Oxazolidinone and/or isoxazoline derivatives as antibacterial agents

The present invention relates to antibiotic compounds and in particular to antibiotic compounds containing substituted oxazolidinone and/or isoxazoline rings. This invention further relates to processes for their preparation, to intermediates useful in their preparation, to their use as therapeutic agents and to pharmaceutical compositions containing them.

The international microbiological community continues to express serious concern that the evolution of antibiotic resistance could result in strains against which currently available antibacterial agents will be ineffective. In general, bacterial pathogens may be classified as either Gram-positive or Gram-negative pathogens. Antibiotic compounds with effective activity against both Gram-positive and Gram-negative pathogens are generally regarded as having a broad spectrum of activity. The compounds of the present invention are regarded as effective against both Gram-positive and certain Gram-negative pathogens.

Gram-positive pathogens, for example Staphylococci, Enterococci, Streptococci and mycobacteria, are particularly important because of the development of resistant strains which are both difficult to treat and difficult to eradicate from the hospital environment once established. Examples of such strains are methicillin resistant staphylococcus (MRSA), methicillin resistant coagulase negative staphylococci (RCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.

The major clinically effective antibiotic for treatment of such resistant Gram-positive pathogens is vancomycin. Vancomycin is a glycopeptide and is associated with various toxicities including nephrotoxicity. Furthermore, and most importantly, antibacterial resistance to vancomycin and other glycopeptides is also appearing. This resistance is increasing at a steady rate rendering these agents less and less effective in the treatment of Gram-positive pathogens. There is also now increasing resistance appearing towards agents such as β-lactams, quinolones and macrolides used for the treatment of upper respiratory tract infections, also caused by certain Gram negative strains including H. influenzae and M. catarrhalis.

Certain antibacterial compounds containing an oxazolidinone ring have been described in the art (for example, Walter A Gregory et al in J. Med. Chem. 1990, 33, 2569-2578 and 1989, 32(8), 1673-81; Chung-Ho Park et al in J. Med. Chem. 1992, 35, 1156-1165). Bacterial resistance to known antibacterial agents may develop, for example, by (i) the evolution of active binding sites in the bacteria rendering a previously active pharmacophore less effective or redundant, and/or (ii) the evolution of means to chemically deactivate a given pharmacophore, and/or (iii) the evolution of efflux pathways. Therefore, there remains an ongoing need to find new antibacterial agents with a favourable pharmacological profile, in particular for compounds containing new, more potent, pharmacophores.

We have discovered a class of bi-aryl antibiotic compounds containing two substituted oxazolidinone and/or isoxazoline rings which has useful activity against Gram-positive pathogens including MRSA and MRCNS and, in particular, against various strains exhibiting resistance to vancomycin and/or linezolid and against E. faecium strains resistant to both aminoglycosides and clinically used β-lactams, but also to fastidious Gram negative strains such as H. influenzae, M. catarrhalis, mycoplasma spp. and chlamydial strains. The compounds of the invention contain two groups capable of acting as pharmacophores. The two groups may independently bind at pharmacophore binding sites where the sites may be similar or different, where the similar or different sites may be occupied simultaneously or not simultaneously within a single organism, or where the relative importance of different binding modes to the similar or different sites may vary between two organisms of different genus. Alternatively one of the groups may bind at a pharmacophore binding site whilst the other group fulfills a different role in the mechanism of action.

Accordingly the present invention provides a compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,
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wherein in (I) C is a biaryl group C′-C″

where C′ and C″ are independently aryl or heteroaryl rings such that the group C is represented by any one of the groups D to O below:

wherein the groups D to O are attached to rings A and B in the orientation [(A-C′) and (C″-B)] shown;

wherein A and B are independently selected from
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wherein A is linked as shown in (I) via the 3-position to ring C′ of group C and independently substituted in the 4 and 5 positions as shown in (I) by one or more substituents —(R₁a)m; and wherein B is linked as shown in (I) via the 3-position to ring C″ of group C and independently substituted in the 5 position as shown in (I) by substituent —CH₂—R₁b; R₂b and R₆b are independently selected from H, F, Cl, OMe, Me, Et and CF₃, and additionally SMe;

R₂b′ and R₆b′ are independently selected from H, OMe, Me, Et and CF₃;

R₂a and R₆a are independently selected from H, Br; F, Cl, OMe, SMe; Me, Et and CF₃;

R₂a′ and R₆a′ are independently selected from H, OMe, SMe; Me, Et and CF₃;

R₃a and R₅a are independently selected from H, (1-4C)alkyl, Br, P, Cl, OH, (1-4C)alkoxy, —S(O)_n(1-4C)alkyl (wherein n=0, 1, or 2), amino, (1-4C)alkylcarbonylamino-, nitro, cyano, —CHO, —CO(1-4C) alkyl, —CONH₂and —CONH(1-4C)alkyl;

R₃a′, R₅a′ are independently selected from H, (1-4C)alkyl, OH, (1-4C)alkoxy, (1-4C)alkylthio, amino, (1-4C)alkylcarbonylamino-, nitro, cyano, —CHO, —CO(1-4C)alkyl, —CONH₂and —CONH(1-4C)alkyl;

wherein one of R₃a, R₅a, R₃a′, R₅a taken together with a substituent R₁a at position 4 of ring A and rings A and C′ may form a 5-7 membered ring;

wherein any (1-4C)alkyl group may be optionally substituted with F, OH, (1-4C)alkoxy, —S(O)_n(1-4C)alkyl (wherein n=0, 1, or 2) or cyano;

wherein when ring C′ is a pyridine ring (ie when group C is group H, I, J, K, N or O) the ring nitrogen may optionally be oxidised to an N-oxide;

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)₂and 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)₂and 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, and additionally (1-6C)alkanoyloxy(1-4C)alkoxy, carboxy(1-4C)alkoxy, halo(1-4C)alkoxy, dihalo(1-4C)alkoxy, trihalo(1-4C)alkoxy, morpholino-ethoxy, (N′-methyl)piperazino-ethoxy, 2-, 3-, or 4-pyridyl(1-6C)alkoxy, N-methyl(imidazo-2 or 3-yl)(1-4C)alkoxy, imidazo-1-yl(1-6C)alkoxy}; 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 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 R¹⁴is AR1, AR2, AR2a, AR2b, (1-4C)alkylamino, or (1-10C)alkyl {optionally substituted as defined for (R₁a3)}, or alternatively R¹⁴is benzyloxy-(1-4C)alkyl, naphthylmethyl, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy, (1-4C)alkoxy-(1-4C)alkoxy, imidazo-1-yl(1-6C)alkyoxy(1-4C)alkyl, morpholino-ethoxy(1-4C)alkyl, (N′-methyl)piperazino-ethoxy(1-4C)alkyl, 2-, 3-, or 4-pyridyl(1-6C)alkyloxy(1-4C)alkyl, 2-, 3-, or 4-pyridyl(1-6C)alkylamino(1-4C)alkyl, 2-, 3-, or 4-pyridyl(1-6C)alkylsulfonyl(1-4C)alkyl, or N-methyl(imidazo-2 or 3-yl)(1-4C)alkyloxy(1-4C)alkyl];

R₁a5: F, Cl, hydroxy, mercapto, (1-4C)alkylS(O)p- (p=0, 1 or 2), —OSO₂(1-4C)alkyl, —NR₁₂R₁₃, —O(1-4C)alkanoyl, —OR₁a3;

m is 0, 1 or 2;

wherein two substituents R₁a both at the 4 or 5 position of ring A taken together may form a 5 to 7 membered spiro ring;

wherein two substituents R₁a at the 4 and 5 positions of ring A taken together may form a 5 to 7 membered fused ring;

provided that if (R₁a)m is a single substituent R₁a at the 5 position of ring A then R₁a is not —CH₂X wherein X is selected from R₁b;

R₁b is independently selected from hydroxy, —OSi(tri-(1-6C)alkyl) (wherein the 3 (1-6C)alkyl groups are independently selected from all possible (1-6C)alkyl groups), —NR₅C(═W)R₄, —OC(═O)R₄,
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wherein W is O or S;

provided that if group C is group H or group I, and if one of substituents R₂b and R₆b is H and the other is F, and if all of substituents R₂a, R₆a, R₂a′, R₆a′, R₃a, R₅a, R₃a′, R₅a′ are H at each occurrence, then R₁b is not —NHC(═O)Me;

