Inhibitors of erk and methods of use

A compound of Formula I:

• or a pharmaceutically acceptable salt or prodrug thereof;
• wherein:
• is
• X1 is C═O, C═S, SO, SO2, or PO2−;
• Y is CR5;
• W is N or C;
• X2 is NR1 or CR1R1′ and X3 is a bond, CR3R3′ or C═O;
• or X2—X3 is R11C═CR3 or R11C═N or N═CR3 or NR12—CR11═CR3;
• X4 is N, CR4, C═O;
• X5 is N or C;
• X6 is N or C;
• X7 is O, N, NR72 or CR71;
• X8 is O, N, NR82 or CR81;
• X9 is O, N, NR22 or CR21;
• X10 is O, N, NR92 or CR91;
• R1 is —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, —C1-10alkyl-C3-10aryl, —C1-10alkyl-C1-10hetaryl, —C1-10alkyl-C3-10cycloalkyl, —C1-10alkyl-C1-10heterocyclyl, —C2-10alkenyl-C3-10aryl, —C2-10alkenyl-C1-10hetaryl, —C2-10alkenyl-C3-10cycloalkyl, —C2-10alkenyl-C1-10heterocyclyl, —C2-10alkynyl-C3-10aryl, —C2-10alkynyl-C1-10hetaryl, —C2-10alkynyl-C3-10cycloalkyl, —C2-10alkynyl-C1-10heterocyclyl, —C1-10alkoxy-C3-10aryl, —C1-10alkoxy-C1-10hetaryl, —C1-10alkoxy-C3-10cycloalkyl, —C1-10alkoxy-C1-10heterocyclyl, —C1-10heteroalkyl-C3-10aryl, —C1-10heteroalkyl-C1-10hetaryl, —C1-10heteroalkyl-C3-10cycloalkyl, —C1-10heteroalkyl-C1-10heterocyclyl, —C3-10aryl-C1-10alkyl, —C3-10aryl-C2-10alkenyl, —C3-10aryl-C2-10alkynyl, —C3-10aryl-C3-10hetaryl, —C3-10aryl-C3-10cycloalkyl, —C3-10aryl-C1-10heterocyclyl, —C1-10hetaryl-C1-10alkyl, —C1-10hetaryl-C2-10alkenyl, —C1-10hetaryl-C2-10alkynyl, —C3-10hetaryl-C3-10aryl, —C1-10hetaryl-C3-10cycloalkyl, —C1-10hetaryl-C1-10heterocyclyl, —C3-10cycloalkyl-C1-10alkyl, —C3-10cycloalkyl-C2-10alkenyl, —C3-10cycloalkyl-C2-10alkynyl, —C3-10cycloalkyl-C3-10aryl, —C3-10cycloalkyl-C1-10hetaryl, —C3-10cycloalkyl-C1-10heterocyclyl, —C1-10heterocyclyl-C1-10alkyl, —C1-10heterocyclyl-C2-10alkenyl, —C1-10heterocyclyl-C2-10alkynyl, —C1-10heterocyclyl-C3-10aryl, —C1-10heterocyclyl-C1-10hetaryl, or —C1-10heterocyclyl-C3-10cycloalkyl, each of which is unsubstituted or substituted by one or more independent R10 or R11 substituents;
• R1′ is hydrogen, —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, —C1-10alkyl-C3-10aryl, —C1-10alkyl-C1-10hetaryl, —C1-10alkyl-C3-10cycloalkyl, —C1-10alkyl-C1-10heterocyclyl, —C2-10alkenyl-C3-10aryl, —C2-10alkenyl-C1-10hetaryl, —C2-10alkenyl-C3-10cycloalkyl, —C2-10alkenyl-C1-10heterocyclyl, —C2-10alkynyl-C3-10aryl, —C2-10alkynyl-C1-10hetaryl, —C2-10alkynyl-C3-10cycloalkyl, —C2-10alkynyl-C1-10heterocyclyl, —C1-10alkoxy-C3-10aryl, —C1-10alkoxy-C1-10hetaryl, —C1-10alkoxy-C3-10cycloalkyl, —C1-10alkoxy-C1-10heterocyclyl, —C1-10