US 6,150,377 AGranted

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

AssigneePfizer Inc.

InventorsJoseph P. Lyssikatos, Susan D. La Greca

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Abstract

The present invention relates to compounds of formula 1 and to pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, and R.sup.11 are as defined herein. The above compounds of formula 1 are useful in the treatment of hyperproliferative disorders, such as cancer, in mammals. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of inhibiting abnormal cell growth, including cancer, in a mammal by administering the compounds of formula 1 to a mammal requiring such treatment.

Claims19

Dependent claims

A compound of the formula 1 ##STR18## 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;
R.sup.1 is selected from H, C.sub.1 -C.sub.10 alkyl, --(CR.sup.13 R.sup.14).sub.q C(O)R.sup.12, --(CR.sup.13 R.sup.14).sub.q C(O)OR.sup.15, --(CR.sup.13 R.sup.14).sub.q OR.sup.12, --(CR.sup.13 R.sup.14).sub.q SO.sub.2 R.sup.15, --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkly), --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.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 R.sup.1 groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4-10 membered heterocyclic group;
and the foregoing R.sup.1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R.sup.6 groups;
R.sup.2 is halo, cyano, --C(O)OR.sup.15, or a group selected from the substituents provided in the definition of R.sup.12 ;
each R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is independently selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --OR.sup.12, --C(O)R.sup.12, --C(O)OR.sup.12, --NR.sup.13 C(O)OR.sup.15, --OC(O)R.sup.12, --NR.sup.13 SO.sub.2 R.sup.15, --SO.sub.2 NR.sup.12 R.sup.13, --NR.sup.13 C(O)R.sup.12, --C(O)NR.sup.12 R.sup.13, --NR.sup.12 R.sup.13, --CH.dbd.NOR.sup.12, --S(O).sub.j R.sup.12 wherein j is an integer from 0 to 2, --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkyl), and --(CR.sup.13 R.sup.14).sub.t C.tbd.CR.sup.16, and wherein in the foregoing R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 groups t is an integer from 0 to 5;
the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 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, --NR.sup.13 SO.sub.2 R.sup.15, --SO.sub.2 NR.sup.12 R.sup.13, --C(O)R.sup.12, --C(O)OR.sup.12, --OC(O)R.sup.12, --NR.sup.13 C(O)OR.sup.15, --NR.sup.13 C(O)R.sup.12, --C(O)NR.sup.12 R.sup.13, --NR.sup.12 R.sup.13, --OR.sup.12, C.sub.1 --C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
R.sup.8 is H, --OR.sup.12, --NR.sup.12 R.sup.13, --NR.sup.12 C(O)R.sup.13, cyano, --C(O)OR.sup.13, --SR.sup.12, --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5, or C.sub.1 -C.sub.6 alkyl, wherein said heterocyclic and alkyl moieties are optionally substituted by 1 to 3 R.sup.6 substituents;
R.sup.9 is --(CR.sup.13 R.sup.14).sub.t (imidazolyl) wherein t is an integer from 0 to 5 and said imidazolyl moiety is optionally substituted by 1 or 2 R.sup.6 substituents;
each R.sup.10 and R.sup.11 is independently selected from the substituents provided in the definition of R.sup.6 ;
each R.sup.12 is independently selected from H, C.sub.1 -C.sub.10 alkyl, --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkyl), --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
said cycloalkyl, aryl and heterocyclic R.sup.12 groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4-10 membered heterocyclic group;
and the foregoing R.sup.12 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --C(O)R.sup.13, --C(O)OR.sup.13, --OC(O)R.sup.13, --NR.sup.13 C(O)R.sup.14, --C(O)NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, hydroxy, C.sub.1 -C.sub.6 alkyl, and C.sub.1 -C.sub.6 alkoxy;
each R.sup.13 and R.sup.14 is independently H or C.sub.1 -C.sub.6 alkyl, and where R.sup.13 and R.sup.14 are as --(CR.sup.13 R.sup.14).sub.q or (CR.sup.13 R.sup.14).sub.t each is independently defined for each iteration of q or t in excess of 1;
R.sup.15 is selected from the substituents provided in the definition of R.sup.12 except R.sup.15 is not H;
R.sup.16 is selected from the list of substituents provided in the definition of R.sup.12 and --SiR.sup.17 R.sup.18 R.sup.19 ;
R.sup.17, R.sup.18 and R.sup.19 are each independently selected from the substituents provided in the definition of R.sup.12 except R.sup.17, R.sup.18 and R.sup.19 are not H;
and
provided that at least one of R.sup.3, R.sup.4 and R.sup.5 is --(CR.sup.13 R.sup.14).sub.t C.tbd.CR.sup.16 wherein t is an integer from 0 to 5 and R.sup.13, R.sup.14, and R.sup.16 are as defined above.

