Substituted pyrazin-2-amines as inhibitors of ATR kinase

• US 10,479,784 B2
• Filed: 04/30/2018
• Issued: 11/19/2019
• Est. Priority Date: 12/19/2008
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charrier, Jean-Damien, Durrant, Steven John, Kay, David, Knegtel, Ronald Marcellus Alphonsus, MacCormick, Somhairle, Mortimore, Michael Paul, O'Donnell, Michael Edward, Pinder, Joanne, Rutherford, Alistair, Virani, Anisa Nizarali, Young, Stephen Clinton, Reaper, Philip Michael
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US15/967,110
• Publication Number:
  US 20190047995A1
• Time in Patent Office: 568 Days
• Field of Search: 51425506, 544405
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 241/28 in which said hetero-bound carbon atoms have double bonds to oxygen, sulfur or nitrogen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention relates to pyrazine 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 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 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 I:

wherein the variables are as defined herein.

Claims

1. A compound selected from the group consisting of:

2. The compound of claim 1, wherein the compound is:

3. The compound of claim 1, wherein the compound is:

4. The compound of claim 1, wherein the compound is:

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. A method of sensitizing a cancer cell in a patient to a DNA damaging agent, comprising administering to a patient in need thereof an effective amount of the compound of claim 1.

7. The method of claim 6, wherein the cancer cell expresses a DNA damaging oncogene.

8. The method of claim 7, wherein the cancer cell has altered expression or activity of one or more proteins selected from the group consisting of K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Cyclin E, Cyclin A and Rb.

9. The method of claim 6, wherein the cancer cell has a defect in ataxia telangiectasia mutated signaling cascade.

10. The method of claim 9, wherein the defect is altered expression or activity of one or more proteins selected from the group consisting of ataxia telangiectasia mutated, p53, checkpoint kinase 2, MRE11, RAD50, NBS1, 53BP1, MDC1 and H2AX.