How to Treat Cancer

Abstract

Disclosed are methods of treating cancer in a subject in need thereof using a dual ATM and DNA-PK inhibitor, optionally in combination with a PARP inhibitor.

Description

[Technical Field]

[0001] The present invention relates to the use of a dual inhibitor of ATM and DNA-PK, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them in the treatment of homologous recombination-deficient cancers. The dual inhibitor of ATM and DNA-PK can be used alone or in combination with a PARP inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing them. [Background technology]

[0002] Several members of the PIKK (PI-3K-like kinase) family of serine-threonine kinases are known mediators of DNA damage signaling.

[0003] Radiation therapy (RT) is used to treat over 50% of all cancer patients at some point during their disease course. Despite significant efforts, previous approaches to developing clinical radiosensitizers have been limited in effectiveness, primarily because they target nonspecific pathways that are not direct regulators of the cellular response to radiation.

[0004] Inhibitors of poly(ADP-ribose) polymerase (PARP inhibitors) target the DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) and closely related paralogs. Several PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) have been approved for the treatment of various cancers (e.g., ovarian cancer, breast cancer, fallopian tube cancer, and primary peritoneal cancer).

[0005] There is a need for new therapies for neoplastic diseases, particularly effective therapies for homologous recombination-deficient cancers. Summary of the Invention

[0006] The present invention generally provides methods for treating cancer using an ATM and DNA-PK dual inhibitor, or a pharmaceutically acceptable salt thereof. These methods may include treating homologous recombination-deficient (HR-deficient) cancer. Examples of HR-deficient cancers include cancers with loss-of-function BRCA (e.g., BRCA1 or BRCA2) mutations. HR-deficient cancers, such as cancers with loss-of-function BRCA mutations, may be sensitized to treatment with an ATM and DNA-PK dual inhibitor as a single agent. In some embodiments, additional benefits may be obtained when the ATM and DNA-PK dual inhibitor is used as part of a combination therapy with a PARP inhibitor or a pharmaceutically acceptable salt thereof.

[0007] In one aspect, the present invention provides a method of treating a homologous recombination (HR) deficient cancer in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a dual inhibitor of ATM and DNA-PK.

[0008] In some embodiments, the HR deficient cancer is a BRCA mutated cancer. In some embodiments, the cancer has a loss-of-function BRCA mutation. In some embodiments, the cancer has previously been identified as a cancer with a loss-of-function BRCA mutation.

[0009] In a further aspect, the present invention provides a method of treating cancer in a subject, the method comprising: (i) identifying the cancer as an HR-deficient cancer; (ii) administering to a subject in need of treatment a therapeutically effective amount of a dual inhibitor of ATM and DNA-PK.

[0010] In yet another aspect, the present invention provides a method of inducing cell death in an HR-deficient cancer cell, the method comprising contacting the cell with an effective amount of a dual ATM and DNA-PK inhibitor.

[0011] In some embodiments of any of the methods described herein, the HR deficient cancer has a loss of function of BRCA1 or BRCA2, or a combination thereof.

[0012] In a further aspect, the present invention provides a method of treating a homologous recombination (HR) deficient cancer in a subject, the method comprising administering to a subject in need of treatment a therapeutically effective amount of a dual ATM and DNA-PK inhibitor and a therapeutically effective amount of a PARP inhibitor.

[0013] In some embodiments, the HR deficient cancer is a BRCA mutated cancer. In some embodiments, the cancer has a loss-of-function BRCA mutation. In some embodiments, the cancer has previously been identified as a cancer with a loss-of-function BRCA mutation.

[0014] In yet another aspect, the present invention provides a method of treating cancer in a subject, the method comprising: (i) identifying the cancer as an HR-deficient cancer; (ii) administering to a subject in need of treatment a therapeutically effective amount of a dual inhibitor of ATM and DNA-PK, and a therapeutically effective amount of a PARP inhibitor.

[0015] In another aspect, the invention provides a method of inducing cell death in HR-deficient cancer cells, the method comprising contacting the cells with an effective amount of a dual ATM and DNA-PK inhibitor and a therapeutically effective amount of a PARP inhibitor.

[0016] In some embodiments of the methods described herein, the HR deficient cancer has a loss of function of BRCA1 or BRCA2, or a combination thereof.

[0017] In some embodiments of any of the methods described herein, the cancer has a BRCA1 mutation. In some embodiments of any of the methods described herein, the cancer has a BRCA2 mutation.

[0018] In some embodiments of the combination therapies described herein, the ATM and DNA-PK dual inhibitor are administered before the PARP inhibitor. In some embodiments, the ATM and DNA-PK dual inhibitor are administered after the PARP inhibitor. In some embodiments, the ATM and DNA-PK dual inhibitor are co-administered with the PARP inhibitor.

[0019] In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof, niraparib or a pharmaceutically acceptable salt thereof, rucaparib or a pharmaceutically acceptable salt thereof, or talazoparib or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is niraparib or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is rucaparib or a pharmaceutically acceptable salt thereof. In some embodiments, the PARP inhibitor is talazoparib or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments of any of the preceding aspects, the dual ATM and DNA-PK inhibitor is a compound of Formula (I): [ka] or a pharmaceutically acceptable salt thereof; During the ceremony, Y is CHR 5 or NR 6 and Z is CH, CR 3 , or N, n is 0, 1, 2, or 3; R 1 is -OLN(R 7 ) 2- or optionally substituted 4-membered saturated N-heterocyclyl; R 2 is C1-3 alkyl, Each R 3 are independently halogen or optionally substituted C 1~3 is alkyl, R 4 is optionally substituted alkyl; R 5 is hydrogen, optionally substituted C 1~3 alkyl, or benzyloxy; R 6 is an arbitrarily substituted C 1~3 is alkyl, Each R 7 are independently H or optionally substituted C 1~3 is alkyl, L is optionally substituted ethylene.

[0021] In some embodiments, the ATM and DNA-PK dual inhibitor of formula II is a compound of formula (IA): [ka] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the ATM and DNA-PK dual inhibitor of formula II is a compound of formula (IB): [ka] or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the ATM and DNA-PK dual inhibitor is [ka] and pharmaceutically acceptable salts thereof.

[0024] In some embodiments, the dual ATM and DNA-PK inhibitor is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the dual ATM and DNA-PK inhibitor is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the dual ATM and DNA-PK inhibitor is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0027] In certain embodiments of any of the foregoing aspects, the inhibitor is administered to the subject simultaneously with radiation therapy. In certain embodiments, the inhibitor is administered to the patient before radiation therapy. In further embodiments, the inhibitor is administered to the patient after radiation therapy. In yet other embodiments, the radiation therapy is administered using, for example, a radionuclide (e.g., a beta-emitting radionuclide (e.g., 32 Phosphorus, 67 copper, 77 bromine, 89 strontium, 90 yttrium, 105 rhodium, 131 iodine, 137 cesium, 149 Prometheum, 153 samarium, 166 holmium, 177 lutetium, 186 rhenium, 188 rhenium, or 199 gold), alpha-emitting radionuclides (e.g., 211 astatine, 213 Bismuth, 223 radium, 225 Actinium, or 227 thorium), gamma-emitting radionuclides (e.g., 192 iridium), or electron capture radionuclides (e.g., 67 gallium, 103 Palladium, or 125 iodine), antibody-radionuclide conjugates (e.g.,90 Y-ibritumomab tiuxetan, 131 I-tositumomab, 225 Ac-lintuzumab tetraxetan, 227 Th-anetumab colixetan, 90 Y-epitumomab sitsukicetan, 90 Y-clivatuzumab tetraxetan, 177 Lu-rilotomabsatetraxetane, 90 Y-losopatamab tetraxetan, 90 Y-tabituximab valzuxetan, or 90 Y-tacatuzumab tetraxetan), or other targeted radionuclide conjugates (e.g., 131 I-PSMA, 90 Y-PSMA, 177 Lu-PSMA, or 177 Radiation therapy includes external, internal, brachytherapy, or whole-body exposure to Lu-satreotide tetraxetane). Preferably, radiation therapy involves administering an antibody-radionuclide conjugate.

