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US 7,115,617 B2Granted
Amino-substituted pyrimidinyl derivatives and methods of use
AssigneeAmgen Inc.
InventorsJohn L. Buchanan, Stuart Chaffee, Jean-Christophe Harmange, Perry M. Novak, Xiaotian Zhu
Life of this patent
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Abstract
The invention encompasses compounds, analogs, prodrugs and pharmaceutically acceptable derivatives thereof, pharmaceutical compositions, uses and methods for prophylaxis and treatment of cancer.
Claims29
A compound of Formula I
- wherein R1 is isoxazolyl, wherein R1 is optionally substituted with 1–2 substituents independently selected from R3;
- wherein R2 is selected from R4 and phenyl optionally substituted with 1–4 substituents independently selected from R3;
- wherein R3 is independently selected from C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, R4, chloro, fluoro, bromo, trifluoromethyl, C1-4-alkoxy, phenoxy, heterocyclyloxy, benzyloxy, C1-4-alkylcarbonyloxy, amino, alkylamino, phenylamino, carboxy, C1-4-alkoxycarbonyl, nitro, cyano, C1-4-alkylcarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, C1-4-alkylsulfonyl, C1-4-alkylaminosulfonyl, benzyl, C1-4-alkoxyalkyl, C1-4-aminoalkyl, C1-4-alkylaminoalkyl, and 5–6-membered heterocyclyl-C1-4-alkyl;
- wherein R4 is independently a 6 membered monocyclic, or 8–10 membered bicyclic saturated, partially saturated or unsaturated ring system comprising 1–3 heteroatoms if monocyclic, 1–6 heteroatoms if bicyclic, said heteroatoms independently selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-4-alkyl, halo, C1-6-haloalkyl, oxo, OR5, NR5R5, COOR5, nitro, cyano, S(O)nR5, S(O)nNR5R5, C(O)R5 and C(O)NR5R5;
- and
- wherein R5 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, —CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, nitro, cyano, C1-4-alkylcarbonyl, C1-4-alkylamnocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- or a pharmaceutically acceptable salt thereof.
4 more elements
A compound of Formula II
- wherein R10 is selected from phenyl, and 6–10 membered heterocyclyl;
- wherein R10 is optionally substituted with 1–2 substituents selected from R11;
- wherein R11 is selected from C1–C4 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, C3–C6 cycloalkyl, C4–C6 cycloalkenyl, phenyl, 5–6 membered heterocyclyl, fluoro, chloro, CF3, —OR12, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, C1–C3 alkyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- and
- C2–C3 alkenyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, —CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, nitro, cyano, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- or a pharmaceutically acceptable salt thereof.
4 more elements
A compound of Formula III
- wherein R10 is selected from phenyl, and 5–10 membered heterocyclyl;
- wherein R10 is optionally substituted with 1–2 substituents selected from R11;
- wherein R11 is selected from C1–C4 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, C3–C6 cycloalkyl, C4–C6 cycloalkenyl, phenyl, 5–6 membered heterocyclyl, fluoro, chloro, CF3, —OR12, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, C1–C3 alkyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- and
- C2–C3 alkenyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, nitro, cyano, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- or a pharmaceutically acceptable salt thereof.
4 more elements
A compound of Formula I′
- wherein R1 is isoxazolyl, where R1 is optionally substituted with 1–3 substituents independently selected from R3;
- wherein R2 is selected from R4 and aryl optionally substituted with 1–3 substituents independently selected from R3;
- wherein R3 is independently selected from C1-4-alkyl, C2-4-alkenyl, C2-4-alkynyl, phenyl, C6-10-cycloalkyl, R4, chloro, fluoro, bromo, trifluoromethyl, C1-4-alkoxy, phenoxy, heterocyclyloxy, benzyloxy, C1-4-alkylcarbonyloxy, amino, alkylamino, phenylamino, carboxy, C1-4-alkoxycarbonyl, nitro, cyano, C1-4-alkylcarbonyl, aminocarbonyl, C1-4-alkylaminocarbonyl, C1-4-alkylsulfonyl, C1-4-alkylaminosulfonyl, benzyl, C1-4-alkoxyalkyl, C1-4-aminoalkyl, C1-4-alkylaminoalkyl, and 5–6-membered heterocyclyl-C1-4-alkyl;
- wherein R4 is independently 2,3-dihydro-indolyl, 1,3-benzodioxolyl, indolyl, 1,3-dioxo-isoindolyl, indazolyl, quinolyl, isoquinolyl, benzothiazolyl, 1,2,3-benzotriazolyl, benzimidazolyl, and pyridyl;
- wherein R4 is optionally substituted with hydroxy, C1-3-alkoxy, cyano, nitro, halo, C1-3-alkyl, di-C1-3-alkylamino, di-C1-3-alkylamino-C1-3-alkyl, di-C1-3-alkylamino-C1-3-alkoxy, C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl, C1-3-alkylcarbonylamino, pyrrolidinylcarbonyl-C2-3-alkenyl, pyrrolidinylcarbonyl-C1-3-alkyl, pyrrolidinyl-C1-3-alkyl, C2-3-alkynyl, acetyl, C1-3-alkylcarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl, (piperidinyl)-C1-3-alkoxy, (piperazinyl)-C1-3-alkoxy, 2-morpholinyl-C1-3-alkoxy, C1-3-haloalkyl, C1-3-haloalkoxy, aminocarbonyl, aminosulfonyl, C1-3-alkylaminosulfonyl, hydroxy-C1-3-alkylaminosulfonyl, (thiazolyl)aminosulfonyl, C1-4-alkylaminosulfonyl, C1-3-alkylcarbonylaminosulfonyl, C1-3-alkylsulfonyl, C1-3-alkoxycarbonyl-piperazinyl, morpholinyl, C1-3-alkylpiperzinyl, piperazinyl, C1-3-alkyl-piperazinyl, and oxazolyl;
- or a pharmaceutically acceptable salt thereof.
3 more elements
A compound of Formula II′
- wherein R10 is selected from 3,4,5-trimethoxyphenyl, 3,4-dimethoxy-6-methylphenyl, 3-methoxy-4-morpholinylphenyl and 5-indazolyl;
- wherein R11 is selected from C1–C4 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, C3–C10 cycloalkyl, C4–C6 cycloalkenyl, phenyl, 5–6 membered heterocyclyl, fluoro, chloro, CF3, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, —OR13, C1–C3 alkyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- and
- C2–C3 alkenyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- and
- wherein R13 is selected from H, C1-6-alkyl, amino-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, aminocarbonyl-C1-6-alkyl, C1-6-alkylaminocarbonyl-C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- or a pharmaceutically acceptable salt thereof;
- provided.
6 more elements
A compound of Formula III′
- wherein R10 is selected from phenyl, and 5–10 membered heterocyclyl;
- wherein R10 is optionally substituted with 1–2 substituents selected from R11;
- wherein R11 is selected from C1–C4 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, C3–C10 cycloalkyl, C4–C6 cycloalkenyl, phenyl, 5–6 membered heterocyclyl, fluoro, chloro, CF3, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, —OR13, C1–C3 alkyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- and
- C2–C3 alkenyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- and
- wherein R13 is selected from H, C1-6-alkyl, amino-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, aminocarbonyl-C1-6-alkyl, C1-6-alkylaminocarbonyl-C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- and pharmaceutically acceptable salts thereof;
- provided R10 is not 5-t-butyl-3-isoxazolyl when R11 is t-butyl;
- or a pharmaceutically acceptable salt thereof.
8 more elements
A compound of Formula IV
- wherein R10 is selected from phenyl, and 5–10 membered heterocyclyl;
- wherein R10 is optionally substituted with 1–2 substituents selected from R11;
- wherein R11 is selected from C1–C4 alkyl, C2–C3 alkenyl, C2–C3 alkynyl, C3–C10 cycloalkyl, C4–C6 cycloalkenyl, phenyl, 5–6 membered heterocyclyl, fluoro, chloro, CF3, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, —OR13, C1–C3 alkyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- and
- C2–C3 alkenyl substituted with 1–3 substituents independently selected from optionally substituted phenyl and optionally substituted 5–6 membered heterocyclyl;
- wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- and
- wherein R13 is selected from H, C1-6-alkyl, amino-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, aminocarbonyl-C1-6-alkyl, C1-6-alkylaminocarbonyl-C1-6-alkyl, and phenyl optionally substituted with 1–3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
- or a pharmaceutically acceptable salts thereof.
6 more elements
Dependencies are inferred from the claim text.