Compounds useful as inhibitors of ATR kinase

• US 9,334,244 B2
• Filed: 05/12/2011
• Issued: 05/10/2016
• Est. Priority Date: 05/12/2010
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charrier, Jean-Damien, Durrant, Steven John, Knegtel, Ronald Marcellus Alphonsus, Virani, Anisa Nizarali, Reaper, Philip Michael
• Primary Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US13/106,184
• Publication Number:
  US 20120122884A1
• Time in Patent Office: 1,825 Days
• Field of Search: 514/255.05, 514/255.06, 544/405, 544/407
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 239/46 Two or more oxygen, sulphur or nitrogen atoms
• CPC Class Codes: C07D 241/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to pyrazine and pyridine compounds useful as inhibitors of ATR protein kinase. The invention also relates to pharmaceutically acceptable compositions comprising the compounds of this invention; methods of treating 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 methods of using the compounds in in vitro applications, such as the study of kinases in biological and pathological phenomena; the study of intracellular signal transduction pathways mediated by such kinases; and the comparative evaluation of new kinase inhibitors.

The compounds of this invention have formula IV:

wherein the variables are as defined herein.

Claims

1. A compound of formula IV:

2. The compound of claim 1, wherein R³ is methyl.

3. The compound of claim 1, wherein R³ is H.

4. The compound of claim 2, wherein n is 0.

5. The compound of claim 4, wherein R¹ is isoxazolyl or oxadiazolyl.

6. The compound of claim 5, wherein R¹ is isoxazolyl.

7. The compound of claim 6, wherein R¹ is optionally substituted with one occurrence of J¹.

11. The compound of claim 2, wherein n is 1.

12. The compound of claim 11, wherein L is C(O)NH and R¹ is phenyl.

13. The compound of claim 1, wherein R³ is methyl or H;

n is 0 or 1;

L is CONH;

R¹ is isoxazolyl or phenyl;

J¹ is phenyl optionally substituted with one occurrence of CH₂NHCH₃; and

R² is phenyl optionally substituted with SO₂(C_1-4alkyl).

14. The compound of claim 1 selected from the following:

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

16. A method for inhibiting ATR in a patient comprising administering a compound of claim 1 or a pharmaceutically acceptable derivative thereof.

17. The method of claim 16, further comprising administering to said patient an additional therapeutic agent selected from a DNA-damaging agent;

wherein said additional therapeutic agent is appropriate for a disease being treated;

and said additional therapeutic agent is administered together with said compound as a single dosage form or separately from said compound as part of a multiple dosage form.

18. The method of claim 17, wherein said DNA-damaging agent is selected chemotherapy or radiation treatment.

19. A method of inhibiting ATR in a biological sample comprising contacting a compound of claim 1 with said biological sample.

8. The compound of 7, wherein J¹ is —

(V²)_m-Q³.

9. The compound of claim 8, wherein J¹ is phenyl.

10. The compound of claim 9, wherein J¹ is phenyl optionally substituted with one occurrence of CH₂NHCH₃.