US 2008/0176833 A1 · DIHYDROPYRIDINE DERIVATIVES AS USEFUL AS PROTEIN KINASE INHIBITORS

Abstract

This invention provides novel dihydropyridine derivatives of the formula I having protein tyrosine kinase inhibitory activity, to process for the manufacture thereof and to the use thereof for the treatment of c-Met-mediated diseases or c-Met-mediated conditions.

Compounds of the formula I

wherein,
R1 is hydrogen, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted hydroxyalkyl, or optionally substituted alkoxyalkyl;
R2 is selected from the groups:
in which
A and B are each independently C—R11 or N;
D and E are each independently N—R12, O, or S;
W, X, Y, and Z are each independently C—R11, C—R14, or N;
n=1, 2 or 3;
R3 is hydrogen, cyano, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
R4 is haloalkyl, R7, R7-aminocycloalkyl, R7-aminocycloalkenyl, aryl, heteroaryl, —(CH2)mNR8R9, or —C(═O)OR8,
R5 is hydrogen, optionally substituted aralkyl, optionally substituted hydroxyalkyl, R7, —C(═O)OR8, —CH2C(═O)NR8R9, or —(CH2)mNR8R9;
or
R4 and R5 together form an alkylene bridge;
R6 is C1-3alkyl or amino;
R7 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl;
R8 is hydrogen or optionally substituted alkyl;
R9 is hydrogen, or optionally substituted alkyl;
R10 is hydrogen, hydroxy, halo, amino, —C(═O)OR8, —CH(═NOR8), —NR8R9, optionally substituted alkyl, or optionally substituted aryl;
R11 in each instance is independently hydrogen, halo, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, —C(═O)OR8, —C(═O)NR8R9, —CH(═NOR8), —NHC(═O)R7, —NHC(═O)NHR7, —NHC(═O)OR7, —NHR7, —N═CHR7, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;
R12 is hydrogen, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, —C(═O)OR8, —C(═O)NR8R9, —CH(═NOR8), —NHC(═O)R7, —NHC(═O)NHR7, —NHC(═O)OR7, —NHR7, —N═CHR7, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl;
R14 in each instance is independently hydrogen, halo, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, —C(═O)OR8, —C(═O)NR8R9, —CH(═NOR8), —NHC(═O)R7, —NHC(═O)NHR7,
—NHC(═O)OR7, —NHR7, —N═CHR7, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, or —R16—C(═O)N(R15)2;
R15 in each instance is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, where each of the above substituents may be optionally substituted as defined herein;
R16 in each instance is independently a direct bond or a straight or branched alkylene or alkenylene chain, where each of the above substituents may be optionally substituted as defined herein;
m is 0, 1, 2, 3 or 4;
provided that, when R1 and R5 are hydrogen, R3 is cyano, and R4 and R6 are methyl, then R2 cannot be 4-hydroxyphenyl;
or their pharmaceutically acceptable derivatives or salts.

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Dihydropyridine derivatives as useful as protein kinase inhibitors

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Dihydropyridine derivatives as useful as protein kinase inhibitors

Life of this patent

Abstract

Claims27