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 N or C—R 6 ;

B represents N or C—R 7 ;

D represents N or C—R 8 ;

X—Q— represents —O—, —O—C(O)—, —C(O)—O—, —O—C(═CH—CN)—, —S—, —SO—, —SO 2 —, —N(R 9 )—, —N(R f )—CO—, —CO—N(R f )—, —N(R f )—SO 2 —, —SO 2 —N(R f )—, —S(O)(NR f )—, —N(R f )—C(S)—, —N═S(O)(CH 3 )—, —O—C(═CH 2 )—or —S(═N—CN)—; or —X—Q— represents —CH 2 —CH 2 —, —O—CH 2 —, —CH 2 —O—, —S—CH 2 —, —SO—CH 2 —, —SO 2 —CH 2 —, —CH 2 —S—, —CH 2 —SO—, —CH 2 —SO 2 —, —N(R 9 )—CH 2 —, —CH 2 —N(R 9 )—, —S(O)(NR f )—CH 2 — or —CH 2 —S(O)(NR f )—, any of which groups can 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 selected from the groups of formula (Ea), (Eb) and (Ec):

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

R 1 represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, —OR a , —SR a , —SOR a , —SO 2 R a , —NR c R c , —NR c COR d , —NR c CO 2 R d , —NHCONR b R c , —NR c SO 2 R e , —COR d , —CO 2 R d , —CONR b R c , —SO 2 NR b R c , or —S(O)(N—R b )R e ; or R 1 represents C 1-6 alkyl, C 3-7 cycloalkyl, C 4-7 cycloalkenyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkenyl, heteroaryl, heteroaryl(C 1-6 )alkyl, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl-aryl-, (C 3-7 )heterocycloalkenyl-aryl-, (C 3-7 )cycloalkyl-heteroaryl-, (C 3-7 )cycloalkyl-(C 1-6 )alkyl-heteroaryl-, (C 4-7 )cycloalkenyl-heteroaryl-, (C 4-9 )bicycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl-heteroaryl-, (C 3-7 )heterocycloalkyl(C 1-6 )alkyl-heteroaryl-, (C 3-7 )heterocycloalkenyl-heteroaryl-, (C 4-9 )heterobicycloalkyl-heteroaryl- or (C 4-9 )spiroheterocycloalkyl-heteroaryl-, any of which groups can 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 hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or —OR a ; or R 2 represents C 1-6 alkyl or heteroaryl, either of which groups may can 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 trifluoromethyl; or C 1-6 alkyl;

R 5 represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OR a or C 1-6 alkylsulphonyl; or R 5 represents C 1-6 alkyl;

R 6 , R 7 and R 8 independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl or C 1-6 alkoxy;

R 12 represents hydrogen or C 1-6 alkyl;

R a represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups can be optionally substituted by one or more C 1-6 alkoxy or oxo;

R b represent hydrogen; or C 1-6 alkyl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, any of which groups can be optionally substituted by one or more substituents selected from C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, hydroxy, cyano, C 2-6 alkoxycarbonyl, di-(C 1-6 )alkylamino and C 2-6 alkoxycarbonylamino;

R c represents hydrogen; or C 1-6 alkyl, C 3-7 cycloalkyl, or C 3-7 heterocycloalkyl, any of which groups may be optionally substituted by C 2-6 alkylcarbonyl or C 2-6 alkoxycarbonyl;

or

R b and R c , when taken together with the nitrogen atom to which they are both attached, represent a heterocyclic moiety selected from azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl, homopiperazin-1-yl, (imino)(oxo)thiazinan-4-yl, (oxo)thiazinan-4-yl and (dioxo)-thiazinan-4-yl, any of which groups can be optionally substituted by one or more substituents selected from C 1-6 alkyl, C 1-6 alkylsulphonyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, cyano, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, C 2-6 alkylcarbonyl-amino, C 2-6 alkylcarbonylamino(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, C 1-6 alkyl-sulphonylamino and aminocarbonyl;

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

R e represents C 1-6 alkyl, aryl or heteroaryl, any of which groups can be optionally substituted by C 1-6 alkyl;

R f represents hydrogen; or R f represents C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, any of which groups can be optionally substituted by one or more hydroxy or carboxy; and

R g represents hydrogen, —SO 2 R a , —COR d or —CO 2 R d ; or R g represents C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 heterocycloalkyl or heteroaryl, any of which groups can 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.

