2Н-[1,4]oxazino- and 2h-[1,4]thiazinО[3,2-c]quinolin-3(4H)-one derivatives as ATM and DNA-PK kinase inhibitors

Abstract

The invention (I) relates to the chemistry of heterocyclic organic compounds and to pharmaceutical compositions containing same. These compounds and their corresponding pharmaceutical compositions inhibit the activity of ataxia teleangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) serine / threonine protein kinases. The invention further relates to a method for using said compounds and compositions in the treatment and / or prophylaxis of oncological diseases as a monotherapy and / or in combination with radiotherapy, chemotherapy and / or immunotherapy. The technical result lies in the activity of the chemical compounds toward ATM and DNA-PK kinases and an increase in selectivity toward related kinases.

Description

[0001] Derivatives of 2H-[1,4]oxazino- and 2H-[1,4]thiazino[3,2-c]quinolin-3(4H)-ones as inhibitors of ATM and DNA-PK kinases

[0002] The invention relates to the chemistry of heterocyclic organic compounds and their pharmaceutical compositions. These compounds and their pharmaceutical compositions selectively inhibit the activity of ataxia teleangiectasia mutated ("ATM" - mutant protein in ataxia-telangiectasia) and DNA-dependent protein kinase ("DNA-РК" - DNA-dependent protein kinase) serine / threonine protein kinases. In this regard, the invention also relates to a method of using such compounds and their compositions for the treatment and / or prevention of oncological diseases as monotherapy and / or in combination with radiotherapy, chemotherapy and / or immunotherapy.

[0003] Members of the phosphatidylinositol 3-kinase related kinases family

[0004] PIKK), ATM and DNA-PK kinases are important cellular modulators, the activity of which is particularly associated with oxidative stress and DNA damage, especially double-strand breaks. In clinical trials, it was shown that inhibition of the activity of these kinases (either individually or both simultaneously) using small drug molecules significantly increases the sensitivity of tumor cells to ionizing radiation in radiotherapy and the action of some classes of antitumor drugs. At the same time, molecules of this class by themselves do not affect normal cells. Thus, dual ATM and DNA-PK inhibitors in combination with radiotherapy, chemotherapy and / or immunotherapy can be used for the effective treatment of oncological diseases, significantly potentiating the effect of these therapeutic approaches.The use of such molecules allows, in particular, to reduce the dose of radiation or DNA-targeted antitumor drug molecule, thereby reducing unwanted side effects. Therapy of a patient with dual ATM / DNA-PK inhibitors leads to a slowdown or cessation of DNA reparation after radiotherapy. Thus, it is possible to significantly enhance the apoptosis of tumor cells that survive the therapeutic effect.

[0005] For example, mice with mutations in the ATM and PRKDC genes that result in loss of function of the ATM and DNA-PK proteins they encode, respectively, exhibit hypersensitivity to ionizing radiation. It is expected that simultaneous inhibition of ATM and DNA-PK will more effectively sensitize tumor cells to radiation or other DNA-damaging agents than inhibition of either kinase alone. Minimizing off-target inhibition of related kinases such as mTOR or PI3Ks may reduce the toxicity of this class of inhibitors. The present invention provides dual inhibitors of ATM and DNA-PK kinases that do not exhibit pharmaceutically significant inhibitory activity against related kinases (PI3Ka, PI3Kβ, PI3K5, PI3Ky, and mTOR). Such molecules are capable of significantly sensitizing tumor cells to radiation and / or certain chemotherapeutic agents.

[0006] Currently, several small molecule drugs are in early-stage clinical trials as monotherapies (MT), chemo- (CS), and radiosensitizers (PC), including: XRD-0394 (ATM / DNA-PK inhibitor, phase 1, XRad Therapeutics, PC), lartesertib (ATM inhibitor, phase 1, Merck, MT), M-3541 (ATM inhibitor, phase 1, Merck, PC), AZD-1390 (ATM inhibitor, phase I, AstraZeneca, PC+CS), CC-115 (DNA-PK / mTOR inhibitor, phase II, Celgene, MT+PC+CS), BR-101801 (DNA-PK / PI3Ky inhibitor, phase 1, Boryung, MT), M-9831 (DNA-PK inhibitor, phase 1, Merck and Vertex, MT+XC), panulisib (DNA-PK / mTOR / PI3Kα / ALKl inhibitor, phase-1, Piramal Enterprises and Piramal Life Sciences, MT), peposertib (DNA-PK inhibitor, phase-I, Merck, PC+MT+XC). There are no molecules of this class on the pharmaceutical market.These compounds are being tested against cancers including: liposarcoma, brain cancer, glioblastoma, non-small cell lung cancer, head and neck cancer, skin cancer, prostate cancer, chronic lymphocytic leukemia, lymphoma (B- and T-cell), hematologic blood cancers, neuroendocrine cancer, adenocarcinoma, bladder cancer, breast cancer and colorectal cancer. One of the features of some molecules in this class is the ability to penetrate the blood-brain barrier (BBB), for example, AZD-1390, which may lead to the development of CNS-targeted chemo- and radiosensitizers.

[0007] The published application of the Chinese Patent Office No. CN 103936762 A, IPC C07D 498 / 04, A61K 31 / 5383, A61P 35 / 00, A61P 35 / 02, July 23, 2014, discusses the synthesis and results of biological testing for derivatives of N-(5-(3,4-dihydro-2H-[1,4]oxazino[3,2-c]quinolin-9-yl)pyridin-3-yl)sulfonamides as inhibitors of mTOR and PI3K kinases, including their 3'-oxo derivatives. Various esters are indicated as possible substituents at position 2 of the pyridine ring. However, activity towards ATM, DNA-PK and ATR kinases is not provided. In addition, the examples present only 2-methoxy-pyridyl and 2-chloro-pyridyl derivatives. Taking into account that within the framework of the submitted application we have obtained selective ATM inhibitors (1C 50 <10 nM) and DNA-PK (1C 50 <10 nM) that showed no activity against mTOR (IC 50 >l µM, IS макс =2,000) and PI3K isoforms (1C 50 >1 µM, IS макc10,000), it is not obvious that the structures described in the application CN 103936762 A will inhibit the enzymatic activity of ATM, DNA-PK and ATR and vice versa. In our case, it was shown that 4-N-Me (R 3 =Me) and 5-N (Zi=N - cinnoline) derivatives affect the selectivity profile of molecules of this class. In addition, cinnoline derivatives are not declared in CN 103936762 A. The influence of the methyl group on selectivity was previously noted in a series of 1H-imidazo[4,5-c]quinolin-2(3H)-ones (Pike KG et al. J Med Chem 2018; 61 : 3823). For the example molecule (8-(6-(3-(dimethyl amino)propoxy)pyridin-3-yl)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1 H-imidazo[4,5-c]quinolin-2(3H)-one), the following activities were obtained (1C 50 μM): 0.00004 (ATM), 0.14 (DNA-PK), 0.20 (mTOR), 0.32 (PI3Kα), 1.8 (PI3Kβ), 1.1 (PI3Ky) and 0.27 (PI3K5). Despite the high activity against ATM kinase, the molecule relatively strongly inhibited the activity of mTOR, PI3Ka and PI3K5.

[0008] Published international application No. WO 2020052688 A1, IPC C07D 487 / 04, A61K 31 / 5025, A61P 35 / 00, 19.03.2020, presents derivatives of 8-(pyridin-3-yl)-III-imidazo[4,5-c]cinnolin-2(3H )-ones as selective ATM kinase inhibitors. In particular, it was shown that cinnoline analogues substituted with fluorine at position 7 in the 8-(pyridin-3-yl)-1 R-imidazo[4,5-c]cinnolin-2(3H )-one substructure selectively inhibit ATM kinase activity (1C50 = 1.9 nM), while the activity towards ATR, PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ and mTOR was greater than 10 μM. However, WO 2020052688 A1 discusses exclusively fluorine-substituted at position 7 1 R-imidazo[4,5-c]quinolin-2(3H )-ones or 1H-imidazo[4,5-c]cinnolin-2(3H )-ones. The authors note that cinnoline modification allows to reduce the affinity of molecules in relation to aldehyde oxidase, which prevents their metabolism, but do not associate it with selectivity.

