperature under nitrogen for 18 hours. The solvent was evaporated and the residue was treated with 300 mL EtOAc and 200 mL water. The organic layer was washed with 150 mL of water and dried over magnesium sulfate. Evaporation gave 54 g of the desired product which was of sufficient quality for use without further purification.

MS (ESP): 341 (MH ⁺ ) for C ₁₆ H ₂₅ FN ₂ O ₃ Si

NMR (CDCl 3) δ: -0.02 (2x s, 6H); 0.74 (s, 9H); 1.79 (br m, IH); 1.97 (m, IH); 3.27 (d, IH); 3.53 (m, 2 H); 3.68 (dt, IH); 4.48 (br m, IH); 6.69 (t, IH); 7.83 (overlap m, 2H).

5-Amino-2 - ((3R) -3-tert-butyldimethylsilyloxy-1-pyrrolidinyl) fluorobenzene g (0.158M) 3-fluoro-4 - ((3R) -3-tert-butyldimethylsilyloxy-1-pyrrolidinyl) The nitrobenzene was treated in the same manner as a suitable intermediate of Example 86 to give 49 g of the desired product of sufficient quality for use without further purification.

• ·

MS (ESP): 311 (MH ⁺ ) for C ₁₆ H ₂₇ FN ₂ OSi

NMR (DMSO-d 6) δ: 0.00 (2x s, 6H); 0.79 (s, 9H); 1.66 (m, IH); 2.01 (m, IH); 2.84 (d, IH); 3.02 (dd, IH); 3.12 (dd, IH); 3.32 (m, 2 H); 4.41 (m, IH); 4.63 (s, 2 H); 6.22 (dd, IH); 6.29 (dd, 1H); 6.49 (t, 1H).

5-Ethoxycarbonylamino-2 - ((3R) -3-tert-butyldimethylsilyloxy-1-pyrrolidinyl) fluorobenzene g (0.158 M) 5-amino-2 - ((3R) -3-tert-butyldimethylsilyloxy-1-pyrrolidinyl) fluorobenzene is treated in essentially the same as the appropriate intermediate of Example 86, except that the product was isolated by extraction into dichloromethane, azeotroped with toluene, and the crude product was purified by silica gel column chromatography, eluting with a gradient of 0 to 20% EtOAc in dichloromethane. The appropriate fractions were combined to give 29.6 g of the desired product.

MS (ESP): 383 (MH ⁺ ) for C ₁₉ H ₃₁ FN ₂ O ₃ Si

NMR (DMSO-d 6) δ: -0.02 (s, 3H); 0.01 (s, 3 H); 0.78 (s, 9H); 1.16 (t, 3 H); 1.72 (m,

1H); 1.98 (m, IH); 2.97 (d, IH); 3.18 (m, IH); 3.27 (dd, IH); 3.48 (m, IH); 4.02 (q, 2 H); 4.43 (m, IH); 6.59 (t, IH); 6.96 (dd, IH); 7.17 (dd, IH); 9.31 (s, 1 H).

3- (4 - ((3R) -3-tert-Butyldimethylsilyloxy-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) hydroxymethyloxazolidin-2-one

29.4 g (0.077 M) of 5-ethoxycarbonylamino-2- (3R) -3-tert-butyldimethylsilyloxy-1-pyrrolidinyl) fluorobenzene were treated in substantially the same manner as the corresponding intermediate of Example 86 except that the product was isolated by extraction into EtOAc and the crude product was purified by silica gel column chromatography eluting with a gradient of 0 to 20%> MeOH in dichloromethane. The appropriate fractions were combined and recovered

29.6 g of the desired product.

MS (ESP): 411 (MH ⁺ ) for C ₂₀ H ₃₁ FN ₂ O ₄ Si

NMR (DMSO-d 6) δ: -0.01 (s, 3H); 0.02 (s, 3H); 0.79 (s, 9H); 1.73 (m, IH); 2.00 (m, IH); 3.02 (d, IH); 3.23 (m overlap H ₂ O, 1H); 3.32 (dd, IH); 3.50 (m, 2 H); 3.57 (m,

1H); 3.69 (dd, IH); 3.94 (t, IH); 4.44 (m, IH); 4.58 (m, IH); 5.09 (t, IH); 6.67 (t, 1 H); 7.03 (dd, IH); 7.34 (dd, IH).

151 • ·······················

3- (4 - ((3R) -3-tert-Butyldimethyhyisilyloxy-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

4.1 g (10 mmol) of 3- (4 - ((3R) -3-tert-butyldimethylsilyloxy-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) -hydroxymethyloxazolidin-2-one is treated essentially as in Example 67 and then purified by flash chromatography eluting with a gradient of 0 to 50% EtOAc in dichloromethane to give 2.0 g of the desired product.

MS (ESP): 478 (MH ⁺ ) for C 23 H 32 FN 3 O 5 Si

NMR (DMSO-d 6) δ: 0.10 (s, 3H); 0.12 (s, 3 H); 0.87 (s, 9H); 1.84 (m, IH); 2.09 (m, IH); 3.13 (d, IH); 3.33 (m overlap H ₂ O, 1H); 3.43 (dd, IH); 3.61 (m, IH); 3.89 (dd, IH); 4.18 (t, IH); 4.49 (m, 2 H); 4.55 (m, IH); 5.07 (m, IH); 6.44 (d, IH); 6.78 (t, IH);

7.15 (dd, IH); 7.44 (dd, IH); 8.72 (d, IH).

Example 110

3- (4- (3-Oxo-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

700 mg (1.9 mmol) of 3- (4 - ((3R) -3-hydroxy-1-pyrrolidinyl-3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one) are dissolved under nitrogen in 5 ml of DMSO and 2.03 g (20 mmol) of triethylamine are added, then a solution of 0.95 g (6 mmol) of sulfur trioxide-pyridine complex in 5 ml of DMSO is added over 20 minutes and the mixture is stirred at ambient temperature for 1 hour. The mixture was then diluted with 100 mL of water and extracted into 150 mL of EtOAc, the organics were washed with 2 x 50 mL of water, 50 mL of brine and dried over magnesium sulfate, and the residue was purified by chromatography on a 20 g Mega Bond Elut® silica gel column. eluting with a gradient of increasing polarity from 0 to 3% MeOH in dichloromethane The relevant fractions were combined and crystallized from 35 ml of ethanol to give 176 mg of the desired product.

MS (ESP): 362 (MH ⁺ ) for C ₁₇ His FN ₃ O ₅

NMR (DMSO-d _s) 5: 2.58 (t, 2H); 3.60 (t, 2 H); 3.66 (d, 2 H); 3.87 (dd, IH); 4.15 (t, 1 H);

4.45 (m, 2 H); 5.03 (m, IH); 6.36 (d, IH); 6.94 (t, 1 H); 7.20 (dd, IH); 7.47 (dd, IH);

8.67 (d, IH).

Example 111

152

3- (4- (2-Oximino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

124 mg (0.34 mmol) of 3- (4- (3-oxo-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one are dissolved in a mixture of 10 ml of dichloromethane and 10 mL of MeOH and treated with a solution of 220 mg (3.17 mmol) of hydroxylamine hydrochloride and 500 mg of sodium acetate in 2 mL of water. The mixture was stirred at ambient temperature for 4 hours, the solvent was evaporated and the residue was triturated with 10 ml of water, the solids were filtered off to give 118 mg of the desired product as a single isomer of unknown geometry.

MS (ESP): 377 (MH ⁺ ) for C ₁₇ H ₁₇ FN ₄ O ₅

NMR (DMSO-d 6) δ: 2.67 (t, 2H); 3.41 (dd, 2 H); 3.88 (dd, IH); 3.96 (s, 2 H); 4.16 (t,

1H); 4.46 (m, 2 H); 5.04 (m, IH); 6.38 (d, IH); 6.91 (m, IH); 7.18 (dd, IH); 7.48 (dd, IH); 8.69 (d, IH); 10.72 (s, 1 H).

Example 112

3- (4 - ((3S) -3-Amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

2.1 g (4.54 mmol) of 3- (4 - ((3S) -3-tert-butylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2 The suspension was stirred in 10 ml of dichloromethane under nitrogen and treated at room temperature with 50 ml of a solution of hydrogen chloride in ethanol (4M). The mixture was stirred for 1 hour, evaporated to a small volume and a mixture of 30 mL of dichloromethane and 30 mL of diethyl ether was added. The resulting precipitate was filtered off and washed with diethyl ether to give 2.0 g of the title compound as the hydrochloride.

MS (ESP): 363 (MH ⁺ ) for C ₁₇ H ₁₉ FN ₄ O ₄

NMR (DMSO-d ₆ ) δ: 2.03 (m, 1H); 2.25 (m, IH); 3.26 (dd, IH); 3.42 (m, IH); 3.52 (m, 2 H); 3.83 (dd overlap m, 2H); 4.13 (t, IH); 4.42 (m, 2 H); 5.02 (m, IH); 6.37 (d, IH); 6.79 (t, IH); 7.14 (dd, IH); 7.44 (dd, IH); 8.43 (br. 3H); 8.68 (d, IH).

153

The intermediate for this compound was prepared as follows:

3-Fluoro-4 - ((3S) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) nitrobenzene

Using essentially the procedure for the equivalent intermediate in Example 86, but starting from 20 g (0.108 M) of (3S) -3-tert-butoxycarbonylpyrrolidine, 33.5 g of the desired product is obtained as a yellow solid of sufficient quality for use without further purification.

MS (ESP): 326 (MH ⁺ ) for C 15 H 20 FN 3 O 4

NMR (DMSO-d 6) δ: 1.36 (s, 9H); 1.87 (m, IH); 2.08 (m, IH); 3.36 (m, IH); 3.54 (m, IH); 3.62 (tm, IH); 3.73 (m, IH); 4.09 (m, IH); 6.72 (t, IH); 7.19 (d, IH); 7.88 (overlap m, 2H).

5-Amino-2 - ((2S) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) fluorobenzene

Using essentially the procedure for the equivalent intermediate in Example 86, but starting from 33.5 g (0.103 M) of 3-fluoro-4 - ((3S) -3-tert-butoxycarbonyl-1-pyrrolidinyl) nitrobenzene, about 30 g. g of the desired product as an oil of sufficient quality for use without further purification.

MS (ESP): 296 (MH +) for C ₁₅ H ₂₂ FN ₃ O ₂

NMR (DMSO-d ₆ ) δ: 1.35 (s, 9H); 1.71 (m, IH); 2.06 (m, IH); 2.87 (dd, IH); 3.05 (m,

1H); 3.11 (m, IH); 3.26 (m overlap H ₂ O, ca. ₁ H); 3.97 (m, IH); 4.68 (s, 2 H); 6.25 (dd, IH); 6.31 (dd, IH); 6.51 (t, 1 H); 7.03 (d, IH).

5-Ethoxycarbonylamino-2 - ((3S) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) fluorobenzene

Using essentially the procedure for the equivalent intermediate in Example 86 but starting from 30.4 g (0.103 M) of 5-amino-2- (3S) -3-tert-butoxycarbonyl-1-pyrrolidinyl) fluorobenzene, 30.4 g was obtained after precipitation. (0.103 M) of the crude product. This product is purified by dissolving in 500 ml of toluene, azeotroping until the product begins to precipitate, and then cooling and adding 500 ml of isohexane to complete precipitation. Filtration gave 35.3 g of the desired product.

• · ·

154

MS (ESP): 368 (MH ⁺ ) for C ₁₈ H ₂₆ FN ₃ O ₄

NMR (DMSO-d ₆ ) δ: 1.21 (t, 3H); 1.37 (s, 9H); 1.77 (m, IH); 2.06 (m, IH); 3.04 (m,

1H); 3.20 (dd, IH); 3.30 (m overlap H ₂ O, 1H); 3.42 (tm, IH); 4.02 (br. 1H); 4.08 (q, 2 H); 6.63 (t, IH); 7.02 (d, IH); 7.08 (br. 1H); 7.22 (d, IH); 9.38 (s, 1 H).

3- (3-Fluoro-4 - ((3S) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) -5 (R) hydroxymethyl-oxazolidin-2-one

35.2 g (0.096 M) of 5-ethoxycarbonylamino-2 - ((3S) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) fluorobenzene are dissolved in 400 ml of dry tetrahydrofuran cooled to -70 ° C under nitrogen and added dropwise over the course of A solution of lithium t-butoxide prepared from 9.3 g (123 mmol) of t-butanol in 70 ml of dry tetrahydrofuran and 66 ml (1.6 M in isohexane) of n-butyllithium for 20 minutes. The mixture was stirred for 20 minutes, 15.2 g (0.102 M) of (R) -glycidyl butyrate in 20 ml of tetrahydrofuran was added over 10 minutes, and the temperature was raised to ambient temperature over 16 hours. To the mixture was added 10 mL of MeOH, the mixture was stirred at ambient temperature for 10 minutes and then treated with a mixture of 250 mL of 5% aqueous sodium bicarbonate and 500 mL of EtOAc. The precipitate was collected and washed well with EtOAc and water to give 19.5 g of the desired product. The organic layer of the filtrate was separated, dried over magnesium sulfate and evaporated. The residue was heated briefly with 100 mL of EtOAc at reflux, cooled and filtered to give 16.6 g of the desired product.

MS (ESP): 396 (MH ⁺ ) for C ₁₉ H ₂₆ FN ₃ O ₅

NMR (DMSO-d ₆ ) δ: 1.37 (s, 9H); 1.79 (m, IH); 2.07 (m, IH); 3.08 (m, IH); 3.24 (m overlap H ₂ O, ca. ₁ H); 3.36 (m, IH); 3.48 (tm, IH); 3.53 (d, IH); 3.63 (d, IH); 3.74 (dd, IH); 3.99 (t, IH); 4.04 (m, IH); 4.63 (m, IH); 5.15 (s, 1 H); 6.71 (t, 1 H); 7.08 (dd overlapping br, 2H); 7.39 (dd, IH).

3- (4 - ((3S) -3-tert-Butoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

The title compound was prepared essentially according to the method of Example 67, starting from 3.95 g (10 mmol) of 3- (4 - ((3S) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) 3-fluorophenyl) -5 (R) -hydroxymethyl) oxazolidin-2-one and flash purification

155 chromatography on silica gel, eluting with a gradient of increasing polarity from 0 to 20% EtOAc in dichloromethane. The relevant fractions were combined, evaporated and the residue recrystallized from 100 ml of toluene to give 2.34 g of the desired product.

MS (ESP): 463 (MH ⁺ ) for C 22 H 27 FN 4 O 6

NMR (DMSO-d 6) δ: 1.37 (s, 9H); 1.81 (m, IH); 2.08 (m, IH); 3.10 (m, IH); 3.24 (t, 1H) 3.35 (dd, 1H); 3.47 (dd, 1 H), 3.83 (dd, 1 H), 4.05 (m, 1 H); 4.12 (t, IH); 4.42 (dd, IH); 4.48 (dd, IH); 5.02 (m, IH); 6.36 (d, IH); 6.71 (t, 1 H); 7.10 (dd overlap br, 1H);

7.38 (dd, IH); 8.66 (d, IH).

Example 113

3- (4 - ((3S) -3-Acetamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

170 mg (0.43 mmol) of 3- (4 - ((3 $) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one hydrochloride salt is stirred in a mixture of 5 ml of saturated sodium bicarbonate solution and 5 ml of dichloromethane in an ice bath. 2 mmol of acetic anhydride are added dropwise and the mixture is stirred for 18 hours while raising the temperature to ambient temperature. 10 ml of dichloromethane are added and the mixture is filtered through filter paper, the organic layer is evaporated and crystallized from ethanol to give 108 mg of the desired product.

MS (ESP): 405 (MH ⁺ ) for C 14 H 21 FN 4 O 5

NMR (DMSO-d 6) δ: 1.79 (m overlap, 4H); 2.11 (hextet, 1H); 3.11 (dt, IH); 3.24 (t, IH); 3.42 (dd, IH); 3.50 (m, IH); 3.84 (dd, IH); 4.12 (t, IH); 4.28 (m, IH); 4.42 (dd, IH); 4.47 (dd, IH); 5.02 (m, IH); 6.37 (d, IH); 6.73 (t, IH); 7.11 (dd, IH); 7.39 (dd, IH); 8.08 (d, IH); 8.67 (d, IH).

Example 114

3- (4 - ((3S) -3-Methylsulfonamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

156

Using essentially the procedure of Example 113, starting from 170 mg (0.43 mmol) of 3- (4 - ((3S) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) hydrochloride salt (isoxazol-3-yloxymethyl) oxazolidin-2-one and methanesulfonyl chloride is obtained after trituration with diethyl ether and isohexane 114 mg of the desired product.

MS (ESP): 441 (MH ⁺ ) for C ₁₈ H ₂₁ FN ₄ O ₆ S

NMR (DMSO-d ₆ ) δ: 1.88 (hextet, 1H); 2.18 (hextet, 1H); 2.94 (s, 3H); 3.20 (m, IH);

3.31 (t, IH); 3.36 (m overlap H ₂ O, ca. 1H); 3.56 (m, IH); 3.84 (dd, IH); 3.98 (hextet, 1H); 4.12 (t, IH); 4.42 (dd, IH); 4.47 (dd, IH); 5.02 (m, IH); 6.37 (d, IH); 6.74 (t, IH);

7.12 (dd, IH); 7.36 (d, IH); 7.40 (dd, IH); 8.68 (d, IH).

Example 115

3- (4 - ((3S) -3-Methoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

Using essentially the procedure of Example 113, starting from 170 mg (0.43 mmol) of 3- (4 - ((3S) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) hydrochloride salt of (isoxazol-3-yioxymethyl) oxazolin-2-one and methyl chloroformate is obtained after trituration with diethyl ether and isohexane 114 mg of the desired product.

MS (ESP): 421 (MH ⁺ ) for C ₁₉ H ₂₁ FN ₄ O ₆

NMR (DMSO-d 6) δ: 1.82 (hextet, 1H); 2.11 (hextet, 1H); 3.14 (m, IH); 3.27 (m overlap H ₂ O, ca. ₁ H); 3.39 (dd, IH); 3.49 (m, IH); 3.53 (s, 3H); 3.84 (dd, IH); 4.11 (t overlap m, 2H); 4.42 (dd, IH); 4.45 (dd, IH); 5.02 (m, IH); 6.37 (d, IH); 6.72 (t, IH);

7.11 (dd, IH); 7.39 (dd, IH); 7.42 (d, IH); 8.67 (d, IH).

Example 116

3- (4 - ((3S) -3-Acetoxyacetylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

Using essentially the procedure of Example 73, starting from 300 mg (0.75 mmol) of the hydrochloride salt of 3- (4 - ((3S) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R). ) • ·

157 (isoxazol-3-yloxymethyl) oxazolidin-2-one and acetoxyacetyl chloride were obtained after trituration with diethyl ether and isohexane 240 mg of the desired product.

MS (ESP): 463 (MH ⁺ ) for ^C 21 H 23 FN 4 O 7

NMR (DMSO-d 6) δ: 1.83 (hextet, 1H); 2.06 (s. 3H); 2.13 (hextet, 1H); 3.15 (m, IH);

3.26 (m overlap H ₂ O, ca. 1H); 3.41 (dd, IH); 3.50 (m, IH); 3.84 (dd, IH); 4.12 (t,

1H); 4.33 (dd, IH); 4.43 (s, 2 H); 4.45 (m, 2 H); 5.03 (m, IH); 6.36 (d, IH); 6.74 (t, IH);

7.11 (dd, IH); 7.41 (dd, IH); 8.24 (d, IH); 8.66 (d, IH).

Example 117

3- (4 - ((3S) -3-Hydroxyacetylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

Using essentially the procedure for Example 74, starting from 140 mg (0.3 mmol) of 3- (4 - ((3S) -3-acetoxyacetylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - ( isoxazol-3yloxymethyl) oxazolidin-2-one is obtained after trituration with water, diethyl ether and drying, 125 mg of the desired product.

MS (ESP): 421 (MH +) for C ₁₉ H ₂₁ FN ₄ O ₆

NMR (DMSO-d _s) δ: 1.91 (hextet, 1H); 2.13 (hextet, 1H); 3.18 (m, IH); 3.29 (m overlap H ₂ O, ca. ₁ H); 3.40 (dd, IH); 3.49 (m, IH); 3.79 (s, 2 H); 3.84 (dd, IH); 4.13 (t, IH); 4.37 (dd, IH); 4.46 (m, 2 H); 5.02 (m, IH); 5.36 (s, 1 H); 6.36 (d, IH); 6.74 (t, IH);

7.11 (dd, IH); 7.40 (dd, IH); 7.84 (d, IH); 8.67 (d, IH).

Example 118

3- (4 - ((3S) -3- (2,2-Dimethyl-1,3-dioxolane-4 (S) -ylcarbamido) -1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazole-3) -yloxymethyl) oxazolidin-2-one

270 mg (0.67 mmol) of the hydrochloride salt of 3- (4 - ((3S) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one was Stir in 5 mL pyridine at room temperature. 270 mg (ca. 50%, 0.85 mmol) of the solution are then added dropwise

_{2,2-dimethyl-1-l} 3-dioxolane-4 (S) -carbonyl chloride in 2 ml dichloromethane and stirred for 18 hours. The solvent was evaporated and the residue was partitioned between 20 mL EtOAc and 20 mL.

• ·

• · · • · · · · · · · 158 • · · • · · · · · • · · • · · · · • · · · · ·

ml of water. The organic layer was washed with 5% aqueous sodium bicarbonate, brine, dried over magnesium sulfate and evaporated. The residue was azeotroped with 15 ml of toluene and purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 100% EtOAc in dichloromethane. The relevant fractions were combined and evaporated to give 205 mg of the desired product.

MS (ESP): 491 (MH ⁺ ) for C ₂₃ H ₂₇ FN ₄ O ₇

NMR (DMSO-d ₆ ) δ: 1.32 (s, 3H); 1.37 (s, 3H); 1.91 (hextet, 1H); 2.13 (hextet, 1H);

3.23 (m, IH); 3.29 (m overlap H ₂ O, ca. ₁ H); 3.38 (m, IH); 3.49 (m, IH); 3.86 (dd, IH); 3.94 (dd, IH); 4.14 (t overlap m, 2H); 4.37 (m, IH); 4.43 (overlap m, 3H); 5.04 (m, IH); 6.40 (d, IH); 6.76 (t, IH); 7.14 (dd, IH); 7.42 (dd, IH); 8.00 (d, IH); 8.69 (d, IH).

Example 119

3- (4 - ((3S) -3- (2 (S), 3-Dihydroxypropanoylamino) -1-pyrrolidinyl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one

170 mg (0.35 mmol) of 3- (4 - ((3S) -3- (2,2-dimethyl-1,3-dioxolane-4 (S) -carbamido) -1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (Isoxazol-3-yloxymethyl) -oxazolidin-2-one was dissolved in 6 mL of tetrahydrofuran and treated with 1 mL of 2 M aqueous hydrochloric acid and stirred at ambient temperature for 17 hours. After dilution with 10 ml of MeOH, 2 g of MP carbonate resin trapping the intermediate or by-products (Argonaut Technologies) are added and the mixture is stirred for 1 hour. The resin was filtered off, the filtrate was evaporated and the residue was evaporated with 10 ml of MeOH / water (1: 1, 3X) and triturated with diethyl ether to give 125 mg of the desired product.

MS (ESP): 451 (MH ⁺ ) for C ₂₀ H ₂₃ FN ₄ O ₇

NMR (DMSO-d 6) δ: 1.91 (hextet, 1H); 2.12 (hextet, 1H); 3.19 (m, IH); 3.28 (m overlap H ₂ O, ca. ₁ H); 3.46 (overlap m, 3H); 3.56 (m, IH); 3.84 (overlap m, 2H); 4.13 (t, IH); 4.33 (dd, IH); 4.44 (m, 2 H); 4.68 (t, IH); 5.02 (m, IH); 5.49 (d, IH); 6.39 (d,

1H); 6.76 (t, IH); 7.12 (dd, IH); 7.43 (dd, IH); 7.84 (d, IH); 8.69 (d, IH).

Example 120

159

3- (4 - ((3S) -3-Amino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one

Using essentially the same procedure as in Example 113, starting from 1 g (2.09 mmol) of 3- (4- (3S) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R). - (3 (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one gave 850 mg of the title compound as its hydrochloride salt.

MS (ESP): 380 (MH ⁺ ) for C ₁₆ H ₁₈ FN ₅ O ₃ S

NMR (DMSO-d 6) δ: 2.06 (m, 1H); 2.26 (m, IH); 3.27 (dd, IH); 3.42 (m overlap with solvent, 1H); 3.54 (m, 2 H); 3.82 (m, IH); 3.89 (dd, IH); 4.16 (t, IH); 4.65 (m, 2 H); 5.06 (m, IH); 6.79 (t, IH); 7.16 (dd, IH); 7.45 (dd, IH); 8.42 (s, 1 H); 8.49 (br. 3H).

The intermediate for this compound was prepared as follows:

3- (4 - ((3S) -3-tert-Butoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one

The title compound was prepared in essentially the same manner as in Example 67, starting from 2 g (5.06 mmol) of 3- (4 - ((3S) -3-tert-butoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 Of (R) -hydroxymethyloxazolidin-2-one and purification by chromatography on a 90 g Biotage silica gel column, eluting with a gradient of increasing polarity from 0 to 5% EtOAc in dichloromethane. The relevant fractions were combined, evaporated and the residue recrystallized from 20 ml of toluene to give 1.67 g of the desired product.

MS (ESP): 480 (MH ⁺ ) for C ₂₁ H ₂₆ FN ₅ O ₅ S

NMR (DMSO-d 6) δ: 1.37 (s, 9H); 1.81 (hextet, 1H); 2.08 (hextet, 1H); 3.11 (m, IH);

3.26 (m overlap H ₂ O, ca. 1 H); 3.37 (dd, IH); 3.48 (t, IH); 3.88 (dd, IH); 4.05 (m, IH); 4.14 (t, 1H) 4.64 (m, 2H); 5.06 (m, IH); 6.71 (t, 1 H); 7.11 (dd overlapping br, 2H); 7.48 (dd, 1H); 8.42 (s, 1H).

Example 121

160 :::

(3- (4 - ((3S) -3-Acetamido-1-pyrrolidinyl) -3-fluorophenyl)) - 5 (R) - (3- (1,2,5-Thiadiazolyl) oxymethyl) oxazolidin-2-one

The title compound was prepared in essentially the same manner as described in Example 115, starting from 250 mg (0.60 mmol) of 3- (4 ((3S) -3-amino-1-pyrrolidinyl) -3-hydrochloride) hydrochloride salt. -fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one. The organic layer was then separated, washed with aqueous ammonium phosphate (2%), brine, and dried over magnesium sulfate. Evaporation gave 170 mg of the desired product.

MS (ESP): 422 (MH ⁺ ) for C 18 H 20 FN 5 O 4 S

NMR (DMSO-d 6) δ: 1.79 (overlapping, 4H); 2.11 (hextet, 1H); 3.11 (m, IH); 3.26 (m H ₂ O overlap, ca. 1H); 3.41 (dd, 1H); 3.49 (m, IH); 3.88 (dd, IH); 4.14 (t, 1H); 4.28 (dd, 1H); 4.65 (m, 2 H); 5.07 (m, IH); 6.74 (t, IH); 7.11 (dd, IH); 7.42 (dd, IH); 8.08 (d, IH); 8.42 (s, 1 H).

Example 122

3- (4 - ((3S) -3-Methanesulfonamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one

The title compound was prepared in essentially the same manner as described in Example 115, starting from 250 mg (0.60 mmol) of 3- (4 ((3S) -3-amino-1-pyrrolidin-1) -pyrrolidine I) -3-hydrochloride salt. fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one and methanesulfonyl chloride. The same treatment afforded 183 mg of the desired product.

MS (ESP): 458 (MH ⁺ ) for ^C 17 H 20 FN 5 O 5 ^{S 2}

NMR (DMSO-d ₆ ) δ: 1.87 (hextet, 1H); 2.20 (hextet, 1H); 2.94 (s, 3H); 3.21 (m, IH);

3.31 (t, IH); 3.38 (m overlap H ₂ O, ca. 1H); 3.56 (m, IH); 3.89 (dd, IH); 3.98 (dd,

1H); 4.15 (t, 1 H); 4.65 (m, 2 H); 5.07 (m, IH); 6.74 (t, IH); 7.13 (dd, IH); 7.36 (d, IH);

7.40 (dd, IH); 8.42 (s, 1 H).

Example 123 • ·

161

3- (4 - ((3S) -3-Acetoxyacetylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one

The title compound was prepared in essentially the same manner as described in Example 73, starting from 350 mg (0.84 mmol) of the 3- (4 ((3S) -3-amino-1-pyrrolidine)) hydrochloride salt - 3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one and acetoxyacetyl chloride. The organic layer was then separated, washed with 10% aqueous sodium dihydrogen phosphate, 5% aqueous sodium bicarbonate, and dried over magnesium sulfate.

Evaporation and trituration with 10 ml of diethyl ether / isohexane (1: 1) afforded 187 mg of the desired product.

MS (ESP): 480 (MH ⁺ ) for ^{C 20} H 22 FN 5 O 8

NMR (DMSO-d 6) δ: 1.86 (hextet, 1H); 2.07 (s. 3H); 2.14 (hextet, 1H); 3.16 (m, IH);

3.26 (m overlap H ₂ O, ca. ₁ H); 3.42 (m, IH); 3.51 (dd, IH); 3.89 (dd, IH); 4.14 (t, 1 H);

4.33 (hextet, 1H); 4.43 (s, 2 H); 4.67 (m, 2 H); 5.07 (m, IH); 6.76 (t, IH); 7.14 (dd, IH);

7.43 (dd, IH); 8.26 (d, IH); 8.45 (s, 1 H).

Example 124

3- (4 - ((3S) -3-hydroxyacetylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidin-2-one

The title compound was prepared in substantially the same manner as in Example 74, starting from 136 mg (0.28 mmol) of 3- (4 - ((3S) -3-acetoxyacetylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one. Evaporation of the reaction mixture and trituration of the residue with water gives 0.27 g of the desired product.

MS (ESP): 438 (MH ⁺⁾ for Ci8H OFN _{2 5} 0 ₅ S

NMR (DMSO-d 6) δ: 1.92 (hextet, 1H); 2.16 (hextet, 1H); about 3.20 (m, H ₂ O overlay, about 3H); 3.51 (m, H ₂ O overlap, ca. 1H); 3.81 (s, 2 H); 3.91 (dd, IH); 4.15 (t, 1 H); 4.38 (hextet, 1H); 4.67 (m, 2 H); 5.08 (m, IH); 6.75 (t, 1 H); 7.12 (dd, IH); 7.41 (dd, IH);

7.87 (d, IH); 8.45 (s, 1 H).

162

Example 125

3- (4 - ((3S) -3-Methoxycarbonylamino-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one

The title compound was prepared in essentially the same manner as in Example 115, starting from 152 mg (0.37 mmol) of 3- (4 ((3S) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) hydrochloride salt -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one and methyl chloroformate. Workup and trituration with diethyl ether gave 53 mg of the desired product.

MS (ESP): 438 (MH ⁺ ) for C ₁₈ H ₂₀ FN ₅ O ₅ S

NMR (DMSO-d 6) δ: 1.83 (hextet, 1H); 2.12 (hextet, 1H); 3.16 (m, IH); 3.28 (m overlap H ₂ O, ca. ₁ H); 3.41 (dd, IH); 3.53 (overlap m, 4H); 3.89 (dd, IH); 4.08 (m, IH); 4.14 (t, 1 H); 4.64 (m, 2 H); 5.06 (m, IH); 6.74 (t, IH); 7.12 (dd, 1 H), 7.40 (dd, 1 H), 7.43 (s, 1 H); 8.45 (s, 1 H).

Example 126

3- (4 - ((3S) -3- (2,2-Dimethyl-1,3-dioxolan-4 (S) -ylcarbonamido-1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (3- (1) (2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one

The title compound was prepared in substantially the same manner as in Example 115, starting from 336 mg (0.81 mmol) of 3- (4 ((3S) -3-amino-1-pyrrolidinyl) -3-fluorophenyl) hydrochloride salt ) -5 (R) - (3- (1,2,5-Thiadiazolyl) oxymethyl) oxazolidin-2-one. Workup and chromatography gave 210 mg of the desired product.

MS (ESP): 508 (MH ⁺ ) for C ₂₂ H ₂₆ FN ₅ O ₆ S

NMR (DMSO-d 6) δ: 1.32 (s, 3H); 1.38 (s, 2 H); 1.89 (hextet, 1H); 2.13 (hextet, 1H);

3.21 (m overlap H ₂ O, ca. 2H); 3.38 (t, IH); 3.48 (m, IH); 3.90 (dd, IH); 3.92 (dd,

1H); 4.12 (dd, IH); 4.14 (t, 1 H); 4.37 (dd, IH); 4.42 (t, IH); 4.64 (m, 2 H); 5.06 (m,

1H); 6.74 (t, IH); 7.11 (dd, IH); 7.40 (dd, IH); 7.94 (d, IH); 8.42 (d, IH).

Excl. 127 • ·

163

3- (4 - ((3S) -3- (2 (S), 3-Dihydroxypropanoylamino) -1-pyrrolidinyl) -3-fluorophenyl) -5 (R) - (3 (1,2,5-thiadiazolyl) oxymethyl) Oxazolidin-2-one

The title compound was prepared in essentially the same manner as described in Example 119, starting from 165 mg (0.33 mmol) of 3- (4 - ((3S) -3 - ((4S) -2,2-dimethyl-1)). 3-dioxolane-4-carbonamido) -1-pyrrolidinyl-3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one. The aqueous organics were treated with solid potassium carbonate, then filtered and evaporated to dryness and the residue triturated with diethyl ether to give 90 mg of the desired product.

MS (ESP): 468 (MH ⁺ ) for C 18 H 16 F 5 O 6 S

NMR (DMSO-d 6) δ: 1.92 (hextet, 1H); 2.13 (hextet, 1H); 3.17 (m, IH); 3.30 (m overlap with H 2 O), ca. 1 H); 3.48 (overlap m, 3H); 3.56 (m, IH); 3.87 (m, IH); 3.90 (dd,

1H); 4.14 (t, 1 H); 4.34 (hextet, 1H); 4.66 (overlap m, 3H); 5.07 (m, IH); 5.48 (br. 1H);

6.76 (t, IH); 7.13 (dd, IH); 7.43 (dd, IH); 7.85 (d, IH); 8.46 (s, 1 H).

Example 128

3- (4- (4- (6-Cyano-3-pyridazinyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) - (isoxazol-3yl) oxymethyloxazolidin-2-one

398 mg (1.0 mmol) of 3- (4- (4- (6-cyano-3-pyridazinyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) hydroxymethyl-oxazolidin-2-one, 93.5 mg (1.1 mmol) of 3-hydroxyisoxazole and 328 mg (1.25 mmol) of triphenylphosphine are suspended in 10 ml of dry tetrahydrofuran with stirring. Diisopropyl azodicarboxylate (242 mg, 1.2 mmol) was added dropwise via syringe and the mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was filtered, evaporated to dryness, dissolved in ETOAc / isohexane (1: 1) and purified on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 75 to 100% EtOAc in isohexane. The relevant fractions were combined and evaporated to give 120 mg of the desired product.

MS (ESP): 466 (MH ⁺ ) for C ₂ H 20 _O FN _{7 O 4}

164 · · · · ···· · ··· ···········

NMR (DMSO-d 6) δ: 3.08 (t, 4H); 3.89 (overlap m, 5H); 4.16 (t, IH); 4.45 (m, 2 H); 5.05 (m, IH); 6.37 (d, IH); 7.10 (t, 1 H); 7.21 (dd, 1H); 7.40 (d, 1H); 7.53 (dd, 1H); 7.88 (d, 1H);

1H); 8.67 (d, IH).

Intermediates for this compound are prepared as follows:

3- (3-Fluoro-4- (piperazin-1-yl) phenyl) -5 (R) -hydroxymethyloxazolidin-2-one hydrochloride

43.1 g (0.11 M) of 3- (3-fluoro-4- (4-tert-butoxycarbonylpiperazin-1-yl) phenyl) -5 (R) hydroxymethyl-oxazolidin-2-one (WO 93/23384) are suspended with stirring and under nitrogen in 1000 ml of ethanol. 400 ml (3.8 M) of ethanolic hydrogen chloride solution are slowly added to give a solution. The mixture was stirred at ambient temperature for 18 hours. The resulting precipitate was filtered, washed with 3 x 250 ml diethyl ether and dried to give the title compound. Another part of the product is obtained by evaporation of the mother liquors. Total yield 38.7 g.

MS (ESP): 296 (MH ⁺ ) for C ₁₄ H ₁₃ FN ₃ O ₃

NMR (DMSO-d 6) δ: 3.17 (m, 8H); 3.53 (dd, IH); 3.64 (dd, IH); 3.79 (dd, IH); 4.03 (t,

1H); 4.66 (m, IH); 7.10 (t, 1H); 7.20 (dd, IH); 7.52 (dd, IH); 9.39 (br s, 2H).

3- (4- (4- (6-Cyano-3-pyridazinyl) piperazin-1-yl) -3-fluorophenyl) -5 (R) -hydroxymethyloxazolidin-2-one

6.63 g (20 mmol) of 3- (3-fluoro-4- (piperazin-1-yl) phenyl) -5 (R) hydroxymethyl-oxazolidin-2-one hydrochloride was suspended by stirring under nitrogen in 200 ml of acetonitrile and 4 44 g (44 mmol) of triethylamine. The mixture was stirred for 10 minutes, 3.79 g (20 mmol) of 3-chloro-6-cyanopyridazine was added and the mixture was heated under reflux for 18 hours. After cooling, the solid was filtered off, washed with 3 x 150 ml of water and 2 x 150 ml of diethyl ether to give 6.3 g of the title compound.

MS (ESP): 398 (MH ⁺ ) for C 20 H 20 FN 5 O 3

NMR (DMSO-d 6) δ: 3.03 (t, 4H); 3.54 (m, 1H); 3.63 (m, IH); 3.78 (t overlap m, 5H); 4.03 (t, IH); 4.66 (m, IH); 5.18 (t, 1 H); 6.97 (d, IH); 7.07 (t, 1 H); 7.20 (dd, IH); 7.53 (dd, IH); 7.85 (dd, IH); 8.49 (d, IH).

165

Example 129

3- (3-Fluoro-4- (2-methyl-imidazol-1-yl) phenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) oxymethyl) oxazolidin-2-one

Using essentially the same procedure as for Intermediate Example 65, but starting from 582 mg (2.0 mmol) of 3- (3-fluoro-4- (2-methylimidazol-1-yl) phenyl) -5 (R) hydroxymethyloxazolidin-2-one and purification on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane, afforded 160 mg of the title compound.

