CN1742009A - Oxazolidinones as antibacterial agents - Google Patents

Abstract

A compound of the formula (I), or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, wherein C is selected from (D) and (E), R2a, R6a, and R3a are independently selected from for example H, CF3, Me and Et; R2b and R6b are independently selected from for example H, F, CF3, Me and Et; R1b is for example optionally substituted diazolyl, triazolyl or tetrazolyl; R4 is for example an optionally substituted 5- or 6-membered heterocyclic ring system. Methods for making compounds of the formula (I), compositions containing them and their use as antibacterial agents are also described.

Description

Oxazolidinones used as antibacterial agents

The present invention relates to antibacterial compounds, especially antibacterial compounds containing substituted oxazolidinone rings. The invention further relates to processes for their preparation, intermediates used in their preparation, their use as therapeutic drugs and pharmaceutical compositions comprising them.

The International Society for Microbiology has been paying close attention to the development of antibiotic resistance, which causes strains of bacteria to develop resistance to currently effective antimicrobials, rendering them ineffective. In general, bacterial pathogens can be classified as Gram-positive or Gram-negative pathogens. Antimicrobial compounds with potent activity against both Gram-positive and Gram-negative pathogens are generally considered to have broad-spectrum activity. The compounds of the present invention are believed to be effective against Gram-positive pathogens and certain Gram-negative pathogens.

Of particular importance are Gram-positive pathogens such as Staphylococci, Enterococci, Streptococci, and mycobacteria, as resistant strains of these, once developed, are difficult to treat and difficult to treat Eradicated from the hospital environment. Examples of such strains are methicillin-resistant Staphylococcus (MRSA), methicillin-resistant coagulase-negative Staphylococcus (MRCNS), penicillin-resistant Streptococcus pneumoniae, and multidrug-resistant Enterococcus faecium .

The main clinically effective antibiotic used to treat such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide associated with various toxicities including nephrotoxicity. In addition, and most importantly, antimicrobial resistance to vancomycin and other glycopeptides is also emerging. This resistance is increasing at a steady rate, making these drugs less and less effective against Gram-positive pathogens. Resistance to drugs such as beta-lactams, quinolones, and macrolides is also increasing today to treat upper respiratory tract infections, which are also caused by certain Gram-negative strains, including influenza haemophilus Bacillus (H. influenzae) and Moraxella catarrhalis (M. catarrhalis).

Certain oxazolidinone ring-containing antibacterial compounds (such as Walter A.Gregory et al, J.Med.Chem.1990, 33, 2569-2578 and 1989, 32 (8), 1673-81; Chung - Ho Park et al, J. Med. Chem. 1992, 35, 1156-1165). Bacteria resistant to known antimicrobial agents may develop through means such as (i) evolution of active binding sites on bacteria such that previously active pharmacophore effects are reduced or made redundant, and/or (ii) formation of chemical killing agents. way of activating a specific pharmacophore, and/or (iii) forming an external pump mechanism. Therefore, it is necessary to continuously search for antibacterial drugs with beneficial pharmacological characteristics, especially compounds containing new and more effective pharmacophore.

Therefore, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof,

wherein group C is selected from groups D and E,

Wherein, the phenyl ring in D and E is connected with the oxazolidinone in (I);

R ₁ b is HET1 or HET2, wherein

i) HET1 is an N-linked 5-membered fully unsaturated or partially unsaturated heterocycle comprising (i) 1-3 additional nitrogen heteroatoms or (ii) one other heteroatom selected from O and S and one optionally The ring is optionally substituted with an oxo or thio group on a C atom other than the connecting N atom adjacent to the C atom; and/or the ring is optionally substituted at the connecting N atom adjacent to the C atom Substituents selected from RT substituents as defined below at any available C atom other than the N atom, and/or at an available nitrogen atom other than the N atom adjacent to the connecting N atom (provided that the ring is not thereby quaternized) Substituted by (1-4C) alkyl;

ii) HET2 is an N-linked 6-membered dihydroheteroaryl ring containing a total (including linking heteroatoms) of up to 3 nitrogen heteroatoms, the ring being oxygenated on suitable C atoms other than the linking N atom adjacent C atoms and/or the ring is optionally substituted by 1-2 RT substituents independently selected from the RT substituents defined below on any available C atom other than the C atom adjacent to the connecting N atom, and/or Substituted by (1-4C)alkyl on an effective nitrogen atom other than the adjacent N atom of the connecting N atom (provided that the ring is not thus quaternized);

The RT substituent is selected from the following groups: (RTal) hydrogen, halogen, (1-4C) alkoxy, (2-4C) alkenyloxy, (2-4C) alkenyl, (2-4C) Alkynyl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, (1-4C) alkylthio, amino, azido, cyano and nitro; or (RTa2) (1- 4C) alkylamino, di-(1-4C) alkylamino and (2-4C) alkenylamino;

Or RT is selected from the following groups

(RTb1) (1-4C)alkyl optionally substituted by one substituent selected from the group consisting of hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, cyano and azido ;or

(RTb2) (1-4C)alkyl optionally substituted by one substituent selected from (2-4C)alkenyloxy, (3-6C)cycloalkyl and (3-6C)cyclo Alkenyl;

Or RT is selected from the following groups

(RTc) a fully saturated 4-membered monocyclic ring containing 1-2 heteroatoms independently selected from O, N and S (optionally oxidized) and attached via a ring nitrogen or ring carbon atom;

When the RT substituent in (RTa1) or (RTa2), (RTb1) or (RTb2), or (RTc) contains an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety, the The group part is optionally substituted on an effective carbon atom by 1-3 or more substituents independently selected from F, Cl, Br, OH and CN;

_R2a and _R6a are independently selected from H, _CF3 , OMe, SMe, Me and Et;

_R2b and _R6b are independently selected from H, F, Cl, _CF3 , OMe, SMe, Me and Et;

R ₃ a is selected from H, (1-4C) alkyl, cyano, Br, F, Cl, OH, (1-4C) alkoxy, -S (O) _n (1-4C) alkyl (wherein n=0, 1 or 2), amino, (1-4C)alkylcarbonylamino, nitro, -CHO, -CO(1-4C)alkyl, _-CONH2 and -CONH(1-4C)alkyl ;

R ₄ is selected from R ₄ a and R ₄ b, wherein

R ₄ a is selected from azido, -NR ₇ R ₈ , OR ₁₀ , (1-4C) alkyl, (1-4C) alkoxy, (3-6C) cycloalkyl, -(CH ₂ ) _k -R ₉ , AR1, AR2, (1-4C) alkanoyl, -CS (1-4C) alkyl, -C (=W) NRvRw [Wherein W is O or S, Rv and Rw are independently H or (1 -4C) alkyl], -(C=O) ₁ -R ₆ , -COO(1-4C) alkyl, -C=OAR1, -C=OAR2, -COOAR1, S(O)n(1-4C )alkyl (where n=1 or 2), -S(O)pAR1, -S(O)pAR2 and -C(=S)O(1-4C)alkyl; where any (1-4C)alkyl The chain can be optionally substituted by (1-4C)alkyl, cyano, hydroxyl or halo; p=0, 1 or 2;

_R4b is selected from HET-3;

R _is selected from hydrogen, (1-4C) alkoxy, amino, (1-4C) alkylamino and hydroxy (1-4C) alkylamino;

k is 1 or 2;

l is 1 or 2;

R ₇ and R ₈ are independently selected from H and (1-4C) alkyl, or R ₇ and R ₈ can form a 5-7 membered ring together with the nitrogen to which they are attached, and the ring optionally has one member selected from N, O , S(O)n (wherein n=1 or 2) replaces 1 carbon atom of the ring thus formed; wherein the ring may be optionally substituted by 1-2 groups independently selected from the following groups: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkanoyl, -COO (1-4C) alkyl, -S (O) n (1-4C) alkyl (where n=1 or 2), AR1, AR2, -C=OAR1, -C=OAR2, -COOAR1, -CS(1-4C) alkyl, -C(=S)O(1-4C) alkyl, - C(=W)NRvRw [Wherein W is O or S, Rv and Rw are independently H or (1-4C) alkyl], -S(O)pAR1 and -S(O)pAR2; wherein any (1-4C )alkyl, (3-6C)cycloalkyl or (1-4C)alkanoyl may be optionally substituted with 1-2 substituents selected from the following substituents (except carbon atoms adjacent to heteroatoms): (1-4C) Alkyl, cyano, hydroxy, halo, amino, (1-4C)alkylamino and di(1-4C)alkylamino; p=0, 1 or 2;

R ₉ is independently selected from the following R ₉ aR ₉ d:

_R9a : AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;

R ₉ b: cyano, carboxyl, (1-4C) alkoxycarbonyl, -C (= W) NRvRw [wherein W is O or S, Rv and Rw are independently H or (1-4C) alkyl, wherein Rv and Rw together with the amide nitrogen or thioamide nitrogen to which they are attached may form a 5-7 membered ring which optionally has one additional heteroatom selected from N, O, S(O)n replacing the thus formed 1 carbon atom of the ring; wherein when the ring is a piperazine ring, the ring may optionally be substituted on another nitrogen by a group selected from: (1-4C)alkyl, (3-6C) Cycloalkyl, (1-4C) alkanoyl, -COO (1-4C) alkyl, -S (O) n (1-4C) alkyl (where n = 1 or 2), -COOAR1, -CS ( 1-4C)alkyl and -C(=S)O(1-4C)alkyl; wherein any (1-4C)alkyl, (3-6C)cycloalkyl or (1-4C)alkanoyl can itself be optionally substituted by cyano, hydroxyl or halo)], vinyl, 2-(1-4C)alkylvinyl, 2-cyanovinyl, 2-cyano-2-((1-4C)alkane Base) vinyl, 2-nitrovinyl, 2-nitro-2-((1-4C) alkyl) vinyl, 2-((1-4C) alkylaminocarbonyl) vinyl, 2-( (1-4C)alkoxycarbonyl)vinyl, 2-(AR1)vinyl, 2-(AR2)vinyl, 2-(AR2a)vinyl;

R ₉ c: (1-6C) alkyl

{Optionally substituted by one or more groups (including gem-disubstituted), each group is independently selected from hydroxyl, (1-10C) alkoxy, (1-4C) alkoxy-(1-4C) alkane Oxygen, (1-4C) alkoxy-(1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkylcarbonyl, phosphoryloxy (phosphoryl) [-OP( O)(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphiryl [-OP(OH) ₂ and its mono- and di-(1-4C) 4C) alkoxy derivatives] and amino; and/or optionally substituted by a group selected from the group consisting of carboxyl, phosphoryl (phosphonate) [phosphono-P (O) (OH) ₂ and its mono- and Di-(1-4C)alkoxy derivatives], phosphinate [-P(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], cyano, halogen radical, trifluoromethyl, (1-4C) alkoxycarbonyl, (1-4C) alkoxy-(1-4C) alkoxycarbonyl, (1-4C) alkoxy-(1-4C) Alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino-, (1-4C) Alkoxycarbonylamino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C(=W)NRvRw [wherein w is O or S, Rv and Rw are as defined Front], (=NORv), wherein Rv is as defined above, (1-4C) alkyl S (O) pNH, (1-4C) alkyl S (O) p-((1-4C) alkyl) N-, fluoro(1-4C)alkylS(O)pNH-, fluoro(1-4C)alkylS(O)p((1-4C)alkyl)N-, (1-4C) Alkyl S(O)q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-O-, AR3-O-, AR1-S(O)q-, AR2-S(O)q -, AR3-S(O)q-, AR1-NH-, AR2-NH-, AR3-NH- (p is 1 or 2, q is 0, 1 or 2) and includes AR2a, AR2b, AR3a and AR3b types The group of AR2 and AR3}; wherein any (1-4C) alkyl group in any substituent of R _9c itself can be substituted by 1-2 groups independently selected from the following groups: cyano group, hydroxyl group, halo group, Amino, (1-4C)alkylamino and di(1-4C)alkylamino, with the proviso that such substituents, if present, are not on carbons adjacent to the heteroatom;

R ₉ d: R ₁₄ C(O)O(1-6C) alkyl-, wherein R ₁₄ is AR1, AR2, (1-4C) alkylamino, benzyloxy-(1-4C) alkyl or ( 1-10C) alkyl {optionally substituted as defined in (R ₉ c)};

R ₁₀ is selected from hydrogen, R ₉ c (as defined above), (1-4C) acyl and (1-4C) alkylsulfonyl;

HET-3 selected from:

a) a 5-membered heterocyclic ring comprising at least 1 nitrogen and/or oxygen, wherein any carbon atom is C=O, C=N or C=S, wherein the ring is of the following formula HET3-A-HET3-E:

b) contains 1-4 carbon-linked 5- or 6-membered heteroaromatic rings independently selected from N, O and S heteroatoms, which are selected from the following HET3-F-HET3-Y:

c) a nitrogen-linked 5- or 6-membered heteroaromatic ring containing 1-4 independently selected from N, O and S heteroatoms, which is selected from the following HET3-Z-HET3-AH:

Wherein, R ₁ a of HET-3 is a substituent on carbon;

R ₁ a is independently selected from the following R ₁ a1-R ₁ a5:

R ₁ a1: AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;

R ₁ a2: cyano, carboxyl, (1-4C) alkoxycarbonyl, -C (= W) NRvRw [wherein W is O or S, Rv and Rw are independently H or (1-4C) alkyl, wherein Rv and Rw together with the amide nitrogen or thioamide nitrogen to which they are attached may form a 5-7 membered ring which optionally has one additional heteroatom selected from N, O, S(O)n replacing the thus formed 1 carbon atom of the ring; wherein when the ring is a piperazine ring, the ring may optionally be substituted on another nitrogen by a group selected from: (1-4C)alkyl, (3-6C) Cycloalkyl, (1-4C) alkanoyl, -COO (1-4C) alkyl, -S (O) n (1-4C) alkyl (where n = 1 or 2), -COOAR1, -CS ( 1-4C) alkyl and -C(=S)O(1-4C) alkyl; where any (1-4C) alkyl, (1-4C) alkanoyl and (3-4C) cycloalkyl substituents itself may be substituted by cyano, hydroxy, or halo, provided that such substituent is not on a carbon adjacent to the nitrogen atom of the piperazine ring], vinyl, 2-(1-4C)alkylvinyl, 2-cyano Vinyl, 2-cyano-2-((1-4C)alkyl)vinyl, 2-nitrovinyl, 2-nitro-2-((1-4C)alkyl)vinyl, 2- ((1-4C)alkylaminocarbonyl)vinyl, 2-((1-4C)alkoxycarbonyl)vinyl, 2-(AR1)vinyl, 2-(AR2)vinyl, 2-(AR2a ) vinyl;

R ₁ a3: (1-10C) alkyl

{Optionally substituted by one or more groups (including gem-disubstituted), each group is independently selected from hydroxyl, (1-10C) alkoxy, (1-4C) alkoxy-(1-4C) alkane Oxygen, (1-4C) alkoxy-(1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkylcarbonyl, phosphoryloxy [-OP (O) ( OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphiteoxy [-OP(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives] and amino; and/or optionally substituted by a group selected from the group consisting of carboxyl, phosphoryl (phosphonate) [phosphono-P (O) (OH) ₂ and its mono- and di- (1-4C ) alkoxy derivatives], phosphorous acid [-P (OH) ₂ and its mono- and di- (1-4C) alkoxy derivatives], cyano, halo, trifluoromethyl, (1 -4C) alkoxycarbonyl, (1-4C) alkoxy-(1-4C) alkoxycarbonyl, (1-4C) alkoxy-(1-4C) alkoxy-(1-4C) Alkoxycarbonyl, (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonylamino-, N- (1-4C)alkyl-N-(1-6C)alkanoylamino-,-C(=W)NRvRw[wherein W is O or S, Rv and Rw are independently H or (1-4C)alkyl, wherein Rv and Rw together with the amide nitrogen or thioamide nitrogen to which they are attached may form a 5-7 membered ring which optionally has one additional heteroatom replacement selected from N, O, S(O)n so formed 1 carbon atom of the ring; wherein when the ring is a piperazine ring, the ring may optionally be substituted on another nitrogen by a group selected from: (1-4C)alkyl, (3-6C ) cycloalkyl group, (1-4C) alkanoyl group, -COO(1-4C) alkyl group, -S(O)n(1-4C) alkyl group (where n=1 or 2), -COOAR1, -CS (1-4C) alkyl and -C(=S)O(1-4C) alkyl], (=NORv), wherein Rv is as defined above, (1-4C) alkylS(O)pNH-, (1-4C)alkylS(O)p-((1-4C)alkyl)N-, fluoro(1-4C)alkylS(O)pNH-, fluoro(1-4C)alkyl S(O)p((1-4C)alkyl)N-, (1-4C)alkylS(O)q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-O- , AR3-O-, AR1-S(O)q-, AR2-S(O)q-, AR3-S(O)q-, AR1-NH-, AR2-NH-, AR3-NH-(p is 1 or 2, q is 0, 1 or 2) and groups comprising AR2a, AR2b, AR3a and AR3b type AR2 and AR3}; wherein any (1-4C) alkyl in any substituent of R ₁ a3, ( 1-4C) alkanoyl and (3-6C) cycloalkyl themselves may be substituted by 1-2 groups independently selected from the following groups: cyano, hydroxyl, halo, amino, (1-4C) alkylamino and Di(1-4C)alkylamino, with the proviso that such a substituent, if present, is not on a carbon adjacent to a heteroatom;

R ₁ a4: R ₁₄ C(O)O(1-6C)alkyl-, wherein R ₁₄ is AR1, AR2, AR2a, AR2b, (1-4C)alkylamino, benzyloxy-(1-4C) Alkyl or (1-10C)alkyl {optionally substituted as defined in (R ₁ a3)};

R ₁ a5: F, Cl, hydroxyl, mercapto, (1-4C) alkyl S(O)p-(p=0, 1 or 2), -NR ₇ R ₈ (wherein R ₇ and R ₈ are as defined former) or -OR ₁₀ (wherein the definition of R ₁₀ is the same as before);

m is 0, 1 or 2;

R ₂₁ is selected from hydrogen, methyl [optionally substituted by the following groups: cyano, trifluoromethyl, -C=WNRvRw (wherein W, Rv and Rw are as defined above for R ₁ a3), (1-4C) Alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy Carbonyl, CY1, CY2, AR1, AR2, AR2a, AR2b (not linked via nitrogen) or AR3], (2-10C) alkyl [optionally replaced by 1- 2 groups independently selected from the optional substituents defined by R ₁ a3 are substituted] and R ₁₄ C(O)O(2-6C)alkyl-, wherein R ₁₄ is as defined above for R ₁ a4, wherein R ₁₄ C(O)O is connected to a carbon other than the carbon connected to the ring nitrogen of HET-3);

R ₂₂ is cyano, -COR ₁₂ , -COOR ₁₂ , -CONHR ₁₂ , -CON(R ₁₂ )(R ₁₃ ), -SO ₂ R ₁₂ (provided R ₁₂ is not hydrogen), -SO ₂ NHR ₁₂ , -SO ₂ N(R ₁₂ )(R ₁₃ ) or NO ₂ , wherein R ₁₂ and R ₁₃ are as defined below;

R ₁₂ and R ₁₃ are independently selected from hydrogen, phenyl (optionally substituted with 1 or more substituents selected from the group consisting of halogen, (1-4C)alkyl and 1-3 or more halogen atoms substituted (1-4C)alkyl) and (1-4C)alkyl (optionally substituted by 1-3 or more halogen atoms), or for any N(R ₁₂ )(R ₁₃ ) group, R ₁₂ and R ₁₃ may together with the nitrogen to which they are attached form a 5-7 membered ring optionally having an additional heteroatom selected from N, O, S(O) replacing 1 carbon atom of the ring so formed ; wherein the ring can be optionally substituted with 1-2 groups independently selected from: (1-4C)alkyl (optionally substituted with cyano, hydroxyl or halo on carbons not adjacent to nitrogen ), (3-6C) cycloalkyl, (1-4C) alkanoyl, -COO (1-4C) alkyl, -S (O) n (1-4C) alkyl (where n = 1 or 2) , AR1, AR2, -C=OAR1, -C=OAR2, -COOAR1, -CS(1-4C)alkyl, -C(=S)O(1-4C)alkyl, -C(=W)NRvRw [Wherein W is O or S, Rv and Rw are independently H or (1-4C) alkyl], -S(O)pAR1 and -S(O)pAR2; wherein any (1-4C) alkyl chain can be any Selected to be substituted by (1-4C) alkyl, cyano, hydroxyl or halo; p=0, 1 or 2;

AR1 is optionally substituted phenyl or optionally substituted naphthyl;

AR2 is an optionally substituted 5- or 6-membered fully unsaturated (i.e., with maximum unsaturation) monocyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N, and S (but no any O-O, O-S or S-S bond), and is connected through a ring carbon atom, or if the ring is not thereby quaternized, may be connected through a ring nitrogen atom;

AR2a is a partially hydrogenated form of AR2 (i.e., the AR2 ring system retains some but not all of its unsaturation), linked through a ring carbon atom, or if the ring is not thus quaternized, via a ring nitrogen atom;

AR2b is a fully hydrogenated AR2 (that is, the AR2 ring system has no unsaturation), connected through ring carbon atoms or ring nitrogen atoms;

AR3 is an optionally substituted 8-, 9-, or 10-membered fully unsaturated (i.e., with maximum unsaturation) bicyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N, and S ( but does not contain any O-O, O-S or S-S bonds), and is connected through a ring carbon atom constituting any ring of the bicyclic system;

AR3a is a partially hydrogenated form of AR3 (i.e., the AR3 ring system retains some rather than complete unsaturation), attached through a ring carbon atom of either ring that makes up the bicyclic ring system, or through any The ring nitrogen atom of a ring is connected;

AR3b is a fully hydrogenated AR3 (that is, the AR3 ring system has no unsaturation), which is connected through a ring carbon atom or a ring nitrogen atom of any ring in the bicyclic ring system;

AR4 is an optionally substituted 13- or 14-membered fully unsaturated (i.e. with maximum unsaturation) tricyclic heteroaryl ring containing up to 4 heteroatoms independently selected from O, N and S (but no any O-O, O-S or S-S bond), and is connected through a ring carbon atom of any ring forming a tricyclic ring system;

AR4a is a partially hydrogenated form of AR4 (i.e., the AR4 ring system retains some but not all of its unsaturation), attached through a ring carbon atom of any ring that makes up the tricyclic system, or, if the ring is not thereby quaternized, through any The ring nitrogen atom of the ring is connected;

CY1 is an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl ring;

Cy2 is an optionally substituted cyclopentenyl or cyclohexenyl ring;

Wherein: the optional substituents of AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are (on effective carbon atoms) at most 3 substituents independently selected from the following: (1- 4C) alkyl {optionally substituted by substituents independently selected from the group consisting of hydroxyl, trifluoromethyl, (1-4C) alkyl S(O)q-(q is 0, 1 or 2), (1- 4C) alkoxy, (1-4C) alkoxycarbonyl, cyano, nitro, (1-4C) alkanoylamino, -CONRvRw or -NRvRw}, trifluoromethyl, hydroxyl, halo, nitro , cyano, mercapto, (1-4C) alkoxy, (1-4C) alkanoyloxy, dimethylaminomethyleneaminocarbonyl, di(N-(1-4C) alkyl) aminomethyl Base imino, carboxyl, (1-4C) alkoxycarbonyl, (1-4C) alkanoyl, (1-4C) alkylSO ₂ amino, (2-4C) alkenyl {optionally carboxyl or ( 1-4C) alkoxycarbonyl substituted}, (2-4C) alkynyl, (1-4C) alkanoylamino, oxo (=O), thio (=S), (1-4C) alkanoyl Amino {(1-4C) alkanoyl optionally substituted by hydroxyl}, (1-4C) alkyl S (O) q-(q is 0, 1 or 2) {(1-4C) alkyl optionally substituted by one or a plurality of groups independently selected from cyano, hydroxyl and (1-4C) alkoxyl substituted}, -CONRvRw or -NRvRw [wherein Rv is hydrogen or (1-4C) alkyl; Rw is hydrogen or (1 -4C) alkyl];

Additional optional substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 (on available carbon atoms) and alkyl (unless otherwise specified) are up to 3 independent Substituents selected from: trifluoromethoxy, benzoylamino, benzoyl, phenyl {optionally substituted with up to 3 substituents independently selected from: halo, (1-4C)alkoxy group or cyano}, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, thiophene, hydroxyimino (1-4C) alkyl, (1-4C) alkoxyimino (1-4C) alkyl, halo-(1-4C) alkyl, (1-4C) alkanesulfonylamino, -SO ₂ NRvRw [wherein Rv is hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl]; and

Optional substituents for AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4a are (on available nitrogen atoms, such substitution will not result in quaternization) (1-4C)alkyl, (1-4C )alkylcarbonyl{wherein (1-4C)alkyl and (1-4C)alkylcarbonyl are optionally substituted by (preferably one) substituent independently selected from: cyano, hydroxyl, nitro, trifluoromethyl , (1-4C) alkyl S (O) q- (q is 0, 1 or 2), (1-4C) alkoxy, (1-4C) alkoxycarbonyl, (1-4C) alkanoyl Amino, -CONRvRw or -NRvRw [where Rv is hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl]}, (2-4C) alkenyl, (2-4C) chain Alkynyl, (1-4C)alkoxycarbonyl or oxo (forming N-oxide).

