An Indolinone Derivative As Tyrosine Kinase Inhibitor

摘要

The present invention relates to a compound represented by general formula (I), a method for preparing said compound, a pharmaceutical formulation containing said compound, and the use of said compound in manufacture of a medicament for treating or preventing the fibrous degeneration disease and treating the excessive proliferation disease:;;wherein ring A, X, R1, R2, R3, R4, R5, R6, R7, R8, R9, a, b and n are defined as those in the description.

主权项

1. A compound represented by general formula (I), a pharmaceutically acceptable salt, a deuteride or a stereoisomer thereof: wherein, X represents O or S; R1 represents H or a prodrug group thereof; R2, R4 and R5 each independently represent H, hydroxy, amino, halogen, C1-6alkyl or C1-6alkyloxy; R3 represents H, carboxyl, or C1-6alkyl-OC(O)—, C1-6alkyl-SC(O)—, 3-14-membered cycloalkyl-OC(O)—, carbamoyl, C1-3alkylcarbamoyl, di(C1-3alkyl)carbamoyl, 6-14-membered aryl-OC(O)—, or 6-14-membered aryl(C1-3alkyl)-OC(O)—, which is unsubstituted or substituted by 1-3 groups represented by Q1, Q1 represents halogen, hydroxy, amino, 6-14-membered aryl, 3-14-membered cycloalkyl, 3-14-membered heterocyclyl, carboxyl, C1-3alkyloxy, C1-3alkyloxycarbonyl, C1-3alkylamino, di(C1-3alkyl)amino, carbamoyl, C1-3alkylcarbamoyl or di(C1-3alkyl)carbamoyl; R6 represents H, or C1-6alkyl, 3-14-membered cycloalkyl, 6-14-membered aryl, 7-12-membered bridged ring group-C0-3alkyl, 7-12-membered spiro ring group-C0-3alkyl or 3-14-membered heterocyclylC0-3alkyl, which is unsubstituted or substituted by 1-3 groups represented by Q2, Q2 represents halogen, hydroxy, cyano, carboxyl, amino, nitro, trifluoromethyl, C1-3alkyl, C1-3alkyloxy, hydroxyC1-3alkyl, aminoC1-3alkyl, C1-3alkyloxyC1-3alkyl, carboxylC1-3alkyloxy, C1-3alkylamino, di(C1-3alkyl)amino, C1-3alkyloxycarbonyl, carbamoyl, C1-3alkylcarbamoyl, di(C1-3alkyl)carbamoyl, C1-3alkylcarbonylamino, N-(C1-3alkyl)C1-3alkylcarbonylamino, C1-3alkylsulfonylamino, N-(C1-3alkyl)C1-3alkylsulfonylamino, or 6-14-membered arylC1-3alkylsulfonylamino; R7 represents H, or C1-3alkyl, 3-14-membered cycloalkyl, or 3-14-membered heterocyclyl, which is unsubstituted or substituted by 1-3 groups represented by Q3; Ring A represents phenyl or 5-7-membered heterocyclyl; R8 represents formula (IIa), wherein, Ra, Rb, Rc and Rd each independently represent H, C1-3alkyl, C1-3alkyloxy, amino, C1-3alkylamino, di(C1-3alkyl)amino, phenylamino, N-(C1-3alkyl)phenylamino, benzylamino, or N-(C1-3alkyl)benzylamino, Re represents H, C1-3alkyl, C1-3alkyloxy, amino, C1-3alkylamino, di(C1-3alkyl)amino, phenylamino, N-(C1-3alkyl)phenylamino, benzylamino, N-(C1-3alkyl)benzylamino, phenyl, or 3-8-membered monocyclic heterocyclyl, the carbon atom on the 3-8-membered monocyclic heterocyclyl can be replaced with 1-3 same or different groups selected from S(O)m and C(O), the C1-3alkyl and the 3-8-membered monocyclic heterocyclyl can be substituted by 1-3 groups as represented by Q3; Q3 represents halogen, hydroxy, cyano, carboxyl, amino, nitro, trifluoromethyl, C1-3alkyl, C1-3alkyloxy, di(C1-3alkyl)amino, C1-3alkyloxycarbonyl, carbamoyl, C1-3alkylcarbamoyl, di(C1-3alkyl)carbamoyl or C1-3alkylcarbonylamino; R9 represents H, halogen, hydroxy, cyano, carboxyl, amino, nitro, C1-3alkyl, trifluoromethyl, C1-3alkyloxy, C1-3alkyloxycarbonyl, acetamido, C1-3alkylsulfonylamino, carbamoyl, C1-3alkylcarbamoyl, di(C1-3alkyl)carbamoyl, aminosulfonyl, C1-3alkylaminosulfonyl or di(C1-3alkyl)aminosulfonyl; a and b each independently represent 0, 1, 2 or 3; n represents 0, 1 or 2, when n is 2, the substituents represented by R9 can be identical or different; n1 represents 0, 1, 2 or 3; n2 represents 0 or 1; n3 represents 0, 1, 2 or 3; m represents 1 or 2.