Method for treating chronic pain using MEK inhibitors

A method for treating chronic pain, wherein said chronic pain is associated with inflammation, said method comprising administering to a subject in need of such treatment a composition comprising a MEK inhibitor selected from a compound of the following formula (I):

• wherein
• W is OR1, NR2OR1, NRARB, NR2NRARB, O(CH2)2-4NRARB, or NR2(CH2)2-4NRARB;
• R1 is H, C1-8alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, phenyl, (phenyl)C1-4alkyl, (phenyl)C3-4alkenyl, (phenyl)C3-4alkynyl, (C3-8cycloalkyl)C1-4alkyl, (C3-8cycloalkyl)C3-4alkenyl, (C3-8cycloalkyl)C3-4alkynyl, C3-8heterocyclic radical, (C3-8heterocyclic radical)C1-4alkyl, (C3-8heterocyclic radical)-C3-4alkenyl, (C3-8heterocyclic radical)C3-4alkynyl or (CH2)2-4NRCRD;
• R2 is H, C1-4alkyl, phenyl, C3-6cycloalkyl, C3-6heterocyclic radical, or (C3-6cycloalkyl)methyl;
• RA is H, C1-6alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, phenyl, (C3-8cycloalkyl)C1-4alkyl, (C3-8cycloalkyl)C3-4alkenyl, (C3-8cycloalkyl)C3-4alkynyl, C3-8heterocyclic radical, (C3-8heterocyclic radical)C1-4alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C1-4alkyl, (aminosulfonyl)C1-6alkyl, (aminosulfonyl)C3-6cycloalkyl, [(aminosulfonyl)C3-6cycloalkyl]C1-4alkyl, or (CH2)2-4NRCRD;
• RB is H, C1-8alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, or phenyl;
• Q is one of the following formulae (i)–(iii):
• R3 is H or F;
• R4 is halo, NO2, SO2NRO(CH2)2-4NRERF, SO2NRERF, or (CO)T;
• T is C1-8alkyl, C3-8cycloalkyl, (NRERF)C1-4alkyl, ORF, —NRO(CH2)2-4NRERF, or NRERF;
• Z is one of the following formula (iv)–(viii):
• one of R5 and R6 is H or methyl and the other of R5 and R6 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, benzyl, or —M-E-G;
• M is O, CO, SO2, NRJ, (CO)NRH, NRH(CO), NRH(SO2), (SO2)NRH, or CH2;
• E is (CH2)1-4 or (CH2)mO(CH2)p where 1≦(each of m and p)≦3 and 2≦(m+p)≦4;
• or E is absent;
• G is RK, ORI or NRJRK, provided that if p=1, then G is H;
• R7 is H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl,
• SO2NRH(CH2)2-4NRJRK, (CO)(CH2)2-4NRJRK or (CO)NRH(CH2)2-4NRJRK;
• X1 is O, S, NR8, or CHR9;
• X2 is O, S, or CHR9;
• and X3 is O or S;
• where if X1 or X2 is CHR9, said compound may also be a tautomerized indole;
• R8 is H, C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, or (C2-4alkyl)NRLRM;
• provided R7 and R8 together have no more than 14 carbon atoms, exclusive of RL, RM, RJ and RK;
• RG is C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, (CO)ORP, (C2-4alkyl)NRLRM, (CO)NRN(CH2)2-4NRLRM, (CO)NRLRM, (CO)(CH2)2-4-NRLRM, or (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• R9 is C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-4alkenyl, C2-4alkynyl,
• C3-6cycloalkyl, (CO)ORP, (C2-4alkyl)NRLRM, (CO)NRN(CH2)2-4NRLRM, (CO)NRLRM, (CO)(CH2)2-4-NRLRM, or (CH2)1-2Ar′, where Ar′ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• RP is H, C1-6alkyl, phenyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, or (CH2)2-4NRLRM;
• R10 is H, methyl, halo, or NO2;
• R11 is H, methyl, halo, or NO2;
• each of RC, RD, RE, RF, RI, RJ, RK, RL and RM is independently selected from H, C1-4alkyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, and phenyl;
• each of NRCRD, NRERF, NRJRK, and NRLRM can also independently be morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl;
• and
• each of RH, RN, and RO is independently H, methyl, or ethyl;
• wherein each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C1-4alkyl, C3-6cycloalkyl, C3-4alkenyl, C3-4alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C1-2alkyl, hydroxyl, amino, and NO2;
• or a pharmaceutically acceptable salt or C1-7 ester thereof.