[0009] In the published international application No. WO 2021022078 A1,

[0010] IPC A61K 31 / 444, A61K 31 / 4545, A61K 31 / 4745, C07D 471 / 04, C07D 471 / 10,

[0011] C07D 491 / 20, 04.02.2021, presents ATM and DNA-PK inhibitors of the class of spiro derivatives of N-(5-(2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]quinolin-8-yl)pyridin-3-yl)sulfonamide, where the introduction of a fluorine atom at position 7 of 1H-pyrrolo[2,3-c]quinolin-2(3H)-one resulted in a significant loss of activity against mTOR. However, for the molecules given in the examples, the inhibitory capacity against P13Kα / δ was retained.

[0012] (mainly 1C parameter values 50 <100 nM), indicating a relatively low selectivity for this class of molecules. Examples of molecules containing cinnoline in their structure have not been described. We have shown that comparable selectivity can be obtained without a fluorine atom in the same position in the structure of 9-(pyridin-3-yl)-2H-[1,4]oxazino[3,2- c]cinnolin-3(4H)-ones.

[0013] Published international application No. WO 2019201283 A1, IPC C07D 471 / 10, A61K 31 / 444, A61K 31 / 4545, A61K 31 / 4745, A61K 31 / 502, A61P 35 / 00, 24.10.2019, describes spiro derivatives of 1H-pyrrolo[2,3-c]quinolin-2(3H)-ones, 1,2-dihydrobenzo[ / ][1,7]naphthyridine-3(4H)-ones and 1,2-dihydropyrazino[2,3-c]quinolin-3(4H)-ones, as well as their cinnoline analogues, as inhibitors of ATM and DNA-PK kinases. Although many spiro derivatives of 1H-pyrrolo[2,3-c]quinolin-2(3 / / )-ones have shown activity against ATM and DNA-PK kinases (1C 50 <0.5 nM), their six-membered analogs: 1 H-spiro[benzo[ / ][1,7]naphthyridine-2,1'-cyclobutane]-3(4H)-ones (one example in the application) and GR-spiro[cyclopropan-1,2'-pyrazino[2,3-c]quinoline]-3'(4'Y)-ones (two examples in the application) did not demonstrate activity against ATM and DNA-PK kinases (IC 50≥100 nM). In addition, WO 2019201283 A1 does not claim 2R-[1,4]oxazino[3,2-c]quinolin-3(47U)-ones and 2R-[1,4]thiazino[3,2-c]quinolin-3(4 / / )-ones, as well as their cinnoline analogues, and selectivity for ATR, PI3Ka, PI3Kβ, PI3Kδ, PI3Kγ and mTOR for example molecules in WO 2019201283 A1 is not presented. In the published Chinese application No. CN 109705139 A, IPC C07D 498 / 04, 03.05.2019, halogenated at position 9 derivatives of 2H-[1,4]oxazino[3,2- c]quinolin-3(4H)-ones are described as inhibitors of c-Met kinase activity, without mentioning ATM and / or DNA-PK kinases.

[0014] The published international application No. WO2009155527, IPC C07D 487 / 04, C07D 487 / 02, C07D 403 / 02, A61K 31 / 437, A61P 35 / 00, 23.12.2009, presents substituted quinolines as multikinase inhibitors. In particular, 1,2-dihydrobenzo[ / ] [1 ,7] naphthyridine-3(4H )-ones and 1 ,2-dihydropyrazino[2,3- c]quinolin-3(4H )-ones fall under the Markush structure. However, the activity with respect to ATM, ATR and DNA-PK is not indicated in the application. In addition, 2 / 7-[1,4]oxazino[3,2-c]quinolin-3(4H)-ones and 2H-[1,4]thiazino[3,2-c]quinolin-3(4H)-ones do not fall under the Markush structure provided in the application. Taking into account the above, it can be stated that the structures claimed in the present invention are new, their activity against the target kinases ATM and DNA-PK, as well as non-target kinases ATR, PI3Ka, PI3Kβ, PI3Kδ, PI3Kγ and mTOR is not obvious and does not clearly follow from previously published patent applications and scientific articles.

[0015] The aim of the present invention is to develop and create new heterocyclic selective dual inhibitors of ATM and DNA-PK kinases, promising in clinical practice for the treatment and / or prevention of oncological diseases as monotherapy and / or in combination with radiotherapy, chemotherapy and / or immunotherapy.

[0016] The technical result of the invention is the activity of chemical compounds with respect to ATM and DNA-PK kinases, and an increase in selectivity with respect to related kinases. The said technical result is achieved by developing and creating compounds of the general formula (I): or a corresponding pharmaceutical composition or salt, wherein:

[0017] - p and q are chosen independently and are equal to 0, 1, 2 or 3;

[0018] - B is selected independently and is a condensed aromatic or non-aromatic carbocycle or heterocycle;

[0019] - M1 and M2 are selected independently and represent hydrogen or M1 and M2 together form =O (keto group);

[0020] - X, W and V are selected independently and represent hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, -R6-CN, -R6-NO2, -R6-OR5, -R6-N(R4)R5, -O-R6-N(R4)R5, -N=C(R4)R5, -S(O) r R4, -OS(O)2CF3, - R6-C(O)R4, -C(S)R4, -R6-C(O)OR4, -C(S)OR4, -R6-C(O)N(R4)R5, - C(S)N(R4)R5, -N(R5)C(O)R4, -N(R5)C(S)R4, -N(R5)C(O)OR4, - N(R5)C(S)OR4, -N(R5)C(O)N(R4)R5, -N(R5)C(S)N(R4)R5, -N(R5)S(O) t R4, - N(R5)S(O) t N(R4)R5, -R6-S(O) t N(R4)R5, -OP(O)(R4)R5, P(O)R4N(R4)R5, -N(R5)-P(O)(R4)R5, -N(R5)-P(O)R4O(R4), -N(R5)- P(O)R4N(R4)R5, -N(R5)-P(O)O(R4)N(R4)R5, -N(R5)-P(O)N(R4)R5N(R4)R5, - N(R5)C(=NR5)R4, -N(R5)C(=NR5)N(R4)R5, and -N(R5)C(=N-CN)N(R4)R5, where r is independently selected and equal to 0, 1, or 2, t is independently selected and equal to 1 or 2; or two adjacent substituents V, or W, or X, together with the carbon atoms of the ring to which they are directly bonded, form a fused aromatic or non-aromatic carbocycle or heterocycle;

[0021] - Y is independently selected and represents -O-, -S- or -SO2-;

[0022] - Z1 and Z2 are chosen independently and represent -C(R 1a )- or N;

[0023] - R 1a is independently selected and is hydrogen, alkyl, halogen, -CN, -NR2R4, or OR2;

[0024] R2, R4 and R5 are independently selected and represent hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted haloalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl;

[0025] - R з is independently selected and is hydrogen or alkyl;

[0026] - is selected independently and represents a direct bond or a linear or branched optionally substituted alkylene chain, a linear or branched optionally substituted alkenylene chain, a linear or branched optionally substituted alkynylene chain, or an optionally substituted heterocyclylene.

[0027] According to the present invention, pharmaceutically acceptable carriers, vehicles or excipients include, but are not limited to, any adjuvant, vehicle, filler, lubricant, sweetener, diluent, preservative, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved for use in humans or domestic animals.

[0028] Pharmaceutically acceptable salts include, but are not limited to, acid addition salts or base addition salts. pharmaceutically acceptable acid addition salts include salts that retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable and which are formed with inorganic acids such as, BUT NOT LIMITED TO, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucinous acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,

[0029] 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0030] Pharmaceutically acceptable base addition salts include salts that retain the biological effectiveness and properties of the free acids, which retain the biological effectiveness and properties of the free acids that are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, N,N-dimethylaminoethanol, N,N-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benetamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.

[0031] Often, the crystallization results in the formation of a solvate of the compound of the invention. As used herein, the term "solvate" refers to an aggregate that contains one or more molecules of the compound of the invention with one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. In some cases, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including a monohydrate, a dihydrate, a hemihydrate, a sesquihydrate, a trihydrate, a tetrahydrate, and the like, as well as the corresponding solvated forms. The compound of the invention may be true solvates, while in other cases the compound of the invention may simply retain extraneous water or be a mixture of water and some extraneous solvent.

[0032] The pharmaceutical composition includes a preparation of the compound that is the subject of the invention and a medium generally accepted in the art for delivering the biologically active compound to mammals, such as humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients.

[0033] Among the compounds of formula (I), the following compounds are preferred:

[0034]

[0035] Compounds of formula (I) are inhibitors of the ATM family and

[0036] DNA-PK kinases. The invention includes the use of a compound of the present invention for inhibiting the activity of ATM and DNA-PK kinases in cells or in a subject, or in the treatment or prevention of conditions associated with the activity or expression of ATM and DNA-PK kinases.

