| abstract |
The invention describes compounds of formula (I), wherein R1 is optionally substituted alkyl, or when Z1 is a direct bond R1 may also represent hydrogen; R2 is optionally substituted aryl, partially saturated bicycloaryl, heteroaryl or R?aRbN-; R3¿ is optionally substituted aryl or heteroaryl group; A1 is a bond, optionally substituted C¿1-6?alkylene, or C2-6alkylene containing a double or triple bond, or interrupted by oxygen, sulphur, phenylene, imino, alkylimino, sulphinyl or sulphonyl; Z?1¿ is oxygen, sulphur or a bond; Z2 is oxygen, sulphur or a bond; Z3 is -C C-, -CH¿2?-CZ-, -CZ-CH2-, -CZ-CZ-, -CH2-NH-, -CH2-O-, -CH2-S-, -CH2-SO-, -CH2-SO2-, -CF2-O-, -CZ-NH-, -NH-CH2-, -O-CH2-, -S-CH2-, -SO-CH2-, -SO2-CH2-, -O-CF2-, -O-CZ-, -NH-CZ-, -N=N-, -NH-SO2-, -SO2-NH-, -CZ-CZ-NH-, -NH-CO-O-, -O-CO-NH-, -C(=NOR?c)CH¿2-, -C(F)=N-, -CH(F)-CH2-, or -NH-CO-NH-; Z is oxygen or sulphur; R?a and Rb¿ each independently are alkyl or arylalkyl, or NRaRb forms a 4-6 membered cyclic amine which optionally contains an additional heteroatom selected from O, S, NH or NRc, or is substituted with an oxo group; Rc is alkyl or arylalkyl; Q?1, Q2 and Q3¿ are each CH or CX1 or N; and X1 is halogen; and N-oxides thereof, and their prodrugs, pharmaceutically acceptable salts, and solvates (e.g. hydrates), thereof. The invention also describes processes for preparing the compounds of formula (I), pharmaceutical compositions comprising such compounds and their use in therapy as inhibitors of TNF and type IV cyclic AMP phosphodiesterase (PDE). |