[0028] In some embodiments of any of the preceding aspects, the cancer is brain cancer, bladder cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gastrointestinal stromal tumor, gastric cancer, head and neck cancer, buccal cancer, oral cancer, hepatocellular carcinoma, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, sarcoma, testicular cancer, urothelial carcinoma, vulvar cancer, or Wilms' tumor. In further embodiments, the neoplastic disease is breast cancer, lung cancer, head and neck cancer, pancreatic cancer, rectal cancer, glioblastoma, hepatocellular carcinoma, cholangiocarcinoma, metastatic liver lesion, melanoma, osteosarcoma, soft tissue sarcoma, endometrial cancer, cervical cancer, prostate cancer, or Merkel cell carcinoma.

[0029] definition It is to be understood that the terminology used herein is for the purpose of describing particular embodiments, and is not intended to be limiting. Furthermore, although any methods, devices, and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are described herein. In addition to the above, as used in this specification and the appended claims, unless otherwise stated, the following terms have the meaning indicated: "Amino" refers to the -NH2 radical. "Cyano" refers to the -CN radical. "Hydroxyl" refers to the -OH radical. "Imino" refers to the =NH substituent. "Nitro" refers to the -NO2 radical. "Oxo" refers to the =O substituent. "Thioxo" refers to the =S substituent. "Trifluoromethyl" refers to the -CF3 radical.

[0030] "Alkyl" refers to a straight-chain, saturated, acyclic, monovalent hydrocarbon radical or a branched, saturated, acyclic, monovalent hydrocarbon radical having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms or 1 to 6 carbon atoms, and attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. Optionally substituted alkyl radicals, where valences permit, include halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, etc. 14 , -OC(O)-R 14 , -N(R 14 )2, -C(O)R 15 , -C(O)OR 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R14 )S(O) t R 16 (t is 1 or 2), -S(O) t OR 16 (t is 1 or 2), -S(O) p R 16 (p is 0, 1, or 2) and -S(O) t N(R 14 )2 (t is 1 or 2), wherein each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl, and each R 15 is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 16 is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0031] "Alkenyl" refers to a straight-chain, acyclic, monovalent hydrocarbon radical or a branched, acyclic, monovalent hydrocarbon radical containing one, two, or three carbon-carbon double bonds, having 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and attached to the remainder of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc. Optionally substituted alkenyl radicals, where valence allows, include halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR 14 , -OC(O)-R 14 , -N(R 14 )2, -C(O)R 15 , -C(O)OR 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14)S(O) t R 16 (t is 1 or 2), -S(O) t OR 16 (t is 1 or 2), -S(O) p R 16 (p is 0, 1, or 2) and -S(O) t N(R 14 )2 (t is 1 or 2), wherein each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 16 is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, or heteroaryl.

[0032] "Alkynyl" refers to a straight-chain, acyclic, monovalent hydrocarbon radical or a branched, acyclic, monovalent hydrocarbon radical containing one or two carbon-carbon triple bonds and, optionally, one, two, or three carbon-carbon double bonds, having 2 to 12 carbon atoms, preferably 2 to 8 carbon atoms, and attached to the remainder of the molecule by a single bond, such as ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-1-en-4-ynyl, etc. Optionally substituted alkynyl radicals include halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, etc. 14 , -OC(O)-R 14 , -N(R 14 )2, -C(O)R 15 , -C(O)OR 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14)S(O) t R 16 (t is 1 or 2), -S(O) t OR 16 (t is 1 or 2), -S(O) p R 16 (p is 0, 1, or 2) and -S(O) t N(R 14 )2 (t is 1 or 2), wherein each R is an alkynyl radical optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 16 is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0033] "Alkylene" or "alkylene chain" refers to a straight, acyclic, saturated, divalent hydrocarbon chain or a branched, acyclic, saturated, divalent hydrocarbon chain having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc. Alkylene chains are linked through single bonds. The points of attachment of the alkylene chains may be on the same carbon atom or on different carbon atoms within the alkylene chain. Optionally substituted alkylene chains, where valence allows, include halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, etc. 14 , -OC(O)-R 14 , -N(R 14 )2, -C(O)R 15 , -C(O)OR 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14 )S(O) t R 16(t is 1 or 2), -S(O) t OR 16 (t is 1 or 2), -S(O) p R 16 (p is 0, 1, or 2) and -S(O) t N(R 14 )2 (t is 1 or 2), wherein each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 16 is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. In some embodiments, alkylene is ethylene.

[0034] "Alkenylene" or "alkenylene chain" refers to a straight, acyclic, divalent hydrocarbon chain or a branched, acyclic, divalent hydrocarbon chain containing one, two, or three carbon-carbon double bonds and having 2 to 12 carbon atoms, such as ethenylene, propenylene, n-butenylene, etc. Alkenylene chains are linked via a single bond. The points of attachment of the alkenylene chains may be on the same carbon atom or on different carbon atoms within the alkenylene chain. Optionally substituted alkenylene chains, where valence allows, include halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, etc. 14 , -OC(O)-R 14 , -N(R 14 )2, -C(O)R 15 , -C(O)OR 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14 )S(O) t R16 (t is 1 or 2), -S(O) t OR 16 (t is 1 or 2), -S(O) p R 16 (p is 0, 1, or 2) and -S(O) t N(R 14 )2 (t is 1 or 2), wherein each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 16 is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0035] "Alkynylene" or "alkynylene chain" refers to a straight-chain, acyclic, divalent hydrocarbon chain or a branched, acyclic, divalent hydrocarbon chain containing one or two carbon-carbon triple bonds and, optionally, one, two, or three carbon-carbon double bonds, and having 2 to 12 carbon atoms, such as propynylene, n-butynylene, and the like. The alkynylene chain is bonded via a single bond. The points of attachment of the alkynylene may be on the same or different carbon atoms within the alkynylene chain. Optionally, alkynylene chains may include halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, trimethylsilanyl, -OR, and the like. 14 , -OC(O)-R 14 , -N(R 14 )2, -C(O)R 15 , -C(O)OR 14 , -C(O)N(R 14 )2, -N(R 14 )C(O)OR 16 , -N(R 14 )C(O)R 16 , -N(R 14 )S(O) t R 16(t is 1 or 2), -S(O) t OR 16 (t is 1 or 2), -S(O) p R 16 (p is 0, 1, or 2) and -S(O) t N(R 14 )2 (t is 1 to 2), wherein each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently hydrogen, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 16 is independently alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl.

