Isoxazoline derivatives useful as antimicrobials

Abstract

Compounds of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein, for example, HET is an N-linked 5-membered, fully or partially unsaturated heterocyclic ring, or HET is an N-linked 6-membered di-hydro-heteroaryl ring; Q is, for example, Q1 or Q2: wherein R 2 and R 3 are independently hydrogen or fluoro; T is selected from a range of groups, for example a group of the formula (TC7) wherein Rc is, for example, hydrogen, R 13 CO—, R 13 SO 2 — or R 13 CS—; wherein R 13 is, for example, optionally substituted (1-10C)alkyl or R 14 C(O)O(1-6C)alkyl wherein R 14 is optionally substituted (1-10C)alkyl; are useful as antibacterial agents; and processes for their manufacture and pharmaceutical compositions containing them are described.

1 . A compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof,  
     
       
         
         
             
             
         
       
     
     wherein 
 HET 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 Rs wherein;  
 Rs is selected from the group  
 (Rsa) halogen, (1-4C)alkoxy, (2-4C)alkenyloxy, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, amino, (1-4C)alkylamino, di-(1-4C)alkylamino, (2-4C)alkenylamino, (1-4C)alkylcarbonylamino, (1-4C)alkylthiocarbonylamino, (1-4C)alkyl-OCO—NH—, (1-4C)alkyl-NH—CO—NH—, (1-4C)alkyl-NH—CS—NH—, (1-4C)alkyl-SO 2 —NH— or (1-4C)alkyl-S(O) q — (wherein q is 0, 1 or 2);  
 or Rs is selected from the group  
 (Rsb) (1-4C)alkyl group which is optionally substituted by one substituent selected from hydroxy, (1-4C)alkoxy, amino, cyano, azido, (2-4C)alkenyloxy, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl, (1-4C)alkylamino, (2-4C)alkenylamino, (1-4C)alkyl-SO 2 —NH—, (1-4C)alkylcarbonylamino, (1-4C)alkylthiocarbonylamino, (1-4C)alkyl-OCO—NH—, (1-4C)alkyl-N H—CO—NH—, (1-4C)alkyl-NH—CS—NH—, (1-4C)alkyl-SO 2 —NH—, (1-4C)alkyl-S(O) q — (wherein q is 0, 1 or 2), (3-6C)cycloalkyl, (3-6C)cycloalkenyl, or an N-linked 5-membered heteroaryl ring, which ring contains 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 carbon atom by an oxo or thioxo group;  
 and/or the ring is optionally substituted on a carbon atom by 1 or 2 (1-4C)alkyl groups; and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl;  
 or Rs is selected from a group of formula (Rsc1) to (Rsc3):— 
 (Rsc1) 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; or  
 (Rsc2) a saturated or unsaturated 5-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidised), and linked via a ring nitrogen atom if the ring is not thereby quaternised, or a ring carbon atom; or  
 (Rsc3) a saturated or unsaturated 6- to 8-membered monocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S (optionally oxidised), and linked via a ring nitrogen atom if the ring is not thereby quaternised, or a ring carbon atom;  
 wherein said rings in (Rsc1) to (Rsc3) are optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from hydroxy, (1-4C)alkoxy, amino, cyano, azido, (2-4C)alkenyloxy, (1-4C)alkylcarbonyl, (1-4C)alkoxycarbonyl, (1-4C)alkylamino, (2-4C)alkenylamino, (1-4C)alkyl-SO 2 —NH—, (1-4C)alkylcarbonylamino, (1-4C)alkylthiocarbonylamino, (1-4C)alkyl-OCO—NH—, (1-4C)alkyl-NH—CO—NH—, (1-4C)alkyl-NH—CS—NH—, (1-4C)alkyl-SO 2 —NH—, (1-4C)alkyl-S(O) q — (wherein q is 0, 1 or 2), (3-6C)cycloalkyl or (3-6C)cycloalkenyl;  
 or Rs is selected from the group  
 (Rsd) cyano, nitro, azido, formyl, (1-4C)alkylcarbonyl or (1-4C)alkoxycarbonyl;  
 and wherein at each occurrence of an Rs substituent containing an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl moiety in (Rsa), (Rsb) or (Rsc1) to (Rsc3) each such moiety is optionally further substituted on an available carbon atom with one or more substituents independently selected from F, Cl and Br and/or by one cyano group;  
 and/or which ring is optionally substituted on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl; or  
 HET 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 Rs, wherein Rs is as hereinbefore defined, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl; and  
 wherein at each occurrence of alkyl, alkenyl and cycloalkyl HET substituents, each is optionally substituted with one or more substituents independently selected from F, Cl and Br and/or by one cyano group;  
 Q is selected from Q1 to Q10:— 
                     