[0037] The compounds of the present invention can be used to treat or prevent cancer in a mammal, preferably a human, wherein the method of treating cancer according to the present invention comprises administering a therapeutically effective amount of the compound of the invention to the body of a mammal in need of stopping, slowing or reversing the growth, development or spread of cancer, including solid tumors or other forms of cancer. In some embodiments, the compound is administered to a mammal receiving radiotherapy.

[0038] In another aspect, the invention provides methods for treating or preventing cancer in mammals, the methods comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the invention. In some embodiments, the compound is administered to the mammal in combination with a DNA damaging agent. Examples of DNA damaging agents include cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, calicheamicin, PARP inhibitors, etc.

[0039] In another aspect, the invention provides pharmaceutical compositions comprising compounds of the invention and pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical composition comprises a compound of the invention in a pharmaceutically acceptable carrier and in an amount effective for treating an oncological disease in a mammal. The compound of the invention, when used in combination therapy, may enhance the effectiveness of another drug treatment or may reduce the incidence and / or severity of adverse events associated with another drug treatment.

[0040] For example, adverse effects of radiotherapy (e.g., oral or gastrointestinal mucositis, dermatitis, pneumonitis, or fatigue) may be reduced in patients receiving a combination therapy comprising a compound of the invention AND radiotherapy (e.g., the incidence of adverse effects may be reduced by at least 1%, 5%, 10%, or 20%) relative to patients receiving radiotherapy without the compound of the invention. In addition, other adverse events that may be reduced in patients receiving a combination therapy comprising a compound of the invention and radiotherapy (e.g., the incidence of adverse events may be reduced by at least

[0041] 1%, 5%, 10% OR 20%) relative to Patients receiving radiotherapy without the compound of the invention may experience late effects of radiotherapy, such as radiation-induced pulmonary fibrosis, cardiac damage, bowel obstruction, nerve damage, vascular damage, lymphedema, brain necrosis, or radiotherapy-induced cancer. Similarly, when the compound is administered in combination therapy with another anticancer drug (such as those described herein), the combination therapy may cause the same or even increased tumor cell death, even if the dose of the other anticancer drug is reduced. Thus, reducing the dosages of other anticancer drugs may reduce the severity of adverse events caused by other anticancer drugs.In another aspect, the present invention is directed to the use of the compounds of the invention as set forth above, as a stereoisomer, enantiomer, tautomer or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, or the use of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of the invention as set forth above, as a stereoisomer, enantiomer, tautomer or mixtures thereof, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for use in the treatment of a disease. In some embodiments, the compound of the invention is administered in combination with radiotherapy. In other embodiments, the compound of the invention is administered in combination with a DNA damaging agent. In some embodiments, the disease is cancer.

[0042] Examples of cancer types that can be treated using the methods and uses disclosed herein include, but are not limited to, leukemias and lymphomas - acute myeloid leukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, chronic neutrophilic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, malignant lymphoma, diffuse large B-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, and follicular lymphoma.

[0043] Examples of cancer types that can be treated using the methods and uses disclosed herein include, but are not limited to, brain cancer (e.g., astrocytoma, glioma, glioblastoma, medulloblastoma, ependymoma), bladder cancer, breast cancer, central nervous system tumors, cervical cancer, rectal cancer, colon cancer, endometrial cancer, esophageal cancer, gastrointestinal stromal tumor, gastric cancer, head and neck cancer, oral cancer, hepatocellular carcinoma, cholangiocarcinoma, metastatic liver disease, Merkel cell carcinoma, lung cancer, melanoma, mesothelioma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, sarcomas, testicular cancer, urothelial cancer, vulvar cancer, and Wilms' tumor.

[0044] In additional embodiments, examples of cancers to be treated using the methods and uses disclosed herein are not limited to metastases and metastatic cancer. For example, the methods and uses disclosed herein for treating cancer may include treating both primary tumors and metastases.

[0045] In some embodiments, the methods and uses disclosed herein include pre-administering to a subject an ATM and DNA-PK inhibitor prior to administering radiotherapy or a DNA damaging agent. Pre-administering a dual ATM and DNA-PK inhibitor can delay or eliminate DNA damage repair following radiotherapy.

[0046] Radiotherapy includes, but is not limited to, external beam radiotherapy using x-rays (photons), cobalt-60 gamma rays or other radioactive isotopes, neutrons, electrons, protons, carbon ions, helium ions, and other charged particles. Radiotherapy also includes brachytherapy and radiopharmaceuticals that emit gamma rays, alpha particles, beta particles, Auger electrons, or other types of radioactive particles from isotopes including iridium-192, iodine-125, cesium-137, palladium-103, phosphorus-32, yttrium-90, gallium-67, astatine-211, radium-223, and other radioactive isotopes. Radiotherapy also includes radioimmunotherapy (RIT) with antibodies or small molecules that are conjugated to radioactive isotopes including iodine-131, yttrium-90, actinium-225, astatine-211, gallium-67, and other radioactive isotopes.

[0047] In some embodiments, the combination therapy comprises administering to the subject an ATM and DNA-PK inhibitor and an antineoplastic agent, such as cisplatin, oxaliplatin, carboplatin, topoisomerase I inhibitors, topoisomerase II inhibitors, anthracyclines, valrubicin, idarucin, calicheamicin, PARP inhibitors

[0048] (eg, olaparib, rucaparib, niraparib, veliparib, talazoparib), as well as other antineoplastic agents known to those skilled in the art.

[0049] In some embodiments, the combination therapy comprises administering to the subject an ATM and DNA-PK inhibitor and anti-tumor immunotherapeutic agents, including, BUT NOT limited to, ipilimumab, ofatumumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, etc.

[0050] In the combination therapy described herein, an ATM and DNA-PK inhibitor may be administered to a subject simultaneously or sequentially (e.g., before or after) another drug or radiotherapy.

[0051] Organic synthesis

[0052] The compounds of the present invention can be prepared using the synthetic methods described below.

[0053] The listed methods are not exhaustive and allow for reasonable modifications. The reactions indicated should be carried out using suitable solvents and materials. When implementing these general methods for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their effect on the reaction. To obtain some substances, it is necessary to change the order of the stages or to give preference to one of several alternative synthesis schemes. It should be understood that these and all examples given in the application materials are not limiting and are given only to illustrate the present invention.

[0054] Method for obtaining N -(2-(3 -(dimethylamino)propoxy)-5 -(4-methyl-3 - oxo-3 ,4-d andhydro-2H - [1 ,4] oxazino [3 ,2-c] quinolin-9-yl) pyridin-3 - yl) benzenesulfonamide (RA-0-00017):

[0055] Compound 3. To a solution of 2.17 g (0.021 mol, 1.25 equiv.) of alcohol (2) in 50 ml of "dry" THF at 0 °C was added in portions 0.95 g of 80% NaH (0.032 mol, 1.9 equiv.), stirred for 15 minutes and a solution of 4 g (0.017 mol, 1 equiv.) of compound (1) in 25 ml of THF was added dropwise. The mixture was stirred for 12 hours, the reaction mixture was poured into 200 ml of water and extracted with EA (3 times 100 ml). The combined organic phases were dried over anhydrous Na2SO4 and evaporated. The resulting residue was purified by chromatography on silica gel, elite QM - QM-MeOH 5%. MS m / z 305.2 (M + H + ). Yield 3 was: 1 g, 16%.

[0056] Compound 4. Compound (3) 1 g (0.0033 mol, 1 equiv.) was dissolved in 50 ml of a 4:1 mixture of acetic acid and water, and 0.74 g (0.0132 mol, 4 equiv.) of iron powder was added in portions. The reaction mixture was stirred for 12 hours. 50 ml of EA was added to the reaction mass, filtered through a zeolite layer, evaporated, dissolved in EA and filtered again through a zeolite layer. The filtrate was washed with a K2CO3 solution, dried over anhydrous Na2SO4 and evaporated. The resulting residue was used in the next step without further purification. The yield of 4 was: 0.8 g, 88%.

[0057] Compound 6. 10 mg DMAP and 0.58 g (0.0033 mol, 3 equiv) of sulfonyl chloride (5) were added to a solution of 0.3 g (0.0011 mol, 1 equiv) of compound (4) in 25 ml of pyridine, and the mixture was stirred at 80 °C for 24 h. Pyridine was evaporated, the residue was poured into water and extracted with EA (3 times 100 ml). The combined organic phases were dried over anhydrous Na2SO4 and evaporated. The resulting residue was purified by chromatography on silica gel, elite XM-MeOH 25%. MS m / z 415.4 (M'H). The yield of 6 was: 0.4 g, 88%.

