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US 6,388,092 B2Granted
Heteroaryl-substituted quinolin-2-one derivatives useful as anticancer agents
AssigneePfizer Inc.
InventorBingwei V. Yang
Life of this patent
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Abstract
The present invention relates to compounds of formula 1 and pharmaceutically acceptable salts and solvates thereof wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, and Z are as defined herein. The invention also relates to pharmaceutical compositions comprising compounds of formula 1 and to methods of inhibiting abnormal cell growth, including cancer, in a mammal by administering compounds of formula 1 to the mammal. The invention also relates to intermediates and methods useful in synthesizing compounds of formula 1.
Claims2
A method of synthesizing a compound of the formula
- 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-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
- wherein Z is as defined above;
- with a compound of the formula
- 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
- and reacting the compound of formula 32 so obtained in an appropriate solvent with acetic acid or with a fluoride reagent.
18 more elements
A method of synthesizing a compound of the formula
- 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 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
- wherein Z is as defined above;
- with a compound of the formula
- wherein R6 is as defined above and R20 is selected from H and phenyl;
- thereby obtaining a compound of the formula
- 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.
20 more elements
Dependencies are inferred from the claim text.