 wherein R 2  and R 3  are independently hydrogen or fluoro;  
 wherein A 1  is carbon or nitrogen; B 1  is O or S (or, in Q9 only, NH); X q  is O, S or N—R′ (wherein R 1  is hydrogen, (1-4C)alkyl or hydroxy-(1-4C)alkyl); and wherein in Q7 each A 1  is independently selected from carbon or nitrogen, with a maximum of 2 nitrogen heteroatoms in the 6-membered ring, and Q7 is linked to T via any of the A 1  atoms (when A 1  is carbon), and linked in the 5-membered ring via the specified carbon atom, or via A 1  when A 1  is carbon; Q8 and Q10 are linked to T via either of the specified carbon atoms in the 5-membered ring, and linked in the benzo-ring via either of the two specified carbon atoms on either side of the linking bond shown; and Q9 is linked via either of the two specified carbon atoms on either side of the linking bond shown;  
 wherein T is selected from the groups in (TA) to (TE) below (wherein AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1 and CY2 are defined hereinbelow);  
 (TA) T is selected from the following groups:— 
 (TAa) AR1, AR1-(1-4C)alkyl-, AR2 (carbon linked), AR3;  
 (TAb) AR1-CH(OH), AR2-CH(OH)—, AR3-CH(OH)—;  
 (TAc) AR1-CO—, AR2-CO—, AR3-CO—, AR4-CO—;  
 (TAd) AR1-O—, AR2-O—, AR3-O—;  
 (TAe) AR1-S(O) q —, AR2-S(O) q —, AR3-S(O) q — (q is 0, 1 or 2);  
 (TAf) an optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms;  
 (TAg) a carbon linked tropol-3-one or tropol-4-one, optionally substituted in a position not adjacent to the linking position; or  
 (TB) T is selected from the following groups  
 (TBa) halo or (1-4C)alkyl {optionally substituted by one or more groups each independently selected from hydroxy, (1-4C)alkoxy, (1-4C)alkanoyl, cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl, —NRvRw, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylS(O) q — (q is 0, 1 or 2), CY1, CY2 or AR1};  
 (TBb)-NRv 1 Rw 1 ;  
 (TBc) 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;  
 (TBd) R 10 CO—, R 10 S(O) q — (q is 0, 1 or 2) or R 10 CS— 
 wherein R 10  is selected from the following groups  
 (TBda) CY1 or CY2;  
 (TBdb) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, —NRvRw, 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 or 2-(AR2)ethenyl; or  
 (TBdc) (1-4C)alkyl {optionally substituted as defined in (TBa) above, or by (1-4C)alkylS(O) p NH— or (1-4C)alkylS(O) p -((1-4C)alkyl)N-(p is 1 or 2)};  
 wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl; Rv 1  is hydrogen, (1-4C)alkyl or -(3-8C)cycloalkyl; Rw 1  is hydrogen, (1-4C)alkyl, (3-8C)cycloalkyl, (1-4C)alkyl-CO— or (1-4C)alkylS(O) q — (q is 1 or 2); or  
 (TC) T is selected from the following groups  
 (TCa) an optionally substituted, fully saturated 4-membered monocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S (optionally oxidised), and linked via a ring nitrogen or sp 3  carbon atom;  
 (TCb) an optionally substituted 5-membered monocyclic ring containing 1 heteroatom selected from O, N and S (optionally oxidised), and linked via a ring nitrogen atom or a ring sp 3  or sp 2  carbon atom, which monocyclic ring is fully saturated other than (where appropriate) at a linking sp 2  carbon atom;  
 (TCc) an optionally substituted 7 or 8-membered monocyclic ring containing 1 or 2 heteroatoms independently selected from O, N and S (optionally oxidised), and linked via a ring nitrogen atom or a ring sp 3  or sp 2  carbon atom, which monocyclic ring is fully saturated other than (where appropriate) at a linking sp 2  carbon atom; or  
 (TD) T is selected from the following groups:— 
 (TDa) a bicyclic spiro-ring system containing 0, 1 or 2 ring nitrogen atoms as the only ring heteroatoms, the structure consisting of a 5- or 6-membered ring system (linked via a ring nitrogen atom or a ring sp 3  or sp 2  carbon atom) substituted (but not adjacent to the linking position) by a 3-, 4- or 5-membered spiro-carbon-linked ring; which bicyclic ring system is  
 (i) fully saturated other than (where appropriate) at a linking sp 2  carbon atom;  
 (ii) contains one —N(Rc)-group in the ring system (at least two carbon atoms away from the linking position when the link is via a nitrogen atom or an sp 2  carbon atom) or one —N(Rc)-group in an optional substituent (not adjacent to the linking position) and is  
 (iii) optionally further substituted on an available ring carbon atom; or  
 (TDb) a 7-, 8- or 9-membered bicyclic ring system (linked via a ring nitrogen atom or a ring sp 3  or sp 2  carbon atom) containing 0, 1 or 2 ring nitrogen atoms (and optionally a further O or S ring heteroatom), the structure containing a bridge of 0, 1 or 2 carbon atoms; which bicyclic ring system is  
 (i) fully saturated other than (where appropriate) at a linking sp 2  carbon atom;  
 (ii) contains one O or S heteroatom, or one —N(Rc)-group in the ring (at least two carbon atoms away from the linking position when the link is via a nitrogen atom or an sp 2  carbon atom) or one —N(Rc)-group in an optional substituent (not adjacent to the linking position) and is  
 (iii) optionally further substituted on an available ring carbon atom; or  
 (TE) T is selected from the following groups (TE1) to (TE3)  
                     
