Aminopiperidine derivatives as antibacterials

A compound of formula (I) or a pharmaceutically acceptable salt or N-oxide thereof:

• wherein:
• one of Z1, Z2 and Z3 is N, and Z4, Z5 and remainder of Z1, Z2 and Z3 not equal to N are CR1a;
• R1 and R1a are independently hydrogen;
• hydroxy;
• (C1-6)alkoxy optionally substituted by (C1-6)alkoxy, amino, piperidyl, guanidino or amidino optionally N-substituted by one or two (C1-6)alkyl, acyl or (C1-6)alkylsulphonyl groups, CONH2, hydroxy, thiol, (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;
• nitro;
• azido;
• acyl;
• acyloxy;
• (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;
• and
• additionally when Z5 is CR1a, R1a may be (C1-4)alkyl-CO2H or (C1-4)alkyl-CONH2 in which the C1-4 alkyl is substituted by R12;
• (C1-4)alkyl substituted by cyano, amino or guanidino;
• aminocarbonyl optionally substituted by hydroxy, (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C1-6)alkenylsulphonyl, (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C2-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl;
• R2 is hydrogen, or (C1-4)alkyl or (C1-4)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, (C1-4)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;
• thiol;
• halogen;
• (C1-4)alkylthio;
• trifluoromethyl;
• azido;
• 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 hydrogen;
• or
• R3 is in the 2-, 3- or 4-position and is:
• carboxy;
• (C1-6)alkoxycarbonyl;
• aminocarbonyl, wherein the amino group is optionally substituted by hydroxy, (C1-6)alkyl, hydroxy(C1-6)alkyl, aminocarbonyl(C1-6)alkyl, (C2-6)alkenyl, (C1-6)alkylsulphonyl, trifluoromethylsulphonyl, (C1-6)alkenylsulphonyl, (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;
• 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;
• or 5-oxo-1,2,4-oxadiazol-3-yl;
• or
• (C1-4)alkyl optionally substituted or ethenyl substituted with any of the substituents listed above for R3 and up to 3 groups for R12 independently selected from:
• thiol;
• halogen;
• (C1-6)alkylthio;
• trifluoromethyl;
• azido;
• (C1-6)alkoxycarbonyl;
• (C1-6)alkylcarbonyl;
• (C2-6)alkenyloxycarbonyl;
• (C2-6)alkenylcarbonyl;
• 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;
• amino 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;
• aminocarbonyl, wherein 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;
• oxo;
• (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;
• in addition when R3 is disubstituted with a hydroxy or amino containing substituent and carboxy containing substituent these may together form a cyclic ester or amide linkage, respectively;
• or
• when R3 is in the 3- or 4-position it may with R2 or R4 form a C3-5 alkylene group optionally substituted by a group R5 selected from:
• (C1-12)alkyl;
• hydroxy(C1-12)alkyl;
• (C1-12)alkoxy(C1-12)alkyl;
• (C1-12)alkanoyloxy(C1-12)alkyl;
• (C3-6)cycloalkyl;
• hydroxy(C3-6)cycloalkyl;
• (C1-12)alkoxy(C3-6)cycloalkyl;
• (C1-2)alkanoyloxy(C3-6)cycloalkyl;
• (C3-6)cycloalkyl(C1-12)alkyl;
• hydroxy-, (C1-12)alkoxy- or (C1-12)alkanoyloxy-(C3-6)cycloalkyl(C1-12)alkyl;
• cyano;
• cyano(C1-12)alkyl;
• (C2-12)alkenyl;
• (C2-12)alkynyl;
• tetrahydrofuryl;
• mono- or di-(C1-12)alkylamino(C1-12)alkyl;
• acylamino(C1-12)alkyl;
• (C1-12)alkyl- or acyl-aminocarbonyl(C1-12)alkyl;
• mono- or di(C1-12)alkylamino(hydroxy) (C1-12)alkyl;
• optionally substituted phenyl(C1-12)alkyl, phenoxy(C1-12)alkyl or phenyl(hydroxy)(C1-12)alkyl;
• optionally substituted diphenyl(C1-12)alkyl;
• optionally substituted phenyl(C2-12)alkenyl;
• optionally substituted benzoyl or benzoyl(C1-12)alkyl;
• optionally substituted heteroaryl(C1-12)alkyl;
• and optionally substituted heteroaroyl or heteroaroyl(C1-12)alkyl;
• wherein phenyl, benzoyl, heteroaryl and heteroaroyl groups are optionally substituted with up to five groups selected from halogen, mercapto, (C1-6)alkyl, phenyl, (C1-6)alkoxy, hydroxy(C1-6)alkyl, mercapto (C1-6)alkyl, halo(C1-6)alkyl, hydroxy, optionally substituted amino, nitro, carboxy, (C1-6)alkylcarbonyloxy, (C1-6)alkoxycarbonyl, formyl, and (C1-6)alkylcarbonyl groups;
• R4 forms a group with R3 as above defined, or is a group —CH2—R5 where R5 is as defined above:
• n is 0, 1 or 2;
• A is NR11 or CR6R7 and B is NR11, O, SO2 or CR8R9;
• and
• wherein:
• each of R6, R7, R8 and R9 is independently selected from:
• hydrogen;
• (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 R12 as defined in R3;
• (C1-6)alkylsulphonyl;
• (C2-6)alkenylsulphonyl;
• or (C1-6)aminosulphonyl, wherein the amino group is optionally substituted by (C1-6)alkyl or (C1-6)alkenyl;
• or R6 and R8 together represent a bond and R7 and R9 are as above defined;
• or R6 and R7 or R8 and R9 together represent oxo;
• provided that:
• when A is NR1 1, B is not NR11, O or SO2;
• when A is CO, B is not CO, O or SO2;
• when n is 0 and A is NR1 1, CR8R9 can only be CO;
• when A is CR6R7 and B is SO2, n is 0;
• when n is 0, B is not NR1 1 or 0;
• and
• when A–B is CR7═CR9, n is 1 or 2;
• R10 is selected from (C1-4)alkyl;
• (C2-4)alkenyl and aryl, each of which is 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, (C1-6)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;
• (C1-6)alkenylsulphonyl;
• (C1-6)alkoxycarbonyl;
• (C1-6)alkylcarbonyl;
• (C2-6)alkenyloxycarbonyl;
• and (C2-6)alkenylcarbonyl;
• R11 is hydrogen;
• trifluoromethyl, (C1-6)alkyl;
• (C1-6)alkenyl;
• (C1-6)alkoxycarbonyl;
• (C1-6)alkylcarbonyl;
• aminocarbonyl, wherein the amino group is optionally substituted by (C1-6)alkoxycarbonyl, (C1-6)alkylcarbonyl, (C1-6)alkenyloxycarbonyl, (C2-6)alkenylcarbonyl, (C1-6)alkyl or (C1-6)alkenyl and optionally further substituted by (C1-6)alkyl or (C1-6)alkenyl.