[0058] Compound 8. To a solution of 0.5 g (0.00185 mol) of compound (7) in 50 ml of MeOH was added 0.5 g of Raney nickel and 0.8 ml of hydrazine hydrate was added dropwise. The mixture was stirred for 12 hours, then 50 ml of MeOH was added to the reaction mixture, the mixture was stirred for 15 minutes, then filtered through a layer of zeolite, and the filtrate was evaporated. The residue was re-evaporated twice with toluene. 380 mg (yield 86%) of compound (8) was obtained, which was immediately used in the next step.

[0059] Compound 9. To a solution of 0.38 g (0.00158 mol, 1 equiv.) of compound (8) in 50 ml of DMF was added 0.83 g (0.00347, 2 equiv.) of K2CO3, and then 0.24 g (0.0019 mol, 1.2 equiv.) of chloroacetyl chloride were added dropwise. The mixture was stirred at 80 °C for 12 hours, then the reaction mixture was poured into 200 ml of water, the precipitate that formed was filtered off and recrystallized from ethanol. MS m / z 280.2 (M + N + ). 1 H NMR (400 MHz, DMSO-<) 5 11.12 (s, 1H), 8.52 (s, 1H), 8.09 (d, J= 1.7 Hz, 1H), 7.86 (d, J= 9.0 Hz, 1H), 7.74 (dd, J= 9.0, 1.8 Hz, 1H), 4.92 (s, 2H). Compound 9 (0.28 g, yield 63%) was obtained.

[0060] Compound 10. To a solution of 0.2 g (0.00071 mol, 1 equiv.) of compound (9) in 25 ml of DMF was added 0.043 g (0.0142 mol, 2 equiv.) of NaH, then 0.126 g (0.00088 mol, 1.25 equiv.) of CH3I were added dropwise. The mixture was stirred for 1 hour, the reaction mixture was poured into 100 ml of water, the precipitate that formed was filtered off and recrystallized from ethanol. MS m / z 294.2 (M + H +). Compound 10 (0.16 g, yield 76%) was obtained.

[0061] Compound RA-0-00017. To a solution of 0.15 g (0.51 mmol, 1 equiv.) of compound (10) in 15 ml of "dry" dioxane were added 0.136 g (0.54 mmol, 1.05 equiv.) of B2Pin2 and 0.16 g (1.63 mmol, 3.2 equiv.) of KO Ac. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol, 0.08 equiv.) of Pd(dppf)Cl2 were added. Then the mixture was stirred at 100 °C under argon for 12 hours, then cooled to room temperature and a solution of 0.35 g (1 mmol, 2 equiv.) of Cs2CO3 in 1.5 ml of water was added. Then 0.185 g (0.44 mmol, 0.88 equiv) of compound (6) was added. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol, 0.08 equiv) of Pd(dppf)Cl2 were added. Then the mixture was stirred at 100 °C under argon for 8 h. The reaction mixture was diluted with 15 ml of EtOAc and filtered through a zeolite layer. 30 ml of water were added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with EtOAc twice with 30 ml each. The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated.The resulting residue was purified by chromatography on silica gel, e-nt XM-MeOH 10%. MS m / z 548.6 (M. + H + ), *H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.50 (s, 1H), 8.89 (s, 1H), 8.42 (s, 1H), 8.08 (s, 2H), 7.98-7.93 (m, 2H), 7.77-7.60 (m, 5H), 5.10 (s, 2H), 4.14 (s, 2H), 3.48 (s, 3H), 3.19 (s, 2H), 2.82 (s, 6H), 1.93 (s, 2H). Compound RA-O-00017 (65 mg, yield 27%) was obtained. Method for obtaining N -(2-(3-(dimethylamino)propoxy)-5-(4-methyl-3- oxo-3,4-dihydro-2H -[1,4]oxazino[3,2-c]quinolin-9-yl)pyridin-3-yl)cyclopropanesulfonamide (RA-O-00018):

[0062] Compounds 4 and 10 were prepared according to the procedure described for RA-

[0063] O-00017.

[0064] Compound 12. To a solution of 0.35 g (0.00127 mol, 1 equiv.) of compound (4) in 25 ml of pyridine were added 10 mg of DMAP and 0.53 g (0.0038 mol, 3 equiv.) of sulfonyl chloride (11), then stirred at 80 °C for 24 h. Pyridine was evaporated, the residue was taken up in 5% K2CO3 solution and extracted with EA (3 times 100 ml). The combined organic phases were dried over anhydrous Na2SO4 and evaporated. The resulting residue was purified by chromatography on silica gel, e-nt QM-MeOH 25%. MS m / z 379.4 (M + H + ). The yield of 12 was: 0.4 g (83%).

[0065] Compound RA-0-00018. To a solution of 0.15 g (0.51 mmol, 1 equiv.) of compound (10) in 15 ml of "dry" dioxane were added 0.136 g (0.54 mmol, 1.05 equiv.) of B2Pin2 and 0.16 g (1.63 mmol, 3.2 equiv.) of KОAc. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol, 0.08 equiv.) of Pd(dppf)Cl2 were added. Then the mixture was stirred at 100 °C under argon for 12 hours, then cooled to room temperature and a solution of 0.35 g (1 mmol, 2 equiv.) of C32CO3 in 1.5 ml of water was added. Then 0.168 g (0.44 mmol, 0.88 equiv) of compound (12) were added. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol, 0.08 equiv) of Pd(dppf)Cl2 were added. Then it was stirred at 100 °C under argon for 8 hours. The reaction mass was diluted with 15 ml of EtO Ac and filtered through a zeolite layer. 30 ml of water were added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with EtO Ac 2 times with 30 ml. The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated.The resulting residue was purified by chromatography on silica gel, e-nt XM-MeOH 10%. MS m / z 512.4 (M. + H + ), 1 H NMR (400 MHz, DMSO-d6) 5 9.54 (s, 1H), 9.35 (s, 1H), 8.89 (s, 1H), 8.48 (d, J= 1.7 Hz, 1H), 8.20 (s, 1H), 8.14 - 8.00 (m, 3H), 5.07 (s, 2H), 4.44 (t, J = 5.6 Hz, 2H), 3.47 (s, 3H), 3.35 (s, 2H), 2.78 (m, 7H), 2.16 (s, 2H), 1.06-0.87 (m, 4H). 55 mg of compound RA-0-00018 were obtained (yield 24%).

[0066] Method for obtaining N-(2-(3-(dimethylamino)propoxy)-5-(4-methyl-3,4-dihydro-2H - [1,4]oxazino[3,2-c]quinolin-9-yl)pyridin-3 - yl)benzenesulfonamide (RA-0-00019):

[0067] Compounds 8 and 6 were prepared according to the procedure described for RA-O-00017.

[0068] Compound 13. To a solution of 0.65 g (0.0027 mol, 1 equiv.) of compound (8) in 50 ml of DMF were added 2.44 g (0.017 mol, 6 equiv.) of K2CO3, and then 1.5 g (0.008 mol, 3 equiv.) of dibromoethane were added dropwise. The mixture was stirred at 80 °C for 12 hours, then the reaction mixture was poured into 200 ml of water, the precipitate that formed was filtered off and recrystallized from ethanol. MS m / z 266.2 (M + H + ). The yield of 13 was: 0.63 g (87%).

[0069] Compound 14. To a solution of 0.35 g (0.0013 mol, 1 equiv.) of compound (13) in 30 ml of DMF was added 0.5 ml of 37% formaldehyde solution, then 2.4 g (0.011 mol, 9 equiv.) of sodium triacetoxyborohydride (STAB). The reaction mixture was stirred for 3 h, then washed with a saturated solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4 and evaporated. The resulting residue was used in the next step without further purification. MS m / z 280.2 (M+H+). The yield of 14 was: 0.15 g (42%).

