Fused pentacyclic imidazole derivatives as modulators of TNF activity

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

wherein

A represents C—R 6 ;

B represents C—R 7 ; and

D represents N;

—X-Q- represents —O—, —O—C(O)—, —O—C(═CH—CN)—, —S—, —SO—, —SO 2 —, —N(R g )—, —N(R f )—CON(R f )—SO 2 —, N(R f )—C(S)—, —N═S(O)(CH 3 )—, —O—C(═CH 2 )—or —S(═N—CN)—; or —X-Q- represents O—CH 2 —, —CH 2 —S—, —CH 2 —SO—, —CH 2 —SO 2 —, —N(R g )—CH 2 —, any of which groups may be optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl, hydroxy(C 1-6 ) alkyl, trifluoromethyl, C 2-6 alkylcarbonyl, carboxy and C 2-6 alkoxycarbonyl

Z represents methylene;

E represents a fused heteroaromatic ring system of formula (Ea):

wherein the asterisks (*) represent the site of attachment of E to the remainder of the molecule;

R 1 represents hydrogen or halogen or —C 3-7 heterocycloalkyl, heteroaryl, (C 3-7 )cycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl-heteroaryl-, or (C 4-9 )heterobicycloalkyl-heteroaryl, any of which groups may be optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, difluoromethyl, hydroxy(C 1-6 )alkyl, oxo, amino and amino(C 1-6 )alkyl;

R 2 represents halogen, or R 2 represents heteroaryl, either of which groups may be optionally substituted by one or more substituents selected from hydroxy(C 1-6 )alkyl and C 2-6 alkoxycarbonyl;

R 3 and R 4 independently represent hydrogen, halogen or or C 1-6 alkyl,

R 5 represents difluoro-methoxy, or —OR a ;

R 6 represents hydrogen, halogen or trifluoromethyl;

R 7 represents hydrogen or trifluoromethyl;

R 8 represents hydrogen or trifluoromethyl;

R 12 represents hydrogen or C 1-6 alkyl;

R a represents C 1-6 alkyl, aryl(C 1-6 )alkyl, or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents selected from C 1-6 alkoxy and oxo;

R f represents hydrogen or C 1-6 alkyl;

R g represents hydrogen, —SO 2 R a , —COR d or —CO 2 R d ; or R g represents C 1-6 alkyl, or heteroaryl, any of which groups may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, C 1-6 alkyl, C 4-9 heterobicycloalkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylsulphonyl, carboxy and C 2-6 alkoxycarbonyl; and

R d represents hydrogen; or R d represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, C 3-7 l heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, oxo, C 2-6 alkylcarbonyl and di(C 1-6 )alkylamino.

2. The compound as claimed in claim 1 represented by formula (IIA) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 2 , R 5 , R 6 , R 7 and R f are as defined in claim 1 .

3. The compound as claimed in claim 1 represented by formula (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 2 , R 5 , R 6 , R 7 and R g are as defined in claim 1 .

4. The compound as claimed in claim 1 which is selected from the group consisting of

2-{5-[(6R,12R)-3-Fluoro-11-methoxy-7,12-dihydro-6H-6,12-methanopyrido[2′,3′:5,6]-[1,4]diazepino[1,2-a]benzimidazol-2-yl]pyrimidin-2-yl}propan-2-ol;

2-{5-[(6R,12R)-2-Fluoro-11-methoxy-7,12-dihydro-6H-6,12-methanopyrido[2′,3′:5,6]-[1,4]diazepino[1,2-a]benzimidazol-3-yl]pyrimidin-2-yl}propan-2-ol; and

(7R,14R)-10-Fluoro-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-1-methoxy-6,7-dihydro-7,14-methanopyrido[2′,3′:6,7][1,4]diazocino[1,2-a]benzimidazol-5(14H)-one.

5. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt 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. The compound as claimed in claim 1 wherein R 1 represents heteroaryl, which group may be optionally substituted by one or more substituents selected from halogen, cyano, C 1-6 alkyl, difluoromethyl, hydroxy(C 1-6 )alkyl, oxo, amino and amino(C 1-6 ) alkyl.

8. The compound as claimed in claim 1 wherein-X-Q- represents —N(R g )— or —N(R f )—CO—.

9. The compound as claimed in claim 1 wherein R 2 represents halogen.

10. The compound as claimed in claim 1 wherein R g represents hydrogen or methyl.