Substituted isoxazolines and their use as antibacterial agents

Abstract

Compounds of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, wherein, for example, X is O, S or NH; HET is an optionally substituted C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S; Q is selected from, for example, Q1 and Q2: R 2 and R 3 are independently hydrogen or fluoro; T is selected from a range of groups, for example, an N-linked (fully unsaturated) 5-membered heteroaryl ring system or a group of formula (TC5): wherein Rc is, for example, R 13 CO—, R 13 SO 2 — or R 13 CS—; wherein R 13 is, for example, optionally substituted ( 1 - 10 C)alkyl or R 14 C(O)O( 1 - 6 C)alkyl wherein R 14 is optionally substituted ( 1 - 10 C)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 
 X is O, NH, S, SO or SO 2 ;  
 HET 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 an available carbon atom by 1 or 2 substituents independently selected from (1-4C)alkyl, amino, (1-4C)alkylamino, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (1-4C)alkyl;  
 or  
 HET is a C-linked 6-membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (1-4C)alkyl, amino, (1-4C)alkylamino, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and halogen;  
 Q is selected from Q1 to Q9:-  
                     
 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 1  (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 is 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 (TD) 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 heteroatom 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 6- or 7-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 s 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 1, 2 or 3 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; 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 or 2,2-dimethyl-1,3-dioxolane;  
 (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, phosphoryl [—O—P(O)(OH) 2 , and mono- and di-(1-4C)alkoxy derivatives thereof], phosphiryl [—O—P(OH) 2  and mono- and di-(1-4C)alkoxy derivatives thereof], and amino; and/or optionally substituted by one group selected from carboxy, phosphonate [phosphono, —P(O)(OH) 2 , and mono- and di-(1-4C)alkoxy derivatives thereof], phosphinate [—P(OH) 2  and mono- and di-(1-4C)alkoxy derivatives thereof], cyano, halo, trifluoromethyl, (1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkoxy-(1-4C)alkoxy-(1-4C)alkoxycarbonyl, (1-4C)alkylamino, di((1-4C)alkyl)amino, (1-6C)alkanoylamino, (1-4C)alkoxycarbonylamino,  
 N-(1-4C)alkyl-N-(1-6C)alkanoylamino, (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 —, 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, 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 17 , —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 O—O, O—S or S—S bonds), and linked via a ring carbon atom, or a ring nitrogen atom if the ring is not thereby quaternised;  
 AR2a is a partially hydrogenated version of AR2 (i.e. AR2 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom if the ring is not thereby quaternised;  
 AR2b is a fully hydrogenated version of AR2 (i.e. AR2 systems having no unsaturation), linked via a ring carbon atom or linked via a ring nitrogen atom;  
 AR3 is an optionally substituted 8-, 9- or 10-membered, fully unsaturated (i.e with the maximum degree of unsaturation) bicyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O—O, O—S or S—S bonds), and linked via a ring carbon atom in either of the rings comprising the bicyclic system;  
 AR3a is a partially hydrogenated version of AR3 (i.e. AR3 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in either of the rings comprising the bicyclic system;  
 AR3b is a fully hydrogenated version of AR3 (i.e. AR3 systems having no unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom, in either of the rings comprising the bicyclic system;  
 AR4 is an optionally substituted 13- or 14-membered, fully unsaturated (i.e with the maximum degree of unsaturation) tricyclic heteroaryl ring containing up to four heteroatoms independently selected from O, N and S (but not containing any O—O, O—S or S—S bonds), and linked via a ring carbon atom in any of the rings comprising the tricyclic system;  
 AR4a is a partially hydrogenated version of AR4 (i.e. AR4 systems retaining some, but not the full, degree of unsaturation), linked via a ring carbon atom, or linked via a ring nitrogen atom if the ring is not thereby quaternised, in any of the rings comprising the tricyclic system;  
 CY1 is an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl ring;  
 CY2 is an optionally substituted cyclopentenyl or cyclohexenyl ring.  
 
