Processes for making compounds useful as inhibitors of ATR kinase

• US 9,862,709 B2
• Filed: 04/03/2015
• Issued: 01/09/2018
• Est. Priority Date: 09/30/2011
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charrier, Jean-Damien, Studley, John, Pierard, Francoise Yvonne Theodora Marie, Durrant, Steven John, Littler, Benjamin Joseph, Hughes, Robert Michael, Siesel, David Andrew, Angell, Paul, Urbina, Armando, Shi, Yi
• Primary Examiner(s): Mauro, John M
• Application Number:
  US14/678,489
• Publication Number:
  US 20150274710A1
• Time in Patent Office: 1,012 Days
• CPC Class Codes: C07C 251/48 with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 241/20 Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to processes and intermediates for preparing compounds useful as inhibitors of ATR kinase, such as aminopyrazine-isoxazole derivatives and related molecules. The present invention also 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 or II:

wherein the variables are as defined herein.

Claims

1. A solid form of a compound of formula I-2:

25. A pharmaceutical composition comprising a solid form of claim 1 and a pharmaceutically acceptable carrier.

2. A solid form of a compound of formula I-2:

3. The solid form of claim 2, having the following unit cell dimensions in Å

when measured at 120 K;

a=8.9677 (1) Å

b=10.1871 (1) Å

c=24.5914 (3) Å

.

4. The solid form of claim 2, characterized by a weight loss of about 1.9% in a temperature range of from about 25°

C. to about 215°

C. as determined by thermogravimetric (TGA) analysis.

5. The solid form of claim 2, characterized by one or more peaks expressed in 2-theta±

0.2 at about 14.2, 25.6, 18.1, 22.0, and 11.1 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.

26. A pharmaceutical composition comprising a solid form of claim 2 and a pharmaceutically acceptable carrier.

27. The solid form of claim 2, characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1a.

6. A solid form of a compound of formula I-2:

7. The solid form of claim 6, having a monoclinic crystal system and a P2₁/n space group.

8. The solid form of claim 6, characterized by a weight loss of about 1.1% in a temperature range of from about 25°

C. to about 100°

C., and by a further weight loss of about 0.8% in a temperature range of from about 110°

C. to about 240°

C. as determined by thermogravimetric (TGA) analysis.

9. The solid form of claim 6, characterized by one or more peaks expressed in 2-theta±

0.2 at about 13.5, 28.8, 15.0, 18.8, and 15.4 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.

28. The solid form of claim 6, characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1b.

30. The solid form of claim 6, characterized by one or more peaks at about 171.7, 153.4, 132.9, 31.8, and 15.7 ppm in solid state ¹³C NMR.

31. The solid form of claim 6, having the following unit cell dimensions in Å

when measured at 120 K;

a=5.3332 (2) Å

b=35.4901 (14) Å

c=13.5057 (5) Å

.

33. A pharmaceutical composition comprising a solid form of claim 6 and a pharmaceutically acceptable carrier.

10. A solid form of a compound of formula I-2:

11. The solid form of claim 10, wherein the form is crystalline Compound I-2•

2HCl.

12. The solid form of claim 11, characterized by one or more peaks at about 15.1, 18.5, 11.5, 13.1, and 5.7 in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.

13. The solid form of claim 11, having a monoclinic crystal system and having a P2₁/n space group.

14. The solid form of claim 11, characterized by a weight loss of about 7% in a temperature range of from about 25°

C. to about 188°

C. as determined by thermogravimetric (TGA) analysis.

15. The solid form of claim 11, characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1c.

16. The solid form of claim 11, characterized by one or more peaks at about 166.5, 137.6, 136.1, 34.2, and 16.4 ppm in solid state ¹³CNMR.

32. The solid form of claim 11, having the following unit cell dimensions in Å

when measured at 120 K;

a=5.3332 (2) Å

b=35.4901 (14) Å

c=13.5057 (5) Å

.

34. A pharmaceutical composition comprising a solid form of claim 10 and a pharmaceutically acceptable carrier.

17. A solid form of a compound of formula I-2:

18. The solid form of claim 17, wherein the form is crystalline Compound I-2•

2HCl•

H₂O.

19. The solid form of claim 18 characterized by a weight loss of about 2.9% in a temperature range of from about 25°

C. to about 100°

C., and by a further weight loss of about 0.6% in a temperature range of from about 100°

C. to about 222°

C. as determined by thermogravimetric (TGA) analysis.

20. The solid form of claim 18 characterized by one or more peaks at about 6.6, 19.5, 24.7, 8.1, and 11.2 degrees in an X-ray powder diffraction pattern obtained using CuK alpha radiation.

29. The solid form of claim 18, characterized as having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1d.

35. A pharmaceutical composition comprising a solid form of claim 17 and a pharmaceutically acceptable carrier.

21. A solid form of a compound of formula I-2:

22. The solid form of claim 21, wherein the form is crystalline Compound I-2•

HCl•

2H₂O.

23. The solid form of claim 22 characterized by a weight loss of about 6% in a temperature range of from about 25°

C. to about 100°

C. as determined by thermogravimetric (TGA) analysis.

24. The solid form of claim 22 characterized by one or more peaks at about 26.6, 7.6, 6.3, 23.3, and 24.6 degrees in an X-ray powder diffraction pattern obtained using Cu K alpha radiation.

36. A pharmaceutical composition comprising a solid form of claim 21 and a pharmaceutically acceptable carrier.