Aminocyclohexene quinolines and their azaisosteric analogues with antibacterial activity

A compound of formula (I) or a pharmaceutically acceptable derivative thereof:

• wherein:
• one of Z1, Z2, Z3, Z4 and Z5 is N, one is CR1a and the remainder are CH, or one of Z1, Z2, Z3, Z4 and Z5 is CR1a and the remainder are CH;
• R1 and R1a are independently selected from hydrogen;
• hydroxy;
• (C1-6)alkoxy optionally substituted by (C1-6)alkoxy, amino, piperidyl, guanidino or amidino any of which is optionally N-substituted by one or two (C1-6)alkyl, acyl or (C1-6)alkylsulphonyl groups, CONH2, hydroxy, (C1-6)alkylthio, heterocyclylthio, heterocyclyloxy, arylthio, aryloxy, acylthio, acyloxy or (C1-6)alkylsulphonyloxy;
• (C1-6)alkoxy-substituted (C1-6)alkyl;
• halogen;
• (C1-6)alkyl;
• (C1-6)alkylthio;
• trifluromethyl;
• nitro;
• azido;
• acyl;
• acyloxy;
• acylthio;
• (C1-6)alkylsulphonyl;
• (C1-6)alkylsulphoxide;
• arylsulphonyl;
• arylsulphoxide or an amino, piperidyl, guanidino or amidino group optionally N-substituted by one or two (C1-6)alkyl, acyl or (C1-6)alkylsulphonyl groups, or when Z1 is CR1a, R1 and R1a may together represent (C1-2)alkylenedioxy, or when Z5 is CR1a, R1a may instead be, cyano, hydroxymethyl or carboxy,
• provided that when Z1, Z2, Z3, Z4 and Z5 are CR1a or CH, then R1 is not hydrogen;
• R2 is hydrogen, or (C1-4)alkyl or (C2-4)alkenyl optionally substituted with 1 to 3 groups selected from:
• amino optionally substituted by one or two (C1-4)alkyl groups;
• carboxy;
• (C1-4)alkoxycarbonyl;
• (C1-4)alkylcarbonyl;
• (C2-4)alkenyloxycarbonyl;
• (C2-4)alkenylcarbonyl;
• aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1-4)alkyl, hydroxy(C1-4)alkyl, aminocarbonyl(C1-4)alkyl, (C2-4)alkenyl, (C1-4)alkylsulphonyl, trifluoromethylsulphonyl, (C2-4)alkenylsulphonyl, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl or (C2-4)alkenylcarbonyl;
• cyano;
• tetrazolyl;
• 2-oxo-oxazolidinyl optionally substituted by R10;
• 3-hydroxy-3-cyclobutene-1,2-dione-4-yl;
• 2,4-thiazolidinedione-5-yl;
• tetrazol-5-ylaminocarbonyl;
• 1,2,4-triazol-5-yl optionally substituted by R10;
• 5-oxo-1,2,4-oxadiazol-3-yl;
• halogen;
• (C1-4)alkylthio;
• trifluoromethyl;
• hydroxy optionally substituted by (C1-4)alkyl, (C2-4)alkenyl, (C1-4)alkoxycarbonyl, (C1-4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl;
• oxo;
• (C1-4)alkylsulphonyl;
• (C2-4)alkenylsulphonyl;
• or (C1-4)aminosulphonyl wherein the amino group is optionally substituted by (C1-4)alkyl or (C2-4)alkenyl;
• R3 is hydroxy optionally substituted by (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl or aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylcarbonyl or (C2-6)alkenylcarbonyl;
• R10 is selected from (C1-4)alkyl and (C2-4)alkenyl either of which may be optionally substituted by a group R12 as defined above;
• carboxy;
• aminocarbonyl wherein the amino group is optionally substituted by hydroxy, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C2-6)alkenylsulphonyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2-6)alkenylcarbonyl and optionally further substituted by (C1-6)alkyl or (C2-6)alkenyl;
• (C1-6)alkylsulphonyl;
• trifluoromethylsulphonyl;
• (C2-6)alkenylsulphonyl;
• (C1-6)alkoxycarbonyl;
• (C1-6)alkylcarbonyl;
• (C2-6)alkenyloxycarbonyl;
• and (C2-6)alkenylcarbonyl;
• R4 is a group —CH2—R51 in which R51 is selected from:
• (C4-8)alkyl;
• hydroxy(C4-8)alkyl;
• (C1-4)alkoxy(C4-8)alkyl;
• (C1-4)alkanoyloxy(C4-8)alkyl;
• (C3-8)cycloalkyl(C4-8)alkyl;