In another aspect, the present invention relates to a compound of formula (1) as defined above or a pharmaceutically acceptable salt thereof.

In a further aspect, the present invention relates to a compound of formula (1) as defined above or a prodrug thereof. Suitable examples of prodrugs of compounds of formula (1) are in vivo hydrolyzable esters of compounds of formula (1). Thus, in a further aspect, the present invention relates to a compound of formula (1) as defined above, or an in vivo hydrolyzable ester thereof.

In yet another aspect, there is provided a compound of formula (I) as defined above, wherein HET3 is selected from:

a) HET3-A-HET3-E;

b) HET3-F-HET3-Y; and

c) HET3-Z-HET3-AE.

When optional substituents are selected from "0, 1, 2 or 3" groups, it is understood that this definition includes all substituents being selected from one of the specified groups, or substituents being selected from 2 or 2 More than one specific group group. Similar conventions apply for substituents selected from "0, 1 or 2" groups and "1 or 2" groups.

In this specification, the term 'alkyl' includes straight chain and branched chain structures. For example (1-4C)alkyl includes propyl and isopropyl. However, referring to a specific alkyl group such as "propyl" only refers to a straight-chain group, and referring to a specific branched-chain alkyl group such as "isopropyl" refers to only a branched-chain group. In the present specification, the terms 'alkenyl' and 'cycloalkenyl' include all positional isomers and geometric isomers. In this specification, the term 'aryl' means unsubstituted carbocyclic aryl groups, especially phenyl, 1- and 2-naphthyl.

For the avoidance of ambiguity, when a carbon atom is mentioned to be substituted by an oxo or thio group in HET1 or HET2, it means that _CH2 is replaced by C=O or C=S, respectively.

In this specification, compound terms are used to describe groups containing more than one functional group, eg (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkyl. Such terms should be interpreted according to the understanding of each constituent group by those skilled in the art. For example (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkyl includes methoxymethoxymethyl, ethoxymethoxypropyl and propoxyethoxy base methyl.

It should be understood that when a defined group is optionally substituted with more than one substituent, then the substitutions must result in a chemically stable compound. For example, it may be trifluoromethyl, but not trihydroxymethyl. This convention applies wherever optional substituents are defined.

The following are specific suitable examples where certain substituents and groups of groups referred to in this specification are appropriate. These groups may be used as appropriate for any of the definitions and embodiments disclosed above or below. For the avoidance of doubt, each specification represents a specific independent aspect of the invention.

Examples of (1-4C)alkyl and (1-5C)alkyl include methyl, ethyl, propyl, isopropyl and tert-butyl; examples of (1-6C)alkyl include methyl, ethyl , propyl, isopropyl, tert-butyl, pentyl and hexyl; examples of (1-10C)alkyl include methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl and nonyl; examples of (1-4C)alkanoylamino-(1-4C)alkyl include formamidomethyl, acetamidomethyl and acetamidoethyl; hydroxy(1-4C)alkyl and Examples of hydroxy(1-6C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl, Ethoxycarbonyl and propoxycarbonyl; examples of (1-4C)alkoxy-(1-4C)alkoxycarbonyl include methoxymethoxycarbonyl, methoxyethoxycarbonyl and propoxy Methoxycarbonyl; (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl Examples include methoxymethoxymethoxycarbonyl, methoxyethyl Oxymethoxycarbonyl and propoxyethoxymethoxycarbonyl; examples of 2-((1-4C)alkoxycarbonyl)ethenyl include 2-(methoxycarbonyl)ethenyl and 2-( ethoxycarbonyl)vinyl; examples of 2-cyano-2-((1-4C)alkyl)vinyl include 2-cyano-2-methylvinyl and 2-cyano-2-ethyl Vinyl; Examples of 2-nitro-2-((1-4C)alkyl)vinyl include 2-nitro-2-methylvinyl and 2-nitro-2-ethylvinyl; 2- Examples of ((1-4C)alkylaminocarbonyl)ethenyl include 2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl; examples of (2-4C)alkenyl include alkenyl Propyl and vinyl; examples of (2-4C)alkenyloxy include allyloxy and vinyloxy; examples of (2-4C)alkynyl include ethynyl and 2-propynyl; Examples of (2-4C)alkynyloxy include ethynyloxy and 2-propynyloxy; examples of (1-4C)alkanoyl include formyl, acetyl and propionyl; (1-4C) Examples of alkylcarbonyl include acetyl and propionyl; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; (1-6C)alkoxy and (1-10C)alkoxy; Examples of oxy include methoxy, ethoxy, propoxy and pentyloxy; examples of (1-4C)alkylthio include methylthio and ethylthio; examples of (1-4C)alkylamino Examples include methylamino, ethylamino, and propylamino; examples of (2-4C)alkenylamino include vinylamino and allylamino; examples of hydroxy(1-4C)alkylamino include 2-hydroxyethylamino; hydroxypropylamino, 2-hydroxypropylamino and 3-hydroxypropylamino; examples of di-((1-4C)alkyl)amino include dimethylamino, N-ethyl-N-methylamino, diethylamino Examples of halo include fluorine, chlorine, and bromine; examples of (1-4C)alkylsulfonyl include methylsulfonyl and ethylsulfonyl Acyl; Examples of (1-4C)alkoxy-(1-4C)alkoxy and (1-6C)alkoxy-(1-6C)alkoxy include methoxymethoxy, 2-methoxy Oxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy Examples include 2-(methoxymethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and 2 -(2-ethoxyethoxy)ethoxy; (1-4C)alkylS(O) _2amino examples include methylsulfonylamino and ethylsulfonylamino; (1-4C)alkanoyl Examples of amino and (1-6C)alkanoylamino include formamido, acetamido and propionylamino; examples of (1-4C)alkoxycarbonylamino include methoxycarbonylamino and ethoxycarbonylamino; Examples of N-(1-4C)alkyl-N-(1-6C)alkanoylamino include N-methylacetamido, N-ethylacetamido and N-methylpropionylamino; (1- 4C) Examples of alkyl S(O)pNH- (wherein p is 1 or 2) include methylsulfinylamino, methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; (1- 4C) Examples of alkyl S(O)p((1-4C)alkyl)N- (wherein p is 1 or 2) include methylsulfinylmethylamino, methylsulfinylmethylamino, 2- (Ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples of fluoro(1-4C)alkylS(O)pNH- (where p is 1 or 2) include three Fluoromethylsulfinylamino and trifluoromethylsulfonylamino; fluoro(1-4C)alkylS(O)p((1-4C)alkyl)NH-(where p is 1 or 2) Examples include trifluoromethylsulfinylmethylamino and trifluoromethylsulfonylmethylamino; examples of (1-4C)alkoxy(hydroxy)phosphoryloxy include methoxy(hydroxy)phosphoryloxy and ethoxy(hydroxy)phosphoryloxy; examples of bis-(1-4C)alkoxyphosphoryloxy include bis-methoxyphosphoryloxy, di-ethoxyphosphoryloxy and Ethoxy(methoxy)phosphoryloxy; (1-4C)alkylS(O)q-(where q is 0, 1 or 2) and -S(O)n(1-4C)alkyl (where n=1 or 2) examples include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; phenyl S(O)q and naphthalene Examples of the group S(O) _q- (wherein q is 0, 1 or 2) are phenylthio, phenylsulfinyl, phenylsulfonyl and naphthylthio and naphthylsulfinyl and naphthyl, respectively sulfonyl; examples of benzyloxy-(1-4C)alkyl include benzyloxymethyl and benzyloxyethyl; examples of (3-4C)alkylene chains are trimethylene or tetramethylene; Examples of (1-6C)alkoxy-(1-6C)alkyl include methoxymethyl, ethoxymethyl and 2-methoxyethyl; hydroxy-(2-6C)alkoxy Examples include 2-hydroxyethoxy and 3-hydroxypropoxy; examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxy and 2-ethylamino Ethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxy include 2-dimethylaminoethoxy and 2-diethylaminoethoxy; phenyl (1 Examples of -4C)alkyl include benzyl and phenethyl; examples of (1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; di((1-4C)alkyl) Examples of carbamoyl include di(methyl)carbamoyl and di(ethyl)carbamoyl; examples of hydroxyimino(1-4C)alkyl include hydroxyiminomethyl, 2-(hydroxyimino) Ethyl and 1-(hydroxyimino)ethyl; examples of (1-4C)alkoxyimino-(1-4C)alkyl include methoxyiminomethyl, ethoxyiminomethyl, 1-(methoxyimino)ethyl and 2-(methoxyimino)ethyl; examples of halo(1-4C)alkyl include halomethyl, 1-haloethyl, 2- haloethyl and 3-halopropyl; examples of nitro(1-4C)alkyl include nitromethyl, 1-nitroethyl, 2-nitroethyl and 3-nitropropyl; Examples of amino(1-4C)alkyl include aminomethyl, 1-aminoethyl, 2-aminoethyl and 3-aminopropyl; examples of cyano(1-4C)alkyl include cyanomethyl, 1-cyanoethyl, 2-cyanoethyl and 3-cyanopropyl; examples of (1-4C)alkanesulfonylamino include methylsulfonamido and ethanesulfonamido; (1-4C)alkanesulfonylamino Examples of aminosulfonyl groups include methylaminosulfonyl and ethylaminosulfonyl; examples of di-(1-4C)alkylaminosulfonyl include dimethylaminosulfonyl, diethylaminosulfonyl and N- Methyl-N-ethylaminosulfonyl; (1-4C) alkanesulfonyloxy examples include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy; (1-4C Examples of )alkanoyloxy include acetyloxy, propionyloxy; examples of (1-4C)alkylaminocarbonyl include methylaminocarbonyl and ethylaminocarbonyl; di((1-4C)alkyl)amino Examples of carbonyl include dimethylaminocarbonyl and diethylaminocarbonyl; examples of (3-6C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; (3-6C)cycloalkenyl Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl; examples of (4-7C)cycloalkyl include cyclobutyl, cyclopentyl, and cyclohexyl; two (N-(1 Examples of -4C) alkyl)aminomethylimino include dimethylaminomethylimino and diethylaminomethylimino.

Specific examples of AR2 include, for example, examples of AR2 containing one heteroatom include furan, pyrrole, and thiophene; examples of AR2 containing 1 to 4 N atoms include pyrazole, imidazole, pyridine, pyrimidine, pyrazine, pyridazine, 1 , 2,3- and 1,2,4-triazoles and tetrazoles; examples of AR2 containing one N atom and one O atom are oxazole, isoxazole and oxazine; Examples of AR2 are thiazole and isothiazole; examples of AR2 containing two N atoms and one S atom are 1,2,4- and 1,3,4-thiadiazoles.

Specific examples of AR2a include, for example, dihydropyrroles (especially 2,5-dihydropyrrol-4-yl) and tetrahydropyridine (especially 1,2,5,6-tetrahydropyridin-4-yl).

Specific examples of AR2b include, for example, tetrahydrofuran, pyrrolidine, morpholine (preferably morpholino), thiomorpholine (preferably thiomorpholin-4-yl), 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 Cyclohexane-2-yl.

Specific examples of AR3 include, for example, bicyclic benzofused systems containing 5- or 6-membered heteroaromatic rings containing a nitrogen atom and optionally 1-3 members selected from oxygen , additional heteroatoms of sulfur and nitrogen. Specific examples of such ring systems include, for example, indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline, quinoxaline , phthalazine, phthalazine and cinnamon.

Other specific examples of AR3 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, purines and naphthyridines.

More specific examples of AR3 include bicyclic heteroaromatic ring systems containing at least one bridgehead nitrogen and optionally 1-3 additional 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, 1H-imidazo[1,5-a]pyrrole, pyrrolo[1,2-b]isoxazole , imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, indazine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazole And[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrazine, pyrrolo[1, 2-a]pyrimidine, pyrido[2,1-c]-s-triazole, s-triazol[1,5-a]pyridine, imidazo[1,2-c]pyrimidine, imidazo[1, 2-a]pyrazine, imidazo[1,2-a]pyrimidine, imidazo[1,5-a]pyrazine, imidazo[1,5-a]pyrimidine, imidazo[1,2-b] - pyridazine, s-triazolo[4,3-a]pyrimidine, imidazo[5,1-b]oxazole and imidazo[2,1-b]oxazole. 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 systems are imidazooxazole or imidazothiazole, especially imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, imidazo[5, 1-b]oxazole or imidazo[2,1-b]oxazole.

Specific examples of AR3a and AR3b include, for example, indoline, 1,3,4,6,9,9a-hexahydropyrido[2,1c][1,4]oxazin-8-yl, 1,2, 3,5,8,8a-hexahydroimidazo[1,5a]pyridin-7-yl, 1,5,8,8a-tetrahydrooxazolo[3,4a]pyridin-7-yl, 1,5 , 6,7,8,8a-hexahydrooxazolo[3,4a]pyridin-7-yl, (7aS)[3H,5H]-1,7a-dihydropyrrolo[1,2c]oxazole- 6-yl, (7aS)[5H]-1,2,3,7a-tetrahydropyrrolo[1,2c]imidazol-6-yl, (7aR)[3H,5H]-1,7a-dihydropyrrole [1,2c]oxazol-6-yl, [3H,5H]-pyrrolo[1,2-c]oxazol-6-yl, [5H]-2,3-dihydropyrrolo[1, 2-c]imidazol-6-yl, [3H,5H]-pyrrolo[1,2-c]thiazol-6-yl, [3H,5H]-1,7a-dihydropyrrolo[1,2- c] Thiazol-6-yl, [5H]-pyrrolo[1,2-c]imidazol-6-yl, [1H]-3,4,8,8a-tetrahydropyrrolo[2,1-c] Oxazin-7-yl, [3H]-1,5,8,8a-tetrahydrooxazolo[3,4-a]pyridin-7-yl, [3H]-5,8-dihydrooxazolo [3,4-a]pyridin-7-yl and 5,8-dihydroimidazo[1,5-a]pyridin-7-yl.

Specific examples of AR4 include, for example, pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyrrolo[a]isoquinoline, 1H-pyrrolo[1,2-a]benzimidazole, 9H- Imidazo[1,2-a]indole, 5H-imidazo[2,1-a]isoindole, 1H-imidazo[3,4-a]indole, imidazo[1,2-a] Quinoline, imidazo[2,1-a]isoquinoline, imidazo[1,5-a]quinoline and imidazo[5,1-a]isoquinoline.

For the nomenclature used see for example "Heterocyclic Compounds (Systems with bridgehead nitrogen), W.L. Mosby (Interscience Publishers Inc., New York), 1961, Parts 1 and 2.

Where optional substituents are listed, such substitutions are preferably not gem-disubstituted, unless otherwise stated. If not otherwise indicated, suitable optional substituents for a particular group are those specified herein for analogous groups.

Ar2b is 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4-bis Preferred optional substituents on oxan-2-yl are mono- or di-substituted with substituents independently selected from: (1-4C)alkyl (including gem-disubstituted), (1-4C) Alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano, trifluoromethyl and phenyl.

Preferred optional substituents on CY1 and CY2 are monosubstituted or disubstituted substituents independently selected from the following: (1-4C)alkyl (including gem-disubstituted), hydroxyl, (1-4C)alkoxy, ( 1-4C)alkylthio, acetylamino, (1-4C)alkanoyl, cyano and trifluoromethyl.

Suitable pharmaceutically acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, citrate, maleate, tartrate and (less preferably) hydrobromide. Suitable salts also include those formed with phosphoric and sulfuric acid. On the other hand, suitable salts are alkali salts such as alkali metal salts, such as sodium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic amine salts, such as with triethylamine, morpholine, N- methylpiperidine, N- ethylpiperidine, procaine, dibenzylamine, N,N- dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucosamine and amino acids (e.g. lysine) salts. There may be more than one cation or anion, depending on the number of charged functional groups and the valency of the cation or anion. The preferred pharmaceutically acceptable salt is the sodium salt.

However, salts that are less soluble in the solvent of choice, whether pharmaceutically acceptable or not, may be preferred in order to facilitate isolation of the salt during manufacture.

The compounds of the invention may be administered in the form of prodrugs which will be broken down in the human or animal body to yield the compounds of the invention. Prodrugs can be used to change or improve the physical and/or pharmacokinetic characteristics of the parent compound. When the parent compound contains suitable groups or substituents that can be derivatized to form prodrugs, prodrugs can be prepared. Examples of prodrugs include in vivo hydrolyzable esters of compounds of the present invention or pharmaceutically acceptable salts thereof.

Various forms of prodrugs are well known in the art, see for example:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42 , p.309-396, edited by K. Widder, etc. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and Application of Prodrugs", H.Bundgaard, p.113-191(1991);

c) H. Bundgaard, Advanced Drug Delivery 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).

Suitable prodrugs of pyridine or triazole derivatives include acyloxymethylpyridinium or triazolium salts, such as halides; for example the following prodrugs:

(Reference: T. Yamazaki et al., ^42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 2002; Abstract F820).

Suitable prodrugs of hydroxyl groups are acyl esters of acetal-carbonates of the formula RCOOC(R,R')OCO-, where R is (1-4C)alkyl and R' is (1-4C)alkyl or H . Further suitable prodrugs are the carbonates and carbamates RCOO- and RNHCOO-.

An in vivo hydrolyzable ester of a compound of the invention comprising a carboxyl or hydroxyl group, or a pharmaceutically acceptable salt thereof, is, for example, a pharmaceutically acceptable ester that hydrolyzes in the human or animal body to yield the parent alcohol.

Suitable pharmaceutically acceptable esters of carboxyl groups include (1-6C)alkoxymethyl esters (e.g. methoxymethyl), (1-6C)alkanoyloxymethyl esters (e.g. pivaloyl oxymethyl), peptidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters (e.g. 1-cyclohexylcarbonyloxyethyl); 1,3-dioxolane Cyclo-2-ylmethyl ester (such as 5-methyl-1,3-dioxolan-2-ylmethyl); and (1-6C)alkoxycarbonyloxyethyl ester (such as 1- methoxycarbonyloxyethyl), said esters may be formed at any carboxyl group of the compounds of the invention.

In vivo hydrolyzable esters of compounds of the invention containing one or more hydroxyl groups, or pharmaceutically acceptable salts thereof, include inorganic esters such as phosphoric acid esters (including phosphoramidate cyclic esters) and alpha-acyloxyalkyl ethers, and Related compounds that decompose to obtain the parent hydroxyl group due to in vivo hydrolysis of the ester. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Groups selected for generation of in vivo hydrolyzable esters of hydroxyl groups include (1-10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C)alkoxycarbonyl (to obtain alkyl carbonate), di-(1-4C)alkylcarbamoyl and N- (di-(1-4C)alkylaminoethyl) -N- (1-4C)alkylcarbamoyl (to obtain carbamate), di-(1-4C)alkylaminoacetyl, carboxy(2-5C)alkylcarbonyl and carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl include chloromethyl or aminomethyl, (1-4C)alkylaminomethyl and di-((1-4C)alkyl)aminomethyl, and Lino or piperazino (attached to the 3- or 4-position of the benzoyl ring via a ring nitrogen atom via a methylene linker). Other relevant in vivo hydrolyzable esters include, for example, ^RA C(O)O(1-6C)alkyl-CO- (where ^RA is, for example, optionally substituted benzyloxy-(1-4C)alkyl or optionally Substituted phenyl; suitable substituents for phenyl in such esters include, for example, 4-(1-4C)piperazino-(1-4C)alkyl, piperazino-(1-4C)alkyl and morpholino-(1-4C)alkyl.