heteroalkyl-C3-10aryl, —C1-10heteroalkyl-C1-10hetaryl, —C1-10heteroalkyl-C3-10cycloalkyl, —C1-10heteroalkyl-C1-10heterocyclyl, —C3-10aryl-C1-10alkyl, —C3-10aryl-C2-10alkenyl, —C3-10aryl-C2-10alkynyl, —C3-10aryl-C3-10hetaryl, —C3-10aryl-C3-10cycloalkyl, —C3-10aryl-C1-10heterocyclyl, —C1-10hetaryl-C1-10alkyl, —C1-10hetaryl-C2-10alkenyl, —C1-10hetaryl-C2-10alkynyl, —C3-10hetaryl-C3-10aryl, —C1-10hetaryl-C3-10cycloalkyl, —C1-10hetaryl-C1-10heterocyclyl, —C3-10cycloalkyl-C1-10alkyl, —C3-10cycloalkyl-C2-10alkenyl, —C3-10cycloalkyl-C2-10alkynyl, —C3-10cycloalkyl-C3-10aryl, —C3-10cycloalkyl-C1-10hetaryl, —C3-10cycloalkyl-C1-10heterocyclyl, —C1-10heterocyclyl-C1-10alkyl, —C1-10heterocyclyl-C2-10alkenyl, —C1-10heterocyclyl-C2-10alkynyl, —C1-10heterocyclyl-C3-10aryl, —C1-10heterocyclyl-C1-10hetaryl, or —C1-10heterocyclyl-C3-10cycloalkyl, each of which is unsubstituted or substituted by one or more independent R10 or R11 substituents;
• R21 is hydrogen, halogen, —OH, —CF3, —OCF3, —OR31, —NR31R32, —C(O)R31, —CO2R31, —C(═O)NR31, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR32R33, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)SR31, —P(O)OR31OR32, —SC(═O)NR31R32, -L-C1-10alkyl, -L-C2-10alkenyl, -L-C2-10alkynyl, -L-C1-10heteroalkyl, -L-C3-10aryl, -L-C1-10hetaryl, -L-C3-10cycloalkyl, -L-C1-10heterocyclyl, -L-C1-10alkyl-C3-10aryl, -L-C1-10alkyl-C1-10hetaryl, -L-C1-10alkyl-C3-10cycloalkyl, -L-C1-10alkyl-C1-10heterocyclyl, -L-C2-10alkenyl-C3-10aryl, -L-C2-10alkenyl-C1-10hetaryl, -L-C2-10alkenyl-C3-10cycloalkyl, -L-C2-10alkenyl-C1-10heterocyclyl, -L-C2-10alkynyl-C3-10aryl, -L-C2-10alkynyl-C1-10hetaryl, -L-C2-10alkynyl-C3-10cycloalkyl, -L-C2-10alkynyl-C1-10heterocyclyl, -L-C1-10alkoxy-C3-10aryl, -L-C1-10alkoxy-C1-10hetaryl, -L-C1-10alkoxy-C3-10cycloalkyl, -L-C1-10alkoxy-C1-10heterocyclyl, -L-C1-10heteroalkyl-C3-10aryl, -L-C1-10heteroalkyl-C1-10hetaryl, -L-C1-10heteroalkyl-C3-10cycloalkyl, -L-C1-10heteroalkyl-C1-10heterocyclyl, -L-C3-10aryl-C1-10alkyl, -L-C3-10aryl-C2-10alkenyl, -L-C3-10aryl-C2-10alkynyl, -L-C3-10aryl-C1-10hetaryl, -L-C3-10aryl-C3-10cycloalkyl, -L-C3-10aryl-C1-10heterocyclyl, -L-C1-10hetaryl-C1-10alkyl, -L-C1-10hetaryl-C2-10alkenyl, -L-C1-10hetaryl-C2-10alkynyl, -L-C1-10hetaryl-C3-10aryl, -L-C1-10hetaryl-C3-10cycloalkyl, -L-C1-10hetaryl-C1-10heterocyclyl, -L-C3-10cycloalkyl-C1-10alkyl, -L-C3-10cycloalkyl-C2-10alkenyl, -L-C3-10cycloalkyl-C2-10alkynyl, -L-C3-10cycloalkyl-C3-10aryl, -L-C3-10cycloalkyl-C1-10hetaryl, -L-C3-10cycloalkyl-C1-10heterocyclyl, -L-C1-10heterocyclyl-C1-10alkyl, -L-C1-10heterocyclyl-C2-10alkenyl, -L-C1-10heterocyclyl-C2-10alkynyl, -L-C1-10heterocyclyl-C3-10aryl, -L-C1-10heterocyclyl-C1-10hetaryl, or -L-C1-10heterocyclyl-C3-10cycloalkyl, each of which is unsubstituted or substituted by one or more independent R12 substituents;
