Alkynyl and azido-substituted 4-anilinoquinazolines
DC
First Claim
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1. A compound of the formula ##STR7## or a pharmaceutically acceptable salt thereof wherein:
- X is halo or hydroxy;
m is 1, 2, or 3;
each R1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C1 -C4 alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH;
or each R1 is independently selected from R9 and C1 -C4 alkyl substituted by cyano, wherein R9 is selected from the group consisting of R5, --OR6, --NR6 R6, --C(O)R7, --NHOR5, --OC(O)R6, cyano, A and --YR5 ;
R5 is C1 -C4 alkyl;
R6 is independently hydrogen or R5 ;
R7 is R5, --OR6 or --NR6 R6 ;
A is selected from piperidino, morpholino, pyrrolidino, 4-R6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C1 -C4 alkylene)(CO2 H), phenoxy, phenyl, phenylsulfanyl, C2 -C4 alkenyl, and -(C1 -C4 alkylene)C(O)NR6 R6 ; and
Y is S, SO, or SO2 ;
wherein the alkyl moieties in R5, --OR6 and --NR6 R6 are optionally substituted by one to three halo substituents and the alkyl moieties in R5, --OR6 and --NR6 R6 are optionally substituted by 1 or 2 R9 groups, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R9, with the proviso that two heteroatoms are not attached to the same carbon atom;
or each R1 is independently selected from --NHSO2 R5, phthalimido-(C1 -C4) -alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10 -(C2 -C4) -alkanoylamino wherein R10 is selected from halo, --OR6, C2 -C4 alkanoyloxy, --C(O)R7, and --NR6 R6 ; and
wherein said --NHSO2 R5, phthalimido-(C1 -C4 -alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10 -(C2 -C4)-alkanoylamino R1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1 -C4 alkyl, cyano, methanesulfonyl and C1 -C4 alkoxy;
or two R1 groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N;
R2 is hydrogen or C1 -C6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C1 -C4 alkoxy, --NR6 R6, and --SO2 R5 ;
n is 1 or 2 and each R3 is independently selected from hydrogen, halo, hydroxy, C1 -C6 alkyl, --NR6 R6, and C1 -C4 alkoxy, wherein the alkyl moieties of said R3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C1 -C4 alkoxy, --NR6 R6, and --SO2 R ; and
,R4 is azido or -(ethynyl)-R11 wherein R11 is hydrogen or C1 -C6 alkyl optionally substituted by hydroxy, --OR6, or --NR6 R6.
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Abstract
The invention relates to compounds of the formula ##STR1## and to pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, n and m are as defined herein. The compounds of formula I are useful in the treatment of hyperproliferative diseases, such as cancer. The invention further relates to processes of making the compounds of formula I and to methods of using such compounds in the treatment of hyperproliferative diseases.
555 Citations
32 Claims
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1. A compound of the formula ##STR7## or a pharmaceutically acceptable salt thereof wherein:
- X is halo or hydroxy;
m is 1, 2, or 3; each R1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C1 -C4 alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH; or each R1 is independently selected from R9 and C1 -C4 alkyl substituted by cyano, wherein R9 is selected from the group consisting of R5, --OR6, --NR6 R6, --C(O)R7, --NHOR5, --OC(O)R6, cyano, A and --YR5 ;
R5 is C1 -C4 alkyl;
R6 is independently hydrogen or R5 ;
R7 is R5, --OR6 or --NR6 R6 ;
A is selected from piperidino, morpholino, pyrrolidino, 4-R6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C1 -C4 alkylene)(CO2 H), phenoxy, phenyl, phenylsulfanyl, C2 -C4 alkenyl, and -(C1 -C4 alkylene)C(O)NR6 R6 ; and
Y is S, SO, or SO2 ;
wherein the alkyl moieties in R5, --OR6 and --NR6 R6 are optionally substituted by one to three halo substituents and the alkyl moieties in R5, --OR6 and --NR6 R6 are optionally substituted by 1 or 2 R9 groups, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R9, with the proviso that two heteroatoms are not attached to the same carbon atom;or each R1 is independently selected from --NHSO2 R5, phthalimido-(C1 -C4) -alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10 -(C2 -C4) -alkanoylamino wherein R10 is selected from halo, --OR6, C2 -C4 alkanoyloxy, --C(O)R7, and --NR6 R6 ; and
wherein said --NHSO2 R5, phthalimido-(C1 -C4 -alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10 -(C2 -C4)-alkanoylamino R1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1 -C4 alkyl, cyano, methanesulfonyl and C1 -C4 alkoxy;or two R1 groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N; R2 is hydrogen or C1 -C6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C1 -C4 alkoxy, --NR6 R6, and --SO2 R5 ; n is 1 or 2 and each R3 is independently selected from hydrogen, halo, hydroxy, C1 -C6 alkyl, --NR6 R6, and C1 -C4 alkoxy, wherein the alkyl moieties of said R3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C1 -C4 alkoxy, --NR6 R6, and --SO2 R ; and