Suitable in vivo hydrolyzable esters of compounds of formula (I) are described below. For example, 1,2-diol can be cyclized to generate formula (PD1) cyclic ester or formula (PD2) pyrophosphate, and 1,3-diol can be cyclized to generate formula (PD3) cyclic ester:

Esters of compounds of formula (I) wherein in (PD1), (PD2) and (PD3) the HO-functional group is protected by (1-4C)alkyl, phenyl or benzyl) can be used to prepare such prodrugs intermediates.

Further in vivo hydrolyzable esters include phosphoramidates, also including compounds of the invention in which any free hydroxyl group independently forms a phosphate (npd of 1) or phosphite (npd of 0) of the formula (PD4):

For the avoidance of ambiguity, phosphono is -P(O)(OH) ₂ ; (1-4C)alkoxy(hydroxy)-phosphoryl is mono-(1-4C)alkane with -OP(O)(OH) ₂ Oxygen Derivatives; Bis-(1-4C)alkoxyphosphoryl is a bis-(1-4C)alkoxy derivative of -OP(O)(OH) ₂ .

Intermediates useful in the preparation of such esters include compounds containing one or more groups of formula (PD4) wherein 1-2 -OH of (PD1) are independently protected by (1-4C)alkyl groups (such compounds themselves is also the object compound), phenyl or phenyl-(1-4C) alkyl (such phenyl is optionally selected from 1-2 independently selected from (1-4C) alkyl, nitro, halo and (1- 4C) Alkoxy radical substitution).

Thus, prodrugs comprising groups such as (PD1), (PD2), (PD3) and (PD4) can be prepared by combining a compound of the invention containing an appropriate hydroxyl group with an appropriately protected phosphorylating agent (e.g. alkylamino leaving group), followed by oxidation (if desired) and deprotection.

Other suitable prodrugs include phosphonooxymethyl ethers and their salts, for example prodrugs of R-OH such as:

When the compound of the present invention contains multiple free hydroxyl groups, the hydroxyl groups that do not need to be converted into prodrug functional groups can be protected first (for example, with tert-butyl-dimethylsilyl), and then deprotected. Additionally, enzymatic methods can be used to selectively phosphorylate or dephosphorylate alcohol functional groups.

When it is possible to form a pharmaceutically acceptable salt of an ester which is hydrolyzable in vivo, this can be done by conventional techniques. Thus, for example, compounds containing groups of formula (PD1), (PD2), (PD3) and/or (PD4) can be ionized (partially or fully) to form salts containing appropriate amounts of counterions. Thus, for example, if the in vivo hydrolyzable ester of a prodrug of a compound of the invention contains two (PD4) groups, there are 4 HO-P- functionalities in the entire molecule, each of which can lead to a suitable salt (i.e. The entire molecule can form, for example, mono-, di-, tri- or tetra-sodium salts).

The compounds of the present invention have a chiral center at the C-5 position of the oxazolidinone ring. This pharmaceutically active diastereomer is of formula (Ia):

It is usually in the (5R) configuration, depending on the identity of R _1b and C.

The present invention includes pure diastereoisomers or mixtures of diastereomers, eg racemic mixtures. If a mixture of enantiomers is used, greater amounts (depending on the ratio of the individual enantiomers) will be required to achieve the same weight-effective effect of the pharmaceutically active enantiomer.

In addition, some of the compounds of the invention may contain other chiral centers, for example on substituents of the group C. It is to be understood that the present invention includes all such optical isomers and diastereoisomers and racemic mixtures which possess antibacterial activity. How to prepare optically active forms (eg resolution of racemic forms by recrystallization techniques, chiral synthesis, enzymatic resolution, biotransformation or chromatographic separations) and how to detect antibacterial activity as described below are well known in the art.

The present invention relates to all tautomeric forms of the compounds according to the invention which possess antibacterial activity.

It should also be understood that some of the compounds of the invention may exist in solvated as well as unsolvated forms, eg hydrated forms. It is to be understood that the present invention includes all such solvated forms which possess antibacterial activity.

It should also be understood that polymorphic forms may exist for certain compounds of the invention and that the invention includes all such antibacterially active forms.

As mentioned above, we have discovered a series of compounds with good activity against many Gram-positive pathogens, including Gram-positive pathogens known to be resistant to the most commonly used antibiotics, as well as difficult-to-culture Gram-positive pathogens. Negative pathogens such as Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma, and Chlamydia strains. The following compounds have good pharmacological and/or physical and/or pharmacokinetic properties.

One embodiment of the present invention provides a compound of formula (I), an alternative embodiment provides a pharmaceutically acceptable salt of a compound of formula (I), another alternative embodiment provides an in vivo hydrolyzable ester of a compound of formula (I), Yet another alternative embodiment provides pharmaceutically acceptable salts of in vivo hydrolyzable esters of compounds of formula (I).

In one aspect, the in vivo hydrolyzable ester of the compound of formula (I) is a phosphate ester (as defined for formula (PD4), npd is 1).

Compounds of formula (I) wherein C is selected from groups D or E, or pharmaceutically acceptable salts or in vivo hydrolyzable esters thereof represent specific independent aspects of the invention.

Particularly preferred compounds of the present invention constitute compounds of the present invention or pharmaceutically acceptable salts or in vivo hydrolyzable esters thereof, wherein the substituents R ₁ a, R ₁ b, R ₂ a, R ₂ b, R ₃ a, R ₆ a and R ₆ b and the other substituents mentioned above have the values disclosed above or any of the following values (any definitions and embodiments disclosed above or below apply and may be used):

One embodiment provides a compound of formula (I), wherein group C is group D, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.

Yet another embodiment provides a compound of formula (I), wherein group C is group E, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof.

In one aspect _R2a and _R6a are both hydrogen.

In one aspect one of _R2b and _R6b is fluoro and the other hydrogen. In yet another aspect, both _R2b and _R6b are fluoro. In yet another aspect, _R2b is fluoro and _R6b is selected from Cl, _CF3 , Me, Et, OMe and SMe.

In one aspect, one of _R2b and _R6b is chlorine and the other is hydrogen.

In another aspect, one of _R2b and _R6b is _CF3 and the other is hydrogen.

In yet another aspect, one of _R2b and _R6b is Me and the other is hydrogen.

In yet another aspect, one of _R2b and _R6b is Et and the other is hydrogen.

In yet another aspect, one of _R2b and _R6b is OMe and the other is hydrogen.

In yet another aspect, one of _R2b and _R6b is SMe and the other is hydrogen.

In one aspect _R3a is selected from H, (1-4C) alkyl, cyano, Br, F, Cl, OH, (1-4C) alkoxy, -S (1-4C) alkyl, amino, nitr base and -CHO. In a further aspect, _R3a is selected from H, Cl, Br, F, Me, Et, OMe and SMe.

In one embodiment, R ₁ b is HET1, wherein HET1 is selected from the following structures (Za)-(Zf):

wherein u and v are independently 0 or 1, RT is as defined above or below in any embodiment or aspect.

In one embodiment, R ₁ b is HET1, wherein HET1 is selected from 1,2,3-triazoles (especially 1,2,3-triazol-1-yl (Zd)), 1,2,4- Triazoles (especially 1,2,4-triazol-1-yl (Zc)) and tetrazoles (preferably tetrazol-2-yl (Zf)), wherein u and v are independently 0 or 1, and RT is as above Or as defined in any embodiment or aspect defined below.

In yet another embodiment, R ₁ b is HET1, wherein HET1 is selected from 1,2,3-triazol-1-yl (Zd) and tetrazol-2-yl (Zf), wherein u and v are independently 0 Or 1, RT is as defined above or below in any embodiment or aspect.

In yet another embodiment, R ₁ b is HET1, wherein HET1 is 1,2,3-triazol-1-yl (Zd), wherein u and v are independently 0 or 1, and RT is any of the above or below defined Definitions in an embodiment or aspect.

In one embodiment, R _1b is HET2, wherein HET2 is a di-hydropyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5 - Triazines and pyridines, wherein RT is as defined above or below in any embodiment or aspect.

In yet another embodiment, R ₁ b is HET2, wherein HET2 is pyrimidinone, pyridazinone, pyrazinone, 1,2,3-triazone, 1,2,4-triazone, 1,3 , 5-triazinone and pyridone, wherein RT is as defined above or below in any embodiment or aspect.

In yet another embodiment, R ₁ b is HET2, wherein HET2 is selected from the group consisting of thiopyrimidinone, thiopyridazinone, thiopyrazinone, thio-1,2,3-triazinone, thio- 1,2,4-Triazones, thio-1,3,5-triazinones and thiopyridones, wherein RT is as defined above or below in any embodiment or aspect.

In one aspect, the RT substituent is preferably selected from the RTa1-RTb2 group substituents, wherein:

(RTa1) hydrogen, halogen, (1-4C) alkoxy, (2-4C) alkenyloxy, (2-4C) alkenyl, (2-4C) alkynyl, (3-6C) Cycloalkyl, (3-6C) cycloalkenyl, (1-4C) alkylthio, amino, azido, cyano and nitro;

(RTa2) (1-4C) alkylamino, di-(1-4C) alkylamino and (2-4C) alkenylamino;

(RTb1) (1-4C)alkyl optionally substituted by one substituent selected from the group consisting of hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, cyano and azido ;

(RTb2) (1-4C)alkyl optionally substituted by one substituent selected from (2-4C)alkenyloxy, (3-6C)cycloalkyl and (3-6C)cyclo Alkenyl;

Wherein, when the RT substituent in (RTa1) or (RTa2), or (RTb1) or (RTb2) contains an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety, the moiety of the group Optionally substituted by 1-3 or more substituents independently selected from F, Cl, Br, OH and CN on effective carbon atoms.

In a further aspect, the RT substituents are preferably selected from the group RTa1-RTb1 wherein: (RTa1) hydrogen, halogen, (1-4C) alkoxy, (2-4C) alkenyloxy, (2-4C) Alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, (1-4C)alkylthio, amino, azido, cyano and nitro base;

(RTb1) (1-4C)alkyl optionally substituted by one substituent selected from the group consisting of hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, cyano and azido and when the RT substituent in (RTa1) or (RTb1) comprises an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety, said moiety is optionally replaced by 1 on an available carbon atom - Substitution with 3 or more substituents independently selected from F, Cl, Br and CN.

In yet another aspect, the most preferred RT is

(a) hydrogen; or

(b) halogen, especially fluorine, chlorine or bromine; or

(c) cyano; or

(d) (1-4C)alkyl, especially methyl; or

(e) monosubstituted (1-4C)alkyl, especially fluoromethyl, chloromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl; or

(f) disubstituted (1-4C) alkyl, such as difluoromethyl, or

(g) Trisubstituted (1-4C)alkyl, eg trifluoromethyl.

In one aspect _R4 is selected from _R4a . In yet another aspect, _R4 is selected from _R4b .

On the one hand R ₄ a is selected from (1-4C) alkyl, (3-6C) cycloalkyl, AR1, AR2, (1-4C) alkanoyl, -CS (1-4C) alkyl, -C (= W) NRvRw [Wherein W is O or S, Rv and Rw are independently H or (1-4C) alkyl], -COO (1-4C) alkyl, -C=OAR1, -C=OAR2, -COOAR1, -S(O)n(1-4C)alkyl (where n=1 or 2), -S(O)pAR1, -S(O)pAR2 and -C(=S)O(1-4C)alkyl ; wherein any (1-4C)alkyl chain may optionally be substituted by (1-4C)alkyl, cyano, hydroxyl or halo; p=0, 1 or 2).

In yet another aspect, R ₄ a is selected from azido, -NR ₇ R ₈ , -OR ₁₀ (1-4C)alkoxy, -(CH2) _m -R ₉ and -(C=O) ₁ -R ₆ .

In one aspect the HET-3 is selected from the group consisting of HET3-A, HET3-B, HET3-C, HET3-D and HET3-E.

In another aspect, HET-3 is selected from HET3-F, HET3-G, HET3-H and HET3-I.

In yet another aspect, the HET-3 is selected from the group consisting of HET3-J, HET3-K, HET3-L, HET3-M, HET3-N, HET3-O, HET3-P, HET3-Q, HET3-R, and HET3-S.

In yet another aspect, the HET-3 is selected from the group consisting of HET3-J, HET3-L, HET3-M, HET3-N, HET3-P, HET3-Q, HET3-R, and HET3-S.

In yet another aspect, HET-3 is selected from HET3-L and HET3-M.

In yet another aspect, HET-3 is selected from HET3-P and HET3-Q.

In yet another aspect, the HET-3 is selected from the group consisting of HET3-T, HET3-U, HET3-V, HET3-W, HET3-X, and HET3-Y.

In yet another aspect, HET-3 is selected from HET3-T, HET3-V, HET3-Y, and HET-3-W.

In yet another aspect, HET-3 is selected from HET3-V and HET3-Y.

In yet another aspect, the HET-3 is selected from the group consisting of HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG, and HET3-AH.

When m=1, on the one hand R ₁ a is selected from R ₁ a1; on the other hand R ₁ a is selected from R ₁ a2; on the other hand R ₁ a is selected from R ₁ a3, and on the other hand R ₁ a is selected from R ₁ a4, in yet another aspect, R ₁ a is selected from R ₁ a5.

When m=2, on the one hand the two R ₁ a are independently selected from the same group R ₁ a1-R ₁ a5. On the other hand, when m=2, each R ₁ a is independently selected from different group groups R ₁ a1-R ₁ a5.

Typically, m is 1 or 2. On the one hand, m is preferably 1. On the other hand, m is preferably 2.

When R ₁ a is selected from R ₁ a1, specific groups of R ₁ a are AR1 and AR2, more preferably AR2.

When R ₁ a is selected from R ₁ a2, specific groups of R ₁ a are cyano and -C(=W)NRvRw [wherein W is O or S, Rv and Rw are independently H or (1-4C) alkane wherein Rv and Rw together with the amide nitrogen or thioamide nitrogen to which they are attached may form a 5-7 membered ring optionally substituted with an additional heteroatom selected from N, O, S(O)n such that 1 carbon atom of the ring formed; wherein when said ring is a piperazine ring, the ring may optionally be substituted on the other nitrogen with a group selected from: (1-4C)alkyl (optional Substitution on a carbon not adjacent to the nitrogen), (3-6C)cycloalkyl, (1-4C)alkanoyl, -COO(1-4C)alkyl, -S(O)n(1- 4C) Alkyl (where n=1 or 2), -COOAR1, -CS(1-4C)alkyl and -C(=S)O(1-4C)alkyl; wherein any (1-4C)alkyl , (1-4C)alkanoyl and (3-6C)cycloalkyl are optionally substituted by cyano, hydroxyl or halo]. When a more specific group of R ₁ a is selected from R ₁ a2, R ₁ a2 is cyano, formyl, -COO(1-4C)alkyl, -C(=O)NH ₂ , -(C=O ) piperazine and -(C=O)morpholine.

When R ₁ a is selected from R ₁ a3, the specific group of R ₁ a is (1-10C) alkyl {optionally substituted by one or more groups (including gem-disubstituted), each group is independently selected from Hydroxy, (1-10C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy-(1- 4C)alkoxy, (1-4C)alkylcarbonyl, phosphoryloxy [-OP(O)(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphorous Acyloxy [-OP(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives] and amino; and/or optionally substituted by a group selected from: carboxyl, cyano , Halo, trifluoromethyl, (1-4C) alkoxycarbonyl, (1-4C) alkoxy-(1-4C) alkoxycarbonyl, (1-4C) alkoxy-(1- 4C) alkoxy-(1-4C) alkoxycarbonyl, (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1- 4C) alkoxycarbonylamino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C(=W)NRvRw [Wherein W is O, Rv and Rw are independently H Or (1-4C) alkyl, wherein Rv and Rw together with their attached amide nitrogen can form a morpholine, pyrrolidine, piperidine or piperazine ring; wherein when the ring is a piperazine ring, the ring can be any Selected on another nitrogen to be substituted by a group selected from (1-4C) alkyl and (1-4C) alkanoyl], (1-4C) alkyl S (O) q-(q is 0, 1 or 2), AR2, AR2-O-, AR2-NH- and groups comprising AR2a, AR2b type AR2}; wherein the ( _1-4C ) alkyl and (1- 4C) The acyl group itself may be substituted by 1-2 groups independently selected from the group consisting of cyano, hydroxy, halo, amino, (1-4C)alkylamino and di(1-4C)alkylamino, provided that is that such a substituent, if present, is not on a carbon adjacent to the heteroatom;

When R ₁ a is selected from R ₁ a3, a more specific group of R ₁ a is (1-10C) alkyl {optionally substituted by one or more groups (including gem-disubstituted), each group is independently selected From hydroxyl, (1-10C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy-(1 -4C)alkoxy, phosphoryloxy [-OP(O)(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphoryloxy[-OP(OH) ) ₂ and its mono- and di-(1-4C)alkoxy derivatives], carboxyl, amino, (1-4C)alkylamino, di(1-4C)alkylamino, (1-4C)alkane The bases S(O)q (preferably q=2), AR2 and AR2b. When R ₁ a is selected from R ₁ a3, a more specific group of R ₁ a is the substituted (1-6C)alkyl group described above. When a further specific group of R ₁ a is selected from R ₁ a3, it is a substituted (1-4C)alkyl group as described above.

Specific substituents of (1-10C)alkyl, (1-6C)alkyl or (1-4C)alkyl constituting R ₁ a3 are hydroxyl, (1-10C)alkoxy, (1-4C)alk Oxygen-(1-4C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy-(1-4C) alkoxy, phosphoryloxy [-OP (O) ( OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphiteoxy [-OP(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives] Object] and carboxyl. Preferably, R ₁ a3 is (1-4C)alkyl substituted by 1-2 hydroxyl groups.

When a specific group of R ₁ a is selected from R ₁ a4, it is R ₁₄ C(O)O(1-6C)alkyl-, wherein R ₁₄ is selected from AR1, AR2, AR2a, AR2b and (1-10C )alkyl (optionally substituted with one or more substituents independently selected from OH and di(1-4C)alkylamino). More specific groups for R ₁₄ are AR2a, AR2b and (1-6C)alkyl substituted by hydroxy. More specific groups for R ₁₄ are AR2a, AR2b and (1-4C)alkyl substituted by hydroxy.

When a specific group of R ₁ a is selected from R ₁ a5, it is fluorine, chlorine and hydroxyl.

Specific groups of other substituents (where any of the definitions and embodiments disclosed above or below are applicable) are:-

a) On the one hand R ₇ and R ₈ are independently H or (1-4C) alkyl

b) In yet another aspect, R _and R together with the nitrogen to which they are attached form a _5-7 membered ring, optionally substituted as defined above or below

c) Preferably R _{and R} together with the nitrogen to which they are attached form a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl ring

d) When R _{and R} are pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl rings, the preferred optional substituents on the rings are (1-4C)alkyl and (1-4C)alkane Acyl, wherein the (1-4C) alkyl or (1-4C) alkanoyl itself may be optionally substituted by 1-2 substituents selected from the group consisting of hydroxyl, amino, (1-4C) alkylamino and Di(1-4C)alkylamino

e) In one aspect, _R9 is selected from _R9a , preferably from AR2, AR2a and AR2b

f) In another aspect, R ₉ is selected from R ₉ b, preferably from -C(=W)NRvRw, wherein w is O, Rv and Rw are independently H or (1-4C)alkyl, wherein Rv and Rw are combined with their The linked amide nitrogens together may form a morpholine, pyrrolidine, piperidine or piperazine ring; wherein when said ring is a piperazine ring, the ring may optionally be substituted on another nitrogen with a group selected from: (1-4C)alkyl and (1-4C)alkanoyl, wherein any (1-4C)alkyl and (1-4C)alkanoyl themselves may be substituted by 1-2 groups independently selected from: cyano radical, hydroxy, halo, amino, (1-4C)alkylamino and di(1-4C)alkylamino, with the proviso that if such substituents are present, they are not on a carbon adjacent to the heteroatom;

g) In yet another aspect, R ₉ is selected from R ₉ c, wherein R ₉ c is (1-6C) alkyl {optionally substituted by 1-3 groups (including gem-disubstituted), each group is independently selected from Hydroxy, (1-10C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy-(1- 4C)alkoxy, (1-4C)alkylcarbonyl, phosphoryloxy [-OP(O)(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphorous Acyloxy [-OP(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives] and amino; and/or optionally substituted by a group selected from: carboxyl, cyano , Halo, trifluoromethyl, (1-4C) alkoxycarbonyl, (1-4C) alkoxy-(1-4C) alkoxycarbonyl, (1-4C) alkoxy-(1- 4C) alkoxy-(1-4C) alkoxycarbonyl, (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1- 4C) alkoxycarbonylamino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C(=W)NRvRw [Wherein W is O, Rv and Rw are independently H Or (1-4C) alkyl, wherein Rv and Rw together with their attached amide nitrogen can form a morpholine, pyrrolidine, piperidine or piperazine ring; wherein when the ring is a piperazine ring, the ring can be any Selected on another nitrogen to be substituted by a group selected from (1-4C) alkyl and (1-4C) alkanoyl], (1-4C) alkyl S (O) q-(q is 0, 1 or 2), AR2, AR2-O-, AR2-NH- and groups comprising AR2a, AR2b type AR2}; wherein any (1-4C) alkyl and (1-4C) in any substituent on R ₉ c )alkanoyl itself may be substituted by 1-2 groups independently selected from the group consisting of cyano, hydroxy, halo, amino, (1-4C)alkylamino and di(1-4C)alkylamino, provided that is that such a substituent, if present, is not on a carbon adjacent to the heteroatom;

h) In another aspect, R ₉ is selected from R ₉ c, wherein R ₉ c is (1-6C) alkyl {optionally substituted by 1-3 groups (including gem-disubstituted), each group is independently selected from Hydroxy, (1-10C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy-(1- 4C) Alkoxy, phosphoryloxy [-OP(O)(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphoryloxy [-OP(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], carboxyl, amino, (1-4C)alkylamino, di(1-4C)alkylamino, (1-4C)alkyl S(O)q (preferably q=2), AR2 and AR2b. A more specific group for R ₉ c is (1-4C)alkyl, optionally substituted as previously described.

i) In yet another aspect, R ₉ is selected from R ₉ d, wherein R ₉ d is R ₁₄ C(O)O(1-6C)alkyl-, R ₁₄ is selected from AR1, AR2, AR2a, AR2b and (1- 10C) alkyl (optionally substituted with 1-2 substituents independently selected from OH and di(1-4C)alkylamino). Specific groups of R ₁₄ are AR2a, AR2b and (1-6C)alkyl substituted by hydroxyl. More specific groups for R ₁₄ are AR2a, AR2b and (1-4C)alkyl substituted by hydroxy.

j) A specific group for R ₂₁ is R ₁₄ C(O)O(2-6C)alkyl-, wherein R ₁₄ is preferably selected from AR1, AR2, AR2a, AR2b and (1-10C)alkyl (optionally replaced by 1 - Substitution with 2 substituents independently selected from OH and di(1-4C)alkylamino.

k) A more specific group of R ₂₁ is (2-10C) alkyl, optionally on a carbon other than the carbon connected to the HET-3 ring nitrogen, 1-2 independently selected from the above or hereinafter defined R ₁ The group substitution of the optional substituent of a3; the more specific group of R ₂₁ is an optionally substituted (2-6C) alkyl group, more preferably an optionally substituted (2-4C) alkyl group.

l) The specific substituents of (2-6C) alkyl or (2-4C) alkyl constituting _R21 are 1-2 substituents independently selected from the following substituents: hydroxyl, (1-10C) alkoxy, ( 1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy-(1-4C) alkoxy, phosphoryloxy [- OP(O)(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphiteoxy [-OP(OH) ₂ and its mono- and di-(1-4C) ) alkoxy derivatives], carboxyl, amino, (1-4C) alkylamino, di(1-4C) alkylamino, (1-4C) alkyl S(O)q (preferably where q=2) , AR2 and AR2bm) The more specific substituent value of (2-6C) alkyl or (2-4C) alkyl constituting R ₂₁ is 1-2 substituents independently selected from the following substituents: hydroxyl, (1-10C ) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy-(1-4C) alkoxy, Phosphoryloxy [-OP(O)(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives], phosphorousyloxy [-OP(OH) ₂ and its mono- and Di-(1-4C)alkoxy derivatives] and carboxyl. Preferably, the substituent of (2-6C)alkyl or (2-4C)alkyl constituting _R21 is 1-2 hydroxyl groups.

n) preferably R ₂₂ is cyano.

o) It is especially preferred that the AR2, AR2a and AR2b groups are basic nitrogen containing groups such as pyridine, pyrrolidine, piperazine and piperidine, optionally substituted as previously described.