 wherein:  
 X 1m  and X 2m  taken together represent R 2s -(E) ms -N═; or  
 X 1m  is O═and X 2m  is R 2s -(E) ms -N—, and vice versa;  
 wherein E is an electron withdrawing group selected from —SO 2 —, —CO—, —O—CO—, —CO—O—, —CS—, —CON(R 5 )—, —SO 2 N(R s )—, or E may represent a group of the formula R 3s -C(═N—O—R 3 S)—C(═O)—, wherein R 3s  is H or as defined in R 2s  at (i) below;  
 or, when E is —CON(R s )— or —SO 2 N(R s )—, R 2s  and R s  may link together to form a carbon chain which defines a 5- or 6-membered saturated, unsaturated or partially unsaturated ring linked via the N atom in E, which ring is optionally further substituted by an oxo substituent, and which ring may be optionally fused with a phenyl group to form a benzo-fused system, wherein the phenyl group is optionally substituted by up to three substituents independently selected from halo, cyano, (1-4C)alkyl and (1-4C)alkoxy;  
 ms is 0 or 1;  
 R 2s  and R s  are independently selected from:  
 (i) hydrogen (except where E is —SO 2 — or —O—CO—), or (1-6C)alkyl {optionally substituted by one or more (1-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, cyano-imino, (1-4C)alkoxy, trifluoromethyl, (1-4C)alkoxycarbonyl, phenyl (optionally substituted as defined for AR1 hereinafter), optionally substituted heteroaryl group of the formula AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY1 all as defined (and optionally substituted as defined) hereinafter, (1-4C)alkylS(O) q — (q is 0, 1 or 2); and/or (with the proviso that where R 2s  is —SO 2  or —O—CO— not on the first carbon atom of the (1-6C) alkyl chain) optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally further substituted, by no more than one of each of, oxo, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,  N -(1-4C)alkyl- N -(1-6C)alkanoylamino, (1-4C)alkylS(O) p NH— or (1-4C)alkylS(O) p -((1-4C)alkyl)N-(p is 1 or 2)}; or  
 (ii) an optionally substituted aryl or optionally substituted heteroaryl group of the formula AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a or CY1 all as defined (and optionally substituted as defined) hereinafter;  
 or (where ms is 0 only);  
 (iii) cyano, —CO—NRvRw, —CO—NRv Rw′, —SO 2 —NRvRw, —SO 2 —NRv Rw′ [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl; Rw′ is phenyl (optionally substituted as defined for AR1 hereinafter), or a heteroaryl group selected from AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a (optionally substituted as defined hereinafter)], (1-4C)alkoxycarbonyl, trifluoromethyl, 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, or 2-(AR2a)ethenyl; and  
 wherein ( )n 1 , ( )o 1,  ( )n 1′ , ( )o 1′,  ( )p 1  and ( )p 1′  represent chains of carbon atoms (optionally substituted as defined for AR1 hereinafter) of length n 1,  o 1,  n 1′,  o 1′,  p 1  and p 1 ′ respectively, and are independently 0-2, with the proviso that in (TE1) and (TE2) the sum of n 1 , o 1 , n 1  and o 1′  does not exceed 8 (giving a maximum ring size of 14 in (TE1) and II in (TE2)), and in (TE3) the sum of n 1,  o 1,  n 1′,  o 1′,  p 1  and p 1′  does not exceed 6 (giving a maximum ring size of 12). wherein Rc is selected from groups (Rc1) to (Rc5):— 