16 more elements

A compound of formula 28 ##STR19## wherein R.sup.1 is selected from H, C.sub.1 -C.sub.10 alkyl, --(CR.sup.13 R.sup.14).sub.q C(O)R.sup.12, --(CR.sup.13 R.sup.14).sub.q C(O)OR.sup.15, --(CR.sup.13 .sup.14).sub.q OR.sup.12, --(CR.sup.13 R.sup.14).sub.q SO.sub.2 R.sup.15, --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkyl), --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.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 R.sup.1 groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4-10 membered heterocyclic group;

and the foregoing R.sup.1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R6 groups;
R.sup.2 is halo, cyano, --C(O)OR.sup.15, or a group selected from the substituents provided in the definition of R.sup.12 ;
each R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is independently selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --OR.sup.12, --C(O)R.sup.12, --C(O)OR.sup.12, --NR.sup.13 C(O)OR.sup.15, --OC(O)R.sup.12, --NR.sup.13 SO.sub.2 R.sup.15, --SO.sub.2 NR.sup.12 R.sup.13, --NR.sup.13 C(O)R.sup.12, --C(O)NR.sup.12 R.sup.13, --NR.sup.12 R.sup.13, --CH.dbd.NOR.sup.12, -S(O).sub.j R.sup.12 wherein j is an integer from 0 to 2, --(CR.sup.13 R.sup.14).sub.t (C.sub.6 --C.sub.10 aryl), --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkyl), and --(CR.sup.13 R.sup.14).sub.t C.tbd.CR.sup.16, and wherein in the foregoing R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 groups t is an integer from 0 to 5;
the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 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, --NR.sup.13 SO.sub.2 R.sup.15, --SO.sub.2 NR.sup.12 R.sup.13, --C(O)R.sup.12, --C(O)OR.sup.12, --OC(O)R.sup.12, --NR.sup.13 C(O)OR.sup.15, --NR.sup.13 C(O)R.sup.12, --C(O)NR.sup.12 R.sup.13, --NR.sup.12 R.sup.13, --OR.sup.12, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
each R.sup.10 and R.sup.11 is independently selected from the substituents provided in the definition of R.sup.6 ;
each R.sup.12 is independently selected from H, C.sub.1 -C.sub.10 alkyl, --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkyl), --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
said cycloalkyl, aryl and heterocyclic R.sup.12 groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4-10 membered heterocyclic group;
and the foregoing R.sup.12 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --C(O)R.sup.13, --C(O)OR.sup.13, --OC(O)R.sup.13, --NR.sup.13 C(O)R.sup.14, --C(O)NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, hydroxy, C.sub.1 -C.sub.6 alkyl, and C.sub.1 -C.sub.6 alkoxy;
each R.sup.13 and R.sup.14 is independently H or C.sub.1 -C.sub.6 alkyl, and where R.sup.13 and R.sup.14 are as --(CR.sup.13 R.sup.14).sub.q or (CR.sup.13 R.sup.14).sub.t each is independently defined for each iteration of q or t in excess of 1;
R.sup.15 is selected from the substituents provided in the definition of R.sup.12 except R.sup.15 is not H;
R.sup.16 is selected from the list of substituents provided in the definition of R.sup.12 and --SiR.sup.17 R.sup.18 R.sup.19 ;
R.sup.17, R.sup.18 and R.sup.19 are each independently selected from the substituents provided in the definition of R.sup.12 except R.sup.17, R.sup.18 and R.sup.19 are not H;
and
provided that at least one of R.sup.3, R.sup.4 and R.sup.5 is --(CR.sup.13 R.sup.14).sub.t C.tbd.CR.sup.16 wherein t is an integer from 0 to 5 and R.sup.13, R.sup.14, and R.sup.16 are as defined above.

