Imidazopyrrolidinone compounds

Abstract

The invention relates to compounds of formula (I): as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4, and combinations comprising such compounds.

What is claimed is: 
     
         1 . The crystalline form A of 4-[5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile, characterized by a x-ray powder diffraction pattern comprising 4 or more 2 theta values selected from the group consisting of 6.54±0.2, 14.29±0.2, 15.72±0.2, 16.78±0.2, 17.82±0.2, 19.41±0.2, 20.10±0.2°, 20.67±0.2, 23.65±0.2 and 25.82±0.2, at a temperature of about 22° C., in particular 16.78±0.2, 19.41±0.2, 23.65±0.2 and 25.82±0.2. 
     
     
         2 . The crystalline form A of 4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile, characterized by a x-ray powder diffraction pattern comprising 4 or more 2 theta values selected from the group consisting of 6.25±0.2, 10.34±0.2, 14.83±0.2, 15.33±0.2, 15.84±0.2, 19.16±0.2, 19.50±0.2°, 20.94±0.2, 22.32±0.2, 25.05±0.2 and 25.74±0.2, at a temperature of about 22° C. 
     
     
         3 . The crystalline form A (ethanol solvate) of (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one, characterized by a x-ray powder diffraction pattern comprising 4 or more 2 theta values selected from the group consisting of 9.89±0.2, 12.33±0.2, 14.61±0.2, 16.21±0.2, 16.66±0.2, 17.50±0.2, 17.78±0.2, 19.83±0.2, 20.56±0.2, 22.35±0.2, 22.98±0.2° at a temperature of about 22° C. 
     
     
         4 . The crystalline form B (succinic acid co-crystal) of (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one, characterized by a x-ray powder diffraction patter comprising 4 or more 2 theta values selected from the group consisting of 9.04±0.2, 17.27±0.2, 19.52±0.2, 20.85±0.2, 21.14±0.2, 23.42±0.2, 23.67±0.2, 24.54±0.2, 26.95±0.2° at a temperature of about 22° C. 
     
     
         5 . The crystalline form C (hydrate) of (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one, characterized by a x-ray powder diffraction pattern comprising 4 or more 2 theta values selected from the group consisting of 10.09±0.2, 14.52±0.2, 14.88±0.2, 16.93±0.2, 17.56±0.2, 19.18±0.2, 20.46±0.2, 20.87±0.2, 21.86±0.2, 25.00±0.2 25.68±0.2, 28.57±0.2, 32.17±0.2° at a temperature of about 22° C. 
     
     
         6 . The crystalline form A of (S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one, characterized by a x-ray powder diffraction pattern comprising 4 or more 2 theta values selected from the group consisting of 9.98±0.2, 12.56±0.2, 14.58±0.2, 14.95±0.2, 15.55±0.2, 17.08±0.2, 17.44±0.2, 19.72±0.2, 23.83±0.2, 25.78±0.2, 26.26±0.2° at a temperature of about 22° C., in particular 14.58±0.2, 17.08±0.2 and 17.44±0.2. 
     
     
         7 . A method for the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4 comprising the step of administering to a subject a therapeutically effective amount of a compound selected from: (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one; 4-[(S)-5-(3-Chloro-2-fluoro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-3-isopropyl-6-oxo-3,4,5,6-tetrahydro-pyrrolo[3,4-d]imidazol-4-yl]-benzonitrile; (S)-5-(5-Chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one; (S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one; and (S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-d6-pyrimidin-5-yl)-1-((R)-1-methoxypropan-2-yl)-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one.