2. The compound as claimed in claim 1 wherein A represents C—R 6 , B represents C—R 7 , and D represents C—R 8 .

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

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

wherein

W represents N, CH or CF;

R 9 represents hydroxy(C 1-6 )alkyl or amino(C 1-6 )alkyl;

R 10 represents hydrogen or C 1-6 alkyl;

R 5 represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OR a or C 1-6 alkylsulphonyl; or R 5 represents C 1-6 alkyl;

R a represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may be optionally substituted by one or more C 1-6 alkoxy or oxo;

R 6 , R 7 and R 8 independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl or C 1-6 alkoxy; and

R f represents hydrogen; or R f represents C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, any of which groups can be optionally substituted by one or more hydroxy or carboxy.

5. The compound as claimed in claim 3 represented by formula (IIA-2) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

R 11 represents a group of formula (a), (b), (c), (d), (e), (f) or (g):

in which the asterisk (*) represents the site of attachment to the remainder of the molecule;

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

R 31 represents hydrogen, cyano(C 1-6 )alkyl, C 1-6 alkyl, trifluoromethyl, 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, tetrazolyl(C 1-6 )alkyl, am inocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl or di(C 1-6 )alkylaminosulphonyl;

R 32 represents hydrogen, halogen, cyano, C 1-6 alkyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, formyl, 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, (C1-6)alkylsulphonylaminocarbonyl, (C 2-6 )alkylcarbonylamino-sulphonyl, (C 1-6 )alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl;

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

R 34 represents hydrogen, halogen, halo(C 1-6 )alkyl, cyano, 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 )-alkylamino, (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;

R 35 represents hydrogen or C 1-6 alkyl;

R 36 and R 37 independently represent C 1-6 alkyl; or

R 36 and R 37 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl;

R 5 represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OR a or C 1-6 alkylsulphonyl; or R 5 represents C 1-6 alkyl;

R a represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups can be optionally substituted by one or more C 1-6 alkoxy or oxo;

R 6 , R 7 and R 8 independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl or C 1-6 alkoxy;

R b represents hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups may can be optionally substituted by one or more substituents selected from C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, hydroxy, cyano, C 2-6 alkoxycarbonyl, di—(C 1-6 )alkylamino and C 2-6 alkoxycarbonylamino;

R f represents hydrogen; or R f represents C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, any of which groups can be optionally substituted by one or more hydroxy or carboxy;

W represents N, CH or CF; and

R 10 represents hydrogen or C 1-6 alkyl.

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

7. The compound as claimed in claim 6 represented by formula (IIB-1) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

R 2 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or —OR a ; or R 2 represents C 1-6 alkyl or heteroaryl, either of which groups can be optionally substituted by one or more substituents selected from hydroxy(C)alkyl and C 2-6 alkoxycarbonyl;

R 5 represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OR a or C 1-6 alkylsulphonyl; or R 5 represents C 1-6 alkyl;

R a represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups can be optionally substituted by one or more C 1-6 alkoxy or oxo;

R 6 , R 7 and R 8 independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl or C 1-6 alkoxy; and

R f represents hydrogen; or R f represents C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, any of which groups can be optionally substituted by one or more hydroxy or carboxy;

W represents N, CH or CF;

R 9 represents hydroxy(C 1-6 )alkyl or amino(C 1-6 )alkyl; and

R 10 represents hydrogen or C 1-6 alkyl.

