Inhibitors of tyrosine kinases

1. A compound of formula I wherein

R 1 represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, or benzyl;

R 2 represents phenyl substituted by one or two substituents selected from the group consisting of lower alkyl, trifluoro-lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkylamino-lower alkyl, di-lower alkylamino-lower alkyl, N-cyclohexyl-N-lower alkylamino-lower alkyl, lower alkoxycarbonylpiperidino-lower alkyl, N-lower alkylpiperazino-lower alkyl, lower alkoxycarbonyl-lower alkyl, hydroxy, lower alkoxy, trifluoro-lower alkoxy, 1H-imidazolyl-lower alkoxy, lower alkanoyloxy, benzoyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, amino, lower alkanoylamino, benzoylamino, amino mono- or disubstituted by lower alkyl, by hydroxy-lower alkyl or by loweralkoxy-lower alkyl, 1H-imidazolyl, lower alkyl-1H-imidazolyl, carboxy-1H-imidazolyl, lower alkyl-estercarboxy-1H-imidazolyl, pyrrolidino, piperidino, piperazino, N-lower alkylpiperazino, morpholino, sulfamoyl, lower alkylsulfonyl, phenyl, pyridyl, halogenyl, or benzoyl; and

R 4 represents hydrogen, lower alkyl or halo;

or a N-oxide or pharmaceutically acceptable salts thereof.

2. A compound of formula I according to claim 1 wherein

R 1 represents hydrogen;

R 2 represents phenyl substituted by trifluoremethyl and optionally a further substituent selected from the group consisting of hydroxy-lower alkyl, lower alkylamino, hydroxy-lower alkylamino, di-lower alkylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, pyrrolidino, piperidino, piperazino, lower alkylpiperazino, morpholino, lower alkoxy, trifluoro-lower alkoxy, phenyl, pyridyl, and halogenyl;

R 4 represents methyl;

or a N-oxide or pharmaceutically acceptable salts thereof.

3. A compound of formula I according to claim 1 wherein

R 1 represents hydrogen;

R 2 represents phenyl substituted by 3-trifluoromethyl and optionally a further substituent selected from the group consisting of 1-hydroxy-1-methylethyl, methylamino, ethylamino, 2-hydroxy-1-propylamino, 2-hydroxy-2-propylamino, diethylamino, 1H-imidazolyl, 2- and 4-methyl-1H-imidazolyl, carbamoyl, methylcarbamoyl, pyrrolidino, piperidino, piperazino, 4-methylpiperazino, morpholino, methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, phenyl, 2-, 3- and 4-pyridyl, chloro, and fluoro;

R 4 represents methyl;

or a N-oxide or pharmaceutically acceptable salts thereof.

4. The compound of formula I according to claim 1 wherein

R 1 represents hydrogen;

R 2 represents 3-(1-hydroxy-1-methylethyl)-5-(trifluoromethyl)phenyl;

R 4 represents methyl;

or a N-oxide or pharmaceutically acceptable salts thereof.

5. A compound according to claim 1 wherein

R 1 is hydrogen;

R 2 represents phenyl which is mono- or disubstituted by imidazol-lower alkoxy, lower alkyl amino, trifluoromethyl, hydroxy lower alkyl amino, bis-(lower alkoxy lower alkyl) amino, lower alkyl piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridyl, imidazolyl which is unsubstituted or mono- or disubstituted by lower alkyl or N-lower alkyl carbamoyl;

R 4 is lower alkyl;

or a N-oxide or pharmaceutically acceptable salts thereof.

6. A compound of formula I according to claim 1 wherein

R 1 represents hydrogen;

R 2 represents phenyl substituted by 3-trifluoromethyl and a further substituent selected from the group consisting of 2-methyl-1H-imidazolyl and 4-methyl-1H-imidazolyl;

R 4 represents methyl;

or a N-oxide or pharmaceutically acceptable salts thereof.

7. A compound of formula I according to claim 1 wherein

R 1 represents hydrogen;

R 2 represents phenyl substituted by 5-trifluoromethyl and optionally a further substituent selected from the group consisting of 2,4-dimethyl-1H-imidazolyl, 5-methyl-1H imidazolyl, 2-methoxymethylamino, propoxy, ethoxy, methylaminocarbonyl, benzoyl, 4-methoxy-2-methyl, acetylamino 2,4-dimethyl-1H-imidazolyl, acetic acid ethyl ester, piperidine carboxylic acid ethyl ester;

R 4 represents methyl;

or a N-oxide or pharmaceutically acceptable salts thereof.

8. 4-Methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol1yl)-3-(trifluoromethyl)phenyl]benzamide or an N-oxide or pharmaceutically acceptable salts thereof.

9. A process for the synthesis of a compound of the formula

or an N-oxide or a salt thereof, wherein the symbols R 1 , R 2 and R 4 are as defined in claim 1 , characterized in that a compound of formula II

wherein R 4 is as defined for a compound of formula I, wherein the carboxyl group —COOH is in activated form, is reacted with an amine of the formula III

R 1 —NH—R 2   (III)

wherein R 1 and R 2 are as defined for a compound of the formula I, optionally in the, presence of a dehydrating agent and an inert base and/or a suitable catalyst, and optionally in the presence of an inert solvent;

where the above starting compounds II and III may also be present with functional groups in protected form if necessary and/or in the form of salts, provided a salt-forming group is present and the reaction in salt form is possible;

any protecting groups in a protected derivative of a compound of the formula I are removed;

and, if so desired, an obtainable compound of formula I is converted into another compound of formula I or a N-oxide thereof, a free compound of formula I is converted into a salt, an obtainable salt of a compound of formula I is converted into the free compound or another salt,

and/or a mixture of stereoisomeric compounds of formula I is separated into the individual stereoisomers.

10. A pharmaceutical composition comprising as an active ingredient a compound of formula I according to claim 1 or a N-oxide or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier.

11. A method for the treatment of leukaemias which comprises administering a compound of formula I according to claim 1 or a N-oxide or a pharmaceutically acceptable salt thereof.