 (Rc1) (1-6C)alkyl {optionally substituted by one or more (1-4C)alkanoyl groups (including geminal disubstitution) and/or optionally monosubstituted by cyano, (1-4C)alkoxy, trifluoromethyl, (1-4C)alkoxycarbonyl, phenyl (optionally substituted as for AR1 defined hereinafter), (1-4C)alkylS(O) q — (q is 0, 1 or 2); or, on any but the first carbon atom of the (1-6C)alkyl chain, optionally substituted by one or more groups (including geminal disubstitution) each independently selected from hydroxy and fluoro, and/or optionally monosubstituted by oxo, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,  N -(1-4C)alkyl- N -(1-6C)alkanoylamino, (1-4C)alkylS(O) p NH— or (1-4C)alkylS(O) p -((1-4C)alkyl)N-(p is 1 or 2)};  
 (Rc2) R 13 CO—, R 13 SO 2 — or R 13 CS— 
 wherein R 13  is selected from (Rc2a) to (Rc2e):— 
 (Rc2a) AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b, AR4, AR4a, CY1, CY2;  
 (Rc2b) hydrogen, (1-4C)alkoxycarbonyl, trifluoromethyl, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], 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;  
 (Rc2c) (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)alkanoyl, carboxy, 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 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, (1-4C)alkylaminocarbonyl, di((1-4C)alkyl)aminocarbonyl, (1-4C)alkylS(O) p NH—, (1-4C)alkylS(O) p -((1-4C)alkyl)N—, fluoro(1-4C)alkylS(O) p NH—, fluoro(1-4C)alkylS(O) p ((1-4C)alkyl)N—, (1-4C)alkylS(O) q -[the (1-4C)alkyl group of (1-4C)alkylS(O) q — being optionally substituted by one substituent selected from hydroxy, (1-4C)alkoxy, (1-4C)alkanoyl, 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], amino, cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, carboxy, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino, N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (1-4C)alkylaminocarbonyl, di((1-4C)alkyl)aminocarbonyl, (1-4C)alkylS(O) p NH—, (1-4C)alkylS(O) p -((1-4C)alkyl)N—, (1-4C)alkylS(O) q —, AR1-S(O) q —, AR2-S(O) q —, AR3-S(O) q — and also AR2a, AR2b, AR3a and AR3b versions of AR2 and AR3 containing groups], 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};  
 (Rc2d) R 14 C(O)O(1-6C)alkyl wherein R 14  is AR1, AR2, (1-4C)alkylamino (the (1-4C)alkyl group being optionally substituted by (1-4C)alkoxycarbonyl or by carboxy), benzyloxy-(1-4C)alkyl or (1-10C)alkyl {optionally substituted as defined for (Rc2c)};  
 (Rc2e) R 15 O— wherein R 15  is benzyl, (1-6C)alkyl {optionally substituted as defined for (Rc2c)}, CY1, CY2 or AR2b;  
 (Rc3) hydrogen, cyano, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl, 2-((1-4C)alkylaminocarbonyl)ethenyl, 2-((1-4C)alkoxycarbonyl)ethenyl, 2-nitroethenyl, 2-nitro-2-((1-4C)alkyl)ethenyl, 2-(AR1)ethenyl, 2-(AR2)ethenyl, or of the formula (Rc3a)  
                     
