# US 11,110,086 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 11,110,086 B2 - Document ID: US11110086B2 - Status: Granted - Kind: B2 - Application number: 16/507,139 - Filed: 2019-07-10 - Published: 2020-07-16 - Granted: 2021-09-07 - 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/US11110086B2 ## 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 in need thereof a therapeutically effective amount of an ATR inhibitor compound of formula: or a pharmaceutically acceptable salt thereof; and an inhibitor of poly(ADP-ribose) polymerase (PARP) I and/or II, 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 inhibitor of PARP I and/or PARP II is Olaparib, Veliparib, Rucaparib, CEP-9722, INO-1001, MK-4827, E7016, BMN673, or AZD2461. ### Claim 3 (depends on 1) The method of claim 1, wherein the ATR inhibitor is administered concurrently with the inhibitor of PARP 1 and/or PARP II. ### Claim 4 (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 selected from radiation, Cisplatin, Oxaliplatin, Carboplatin, Nedaplatin, Lobaplatin, Triplatin Tetranitrate, Picoplatin, Satraplatin, ProLindac, Aroplatin, Camptothecin, Topotecan, Irinotecan/SN38, Rubitecan, Belotecan, Idarubicin, Amrubicin, Pirarubicin, Valrubicin, Zorubicin, Teniposide, Aminopterin, Methotrexate, Pemetrexed, Raltitrexed, Pentostatin, Cladribine, Clofarabine, Fludarabine, Thioguanine, Mercaptopurine, Fluorouracil, Capecitabine, Tegafur, Carmofur, Floxuridine, Cytarabine, Gemcitabine, Azacitidine, Hydroxyurea, Mechlorethamine, Cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Melphalan, Prednimustine, Bendamustine, Uramustine, Estramustine, Carmustine, Lomustine, Semustine, Fotemustine, Nimustine, Ranimustine, Streptozocin, Busulfan, Mannosulfan, Treosulfan, Carboquone, ThioTEPA, Triaziquone, Triethylenemelamine, Procarbazine, Dacarbazine, etopside, Tern ozolom ide, Altretamine, Mitobronitol, Actinomycin, Bleomycin, Mitomycin or Plicamycin. ### Claim 5 (depends on 4) The method of claim 4, wherein the DNA damaging agent is cisplatin, carboplatin, gemcitabine, camptothecin, topotecan, irinotecan/SN38, rubitecan, belotecan, etoposide, or temozolomide. ### Claim 6 (depends on 4) The method of claim 4, wherein the DNA damaging agent is ionizing radiation. ### Claim 7 (depends on 4) The method of claim 4, wherein the DNA damaging agent is gemcitabine. ### Claim 8 (depends on 4) The method of claim 4, wherein the DNA damaging agent is cisplatin or carboplatin. ### Claim 9 (depends on 4) The method of claim 4, wherein the DNA damaging agent is etoposide. ### Claim 10 (depends on 4) The method of claim 4, wherein the DNA damaging agent is temozolomide. ### Claim 11 (depends on 4) The method of claim 4, wherein the DNA damaging agent is administered sequentially with the ATR inhibitor. ### Claim 12 (depends on 1) The method of claim 1, wherein the cancer is melanoma, lung cancer, ovarian cancer, colorectal cancer or breast cancer. ### Claim 13 (depends on 12) The method of claim 12, wherein the cancer is lung cancer. ### Claim 14 (depends on 13) The method of claim 13, wherein the lung cancer is non-small cell lung cancer. ### Claim 15 (depends on 12) The method of claim 12, wherein the cancer is colorectal cancer. ### Claim 16 (depends on 12) The method of claim 12, wherein the cancer is ovarian cancer. ### Claim 17 (depends on 12) The method of claim 12, wherein the cancer is breast cancer. ### Claim 18 (depends on 17) The method of claim 17, wherein the breast cancer is triple negative breast cancer. ### Claim 19 (depends on 1) The method of claim 1, wherein the cancer has one or more defects in ATM signaling cascade. ### Claim 20 (depends on 19) The method of claim 19, wherein said defect is altered expression or activity of one or more of the following: ATM, p53, CHK2, MRE11, RAD50, NBS1, 53BP1,MDC1, H2AX, MCPH1/BRIT1, CTIP, and SMC1.