A method for treating chronic pain, wherein said chronic pain is associated with arthritis, said method comprising administering to a subject in need of such treatment a composition comprising a MEK inhibitor selected from a compound of the following formula (I):

• wherein
• W is OR1, NR2OR1, NRARB, NR2NRARB, O(CH2)2-4NRARB, or NR2(CH2)2-4NRARB;
• R1 is H, C1-8alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, phenyl, (phenyl)C1-4alkyl, (phenyl)C3-4alkenyl, (phenyl)C3-4alkynyl, (C3-8cycloalkyl)C1-4alkyl, (C3-8cycloalkyl)C3-4alkenyl, (C3-8cycloalkyl)C3-4alkynyl, C3-8heterocyclic radical, (C3-8heterocyclic radical)C1-4alkyl, (C3-8heterocyclic radical)-C3-4alkenyl, (C3-8heterocyclic radical)C3-4alkynyl or (CH2)2-4NRCRD;
• R2 is H, C1-4alkyl, phenyl, C3-6cycloalkyl, C3-6heterocyclic radical, or (C3-6cycloalkyl)methyl;
• RA is H, C1-6alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, phenyl, (C3-8cycloalkyl)C1-4alkyl, (C3-8cycloalkyl)C3-4alkenyl, (C3-8cycloalkyl)C3-4alkynyl, C3-8heterocyclic radical, (C3-8heterocyclic radical)C1-4alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C1-4alkyl, (aminosulfonyl)C1-6alkyl, (aminosulfonyl)C3-6cycloalkyl, [(aminosulfonyl)C3-6cycloalkyl]C1-4alkyl, or (CH2)2-4NRCRD;
• RB is H, C1-8alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, or phenyl;
• Q is one of the following formulae (i)–(iii):
• R3 is H or F;
• R4 is halo, NO2, SO2NRO(CH2)2-4NRERF, SO2NRERF, or (CO)T;
• T is C1-8alkyl, C3-8cycloalkyl, (NRERF)C1-4alkyl, ORF, —NRO(CH2)2-4NRERF, or NRERF;
• Z is one of the following formula (iv)–(viii):
• one of R5 and R6 is H or methyl and the other of R5 and R6 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, benzyl, or —M-E-G;
• M is O, CO, SO2, NRJ, (CO)NRH, NRH(CO), NRH(SO2), (SO2)NRH, or CH2;
• E is (CH2)1-4 or (CH2)mO(CH2)p where 1≦(each of m and p)≦3 and 2≦(m+p)≦4;
• or E is absent;
• G is RK, ORI or NRJRK, provided that if p=1, then G is H;
• R7 is H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl,
• SO2NRH(CH2)2-4NRJRK, (CO)(CH2)2-4NRJRK or (CO)NRH(CH2)2-4NRJRK;
• X1 is O, S, NR8, or CHR9;
• X2 is O, S, or CHR9;
• and X3 is O or S;
• where if X1 or X2 is CHR9, said compound may also be a tautomerized indole;
• R8 is H, C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, or (C2-4alkyl)NRLRM;
• provided R7 and R8 together have no more than 14 carbon atoms, exclusive of RL, RM, RJ and RK;
• RG is C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, (CO)ORP, (C2-4alkyl)NRLRM, (CO)NRN(CH2)2-4NRLRM, (CO)NRLRM, (CO)(CH2)2-4-NRLRM, or (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• R9 is C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-4alkenyl, C2-4alkynyl,
• C3-6cycloalkyl, (CO)ORP, (C2-4alkyl)NRLRM, (CO)NRN(CH2)2-4NRLRM, (CO)NRLRM, (CO)(CH2)2-4-NRLRM, or (CH2)1-2Ar′, where Ar′ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• RP is H, C1-6alkyl, phenyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, or (CH2)2-4NRLRM;
• R10 is H, methyl, halo, or NO2;
• R11 is H, methyl, halo, or NO2;
• each of RC, RD, RE, RF, RI, RJ, RK, RL and RM is independently selected from H, C1-4alkyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, and phenyl;
• each of NRCRD, NRERF, NRJRK, and NRLRM can also independently be morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl;
• and
• each of RH, RN, and RO is independently H, methyl, or ethyl;
• wherein each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C1-4alkyl, C3-6cycloalkyl, C3-4alkenyl, C3-4alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C1-2alkyl, hydroxyl, amino, and NO2;
• or a pharmaceutically acceptable salt or C1-7 ester thereof.