MS (ESP): 376 (MH ⁺ ) for C ₁₆ H ₁₄ FN ₅ O ₃ S

NMR (DMSO-d ₆ ) δ: 2.15 (s, 3H); 4.02 (dd, IH); 4.27 (t, IH); 4.66 (dd, IH); 4.72 (dd, IH); 5.18 (m, IH); 6.92 (d, IH); 7.20 (d, IH); 7.48 (dd, IH); 7.55 (t, 1 H); 7.74 (dd,

1H); 8.42 (s, 1 H).

Example 130

3- (4- (4-Hydroxymethylimidazol-1-yl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) methyl) oxazolidin-2-one

Using essentially the same procedure as for Intermediate Example 65 but starting with 842 mg (2.0 mmol) of 3- (4- (4-tert-butyldimethylsilyloxymethylimidazol-1-yl) -3-fluorophenyl) -5 (R) -hydroxymethyloxazolidine -2-one and 224 mg (2.2 mmol) of 3-hydroxy-1,2,5-thiadiazole. After filtration of the reduced azo compound, the solution is treated with 10% TFA in 10 ml of acetonitrile, then the solution is evaporated to dryness and purified on a 10 g Mega Bond Elut® silica gel column, eluting with increasing polarity gradient of 0 to 20% MeOH in dichloromethane. 65 mg of the title compound.

MS (ESP): 392 (MH ⁺⁾ for C _1s H _{14 FN 4} O S

NMR (DMSO-d 6) δ: 4.02 (dd, 1H); 4.27 (t, IH); 4.50 (s, 2 H); 4.60 (br. 1H); 4.66 (dd, IH); 4.72 (dd, IH); 5.18 (m, IH); 7.53 (dd, IH); 7.69 (s, 1 H); 7.74 (t, 1 H); 7.80 (dd, IH); 8.42 (s, 1 H); 8.81 (s, 1 H).

Example 131

166

3- (4- (1- (2,2-Dimethyl-1,3-dioxolane-4 (S) -ylmethoxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3-fluorophenyl) -5 (R) 1- (isoxazol-3-yloxymethyl) oxazolidin-2-one

144 mg (0.36 mmol) of 3- (4- (1,2,5,6-tetrahydro-4-pyridinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2- hydrochloride The mixture was stirred in 5 mL of dichloromethane at ambient temperature and then treated with 67 mg (0.52 mmol) of diisopropylethylamine to give a solution. A solution of 202 mg (0.68 mmol) of (4S) -2,2-dimethyl-4- (1,3-dioxolane) methyl-4-nitrophenyl carbonate in 2.5 ml of dichloromethane was added dropwise and the mixture was stirred for 18 hours. The mixture was diluted with 10 mL of dichloromethane and washed with 4 x 15 mL of water. After drying over magnesium sulfate, the evaporation residue is purified on a 10 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 0 to 5% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 152 mg of the desired product.

MS (ESP): 518 (MH ⁺ ) for C ₂₅ H ₂₈ FN ₃ O ₃

NMR (DMSO-d ₆ ) δ: 1.26 (s, 3H); 1.31 (s, 3H); 2.43 (m, 2 H); 3.56 (m, 2 H); 3.69 (dd, IH); 3.92 (dd, 1H); 4.02 (overlapping, 4H); 4.11 (dd, IH); 4.20 (t, 1H) 4.25 (m, 1H);

4.44 (dd, IH); 4.49 (dd, IH); 5.06 (m, IH); 5.98 (brs, 1H); 6.36 (d, IH); 7.31 (dd, IH);

7.37 (t, IH); 7.49 (dd, IH); 8.66 (d, IH).

Example 132

3- (4- (1- (2 (S), 3-Dihydroxypropyloxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidine -2-on

130 mg (0.25 mmol) of 4- (4- (1- (2,2-dimethyl-1,3-dioxolan-4 (S) -ylmethoxycarbonyl) 1,2,5,6-tetrahydro-4-pyridinyl) -3 -fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one is dissolved in 5 ml of tetrahydrofuran, treated with 2 ml of 2M hydrochloric acid and stirred at room temperature for 72 hours. the acid and water were removed and the solution was filtered The filtrate was evaporated and the residue was purified on a 10 g Biotage silica gel column, eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane to combine the relevant fractions and evaporate to give 103 mg of compound. listed in the title.

167 ··· ····················

MS (ESP): 478 (MH ⁺ ) for C 22 H 24 FN 3 O 8

NMR (DMSO-d 6) δ: 2.42 (m, 2H); 3.37 (t, 2 H); 3.57 (m, 2 H); 3.65 (dd, IH); 3.93 (overlap m, 2H); 4.06 (overlap m, 3H); 4.19 (t, IH); 4.47 (m, 2 H); 4.59 (t, 1 H); 4.84 (d, IH); 5.07 (m, IH); 5.99 (brs, 1H); 6.37 (d, IH); 7.32 (dd, IH); 7.39 (t, IH); 7.51 (dd, IH); 8.78 (d, IH).

Example 133

3- (4- (1- (2,2-Dimethyl-1,3-dioxolane-4 (S) -ylmethoxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) -5 (R) - (Isoxazol-3-yloxymethyl) -oxazolidin-2-one

Using essentially the same procedure as in Example 131, but starting from 151 mg (0.36 mmol) of 3- (4- (1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) hydrochloride -5 (R) (Isoxazol-3-yloxymethyl) -oxazolidin-2-one gave 170 mg of the title compound.

MS (ESP): 536 (ΜΡΓ) for C 25 H 27 FN 2 O 3

NMR (DMSO-d 6) δ: 1.26 (s, 3H); 1.32 (s, 3H); 2.31 (m, 2 H); 3.58 (m, 2 H); 3.69 (dd, IH); 3.91 (dd, IH); 4.03 (overlap, 4H) 4.12 (dd, 1H); 4.18 (t, IH); 4.26 (m, IH);

4.43 (m, 2 H); 5.08 (m, IH); 5.85 (brs, 1H); 6.37 (d, IH); 7.34 (d, 2 H); 8.67 (d, IH).

Example 134

3- (4- (1- (2 (S), 3-Dihydroxypropyloxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) Oxazolidin-2-one

Using essentially the same procedure as in Example 132, but starting from 140 mg (0.26 mmol) of 3- (4- (1- (2,2-dimethyl-1,3-dioxolan-4 (S) -ylmethoxycarbonyl)) -1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one gave 116 mg of the title compound.

MS (ESP): 496 (MH ⁺ ) for C 22 H 23 F 2 N 3 O 8

NMR (DMSO-d 6) δ: 2.32 (m, 2H); 3.36 (t, 2 H); 3.59 (m, 2 H); 3.66 (dd, IH); 3.94 (overlap m, 2H); 4.06 (overlap m, 3H); 4.19 (t, IH); 4.49 (m, 2 H); 4.57 (t, 1 H); 4.85 (d, IH); 5.10 (m, IH); 5.87 (brs, 1H); 6.37 (d, IH); 7.34 (d, 2 H); 8.78 (d, 1H).

168

Example 135

3- (4- (1- (2-Hydroxyethoxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3-fluorophenyl) -5 (R) (isoxazol-3-yloxymethyl) oxazolidin-2-one

Resin-bound 200 mg (0.118 mmol) of 3- (4- (1- (2-hydroxyethoxycarbonyl) 1,2,5,6-tetrahydro-4-pyridinyl) -3-fluorophenyl) -5 (R) - (isoxazole- 3-Yloxymethyl) oxazolidin-2-one) was swelled in 2 mL of dichloromethane for 1 hour. The solvent was removed and the resin was treated with 2 ml of TFA (1% in dichloromethane) to develop a red color from the bound trityl cation. The resin was washed with 6 x 1 mL of dichloromethane and the combined washings were evaporated to dryness then azeotroped with 3 portions of isohexane / dichloromethane to give 46 mg of the title compound as a white powder.

MS (ESP): 448 (MH ⁺ ) for C ₂₁ H ₂₂ FN ₃ O ₇

NMR (DMSO-d 6) δ: 2.42 (m, 2H); 3.56 (m, 4H); 3.92 (dd, IH); 4.02 (m, 4H); 4.19 (t, IH); 4.45 (m, 2 H); 5.07 (m, IH); 5.98 (s, 1 H); 6.36 (d, IH); 7.32 (dd, IH); 7.39 (t, IH);

7.48 (dd, 1H), 8.66 (d, 1H).

The intermediate for this compound was prepared as follows:

Resin-bound 2-hydroxymethyl 4-nitrophenyl carbonate

400 mg (0.236 mmol) of ethylene glycol 2-chlorotrityl resin (Novabiochem, polystyrene backbone, 0.59 mmol / g) was swelled in 2 mL of dichloromethane washed with base for 30 minutes. The solvent was removed and a previously prepared solution of 237 mg (1.18 mmol) of 4-nitrophenylchloroformate and 357 mg (3.54 mmol) of triethylamine in 2 ml of dichloromethane washed with base was added and the resin was washed with 6 x 1 ml of dichloromethane then 2 x 2 ml of diethyl ether to give the title compound. IR (single grain) v: 1767 cm ^-1

Resin-bound 3- (4- (1- (2-hydroxyethoxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2 -on

169 · · · · · · · · · · · · · · · · · · · · · · · ·

200 mg (0.118 mmol) of resin-bound 2-hydroxyethyl-4-nitrophenyl carbonate was swelled in 2 mL of base-washed dichloromethane for 30 minutes. The solvent was removed and a previously prepared solution of 233 mg (0.59 mmol) of 1,2,5,6-tetrahydro-4-pyridinyl) -3-fluorophenyl) -5 (R) - (isoxazol-3yloxymethyl) oxazolidine- Of 2-one and 227 mg (1.77 mmol) of diisopropylethylamine in 3 ml of base-washed dichloromethane and shaken for 6 hours. Solvent and reagents were removed and the resin was washed with 6 x 1 mL dichloromethane, then 2 x 2 mL diethyl ether to give the title compound. IR (single grain) δ: 1761, 1695 cm ^-1 .

Example 136

3- (4- (1- (2-Hydroxyethoxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) 5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2 -he

Using the same method as in Example 135, but starting from 200 mg (0.118 mmol) of resin-bound 3- (4- (1- (2-hydroxyethoxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3), 5-difluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one gave 44 mg of the title compound as a gum.

MS (ESP): 466 (MH ⁺ ) for C 21 H 21 F 2 N 3 O 7

NMR (DMSO-d ₆ ) δ: 2.30 (m, 2H); 3.54 (m, 4 H); 3.90 (dd, IH); 4.03 (m, 4H); 4.18 (t, IH); 4.45 (m, 2 H); 5.08 (m, IH); 5.85 (s, 1 H); 6.35 (d, IH); 7.32 (d, 2 H); 8.66 (d, IH).

The intermediate for this compound was prepared as follows:

3- (4- (1- (2-hydroxyethoxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidine -2-on

Using the same procedure as in Example 72, but starting from 244 mg (0.118 mmol) of 3- (4- (1- (2-hydroxyethoxycarbonyl) -1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) ) -5 (R) - (Isoxazol-3-yloxymethyl) -oxazolidin-2-one yields the title compound. IR (single grain) δ: 1764, 1696 cm ^-1 .

170 • · · • · · · • · · • · · • · · · · • 4 · 4 • · · · · • · · · · ·

Example 137

3- (4- (1-Benzyl-1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) -5- (3-methyl-5 (R) isoxazolyloxymethyl) oxazolidin-2-one

1.28 g (3.2 mmol) of 3- (4- (1-benzyl-1,2,5,6-tetrahydro-4-pyridinyl) -3,5-difluorophenyl) -5 (R) hydroxymethyl-oxazolidin-2- One, 291 mg (3.5 mmol) of 3-methyl-5-hydroxyisoxazole and 0.97 g (4.8 mmol) of tributylphosphine are dissolved by stirring in 20 ml of dry tetrahydrofuran under nitrogen. The mixture was cooled in an ice bath and 1,11 g (4,8 mmol) of 1,1 '- (azodicarbonyl) dipiperidine was added dropwise over 10 minutes. The solution was stirred for 18 hours while allowing the temperature to rise to ambient temperature. The reduced azo compound is filtered off and the solution is evaporated to dryness. The residue was purified by chromatography on a 90 g Biotage silica gel column, eluting with diethyl ether / dichloromethane 1: 1. The relevant fractions were combined and evaporated to give 0.58 g of the title product. The starting isoxazole is described in Bull. Soc. Chim.

France, 1970, 2690.

MS (ESP): 482 (ΜΡΓ) for C 26 H 25 F 2 N 3 O 4

NMR (500 MHz, DMSO- d ₆₎ δ: 2.20 (s, 3H); 2.43 (brs, 2H); 2.70 (t, 2 H); 3.18 (m, 2 H); 3.65 (s, 2 H); 3.95 (dd, 2 H); 4.13 (t, IH); 4.40 (dd, IH); 4.50 (dd, IH); 4.97 (m, IH);

5.15 (s, 1 H); 5.81 (s, 1 H); 7.13 (d, 2 H); 7.26 (t, IH); 7.33 (m, 2 H); 7.37 (m, IH).

Example 138

3- (3-Fluoro-4- (4-methylimidazol-1-yl) phenyl) -5 (R) - (5- (1,2,3-triazolyl) thiomethyl) oxazolidin-2-one

369 mg (1 mmol) of 3- (3-fluoro-4- (4-methylimidazol-1-yl) phenyl) -5 (R) methanesulfonyloxymethyl-oxazolidin-2-one (see Example 141) and 186 mg (1.5 mmol) sodium salt of 5-mercapto-1,2,3-triazole was dissolved in 7 mL of DMF and the mixture was heated to 75 ° C for 1 hour. The mixture was diluted with 25 mL (5%) sodium bicarbonate solution, extracted with 50 mL EtOAc, washed with 2 x 15 mL water, 15 mL brine, dried over magnesium sulfate and purified on a 10 g Mega Bond Elut® silica gel column. ·

171 eluting with a gradient of increasing polarity from 0 to 10% MeOH in dichloromethane to give 110 mg of the title compound.

MS (ESP): 375 (MH ⁺ ) for C ₁₆ H ₅ FN ₆ O ₂ S

NMR (DMSO-d 6) δ: 2.14 (s, 3H); 3.31 (m, 2 H); 3.91 (dd, IH); 4.26 (t, IH); 4.89 (m, IH); 7.22 (s, 1 H); 7.42 (dd, IH); 7.61 (t, 1 H); 7.73 (dd, IH); 7.87 (s, 1 H); 8.02 (s, 1 H);

15.23 (br. 1H).

Example 139

3- (3-Fluoro-4- (4-methylimidazol-1-yl) phenyl) -5 (R) - (5- (1-methyltetrazolyl) thiomethyl) oxazolidin-2-one

Using the same procedure as Example 138 but starting from 174 mg (1.5 mmol).

1-methyl-5-mercaptotetrazole gave 220 mg of the title compound.

MS (ESP): 390 (MH ⁺ ) for C ₁₆ H ₁₆ FN ₇ O ₂ S

NMR (DMSO-d ₆ ) δ: 2.16 (s, 3H); 3.73 (d, IH); 3.96 (overlap dd, 4H); 4.28 (t, IH); 5.04 (m, IH); 7.22 (s, 1 H); 7.45 (dd, IH); 7.64 (t, 1 H); 7.72 (dd, IH); 7.87 (s, 1 H).

Example 140

3- (4- (4-Methylimidazol-1-yl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) methyl) oxazolidin-2-one mg (1.5 mmol) hydride sodium (50% in oil) was stirred in suspension in 7 ml DMF under nitrogen and at room temperature. Then 153 mg (1.5 mmol) of 3-hydroxy-1,2,5-thiadiazole are added and stirring is continued for 10 minutes, then 369 mg (1 mmol) of 3- (3-fluoro-4- (4-methylimidazole-1-) is added. yl) phenyl) -5 (R) -methanesulfonyloxymethyloxazolidin-2-one and the mixture was heated at 75 ° C for 2 hours. The mixture was diluted with 25 mL (5%) sodium bicarbonate solution, extracted with 50 mL EtOAc, washed with 2 x 15 mL water, mL brine, dried over magnesium sulfate and purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with gradient of increasing polarity from 0 to 10% MeOH in dichloromethane gave 330 mg of the title compound. MS (ESP): 376 (MH ⁺ ) for C ₁₆ H ₁₄ FN ₅ O ₃ S

172

NMR (DMSO-d 6) δ: 2.17 (s, 2H); 4.02 (dd, IH); 4.26 (t, IH); 4.80 (m, 2 H); 5.16 (m, IH); 7.22 (s, 1 H); 7.48 (dd, IH); 7.63 (t, IH); 7.77 (dd, IH); 7.88 (s, 1 H); 8.47 (s, 1 H).

Example 141 (3- (4- (5-Methylimidazol-1-yl) -3-fluorophenyl) -5 (R) - (3- (1,2,5-thiadiazolyl) methyl) oxazolidin-2-one

110 mg (2.75 mmol) of sodium hydride (60% in oil) was added to a solution of 229 mg (2.7 mmol) of 3-hydroxyisoxazole in 15 ml of DMF under nitrogen at 0 ° C and the mixture was stirred for 15 minutes. Then a solution of 680 mg (1.8 mmol) of 3- (3-fluoro-4- (5-methylimidazol-1-yl) phenyl-5 (R) -methanesulfonyloxymethyl-oxazolidin-2-one in 7 mL of DMF) was added and the mixture was stirred for 18 hours The solvent was evaporated, the residue was dissolved in 50 mL EtOAc, washed with 2 x 30 mL water, 15 mL brine, dried over magnesium sulfate, and purified by chromatography on a 10 g Mega Bond Elut® silica gel column, eluting with gradient of increasing polarity from 0 to 3% MeOH in dichloromethane to give 149 mg of the title compound.

MS (ESP): 359 (MH ⁺ ) for C 24 H 25 FN 4 O 2

NMR (CDCl ₃ ) δ: 2.12 (s, 3H); 4.03 (dd, IH); 4.21 (t, IH); 4.53 (dd, IH); 4.61 (dd, IH); 5.08 (m, IH); 6.01 (d, IH); 6.91 (d, IH); 7.29 (dd, IH); 7.36 (t, IH); 7.48 (d, IH); 7.71 (dd, IH); 8.16 (d, IH).

The intermediates for the compounds of Examples 106, 140 and 141 were prepared as follows:

3-Fluoro-4- (4-methylimidazol-1-yl) nitrobenzene and 3-fluoro-4- (5-methylimidazol-1-yl) nitrobenzene

45.1 g (0.55 M) of 4-methylimidazole and 161 g (1.25 M) of Ν, Ν-diisopropylethylamine are dissolved in 800 ml of acetonitrile and 79.5 g (0.5 M) of 3,4- difluomitrobenzene. The mixture was stirred and refluxed under nitrogen for 24 hours. The solvent was evaporated, the residue was dissolved in 800 L of EtOAc, washed with 400 mL of water, 200 mL of brine, and dried over magnesium sulfate. The residue was dissolved in 250 ml of toluene and worked up.

173 DEG C., activated carbon, filtered and diluted with 75 ml hot cyclohexane and crystallized 64.7 g of 3-fluoro-4- (4-methylimidazol-1-yl) nitrobenzene.

MS (ESP): 222 (MH ⁺ ) for C ₁₀ H ₈ FN ₃ O ₂

NMR (DMSO-d ₆ ) δ: 2.18 (s, 3H); 7.29 (s, 1 H); 7.92 (t, IH); 8.07 (s, 1 H); 8.18 (dd,

1H); 8.38 (dd, IH).