 wherein X 00  is —OR 7 , —SR 17 , —NHR 17  and —N(R 17 ) 2 ;  
 wherein R 17  is hydrogen (when X 00  is —NHR 17  and —N(R 17 ) 2 ), and R 17  is (1-4C)alkyl, phenyl or AR2 (when X 00  is —OR 17 , —SR 17  and —NHR 17 ); and R 16  is cyano, nitro, (1-4C)alkylsulfonyl, (4-7C)cycloalkylsulfonyl, phenylsulfonyl, (1-4C)alkanoyl and (1-4C)alkoxycarbonyl;  
 (Rc4) trityl, AR1, AR2, AR2a, AR2b, AR3, AR3a, AR3b;  
 (Rc5) RdOC(Re)=CH(C═O)—, RfC(═O)C(═O)—, RgN═C(Rh)C(═O)— or RiNHC(Rj)=CHC(═O)—wherein Rd is (1-6C)alkyl; Re is hydrogen or (1-6C)alkyl, or Rd and Re together form a (3-4C)alkylene chain; Rf is hydrogen, (1-6C)alkyl, hydroxy(1-6C)alkyl, (1-6C)alkoxy(1-6C)alkyl, —NRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl], (1-6C)alkoxy, (1-6C)alkoxy(1-6C)alkoxy, hydroxy(2-6C)alkoxy, (1-4C)alkylamino(2-6C)alkoxy, di-(1-4C)alkylamino(2-6C)alkoxy; Rg is (1-6C)alkyl, hydroxy or (1-6C)alkoxy; Rh is hydrogen or (1-6C)alkyl; Ri is hydrogen, (1-6C)alkyl, AR1, AR2, AR2a, AR2b and Rj is hydrogen or (1-6C)alkyl;  
 wherein  
 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 0-0, 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 0-0,0-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.  
 