• R22 is hydrogen, —OH, —CF3, —C(O)R31, —CO2R31, —C(═O)NR31, —S(O)0-2R31, —C(═S)OR31, —C(═O)SR31, -L-C1-10alkyl, -L-C2-10alkenyl, -L-C2-10alkynyl, -L-C1-10heteroalkyl, -L-C3-10aryl, -L-C1-10hetaryl, -L-C3-10cycloalkyl, -L-C1-10heterocyclyl, -L-C1-10alkyl-C3-10aryl, -L-C1-10alkyl-C1-10hetaryl, -L-C1-10alkyl-C3-10cycloalkyl, -L-C1-10alkyl-C1-10heterocyclyl, -L-C2-10alkenyl-C3-10aryl, -L-C2-10alkenyl-C1-10hetaryl, -L-C2-10alkenyl-C3-10cycloalkyl, -L-C2-10alkenyl-C1-10heterocyclyl, -L-C2-10alkynyl-C3-10aryl, -L-C2-10alkynyl-C1-10hetaryl, -L-C2-10alkynyl-C3-10cycloalkyl, -L-C2-10alkynyl-C1-10heterocyclyl, -L-C1-10alkoxy-C3-10aryl, -L-C1-10alkoxy-C1-10hetaryl, -L-C1-10alkoxy-C3-10cycloalkyl, -L-C1-10alkoxy-C1-10heterocyclyl, -L-C1-10heteroalkyl-C3-10aryl, -L-C1-10heteroalkyl-C1-10hetaryl, -L-C1-10heteroalkyl-C3-10cycloalkyl, -L-C1-10heteroalkyl-C1-10heterocyclyl, -L-C3-10aryl-C1-10alkyl, -L-C3-10aryl-C2-10alkenyl, -L-C3-10aryl-C2-10alkynyl, -L-C3-10aryl-C1-10hetaryl, -L-C3-10aryl-C3-10cycloalkyl, -L-C3-10aryl-C1-10heterocyclyl, -L-C1-10hetaryl-C1-10alkyl, -L-C1-10hetaryl-C2-10alkenyl, -L-C1-10hetaryl-C2-10alkynyl, -L-C1-10hetaryl-C3 -10aryl, -L-C1-10hetaryl-C3 -10cycloalkyl, -L-C1-10hetaryl-C1-10heterocyclyl, -L-C3-10cycloalkyl-C1-10alkyl, -L-C3-10cycloalkyl-C2-10alkenyl, -L-C3-10cycloalkyl-C2-10alkynyl, -L-C3-10cycloalkyl-C3-10aryl, -L-C3-10cycloalkyl-C1-10hetaryl, -L-C3-10cycloalkyl-C1-10heterocyclyl, -L-C1-10heterocyclyl-C1-10alkyl, -L-C1-10heterocyclyl-C2-10alkenyl, -L-C1-10heterocyclyl-C2-10alkynyl, -L-C1-10heterocyclyl-C3-10aryl, -L-C1-10heterocyclyl-C1-10hetaryl, or -L-C1-10heterocyclyl-C3-10cycloalkyl, each of which is unsubstituted or substituted by one or more independent R12 substituents;
• L is a bond, —O—, —N(R31)—, —S(O)0-2—, —C(═O)—, —C(═O)O—, —OC(═O)—, —C(═O)N(R31)—, —N(R31)C(═O)—, —NR31C(═O)O—, —NR31C(═O)NR32—, —NR31S(O)0-2—, —S(O)0-2N(R31)—, —C(═S)O—, —C(═O)S—, —NR31C(═NR32)NR32—, —NR31C(═NR32)O—, —NR31C(═NR32)S—, —OC(═O)O—, —OC(═O)NR31—, —OC(═O)S—, —SC(═O)S—, —P(O)OR31O—, —SC(═O)NR31—;