,R4 is azido or -(ethynyl)-R11 wherein R11 is hydrogen or C1 -C6 alkyl optionally substituted by hydroxy, --OR6, or --NR6 R6. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)
- X is halo or hydroxy;
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17. A process for preparing a compound of the formula ##STR8## or a pharmaceutically acceptable salt or prodrug thereof, wherein:
- m is 1, 2, or 3;
each R1 is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and -(C1 -C4 alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH; or each R1 is independently selected from R9 and (C1 -C4)-alkyl substituted by cyano, wherein R9 is selected from the group consisting of R5, --OR6, --NR6 R6, --C(O)R7, --NHOR5, --OC(O)R6, cyano, A and --YR5 ;
R5 is C1 -C4 alkyl;
R6 is independently hydrogen or R5 ;
R7 is R5, --OR6 or --NR6 R6 ;
A is selected from piperidino, morpholino, pyrrolidino, 4-R6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, -(C1 -C4 alkylene)(CO2 H), phenoxy, phenyl, phenylsulfanyl, C2 -C4 alkenyl, and --(C1 -C4 alkylene)C(O)NR6 R6 ; and
Y is S, SO, or SO2 ;
wherein the alkyl moieties in R5, --OR6 and --NR6 R6 are optionally substituted by one to three substituents independently selected from halo and R9, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R9, with the proviso that two heteroatoms are not attached to the same carbon atom, and with the further proviso that no more than three R9 groups may comprise a single R1 group;or each R1 is independently selected from --NHSO2 R5, phthalimido-(C1 -C4)-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R10 -(C2 -C4)-alkanoylamino wherein R10 is selected from halo, --OR6, C2 -C4 alkanoyloxy, --C(O)R7, and --NR6 R6 ; and
wherein the foregoing R1 groups are optionally substituted by 1 or 2 substituents independently selected from halo, C1 -C4 alkyl, cyano, methanesulfonyl and C1 -C4 alkoxy;or two R1 groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N; R2 is hydrogen or C1 -C6 alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C1 -C4 alkoxy, --NR6 R6, and --SO2 R5 ; n is 1 or 2 and each R3 is independently selected from hydrogen, halo, hydroxy, C1 -C6 alkyl, --NR6 R6, and C1 -C4 alkoxy, wherein the alkyl moieties of said R3 groups are optionally substituted by 1 to 3 substituents independently selected from halo, C1 -C4 alkoxy, --NR6 R6, and --SO2 R5 ; and
,R4 is azido or -(ethynyl)-R11 wherein R11 is hydrogen or C1 -C6 alkyl optionally substituted by hydroxy, --OR6, or --NR6 R6 ; which comprises a) treating a compound of the formula ##STR9## wherein R1 and m are as defined above, with CCl4 and (C6 -C10 aryl)3 P, optionally supported on an inert polymer, wherein the aryl moieties of said (C6 -C10 aryl)3 P are optionally substituted by C1 -C6 alkyl; and b) treating the product of step a) with a compound of the formula ##STR10## wherein R2, R3 and n are as defined above, and J is Y or R4, wherein R4 is as defined above and wherein Y is NH2, Br, I or trifluoromethanesulfonyloxy, with the proviso that when J is Y then the product of step b) must further be treated with an alkyne where Y is Br, I or trifluoromethanesulfonyloxy, or an azide where Y is NH2. - View Dependent Claims (18, 19, 20, 21)
- m is 1, 2, or 3;
Specification
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Litigation Data
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Current AssigneeOSI Pharmaceuticals LLC (Astellas Pharma Incorporated), Oncogene Science, Inc. (Bayer AG), Pfizer Inc.
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Original AssigneePfizer Inc.
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InventorsSchnur, Rodney Caughren, Arnold, Lee Daniel
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Primary Examiner(s)Grumbling, Matthew V.
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Application NumberUS08/653,786Time in Patent Office707 DaysField of Search544/283, 544/293, 514/259US Class Current514/266.4CPC Class CodesA61P 17/06 AntipsoriaticsA61P 35/00 Antineoplastic agentsC07D 231/12 with only hydrogen atoms, h...C07D 233/56 with only hydrogen atoms or...C07D 239/94 Nitrogen atomsC07D 249/08 1,2,4-Triazoles; Hydrogenat...C07D 401/12 linked by a chain containin...C07D 403/12 linked by a chain containin...C07D 491/04 Ortho-condensed systems