R₄is selected from hydrogen, amino, (1-8C)alkyl, —NHR₁₂, —N(R₁₂)(R₁₃), —OR₁₂or —SR₁₂, (2-4C)alkenyl, -(1-8C)alkylaryl, mono-, di-, tri- and per-halo(1-8C)alkyl, —(CH₂)p(3-6C)cycloalkyl and —(CH₂)_p(3-6C)cycloalkenyl wherein p is 0, 1 or 2, and additionally (2-6C)alkyl (substituted by 1, 2 or 3 substituents independently selected from methyl, chloro, bromo, fluoro, methoxy, methylthio, azido and cyano), and 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);

R₅is selected from hydrogen, (3-6C)cycloalkyl, phenyloxycarbonyl tert-butoxycarbonyl, fluorenyloxycarbonyl, benzyloxycarbonyl, (1-6C)alkyl (optionally substituted by cyano or (1-4C)alkoxycarbonyl), —CO₂R₈, —C(═O)R₈, —C(═O)SR₈, —C(═S)R₈, P(O)(OR₉)(OR₁₀) and —SO₂R₁₁, wherein R₈, R₉, R₁₀and R₁₁are as defined hereinbelow;

HET-1 is selected from HET-1A and HET-1B wherein:

HET-1A is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S; which ring is optionally substituted on a C atom by an oxo or thioxo group; and/or which ring is optionally substituted on any available C atom by one or two substituents selected from RT as hereinafter defined and/or on an available nitrogen atom, (provided that the ring is not thereby quaternised) by (1-4C)alkyl;

HET-1B is a C-linked 6-membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, which ring is optionally substituted on a C atom by an oxo or thioxo group; and/or which ring is optionally substituted on any available C atom by one, two or three substituents selected from RT as hereinafter defined and/or on an available nitrogen atom, (provided that the ring is not thereby quaternised) by (1-4C)alkyl;

HET-2 is selected from HET-2A and HET-2B wherein

HET-2A is an N-linked 5-membered, fully or partially unsaturated heterocyclic ring, containing either (i) 1 to 3 further nitrogen heteroatoms or (ii) a further heteroatom selected from O and S together with an optional further nitrogen heteroatom; which ring is optionally substituted on a C atom, other than a C atom adjacent to the linking N atom, by an oxo or thioxo group; and/or which ring is optionally substituted on any available C atom, other than a C atom adjacent to the linking N atom, by a substituent selected from RT as hereinafter defined and/or on an available nitrogen atom, other than a N atom adjacent to the linking N atom, (provided that the ring is not thereby quaternised) by (1-4C)alkyl;

HET-2B is an N-linked 6-membered di-hydro-heteroaryl ring containing up to three nitrogen heteroatoms in total (including the linking heteroatom), which ring is substituted on a suitable C atom, other than a C atom adjacent to the linking N atom, by oxo or thioxo and/or which ring is optionally substituted on any available C atom, other than a C atom adjacent to the linking N atom, by one or two substituents independently selected from RT as hereinafter defined and/or on an available nitrogen atom, other than a N atom adjacent to the linking N atom, (provided that the ring is not thereby quaternised) by (1-4C)alkyl;

RT is selected from a substituent from the group:

(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, and additionally (1-4C)alkoxycarbonyl; or

(RTa2) (1-4C)alkylamino, di-(1-4C)alkylamino, and (2-4C)alkenylamino; or RT is selected from the group

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

(RTb2) (1-4C)alkyl group which is optionally substituted by one substituent selected from (2-4C)alkenyloxy, (3-6C)cycloalkyl, and (3-6C)cycloalkenyl;

or RT is selected from the group

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

and wherein at each occurrence of an RT substituent containing an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety in (RTa1) or (RTa2), (RTb1) or (RTb2), or (RTc) each such moiety is optionally substituted on an available carbon atom with one, two, three or more substituents independently selected from F, Cl, Br, OH and CN;

R₆is cyano, —COR₁₂, —COOR₁₂, —CONHR₁₂, —CON(R₁₂)(R₁₃), —SO₂R₁₂, —SO₂NHR₁₂, —SO₂N(R₁₂)(R₁₃) or NO₂, wherein R₁₂and R₁₃are as defined hereinbelow;

R₇is hydrogen, amino, (1-8C)alkyl, —NHR₁₂, —N(R₁₂)(R₁₃), —OR₁₂or —SR₁₂, (2-4C)alkenyl, -(1-8C)alkylaryl, mono-, di-, tri- and per-halo(1-8C)alkyl, —(CH₂)p(3-6C)cycloalkyl or —(CH₂)p(3-6C)cycloalkenyl wherein p is 0, 1 or 2;

R₈is 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 R₁₅and R₁₆are 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, R₁₅and R₁₆may additionally be taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl or morpholinyl ring);

R₉and R₁₀are independently selected from hydrogen and (1-4C)alkyl;

R₁₁is (1-4C)alkyl or phenyl;

R₁₂and R₁₃are 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, R₁₂and R₁₃may additionally be taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl or morpholinyl ring, which ring may be optionally substituted by a group selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)alkanoyll, —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;

AR1 is an optionally substituted phenyl or optionally substituted naphthyl;

AR2 is an optionally substituted 5- or 6-membered, fully unsaturated (ie 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 (ie. 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 (ie. 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 (ie. 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 quatemised, 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).

In this specification, HET-1A and HET-1B are fully unsaturated ring systems.

In this specification, HET-2A may be a fully or partially unsaturated heterocyclic ring, provided there is some degree of unsaturation in the ring.

Examples of 5-membered heteroaryl rings containing 2 to 4 heteroatoms independently selected from N, O and S (with no O—O, O—S or S—S bonds) are pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, isothiazole, 1,2,5-thiadiazole, 1,2,4-thiadiazole and 1,2,3-thiadiazole.

Examples of 6-membered heteroaryl ring systems containing up to three nitrogen heteroatoms are pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine and 1,3,5-triazine.

Examples of N-linked 5-membered, fully or partially unsaturated heterocyclic rings, containing either (i) 1 to 3 further nitrogen heteroatoms or (ii) a further heteroatom selected from O and S together with an optional further nitrogen heteroatom include, for example, pyrazole, imidazole, 1,2,3-triazole (preferably 1,2,3-triazol-1-yl), 1,2,4-triazole (preferably 1,2,4-triazol-1-yl), tetrazole (preferably tetrazol-2-yl) and furazan.

Examples of N-linked 6-membered di-hydro-heteroaryl rings containing up to three nitrogen heteroatoms in total (including the linking heteroatom) include di-hydro versions of pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine and pyridine.

Particular examples of halogen-substituted alkyl substituents in HET-1 and HET-2 are monofluoromethyl, difluoromethyl, chloromethyl, dichloromethyl and trifluoromethyl.

A particular example of R₈as a halogen-substituted alkyl group is trifluoromethyl.

In this specification the term ‘alkyl’ includes straight chain and branched structures. For example, (1-4C)alkyl includes propyl and isopropyl. However, references to individual alkyl groups such as “propyl” are specific for the straight chain version only, and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. A similar convention applies to other radicals, for example halo(1-4C)alkyl includes 1-bromoethyl and 2-bromoethyl.

In this specification, the terms ‘alkenyl’ and ‘cycloalkenyl’ include all positional and geometrical isomers.

In this specification, the term ‘aryl’ is an unsubstituted carbocyclic aromatic group, in particular phenyl, 1- and 2-naphthyl.

In this specification, where it is stated that a ring may be linked via an sp²carbon atom it is to be understood that the ring is linked via one of the carbon atoms in a C═C double bond.

For the avoidance of doubt, reference to a carbon atom in HET1 or HET2 being substituted by an oxo or thioxo group means replacement of a CH2 by C═O or C═S respectively.

Within this specification composite terms are used to describe groups comprising more that one functionality such as (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkyl. Such terms are to be interpreted in accordance with the meaning which is understood by a person skilled in the art for each component part. For example (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkyl includes methoxymethoxymethyl, ethoxymethoxypropyl and propxyethoxymethyl.

