Compounds useful as inhibitors of ATR kinase and combination therapies thereof

• US 10,478,430 B2
• Filed: 08/03/2015
• Issued: 11/19/2019
• Est. Priority Date: 04/05/2012
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Pollard, John Robert, Reaper, Philip Michael, Asmal, Mohammed
• Primary Examiner(s): Ramachandran, Umamaheswari
• Application Number:
  US14/816,432
• Publication Number:
  US 20160030424A1
• Time in Patent Office: 1,569 Days
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to compounds useful as inhibitors of ATR protein kinase and combination therapies thereof. 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 method of treating cancer in a patient, comprising administering to a patient with cancer a therapeutically effective amount of a compound of the following formula:

2. The method of claim 1, wherein the cancer is lung cancer.

3. The method of claim 2, wherein the lung cancer is non-small cell lung cancer.

4. The method of claim 1, wherein the cancer is ovarian cancer.

5. The method of claim 1, wherein the cancer is breast cancer.

6. The method of claim 5, wherein the breast cancer is triple negative breast cancer.

7. The method of claim 1, wherein the cancer is colorectal cancer.

8. The method of claim 1, wherein the compound VE-822, or the pharmaceutical salt thereof, and the PARP inhibitor are co-administered.

9. The method of claim 1, wherein the compound VE-822, or the pharmaceutical salt thereof, and the PARP inhibitor are administered sequentially.

10. The method of claim 1, further comprising administering to the patient a therapeutically effective amount of a DNA damaging agent, wherein the DNA damaging agent is ionizing radiation, cisplatin, carboplatin, etoposide or gemcitabine.

11. The method of claim 10, wherein the DNA damaging agent is administered together with the compound or the pharmaceutical salt thereof as a single dosage form or separately from the compound as part of a multiple dosage form.

12. A method of treating lung cancer in a patient, comprising administering to a patient with lung cancer a therapeutically effective amount of a compound of the following formula:

13. The method of claim 12, wherein the lung cancer is non-small cell lung cancer.

14. The method of claim 12, wherein the compound VE-822, or the pharmaceutical salt thereof, and the PARP inhibitor are co-administered.

15. The method of claim 12, wherein the compound VE-822, or the pharmaceutical salt thereof, and the PARP inhibitor are administered sequentially.

16. The method of claim 12, further comprising administering to the patient a therapeutically effective amount of a DNA damaging agent, wherein the DNA damaging agent is ionizing radiation, cisplatin, carboplatin, etoposide or gemcitabine.

17. The method of claim 12, wherein the PARP inhibitor is Olaparib.

18. The method of claim 12, wherein the PARP inhibitor is Veliparib (ABT-888).

19. The method of claim 12, wherein the PARP inhibitor is MK-4827.

20. The method of claim 12, wherein the PARP inhibitor is BMN673.