The mother liquors were evaporated and chromatographed on a 90 g Biotage silica gel column, eluting with a gradient from dichloromethane to 1: 1 dichloromethane / acetonitrile. The relevant fractions were collected and evaporated to give a mixture of 8 g of 2: 1 5-methyl: 4-methyl isomers. This mixture was subjected to Merck Lichro Prep silica gel HPLC eluting with EtOAc / MeOH (95: 5) at a flow rate of 400 mL / min. to separate 5.2 g of 3-fluoro-4- (5-methylimidazol-1-yl) nitrobenzene.

NMR (DMSO-d 6) δ: 2.09 (s, 3H); 6.87 (d, IH); 7.81 (d, IH); 7.87 (t, IH); 8.23 (dd,

1H); 8.42 (dd, IH).

MS (ESP): 222 (MH ⁺ ) for C ₁₀ H ₈ FN ₃ O ₂

5-Amino-2- (4-methylimidazol-1-yl) fluorobenzene

64.7 g (0.293 M) of 3-fluoro-4- (4-methylimidazol-1-yl) nitrobenzene are dissolved in a mixture of 200 ml of MeOH and 800 ml of tetrahydrofuran, cooled to 0 DEG C. under nitrogen and subjected to treatment 99, 3 g (1.46 M) with ammonium formate and then 2.5 g palladium (10%) on charcoal. The mixture was stirred at ambient temperature for 48 hours, filtered through celite, washed with 200 mL of MeOH and the filtrate evaporated to dryness. The residue was partitioned between 800 mL EtOAc and 250 mL 10% aqueous sodium bicarbonate. The organic layer was separated, washed with 250 mL of brine, dried over magnesium sulfate and evaporated to give 50.6 g of the title compound.

MS (ESP): 192 (MH ⁺ ) for C ₁₀ H ₁₀ FN ₃

NMR (DMSO-d 6) δ: 2.12 (s, 3H); 5.60 (brs, 2H); 6.42 (dd, IH); 6.47 (dd, IH); 6.98 (s, IH); 7.11 (t, 1 H); 7.60 (s, 1 H).

5-Amino-2- (5-methylimidazol-1-yl) fluorobenzene

174

Using essentially the same procedure as for the 4-methylisomer, but starting from 5.2 g (23.5 mmol) of (5-methylimidazol-1-yl) nitrobenzene, 3.45 g of the title compound is obtained.

MS (ESP): 192 (MH ⁺ ) for C ₁₀ H ₁₀ FN ₃

5-Benzyloxycarbonylamino-2- (4-methylimidazol-1-yl) fluorobenzene

50.6 g (0.265 M) of 5-amino-2- (4-methylimidazol-1-yl) fluorobenzene are dissolved in 800 ml of dry dichloromethane under nitrogen and cooled to -5 ° C. Then pyridine (26.1 g, 0.33 M) and benzyl chloroformate (49.9 g, 0.292 M) are added over 30 minutes. The mixture was stirred at room temperature while raising to room temperature over 16 hours. Sodium bicarbonate (350 mL, 5%) was added, the organic layer was separated and the aqueous layer was re-extracted with dichloromethane (2 x 200 mL) and the combined organics dried over magnesium sulfate. After filtration and evaporation, the residue is recrystallized from 300 ml of toluene to give 80 g of the title compound.

MS (ESP): 326 (MH ⁺ ) for C ₁₈ H ₁₆ FN ₃ O ₂

NMR (DMSO-d ₆ ) δ: 2.15 (s, 3H); 5.16 (s, 2 H); 7.13 (s, 1 H); 7.31 (dd, IH); 7.41 (m, 5H); 7.48 (t, 1H) 7.57 (dd, 1H); 7.78 (s, 1 H); 10.15 (brs, 1H).

5-Benzyloxycarbonylamino-2- (5-methylimidazol-1-yl) fluorobenzene

Using essentially the same procedure as for the 4-methylisomer, but starting from 3.45 g (18.1 mmol) of 5-amino-2- (5-methylimidazol-1-yl) fluorobenzene, after trituration of the crude product in diethyl ether / isohexane 1: 1 gives 3.35 g of the title compound.

MS (ESP): 326 (MH ⁺ ) for C ₁₈ H ₁₆ FN ₃ O ₂

NMR (DMSO-d 6) δ: 2.00 (s, 3H); 5.17 (s, 2 H); 6.78 (s, 1 H); 7.37 (overlap m, 7H);

7.61 (dd, IH); 7.63 (s, 1 H); 10.21 (brs, 1H).

3- (3-Fluoro-4- (4-methylimidazol-1-yl) phenyl) -5 (R) -hydroxymethyloxazolidin-2-one g (0.166 M) 5-benzyloxycarbonylamino-2- (4-methylimidazol-1-yl) Dissolve fluorobenzene in a mixture of 600 ml dry tetrahydrofuran and 100 ml 1,3-dimethyl-2, 4,5,6 tetrahydro-2 (1H) - pyrimidinone under nitrogen, cooled to -70 ° C, and the mixture was treated with a solution of 114 mL (1.6 M in isohexane) of n-butyllithium for 30 minutes. The mixture was stirred at -70 ° C for 30 min and a solution of 26.35 g (0.183 M) of (R) -glycidyl butyrate in 50 mL of dry tetrahydrofuran was added over 15 min. Stirring was continued for 16 hours while allowing the temperature to rise to ambient temperature. The mixture was treated with 500 mL (5%) aqueous sodium bicarbonate and 800 mL EtOAc, the undissolved solids were removed and washed with diethyl ether to give 16.3 g of the title compound.

The aqueous layer was further extracted with 2 x 750 mL EtOAc, the combined extracts were dried over magnesium sulfate and, after evaporation, the residue was triturated with diethyl ether. The resulting solid was recrystallized from ethanol to give 10.9 g of product.

MS (ESP): 292 (MH ⁺⁾ for C ₄ H ₁₄ FN ₃ O ₃

NMR (DMSO-d 6) δ: 2.13 (s, 3H); 3.56 (dd, 1H); 3.68 (dd, IH); 3.86 (dd, IH); 4.11 (t, IH); 4.73 (m, IH); 5.21 (br. 1H); 7.18 (s, 1 H); 7.45 (dd, IH); 7.60 (t, IH); 7.73 (dd, IH); 7.83 (s, 1H).

3- (3-Fluoro-4- (5-methylimidazol-1-yl) phenyl) -5 (R) -hydroxymethyloxazolidin-2-one

3.2 g (9.85 mmol) of 5-benzyloxycarbonylamino-2- (5-methylimidazol-1-yl) fluorobenzene are dissolved in 40 ml of dry tetrahydrofuran under nitrogen, cooled to -70 ° C and treated with solution 6, 81 ml (1.6 M in isohexane) of n-butyllithium. The mixture was stirred at -70 ° C for 20 minutes and a solution of (R) -glycidylbutyrate (1.57 g, 10.09 mmol) was added at -70 ° C. Stirring was continued for 16 hours while allowing the temperature to rise to ambient temperature. The mixture was treated with 10 mL of MeOH, stirred for 15 min and then poured into 100 mL (5%) aqueous sodium bicarbonate and extracted with 3 x 40 mL EtOAc. The combined extracts were washed with brine (20 ml), dried over magnesium sulphate and, after evaporation, the residue was purified by chromatography on a 20 g Mega Bond Elut® silica gel column, eluting with a gradient of increasing polarity from 5 to 10% MeOH in dichloromethane. The relevant fractions were combined and evaporated to give 0.86 g of the desired product.

MS (ESP): 292 (MH ⁺ ) for C ₁₄ H ₁₄ FN ₃ O ₃ · ·

176 •• · * ί · ** ΪΣί · ··· ···········

NMR (DMSO-d ₆ ) δ: 2.03 (s, 3H); 3.57 (dt, IH); 3.69 (dt, IH); 3.87 (dd, IH); 4.14 (t, 1 H); 4.74 (m, IH); 5.22 (t, IH); 6.81 (s, 1 H); 7.50 (overlap m, 2H); 7.66 (s, 1 H); 7.75 (t, 1 H).

3- (3-Fluoro-4- (4-methyl-imidazol-1-yl) -phenyl) -5 (R) -methyl-sulfonyloxymethyl-oxazolidin-2-one

11.8 g (40.5 mmol) of 3- (3-fluoro-4- (4-methylimidazol-1-yl) phenyl) -5 (R) hydroxymethyl-oxazolidin-2-one are stirred in a mixture of 200 ml of pyridine and 4, 86 g (48.2 mmol) of triethylamine under nitrogen and in an ice bath. Methanesulfonyl chloride (5.16 g, 45 mmol) was added dropwise and the mixture was stirred for 2 hours while raising the temperature to ambient temperature. The solvent was evaporated and the residue was stirred vigorously with a mixture of 200 ml of aqueous sodium bicarbonate solution (5%) and 200 ml of isohexane. The precipitate was filtered, washed with water and isohexane and dried. The residue was recrystallized from 200 mL of hot acetone diluted with 300 mL of isohexane to give 11.7 g of the title compound, mp 151-153 ° C.

MS (EI): 369 (M ⁺ ) for C ₁₅ H ₆ FN ₃ O ₅ S

NMR (DMSO-d ₆ ) δ: 2.16 (s, 3H); 3.27 (s, 3H); 3.88 (dd, IH); 4.24 (t, IH); 4.47 (dd,

1H); 4.54 (dd, IH); 5.04 (m, IH); 7.20 (d, IH); 7.45 (dd, IH); 7.63 (t, IH); 7.73 (dd, IH); 7.85 (t, 1 H).

3- (3-Fluoro-4- (5-methylimidazol-1-yl) phenyl) -5 (R) -methanesulfonyloxymethyloxazolidin-2-one

0.86 g (2.96 mmol) of 3- (3-fluoro-4- (5-methylimidazol-1-yl) phenyl) -5 (R) hydroxymethyl-oxazolidin-2-one is stirred in a mixture of 30 ml of pyridine and 0.36 g (3.55 mmol) of triethylamine under nitrogen and in an ice bath. Methanesulfonyl chloride (0.37 g, 3.26 mmol) was added dropwise and the mixture was stirred for 2 hours while raising the temperature to ambient temperature. The solvent was evaporated and the residue was dissolved in 50 mL of dichloromethane and washed with 25 mL of aqueous sodium bicarbonate (5%), 2 x 25 mL of water, 20 mL of brine, and dried over magnesium sulfate. The residue was evaporated and triturated with diethyl ether to give 0.68 g of the title compound.

MS (ESP): 370 (MH ⁺ ) for C ₁₅ H ₁₆ FN ₃ O ₅ S · ·

177

Example 142

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4- [3,6-dihydro- (2H) -pyran-4-yl] -3-fluorophenyl) oxazolidin-2-one

0.22 g (1.1 mmol) of diisopropyl azodicarboxylate is added dropwise at ambient temperature to a stirred solution of 0.275 g (0.93 mmol) of 5 (R) -hydroxymethyl-3- (4- [3,6-dihydro- (2H) (pyran-4-yl) -3-fluorophenyl) oxazolidin-2-one (WO 97/09328), 0.112 g (1.1 mmol) of 3-hydroxy-1,2,5-thiadiazole (Weinstock et al., Journal of Organic Chemistry, 32, 2823 [1967]) and 0.288 g (1.1 mmol) of triphenylphosphine in 7 mL of dry THF. The solution is left for 1.5 hours. The solvent was evaporated and the residue was purified by flash chromatography, eluting with EtOAc / isohexane (1: 1) to give 0.256 g (73% of the title compound as a solid, mp 146-148 ° C).

MS: 378 (MH ^&lt; ⁺ &gt;);

NMR: 2.4 (1 H, bs); 3.78 (3 H, t); 3.96 (1 H, m); 4.2 (3 H, m); 4.66 (2 H, m); 5.1 (1 H, m); 6.05 (1 H, s); 7.27-7.5 (3H, m); 8.41 (1 H, s).

Example 143

5 (R) - (3-Methyl-1,2,5-oxadiazol-5-oxide-4-yl) oxymethyl-3- (4- [3,6-dihydro- (2H) -pyran-4-yl) -3 -fluorophenyl) oxazolidin-2-one mg (0.69 mmol) of sodium hydride (60% suspension in mineral oil) is added portionwise to a solution of 0.2 g (0.69 mmol) of 3- (4- [3] 6-dihydro- (2H) -pyran-4-yl] -3-fluoro-phenyl) -oxazolidin-2-one in 3 ml of dry dimethoxyethane and the mixture is stirred for 40 minutes. 0.1 g (0.69 mmol) of 3-methyl-4-nitro-1,2,5-oxadiazole-5-oxide [Nikolaeva et al., Izv. Akad. Nauk USSR, Ser. Khim. 965 (1972)] and the cloudy solution was stirred for 40 minutes. 20 mL of water was added and the mixture was extracted three times with EtOAc. The combined extracts were dried by filtration through filter paper (Whatman IPS) and then evaporated. The residue was purified by flash chromatography eluting with EtOAc / isohexane (7: 3) to give 0.112 g (41%) of the title compound as a solid, mp-138-140 ° C.

178

NMR _(CDCl?): 2.07 (3H, s); 2.5 (2H, bs); 3.91 (3 H, t); 4.2 (1 H, t); 4.31 (2 H, m); 4.62 (2 H, m); 5.06 (1 H, m); 6.05 (1 H, s); 7.2-7.42 (3H, m).

Example 144

5 (R) - (2-Methyl-1,3,4-oxadiazol-5-yl) oxymethyl-3- (4- [3,6-dihydro- (2H) -pyran-4-yl] -3-fluorophenyl) oxazolidine -2-one mg (0.69 mmol) of sodium hydride (60% suspension in mineral oil) was added to a solution of 0.2 g (0.69 mmol) of (5R) -hydroxymethyl-3- (4- [3,6] -dihydro- (2H) -pyran-4-yl] -3-fluoro-phenyl) -oxazolidin-2-one in 5 mL of DMSO and stirred for 1 hour. 0.11 g (0.69 mmol) of 2-methyl-5-sulfonylmethyl-1,3,4-oxadiazole (RB Woodward et al., Journal of the American Chemical Society 105, 904 [1983]) was added and the solution was Heat at 110 ° C for 9 hours. Water (40 ml) was added and the mixture was extracted three times with EtOAc. The combined extracts were dried by filtration through filter paper (Whatman IP) and evaporated. The residue was purified by flash chromatography eluting first with EtOAc and then with EtOAc / MeOH (20: 1) to give 23 mg (9%) of the title compound as a solid (mp 146-147 ° C).

MS; 376 (MH ^&lt; ⁺ &gt;);

NMR (CDCl 3): 2.41 (3H, s); 2.49 (2 H, bs); 3.91 (3 H, t); 4.18 (1 H, t); 4.31 (2 H, m); 4.7 (2 H, m); 5.05 (1 H, m); 6.04 (1 H, s); 7.23 (2 H, m); 7.4 (1 H, s).

Example 145

5 (R) - (5-Methoxycarbonylisoxazol-3-yl) oxymethyl-3- (4- [3,6-dihydro- (2H) -pyran-4-yl] -3-fluorophenyl) oxazolidin-2-one

Using the procedure of Example 142, but starting from 5-methoxycarbonyl-3-hydroxyisoxazole, the title compound was obtained in 65% yield as a solid, mp 145-147 ° C.

MS: 419 (MH ^&lt; ⁺ &gt;);

NMR (CDCl3): 2.5 (2H, bs); 3.93 (3H, s + 3H, m); 4.18 (1 H, t); 4.32 (2 H, s); 4.59 (2 H, m); 5.04 (1 H, m); 6.06 (1 H, s); 6.58 (1 H, s); 7.24 (2 H, m); 7.4 (1 H, d).

179

Example 146

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4-iodophenyl) oxazolidin-2-one

0.67 g (2.64 mmol) of iodine was added portionwise to a stirred solution of 0.7 g (2.53 mmol) of 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3-phenyloxazolidin-2. -one and 0.727 g (3.29 mmol) of silver trifluoroacetate in 4 ml of acetonitrile and 6 ml of chloroform. The mixture was stirred for 24 hours in the absence of light. The mixture was filtered and the filtrate was evaporated. The residue was extracted with EtOAc and the extract was washed with water, dilute ammonia (0.1 mL 0.88SG ammonia in 25 mL water), water and brine, dried over sodium sulfate and evaporated to give 0.749 g (73%) of the title compound. as a solid.

MS: 404 (MH ^&lt; ⁺ &gt;);

NMR: 3.94 (1 H, m); 4.18 (1 H, t); 4.67 (2 H, m); 5.1 (1 H, m); 7.38 (2 H, d); 7.7 (2 H, d)

8.41 (1 H, s).

The necessary starting material, 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3-phenyloxazolidin-2-one was prepared according to the procedure described in Example 142, but starting from 5 (R) hydroxymethyl-3-phenyloxazolin-2. (Gregory, WA et al., J. Med. Chem. (1989), 32, 1673-81) to give the title compound as a solid in 83% yield. MS: 278 (MH ^&lt; ⁺ &gt;);

NMR (CDCl 3): 4.0 (1H, m); 4.2 (1 H, t); 4.68 (2 H, m); 5.04 (1 H, m); 7.18 (1 H, t); 7.4 (2 H, t); 7.55 (2 H, d); 8.0 (1H, s).

Example 147

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (3 - (- 4- [2,5-dihydrothiophen-1,1-dioxo-3-yl) phenyl) oxazolidin-2-one

A mixture of 0.6 g (1.49 mmol) of 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (4-iodophenyl) oxazolidin-2-one (Example 146), 0.185 g (1.57) mmol) of 2,5-dihydrothiophene-1,1-dioxide, 0.26 ml (1.87 mmol) of triethylamine, 0.48 g (1.49 mmol) of tetrabutylammonium bromide and 17 mg of 0.0759 mmol) of palladium acetate in 4 ml The DMF was heated at 60 ° C for 19 hours under nitrogen. After cooling, the mixture was partitioned between water and EtOAc and the aqueous layer ·

180

was extracted twice with EtOAc. The combined extracts were washed with brine and water, dried over sodium sulfate and evaporated. The residue was triturated with acetonitrile to give 71 mg (12%) of the title compound as a solid.

MS: 394 (MH ^&lt; ⁺ &gt;);

NMR (400MHz): 4.0 (1H, m); 4.1 (2 H, m); 4.25 (1 H, t); 4.4 (2 H, s); 4.7 (2 H, m); 5.15 (1 H, m); 6.57 (1 H, s); 7.6 (4 H, m); 8.45 (1 H, s).

Example 148

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (3-fluoro-4- (1- (2 (S), 3-dihydroxypropanoyl)) 1,2,5,6-tetrahydropyrid-4 -yl) phenyl) oxazolidin-2-one 1N aqueous HCl is added to a solution of 0.154 g (0.32 mmol) of 5 (R) - (1,2,5-thiadiazol-3-yloxymethyl) -3- (3-fluoro- 4- (1- (2,2-dimethyl-1,3-dioxolane-4 (S) -ylcarbonyl) -1,2,5,6-tetrahydropyrid-4-yl) phenyl) oxazolidin-2-one in 3 ml THF and the solution was allowed to stand for 2 days. The solution was evaporated and the residue azeotroped twice with ethanol. The residue was purified by chromatography on a BondElut silica gel column, eluting first with dichloromethane and then with 2% MeOH / dichloromethane to give 37 mg (26%) of the title compound as a solid.

