4,6-disubstituted pyrimidines and their use as protein kinase inhibitors

1. A compound of formula Ia

in which

R1 is dibenzofuran-4-yl,

R2 is hydrogen,

R3 is —U—Ar2, or —V—Har2, in which

U is a bond,

Ar2 is 3-(R31)-phenyl, 4-(R31)-phenyl, or 2-fluoro-4-(R31)-phenyl, in which

R31 is amidino, or —W—R311, in which

W is methylene, ethylene, or 1,1-dimethyl-methylene,

R311 is —N(R312)R313, in which

R312 is hydrogen, or methyl,

R313 is hydrogen,

V is a bond,

Har2 is 1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-6-yl, or R33-substituted pyridyl, in which

R33 is aminomethyl,

or a salt thereof.

2. A compound according to claim 1 , which is from formula Ia in which

R1 is dibenzofuran-4-yl,

R2 is hydrogen,

R3 is —U—Ar2, in which

U is a bond,

Ar2 is 3-(R31)-phenyl, or 4-(R31)-phenyl, in which

R31 is amidino, or —W—R311, in which

W is methylene,

R311 is —N(R312)R313, in which

R312 is hydrogen,

R313 is hydrogen,

or a salt thereof.

3. A compound according to claim 1 , which is from formula Ia in which

R1 is dibenzofuran-4-yl,

R2 is hydrogen,

R3 is —V—Har2, in which

V is a bond,

Har2 is 1,2,3,4-tetrahydroisoquinolin-7-yl, or 1,2,3,4-tetrahydroisoquinolin-6-yl, 6-(R33)-pyrid-3-yl, 6-(R33)-pyrid-2-yl, 2-(R33)-pyrid-4-yl, 4-(R33)-pyrid-2-yl, or 5-(R33)-pyrid-2-yl, in which

R33 is aminomethyl;

or a salt thereof.

4. A compound according to claim 1 selected from the group consisting of

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-morpholin-4-yl-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-dimethylamino-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-(4-methyl-piperazin-1-ylmethyl)-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-2-(4-dimethyl-amino-phenyl)-acetamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-2-dimethylamino-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-3-pyrrolidin-1-ylbenzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

4-tert-Butyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

3,4-Dichloro-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-3-dimethylamino-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-isonicotinamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-dimethylaminomethyl-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-morpholin-4-ylmethyl-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-(4-methylpiperazin-1-yl)-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-6-morpholin-4-yl-nicotinamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-3-[3-methoxy-1-(2-methoxyethyl)-propyl]-benzamide,

tert-Butyl N-{4-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-benzyl}-carbamate,

tert-Butyl N-{2-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-carbamate,

tert-Butyl N-{3-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-carbamate,

tert-Butyl 3-{4-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-piperidin-1-carboxylate,

tert-Butyl N-(4-{[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-methyl}-phenyl)-carbamate,

tert-Butyl N-{3-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-benzyl}-carbamate,

tert-Butyl N-(2-{4-[4-(6-Dibenzofurane-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]phenyl}-ethyl)-carbamate,

tert-Butyl N-{2-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-pyridin-4-ylmethyl}-carbamate,

tert-Butyl N-{4-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-benzyl}-methyl-carbamate,

tert-Butyl {5-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-pyridin-2-ylmethyl}-carbamate,

tert-Butyl {4-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-pyridin-2-ylmethyl}-carbamate,

tert-Butyl (4-{[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-methyl}-benzyl)-carbamate,

tert-Butyl N-(1-{4-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-1-methyl-ethyl)-carbamate,

tert-Butyl N-(2-{3-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-ethyl)-carbamate,

tert-Butyl {4-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-(2-methoxyethyl)-carbamate,

tert-Butyl N-{4-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-3-fluorobenzyl}carbamate,

tert-Butyl {6-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-pyridin-2-ylmethyl}-carbamate,

tert-Butyl N-{5-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-pyridin-3-ylmethyl}-carbamate,

3-Cyano-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

3-Carbamimidoyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

4-Cyano-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

4-Carbamimidoyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

4-Aminomethyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

2-Amino-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

3-Amino-N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-piperidin-3-yl-benzamide,

2-(4-Amino-phenyl)-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-acetamide,

3-Aminomethyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

4-(2-Amino-ethyl)-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

4-Aminomethyl-pyridin-2-carbonsäure-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-amide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-methylaminomethyl-benzamide,

6-Aminomethyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-nicotinamide,

2-Aminomethyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-isonicotinamide,

2-(4-Aminomethyl-phenyl)-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-acetamide,

1,2,3,4-Tetrahydro-isochinolin-7-carbonsäure-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-amide,

4-(1-Amino-1-methyl-ethyl)-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

3-(2-Amino-ethyl)-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

N-[4-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-(2-methoxyethylamino)benzamide,

4-Aminomethyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-2-fluorobenzamide,

6-Aminomethyl-pyridin-2-carbonsäure-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-amide,

5-Aminomethyl-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-nicotinamide,

3-Amino-N-[4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-2-(3,4-dichloro-phenyl)-propionamide,

5-Aminomethyl-pyridine-2-carboxylic acid [4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-amide,

1,2,3,4-Tetrahydro-isoquinoline-6-carboxylic acid [4-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-amide;

and the salts of these compounds.

5. A compound according to claim 1 selected from the group consisting of

tert-Butyl {4-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-benzyl}-carbamate,

tert-Butyl N-(2-{4-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-ethyl)-carbamate,

tert-Butyl N-{2-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-carbamate,

tert-Butyl {3-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-carbamate,

tert-Butyl N-{3-[3-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-benzyl}-carbamate,

tert-Butyl N-{4-[3-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenylcarbamoyl]-phenyl}-carbamate,

tert-Butyl N-{4-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-4-methyl-phenylcarbamoyl]-benzyl}-carbamate,

N-[3-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-dimethylamino-benzamide,

N-[3-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-4-dimethylaminomethyl-benzamide,

N-[3-(6-Dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-3-dimethylamino-benzamide,

4-Aminomethyl-N-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamid,

4-(2-Amino-ethyl)-N-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

2-Amino-N-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

3-Amino-N-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

3-Aminomethyl-N-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

4-Amino-N-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-benzamide,

4-Aminomethyl-N-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-4-methyl-phenyl]-benzamide,

3-Amino-N-[3-(6-dibenzofuran-4-yl-pyrimidin-4-ylamino)-phenyl]-2-(3,4-dichlorophenyl)-propionamide;

and the salts of these compounds.

6. A pharmaceutical composition comprising one or more compounds according to claim 1 or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutical excipients and/or vehicles.

7. A combination comprising one or more first active ingredient selected from a compound according to claim 1 or a pharmaceutically acceptable salt thereof, and one or more second active ingredient selected from the group consisting of chemotherapeutic anti-cancer agents and target-specific anti-cancer agents, for separate, sequential, simultaneous or chronologically staggered use in therapy to treat or ameliorate a hyperproliferative disease of benign or malignant behaviour and/or a disorder responsive to the induction of apoptosis in a mammal.

8. A method of treating breast cancer in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.