SUBSTITUTED UREA DERIVATIVES AND PHARMACEUTICAL USES THEREOF

摘要

Provided herein are novel substituted urea derivatives, and pharmaceutical compositions thereof. Also provided herein are uses of the compounds or pharmaceutical compositions thereof for preventing, managing, treating or lessening a proliferative disease, and modulating the activity of protein kinase.

主权项

1. A compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof, wherein each of ring A and ring E is independently C6-10 aryl or C1-12 heteroaryl; each J is -G-(CH2)n—R2; each G is independently —O—, —S(═O)t—, —S—, —C(═O)—, —OC(═O)—, —C(═S)—, —C(═S)—N(R4)— or —(CH2)n—C(═O)—; each R1 and R1a is independently H, F, Cl, Br, cyano, nitro, hydroxy, mercapto, amino, carboxy, C1-4 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C1-4 alkylamino, C1-4 alkyl-C(═O)—NH—, C1-4 alkylthio, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-6 alkoxy-C1-6-alkyl or C1-4 hydroxyalkyl; each R2 is independently —NR3R3a, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, heterocyclyl, alkyl-S(═O)t—, hydroxyalkyl, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkoxyalkyl, alkyl, alkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylamino, heterocyclylalkylaryl, heterocylylalkylheteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, aryl, arylalkyl, heteroarylalkyl, heteroaryl, bridged heterobicyclyl, spiro heterobicyclyl or fused heterobicyclyl; each R3 and R3a is independently C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-6 alkoxy-C1-6-alkyl or C1-4 hydroxyalkyl; each R4 is independently H, C1-4 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-6 alkoxy-C1-6-alkyl or C1-4 hydroxyalkyl; ring K is 5- to 6-membered heteroaryl; each L is independently amino, nitro, C1-4 alkylthio, C1-6 alkyl, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-4 haloalkyl, C1-4 alkylamino, hydroxy, F, Cl, Br, I, C1-4 alkyl-C(═O)—NH—, C1-4 alkoxy, C1-4 hydroxyalkyl or cyano; each a and e is independently 0, 1, 2, 3 or 4; each n, d and b is independently 1, 2, 3 or 4; and each t is independently 0, 1 or 2; wherein optionally each aryl, —(CH2)n—C(═O)—, alkyl-S(═O)t—, hydroxyalkyl, arylalkyl, heteroarylalkyl, heteroaryl, heterocyclyl, bridged heterobicyclyl, spiro heterobicyclyl, fused heterobicyclyl, alkyl, alkoxy, alkoxyalkyl, haloalkyl, alkylamino, hydroxyalkoxy, aminoalkoxy, haloalkoxy, cycloalkylalkyl, heterocyclylalkyl, alkylaminohaloalkoxy, alkylaminoalkoxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylamino, heterocyclylalkylaryl, heterocyclylalkylheteroaryl, cycloalkyloxy, cycloalkylamino, heterocyclylalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryloxyalkoxy, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, fused bicyclyloxy, fused bicyclylalkyl, fused heterobicyclylalkyl, fused heterobicyclyloxy, fused heterobicyclylamino, fused heterobicyclylalkoxy, fused heterobicyclylalkylamino, fused heterobicyclyloxyalkoxy, fused heterobicyclyloxyalkylamino, spiro heterobicyclylalkyl, spiro heterobicyclylalkoxy, bridged heterobicyclylalkyl, bridged heterobicyclyloxy, bridged heterobicyclylalkoxy, bridged heterobicyclylalkylamino, alkyl-C(═O)—NH—, alkylthio and cycloalkyl described in R1, R1a, R2, R3, R3a, A, E, J, G, L and/or K is independently substituted with one or more R2a which are the same or different, and wherein each R2a is independently H, F, Cl, Br, I, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkylamino, di-C1-4 alkylamino, di(C1-4 alkyl)amino, hydroxy, cyano, nitro, —C(═O)—NH2, carboxy, —S(═O)tO—H, —OS(═O)t—H, —S(═O)tNH2, triazolyl, tetrazolyl, —(CR3bR3c)n—NH2, amino, oxo (═O), C1-4 alkyl-C(═O)—, benzyl, phenyl, C1-6 alkyl-S(═O)t—, C1-6 alkoxy-C1-6-alkyl, C1-4 alkyl-C(═O)—NH—, C1-4 alkoxy, C1-4 hydroxyalkyl or C1-4 alkylthio; and each R3b and R3c is independently H, F, Cl, Br, cyano, nitro, hydroxy, mercapto, amino, carboxy, C1-4 alkyl, C1-4 haloalkyl, C1-6 alkoxy, C3-10 cycloalkyl, C2-10 heterocyclyl, C1-6 alkoxy-C1-6-alkyl or C1-4 hydroxyalkyl.