[0036] "Alkoxy" means a group of the formula -OR a where R a is an alkyl radical, as defined above, containing 1 to 12 carbon atoms. The alkyl portion of an optionally substituted alkoxy radical is optionally substituted as defined above for an alkyl radical.

[0037] "Alkoxyalkyl" means a group of the formula -R a -OR b where R a is alkylene as defined above, and R b is alkyl as defined above. The alkyl and alkylene portions of an optionally substituted alkoxyalkyl radical are optionally substituted as defined above for the alkyl radical and alkylene chain, respectively.

[0038] "Aralkyl" means a group of the formula -R a -R b where R a is alkylene as described herein, and R bis aryl, as described herein. The alkylene and aryl portions of an optionally substituted aralkyl are optionally substituted as described herein for alkylene and aryl, respectively.

[0039] "Aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system radical containing 6 to 18 carbon atoms, where polycyclic aryl ring systems are bicyclic, tricyclic, or tetracyclic ring systems. Aryl radicals include, but are not limited to, groups such as fluorenyl, phenyl, and naphthyl. Optionally substituted aryl includes alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, aryl, heteroaryl, heteroarylalkyl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (t is 1 or 2), -R 15 -S(O) t OR 16 (t is 1 or 2), -R 15 -S(O) p R 16 (p is 0, 1, or 2), and -R 15 -S(O) t N(R 14 )2 (t is 1 or 2), wherein each R14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R 16 is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, heterocyclyl, or heteroaryl.

[0040] "Arylalkoxy" refers to a group of formula -OR, where R is aralkyl. Optionally substituted arylalkoxy is optionally substituted arylalkoxy as described herein for aralkyl. In some embodiments, arylalkoxy is benzyloxy.

[0041] As used herein, "BRCA" refers to both BRCA1 and BRCA2, where BRCA1 and BRCA2 are as defined herein.

[0042] As used herein, "BRCA1" refers to the breast cancer type 1 susceptibility gene or protein.

[0043] As used herein, "BRCA2" refers to the breast cancer type 2 susceptibility gene or protein.

[0044] "Cycloalkyl" refers to a stable, non-aromatic, monocyclic or polycyclic hydrocarbon radical having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, saturated or unsaturated, and attached to the rest of the molecule by a single bond. Polycyclic hydrocarbon radicals are bicyclic, tricyclic, or tetracyclic ring systems. Unsaturated cycloalkyls contain one, two, or three carbon-carbon double bonds and / or one carbon-carbon triple bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl, decalinyl, and the like. Optionally substituted cycloalkyls include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (t is 1 or 2), -R 15 -S(O) t OR 16 (t is 1 or 2), -R 15 -S(O) p R 16 (p is 0, 1, or 2) and -R 15 -S(O) t N(R 14)2 (t is 1 or 2), wherein each R 14 is independently hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R 16 is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, or heteroaryl.

[0045] "Fused" refers to any ring system described herein that is fused to an existing ring structure in the compounds of the present invention. When the fused ring system is a heterocyclyl or heteroaryl, any carbon atom on the existing ring structure that becomes part of the fused ring system may be replaced with a nitrogen atom.

[0046] "Halo" refers to a halogen substituent such as bromo, chloro, fluoro, and iodo.

[0047] "Haloalkyl" refers to an alkyl radical, as defined above, further substituted with one or more halogen substituents. The number of halo substituents contained in the haloalkyl ranges from 1 to the total number of hydrogen atoms replaceable with halo substituents (e.g., perfluoroalkyl). Non-limiting examples of haloalkyl include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. For optionally substituted haloalkyl, a hydrogen atom attached to a carbon atom of the alkyl portion of the haloalkyl radical can be optionally substituted with a substituent as defined above for an optionally substituted alkyl.

[0048] "Haloalkenyl" refers to an alkenyl radical, as defined above, further substituted with one or more halo substituents. The number of halo substituents contained in the haloalkenyl ranges from 1 to the total number of hydrogen atoms replaceable with halo substituents (e.g., perfluoroalkenyl). Non-limiting examples of haloalkenyls include 2,2-difluoroethenyl, 3-chloroprop-1-enyl, and the like. For optionally substituted haloalkenyls, the hydrogen atoms attached to the carbon atoms of the alkenyl portion of the haloalkenyl radical can be optionally substituted with substituents as defined above for optionally substituted alkenyl groups.

[0049] "Haloalkynyl" refers to an alkynyl radical, as defined above, further substituted with one or more halo substituents. The number of halo substituents contained in the haloalkynyl ranges from 1 to the total number of hydrogen atoms replaceable with halo substituents (e.g., perfluoroalkyl). Non-limiting examples of haloalkynyl include 3-chloroprop-1-ynyl and the like. The alkynyl portion of the haloalkynyl radical may be further optionally substituted as defined above for an alkynyl group.

[0050] "Heteroarylalkyl" means a heteroaryl group of the formula -R a -R b where R a is alkylene as described herein, and R b is heteroaryl as described herein. The alkylene and heteroaryl portions of an optionally substituted heteroarylalkyl are optionally substituted as described herein for alkylene and heteroaryl, respectively.

[0051] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring system radical having 2 to 12 carbon atoms and a total of 1 to 6 heteroatoms independently selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. Heterocyclyl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems. Bicyclic, tricyclic, or tetracyclic heterocyclyls are fused, spiro, and / or bridged ring systems. Heterocyclyl radicals can be saturated or unsaturated. Unsaturated heterocyclyls contain 1, 2, or 3 carbon-carbon double bonds and / or 1 carbon-carbon triple bond. Optionally substituted heterocyclyls include alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (t is 1 or 2), -R 15 -S(O) t OR 16 (t is 1 or 2), -R 15 -S(O) p R 16 (p is 0, 1, or 2), and -R 15 -S(O) t N(R 14)2 (t is 1 or 2), wherein each R 14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R 16 is independently alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atom in a heterocyclyl radical can be optionally oxidized (if the substituent is oxo and on the heteroatom), and the nitrogen atom can be optionally quaternized (if the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (t is 1 or 2), -R 15 -S(O) t OR 16 (t is 1 or 2), -R 15 -S(O) p R 16 (p is 0, 1, or 2), and -R 15 -S(O) t N(R 14)2 (t is 1 or 2) (where R 15 is a linear or branched alkylene or alkenylene chain, and R 14 and R 16 is as defined above). Examples of optionally substituted heterocyclyl radicals include, but are not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0052] "Heterocyclylene" refers to a heterocyclyl in which one hydrogen atom is replaced at a valence. An optionally substituted heterocyclylene is optionally substituted as described herein for heterocyclyl.

