Heterocyclic compounds as mek inhibitors

A compound of formula I or formula II

• wherein
• R0 is H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl or C2-C6 alkynyl;
• wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, and one or two ring carbon atoms of said C3-C6 cycloalkyl groups are optionally replaced with, independently, O, N, or S;
• and
• R1 is H, C1-C4 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl C2-C6 alkynyl, or halogen;
• wherein each alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R1 is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl;
• or
• R1 is —CH2X′ where X′ represents a group according to formula (III)
• wherein
• Y1 and Y2 may be the same or different, each represents a single bond, —CO—, —COO, —O—, —OCO—, —NRa or —SO2—;
• Y3 represents a C1-5 alkyl which may be substituted by one to three groups represented by Z;
• Z may be the same or different and represent a C1-5 alky group, halogen atom, an oxo group, —ORa, —COORa, —COOCORa, —CO-halogen atom, —OCORa, —CONRaRb, —SRa, —SO2Ra, —NRaRb, —NRaCORb, NRaSO2Rb, —SO2NRaRb, a 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heterocyclic group, or a 5 or 6 membered monocyclic or 9 to 13 membered bicyclic heteroaryl group which may be optionally substituted with one or more substituents selected from the group consisting of a C1-5 alkyl group, —ORa, and NRaRb;
• the alkyl group may be substituted by a hydroxyl group, a C1-5 alkoxy group, or an amino group;
• the above substituents except the oxo group and the halogen may be linked to each other to form a cycloalkyl group or a heterocyclic group which may has one or more substituents selected from the group consisting of —ORa, NRaRb, and a C1-5 alkyl group that may be substituted with —ORa;
• Ra and Rb may be the same or different and each represents a hydrogen atom or a C1-5 alkyl group which may be substituted by one to three groups selected from the group consisting of a hydroxyl group, a C1-5 alkoxy group and an amino group
• The symbol “” used in formula III implies the site of bonding;
• and
• X is O, N, S or bond;
• R2 is C1-C6 alkyl, C3-C6 cyclo alkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl or C2-C6 alkynyl;
• wherein each alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R2 is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when Y═C or X—R2=nothing when Y═N;
• or
• R3 is selected from the group consisting of H, Me, Et, OH, OMe, EtO, HOCH2CH2O—, MeCH(OH)CH2O—, HOCH2CH(OH)CH2O—, cyclopropyl-CH2O—, HOCH2CH2O—, HOCH(CH2CH3)CH2O—, HOCH2C(CH3)2CH2O—, HOCH2C(CH3)2O—, HOCH(CH3)CH2O—, MeOCH2CH2O—, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heteroarycycloalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, heteroarycycloalkyl, and heterocyclyl is unsubstituted or substituted with 1-3 substituents selected independently from halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, cyano, trifluoromethyl, difluoromethoxy, phenyl or substituted phenyl with 1-3 substituents selected independently from halogen, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy, cyano trifluoromethyl, or difluoromethoxy;
• R4 and R5 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, SR9, OR9, C(O)R9, NR10C(O)OR12, OC(O)R9, NR10S(O)jR12, S(O)jNR9R10, S(O)jNR10C(O)R9, C(O)NR10S(O)jR12, S(O)jR12, NR10C(O)R9, C(O)NR9R10, NR11C(O)NR9R10, NR11C(NCN)NR9R10, NR9R10 and C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, S(O)j(C1-C6 alkyl), S(O)j(CR10R11)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, O(CR10R10)m-aryl, NR10(CR10R11)m-aryl, O(CR10R11)m-heteroaryl, NR10(CR10R11)m-heteroaryl, O(CR10R11)m-heterocyclyl, NR10(CR10R11)m-heterocyclyl, and S(C1-C2 alkyl) optionally substituted with 1-5 fluorine atoms;
• R9 is selected from the group consisting of hydrogen, trifluoromethyl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, hydroxyl and amino;
• R10 is selected from hydrogen or C1-C6 alkyl where alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, hydroxyl and amino;
• or
• R9 and R10 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, hydroxyl and amino;
• R11 is selected from hydrogen or C1-C6 alkyl where alkyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, hydroxyl and amino;
• or
• R10 and R11 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, hydroxyl and amino;
• R12 is selected from trifluoromethyl, C1-C10 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of halogen, C1-C4 alkyl, hydroxyl and amino;
• m is 0, 1, 2, 3, 4, or 5;
• and
• j is 1 or 2.
• T, U, V and W are each independently C, O, N or S to form a heterocycle
• R6 is H, C1-C4 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl C2-C6 alkynyl, or halogen;
• wherein each alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R1 is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, (CH2)nNRcRd, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when U═C and;
• R7 is H, C1-C4 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl C2-C6 alkynyl, or halogen;
• wherein each alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R1 is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, (CH2)nNRcRd, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when V═C and;
• R8 is H, C1-C4 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl C2-C6 alkynyl, or halogen;
• wherein each alkoxy, alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl, or R1 is 5 or 6-atom heterocyclic group, which group may be saturated, unsaturated, or aromatic, containing 1-5 heteroatoms selected independently from the group consisting of O, N, and S, which heterocyclic group is optionally substituted with 1-3 substituents selected independently from the group consisting of halogen, hydroxy, C1-C4 alky, C1-C4 alkoxy, (CH2)nNRcRd, cyano, cyanomethyl, trifluoromethyl, difluoromethoxy and phenyl when W═C and;
• n is 0, 1, 2, 3 or 4
• Rc═H, C1-C4, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl C2-C6 alkynyl, or halogen;
• wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of C1-C4 alky, C1-C4 alkoxy, trifluoromethyl, difluoromethoxy and phenyl;
• and
• Rd═H, C1-C4, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl C2-C6 alkynyl, or halogen;
• wherein each alkyl, cycloalkyl, alkenyl, cycloalkenyl or alkynyl group is optionally substituted with 1-3 substituents selected independently from the group consisting of C1-C4 alky, C1-C4 alkoxy, trifluoromethyl, difluoromethoxy and phenyl;
• or
• Rc and Rd taken together form a 5 or 6 membered heterocyclic group containing 1-2 heteroatoms selected independently from the group consisting of O, N or S and is optionally substituted with 1-2 substituents selectly independently form the group consisting of C1-C4 alkyl or C1-C4 alkoxy;
• or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.