Alkynyl-substituted quinolin-2-one derivatives useful as anticancer agents

A pharmaceutical composition for the treatment of abnormal cell growth in a mammal which comprises a therapeutically effective amount of a compound of formula 1

• or a pharmaceutically acceptable salt, prodrug or solvate thereof wherein:
• the dashed line indicates that the bond between C-3 and C-4 of the quinolin-2-one ring is a single or double bond;
• R1 is selected from H, C1-C10 alkyl, —(CR13R14)qC(O)R12, —(CR13R14)qC(O)OR15, —(CR13R14)qOR12, —(CR13R14)qSO2R15, —(CR13R14)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5 and q is an integer from 1 to 5, said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
• R2 is halo, cyano, —C(O)OR15, or a group selected from the substituents provided in the definition of R12;
• each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, halo cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR12, —C(O)R12, —C(O)OR12, —NR13C(O)OR15, —OC(O)R12, —NR13SO2R15, —SO2NR12R13, —NR13C(O)R12, —C(O)NR12R13, —NR12R13, —CH═NOR12, —S(O)jR12 wherein j is an integer from 0 to 2, —(CR13R14)t(C6-C10 aryl), —(CR13R14)t(4-10 membered heterocyclic), —(CR13R14)t(C3-C10 cycloalkyl), and —(CR13R14)tC≡CR16, and wherein in the foregoing R3, R4, R5, R6, and R7 groups t is an integer from 0 to 5;
• the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR13SO2R15, —SO2NR12R13, —C(O)R12, —C(O)OR12, —OC(O)R12, —NR13C(O)OR15, —NR13C(O)R12, —C(O)NR12R13, —NR12R13, —OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• R8 is H, —OR12, —NR12R13, —NR12C(O)R13, cyano, —C(O)OR13, —SR12, —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, or C1-C6 alkyl, wherein said heterocyclic and alkyl moieties are optionally substituted by 1 to 3 R6 substituents;
• R9 is —(CR13R14)t(imidazolyl) wherein t is an integer from 0 to 5 and said imidazolyl moiety is optionally substituted by 1 or 2 R6 substituents;
• each R10 and R11 is independently selected from the substituents provided in the definition of R6;
• each R12 is independently selected from H, C1-C10 alkyl, —(CR13R14)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R12 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R13, —C(O)OR13, —OC(O)R13, —NR13C(O)R14, —C(O)NR13R14, —NR13R14, hydroxy C1-C6 alkyl, and C1-C6 alkoxy;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14)q or (CR13R14)t each is independently defined for each iteration of q or t in excess of 1;
• R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
• R16 is selected from the list of substituents provided in the definition of R12 and —SiR17R18R19;
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except R17, R18 and R19 are not H;
• and provided that at least one of R3, R4 and R5 is —(CR13R14)tC≡CR16 wherein t is an integer from 0 to 5 and R13, R14, and R16 are as define above, in combination with a pharmaceutically acceptable carrier and an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, and anti-androgens.

A method for the treatment of an infection in a mammal, wherein said infection is facilitated by farnesyl protein transferase, which comprises administering to said mammal a therapeutically effective amount of a compound of formula 1

