Substituted pyridinone compounds as mek inhibitors

A compound of formula I or formula II

• wherein
• R1 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
• R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, —SR9, —OR9, —C(O)R9, —NR10C(O)OR12, —OC(O)R9, —NR10, —S(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 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, and
• 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;
• W is —C(O)OR6, —C(O)NR6R7, —C(O)NR7OR6, —C(O)R7OR6, heteroaryl, heterocyclyl, —NHSO2R6, —NHC(O)OR6, —NHC(O)NR6R7, —NHC(O)R6, —NR6R7, —C(O)(C3-C10 cycloalkyl), —C(O)(C1-C10 alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)NHSO2CH3, or —CR6OR6, wherein any of said heteroaryl, heterocyclyl, —C(O)OR6, —C(O)NR6R7, —C(O)NR7OR6, —C(O)R7OR6, —NHSO2R6, —NHC(O)OR6, —NHC(O)NR6R7, —NHC(O)R6, —NR6R7, —C(O)(C3-C10 cycloalkyl), —C(O)(C1-C10 alkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)NHSO2CH3 and —CR6OR6 are optionally substituted independently with one or more groups independently selected from halogen, cyano, nitro, azide, —NR6R7, —OR6, C1-C10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted independently with 1 or more groups independently selected from —NR6R7 and —OR6;
• R6 is hydrogen, trifluoromethyl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that is not substituted on a aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR13SO2R16, —SO2NR13R14, —C(O)R13, —C(O)OR13, —OC(O)R13, —NR13C(O)OR16, —NR13C(O)R14, —C(O)NR13R14, —SR13, —S(O)R16, —SO2R16, —NR13R14, —NR13C(O)NR14R15, —NR13C(NCN)NR14R15, —OR13, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl,
• or R6 and R7 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said carbocyclic, heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR13SO2R16, —SO2NR13R14, —C(O)R13, —C(O)OR13, —OC(O)R13, —NR13C(O)OR16, —NR13C(O)R14, —C(O)NR13R14, —SO2R16, —NR13R14, —NR13C(O)NR14R15, —NR13C(NCN)NR14R15, —OR13, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
• R7 is hydrogen or C1-C6 alkyl;
• each X is independently N or CR5;
• each Y is independently CH2, C(CH3)2 or CR17R17;
• m is 0, 1, 2, 3, 4 or 5;
• and
• j is 1 or 2;
• R5 is H, F, Cl, Br, CF3, CN, —C(O)R6, —C(O)OR6, —C(O)NR6R7, —NR6R7, —NR6C(O)R7, —NR8C(O)OR7, —NR8C(O)NR6R7, —NR8, —SO2NR6R7, —OR6, —OC(O)R6, —OC(O)OR6, —OC(O)NR6R7, —SR6, —SO2R6, —SO2NR6R7, C1-C12 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl;
• R8 is selected from the group consisting of trifluoromethyl, 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;
• R13, R14 and R15 independently are hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl, and R16 is lower alkyl, lower alkenyl, aryl and arylalkyl, or any two of R13, R14, R15 or R16 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
• each R17 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, C1-C10 alkoxy, C4-C12 aryloxy, heteroC1-C10 aryloxy, carbonyl, xoycarbonyl, aminocarbonyl, amino, C1-C10 alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, C1-C10 alkyl, haloC1-C10 alkyl, hydroxylC1-C10 alkyl, carbonylC1-C10 alkyl, thiocarbonylC1-C10 alkyl, sulfonylC1-C10 alkyl, sulfinylC1-C10 alkyl, C1-C10 alzalkyl, iminoC1-C10 alkyl, C3-C12 cycloalkylC1-C5 alkyl, heteroC3-C12 cycloalkylC1-C10 alkyl, arylC1-C10 alkyl, heteroC1-C10 arylC1-C5 alkyl, C9-C12 bicycloarylC1-C5 alkyl, heteroC8-C12 bicycloarylC1-C5 alkyl, C3-C12 cycloalkyl, heteroC3-C12 cycloalkyl, C9-C12 bicycloalkyl, heteroC3-C12 bicycloalkyl, C4-C12 aryl, heteroC1-C10 aryl, C9-C12 bicycloaryl and heteroC4-C12 bicycloaryl, each substituted or unsubstituted, or two R17 are taken together to form a substituted or unsubstituted ring,
• or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof.