Processes for preparing ATR inhibitors

• US 10,208,027 B2
• Filed: 12/20/2017
• Issued: 02/19/2019
• 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:
  US15/849,241
• Publication Number:
  US 20180244662A1
• Time in Patent Office: 426 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 compound of formula II:

2. The compound of claim 1, wherein each of R^1a, R^1b, and R^1c is deuterium.

3. The compound of claim 1, wherein R² is deuterium.

4. The compound of claim 1, wherein each of R^3a, R^3b, and R^3c is deuterium.

5. The compound of claim 1, wherein each of R^1a, R^1b, R^1c, R^3a, R^3b, and R^3c is deuterium.

6. The compound of claim 1, wherein each of R^1a, R^1b, R^1c, R², R^3a, R^3b, and R^3c is deuterium.

7. The compound of claim 1, wherein at least one of R^9a and R^9b is deuterium.

8. The compound of claim 1, wherein each of R^9a and R^9b is deuterium.

9. The compound of claim 1, wherein at least one of R¹⁰, R¹¹, and R¹² is deuterium.

10. The compound of claim 1, wherein at least two of R¹⁰, R¹¹, and R¹² is deuterium.

11. The compound of claim 1, wherein each of R¹⁰, R¹¹, and R¹² is deuterium.

12. The compound of claim 1, wherein each of R^9a, R^9b, R¹⁰, R¹¹, and R¹² is deuterium.

13. The compound of claim 1, wherein at least one of R⁴, R⁵, R⁶, R⁷, and R⁸ is deuterium.

14. The compound of claim 7, wherein at least one of R⁴, R⁵, R⁶, R⁷, and R⁸ is deuterium.

15. The compound of claim 9, wherein at least one of R⁴, R⁵, R⁶, R⁷, and R⁸ is deuterium.

16. The compound of claim 7, wherein R² is deuterium.

17. The compound of claim 9, wherein R² is deuterium.

18. The compound of claim 1, selected from the group consisting of:

19. The compound of claim 18, selected from the group consisting of compounds II-1, II-2, II-3, and II-4.

20. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.