Oxazolidinone derivatives as antibacterial agents

A compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,

• wherein C is selected from D and E,
• wherein in D and E the phenyl ring is attached to the oxazolidinone in (I);
• R1b is —NR25C(═W)R24;
• wherein W is O or S;
• R24 is hydrogen, amino, (2-6C)alkyl (optionally substituted by 1, 2 or 3 substituents independently selected from methyl, chloro, bromo, fluoro, methoxy, methylthio, azido and cyano), methyl (substituted by 1, 2 or 3 substituents independently selected from methyl, chloro, bromo, fluoro, methoxy, methylthio, hydroxy, benzyloxy, ethynyl, (1-4C)alkoxycarbonyl, azido and cyano), 5-halo-2-thienyl, —NHR26, —N(R26)(R27), —OR26 or —SR26, (2-4C)alkenyl, -(1-8C)alkylaryl, per-halo(1-8C)alkyl, —(CH2)p(3-6C)cycloalkyl or —(CH2)p(3-6C)cycloalkenyl wherein p is 0, 1 or 2;
• R25 is hydrogen, (3-6C)cycloalkyl, phenyloxycarbonyl, tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl, (1-6C)alkyl (optionally substituted by cyano or (1-4C)alkoxycarbonyl), —CO2R28, —C(═O)R28, —C(═O)SR28, —C(═S)R29, P(O)(OR29)(OR30) and —SO2R31, wherein R28, R29, R30 and R3, are as defined hereinbelow;
• R28 is hydrogen, (3-6C)cycloalkyl, phenyl, benzyl, (1-5C)alkanoyl, (1-6C)alkyl (optionally substituted by substituents independently selected from (1-5C)alkoxycarbonyl, hydroxy, cyano, up to 3 halogen atoms and —NR15R16 (wherein R15 and R16 are independently selected from hydrogen, phenyl (optionally substituted with one or more substituents selected from halogen, (1-4C)alkyl and (1-4C)alkyl substituted with one, two, three or more halogen atoms) and (1-4C)alkyl (optionally substituted with one, two, three or more halogen atoms), or for any N(R15)(R16) group, R15 and R16 may additionally be taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl or morpholinyl ring));
• R29 and R30 are independently selected from hydrogen and (1-4C)alkyl;
• R31 is (1-4C)alkyl or phenyl;
• R26 and R27 are independently selected from hydrogen, phenyl (optionally substituted with one or more substituents selected from halogen, (1-4C)alkyl and (1-4C)alkyl substituted with one, two, three or more halogen atoms) and (1-4C)alkyl (optionally substituted with one, two, three or more halogen atoms), or for any N(R26)(R27) group, R26 and R27 may additionally be taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted pyrrolidinyl, piperidinyl or morpholinyl ring, which ring may be optionally substituted by a group selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)alkanoyl, —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;
• 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;
• R3a 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;
• R4 is selected from R4a and R4b wherein
• R4a is selected from azido, —NR7R8, OR10, (1-4C)alkyl, (1-4C)alkoxy, (3-6C)cycloalkyl, —(CH2)k—R9, 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)l—R6, —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 may be optionally substituted by (1-4C)alkyl, cyano, hydroxy or halo;
• p=0, 1 or 2;
• R4b is selected from HET-3;
• R6 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;
• R7 and R8 are independently selected from H and (1-4C)alkyl, or wherein R7 and R8 taken together with the nitrogen to which they are attached can form a 5-7 membered ring optionally with an additional heteroatom selected from N, O, S(O)n (wherein n=1 or 2) in place of 1 carbon atom of the so formed ring;
• wherein the ring may be optionally substituted by one or two groups independently selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)alkanoyl, —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 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 group may be optionally substituted (except on a carbon atom adjacent to a heteroatom) by one or two substituents selected from (1-4C)alkyl, cyano, hydroxy, halo, amino, (1-4C)alkylamino and di(1-4C)alkylamino;
• p=0, 1 or 2;
• R9 is independently selected from R9a to R9d below:
• R9a:
• AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;
• R9b:
• cyano, carboxy, (1-4C)alkoxycarbonyl, —C(═W)NRvRw [wherein W is O or S, Rv and Rw are independently H, or (1-4C)alkyl and wherein Rv and Rw taken together with the amide or thioamide nitrogen to which they are attached can form a 5-7 membered ring optionally with an additional heteroatom selected from N, O, S(O)n in place of 1 carbon atom of the so formed ring;
• wherein when said ring is a piperazine ring, the ring may be optionally substituted on the additional nitrogen by a group selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)alkanoyl, —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 alkyl, alkanoyl or cycloalkyl may itself optionally be substituted by cyano, hydroxy or halo)], ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, 2-(AR2a)ethenyl;
• R9c:
• (1-6C)alkyl
• {optionally substituted by one or more groups (including geminal disubstitution) each 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, phosphoryl [—O—P(O)(OH)2, and mono- and di-(1-4C)alkoxy derivatives thereof], phosphiryl [—O—P(OH)2 and mono- and di-(1-4C)alkoxy derivatives thereof], and amino;