MS: 465 (MH ^&lt; ⁺ &gt;);

NMR (400MHz): 2.5 (2H + DMSO); 3.3 (1H, s); 3.4 (1 H, m); 3.5 (1 H, m); 3.76 (1 H, m); 4.0 (1 H, t); 4.15 (1 H, s); 4.26 (1 H, t); 4.4 (1 H, m); 4.8 (3 H, m); 4.97 (1 H, m); 5.18 (1 H, m); 6.03 (1 H, s); 7.32-7.46 (2 H, m); 7.53 (1 H, d); 8.47 (1 H, s).

The necessary starting material was prepared according to the method described in Example 142, but starting from 5 (R) -hydroxymethyl-3- (3-fluoro-4- (1- (2,2-dimethyl-1,3-dioxolane-4)). (ylcarbonyl) -1,2,5,6-tetrahydropyrid-4-yl) phenyl) oxazolidin-2-one (prepared analogously to Example 11) to give the title compound in 56% yield.

MS: 505 (MH ^&lt; ⁺ &gt;);

NMR: 1.32 (6H, s); 2.41 (2H + DMSO); 3.58 (1 H, m); 3.66 (2 H, m); 3.82 (1 H, t); 4.02-4.27 (5 H, m); 4.69 (1 H, m); 4.9 (1 H, m); 5.19 (1 H, t); 6.0 (1 H, s); 7.32 (2 H, m); 7.5 (1 H, d); 8.47.

Example 149

181

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4- (1- (2 (R), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3) (fluorophenyl) oxazolidin-2-one

Using the procedure described in Example 148 but starting from 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolane-4) ( R) -ylcarbonyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one gives the title compound in 50% yield as a solid.

MS: 465 (MH ^&lt; ⁺ &gt;);

NMR (400MHz): 2.42 (2H + DMSO); 3.5 (1 H, m); 3.58 (1 H, m); 3.71 (1 H, m); 3.98 (1 H, t); 4.1 (1 H, s); 4.2 (1 H, t); 4.35 (1 H, m); 4.77 (3 H, m); 4.93 (1 H, m); 5.12 (1 H, m); 6.02 (1 H, s); 7.3 - 7.42 (2H, m); 7.5 (1 H, d); 8.42 (1 H, s).

Necessary starting material 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolane-4 (R) -ylcarbonyl)) -1,2 (5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one is prepared as follows: i) 5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (3-fluoro-4) - (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) phenyl) oxazolidin-2-one was prepared according to the procedure described in Example 142 but starting from 5 (R) -hydroxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one (WO 97/30995 & analogous to Reference Example 4) in 58% yield.

MS: 467 (MH ^&lt; ⁺ &gt;);

NMR: 2.4 (2H + DMSO); 2.6 (2 H, m); 3.02 (2 H, m); 3.57 (2 H, s); 3.92 (1 H, m); 4.2 (1 H, t); 4.62 (2 H, m); 5.1 (1 H, m); 5.91 (1 H, s); 7.2-7.4 (7H, m); 7.48 (1 H, d); 8.4 (1 H, s).

ii) 0.39 ml (2.24 mmol) of diisopropylethylamine was added dropwise to a stirred solution at 5 ° C and under nitrogen 3.48 g (7.47 mmol) of 5 (R) -1,2,5-thiadiazole- 3yloxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one in 60 ml dichloromethane and then treated with 1.05 ml (9 , 73 mmol) of 1-chloroethyl chloroformate. The mixture was stirred at 5 ° C for 2 hours to remove the benzyl chloride from the carbamate intermediate by flash chromatography (Merck 7736 silica gel), eluting with a gradient of 10 to 30% EtOAc in isohexane. The carbamate was refluxed with MeOH for 1 hour. The solvent is evaporated and the residue is triturated with ether to give the hydrochloride 5. (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (3-fluoro-4- (1,2,5,6-tetrahydropyrid-4-yl) oxazolidin-2-one as a solid in 82% yield MS: 376 (MH ⁺ ) (free base);

NMR: 2.67 (2 H, s); 3.3 (2H + DMSO); 3.75 (2 H, s); 4.0 (1 H, m); 4.25 (1 H, t); 4.7 (2 H, m); 5.14 (1 H, m); 6.05 (1 H, s); 7.4 (2 H, m); 7.55 (1 H, d); 8.42 (1 H, s); 9.35 (1 H, bs).

iii) 0.597 g (3.63 mmol) of (R) -2,2-dimethyl-1,3-dioxolan-4-ylcarbonyl chloride solution (S. Handa et al., Synth. Commun. (1995), 25, 2837) in 5 mL of dichloromethane was added dropwise under nitrogen at -10 ° C to a stirred mixture of 1 g (2.42 mmol) of 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (3) hydrochloride. -fluoro-4- (1,2,5,6-tetrahydropyrid-4-yl) oxazolidin-2-one and 0.49 mL (6.06 mmol) of pyridine in 30 mL of dichloromethane. 30 ml of water was added and the organic layer was washed with brine, dried over sodium sulfate and evaporated, the residue was triturated with ether and filtered to give 1.13 g (93%) of 5 (R) -1.2 5-thiadiazol-3-yloxymethyl-3- (4- (1- (2,2-dimethyl-1,3-dioxolane-4 (R) yl) carbonyl) -1,2,5,6-tetrahydropyrid-4 (yl) -3-fluorophenyl) oxazolidin-2-one as a solid.

MS: 504 (MH ^&lt; ⁺ &gt;);

NMR: 1.32 (6H, s); 2.42 (2H + DMSO); 3.7 (2 H, m); 4.0 (1 H, m); 4.11 (2 H, m); 4.25 (2 H, m); 4.8 (2 H, m); 4.91 (1 H, m); 5.12 (1 H, m); 6.02 (1 H, s); 7.29-7.43 (2 H, m);

7.5 (1 H, d); 8.42 (1 H, s).

Example 150

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (3,5-difluoro-4- (1- (2 (S), 3-dihydroxypropanoyl)) 1,2,5,6-tetrahydropyridine -4-yl) phenyl) oxazolidin-2-one

Using the procedure described in Example 148 but starting from 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (3,5-difluoro-4- (1- (2,2-dimethyl-1,3)). dioxolane-4 (S) -ylcarbonyl) -1,2,5,6-tetrahydropyrid-4-ylphenyl) oxazolidin-2-one gave the title compound in 51% yield as a solid.

MS: 483 (MH ^&lt; ⁺ &gt;);

• ·

183 «·.:. .: ..: .. · .. ··,

NMR: 2.48 (2H + DMSO); 3.48 (1 H, m); 3.54 (1 H, m); 3.97 (1 H, t); 4.1 (1 H, s); 4.17 (1 H, t); 4.34 (1 H, m); 4.67 (3 H, m); 4.95 (1 H, m); 5.12 (1 H, m); 5.88 (1 H, s); 7.33 (1H, s); 7.36 (1H, s); 8.42 (1 H, s).

The necessary starting material is obtained as follows:

i) Using the method described in Example 149, step i), but starting from 5 (R) hydroxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3, Of 5-difluorophenyl) oxazolidin-2-one is obtained in 58% yield of 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-) yl) -3,5-difluorophenyl) oxazolidin-2-one as a solid.

MS: 485 (MH ^&lt; ⁺ &gt;);

NMR: 2.3 (2H, bs); 2.6 (2 H, t); 3.03 (2 H, s); 3.39 (2 H, s); 3.95 (1 H, m); 4.2 (1 H, t);

4.65 (2 H, m); 5.12 (1 H, s); 5.77 (1 H, s); 7.2-7.38 (7H, m); 8.41 (1 H, s).

ii) Using the procedure described in Example 149, step ii), but starting from 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (4- (1-benzyl-1,2,5,6-) - tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one is obtained in 84% yield 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (3,5-difluoro-4- ( 1,2,5,6-tetrahydropyrid-4-yl) phenyl) oxazolidin-2-one as a solid.

MS: 395 (MH +) (free base);

NMR: 2.51 (2H, s); 3.28 (2H + DMSO); 3.71 (2 H, s); 3.98 (1 H, m); 4.2 (1 H, t); 4.65 (2 H, m); 5.1 (1 H, m); 5.88 (1 H, s); 7.33 (1 H, s); 7.39 (1 H, s); 8.41 (1 H, s); 9.32 (1 H, bs).

iii) Using the procedure described in Example 149, step iii) but starting from 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (3,5-difluoro-4- (1,2-hydrochloride) hydrochloride 5,6-Tetrahydropyrid-4-yl) phenyl) oxazolidin-2-one and the corresponding (S) -dioxolane were obtained in 86% yield of 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (4). - (1- (2,2-Dimethyl-1,3-dioxolane4 (S) -ylcarbonyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin-2-one as solid.

MS: 523 (MH ^&lt; ⁺ &gt;);

NMR: 1.31 (6H, 2s); 2.4 (2H + DMSO); 3.6-3.8 (2H, m); 4.08-4.2 (5H, m); 4.9 (1 H, m); 5.12 (1 H, m); 5.89 (1 H, s); 7.32 - 7.37 (2H, 2s); 8.41 (1 H, s).

Example 151

184 • · · · ··· · * ··· ········ · ·

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4- (1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one ml a saturated solution of ammonia in methanol was added to a stirred solution of 0.275 g (0.576 mmol) of 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (4- (1-acetoxyacetyl1,2,5,6-tetrahydropyrid) (4-yl) -3-fluorophenyl) oxazolidin-2-one in 8 mL of methanol and the solution was allowed to stand for 20 hours. Then a small amount of insoluble material is filtered off and the filtrate is concentrated. A solid was obtained at 5 ° C, which was filtered and washed with a small amount of cold MeOH and then cold ether to give 0.161 g (64%) of the title compound as a solid.

MS: 435 (MH ^&lt; ⁺ &gt;);

NMR: 2.42 (2H + DMSO); 3.52 (1 H, m); 3.67 (1 H, m); 3.94 (1 H, m); 4.0-4.17 (4 H, m); 4.2 (1 H, t); 4.5 - 4.73 (3H, m); 5.12 (1 H, m); 6.0 (1 H, m); 7.28-7.42 (2 H, m); 7.5 (1 H, dd); 8.42 (1 H, s).

The necessary starting material was prepared as follows: 0.21 ml of acetoxyacetyl chloride (1.95 mmol) was added at 5 ° C to a stirred mixture of 0.412 g (1 mmol) of 5 (R) -1,2,5-thiadiazol-3-yloxymethyl hydrochloride -3- (3-fluoro-4- (1,2,5,6-tetrahydro-pyridin-4-yl) -oxazolidin-2-one (product of step ii, Example 149) and 0.42 g (5 mmol) of sodium bicarbonate in 15 ml of acetone / water (2: 1), the mixture is allowed to warm to room temperature after 10 minutes and stirred for 18 hours, an additional 0.3 ml of acetoxyacetyl chloride and 0.42 g of sodium bicarbonate are added, followed by 6 hours of water. and the mixture was extracted three times with EtOAc. The combined extracts were washed sequentially with water, 1N HCl and brine, dried and evaporated. The residue was triturated with ether and the solids were filtered to give 0.3 g (63% yield). R) -1,2,5-thiadiazol-3-y (oxymethyl-3- (4- (1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2-one

MS: 477 (MH ^&lt; ⁺ &gt;);

NMR: 2.08 (3H, s); 2.42 (2H + DMSO); 3.4 (2 H, m); 3.98 (1 H, m); 4.08 (2 H, bs); 4.21 (1 H, t); 4.65 (2 H, m); 4.8 (2 H, m); 5.12 (1 H, m); 6.0 (1 H, m); 7.31 (2 H, m); 7.5 (1 H, d);

8.4 (1 H, s).

Example 152 • ·

185

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4- {1-hydroxyacetyl-1,2,5,6-tetrahydropyrid-4-yl} -3,5-difluorophenyl) oxazolidin-2- he

Using the procedure described in Example 151 but starting from 5 (R) -1,2,5-thiadiazazol-3-yloxymethyl-3- (4- (1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl)). (-3,5-difluorophenyl) oxazolidin-2-one gives the title compound in 80% yield as a solid.

MS: 453 (MH ^&lt; ⁺ &gt;);

NMR: 2.34 (2 H, m); 3.54 (1 H, m); 3.71 (1 H, m); 4.1 (1 H, m); 4.05 - 4.28 (5H, m); 4.2 (1 H, t); 4.54-4.72 (3 H, m); 5.15 (1 H, m); 5.89 (1 H, m); 7.39 (2 H, d); 8.45 (1 H, s). The necessary starting material was prepared according to the method used to prepare the starting material of Example 151, but starting from 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (3,5-difluoro-4- (1,2,5,5-difluoro-4-) hydrochloride. (6-tetrahydropyrid-4-yl) phenyl) oxazolin-2-one (see Example (ii)) to give the product in 78% yield.

MS: 477 (MH ^&lt; ⁺ &gt;);

NMR: 2.08 (3H, s); 2.42 (2H + DMSO); 3.4 (2 H, m); 3.98 (1 H, m); 4.08 (2 H, bs); 4.21 (1 H, t); 4.65 (2 H, m); 4.8 (2 H, m); 5.12 (1 H, m); 6.0 (1 H, m); 7.31 (2 H, m); 7.5 (1 H, d);

8.4 (1 H, s).

Example 153

5 (R) -imidazol-2-ylthiomethyl-3- (4- [3,6-dihydro- (2H) -pyran-4-yl] -3-fluorophenyl) oxazolidin-2-one

0.1 ml (0.674 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene was added to a stirred suspension of 0.25 g (0.674 mmol) of 5 (R) -methanesulfonyloxymethyl 3- (4) under nitrogen. - (3,6dihydro- (2H) -pyran-4-yl] -3-fluorophenyl) oxazolidin-2-one (prepared from 5 (R) hydroxymethyl compound (WO 97/09328) by reaction with methylsulfonyl chloride) and 0.067 g (0.674) mmol) of 2-mercaptoimidazole in 2 ml dioxane The mixture was heated at 60 ° C for 4 hours and then evaporated The residue was purified by column chromatography eluting first with 2% MeOH / EtOAc and then 4% MeOH / EtOAc to give 0.077 g (30%) of the title compound as a solid, mp 178-179 ° C (dec.).

• ·

186

MS: 476 (MH ^&lt; ⁺ &gt;);

NMR: 2.39 (2H, bs); 3.42 (2 H, m); 3.79 (2 H, t); 3.86 (1 H, m); 4.19 (3 H, m); 4.89 (1 H, m); 6.07 (1 H, s); 7.04 (2 H, s); 7.26 (1 H, dd); 7.38 (1 H, t); 7.46 (1 H, d).

Example 154

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4 - ((1S) (4S) -2-benzyl-2,5-diazabicyclo {2.2.1} heptan-5-yl) -3 (fluorophenyl) oxazolidin-2-one

A mixture of 0.13 g (0.438 mmol) of 1-amino-4 - [(1S) (4S) -2-benzyl-2,5-diazabicyclo {2.2.1} heptan-5-yl] -3-fluorobenzene and 0.069 g (0.483) mmol) of 3 (S) oxiranylmethoxy-1,2,5-thiadiazole in 2 mL of MeOH was stirred and heated to 60 ° C for 20 hours. The solvent was evaporated and the residue was partially purified by flash chromatography eluting with 4/96 / 0.8 MeOH / dichloromethane / 0.88SG ammonia. 0.144 g of crude ethanolamine is obtained, which is stirred and heated at 110 ° C for 5 hours with 0.2 ml of diethyl carbonate, 9 mg of sodium methoxide and 0.05 ml of MeOH. The reaction mixture was purified by flash chromatography eluting with EtOAc / 0.1% 0.88SG ammonia to give an oil which was triturated with ether to give 0.049 g (23% over two steps) of the title compound as a solid (melting point). 97-98 ° C). MS: 482 (MH ^&lt; ⁺ &gt;);

NMR (CDCl ₃ ): 1.83-2.0 (2H, dd); 2.72 - 2.96 (2H, dd); 3.41 (1 H, m); 3.5 (2 H, s);

3.91 (1 H, m); 4.13 (1 H, t); 4.3 (1 H, s); 4.67 (2 H, m); 5.0 (1 H, m); 6.6 (1 H, t); 7.05 (1 H, dd); 7.2-7.38 (6H, m); 8.02 (1 H, s).

The necessary starting material is prepared as follows:

1-Amino-4 - [(1S) (4S) -2-benzyl-2,5-diazabicyclo {2.2.1} heptan-5-yl] -3-fluorobenzene: i) Mix 1.05 g (3 mmol) (1S) (4S) -2-benzyl-2,5-diazabicyclo {2.2.1} heptane dihydrobromide [Henry et al. J. Med. Chem. (1974), 17, 481], 0.48 g (3 mmol) of 3,4-difluoronitrobenzene and 1.38 g (9 mmol) of 1,8-diazabicyclo [5.4.0] undec-7-ene

187 • »» in 10 ml of acetonitrile was stirred and refluxed for 2 hours. The solvent was evaporated and the residue was partitioned between EtOAc and water. The organic layer was filtered (IPS paper) and the filtrate was evaporated to give 0.95 g (97%) of 4 - [(1S) (4S) -2-benzyl-2,5-diazabicyclo {2.2.1} heptan-5-yl 3-Fluoro-1-nitrobenzene as a solid.

MS: 328 (MH ^&lt; ⁺ &gt;);

NMR (CDCl ₃ ): 1.82-2.07 (2H, dd); 2.77-2.98 (2H, dd); 3.59 (2 H, 1H, s); 3.72 (2 H, s); 3.91 (1 H, m); 4.58 (1 H, s); 6.6 (1 H, t); 7.2 to 7.34 (5H + _CHCl3);

ii) 0.57 ml of hydrazine hydrate was added with stirring to a suspension of 1.63 g (5 mmol) of 4 [(1S) (4S) -2-benzyl-2,5-diazabicyclo {2.2.1} heptan-5-yl] 3-fluoro-1-nitrobenzene in 35 ml of ethanol, and then about 1 g of Raney nickel is added. Heat the mixture at 60 ^° C for 1.5 hours. Additional hydrazine hydrate (0.2 mL) and Raney nickel (ca. 0.5 g) were added and heating was continued for an additional 3 hours. The mixture was cooled and stirred with 0.5 g of activated carbon for 1 hour and filtered. The filtrate was evaporated to give 1.28 g (86%) of 1-amino-4 - [(1S) (4S) -2-benzyl-2,5-diazabicyclo {2.2.1} heptan-5-yl] -3-fluorobenzene .

MS: 287 (MH +);

NMR (CDCl ₃ ); 1.8-1.95 (2H, dd); 2.73-2.9 (2H, dd); 3.17-3.5 (5H, m); 3.71 (2H, s); 4.12 (1H, s); 6.32-6.52 (3 H, m); 7.18-7.35 (5H + _CHCl3). 3 (S) -oxiranylmethoxy-1,2,5-thiadiazole:

4.2 g of diisopropyl azodicarboxylate are added at ambient temperature to a stirred solution of 1.54 9 (S) -glycidol, 2.12 g (20.8 mmol) of 3-hydroxy-1,2,5-thiadiazole and 5.45 g ( 20.8 mmol) triphenylphosphine in 25 mL dry THF. The solution was allowed to stand for 21 hours. The solvent was evaporated and the residue was extracted twice with isohexane (2 x 50 mL). The combined extracts were evaporated and the residue was purified by flash chromatography eluting with EtOAc / isohexane (1: 3) to give 0.41 g of the title compound as an oil.

NMR (CDCl 3): 2.75 (1H, m); 2.9 (1 H, m); 3.38 (1 H, m); 4.28 (1 H, m); 4.7 (1 H, m); 8.0 (1 H, s).