• each of R3, R3′ and R4 is independently hydrogen, halogen, —OH, —CF3, —OCF3, —OR31, —NR31R32, —C(O)R31, —OO2R31, —C(═O)NR31, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR32R33, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)SR31, —P(O)OR31OR32, —SC(═O)NR31R32, —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, —C1-10alkyl-C3-10aryl, —C1-10alkyl-C1-10hetaryl, —C1-10alkyl-C3-10cycloalkyl, —C1-10alkyl-C1-10heterocyclyl, —C2-10alkenyl-C3-10aryl, —C2-10alkenyl-C1-10hetaryl, —C2-10alkenyl-C3-10cycloalkyl, —C2-10alkenyl-C1-10heterocyclyl, —C2-10alkynyl-C3-10aryl, —C2-10alkynyl-C1-10hetaryl, —C2-10alkynyl-C3-10cycloalkyl, —C2-10alkynyl-C1-10heterocyclyl, —C1-10alkoxy-C3-10aryl, —C1-10alkoxy-C1-10hetaryl, —C1-10alkoxy-C3-10cycloalkyl, —C1-10alkoxy-C1-10heterocyclyl, —C1-10heteroalkyl-C3-10aryl, —C1-10heteroalkyl-C1-10hetaryl, —C1-10heteroalkyl-C3-10cycloalkyl, —C1-10heteroalkyl-C1-10heterocyclyl, —C3-10aryl-C1-10alkyl, —C3-10aryl-C2-10alkenyl, —C3-10aryl-C2-10alkynyl, —C3-10aryl-C3-10hetaryl, —C3-10aryl-C3-10cycloalkyl, —C3-10aryl-C1-10heterocyclyl, —C1-10hetaryl-C1-10alkyl, —C1-10hetaryl-C2-10alkenyl, —C1-10hetaryl-C2-10alkynyl, —C3-10hetaryl-C3-10aryl-C1-10hetaryl-C3-10cycloalkyl, —C1-10hetaryl-C1-10heterocyclyl, —C3-10cycloalkyl-C1-10alkyl, —C3-10cycloalkyl-C2-10alkenyl, —C3-10cycloalkyl-C2-10alkynyl, —C3-10cycloalkyl-C3-10aryl, —C3-10cycloalkyl-C1-10hetaryl, —C3-10cycloalkyl-C1-10heterocyclyl, —C1-10heterocyclyl-C1-10alkyl, —C1-10heterocyclyl-C2-10alkenyl, —C1-10heterocyclyl-C2-10alkynyl, —C1-10heterocyclyl-C3-10aryl, —C1-10heterocyclyl-C1-10hetaryl, or —C1-10heterocyclyl-C3-10cycloalkyl, each of which is unsubstituted or substituted by one or more independent R13 substituents;
• or R3′ is —OR6, —NR6R34, —S(O)0-2R6, —C (═O)R6, —C(═O)OR6, —OC(═O)R6, —C(═O)N(R34)R6, or —N(R34)C(═O)R6, wherein R6 together with R34 can optionally form a heterocyclic ring;
• each of R5, R71, R81 and R91 is independently hydrogen, halogen, —C1-10alkyl, —C2-10alkenyl, —C2-10 alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, —OH, —CF3, —OCF3, —OR31, —NR31R32, —C(O)R31, —CO2R31, —C(═O)NR31, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR32R33, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)SR31, —P(O)OR31OR32, or —SC(═O)NR31NR32;
