New Methylenebisphenyl Compounds Useful in the Treatment of Inflammation

A compound of formula I,

• wherein
• Y1 represents H or —Ar1;
• Y2 represents H or —Ar2;
• wherein at least one of Y1 and Y2 is other than H;
• X1 and X2 each independently represent one or more optional substituents selected from halo, —R3a, —CN, —C(O)R3b, —C(O)OR3c, —C(O)N(R4a)R5a, —N(R4b)R5b, —N(R3d)C(O)R4c, —N(R3e)C(O)N(R4d)R5d, —N(R3f)C(O)OR4e, —N3, —NO2, —N(R3g)S(O)2N(R4f)R5f, —OR3b, —OC(O)N(R4g)R5g, —OS(O)2R3i, —S(O)mR3j, —N(R3k)S(O)2R3m, —OC(O)R3n, —OC(O)OR3p, —S(O)2N(R4b)R5h or —OS(O)2N(R4i)R5i;
• m represents 0, 1 or 2;
• R3b to R3h, R3j, R3k, R3n, R4a to R4i, R5a, R5b, R5d and R5f to R5i each independently represent H or R3a;
• or
• any of the pairs R4a and R5a, R4b and R5b, R4d and R5d, R4f and R5f, R4g and R5g, R4h and R5h or R4i and R5i may be linked together to form a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by F, Cl, ═O or R3a;
• R3i, R3m and R3p each independently represent R3a;
• R3a represents C1-6 alkyl optionally substituted by one or more substituents selected from F, Cl, —CN, —N3, ═O, —OR6a, —N(R6b)R7b, —S(O)nR6c, —S(O)2N(R6d)R7d or —OS(O)2N(R6e)R7e;
• n represents 0, 1 or 2;
• R6a, R6b, R6c, R6d and R6e each independently represent H or C1-6 alkyl optionally substituted by one or more substituents selected from F, Cl, ═O, —OR8a, —N(R9a)R10a or —S(O)2-M1;
• R7b, R7d and R7e each independently represent H, —S(O)2CH3, —S(O)2CF3 or C1-6 alkyl optionally substituted by one or more substituents selected from F, Cl, ═O, —OR11a, —N(R12a)R13a or —S(O)2-M2;
• or
• R6b and R7b, R6d and R7d or R6e and R7e may be linked together to form a 3- to 6-membered ring, which ring optionally contains a further heteroatom (such as nitrogen or oxygen) in addition to the nitrogen atom to which these substituents are necessarily attached, and which ring is optionally substituted by F, Cl, ═O or C1-3 alkyl optionally substituted by one or more substituents selected from ═O and fluoro;
• M1 and M2 each independently represent —CH3, —CH2CH3, —CF3 or —N(R14a)R15a;
• R8a and R11a each independently represent H, —CH3, —CH2CH3, —CF3 or —CHF2;
• R9a, R10a, R12a, R13a, R14a and R15a each independently represent H, —CH3 or —CH2CH3,
• Ar1 and Ar2 each independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
• A represents:
• I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
• II) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1;
• or
• III) a G1 group;
• G1 represents halo, cyano, —N3, —NO2, —ONO2 or -A1R16a;
• wherein A1 represents a single bond or a spacer group selected from —C(O)A2-, —S—, —S(O)2A3-, —N(R17a)A4- or —OA5-, in which:
• A2 represents a single bond, —O—, —N(R17b)— or —C(O)—;
• A3 represents a single bond, —O— or —N(R17c)—;
• A4 and A5 each independently represent a single bond, —C(O)—, —C(O)N(R17d)—, —C(O)O—, —S(O)2— or —S(O)2N(R17e)—;
• Z1 represents ═O, ═S, ═NOR16b, ═NS(O)2N(R17f)R16c, ═NCN or ═C(H)NO2;
• B represents:
• I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G2;
• II) O1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G2 and/or Z2;
• or
• III) a G2 group;
• G2 represents halo, cyano, —N3, —NO2, —ONO2 or -A6-R18a;
• wherein A6 represents a single bond or a spacer group selected from —C(O)A7-, —S—, —S(O)2A8-, —N(R19a)A9- or —OA10-, in which:
• A7 represents a single bond, —O—, —N(R19b)— or —C(O)—;
• A8 represents a single bond, —O— or —N(R19c)—;