   
   
       2 . The compound of  claim 1 , wherein Q is selected from Q1, Q2; Q4, Q6 and Q9.  
   
   
       3 . The compound of  claim 1 , wherein Q is Q1 or Q2.  
   
   
       4 . The compound of  claim 1 , wherein HET is an N-linked 5-membered heterocyclic ring.  
   
   
       5 . A compound of the formula (IB)  
     
       
         
         
             
             
         
       
       wherein HET is 1,2,3-triazole (especially 1,2,3-triazol-1-yl), 1,2,4-triazole (especially 1,2,4-triazol-1-yl) and tetrazole (preferably tetrazol-2-yl) or HET is a di-hydro version of pyrimidine, pyridazine, pyrazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine and pyridine;  
       R 2  and R 3  are independently hydrogen or fluoro; and  
       T is selected from (TAa1 to TAa6), (TAf1 to 6), (TC5), (TC7), (TC9), (TC12), (TC13) and (TE1) to (TE3); or in-vivo hydrolysable esters or pharmaceutically-acceptable salts thereof.  
     
   
   
       6 . A compound of the formula (IB) wherein HET is 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, tetrazol-2-yl; 
 R 2  and R 3  are independently hydrogen or fluoro;    T is selected from (TAa1 & 2), (TC5), (TC9), (TC12a & b), (TC13a) and (TE1a & b); or in-vivo hydrolysable esters or pharmaceutically-acceptable salts thereof.    
   
   
       7 . A compound of the formula (I) as claimed in  claim 1 , or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof, wherein Rs is selected from fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, cyanomethyl, cyano, amino, azido, alkylthioalkyl such as methylthiomethyl and 2-propynyl.  
   
   
       8 . (canceled)  
   
   
       9 . (canceled)  
   
   
       10 . A pharmaceutical composition which comprises a compound of  claim 1  or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof, and a pharmaceutically-acceptable diluent or carrier.  
   
   
       11 . (canceled)  
   
   
       12 . A method for producing an antibacterial effect in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically-acceptable salt, or in-vivo hydrolysable ester thereof  
   
   
       13 . A process for the manufacture of a compound of the formula (I) comprising one or more of the processes (a) to (h) below: 
 (a) by modifying a substituent in or introducing a substituent into another compound of formula (I).    (b) by reaction of a compound of formula (II):                          wherein Y is a displaceable group (which may be (i) generated in-situ, for example under Mitsunobu conditions, or (ii) preformed, such as chloro or mesylate) with a compound of the formula (III):      HET  (III)    wherein HET is HET-H free-base form or HET-anion formed from the free base form; or    (c) by reaction of a compound of formula (IV)                          wherein Y 1  is HET, X is a displaceable substituent and Qn is as defined herein for Q1-Q8 but with X in place of the substituent T; with a compound of the formula (V):      T  (V)    wherein T is T-H free-base form or T-anion formed from the free base form T-H as hereinabove defined for T; or    (d) by reaction of a compound of the formula (VI):      Q-C≡N + —O −   (VI)    wherein the group C≡N + —O −  is a nitrile oxide; with an allylic derivative such as an olefin of the formula (VII):                          (e) by transition metal mediated coupling of a compound of formula (IV), wherein Y′ is HET, X is a replaceable substituent (such as trimethylstannyl) and Qn is as defined herein for Q1-Q8 but with X in place of the substituent T; with a compound of the formula (VIII):      T-X′  (VIII)    wherein X and X′ are complementary substitutents capable of entering into such coupling reactions; or    (f) for HET as optionally substituted 1,2,3-triazole by cycloaddition via the azide (wherein e.g. Y in (II) is azide) to acetylenes, or to acetylene equivalents such as optionally substituted cylcohexa-1,4-dienes or optionally substituted ethylenes bearing eliminatable substituents such as arylsulfonyl; or    (g) for HET as 4-substituted 1,2,3-triazole compounds of formula (I) may be made by reacting aminomethylisoxazolines with 1,1-dihaloketone sulfonylhydrazones;    (h) for HET as 4-substituted 1,2,3-triazole compounds of formula (I) may also be made by reacting azidomethyl isoxazolines with terminal alkynes using Cu(1) catalysis;    and thereafter if necessary: (i) removing any protecting groups; (ii) forming a pharmaceutically-acceptable salt; (iii) forming an in-vivo hydrolysable ester.    
   
   
       14 . A compound selected from 
 (5RS)-3-(3-Fluoro-4-imidazol-1-ylphenyl)-5-(1,2,3-triazol-1-ylmethyl)4,5-dihydro-isoxazole;    (5RS)-3-(3-Fluoro-4-pyrazol-1-ylphenyl)-5-(1,2,3-triazol-1-ylmethyl)-4,5-dihydro-isoxazole;    (5RS)-3-(3-Fluoro-4-(1,2,3-triazol-1-yl)phenyl)-5-(1,2,3-triazol-1-ylmethyl)4,5-dihydro-isoxazole; 
 or a pharmaceutically-acceptable salt or an in-vivo hydrolysable ester thereof.