• or a pharmaceutically acceptable salt, prodrug or solvate thereof wherein:
• the dashed line indicates that the bond between C-3 and C-4 of the quinolin-2-one ring is a single or double bond;
• R1 is selected from H, C1-C10 alkyl, —(CR13R14)qC(O)R12, —(CR13R14)q C(O)OR15, —(CR13R14)qOR12, —(CR13R14)qSO2R15, —(CR13R14)t(C13-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5 and q is an integer from 1 to 5, said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
• R2 is halo, cyano, —C(O)OR15, or a group selected from the substituents provided in the definition of R12;
• each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR12, —C(O)R12, —C(O)OR12, —NR13C(O)OR15, —OC(O)R12, —NR13SO2R15, —SO2NR12R13, —NR13C(O)R12, —C(O)NR12R13, —NR12R13, —CH═NOR12, —S(O)jR12 wherein j is an integer from 0 to 2, —(CR13R14)t(C6-C10 aryl), —(CR13R14)t(4-10 membered heterocyclic), —(CR13R14)t(C3-C10 cycloalkyl), and —(CR13R14)tC≡CR16, and wherein in the foregoing R3, R4, R5, R6, and R7 groups t is an integer from 0 to 5;
• the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR13SO2R15, —SO2NR12R13, —C(O)OR12, —C(O)OR12, —OC(O)R12, —NR13C(O)OR15, —NR13C(O)R12, —C(O)NR12R13, —NR12R13, —OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• R8 is H, —OR2, —NR12R13, —NR12C(O)R13, cyano, —C(O)OR13, —SR12, —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, or C1-C6 alkyl, wherein said heterocyclic and alkyl moieties are optionally substituted by 1 to 3 R6 substituents;
• R9 is —(CR13R14)t(imidazolyl) wherein t is an integer from 0 to 5 and said imidazolyl moiety is optionally substituted by 1 or 2 R6 substituents;
• each R10 and R11 is independently selected from the substituents provided in the definition of R6;
• each R12 is independently selected from H, C1-C10 alkyl, —(CR13R14)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5—C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R12 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R13, —C(O)OR13, —OC(O)R13, —NR13C(O)R14, —C(O)NR13R14, —NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14)q or (CR13R14)t each is independently defined for each iteration of q or t in excess of 1;
• R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
• R16 is selected from the list of substituents provided in the definition of R12 and —SiR17R18R19;
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except R17, R18 and R19 are not H;
• and provided that at least one of R3, R4 and R5 is —(CR13R14)tC≡CR16 wherein t is an integer from 0 to 5 and R13, R14, and R16 are as defined above, and a pharmaceutically acceptable carrier.

A pharmaceutical composition for the treatment of an infection in a mammal, wherein said infection is facilitated by farnesyl protein transferase, which comprises a therapeutically effective amount of a compound of formula 1

• or a pharmaceutically acceptable salt, prodrug or solvate thereof wherein:
• the dashed line indicates that the bond between C-3 and C-4 of the quinolin-2-one ring is a single or double bond;
• R1 is selected from H, C1-C10 alkyl, —(CR13R14)qC(O)R12, —(CR13R14)qC(O)OR15, —(CR13R14)qOR12, —(CR13R14)qSO2R15, —(CR13R14)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5 and q is an integer from 1 to 5, said cycloalkyl, aryl and heterocyclic R1 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
• R2 is halo, cyano, —C(O)OR15, or a group selected from the substituents provided in the definition of R12;
• each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR12, —C(O)R12, —C(O)OR12, —NR13C(O)OR15, —OC(O)R12, —NR13SO2R15, —SO2NR12R13, —NR13C(O)R12, —C(O)NR12R13, —NR12R13, —CH═NOR12, —S(O)jR12 wherein j is an integer from 0 to 2, —(CR13R14)t(C6-C10 aryl), —(CR13R14)t(4-10 membered heterocyclic), —(CR13R14—)t(C3-C10 cycloalkyl), and —(CR13R14)tC≡CR16, and wherein in the foregoing R3, R4, R5, R6, and R7 groups t is interger from 0 to 5;
• the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and said alkyl, alkenyl, cycloalkyl, aryl and heterocyclic groups are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —NR13SO2R15, —SO2NR12R13, —C(O)R12, —C(O)OR12, —OC(O)R12, —NR13C(O)OR15, —NR13C(O)R12, —C(O)NR12R13, —NR12R13, —OR12, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• R8 is H, —OR12, —NR12R13, —NR12C(O)R13, cyano, —C(O)OR13, —SR12, —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5, or C1-C6 alkyl, wherein said heterocyclic and alkyl moieties are optionally substituted by 1 to 3 R6 substituents;
• R9 is —(CR13R14)t(imidazolyl) wherein t is an integer from 0 to 5 and said imidazolyl moiety is optionally substituted by 1 or 2 R6 substituents;
• each R10 and R11 is independently selected from the substituents provided in the definition of R6;
• each R12 is independently selected from H, C1-C10 alkyl, —(CR13R14)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
• said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C8 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R12 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R13, —C(O)OR13, —OC(O)R13, —NR13C(O)R14, —C(O)NR13R14, —NR13R14, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14)q or (CR13R14)t each is independently defined for each iteration of q or t in excess of 1;
• R15 is selected from the substituents provided in the definition of R12 except R15 is not H;
• R16 is selected from the list of substituents provided in the definition of R12 and —SiR17R18R19;
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except R17, R18 and R19 are not H;
• and provided that at least one of R3, R4 and R5 is —(CR13R14)tC≡CR16 wherein t is an integer from 0 to 5 and R13, R14, and R16 are as defined above, and a pharmaceutically acceptable carrier.