8. The compound as claimed in claim 6 represented by formula (IIB-2) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

R 2 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or —OR a ; or R 2 represents C 1-6 alkyl or heteroaryl, either of which groups can be optionally substituted by one or more substituents selected from hydroxy(C)alkyl and C 2-6 alkoxycarbonyl;

R 5 represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —OR a or C 1-6 alkylsulphonyl; or R 5 represents C 1-6 alkyl;

R a represents C 1-6 alkyl, C 3-7 cycloalkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups can be optionally substituted by one or more C 1-6 alkoxy or oxo;

R 6 , R 7 and Fe independently represent hydrogen, halogen, trifluoromethyl, C 1-6 alkyl or C 1-6 alkoxy; and

R f represents hydrogen; or R f represents C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, any of which groups can be optionally substituted by one or more hydroxy or carboxy;

W represents N, CH or CF;

R 10 represents hydrogen or C 1-6 alkyl; and

R 11 represents a group of formula (a), (b), (c), (d), (e), (f) or (g):

in which the asterisk (*) represents the site of attachment to the remainder of the molecule;

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

R 31 represents hydrogen, cyano(C 1-6 )alkyl, C 1-6 alkyl, trifluoromethyl, 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, tetrazolyl(C 1-6 )alkyl, am inocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulphonyl, C 1-6 alkylaminosulphonyl or di(C 1-6 )alkylaminosulphonyl;

R 32 represents hydrogen, halogen, cyano, C 1-6 alkyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkylsulphonyl, formyl, 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, (C 1-6 )alkylsulphonylaminocarbonyl, (C 2-6 )alkylcarbonylamino-sulphonyl, (C 1-6 )alkoxyaminocarbonyl, tetrazolyl or hydroxyoxadiazolyl;

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

R 34 represents hydrogen, halogen, halo(C 1-6 )alkyl, cyano, 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 )-alkylamino, (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;

R 35 represents hydrogen or C 1-6 alkyl;

R 36 and R 37 independently represent C 1-6 alkyl; or

R 36 and R 37 , when taken together with the carbon atom to which they are both attached, represent C 3-7 cycloalkyl; and

R b represents hydrogen or trifluoromethyl; or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of which groups can be optionally substituted by one or more substituents selected from C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylsulphinyl, C 1-6 alkylsulphonyl, hydroxy, cyano, C 2-6 alkoxycarbonyl,di—(C 1-6 )alkylamino and C 2-6 alkoxycarbonylamino.

9. The compound as claimed in claim 1 selected from the group consisting of:

(7R,14R)-1142-(1-Aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanopyrido[3′,2′:4,51imidazo[1,2-b[2,5benzodiazocin-5(14H)-one;

(7R,14R)-1-(Difluoromethoxy)-1142-(2-hydroxypropan-2-yl)pyrimidin-5-yl1-6-methyl-6,7-dihydro-7,14-methanopyrido[3′,2′:4,5]imidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;

(7R,14R)-11-[2-(1-Aminocyclobutyl)pyrimidin-5-yl1-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanopyrido[3′,4′:4,51imidazo[1,2-b1[2,51benzodiazocin-5(14H)-one;

(7R,14R)-1-(Difluoromethoxy)-11-[2-(2-hydroxypropan-2-yl)pyrimidin-5-yl]-6,7-dihydro-7,14-methanopyrido[3′,4′:4,5]imidazo[1,2-b][2,5]benzodiazocin-5(14H)-one;

(7R,14R)-11-(2-{cis-1-Amino-3-[hydroxy(dideutero)methyl]-3-methylcyclobutyl}-pyrimidin-5-yl)-1-(difluoromethoxy)-6,7-dihydro-7,14-methanopyrido[3′,2′:4,51imidazo-11,2-b][2,5]benzodiazocin-5(14H)-one; and

trans-3-Amino-1-{5-[(7R,14R)-1-(difluoromethoxy)-6-trideuteromethyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanopyrido[3′,2′:4,5]imidazo┌1,2-b┐┌2,5┐benzodiazocin-11-yl]-3-fluoropyridin-2-yl}-3-methylcyclobutanecarbonitrile.

10. 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.

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

12. A method for the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriatric arthritis or psoriasis, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.