It will be understood that where a group is defined such that is optionally substituted by more than one substituent, then substitution is such that chemically stable compounds are formed. For example, a trifluoromethyl group may be allowed but not a trihydroxymethyl group. This convention is applied wherever optional substituents are defined.

There follow particular and suitable values for certain substituents and groups referred to in this specification. These values may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore, or hereinafter. For the avoidance of doubt each stated species represents a particular and independent aspect of this invention.

Examples of (1-4C)alkyl and (1-5C)alkyl include methyl, ethyl, propyl, isopropyl and t-butyl; examples of (1-6C)alkyl include methyl, ethyl, propyl, isopropyl, t-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; examples of hydroxy(1-4C)alkyl and hydroxy(1-6C)alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 3-hydroxypropyl; examples of hydroxy(2-4C)alkyl include 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl and 2-hydroxyisopropyl; examples of dihydroxy(1-4C)alkyl include 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 2,3-dihydroxypropyl and 1,3-dihydroxypropyl; examples of trihydroxy(1-4C)alkyl include 1,2,3-trihydroxypropyl; examples of (1-4C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; examples of (1-5C)alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and pentoxycarbonyl; examples of 2-((1-4C)alkoxycarbonyl)ethenyl include 2-(methoxycarbonyl)ethenyl and 2-(ethoxycarbonyl)ethenyl; examples of 2-cyano-2-((1-4C)alkyl)ethenyl include 2-cyano-2-methylethenyl and 2-cyano-2-ethylethenyl; examples of 2-nitro-2-((1-4C)alkyl)ethenyl include 2-nitro-2-methylethenyl and 2-nitro-2-ethylethenyl; examples of 2-((1-4C)alkylaminocarbonyl)ethenyl include 2-(methylaminocarbonyl)ethenyl and 2-(ethylaminocarbonyl)ethenyl; examples of (2-4C)alkenyl include allyl and vinyl; examples of (2-4C)alkynyl include ethynyl and 2-propynyl; examples of (1-4C)alkanoyl include formyl, acetyl and propionyl; examples of (1-4C)alkoxy include methoxy, ethoxy and propoxy; examples of (1-6C)alkoxy and (1-10C)alkoxy include methoxy, ethoxy, propoxy and pentoxy; examples of (1-4C)alkylthio include methylthio and ethylthio; examples of (1-4C)alkylamino include methylamino, ethylamino and propylamino; examples of di-((1-4C)alkyl)amino include dimethylamino, N-ethyl-N-methylamino, diethylamino, N-methyl-N-propylamino and dipropylamino; examples of halo groups include fluoro, chloro and bromo; examples of (1-4C)alkylsulfonyl include methylsulfonyl and ethylsulfonyl; examples of (1-4C)alkoxy-(1-4C)alkoxy and (1-6C)alkoxy-(1-6C)alkoxy include methoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy and 3-methoxypropoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include 2-(methoxymethoxy)ethoxy, 2-(2-methoxyethoxy)ethoxy; 3-(2-methoxyethoxy)propoxy and 2-(2-ethoxyethoxy)ethoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include methoxyethoxyethoxyethoxyethoxyethoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include methoxyethoxyethoxyethoxyethoxy; examples of (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxy include methoxyethoxyethoxyethoxy; examples of (1-4C)alkylS(O)₂amino include methylsulfonylamino and ethylsulfonylamino; examples of (1.4C)alkanoylamino 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-methylpropionamido; examples of (1-4C)alkylS(O)_pNH— wherein p is 1 or 2 include methylsulfinylamino, methylsulfonylamino, ethylsulfinylamino and ethylsulfonylamino; examples of (1-4C)alkylS(O)_p((1-4C)alkyl)N— wherein p is 1 or 2 include methylsulfinylmethylamino, methylsulfonylmethylamino, 2-(ethylsulfinyl)ethylamino and 2-(ethylsulfonyl)ethylamino; examples of fluoro(1-4C)alkylS(O)_pNH— wherein p is 1 or 2 include trifluoromethylsulfinylamino and trifluoromethylsulfonylamino; examples of fluoro(1-4C)alkylS(O)_p((1-4C)alkyl)NH— wherein p is 1 or 2 include trifluoromethylsulfylmethylamino and trifluoromethylsulfonylmethylamino examples of (1-4C)alkoxy(hydroxy)phosphoryl include methoxy(hydroxy)phosphoryl and ethoxy(hydroxy)phosphoryl; examples of di-(1-4C)alkoxyphosphoryl include di-methoxyphosphoryl di-ethoxyphosphoryl and ethoxy(methoxy)phosphoryl; examples of (1-4C)alkylS(O)_q— wherein q is 0, 1 or 2 include methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl and ethylsulfonyl; examples of phenyls(O)_qand naphthylS(O)_q— wherein q is 0, 1 or 2 are phenylthio, phenylsulfinyl, phenylsulfonyl and naphthylthio, naphthylsulfinyl and naphthylsulfonyl respectively; examples of benzyloxy-(1-4C)alkyl include benzyloxymethyl and benzyloxyethyl; examples of a (3-4C)alkylene chain are trimethylene or tetramethylene; examples of hydroxy-(2-6C)alkoxy include 2-hydroxyethoxy and 3-hydroxypropoxy; e examples of (1-6C)alkoxy-(1-6C)alkyl and (1-4C)alkoxy(1-4C)alkyl include methoxymethyl ethoxymethyl and propoxyethyl; examples of di(1-4C)alkoxy(1-4C)alkyl include dimethoxymethyl diethoxymethyl 1,2-dimethoxyethyl, 1,2-diethoxyethyl, 2,3-dimethoxypropyl and 1,3-dimethoxypropyl; examples of (1-4C)alkoxy-hydroxy(1-4C)alkyl include 3-methoxy-2-hydroxypropyl, 3-hydroxy-2-methoxypropyl, 3-ethoxy-2-hydroxypropyl and 2-methoxy-2-hydroxyethyl; examples of halomethoxy(1-4C)alkyl include chloromethoxymethyl, chloromethoxyethyl, chloromethoxypropyl, chloromethoxybutyl fluoromethoxymethyl, fluoromethoxyethyl, fluoromethoxypropyl and fluoromethoxybutyl; examples of difluoromethoxy(1-4C)alkyl include difluoromethoxymethyl, difluoromethoxyethyl and difluoromethoxypropyl; examples of dihalomethoxy(1-4C)alkyl include difluoromethoxy(1-4C)alkyl; examples of trifluoromethoxy(1-4C)alkyl include trifluoromethoxymethyl, trifluoromethoxyethyl and trifluoromethoxypropyl; examples of tnhalomethoxy(1-4C)alkyl include trifluoromethoxy(1-4C)alkyl; examples of halomethoxy include chloromethoxy, chloromethoxypropyl, and fluoromethoxymethyl; examples of dihalomethoxy include difluoromethoxy; examples of trihalomethoxy include trifluoromethoxy; examples of (1-4C)alkylamino-(2-6C)alkoxy include 2-methylaminoethoxy and 2-ethylaminoethoxy; examples of di-(1-4C)alkylamino-(2-6C)alkoxy include 2-dimethylaminoethoxy and 2-diethylaminoethoxy; examples of -(1-8C)alkylaryl include benzyl and phenethyl; examples of (1-4C)alkylcarbamoyl include methylcarbamoyl and ethylcarbamoyl; examples of di((1-4C)alkyl)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 groups include fluoro, chloro and bromo; examples of halo(1-4C)alkyl include, halomethyl, 1-haloethyl, 2-haloethyl, and 3-halopropyl; examples of dihalo(1-4C)alkyl include difluoromethyl and dichloromethyl; examples of txihalo(1-4C)alkyl include trifluoromethyl; 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)alkanesulfonamido include methanesulfonamido and ethanesulfonamido; examples of (1-4C)alkylaminosulfonyl include methylaminosulfonyl and ethylaminosulfonyl; and examples of di-(1-4C)alkylaminosulfonyl include dimethylaminosulfonyl, diethylaminosulfonyl and N-methyl-N-ethylaminosulfonyl; examples of (1-4C)alkanesulfonyloxy include methylsulfonyloxy, ethylsulfonyloxy and propylsulfonyloxy; examples of (1-4C)alkanoyloxy include acetoxy, propanoyloxy; examples of (1-6C)alkanoyloxy include acetoxy, propanoyloxy and tert-butanoyloxy; examples of (1-6C)alkanoyloxy(1-4C)alkoxy include acetoxymethoxy, propanoyloxyethoxy and tert-butylcarbonyloxymethoxy; examples of carboxy(1-4C)alkoxy include carboxymethoxy, carboxyethoxy and carboxypropoxy; examples of (1-4C)alkylaminocarbonyl include methylaminocarbonyl and ethylaminocarbonyl; examples of di((1-4C)alkyl)aminocarbonyl include dimethylaminocarbonyl and diethylaminocarbonyl; examples of (3-8C)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; examples of (4-7C)cycloalkyl include cyclobutyl, cyclopentyl and cyclohexyl; examples of (3-6C)cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl; examples of di(N-(1-4C)alkyl)aminomethylimino include dimethylaminomethylimino and diethylaminomethylimino; examples of (1-4C)alkyl-S(O)q -hydroxy(1-4C)alkyl where q is 0, 1 or 2 include 3-(methylthio)-2-hydroxypropyl, 2-(methylthio)-3-hydroxypropyl, 3-(methylsulfinyl)-2-hydroxypropyl and 3-(methylsulfonyl)-2-hydroxypropyl; examples of cyano-(hydroxy)(1-4C)alkyl include 2-cyano-3-hydroxypropyl, 3-cyano-2-hydroxypropyl, Examples of morpholino-ethoxy(1-4C)alkyl and (N′-methyl)piperazino-ethoxy(1-4C)alkyl are illustrated by:
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Examples of 2-, 3-, or 4-pyridyl(1-6C)alkyloxy(1-4C)alkyl are illustrated by