• R6 is hydrogen, —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, —C1-10alkyl-C3-10aryl, —C1-10alkyl-C1-10hetaryl, —C1-10alkyl-C3-10cycloalkyl, —C1-10alkyl-C1-10heterocyclyl, —C2-10alkenyl-C3-10aryl, —C2-10alkenyl-C1-10hetaryl, —C2-10alkenyl-C3-10cycloalkyl, —C2-10alkenyl-C1-10heterocyclyl, —C2-10alkynyl-C3-10aryl, —C2-10alkynyl-C1-10hetaryl, —C2-10alkynyl-C3-10cycloalkyl, —C2-10alkynyl-C1-10heterocyclyl, —C1-10alkoxy-C3-10aryl, —C1-10alkoxy-C1-10hetaryl, —C1-10alkoxy-C3-10cycloalkyl, —C1-10alkoxy-C1-10heterocyclyl, —C1-10heteroalkyl-C3-10aryl, —C1-10heteroalkyl-C1-10hetaryl, —C1-10heteroalkyl-C3-10cycloalkyl, —C1-10heteroalkyl-C1-10heterocyclyl, —C3-10aryl-C1-10alkyl, —C3-10aryl-C2-10alkenyl, —C3-10aryl-C2-10alkynyl, —C3-10aryl-C3-10hetaryl, —C3-10aryl-C3-10cycloalkyl, —C3-10aryl-C1-10heterocyclyl, —C1-10hetaryl-C1-10alkyl, —C1-10hetaryl-C2-10alkenyl, —C1-10hetaryl-C2-10alkynyl, —C3-10hetaryl-C3-10aryl, —C1-10hetaryl-C3-10cycloalkyl, —C1-10hetaryl-C1-10heterocyclyl, —C3-10cycloalkyl-C1-10alkyl, —C3-10cycloalkyl-C2-10alkenyl, —C3-10cycloalkyl-C2-10 alkynyl, —C3-10cycloalkyl-C3-10aryl, —C3-10cycloalkyl-C1-10hetaryl, —C3-10cycloalkyl-C1-10heterocyclyl, —C1-10heterocyclyl-C1-10alkyl, —C1-10heterocyclyl-C2-10alkenyl, —C1-10heterocyclyl-C2-10alkynyl, —C1-10heterocyclyl-C3-10aryl, —C1-10heterocyclyl-C1-10hetaryl, or —C1-10heterocyclyl-C3-10cycloalkyl, each of which is unsubstituted or substituted by one or more independent R14 or R15 substituents;
• each of R72, R82 and R92 is independently hydrogen, —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, —OH, —CF3, —C(O)R31, —CO2R31, —C(═O)NR31, —S(O)0-2R31, —C(═S)OR31, —C(═O)SR31;
• each of R10 and R14 is —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, optionally substituted by one or more independent R11 substituents;
• each of R11, R12, R13 and R15 is independently hydrogen, halogen, —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, —OH, —CF3, —OCF3, —OR31, —NR31R32, —C(O)R31, —CO2R31, —C(═O)NR31, —NO2, —CN, —S(O)0-2R31, —SO2NR31R32, —NR31C(═O)R32, —NR31C(═O)OR32, —NR31C(═O)NR32R33, —NR31S(O)0-2R32, —C(═S)OR31, —C(═O)SR31, —NR31C(═NR32)NR32R33, —NR31C(═NR32)OR33, —NR31C(═NR32)SR33, —OC(═O)OR33, —OC(═O)NR31R32, —OC(═O)SR31, —SC(═O)SR31, —P(O)OR31OR32, or —SC(═O)NR31NR32;
• each of R31, R32, R33 and R34 is independently hydrogen, halogen, —C1-10alkyl, —C2-10alkenyl, —C2-10alkynyl, —C1-10heteroalkyl, —C3-10aryl, —C1-10hetaryl, —C3-10cycloalkyl, —C1-10heterocyclyl, or wherein R31 together with R32 form a heterocyclic ring;
• wherein ring A comprises one or more heteroatoms selected from N, O, or S;
• and
• wherein if X7 is O or X2—X3 is R1C═CR3, ring A comprises at least two heteroatoms selected from N, O, or S;
• and
• wherein if X3 is O or N, or X2—X3 is R1C═N, at least one of X7 or X9 is not N.