Example 155

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4 - [(1S) (4S) -2,5-diazabicyclo {2.2.1} heptan-5-yl] -3-fluorophenyl) oxazolidine -2-one hydrochloride

188

mg (0.4 mmol) of diisopropylethylamine was added dropwise at 5 ° C and under nitrogen to a stirred solution of 0.65 g (1.35 mmol) of 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (4 - [(1S) (4S) -2-Benzyl-2,5-diazabicyclo (2.2.1) heptan-5-yl] -3-fluorophenyl) oxazolidin-2-one in 10 mL dichloromethane followed by addition of 0.19 mL (1.76 mmol) of 1-chloroethyl chloroformate. The mixture was stirred at 5 ° C and the intermediate carbamate was freed from benzyl chloride by trituration with three portions of isohexane (3x15 mL). The carbamate was heated to reflux with 10 mL of MeOH for 1 hour. The solvent was evaporated and the residue was triturated with acetone to give 0.366 g (63% yield) of the title compound as a solid.

MS: 391 (MH ^&lt; ⁺ &gt;);

NMR (CDCl ₃ ): 2.0 (2H, dd); 3.2 - 3.34 (2H + DMSO); 3.56 (2 H, dd); 3.9 (1H, m); 4.18 (1H, t); 4.34 (1 H, s); 4.5 (1 H, s); 5.07 (1 H, m); 6.86 (1 H, t); 7.15 (1 H, d); 7.45 (1 H, d);

8.42 (1 H, s); 9.04 (1 H, bs); 9.57 (1 H, bs).

Example 156

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4 - [(1S) (4S) -2-acetoxyacetyl-2,5-diazabicyclo {2.2.1} heptan-5-yl) -3- fluorophenyl) oxazolidin-2-one

Using the procedure described for the preparation of the starting material for Example 151 but starting from the title compound of Example 155, the title compound was obtained as an amorphous solid in 46% yield.

MS: 491 (MH +);

189 9 9 9 9 9 9 9 9 9

NMR (CDCl 3): 1.85-2.02 (2H, dd); 2.03 (3 H, s); 3.28 (1 H, d); 3.57 (1 H, s); 3.63 3.83 (2H, m); 3.91 (1 H, m); 4.1 (1 H, t); 4.42-4.73 (5 H, m); 5.0 (2 H, m); 6.6 (1 H, m); 7.07 (1 H, m); 7.4 (1 H, d); 8.01 (1 H, s).

Example 157

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4 - [(1S) (4S) -2-hydroxyacetyl-2,5-diazabicyclo {2.2.1} heptan-5-yl] -3-fluorophenyl) oxazolidin-2-one

mg (0.185 mmol) of a solution of the title compound of Example 156 in 2.5 mL of MeOH saturated with ammonia was maintained for 22 hours. The solvent was evaporated and the residue was redissolved in 5 ml of dichloromethane and the solution was washed with water. The organic layer was dried by filtration through filter paper (Whatman IPC) and evaporated to give 57 mg (69%) of the title compound as a foam.

MS: 450 (MH ^&lt; ⁺ &gt;);

NMR (CDCl 3): 1.85-2.17 (2H, m); 3.14-3.84 (5 H, m); 3.88 (4.29 (4H, m); 4.64.74 (3H, m); 5.0 (2H, m); 6.6 (1H, m); 7.08 (1H, m) 7.38 (1H, d) 8.02 (1H, s).

Example 158

5 (R) -1,2,5-Thiadiazol-3-yloxymethyl-3- (4 - [(1S) (4S) -2- (2 (S), 3-dihydroxypropanoyl) 2,5-diazabicyclo {2.2. 1} Heptan-5-yl] -3-fluorophenyl) oxazolidin-2-one

O • 4

Using a procedure to prepare a starting material for the compound of Example 148 but starting from 5 (R) -1,2,5-thiadiazol-3-yloxymethyl-3- (3-fluoro-4- (2- (2,2-dimethyl)) -1,3-dioxolane-4 (S) -ylcarbonyl) -2,5-diazabicyclo (2.2.1} heptan-5-yl) phenyl) oxazolidin-2-one, yielding the title compound as an amorphous solid in 79% yield.

MS: 480 (MH ^&lt; ⁺ &gt;);

NMR (400MHz, DMSO-d 6 + acetic acid-d 4): 1.87-2.0 (2H, m); 3.12 (1 H, m);

3.31 (1 H, d); 3.48 (2 H, m); 3.65 (2 H, m); 3.86 (1 H, m); 4.11 (1 H, m); 4.45 (1 H, m);

4.62 (1 H, m); 4.78 (1 H, m); 5.02 (1 H, m); 6.78 (1 H, m); 7.12 (1 H, m); 7.4 (1 H, dd);

8.33 (1 H, s).

The necessary starting material was prepared as a solid in 63% yield (MS: 520 (MH ⁺ )) by the method used to prepare the starting compound for Example 149, step iii) but starting from the title compound of Example 155 and the appropriate (S) dioxolane .

Example 159

5 (R) -1xoxazol-3-yloxymethyl-3- (4- {8-acetoxyacetyl-8-azabicyclo [3.2.1] oct-2-en-3-yl} 3-fluorophenyl) oxazolidin-2-one

0.3 ml (2.72 mmol) of acetoxyacetyl chloride is added dropwise to a stirred mixture of 0.35 g (0.91 mmol) of 5 (R) -isoxazol-3-yloxymethyl-3- (4- {8-azabicyclo [2.2.1 mmol]). 3.2.1] oct-2-en-3-yl} -3-fluorophenyl) oxazolidin-2-one, 7 ml acetone, 0.35 g (4.17 mmol) sodium bicarbonate and 3.5 ml water and the mixture is stirred for 2 hours clock. An additional 0.7 g of sodium bicarbonate and 0.15 ml of acetoxyacetyl chloride were added, and after 2.5 hours an additional 0.7 g of sodium bicarbonate was added and the mixture was stirred for 20 hours. The solvent was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with sodium bicarbonate solution, dried over sodium sulfate and evaporated. The rest «· · · · · · · · · · ·

191 was purified by MegaBondElut column chromatography eluting with a gradient of dichloromethane-6% MeOH / dichloromethane to afford 0.16 g of the title compounds as an oil (36%).

MS: 486 (MH ^&lt; ⁺ &gt;);

NMR (400MHz): 1.79 (2H, m); 1.88-2.1 (5H, s + m); 2.25 (2 H, d); 3.56 (1 H, t); 3.62 (1 H, m); 3.9 (1 H, m); 4.19 (1 H, t); 4.48 (3 H, m); 4.62 (1 H, m); 4.78 (2 H, m); 5.06 (1 H, m); 6.32 (1 H, m); 6.35 (1 H, s); 7.3 (2 H, m); 7.48 (1 H, dd); 8.66 (1 H, s).

The necessary starting material is prepared as follows: i) 0.19 g (0.208 mmol) of tris (dibenzylideneacetone) dipalladium (0), 0.13 g (0.425 mmol) of triphenylarsine and 0.265 g (6.31 mmol) of lithium chloride are added to the stirred of a solution of 0.85 g (2.1 mmol) of 5 (R) -isoxazol-3-yloxymethyl-3- (3-fluoro-4-iodophenyl) oxazolidin-2-one (prepared in analogy to Reference Example 28) in 35 ml of degassed DMF under nitrogen. After 5 minutes, a solution of 0.78 g (2.1 mmol) of 8-tert-butyloxycarbonyl-3-trimethylstannyl-8-azabicyclo [3.2.1] oct-2-ene (GB 2298647) in 4 mL of DMF is added and the mixture is heated to 60 ° C for 18 hours. 30 ml of 2M potassium fluoride solution are then added and the mixture is stirred for 40 minutes. The solvent was evaporated and the residue was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined extracts were dried over sodium sulfate and evaporated. The residue was purified by column chromatography eluting with a gradient of dichloromethane-5% MeOH / dichloromethane to afford 0.97 g (81%) of 5 (R) -isoxazol-3-yloxymethyl-3- (4- {8-tert-butyloxycarbonyl- 8-azabicyclo [3.2.1] oct-2-en-3-yl} -3-fluorophenyl) oxazolidin-2-one as an oil in 85% purity [HPLC],

MS: 486 (MH ^&lt; ^{+ &gt;} ).

ii) 1 mL of saturated methanolic HCl was added to a solution of 0.07 g (0.144 mmol) of the product of step i) in 1 mL of MeOH and the mixture was maintained for 20 hours. The solvent was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with brine, dried over sodium sulfate and evaporated to give 0.03 g (54% yield) of 5 (R) -isoxazol-3-yloxymethyl-3- (3-fluoro-4-iodophenyl) oxazolidine- 2-one like oil.

MS: 386 (MH ^&lt; ^{+ &gt;} ).

Example 160

5 (R) -1xoxazol-3-yloxymethyl-3- (4- {8-hydroxyacetyl-8-azabicyclo [3.2.1] oct-2-en-3-yl} 3-fluorophenyl) oxazolidin-2-one

192 \\

O

mL of saturated methanolic ammonia was added to a 0.21 g solution of the title compound of Example 159 in 1 mL of MeOH / dichloromethane (1/1) and held for 44 hours. The solvent was evaporated and the residue was purified by MegaBondElut column chromatography eluting with a gradient of 10% EtOAc / dichloromethane-50% EtOAc / dichloromethane-5% MeOH / dichloromethane-10% MeOH / dichloromethane to give 0.03 g (27%) of the title compound. in the title like oil.

MS: 444 (MH ^&lt; ⁺ &gt;);

NMR 1.75 (2H, m); 1.98 (2 H, m); 2.24 (2 H, m); 2.82 (1 H, bd); 3.9 (1 H, m); 4.10 (1 H, t); 4.19 (1 H, t); 4.46 (3 m); 4.66 (1 H, t); 5.08 (1 H, m); 6.32 (1 H, d); 6.36 (1 H, s); 7.29 (1 H, m); 7.34 (1 H, m); 7.48 (1 H, dd); 8.68 (1 H, s).

Note: The stereochemistry of the azabicyclic rings in Examples 159 and 160 is a mixture of (1S), (5R) and (1R), (5S), in the numbering order so that the double bond has the lowest number.

Example 161

3- (4-Methylthio) phenyl-5 (R) - (2-thiazoyloxymethyl) oxazolidin-2-one

378 mg (10 mmol) of sodium hydride (60% w / w in oil) was washed with isohexane and suspended under nitrogen in 2 ml of DMF. Then, 1.39 g (5.8 mmol) of 5 (R) -hydroxymethyl-3- (4-methylthiophenyl) oxazolin-2-one is dissolved in DMF and added dropwise to the hydride suspension. Gas evolution and stirring continued at room temperature for 2 hours. 0.52 ml (5.8 mmol) of 2-bromothiazole in 10 ml of DMF is added slowly, raising the reaction temperature from 22 to 29 ° C. The reaction mixture was then stirred at ambient temperature for 4 hours and poured into water. The product was extracted into dichloromethane, dried over magnesium sulfate and concentrated to give a dark brown gum.

Purify by silica gel flash chromatography eluting with EtOAc: isohexane 2: 1. The relevant fractions were combined and evaporated to give 740 mg of the product as a white powder, mp 83-86 ° C.

MS: 322 (M ⁺ ), 323 (MH ⁺ ) for C ₁₄ H ₁₄ N ₂ O ₃ S ₂

NMR (CDCl ₃ ) 7.5 (m, 2H); 7.3 (m. 2H); 7.11 (d, IH); 6.75 (d, IH); 5.05 (m, IH); 4.7 (dd, 2 H); 4.15 (t, 1 H); 4.00 (dd, IH); 2.5 (s. 3H).

Example 162

3- (4-Methylsulfonylphenyl) -5 (R) - (2-thiazoyloxymethyl) oxazolidin-2-one

600 mg (20 mmol) of 3- (4-methylthiophenyl) -5 (R) - (2-thiazolyloxymethyl) oxazolidin-2-one are dissolved in 20 ml of dichloromethane. 1.42 g (4.13 mmol) of 3-chloroperoxybenzoic acid (50% w / w) are added in portions, maintaining the temperature at less than 20 ° C under external cooling. The resulting white suspension was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a white solid. This product was triturated twice, first with diethyl ether and then with dichloromethane to give 285 mg of the oxidized product as a white powder, m.p. 136 ° C.

MS: 354 (M ⁺ ), 355 (MH ⁺ ) for C ₁₄ H ₁₄ N ₂ O ₅ S ₂

NMR (DMSO-d ₆ ) 7.95 (m, 2H); 7.82 (m, 2 H); 7.12 (d, IH); 6.82 (d, IH); 5.15 (m, IH);

4.74 (m, 2 H); 4.32 (t, IH); 4.08 (dd, IH); 3.09 (s, 3H).

Example 163

3- (4-Methylsulfonylphenyl) -5 (R) - (isoxazol-3-yloxymethyl) oxazolidin-2-one

1.0 g (4.18 mmol) of 5 (R) -hydroxymethyl-3- (4-methylthiophenyl) oxazolidin-2-one (see Example 42), 0.43 g (5.05 mmol) of 3-hydroxyisoxazole and 1 Tributylphosphine (4 g, 5.34 mmol) was suspended in tetrahydrofuran (10 mL) under nitrogen. 0.79 ml (5.02 mmol) of diethyl azodicarboxylate was added dropwise, raising the reaction temperature from 19 to 33 ° C. The resulting yellow solution was stirred at ambient temperature for 2 hours. The reaction mixture was flash chromatographed on a silica gel column eluting with EtOAc: isohexane = 7: 3.

194

The relevant fractions were combined and evaporated to give 1.4 g of crude product as a white powder. 388 mg of this crude product was dissolved in 20 ml of dichloromethane. 0.872 g (2.5 mmol) of 3-chloroperoxybenzoic acid (50% w / w) was added portionwise while maintaining the temperature at less than 20 ° C under external cooling. The reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give a white solid. This product was triturated with diethyl ether and filtered to give 300 mg of the oxidized product as a white powder, mp 180 ° C.

MS: 339 (MH ⁺ ) for C ₁₄ H ₁₄ N ₂ O ₆ S

NMR (CDCl ₃ ) 8.18 (d, 1H); 7.98 (m, 2 H); 7.8 (m. 2H); 6.0 (d, IH); 5.1 (m, 1H); 4.5 (m, 2H); 4.25 (t, IH); 4.08 (dd, IH); 3.09 (s, 3H).

Example 164

5 (R) -1-Oxazol-3-yloxymethyl-3- (4-bromo-pyrid-2-yl) -oxazolidin-2-one

To a stirred solution of 3.75 g (13.7 mmol) of 5 (R) -hydroxymethyl-3- (4-bromopyrid-2-yl) oxazolidin-2-one (EP 694543), 1.28 g (15.1 mmol) 3 -hydroxyisoxazole and 4.31 g (16.4 mmol) of triphenylphosphine in 83 ml of anhydrous THF were added dropwise 3.20 g (3.11 ml, 15.8 mmol) of diisopropyl azodicarboxylate and the mixture was stirred at room temperature for 5 hours . The solvent was removed by rotary evaporation and the product was purified by MPLC (Merck silica gel 9385, eluting with CH ₂ Cl ₂ ) and trituration with diethyl ether gave

2.93 g (63%) of the title compound as a white solid.

NMR (300MHz, _DMSO-d) δ / ppm: 3.98 (dd, 1H), 4.28 (t, 1H), 4.50 (m, 2H), 5.08 (m,

1H), 6.38 (d, 1H), 8.07 (br s, 2H), 8.50 (d, 1H), 8.69 (d, 1H).

MS: (M + H) ⁺ = 340 - Br.

Example 165

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-tert-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl) pyrid-2-yl) oxazolidin-2-one

195

To a stirred solution of 340 mg (10 mmol) of Example 164 in 8 mL of anhydrous deoxygenated DMF was added 113.6 mg (3.0 mmol) of lithium chloride under nitrogen,

91.6 mg (0.10 mmol) of bis (dibenzylideneacetone) palladium, 124 mg (0.40 mmol) of triphenylarsine and 502 mg (1.5 mmol) of vinylstannane (CAS [162046-38-0] and the reaction mixture is heated to 55 ° C and stirred for 64 hours The solvent was removed by high vacuum evaporation on a rotary evaporator to give an oil which was taken up in CH 2 Cl 2, filtered and purified by MPLC (Merck silica gel 9385, eluting with 40% EtOAc / isohexane) and triturated with diethyl ether gave 202 mg (46%) of the title compound as a white powder.

MS: (M + H) &lt; + & gt ^; = 443.

NMR (300MHz, _DMSO-d) δ / ppm: 1.35 (s, 9H), 2.40 (m, partly unclear, 2H), 3.51 (t, 2H), 3.95 (m, 3H) 4.27 (t, 1H), 4.44 (m, 2H), 5.03 (m, 1H), 6.13 (brs, 1H), 6.28 (d, 1H), 7.85 ( dd, 1H), 8.02 (dd, 1H), 8.38 (d, 1H), 8.54 (d, 1H).

Reference Example 38

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1,2,5,6-tetrahydropyrid-4-yl) pyrid-2-yl) oxazolidin-2-one

To 185 mg (0.42 mmol) of the compound of Example 165 was added 0.45 mL of TFA with stirring and heating in a water bath at 60 ° C for 1 minute to give an orange-yellow solution which was triturated with diethyl ether to give 118 mg (94%) of the title compound as a yellow powder.

MS: (M + H) &lt; + & gt ^; = 343.

Example 166

5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1-formyl-1,2,5,6-tetrahydropyrid-4-yl) pyrid-2-yl) oxazolidin-2-one mg (0.13 mmol) ) of the compound of Reference Example 38 and 71 μΙ (0.51 mmol) of triethylamine are dissolved in 1.0 ml of ethyl formate and the mixture is heated under reflux for 5 days, then the solvent is removed by rotary evaporation under high vacuum; and

196 to obtain a gum which was redissolved in CH 2 Cl 2, washed with water, concentrated and triturated with diethyl ether to give 38 mg (81%) of the title compound as a pale yellow powder.

MS: (M + H) + = 371.

NMR (300MHz, DMSO-d ₆₎ δ / ppm: 2.55 (m, partly unclear, 2H), 3.59 (m, 2H), 4.02 (m, 3H), 4.27 (m, 1H) 4.47 (m, 2H), 5.05 (m, 1H), 6.18 (br s, 1H), 6.31 (d, 1H), 7.86 (dd, 1H), 8.02 (m, 1H), 8.09 (m, 1H), 8.40 (d, 1H), 8.61 (d, 1H).

Example 167

5 (R) - (3-Methyl-1,2,4-oxadiazol-5-yloxymethyl) -3- (4- (1-benzyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5- difluorophenyl) oxazolidin-2-one

Prepared according to the general method of Example 1, using 3.57 g (8.93 mmol) of the compound of Reference Example 4, 1.00 g (0.01 M) of 3-methyl-1,2,4-oxadiazole-5. -one, 2.02 g (0.01 M) of diisopropyl azodicarboxylate and 2.81 g (0.011 M) of triphenylphosphine in 70 ml of dry THF. The resulting product was purified by MPLC (Merck silica gel 9385, 20-30% EtOAc in tert-butyl methyl ether plus 0.5% MeOH) to give 0.340 g (8%) of the title compound as a yellow oil.

MS: ESP + (M + H) + = 483.

¹ H-NMR (300MHz, CDCl ₃ ): δ = 2.27 (s, 3H), 2.44 (m, 2H), 2.60 (t, 2H), 3.17 (m, 2H),

3.64 (s, 2H), 3.89 (dd, 1H), 4.12 (m, 1H), 4.62 (m, 2H), 5.02 (m, 1H), 5.83 (s (1H),

7.12 (m, 2H); 7.23-7.41 (m, 5H).