• hydroxy-, (C1-6)alkoxy- or (C1-6)alkanoyloxy-(C3-8)cycloalkyl(C4-8)alkyl;
• cyano(C4-8)alkyl;
• (C4-8)alkenyl;
• (C4-8)alkynyl;
• tetrahydrofuryl;
• mono- or di-(C1-6)alkylamino(C4-8)alkyl;
• acylamino(C4-8)alkyl;
• (C1-6)alkyl- or acyl-aminocarbonyl(C4-8)alkyl;
• mono- or di-(C1-6)alkylamino(hydroxy)(C4-8)alkyl;
• or
• R4 is a group —U—R52 where R52 is an optionally substituted bicyclic carbocyclic or heterocyclic ring system (A):
• containing up to four heteroatoms in each ring in which
• at least one of rings (a) and (b) is aromatic;
• X1 is C or N when part of an aromatic ring or CR14 when part of a non aromatic ring;
• X2 is N, NR13, O, S(O)x, CO or CR14 when part of an aromatic or non-aromatic ring or may in addition be CR14R15 when part of a non aromatic ring;
• X3 and X5 are independently N or C;
• Y1 is a 0 to 4 atom linker group each atom of which is independently selected from N, NR13, O, S(O)x, CO and CR14 when part of an aromatic or non-aromatic ring or may additionally be CR14R15 when part of a non aromatic ring,
• Y2 is a 2 to 6 atom linker group, each atom of Y2 being independently selected from N, NR13, O, S(O)x, CO and CR14 when part of an aromatic or non-aromatic ring or may additionally be CR14R15 when part of a non aromatic ring;
• each of R14 and R15 is independently selected from:
• H;
• (C1-4)alkylthio;
• halo;
• carboxy(C1-4)alkyl;
• halo(C1-4)alkoxy;
• halo(C1-4)alkyl;
• (C1-4)alkyl;
• (C2-4)alkenyl;
• (C1-4)alkoxycarbonyl;
• formyl;
• (C1-4)alkylcarbonyl;
• (C2-4)alkenyloxycarbonyl;
• (C2-4)alkenylcarbonyl;
• (C1-4)alkylcarbonyloxy;
• (C1-4)alkoxycarbonyl(C1-4)alkyl;
• hydroxy;
• hydroxy(C1-4)alkyl;
• mercapto(C1-4)alkyl;
• (C1-4)alkoxy;
• nitro;
• cyano;
• carboxy;
• amino or aminocarbonyl optionally substituted as for corresponding substituents in R3;
• (C1-4)alkylsulphonyl;
• (C2-4)alkenylsulphonyl;
• or aminosulphonyl wherein the amino group is optionally substituted by (C1-4)alkyl or (C2-4)alkenyl;
• aryl;
• aryl(C1-4)alkyl;
• aryl(C1-4)alkoxy;
• each R13 is independently H;
• trifluoromethyl;
• (C1-4)alkyl optionally substituted by hydroxy, carboxy, (C1-6)alkoxycarbonyl, (C1-6)alkoxy, (C1-6)alkylthio, halo or trifluoromethyl;
• (C2-4)alkenyl;
• aryl;
• aryl (C1-4)alkyl;
• arylcarbonyl;
• heteroarylcarbonyl;
• (C1-4)alkoxycarbonyl;
• (C1-4)alkylcarbonyl;
• formyl;
• (C1-6)alkylsulphonyl;
• or aminocarbonyl wherein the amino group is optionally substituted by (C1-4)alkoxycarbonyl, (C1-4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl, (C1-4)alkyl or (C2-4)alkenyl and optionally further substituted by (C1-4)alkyl or (C2-4)alkenyl;
• each x is independently 0, 1 or 2;
• U is CO, SO2 or CH2;
• or
• R4 is a group —X1a—X2a—X3a—X4a in which:
• X1a is CH2, CO or SO2;
• X2a is CR14aR15a;
• X3a is NR13a, O, S, SO2 or CR14aR15a;
• wherein:
• each of R14a and R15a is independently selected from the groups listed above for R14 and R15, provided that R14a and R15a on the same carbon atom are not both selected from optionally substituted hydroxy and optionally substituted amino;
• or
• R14a and R15a together represent oxo;
• R13a is hydrogen;
• trifluoromethyl;
• (C1-6)alkyl;
• (C2-6)alkenyl;
• (C1-6)alkoxycarbonyl;
• (C1-6)alkylcarbonyl;
• or aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (C1-6)alkyl or (C2-6)alkenyl and optionally further substituted by (C1-6)alkyl or (C2-6)alkenyl;
• or
• two R14a groups or an R13a and an R14a group on adjacent atoms together represent a bond and the remaining R13a, R14a and R15a groups are as above defined;
