Imidazopyridine derivatives as modulators of TNF activity

1. A compound of formula (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof:

wherein

V represents C—R 22 or N;

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, halo(C 1-6 )alkyl, cyano, C 1-6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, (C 1-6 )alkoxy-(C 1-6 )alkyl, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, carboxy(C 3-7 )cycloalkyl-oxy, C 1-6 alkylthio, C 1-6 alkylsulphonyl, (C 1-6 )alkylsulphonyl(C 1-6 )alkyl, amino, amino-(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, (C 1-6 )alkoxy(C 1-6 )alkylamino, N—[(C 1-6 )alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, C 2-6 alkylcarbonylamino, (C 2-6 )alkylcarbonylamino-(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, N—[(C 1-6 )alkyl]-N-[carboxy(C 1-6 )alkyl]amino, carboxy(C 3-7 )cycloalkylamino, carboxy(C 3-7 )cycloalkyl(C 1-6 )alkylamino, C 1-6 alkylsulphonylamino, C 1-6 alkylsulphonylamino(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, (C 2-6 )alkylcarbonyloxy(C 1-6 )alkyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, morpholinyl(C 1-6 )alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, C 2-6 alkoxycarbonyl-methylidenyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl, di(C 1-6 )alkylaminosulphonyl, (C 1-6 )alkyl-sulphoximinyl or [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl; 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 )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, C 1-6 alkyl, trifluoromethyl or C 1-6 alkoxy;

E represents a covalent bond; or E represents —S(O) 2 — or —N(R 4 )—; or E represents an optionally substituted straight or branched C 1-4 alkylene chain;

Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, 13 S(O) 2 —, —S(O)(NR 5 )—, —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 —, —S(O)(NR 5 )—, —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 or heteroaryl; and

R 4 and R 5 independently represent hydrogen or C 1-6 alkyl.

2. The compound as claimed in claim 1 represented by formula (IIC), (IID), (IIE), (IIF), (IIG), (IIH), (IIJ), (IIK) or (IIL) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof:

wherein

T represents —CH 2 — or —CH 2 CH 2 —;

U represents C(O) or S(O) 2 ;

W represents O, S, S(O), S(O) 2 , S(O)(NR 5 ), N(R 31 ) or C(R 32 )(R 33 );

-M- represents —CH 2 — or —CH 2 CH 2 —;

R 31 represents hydrogen, cyano(C 1-6 )alkyl, C 1-6 alkyl, trifluoromethyl, trifluoro-ethyl, 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 )alkylamino-sulphonyl;

R 32 represents hydrogen, halogen, cyano, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, aminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl, a carboxylic acid isostere or prodrug moiety Ω, or —(C 1-6 )alkyl-Ω;

R 33 represents hydrogen, halogen, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy-(C 1-6 )alkyl, C 1-6 alkoxy, amino or carboxy;

R 34 represents hydrogen, halogen, halo(C 1-6 )alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, amino, C 1-6 alkylamino, di(C 1-6 )alkyl-amino, (C 2-6 )alkylcarbonylamino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, (C 1-6 )alkyl-sulphonylamino or (C 1-6 )alkylsulphonylamino(C 1-6 )alkyl;

E represents a covalent bond; or E represents —S(O) 2 — or —N(R 4 )—; or E represents an optionally substituted straight or branched C 1-4 alkylene chain;

Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O) 2 —, —S(O)(NR 5 )—, —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 —, —S(O)(NR 5 )—, —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 or heteroaryl;

R 4 and R 5 independently represent hydrogen or 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.

3. The compound as claimed in claim 1 wherein E represents —CH 2 —.

4. The compound as claimed in claim 1 wherein R 15 represents chloro or difluoromethoxy.

5. A pharmaceutical composition comprising a compound of formula (IIB) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, in association with a pharmaceutically acceptable carrier.

6. The pharmaceutical composition as claimed in claim 5 further comprising an additional pharmaceutically active ingredient.

