TNF -α modulating benzimidazoles
A series of benzimidazole derivatives, being potent modulators of human TNFα activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
1. A compound represented by formula (IIB) or a pharmaceutically acceptable salt thereof:
wherein
V represents C—R 22 or N;
R 21 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 alkoxy(C 1-6 )alkyl, C 1-6 alkylthio, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, hydroxy(C 1-6 )alkylamino, (C 1-6 )alkoxy(C 1-6 )alkylamino, [(C 1-6 )alkoxy](hydroxy)(C 1-6 )alkylamino, N—[(C 1-6 )alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, [(C 1-6 )alkylthio](hydroxy)(C 1-6 )alkylamino, di(C 1-6 )alkylamino(C 1-6 )alkylamino, N-[di(C 1-6 )alkylamino(C 1-6 )alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, hydroxy(C 1-6 )alkyl(C 3-7 )cycloalkylamino, (hydroxy)[(C 3-7 )cycloalkyl(C 1-6 )alkyl]amino, (C 3-7 )heterocycloalkyl(C 1-6 )alkylamino, oxo(C 3-7 )heterocycloalkyl(C 1-6 )alkylamino, (C 1-6 )alkylheteroarylamino, heteroaryl(C 1-6 )alkylamino, (C 1-6 )alkylheteroaryl(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, N—[(C 1-6 )alkyl]-N—[(C 2-6 )alkylcarbonyl]amino, bis[(C 3-6 )alkenyl-carbonyl]amino, N-[carboxy(C 1-6 )alkyl]-N—[(C 1-6 )alkyl]amino, C 2-6 alkoxycarbonylamino, C 2-6 alkoxycarbonyl(C 1-6 )alkylamino, C 1-6 alkyl sulphonylamino, N—[(C 1-6 )alkyl]-N—[(C 1-6 )alkylsulphonyl]amino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, hydroxy(C 1-6 )alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminocarbonyl(C 1-6 )alkyl, aminosulphonyl, C 1-6 alkylaminosulphonyl or di(C 1-6 )alkylaminosulphonyl; or R 21 represents (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl(C 1-6 )alkyl, (C 4-7 )cycloalkenyl, (C 4-9 )bicycloalkyl, (C 3-7 )heterocycloalkyl, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl, (C 3-7 )heterocycloalkenyl, (C 4-9 )heterobicycloalkyl or (C 4-9 )spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents;
R 22 represents hydrogen, halogen or C 1-6 alkyl;
R 23 represents hydrogen or C 1-6 alkyl;
E represents —N(R 4 )—, —CH 2 —, —CH(CH 3 )— or —CH(CH 2 CH 3 )—;
Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )— or —N(R 5 )S(O) 2 —; or Q represents an optionally substituted straight or branched C 1-6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )— and —N(R 5 )S(O) 2 —;
Z represents hydrogen, halogen or trifluoromethyl; or Z represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z 1 —Z 2 or —Z 1 —C(O)—Z 2 , either of which moieties may be optionally substituted by one or more substituents;
Z 1 represents a divalent radical derived from an aryl, C 3-7 heterocycloalkyl or heteroaryl group;
Z 2 represents aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl, (C 4-9 )heterobicycloalkyl, (C 4-9 )spiroheterocycloalkyl or heteroaryl;
R 4 and R 5 independently represent hydrogen or C 1-6 alkyl;
R 12 represents hydrogen, halogen, trifluoromethyl or optionally substituted C 1-6 alkyl; and
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, arylamino, C 2-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 heterocycloalkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl or di(C 1-6 )alkylaminosulfonyl.
2. A compound as claimed in claim 1 wherein R 21 represents hydroxy(C 1-6 )alkyl.
3. A compound as claimed in claim 1 represented by formula (IIC), (IIE), (IIF), (IIG), (IIH), (IIJ), (IIK) or (IIL) or a pharmaceutically acceptable salt thereof:
wherein
T represents —CH 2 — or —CH 2 CH 2 —;
W represents O, S, S(O), S(O) 2 , N(R 31 ) or C(R 32 )(R 33 );
-M- represents —CH 2 — or —CH 2 CH 2 —;
R 31 represents hydrogen, hydroxy(C 1-6 )alkyl, cyano(C 1-6 )alkyl, C 1-6 alkyl, trifluoromethyl, difluoroethyl, trifluoroethyl, C 1-6 alkylsulphonyl, (C 1-6 )alkylsulphonyl(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, a carboxylic acid isostere or prodrug moiety Ω, —(C 1-6 )alkyl-Ω, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl or di(C 1-6 )alkylaminosulphonyl;
R 32 represents halogen, C 1-6 alkoxy, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, aminocarbonyl, a carboxylic acid isostere or prodrug moiety Ω, or —(C 1-6 )alkyl-Ω;
R 33 represents hydrogen, halogen, C 1-6 alkyl or amino;
R 34 represents hydrogen, halogen, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino or di(C 1-6 )alkylamino;
E represents —N(R 4 )—, —CH 2 —, —CH(CH 3 )— or —CH(CH 2 CH 3 )—;
Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )— or —N(R 5 )S(O) 2 —; or Q represents an optionally substituted straight or branched C 1-6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )— and —N(R 5 )S(O) 2 —;
Z represents hydrogen, halogen or trifluoromethyl; or Z represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z 1 —Z 2 or —Z 1 C(O)—Z 2 , either of which moieties may be optionally substituted by one or more substituents;
Z 1 represents a divalent radical derived from an aryl, C 3-7 heterocycloalkyl or heteroaryl group;
Z 2 represents aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl, (C 4-9 )heterobicycloalkyl, (C 4-9 )spiroheterocycloalkyl or heteroaryl;
R 4 and R 5 independently represent hydrogen or C 1-6 alkyl;
R 12 represents hydrogen, halogen, trifluoromethyl or optionally substituted C 1-6 alkyl; and
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, aryl-amino, C 2-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 heterocycloalkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, or di(C 1-6 )alkylaminosulfonyl.