   
   
       2 . A compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, as claimed in  claim 1  wherein the optionally substituted N-linked (fully unsaturated) 5-membered heteroaryl ring system containing 1, 2 or 3 nitrogen atoms (group (TAf)) is selected from a group of formula (TAf1) to (TAf6):-  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 6  is selected (independently where appropriate) from hydrogen, (1-4C)alkyl, (1-4C)alkoxycarbonyl, (1-4C)alkanoyl, carbamoyl and cyano;  
 R 4  and R 5  are independently selected from hydrogen, halo, trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O) q — (q is 0, 1 or 2), (1-4C)alkanoyl, (1-4C)alkoxycarbonyl, (2-4C)alkanoyloxy-(1-4C)alkyl, benzoxy-(1-4C)alkyl, (2-4C)alkanoylamino, —CONRvRw, —NRvRw and (1-4C)alkyl {optionally substituted by hydroxy, trifluoromethyl, cyano, nitro, (1-4C)alkoxy, (1-4C)alkylS(O) q — (q is 0, 1 or 2), (1-4C)alkoxycarbonyl, (1-4C)alkanoylamino, —CONRvRw, —NRvRw; wherein RvRw is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl};  
 or R 4  is selected from one of the groups in (TAfa) to (TAfc) below, or (where appropriate) one of R 4  and R 5  is selected from the above list of R 4  and R 5  values, and the other is selected from one of the groups in (TAfa) to (TAfc) below:-  
 (TAfa) a group of the formula (TAfa1)  
                     
 wherein Z 0  is hydrogen or (1-4C)alkyl;  
 X 0  and Y 0  are independently selected from hydrogen, (1-4C)alkyl, (1-4C)alkoxycarbonyl, halo, cyano, nitro, (1-4C)alkylS(O) q — (q is 0, 1 or 2), RvRwNSO 2 —, trifluoromethyl, pentafluoroethyl, (1-4C)alkanoyl and —CONRvRw [wherein Rv is hydrogen or (1-4C)alkyl; Rw is hydrogen or (1-4C)alkyl]; or  
 one of X 0  and Y 0  is selected from the above list of X 0  and Y 0  values, and the other is selected from phenyl, phenylcarbonyl, —S(O) q -phenyl (q is 0, 1 or 2), N-(phenyl)carbamoyl, phenylaminosulfonyl, AR2, (AR2)-CO—, (AR2)-S(O) q — (q is 0, 1 or 2), N-(AR2)carbamoyl and (AR2)aminosulfonyl; wherein any phenyl group in (TAfa) may be optionally substituted by up to three substituents independently selected from (1-4C)alkyl, cyano, trifluoromethyl, nitro, halo and (1-4C)alkylsulfonyl;  
 (TAfb) an acetylene of the formula -≡—H or -≡-(1-4C)alkyl;  
 (TAfc) —X 1 —Y 1 -AR2, —X 1 —Y 1 -AR2a, —X 1 —Y 1 -AR2b, —X 1 —Y 1 -AR3, —X 1 —Y 1 -AR3a or —X 1 —Y 1 -AR3b;  
 wherein X 1  is a direct bond or —CH(OH)— and  
 Y 1  is —(CH 2 ) m —, —(CH 2 ) n —NH—(CH 2 ) m —, —CO—(CH 2 ) m —, —CONH—(CH 2 ) m —, —C(═S)NH—(CH 2 ) m — or —C(═O)O—(CH 2 ) m —;  
 or wherein X 1  is —(CH 2 ) n — or —CH(Me)-(CH 2 ) m — and  
 Y 1  is —(CH 2 ) m —NH—(CH 2 ) m —, —CO—(CH 2 ) m —, —CONH—(CH 2 ) m —, —C(═S)NH—(CH 2 ) m —, —C(═O)O—(CH 2 ) m — or —S(O) q —(CH 2 ) m —;  
 or wherein X 1  is —CH 2 O—, —CH 2 NH— or —CH 2 N((1-4C)alkyl)- and  
 Y 1  is —CO—(CH 2 ) m —, —CONH—(CH 2 ) m — or —C(═S)NH—(CH 2 ) m —;  
 and additionally Y 1  is —SO 2 — when X 1  is —CH 2 NH— or —CH 2 N((1-4C)alkyl)-, and Y 1  is —(CH 2 ) m — when X 1  is —CH 2 O— or —CH 2 N((1-4C)alkyl)-; wherein n is 1, 2 or 3; m is 0, 1, 2 or 3 and q is 0, 1 or 2; and when Y 1  is —(CH 2 ) m —NH—(CH 2 ) m — each m is independently selected from 0, 1, 2 or 3.  
 
