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US 2003/0199534 A1Published application
Kinase inhibitors
AssigneeAmgen Inc.
InventorsDavid M. Armistead, Jean E. Bemis, Lucian V. DiPietro, Stephanie D. Geuns-Meyer, Gregory J. Habgood, Joseph L. Kim, Joseph J. Nunes, Vinod F. Patel, Leticia M. Toledo-Sherman
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Abstract
The invention relates to inhibitors of kinases, compositions comprising the inhibitors, and methods of using the inhibitors and inhibitor compositions. The inhibitors and compositions comprising them are useful for treating disease or disease symptoms. The invention also provides for methods of making kinase inhibitor compounds, methods of inhibiting kinase activity, and methods for treating disease or disease symptoms.
Claims29
A compound of the formula:
- 115
- wherein,
- Each R1 and R2 is independently R3;
- R8;
- NHR3;
- NHR5;
- NHR6;
- NR5 R5;
- NR5R6;
- SR5;
- SR6;
- OR5;
- OR6;
- C(O)R3;
- heterocyclyl optionally substituted with 1-4 independent R4 on each ring;
- or C1-C10 alkyl substituted with 1-4 independent R4;
- Each R3 is independently aryl;
- phenyl optionally substituted with 1-4 independent R4;
- or heteroaryl optionally substituted with 1-4 independent R4 on each ring;
- Each m is independently 0, 1, 2 or 3;
- Each n is independently 1 or 2;
- Each X is O or S;
- Each R4 is independently selected from H, C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- aryl;
- R8;
- halo;
- haloalkyl;
- CF3;
- SR5;
- OR5;
- OC(O)R5;
- NR5R5;
- NR5R6;
- COOR5;
- NO2;
- CN;
- C(O)R5;
- C(O)C(O)R5;
- C(O)NR5R5;
- S(O)nR5;
- S(O)nNR5R5;
- NR5C(O)NR5R5;
- NR5C(O)C(O)R;
- NR5C(O)R5;
- NR5(COOR5);
- NR5C(O)R8;
- NR5S(O)nNR5R5;
- NR5S(O)nR5;
- NR5S(O)nR8;
- NR5C(O)C(O)NR5R5;
- NR5C(O)C(O)NR5R6;
- C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8;
- or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R8;
- Each R5 is independently H;
- C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- aryl;
- R9;
- haloalkyl;
- C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R9 groups;
- C3-C10 cycloalkyl substituted with 1-3 independent aryl, R7 or R9 groups;
- or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R9;
- Each R is independently C(O)R5, COOR5, C(O)NR5R5, or S(O)nR5;
- Each R7 is independently halo, CF3, SR10, OR1, OC(O)R10, NR10R10, NR10R1, NR11R11, COOR10, NO2, CN, C(O)R10, OC(O)NR10R10, C(O)NR10R10, N(R10)C(O)R10, N(R10) (COOR10), S(O)nNR10R10;
- Each R8 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted by a substituent independently selected from C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- aryl;
- R9;
- halo;
- sulfuir;
- oxygen;
- CF3;
- SR5;
- OR5;
- OC(O)R5;
- NR5R5;
- NR5R6;
- NR6R6;
- COOR5;
- NO2;
- CN;
- C(O)R5;
- C(O)NR5R5;
- S(O)nNR5R5;
- NR5C(O)NR5R5;
- NR5C(O)R9;
- NR5S(O)nNR5R5;
- NR5S(O)NR9;
- C1 C10 alkyl substituted with 1-3 independent R7, R9 or aryl;
- or C2-C10 alkenyl substituted with 1-3 independent R7, R9 or aryl;
- Each R9 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, 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-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- halo;
- sulfur;
- oxygen;
- CF3;
- SR10;
- OR10;
- NRtR10;
- NR10R11;
- NR1, R11;
- COOR10;
- NO2;
- CN;
- S(O)NR11;
- S(O)nNR10R10;
- C(O)R10;
- or C(O)NR10R10;
- Each R10 is independently H;
- C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- haloalkyl;
- C1-C10 alkyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NR12C(O)R12, N(R12)(COOR12), S(O)nR12R12, or OC(O)R12;
- or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR12, SR12, NR12R12, COOR12, NO2, CN, C(O)R12, C(O)NR12R12, NR12C(O)R12, N(R12)(COOR12), S(O)nNR12R12, or OC(O)R12;
- Each R11 is independently C(O)R10, COOR10, C(O)NR10R10 or S(O)nR10;
- Each R12 is independently H;
- C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- C1-C10 alkyl substituted with 1-3 independent C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NR13C(O)R13, or OC(O)R13;
