Thiophene carboxamide compounds as inhibitors of enzyme IKK-2

A compound of formula (I)

• in which:
• R1 represents NH2;
• X represents O;
• R2 represents hydrogen, halogen, cyano, nitro, —NR6R7, C1–C2 alkyl, or trifluoromethyl;
• A represents a pyridyl group;
• said pyridyl group being optionally substituted by one or more substituents selected independently from halogen, cyano, nitro, —NR8R9, —CONR8R9, —COOR8, —NR8COR9, —S(O)SR8, —SO2NR8R9, —NR8SO2R9, C1–C6 alkyl, trifluoromethyl, —(CH2)tR10, —O(CH2)tR11 or —OR12;
• n represents an integer 1 or 2;
• and when n represents 2, each R3 group may be selected independently;
• R3 represents a group —W—Y—Z wherein:
• W represents O or S;
• Z represents a bond;
• Z represents:
• (a) a phenyl ring or a 5- or 6-membered heteroaromatic ring containing one to three heteroatoms selected independently from O, N and S;
• said phenyl or heteroaromatic ring being optionally substituted by one or more substituents selected independently from halogen, cyano, —NR16R17, —CONR16R17, —COOR16—COR16—NR16COR17, —S(O)uR16, —SO2NR16R17, —NR16 SO2R17, hydroxyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkyl and C1–C6 alkoxy;
• said alkyl or alkoxy group being optionally further substituted by one or more groups selected from halogen, cyano, hydroxyl, C1–C4 alkoxy and NR18R19;
• or
• (b) a 3- to 8-membered saturated or partially unsaturated monocyclic or saturated bicyclic ring system optionally incorporating one or two heteroatoms selected independently from O, N and S, and optionally incorporating a carbonyl group;
• said ring system being optionally substituted by one or more substituents selected independently from halogen, cyano, —NR16R17, —CONR16R17, —COOR16, —COR16, —NR16COR17, —S(O)uR16, —SO2NR16R17, —NR16 SO2R17, hydroxyl, C2–C6 alkenyl, C2–C6 alkynyl, C1–C6 alkyl, C3–C6 cycloalkyl and C1–C6 alkoxy;
• said alkyl or alkoxy group being optionally further substituted by one or more groups selected from halogen, cyano, hydroxyl, C3–C6 cycloalkyl, C1–C4 alkoxy and NR18R19;
• provided that said saturated monocyclic ring Z is not bonded to Y through nitrogen if the group —W—Y— represents —(CH2)2-4— or —O—(CH2)2-4— when the saturated ring Z is also unsubstituted;
• or
• (c) if W represents O, then Z may also represent hydroxyl, CF3, CHF2 or CH2F, cyclopentylmethyl, CH2CHF2, tetrahydro-2-furanylmethyl, 2-furanylmethyl, 2-thienylmethyl, tetrahydro-3-furanyl, cyclopropylmethyl, benzyloxyethyl, tereohydro-2-furanyl, benzyl, 2-(1-pyrrolidin-2-one)ethyl, 1-methylpyrrolidin-2-on-4-yl)methyl, or 2,2-dimethyl-3-pyrrolidinyl-propyl, provided that the group —Y—Z does not thereby represent —O—(CH2)2-4—OCH3;
• R10 and R11 independently represent NR20R21 where R20 and R21 are independently hydrogen or C1–C6 alkyl optionally substituted by C1–C4 alkoxy;
• or the group NR20R21 represents a 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR22 group;
• where R22 is hydrogen or C1–C6 alkyl;
• or R10 and R11 independently represent C1–C6 alkoxy;
• R4 and R5 independently represent H or C1–C4 alkyl;
• or the group NR4R5 represents a 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR23 group;
• where R23 is hydrogen or C1–C4 alkyl;
• R6 and R7 independently represent H or C1–C2 alkyl;
• R8, R9 and R12 independently represent H or C1–C6 alkyl;
• R16 and R17 independently represent H or C1–C6 alkyl optionally substituted by OH, C1–C4 alkoxy or one or more fluoro atoms;
• or the group NR16R17 represents a 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR24 group;
• where R24 is hydrogen or C1–C6 alkyl optionally substituted by OH, C1–C4 alkoxy or one or more fluoro atoms;
• R18 and R19 independently represent H or C1–C4 alkyl;
• or the group NR18R19 represents a 5- or 6-membered saturated azacyclic ring optionally containing a further O, S or NR25 group;
• where R25 is hydrogen or C1–C4 alkyl;
• m, s, u and v independently represent an integer 0, 1 or 2;
• t represents an integer 2, 3 or 4;
• and pharmaceutically acceptable salts thereof:
• with the proviso that the following two compounds are excluded:
• 2-[(aminocarbonyl)amino]-5-(4-[2-(1-(2,2,6,6-tetramethyl)piperidinyl)ethoxy]phenyl)-3-thiophenecarboxamide;
• 2-[(aminocarbonyl)amino]-5-(4-(thiazol-4-yl-methoxy)phenyl)-3-thiophenecarboxamide.