5-anilinoimidazo[1,5-a]-pyridines inhibitors of MEK kinase

A compound of formula I:

• and pharmaceutically acceptable salts thereof, wherein:
• Z1 is CR1;
• R1 is H, C1-C3 alkyl, halo, CF3, CHF2, CN, ORA or NRARA;
• R1′is H, C1-C3 alkyl, halo, CF3, CHF2, CN, ORA, or NRARA;
• wherein each RA is independently H or C1-C3 alkyl;
• Z2 is CR2;
• Z3 is CR3;
• R2 and R3 are independently selected from H, halo, CN, CF3, —OCF3, —NO2, —(CR14R15)nC(═Y′)R11, —(CR14R15)nC(═Y′)OR11, —(CR14R15)nC(═Y′)NR11R12, —(CR14R15)nNR11R12, —(CR14R15)nOR11, —(CR14R15)nSR11, —(CR14R15)nNR12C(═Y′)R11, —(CR14R15)nNR12C(═Y′)OR11, —(CR14R15)nNR13C(═Y′)NR11R12, —(CR14R15)nNR12SO2R11, —(CR14R15)nOC(═Y′)R11, —(CR14R15)nOC(═Y′)OR11, —(CR14R15)nOC(═Y′)NR11R12, —(CR14R15)nOS(O)2(OR11), —(CR14R15)nOC(═Y′)(OR11)(OR12), —(CR14R15)nOP(OR11)(OR12), —(CR14R15)nS(O)R11, —(CR14R15)nS(O)2R11, —(CR14R15)n S(O)2NR11R12, —(CR14R15)nS(O)(OR11), —(CR14R15)nS(O)2(OR11), —(CR14R15)n SC(═Y″)R11, —(CR14R15)nSC(═Y′)OR11, —(CR14R15)nSC(═Y′)NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;
• R4 is H, C1-C6 alkyl or C3-C4 carbocyclyl;
• Y is W—C(O)— or W′;
• W is
• R5 is H or C1-C12 alkyl;
• X1 is selected from R11′ and —OR11′;
• when X1 is R11′, X1 is optionally taken together with R5 and the nitrogen atom to which they are bound to form a 4-7 membered saturated or unsaturated ring having 0-2 additional heteroatoms selected from 0, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, CF3, —OCF3, —NO2, oxo, —(CR19R20)nC(═Y′)R16, —(CR19R20)nC(═Y′)OR16, —(CR19R20)nC(═Y′)NR16R17, —(CR19R20)—NR16R17, —(CR19R20)nOR16, —(CR19R20)n—SR16, —(CR19R20)n NR16C(═Y′)R17, —(CR19R20)n NR16C(═Y′)OR17, —(CR19R20)n NR18C(═Y′)NR16R17, —(CR19R20)nNR17SO2R16, —(CR19R20)nOC(═Y′)R16, —(CR19R20)nOC(═Y′)OR16, —(CR19R20)nOC(═Y′)NR16R17, —(CR19R20)nOS(O)2(OR16), —(CR19R20)nOP(═Y′)(OR16)(OR17), —(CR19R20)nOP(OR16)(OR17), —(CR19R20)nS(O)R16, —(CR19R20)nS(O)2R16, —(CR19R20)nS(O)2NR16R17, —(CR19R20)nS(O)(OR16), —(CR19R20)n S(O)2(OR16), —(CR19R20)n SC(═Y′)R16, —(CR19R20)n SC(═Y′)OR16, —(CR19R20)n SC(═Y′)NR16R17, and R21;
• each R11′ is independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
• R11, R12 and R13 are independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl,
• or R11 and R12 together with the nitrogen to which they are attached form a 3-8 membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from O, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, CF3, —NO2, C1-C6 alkyl, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —SO2(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)(C1-C6 alkyl), —NHC(O)(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), —N(C1-C6 alkyl)SO2(C1-C6 alkyl), —SO2NH2, —SO2NH(C1-C6 alkyl), —SO2N(C1-C6 alkyl)2, —OC(O)NH2, —OC(O)NH(C1-C6 alkyl), —OC(O)N(C1-C6 alkyl)2, —OC(O)O(C1-C6 alkyl), —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)NH(C1-C6 alkyl), —N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —NHC(O)O(C1-C6 alkyl), and —N(C1-C6 alkyl)C(O)O(C1-C6 alkyl);