One embodiment provides a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof,

Wherein group C is group D; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b are independently hydrogen or fluorine;

_R4 is selected from HET-3.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group D; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group D; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group D; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH; m =1 and R ₁ a is selected from R ₁ a3.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH; m =1 and R ₁ a is selected from R ₁ a3.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group D; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y, R1b is selected from Zd and Zf, u and v are independently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, chloromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl and trifluoro methyl.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group D; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, R ₁ b is selected from Zd and Zf, u and v are independently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, chloromethyl, bromomethyl, cyanomethyl, azido Methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group D; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH; m =1, R ₁ a is selected from R ₁ a3, R ₁ b is selected from Zd and Zf, u and v are independently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, chloromethyl , bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl and trifluoromethyl

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is selected from HET3-T, HET3-U, HET3-V, HET3-W, HET3-X and HET3-Y, R ₁ b is selected from Zd and Zf, u and v are independently is 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, chloromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl and Trifluoromethyl

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH, R ₁ b is selected from Zd and Zf, u and v are independently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, chloromethyl, bromomethyl, cyanomethyl, azido Methyl, hydroxymethyl, difluoromethyl and trifluoromethyl

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and _R6b is independently hydrogen or fluorine; _R4 is selected from HET3-Z, HET3-AA, HET3-AB, HET3-AC, HET3-AD, HET3-AE, HET3-AF, HET3-AG and HET3-AH; m =1, R ₁ a is selected from R ₁ a3, R ₁ b is selected from Zd and Zf, u and v are independently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, chloromethyl , bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl and trifluoromethyl.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is HET3-V, R ₁ b is selected from Zd and Zf, u and v are independently 0 or 1 and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl , chloromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl and trifluoromethyl.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is HET3-V, R ₁ b is Zd or Zf, u and v are independently 0 or 1, R ₂₁ is methyl or (2-4C) alkyl (optionally Substitution with 1-2 substituents independently selected from: hydroxyl, (1-10C) alkoxy, (1-4C) alkoxy-(1-4C) alkoxy, (1-4C) alkoxy -(1-4C)alkoxy-(1-4C)alkoxy, phosphoryloxy [-OP(O)(OH) ₂ and their mono- and di-(1-4C)alkoxy derivatives ], phosphiteoxy [-OP(OH) ₂ and its mono- and di-(1-4C)alkoxy derivatives] and carboxyl), and RT is selected from hydrogen, halogen, cyano, methyl, Fluoromethyl, chloromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl and trifluoromethyl.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is HET3-V, R ₁ b is Zd, u and v are independently 0 or 1, R ₂₁ is methyl or (2-4C) alkyl (optionally 1- 2 hydroxyl groups), and RT is selected from hydrogen, halogen, cyano, methyl, fluoromethyl, chloromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl, difluoromethyl group and trifluoromethyl group.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is HET3-V, R ₁ b is Zd, u and v are independently 0 or 1, R ₂₁ is methyl or (2-4C) alkyl (optionally 1- 2 hydroxyl groups), and RT is selected from hydrogen, halogen, methyl, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl and trifluoromethyl.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is HET3-V, R ₁ b is Zd, u and v are independently 0 or 1, R ₂₁ is methyl or (2-4C) alkyl (optionally 1- 2 hydroxyl groups), and RT is selected from hydrogen, fluorine, chlorine, methyl, fluoromethyl, chloromethyl, difluoromethyl and trifluoromethyl.

Yet another embodiment provides a compound of formula (Ia), or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof, wherein group C is group E; R ₂ a and R ₆ a are both hydrogen; R ₂ b and R ₆ b is independently hydrogen or fluorine; R ₄ is HET3-V, R ₁ b is Zd, u and v are independently 0 or 1, R ₂₁ is methyl or (2-4C) alkyl (optionally 1- 2 hydroxyl groups), and RT is selected from hydrogen, chlorine, fluoromethyl and difluoromethyl.

In all the above definitions, preferred compounds are those represented by formula (Ia).

Specific compounds of the invention include individual compounds described in the examples, each compound providing a separate aspect of the invention. A particularly preferred compound is the compound of Example 1.

Method section :

In yet another aspect, the present invention provides a process for the preparation of a compound of the present invention, or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof. It is to be understood that in some of the following preparations certain substituents may require protection against undesired reactions. The skilled chemist knows when such protecting groups are required, and how to add such protection at appropriate positions, and subsequently deprotect.

For examples of protecting groups, see one of several general literatures on the subject, eg "Protective Groups in Organic Synthesis", Theodora Green (Publisher: John Wiley and Sons). Protecting groups can be removed by any suitable method in the literature or known to the skilled chemist as suitable for removing the protecting group in question, the method chosen being such that the protecting group is removed and the other groups in the molecule are unaffected. Minimal distractions.

Thus, if reactants contain, for example, amino, carboxy, or hydroxyl groups, it may be desirable to protect such groups in some of the reactions mentioned herein.

Suitable protecting groups for amino or alkylamino groups are for example acyl, for example alkanoyl (for example acetyl); alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl; arylmethoxy carbonyl, such as benzyloxycarbonyl; or aroyl, such as benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl (eg alkanoyl or alkoxycarbonyl) or aroyl group may be removed eg by hydrolysis with a suitable base (eg an alkali metal hydroxide, eg lithium or sodium hydroxide). Alternatively, an acyl group (e.g. tert-butoxycarbonyl) can be removed by, for example, treating it with a suitable acid (hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid), an arylmethoxycarbonyl group (e.g. benzyloxycarbonyl ) can be removed by, for example, hydrogenation with a catalyst such as palladium on carbon, or treatment with a Lewis acid such as boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is eg a phthaloyl group which can be removed by treatment with an alkylamine such as dimethylaminopropylamine or by treatment with hydrazine.

Suitable protecting groups for hydroxy are eg acyl, eg alkanoyl (eg acetyl); aroyl, eg benzoyl; or arylmethyl, eg benzyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium or sodium hydroxide. Alternatively, arylmethyl groups such as benzyl groups can be removed by, for example, hydrogenation with a catalyst such as palladium on carbon.

Suitable protecting groups for carboxyl groups are, for example, esterifying groups such as methyl or ethyl, which can be removed by hydrolysis with a base (for example, sodium hydroxide); , such as trifluoroacetic acid) or, for example, a benzyl group, which can be removed, for example, by hydrogenation with a catalyst such as palladium on carbon. Resins can also be used as protecting groups.

Protecting groups may be removed at any appropriate stage in the synthesis by conventional techniques well known in the chemical arts.

Compounds of the present invention, or pharmaceutically acceptable salts or in vivo hydrolyzable esters thereof, may be prepared by any known method suitable for the preparation of chemically related compounds. Such methods, when used to prepare compounds of the invention, or pharmaceutically acceptable salts or in vivo hydrolyzable esters thereof, are provided as a further feature of the invention, as illustrated by the following representative examples. The necessary starting materials can be obtained by standard methods of organic chemistry (see for example Advanced Organic Chemistry (Wiley-Interscience), Jerry March or Houben-Weyl, Methoden der Organischen Chemie). The non-limiting examples that follow describe the preparation of such starting materials. Alternatively, the necessary starting materials can be obtained by methods analogous to those illustrated, which are within the routine skills of organic chemists. Information on the preparation of the requisite starting materials or related compounds which may be modified for the preparation of the requisite starting materials can be found in the following patent application publications, the contents of which are incorporated herein by reference in the relevant method sections: e.g. WO 94/13649; WO 98/ 54161; WO 99/64416; WO 99/64417; WO 00/21960; WO 01/40222.

We refer in particular to our PCT patent applications WO 99/64417 and WO 00/21960 which give general procedures for the preparation of oxazolidinone compounds.

A skilled organic chemist will be able to use and modify the information contained and referred to in the above references and the Examples therein, as well as the Examples herein, in order to obtain the necessary starting materials and products. For example, a skilled chemist will be able to apply the teachings herein of compounds of formula (I) in which a pyridyl-phenyl group is present (i.e. when the group C is a group D) to prepare the pyridyl-phenyl group defined above in the presence of a pyridyl-phenyl group. group (ie when group C is group E), and vice versa.

Therefore, the present invention also provides that the compounds of the present invention and their pharmaceutically acceptable salts and in vivo hydrolyzable esters can be prepared by methods (a)-(j); then, if necessary, the following steps are carried out:

i) removal of any protecting group;

ii) generation of prodrugs (e.g. in vivo hydrolyzable esters); and/or

iii) forming a pharmaceutically acceptable salt;

The methods (a)-(j) described therein are as follows (unless otherwise specified, the definitions of the variables are the same as above):

a) Modifying a substituent on or introducing a substituent into another compound of the invention by standard chemical methods (see, e.g., Comprehensive Organic Functional Group Transformations (Pergamon), Katritzky, Meth-Cohn and Rees or Advanced Organic Chemistry (Wiley-Interscience), Jerry March or Houben-Weyl, Methoden der Organischen Chemie)); for example:

Acylamino can be converted to thioacylamino;

Acylamino or thioacylamino can be converted into other acylamino or thioacylamino; heterocyclyl such as tetrazolyl or thiazolyl, or heterocyclylamino (optionally substituted or protected on the amino-nitrogen atom);

an acyloxy group can be converted into a hydroxyl group or into a group obtainable from a hydroxyl group (directly or via an intermediate hydroxyl group);

Alkyl halides such as alkyl bromides or iodides can be converted to alkyl fluorides or nitriles;

Alkyl sulfonates such as alkyl methanesulfonate can be converted into alkyl fluorides or nitriles;

Alkylthio groups such as methylthio can be converted to methylsulfinyl or methylsulfonyl;

Arylthio groups such as phenylthio (phentlthio) can be converted into phenylsulfinyl or benzenesulfonyl;

Amino or guanidino groups can be converted into 2-substituted 1,3-oxadiazoles and 1,3-diazines;

Amino groups can be converted, for example, into acylamino or thioacylamino groups such as acetamide (optionally substituted), alkyl- or dialkyl-amino groups and thus into further N-alkyl-amine derivatives, sulfonylamino groups, Sulfinylamino, amidino, guanidino, arylamino, heteroarylamino, N-linked heterocycles such as optionally 4-substituted 1,2,3-triazol-1-yl;

Aryl- or heteroaryl-halogen groups such as aryl- or hetero-aryl chloride or bromine or iodine can be converted by transition metal-mediated coupling reactions, especially Pd(0)-mediated coupling reactions, to Aryl-, heteroaryl, alkenyl, alkynyl, acyl, alkylthio or alkyl- or dialkyl-amino substituted aryl or heteroaryl;

Aryl- or heteroaryl-sulfonate groups such as aryl- or hetero-aryl triflate can be coupled via transition metal-mediated coupling reactions (especially Pd(0)-mediated coupling reactions) Conversion to aryl-, heteroaryl, alkenyl, alkynyl, acyl, alkylthio or alkyl- or dialkyl-amino substituted aryl or heteroaryl;

Aryl- or heteroaryl-halogen groups such as aryl- or hetero-aryl chloride or bromine or iodine can be converted by transition metal-mediated coupling reactions, especially Pd(0)-mediated coupling reactions, to Trialkyltins, dialkyl borates, trialkoxysilyls, substituted aryls or heteroaryls used as intermediates in the synthesis of compounds of the invention;

The azido group can be converted, for example, to a 1,2,3-triazolyl or amine, and thus to any common amine derivative, such as an acylamino group (e.g. acetamido), by methods well known in the art;

The carboxylic acid group can be converted into trifluoromethyl, hydroxymethyl, alkoxycarbonyl, aminocarbonyl optionally substituted on nitrogen, formyl or acyl;

The cyano group can be converted into a tetrazole or imidate group (imidate), amidine, amidrazone, N-hydroxyamizone, amide, thioamide, ester or acid, and thus into a derivative by methods known in the art. Any heterocycle in such nitrile derivatives;

Hydroxy groups can be converted, for example, into alkoxy, cyano, azido, alkylthio, keto and oxime groups, fluorine, bromine, chlorine, iodine, alkyl- or aryl-sulfonyloxy groups such as trifluoromethanesulfonyl ester, mesylate or tosylate, silyloxy; acylamino or thioacylamino, such as acetamide (optionally substituted or protected at the amido-nitrogen atom); acyloxy, such as acetyl Oxygen; phosphonooxy, heterocyclylamino (optionally substituted or protected at the amino-nitrogen atom), for example isoxazol-3-ylamino or 1,2,5-thiadiazol-3-ylamino ; a heterocyclic group attached through nitrogen (optionally substituted on a carbon atom not adjacent to the ring atom attached to the nitrogen), such as optionally 4-substituted 1,2,3-triazol-1-yl; or amidino, such as 1-(N-cyanoimino)ethylamino; such conversion of the hydroxyl group can be done directly (for example by acylation or Mitsunobu reaction) or by one or more intermediate derivatives (for example mesylate or azide Nitride) conversion;

A siloxy group can be converted into a hydroxyl group or into a group accessible from a hydroxyl group (directly or via an intermediate hydroxyl group);

The ketone group can be converted into hydroxyl, thiocarbonyl, oxime or difluoro;

A nitro group can be converted to an amino group, and thus to any common amine derivative, such as an acylamino group (such as an acetamido group), by methods well known in the art;

2-, 4- or 6-pyridyl or 2-, 4- or 6-pyrimidinyl halide such as chloride or sulfonate (e.g. mesylate) substituents can be converted to alkoxy, alkylthio, Amino, alkylamino, dialkylamino or N-linked heterocyclic substituents;

In addition, optionally substituted heteroaromatic rings D or E can be modified by introducing new substituents ( _R2a , _R3a or _R6a ) or refunctionalizing existing substituents ( _R2a , _R3a or R ₆ a) into other heteroaromatic rings D or E

Heterocyclylamino groups (optionally substituted or protected at the amino-nitrogen atom) can be converted into other heterocyclylamino groups (optionally substituted or protected at the amino-nitrogen atom) by refunctionalization (e.g. protection or de-protection) protection) amino-nitrogen atom, introduction of new ring substituents or refunctionalization of existing ring substituents;

Heterocyclyls linked through nitrogen (optionally substituted on carbon atoms not adjacent to the nitrogen ring atom) can be converted to other heterocyclyls linked through nitrogen (optionally substituted on carbon atoms not adjacent to the nitrogen ring atom) by Substitution on): introduction of new ring substituents or refunctionalization of existing ring substituents, e.g. modification of the 4-substituent of a 4-substituted 1,2,3-triazol-1-yl;

For example, the following scheme illustrates the conversion of a hydroxy group to an optionally substituted triazolyl group:

Methods (h), (i) and (j) illustrate a regioselective approach under very mild conditions;

b) Molecules of compounds of formula (IIa) [wherein X is a leaving group for palladium coupling (e.g. chloride, bromide, iodide, trifluoromethanesulfonyloxy, trimethylstannyl, trimethylstannyl, alkoxysilyl or boronic acid residue) and in this case A is N or CR ₃ a] with a compound molecule of formula (IIb) where X' is a leaving group for palladium coupling, such as chloride , bromide, iodide, trifluoromethanesulfonyloxy, trimethylstannyl, trialkoxysilyl, or boronic acid residue) reaction, wherein X and X' are selected such that the aryl-aryl , heteroaryl-aryl or heteroaryl-heteroaryl linkages in place of aryl-X (or heteroaryl-X) and aryl-X' (or heteroaryl-X') linkages. Such methods are now well known, see for example JKStille, AngewChem.Int.Ed.Eng., 1986, 25, 509-524; .Baranano, G.Mann, and JF Hartwig, Current Org.Chem., 1997, 1, 287-305, SP Stanforth, Tetrahedron, 541998, 263-303; PRParry, C. Wang, AS Batsanov, MRBryce, and B. Tarbit, J . Org. Chem., 2002, 67, 7541-7543;

The leaving groups X and X' can be selected from different groups and produce the desired cross-linked product of formula (I);

For example

用作方法(b)的试剂或者用于制备方法(b)试剂的中间体所需的吡啶、嘧啶和芳基噁唑烷酮可通过标准有机方法制备，例如通过在方法部分(c)-(j)介绍的类似方法制备，本领域公知基团X和X’的引入和互变的方法；

The pyridines, pyrimidines and aryl oxazolidinones required for use as reagents in process (b) or as intermediates for the preparation of reagents in process (b) can be prepared by standard organic methods, for example by means of methods in parts (c)-( j) Preparation by a method similar to the introduction, methods of introduction and interconversion of groups X and X' well known in the art;

c) reacting a heterobiaryl derivative carbamate of formula (III) with a suitably substituted oxirane to form an oxazolidinone ring;

Variations of this method are known in the art, wherein the carbamate is replaced by an isocyanate or by an amine, or/and wherein the oxirane is replaced by the equivalent reagent X—CH ₂ CH (O-optionally protected) CH ₂ R ₁ b (wherein X is a displaceable group) displacement.

For example

(d) reacting a compound of formula (VI) with a compound of formula (VII):

where X is a displaceable substituent - such as chloride, bromide, iodide, trifluoromethanesulfonyloxy, trimethylstannyl, trialkoxysilyl, or a boronic acid residue, of the formula (VII):

T-X’

(VII)

wherein T-X' is HET3 as defined above and X' is a displaceable C-linked substituent - for example chloride, bromide, iodide, trifluoromethanesulfonyloxy, trimethylstannyl, trimethylstannyl, Alkoxysilyl or boronic acid residues; wherein said substituents X and X' are selected from complementary pairs of substituents known in the art to be suitable as complementary reactants for coupling reactions using a transition metal such as palladium (0 )catalytic;

(d(i)) reacting a compound of formula (VIII) with a compound of formula (IX) via a transition metal such as palladium (0):

where X is a displaceable substituent - such as chloride, bromide, iodide, trifluoromethanesulfonyloxy, trimethylstannyl, trialkoxysilyl, or a boronic acid residue; the formula (IX) (Tetrahedron Letts., 2001, 42(22), 3681-3684);

(d(ii)) reacting a compound of formula (X) with a compound of formula (XI):

X is a displaceable substituent - for example chloride, bromide, iodide, trifluoromethanesulfonyloxy, the following is formula (XI):

T-H

(XI)

where TH is an amine R ₇ R ₈ NH, an alcohol R ₁₀ OH or an azole containing an effective ring -NH moiety, yields compounds (XIIa), (XIIb) or (XIIc), where in this case A is nitrogen or CR ₃ a and A' is nitrogen or carbon optionally substituted by one or more groups Rla;

(e) reacting a compound of formula (XIII) with a compound of formula (XIV):

Wherein X ₁ and X ₂ are independently optionally substituted heteroatom combinations selected from O, N and S, such that C(X ₁ )X ₂ constitutes a carboxylic acid derivatized substituent, the following is formula (XIV), wherein X ₃ and _X is an independently optionally substituted heteroatom combination selected from O, N and S:

One of C(X ₁ )X ₂ and C(X ₃ )X ₄ constitutes an optionally substituted hydrazide, thiohydrazide or amidrazone, hydroximidate or hydroxamidine, and C( The other of X ₁ )X ₂ and C(X ₃ )X ₄ constitutes an optionally substituted acylating agent, thioacylating agent or imidoacylating agent, such that C(X ₁ )X ₂ and C(X ₃ ) _X can be fused together by methods well known in the art to form a 1,2,4-heteroatom 5-membered heterocycle comprising 3 combinations of heteroatoms selected from O, N and S, such as thiadiazole;

(e(i)) reacting a compound of formula (XV) with a source of an azide anion such as sodium azide:

where _X is a displaceable group such as ethoxy or diphenylphosphonooxy to give tetrazole (XVI)

Or the nitrile of formula (XVII)

Can be reacted directly with an azide such as ammonium azide or trialkylstannyl azide to give the tetrazole (XVI, Rla=H), followed by alkylation with the group Rla≠H to give the tetrazole (XVIIIa ) and (XVIIIb);

(f) a compound of formula (XIX):

Reaction with compounds of formula (XX):

One of C(X ₅ )X ₆ and C(X ₇ )X ₈ constitutes an optionally substituted α-(leaving group substituted) ketone, where the leaving group is, for example, halo or (alkyl or aryl) -sulfonyloxy-, and the other of C(X ₅ )X ₆ and C(X ₇ )X ₈ constitutes an optionally substituted amide, thioamide or amidine, such that C(X ₅ )X ₆ and C( X ₇ ) X ₈ can be fused together by methods well known in the art to form a 1,3-heteroatom 5-membered heterocycle comprising 2 heteroatoms selected from O, N and S, such as thiazole;

(g) Compounds of formula (I) in which HET is an optionally substituted 1,2,3-triazole can be prepared by cycloaddition of an azide (where, for example, Y in (II) is azido) to acetylene or acetylene equivalents such as optionally substituted cyclohexa-1,4-diene or optionally substituted ethylene bearing removable substituents such as arylsulfonyl;

(h) Compounds of formula (I) in which HET is a 4-substituted 1,2,3-triazole can be prepared by reacting an aminomethyloxazolidinone with a 1,1-dihaloketonesulfonylhydrazone (Sakai , Kunihazu; Hida, Nobuko; Kondo, Kiyosi; Bull.Chem.Soc.Jpn., 59, 1986, 179-183; Sakai, Kunikazu; Tsunemoto, Daiei; Kobori, Takeo; Kondo, Kiyoshi; 19840328);

(i) Compounds of formula (I) in which HET is a 4-substituted 1,2,3-triazole can also be prepared by reacting an azidomethyloxazolidinone with a terminal alkyne catalyzed by Cu(I), The reaction is carried out, for example, in aqueous alcoholic solution at room temperature to obtain 4-substituted 1,2,3-triazoles (V.V.Rostovtsev, L.G.Green, V.V.Fokin, and K.B.Sharpless, Angew.Chem.Int.Ed., 2002, 41, 2596-2599);

(j) It is also possible to prepare the compound of formula (I) in which HET is 4-halogenated 1,2,3-triazole: make azidomethyloxazolidinone at 0°C-100°C with halogenated vinyl The sulfonyl chloride reaction, which can be carried out without diluent or in an inert diluent such as chlorobenzene, chloroform or dioxane.