• A9 and A10 each independently represent a single bond, —C(O)—, —C(O)N(R19d)—, —C(O)O—, —S(O)2— or —S(O)2N(R19e)—;
• Z2 represents ═O, ═S, ═NOR18b, ═NS(O)2N(R19f)R18c, ═NCN or ═C(H)NO2;
• R16a, R16b, R16c, R17a, R17b, R17c, R17d, R17e, R17f, R18a, R18b, R18c, R19a, R19b, R19c, R19d, R19e and R19f are each independently selected from:
• i) hydrogen;
• ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G3;
• iii) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G3 and/or Z3;
• or
• any pair of R16a to R16c and R17a to R17f, and/or R18a to R18c and R19a to R19f, may, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G3 and/or Z3;
• G3 represents halo, cyano, —N3, —NO2, —ONO2 or -A11-R20a;
• wherein A11 represents a single bond or a spacer group selected from —C(O)A12-, —S—, —S(O)2A13-, —N(R21a)A14- or —OA15-, in which:
• A12 represents a single bond, —O—, —N(R21b)— or —C(O)—;
• A13 represents a single bond, —O— or —N(R21c)—;
• A14 and A15 each independently represent a single bond, —C(O)—, —C(O)N(R21d)—, —C(O)O—, —S(O)2— or —S(O)2N(R21e)—;
• Z3 represents ═O, ═S, ═NOR20b, ═NS(O)2N(R21f)R20c, ═NCN or ═C(H)NO2;
• R20a, R20b, R20c, R21a, R21b, R21c, R21d, R21e and R21f are each independently selected from:
• i) hydrogen;
• ii) C1-6 alkyl or a heterocycloalkyl group, both of which groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, —N(R22a)R23a, —OR22b and ═O;
• and
• iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, C1-4 alkyl (optionally substituted by one or more substituents selected from ═O, fluoro and chloro), —N(R22c)R23b and —OR22d;
• or
• any pair of R20a to R20c and R21a to R21f may be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 or 2 double bonds, which ring is optionally substituted by one or more substituents selected from halo, C1-4 alkyl, —N(R22e)R23c, —OR22f and ═O;
• L1 represents —N(Rw)A19-;
• L2 represents —N(Rz)A20-;
• A19 represents a single bond, —C(O)N(Rw)—, —S(O)2— or —CH2—;
• A20 represents a single bond, —C(O)N(Rz)—, —S(O)2— or —CH2—;
• but wherein when A19 represents —S(O)2—, Y1 represents Ar1, and when A20 represents —S(O)2—, then Y2 represents Ar2;
• Rx, Ry, Rw and Rz each independently represent H, C1-14 alkyl (optionally substituted by one or more substituents selected from halo, —CN, —N(R24a)R25a, —OR24b, ═O, aryl and heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl (optionally substituted by one or more substituents selected from fluoro, chloro and ═O), —N(R24c)R25b and —OR24d));
• R22a, R22b, R22c, R22d, R22e, R22f, R23a, R23b, R23c, R24a, R24b, R24c, R24d, R25a and R25b are each independently selected from hydrogen and C1-4 alkyl, which latter group is optionally substituted by one or more substituents selected from fluoro, chloro or ═O,
• or a pharmaceutically-acceptable salt thereof, provided that, when X1 and X2 are not present, and:
• (a) Rx and Ry each independently represent H or methyl and L1 and L2 both represent —N(H)—CH2—, then Ar1 and Ar2 do not both represent unsubstituted phenyl;
• (b) Rx and Ry each independently represent H or methyl optionally substituted by unsubstituted phenyl, or one of Rx and Ry represents H and the other represents methyl, and L1 and L2 both represent —N(H)—S(O)2—, then Ar1 and Ar2 do not both represent 4-methylphenyl;
• and
• (c) when Rx and Ry both represent H, and L1 and L2 both represent —N(H)—S(O)2, then Ar1 and Ar2 do not both represent 1-hydroxynaphthyl.