   
   
       3 . A compound of the formula (I), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof, as claimed in  claim 1  wherein the 7-, 8- or 9-membered bicyclic ring system containing a bridge of 1, 2 or 3 carbon atoms (group (TDb)) is selected from a group defined by the ring skeletons shown in formulae (TDb1) to (TDb14):-  
     
       
         
         
             
             
         
       
     
     wherein; 
 (i) the ring system contains 0, 1 or 2 ring nitrogen atoms (and optionally a further O or S ring heteroatom),and when present the ring nitrogen, O or S heteroatom/s are at any position other than as part of the 3-membered ring in (TDb1);  
 (ii) the ring system is linked via a ring nitrogen atom or a ring sp 3  or sp 2  carbon atom (with the double bond, where appropriate, orientated in either direction) from any position in either ring [other than from a bridgehead position or from an sp 2  carbon atom in the 4-membered ring in (TDb2), (TDb6) and (TDb11)];  
 (iii) one of the ring carbon atoms at a position not adjacent to the linking position, is replaced (other than when the ring contains an O or S heteroatom) by one of the following groups —NRc-[not at a bridgehead position], >C(H)—NHRc, >C(H)—NRc-(1-4C)alkyl, >C(H)—CH 2 —NHRc, >C(H)—CH 2 —NRc-(1-4C)alkyl [wherein the hydrogen atom shown in brackets is not present when the replacement is made at a bridgehead position and wherein a central —CH 2 — chain link is optionally mono- or di-substituted by (1-4C)alkyl]; with the proviso that when the ring system is linked via a ring nitrogen atom or an sp 2  carbon atom any replacement of a ring carbon atom by —NRc-, O or S is at least two carbon atoms away from the linking position; and  
 (iv) the ring system is optionally (further) substituted on an available ring carbon atom as for the bicyclic spiro-ring systems described in (TDa); wherein Rc is as defined in  claim 1 .  
 
   
   
       4 . (canceled)  
   
   
       5 . (canceled)  
   
   
       6 . A compound of the formula (I) as claimed in  claim 1 , being a compound of the formula (IC), or a pharmaceutically-acceptable salt, or an in-vivo-hydrolysable ester thereof  
     
       
         
         
             
             
         
       
       wherein HET is isoxazol-3-yl, 1,2,4-oxadiazol-3-yl, isothiazol-3-yl or 1,2,5-thiadiazol-3-yl;  
       X is O, S or NH;  
       R 2  and R 3  are independently hydrogen or fluoro; Rp1 and Rp2 are independently hydrogen, AR-oxymethyl or AR-thiomethyl (wherein AR is phenyl, phenyl-(1-4C)alkyl, naphthyl, furan, pyrrole, pyrazole, imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole or thiophene), (1-4C)alkyl, carboxy, (1-4C)alkoxycarbonyl, hydroxymethyl, (1-4C)alkoxymethyl or carbamoyl and Rcp is cyano, pyrimidin-2-yl, 2-cyanoethenyl, 2-cyano-2-((1-4C)alkyl)ethenyl or Rcp is of the formula R 13p CO—, R 13p SO 2 — or R 13p CS— (wherein R 13p  is hydrogen, (1-5C)alkyl [optionally substituted by one or more groups each independently selected from hydroxy and amino, or optionally monosubstituted by (1-4C)alkoxy, (1-4C)alkylS(O) q —, (1-4C)alkylamino, (1-4C)alkanoyl, naphthoxy, (2-6C)alkanoylamino or (1-4C)alkylS(O) p NH— wherein p is 1 or 2 and q is 0, 1 or 2], imidazole, triazole, pyrimidine, pyridazine, pyridine, isoxazole, oxazole, isothiazole, thiazole, pyridoimidazole, pyrimidoimidazole, quinoxaline, quinazoline, phthalazine, cinnoline or naphthyridine, or R 13p  is of the formula R 14p C(O)O(1-6C)alkyl wherein R 14p  is (1-6C)alkyl), or Rcp is of the formula RfC(═O)C(═O)— wherein Rf is (1-6C)alkoxy.  
     
   
   
       7 . (canceled)  
   
   
       8 . A compound as claimed in  claim 1  being 
 (5RS)-3-(3-Fluoro-4-imidazol-1-ylphenyl)-5-isoxazol-3-ylaminomethyl-4,5-dihydro-isoxazole; or    (5RS)-3-(3-Fluoro-4-imidazol-1-ylphenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole.    
   
   
       9 . (canceled)  
   
   
       10 . (canceled)  
   
   
       11 . (canceled)  
   
   
       12 . (canceled)  
   
   
       13 . (canceled)