[0070] Compound RA-0-00019. To a solution of 0.07 g (0.25 mmol, 1 equiv.) of compound (14) in 15 ml of "dry" dioxane were added 0.068 g (0.27 mmol, 1.05 equiv.) of B2Pin2 and 0.08 g (0.8 mmol, 3.2 equiv.) of KO Ac. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.02 mmol, 0.08 equiv.) of Pd(dppf)Cl2 were added. Then it was stirred at 100 °C under argon for 12 hours, then cooled to room temperature and a solution of 0.17 g (1 mmol, 2 equiv.) of Cs2CO3 in 1.5 ml of water was added. Then 0.093 g (0.44 mmol, 0.88 equiv) of compound (6) were added. The solution was degassed by passing a current of Ar for 10 min and 15 mg (0.02 mmol, 0.08 equiv) of Pd(dppf)Cl2 were added. Then it was stirred at 100 °C under argon for 8 h. The reaction mass was diluted with 15 ml of EtO Ac and filtered through a zeolite layer. 30 ml of water were added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with EtO Ac 2 times with 30 ml. The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated.The resulting residue was purified by chromatography on silica gel, e-nt XM-MeOH 5%. MS m / z 534.6 (M. + H + ), 1 H NMR (400 MHz, DMSO-d6) 5 8.59 (s, SH), 8.18 (s, SH), 7.90 - 7.85 (m, 2H), 7.81 - 7.73 (m, 3H), 7.67 - 7.52 (m, 5H), 4.57 (s, 2H), 4.17 (s, 2H), 3.32 (s, 2H), 3.15 (t, J = 7.0 Hz, 2H), 3.02 (s, 3H), 2.78 (s, 6H), 1.98 (s, 2H). 15 mg of compound RA-0-00019 were obtained (yield 6%).

[0071] Method for obtaining N-(2-(3-(dimethylamino)propoxy)-5-(3-oxo-3,4- d and hydro-2 H - [ 1 ,4] oxazino [3 ,2-c] quinolin-9-yl) pyridin-3 - yl) benzenesulfonamide (RA-0-00020): Compounds 10 and 6 were prepared according to the procedure described for RA-0-00017.

[0072] Compound RA-0-00020. To a solution of 0.15 g (0.53 mmol, 1 equiv.) of compound (10) in 15 ml of "dry" dioxane were added 0.136 g (0.53 mmol, 1 equiv.) of B2Pin2 and 0.16 g (1.63 mmol, 3 equiv.) of K O Ac. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol, 0.08 eq.) of Pd(dppf)Cl2 were added. Then the mixture was stirred at 100 °C under argon for 12 hours, then cooled to room temperature and a solution of 0.35 g (1 mmol, 2 equiv.) of Cs2CO3 in 1.5 ml of water was added. Then 0.185 g (0.44 mmol, 0.88 equiv) of compound (6) was added. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol, 0.08 equiv) of Pd(dppf)Cl2 were added. Then it was stirred at 100 °C under argon for 8 hours. The reaction mass was diluted with 15 ml of EtO Ac and filtered through a zeolite layer. 30 ml of water were added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with EtO Ac twice with 30 ml each. The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated.The resulting residue was purified by chromatography on silica gel, using 10% hexane-MeOH as eluent. 70 mg of product was obtained, which was additionally recrystallized from EtOH, and the resulting precipitate was washed with diethyl ether. MS m / z 534.6 (M. + H + ). 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.49 (s, 1H), 7.98 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.87 (s, 1H), 7.84 - 7.72 (m, 3H), 7.63- 7.48 (m, 4H), 5.00 (s, 2H), 4.25 (t, J = 5.6 Hz, 2H), 3.13 (t, J = 5.8 Hz, 2H), 2.80 (s, 6H), 2.05 (m, 2H). The yield of compound RA-0-00020 was 20 mg (9%).

[0073] Method for obtaining N -(2-(3 -(dimethylamino)propoxy)-5-(4-methyl-3 - oxo-3,4-dihydro-2H -[1 ,4]thiazino[3,2-c]quinolin-9-yl)pyridin-3-yl)cyclopropanesulfonamide (RA-S-00016):

[0074]

[0075] Compound 12 was prepared according to the procedure described for RA-O-00017.

[0076] Compound 17. To a solution of 0.225 g (0.00187 mol, 1.2 equiv.) of compound (16) in 30 ml of acetone was added 0.26 ml of Et3N (0.00187 mol, 1.2 equiv.) and then 0.45 g (0.00156 mmol / l, 1 equiv.) of compound (15) was added in portions. The reaction mixture was stirred for 12 h, the formed precipitate was filtered off, the filtrate was evaporated, covered with water and extracted with EA (3 times 50 ml). The combined organic phases were dried over anhydrous Na2SO4 and evaporated. The resulting residue was purified by chromatography on silica gel, e-nt toluene. MS m / z 372.4 (M + N + ). The yield of 17 was 0.3 g (52%).

[0077] Compound 18. Compound 17 0.3 g (0.00081 mol, 1 equiv.) was dissolved in 20 ml of acetic acid and 0.226 g (0.00404 mol, 5 equiv.) of iron powder was added in portions and stirred for 1 hour, then 12 hours at 70 °C. The resulting precipitate was filtered off, the precipitate was poured with dioxane, boiled, then filtered. The filtrate was purified by chromatography on silica gel without preliminary evaporation, el-nt dioxane, MS m / z 297.2 (M + N + ). The yield of 18 was 0.2 g (84%).

[0078] Compound 19. To a solution of 0.2 g (0.00068 mol, 1 equiv.) of compound 18 in 25 ml of DMF was added 0.024 g (0.00102 mol, 1.5 equiv.) of 60% NaH, and then 0.120 g (0.00085 mol, 1.25 equiv.) of CH3I were added dropwise. The reaction mixture was stirred for 1 hour, then poured into 100 ml of water, and the formed precipitate was filtered off. MS m / z 309.2 (M + H + ). Received 19 (0.14 g, 67%).

[0079] Compound RA-S-00016. To a solution of 0.1 g (0.32 mmol, 1 equiv.) of compound 19 in 15 mL of "dry" dioxane were added 0.86 g (0.34 mmol, 1.05 equiv.) of B2Pin2 and 0.095 g (0.97 mmol, 3.2 equiv.) of KOAc. The solution was degassed by passing an Ar current for 10 min and 19 mg (0.025 mmol, 0.08 eq.) of Pd(dppf)Cl2 were added. The mixture was then stirred at 100 °C under argon for 12 h, then cooled to room temperature and a solution of 0.2 g (0.64 mmol, 2 equiv.) of Cs2CC3 in 1.5 mL of water was added. Then 0.108 g (0.28 mmol, 0.88 equiv) of compound (12) were added. The solution was degassed by passing a current of Ar for 10 min and 19 mg (0.025 mmol, 0.08 equiv) of Pd(dppf)Cl2 were added. Then it was stirred at 100 °C under argon for 8 hours. The reaction mass was diluted with 15 ml of EtO Ac and filtered through a zeolite layer. 30 ml of water were added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with EtO Ac 2 times with 30 ml. The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated.The resulting residue was purified by chromatography on silica gel, e-nt XM-MeOH 10%. MS m / z 528.4 (M. + H + ), 1 H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.37 (s, 1H), 8.91 (s, 1H), 8.49 (d, J= 2.3 Hz, 1H), 8.11 (m, ZH), 8.03 (dd, J= 8.7, 2.0 Hz, 1H), 4.45 (t, J = 5.9 Hz, 2H), 3.76 (s, 2H), 3.55 (s, ZN), 3.35 (m, 2H), 2.84 (m, 6H), 2.79 (m, 1H), 2.16 (t, J = 7.8 Hz, 2H), 0.97 (m, 4H). Compound RA-S-00016 (15 mg, 4%) was obtained.

[0080] Method for obtaining N-(2-(3-(dimethylamino)propoxy)-5-(4-methyl-1,1-dioxido-3-oxo-3,4-dihydro-2H-[1,4]thiazino[3,2-c]quinolin-9-yl)pyridin-3-yl)cyclopropanesulfonamide (Y AI-22-0023):

[0081] Compound 19 was prepared according to the procedure described for RA-O-00018. Compound 12 was prepared according to the procedure presented for compound RA-0-00017.

[0082] Compound 20. To a solution of 0.766 g (0.00247 mol) of compound (19) in 25 ml of CH2CI2 at 0 °C was added in portions 1.71 g (0.01 mol) of meta-chloroperbenzoic acid (mCPBA), the mixture was stirred for 4 hours. The reaction mass was washed with 5% K2CO3 solution, the organic phase was dried over anhydrous Na2SO4 and evaporated. The resulting residue was purified by chromatography on silica gel, CM-MeOH 10%. MS m / z 360.4 (M + H + ). The yield of 20 was 0.275 g (31%).

