6-pyrimidin-isoindole derivative as ERK1/2 inhibitor

1. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide, having the formula (1):

or a tautomeric form thereof, in a substantially crystalline form.

2. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 55% crystalline.

3. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 having an X-ray powder diffraction pattern characterised by the presence of major peaks at the diffraction angles 14.0° and/or 20.6° and/or 24.0° and/or 24.2° (±0.2°).

4. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 having an X-ray power diffraction pattern characterised by the presence of major peaks at the diffraction angles and interplanar spacing set forth in Table A:

TABLE A

Diffraction Angle (°)

Relative Intensity

14.0

100

20.6

85

24.0

74

24.2

71.

5. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 4 wherein the X-ray powder diffraction pattern is further characterised by the presence of one or more additional peaks at the diffraction angles and interplanar spacings set forth in Table B.

TABLE B

Diffraction Angle (°)

Relative Intensity

8.8

23

13.0

23

13.8

39

14.4

20

17.3

22

19.3

36

21.3

45

28.7

22.

6. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which exhibits peaks at substantially the same diffraction angles as those of the X-ray powder diffraction pattern shown in FIG. 2 .

7. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 having an X-ray powder diffraction pattern substantially as shown in FIG. 2 .

8. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which exhibits an endothermic event having an onset temperature between 100° C. to 110° C. when subjected to differential scanning calorimetry.

9. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which exhibits an endothermic event having a peak between 110° C. and 125° C. when subjected to differential scanning calorimetry.

10. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which exhibits a weight loss between 85° C. and 130° C. when subjected to thermogravimetric analysis.

11. A process for making a substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 ; which method comprises:

(i) forming an aqueous suspension of an acid addition salt of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide and stirring the suspension at a temperature of between 25° C. and 75° C. for a period of time sufficient to allow disproportionation of the acid addition salt and formation of the crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide to occur, and thereafter isolating the crystalline form; or

(ii) forming an aqueous suspension of an amorphous form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide, wherein the aqueous suspension is unbuffered or is buffered to a pH of from 1.75 to 7.25, and stirring the aqueous suspension at a temperature of between 25° C. and 55° C. for a period of time sufficient to allow conversion of the amorphous form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide to the crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide to occur, and thereafter isolating the crystalline form.

12. A process for making (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide, which process comprises:

a) reacting a compound of formula (5):

with a compound of formula (6)

to give a compound of formula (2):

and:

b) reacting the compound of formula (2) with a compound of formula (3):

to give the compound of formula (1):

and thereafter optionally forming a salt or crystalline form thereof.

13. A pharmaceutical composition comprising (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide and a vehicle selected from:

a C 2-4 alcohol;

a polyether compound;

mono-esters of C 8 to C 18 long chain fatty acids with glycerol or propylene glycol;

di- or tri-glycerides of C 8 to C 10 long chain fatty acids;

and mixtures thereof; and optionally a non-ionic surfactant.

14. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide in the form of particles having a mass median diameter of between 1 μm and 100 μm.

15. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 8 which exhibits an endothermic event having an onset temperature of 101° C. to 108° C. when subjected to differential scanning calorimetry.

16. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 9 which exhibits an endothermic event having a peak between 111° C. and 113° C. when subjected to differential scanning calorimetry.

17. A substantially crystalline form of (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 10 which exhibits a weight loss at 90-120° C. when subjected to thermogravimetric analysis.

18. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 60% crystalline.

19. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 70% crystalline.

20. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 80% crystalline.

21. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 90% crystalline.

22. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 95% crystalline.

23. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 98% crystalline.

24. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 99% crystalline.

25. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 99.5% crystalline.

26. (2R)-2-(6-{5-chloro-2-[(oxan-4-yl)amino]pyrimidin-4-yl}-1-oxo-2,3-dihydro-1H-isoindol-2-yl)-N-[(1S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl]propanamide according to claim 1 which is at least 99.9% crystalline.