The literature discloses similar cycloadditions to compounds shown in (j) using unrelated azides to obtain unrelated triazoles, the halogen being bromine in the vinylsulfonyl chloride reagent mentioned above (CS Rondestvedt, Jr. and PK Chang, J .Amer.Chem.Soc., 77,1955,6532-6540; Preparation of 1-bromo-1-ethylenesulfonate by the method described by CS Rondestvedt, Jr., J.Amer.Chem.Soc., 76,1954,1926-1929 acid chloride). However, the reaction of vinylsulfonyl chloride cannot be terminated at the point of obtaining the desired product with formation of undesired by-products. Additionally, there is no disclosure in the literature of how to control the reaction elements that form the unwanted triazole by elimination of the H-halogen component with the intermediate cycloadduct or form the desired triazole with the elimination of the HCl and _SO2 components with the intermediate cycloadduct. of triazoles.

We have surprisingly found that when the halogen is chlorine, i.e. when the reagent is the compound 1-chloro-1-ethylenesulfonyl chloride,

The cycloaddition reaction is highly regioselective, leading to high yields of the desired product. In addition, the reagent 1-chloro-1-ethylenesulfonyl chloride is a new compound. Accordingly, a further aspect of the present invention includes the compound 1-chloro-1-ethylenesulfonyl chloride. A further aspect of the invention includes the use of 1-chloro-1-ethylenesulfonyl chloride with azide in a cycloaddition reaction to form 4-chloro-1,2,3-triazole. Another aspect of the present invention includes 1-chloro-1-ethylenesulfonyl chloride and azide derivatives in the process to form a compound of formula (I) (wherein R ₁ b is 4-chloro-1,2,3-triazole, and R4 is the use of 4-chloro-HET3-AB).

1-Chloro-1-ethylenesulfonyl chloride and azide derivatives are used in the scheme to form compounds of formula (I) (wherein R ₁ b is 4-chloro-1,2,3-triazole and or R ₄ is 4- The cycloaddition reaction of chloro-HET3-AB) is carried out at 0°C-100°C (preferably room temperature), and the reaction can be carried out in an inert solvent (preferably chlorobenzene, chloroform or dioxane) or more preferably without solvent .

One of ordinary skill in organic chemistry can use standard techniques to remove any protecting groups to form pharmaceutically acceptable salts and/or to form in vivo hydrolyzable esters. In addition, specific details of steps such as preparation of prodrugs of in vivo hydrolyzable esters are found above in relation to such esters.

When an optically active form of a compound of the invention is desired, it can be obtained by one or more methods using an optically active starting material (e.g., by asymmetric induction of an appropriate reaction step), or by standard methods of resolution of the racemic compound or intermediate. Obtained in the rotatory form, or by chromatographic separation of the diastereoisomers, if produced. Enzymatic techniques can also be used to prepare optically active compounds and/or intermediates.

Similarly, when a pure positional isomer of a compound of the invention is desired, it may be obtained using the pure positional isomer as starting material by more than one method, or by resolution of a mixture of positional isomers or intermediates by standard methods.

According to yet another feature of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt or in vivo hydrolyzable ester thereof for use in a method of treatment of the human or animal body.

According to yet another feature of the invention, the invention provides a method of producing an antibacterial effect in a warm-blooded animal (such as a human) in need of such treatment, the method comprising administering to said animal an effective amount of a compound of the invention or a pharmaceutically acceptable Accepted salts or in vivo hydrolyzable esters.

The present invention also provides a compound of the present invention or a pharmaceutically acceptable salt or an in vivo hydrolyzable ester thereof for use as a medicament; Use in medicine to produce antibacterial effects in blood animals (such as humans).

In order to use the compounds of the present invention, their in vivo hydrolyzable esters or pharmaceutically acceptable salts, including the pharmaceutically acceptable salts of in vivo hydrolyzable esters (hereinafter referred to as "compounds of the present invention" in the section relating to pharmaceutical compositions) ”) for use in the therapeutic (including prophylactic) treatment of mammals (including man), especially in the treatment of infections, are generally formulated as pharmaceutical compositions in accordance with standard pharmaceutical practice.

Thus in another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, an in vivo hydrolyzable ester or a pharmaceutically acceptable salt thereof (including a pharmaceutically acceptable salt of an in vivo hydrolyzable ester) and Pharmaceutically acceptable diluent or carrier.

The composition of the present invention can be a dosage form suitable for the following modes of administration: oral administration (such as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups) or elixirs), topical (such as creams, ointments, gels, or aqueous or oily solutions or suspensions), ophthalmic (drops), inhalation (such as fine powder or liquid aerosol ), insufflation (e.g. fine powder) or parenteral (e.g. sterile aqueous or oily solution for intravenous, subcutaneous, sublingual, intramuscular or intramuscular administration), or rectal suppositories.

In addition to the compounds of the present invention, the pharmaceutical composition of the present invention may also contain (i.e. by co-formulation) or co-administer (simultaneously, sequentially or separately) one or more known drugs selected from other clinically effective Antimicrobials (eg, beta-lactams, macrolides, quinolones, or aminoglycosides) and/or other anti-infectives (eg, antifungal triazoles or amphotericins). These drugs may include carbapenems (such as meropenem or imipenem) for added efficacy. Compounds of the invention may also be co-formulated or co-administered with bactericidal/permeability-increasing protein (BPI) products or efflux pump inhibitors to improve activity against Gram-negative bacteria as well as antimicrobial-resistant bacteria. The compounds of the invention may also be formulated or co-administered with vitamins (eg, B vitamins, such as vitamin B2, vitamin B6, vitamin B12, and folic acid). The compounds of the invention may also be formulated or administered in combination with cyclooxygenase (COX) inhibitors, especially COX-2 inhibitors.

In one aspect of the invention, the compounds of the invention are formulated in combination with an antibacterial agent effective against Gram-positive bacteria.

In yet another aspect of the invention, the compounds of the invention are formulated in combination with an antibacterial drug effective against Gram-negative bacteria.

In yet another aspect of the invention, the compounds of the invention are administered in combination with an antibacterial drug effective against Gram-positive bacteria.

In yet another aspect of the invention, the compounds of the invention are administered in combination with an antibacterial agent effective against Gram-negative bacteria.

The compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients, which are well known in the art. Thus, compositions for oral administration may contain, for example, one or more colouring, sweetening, flavoring and/or preservative agents. Pharmaceutical compositions for intravenous administration may advantageously (eg, enhance stability) contain suitable bactericides, antioxidants, reducing agents or suitable chelating agents.

For tablet formulation, suitable pharmaceutically acceptable excipients include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as cornstarch or alginic acid ); binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl paraben; and antioxidants such as ascorbic acid. The tablets may be uncoated, or coated to improve their disintegration in the gastrointestinal tract and subsequent absorption of the active ingredient, or to improve their stability and/or appearance, in either case, using conventional coatings agents and methods well known in the art.

Oral compositions can be in the form of hard gelatin capsules in which the active ingredient is admixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil).

Aqueous suspensions generally contain the active ingredient in finely divided powder form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, Tragacanth and gum arabic; dispersing or wetting agents such as lecithin or condensation products of alkylene oxides with fatty acids (for example polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (for example seventeen carbenyloxycetyl alcohol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g. polyoxyethylene sorbitan monooleate), condensation products of ethylene oxide with long-chain fatty alcohols (e.g. heptaceneoxycetyl alcohol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g. polyoxyethylene sorbitan monooleate), or ethylene oxide with polyoxyethylene derived from fatty acids and hexitol anhydrides Condensation products of partial esters (eg polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives (such as ethyl or propylparaben), antioxidants (such as ascorbic acid), coloring, flavoring and/or sweetening agents ( such as sucrose, saccharin, or aspartame).

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or mineral oil such as liquid paraffin. Oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those described above and flavoring agents may be added to provide a palatable oral preparation. Antioxidants such as ascorbic acid may be added to these compositions for preservation.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified above. Other excipients, for example sweetening, flavoring and coloring agents, may also be included.

The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture of any of the above oils. Suitable emulsifiers may be, for example, naturally occurring gums such as acacia or tragacanth, naturally occurring phospholipids such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate acid esters) and condensation products of said partial esters with ethylene oxide (e.g. polyoxyethylene sorbitan monooleate). The emulsions may also contain sweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical composition can also be a sterile injectable aqueous or oily suspension, which can be formulated according to known methods using one or more appropriate dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Solubility enhancers such as cyclodextrins can be used.

Compositions for inhalation administration may be conventional pressurized aerosols such that the active ingredient is dispersed as a mist containing finely divided solids or as small liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used, and aerosol devices are commonly used to dispense metered doses of active ingredients.

Further information on formulation can be found in Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.2, (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient which may be combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, preparations for oral administration to humans generally contain, for example, 50mg-5g of active drug and appropriate amounts of excipients, which may account for about 5-98% by weight of the entire composition. Unit dosage forms will generally contain from about 200 mg to about 2 g of active ingredient. Further information on routes of administration and dosage regimens can be found in Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.3, (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

A suitable pharmaceutical composition of the invention is a unit dosage form suitable for oral administration, eg a tablet or capsule comprising 1 mg to 1 g of a compound of the invention, preferably 100 mg to 1 g of the compound. Especially preferred are tablets or capsules comprising 50 mg to 800 mg, especially 100 mg to 500 mg, of a compound of the invention.

In another aspect, the pharmaceutical composition of the present invention is a composition suitable for intravenous, subcutaneous or intramuscular injection, for example comprising 0.1% w/v-50% w/v (1 mg/ml-500 mg/ml) of the present invention Injection of the compound.

Each patient can be administered the composition 1-4 times a day by, for example, intravenously, subcutaneously or intramuscularly injecting 0.5 mgkg ^-1 -20 mgkg ^-1 of the compound of the present invention per day. In another embodiment, 5 mgkg ^-1 to 20 mgkg ^-1 of a compound of the invention is administered daily. Intravenous, subcutaneous and intramuscular administration can be given by bolus injection. Alternatively, intravenous administration may be given by continuous infusion over a period of time. Alternatively, individual patients may receive a daily oral dosage approximately equivalent to the daily parenteral dosage, administered 1-4 times daily of the composition.

In the above other pharmaceutical compositions, processes, methods, uses and pharmaceutical preparation features, the alternative and preferred embodiments of the compounds of the invention presented here also apply.

Antibacterial activity :

The pharmaceutically acceptable compounds of the present invention are effective antibacterial drugs with good activity spectrum in vitro against standard Gram-positive microorganisms used for screening activity against pathogenic bacteria. The pharmaceutically acceptable compounds of the present invention show inter alia against Enterococcus, Pneumococcus, methicillin-resistant Staphylococcus aureus (S.aureus) and coagulase-negative Staphylococcus, and Haemophilus strains and Bacteria strains are active. The antimicrobial spectrum and potency of a particular compound can be tested using standard testing systems.

The (antibacterial) properties of the compounds of the invention can also be demonstrated and evaluated using routine tests in vivo, eg by administering the compounds orally and/or intravenously to warm-blooded mammals using standard techniques.

The following results were obtained with standard in vitro test systems. Activity was expressed as the minimum inhibitory concentration (MIC), which was measured at a seeding density of 10 ⁴ CFU/spot using the agar dilution technique. Typically, compounds have an activity in the range of 0.01-256 μg/ml.

Staphylococci were detected on the agar, using the standard test conditions for expressing methicillin resistance: inoculate 10 ⁴ CFU/point, inoculate at 37°C, and incubate for 24 hours.

Detect streptococcus and enterococcus on agar, add 5% defibrinated horse blood to the agar, inoculate 10 ⁴ CFU/point, cultivate at 37°C, 5% carbon dioxide atmosphere, 48 hours, the blood is part of the growth of the tested microorganisms required condition. Refractory Gram-negative microorganisms were tested in Mueller-Hinton medium supplemented with hemin and NAD, grown aerobically at 37°C for 24 hours, and seeded at 5 x ¹⁰⁴ CFU/well.

For example, the following are the test results of the compound of Example 1:

Microbial MIC(μg/ml)

Staphylococcus aureus: MSQS 0.25

                                                                                     

Streptococcus pneumoniae ＜0.06

Enterococcus faecium 0.25

Haemophilus influenzae 2

Moraxella catarrhalis 0.25

Streptococcus pneumoniae resistant to linezolid 0.5

MSQS = methicillin sensitive and quinolone sensitive

MRQR = resistance to methicillin and quinolones

Certain intermediates and/or reference examples described below within the scope of the present invention may also have potent activity and provide a further feature of the present invention.

The present invention is illustrated non-limitatively by the following examples, in which, unless otherwise stated:-

(i) Evaporation is accomplished by vacuum rotary evaporation, followed by subsequent processing steps after removal of residual solids by filtration;

(ii) Various operations are carried out at room temperature, usually 18-26°C, unless otherwise stated, or unless the skilled technician needs to operate under an inert atmosphere, there is no need to vent the air;

(iii) column chromatography (by flash operation) was used to purify the compounds and was performed on Merck Kieselgel silica (Art.9385) unless otherwise stated;

(iv) The yields given are for illustration purposes only and are not necessarily the maximum achievable yields;

(v) In general, the structure of the final product of the present invention is confirmed by NMR and mass spectrometry techniques [proton magnetic resonance spectroscopy is usually detected with DMSO-d ₆ unless otherwise stated, using a VarianGemini 2000 spectrometer operating at a field strength of 300 MHz, or using Bruker AM250 spectrometer, the operating field strength is 250MHz; the chemical shift is expressed as parts per million (δ scale) with tetramethylsilane as the internal standard, and the multiplicity of peaks is expressed as: s, single peak; d, double peak; AB or dd, double doublet; dt, double triplet; dm, double multit; t, triplet, m, multiplet; Micromass), electrospray, and collect cation or anion data when appropriate]; optical rotation was measured with a Perkin Elmer Polarimeter 341 at 589 nm at 20 ° C in 0.1 M methanol solution;

(vi) Each intermediate is purified to the standard required in subsequent stages and characterized with sufficient specific data to confirm that the assigned structure is correct; purity is checked by HPLC, TLC or NMR, and by infrared spectroscopy (IR), mass spectroscopy or NMR as required Spectrally identified compounds; NOE is Nuclear Polarization Effect;

(vii) where the following abbreviations may be used:-

DMF N, N-dimethylformamide; DMA N, N-dimethylacetamide; TLC thin-layer chromatography; HPLC high-pressure liquid chromatography; MPLC medium-pressure liquid chromatography; NMP N-methylpyrrolidone; DMSO Dimethyl sulfoxide; CDCl ₃ deuterated chloroform; MS mass spectrometry; ESP electrospray; EI electron impact; CI chemical ionization; APCI atmospheric pressure chemical ionization; EtOAc ethyl acetate; MeOH _methanol ; (O)-O-; Phosphorous Oxygen (HO) ₂ -PO-; Bleach "Clorox" 6.15% Sodium Hypochlorite; THF Tetrahydrofuran;

(viii) The temperature is °C.

Example 1: (5R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-5- (1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one

(5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidine-2- A mixture of ketone (370 mg, 0.95 mmol), dipivaleroyl diboron (605 mg, 2.4 mmol) and potassium acetate (326 mg, 3.3 mmol) was degassed in dimethylsulfoxide (5 mL), flushed with nitrogen and washed with dichloro[ 1,1']bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (69 mg, 10 mol%) was treated. The mixture was heated to 80°C for 1.5 hours, cooled to room temperature, filtered through celite and extracted with ethyl acetate. The organic phase was washed with aqueous ammonium chloride, dried over magnesium sulfate and evaporated to dryness. The non-volatile residue was purified by silica gel chromatography [eluting with hexane:ethyl acetate (3:2)] to obtain the mixture (5R)-3-(3-fluoro-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1 , 2-oxazolidin-2-one and the corresponding boronic acid (210 mg, ~0.54 mmol, 57%) were used without further purification.

The mixture of boronate and boronic acid prepared in the previous step, 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (160mg, 0.67mmol) and potassium carbonate (448mg, 3.24mmol ) in N,N-dimethylformamide and water (10 mL, 7:1), degassed, flushed with nitrogen, and treated with tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.054 mmol). The reaction mixture was heated at 80°C for 1.5 hours, cooled to room temperature, filtered through celite, extracted with ethyl acetate, dried over magnesium sulfate and evaporated to dryness. The non-volatile residue was purified by silica gel chromatography [eluting with ethyl acetate:hexane (3:2)] to obtain the product as a colorless amorphous (140 mg, 61%).

MS (ESP) : 422.47 (MH ⁺ ) C ₁₉ H ₁₆ FN ₉ O ₂

¹ H-NMR (DMSO-d ₆ ) δ: 3.98(dd, 1H); 4.31(dd, 1H); 4.47(s, 3H); 4.86(m, 2H); 5.18(m, 1H); 7.45(m , 1H); 7.61 (m, 1H); 7.74 (m, 1H); 7.77 (brs, 1H); 8.12-8.27 (m, 3H); 8.93 (s, 1H).

The intermediate of Example 1 was prepared as follows:

(5R)-3-(3-fluorophenyl)-1,3- oxazolidin-2-one-5-ylmethyl acetate

(5R)-3-(3-Fluorophenyl)-5-hydroxymethyl-1,3-oxazolidin-2-one (40 g, 0.189M, see Upjohn WO 94-13649) was stirred under nitrogen atmosphere Suspend in dry dichloromethane (400 mL). Triethylamine (21g, 0.208M) and 4-dimethylaminopyridine (0.6g, 4.9mM) were added, then acetic anhydride (20.3g, 0.199M) was added dropwise within 30 minutes, and stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate (250 mL) was added and the organic phase was separated, washed with 2% sodium dihydrogen phosphate, dried (magnesium sulfate), filtered and evaporated to give the desired product as an oil (49.6 g).

MS(ESP) : 254(MH ⁺ )C ₁₂ H ₁₂ FNO ₄

NMR(CDCl ₃ ) δ: 2.02(s, 3H); 3.84(dd, 1H); 4.16(t, 1H); 4.25(dd, 1H); 4.32(dd, 1H); 4.95(m, 1H); (td, 1H); 7.32(d, 1H); 7.43(t, 1H); 7.51(d, 1H).

(5R)-3-(3-fluoro-4-iodo-phenyl)-1,3- oxazolidin-2-one-5-ylmethyl acetate

(5R)-3-(3-fluoro-phenyl)-1,3-oxazolidin-2-on-5-ylmethyl acetate (15.2 g, 60 mM) was dissolved in the mixture chloroform ( 100mL) and acetonitrile (100mL), silver trifluoroacetate (16.96g, 77mM) was added. Iodine (18.07 g, 71 mM) was added portionwise to the vigorously stirred solution over 30 minutes and stirred at room temperature for 18 hours. When the reaction was not completed, silver trifluoroacetate (2.64 g, 12 mM) was added and stirred for 18 hours. After filtration, the mixture was added to sodium thiosulfate solution (3%, 200mL) and dichloromethane (200mL), the organic phase was separated, washed with sodium thiosulfate (200mL), saturated aqueous sodium bicarbonate (200mL), brine (200mL ), dried (magnesium sulfate), filtered and evaporated. The crude product was suspended in isohexane (100 mL), stirred for 1 hour while adding enough diethyl ether to dissolve the brown impurities. Filtration afforded the desired cream solid product (24.3g).

MS(ESP) : 380(MH ⁺ )C ₁₂ H ₁₁ FINO ₄

NMR (DMSO-d ₆ ) δ: 2.03(s, 3H); 3.82(dd, 1H); 4.15(t, 1H); 4.24(dd, 1H); 4.30(dd, 1H); 4.94(m, 1H) ; 7.19 (dd, 1H); 7.55 (dd, 1H); 7.84 (t, 1H).

(5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-1,3- oxazolidin-2-one

Acetate (5R)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one-5-ylmethyl ester (30g, 79mM) was dissolved in potassium carbonate (16.4 g, 0.119 mM) was treated in a mixture of methanol (800 mL) and dichloromethane (240 mL) for 25 minutes, then immediately neutralized by the addition of acetic acid (10 mL) and water (500 mL). The precipitate was filtered, washed with water and dissolved in dichloromethane (1.2 L). The solution was washed with saturated sodium bicarbonate solution and dried (magnesium sulfate). Filtration and evaporation gave the desired product (23g).

MS(ESP) : 338(MH ⁺ )C ₁₀ H ₉ FINO ₃

NMR (DMSO-d ₆ ) δ: 3.53(m, 1H); 3.67(m, 1H); 3.82(dd, 1H); 4.07(t, 1H); 4.70(m, 1H); 5.20(t, 1H) ; 7.21 (dd, 1H); 7.57 (dd, 1H); 7.81 (t, 1H).