[0083] Compound 21. Compound 20 0.27 g (0.00075 mol, 1 equiv.) was dissolved in 20 ml of acetic acid and 0.167 g (0.003 mol, 5 equiv.) of iron powder was added in portions and stirred for 1 hour, then 12 hours at 70 °C. 50 ml of EA were added to the reaction mass, the precipitate was filtered off. The filtrate was evaporated, the residue was dissolved in 100 ml and washed with 5% K2CO3 solution, the organic phase was dried over anhydrous Na2SO4 and evaporated. The resulting residue was purified by chromatography on silica gel, CM-MeOH 10%. MS m / z 342.4 (M + H +). The yield of 21 was 0.097 g (37%).

[0084] Compound YAI-22-0023. To a solution of 0.09 g (0.26 mmol, 1 equiv.) of compound (21) in 15 ml of "dry" dioxane were added 0.070 g (0.27 mmol, 1.05 equiv.) of B2Pin2 and 0.083 g (0.84 mmol, 3.2 equiv.) of KO Ac. The solution was degassed by passing a current of Ar for 10 min and 19 mg (0.025 mmol) of Pd(dppf)C12 were added. Then the mixture was stirred at 100 °C under argon for 12 hours, then cooled to room temperature and a solution of 0.17 g (0.52 mmol, 2 equiv.) of Cs2CO3 in 1.5 ml of water was added. Then 0.10 g (0.26 mmol, 1 equiv.) of compound (12) was added. The solution was degassed by passing a current of Ar for 10 min and 19 mg (0.025 mmol) of Pd(dppf)Cl2 were added. Then it was stirred at 100 °C under argon for 8 h. The reaction mass was diluted with 15 ml of EtOAc and filtered through a zeolite layer. 30 ml of water were added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with EtOAc twice with 30 mmol. The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated.The resulting residue was purified by chromatography on silica gel, eluent 10% CM-MeOH (MS m / z 560.4 (M H. + )), zzaatteemm on a preparative chromatograph in both acidic and neutral media. Compound YAI22-0023 (12 mg, 14%) was obtained. Spectrum 1 H NMR of the obtained compound corresponded to 1 H NMR spectrum for the RA-S-00016 molecule. Compound YAI-22-0023 has a relatively low stability.

[0085] Method for obtaining N-(2-(3-(dimethylamino)propoxy)-5-(4-methyl-3- oxo-3,4-dihydro-2 H-[1,4]oxazino[3,2-c]cinnolin-9-yl)pyridin-3-yl)benzenesulfonamide (YAI-22-0025):

[0086] Compound 23. To a solution of 3.6 g (0.0266 mol) of compound (22) in 50 ml of dry acetonitrile at 0°C was added dropwise a solution of 6.16 g (0.034 mol) of N-bromosuccinimide (NBS) in 10 ml of dry acetonitrile. The mixture was stirred at room temperature for 12 hours, the reaction mass was evaporated, the residue was purified by column chromatography on silica gel, eluent CH2CI2. MS m / z 215.06 (M + H + ). The yield of 23 was 5.3 g (93%).

[0087] Compound 24. A solution of 1.7 g (0.0247 mol) of NaNO2 in 3 ml of water was added dropwise to a solution of 5.3 g (0.0247 mol) of compound (23) in 30 ml of aqueous concentrated HCl at 0 °C. The mixture was stirred at room temperature for 12 hours, then heated at boiling for 6 hours. The reaction mixture was cooled, the precipitate that formed was filtered off, dried and then washed with diethyl ether. MS m / z 226.06 (M + N +). The yield of 24 was 4 g (72%). Compound 25. Compound (24) (4 g, 0.0177 mol) was added to 40 ml of propionic acid and stirred at 110 °C for 30 minutes, then 5 ml of concentrated HNO3 were added dropwise, the reaction mixture was stirred at 110 °C for 2 hours. Then heating was stopped and the mixture was stirred for 12 hours. The precipitate that formed was filtered off and dried over solid NaOH in a desiccator. MS m / z 271.2 (M + H + ). Compound 25 (2.7 g, 56%) was obtained.

[0088] Compound 26. To a solution of 2.7 g (0.001 mol) of compound (25) in 50 ml of MeOH was added 0.5 g of Raney nickel and 0.8 ml of hydrazine hydrate was added dropwise. The reaction mixture was stirred for 12 hours, then 50 ml of MeOH was added and the mixture was stirred for 15 minutes, then filtered through a layer of zeolite, the filtrate was evaporated. The residue was re-evaporated twice with toluene. Compound 26 (0.73 g, 30%) was obtained, which was immediately used in the next step.

[0089] Compound 27. To a solution of 0.73 g (0.003 mol, 1 equiv.) of compound (26) in 50 ml of DMF was added 1.57 g (0.0114, 3.8 equiv.) of K2CO3, and then 0.4 g (0.0036 mol, 1.2 equiv.) of chloroacetyl chloride were added dropwise. The mixture was stirred at 80 °C for 12 hours, the reaction mixture was poured into 200 ml of water, the precipitate that formed was filtered off and recrystallized from ethanol. MS m / z 281.2 (M + N + ). Compound 27 (0.6 g, 70%) was obtained.

[0090] Compound 28. To a solution of 0.6 g (0.0021 mol, 1 equiv.) of compound (27) in 25 ml of DMF was added 0.15 g (0.0042 mol, 2 equiv.) of NaH and then 0.377 g (0.00267 mol, 1.25 equiv.) of CH3I were added dropwise. The reaction mixture was stirred for 1 hour, then poured into 100 ml of water, the precipitate that formed was filtered off and recrystallized from ethanol. MS m / z 295.2 (M + H + ). Compound 28 (0.14 g, 22%) was obtained.

[0091] Compound YAI-22-0025. To a solution of 0.14 g (0.00047 mmol, 1 equiv.) of compound (28) in 15 ml of "dry" dioxane were added 0.126 g (0.0005 mmol, 1.05 equiv.) of B2Pin2 and 0.15 g (0.0015 mmol, 3.2 equiv.) of KOAc. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol) of Pd(dppf)Cl2 were added. Then the mixture was stirred at 100 °C under argon for 12 hours, then cooled to room temperature and a solution of 0.35 g (1 mmol) of CS2CO3 in 1.5 ml of water was added. Then 0.23 g (0.0057 mmol, 1.2 equiv.) of compound (6) was added. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol) of Pd(dppf)Cl2 were added. Then the mixture was stirred at 100 °C under argon for 8 h. The reaction mass was diluted with 15 ml of EtOAc and filtered through a zeolite layer. 30 ml of water were added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with EtOAc 2 times with 30 ml. The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated.The obtained residue was purified by chromatography on silica gel, e-nt XM-MeOH 10% and preparative chromatography in the presence of trifluoroacetic acid. MS m / z 549.4 (M. + H + ), 1 H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.45 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.12 - 8.02 (m, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H), 5.17 (s, 2H), 4.14 (t, J = 5.9 Hz, 2H), 3.62 (s, 3H), 3.28 - 3.10 (m, 2H), 2.82 (s, 6H), 2.01 - 1.81 (m, 2H). 12 mg of compound YAI-22-0025 (CF3COO-) were obtained. The yield was 7%.

[0092] Method for the preparation of N-(2-(3-(dimethylamino)propoxy)-5-(3-oxo-3,4-dihydro-2R-[1,4]oxazino[3,2-c][1,5]naphthyridin-9-yl)pyridin-3-yl)benzene sulfonamide (YAI-22-0024):

[0093] Compound 30. 7 g (0.0485 mol) of Meldrum's acid (29) in 25 ml of trimethyl orthoformate were heated at boiling for 2 hours. The reaction mass was evaporated, the residue was re-evaporated twice with toluene. 9.22 g (yield 99%) of compound (30) were obtained, which was immediately used in the next step.

[0094] Compound 31. To a solution of 9 g (0.048 mol, 1 equiv.) of compound (30) in 50 ml of isopropanol were added 6 g (0.048, 1 equiv.) of 6-methoxypyridin-3-amine (30a). The mixture was stirred at boiling for 2 hours, the reaction mass was cooled, and the precipitate that formed was filtered off. MS m / z 293.2 (M + H). Compound 31 (9.4 g, 67%) was obtained.

[0095] Compound 32. 30 ml of diphenyl ether were heated to 220 °C and 9 g (0.03 mol) of compound (31) were added. The mixture was stirred at this temperature for 15 minutes, then cooled and 30 ml of hexane was added.

[0096] The resulting precipitate was filtered, washed with diethyl ether and dried. MS m / z 177.2 (M + N +). Compound 32 (4.5 g, 83%) was obtained.