Reference Example 39

5 (R) - (3-Methyl-1,2,4-oxadiazol-5-yloxymethyl) -3- (4- (1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidin- 2-on

Prepared according to the general method of Reference Example 6, using 0.33 g (0.68 mmol) of the compound of Example 167, 0.03 g (0.21 mmol) of diisopropylamine and 0.13 g (0.89 mmol). chloromethyl chloroformate in 8 mL of dichloromethane to give 0.21 g (72%) of the title compound as a yellow solid.

MS: ESP + (M + H) + = 393.

197 ¹ H-NMR (300MHz, DMSO-d 6): δ = 2.22 (s, 3H), 2.54 (partially unclear DMSO, 2H),

3.25 (partially unclear with water, 2H), 3.74 (m, 2H), 3.95, 4.20 (dd x 2, 2H), 4.66 (m, 2H), 5.14 (m, 1H), 5.88 (broad s, 1H), 7.35 (m, 2H), 9.25 (broad s, 2H).

Example 168

5 (R) - (3-Methyl-1,2,4-oxadiazol-5-yloxymethyl) -3- (4- (1-acetoxyacetyl-1,2,5,6-tetrahydropyrid-4-yl) -3,5- difluorophenyl) oxazolidin-2-one

198 mg (0.46 mmol) of the compound of Reference Example 39 and 0.39 g (4.62 mmol) of sodium bicarbonate were stirred at 0 ° C in 9 ml of acetone / water (2: 1). 0.13 g (0.92 mmol) of acetoxyacetyl chloride was added dropwise and the reaction mixture was stirred at 0 ° C for 30 minutes. An additional 0.03 g (0.23 mmol) of acetoxyacetyl chloride was then added and the mixture was stirred for an additional 30 minutes. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated sodium chloride solution, dried over MgSO ₄ and the solvent was evaporated, and trituration with diethyl ether gave 170 mg (75%) of the title compound. ¹ H-NMR (300MHz, DMSO-d 6): δ = 2.09 (s, 3H), 2.23 (s, 3H), 2.31, 2.43 (2 xm, 2H), 3.57, 3.66 (2 xt, 2H), 3.97, 4.22 (2 x dd, 2H), 4.10 (broad d, 2H), 4.78 (m, 2H), 4.86 (d, 2H), 5.14 (m, 1H), 5.88 (m, 1H), 7.34 (m, 2H).

MS: ESP + (M + H) ⁺ = 493.

Example 169

The following are illustrative representative pharmaceutical dosage forms comprising a compound of Formula I, an in-vivo hydrolysable ester thereof, or a pharmaceutically acceptable salt thereof, including a pharmaceutically acceptable salt of an in vivo hydrolysable ester (referred to herein as Compound X) for therapeutic or prophylactic prophylactic use in humans.

(a) Tablet I mg / tablet

Compound X ................................ 500

Lactose Ph.Eur ...................... 430

198

Sodium croscarmellose ........... 40

Polyvinylpyrrolidone .......... ......... 20 Magnesium stearate ............ ......... 10 (b) Tablet II mq / tablet Compound X ................... ...... 100 Lactose Ph.Eur ................ ....... 179 Sodium croscarmellose ..... ......... 12 Polyvinylpyrrolidone .......... ........... 6 Magnesium stearate ............ ............ 3 (C) Tablet III mq / tablet Compound X ................... ....... 50 Lactose Ph.Eur ............... ....... 229 Sodium croscarmellose ..... ......... 12 Polyvinylpyrrolidone .......... ............ 6 Magnesium stearate ........... ............ 3 (d) Tablet IV mq / tablet Compound X .................. ........... 1 Lactose Ph.Eur ............... ......... 92 Sodium croscarmellose ..... ........... 4 Polyvinylpyrrolidone .......... ............ 2 Magnesium stearate ........... ............ 1 (E) Capsule mq / capsule Compound X ................... ......... 10 Lactose Ph.Eur ............... ....... 389 Sodium croscarmellose ..... ....... 100 Magnesium stearate ........... ............ 1 (F) Solution for injection Compound X ................... % 50 wt Isotonic aqueous solution .. ... up to 100%

• ·

199 (g) Solution for injection II (eg bolus)

Compound X ........................... 10% w / v.

Isotonic aqueous solution ..... up to 100% (h) Solution for injection III

Compound X ............................. 5% w / v.

Isotonic aqueous solution ..... up to 100% (i) Solution for injection IV (eg infusion)

Compound X ............................. 1% w / v.

Isotonic aqueous solution ..... up to 100%

Buffers, pharmaceutically acceptable surfactants, oils, cosolvents such as polyethylene glycol, glycerol or ethanol, glidants (such as silica) or complexing agents such as cyclodextrin (for example hydroxypropyl β-cyclodextrin or sulfobutyl ether β-cyclodextrin) can be used to prepare the formulation ). Further, if improvement in water solubility is desired, the compounds of the formula can be used, for example, in conjunction with phospholipids (such as (phospho) choline derivatives) to form a micellar emulsion.

Note: The above formulations may be obtained by conventional procedures well known in the pharmaceutical art, for example as described in "Remington: Tke Science & Practice of Pharmacy", Volume I & II (ed. By AR Gennaro et al .; edited by Mack Publishing Company). , Easton, Pennsylvania; 19th Ed. - 1995) and "Pharmaceutics - The Science of Dosage Form Design" (ed. ME Aulton; Publisher: Churchil Livingstone; 1st publication 1988). Tablets (a) to (d) may be (polymer) coated by conventional methods, for example, to obtain enteric coatings based on cellulose acetate phthalate.

Claims (2)

