COMPOUNDS AND COMPOSITIONS AS PROTEIN KINASE INHIBITORS

摘要

The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of the Abl, BCR-Abl, CSK, JNK1, JNK2, PDGF-R, p38, p70S6K, TGF.beta., SRC, EGFR, c-Kit, trkB, FGFR3, Fes, Lck, Syk, RAF, MKK4, MKK6 and SAPK2.beta. kinases. The novel class of compounds relates to a compound of Formula I: (see formula I) in which: n is 0, 1 or 2; Y is selected from -C(H)= and -N=; Z is selected from -C(H)= and N=; R1 is selected from hydrogen, halo and -R4; R2 is selected from hydrogen and C1-6alkyl; R3 is selected from halo, nitro, C1-6alkyl and C1-6alkoxy; R4 is selected from C3-8heterocycloalkyl, - NR5R6, -XNR5C(O)R6, --XC(O)NR5R6 and -XNR5S(O)0-2R6; wherein X is a bond or C1-4alkylene; R5 is selected from hydrogen and C1-6alkyl; R6 is selected from C1-6alkyl, C6-10aryl-C0-4alkyl, C5-10heteroaryl-C0-4alkyl, C3-12cycloalkyl-C0-4alkyl and C3-8heterocycloalkyl-C0-4alkyl; wherein any aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R4 is optionally substituted by 1 to 3 radicals independently selected from halo, hydroxy, nitro, cyano, C1-6alkyl optionally substituted with hydroxy, C1-6alkoxy, halo-substituted-C1-6alkyl, halo-substituted-C1-6alkoxy, --XOXNR7R8, -XS(O)0-2R7, -XS(O)0-2NR7R8, -XOR7, -XC(O)NR7R8, XNR7R8, -XNR7S(O)0-2R7 and -XR9; wherein X is a bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-6alkyl; R9 is selected from C6-10aryl, C5-10heteroaryl C3--12cycloalkyl and C3-8heterocycloalkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R9 is optionally substituted with 1 to 3 C1-6alkyl radicals; R10 is selected from hydrogen, halo and C1-6alkyl; or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof.