Methods of using MEK inhibitors

A method of treating cancer which method comprises administering to a patient a therapeutically effective amount of a compound of Formula I:

• or a pharmaceutically acceptable salt or solvate, thereof;
• or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I and a pharmaceutically acceptable carrier, excipient, or diluent in combination with one or more treatment(s) selected from surgery, one or more chemotherapeutic agent(s), one or more hormone therapy(s), one or more antibody(s), hypothermia therapy, radioactive iodine therapy, and radiation;
• wherein the Compound of Formula I is that where A, X, R1, R2, R3, R4, R5, R6, and R7 are as defined in Group A, Group B, Group C, or Group D:
• Group A:
• A is arylene optionally substituted with one, two, three or four groups selected from R10, R12, R14, and R16 where R10, R12, R14 and R16 are independently hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, —NHS(O)2R8, —CN, —C(O)R8, —C(O)OR8, —C(O)NR8R8′ and —NR8C(O)R8′;
• X is alkyl, halo, haloalkyl, or haloalkoxy;
• R1, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, —NR8R8′, —OR8, —NHS(O)2R8, —CN, —S(O)mR8, —S(O)2NR8R8′, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)OR8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′, —NR8C(O)R8′, —CH2N(R25)(NR25aR25b), —CH2NR25C(═NH)(NR25aR25b), —CH2NR25C(═NH)(N(R25a)(NO2), —CH2NR25C(═NH)(N(R25a)(CN), —CH2NR25C(═NH)(R25), —CH2NR25C(NR25aR25b)═CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR8, —NR8R8′, —NR8S(O)2R9, —CN, —S(O)mR9, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′ and —NR8C(O)R8′;
• or one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R5 and R6 together with the carbon to which they are attached form C(O) or C(═NOH);
• m is 0, 1, or 2;
• R7 is hydrogen, halo or alkyl;
• R8, R8′ and R8″ are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;
• where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxycarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkyloxycarbonyl, nitro, cyano, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, —S(O)nR31 (where n is 0, 1, or 2 and R31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —NR34SO2R34a (where R34 is hydrogen or alkyl and R34a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl), —SO2NR35R35a (where R35 is hydrogen or alkyl and R35a is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl), —NR32C(O)R32a (where R32 is hydrogen or alkyl and R32a is alkyl, alkenyl, alkoxy, or cycloalkyl), —NR30R30′ (where R30 and R30′ are independently hydrogen, alkyl, or hydroxyalkyl), and —C(O)NR33R33a (where R33 is hydrogen or alkyl and R33a is alkyl, alkenyl, alkynyl, or cycloalkyl);
• R9 is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl;
• where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, or five groups selected from halo, hydroxy, alkyl, haloalkyl, haloalkoxy, amino, alkylamino, and dialkylamino;
• R25 and R25b are independently hydrogen, alkyl, alkenyl, optionally substituted cycloalkyl, or optionally substituted aryl;
• and
• R25a is hydrogen, alkyl, or alkenyl;
• Group B:
• A is heteroarylene optionally substituted with one, two, three, or four groups selected from R10, R12, R14, R16 and R19 where R10, R12, R14 and R16 are independently hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, alkoxy, cyano, amino, alkylamino, dialkylamino, haloalkyl, alkylsulfonylamino, alkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, alkenyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or alkylcarbonylamino;
• where R19 is hydrogen, alkyl, or alkenyl;
• and where each alkyl and alkenyl, either alone or as part of another group within R10, R12, R14, R16, and R19 is independently optionally substituted with halo, hydroxy, or alkoxy;
• X is alkyl, halo, haloalkyl, or haloalkoxy;
• R1, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, —NR8R8′, —OR8, —NHS(O)2R8, —CN, —S(O)mR8, —S(O)2NR8R8′, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)OR8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′, —NR8C(O)R8′, —CH2N(R25)(NR25aR25b), —CH2NR25C(═NH)(NR25aR25b), —CH2NR25C(═NH)(N(R25a)(NO2), —CH2NR25C(═NH)(N(R25a)(CN), —CH2NR25C(═NH)(R25), —CH2NR25C(NR25aR25b)═CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR8, —NR8R8′, —NR8S(O)2R9, —CN, —S(O)mR9, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′ and —NR8C(O)R8′;
• or one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R5 and R6 together with the carbon to which they are attached form C(O) or C(═NOH);
• m is 1 or 2;
• R7 is hydrogen, halo or alkyl;
• and
