US 2004/0176385 A1Published application

Small molecule PI 3-kinase inhibitors and methods of their use

AssigneeChiron Corporation

InventorsJohn N. Nuss, Sabina Pecchi, Paul A. Renhowe

Life of this patent

Estimating the term…

Abstract

Compounds having formula I are provided where the variables have the values described herein. 1 Pharmaceutical formulations include the compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier and combinations with other agents. A method of treating a patient comprises administering a pharmaceutical formulation according to the invention to a patient in need thereof.

Claims37

Dependent claims

A compound having the formula I:

238
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
239
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
240
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and r is 0, 1, or 2;
with the proviso that when X is O, then Y is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;
with the proviso that when W is morpholino, thiomorpholino, 1-oxidothiomorpholino, 1,1-dioxido morpholino, piperazino, or N-substituted piperazino, R2 is morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, or N′-[acetyl(alkanoyl of 1 to 3 carbon atoms)]piperazino, and X is NH, then Y is not hydrogen, alkyl of 1 to 3 carbon atoms, cyclohexyl, phenyl, chloro-phenyl, carboxy-phenyl, carbomethoxy-phenyl, or pyridyl;
with the proviso that when W is morpholino, thiomorpholino, 1-oxidothiomorpholino, 1,1-dioxido morpholino, piperazino, or N-substituted piperazino, R2 is morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, or N′-[acetyl(alkanoyl of 1 to 3 carbon atoms)]piperazino, and X is a direct link, then Y is not phenyl, substituted or unsubstituted C1-C6-alkyl, or 1-oxidothiomorpholino;
and
with the proviso that when R2 is phenyl independently substituted with one to five substituents selected from hydrogen, cycloalkyl, heterocycloalkyl, halo, nitro, amino, sulphonamido, or alkylsulphonylamino, R1 is hydrogen, haloalkyl, alkyl, or halo, and X is NR1x, then Y is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

74 more elements

A composition, comprising a pharmaceutically acceptable carrier and an amount of a compound effective to inhibit phosphotidylinositol (PI) 3-kinase activity in a human or animal subject when administered thereto, wherein the compound has the formula I:

281
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
282
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
283
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

70 more elements

A method for treating a condition by modulation of phosphotidylinositol (PI) 3-kinase activity comprising administering to a human or animal subject in need of such treatment an effective amount of a compound having the formula I:

284
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
285
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
286
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

70 more elements

A method for inhibiting phosphotidylinositol (PI) 3-kinase activity in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound effective to inhibit phosphotidylinositol (PI) 3-kinase activity in the human or animal subject, wherein the compound has the formula I:

287
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
288
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
289
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

70 more elements

A method for treating a cancer disorder in a human or animal subject, comprising administering to the human or animal subject a composition comprising an amount of a compound effective to inhibit phosphotidylinositol (PI) 3-kinase activity in the human or animal subject, wherein the compound has the formula I:

290
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
291
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
292
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

70 more elements

A method for inhibiting tumor growth in a human or animal subject, comprising administering to the human or animal subject in need thereof an effective amount of a compound having the formula I:

293
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
294
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
295
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

70 more elements

A method for inhibiting the proliferation of capillaries in a human or animal subject, comprising administering to the human or animal subject in need thereof an effective amount of a compound having the formula I:

296
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
297
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
298
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

70 more elements

302
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
303
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl, (g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
304
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

69 more elements

A compound for use in the treatment of cancer, wherein the compound has the formula I:

299
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
300
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
301
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

70 more elements

Use of a compound in the manufacture of a medicament for the treatment of cancer, wherein the compound has the formula I:

305
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
306
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
307
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and
r is 0, 1, or 2.