(5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-1,3- oxazolidin-2-one

Methanesulfonyl chloride (17.9 mL) was added dropwise to (5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-1,3-oxazolidin-2-one under dry nitrogen atmosphere (55.8 g) and triethylamine (46.1 mL) were dissolved in dry dichloromethane (800 mL) with a stirred solution kept below room temperature in an ice bath. The stirred reaction mixture was allowed to warm to room temperature over 3 hours, washed sequentially with water and brine and _dried ( _Na2SO4 ). The solvent was removed under reduced pressure to afford the intermediate mesylate (68 g) as a yellow solid which was used without further purification.

A stirred solution of a mixture of the intermediate mesylate (68 g) and sodium azide (32.3 g) in DMF (800 mL) was heated at 75 °C overnight. The mixture was allowed to cool to room temperature, diluted with water and extracted twice with ethyl acetate. The combined extracts were washed successively with water and brine and _dried ( _Na2SO4 ). The solvent was removed under reduced pressure to obtain a yellow oil which was purified by silica gel column chromatography [eluting with ethyl acetate:hexane (1:1)] to obtain the azide product as a milky white solid (49 g). The product was further purified by trituration with ethyl acetate/hexanes.

¹ H-NMR (DMSO-d ₆ ) δ: 3.57-3.64 (dd, 1H); 3.70-3.77 (dd, 1H); 3.81-3.87 (dd, 1H); 4.06 (t, 1H); 4.78-4.84 ( m, 1H); 7.05-7.09 (ddd, 1H); 7.45 (dd, 1H); 7.68-7.74 (dd, 1H).

(5R)-3-(3-fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3- oxazolidin-2-one

The mixture (5R)-5-azidomethyl-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one (30g) and bicyclo[2.2.1] A stirred solution of heptadiene (30 mL) in dioxane (300 mL) was heated at reflux overnight. The mixture was allowed to cool to room temperature and evaporated to dryness under reduced pressure to obtain a tan solid. The brown solid was purified by column chromatography on silica gel [eluting with a gradient of 98:2-95:5 methanol:chloroform] to give the product triazole as a pale yellow solid (20 g). The product was further purified by trituration with dichloromethane/hexane (1:1) to obtain a milky white solid.

¹ H-NMR (DMSO-d ₆ ) δ: 3.86-3.92 (dd, 1H); 4.23 (t, 1H); 4.83 (d, 2H); 5.11-5.19 (m, 1H); 7.12-7.16 (dd, 1H); 7.47-7.51 (dd, 1H); 7.76 (s, 1H); 7.79-7.85 (dd, 1H); 8.16 (s, 1H).

3-Bromo-6-cyano-pyridine

A stirred solution of 2,5-dibromopyridine (39.465 g, 0.17 mol) in anhydrous NMP (100 mL) was treated with CuCN (14.42 g, 0.17 mol) at 110° C. for 20 hours under nitrogen atmosphere. The reaction mixture was cooled to 40 °C and treated sequentially with aqueous sodium hydroxide (2M; 200 mL) and ethyl acetate (200 mL). The mixture was stirred for 1 hour, then the resulting precipitate was removed by filtration through celite. The remaining solid was washed sequentially with aqueous sodium hydroxide (2M; 600 mL) and ethyl acetate (600 mL). The combined organic layers were washed with aqueous ammonium hydroxide (5M; 800 mL), dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The non-volatile residue was purified by silica gel chromatography [elution gradient 1% - 7% ethyl acetate/hexane] to obtain the title compound (8.538 g, 28%) as a colorless amorphous.

¹ H-NMR (DMSO-d ₆ ) (300 MHz) δ8.05 (d, 1H); 8.40 (dd, 1H); 8.95 (d, 1H).

5-Bromo-2-tetrazol-5-ylpyridine

3-Bromo-6-cyano-pyridine (2g, 10.9mmol), sodium azide (0.85g, 13mmol) and ammonium chloride (0.59g, 11mmol) in N,N dimethylformamide (20mL) The mixture in was heated at 120°C for 1 hour. The reaction mixture was diluted with ethyl acetate (-100 mL) and the product was isolated by filtration and washed with ethyl acetate to afford the title compound as an off-white amorphous which was used directly in the next step without further purification.

5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine and 5-bromo-2-(1-methyl-1H-tetrazol-5-yl)pyridine Pyridine

5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine and 5-bromo-2-(1-methyl-1H-tetrazol-5-yl)pyridine according to Dong A Pharmaceuticals ( WO 01/94342) prepared by the method introduced.

A mixture of 6.5 g of unpurified 5-bromo-2-tetrazol-5-ylpyridine [Dong AP Pharmaceuticals (WO 01/94342)] (~28 mmol) and sodium hydroxide (9 g, 125 mmol) in dry DMF was decompressed Evaporate to dryness. A stirred solution of the non-volatile residue dissolved in dry DMF (50 mL) was treated dropwise with iodomethane (3.0 mL, 48 mmol) at ice-bath temperature. The stirred reaction mixture was allowed to warm and then maintained at room temperature for 2 hours. The reaction mixture was partitioned between ice water and ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained was purified by silica gel chromatography [eluting with dichloromethane:ethyl acetate (60:1)] to obtain:

1. 5-Bromo-2-(1-methyl-1H-tetrazol-5-yl)pyridine (1.397g), colorless solid, (TLC: silica gel, hexane:ethyl acetate (4:1), Rf: 0.3), ¹ H-NMR (DMSO-d ₆ ) (300MHz)

δ: 4.38 (s, 3H); 8.17 (d, 1H); 8.35 (dd, 1H); 8.96 (d, 1H).

2. 5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (1.07 g), colorless solid, (TLC: silica gel, hexane:ethyl acetate (4:1), Rf: 0.1). ¹ H-NMR (DMSO-d ₆ ) (300MHz)

δ: 4.46 (s, 3H); 8.09 (d, 1H); 8.28 (dd, 1H); 8.88 (d, 1H). The structure was determined based on the nmr HMBC (Heteronuclear Multiple Bond Correlation) experiment, in which the long-range coupling of the _CH3 proton to the C5 of the tetrazole ring occurred at the 1-methyl-1H-isomer of Rf0.3, but not at the 2 of Rf0.1 -methyl-2H-isomer). Compound 5-bromo-2-(1-methyl-1H-tetrazol-5-yl)pyridine is therefore an isomer of Rf0.3 and compound 5-bromo-2-(2-methyl-2H-tetrazole -5-yl)pyridine is therefore an isomer of Rf0.1

Example 2: (5R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-5-( 4- Fluoromethyl-1H-1,2,3-triazol-1-ylmethyl)-13- oxazolidin-2-one

(5R)-3-(3-fluoro-4-iodophenyl)-5-(4-fluoromethyl-1H-1,2,3-triazol-1-ylmethyl)-1,3- A mixture of oxazolidin-2-one (1.5 g, 3.57 mmol), bisvaleryl diboron (2.26 g, 8.9 mmol) and potassium acetate (1.22 g, 12.5 mmol) in dimethyl sulfoxide (15 mL) was washed with di Chloro[1,1']bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (261 mg, 10 mol%) was treated and reacted as described in Example 1. The reaction mixture was purified by silica gel chromatography [eluting with hexane:ethyl acetate (3:2)] to obtain the compound containing the corresponding boronic acid and (5R)-3-(3-fluoro-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-fluoromethyl-1H-1,2,3-triazole-1 A mixture of -ylmethyl)-1,3-oxazolidin-2-ones (562 mg, ~37%) was pure enough to proceed to the next step.

A mixture of borate and boric acid (337mg, 0.8mmol) prepared in the previous step, 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (175mg, 0.73mmol) and potassium carbonate (504 mg, 3.65 mmol) in N,N-dimethylformamide:water (10 mL, 7:1) was treated with tetrakis(triphenylphosphine)palladium(0) (84 mg, 10 mol%) React as described in Example 1. The reaction mixture was purified by silica gel chromatography [eluting with ethyl acetate:hexane (1:2)] to obtain the product as a colorless amorphous (180 mg, 49%).

MS(ESP) : 454.45(MH ⁺ )

¹ H-NMR (DMSO-d ₆ ) δ: 3.98(dd, 1H); 4.32(dd, 1H); 4.47(s, 3H); 4.88(m, 2H); 5.19(m, 1H); , 2H, J _{H, F} 48Hz); 7.45(m, 1H); 7.63(m, 1H); 7.75(m, 1H); 8.15-8.24(m, 2H); 8.38(d, 1H); 8.93(s , 1H).

The intermediate of Example 2 was prepared as follows:

(5R)-3-(3-fluoro-4-iodophenyl)-5-(4-hydroxymethyl-1H-1,2,3-triazol-1-ylmethyl)-1,3- oxa oxazolidin-2-one

(5R)-3-(3-Fluoro-4-iodophenyl)-5-azidomethyl-1,3-oxazolidin-2-one (10 g, 28 mmol) and propargyl alcohol (3.2 mL , 56 mmol) in acetonitrile (80 mL) was treated with CuI (526 mg, 2.8 mmol) and stirred overnight. The solidified reaction mixture was extracted with ethyl acetate: acetonitrile, washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give the crude product (12.3 g, quantitative) sufficiently pure for use.

MS(ESP) : 41913(MH ⁺ )C ₁₃ H ₁₂ FIN ₄ O ₃

¹ H-NMR (DMSO-d ₆ ) δ: 3.88 (dd, 1H); 423 (dd, 1H); 451 (d, 2H); 4.80 (m, 2H); 5.14 (m, 1H); , 1H); 7.16(m, 1H); 7.51(m, 1H); 7.83(m, 1H); 8.01(d, 1H).

(5R)-3-(3-fluoro-4-iodophenyl)-5-(4-bromomethyl-1H-1,2,3-triazol-1-ylmethyl)-1,3-oxa oxazolidin -2-one

(5R)-3-(3-fluoro-4-iodophenyl)-5-(4-hydroxymethyl-1H-1,2,3-triazol-1-ylmethyl)-1,3- A stirred mixture of oxazolidin-2-one (14.7g, 35.1mmol) and carbon tetrabromide (12.16g, 36.7mmol) in dichloromethane (1L) was treated with triphenylphosphine (12.34g, 61.2 mmol) treatment. The reaction mixture was stirred at 0°C for 30 minutes and then at room temperature overnight. The reaction mixture was added to a silica gel column and eluted sequentially with hexane:ethyl acetate (1:1) and ethyl acetate:methanol (95:5). The obtained product was purified by recrystallization from ethyl acetate to obtain a colorless solid The title compound (14g).

MS (ESP) : 482.69 (MH ⁺ , Br ⁸¹ ) C ₁₃ H ₁₁ BrFIN ₄ O ₂

¹ H-NMR (DMSO-d ₆ ) δ: 3.87(dd, 1H); 4.23(dd, 1H); 4.74(s, 2H); 4.81(m, 2H); 5.12(m, 1H); 7.14(m , 1H); 7.49(m, 1H); 7.81(m, 1H); 8.22(d, 1H).

(5R)-3-(3-fluoro-4-iodophenyl)-5-[(4-fluoromethyl-1H-1,2,3-triazol-1-yl)methyl] oxazolidine- 2-keto

(5R)-3-(3-fluoro-4-iodophenyl)-5-(4-bromomethyl-1H-1,2,3-triazol-1-ylmethyl)-1,3- Oxazolidin-2-one (6.94g, 14.4mmol), potassium fluoride (4.19g, 72.1mmol) and 1-butyl-3-methylimidazolium tetrafluoroborate (18.4mL) in acetonitrile (250mL ) and water (1.5 mL) was heated to 90 °C overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness. The non-volatile residue was purified by silica gel chromatography [eluting with ethyl acetate] to obtain the title compound (2.7 g, 45%) as a milky white amorphous.

MS(ESP) : 421.34(MH ⁺ )C ₁₃ H ₁₁ F ₂ IN ₄ O ₂

¹ H-NMR (DMSO-d ₆ ) δ: 3.88 (dd, 1H); 4.23 (dd, 1H); 4.84 (m, 2H); 5.14 (m, 1H) _; 52 Hz); 7.14 (m, 1H); 7.49 (m, 1H); 7.81 (m, 1H); 8.34 (d, 1H).

Example 3: (5R)-3-(3-fluoro-4-(6-(2-methyl-2H-tetrazol-5-yl)pyridin-3-yl)phenyl)-5-( 4- Chloro-1H-1,2,3-triazol-1-ylmethyl)-1,3- oxazolidin-2-one

(5R)-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)- 5-(4-chloro-1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (300mg, 0.71mmol), 5-bromo-2-( 2-Methyl-2H-tetrazol-5-yl)pyridine (170 mg, 0.71 mmol) and sodium carbonate (226 mg, 2.13 mmol) in N,N-dimethylformamide:water (5 mL, 10:1) The mixture was degassed, flushed with nitrogen, and treated with tetrakis(triphenylphosphine)palladium(0) (82 mg, 10 mol%). The reaction mixture was heated at 70°C for 3 hours, cooled to room temperature and evaporated to dryness under reduced pressure. The non-volatile residue was purified by silica gel chromatography [eluting with dichloromethane:N,N-dimethylformamide (25:1-20:1)]. The product fraction was concentrated to a small volume (-3 mL) and treated with dichloromethane (5 mL) and hexane (15 mL) to precipitate the product as a colorless amorphous (229 mg, 71%).

MS (ESP) : 456.27 (MH ⁺ ) C ₁₉ H ₁₅ FN ₉ O ₂

¹ H-NMR (DMSO-d ₆ ) δ: 3.98(dd, 1H); 4.32(dd, 1H); 4.47(s, 3H); 4.86(m, 2H); 5.19(m, 1H); 7.46(m , 1H); 7.63 (m, 1H); 7.76 (m, 1H); 8.15-8.27 (m, 2H); 8.47 (s, 1H); 8.93 (s, 1H).

The intermediate of Example 3 was prepared as follows:

Ethylenesulfonyl chloride

A stirred solution of 2-chloroethanesulfonyl chloride (50 g, 0.307 mol) dissolved in dry diethyl ether (400 mL) was dissolved in 2,6-lutidine (42.2 mL, 0.36 mol) at -60°C to -50°C under nitrogen atmosphere. Treated in dry diethyl ether (60 mL) and then with dry diethyl ether (200 mL). The stirred reaction mixture was allowed to warm to room temperature, cooled to 0 °C and treated slowly with dilute aqueous sulfuric acid (1%; 125 mL). The ether phase was separated, washed with dilute aqueous sulfuric acid (1%; 125 mL) and brine (2 x 120 mL), dried over magnesium sulfate and concentrated under reduced pressure (500 mmHg) to give a crude oil which was purified by distillation to give ethylene sulfonate Acid chloride (C.S. Rondestveldt, J. Amer. Chem. Soc., 76, 1954, 1926) (24.6 g, 63%),

b.p. 27.2°C/0.2mmHg.

¹ H-nmr(CDCl ₃ )δ7.20 (dd, J=16.2 and 9.4Hz, 1H), 6.55 (dd, J=16.2 and 1.7Hz, 1H), 6.24 (dd, J=9.4 and 1.7Hz, 1H ).

1,2-Dichloroethanesulfonyl chloride

A stirred solution of chlorine in ethylenesulfonyl chloride (32 g, 0.25 mol) in carbon tetrachloride was irradiated at about room temperature (200 W lamp) for 5 hours. The reaction mixture was concentrated under reduced pressure (50 mmHg), and the non-volatile residue was fractionally distilled to obtain 1,2-dichloroethanesulfonyl chloride (Goldstein et al. Zh. Obshch. Khim., 28, 1958, 2107) (15, 5 g, 31 %), b.p.75°C/0.7mmHg.

¹ H-nmr(CDCl ₃ ) δ 5.29 (dd, J=8.9 and 3.3Hz, 1H), 4.40 (dd, J=12.4 and 3.3Hz, 1H), 3.97 (dd, J=12.4 and 8.9Hz, 1H ).

1-Chloro-1-ethylenesulfonyl chloride

A stirred solution of 1,2-dichloroethanesulfonyl chloride (14.54 g, 73.62 mmol) dissolved in dry diethyl ether (140 mL) was treated with 2,6-lutidine (10.30 mL, 88.34mmol) treatment. The stirred reaction mixture was allowed to warm to room temperature, cooled to 0 °C and treated slowly with dilute aqueous sulfuric acid (1%; 50 mL). The ether phase was separated, washed with diluted sulfuric acid aqueous solution (1%; 2×60mL) and brine (3×60mL), dried over magnesium sulfate and concentrated under reduced pressure (60mmHg), and the obtained oil was purified by distillation to obtain 1-chloro - 1-Ethylenesulfonyl chloride (7.2 g, 61%), b.p. 26°C/2 mmHg.

¹ H-nmr(CDCl ₃ ) δ 6.70 (d, J=3.8Hz, 1H) and 6.22 (d, J=3.8Hz, 1H).

(5R)-3-(3-fluoro-4-iodophenyl)-5-(4-chloro-1H-1,2,3-triazol-1-ylmethyl)-1,3- oxazolidine -2- one

(5R)-3-(3-fluoro-4-iodophenyl)-5-azidomethyl-1,3-oxazolidin-2-one (1g, 28mmol) and 1-chloro-1- A stirred mixture of ethylenesulfonyl chloride (1 g, 6.2 mmol) was heated in a pressure tube at 80°C for 1 hour. The reaction mixture was allowed to cool to room temperature, diluted with chloroform (15 mL), and heated at 80 °C for an additional 4 hours. The reaction mixture was allowed to cool to room temperature and the precipitate was collected by filtration and washed with a little dichloromethane to afford the title compound (725 mg, 62%) as a colorless amorphous.

MS(ESP) : 423.3(MH ⁺ )C ₁₂ H ₉ FIN ₄ O ₂

¹ H-NMR (DMSO-d ₆ ) δ: 3.89(dd, 1H); 4.22(dd, 1H); 4.82(m, 2H); 5.15(m, 1H); 7.15(m, 1H); 7.49(m , 1H); 7.82 (m, 1H); 8.44 (s, 1H).

(5R)-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5 - (4-Chloro-1H-1,2,3-triazol-1-ylmethyl)-1,3- oxazolidin-2-one

(5R)-3-(3-fluoro-4-iodophenyl)-5-(4-chloro-1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazole A mixture of alkan-2-ones (725 mg, 1.7 mmol), bisvaleryl diboron (1.09 g, 4.3 mmol) and potassium acetate (590 mg, 6 mmol) in dimethyl sulfoxide (10 mL) was treated with dichloro[1,1 '] Bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (90 mg, 0.11 mmol) and reacted as described in Example 1. After 45 minutes, the reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate and washed with aqueous ammonium chloride. The aqueous layer was extracted twice with ethyl acetate, the combined organic layers were washed with water, dried over sodium sulfate and evaporated to dryness. The non-volatile residue was purified by silica gel chromatography [eluting with hexane:acetone (2:1)] and further purified by precipitation with dichloromethane and hexane to give the product as a colorless amorphous (590 mg, 81%), It was pure enough for the next reaction.

MS(ESP) : 423(MH ⁺ )C ₁₈ H ₂₁ BFN ₄ O ₄

¹ H-NMR (DMSO-d ₆ ) δ: 1.28(s, 12H); 3.92(dd, 1H); 4.24(dd, 1H); 4.83(m, 2H); 5.16(m, 1H); 7.30(m , 1H); 7.39(m, 1H); 7.63(m, 1H); 8.45(s, 1H).

Example 4: (5R)-3-{3-fluoro-4-[6-(2-methyl-2H-tetrazol-5-yl)-1-oxypyridin-3-yl] phenyl}-5 -(1H-1,2,3-triazol-1-ylmethyl)-1,3- oxazolidin-2-one

5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (175 mg, 0.73 mM) and 3-chloroperbenzoic acid (nominal wet weight, 70%: 0.50 g, 2.05 mM ) was dissolved in 1,2-dichloroethane (5ml) and heated at 80°C for 1.5 hours. The mixture was directly purified by silica gel chromatography, eluting with 25% acetonitrile/dichloromethane. 5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine 1-oxide (165 mg) was thus obtained as a white solid. This material was homogeneous by tlc analysis and it was used directly in the next step without further characterization or purification.

The above sample oxidized pyridine and (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (335mg, 0.86mMol, prepared as in Example 1), Potassium carbonate (400mg, 2.9mMol) and tetrakis(triphenylphosphino)palladium(0) (80mg, 0.07mMol) were combined and suspended in THF (10ml) and water (1ml). The mixture was heated at 75°C for 2 hours and diluted with water. The solid precipitated on the filter was collected, rinsed with water, diethyl ether and 1:1 dichloromethane:hexane, and dried in vacuo to give pure product as an off-white solid, 134 mg.

MS (electrospray): 438(M+1)C ₁₉ H ₁₆ FN ₉ O ₃

¹ H-NMR (300MHz, DMSO-d ₆ ) δ: 3.97(dd, 1H); 4.30(t, 1H); 4.49(s, 3H); 4.86(d, 2H); 5.19(m, 1H); 7.43 (dd, 1H); 7.61(dd, 1H); 7.68(dd, 1H); 7.77(t, 2H); 8.06(d, 1H); 8.18(s, 1H); 8.68(s, 1H).

Example 5: (5R)-3-[3-fluoro-4-[6-(2-(2-hydroxyethyl)-2H-1,2,3,4-tetrazol-5-yl)-3 -pyridyl ]phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl) oxazolidin-2-one

2-[5-(5-Bromopyridin-2-yl)-2H-tetrazol-2-yl]ethanol (167 mg, 0.62 mmol), (5R)-3-[3-fluoro-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-[(1H-1,2,3-triazol-1-yl) Methyl]oxazolidin-2-one (240mg, 0.62mmol) and sodium carbonate (262mg, 2.47mmol) were dissolved/suspended in N,N-dimethylformamide/water (5ml, 10:1). It was degassed, flushed with nitrogen and tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.061 mmol) was added. Heated at 70°C for 3 hours, cooled to room temperature, and evaporated the solvent. Purification by silica gel chromatography (dichloromethane/DMF (20:1)) afforded the desired product (198 mg, 71%) as a colorless solid.

MS (ESP) : 452.18 (MH ⁺ ) C ₂₀ H ₁₈ FN ₉ O ₃

¹ H-NMR (DMSO-d ₆ ) δ: 3.97 (m, 3H); 4.31 (dd, 1H); 4.70-4.90 (m, 4H); 5.05-5.25 (m, 2H); 4H); 8.15-8.30 (m, 3H); 8.93 (s, 1H).