[0097] Compound 33. 4.5 g (0.0255 mol) of compound (32) were added to 50 ml of propionic acid and stirred at 110 °C for 30 minutes, then 5 ml of concentrated HNO3 were added dropwise. The reaction mixture was stirred at this temperature for 2 hours, heating was stopped and the mixture was stirred for 12 hours. The precipitate that formed was filtered off and dried over solid NaOH in a desiccator. MS m / z 222.2 (M + H + ). Compound 33 (1.1 g, 19.5%) was obtained.

[0098] Compound 34. 0.1 g of 10% Pd / C was added to a solution of 0.7 g (0.0031 mol) of compound (33) in 25 ml of methanol and the mixture was hydrogenated at atmospheric pressure for 3 hours. The reaction mixture was filtered through a zeolite layer, the residue was washed with methanol, the filtrate was evaporated, and 0.56 g of compound (34) was obtained, which was immediately used in the next step.

[0099] Compound 35. To a solution of 0.56 g (0.0029 mol, 1 equiv.) of compound (34) in 50 ml of DMF was added 1.61 g (0.012, 4 equiv.) of K2CO3, then 0.4 g (0.0035 mol, 1.2 equiv.) of chloroacetyl chloride were added dropwise. The mixture was stirred at 80 °C for 12 hours, then poured into 200 ml of water, the precipitate that formed was filtered off and recrystallized from ethanol. MS m / z 232.2 (M + H + ). Compound 35 (0.26 g, 38%) was obtained.

[0100] Compound 36. 2 ml of conc. HBr were added dropwise to a solution of 0.26 g (0.00112 mol) of compound (35) in 6 ml of acetic acid, the reaction mixture was stirred at 50 °C for 24 hours, evaporated, the residue was poured into 25 ml of 10% Na2CO3 solution, the resulting precipitate was filtered off, dried over NaOH in a desiccator. MS m / z 218.2 (M + H + ). Compound 36 (0.162 g, 66%) was obtained.

[0101] Compound 37. 0.16 g (0.00073 mol) of compound (36) was heated at boiling in 20 ml of POCI зfor 4 hours, then the reaction mass was evaporated, the residue was poured into 25 ml of 10% Na2CO3 solution, the resulting precipitate was filtered off, dried over NaOH in a desiccator. MS m / z 236.4 (M + H + ). Compound 37 (0.093 g, 53%) was obtained.

[0102] Compound YAI-22-0024. To a solution of 0.136 g (0.000328 mmol, 1 equiv.) of compound (37) in 15 ml of "dry" dioxane were added 0.087 g (0.000344 mol, 1.05 equiv.) of B2Pin2 and 0.1 g (0.001 mol, 3.2 equiv.) of KOAc. The solution was degassed by passing an Ar current for 10 min and 30 mg (0.041 mmol) of Pd(dppf)Cl2 were added. Then it was stirred at 100 °C under argon for 12 h, then cooled to room temperature and a solution of 0.35 g (1 mmol, 2 equiv.) of Cs2CO3 in 1.5 ml of water was added. Then 0.067 g (0.00028 mmol, 0.88 equiv) of compound (6) were added. The solution was degassed by passing a current of Ar for 10 min and 30 mg (0.041 mmol) of Pd(dppf)Cl2 were added. Then the mixture was stirred at 100 °C under argon for 8 h. The reaction mass was diluted with 15 ml of EtOAc and filtered through a zeolite layer. 30 ml of water were added to the filtrate. The organic layer was separated, and the aqueous layer was extracted with EtOAc 2 times with 30 ml. The organic phases were combined, washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated.The resulting residue was purified by chromatography on silica gel, e-nt XM-MeOH 10%. MS m / z 548.6 (M. + H + ), 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.68 - 8.51 (m, 2H), 8.42 - 8.27 (m, 2H), 8.15 (d, J= 9.0 Hz, 1H), 7.83 (d, J= 7.7 Hz, 2H), 7.61 - 7.48 (m, ZN), 5.03 (s, 2H), 4.21 (t, J= 5.8 Hz, 2H), 3.09 (t, J= 6.9 Hz, ZN), 2.74 (s, 6H), 2.04 - 1.87 (m, 2H). 15 mg of compound YAI-22-0024 was obtained. The yield was 10%. Method for obtaining N -(2-(3-(dimethylamino)propoxy)-5-(4-methyl-3- oxo-3,4-dihydro-2H-[1,4]oxazino[3,2-c]cinnolin-9-yl)pyridin-3-yl)cyclopropanesulfonamide (YAI-22-0025a):

[0103] Compound 28 was prepared according to the procedure described for YAI-22-0025, compound 12 was prepared according to the procedure described for RA-O-00017. Compound YAI-22-0025a was prepared by a cross-coupling reaction similar to YAI-22-0025. The following analytical characteristics were obtained for compound YAI-22-0025a: MS m / z 513.16 (M+ H + ), 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 9.33 (br s, 1H), 8.3 (s, 1H), 8.35 (d, J= 7.2 Hz, 1H), 8.22 (d, 7.2 Hz, 1H), 8.17 (s, 1H), 7.75 (s, 1H), 5.21 (s, 2H), 4.22 (t, J

[0104] = 5.8 Hz), 4.17-3.61 (m, 4H), 3.66 (s, 3H), 3.23 (br s, 2H), 2.33 (s, 6H), 1.92 (br s, 2H). 12 mg of compound YAI-22-0025a (CF3COO-) were obtained. The yield of compound YAI-22-0025F was 10 mg (10%).

[0105] Method for obtaining N-(2-(3-(dimethylamino)propoxy)-5-(8-fluoro-4-methyl-3-oxo-3,4-dihydro-2Н-[1,4]oxazino[3,2-c]cinnolin-9-yl)pyridin-3-yl)benzenesulfonamide (YAI-22-0025F): p

[0106] Compound 39. To a solution of BC13 (5.9 mL, 1 M) in DCM (5.9 mmol) was added dropwise 1-bromo-2-fluoro-4-nitrobenzene (38) (1 g, 5.26 mmol) in CHCl2CHCl2 (10 mL) with stirring at 0 °C. Then MeCN (1 mL) and AICI3 (0.8 g, 5.9 mmol) were added portionwise to the mixture. The resulting mixture was stirred at 120 °C for 16 h. After cooling the mixture, 2N aqueous HCl (13 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 100 °C for 2 h, then poured into ice water and extracted with DCM (15 mL x 2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel. Compound 39 (0.27 g, 22%), MS m / z 232 ( (M + H + ).

[0107] Compound 40 was prepared by analogy with the procedure described for compound 28, using starting reagent 39. Compound YAI-22-0025F was prepared under Suzuki-Miyaura reaction conditions by analogy with compound YAI-22-0025. The following analytical characteristics were obtained for compound YAI-22-0025F: MS m / z 567.2 (M + H + ), 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.47 (br s, 1H), 8.5 (s, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.82-7.5 (m, 5H), 5.21 (s, 2H), 4.22 (t, J = 5.8 Hz), 3.66 (s, 3H), 3.23 (br s, 2H), 2.33 (s, 6H), 1.92 (br s, 2H). We obtained 10 mg (10%) of compound YAI-22-0025F.

[0108] The compounds of the present invention can be prepared by the above methods or similar methods using appropriate starting materials according to the selected substituents and their positions.

[0109] Biological tests

[0110] The use of the compounds of the present invention as an inhibitor of ATM and DNA-PK kinases can be determined by the methods of the following examples, and the activity levels of the compounds can be determined by the 1C values. 50 (the concentration of the compound that results in 50% inhibition of enzyme activity).

[0111] The pharmacological tests and results are summarized as follows: (1) ATM kinase inhibitory activity assay

[0112] The inhibitory activity of the synthesized compounds against ATM was determined by fluorescence resonance energy transfer (FRET) and compared with the positive control, KU-55933.

[0113] ATM(h) was incubated in a buffer containing 30 nM GST-cMyc-p53 and Mg / ATP (concentration as needed). The reaction was initiated by adding the Mg / ATP mixture. After incubation for 30 min at room temperature, the reaction was stopped by adding a stop solution containing EDTA. Then, a detection buffer containing d2-labeled monoclonal antibody against GST and europium-labeled anti-phospho-Serl 5 antibody against phosphorylated p53 was added. The plate was read in time-resolved fluorescence mode and the homogeneous time-resolved fluorescence signal (HTRF) was determined using the formula HTRF = 10,000 x (Em665nm / Em620nm). The IC values 50 were calculated using the Hill equation and a standard dose-response curve.

[0114] (2) DNA-PK kinase inhibitory activity assay

[0115] The inhibitory activity of the synthesized compounds against DNA-PK was determined by fluorescence resonance energy transfer (FRET) and compared with the positive control, PI-103.