Examples of 2-, 3-, or 4-pyridyl(1-4C)alkyloxy(1-4C)alkyl are as illustrated above for 2-, 3-, or 4-pyridyl(1-6C)alkyloxy(1-4C)alkyl but wherein m=1 to 4. Examples of 2-, 3-, or 4-pyridyl(1-6C)alkylamino(1-4C)alkyl, are analogous to the alkyloxy compounds above, with NH replacing the O; similarly, examples of 2-, 3-, or 4-pyridyl(1-6C)alkylsulfonyl(1-4C)alkyl are compounds as shown above with SO₂replacing the O.

Examples of N-methyl(imidazo -2 or 3-yl)(1-4C)alkyloxy(1-4C)alkyl are illustrated by
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Examples of imidazo-1-yl(1-6C)alkyoxy(1-4C)alkyl are illustrated by

Examples of 5- and 6-membered ring acetals and methyl and phenyl derivatives thereof are 3-dioxolan-4-yl, 2-methyl-1,3-dioxolan-4-yl, 2,2-dimethyl-1,3-dioxolan-4-yl, 2,2-dimethyl-1,3-dioxan-4-yl, 2,2-dimethyl-1,3-dioxan-5-yl, 1,3-dioxan-2-yl, 2-phenyl-1,3-dioxolan-4-yl and 2-(4-methylphenyl)-1,3-dioxolan-4-yl.

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

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

Particular examples of AR2b include, for example, tetrahydrofuran, pyrrolidine, morpholine (preferably morpholino), thiomorpholine (preferably thiomorpholino), piperazine (preferably piperazino), imidazoline and piperidine, 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl. Further particular examples are 5- and 6-membered ring acetals as hereinbefore defined.

Particular values for AR3 include, for example, bicyclic benzo-fused systems containing a 5- or 6-membered heteroaryl ring containing one nitrogen atom and optionally 1-3 further heteroatoms chosen from oxygen, sulfur and nitrogen. Specific examples of such ring systems include, for example, indole, benzofuran, benzothiophene, benzimidazole, benzothiazole, benzisothiazole, benzoxazole, benzisoxazole, quinoline, quinoxaline, quinazoline, phthalazine and cinnoline.

Other particular examples of AR3 include 5/5-, 5/6 and 6/6 bicyclic ring systems containing heteroatoms in both of the rings. Specific examples of such ring systems include, for example, purine and naphthyridine.

Further particular examples of AR3 include bicyclic heteroaryl ring systems with at least one bridgehead nitrogen and optionally a further 1-3 heteroatoms chosen 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, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, pyrazolo[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-triazole[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 ring systems are imidazooxazole or imidazothiazole, in particular imidazo[5,1-b]thiazole, imidazo[2,1-b]thiazole, imidazo[5,1-b]oxazole or imidazo[2,1-b]oxazole.

Particular 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]oxazol-6-yl, (7aS)[5H]-1,2,3,7a-tetrahydropyrrolo[1,2c]imidazol-6-yl, (7aR)[3H,5H]-1,7a-dihydropyrrolo[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]pyrid-7-yl, [311]-5,8-dihydroxazolo[3,4-a]pyrid-7-yl and 5,8-dihydroimidazo-[1,5-a]pyrid-7-yl.

Particular values for AR4 include, for example, pyrrolo[a]quinoline, 2,3-pyrroloisoquinoline, pyirolo[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.

The nomenclature used is that found in, 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 substitution is preferably not geminal disubstitution unless stated otherwise. If not stated elsewhere, suitable optional substituents for a particular group are those as stated for similar groups herein.

Preferable optional substituents on Ar2b as 1,3-dioxolan-4-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl or 1,4-dioxan-2-yl are mono- or disubstitution by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (1-4C)alkanoyl, cyano, trifluoromethyl and phenyl].

Preferable optional substituents on CY1 & CY2 are mono- or disubstitution by substituents independently selected from (1-4C)alkyl (including geminal disubstitution), hydroxy, (1-4C)alkoxy, (1-4C)alkylthio, acetamido, (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. Also suitable are salts formed with phosphoric and sulfuric acid. In another aspect suitable salts are base salts such as an alkali metal salt for example sodium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamine and amino acids such as lysine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.

The compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the invention. A prodrug may be used to alter or improve the physical and/or pharmacokinetic profile of the parent compound and can be formed when the parent compound contains a suitable group or substituent which can be derivatised to form a prodrug. Examples of pro-drugs include in-vivo hydrolysable esters of a compound of the invention or a pharmaceutically-acceptable salt thereof.

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

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol, 42, p. 309-396, edited by K Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. 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 pro-drugs for pyridine or triazole derivatives include acyloxymethyl pyridinium or triazolium salts eg halides; for example a pro-drug such as:
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(Ref: T. Yamazaki et al. 42^ndInterscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, 2002; Abstract F820).

Suitable pro-drugs of hydroxyl groups are acyl esters of acetal-carbonate esters of formula RCOOC(R,R′)OCO—, where R is (1-4C)alkyl and R′ is (1-4C)alkyl or H. Further suitable prodrugs are carbonate and carabamate esters RCOO— and RNHCOO—.

An in-vivo hydrolysable ester of a compound of the invention or a pharmaceutically-acceptable salt thereof containing a carboxy or hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent alcohol.

Suitable pharmaceutically-acceptable esters for carboxy include (1-6C)alkoxymethyl esters for example methoxymethyl, (1-6C)alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, (3-8C)cycloalkoxycarbonyloxy(1-6C)alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolan-2-onylmethyl esters for example 5-methyl-1,3-dioxolan-2-ylmethyl; and (1-6C)alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl and may be formed at any carboxy group in the compounds of this invention.

An in-vivo hydrolysable ester of a compound of the invention or a pharmaceutically-acceptable salt thereof containing a hydroxy group or groups includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include (1-10C)alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, (1-10C)alkoxycarbonyl (to give alkyl carbonate esters), di-(1-4C)alkylcarbamoyl and N-(di-(1-4C)alkylaminoethyl)-N-(1-4C)alkylcarbamoyl (to give carbamates), 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 morpholino or piperazino linked from a ring nitrogen atom via a methylene linking group to the 3- or 4-position of the benzoyl ring. Other interesting in-vivo hydrolysable esters include, for example, R^AC(O)O(1-6C)alkyl-CO— (wherein R^Ais for example, optionally substituted benzyloxy-(1-4C)alkyl, or optionally substituted phenyl; suitable substituents on a phenyl group 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 hydrolysable esters of a compound of the formula (I) are described as follows. For example, a 1,2-diol may be cyclised to form a cyclic ester of formula (PD1) or a pyrophosphate of formula (PD2), and a 1,3-diol may be cyclised to form a cyclic ester of the formula (PD3):
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Esters of compounds of formula (I) wherein the HO— function/s in (PD1), (PD2) and (PD3) are protected by (1-4C)alkyl, phenyl or benzyl are useful intermediates for the preparation of such pro-drugs.

Further in-vivo hydrolysable esters include phosphoramidic esters, and also compounds of invention in which any free hydroxy group independently forms a phosphoryl (npd is 1) or phosphiryl (npd is 0) ester of the formula (PD4):
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For the avoidance of doubt, phosphono is —P(O)(OH)₂; (1-4C)alkoxy(hydroxy)-phosphoryl is a mono-(1-4C)alkoxy derivative of —O—P(O)(OH)₂; and di-(1-4C)alkoxyphosphoryl is a di-(1-4C)alkoxy derivative of —O—P(O)(OH)₂.

Useful intermediates for the preparation of such esters include compounds containing a group/s of formula (PD4) in which either or both of the —OH groups in (PD1) is independently protected by (1-4C)alkyl (such compounds also being interesting compounds in their own right), phenyl or phenyl-(1-4C)alkyl (such phenyl groups being optionally substituted by 1 or 2 groups independently selected from (1-4C)alkyl, nitro, halo and (1-4C)alkoxy).

Thus, prodrugs containing groups such as (PD1), (PD2), (PD3) and (PD4) may be prepared by reaction of a compound of invention containing suitable hydroxy group/s with a suitably protected phosphorylating agent (for example, containing a chloro or dialkylamino leaving group), followed by oxidation (if necessary) and deprotection.

Other suitable prodrugs include phosphonooxymethyl ethers and their salts, for example a prodrug of R—OH such as:
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When a compound of invention contains a number of free hydroxy group, those groups not being converted into a prodrug functionality may be protected (for example, using a t-butyl-dimethylsilyl group), and later deprotected. Also, enzymatic methods may be used to selectively phosphorylate or dephosphorylate alcohol functionalities.

Where pharmaceutically-acceptable salts of an in-vivo hydrolysable ester may be formed this is achieved by conventional techniques. Thus, for example, compounds containing a group of formula (PD1), (PD2), (PD3) and/or (PD4) may ionise (partially or fully) to form salts with an appropriate number of counter-ions. Thus, by way of example, if an in-vivo hydrolysable ester prodrug of a compound of invention contains two (PD4) groups, there are four HO—P— functionalities present in the overall molecule, each of which may form an appropriate salt (i.e. the overall molecule may form, for example, a mono-, di-, tri- or tetra-sodium salt).

The compounds of the present invention have a chiral centre at the C-5 position of the oxazolidinone or isoxazoline ring B. Where m>0 there may be additional chiral centres at C-4 and/or C-5 position of Ring A The pharmaceutically active diastereomers are of the formula (Ia):
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wherein the chiral centre of ring B is fixed in the orientation shown (generally the (5R) configuration, depending on the nature of R₁b, C and B) and ring B is acting as a pharmacophoric group; and wherein the substitution pattern and orientation of the chiral centre(s) at ring A may vary and may influence whether ring A also independently binds to a pharmacophore binding site.

For example when ring A is an isoxazoline ring and ring B is an oxazolidinone, the compounds of the present invention have a chiral centre at the C-5 positions of the oxazolidinone ring and, at the C-4 and/or C-5 position of the isoxazoline ring depending on the value of n (and provided that if n is 2, the isoxazoline ring is not geminally disubstituted by identical substituents). The pharmaceutically active diastereomer is then of the formula (Ib) (illustrated where group C is represented by group H):
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and a preferred diastereomer is of the formula (Ic):

The present invention includes the pure diastereomer (Ic) depicted above, or a mixture of diastereomers wherein the substituent on the isoxazoline ring (C-5′ in structure (Ic)) is a mixture of epimers.

Where R₁b is N-linked-1,2,3-triazole, the pure diastereomer represented by (Ic) has the (5R) configuration on the oxazolidinone ring. Where R₁b is —NH(C═O)R₄, the pure diastereomer represented by (Ic) has the (5S) configuration on the oxazolidinone ring. The diasteromer (Ic) depicted above generally has the (5′S) configuration on the isoxazoline ring, although certain compounds (dependant on the nature of R₁a) have the (5′R) configuration on the isoxazoline ring.

Where R₁b is N-linked-1,2,3-triazole, a mixture of diastereomers represented by (Ic) is described herein as a mixture of the (5R,5′S) and (5R,5′R) diastereomers. Where R₁b is —NH(C═O)R₄, a mixture of diastereomers represented by (Ic) is described herein as a mixture of the (5S,5′S) and (5S,5′R) diastereomers.

If a mixture of epimers on the oxazolidinone chiral center is used, a larger amount (depending upon the ratio of the diastereoisomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer.

Furthermore, some compounds of the invention may have other chiral centres, for example at C-4′. Where the substituent on an isoxazoline ring is at C-4′, a similar convention applies to that described above for substituents at C-5′. There is also, for example, the possibility of a substituent at both C-4′ and C-5′, and the possibility that such substituents may themselves contain chiral centres. It is to be understood that the invention encompasses all such optical and diastereoisomers, and racemic mixtures, that possess antibacterial activity. It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation) and how to determine antibacterial activity as described hereinafter.

Some compounds of the invention may have more favourable MAO profiles than other compounds of the invention, which may arise from the stereochemistry and/or steric bulk of the substituent(s) on the isoxazoline ring. This is illustrated by the following examples, wherein the MAO activity is dependent on the stereochemical configration of the substituent R₄on the isoxazoline ring. These examples illustrate that their (5′S) epimer has the higher Ki value (lower potency).

ExampleMAO-A KINoStructure(μM)51 embedded image

60*52

35*53

60 54

8
*= approximate values

The invention relates to all tautomeric forms of the compounds of the invention that possess antibacterial activity.

It is also to be understood that certain compounds of the invention can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity.

It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms which possess antibacterial activity.

As stated before, we have discovered a range of compounds that have good activity against a broad range of Gram-positive pathogens including organisms known to be resistant to most commonly used antibiotics, together with activity against fastidious Gram negative pathogens such as H. influenzae, M. catarrhalis, Mycoplasma and Chlamydia strains. The following compounds possess preferred pharmaceutical and/or physical and/or pharmacokinetic properties.

In one embodiment of the invention are provided compounds of formula (I), in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (I), in a further alternative embodiment are provided in-vivo hydrolysable esters of compounds of formula (I), and in a further alternative embodiment are provided pharmaceutically-acceptable salts of in-vivo hydrolysable esters of compounds of formula (I).

In one aspect, an in-vivo hydrolysable ester of a compound of the formula (I) is a phosphoryl ester (as defined by formula (PD4) with npd as 1).

Compounds of the formula (I), or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein C is selected from any one of groups D to 0 represent separate and independent aspects of the invention.

Particularly preferred compounds of the invention comprise a compound of the invention, or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein the substituents A, B, C, RT, R₁a, R₁b, R₂a, R₂b, R₃a, R₃b R₅a, R₅a′, R₆a and R₆a′and other substituents mentioned above have values disclosed hereinbefore, or any of the following values (which may be used where appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter):

In one embodiment are provided compounds as defined herein in formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, in which group C is represented by group D.

In another embodiment are provided compounds as defined herein in formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, in which group C is represented by group E.

In another embodiment are provided compounds of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, in which group C is represented by a group selected from groups D, E, H and I as hereinbefore defined.

In a further embodiment are provided compounds of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, in which group C is represented by a group selected from groups D and E as hereinbefore defined.

In a most particular aspect group C is represented by group H.

In one aspect both A and B are oxazolidinone rings.

In another aspect, either A or B is an oxazolidinone ring and the other is an isoxazoline ring.

In a further aspect both A and B are isoxazoline rings.

In a most particular aspect A is an isoxazoline ring and B is an oxazolidinone ring.

In a most particular aspect, R₂b and R₆b are independently selected from H, F, Cl, CF₃, OMe, SMe, Me and Et.

In one aspect, R₂b and R₆b are independently selected from H, F, Cl, CF₃, OMe, Me and Et.

