Compounds useful as inhibitors of ATR kinase
The present invention relates to compounds useful as inhibitors of ATR protein kinase. The invention relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating of various diseases, disorders, and conditions using the compounds of this invention; processes for preparing the compounds of this invention; intermediates for the preparation of the compounds of this invention; and solid forms of the compounds of this invention. The compounds of this invention have formula I-A or I-B: wherein the variables are as defined herein.
1. A solid form of a compound of formula I-1:
wherein the form is crystalline Compound I-1 anhydrous form A.
2. A crystal form of a compound I-1:
having a monoclinic crystal system, a P21/c centrosymmetric space group, and the following unit cell parameters:
a=15.29(3)Å α=90°
b=12.17(2)Å β=107.22(3)°
c=14.48(3)Å γ=90°.
3. A process for preparing Compound I-1•anhydrous form A:
comprising stirring a suspension containing Compound I-1•ethanol solvate and tetrahydrofuran, and removing at least a portion of the ethanol and the tetrahydrofuran.
4. A process for preparing Compound I-1•anhydrous form A:
comprising stirring a suspension containing Compound I-1•amorphous, isopropanol, and water; and removing at least a portion of the water and the isopropanol.
5. The solid form of claim 1 , characterized by three or more peaks expressed in 2-theta±0.2 at about 6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.
6. The solid form of claim 1 , characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 c.
7. The solid form of claim 1 , characterized as having three or more peaks corresponding to 175.9±0.3 ppm, 138.9±0.3 ppm, 74.1±0.3 ppm, 42.8±0.3 ppm, and 31.5±0.3 ppm in a 13 C ssNMR spectrum.
8. The solid form of claim 1 , characterized as having peaks corresponding to −136.8±0.3 ppm and −155.7±0.3 ppm in an 19 F ssNMR spectrum.
9. A solid form of a compound of formula I-1:
wherein the form is crystalline Compound I-1 hydrate I.
10. The solid form of claim 9 , characterized by three or more peaks expressed in 2-theta±0.2 at about 6.5, 12.5, 13.7, 18.8, and 26.0 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.
11. The solid form of claim 10 , wherein the crystalline compound I-1•hydrate I has a Compound I-1 to H 2 O ratio of about 1:4.5.
12. The solid form of claim 9 , characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 b.
13. A solid form of a compound of formula I-1:
wherein the form is crystalline Compound I-1 anhydrous form B.
14. The solid form of claim 13 , characterized by three or more peaks expressed in 2-theta±0.2 at about 7.2, 8.3, 12.9, 19.5, and 26.6 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.
15. The solid form of claim 13 , characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 d.
16. The solid form of claim 13 , characterized as having three or more peaks corresponding to 173.4±0.3 ppm, 164.5±0.3 ppm, 133.5±0.3 ppm, 130.8±0.3 ppm, 67.7±0.3 ppm, 45.3±0.3 ppm, and 25.9±0.3 ppm in a 13 C ssNMR spectrum.
17. The solid form of claim 13 , characterized as having peaks corresponding to −138.0±0.3 ppm and −153.5±0.3 ppm in an 19 F ssNMR spectrum.
18. A solid form of a compound of formula I-1
wherein the form is crystalline Compound I-1 anhydrous form C.
19. The solid form of claim 18 , characterized by three or more peaks expressed in 2-theta±0.2 at about 6.8, 13.4, 15.9, 30.9, and 32.9 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.
20. The solid form of claim 18 , characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 e.
21. The solid form of claim 18 , characterized as having three or more peaks corresponding to 175.2±0.3 ppm, 142.5±0.3 ppm, 129.6±0.3 ppm, 73.5±0.3 ppm, 54.0±0.3 ppm, and 46.7±0.3 ppm in a 13 C ssNMR spectrum.
22. The solid form of claim 18 , characterized as having peaks corresponding to −131.2±0.3 ppm and −150.7±0.3 ppm in an 19 F ssNMR spectrum.
23. A solid form of a compound of formula I-1:
wherein the form is crystalline Compound I-1 DMSO solvate.
24. The solid form of claim 23 , characterized by three or more peaks expressed in 2-theta±0.2 at about 8.9, 14.8, 16.5, 18.6, 20.9, 22.2, and 23.4 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.
25. The solid form of claim 24 , wherein the crystalline compound I-1•DMSO solvate has a compound I-1 to DMSO ratio of about 1:1.
26. The solid form of claim 23 , characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 g.
27. A solid form of a compound of formula I-1:
wherein the form is crystalline Compound I-1 dimethylacetamide solvate.
28. The solid form of claim 27 , characterized by three or more peaks expressed in 2-theta±0.2 at about 6.0, 15.5, 17.7, 18.1, 20.4, and 26.6 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation.