• and/or optionally substituted by one group selected from carboxy, phosphonate [phosphono, —P(O)(OH)2, and mono- and di-(1-4C)alkoxy derivatives thereof], phosphinate [—P(OH)2 and mono- and di-(1-4C)alkoxy derivatives thereof], cyano, halo, 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 hereinbefore defined], (═NORv) wherein Rv is as hereinbefore defined, (1-4C)alkylS(O)pNH, (1-4C)alkylS(O)p-((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O)pNH—, fluoro(1-4C)alkylS(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 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups};
• wherein any (1-4C)alkyl present in any substituent on R9c may itself be substituted by one or two groups independently selected from cyano, hydroxy, halo, amino, (1-4C)alkylamino and di(1-4C)alkylamino, provided that such a substituent is not on a carbon adjacent to a heteroatom atom if present;
• R9d:
• R14C(O)O(1-6C)alkyl- wherein R14 is AR1, AR2, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or (1-10C)alkyl {optionally substituted as defined for (R9c)};
• R10 is selected from hydrogen, R9c (as hereinbefore defined), (1-4C)alkanoyl and (1-4C)alkylsulfonyl;
• HET-3 is selected from:
• a) a 5-membered heterocyclic ring contining at least one nitrogen and/or oxygen in which any carbon atom is a C═O, C═N, or C═S group, wherein said ring is of the formula HET3-A to HET3-E below:
• b) a carbon-linked 5- or 6-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N, O and S selected from HET3-F to HET3-Y below:
• c) a nitrogen-linked 5- or 6-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms independently selected from N. O and S selected from HET3-Z to HET3-AH below:
• wherein in HET-3, R1a is a substituent on carbon;
• R1a is independently selected from R1a1 to R1a5 below:
• R1a1:
• AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;
• R1a2:
• cyano, carboxy, (1-4C)alkoxycarbonyl, —C(═W)NRvRw [wherein W is O or S, Rv and Rw are independently H, or (1-4C)alkyl and wherein Rv and Rw taken together with the amide or thioamide nitrogen to which they are attached can form a 5-7 membered ring optionally with an additional heteroatom selected from N, O, S(O)n in place of 1 carbon atom of the so formed ring;
• wherein when said ring is a piperazine ring, the ring may be optionally substituted on the additional nitrogen by a group selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)alkanoyl, —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)alkanoyl and (3-6C)cycloalkyl substituent may itself be substituted by cyano, hydroxy or halo, provided that, such a substituent is not on a carbon adjacent to a nitrogen atom of the piperazine ring], ethenyl, 2-(1-4C)alkylethenyl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, 2-(AR2a)ethenyl;
• R1a3:
• (1-10C)alkyl
• {optionally substituted by one or more groups (including geminal disubstitution) each 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, phosphoryl [—O—P(O)(OH)2, and mono- and di-(1-4C)alkoxy derivatives thereof], phosphiryl [—O—P(OH)2 and mono- and di-(1-4C)alkoxy derivatives thereof], and amino;
• and/or optionally substituted by one group selected from carboxy, phosphonate [phosphono, —P(O)(OH)2, and mono- and di-(1-4C)alkoxy derivatives thereof], phosphinate [—P(OH)2 and mono- and di-(1-4C)alkoxy derivatives thereof], cyano, halo, 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 independently H, or (1-4C)alkyl and wherein Rv and Rw taken together with the amide or thioamide nitrogen to which they are attached can form a 5-7 membered ring optionally with an additional heteroatom selected from N, O, S(O)n in place of 1 carbon atom of the so formed ring;
• wherein when said ring is a piperazine ring, the ring may be optionally substituted on the additional nitrogen by a group selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)alkanoyl, —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 Rv is as hereinbefore defined, (1-4C)alkylS(O)pNH—, (1-4C)alkylS(O)p-((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O)pNH—, fluoro(1-4C)alkylS(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 and q is 0, 1 or 2), and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups};
• wherein any (1-4C)alkyl, (1-4C)alkanoyl and (3-6C)cycloalkyl present in any substituent on R1a3 may itself be substituted by one or two groups independently selected from cyano, hydroxy, halo, amino, (1-4C)alkylamino and di(1-4C)alkylamino, provided that such a substituent is not on a carbon adjacent to a heteroatom atom if present;
• R1a4:
• R14C(O)O(1-6C)alkyl- wherein R14 is AR1, AR2, AR2a, AR2b, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or (1-10C)alkyl {optionally substituted as defined for (R1a3)};
• R1a5:
• F, Cl, hydroxy, mercapto, (1-4C)alkylS(O)p— (p=0, 1 or 2), —NR7R8 (wherein R7 and R8 are as hereinbefore defined) or —OR10 (where R10 is as hereinbefore defined);
• m is 0, 1 or 2;
• R21 is selected from hydrogen, methyl [optionally substituted with cyano, trifluoromethyl, —C═WNRvRw (where W, Rv and Rw are as hereinbefore defined for R1a3), (1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, CY1, CY2, AR1, AR2, AR2a, AR2b (not linked through nitrogen) or AR3], (2-10C)alkyl [optionally substituted other than on a carbon attached to the HET-3 ring nitrogen with one or two groups independently selected from the optional subsituents defined for R1a3] and R14C(O)O(2-6C)alkyl-, wherein R14 is as defined hereinbefore for R1a4 and wherein R14C(O)O group is attached to a carbon other than the carbon attached to the HET-3 ring nitorogen;