70 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/719,896Filed 21 Nov 2003
Priority: 21 Nov 2002
Published: 9 Sep 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 239/42
One oxygen, sulfur or nitrogen atom: one nitrogen atom
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 239/47
Two or more oxygen, sulphur or nitrogen atoms: one nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Family

Application60/428,473Us provisional application · filed 21 Nov 2002
Application60/438,568Us provisional application · filed 7 Jan 2003
Application60/523,081Us provisional application · filed 19 Nov 2003
US 7,423,148 B2Related patent
US 2004/0176385 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Citations

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Abstract

A compound having the formula I:

238
or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein
Y is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) substituted or unsubstituted C2-C6-alkenyl,
(3) substituted or unsubstituted C2-C6-alkynyl,
(4) substituted or unsubstituted aryl,
(5) substituted or unsubstituted heterocyclyl, and
(6) substituted or unsubstituted heteroaryl;
X is selected from the group consisting of
(1) a direct link,
(2) —N(R1x)—,
(3) —(CH2)m—C(R2x, R3x)—N(R1x)—,
(4) —O—,
(5) —S—,
(6) —SO—,
(7) —SO2—,
(8) —C(R2x, R3x)—, and
(9)
239
wherein R1x, R2x, and R3x are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted C2-C6-alkenyl,
(d) substituted or unsubstituted C2-C6-alkynyl,
(e) substituted or unsubstituted aryl,
(f) substituted or unsubstituted heterocyclyl,
(g) substituted or unsubstituted heteroaryl;
and
m is 0, 1, 2, 3, or 4;
R1 is selected from the group consisting of
(1) H,
(2) substituted or unsubstituted C1-C6-alkyl,
(3) —COOH,
(4) halo,
(5) —OR1t, and
(6) —NHR1t,
wherein R1t is H or C1-C6-alkyl;
R2 is selected from the group consisting of
(1) substituted or unsubstituted aryl,
(2) substituted or unsubstituted heteroaryl, and
(3) substituted or unsubstituted heterocyclyl;
and
W is selected from the group consisting of
(1) substituted or unsubstituted C1-C6-alkyl,
(2) —N(R1w, R2w), and
(3)
240
wherein R1w and R2w are selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocyclyl, and
(e) substituted or unsubstituted heteroaryl, wherein R1w and R2w are not both H;
Z is selected from the group consisting of
(a) —O—,
(b) —NRz—,
(c) —S—,
(d) —SO—,
(e) —SO2—, and
(f) —CH2—,
wherein Rz is H or substituted or unsubstituted alkyl group;
and
R4w is selected from the group consisting of
(a) H,
(b) substituted or unsubstituted C1-C6-alkyl,
(c) —COOR5w,
(d) —CONH2,
(e) —OR5w, and
(f) —NHR5w,
wherein R5w is H or C1-C6-alkyl;
and r is 0, 1, or 2;
with the proviso that when X is O, then Y is substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl;
with the proviso that when W is morpholino, thiomorpholino, 1-oxidothiomorpholino, 1,1-dioxido morpholino, piperazino, or N-substituted piperazino, R2 is morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, or N′-[acetyl(alkanoyl of 1 to 3 carbon atoms)]piperazino, and X is NH, then Y is not hydrogen, alkyl of 1 to 3 carbon atoms, cyclohexyl, phenyl, chloro-phenyl, carboxy-phenyl, carbomethoxy-phenyl, or pyridyl;
with the proviso that when W is morpholino, thiomorpholino, 1-oxidothiomorpholino, 1,1-dioxido morpholino, piperazino, or N-substituted piperazino, R2 is morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, or N′-[acetyl(alkanoyl of 1 to 3 carbon atoms)]piperazino, and X is a direct link, then Y is not phenyl, substituted or unsubstituted C1-C6-alkyl, or 1-oxidothiomorpholino;
and
with the proviso that when R2 is phenyl independently substituted with one to five substituents selected from hydrogen, cycloalkyl, heterocycloalkyl, halo, nitro, amino, sulphonamido, or alkylsulphonylamino, R1 is hydrogen, haloalkyl, alkyl, or halo, and X is NR1x, then Y is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl.

74 more elements

Facts

Application

10/719,896Filed 21 Nov 2003

Priority

21 Nov 2002

Published

9 Sep 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 239/42
One oxygen, sulfur or nitrogen atom: one nitrogen atom
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07D 239/47
Two or more oxygen, sulphur or nitrogen atoms: one nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Family

Application60/428,473Us provisional application · filed 21 Nov 2002

Application60/438,568Us provisional application · filed 7 Jan 2003

Application60/523,081Us provisional application · filed 19 Nov 2003

US 7,423,148 B2Related patent

US 2004/0176385 A1This patent

From the US filing history. Foreign family members aren’t listed.