12 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of the formula 1 ##STR18## 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;
R.sup.1 is selected from H, C.sub.1 -C.sub.10 alkyl, --(CR.sup.13 R.sup.14).sub.q C(O)R.sup.12, --(CR.sup.13 R.sup.14).sub.q C(O)OR.sup.15, --(CR.sup.13 R.sup.14).sub.q OR.sup.12, --(CR.sup.13 R.sup.14).sub.q SO.sub.2 R.sup.15, --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkly), --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.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 R.sup.1 groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4-10 membered heterocyclic group;
and the foregoing R.sup.1 groups, except H but including any optional fused rings referred to above, are optionally substituted by 1 to 4 R.sup.6 groups;
R.sup.2 is halo, cyano, --C(O)OR.sup.15, or a group selected from the substituents provided in the definition of R.sup.12 ;
each R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is independently selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --OR.sup.12, --C(O)R.sup.12, --C(O)OR.sup.12, --NR.sup.13 C(O)OR.sup.15, --OC(O)R.sup.12, --NR.sup.13 SO.sub.2 R.sup.15, --SO.sub.2 NR.sup.12 R.sup.13, --NR.sup.13 C(O)R.sup.12, --C(O)NR.sup.12 R.sup.13, --NR.sup.12 R.sup.13, --CH.dbd.NOR.sup.12, --S(O).sub.j R.sup.12 wherein j is an integer from 0 to 2, --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkyl), and --(CR.sup.13 R.sup.14).sub.t C.tbd.CR.sup.16, and wherein in the foregoing R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 groups t is an integer from 0 to 5;
the cycloalkyl, aryl and heterocyclic moieties of the foregoing groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 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, --NR.sup.13 SO.sub.2 R.sup.15, --SO.sub.2 NR.sup.12 R.sup.13, --C(O)R.sup.12, --C(O)OR.sup.12, --OC(O)R.sup.12, --NR.sup.13 C(O)OR.sup.15, --NR.sup.13 C(O)R.sup.12, --C(O)NR.sup.12 R.sup.13, --NR.sup.12 R.sup.13, --OR.sup.12, C.sub.1 --C.sub.10 alkyl, C.sub.2 -C.sub.10 alkenyl, C.sub.2 -C.sub.10 alkynyl, --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
R.sup.8 is H, --OR.sup.12, --NR.sup.12 R.sup.13, --NR.sup.12 C(O)R.sup.13, cyano, --C(O)OR.sup.13, --SR.sup.12, --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5, or C.sub.1 -C.sub.6 alkyl, wherein said heterocyclic and alkyl moieties are optionally substituted by 1 to 3 R.sup.6 substituents;
R.sup.9 is --(CR.sup.13 R.sup.14).sub.t (imidazolyl) wherein t is an integer from 0 to 5 and said imidazolyl moiety is optionally substituted by 1 or 2 R.sup.6 substituents;
each R.sup.10 and R.sup.11 is independently selected from the substituents provided in the definition of R.sup.6 ;
each R.sup.12 is independently selected from H, C.sub.1 -C.sub.10 alkyl, --(CR.sup.13 R.sup.14).sub.t (C.sub.3 -C.sub.10 cycloalkyl), --(CR.sup.13 R.sup.14).sub.t (C.sub.6 -C.sub.10 aryl), and --(CR.sup.13 R.sup.14).sub.t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5;
said cycloalkyl, aryl and heterocyclic R.sup.12 groups are optionally fused to a C.sub.6 -C.sub.10 aryl group, a C.sub.5 -C.sub.8 saturated cyclic group, or a 4-10 membered heterocyclic group;
and the foregoing R.sup.12 substituents, except H, are optionally substituted by 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, --C(O)R.sup.13, --C(O)OR.sup.13, --OC(O)R.sup.13, --NR.sup.13 C(O)R.sup.14, --C(O)NR.sup.13 R.sup.14, --NR.sup.13 R.sup.14, hydroxy, C.sub.1 -C.sub.6 alkyl, and C.sub.1 -C.sub.6 alkoxy;
each R.sup.13 and R.sup.14 is independently H or C.sub.1 -C.sub.6 alkyl, and where R.sup.13 and R.sup.14 are as --(CR.sup.13 R.sup.14).sub.q or (CR.sup.13 R.sup.14).sub.t each is independently defined for each iteration of q or t in excess of 1;
R.sup.15 is selected from the substituents provided in the definition of R.sup.12 except R.sup.15 is not H;
R.sup.16 is selected from the list of substituents provided in the definition of R.sup.12 and --SiR.sup.17 R.sup.18 R.sup.19 ;
R.sup.17, R.sup.18 and R.sup.19 are each independently selected from the substituents provided in the definition of R.sup.12 except R.sup.17, R.sup.18 and R.sup.19 are not H;
and
provided that at least one of R.sup.3, R.sup.4 and R.sup.5 is --(CR.sup.13 R.sup.14).sub.t C.tbd.CR.sup.16 wherein t is an integer from 0 to 5 and R.sup.13, R.sup.14, and R.sup.16 are as defined above.

16 more elements