Piperidinones Useful in the Treatment of Inflammation

A compound of formula (I),

• wherein:
• m represents 0, 1, 2, 3, 4 or 5;
• n represents 0, 1, 2 or 3;
• R1 represents hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A1-Tz-B1, -A1a-N(R9)R10, -A1b-OR9, -A1c-C(O)R9, -A1d-C(O)OR9 or -A1e-C(O)N(R9)R10, wherein C1-12 alkyl, C2-12 alkenyl, and C2-12 alkynyl are optionally substituted by one or more substituents selected from X1;
• R2 represents hydrogen, —OR4, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from X1;
• or
• R1 and R2 together form ═C(R9)R10;
• R3 represents hydrogen, —OR4, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or -A2-B2, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X2;
• represents hydrogen, —R8—OR9, —R8—C(O)OR9, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or -A3-B3, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X3;
• R5 represents hydrogen, -A4-B4, —C(O)R9, —C(O)OR10, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from X4;
• R6 represents halo, —R11—OR9, —R11—CN, —R11—NO2, —R11—C(O)OR9, —R11—N(R9)R10, —R11—C(O)N(R9)R10, —R11—N(Rw3)C(O)R9, —R11—N(Rw3)C(O)N(R9)R10, —R11—N(Rw3)S(O)tR9x, —R11—N(Rw3)S(O)tOR9x, —R11—OC(O)R9, —R11—OC(O)N(R)R10, —R11—OS(O)tR9x, —R11—S(O)pR9, —R11—S(O)tN(Rw3)R9, —R11—S(O)tOR9;
• —R11—Si(R16)3, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-15 cycloalkyl or heterocyclyl which latter five groups are optionally substituted by one or more substituents selected from X5;
• or
• any two R6 groups, or R2 and any R6 group, may be linked together to form a further ring, which is formed either by the two relevant groups being linked together by a direct bond or C1-5 alkylene;
• R7 represents halo, —R11—OR9, —R11—CN, —R11—NO2, —R11—C(O)OR9, —R11—N(R9)R10, —R11—C(O)N(R9)R10, —R11—N(Rw3)C(O)R9, —R11—N(Rw3)C(O)N(R9)R10, —R11—N(Rw3)S(O)tR9x, —R11—N(Rw3)S(O)tOR9x, —R11—OC(O)R9, —R11—OC(O)N(R)R10, —R11—OS(O)tR9x, —R11—S(O)pR9, —R11—S(O)tN(Rw3)R9, —R11—S(O)tOR9, —R11—Si(R16)3, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-15 cycloalkyl or heterocyclyl which latter five groups are optionally substituted by one or more substituents selected from X5;
• Tz represents a direct bond, —N(Rw1)— or —C(O)N(Rw2)—;
• R9x represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A5-O-A6 and/or -A7-B7, wherein C1-12 alkyl, C2-12 alkenyl C2-12 alkynyl are optionally substituted by one or more substituents selected from X6;
• R9, R10, Rw1, Rw2 and Rw3 each independently represent hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl -A5-O-A6 and/or -A7-B7, wherein C1-12 alkyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X6;
• or R9 and R10, together with the carbon or nitrogen atom to which they are both attached, may be linked together to form a cycloalkyl or heterocyclyl group both of which are optionally substituted by one or more substituents selected from Z1a or an aryl or heteroaryl group (both of which are optionally substituted by one or more substituents selected from Z1b;
• and
• R11 represents a direct bond or R8;
• A1, A1a, A1b, A1c, A1d, A1e, A4 and A5 each independently represent C1-12 alkylene, C2-12 alkenylene or C2-12 alkynylene, which latter three groups are optionally substituted by one or more substituents selected from X7;
• A2, A3 and A7 each independently represent a direct bond, C1-12 alkylene, C2-12 alkenylene or C2-12 alkynylene, which latter three groups are optionally substituted by one or more substituents selected from X8;
• A6 represents C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, all of which are optionally substituted by one or more substituents selected from X9;
• R8 represents C1-12 alkylene, C2-12 alkenylene or C2-12 alkynylene, all of which are optionally substituted by one or more substituents selected from X10;
• B1 represents heteroaryl Optionally substituted by one or more substituents selected from Z2a or a heterocyclyl Optionally substituted by one or more substituents selected from Z2b, wherein when B1 represents a polycyclic heteroaryl group, then the point of attachment of B1 to the Tz is via a heterocyclyl or heteroaromatic ring of the polycycle;
• B2, B3 and B7 each independently represent aryl Optionally substituted by one or more substituents selected from Y1), cycloalkyl, which cycloalkyl group is optionally substituted by one or more substituents selected from Z3, heterocyclyl Optionally substituted by one or more substituents selected from Z4a or heteroaryl Optionally substituted by one or more substituents selected from Z4b;
• B4 represents aryl optionally substituted by one or more substituents selected from Y2;
• X1 represents G1, C3-15 cycloalkyl Optionally substituted by one or more T2 substituents, heterocyclyl optionally substituted by one or more T3 substituents, heteroaryl optionally substituted by one or more T4 substituents, ═O, —Si(R16)3, —OR14, —OC(O)—R14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —N(R14)C(O)OR16, —N(R14)C(O)R16, —N(R14)S(O)tR16, —S(O)tOR16, —S(O)pR16, —S(O)tN(R14)2, —N(R14)C(O)N(R14)2, —N(R14)S(O)tOR16, —OC(O)N(R14)2 or —OS(O)tR9x;
• X2, X3, X4, X5, X6, X7, X8, X9 and X10 each independently represent G1, aryl Optionally substituted by one or more T1 substituents, C3-15 cycloalkyl optionally substituted by one or more T2 substituents, heterocyclyl Optionally substituted by one or more T3 substituents, heteroaryl Optionally substituted by one or more T4 substituents, ═O, —Si(R16)3, —OC(O)—R14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —N(R14)C(O)OR16, —N(R14)C(O)R16, —N(R14)S(O)tR16, —S(O)tOR16, —S(O)pR16, —S(O)tN(R14)2, —N(R14)C(O)N(R14)2, —N(R14)S(O)tOR16, —OC(O)N(R14)2 or —OS(O)tR9x;
• Y1 and Y2 each independently represent -Ax-By, G1, G2, —R15—OR17-N(R14)2 or —R15—O—R17—N(R14)S(O)tR16;
• Z1a, Z1b, Z2a, Z2b, Z3, Z4a and Z4b each independently represent G1, ═O, ═S, -Ax-By or G2;
• G1 represents C1-12 alkyl optionally substituted by one or more substituents selected from T5, C2-12 alkenyl, C2-12 alkynyl, halo, —CN, —NO2 or ═O, wherein C2-12 alkenyl, and C2-12 alkynyl are optionally substituted by one or more substituents selected from T6;
• G2 represents -Ax-Bx, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)S(O)tR16, —R15—S(O)tOR16, —R15—S(O)pR16 and/or —R15—S(O)tN(R14)2;
• Ax represents a direct bond or O1-12 alkylene optionally substituted by one or more halo or ═O substituents;
• Bx represents aryl or heteroaryl, which groups are optionally substituted by one or more substituents selected from T7 and T8, respectively;
• By represents cycloalkyl or heterocyclyl, both of which are optionally substituted by one or more substituents selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —OCH3, —OCHF2, —OCF3 or ═O, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted by one or more halo substituents;
• T1, T4, T5, T6, T7 and T8 each independently represent halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-6 alkynyl —OH, —O—C1-6 alkyl, —OC2-6 alkenyl, —OC2-6 alkynyl, —N(Rw)2, —NO2 and/or —CN;
• or
• T5 and T6 may alternatively or additionally represent ═O, wherein C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted by one or more substituents selected from Qx1 and —O—C1-6 alkyl, —OC2-6 alkenyl, and —OC2-6 alkynyl are optionally substituted by one or more substituents selected from Qx2;
• T2 and T3 each independently represent halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl —OCH3, —OCHF2, —OCF3 or ═O, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted by halo;
• Qx1 and Qx2 each independently represent halo, —OCH3, —OCHF2, —OCF3, —N(Rw)2 or ═O;
• Rw represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from halo, —OCH3, —OCHF2, —OCF3 or ═O;
• or
• two Rw groups, when attached to the same nitrogen atom, may be linked together to form, together with the nitrogen atom to which they are necessarily attached, a 5- or 6-membered ring, optionally containing a further heteroatom and optionally substituted by one or more substituents selected from fluoro, —CH3 and ═O;
• t represents 1 or 2;
• p represents 0, 1 or 2;
• R14 represents hydrogen, -Ax1-Bx1, C1-12 alkyl, C2-6 alkenyl or C2-6 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from E1;
• R15 represents a direct bond, C1-12 alkylene or C2-12 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from halo, —OCH3, —OCHF2, —OCF3 and ═O;
• R16 represents C1-12 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more halo and/or ═O groups) or Ay1-By1;
• R17 represents C1-12 alkylene or C2-12 alkenylene, both of which are optionally substituted by one or more substituents selected from halo and ═O;
• Ax1 and Ay1 each independently represent a direct bond or C1-12 alkylene optionally substituted by one or more halo or ═O groups;
• Bx1 and By1 each independently represent cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl are optionally substituted by one or more substituents selected from halo and ═O and aryl or heteroaryl are optionally substituted by one or more halo atoms;
• E1 represents halo, —CN, —NO2, ═O, —OR18, —OC(O)—R18, —N(R18)2, —C(O)R18, —C(O)OR18, —C(O)N(R18)2, —N(R18)C(O)OR19, —N(R18)C(O)R19, —N(R18)S(O)ti R19, —S(O)t1OR19, —S(O)p1R19, —S(O)t1N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)S(O)t1OR19x, —OC(O)N(R18)2, —OS(O)t1R19x and/or —Si(R19x)3;
• R18 and R19 each independently represents hydrogen, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, which latter three groups are optionally substituted by one or more halo atoms;
• R19x represents C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, which latter three groups are optionally substituted by one or more halo atoms;
• t1 represents 1 or 2;
• p1 represents 0, 1 or 2,
• or a pharmaceutically acceptable salt, solvate, prodrug or polymorph thereof,
• provided that:
• (B) when R4 represents methyl, R2, R3 and R5 all represent hydrogen, n represents 0, m represents 1, and R6 represents methyl substituted α to the —N(R5)— moiety, then R1 does not represent unsubstituted methyl;
• (C) when R2 represents hydrogen, m and n both represent O, R4 represents methyl, then R1 does not represent hydrogen when R3 represents —OR4 in which wherein R4 represents cyclopentyl or methyl and R5 represents hydrogen, benzyl or —C(O)OR10, wherein R10 represents tert-butyl;
• (D) when R2 represents hydrogen, m and n both represent O, R3 represents hydrogen, R5 represents methyl, then R1 does not represent hydrogen when R4 represents methyl substituted by X3, wherein X3—C(O)N(R14)2 and R14 represents isopropyl.