4. A compound as claimed in claim 3 wherein R 34 represents hydrogen or hydroxy.
5. A compound as claimed in claim 1 wherein E represents —CH 2 — or —CH(CH 3 )—.
6. A compound as claimed in claim 1 wherein R 12 represents hydrogen or fluoro.
7. A compound as claimed in claim 1 wherein R 15 represents difluoromethoxy.
8. A pharmaceutical composition comprising a compound of formula (IIB),
or a pharmaceutically acceptable salt thereof wherein
V represents C—R 22 or N;
-E represents —N(R 4 )—, —CH 2 —, —CH(CH 3 )— or —CH(CH 2 CH 3 )—;
Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )— or —N(R 5 )S(O) 2 —; or Q represents an optionally substituted straight or branched C 1-6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from —O—, —S—, —S(O)—, —S(O) 2 —, —N(R 5 )—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —S(O) 2 N(R 5 )— and —N(R 5 )S(O) 2 —;
Z represents hydrogen, halogen or trifluoromethyl; or Z represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents —Z 1 —Z 2 or —Z 1 —C(O)—Z 2 , either of which moieties may be optionally substituted by one or more substituents;
Z 1 represents a divalent radical derived from an aryl, C 3-7 heterocycloalkyl or heteroaryl group;
Z 2 represents aryl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl, (C 4-9 )heterobicycloalkyl, (C 4-9 )spiroheterocycloalkyl or heteroaryl;
R 4 and R 5 independently represent hydrogen or C 1-6 alkyl;
R 12 represents hydrogen, halogen, trifluoromethyl or optionally substituted C 1-6 alkyl; and
R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, C 1-6 alkyl, trifluoromethyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, arylamino, C 2-6 alkylcarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, C 3-6 heterocycloalkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl or di(C 1-6 )alkylaminosulfonyl;
R 21 represents hydrogen, halogen, cyano, C 1-6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoromethoxy, trifluoro-methoxy, trifluoroethoxy, C 1-6 alkoxy(C 1-6 )alkyl, C 1-6 alkylthio, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkylamino, hydroxy(C 1-6 )alkylamino, (C 1-6 )alkoxy(C 1-6 )alkylamino, [(C 1-6 )alkoxy](hydroxy)(C 1-6 )alkylamino, N—[(C 1-6 )alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, [(C 1-6 )alkylthio](hydroxy)(C 1-6 )alkylamino, di(C 1-6 )alkylamino(C 1-6 )alkylamino, N-[di(C 1-6 )alkylamino(C 1-6 )alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, hydroxy(C 1-6 )alkyl(C 3-7 )cycloalkylamino, (hydroxy)[(C 3-7 )cycloalkyl(C 1-6 )alkyl]amino, (C 3-7 )heterocycloalkyl(C 1-6 )alkylamino, oxo(C 3-7 )heterocycloalkyl(C 1-6 )alkylamino, (C 1-6 )alkylheteroarylamino, heteroaryl(C 1-6 )alkylamino, (C 1-6 )alkylheteroaryl, (C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, N—[(C 1-6 )alkyl]-N—[(C 2-6 )alkylcarbonyl]amino, bis[(C 3-6 )alkenylcarbonyl]amino, N-[carboxy(C 1-6 )alkyl]-N—[(C 1-6 )alkyl]amino, C 2-6 alkoxycarbonylamino, C 2-6 alkoxycarbonyl(C 1-6 )alkylamino, C 1-6 alkyl sulphonylamino, N—[(C 1-6 )alkyl]-N—[(C 1-6 )alkylsulphonyl]amino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, hydroxy(C 1-6 )alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminocarbonyl(C 1-6 )alkyl, aminosulphonyl, C 1-6 alkylaminosulphonyl or di(C 1-6 )alkylaminosulphonyl; or R 21 represents (C 3-7 )cycloalkyl, (C 3-7 )cycloalkyl(C 1-6 )alkyl, (C 4-7 )cycloalkenyl, (C 4-9 )bicycloalkyl, (C 3-7 )heterocycloalkyl, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl, (C 3-7 )heterocycloalkenyl, (C 4-9 )heterobicycloalkyl or (C 4-9 )spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents;
R 22 represents hydrogen, halogen or C 1-6 alkyl;
R 23 represents hydrogen or C 1-6 alkyl;
in association with a pharmaceutically acceptable carrier.
9. A pharmaceutical composition as claimed in claim 8 further comprising an additional pharmaceutically active ingredient.
10. The compound according to claim 2 wherein R 21 represents 2-hydroxyprop-2-yl.