- or phenyl optionally substituted with 1-3 independent C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C4-C10 cycloalkenyl, halo, CF3, OR13, SR13, NR13R13, COOR13, NO2, CN, C(O)R13, C(O)NR13R13, NR13C(O)R13, or OC(O)R13;
- Each R13 is independently H;
- C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- C1-C10 alkyl optionally substituted with halo, CF3, OR14, SR14, NR14R14, COOR14, NO2, CN;
- or phenyl optionally substituted with halo, CF3, OR14, SR14, NR14R14, COOR14, NO2, CN;
- Each R14 is independently H;
- C1-C10 alkyl;
- C3-C10 cycloalkyl or phenyl;
- Each R15 is independently H;
- CF3;
- CN;
- COOR5;
- or C1-C10 alkyl substituted with 1-3 independent OR5, SR5, or NR5R5;
- Each R is independently H, C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- aryl;
- R8;
- halo;
- haloalkyl;
- CF3;
- COOR5;
- C(O)R5;
- C(O)C(O)R5;
- C(O)NR5R5;
- S(O)nR5:
- S(O)nNR5R4;
- C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8;
- or C2-C10 alkenyl substituted with 1-3 independent aryl, R7 or R8;
- Each R17 is independently H;
- C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- aryl;
- R17;
- halo;
- haloalkyl;
- CF3;
- SR5;
- OR18;
- OC(O)R5;
- NR5R5;
- NR5R6;
- COOR5;
- NO2;
- CN;
- C(O)R5;
- C(O)C(O)R5;
- C(O)NR5R5;
- S(O)nR5;
- S(O)nNR5R5;
- NR5C(O)NR5R5;
- NR5C(O)C(O)R5;
- NR5 C(O)R5;
- NR5 (COOR5);
- NR5C(O)R8;
- NR5S(O)nNR5R5;
- NR5S(O)nR5;
- NR5S(O)nR8;
- NR5C(O)C(O)NR5R5;
- NR5C(O)C(O)NR5R6;
- C1-C10 alkyl substituted with 1-3 independent aryl, R7 or R8;
- or C1-C10 alkenyl substituted with 1-3 independent aryl, R7 or R8;
- Each R18 is independently aryl;
- R8;
- C1-C10 alkyl substituted with 1-3 independent aryl, CF3, OC(O)R10, NHR19, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, OC(O)NR10R10, C(O)NR10R10, N(R10)C(O)R10, N(R10 (COOR10), S(O)nNR10R10, or R8;
- or C2-C10 alkenyl substituted with 1-3 independent aryl, CF3, OC(O)R10, NHR19, NR10R11, NR11R11, COOR10, NO2, CN, C(O)R10, OC(O)NR10R10, C(O)NR10R10, N(R10)C(O)R10, N(R10)(COOR10), S(O)nNR10OR10, or R8;
- Each R19 is independently C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- aryl;
- R9;
- haloalkyl;
- Each R20 is independently NR5R16;
- OR5;
- SR5;
- or halo;
- Each haloalkyl is independently a C1-C10 alkyl substituted with one or more halogen atoms, selected from F, Cl, Br, or I, wherein the number of halogen atoms may not exceed that number that results in a perhaloalkyl group;
- Each aryl is independently a 6-carbon monocyclic, 10-carbon bicyclic or 14-carbon tricyclic aromatic ring system optionally substituted with 1-3 independent C1-C10 alkyl;
- C2-C10 alkenyl;
- C2-C10 alkynyl;
- C3-C10 cycloalkyl;
- C4-C10 cycloalkenyl;
- R9;
- halo;
- haloalkyl;
- CF3;
- OR10;
- SR10;
- NR10R11;
- NR10R11;
- COOR10;
- NO2;
- CN;
- C(O)R10;
- C(O)C(O)R10;
- C(O)NR10R10;
- N(R10)C(O)NR10 R10;
- N(R10)C(O)R;
- N(R10)S(O)R10;
- N(R10)(COOR10);
- NR10C(O)C(O)R10;
- NR10C(O)R9;
- NR10S(O)nNR10R10;
- NR10S(O)nR9;
- NR12C(O)C(O)NR12R2;
- S(O)n10;
- S(O)nNR10R10;
- OC(O)R10;
- C1-C10 alkyl substituted with 1-3 independent R9, halo, CF3, OR10, SR10, OC(O)R10, NR11R11, NR10R10, NR10R11, COOR10, NO2, CN, C(O)R10, OC(O)NR10R10, C(O)NR10R10, N(R10)C(O)R10, N(R10) (COOR10), S(O)nNR10R10;
- R10;
- or C2-C10 alkenyl substituted with 1-3 independent R9, halo, CF3, OR10, SR10, OC(O)R10, NR11R11, NR10R10, NR10R11, COOR10, NO2, CN, C(O)R10, OC(O)NR10R10, C(O)NR10R10, N(R10)C(O)R10, N(R10) (COOR10), S(O)nNR10R10;
- Each heterocyclyl is independently a 5-8 membered nonaromatic monocyclic, 8-12 membered nonaromatic bicyclic, or 11-14 membered nonaromatic tricyclic, ring system comprising 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S;
- Each heteroaryl is independently a 5-8 membered aromatic monocyclic, 8-12 membered aromatic bicyclic, or 11-14 membered aromatic tricyclic ring system comprising 1-4 heteroatoms if monocyclic, 1-8 heteroatoms if bicyclic, or 1-10 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S.
258 more elements
Dependencies are inferred from the claim text.