• R14 and R15 are independently selected from H, C1-C12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl;
• W′ is
• wherein
• each X2 is independently O, S, or NR9;
• each R7 is independently selected from H, halo, CN, CF3, —OCF3, —NO2, —(CR14R15)nC(═Y′)R11, —(CR14R15)nC(═Y′)OR11, —(CR14R15)nC(═Y′)NR11R12, —(CR14R15)nNR11R12, —(CR14R15)nOR11, —(CR14R15)nSR11, —(CR14R15)nNR12C(═Y′)R11, —(CR14R15)nNR12C(═Y′)OR11, —(CR14R15)nNR13C(═Y′)NR11R12, —(CR14R15)nNR12SO2R11, —(CR14R15)nOC(═Y′)R11, —(CR14R15)nOC(═Y′)OR11, —(CR14R15)nOC(═Y′)NR11R12, —(CR14R15)nOS(O)2(OR11), —(CR14R15)nOP(═Y′)(OR11)(OR12), —(CR14R15)nOP(OR11)(OR12), —(CR14R15)nS(O)R11, —(CR14R15)nS(O)2R11, —(CR14R15)n S(O)2NR11R12, —(CR14R15)nS(O)(OR11), —(CR14R15)nS(O)2(OR11), —(CR14R15)n SC(═Y′)R11, —(CR14R15)nSC(═Y′)OR11, —(CR14R15)nSC(═Y′)NR11R12, C1-C2 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;
• each R8 is independently selected from C1-C12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl;
• R9 is selected from H, —(CR14R15)nC(═Y′)R11, —(CR14R15)nC(═Y′)OR11, —(CR14R15)nC(═Y′)NR11R12, —(CR14R15)qNR11R12, —(CR14R15)qOR11, —(CR14R15)qSR11, —(CR14R15)qNR12C(═Y′)R11, —(CR14R15)qNR12C(═Y′)OR11, —(CR14R15)qNR13C(═Y′)NR11R12, —(CR14R15)qNR12SO2R11, —(CR14R15)qOC(≡Y′)R11, —(CR14R15)qOC(═Y′)OR11, —(CR14R15)qOC(═Y′)NR11R12, —(CR14R15)qOS(O)2(OR11), —(CR14R15)qOP(═Y′)(OR11)(OR12), —(CR14R15)qOP(OR11)(OR12), —(CR14R15)nS(O)R11, —(CR14R15)nS(O)2R11, —(CR14R15)n S(O)2NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl;
• R10 is H, C1-C6 alkyl or C3-C4 carbocyclyl;
• X4 is
• R6 is H, halo, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heteroaryl, heterocyclyl, —OCF3, —NO2, —Si(C1-C6 alkyl), —(CR19R20)nNR16R17, —(CR19R20)nOR16, or —(CR19R20)n—SR16;
• R6′ is H, halo, C1-C6 alkyl, carbocyclyl, CF3, —OCF3, —NO2, —Si(C1-C6 alkyl), —(CR19R20)nNR16R17, —(CR19R20)nOR16, —(CR19R20)n—SR16, C2-C8 alkenyl, C2-C8 alkynyl, heterocyclyl, aryl, or heteroaryl;
• p is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• q is 2 or 3;
• wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl of R1, R2, R3, R4, R5, R6, R6′, R7, R8, R9, R10, R11, R11′, R12, R13, R14, R15, and RA is independently optionally substituted with one or more groups independently selected from halo, CN, CF3, —OCF3, —NO2, oxo, —Si(C1-C6 alkyl) —(CR19R20)nC(═Y′)R16, —(CR19R20)n C(═Y′)OR16, —(CR19R20)nC(═Y′)NR16R17, —(CR19R20)nNR16R17, —(CR19R20)nOR16, —(CR19R20)nSR16, —(CR19R20)nNR16C(═Y′)R17, —(CR19R20)nNR16C(═Y′)OR17, —(CR19R20)nNR18C(═Y′)NR16R17, —(CR19R20)nNR17SO2R16, —(CR19R20)nOC(═Y′)R16, —(CR19R20)nOC(═Y′)OR16, —(CR19R20)nOC(═y′)NR16R17, —(CR19R20)nOS(O)2(OR16), —(CR19R20)nOP(═Y′)(OR16)(OR17), —(CR19R20)nOP(OR16)(OR17), —(CR19R20)nS(O)R16, —(CR19R20)nS(O)2R16, —(CR19R20)nS(O)2NR16R17, —(CR19R20)nS(O)(OR16), —(CR19R20)n S(O)2(OR16), —(CR19R20)nSC(═Y′)R16, —(CR19R20)nSC(═Y′)OR16, —(CR19R20)n SC(═Y′)NR16R17, and R21;
