US 8,476,434 B2 · Protein kinase modulators and method of use

Abstract

The present invention relates to chemical compounds having a general formula I wherein A, B, D, E, G, H1-5 and R1-4 are defined herein, and synthetic intermediates, which are capable of modulating various protein kinase receptor enzymes and, thereby, influencing various disease states and conditions related to the activities of these kinases. For example, the compounds are capable of modulating kinase enzymes thereby influencing the process of angiogenesis and treating angiogenesis-related diseases and other proliferative disorders, including cancer and inflammation. The invention also includes pharmaceutical compositions, including the compounds, and methods of treating disease states related to the activity of protein kinases.

A compound of Formula II:

or a stereoisomer, solvate, hydrate or pharmaceutically acceptable salt thereof, wherein
A is N or CR10;
B is N or CR11;
D is N or CR12;
G is NR13, O, S;
R1 is H, halo, haloalkyl, NO2, CN, NR13R13, OR13, SR13, (CHR13)nR13 ;
alternatively R1 taken together with R10 forms a partially or fully unsaturated 5- or 6-membered ring of carbon atoms optionally including 1-3 heteroatoms selected from O, N and S, and the ring optionally substituted independently with 1-3 substituents of R13, halo, haloalkyl, oxo, NO2, CN, SR13, OR13, OC(O)R13, COOR13, C(O)R13, C(O)NR13R13, NR13R13 or NR13R14;
R2 is H, halo, haloalkyl, CN, SR13, OR13, C(O)R13, C1-10alkynyl, C1-10alkynyl, or C3-8cycloalkyl wherein the C1-10alkyl, C1-10alkyenyl, C1-10alkynyl and C3-8cycloalkyl is optionally substituted with one or more substituents of R13;
each of R3 and R4, independently, is H, halo, haloalkyl, CN, SR13, OR13, NR13R13, NR13R14, C(O)R13,
each of R5 and R6, independently, is H, halo, haloalkyl, CN, SR13, OR13, NR13R13, NR13R14, C(O)R13, COOR13, C1-10alkyl, C1-10alkenyl, C1-10alkynyl or C3-8cycloalkyl, wherein the C1-10alkyl, C1-10alkyenyl, C1-10alkynyl and C3-8cycloalkyl is optionally substituted with one or more substituents of R13;
one of R7 and R8 is SR13, OR13, NR13R13, NR13R14, C(O)NR13R13, C(O)NR13R14, NR13C(O)R13, NR13(COOR13), NR13C(O)NR13R13, S(O)2NR13R13, S(O)2NR13R14, NR13S(O)2NR13R13, NR13S(O)2R13, NR13S(O)2R13S(O)2R14, C1-3alkyl optionally substituted with one or more substituents of R15 or R16;
and
the other of R7 and R8 is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO2, NH2, SH, acetyl, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl or C1-10-thioalkoxyl;
each of R9, R10, and R11 , independently, is H, halo, haloalkyl, NO2, CN, C1-4alkyl, C1-4alkoxyl, C1-4alkenyl, C1-4alkynyl or C3-6cycloalkyl;
each R13, independently, is H, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, R15 or R16, each of which is optionally substituted with one or more substituents of R15, R16 or R18;
R14 is C(O)R18, COOR18, S(O)2R18 or R16;
R15 is halo, haloalkyl, NO2, CN, SR18, OR18, OC(O)R18, NR16R18, NR18R18, COOR16, C(O)R16, COOR18, C(O)R18, C(O)NR16R18, C(O)NR18R18, S(O)2NR16R18, S(O)2NR18R18, S(O)2R16, S(O)2R18, C(O)C(O)R18, NR18C(O)NR16R18, NR18C(O)NR18R18, NR18C(O)C(O)R18, NR18C(O)R16, NR18C(O)R18, NR18(COOR16), NR18(COOR18), NR18S(O)2NR16R18, NR18S(O)2NR18R18, NR18S(O)2R18, NR18S(O)2R16, NR18C(O)C(O)NR16R18 or NR18C(O)C(O)NR18R18;
R16 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of R17, R20, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C3-8cycloalkyl or C4-8cycloalkenyl, each of which is optionally substituted with one or more substituents of R17, R18 or R20;
R17 is halo, haloalkyl, oxo, NO2, CN, SR18, OR18, OC(O)R18, NR18R18, NR18R20, COOR18, C(O)R18, COOR20, C(O)R20, C(O)NR18R18, C(O)NR18R20, S(O)2NR18R18, S(O)2NR18R20, S(O)2R18, S(O)2R20, C(O)C(O)R18, NR18C(O)NR18R18, NR18C(O)NR18R20, NR18C(O)C(O)R18, NR18C(O)R18, NR18C(O)R20, NR18(COOR18), NR18(COOR20), NR18S(O)2NR18R18, NR18S(O)2NR18R20, NR18S(O)2R18, NR18S(O)2R20, NR18C(O)C(O)NR18R18 or NR18C(O)C(O)NR18R20;
each R18, independently, is H, C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C3-8cycloalkyl, C4-8cycloalkenyl, R19 or R20, each of which is optionally substituted with 1-3 substituents of R21;
R19, independently, is C(O)R20, C(O)R21, COOR20, COOR21, S(O)2R20 or S(O)2R21;
R20 is a saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, the ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S, wherein 0, 1, 2 or 3 atoms of each ring is optionally substituted independently with 1-3 substituents of C1-10alkyl, C1-10alkenyl, C1-10alkynyl, C3-8cycloalkyl or C4-8cycloalkenyl, each of which is optionally substituted with one or more substituents of R21;
each R21, independently, is H, halo, haloalkyl, haloalkoxyl, oxo, CN, OH, SH, NO2, NH2, acetyl, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl or a saturated or partially or fully unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic, or 7-14 membered tricyclic ring system, said ring system formed of carbon atoms optionally including 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S, wherein each of the C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, C1-10-alkylamino-, C1-10-dialkylamino-, C1-10-alkoxyl, C1-10-thioalkoxyl and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, dipropylamino, diisopropylamino, benzyl or phenyl;
and
n is 0, 1, 2, 3, 4 or 5,
provided that (1) when A is N, then B is not N, and when B is N, then A is not N;
and (2) when either of R1 or R2 is substituted or unsubstituted NH-phenyl, then no more than four of R5, R6, R7, R8 and R9 is H.

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Protein kinase modulators and method of use

Life of this patent

Protein kinase modulators and method of use

Life of this patent

Abstract

Claims9