7. A compound represented by formula (IIM) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof:

wherein

E represents a covalent bond; or E represents —S(O) 2 — or —N(R 4 )—; or E represents an optionally substituted straight or branched C 1-4 alkylene chain;

Q represents a covalent bond; or Q represents —O—, —S—, —S(O)—, —S(O) 2 —, —S(O)(NR 5 )—, —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 —, —S(O)(NR 5 )—, —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 or heteroaryl;

R 4 and R 5 independently represent hydrogen or C 1-6 alkyl;

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, halo(C 1-6 )alkyl, cyano, C 1-6 alkyl, trifluoromethyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, (C 1-6 )alkoxy-(C 1-6 )alkyl, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, carboxy(C 3-7 )cycloalkyl-oxy, C 1-6 alkylthio, C 1-6 alkylsulphonyl, (C 1-6 )alkylsulphonyl(C 1-6 )alkyl, amino, amino-(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, (C 1-6 )alkoxy(C 1-6 )alkylamino, N—[(C 1-6 )alkyl]-N-[hydroxy(C 1-6 )alkyl]amino, C 2-6 alkylcarbonylamino, (C 2-6 )alkylcarbonylamino(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, N—[(C 1-6 )alkyl]-N-[carboxy(C 1-6 )alkyl]amino, carboxy(C 3-7 )cycloalkylamino, carboxy(C 3-7 )cycloalkyl(C 1-6 )alkylamino, C 1-6 alkylsulphonylamino, C 1-6 alkylsulphonylamino(C 1-6 )alkyl, formyl, C 2-6 alkylcarbonyl, (C 2-6 )alkylcarbonyloxy(C 1-6 )alkyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, morpholinyl(C 1-6 )alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, C 2-6 alkoxycarbonyl-methylidenyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl, di(C 1-6 )alkylaminosulphonyl, (C 1-6 )alkyl-sulphoximinyl or [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl; 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 )heterocycloalkenyl, (C 4-9 )heterobicycloalkyl or (C 4-9 )spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents;

W represents O, S, S(O), S(O) 2 , S(O)(NR 5 ), N(R 31 ) or C(R 32 )(R 33 );

R 31 represents hydrogen, cyano(C 1-6 )alkyl, C 1-6 alkyl, trifluoromethyl, trifluoro-ethyl, 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 )alkylamino-sulphonyl;

R 32 represents hydrogen, halogen, cyano, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, aminosulphonyl, (C 1-6 )alkylsulphoximinyl, [(C 1-6 )alkyl][N—(C 1-6 )alkyl]sulphoximinyl, a carboxylic acid isostere or prodrug moiety Ω, or —(C 1-6 )alkyl-Ω; and

R 33 represents hydrogen, halogen, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy-(C 1-6 )alkyl, C 1-6 alkoxy, amino or carboxy.

8. The compound as claimed in claim 7 wherein E represents —CH 2 —.

9. The compound as claimed in claim 7 wherein R 15 represents chloro or difluoromethoxy.

10. A pharmaceutical composition comprising a compound of formula (IIM) as defined in claim 7 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof, in association with a pharmaceutically acceptable carrier.

11. The pharmaceutical composition as claimed in claim 10 further comprising an additional pharmaceutically active ingredient.

12. A compound

5-{1-[(2,5-Dichlorophenyl)methyl]-2-methylimidazo[4,5-c]pyridin-6-yl}-1H-pyridin -2-one,

4-(5-{1-[(2,5-Dichlorophenyl)methyl]-2-methylimidazo[4,5-c]pyridin-6-yl}pyrimidin-2-yl)morpholine,

5-{1-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)imidazo[4,5-c]pyridin-6-yl}-1H-pyridin-2-one,

1-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)6-[6-(piperazin-1-yl)pyridin-3-yl]-imidazo[4,5-c]pyridine,

4-(5-{1-[(2,5-Dichlorophenyl)methyl]-2-(methoxymethyl)imidazo[4,5-c]pyridin-6-yl}-pyrimidin-2-yl)morpholine,

1-[(2,5-Dichlorophenyl)methyl]-2-methyl-6-[6-(piperazin-1-yl)pyridin-3-yl]imidazo[4,5-c]pyridine,

5-(1-{[2-(Difluoromethoxy)phenyl]methyl}-2-methylimidazo[4,5-c]pyridin-6-yl)1H-pyridin-2-one,

1-{[2-(Difluoromethoxy)phenyl]methyl}-6-(6-methoxypyridin-3-yl)2-methylimidazo-[4,5-c]pyridine,

5-(1-{[2-(Difluoromethoxy)phenyl]methyl}-2-(methoxymethyl)imidazo[4,5-c]pyridin-6-yl)1H-pyridin-2-one,

1-{[2-(Difluoromethoxy)phenyl]methyl}-2-(methoxymethyl)6-(6-methoxypyridin-3-yl)imidazo[4,5-c]pyridine, or

1-{[2-(Difluoromethoxy)phenyl]methyl}-2-(methoxymethyl)6-(2-methoxypyrimidin-5-yl)imidazo[4,5-c]pyridine.

13. A method for the treatment of disorders for which the administration of a modulator of TNFα function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (IIB) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof.

14. A method for the treatment of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (IIB) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a co-crystal thereof.