• R8, R8′ and R8″ are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, —S(O)nR31 (where n is 0, 1, or 2 and R31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —NR36S(O)2R36a (where R36 is hydrogen, alkyl, or alkenyl and R36a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —S(O)2NR37R37a (where R37 is hydrogen, alkyl, or alkenyl and R37a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R32 (where R32 is alkyl, alkenyl, alkoxy, or cycloalkyl) and —NR30R30′ (where R30 and R30′ are independently hydrogen, alkyl, or hydroxyalkyl), and —C(O)NHR33 (where R33 is alkyl, alkenyl, alkynyl, or cycloalkyl);
• Group C:
• A is
• where R10 is hydrogen, alkyl, alkenyl, alkynyl, halo, haloalkoxy, hydroxy, alkoxy, amino, alkylamino, dialkylamino, haloalkyl, —NHS(O)2R8, —CN, —C(O)R8, —C(O)OR8, —C(O)NR8R8′ and —NR8C(O)R8′;
• R10a is hydrogen, alkyl, or alkenyl;
• Y1 is ═CH— or ═N—;
• X is alkyl, halo, haloalkyl, or haloalkoxy;
• R1, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, —NR8R8′, —OR8, —NHS(O)2R8, —CN, —S(O)mR8, —S(O)2NR8R8′, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)OR8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′, —NR8C(O)R8′, —CH2N(R25)(NR25aR25b), —CH2NR25C(═NH)NR25aR25b), —CH2NR25C(═NH)(N(R25a)(NO2), —CH2NR25C(═NH)(N(R25a)(CN), —CH2NR25C(═NH)(R25), —CH2NR25C(NR25b)═CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR8, —NR8R8′, —NR8S(O)2R9, —CN, —S(O)nR9, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′ and —NR8C(O)R8′;
• or one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R5 and R6 together with the carbon to which they are attached form C(O) or C(═NOH);
• m is 1 or 2;
• R7 is hydrogen, halo or alkyl;
• and
• R8, R8′ and R8″ are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, —S(O)nR31 (where n is 0, 1, or 2 and R31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —NR36S(O)2R36a (where R36 is hydrogen, alkyl, or alkenyl and R36a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —S(O)2NR37R37a (where R37 is hydrogen, alkyl, or alkenyl and R37a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R32 (where R32 is alkyl, alkenyl, alkoxy, or cycloalkyl) and —NR30R30 (where R30 and R30′ are independently hydrogen, alkyl, or hydroxyalkyl), and —C(O)NHR33 (where R33 is alkyl, alkenyl, alkynyl, or cycloalkyl);
• or
• Group D:
• A is
• R40 and R40a are independently hydrogen or alkyl;
• X is alkyl, halo, haloalkyl, or haloalkoxy;
• R1, R2, R3, R4, R5 and R6 are independently hydrogen, halo, nitro, —NR8R8′, —OR8, —NHS(O)2R8, —CN, —S(O)mR8, —S(O)2NR8R8′, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)OR8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′, —NR8C(O)R8′, —CH2N(R25)(NR25aR25b), —CH2NR25C(═NH)(NR25aR25b), —CH2NR25C(═NH)(N(R25a)(NO2), —CH2NR25C(═NH)(N(R25a)(CN), —CH2NR25C(═NH)(R25), —CH2NR25C(NR25aR25b)═CH(NO2), alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, or heterocycloalkyl, where the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two, three, four, five, six or seven groups independently selected from halo, alkyl, haloalkyl, nitro, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, —OR8, —NR8R8′, —NR8S(O)2R9, —CN, —S(O)mR9, —C(O)R8, —C(O)OR8, —C(O)NR8R8′, —NR8C(O)NR8′R8″, —NR8C(O)OR8′ and —NR8C(O)R8′;
• or one of R1 and R2 together with the carbon to which they are attached, R3 and R4 together with the carbon to which they are attached, and R5 and R6 together with the carbon to which they are attached form C(O) or C(═NOH);
• m is 1 or 2;
• R7 is hydrogen, halo or alkyl;
• and
• R8, R8′ and R8″ are independently selected from hydrogen, hydroxy, optionally substituted alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, where the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl are independently optionally substituted with one, two three, four, or five groups independently selected from alkyl, halo, hydroxy, hydroxyalkyl, optionally substituted alkoxy, alkoxyalkyl, haloalkyl, carboxy, carboxy ester, nitro, cyano, —S(O)nR31 (where n is 0, 1, or 2 and R31 is optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —NR36S(O)2R36a (where R36 is hydrogen, alkyl, or alkenyl and R36a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), —S(O)2NR37R37a (where R37 is hydrogen, alkyl, or alkenyl and R37a is alkyl, alkenyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl), optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted heteroaryl, —NHC(O)R32 (where R32 is alkyl, alkenyl, alkoxy, or cycloalkyl) and —NR30R30′ (where R30 and R30′ are independently hydrogen, alkyl, or hydroxyalkyl), and —C(O)NHR33 (where R33 is alkyl, alkenyl, alkynyl, or cycloalkyl).