• R22 is cyano, —COR12, —COOR12, —CONHR12, —CON(R12)(R13), —SO2R12 (provided that R12 is not hydrogen), —SO2NHR12, —SO2N(R12)(R13) or NO2, wherein R12 and R13 are as defined hereinbelow;
• R12 and R13 are independently selected from hydrogen, phenyl (optionally substituted with one or more substituents selected from halogen, (1-4C)alkyl and (1-4C)alkyl substituted with one, two, three or more halogen atoms) and (1-4C)alkyl (optionally substituted with one, two, three or more halogen atoms), or for any N(R12)(R13) group, R12 and R13 may be taken together with the nitrogen to which they are attached to form a 5-7 membered ring optionally with an additional heteroatom selected from N, O, S(O)n in place of 1 carbon atom of the so formed ring;
• wherein the ring may be optionally substituted by one or two groups independently selected from (1-4C)alkyl (optionally substituted on a carbon not adjacent to the nitrogen by cyano, hydroxy or halo), (3-6C)cycloalkyl, (1-4C)alkanoyl, —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 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 may be optionally substituted by (1-4C)alkyl, cyano, hydroxy or halo;
• p=0, 1 or 2;
• AR1 is an optionally substituted phenyl or optionally substituted naphthyl;
• AR2 is an optionally substituted 5- or 6-membered, fully unsaturated (i.e with the maximum degree of unsaturation) monocyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O—O, O—S or S—S bonds), and linked via a ring carbon atom, or a ring nitrogen atom if the ring is not thereby quaternised;
• AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom if the ring is not thereby quaternised;
• AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having no unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom;
• AR3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (i.e with the maximum degree of unsaturation) bicyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O—O, O—S or S—S bonds), and linked via a ring carbon atom in either of the rings comprising the bicyclic system;
• AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in either of the rings comprising the bicyclic system;
• AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having no unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom, in either of the rings comprising the bicyclic system;
• AR4 is an optionally substituted 13- or 14-membered, fully unsaturated (i.e with the maximum degree of unsaturation) tricyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O—O, O—S or S—S bonds), and linked via a ring carbon atom in any of the rings comprising the tricyclic system;
• AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in any of the rings comprising the tricyclic system;
• CY1 is an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl ring;
• CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring;
• wherein;
• optional substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are (on an available carbon atom) up to three substituents independently selected from (1-4C)alkyl {optionally substituted by substituents selected independently from hydroxy, 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, hydroxy, halo, nitro, cyano, thiol, (1-4C)alkoxy, (1-4C)alkanoyloxy, dimethylaminomethyleneaminocarbonyl, di(N-(1-4C)alkyl)aminomethylimino, carboxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, (1-4C)alkylSO2amino, (2-4C)alkenyl {optionally substituted by carboxy or (1-4C)alkoxycarbonyl}, (2-4C)alkynyl, (1-4C)alkanoylamino, oxo (═O), thioxo (═S), (1-4C)alkanoylamino {the (1-4C)alkanoyl group being optionally substituted by hydroxy}, (1-4C)alkyl S(O)q— (q is 0, 1 or 2) {the (1-4C)alkyl group being optionally substituted by one or more groups independently selected from cyano, hydroxy and (1-4C)alkoxy}, —CONRvRw or —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl;
• Rw is hydrogen or (1-4C)alkyl];
• and further optional substituents on AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 (on an available carbon atom), and also on alkyl groups (unless indicated otherwise) are up to three substituents independently selected from trifluoromethoxy, benzoylamino, benzoyl, phenyl {optionally substituted by up to three substituents independently selected from halo, (1-4C)alkoxy 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)alkanesulfonamido, —SO2NRvRw [wherein Rv is hydrogen or (1-4C)alkyl;
• Rw is hydrogen or (1-4C)alkyl];
• and
• optional substituents on AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4 and AR4a are (on an available nitrogen atom, where such substitution does not result in quaternization) (1-4C)alkyl, (1-4C)alkanoyl {wherein the (1-4C)alkyl and (1-4C)alkanoyl groups are optionally substituted by (preferably one) substituents independently selected from cyano, hydroxy, nitro, trifluoromethyl, (1-4C)alkyl S(O)q— (q is 0, 1 or 2), (1-4C)alkoxy, (1-4C)alkoxycarbonyl, (1-4C)alkanoylamino, —CONRvRw or —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl;
• Rw is hydrogen or (1-4C)alkyl]}, (2-4C)alkenyl, (2-4C)alkynyl, (1-4C)alkoxycarbonyl or oxo (to form an N-oxide).