[0053] "Heteroaryl" refers to a 5- to 18-membered ring system radical containing at least one aromatic ring, having 1 to 17 carbon atoms, and containing a total of 1 to 10 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heteroaryl radicals are monocyclic, bicyclic, tricyclic, or tetracyclic ring systems. Bicyclic, tricyclic, or tetracyclic heteroaryl radicals are fused and / or bridged ring systems. Optionally substituted heteroaryl includes alkyl, alkenyl, alkoxy, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, oxo, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, or heteroarylalkyl, -R 15 -OR 14 , -R 15 -OC(O)-R 14 , -R 15-N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (t is 1 or 2), -R 15 -S(O) t OR 16 (t is 1 or 2), -R 15 -S(O) t R 16 (p is 0, 1, or 2), and -R 15 -S(O) t N(R 14 )2 (t is 1 or 2), wherein each R is a heteroaryl radical optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of 14 is independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, and each R 15 is independently a direct bond or a straight or branched alkylene or alkenylene chain, and each R 16 is alkyl, alkenyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl. The nitrogen, carbon, or sulfur atom in a heterocyclyl radical may be optionally oxidized (when the substituent is oxo and present on the heteroatom), provided that at least one ring in the heteroaryl remains aromatic, and the nitrogen atom may be optionally quaternized (when the substituent is alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, -R 15 -OR14 , -R 15 -OC(O)-R 14 , -R 15 -N(R 14 )2, -R 15 -C(O)R 14 , -R 15 -C(O)OR 14 , -R 15 -C(O)N(R 14 )2, -R 15 -N(R 14 )C(O)OR 16 , -R 15 -N(R 14 )C(O)R 16 , -R 15 -N(R 14 )S(O) t R 16 (t is 1 or 2), -R 15 -S(O) t OR 16 (t is 1 or 2), -R 15 -S(O) p R 16 (p is 0, 1, or 2), and -R 15 -S(O) t N(R 14 )2(t is 1 or 2) if (R 15 is a linear or branched alkylene or alkenylene chain, and R 14 and R 16is as defined above). Examples of optionally substituted heteroaryl radicals include azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, Examples include, but are not limited to, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl).

[0054] As described herein, the compounds of formula (I) and formula (II) also encompass all pharmaceutically acceptable compounds that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N,15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. These radiolabeled compounds may be useful, for example, to help determine or measure the efficacy of compounds by characterizing the site or mode of action on ATM and DNA-PK enzymes, or the binding affinity to pharmacologically important sites of action on ATM and DNA-PK enzymes. Certain isotopically labeled compounds of formula (I) or formula (II), for example, those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C is particularly useful for this purpose given its ease of incorporation and ready means of detection.

[0055] Deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances.

[0056] 11 C. 18 F, 15 O and 13 Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of Formula (I) or Formula (II) can generally be prepared by conventional techniques well known to those skilled in the art, or by processes analogous to those described in the Examples and Preparations below, using an appropriate isotopically labeled reagent in place of a previously used non-labeled reagent.

[0057] The compounds disclosed herein also encompass in vivo metabolic products of the disclosed compounds. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, esterification, and the like, primarily through enzymatic processes, of the administered compound. Accordingly, the present invention includes compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound of the present invention to an animal, such as a rat, mouse, guinea pig, dog, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0058] "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0059] "Homologous recombination deficiency" and "HR deficiency" are used interchangeably herein and refer to cancers with a reduced ability to repair DNA double-strand breaks via the homology-directed repair (HRR) pathway. HR deficiency can be caused by defects in genes involved in the HRR pathway (e.g., by loss-of-function mutations in one or more of these genes, such as BRCA1 and / or BRCA2).

[0060] "Mammal" includes humans and both domestic animals, such as laboratory animals and pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits), and non-domestic animals, such as wild animals.

[0061] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted aryl" means that the aryl radical may be substituted or unsubstituted, and the description includes both substituted and unsubstituted aryl radicals.

[0062] "PARP," as used herein, refers to poly ADP-ribose polymerase.

[0063] By "patient" or "subject" is meant a human or non-human animal (e.g., a mammal) suffering from a disease or condition as determined by a qualified professional (e.g., a physician, nurse practitioner, or veterinarian) with or without clinical test(s) of a sample(s) from the patient, as known in the art.

[0064] A "pharmaceutically acceptable carrier, diluent, or excipient" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the United States Food and Drug Administration as acceptable for human or veterinary use.

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Pharmaceutically acceptable salts include acid addition salts and base addition salts.

[0066] "Pharmaceutically acceptable acid addition salts" refer to those salts which retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and which are formed from inorganic acids (e.g., but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.) and organic acids (e.g., 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, etc.). , 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, mucic 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, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0067] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids and are not biologically or otherwise undesirable. These salts are prepared from the addition of 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 salts, 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, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0068] Crystallization often produces solvates of the compounds of the present invention. As used herein, the term "solvate" refers to an aggregate containing one or more molecules of the compounds of the present invention with one or more molecules of a solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as corresponding solvate forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may simply retain extraneous water or may be a mixture of water and some extraneous solvent.

[0069] A "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, e.g., a human. Such a vehicle includes any pharmaceutically acceptable carrier, diluent, or excipient therefor.

[0070] The term "therapeutically effective amount" refers to the amount of a compound of the present invention sufficient to achieve treatment, as defined below, in a mammal, preferably a human or a dog, when the compound is administered to the mammal, preferably a human. The amount of a compound of the present invention or another pharmaceutical agent (e.g., an antitumor agent) that constitutes a "therapeutically effective amount" varies depending on the compound, the condition and its severity, the method of administration, and the age of the mammal being treated, but can be determined routinely by one of ordinary skill in the art having regard to their own knowledge and this disclosure.

[0071] As used herein, "treating" or "treatment" includes treatment of a disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest; (i) preventing the occurrence of a disease or condition in a mammal, particularly where such mammal is susceptible to the condition but has not yet been diagnosed as having the condition; (ii) inhibiting the disease or condition, i.e., arresting its progression; (iii) alleviating the disease or condition, i.e., causing regression of the disease or condition; or (iv) Relieving symptoms resulting from a disease or condition, including relieving pain without addressing the underlying disease or condition. As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that the causative factors for a particular illness or condition may not be known (and thus the etiology has not yet been determined) and therefore may not yet be recognized as a disease, but only as an undesirable state or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

[0072] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or (D)- or (L)- for amino acids. The present invention is intended to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional recrystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0073] "Stereoisomers" refer to compounds composed of the same atoms joined by the same bonds, but with different, incompatible three-dimensional structures. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0074] "Tautomer" refers to a proton migration from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of any of the above compounds.

[0075] Also included within the scope of the present invention are intermediate compounds of formula (I), as well as all polymorphs of the aforementioned species and their crystal habits. [Brief explanation of the drawings]

[0076] [Figure 1A] Figure 1 shows the results of a cell viability assay in which A549 cells were treated with vehicle or increasing concentrations of Compound A for 8 days after transduction with control shRNA or shBRCA2 in a clonogenic survival assay, after which colonies were counted. [Figure 1B] In a clonogenic survival assay, UWB1.289 (BRCA1 mutant) and UWB1.289+BRCA1 were treated with DMSO or increasing concentrations of Compound A for 8 days, after which surviving colonies were counted. Results of the assay are shown. [Figure 1C] Figure 1 shows the results of an assay in which HCC1937 cells were treated with increasing concentrations of niraparib, Compound A, or their combination for 7 days, after which growth inhibition was monitored by CTG and the combination index (CI) was measured according to the method of Chou (1984). [Figure 1D] Figure 1 shows the results of an assay in which Capan-1 cells were treated with increasing concentrations of niraparib, Compound A, or their combination for 7 days, after which growth inhibition was monitored by CTG and the combination index (CI) was measured according to the method of Chou (1984). [Figure 1E]Figure 1 shows the results of an assay in which UWB1.289 cells were treated with increasing concentrations of niraparib, Compound A, or their combination for 7 days, after which growth inhibition was monitored by CTG and the combination index (CI) was measured according to the method of Chou (1984). [Figure 1F]