PATENT CLAIMS A compound of formula I, or a pharmaceutically acceptable salt thereof, or an involyzable hydrolyzable ester thereof, O (I) wherein X is -O-, -S-, -SO- or -SO 2 -; HET is a C-linked 5-membered heteroaryl ring containing 2-4 heteroatoms independently selected from N, O and S, wherein the ring is optionally substituted on an available carbon atom with 1 or 2 substituents independently selected from the group consisting of C 1-4 alkyl carbon atoms, amino, C 1 -C 4 alkylamino, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl and halogen and / or on an available nitrogen atom (provided that the nitrogen atom is not quaternized thereby) (C 1 -C 4) alkyl; Q is selected from Q1 to Q9: Q8 Wherein R ² and R ³ are independently hydrogen or fluoro; wherein A 1 is a carbon atom or a nitrogen atom; Bi is O or S (or, only in Q 9 is NH); Xq is O, S or NR ¹ (wherein R ¹ is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 hydroxyalkyl); and wherein in Q7, A 1 is always independently selected from carbon or nitrogen, with a maximum of 2 nitrogen heteroatoms in the 6-membered ring, and Q7 binds to T through any of A 1 (when At is a carbon atom) and in the 5-membered ring binds via a specific carbon atom or via A 1 when A 1 is a carbon atom; Q 8 binds to T via any specific carbon atom in the 5-membered ring and binds in the benzene ring via any of the two specific atoms on either side of said linker; and Q 9 binds through any of the 2 specific atoms on either side of said bond; wherein T is selected from (TA) to (TD) below (wherein AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are as defined below); (TA) T is selected from the following groups: (TAa) AR 1, AR 1 -alkyl- having 1 to 4 carbon atoms in the alkyl moiety, AR 2 (carbon-linked), AR 3; (TAb) AR 1 -CH (OH) -, AR 2 -CH (OH) -, AR 3 -CH (OH) -; (TAc) AR 1 -CO-, AR 2 -CO-, AR 3 -CO-, AR 4 -CO-; (TAd) AR1-O-, AR2-O-, AR3-O-; (TAe) AR 1 -S (O) _q -, AR 2 -S (O) _q -, AR 3 -S (O) _q - (q is 0, 1 or 2); (TAf) an optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms; (TAg) carbon-bonded tropol-3-one or tropol-4-one, optionally substituted at a position not adjacent to the linker position; or (TB) T is selected from the following groups: (TBa) a halogen atom or a C 1 -C 4 alkyl group (optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4 alkoxy), C 1 -C 4 alkanoyl, cyano, halogen, trifluoromethyl, C 1 -C 4 alkoxycarbonyl, -NRv R w, C 1 -C 6 alkanoylamino, C 1 -C 4 alkoxycarbonylamino alkoxy moieties, N-alkyl-Nalkanoylamino group having 1 to 4 carbon atoms in the alkyl portion and 1 to 6 atoms 9 9 · · ··· · φ · 99 202 ·· ·· ···· 99 in the alkanoylamino moiety, alkylS (O) _q - of 1 to 4 carbon atoms (q is 0, 1 or 2), CY1, CY2 or AR1}; (TBb) -NR ¹ R w ¹ ; (TBc) ethenyl, C 1 -C 4 alkyl-ethenyl, 2-cyanethenyl, C 2 -C 4 alkyl-alkyl, 2-nitroethenyl, 2- (C 1 -C 4) nitro-2-alkylethenyl, (C 1 -C 4) alkyl-2-alkylaminocarbonylethenyl, (C 1 -C 4) alkoxycarbonylethenyl, 2- (AR 1) ethenyl a group of 2- (AR2) ethenyl; (TBd) R ¹⁰ CO-, R ¹⁰ S (O) _q - (q is 0, 1 or 2) or R ¹⁰ CSwhere R ¹⁰ is selected from the following groups: (TBda) CY1 or CY2; (TBdb) a hydrogen atom, a (C1-C4) alkoxycarbonyl group, a trifluoromethyl group, -NRvRw, an ethenyl group, a (C1-C4) alkylethenyl group, a 2-cyanethenyl group, a 2-cyano-2- (C 1 -C 4) alkylethenyl, 2-nitroethenyl, 2-nitro-2-C 1 -C 4 alkyl, 2-C 1 -C 4 alkylaminocarbonylethenyl, 2 - (C 1 -C 4) alkoxycarbonylethenyl, 2- (AR 1 -ethenyl or 2- (AR 2) ethenyl; or (TBdc) C 1 -C 4 alkyl (optionally substituted as in (TBa)) from above or an alkylS (O) _p NH- group having from 1 to 4 carbon atoms or an alkylS (O) _p alkylN- group having from 1 to 4 carbon atoms in the alkyl moieties (p is 1 or 2)}; wherein Rv is hydrogen or C1-C4alkyl; R w is hydrogen or C 1 -C 4 alkyl; R ¹¹ is hydrogen, C 1 -C 4 alkyl or C 3 -C 8 cycloalkyl; Rw ¹ is hydrogen, C 1 -C 4 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 4 alkylCO- or C 1 -C 4 alkylS (O) _q - (q is 1 or 2); or 203 (TC) T is selected from the following groups: (TCa) optionally substituted, fully saturated 4-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidized) and bonded via a ring nitrogen atom or an sp ³ carbon atom; (TC b) an optionally substituted 5-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidized) and bonded via a ring nitrogen atom or via a ring sp ³ or sp ² carbon atom, wherein the monocyclic ring is fully saturated, with with the exception (where appropriate) of a linking carbon atom sp ² ; (TCc) an optionally substituted 6- or 7-membered monocyclic ring containing 1 or 2 2 heteroatoms independently selected from O, N and S (optionally oxidized) and bonded via a ring nitrogen atom or via a ring sp ³ or sp ² carbon atom, wherein the monocyclic ring is fully saturated, except where appropriate a bonding carbon atom sp ² ; or (TD) T is selected from the following groups: (TDa) a bicyclic spirocyclic system containing 0, 1 or 2 nitrogen atoms as the only ring heteroatoms, wherein the structure comprises a 5- or 6-membered ring system (bonded via a ring nitrogen atom or a ring sp ^J or sp ^of a carbon atom) substituted (not adjacent to the linking position) with a 3-, 4- or 5-membered spiro via a carbon-linked ring; wherein the bicyclic ring system is fully saturated except where appropriate, the bonding carbon atom contains one -N (Rc) group - in the ring system (at least two carbon atoms distant from the bonding position if the bond is through a nitrogen atom or via an sp ² atom carbon) or one -N (R c) - group in the optional substituent (not adjacent the linking position) and is (iii) optionally further substituted on the available ring carbon atom; or (TDb) a 7-, 8- or 9-membered bicyclic ring system (bonded via a ring nitrogen atom or a ring sp ³ or sp ² carbon atom) containing 0, 1 or 2 nitrogen atoms (and optionally another O or S atom as a ring) heteroatom), wherein the structure comprises a bridge of 1, 2 or 3 carbon atoms; wherein the bicyclic ring system is (i) fully saturated with the exception of (where appropriate) the bonding carbon atom (') sp ^: (ii) 204 (ii) contains one O or S as heteroatom or one -N (Rc) group in the ring system (at least two carbon atoms distant from the bonding position if the bond is through a nitrogen atom or sp ² carbon atom) or one N (Rc) - in the optional substituent (not adjacent the linking position) and (iii) optionally further substituted on the available ring carbon atom; wherein R c is selected from (R c1) to (R c5)> (R c) C 1 -C 6 alkyl (optionally substituted with one or more C 1 -C 4 alkanoyl groups (including geminal disubstitution) and / or optionally monosubstituted with cyano, C 1 -C 4 alkoxy, trifluoromethyl, alkoxycarbonyl C 1 -C 4 alkoxy, phenyl (optionally substituted as mentioned for AR 1 above), alkylS (O) _q - C 1 -C 4 (q is 0, 1 or 2); or on any one, except the first carbon atom of the C 1-6 alkyl chain, optionally substituted with one or more groups (including geminal disubstitution) independently selected from the group consisting of hydroxy and fluorine and / or optionally monosubstituted with oxo, -NRvRw [wherein R v is hydrogen or C 1 -C 4 alkyl; Rw is hydrogen or (C1-C4) -alkyl], C1-C6-alkanoylamino, C1-C4-alkoxycarbonylamino, N-alkyl-N-C1-C4-alkanoylamino alkyl moieties having 1 to 6 carbon atoms in the alkanoyl moiety, alkylS (O) _p NH- having 1 to 4 carbon atoms or alkyls (O) _p alkyl having 1 to 4 carbon atoms in the alkyl moieties (p is 1 or 2) )}; (Rc2) R ¹³ CO-, R ¹³ SO ₂ - or R ¹³ CSwhere R ¹³ is selected from (Rc2a) to (Rc2e) :( Rc2a) AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a , CY1, CY2; (R c2b) hydrogen, C 1 -C 4 alkoxycarbonyl, trifluoromethyl, -NR v R w [wherein R v is hydrogen or C 1 -C 4 alkyl; R w is hydrogen or (C 1 -C 4) -alkyl], ethenyl, 2-C 1 -C 4 -alkylethenyl, 2-cyanethenyl, 2-cyan-2-C 1 -C 4 -alkylethenyl Alkyl in the alkyl moiety, 2-nitroethenyl, 2-nitro-2205, C1 -C4 alkylethenyl group in the alkyl moiety C1-C4alkylaminocarbonylethenyl, C1-C4alkoxycarbonylethenyl, 2 (AR1) ethenyl, 2- (AR2) ethenyl or 2- (AR2a) ethenyl; (R c2c) C 1 -C 10 alkyl (optionally substituted by one or more groups (including geminal disubstitution), each independently selected from hydroxy, C 1 -C 10 alkoxy, C 1 -C 4 alkoxyalkoxy each alkoxy moiety, (C 1 -C 4) alkoxyalkoxyalkoxy, (C 1 -C 4) alkanoyl, phosphoryl [-OP (O) (OH) 2 group, and its 1 to 1 mono- and di-alkoxy derivatives 4 carbon atoms in each alkoxy moiety], a phosphiryl group [the -OP (OH) 2 group and its mono- and dialkoxy derivatives of 1 to 4 carbon atoms in each alkoxy moiety] and an amino group; and / or optionally substituted with one group selected from the group consisting of carboxy, phosphonate [phosphon, -P (O) (OH) 2, and mono- and di-alkoxy derivatives of 1 to 4 carbon atoms in each alkoxy part], a phosphinate group [-P (OH) ₂ and its mono- and di-alkoxy derivatives of 1 to 4 carbon atoms in each alkoxy moiety], cyano, halogen, trifluoromethyl, alkoxycarbonyl of 1 to 4 carbon atoms in alkoxy moieties, C 1 -C 4 alkoxyalkoxycarbonyl, C 1 -C 4 alkoxyalkoxyalkoxycarbonyl, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino in each alkyl moiety, alkanoylamino C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkoxycarbonylamino; C 1 -C 6 alkyl and C 1 -C 4 alkylaminocarbonyl, C 1 -C 4 dialkylaminocarbonyl in each alkyl moiety, C 1 -C 4 alkylS (O) _p NH- C ( _C 1 -C 4) alkyl (SO) _p alkylN- ₍ C 1 -C 4) alkyl, fluoroalkyl _S (O) _p NH- ( _C 1 -C 4), fluoroalkyl _S (O) _{p (} C 1 -C 4) alkyl in each alkyl moiety, C1-C4 alkylS (O) _q , CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-0-, AR3-0-, AR1 -S (O) _q , AR2206 S (O) _q , AR 3 -S (O) _q , AR 1 -NH-, AR 2 -NH-, AR 3 -NH- (p is 1 or 2 and q is 0, 1 or 2), and furthermore AR 2a, AR 2b, AR 3a groups and AR3b versions AR2 and AR3}; (R c2d) R ¹⁴ C (O) C 1 -C 6 alkyl in the alkyl moiety, wherein R ¹⁴ is AR 1, AR ^2, C 1 -C 4 alkylamino, C 1 -C 4 benzyloxyalkyl, or (C 1 -C 10) alkyl group {optionally substituted as defined for (R c2c)}; (R c2e) R ¹⁵ O-, wherein R ¹⁵ is a benzyl group, an alkyl group having 1 to 6 carbon atoms {optionally substituted as defined for (RC2c)}, CY1, CY2 or AR2b; (Rc3) hydrogen, cyano, 2-cyanethenyl, 2-cyano-2alkylethenyl of 1-4 carbon atoms, 2alkylaminocarbonylethenyl of 1-4 carbon atoms, 2alkoxycarbonylethenyl of 1-4 carbon atoms alkoxy moieties, 2-nitroethenyl, 2-nitro-2-alkylethenyl of 1 to 4 carbon atoms in the alkyl moiety, 2- (AR 1) ethenyl, 2- (AR 2) ethenyl, or a group of formula (R c3a); NX ⁰⁰ R 16 (R c 3a) wherein X ⁰⁰ is -OR ¹⁷ , -SR ¹⁷ , -NHR ^17, and -N (R ¹⁷ ) ₂ ; wherein R ¹⁷ is hydrogen (where X ⁰⁰ is -NHR ¹⁷ and -N (R ¹⁷ ) ₂ ) and R ¹⁷ is C 1-4 alkyl, phenyl or AR 2 (wherein X ⁰⁰ is -OR ¹⁷ , - SR ¹⁷ and -NHR ¹⁷ ); and R ¹⁵ is cyano, nitro, C 1 -C 4 alkylsulfonyl, C 4 -C 7 cycloalkylsulfonyl, phenylsulfonyl, C 1 -C 4 alkanoyl, C 1 -C 4 alkoxycarbonyl; (R c4) trityl, AR 1, AR 2, AR 2a, AR 2b, AR 3, AR 3a, AR 3b; (Rc5) of the group RdOC (Re) = CH (C = O) -, RfC (= O) C (= O) -, RgN = C (Rh) C (= O) - or RiNHC (Rj) = CHC (= O) -, wherein R d is C 1 -C 6 alkyl; R 6 is a hydrogen atom or an alkyl group having 1 to 6 hydrogen atoms or R d and R e together form an alkylene chain having 3 to 4 carbon atoms; Rf is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms; 207 • 99 · 9 9 9 · 9 · 99999 * 9 9 9 · 9 6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms in the alkoxy moiety and 1-6 carbon atoms in the alkyl moiety, -NRvRw [wherein Rv is hydrogen or alkyl of 1 to 4 atoms carbon; Rw is hydrogen or (C1-C4) alkyl], (C1-C6) alkoxy, (C1-C6) alkoxyalkoxy in each alkyl moiety, (C2-C6) hydroxyalkoxy, (C1-C6) alkylaminoalkoxy 4 carbon atoms in the alkyl portion and 2 to 6 carbon atoms in the alkoxy portion, a di-alkylaminoalkoxy group having 1 to 4 carbon atoms in the alkyl portion and 2 to 6 carbon atoms in the alkoxy portion; R 8 is C 1 -C 6 alkyl, hydroxy or C 1 -C 6 alkoxy; Rh is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, AR 1, AR 2, AR 2a, AR 2b and R 1 is hydrogen or alkyl of 1 to 6 carbon atoms; where AR 1 is optionally substituted phenyl or optionally substituted naphthyl; AR 2 is an optionally substituted 5- or 6-membered, fully unsaturated (ie, with a maximum degree of unsaturation) monocyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N and S (but containing no 0-0, 0-S or SS bonds) ) and bound via a ring carbon atom or a ring nitrogen atom, unless quaternized; AR2a is a partially hydrogenated version of AR2 (i.e., AR2 systems having a certain but not full degree of unsaturation) bonded via a ring carbon atom or ring nitrogen atom, unless quaternized; AR2b is a fully hydrogenated version of AR2 (i.e., AR2 systems having no unsaturation) bonded via a ring carbon atom or ring nitrogen atom; AR 3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (ie, maximum degree of unsaturation) bicyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N and S (but containing no 0-0, 0- bonds) S or SS) and bonded via a carbon atom in any of the rings including the bicyclic system; AR3a is a partially hydrogenated version of the group AR3 (ie, systems of AR3 having a certain but not full degree of unsaturation) bonded via a ring carbon atom; or 208 a nitrogen atom in the ring, if not quaternized, in any of the rings including the bicyclic system; AR3b is a fully hydrogenated version of the group AR3 (i.e., systems of AR3 having no unsaturation) bonded via a ring carbon atom or a ring nitrogen atom in any of the rings including the bicyclic system; AR 4 is an optionally substituted 13- or 14-membered, fully unsaturated (ie, maximum degree of unsaturation) tricyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N, and S (but not containing any OO, O-S or SS bonds); bonded via a carbon atom in any of the rings comprising a tricyclic system; AR 4a is a partially hydrogenated version of the AR 4 group (ie, AR 4 systems having a certain but not full degree of unsaturation) bonded via a ring carbon atom or a ring nitrogen atom, unless quaternized, in any of the rings including the tricyclic system; CY 1 is an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl ring; CY 2 is an optionally substituted cyclopentenyl or cyclohexenyl ring. A compound of formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof as claimed in claim 1, wherein the optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms (group (TAf)). )) is selected from the group of formulas (TAf1) to (TAf6): - (TAf1) R ⁵ (TAf 4) (TAf 5) (TAf 6) where: R ⁶ is selected (independently, where appropriate) from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkanoyl, carbamoyl and cyano; R ⁴ and R ⁵ are independently selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, C 1 -C 4 alkoxy, C 1 -C 4 alkylS (O) _q (q is 0 , 1 or 2), (C1-C4) alkanoyl, (C1-C4) alkoxycarbonyl, (C2-C4) alkanoyloxyalkyl and (C1-C4) alkyl, benzoxyalkyl C 1 -C 4 alkyl, C 2 -C 4 alkanoylamino, -CONR v R w, -NR v R w, and C 1 -C 4 alkyl (optionally substituted by hydroxy, trifluoromethyl, cyano, nitro, C 1 -C 4 alkoxy) carbon atoms, C1-C4 alkylS (O) _q - (q is 0.1 or 2), C1-C4 alkoxycarbonyl, C1-C4 alkanoylamino, -CONRvRw, - NRvRw; wherein R v R w is hydrogen or C 1 -C 4 alkyl; Rw is hydrogen or (C1-C4) alkyl}; or R ⁴ is selected from one of (TAfa) to (TAfc) below or (where appropriate) one of R ⁴ and R ⁵ is selected from the above list of values for R ⁴ and R ⁵ and the other is selected from (TAfa) to (TAfc) below: (TAfa) a group of formula TAfal X ° • · 210 wherein Z 0 is hydrogen or C 1 -C 4 alkyl; X 0 and Y 0 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, halogen, cyano, nitro, alkylS (O) _q - having one to four carbon atoms (q is 0, 1 or 2), RvRwNS0 ₂ -, trifluoromethyl, pentafluoroethyl, alkanoyl of 1-4 carbon atoms and -CONRvRw [wherein Rv is hydrogen or an alkyl group having 1 to 4 carbon atoms; R w is hydrogen or C 1 -C 4 alkyl]; or one of X ° and Y ° is independently selected from the above values for X ° and Y ° and the remaining is selected from phenyl, phenylcarbonyl, -S (O) _q -phenyl (q is 0, 1 or 2), N- (phenyl) carbamoyl, phenylaminosulfonyl, AR 2, (AR 2) -CO-, (AR 2) -S (O) _q - (q is 0, 1 or 2), N- (AR 2) a carbamoyl group and an (AR2) aminosulfonyl group; wherein any phenyl group in (TAfa) may be optionally substituted with up to three substituents independently selected from the group consisting of C 1 -C 4 alkyl, cyano, trifluoromethyl, nitro, halogen and C 1 -C 4 alkylsulfonyl; (TAfb) an acetylene group of the formula -ξ-H or -Ξ-C 1-4 alkyl; (TAfc) -X ¹ -Ar 2 -Y ¹ -X ¹ -Ar 2 -Y ¹ -X ¹ -Y ¹ -AR2b -X ¹ -Y'-Ar 3 -X ¹ or Y'-Ar3-X ¹ -Y'AR3b; wherein X ¹ is a direct bond or -CH (OH) - a Y ¹ is - (CH ₂ ) _m -, - (CH ₂ ) _n -NH- (CH ₂ ) _m -, -CO- (CH ₂ ) _m - -CONH- (CH ₂ ) _m -, -C (= S) NH (CH ₂ ) _m - or C (= O) O- (CH ₂ ) _m -; or wherein X ¹ is - (CH ₂ ) _m - or -CH (Me) - (CH ₂ ) _m - and Y ¹ is - (CH ₂ ) _m -NH- (CH ₂ ) _m - -CO- (CH ₂ ) _m -, -CONH- (CH ₂ ) _m -, -C (= S) NH- (CH ₂ ) _m -, -C (= O) O- (CH ₂ ) _m - or -S (O) _q - (CH ₂ ) _m -; or wherein X ¹ is -CH 2 O-, -CH 2 NH- or -CH 2 -Nalkyl- with 1 to 4 carbon atoms and Y ¹ is -CO- (CH 2) _m - -CONH- (CH ₂ ) _m -, -C (= S) NH- (CH ₂ ) _m -; and further Y ¹ is -SO 2 - when X ¹ is -CH ₂ NH - or -CH ₂ N -alkyl- with 1 to 4 carbon atoms in the alkyl moiety and Y ¹ is - (CH 2) m when X ¹ is -CH 2 O- or -CH ₂ Nalkyl - having 1 to 4 carbon atoms in the alkyl moiety; wherein n is 1, 2 or 3; m is 0, 1, 2 or 3 and q is 0, 1 or 2; and wherein Y ¹ is - (CH 2 m -NH-CH 2 m -), wherein each m is independently selected from 0, 1, 2 or 3. 211 A compound of formula I, or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, as claimed in claim 1, wherein the 7-, 8- or 9-membered bicyclic ring system containing a 1, 2 or 3 carbon bridge as defined above. v (TDb), is selected from the group defined by the scaffolds shown in formulas (TDb1) to (TDb14): 7-membered scaffolds <7 □ + 77 [4.1.0] [3.2,0] (TDb1) (TDb2) [ 3.1.1] [2.2.1] (TDb3) 8-membered circular skeletons [3.3.0] [4.2,0] (TDbS) (TDbS) [4.1.1] (TDb7) [3.2.1] (TDbS) [2.2.2] (TDb9) 9-membered ring skeletons [4.3,0] [5,2,0] (TDb10) (TDb11) [4.2.1] (TDb12) [3,2,2] (TDb14) where (i) the ring system contains 0, 1 or 2 ring nitrogen atoms (and optionally other ring heteroatoms O or S), and if a ring nitrogen atom is present, the O or S heteroatoms are at any position other than that of the 3-membered ring in (TDb1); (ii) the ring system is bonded through a ring nitrogen atom or ring carbon atom sp ³ or sp ² carbon atom (with a double bond, where appropriate, oriented in the 212 • from any position in any circle [other than from the bridge end position or from a carbon atom sp ² in 4 a membered ring in (TDb2), (TDb6) and (TDb11)]; (iii) one of the ring carbon atoms in the position not adjacent to the linking position is replaced (in cases other than when the ring contains O or S as a heteroatom) by one of the following -NRc- [not at the bridge end position],> CHN (H) R,> C (H) -NRc-C 1 -C 4 alkyl,> C (H) -CH2NHRc,> C (H) -CH ₂ -NR c C 1 -C 4 alkyl in the alkyl moiety [wherein the hydrogen atom in parentheses is not present when the substitution is made at the terminal position of the bridge and wherein the central -CH ₂ - chain bond is optionally mono- or disubstituted with C 1 -C 4 alkyl]; with the proviso that when the ring system is bonded via a nitrogen atom or a carbon atom of sp ² , any replacement of the ring carbon atom by an -NR c -, O or S group is at least two carbon atoms distant from the bonding position; and (iv) the ring system is optionally (further) substituted on an available ring carbon atom as described for (bpa) for the bicyclic spirocyclic system; wherein R c has any of the meanings specified in claim 1. A compound of formula I or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof as claimed in claim 1, wherein the groups defined in (TCa) to (TCc) are defined in formulas (TC1) to (TC4): L_ ^B 3 I ’A3 \ σα) ml (rV * <> G- ^z G - B3 (T () _m - m () __ / ^G \ / () 3 O7 ^B (TC2) (TC3) (' (TC4) Rp where v (TC1):> A ₃ -B ₃ -is> C (Rq) -CH (Rr) - and G is -O-, -S-, -SO-, -SO ₂ - or> N (Rc) ); wherein at (TC 2): m 1 is 0, 1 or 2; > A ₃ -B ₃ - is> C = C (Rr) - or> C (Rq) -CH (Rr) - and G is O-, -S-, -SO-, -SO ₂ - or> N ( Rc); wherein v (TC3); m 1 is 0, 1 or 2; > A ₃ -B ₃ -is> C (Rq) -CH (Rr) - (when Rq and Rr are not both hydrogen) and G is -O-, -S-, -SO-, -SO ₂ - or> N (R c); • · 213 where v (TC4): n1 is 1 or 2; o1 is 1 or 2 and n1 + o1 = 2 or 3; > A ₃ -B ₃ - is> C = C (Rr) - or> C (Rq) -CH (Rr) - or> N-CH 2 - and G is -O-, -S-, -SO-, - S0 ₂ - or> N (Rc); R _p is hydrogen, C 1 -C 4 alkyl (in the case where such substitution is not defined by> A ₃ -B ₃ -), hydroxy, C 1 -C 4 alkoxy or C 1 -C 4 alkanoyloxy; wherein at (TC1), (TC2), and (TC4); m1, n1 and o1 have the meanings given above: > A ₃ -B ₃ -is> N-CH ₂ - and G is> C (R ¹¹ ) (R ¹² ),>00,>C-OH,> C 1 -C 4 alkoxy in the alkoxy moiety,> C = N-OH,> C = N-C 1 -C 4 alkoxy,> C = N-NH-α (C 1 -C 4 alkyl,> C = NN- (alkyl) group having 1 to 4 carbons) ₂ (which latter two alkyl groups having 1 to 4 carbon atoms in G being optionally substituted by hydroxy) or> C = NN-CO-C 1 -C 4 -alkoxy); where> represents two single bonds; Rq is hydrogen, hydroxy, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkanoyloxy; R 1 is (independently, where appropriate) hydrogen or C 1 -C 4 alkyl; R ¹¹ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 alkylthioalkyl in each alkyl moiety or C 1 -C 4 hydroxyalkyl, and R ¹² is - [C (Rr) (Rr)] m 2 -N (R c) (R c) wherein m 2 is 0, 1 or 2; in cases where the substitution on the ring is not defined by G,> A ₃ -B ₃ - and R p, each ring system may be optionally substituted on a carbon atom not adjacent to a> A ₃ - bond by up to two substituents independently selected from the group consisting of (C 1 -C 4) alkyl, (C 1 -C 4) fluoroalkyl (including trifluoromethyl), (C 1 -C 4) alkylthioalkyl, (C 1 -C 4) hydroxyalkyl, amino, (C 1 -C 4) alkyl group (C 1 -C 4), (C 1 -C 4) alkanoylamino, (C 1 -C 4) alkanoylaminoalkyl (C 1 -C 4) alkyl, carboxy, (C 1 -C 4) alkoxycarbonyl (C 1 -C 4) alkoxy, AR-oxymethyl, ARthiomethyl, oxo (= 0) (in other cases than when G is> N-Rc and R ee (Rc2) defined in n in 1) or independently selected from Rc; and also 214 hydroxy and halogen (the last two optional substituents are present only when G is -O- or -S-); wherein AR is optionally substituted phenyl, optionally substituted phenylalkyl; C 1 -C 4 alkyl, optionally substituted naphthyl, optionally substituted 5- or 6-membered heteroaryl; an optionally substituted 5/6 or 6/6 bicyclic heteroaryl ring system, wherein the bicyclic heteroaryl system may be bonded via an atom in any of the rings including the bicyclic system and wherein both the monocyclic and bicyclic heteroaryl system are bonded via a carbon atom and may be (partially) hydrogenated and wherein R c is as defined in claim 1. A compound of formula I or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof as claimed in claims 1 to 4, wherein the groups defined in (TCa) to (TCc) are defined by formulas (TC5) to (TC11): (TCS) (TC9) (TC10) (TC11) wherein Rc is as defined in claim 1. A compound of formula I as claimed in claim 1 which is a compound of formula (IC) or a pharmaceutical salt thereof or an in vivo hydrolysable ester (IC) wherein HET is isoxazol-3-yl, 1,2,4-oxadiazole -3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl; R ² and R ³ are independently hydrogen or fluorine; Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenylalkyl having 1 to 4 carbon atoms in the alkyl moiety, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), (C1-C4) alkyl, carboxy, (C1-C4) alkoxycarbonyl, hydroxymethyl, (C1-C4) alkoxymethyl, or carbamoyl and Rcp is cyano, pyrimidin-2-yl, 2-cyanethenyl, 2-cyano-2-alkylethenyl of 1 to 4 carbon atoms in the alkyl moiety or Rcp is a group of formula R ^13p CO-, R ^13p SO 2 or R ^13p CS- (wherein R ^13p is hydrogen, C 1 -C 5 alkyl [optionally substituted with one or more groups selected independently from the group consisting of hydroxy and amino, or optionally monosubstituted alkoxy) C 1 -C 4 -alkyl, C 1 -C 4 -alkylS (O) _q -, C 1 -C 4 -alkylamino, C 1 -C 4 -alkanoyl, naphthoxy, C 2 -C 6 -alkanoylamino or C 1 -C 4 -alkanoylamino; alkylS (O) _p NH- having 1 to 4 carbon atoms, wherein p is 1 or 2 and q is 0, 1 or 2], imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, pyridoimidazole, pyrimidoimidazole , quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine or R ^13p is a group of the formula R ^14p (C (O) O (C 1 -C 6) alkyl (where R ^14p is a C 1 -C 6 alkyl) or Rcp is a group of formula RfC (= O) C (= O), wherein Rf is C 1 -C 6 alkoxy. A compound as claimed in claims 1, 4, 5 or 6 which is 5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) -oxazolidine- 2-on; or 5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-dihydroxypropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) -oxazolidin-2-one or a pharmaceutically acceptable salt thereof or an in-vivo hydrolysable ester thereof. A compound according to claim 1, 4, 5, 6 or 7 which is 216 :::. :. ·. :::: ··· · ···· · · · · ······ · · ·· 5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidine -2-one; 5 (R) -1xoxazol-3-yloxymethyl-3- (4- (1- (2 (S) -hydroxy-3-phosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl Oxazolidin-2-one. 5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-diphosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3-fluorophenyl) oxazolidin-2 -he; 5 (R) -1soxazol-3-yloxymethyl-3- (4- (1- (2 (S), 3-diphosphorylpropanoyl) -1,2,5,6-tetrahydropyrid-4-yl) -3,5-difluorophenyl) oxazolidine -2-one or a pharmaceutically acceptable salt thereof. A process for the preparation of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof, comprising (a) to (i) :( a) modifying a substituent in a compound of formula Or introducing a substituent into another compound of Formula I; (b) reacting a compound of formula II O Λ Q - N O (Π) wherein Y p is a hydroxy group with a compound of formula (b1) HET-OH or (b2) HET-Lg, wherein Lg is a suitable leaving group; (c) reacting a compound of formula II wherein Yp is a leaving group with a metal alkoxide of HET-OM, wherein M is an alkali metal or other metal known to promote alkylation; (d) reacting a compound of formula Q-Zp wherein Zp is an isocyanate or amino group with an epoxide of formula CH ₂ (O) CH-CH ₂ O-HET; (e) when X is -S-, using a method analogous to process (c) using (e1) a thioxide compound of a metal of general formula HET-SM, wherein M is an alkali metal or other metal known to promote S-alkylation; or (e2) using HET-SH and a compound of formula II, wherein Y p is a suitable leaving group; (f) when X is -SO- or -SO ₂ - oxidizing a compound wherein X is -S-; (G) converting a compound of formula I wherein HET carries a quaternary nitrogen atom to a non-quaternary compound; (h) when HET is an isoxazole ring, reacting a compound of formula II wherein Yp is O-CH = N-OH with acetylene; (i) reacting a urethane compound of formula III with a compound of formula IV qn OR ² ' X (ΪΙΙ) (IV) wherein R ²¹ is C 1 -C 6 alkyl or benzyl; and then, if necessary: (i) removing any protecting group; (ii) forming a pharmaceutically acceptable salt; (iii) forming an in vivo hydrolysable ester. 10. A method of producing an antibacterial effect in a warm-blooded animal, comprising administering to said animal an effective amount of a compound of formula I as claimed in claims 1-8, or a pharmaceutically acceptable salt thereof, or an in vivo hydrolysable ester thereof. A compound of formula I as claimed in claims 1 to 8 or a pharmaceutically acceptable salt thereof or an in vivo hydrolysable ester thereof for use as a medicament. Use of a compound of formula I as claimed in claims 1 to 8 or a pharmaceutically acceptable salt thereof or an in-vivo hydrolysable ester thereof for the preparation of a medicament for producing an antibacterial effect in a warm-blooded animal. 13. A pharmaceutical composition comprising a compound of formula I as claimed in claims 1 to 8, or a pharmaceutically acceptable salt thereof. 218 an acceptable salt or an in-vivo hydrolysable ester thereof and a pharmaceutically acceptable diluent or carrier.