A method for treating chronic pain, wherein said chronic pain is associated with post-operative pain, said method comprising administering to a subject in need of such treatment a composition comprising a MEK inhibitor selected from a compound of the following formula (I):

• wherein
• W is OR1, NR2OR1, NRARB, NR2NRARB, O(CH2)2-4NRARB, or NR2(CH2)2-4NRARB;
• R1 is H, C1-8alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, phenyl, (phenyl)C1-4alkyl, (phenyl)C3-4alkenyl, (phenyl)C3-4alkynyl, (C3-8cycloalkyl)C1-4alkyl, (C3-8cycloalkyl)C3-4alkenyl, (C3-8cycloalkyl)C3-4alkynyl, C3-8heterocyclic radical, (C3-8heterocyclic radical)C1-4alkyl, (C3-8heterocyclic radical)-C3-4alkenyl, (C3-8heterocyclic radical)C3-4alkynyl or (CH2)2-4NRCRD;
• R2 is H, C1-4alkyl, phenyl, C3-6cycloalkyl, C3-6heterocyclic radical, or (C3-6cycloalkyl)methyl;
• RA is H, C1-6alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, phenyl, (C3-8cycloalkyl)C1-4alkyl, (C3-8cycloalkyl)C3-4alkenyl, (C3-8cycloalkyl)C3-4alkynyl, C3-8heterocyclic radical, (C3-8heterocyclic radical)C1-4alkyl, (aminosulfonyl)phenyl, [(aminosulfonyl)phenyl]C1-4alkyl, (aminosulfonyl)C1-6alkyl, (aminosulfonyl)C3-6cycloalkyl, [(aminosulfonyl)C3-6cycloalkyl]C1-4alkyl, or (CH2)2-4NRCRD;
• RB is H, C1-8alkyl, C3-8alkenyl, C3-8alkynyl, C3-8cycloalkyl, or phenyl;
• Q is one of the following formulae (i)–(iii):
• R3 is H or F;
• R4 is halo, NO2, SO2NRO(CH2)2-4NRERF, SO2NRERF, or (CO)T;
• T is C1-8alkyl, C3-8cycloalkyl, (NRERF)C1-4alkyl, ORF, —NRO(CH2)2-4NRERF, or NRERF;
• Z is one of the following formula (iv)–(viii):
• one of R5 and R6 is H or methyl and the other of R5 and R6 is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, phenyl, benzyl, or —M-E-G;
• M is O, CO, SO2, NRJ, (CO)NRH, NRH(CO), NRH(SO2), (SO2)NRH, or CH2;
• E is (CH2)1-4 or (CH2)mO(CH2)p where 1≦(each of m and p)≦3 and 2≦(m+p)≦4;
• or E is absent;
• G is RK, ORI or NRJRK, provided that if p=1, then G is H;
• R7 is H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl,
• SO2NRH(CH2)2-4NRJRK, (CO)(CH2)2-4NRJRK or (CO)NRH(CH2)2-4NRJRK;
• X1 is O, S, NR8, or CHR9;
• X2 is O, S, or CHR9;
• and X3 is O or S;
• where if X1 or X2 is CHR9, said compound may also be a tautomerized indole;
• R8 is H, C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, C2-4alkenyl, C2-4alkynyl, C3-6cycloalkyl, or (C2-4alkyl)NRLRM;
• provided R7 and R8 together have no more than 14 carbon atoms, exclusive of RL, RM, RJ and RK;
• RG is C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, (CO)ORP, (C2-4alkyl)NRLRM, (CO)NRN(CH2)2-4NRLRM, (CO)NRLRM, (CO)(CH2)2-4-NRLRM, or (CH2)1-2Ar, where Ar is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• R9 is C1-4alkyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-4alkenyl, C2-4alkynyl,
• C3-6cycloalkyl, (CO)ORP, (C2-4alkyl)NRLRM, (CO)NRN(CH2)2-4NRLRM, (CO)NRLRM, (CO)(CH2)2-4-NRLRM, or (CH2)1-2Ar′, where Ar′ is phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl;
• RP is H, C1-6alkyl, phenyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, or (CH2)2-4NRLRM;
• R10 is H, methyl, halo, or NO2;
• R11 is H, methyl, halo, or NO2;
• each of RC, RD, RE, RF, RI, RJ, RK, RL and RM is independently selected from H, C1-4alkyl, C3-4alkenyl, C3-4alkynyl, C3-6cycloalkyl, and phenyl;
• each of NRCRD, NRERF, NRJRK, and NRLRM can also independently be morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl;
• and
• each of RH, RN, and RO is independently H, methyl, or ethyl;
• wherein each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C1-4alkyl, C3-6cycloalkyl, C3-4alkenyl, C3-4alkynyl, phenyl, hydroxyl, amino, (amino)sulfonyl, and NO2, wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C1-2alkyl, hydroxyl, amino, and NO2;
• or a pharmaceutically acceptable salt or C1-7 ester thereof.