[0023] Figure 1 shows the results of an assay in which HCC1937 cells were treated with DMSO or 0.25 μM Compound A and increasing concentrations of niraparib for 7 days. Relative cell numbers were estimated by CTG and plotted as a percentage of the DMSO control. [Figure 1G]

[0023] Figure 1 shows the results of an assay in which UWB1.289 cells were treated with niraparib or a combination of 0.25 μM Compound A and niraparib for 3 days. The compounds were removed, niraparib alone was added back in, and cells were allowed to continue growing for an additional 4 days, after which growth inhibition was monitored by CTG. Combined data represents the mean + SEM. [Figure 1H] Figure 1 shows the results of an assay in which UWB1.289+BRCA1 cells were treated with niraparib or a combination of 0.25 μM Compound A and niraparib for 3 days. The compounds were removed, niraparib alone was added back in, and cells were allowed to continue growing for an additional 4 days, after which growth inhibition was monitored by CTG. Combined data represents the mean + SEM. DETAILED DESCRIPTION OF THE INVENTION

[0077] ATM and DNA-PK dual inhibitor The methods of treating cancer described herein include administering a dual inhibitor of ATM and DNA-PK, which may be useful in treating neoplastic diseases (e.g., HR-deficient cancer, BRCA-mutated cancer, or any other cancer described herein). In some embodiments, the dual inhibitor of ATM and DNA-PK can be used in combination with a PARP inhibitor and / or in combination with radiation therapy.

[0078] Advantageously, the combination of a PARP inhibitor with the dual ATM and DNA-PK inhibitors described herein may be synergistically active in patients with HR-deficient cancers, such as BRCA-mutated cancers, particularly in patients undergoing radiation therapy.

[0079] The ATM and DNA-PK dual inhibitors are, for example, compounds of formula (I): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, Z is CH, CR 3 , or N, Y is CHR 5 or NR 6 and n is 0, 1, 2, or 3; R 1 is -OLN(R 7 ) 2- or optionally substituted 4-membered saturated N-heterocyclyl; R 2 is C1-3 alkyl, Each R 3 are independently halogen or optionally substituted C 1~3 is alkyl, R 4 is optionally substituted alkyl; R 5 is hydrogen, optionally substituted C 1~3 alkyl, or benzyloxy; R 6 is an arbitrarily substituted C 1~3 is alkyl, Each R 7 are independently H or optionally substituted C 1~3 is alkyl, L is optionally substituted ethylene.

[0080] Advantageously, the ATM and DNA-PK dual inhibitors of the present invention may exhibit superior inhibitory activity against ATM and DNA-PK. Advantageously, the ATM and DNA-PK dual inhibitors of the present invention may exhibit superior selectivity as measured by reduced off-target activity (e.g., mTOR inhibition, PI3K α / δ inhibition, and / or hERG inhibition). For example, the ATM and DNA-PK dual inhibitors of the present invention may exhibit reduced ATM IC 50 or DNA-PK IC 50 At least 10-fold (e.g., at least 20-fold) higher mTOR IC 50 The ATM and DNA-PK dual inhibitors of the present invention may have an mTOR IC of 10 nM or greater (e.g., >100 nM). 50 Additionally or alternatively, the ATM and DNA-PK dual inhibitors of the present invention may have an ATM IC 50 or DNA-PK IC 50 hERG IC at least 100-fold (e.g., at least 500-fold, at least 1000-fold, or at least 3000-fold) higher than 50 The ATM and DNA-PK dual inhibitors of the present invention may have a hERG IC of 3 μM or greater (e.g., 10 μM or greater). 50 may have:

[0081] Advantageously, the ATM and DNA-PK dual inhibitors of the present invention have excellent pharmacokinetic properties (e.g., C max , AUC, and / or t 1 / 2 ) can be shown.

[0082] In some embodiments, the ATM and DNA-PK dual inhibitor is selected from the group consisting of: [Table 1]

[0083] The ATM and DNA-PK dual inhibitors of the present invention are advantageous in that they can inhibit ATM (ataxia telangiectasia mutated) kinase and DNA-PK kinase. ATM (ataxia telangiectasia mutated) kinase and DNA-PK kinase, in particular, are key regulators of cellular responses to DNA breaks, and inhibition of either of these molecules significantly increases cellular sensitivity to ionizing radiation. Therefore, the ATM and DNA-PK dual inhibitors of the present invention can be effective inhibitors of the action of ATM and DNA-PK, with or without radiation therapy and with or without chemotherapy or immunotherapy, providing an effective therapy for the treatment of neoplastic diseases (e.g., cancer, e.g., cancers described herein). Treatment of patients with the ATM and DNA-PK dual inhibitors of the present invention can delay or eliminate the repair of DNA damage caused by radiation therapy. As a result, patients receiving the compounds of the present invention may have a better response to antitumor therapy. Advantageously, patients receiving the ATM and DNA-PK dual inhibitors of the present invention can benefit from treatment by increasing tumor control from standard doses of radiation therapy or by achieving similar levels of tumor control from lower doses of ionizing radiation than are routinely used in patients not receiving the compounds of the present invention. Advantageously, the lower dose of ionizing radiation may be less damaging to non-cancerous tissue than the dose required in a patient not receiving a compound of the invention.

[0084] Humans and mice with loss-of-function mutations in the ATM or PRKDC genes, which encode ataxia-telangiectasia-mutated (ATM) kinase and DNA-dependent protein kinase (DNA-PK), respectively, are hypersensitive to ionizing radiation. Simultaneous inhibition of ATM kinase and DNA-PK kinase can be effective in sensitizing tumor cells to radiation or DNA-damaging agents (e.g., antitumor agents). The efficacy of dual inhibition of ATM kinase and DNA-PK kinase may be superior to inhibition of either kinase alone.

[0085] Furthermore, compounds of the invention may advantageously have reduced inhibition of other kinases (ATR and mTOR) and therefore reduced toxicity.

[0086] The compounds of the present invention are capable of sensitizing tumor cells to radiation and / or antitumor agents.

[0087] PARP inhibitors PARP inhibitors that can be used in the present invention include those that, upon contact with PARP, either in vitro, in cell culture, or in animals, reduce the IC of PARP measured. 50 For certain PARP inhibitors, the PARP IC 50 The IC of PARP may be 100 nM or less (e.g., 10 nM or less or 1 nM or less), or may be as low as 100 pM or 10 pM. 50 is 0.1 nM to 1 μM (e.g., 0.1 nM to 750 nM, 0.1 nM to 500 nM, or 0.1 nM to 250 nM).

[0088] PARP inhibitors include: [ka] KU-0059436 (AZD2281), PF-01367338, and pharmaceutically acceptable salts thereof.

[0089] Non-limiting examples of PARP inhibitors include those described in, for example, U.S. Patent Nos. 8,716,493, 8,236,802, 8,071,623, 8,012,976, 7,732,491, 7,550,603, 7,531,530, 7,151,102, and 6,495,541, and U.S. Patent Application Publication Nos. 2021 / 0040084 and 2022 / 0009901, each of which is incorporated herein by reference.

[0090] The PARP inhibitor may be isotopically enriched (eg, enriched with deuterium).

[0091] method The present invention provides methods for treating neoplastic diseases (e.g., cancer, HR-deficient cancer, and BRCA-mutated cancer) in a mammal, preferably a human or a dog, comprising administering to the mammal in need thereof a therapeutically effective amount of a dual ATM and DNA-PK inhibitor, optionally in combination with a PARP inhibitor. In some embodiments, the compound is administered to the mammal undergoing radiation therapy.

[0092] In some embodiments, the present invention provides methods for treating homologous recombination deficient (HR deficient) cancers. HR deficient cancers can have a loss of function of genes involved in the homologous recombination DNA repair pathway. Exemplary genes involved in the HR pathway include BRCA1, BRCA2, 53BP1, ATM, ATR, ATRIP, BARD1, BLM, BRIP1, DMC1, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RIF1, RMI1, RMI2, RPA1, TOP3A, TOPBP1, XRCC2, XRCC3, HELQ, SWI5, SWSAP1, ZSWIM7, SPIDR, PDS5B, RAD52, RAD54L, RAD54B, BARD1, ABRAXAS1, PAXIP1, SMC5, SMC6, SHLD1, SHLD2, SHLD3, SEM1, RBBP8, MUS81, EME1, EME2, SLX1A, SLX1B, and GEN1.

[0093] In some embodiments, the invention provides methods of treating a BRCA-mutated cancer, which may, for example, have a loss-of-function BRCA mutation (e.g., a loss-of-function BRCA1 mutation and / or a loss-of-function BRCA2 mutation).

[0094] In some embodiments, the method may include identifying the cancer as being an HR-deficient cancer (e.g., a BRCA-mutated cancer) or as having a loss-of-function BRCA mutation.

[0095] In some embodiments, the ATM and DNA-PK dual inhibitor and / or PARP inhibitor is provided as a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition comprises the compound in a pharmaceutically acceptable carrier in an amount effective to treat a neoplastic disease in an animal, preferably a mammal.

[0096] When the inhibitors of the present invention are used in combination therapy, the efficacy of other radiation therapy or drug therapy can be increased if the dose of the other treatment can be reduced, thereby reducing the frequency and / or severity of adverse events associated with other drug therapy. For example, the side effects of radiation (e.g., oral or gastrointestinal mucositis, dermatitis, interstitial pneumonitis, or fatigue) can be reduced in patients receiving combination therapy with the compounds of the present invention and low-dose radiation therapy compared to patients receiving standard full-dose radiation therapy without the compounds of the present invention (e.g., the incidence of adverse events can be reduced by at least 1%, 5%, 10%, or 20%). Furthermore, other adverse events that can be reduced in patients receiving combination therapy with the compounds of the present invention and low-dose radiation therapy compared to patients receiving standard full-dose radiation therapy without the compounds of the present invention (e.g., the incidence of adverse events can be reduced by at least 1%, 5%, 10%, or 20%) can be delayed effects of radiation, such as radiation-induced pulmonary fibrosis, cardiac injury, intestinal obstruction, nerve damage, vascular damage, lymphedema, brain necrosis, or radiation-induced cancer. Similarly, when the compound is administered in combination with other anticancer drugs (e.g., those described herein), the combination may cause the same or even increased tumor cell death even if the dose of the other anticancer drug is reduced. Thus, reducing the dose of the other anticancer drug may reduce the severity of adverse events caused by the other anticancer drug.

[0097] In another aspect, the present invention is directed to the use of a compound described herein above (e.g., an ATM and DNA-PK dual inhibitor and / or a PARP inhibitor) as a stereoisomer, enantiomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for use in the treatment of a disease, or to the use of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound described herein above as a stereoisomer, enantiomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound described herein is administered in combination with radiation therapy. In other embodiments, the compound described herein is administered in combination with a DNA damaging agent. In further embodiments, the compounds described herein are administered in combination with an anti-tumor immunotherapeutic agent (e.g., ipilimumab, ofatumumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, obinutuzumab, ocaratuzumab, tremelimumab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, veltuzumab, INCMGA00012, AMP-224, AMP-514, KN035, CK-301, AUNP12, CA-170, or BMS-986189). In other embodiments, the anti-tumor immunotherapeutic agent is ofatumumab, obinutuzumab, ocaratuzumab, or veltuzumab. In still other embodiments, the anti-tumor immunotherapeutic agent is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostallimab, INCMGA00012, AMP-224, or AMP-514. In yet other embodiments, the anti-tumor immunotherapeutic agent is atezolizumab, avelumab, durvalumab, KN035, CK-301, AUNP12, CA-170, or BMS-986189. In certain embodiments, the compounds described herein are administered in combination with an anti-tumor immunotherapeutic agent.

[0098] The method of the present invention can be used to treat the neoplastic disease described herein.The neoplastic disease can be, for example, a precancerous tumor or a malignant tumor (for example, a solid tumor or a liquid tumor).A malignant tumor is typically called cancer.In certain embodiments, the neoplastic disease is cancer.

[0099] In further embodiments, examples of cancers to be treated using the methods and uses disclosed herein include, but are not limited to, blood cancers such as leukemia and lymphoma. Non-limiting examples of cancers include 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.

[0100] In further embodiments, examples of cancers that may be treated using the methods and uses disclosed herein include, but are not limited to, solid tumors. Non-limiting examples of solid tumors include brain cancer (e.g., astrocytoma, glioma, glioblastoma, medulloblastoma, or ependymoma), bladder cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gastrointestinal stromal tumor, gastric cancer, head and neck cancer, buccal cancer, oral cancer, hepatocellular carcinoma, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, sarcoma, testicular cancer, urothelial carcinoma, vulvar cancer, or Wilms' tumor. Preferably, the methods of the present invention are used to treat lung cancer, head and neck cancer, pancreatic cancer, rectal cancer, glioblastoma, hepatocellular carcinoma, cholangiocarcinoma, metastatic liver lesions, melanoma, osteosarcoma, soft tissue sarcoma, endometrial cancer, cervical cancer, prostate cancer, or Merkel cell carcinoma.

[0101] In further embodiments, examples of cancers that may be treated using the methods and uses disclosed herein include, but are not limited to, metastases and metastatic cancers. For example, the methods and uses disclosed herein for treating cancer may include treatment of both the primary tumor and metastases.

[0102] In some embodiments, the methods of the present invention can reduce tumor size in a subject by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% (e.g., compared to tumor size at the start of treatment or compared to a reference subject receiving a placebo instead of a compound of the present invention), or can eliminate the tumor. In some embodiments, the methods of the present invention can reduce tumor burden in a subject by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% (e.g., compared to tumor burden at the start of treatment or compared to a reference subject receiving a placebo instead of a compound of the present invention), or can eliminate the tumor. In some embodiments, the methods of the present invention can increase the mean survival time of a subject by, for example, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200% (e.g., compared to a reference subject receiving a placebo instead of a compound of the present invention). In some embodiments, the methods of the invention can increase the ability of radiation therapy or drug therapy to relieve pain or other symptoms in a subject over a longer average time period (e.g., compared to a reference subject receiving a placebo instead of a compound of the invention), e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, or 200%.

[0103] In some embodiments, the methods and uses disclosed herein include pre-treating a patient with a dual ATM and DNA-PK inhibitor prior to administration of radiation therapy or a DNA damaging agent. Pre-treatment of a patient with a dual ATM and DNA-PK inhibitor may delay or eliminate repair of DNA damage following radiation therapy.

[0104] Radiation therapy includes X-rays (photons), 60 Radiation therapy includes, but is not limited to, external beam radiation therapy using gamma rays from cobalt or other radioactive isotopes, neutrons, electrons, protons, carbon ions, helium ions, and other charged particles. 32 Phosphorus, 67 copper, 77 bromine, 89 strontium, 90 yttrium, 105 rhodium, 131 iodine, 137 cesium, 149 Prometheum, 153 samarium, 166 holmium, 177 lutetium, 186 rhenium, 188 rhenium, 199 gold, 211 astatine, 213 Bismuth, 223 radium, 225 Actinium, or 227 thorium, 192 iridium, 67 gallium, 103 palladium, 125 Iodine, and other radioisotopes (e.g., 192 iridium, 125 iodine, 137 cesium, 103 palladium, 32 Phosphorus, 90 yttrium, 67 gallium, 211 astatine, or 223 Radiation therapy also includes brachytherapy and radiopharmaceuticals that emit gamma rays, alpha particles, beta particles, Auger electrons, or other types of radioactive particles from isotopes, including radium. 131 iodine, 90 yttrium, 225 Actinium, 211 astatine, 67 gallium, 177 lutetium, 227Also included is radioimmunotherapy (RIT) using antibodies or small molecules conjugated to radioisotopes, including thorium and other radioisotopes.

[0105] In some embodiments, the combination therapy comprises administering to the patient an ATM and DNA-PK inhibitor and a PARP inhibitor, hi some embodiments, the combination therapy further comprises an additional anti-tumor agent (e.g., cisplatin, oxaliplatin, carboplatin, anthracycline, valrubicin, idarubicin, calicheamicin), as well as other anti-cancer agents known to those skilled in the art.

[0106] In certain embodiments, the combination therapy includes an anti-tumor immunotherapeutic agent, such as ipilimumab, ofatumumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, etc.

[0107] In the combination therapies described herein, the ATM and DNA-PK inhibitor may be administered to the patient simultaneously with the other drug or sequentially (eg, before or after the other drug).

[0108] Preparation of inhibitors The compounds of the present invention can be prepared using methods and techniques known in the art. Generally, ATM and DNA-PK dual inhibitors can be prepared as described in WO2019 / 201283 and WO2021 / 022078, the disclosures of which are incorporated herein by reference.

[0109] PARP inhibitors can be prepared using reactions and techniques well known in the art.For example, certain PARP inhibitors can be prepared using the techniques and methods disclosed in, for example, U.S. Patent Nos. 8,716,493, 8,236,802, 8,071,623, 8,012,976, 7,732,491, 7,550,603, 7,531,530, 7,151,102 and 6,495,541, and U.S. Patent Application Publication Nos. 2021 / 0040084 and 2022 / 0009901, each of which is incorporated herein by reference.

[0110] Pharmaceutical compositions and methods of administration In practicing the methods of the present invention, an effective amount of any one of the compounds of the present invention, or any combination of compounds of the present invention, or pharmaceutically acceptable salts thereof, is administered, alone or in combination, by any of the conventional and accepted methods known in the art. Thus, the compounds or compositions can be administered orally (e.g., bucally), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., via suppositories or irrigants), transdermally (e.g., via skin electroporation), or by inhalation (e.g., via aerosols), as well as in solid, liquid, or gaseous dosage forms, including tablets and suspensions. Administration can be in a single unit dosage form with continuous therapy, or in a single-dose therapy as needed. Therapeutic compositions can also be in the form of oil emulsions or dispersions in combination with lipophilic salts such as pamoic acid, or in the form of biodegradable sustained-release compositions for subcutaneous or intramuscular administration.

[0111] Pharmaceutical carriers useful for preparing the compositions can be solid, liquid, or gaseous; thus, the compositions can take the form of tablets, pills, capsules, suppositories, powders, enteric-coated or other protected preparations (e.g., bound to ion exchange resins or packaged in lipid-protein vesicles), sustained-release formulations, solutions, suspensions, elixirs, aerosols, and the like. Carriers can be selected from a variety of oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions (when isotonic with blood). For example, formulations for intravenous administration include sterile aqueous solutions of the active ingredient(s) prepared by dissolving the solid active ingredient(s) in water to produce an aqueous solution, and sterilizing the solution. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. Conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents or emulsifiers, salts for adjusting osmotic pressure, buffers, etc. may also be added to the compositions. Suitable pharmaceutical carriers and their formulation are described in Remington's Pharmaceutical Sciences by E.W. Martin. Such compositions, in any case, contain an effective amount of the active compound together with a suitable carrier to prepare the appropriate dosage form for proper administration to the recipient.

[0112] The dosage of the compounds of the present invention depends on many factors, such as the method of administration, the age and weight of the patient, and the condition of the patient being treated, and is ultimately determined by the attending physician or veterinarian. Such an amount of active compound determined by the attending physician or veterinarian is referred to herein and in the claims as an "effective amount."

[0113] The present invention will now be further described in the following examples, which are intended for illustrative purposes only and are not intended to limit the scope of the invention. [Example]

[0114] In the examples described herein, Compound A is of the following structure: [ka]

[0115] Compound A can be prepared as described in WO2021 / 022078.

[0116] Example 1. Treatment of BRCA-mutated cancer cell culture The A549 human lung cancer cell line, the UWB1.289 BRCA1-mutated human ovarian cancer cell line, and the UWB1.289+BRCA1 stable cell line derived from UWB1.289 (in which wild-type BRCA1 was restored) were obtained from the American Type Culture Collection (ATCC). The Capan-1 BRCA2-mutated human pancreatic cell line was obtained from the Duke Cell Culture Facility (Duke University, Durham, NC). The HCC1937 BRCA1-mutated breast cancer cell line was obtained from Simon Powell (Memorial-Sloan Kettering, NY, NY). All cell lines were authenticated by short tandem repeat profiling and tested negative for mycoplasma. A549 cells were cultured in RPMI 1640 medium (Gibco) supplemented with 10% fetal bovine serum (FBS) (Corning) and 1X antibiotic-antimycotic (AA) (Gibco). Capan-1 cells were grown in Iscove's Modified Dulbecco's Medium (IMDM) (Gibco) containing 20% ​​FBS and 1X AA. HCC1937 cells were grown in Iscove's Modified Dulbecco's Medium (IMDM) containing 15% serum and L-glutamine (2 mM). UWB1.289 and UWB1.289+BRCA1 cells were grown in 50% RPMI 1640 supplemented with 1 mM sodium pyruvate, 10 mM HEPES, and 4500 mg / L glucose, and 50% Mammary Epithelial Growth Medium (MEGM) (Clonetics) containing 200 μg / ml G-418 (Gibco) and supplemented with 3% FBS and 1X AA. All cell lines were grown in 5% CO2 at 37°C.