[0116] DNA-PK(h) was incubated in a buffer containing 50 nM GST-cMyc-p53 and Mg / ATP (concentration as needed). The reaction was initiated by adding the Mg / ATP mixture. After incubation for 30 min at room temperature, the reaction was stopped by adding a stop solution containing EDTA. Then, a detection buffer containing d2-labeled monoclonal antibody against GST and europium-labeled anti-phospho-Ser15 antibody against phosphorylated p53 was added. The plate was read in time-resolved fluorescence mode and the homogeneous time-resolved fluorescence signal (HTRF) was determined using the formula HTRF = 10,000 x (Em665nm / Em620nm).

[0117] Values ​​of the IC parameter 50were calculated using the Hill equation and a standard dose-response curve.

[0118] Illustrative examples of compounds with high inhibitory activity against ATM and DNA-PK kinases are given in

[0119] Table 1.

[0120] Activity ranges

[0121] A 1C 50 10 nM

[0122] In 10 nM < IC 50 100 nM

[0123] From 100 nM < 1C 50 < 1,000 nM

[0124] Table 1. (3) Analysis of selectivity of compounds against related kinases of the PIKK and PI3K families

[0125] The compounds of the invention were tested for inhibitory activity (IC 50 ) against related kinases of the PIKK and PI3K families.

[0126] ATR kinase inhibitory activity assay

[0127] The inhibitory activity of the synthesized compounds towards ATR was determined by fluorescence resonance energy transfer (FRET) and compared with the positive control, VE-822.

[0128] ATR / ATRIP(h) was incubated in a buffer containing 50 nM GST-cMyc-p53 and Mg / ATP (concentration as needed). The reaction was initiated by adding the Mg / ATP mixture. After incubation for 30 min at room temperature, the reaction was stopped by adding a stop solution containing EDTA. Then, detection buffer containing d2-labeled monoclonal antibody against GST and europium-labeled anti-phospho-Ser15 antibody against phosphorylated p53 was added. The plate was then read in time-resolved fluorescence mode and the homogeneous time-resolved fluorescence signal (HTRF) was determined using the formula HTRF = 10,000 x (Em665nm / Em620nm). IC values 50 were calculated using the Hill equation and a standard dose-response curve.

[0129] Assay for mTOR kinase inhibitory activity

[0130] The inhibitory activity of the synthesized compounds towards mTOR was determined radiometrically and compared with the positive control, PI-103. mTOR / FKBP12 (h) was incubated with 50 mM 2-(4-(2-hydroxyethyl)-1-piperazinyl)ethanesulfonic acid (HEPES), pH=7.5, 1 mM EDTA, 0.01% Tween 20, 2 mg / ml substrate, 10 μM FKBP12, 3 mM MnCl2 and [gamma- 33 P]-ATP (specific activity and concentration as required). The reaction was initiated by adding Mn / ATP mixture. After incubation for 40 min at room temperature, the reaction was stopped by adding phosphoric acid to a concentration of 0.5%. An aliquot of the reaction mixture was then applied to a filter and washed four times for 4 min in 0.425% phosphoric acid and once in methanol before drying and scintillation counting. IC values 50 were calculated using the Hill equation and a standard dose-response curve.

[0131] PI3K kinase inhibitory activity assay

[0132] The inhibitory activity of the synthesized compounds against

[0133] PI3K kinase activity was determined by fluorescence resonance energy transfer (FRET) and compared with the positive control, PI-103.

[0134] PI3K (pl l0a / p85a)(h), PI3K (p110α(E542K) / p85α)(h), PI3K (p110β / p85α)(h), PI3K (p110δ / p85α)(h) and PI3K (p120γ)(h) were incubated in a buffer containing 10 μM phosphatidylinositol-4, 5-bisphosphate and Mg / ATP (concentration as needed). The reaction was initiated by adding ATP solution or Mg / ATP mixture. After incubation for 30 min at room temperature, the reaction was stopped by adding a stop solution containing biotinylated phosphatidylinositol-3, 4, 5-triphosphate. Then, a detection buffer containing europium-labeled anti-GST monoclonal antibodies, GST-labeled GRP1 PH domain, and streptavidin-allophycocyanin was added. The plate was then read in time-resolved fluorescence mode, and the homogeneous time-resolved fluorescence (HTRF) signal was determined by the formula HTRF = 10,000 X (Em665nm / Em620nm). The IC values 50were calculated using the Hill equation and a standard dose-response curve. The activities of illustrative example molecules against ATR, mTOR, and PI3K kinase isoforms are given in Table 2.

[0135] Activity ranges

[0136] A 1C 50 10 nM

[0137] In 10 nM < 1C 50 100 nM

[0138] From 100 nM < 1C 50 1,000 nM

[0139] D 1,000 nM < 1C 50 10,000 nM

[0140] E 1C 50 10,000 nM

[0141] Table 2.

[0142] The results indicate that the synthesized compounds exhibit pharmacologically significant activity and selectivity towards ATM and DNA-PK, while not demonstrating significant activity towards ATR and mTOR, as well as a number of PI3K kinases such as PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ. The compounds exhibit inhibitory activity against ATM and DNA-PK, simultaneously with high reliability, as established in a direct in vitro test, according to a generally accepted and approved method.

Claims

Invention formula 1. A compound defined by formula (I): or a pharmaceutically acceptable salt thereof, where - Y may be -S- or -SO2-, then Z1 and Z2 are independently selected and are -CH- or N; or Y may represent -O-, then one of Z1 and Z2 represents N and the other represents -CH-; - Mi and M2 represent hydrogen or M1 and M2 together form =0 (keto group); - n is equal to 0 or 1; - Ri is -OLN(R a ,R b ); - R2 is C 1-3 alkyl, C3 cycloalkyl or phenyl; - R3 is a halogen; - R4 represents hydrogen or C 1-2 alkyl; - each R a and R b independently represents hydrogen or C 1-3 alkyl; - L represents ethylene or n-propylene.

2. A pharmaceutical composition having inhibitory activity against ATM and DNA-PK, containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

3. Use of a compound specified in paragraph 1, or a pharmaceutical composition thereof according to paragraph 2, for the manufacture of a medicinal product for the treatment of an oncological disease treatable with a dual inhibitor of ATM and DNA-PK.

4. The use according to claim 3, wherein the oncological disease is acute myeloid leukemia, acute lymphoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, lymphoblastic T-cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, chronic neutrophilic leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, malignant lymphoma, diffuse large B-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, brain cancer (e.g. astrocytoma, glioma, glioblastoma, medulloblastoma, ependymoma), bladder cancer, breast cancer, central nervous system tumors, cervical cancer, rectal cancer, colon cancer, endometrial cancer, esophageal cancer, gastrointestinal stromal tumor, gastric cancer, head and neck cancer, oral cancer,Hepatocellular carcinoma, cholangiocarcinoma, metastatic liver disease, Merkel cell carcinoma, lung cancer, melanoma, mesothelioma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, sarcomas, testicular cancer, urothelial cancer, vulvar cancer, and Wilms' tumor.

5. Use of a compound as specified in paragraph 1 or a pharmaceutical composition thereof according to paragraph 2 for the manufacture of a medicament for the treatment of an oncological disease treatable with a dual inhibitor of ATM and DNA-PK in a patient undergoing radiotherapy.

6. The use according to claim 5, wherein the compound or pharmaceutical composition is administered to the patient simultaneously with radiotherapy.

7. The use according to claim 5, wherein the compound or pharmaceutical composition is administered to the patient prior to radiotherapy.

8. The use according to claim 5, wherein the compound or pharmaceutical composition is administered to the patient after radiotherapy.

9. Use of the compound specified in paragraph 1, or a pharmaceutical composition thereof according to paragraph 2, for the manufacture of a medicinal product for the treatment of an oncological disease treatable with a dual ATM and DNA-PK inhibitor, in a patient who receives an antitumor agent selected from the following list: cisplatin, oxaliplatin, carboplatin, valrubicin, idarucin, calicheamicin, olaparib, rucaparib, niraparib, veliparib, talazoparib, ipilimumab, ofatumumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab.

10. The use according to claim 9, wherein the compound or pharmaceutical composition is administered to the patient simultaneously with an antitumor agent.

11. The use according to claim 9, wherein the compound or pharmaceutical composition is administered to the patient before the antitumor agent.

12. The use according to claim 9, wherein the compound or pharmaceutical composition is administered to the patient after the antitumor agent.

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