• or
• two R14a groups and two R15a groups on adjacent atoms together represent bonds such that X2a and X3a is triple bonded;
• X4a is phenyl or C or N linked monocyclic aromatic 5- or 6-membered heterocycle containing up to four heteroatoms selected from O, S and N and:
• optionally C-substituted by up to three groups selected from (C1-4)alkylthio;
• halo;
• carboxy(C1-4)alkyl;
• halo(C1-4)alkoxy;
• halo(C1-4)alkyl;
• (C1-4)alkyl;
• (C2-4)alkenyl;
• (C1-4)alkoxycarbonyl;
• formyl;
• (C1-4)alkylcarbonyl;
• (C2-4)alkenyloxycarbonyl;
• (C2-4)alkenylcarbonyl;
• (C1-4)alkylcarbonyloxy;
• (C1-4)alkoxycarbonyl(C1-4)alkyl;
• hydroxy;
• hydroxy(C1-4)alkyl;
• mercapto(C1-4)alkyl;
• (C1-4)alkoxy;
• nitro;
• cyano;
• carboxy;
• amino or aminocarbonyl optionally substituted as for corresponding substituents in R3;
• (C1-4)alkylsulphonyl;
• (C2-4)alkenylsulphonyl;
• or aminosulphonyl wherein the amino group is optionally substituted by (C1-4)alkyl or (C2-4)alkenyl;
• aryl, aryl(C1-4)alkyl or aryl(C1-4)alkoxy;
• and
• optionally N substituted by trifluoromethyl;
• (C1-4)alkyl optionally substituted by hydroxy, (C1-6)alkoxy, (C1-6)alkylthio, halo or trifluoromethyl;
• (C2-4)alkenyl;
• aryl;
• aryl(C1-4)alkyl;
• (C1-4)alkoxycarbonyl;
• (C1-4)alkylcarbonyl;
• formyl;
• (C1-6)alkylsulphonyl;
• or aminocarbonyl wherein the amino group is optionally substituted by (C1-4)alkoxycarbonyl, (C1-4)alkylcarbonyl, (C2-4)alkenyloxycarbonyl, (C2-4)alkenylcarbonyl, (C1-4)alkyl or (C2-4)alkenyl and optionally further substituted by (C1-4)alkyl or (C2-4)alkenyl;
• n is 0 or 1 and AB is NR11CO, CONR11, CO—CR8R9, CR6R7—CO, O—CR8R9, CR6R7—O, NHR11—CR8R9, CR6R7—NHR11, NR11SO2, CR6R7—SO2 or CR6R7—CR8R9,
• provided that n=0, B is not NR11, O or SO2,
• and provided that R6 and R7, and R8 and R9 are not both optionally substituted hydroxy or amino;
• and wherein:
• each of R6, R7, R8 and R9 is independently selected from:
• H;
• (C1-6)alkoxy;
• (C1-6)alkylthio;
• halo;
• trifluoromethyl;
• azido;
• (C1-6)alkyl;
• (C2-6)alkenyl;
• (C1-6)alkoxycarbonyl;
• (C1-6)alkylcarbonyl;
• (C2-6)alkenyloxycarbonyl;
• (C2-6)alkenylcarbonyl;
• hydroxy, amino or aminocarbonyl optionally substituted as for corresponding substituents in R3;
• (C1-6)alkylsulphonyl;
• (C2-6)alkenylsulphonyl;
• or (C1-6)aminosulphonyl wherein the amino group is optionally substituted by (C1-6)alkyl or (C2-6)alkenyl;
• or R6 and R8 together represent a bond and R7 and R9 are as above defined;
• in optionally substituted amino the amino group is optionally mono- or disubstituted by (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, (C2-6)alkenylsulphonyl or aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkyl or (C2-6)alkenyl;
• in optionally substituted aminocarbonyl the amino group is optionally substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl or (C2-6)alkenylcarbonyl and optionally further substituted by (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl or (C2-6)alkenyl;
• and each R11 is independently H;
• trifluoromethyl;
• (C1-6)alkyl;
• (C2-6)alkenyl;
• (C1-6)alkoxycarbonyl;
• (C1-6)alkylcarbonyl;
• or aminocarbonyl wherein the amino group is optionally substituted by (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (C1-6)alkyl or (C2-6)alkenyl and optionally further substituted by (C1-6)alkyl or (C2-6)alkenyl;
• or where one of R6, R7, R8 or R9 contains a carboxy group they may together with R3 form a cyclic ester linkage.