• each R16, R17 and R18 is independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from halo, CN, —OCF3, CF3, —NO2, C1-C6 alkyl, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —SO2(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)(C1-C6 alkyl), —NHC(O)(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), —N(C1-C6 alkyl)SO2(C1-C6 alkyl), —SO2NH2, —SO2NH(C1-C6 alkyl), —SO2N(C1-C6 alkyl)2, —OC(O)NH2;
• —OC(O)NH(C1-C6 alkyl), —OC(O)N(C1-C6 alkyl)2, —OC(O)O(C1-C6 alkyl), —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)NH(C1-C6 alkyl), —N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —NHC(O)O(C1-C6 alkyl), and —N(C1-C6 alkyl)C(O)O(C1-C6 alkyl);
• or R16 and R17 together with the nitrogen to which they are attached form a 3-8 membered saturated, unsaturated or aromatic ring having 0-2 heteroatoms selected from 0, S and N, wherein said ring is optionally substituted with one or more groups selected from halo, CN, —OCF3, CF3, —NO2, C1-C6 alkyl, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —SO2(C1-C6 alkyl), —CO2H, —OC2(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)(C1-C6 alkyl), —NHC(O)(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), —N(C1-C6 alkyl)SO2(C1-C6 alkyl), —SO2NH2, —SO2NH(C1-C6 alkyl), —SO2N(C1-C6 alkyl)2, —OC(O)NH2, —OC(O)NH(C1-C6 alkyl), —OC(O)N(C1-C6 alkyl)2, —OC(O)O(C1-C6 alkyl), —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)NH(C1-C6 alkyl), —N(C1-C6 alkyl)C(O)N(C1-Co alkyl)2, —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —NHC(O)O(C1-C6 alkyl), and —N(C1-C6 alkyl)C(O)O(C1-C6 alkyl);
• R19 and R20 are independently selected from H, C1-C12 alkyl, —(CH2)n-aryl, —(CH2)n-carbocyclyl, —(CH2)n-heterocyclyl, and —(CH2)n-heteroaryl;
• R21 is C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each member of R21 is optionally substituted with one or more groups selected from halo, oxo, CN, —OCF3, CF3, —NO2, C1-C6 alkyl, —OH, —SH, —O(C1-C6 alkyl), —S(C1-C6 alkyl), —NH2, —NH(C1-C6 alkyl), —N(C1-C6 alkyl)2, —SO2(C1-C6 alkyl), —CO2H, —CO2(C1-C6 alkyl), —C(O)NH2, —C(O)NH(C1-C6 alkyl), —C(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)(C1-C6 alkyl), —NHC(O)(C1-C6 alkyl), —NHSO2(C1-C6 alkyl), —N(C1-C6 alkyl)SO2(C1-C6 alkyl), —SO2NH2, —SO2NH(C1-C6 alkyl), —SO2N(C1-C6 alkyl)2, —OC(O)NH2, —OC(O)NH(C1-C6 alkyl), —OC(O)N(C1-C6 alkyl)2, —OC(O)O(C1-C6 alkyl), —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —N(C1-C6 alkyl)C(O)NH(C1-C6 alkyl), —N(C1-C6 alkyl)C(O)N(C1-C6 alkyl)2, —NHC(O)NH(C1-C6 alkyl), —NHC(O)N(C1-C6 alkyl)2, —NHC(O)O(C1-C6 alkyl), and —N(C1-C6 alkyl)C(O)O(C1-C6 alkyl);
• each Y′ is independently O, NR22, or S;
• and
• R22 is H or C1-C12 alkyl.