In another aspect, R₂b and R₆b are independently H or F.

In one aspect R₂b′ and R₆b′ are both H.

In a most particular aspect R₂a′ and R₆a′ are both H.

In a most particular aspect R₃a and R₅a are both H.

In a most particular aspect R₃a′, R₅a′ are both H.

In one aspect R₁a is selected from R₁a1 to R₁a4.

When m=1, in one aspect R₁a is selected from R₁a1; in another aspect R₁a is selected from R₁a2; in a further aspect R₁a is selected from R₁a3 and in a further aspect R₁a is selected from R₁a4.

When m=2, in one aspect both groups R₁a are independently selected from the same group R₁a1 to R₁a4. In a further aspect when m=2, each R₁a is independently selected from different groups R₁a1 to R₁a4.

Conveniently, m is 1 or 2. In one embodiment preferably m is 1. In another embodiment, preferably m is 2.

In one aspect, when m is 2, both substituents R₁a are attached to position 4 of ring A and joined together to form a 5-7 membered spiro-ring.

In one aspect, when m is 2, both substituents R₁a are attached to position 5 of ring A and joined together to form a 5-7 membered spiro-ring.

In another aspect, when m is 2, one substituent R₁a is attached to position 4 of ring A, and the other is attached to position 5 of ring A, such that taken together with A they form a 5-7 membered fused-ring.

In a particular aspect when m is 2, the two substituents R₁a are identical to each other, preferably selected from R₁a3 and are attached to the same position (4 or 5) of ring A such that ring A does not have a chiral centre. Suitably both R₁a are hydroxymethyl.

In a particular aspect is provided a compound of formula (Ib) as hereinbefore defined, wherein:

a) m is 1 and R₁a is a substituent on C-4′ (in one embodiment the isoxazoline ring is of the (4′S) configuration; in another the isoxazoline ring is of the (4′R) configuration); or

b) m is 1 and R₁a is a substituent on C-5′ (in one embodiment the isoxazoline ring is of the (5′S) configuration, in another the isoxazoline ring is of the (5′R) configuration); or

c) m is 2 and both substituents R₁a are substituents on C-4′; or

d) m is 2 and both substituents R₁a are substituents on C-5′; or

e) m is 2, one substituent R₁a is on C-4′ and the other is on C-5′; in one embodiment, both substituents R₄are the same; in another the substituents R₁a are not the same;

f) when m is 2 and one R₁a is a substituent on C-4′ and the other R₁a is a substituent on C-5′, in one aspect the isoxazoline ring is of the (5′S) configuration.

Particular values for R₁a when selected from R₁a1 are AR1 and AR2, more particularly AR2.

Particular values for R₁a when selected from R₁a2 are cyano and —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 (optionally substituted on a carbon not adjacent to the nitrogen), (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 is optionally substituted by cyano, hydroxy or halo]. More particular values for R₁a when selected from R₁a2 are cyano, formyl, —COO(1-4C)alkyl, —C(═O)NH₂, —(C═O)piperazine and —(C═O)morpholine.

Particular values for R₁a when selected from R₁a3 are (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)akylcarbonyl, phosphoryl [—O—P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivatives thereof], phosphiryl [—O—P(OH)₂and mono- and di-(1-4C)alkoxy derivatives thereof], and amino; and/or optionally substituted by one group selected from carboxy, 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, Rv and Rw are independently H, or (1-4C)alkyl and wherein Rv and Rw taken together with the amide nitrogen to which they are attached can form a morpholine, pyrrolidine, piperidine or piperazine 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 and (1-4C)alkanoyl], (1-4C)alkylS(O)_q—, (q is 0, 1 or 2), AR2, AR2-O—, AR2-NH—, and also AR2a, AR2b versions of AR2 containing groups}; wherein any (1-4C)alkyl and (1-4C)acyl 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;

More particular values for R₁a when selected from R₁a3 are (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, phosphoryl [—O—P(O)(OH)₂, and mono- and di-(1-4C)alkoxy derivatives thereof), phosphiryl [—O—P(OH)₂and mono- and di-(1-4C)alkoxy derivatives thereof), carboxy, amino, (1-4C)alkylamino, di(1-4C)alkylamino, (1-4C)alkylS(O)q (preferably where q=2), AR2 and AR2b. More particular values for R₁a when selected from R₁a3 are (1-6C)alkyl substituted as hereinbefore described. Even more particular values for R₁a when selected from R₁a3 are (1-4C)alkyl substituted as hereinbefore described.

In one aspect R₁a4: is R¹⁴C(O)O(1-6C)alkyl [wherein R¹⁴is AR1, AR2, AR2a, AR2b, (1-4C)alkylamino, benzyloxy-(1-4C)alkyl or (1-10C)alkyl {optionally substituted as defined for (R₁a3)].

Particular values for R₁a when selected from R₁a4 are R¹⁴C(O)O(1-6C)alkyl—wherein R¹⁴is selected from AR1, AR2, AR2a, AR2b and (1-10C)alkyl (optionally substituted by one or more substituents independently selected from OH and di (1-4C)alkylamino. More particular vales for R¹⁴are AR2a, AR2b and (1-6C)alkyl substituted with hydroxy. More particular values for R¹⁴are AR2a, AR2b and (1-4C)alkyl substituted with hydroxy.

Particular values for R₁a when selected from R₁a5 are fluoro, chloro and hydroxy.

In a most particular aspect, R₁a is selected from (1-4C)alkyl (optionally substituted on an available carbon atom with one, two, three or more substituents independently selected from F, Cl and Br), hydroxy(2-4C)alkyl, dihydroxy(1-4C)alkyl, trihydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, trifluoromethoxy(1-4C)alkyl, difluoromethoxy(1-4C)alkyl, halomethoxy(1-4C)alkyl, di[(1-4C)alkoxy](1-4C)alkyl, (1-4C)alkoxy-(hydroxy)(1-4C)alkyl, (1-4C)alkyl-S(O)_q-hydroxy(1-4C)alkyl (where q is 0, 1 or 2), cyano(hydroxy)(1-4C)alkyl, morpholino-ethoxy(1-4C)alkyl, (N′-methyl)piperazino-ethoxy(1-4C)alkyl, 2-, 3-, or 4-pyridyl(1-6C)alkoxy(1-4C)alkyl, N-methyl(imidazo-2 or 3-yl)(1-4C)alkoxy(1-4C)alkyl, imidazo-1-yl(1-6C)alkoxy(1-4C)alkyl, and 5- and 6-membered ring acetals (optionally substituted with one or two substituents independently selected from methyl and phenyl (wherein the phenyl group is itself optionally substituted with one or two substituents selected from methyl, methoxy, chloro and bromo)).

In an alternative most particular aspect, R₁a is selected from (1-4C)alkyl, hydroxy(2-4C)alkyl, dihydroxy(1-4C)alkyl, trihydroxy(1-4C)alkyl, (1-4C)alkoxy(1-4C)alkyl, di[(1-4C)alkoxy](1-4C)alkyl, (1-4C)alkoxy-(hydroxy)(1-4C)alkyl, (1-4C)alkyl-S(O)q-hydroxy(1-4C)alkyl (where q is 0, 1 or 2), cyano-(hydroxy)(1-4C)alkyl, morpholino-ethoxy(1-4C)alkyl, (N′-methyl)piperazino-ethoxy(1-4C)alkyl, 2-, 3-, or 4-pyridyl(1-6C)alkoxymethyl, N-methyl(imidazo-2 or 3-yl)(1-6C) alkoxymethyl, imidazo-1-yl(1-6C)alkyl, 5- and 6-membered ring acetals (optionally substituted with one or two substituents independently selected from methyl and phenyl (wherein the phenyl group is itself optionally substituted with one or two substituents selected from methyl methoxy, chloro and bromo)).

Further particular values for R₁a are (1-4C)alkylS(O)_q—, where q is 0, 1 or 2 and wherien the (1-4C)alkyl group is optionally substitued with hydroxy.

When R₁a is selected from 2-, 3-, or 4-pyridyl(1-4C)alkyloxy(1-4C)alkyl, N-methyl(imidazo-2 or 3-yl)(1-4C)alkyloxy(1-4C)alkyl, and imidazo-1-yl(1-6C)alkyoxy(1-4C)alkyl, it is preferably selected from 2-, 3-, or 4-pyridyl(1-4C)alkyloxymethyl, N-methyl(imidazo-2 or 3-yl)(1-4C)alkyloxymethyl, and imidazo-1-yl(1-6C)alkyoxymethyl.

References hereinafter to R₁a being selected from (1-4C)alkyl include (1-4C)alkyl optionally substituted on an available carbon atom with one, two, three or more substituents independently selected from P, Cl and Br. In one embodiment, such a (1-4C)alkyl group is optionally substituted by one, two or three substituents independently selected from F, Cl and Br. In another embodiment, such a (1-4C)alkyl group is optionally substituted by one, two or three substituents independently selected from F and Cl, so that R₁a is selected from, for example, chloromethyl fluoromethyl, difluoromethyl, trifluoromethyl, chloroethyl and fluoroethyl.

When m is 1:

in one aspect R₁a is selected from (1-4C)alkyl hydroxy(2-4C)alkyl, dihydroxy(1-4C)alkyl and trihydroxy(1-4C)alkyl;

in another aspect, R₁a is selected from (1-4C)alkoxy(1-4C)alkyl, di[(1-4C)alkoxy](1-4C)alkyl, 3-dioxolan-4-yl, 2-methyl-1,3-dioxolan-4-yl, 2,2-dimethyl-1,3-dioxolan-4-yl, 2,2-dimethyl-1,3-dioxan-4-yl, 2,2-dimethyl-1,3-dioxan-5-yl and 1,3-dioxan-2-yl;

in a further aspect, R₁a is selected from halomethoxy(1-4C)allyl and 2-, 3-, or 4-pyridyl(1-4C)alkyloxymethyl;

in a further aspect, R₁a is selected from trifluoromethoxy(1-4C)alkyl, difluoromethoxy(1-4C)alkyl and fluoromethoxy(1-4C)alkyl;

in a further aspect, R₁a is selected from morpholino-ethoxy(1-4C)alkyl, (N′-methyl)piperazino-ethoxy(1-4C)alkyl, 2-, 3-, or 4-pyridyl(1-4C)alkyloxy(1-4C)alkyl, N-ethyl(imidazo-2 or 3-yl)(1-4C)alkyloxy(1-4C)alkyl, and imidazo-1-yl(1-6C)alkyoxy(1-4C)alkyl,

When m is 1, suitably R₁a is selected from hydroxy(2-4C)alkyl and dihydroxy(1-4C)alkyl, More suitably, R₁a is selected from hydroxyethyl and 1,2-dihydroxyethyl, Preferably, when m is 1, R₁a is 1,2-dihydroxyethyl.

When m is 2:

in one aspect each R₁a is independently selected from (1-4C)alkyl, hydroxy(1-4C)alkyl, dihydroxy(1-4C)alkyl and trihydroxy(1-4C)alkyl;

in another aspect, each R₁a is independently selected from (1-4C)alkoxy(1-4C)alkyl and di[(1-4C)alkoxy](1-4C)alkyl;

in a further aspect, at least one R₁a is selected from halomethoxy(1-4C)alkyl and 2-, 3- or 4-pyridyl(1-4C)alkyloxymethyl;

in a further aspect, at least one R₁a is selected from trifluoromethoxy(1-4C)alkyl, difluoromethoxy(1-4C)alkyl and fluoromethoxy(1-4C)alkyl;

in a further aspect, one R₁a is selected from (1-4C)alkyl, hydroxy(1-4C)alkyl, dihydroxy(1-4C)alkyl and trihydroxy(1-4C)alkyl; and the other R₁a is selected from (1-4C)alkoxy(1-4C)alkyl and di[(1-4C)alkoxy](1-4C)alkyl;

in a further aspect, one R₁a is selected from (1-4C)alkyl, hydroxy(1-4C)alkyl, dihydroxy(1-4C)alkyl and trihydroxy(1-4C)alkyl; and the other R₁a is selected from halomethoxy(1-4C)alkyl and 2-, 3-, or 4-pyridyl(1-4C)alkyloxymethyl.

When m is 2, preferably both R₁a are hydroxymethyl or both hydroxyethyl. In another aspect, when m is 2, preferably one R₁a is hydroxymethyl and the other is methoxymethyl.

In all of the embodiments, aspects and preferable values for R₁b defined hereinbefore or hereinafter, any (1-4C)alkyl group may be optionally substituted as hereinbefore defined. Particular substituents for (1-4C)alkyl groups in definitions for R₁b are one or two halogen groups, particularly geminal disubstitution (provided that such substitution is not on a carbon atom attached to an oxygen) and cyano. Examples of di-halosubstituted groups are —NHCOCF₂H and —NHCSCCl₂H.

When R₁b is —N(R₅)HET-1, R₅is preferably hydrogen.

In one embodiment R₁b is selected from hydroxy, —NHCO(1-4C)alkyl, 5-NHCO(3-6C)cycloalkyl, —NHCS(1-4C)alkyl, —NHCOO(1-4C)alkyl, —NH(C═S)O(1-4C)alkyl, —OCO(1-4C)alkyl, —N(R₅)-HET-1 and HET-2.

In another embodiment R₁b is selected from —NHCO(1-4C)alkyl, —NHCO(3-6C)cycloalkyl, —NHCS(1-4C)alkyl, —N(R₅)-HET-I and HET-2.

More preferably R₁b is selected from —NHCO(1-4C)alkyl, —NHCS(1-4C)alkyl, —N(R₅)-HET-1 and HET-2.

In one aspect, R₁b is selected from OH, —NR₅C(═W)R₄and —OC(═O)R₄, in particular OH, —NHCOMe and —NHCOOMe.

In a further aspect, R₁b is selected from —N(R₅)-HET-1 and HET-2, in particular HET-1 as isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2 as 1,2,3-triazol-1-yl (optionally substituted) or tetrazol-2-yl, In a most particular aspect, R₄is selected from the values given hereinbefore.

In one aspect R₄is selected from hydrogen, amino, (1-8C)alkyl, —NHR₁₂, —N(R₁₂)(R₁₃), —OR₁₂or —SR₁₂, (2-4C)alkenyl, -(1-8C)alkylaryl, mono-, di-, tri- and per-halo(1-8C)alkyl, —(CH₂)_p(3-6C)cycloalkyl and —(CH₂)p(3-6C)cycloalkenyl wherein p is 0, 1 or 2;

In one embodiment R₁b is selected from hydroxy, —NHC(═W)R₄, —OC(═O)R₄, and
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wherein W, R₅and R₆are as defined hereinbefore, R₄is selected from hydrogen, amino, (1-4C)alkyl, —NH(1-4C)alkyl, —N(di-(1-4C)alkyl), —O(1-4C)alkyl, —S(1-4C)alkyl, (2-4C)alkenyl, —(CH₂)_p(3-6C)cycloalkyl and —(CH₂)_p(3-6C)cycloalkenyl wherein p is 0, 1 or 2; and R₇is selected from hydrogen, (1-8C)alkyl, —OR₁₂, —SR₁₂, amino, NHR₁₂, N(R₁₂)(R₁₃), (1-8C)alkylaryl and mono-, di-, tri- and per-halo(1-8C)alkyl.

In another embodiment, R₁b is selected from hydroxy, —NHC(═W)R₄, —OC(═O)R₄, and
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wherein W, R₄, R₅, R₆and R₇are as defined hereinbefore, especially wherein R₄is (1-4C)alkyl, (1-4C)alkoxy, cycloalkyl (particularly cyclopropyl) or haloalkyl (particularly dichloromethyl).

In another embodiment, R₁b is selected from hydroxy, —NHC(═W)₄, —OC(═O)R₄, and
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wherein W, R₄, R₅, R₆and R₇are as defined hereinbefore, especially wherein R is (1-4C)alkyl or (1-4C)alkoxy.

Particular values for R₅(which may be used as appropriate with any of the definitions and embodiments disclosed hereinbefore or hereinafter) are hydrogen, tert-butoxycarbonyl and benzyloxycarbonyl. More particularly, R₅is hydrogen.

