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

A compound of the formula

• 43
• wherein:
• the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinoline ring;
• R is C1-C6 alkyl;
• 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, C2-C10alkynyl, 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 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• R8 is H, —OR12, —OC(O)R12, —NR12R13, —NR12C(O)R13, cyano, —C(O)OR13, —SR12, or —(CR13R14)t(4-10 membered heterocyclic), wherein said heterocyclic R8 groups are substituted by 1 to 4 R6 groups;
• R9 is —(CR13R14)t(imidazolyl) or —(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents;
• 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);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14)t each is independently defined for each iteration of 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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.

A compound of the formula

• 44
• wherein:
• the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinolin-2-one ring;
• W is selected from fluoro, chloro, bromo, and iodo;
• R1 is selected from H, C1-C10 alkyl, —(CR13R14)qC(O)R12, —(CR13R14)qC(O)OR15, —(CR13R14)qOR12, —(CR13R14)qCSO2R15, —(CR13R14)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein 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, C2-C10alkynyl, 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 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• R9 is —(CR13R14)t(imidazolyl) or —(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents;
• 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);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5 and each q is independently an integer from 1 to 5;
• 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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.

A compound of the formula

• 45
• wherein:
• R is C1-C6 alkyl;
• 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, C2-C10alkynyl, 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 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• each R12 is independently selected from H, C1-C10 alkyl, —(CR3R_4)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14) each is independently defined for each iteration 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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.

A compound of the formula

• 46
• or pharmaceutically acceptable salt or solvate thereof wherein:
• the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinolin ring;
• 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, C2-C10alkynyl, 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 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• R8 is H, —OR12, —OC(O)R12, —NR12R13, —NR12C(O)R13, cyano, —C(O)OR13, —SR12, or —(CR13R14)t(4-10 membered heterocyclic), wherein said heterocyclic R8 groups are substituted by 1 to 4 R6 groups;
• R9 is —(CR13R14)t(imidazolyl) or —(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents;
• 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);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.

A compound of the formula

• 47
• or pharmaceutically acceptable salt or solvate thereof wherein:
• the dashed line indicates an optional second bond connecting C-3 and C-4 of the quinolin ring;
• 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, C2-C10alkynyl, 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 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• R8 is H, —OR12, —OC(O)R12, —NR12R13, —NR12C(O)R13, cyano, —C(O)OR13, —SR12, or —(CR13R14)t(4-10 membered heterocyclic), wherein said heterocyclic R8 groups are substituted by 1 to 4 R6 groups;
• R9 is —(CR13R14)t(imidazolyl) or —(CR13R14)t(pyridinyl) wherein said imidazolyl or pyridinyl moiety is substituted by 1 or 2 R6 substituents;
• 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);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14)t each is independently defined for each iteration of 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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.

A compound of the formula

• 48
• wherein:
• R1 is selected from H, C1-C10 alkyl, —(CR13R14)qC(O)R12, —(CR13R14)qC(O)OR15, —(CR13R14)qOR12, —(CR13R14)qCSO2R15, —(CR13R14)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein 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, C2-C10alkynyl, 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 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• 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);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5 and each q is independently an integer from 1 to 5;
• 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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.

A compound of the formula

• 49
• wherein:
• R24 is selected from —SR20 and —SiR21R22R23, wherein R20 is selected from H and phenyl, and R21, R22, and R23 are independently selected from C1-C6 alkyl and phenyl;
• R1 is selected from H, C1-C10 alkyl, —(CR13R14)qC(O)R12, —(CR13R14)qC(O)OR15, —(CR13R14)qOR12, —(CR13R14)qCSO2R15, —(CR13R14)t(C3-C10 cycloalkyl), —(CR13R14)t(C6-C10 aryl), and —(CR13R14)t(4-10 membered heterocyclic), wherein 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, C2-C10alkynyl, 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 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• 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);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5 and each q is independently an integer from 1 to 5;
• 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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H.

A method of synthesizing a compound of the formula

• 50
• wherein
• R6 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, 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 the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C6-C10 aryl group, a C5-C6 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• 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);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14)t each is independently defined for each iteration of 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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H;
• which method comprises reacting in an appropriate solvent in the presence of a suitable base a compound of the formula
• 51
• wherein Z is as defined above;
• with a compound of the formula
• 52
• wherein R6 is as defined above, and
• R21, R22, and R23 are each independently selected from C1-C6 alkyl and phenyl;
• thereby obtaining a compound of the formula
• 53
• and reacting the compound of formula 32 so obtained in an appropriate solvent with acetic acid or with a fluoride reagent.

A method of synthesizing a compound of the formula

• 54
• wherein
• R6 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, 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 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);
• Z is an aromatic 4-10 membered heterocyclic group, substituted by 1 to 4 R6 substituents;
• 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);
• said cycloalkyl, aryl and heterocyclic R12 groups are optionally fused to a C6-C10 aryl group, a C5-C10 saturated cyclic group, or a 4-10 membered heterocyclic group;
• and the foregoing R12 substituents, except H but including any optional fused rings, 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 t is independently an integer from 0 to 5;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14)t each is independently defined for each iteration of 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;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H;
• which method comprises reacting in an appropriate solvent in the presence of a suitable base a compound of the formula
• 55
• wherein Z is as defined above;
• with a compound of the formula
• 56
• wherein R6 is as defined above and R20 is selected from H and phenyl;
• thereby obtaining a compound of the formula
• 57
• and removing from the compound of formula 31 so obtained the —SR20 group, either:
• a) reductively, with a nickel catalyst;
• or
• b) oxidatively, with nitric acid or with aqueous hydrogen peroxide in acetic acid.

A method of synthesizing a compound of the formula

• 58
• wherein
• each R3, R4, R5, R6, and R7 is independently selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, 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)C≡CR16;
• and wherein 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);
• 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);
• 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 but including any optional fused rings, 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 t is independently an integer from 0 to 5;
• each R13 and R14 is independently H or C1-C6 alkyl, and where R13 and R14 are as —(CR13R14 )t each is independently defined for each iteration of 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 —SiR17R18R19R;
• and,
• R17, R18 and R19 are each independently selected from the substituents provided in the definition of R12 except at least one of R17, R18 and R19 is not H;
• which method comprises reacting, at a temperature of from about −78° C. to about 0° C., in the presence of a suitable base and in an appropriate solvent a compound of formula
• 59
• wherein W is an appropriate leaving group, and R3, R4 and R5 are as defined above, with a compound of the formula
• 60
• wherein R6 and R7 are as defined above.

A method of synthesizing a compound of the formula

• 61
• wherein R6 is selected from H, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, 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), —(CR13R14R)t(C3-C10 cycloalkyl), and —(CR13R14)tC≡CR16;
• and wherein 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);
• which method comprises
• a) reacting with a metal cyanide, in the presence of a palladium catalyst and in an appropriate solvent, at a temperature of about 25° C. to about 100° C., a compound of the formula
• 62
• wherein Tf is —SO2-CF3 and R6 is as defined above;
• thereby obtaining a compound of the formula 37.