Pyrrolotriazine derivatives useful for treating cancer through inhibition of aurora kinase

1. A compound having the formula (I):

or a physiologically acceptable salt or stereoisomer thereof, wherein:

R 1 is -(C 1 -C 4 )alkyl, -(C 1 -C 4 )alkyl-CF 3 , -(C 3 -C 6 )cycloalkyl, or -(C 2 -C 4 )alkyl-NR 5 R 6 ;

R 2 is hydrogen or -(C 1 -C 4 )alkyl;

R 3 is halogen;

R 4 is methyl or ethyl; and

R 5 and R 6 , may be the same or different, and are independently hydrogen, methyl, ethyl, or R 5 and R 6 may be taken together with the nitrogen to which they are bound to form a pyrrolidine ring.

2. The compound of claim 1 , wherein R 1 is methyl, ethyl, n-propyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, 2,2,2-trifluoroethyl, or 2-(dimethylamino)-ethyl.

3. The compound of claim 1 , wherein R 2 is hydrogen.

4. The compound of claim 1 , wherein R 3 is fluorine or chlorine.

5. The compound of claim 1 , wherein R 3 is fluorine or chlorine and R 4 is methyl or ethyl.

6. The compound of claim 1 , which is a salt of formula (I).

7. The compound of claim 6 , wherein the salt is an acetate, an adipate, an alginate, an ascorbate, an aspartate, a benzoate, a benzenesulfonate, a bis(benzenesulfonate), a bisulfate, a butyrate, a bis(maleate), a fumarate, a hemi-fumarate, a citrate, a camphorate, a camphorsulfonate, a cinnamate, a cyclopentanepropionate, a digluconate, a dodecylsulfate, a ethanesulfonate, a fumarate, a glucoheptanoate, a glycerophosphate, a hemisulfate, a heptanoate, a hexanoate, a hydrochloride, a hydrobromide, a hydroiodide, a 2-hydroxyethanesulfonate, an itaconate, a lactate, a maleate, a mandelate, a methanesulfonate, a 2-naphthalenesulfonate, a nicotinate, a nitrate, an oxalate, a pamoate, a pectinate, a persulfate, a 3-phenylpropionate, a picrate, a pivalate, a propionate, a succinate, a sulfonate, a bis(methanesulfonate), a tartrate, a thiocyanate, a tosylate, or an undecanoate salt.

8. The compound of claim 7 , wherein the salt is a bis(methanesulfonate), a hydrochloride, a bis(maleate), a hemi-fumarate, a hydrobromide, an oxalate, or a bis(benzenesulfonate) salt.

9. A compound having the IUPAC name:

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-methylpyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-N-ethyl-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide;

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-propylpyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide;

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-isobutylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide;

4-amino-N-cyclopropyl-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)pyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-N-ethyl-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-methylpyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-N-[2-(dimethylamino)ethyl]-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)pyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-N-tert-butyl-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)pyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-N-tert-butyl-5-(4-{[(6-ethylpyridin-2-yl)carbamoyl]amino}-3-fluorophenyl)pyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-5-(4-{[(6-ethylpyridin-2-yl)carbamoyl]amino}-3-fluorophenyl)-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide;

4-amino-5-(3-chloro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-ethylpyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-5-(3-chloro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-propylpyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-5-(3-chloro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-cyclopropylpyrrolo[cyclopropylpyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-5-(3-chloro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-[2-(dimethylamino)ethyl]pyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-5-(3-chloro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyppyrrolo[trifluoroethyppyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

4-amino-5-(3-chloro-4-{[(6-ethylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyppyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide;

or a physiologically acceptable salt or stereoisomer thereof.

10. A salt having the IUPAC name:

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyppyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide dimethanesulfonate;

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyppyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide hydrochloride;

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyppyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide di[(2Z)-but-2-enedioate];

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyppyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide (2E)-but-2-enedioate (2:1);

4-amino-5-(3-fluoro-4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyppyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide hydrobromide;

4-amino-5-(4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1 ,2,4]triazine-6-carboxamide oxalate; or 4-amino-5-(4-{[(6-methylpyridin-2-yl)carbamoyl]amino}phenyl)-N-(2,2,2-trifluoroethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide bisbenzenesulfonate.

11. A pharmaceutical composition comprising a compound according to claim 1 or a physiologically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable diluent or carrier.

12. The pharmaceutical composition of claim 11 wherein the compound is present in a therapeutically effective amount.

13. The pharmaceutical composition of claim 11 further comprising at least one further active compound.

14. A packaged pharmaceutical composition comprising a container, the pharmaceutical composition of claim 11 and instructions for using the pharmaceutical composition to treat cancer of the breast in a mammal.

15. A method of treating cancer of the breast in a mammal comprising administering to a mammal in need thereof, a therapeutically effective amount of one or more compounds of claim 1 .