# US 10,478,430 B2 · Compounds useful as inhibitors of ATR kinase and combination therapies thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 10,478,430 B2 - Document ID: US10478430B2 - Status: Granted - Kind: B2 - Application number: 14/816,432 - Filed: 2015-08-03 - Published: 2016-02-04 - Granted: 2019-11-19 - Earliest claimed: 2012-04-05 - Assignees: Vertex Pharmaceuticals Incorporated - Applicants: Vertex Pharmaceuticals Incorporated - Inventors: John Robert Pollard; Philip Michael Reaper; Mohammed Asmal - Web page: https://patentgrep.com/patent/US10478430B2 ## CPC - A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin - A61K 31/4965: Non-condensed pyrazines - A61K 31/497: containing further heterocyclic rings - A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole - A61K 33/243: Platinum; Compounds thereof - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like - A61P 17/06: Antipsoriatics - A61P 35/00: Antineoplastic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 413/04: directly linked by a ring-member-to-ring-member bond - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## 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 ### Claim 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: or a pharmaceutically acceptable salt thereof; and a poly(ADP-ribose) polymerase (PARP) inhibitor, wherein the PARP inhibitor is Rucaparib and wherein the cancer is selected from the group consisting of melanoma, lung cancer, osteosarcoma, ovarian cancer, colorectal cancer, and breast cancer. ### Claim 2 (depends on 1) The method of claim 1, wherein the cancer is lung cancer. ### Claim 3 (depends on 2) The method of claim 2, wherein the lung cancer is non-small cell lung cancer. ### Claim 4 (depends on 1) The method of claim 1, wherein the cancer is ovarian cancer. ### Claim 5 (depends on 1) The method of claim 1, wherein the cancer is breast cancer. ### Claim 6 (depends on 5) The method of claim 5, wherein the breast cancer is triple negative breast cancer. ### Claim 7 (depends on 1) The method of claim 1, wherein the cancer is colorectal cancer. ### Claim 8 (depends on 1) The method of claim 1, wherein the compound VE-822, or the pharmaceutical salt thereof, and the PARP inhibitor are co-administered. ### Claim 9 (depends on 1) The method of claim 1, wherein the compound VE-822, or the pharmaceutical salt thereof, and the PARP inhibitor are administered sequentially. ### Claim 10 (depends on 1) 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. ### Claim 11 (depends on 10) 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. ### Claim 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: or a pharmaceutically acceptable salt thereof; and a poly(ADP-ribose) polymerase (PARP) inhibitor selected from the group consisting of Olaparib, Veliparib (ABT-888), Rucaparib, MK-4827, and BMN673. ### Claim 13 (depends on 12) The method of claim 12, wherein the lung cancer is non-small cell lung cancer. ### Claim 14 (depends on 12) The method of claim 12, wherein the compound VE-822, or the pharmaceutical salt thereof, and the PARP inhibitor are co-administered. ### Claim 15 (depends on 12) The method of claim 12, wherein the compound VE-822, or the pharmaceutical salt thereof, and the PARP inhibitor are administered sequentially. ### Claim 16 (depends on 12) 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. ### Claim 17 (depends on 12) The method of claim 12, wherein the PARP inhibitor is Olaparib. ### Claim 18 (depends on 12) The method of claim 12, wherein the PARP inhibitor is Veliparib (ABT-888). ### Claim 19 (depends on 12) The method of claim 12, wherein the PARP inhibitor is MK-4827. ### Claim 20 (depends on 12) The method of claim 12, wherein the PARP inhibitor is BMN673.