29. The solid form of claim 28 , wherein the crystalline Compound I-1•dimethylacetamide solvate has a compound I-1 to dimethylacetamide ratio of about 1:1.3.
30. The solid form of claim 27 , characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 h.
31. A solid form of a compound of formula I-1:
wherein the form is crystalline Compound I-1 acetone solvate.
32. The solid form of claim 31 , characterized by three or more peaks expressed in 2-theta±0.2 at about 8.9, 15.5, 15.8, 16.7, 22.3, 25.7, and 29.0 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation.
33. The solid form of claim 32 , wherein the crystalline compound I-1•acetone solvate has a compound I-1 to acetone ratio of about 1:0.44.
34. The solid form of claim 31 , characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 i.
35. A solid form of a compound of formula I-1:
wherein the form is crystalline Compound I-1 isopropanol solvate.
36. The solid form of claim 35 , characterized by three or more peaks expressed in 2-theta±0.2 at about 6.9, 17.1, 17.2, 19.1, 19.6, 23.7, 24.4, and 28.9 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation.
37. The solid form of claim 36 , wherein the crystalline compound I-1•isopropanol solvate has a compound I-1 to isopropanol ratio of about 1:0.35.
38. The solid form of claim 35 , characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 j.
39. A composition comprising,
a) an amount of the solid form of claim 1 in the range of about 5 wt % to about 50 wt % by the total weight of the composition;
b) an amount of one or more lubricants in the range of about 0.1 wt % to about 10 wt % by the total weight of the composition;
c) an amount of one or more disintegrants in the range of about 1 wt % to about 15 wt % by the total weight of the composition; and
d) an amount of one or more fillers in the range of about 10 wt % to about 90 wt % by the total weight of the composition.
40. A composition, comprising:
a) an amount of the solid form of claim 1 of about 10 wt % by the total weight of the composition;
b) an amount of lactose monohydrate of about 28 wt % by the total weight of the composition;
c) an amount of microcrystalline cellulose of about 55 wt % by the total weight of the composition;
d) an amount of croscarmellose sodium of about 5 wt % by the total weight of the composition; and
e) an amount of sodium stearyl fumarate of about 3 wt % by the total weight of the composition.
41. A composition comprising the solid form of claim 1 , wherein at least 90% by weight of Compound I-1 is crystalline Compound I-1 anhydrous form A.
42. The composition of claim 41 , wherein at least 95% by weight of Compound I-1 is crystalline Compound I-1 anhydrous form A.
43. The composition of claim 41 , wherein at least 98% by weight of Compound I-1 is crystalline Compound I-1 anhydrous form A.
44. A pharmaceutical composition comprising the solid form of claim 1 and one or more excipients.
45. A pharmaceutical composition comprising the solid form of claim 9 , and one or more excipients.
46. A pharmaceutical composition comprising the solid form of claim 13 , and one or more excipients.
47. A pharmaceutical composition comprising the solid form of claim 18 , and one or more excipients.
48. A pharmaceutical composition comprising the solid form of claim 23 , and one or more excipients.
49. A pharmaceutical composition comprising the solid form of claim 27 , and one or more excipients.
50. A pharmaceutical composition comprising the solid form of claim 31 , and one or more excipients.
51. A pharmaceutical composition comprising the solid form of claim 35 , and one or more excipients.
52. The solid form of claim 1 , characterized by a weight loss of about 0.96% in a temperature range of about 25° C. to about 265° C.
53. The solid form of claim 9 , characterized by a weight loss of about 14.56% in a temperature range of about 25° C. to about 100° C.
54. The solid form of claim 13 , characterized by a weight loss of about 2.5% in a temperature range of about 25° C. to about 175° C.
55. The solid form of claim 23 , characterized by a weight loss of about 12.44% in a temperature range of about 146° C. to about 156° C.
56. The solid form of claim 27 , characterized by a weight loss of about 17.76% in a temperature range of about 85° C. to about 100° C.
57. The solid form of claim 31 , characterized by a weight loss of about 4.55% in a temperature range of about 124° C. to about 151° C.
58. The solid form of claim 35 , characterized by a weight loss of about 3.76% in a temperature range of about 136° C. to about 180° C.
59. The solid form of claim 1 , wherein the solid form is over 95% (w/w) crystalline Compound I-1 anhydrous form A.
60. The solid form of claim 1 , wherein the solid form is over 98% (w/w) crystalline Compound I-1 anhydrous form A.
61. The solid form of claim 1 , wherein the solid form is over 99% (w/w) crystalline Compound I-1 anhydrous form A.
62. The solid form of claim 59 , wherein the crystalline Compound I-1 anhydrous form A is characterized by three or more peaks expressed in 2-theta±0.2 at about 6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.
63. The solid form of claim 1 , having a monoclinic crystal system, a P21/c centrosymmetric space group.