Fused Hexacyclic Imidazole Derivatives as Modulators of TNF Activity

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

• wherein
• A represents N or C—R6;
• B represents N or C—R7;
• D represents N or C—R8;
• —(X-M-Q)- represents an optionally substituted five-membered heteroaromatic ring selected from furyl, thienyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl;
• or
• —(X-M-Q)- represents a saturated or partially saturated five- or six-membered heterocyclic ring containing n carbon atoms, p oxygen atoms and q nitrogen atoms, which ring may be optionally substituted by one or more substituents;
• n is 2, 3, 4 or 5;
• p is zero or 1;
• and
• q is 1, 2 or 3, such that (n+p+q) is 5 or 6;
• 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;
• R1 represents hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, —ORa, —SRa, —SORa, —SO2Ra, —NRbRc, —NRcCORd, —NRcCO2Rd, —NHCONRbRc, —NRcSO2Re, —CORd, —CO2Rd, —CONRbRc, —SO2NRbRc, or —S(O)(N—Rb)Rc;
• or R1 represents C1-6 alkyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, heteroaryl(C1-6)alkyl, (C3-7)heterocycloalkyl(C1-6)alkyl-aryl-, (C4-7)heterocycloalkenyl-aryl-, (C3-7)cycloalkyl-heteroaryl-, (C3-7)cycloalkyl-(C1-6)alkyl-heteroaryl-, (C4-7)cycloalkenyl-heteroaryl-, (C4-9)bicycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(C1-6)alkyl-heteroaryl-, (C3-7)heterocycloalkenyl-heteroaryl-, (C4-9)heterobicycloalkyl-heteroaryl- or (C4-9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents;
• R2 represents hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy or —ORa:
• or R2 represents C1-6 alkyl or heteroaryl, either of which groups may be optionally substituted by one or more substituents;
• R3 and R4 independently represent hydrogen, halogen or trifluoromethyl:
• or C1-6 alkyl, which group may be optionally substituted by one or more substituents;
• R5 represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, difluoromethoxy, trifluoromethoxy, —ORa or C1-6 alkylsulphonyl;
• or R5 represents C1-6 alkyl, which group may be optionally substituted by one or more substituents;
• R6, R7 and R8 independently represent hydrogen, halogen, trifluoromethyl, C1-6 alkyl or C1-6 alkoxy,
• R12 represents hydrogen or C1-6 alkyl;
• Ra represents C1-6 alkyl, C3-7 cycloalkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
• Rb and Rc independently represent hydrogen or trifluoromethyl;
• or C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
• or
• Rb and Rc, 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 may be optionally substituted by one or more substituents;
• Rd represents hydrogen;
• or Rd represents C1-6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
• and
• Re represents C1-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.