The intermediate of Example 5 was prepared as follows:

(5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- [ (1H-1,2,3-triazol-1-yl)methyl] oxazolidin-2-one

(with embodiment 1)

2-[5-(5-Bromopyridin-2-yl)-2H-tetrazol-2-yl]ethanol

Dissolve/suspend 5-bromo-2-(2H-tetrazol-5-yl)pyridine (WO 0194342 A1) (1.2g, 5.3mmol) in 1-propanol (15ml), add potassium hydroxide (250mg, 4.5 mmol) in 1-propanol (15 ml), which was heated at 80°C for 1 hour. Add 2-bromoethanol (0.344ml, 4.8mmol) and reflux for 1 day. Further potassium hydroxide (270mg) and 2-bromoethanol (0.35ml) were added and the mixture was heated at reflux for a further 4 hours. Potassium hydroxide and 2-bromoethanol were added again and the mixture was refluxed for 14 hours. The reaction mixture was filtered through a 0.45 μM membrane, and the filter cake was washed with ethanol and dichloromethane. Purification by silica gel chromatography (hexane/ethyl acetate 1:1-ethyl acetate) afforded the title compound (0.342 g, 24%) and the corresponding 1H-tetrazole positional isomer (0.225 g).

¹ H-NMR (DMSO-d ₆ ) δ: 3.90-4.02 (dt, 2H); 4.78 (t, 2H); 5.091H); 8.10 (m, 1H); 8.27 (dd, 1H); 1H).

HMBC NMR experiments of the 1H-tetrazole isomers determined the structures of the positional isomers.

Example 6: (5R)-3-[3-fluoro-4-[6-(1-(propane-1,3-diol-2-yl)-1H-1,2,3,4-tetrazole -5 -yl)-3-pyridyl]phenyl]-5-[(4-fluoromethyl-1H-1,2,3-triazol-1-yl)methyl]oxazolidin - 2-one

2-[5-(5-Bromopyridin-2-yl)-1H-tetrazol-1-yl]propane-1,3-diol (170mg, 0.57mmol), (5R)-3-[3- Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-[(1H-1,2,3- Triazol-1-yl)methyl]oxazolidin-2-one (220mg, 0.57mmol) and sodium carbonate (240mg, 2.27mmol) were dissolved/suspended in N,N-dimethylformamide/water (5mL , 10:1). It was degassed, flushed with nitrogen and tetrakis(triphenylphosphine)palladium(0) (65 mg, 0.056 mmol) was added. Heated at 70°C for 3 hours, cooled to room temperature, and evaporated the solvent. Purification by silica gel chromatography (dichloromethane/DMF (20:1)) afforded 189 mg (69%) of the product as a colorless solid.

MS (ESP) : 482.17 (MH ⁺ ) C ₂₀ H ₁₈ FN ₉ O ₃

¹ H-NMR (DMSO-d ₆ ) δ: 3.85-4.00 (m, 5H); 4.31 (dd, 1H); 4.86 (m, 2H); 5.03 (dd, 2H); 5.19 (m, 1H); 5.84 (m, 1H); 7.46(dd, 1H); 7.62(dd, 1H); 7.73-7.82(m, 2H); 8.19(s, 1H); 8.22-8.35(m, 2H); 8.98(s, 1H ).

The intermediate of Example 6 was prepared as follows:

2-[5-(5-Bromopyridin-2-yl)-1H-tetrazol-1-yl]propane-1,3-diol

5-Bromo-2-(2H-tetrazol-5-yl)pyridine (0.56 g, 2.5 mmol) (WO 0194342 Al, preparation of free acid: material prepared according to the method described in WO 0194342 Al (1 g) was dissolved in Hot water (70mL, 90°C); then add HCl (aqueous solution, 1M, 4mL) and cool to room temperature, collect the precipitated free acid by filtration, wash with water and dry under high vacuum to obtain 0.56g free acid), triphenylphosphine ( 0.65g, 2.5mmol) and 1,3-bis-(tert-butyl-dimethyl-silyloxy)-propan-2-ol (0.79g, 2.5mmol) (D.P.Curran and J.-C.Chao , Synth.Commun.20, No 22, 1990, 3575-3584) dissolved/suspended in dry THF (25mL), cooled to 0°C and added diisopropyl azodicarboxylate (0.49mL, 2.5mmol) , and the reaction mixture was allowed to warm to room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate (30:1)) to obtain a mixture of di-silyl ether title compound and the corresponding 2H-tetrazole positional isomer (809 mg) . The mixture was dissolved in dry THF (10 mL), cooled to 0 °C and tetrabutylammonium fluoride (1M in THF, 5 mL, 5 mmol) was added dropwise. After 1 hour the solvent was evaporated and the residue was purified by silica gel chromatography (dichloromethane/acetone (3:1-2:1)) to obtain the title compound (318 mg) and the corresponding regioisomeric 2H-substituted tetrazole (69 mg ). NOE-NMR experiment confirmed the structure of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ: 3.80-3.95 (m, 4H); 5.01 (t, 2H); 5.69 (m, 1H); 8.14 (m, 1H); 8.35 (m, 1H); 8.94 (m, 1H).

Example 7: (5R)-5-{[4-(difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-3-{3-fluoro-4- [ 6-(2-Methyl-2H-tetrazol-5-yl)pyridin-3-yl]phenyl}-1,3- oxazolidin-2-one

(5R)-5-{[4-(Difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-3-[3-fluoro-4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-oxazolidin-2-one (0.25g, 0.586mmol) Dissolve with 5-bromo-[2-(2-methyl-2H-1,2,3,4-tetrazol-5-yl)]pyridine (155mg, 0.645mmol) and potassium carbonate (404mg, 2.93mmol) In/suspended in N,N-dimethylformamide/water (10mL, 7:1), using tetrakis(triphenylphosphine)palladium(0)(67mg, 10mol%) as catalyst, react as described in Example 1 . Purification by silica gel chromatography (ethyl acetate/hexane (1:2)) afforded 200 mg of the product as a colorless amorphous.

MS (ESP) : 472.15 (MH ⁺ ) C ₂₀ H ₁₆ F ₃ N ₉ O ₂

¹ H-NMR (DMSO-d ₆ ) δ: 3.98(dd, 1H); 4.32(dd, 1H); 4.47(s, 3H); 4.88(d, 2H); 5.22(m, 1H); 7.05～7.42 (t, br, 1H); 7.46(m, 1H); 7.60(m, 1H); 7.75(m, 1H); 8.15-8.24(m, 2H); 8.65(s, 1H); 8.93(s, 1H ).

The intermediate of Example 7 was prepared as follows:

(5R)-5-{[4-(Difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-3-[3-fluoro-4-(4,4, 5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3- oxazolidin-2-one

(5R)-5-{[4-(Difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-3-(3-fluoro-4-iodophenyl) -1,3-oxazolidin-2-one (2.56g, 5.84mmol), bis-valeryl diboron (3.71g, 14.6mmol), potassium acetate (2.0g, 20.44mmol) and 1,1'-[two (Diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.427g, 0.584mmol) was suspended in DMSO (10ml). The mixture was heated at 80°C for 90 minutes to obtain a clear black solution. After cooling to room temperature, ethyl acetate (150ml) was added, the mixture was filtered through celite, washed with saturated brine solution (2×100ml), dried over sodium sulfate and concentrated to dryness. The dark residue was dissolved in dichloromethane (20ml), then hexane (100ml) was added slowly, the resulting precipitate was filtered and washed with 5% dichloromethane/hexane to collect the desired product (1.73g), which was used directly as The intermediate was used without further purification.

¹ H-NMR (DMSO-d ₆ ) δ: 1.12 (s, 12H); 3.88 (dd, 1H); 4.23 (dd, 1H); 4.84 (m, 2H); 5.14 (m, 1H); (t, br, 1H); 7.14(m, 1H); 7.28(m, 1H); 7.51(m, 1H); 8.45(s, 1H).

(5R)-5-{[4-(Difluoromethyl)-1H-1,2,3-triazol-1-yl]methyl}-3-(3-fluoro-4-iodophenyl)- 1,3- oxazolidin-2-one

1-{[(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-1H-1,2, 3-Triazole-4-carbaldehyde (3.6g, 8.65mmol) and [bis(2-methoxyethyl)amino]-sulfur trifluoride (2.3g, 10.38mmol) in dry dichloromethane (20ml) After mixing, ethanol (20ul) was added, and the reaction mixture was refluxed for 14 hours, cooled to room temperature, washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The concentrated crude sample was purified by column chromatography eluting with hexane/ethyl acetate (1.5:1) to obtain the title compound (2.58 g).

MS(ESP) : 439.02(MH ⁺ )C ₁₃ H ₁₀ F ₃ IN ₄ O ₂

¹ H-NMR (DMSO-d ₆ ) δ: 4.02(dd, 1H); 4.40(dd, 1H); 5.03(d, 2H); 5.30(m, 1H); 7.15～7.53(t, br, 1H) 7.28 (dd, 1H); 7.6 (dd, 1H); 7.95 (t, 1H); 8.70 (s, 1H).

1-{[(5R)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}-1H-1,2,3 -three Azole-4-carbaldehyde

(5R)-3-(3-fluoro-4-iodophenyl)-5-[(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)methyl]oxazolidine -2-Kone (5.7g, 13.6mmol) and manganese oxide (3.56g, 40.9mmol) were mixed, heated to 100°C in dry 1,4-dioxane for 48 hours, then the mixture was cooled to 70°C , filtered through celite. The filtrate was concentrated, dissolved in 5% methanol/dichloromethane, added with hexane, and the resulting precipitate was filtered to collect the title compound (3.6 g).

MS (ESP) : 416.91 (MH ⁺ ) C ₁₃ H ₁₀ FIN ₄ O ₃

¹ H-NMR (DMSO-d ₆ ) δ: 3.87(m, 1H); 4.18(dd, 1H); 4.85(d, 2H); 5.15(m, 1H); 7.12(d, 1H); 7.42(d , 1H); 7.8(dd, 1H); 8.88(s, 1H); 10.01(s, 1H).

(5R)-3-(3-fluoro-4-iodophenyl)-5-[(4-hydroxymethyl-1H-1,2,3-triazol-1-yl)methyl ] oxazolidine- 2-keto

(5R)-3-(3-Fluoro-4-iodophenyl)-5-(azidomethyl)oxazolidin-2-one (10 g, 28 mmol) was dissolved in acetonitrile (80 mL). Propargyl alcohol (3.2 mL, 56 mmol) and CuI (526 mg, 2.8 mmol) were added sequentially and stirred overnight. The solidified reaction mixture was extracted with ethyl acetate/acetonitrile, washed with water and dried over magnesium sulfate. The solvent was evaporated in vacuo to obtain 12.3 g of crude product (quantitative).

MS(ESP) : 419.13(MH ⁺ )C ₁₃ H ₁₂ FIN ₄ O ₃

¹ H-NMR (DMSO-d ₆ ) δ: 3.88 (dd, 1H); 4.23 (dd, 1H); 4.51 (d, 2H); 4.80 (m, 2H); 5.14 (m, 1H); , 1H); 7.16(m, 1H); 7.51(m, 1H); 7.83(m, 1H); 8.01(d, 1H).

Example 8: (5R)-3-{3-fluoro-4-[2-methyl-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridine- 3- Base] phenyl}-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3- oxazolidin-2-one

3-Bromo-2-methyl-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridine (196mg, 0.773mmol), (5R)-3-[3- Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3 -Triazol-1-ylmethyl)-1,3-oxazolidin-2-one (300mg, 0.773mmol), potassium carbonate (320mg, 2.31mmol) and tetrakis(triphenylphosphino)palladium(0) (89mg, 0.077mmol) were combined and suspended in DMF (3ml) and water (0.3ml). The mixture was heated at 80°C for 2 hours, then diluted to 7ml with water. The solid was collected, rinsed with water and resuspended in lukewarm DMSO (3ml). The suspension was diluted with dichloromethane (5ml) and ether (4ml). The solid was collected, rinsed with ether and methanol, and dried in vacuo to give the pure product as a white solid (110 mg).

MS(APCI): 435(M+1)C ₂₁ H ₁₉ N ₈ O ₂ F

NMR (DMSO-d ₆ ) δ: 2.36(s, 3H); 2.41(s, 3H); 3.95(dd, 1H); 4.31(t, 1H); 4.88(d, 2H); 1H); 7.44(dd, 1H); 7.50(t, 1H); 7.62(dd, 1H); 7.79(d, 1H); 7.95(q, 2H); 8.20(d, 1H); 8.61(d, 1H ).

Intermediates of the above compounds are prepared as follows:

3-Bromo-2-methyl-6-(4-methyl-1H-1,2,3-triazol-1-yl)pyridine

To a solution of 6-amino-3-bromo-2-methylpyridine (1.0 g, 5.3 mmol) in methanol (20 ml) was added diisopropylethylamine (2.8 ml, 16.0 mmol) at room temperature. The solution was stirred for 10 minutes, and [(1E)-2,2-dichloro-1-methylethylene]hydrazide-4-methyl-benzenesulfonic acid (2.0g, 6.95mmol) was added at 4°C, and the reaction mixture Stir at room temperature over weekend. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography eluting with 25% ethyl acetate/hexanes to give the title compound (758 mg).

MS(APCI) _{: 254} (M+1) _C9H9BrN4

¹ H-NMR (DMSO-d ₆ ) δ: 2.34 (s, 3H); 2.64 (s, 3H); 7.83 (d, 2H); 8.26 (d, 1H); 8.56 (s, 1H).

(5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5 - (1H-1,2,3-triazol-1-ylmethyl)-1,3- oxazolidin-2-one

See Example 1.

Claims (25)

1. hydrolyzable ester in acceptable salt or the body on formula (I) compound or its pharmacology,

Wherein C is selected from D and E,

Wherein (I) De oxazolidone is connected the benzyl ring among D and the E with formula;

R ₁B is HET1 or HET2, wherein

I) HET1 is a N connection 5-unit unsaturated or part unsaturated heterocycle fully, and it comprises (i) 1-3 other nitrogen heteroatom or (ii) an other heteroatoms that is selected from O and S and an optional other nitrogen heteroatom; This ring is chosen wantonly on the C atom beyond the connectivity N atom adjacent C atom and is replaced by oxo or thio group; And/or this ring chooses wantonly and is selected from hereinafter on any effective C atom beyond the connectivity N atom adjacent C atom that the substituting group of the RT of definition replaces, and/or on the available nitrogen atom beyond the adjacent N atom of connectivity N atom (precondition is that this ring is not therefore by quaternized) by the replacement of (1-4C) alkyl;

Ii) HET2 is a N connection 6-unit dihydro heteroaryl ring, comprises sum (comprising the connectivity heteroatoms) 3 nitrogen heteroatoms at the most, and this ring is replaced by oxo or thio group on the suitable C atom beyond the connectivity N atom adjacent C atom; And/or this ring chooses wantonly and is selected from independently hereinafter by 1-2 on any effective C atom beyond the connectivity N atom adjacent C atom that the substituting group of the RT of definition replaces, and/or (precondition is that this ring is not so by quaternized) quilt (1-4C) alkyl replacement on the available nitrogen atom beyond the adjacent N atom of connectivity N atom;

The RT substituting group is selected from following group:

(RTa1) hydrogen, halogen, (1-4C) alkoxyl group, (2-4C) alkenyl oxy, (2-4C) alkenyl, (2-4C) alkynyl group, (3-6C) cycloalkyl, (3-6C) cycloalkenyl group, (1-4C) alkylthio, amino, azido-, cyano group and nitro; Or

(RTa2) (1-4C) alkylamino, two-(1-4C) alkylaminos and (2-4C) alkenyl amino;

Perhaps RT is selected from following group

(RTb1) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: hydroxyl, (1-4C) alkoxyl group, (1-4C) alkylthio, cyano group and azido-; Or

(RTb2) (1-4C) alkyl, it is optional to be selected from following substituting group by one and to replace: (2-4C) alkenyl oxy, (3-6C) cycloalkyl and (3-6C) cycloalkenyl group;

Perhaps RT is selected from following group

(RTc) the first monocycle of complete saturated 4-comprises 1-2 heteroatoms (optional oxidation) that independently is selected from O, N and S, and connects through ring nitrogen or ring carbon atom;

As (RTa1) or (RTa2), (RTb1) or (RTb2) or the RT substituting group (RTc) when comprising alkyl, alkenyl, alkynyl group, cycloalkyl or cycloalkenyl group part, described group is partly chosen wantonly on effective carbon atom by 1-3 or more independently is selected from the substituting group replacement of F, Cl, Br, OH and CN;

R ₂A and R ₆A independently is selected from H, CF ₃, OMe, SMe, Me and Et;

R ₂B and R ₆B independently is selected from H, F, Cl, CF ₃, OMe, SMe, Me and Et;

R ₃A be selected from H, (1-4C) alkyl, cyano group, Br, F, Cl, OH, (1-4C) alkoxyl group ,-S (O) _n(1-4C) alkyl (wherein n=0,1 or 2), amino, (1-4C) alkyl-carbonyl-amino, nitro ,-CHO ,-CO (1-4C) alkyl ,-CONH ₂With-CONH (1-4C) alkyl;

R ₄Be selected from R ₄A and R ₄B, wherein

R ₄A be selected from azido-,-NR ₇R ₈, OR ₁₀, (1-4C) alkyl, (1-4C) alkoxyl group, (3-6C) cycloalkyl ,-(CH ₂) _k-R ₉, AR1, AR2, (1-4C) alkyloyl ,-CS (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-(C=O) ₁-R ₆,-COO (1-4C) alkyl ,-C=OAR1 ,-C=OAR2 ,-COOAR1, S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-S (O) pAR1 ,-S (O) pAR2 and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl chain can be chosen wantonly by (1-4C) alkyl, cyano group, hydroxyl or halogen and replace; P=0,1 or 2;

R ₄B is selected from HET-3;

R ₆Be selected from hydrogen, (1-4C) alkoxyl group, amino, (1-4C) alkylamino and hydroxyl (1-4C) alkylamino;

K is 1 or 2;

L is 1 or 2;

R ₇And R ₈Independently be selected from H and (1-4C) alkyl, perhaps R ₇And R ₈The nitrogen that connects with their can form 5-7 unit ring, and this ring is chosen wantonly to have 1 and be selected from N, O, S (O) _n1 carbon atom of the ring that the other heteroatoms displacement of (wherein n=1 or 2) so forms; Wherein this ring can be chosen wantonly and independently is selected from following group by 1-2 and replace: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2), AR1, AR2 ,-C=OAR1 ,-C=OAR2 ,-COOAR1 ,-CS (1-4C) alkyl ,-C (=S) O (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-S (O) _pAR1 and-S (O) _pAR2; Wherein any (1-4C) alkyl, (3-6C) cycloalkyl or (1-4C) alkyloyl can choose wantonly and be selected from following substituting group by 1-2 and replace (except the contiguous heteroatomic carbon atom): (1-4C) alkyl, cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino; P=0,1 or 2;

R ₉Independently be selected from following R ₉A-R ₉D:

R ₉a：AR1、AR2、AR2a、AR2b、AR3、AR3a、AR3b、AR4、AR4a、CY1、CY2；

R ₉B: cyano group, carboxyl, (1-4C) alkoxy carbonyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv can form 5-7 unit ring with Rw with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly has 11 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein when described ring is piperazine ring, this ring can be chosen wantonly and is selected from following group replace on another nitrogen: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-COOAR1 ,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl, (3-6C) cycloalkyl or (1-4C) alkyloyl self can choose wantonly by cyano group, hydroxyl or halogen replace)], vinyl, 2-(1-4C) alkyl vinyl, 2-cyano group vinyl, 2-cyano group-2-((1-4C) alkyl) vinyl, 2-nitroethylene base, 2-nitro-2-((1-4C) alkyl) vinyl, 2-((1-4C) alkyl amino-carbonyl) vinyl, 2-((1-4C) alkoxy carbonyl) vinyl, 2-(AR1) vinyl, 2-(AR2) vinyl, 2-(AR2a) vinyl;

R ₉C:(1-6C) alkyl

{ optional replaced (comprising together with two replacements) by one or more groups, each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, (1-4C) alkyl-carbonyl, phosphorus acyloxy, and [O-P (O) (OH) ₂And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) ₂And single-and two-(1-4C) alkoxy derivative] and amino; And/or optional be selected from following group by one and replace: [phosphono-P (O) (OH) for carboxyl, phosphoryl ₂And single-and two-(1-4C) alkoxy derivative], inferior phosphoryl [P (OH) ₂And single-and two-(1-4C) alkoxy derivative], cyano group, halogen, trifluoromethyl, (1-4C) alkoxy carbonyl, (1-4C) alkoxy carbonyl of alkoxyl group-(1-4C), (1-4C) alkoxy carbonyl of the alkoxyl group of alkoxyl group-(1-4C)-(1-4C), (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonyl amino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C (=W) NRvRw[wherein W be O or S, the definition of Rv and Rw is the same], (=NORv), wherein the definition of Rv is the same, (1-4C) alkyl S (O) pNH, (1-4C) alkyl S (O) p-((1-4C) alkyl) N-, fluoro (1-4C) alkyl S (O) pNH-, fluoro (1-4C) alkyl S (O) p ((1-4C) alkyl) N-, (1-4C) alkyl S (O) q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-O-, AR3-O-, AR1-S (O) q-, AR2-S (O) q-, AR3-S (O) q-, AR1-NH-, AR2-NH-, (p is 1 or 2 to AR3-NH-, and q is 0,1 or 2) and comprise AR2a, AR2b, the group of AR3a and AR3b type AR2 and AR3 }; R wherein ₉Any (1-4C) alkyl self in any substituting group of c can independently be selected from following group by 1-2 and replace: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if such substituting group exists, and then it is not on contiguous heteroatomic carbon;

R ₉D:R ₁₄C (O) O (1-6C) alkyl-, R wherein ₁₄Be AR1, AR2, (1-4C) alkylamino, benzyloxy-(1-4C) alkyl or (1-10C) alkyl { optional as (R ₉C) definition replaces };

R ₁₀Be selected from hydrogen, R ₉C (definition the same), (1-4C) acyl group and (1-4C) alkyl sulphonyl;

HET-3 is selected from:

A) comprise the 5-unit heterocycle of at least 1 nitrogen and/or oxygen, wherein any carbon atom is C=O, C=N or C=S, and wherein said ring is with following formula HET3-A-HET3-E:

B) comprise 1-4 and independently be selected from N, O and heteroatomic carbon connection 5-of S or 6-unit hetero-aromatic ring, it is selected from following HET3-F-HET3-Y:

C) comprise 1-4 and independently be selected from N, O and heteroatomic nitrogen connection 5-of S or 6-unit hetero-aromatic ring, it is selected from following HET3-Z-HET3-AH:

The R among the HET-3 wherein ₁A is the substituting group on the carbon;

R ₁A independently is selected from following R ₁A1-R ₁A5:

R ₁a1：AR1、AR2、AR2a、AR2b、AR3、AR3a、AR3b、AR4、AR4a、CY1、CY2；

R ₁A2: cyano group, carboxyl, (1-4C) alkoxy carbonyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv can form 5-7 unit ring with Rw with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly has 11 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein when described ring is piperazine ring, this ring can be chosen wantonly and is selected from following group by one replace on another nitrogen: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2) ,-COOAR1 ,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl; Wherein any (1-4C) alkyl, (1-4C) alkyloyl is with (3-4C) naphthenic substituent self can be by cyano group, hydroxyl or halogen replace, and precondition is that such substituting group is not on the carbon adjacent with the piperazine ring nitrogen-atoms], vinyl, 2-(1-4C) alkyl vinyl, 2-cyano group vinyl, 2-cyano group-2-((1-4C) alkyl) vinyl, 2-nitroethylene base, 2-nitro-2-((1-4C) alkyl) vinyl, 2-((1-4C) alkyl amino-carbonyl) vinyl, 2-((1-4C) alkoxy carbonyl) vinyl, 2-(AR1) vinyl, 2-(AR2) vinyl, 2-(AR2a) vinyl;

R ₁A3:(1-10C) alkyl

{ optional replaced (comprising together with two replacements) by one or more groups, each group independently is selected from the alkoxyl group of the alkoxyl group of hydroxyl, (1-10C) alkoxyl group, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) alkoxyl group, (1-4C) alkyl-carbonyl, phosphorus acyloxy, and [O-P (O) (OH) ₂And single-and two-(1-4C) alkoxy derivative], inferior phosphorus acyloxy [O-P (OH) ₂And single-and two-(1-4C) alkoxy derivative] and amino; And/or optional be selected from following group by one and replace: [phosphono-P (O) (OH) for carboxyl, phosphoryl ₂And single-and two-(1-4C) alkoxy derivative], inferior phosphoryl [P (OH) ₂And single-and two-(1-4C) alkoxy derivative], cyano group, halogen, trifluoromethyl, (1-4C) alkoxy carbonyl, (1-4C) alkoxy carbonyl of alkoxyl group-(1-4C), (1-4C) alkoxy carbonyl of the alkoxyl group of alkoxyl group-(1-4C)-(1-4C), (1-4C) alkylamino, two ((1-4C) alkyl) amino, (1-6C) alkanoylamino-, (1-4C) alkoxycarbonyl amino-, N-(1-4C) alkyl-N-(1-6C) alkanoylamino-,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl, wherein Rv and Rw can form 5-7 unit ring with amide nitrogen or the thioamides nitrogen that they are connected, and this ring is chosen wantonly to have 1 and be selected from N, O, 1 carbon atom of the ring that the other heteroatoms displacement of S (O) n so forms; Wherein when described ring is piperazine ring, this ring can be chosen wantonly on another nitrogen and is selected from following group replacement by one: (1-4C) alkyl, (3-6C) cycloalkyl, (1-4C) alkyloyl,-COO (1-4C) alkyl,-S (O) n (1-4C) alkyl (wherein n=1 or 2),-COOAR1,-CS (1-4C) alkyl and-C (=S) O (1-4C) alkyl], (=NORv), wherein the definition of Rv is the same, (1-4C) alkyl S (O) pNH-, (1-4C) alkyl S (O) p-((1-4C) alkyl) N-, fluoro (1-4C) alkyl S (O) pNH-, fluoro (1-4C) alkyl S (O) p ((1-4C) alkyl) N-, (1-4C) alkyl S (O) q-, CY1, CY2, AR1, AR2, AR3, AR1-O-, AR2-O-, AR3-O-, AR1-S (O) q-, AR2-S (O) q-, AR3-S (O) q-, AR1-NH-, AR2-NH-, (p is 1 or 2 to AR3-NH-, and q is 0,1 or 2) and comprise AR2a, AR2b, the group of AR3a and AR3b type AR2 and AR3 }; R wherein ₁Any (1-4C) alkyl in any substituting group of a3, (1-4C) alkyloyl and (3-6C) cycloalkyl self can independently be selected from following group replacement by 1-2: cyano group, hydroxyl, halogen, amino, (1-4C) alkylamino and two (1-4C) alkylamino, precondition is if such substituting group exists, and then it is not on contiguous heteroatomic carbon;

R ₁A4:R ₁₄C (O) O (1-6C) alkyl-, R wherein ₁₄Be AR1, AR2, AR2a, AR2b, (1-4C) alkylamino, benzyloxy-(1-4C) alkyl or (1-10C) alkyl { optional as (R ₁A3) definition replaces };

R ₁A5:F, Cl, hydroxyl, sulfydryl, (1-4C) alkyl S (O) p-(p=0,1 or 2) ,-NR ₇R ₈(R wherein ₇And R ₈Definition the same) or-OR ₁₀(R wherein ₁₀Definition the same);

M is 0,1 or 2;

R ₂₁Be selected from hydrogen, methyl [optionally replaced by following group: cyano group, trifluoromethyl ,-(wherein W, Rv and Rw are with R above for C=WNRvRw ₁The definition of a3), alkoxy carbonyl, CY1, CY2, AR1, AR2, AR2a, AR2b (connecting) or the AR3 of the alkoxyl group of the alkoxy carbonyl of (1-4C) alkoxy carbonyl, (1-4C) alkoxyl group-(1-4C), (1-4C) alkoxyl group-(1-4C)-(1-4C) without nitrogen], (2-10C) alkyl [chooses wantonly on the carbon beyond HET-3 ring nitrogen connects carbon and independently is selected from R by 1-2 ₁The optional substituent group of a3 definition replaces] and R ₁₄C (O) O (2-6C) alkyl-, R wherein ₁₄Same above R ₁The definition of a4, wherein R ₁₄C (O) O is connected carbon carbon in addition with HET-3 ring nitrogen and connects;

R ₂₂For cyano group ,-COR ₁₂,-COOR ₁₂,-CONHR ₁₂,-CON (R ₁₂) (R ₁₃) ,-SO ₂R ₁₂(precondition is R ₁₂Be not hydrogen) ,-SO ₂NHR ₁₂,-SO ₂N (R ₁₂) (R ₁₃) or NO ₂, R wherein ₁₂And R ₁₃With hereinafter definition;

R ₁₂And R ₁₃Independently be selected from hydrogen, phenyl (optionally be selected from following substituting group by one or more and replace: halogen, (1-4C) alkyl and (1-4C) alkyl that is replaced by 1-3 or more halogen atoms) and (1-4C) alkyl (optional) by 1-3 or the replacements of more halogen atoms, or for any N (R ₁₂) (R ₁₃) group, R ₁₂And R ₁₃Can form 5-7 unit ring with the nitrogen of their connections, this ring is chosen wantonly has 1 carbon atom that is selected from the other heteroatoms displacement ring that forms like this of N, O, S (O) n; Wherein said ring can be chosen wantonly and independently is selected from following group by 1-2 and replace: (1-4C) alkyl (choose wantonly on not adjacent carbon and replaced), (3-6C) cycloalkyl, (1-4C) alkyloyl by cyano group, hydroxyl or halogen with nitrogen ,-COO (1-4C) alkyl ,-S (O) n (1-4C) alkyl (wherein n=1 or 2), AR1, AR2 ,-C=OAR1 ,-C=OAR2 ,-COOAR1 ,-CS (1-4C) alkyl ,-C (=S) O (1-4C) alkyl ,-C (=W) NRvRw[wherein W be O or S, Rv and Rw independently are H or (1-4C) alkyl] ,-S (O) pAR1 and-S (O) pAR2; Wherein any (1-4C) alkyl chain can be chosen wantonly by (1-4C) alkyl, cyano group, hydroxyl or halogen and replace; P=0,1 or 2;

AR1 is optional phenyl that replaces or the optional naphthyl that replaces;

AR2 is optional 5-or 6-unit unsaturated fully (promptly having maximum degree of unsaturation) the bicyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and connect by ring carbon atom, if perhaps should encircle, can connect by theheterocyclic nitrogen atom not therefore by quaternized;

AR2a is partial hydrogenation type AR2 (is AR2 ring system retained part degree of unsaturation but not fully degree of unsaturation), connect by ring carbon atom, if perhaps should ring not therefore by quaternized, can connect by theheterocyclic nitrogen atom;

AR2b is complete hydrogenation type AR2 (being that the AR2 ring system does not have unsaturation), connects by ring carbon atom or theheterocyclic nitrogen atom;

AR3 is optional 8-, 9-or 10-unit unsaturated fully (promptly having maximum degree of unsaturation) the bicyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and passes through the ring carbon atom connection of arbitrary ring of formation second cycle line;

AR3a is partial hydrogenation type AR3 (is AR3 ring system retained part degree of unsaturation but not fully degree of unsaturation), and the ring carbon atom of the arbitrary ring by constituting second cycle line connects, if perhaps should ring not have therefore by quaternized then can be by the theheterocyclic nitrogen atom connection of arbitrary ring;

AR3b is complete hydrogenation type AR3 (being that the AR3 ring system does not have unsaturation), and the ring carbon atom or the theheterocyclic nitrogen atom of the arbitrary ring by constituting second cycle line connect;

AR4 is optional 13-or 14-unit unsaturated fully (promptly having maximum degree of unsaturation) the tricyclic heteroaryl ring that replaces, it comprises 4 heteroatomss (but not containing any O-O, O-S or S-S key) that independently are selected from O, N and S at the most, and passes through the ring carbon atom connection of any ring of formation three ring systems;

AR4a is partial hydrogenation type AR4 (is AR4 ring system retained part degree of unsaturation but not fully degree of unsaturation), and the ring carbon atom of any ring by constituting three ring systems connects, if perhaps should ring not have therefore by quaternized then can be by the theheterocyclic nitrogen atom connection of any ring;

CY1 is optional cyclobutyl, cyclopentyl or the cyclohexyl ring that replaces;

CY2 is optional cyclopentenyl or the tetrahydrobenzene basic ring that replaces;

Wherein: AR1; AR2; AR2a; AR2b; AR3; AR3a; AR3b; AR4; AR4a; the optional substituting group of CY1 and CY2 for (on effective carbon atom) at the most 3 independently be selected from following substituting group: (1-4C) alkyl { optionally independently is selected from following substituting group replacement: hydroxyl; trifluoromethyl; (1-4C) (q is 0 to alkyl S (O) q-; 1 or 2); (1-4C) alkoxyl group; (1-4C) alkoxy carbonyl; cyano group; nitro; (1-4C) alkanoylamino;-CONRvRw or-NRvRw}; trifluoromethyl; hydroxyl; halogen; nitro; cyano group; sulfydryl; (1-4C) alkoxyl group; (1-4C) alkanoyloxy; dimethylamino methene amido carbonyl; two (N-(1-4C) alkyl) amino methyl imino-; carboxyl; (1-4C) alkoxy carbonyl; (1-4C) alkyloyl; (1-4C) alkyl SO ₂Amino, (2-4C) alkenyl { optional } by carboxyl or (1-4C) alkoxy carbonyl replacement, (2-4C) alkynyl group, (1-4C) alkanoylamino, oxo (=O), sulfo-(=S), (1-4C) alkanoylamino { (1-4C) alkyloyl is optional is replaced by hydroxyl }, (1-4C) (q is 0 to alkyl S (O) q-, 1 or 2) { (1-4C) alkyl is optional by one or more cyano group that independently are selected from, hydroxyl and (1-4C) the group replacement of alkoxyl group },-CONRvRw or-NRvRw[wherein Rv be hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl];

At AR1; AR2; AR2a; AR2b; AR3; AR3a; AR3b; AR4; AR4a; CY1 and CY2 (on effective carbon atom) and alkyl (except as otherwise noted) go up other optional substituting group at the most 3 independently be selected from following substituting group: trifluoromethoxy; benzoyl-amido; benzoyl; phenyl optional by at the most 3 independently be selected from following substituting group and replace: halogen; (1-4C) alkoxyl group or cyano group }; furans; the pyrroles; pyrazoles; imidazoles; triazole; pyrimidine; pyridazine; pyridine isoxazole oxazole; isothiazole; thiazole; thiophene; oxyimino (1-4C) alkyl; (1-4C) Alkoximino (1-4C) alkyl; the alkyl of halogen-(1-4C); (1-4C) alkane sulfonamido;-SO ₂NRvRw[wherein Rv is hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl]; And

AR2, AR2a, AR2b, AR3, AR3a, AR3b, the optional substituting group of AR4 and AR4a has (on the available nitrogen atom, such replacement can not cause quaternized) (1-4C) alkyl, (1-4C) alkyl-carbonyl { (1-4C) alkyl and (1-4C) alkyl-carbonyl is optional independently is selected from following substituting group (preferred) replacement: cyano group wherein, hydroxyl, nitro, trifluoromethyl, (1-4C) (q is 0 to alkyl S (O) q-, 1 or 2), (1-4C) alkoxyl group, (1-4C) alkoxy carbonyl, (1-4C) alkanoylamino,-CONRvRw or-NRvRw[wherein Rv be hydrogen or (1-4C) alkyl; Rw is hydrogen or (1-4C) alkyl] }, (2-4C) alkenyl, (2-4C) alkynyl group, (1-4C) alkoxy carbonyl or oxo (constituting the N-oxide compound).

2. hydrolyzable ester, wherein R in acceptable salt or the body on claimed formula (I) compound of claim 1 or its pharmacology ₁B is HET1, and wherein HET1 is selected from following structure (Za)-(Zf):

Wherein u and v are 0 or 1 independently, and RT is selected from:

(a) hydrogen;

(b) halogen;

(c) cyano group;

(d) (1-4C) alkyl;

(e) single (1-4C) alkyl that replaces;

(f) two replace (1-4C) alkyl and

(g) three replace (1-4C) alkyl.

3. hydrolyzable ester, wherein R in acceptable salt or the body on claim 1 or 2 claimed formula (I) compounds or its pharmacology ₄Be R ₄B.

4. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology, wherein HET-3 is selected from HET3-T, HET3-V, HET3-Y and HET-3-W.

5. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology, wherein HET-3 is selected from HET3-V and HET3-Y.

6. hydrolyzable ester, wherein R in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology ₁A is R ₁A3.

7. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology, wherein group C is group D.

8. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of each aforementioned claim or its pharmacology, wherein group C is group E.

9. hydrolyzable ester in acceptable salt or the body on claimed formula (I) compound of claim 1 or its pharmacology, wherein group C is group E; R ₂A and R ₆A is a hydrogen; R ₂B and R ₆B independently is hydrogen or fluorine; And R ₄Be HET3-V, R ₁B is selected from Zd and Zf, and u and v independently are 0 or 1, and RT is selected from hydrogen, halogen, cyano group, methyl, methyl fluoride, chloromethyl, brooethyl, cyano methyl, azido methyl, hydroxymethyl, difluoromethyl and trifluoromethyl.

Each aforementioned claim claimed with hydrolyzable ester in acceptable salt or the body on following formula (Ia) compound or its pharmacology

11. the prodrug of the compound that each aforementioned claim is claimed.

12. a method that produces anti-microbial effect in the warm-blooded animal body, this method comprise on each claimed The compounds of this invention of claim 1-11 of giving described animal effective dose or its pharmacology hydrolyzable ester in acceptable salt or the body.

13. as hydrolyzable ester in acceptable salt or the body on each claimed The compounds of this invention of claim 1-11 of medicine or its pharmacology.

14. the purposes of hydrolyzable ester on the preparation medicine in acceptable salt or the body on each claimed The compounds of this invention of claim 1-11 or its pharmacology, described medicine is used for producing anti-microbial effect in the warm-blooded animal body.

15. a medicinal compositions, said composition comprise on each claimed The compounds of this invention of claim 1-11 or its pharmacology in acceptable salt or the body acceptable diluent or carrier on hydrolyzable ester and the pharmacology.

16. a method for preparing hydrolyzable ester in acceptable salt on the claimed formula of claim 1 (I) compound or its pharmacology or the body, described method comprises the method for a kind of (a)-(i); Then if desired, carry out following steps:

I) slough any protecting group;

Ii) form prodrug (for example hydrolyzable ester in the body); And/or

Iii) form acceptable salt on the pharmacology;

Wherein said method (a)-(i) is:

A) substituting group on another compound of modification the present invention is perhaps introduced substituting group on another compound of the present invention;

B) [wherein X is the leavings group that is used for the palladium coupling, and A is N or C-R to make formula (IIa) compound molecule ₃A] with formula (IIb) compound molecule [wherein X ' is for being used for the leavings group of palladium coupling] reaction, wherein X and X ' make and replace aryl-X (or heteroaryl-X) and aryl-X ' (or heteroaryl-X ') key with aryl-aryl, heteroaryl-aryl or heteroaryl-heteroaryl key; And select different X and X ' so that produce required formula (I) cross-linking products;

C) make heterobiaryl derivative (III) carbamate Cheng the oxazolidone ring with the reacting ethylene oxide Xing of suitable replacement;

(d) make the reaction of formula (VI) compound and formula (VII) compound:

Wherein X is replaceable substituting group, below is formula (VII):

T-X’

(VII)

Wherein T-X ' is HET1 defined above or HET2, and X ' is that replaceable C connects substituting group; Wherein said substituent X and X ' are chosen as the substituting group complementary pair of the complementary substrate that is suitable as coupled reaction, and this coupled reaction is with for example palladium (O) catalysis of transition metal;

(d (i)) makes formula (VIII) compound react with formula (IX) compound by transition metal-catalyzed:

Wherein X is replaceable substituting group, below is formula (IX);

(d is (ii)) makes formula (X) compound and the reaction of formula (XI) compound:

X is replaceable substituting group, below is formula (XI):

T-H

(XI)

Wherein T-H is amine R ₇R ₈NH, pure R ₁₀OH or contain the azoles of effective ring-NH obtains compound (XIIa), (XIIb) or (XIIc), A is nitrogen or C-R in this case ₃A and A ' are optional nitrogen or the carbon that is replaced by one or more radicals R 1a;

(e) make the reaction of formula (XIII) compound and formula (XIV) compound:

X wherein ₁And X ₂Be the independent optional heteroatoms combination that is selected from O, N and S that replaces, make C (X ₁) X ₂Constituting the carboxylic acid derivative substituting group, below is formula (XIV), wherein X ₃And X ₄Be the independent optional heteroatoms combination that is selected from O, N and S that replaces:

C (X wherein ₁) X ₂And C (X ₃) X ₄In one constitute optional hydrazides, thio-hydrazide or amidrazone, hydroximic acid base or the hydroxyl amidine that replaces, and C (X ₁) X ₂And C (X ₃) X ₄In another constitutes optional acylating agent, sulfo-acylating agent or the imido acylating agent that replaces, make C (X ₁) X ₂And C (X ₃) X ₄Can condense and form 1,2 together, 4-heteroatoms 5-unit heterocycle, it comprises 3 the heteroatoms combinations that are selected from O, N and S, for example thiadiazoles;

(e (i)) makes formula (XV) compound and the reaction of trinitride negative ion source:

X wherein ₂Be replaceable group, obtain tetrazolium (XVI);

The perhaps nitrile of formula (XVII)

Can with the trinitride direct reaction, (XVI R1a=H), uses radicals R 1a ≠ H alkanisation then, obtains tetrazolium (XVIIIa) and (XVIIIb) to obtain tetrazolium;

(f) make the reaction of formula (XIX) compound and formula (XX) compound:

Below be formula (XX):

C (X wherein ₅) X ₆And C (X ₇) X ₈In one constitute optional α-(leavings group replacement) ketone that replaces, wherein leavings group for for example halogen or (alkyl or aryl)-alkylsulfonyl oxygen base-, and C (X ₅) X ₆And C (X ₇) X ₈In another constitutes optional acid amides, thioamides or the amidine that replaces, make C (X ₅) X ₆And C (X ₇) X ₈Can condense and form 1 together, 3-heteroatoms 5-unit heterocycle, it comprises 2 the heteroatoms combinations that are selected from O, N and S, for example thiazoles;

(g) preparation HET is 1 of optional replacement, 2, the method of the formula of 3-triazole (I) compound is: make the trinitride cycloaddition to acetylene or acetylene equivalent, and for example optional hexamethylene-1 that replaces, 4-diene or optional carrying of replacing can be removed for example ethene of aryl sulfonyl of substituting group;

(h) be formula (I) compound of the 1,2,3-triazoles of 4-replacement for HET, can make amino methyloxazolidinonesas and 1, the preparation of 1-dihalo ketone alkylsulfonyl hydrazone reaction;

(i) preparation HET is that the method for formula (I) compound of the 1,2,3-triazoles that replaces of 4-is: make azido methyl oxazolidinone and terminal alkyne reaction with Cu (I), the 1,2,3-triazoles of acquisition 4-replacement.

17. method for preparing hydrolyzable ester in acceptable salt on the claimed formula of claim 1 (I) compound or its pharmacology or the body; wherein HET-1 is 4-halogenated 1; 2; the 3-triazole; this method comprises makes the azido methyl oxazolidinone react with vinyl halides base SULPHURYL CHLORIDE in 0 ℃-100 ℃, and this reaction can not have thinner or carries out in inert diluent

18. the method for claim 17, wherein vinyl halides base SULPHURYL CHLORIDE is a 1-chloro-1-ethene SULPHURYL CHLORIDE.

19. compound 1-chloro-1-ethene SULPHURYL CHLORIDE

20.1-chloro-1-ethene SULPHURYL CHLORIDE is forming purposes in the cycloaddition reaction of 4-chloro-1,2,3-triazoles with trinitride.

21.1-chloro-1-ethene SULPHURYL CHLORIDE is forming purposes in the method for formula (I) compound, wherein R with azide derivatives ₁B is 4-chloro-1,2,3-triazoles, perhaps R ₄Be 4-chloro-HET3-AB.

22. the medicinal compositions that claim 15 is claimed, wherein said composition comprises VITAMIN.

23. the medicinal compositions that claim 22 is claimed, wherein said VITAMIN are vitamins B.

24. the medicinal compositions that claim 15 is claimed, wherein said composition comprise formula (I) compound combined and effective antibacterials of resisting gram-positive bacterium.

25. the medicinal compositions that claim 15 is claimed, wherein said composition comprise formula (I) compound combined and the antibacterials of effective anti-gram negative bacterium.