In one aspect R₁₂and R₁₃are independently selected from hydrogen, alkyl and aryl, or for any N(R₁₂)(R₁₃) group, R₁₂and R₁₃may additionally be taken together with the nitrogen atom to which they are attached to form a pyrrolidinyl, piperidinyl or morpholinyl group, optionally substituted as hereinbefore described. In one aspect R₁₅and R₁₆are independently selected from hydrogen, phenyl and (1-4C)alkyl).

In a most particular aspect, R₁₂and R₁₃are independently selected from hydrogen and methyl

In one embodiment HET-1 and HET-2 are unsubstituted. When substituted, preferred substituents are selected from halo (particularly chloro), (1-4C)alkyl, especially methyl, mono- and di-halo methyl (wherein halo is preferably fluoro, chloro or bromo), trifluoromethyl and cyanomethyl.

Preferred are HET-1 and HET-2 as 5-membered rings, ie HET-1 as HET-1A and HET_—2 as HET-2A, in particular HET-1A as isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2A as 1,2,3-triazol-1-yl or tetrazol-2-yl.

In one aspect, HET-2A as 1,2,3-triazol-1-yl is substituted, preferably by halo (particularly chloro), methyl difluoromethyl, fluoromethyl chloromethyl, cyanomethyl or trifluoromethyl.

In one embodiment HET-2A is selected from the structures (Za) to (Zf) below:
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wherein u and v are independently 0 or 1 and RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter.

In one embodiment HET-2A is selected from 1,2,3-triazole (especially 1,2,3-triazol-1-yl (Zd)), 1,2,4-triazole (especially 1,2,4-triazol-1-yl (Zc)) and tetrazole (preferably tetrazol-2-yl (Zf)) and wherein u and v are independently 0 or 1 and RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter.

In another embodiment HET-2A is selected from 1,2,3-triazol-1-yl (Zd) and tetrazol-2-yl (Zf) and wherein u and v are independently 0 or 1 and RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter.

In another embodiment HET-2A is 1,2,3-triazol-1-yl (Zd) and wherein u and v are independently 0 or 1 and RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter.

In one embodiment HET-2B is a di-hydro version of pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine and pyridine and wherein RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter.

In another embodiment HET-2B is selected from pyrimidone, pyridazinone, pyrazinone, 1,2,3-triazinone, 1,2,4-triazinone, 1,3,5-triazinone and pyridone and wherein RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter.

In another embodiment HET-2B is selected from thiopyrimidone, thiopyridazinone, thiopyrazinone, thio-1,2,3-triazinone, thio-1,2,4-triazinone, thio-1,3,5-triazinone and thiopyridone and wherein RT is as defined in any of the embodiments or aspects defined hereinbefore or hereinafter.

In a most particular aspect, R₁b is —NH(C═W)R₄or (Zd).

In one aspect R₁b is —NH(C═O)R₄.

In another aspect R₁b is (Zd).

When W is O, suitably R is selected from methyl ethyl, dichloromethyl and cyclopropyl.

When W is S, suitably R₄is selected from (1-4C)alkyl (optionally substituted by 1, 2 or 3 substituents independently selected from methyl, chloro, bromo, fluoro and methoxy), —N(R₁₂)(R₁₃) and —OR₁₂. More suitably, when W is S, R₄is selected from —NH₂, —NHMe, —OMe, —SMe and methyl.

In one aspect (RTa1) is selected from 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.

In one aspect RT is preferably selected from a substituent from the group

(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; or,

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

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

(RTb2) a (1-4C)alkyl group which is optionally substituted by one substituent selected from (2-4C)alkenyloxy, (3-6C)cycloalkyl and (3-6C)cycloalkenyl;

and wherein at each occurrence of an RT substituent containing an alkyl, alkenyl alkynyl, cycloalkyl or cycloalkenyl moiety in (RTa1) or (RTa2), or (RTb1) or (RTb2) each such moiety is optionally substituted on an available carbon atom with one, two, three or more substituents independently selected from F, Cl, Br, OH and CN.

In another aspect RT is preferably selected from a substituent from the group:

(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; or

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

and wherein at each occurrence of an RT substituent containing an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety in (RTa1) or (RTb1) each such moiety is optionally substituted on an available carbon atom with one, two, three or more substituents independently selected from F, CL Br, and CN.

In a further aspect RT is most preferably

(a) hydrogen; or
(b) halogen, in particular fluorine, chlorine, or bromine; or
(c) cyano; or
(d) (1-4C)alkyl, in particular methyl; or
(e) monosubstituted (1-4C)alkyl, in particular fluoromethyl, choromethyl, bromomethyl, cyanomethyl, azidomethyl, hydroxymethyl; or
(f) disubstituted (1-4C)alkyl, for example difluoromethyl, or trisubstituted (1-4C)alkyl, for example trifluoromethyl.

In a most particular aspect, RT is selected from hydrogen, halogen, cyano, (1-4C)alkyl, cyano(1-4C)alkyl, halo(1-4C)alkyl, dihalo(1-4C)alkyl, trihalo(1-4C)alkyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (1-4C)alkylthio, (1-4C)alkoxy, 1-4C)alkoxy(1-4C)alkyl, (2-4C)alkenyloxy, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl and (1-4C)alkoxycarbonyl; and wherein at each occurrence of an RT substituent containing an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety each such moiety is optionally substituted on an available carbon atom with one, two, three or more substituents independently selected from F, Cl, Br, OH and CN.

In one embodiment of this most particular aspect, RT is selected from hydrogen, halogen, cyano, (1-4C)alkyl, halo(1-4C)alkyl, dihalo(1-4C)alkyl and (2-4C)alkynyl; suitably, RT is selected from hydrogen, chloro, bromo, fluoro, methyl, fluoromethyl, chloromethyl, bromomethyl, difluoromethyl and dichloromethyl, ethynyl and propynyl; more suitably, RT is selected from hydrogen, chloro, bromo, methyl and fluoromethyl.

In one embodiment is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein each of the groups A, B, C, RT, R₄, R₁₂, R₁₃, R₁a, R₁b, R₂a′, R₂b, R₃a, R₆b and R₆a′ is selected from the most particular aspect for that group as described hereinbefore.

In one embodiment is provided a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein group C is represented by any one of groups D, E and H; R₂b and R₆b are independently H or F; A and B are both oxazolidinones; m=0; and R₁b is selected from OH, —NHCOMe, —NHCOcyclopropyl, —NH(C═S)OMe and —NHCOOMe.

In one embodiment is provided a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein group C is represented by any one of groups D, E and H; R₂b and R₆b are independently H or F; A and B are both isoxazolines; m=0; and R₁b is selected from OH, —NHCOMe, —NHCOcyclopropyl, —NH(C═S)OMe and —NHCOOMe.

In one embodiment is provided a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein group C is represented by any one of groups D, E and H; R₂b and R₆b are independently H or F; either A or B is an oxazolidinone and the other is an isoxazoline; m=0; and R₁b is selected from —N(R₅)-HET-1A and HET-2A, in particular HET-1A as isoxazolyl, 1,2,5-thiadiazolyl or isothiazolyl and HET-2A as 1,2,3-triazol-1-yl (optionally substituted) or tetrazol-2-yl. In one embodiment is provided a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein group C is represented by any one of groups D, B and H; R₂b and R₆b are independently H or P; A and B are both oxazolidinones; m=1; R₁a is selected from R₁a1; and R₁b is selected from OH, —NHCOMe, —NHCOcyclopropyl, —NH(C═S)OMe and —NHCOOMe.

In one embodiment is provided a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein group C is represented by any one of groups D, E and H; R₂b and R₆b are independently H or F; A and B are both oxazolidinones; m=2; and R₁b is selected from OH, —NHCOMe, —NHCOcyclopropyl, —NH(C═S)OMe and —NHCOOMe.

In one embodiment is provided a compound of formula (I) or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, wherein group C is represented by any one of groups D, E and H; R₂b and R₆b are independently H or F; A and B are both isoxazolines; m=2; and R₁b is selected from OH, —NHCOMe, —NHCOcyclopropyl, —NH(C═S)OMe and —NHCOOMe.

In all of the above definitions the preferred compounds are as shown in formula (Ia).

In one embodiment is provided a compound of the formula (Id), or a pharmaceutically-acceptable salt or in-vivo hydrolysable ester thereof:
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wherein