[0117] Clonogenic survival assay for synthetic lethality UWB1.289 and UWB1.289+BRCA1 cells were seeded at 1000 cells / well in 6-well plates and treated with DMSO or 250, 500, or 1000 nM Compound A for 8 days, followed by colony counting. For shRNA experiments, A549 cells were transduced with control shRNA or shBRCA2, and then treated with DMSO or 250, 500, or 1000 nM Compound A for 8 days, followed by colony counting. Results were plotted using GraphPad Prism (v9.3.1).

[0118] Combination study with niraparib Cell growth inhibition was measured by CellTiter-Glo (CTG) assay (Promega). Cells were seeded in 96-well plates and exposed to 3-fold serial dilutions of Compound A or Niraparib, either alone or in combination with the indicated two drugs, approximately 18 hours later. HCC1937 cells and UWB1.289 cells were treated with increasing concentrations of Compound A, Niraparib, or a combination for 7 days. Capan-1 cells were similarly treated for 13 days, after which growth inhibition was monitored by CTG and combination index (CI) values ​​were measured according to Chou TC, Talalay, P. Adv Enzyme Regul. 1984;22:27-55.

[0119] In another experiment, HCC 1937 and Capan-1 cells were treated with vehicle, 0.25 μM Compound A, or 0.5 μM Compound A together with increasing concentrations of niraparib for 7 or 13 days, respectively, and then the IC 50 The IC values ​​were measured. UWB1.289 and UWB1.289+BRCA1 cells were also treated with vehicle or 0.25 μM Compound A and increasing concentrations of Niraparib for 3 days. The compounds were removed, medium containing increasing concentrations of Niraparib was added back, and the cells were grown for an additional 4 days, after which growth inhibition was monitored by CTG. All IC values ​​were measured. 50 Values ​​were measured in Microsoft Excel and graphed using GraphPad Prism (v9.3.1). Chou TC, Talalay, P. Adv Enzyme Regul. 1984;22:27-55.

[0120] Results – Sensitization of BRCA-mutated cancers to Compound A Knockdown of BRCA2 in A549 cells resulted in a dose-dependent decrease in viability in clonogenic assays following treatment with Compound A (Figure 1A). Furthermore, the BRCA1-mutant ovarian cancer cell line UWB1.289 also exhibited sensitivity to Compound A in clonogenic assays, and this sensitivity was restored by re-expression of wild-type BRCA1 (Figure 1B).

[0121] Results: Synergistic effects of ATM and DNA-PK dual inhibitors and PARP inhibitors Addition of Compound A significantly reduced the BRCA1-mutated breast cancer cell line HCC1937 (CI 50 =0.3), BRCA2-mutated pancreatic cancer cell line Capan-1 (CI 50 =0.5), and the BRCA1 mutant ovarian cancer cell line UWB1.289 (CI 50 =0.4) sensitized UWB1.289 cells to niraparib (a PARP inhibitor), demonstrating a synergistic effect (Figures 2C, 2D, 2E, and Table 2). Of note, the addition of 0.25 μM (HCC1937, Figure 1F, Table 2) or 0.5 μM Compound A Capan-1 (Table 2) in combination with niraparib shifted the niraparib dose-response curve by 10-fold and -5-fold, respectively. Addition of 0.25 μM Compound A to UWB1.289 cells for 3 days of 7 days of niraparib treatment also shifted the niraparib dose-response curve (>23-fold) (Figure 1G, Table 2). Similar treatment of UWB1.289+BRCA1 cells also shifted the niraparib dose-response curve, although not to the same extent (10-fold) (Figure 1H and Table 2). Collectively, these data suggest that tumors with BRCA mutations may benefit from dual inhibition of ATM and DNA-PKcs with a dual ATM and DNA-PK inhibitor, and that the use of PARP inhibitors may enhance the therapeutic efficacy of dual ATM and DNA-PK inhibitors. [Table 2]

[0122] Other embodiments Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the present invention.

[0123] Other embodiments are within the claims.

Claims

1. A method of treating homologous recombination (HR) deficient cancer in a subject, comprising administering to said subject in need thereof a therapeutically effective amount of a dual inhibitor of ATM and DNA-PK.

2. 2. The method of claim 1, wherein the HR-deficient cancer is a BRCA-mutated cancer.

3. 3. The method of claim 1 or 2, wherein the cancer has a loss-of-function BRCA mutation.

4. 3. The method of claim 1 or 2, wherein the cancer has previously been identified as a cancer with a loss-of-function BRCA mutation.

5. 1. A method of treating cancer in a subject, comprising: (i) identifying the cancer as an HR-deficient cancer; (ii) administering to said subject in need of treatment a therapeutically effective amount of ATM and a DNA-PK dual inhibitor.

6. A method of inducing cell death in HR-deficient cancer cells, comprising contacting said cells with an effective amount of a dual ATM and DNA-PK inhibitor.

7. 7. The method of claim 5 or 6, wherein the HR-deficient cancer has a loss of function of BRCA1 or BRCA2, or a combination thereof.

8. A method for treating a homologous recombination (HR) deficient cancer in a subject, the method comprising administering to the subject in need of treatment a therapeutically effective amount of an ATM and DNA-PK dual inhibitor and a therapeutically effective amount of a PARP inhibitor.

9. 9. The method of claim 8, wherein the HR-deficient cancer is a BRCA-mutated cancer.

10. 10. The method of claim 8 or 9, wherein the cancer has a loss-of-function BRCA mutation.

11. 10. The method of claim 8 or 9, wherein the cancer has previously been identified as having a loss-of-function BRCA mutation.

12. 1. A method of treating cancer in a subject, comprising: (i) identifying the cancer as an HR-deficient cancer; (ii) administering to said subject in need of treatment a therapeutically effective amount of an ATM and DNA-PK dual inhibitor, and a therapeutically effective amount of a PARP inhibitor.

13. A method of inducing cell death in HR-deficient cancer cells, comprising contacting the cells with an effective amount of a dual ATM and DNA-PK inhibitor and a therapeutically effective amount of a PARP inhibitor.

14. 14. The method of claim 12 or 13, wherein the HR-deficient cancer has loss of function of BRCA1 or BRCA2, or a combination thereof.

15. The method of any one of claims 1 to 14, wherein the cancer has a BRCA1 mutation.

16. The method of any one of claims 1 to 15, wherein the cancer has a BRCA2 mutation.

17. The method of any one of claims 8 to 16, wherein the ATM and DNA-PK dual inhibitor is administered before the PARP inhibitor.

18. The method of any one of claims 8 to 16, wherein the ATM and DNA-PK dual inhibitor is administered after the PARP inhibitor.

19. The method of any one of claims 8 to 16, wherein the dual ATM and DNA-PK inhibitor is co-administered with the PARP inhibitor.

20. 20. The method of any one of claims 8 to 19, wherein the PARP inhibitor is olaparib or a pharmaceutically acceptable salt thereof, niraparib or a pharmaceutically acceptable salt thereof, rucaparib or a pharmaceutically acceptable salt thereof, or talazoparib or a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 8 to 19, wherein the PARP inhibitor is niraparib or a pharmaceutically acceptable salt thereof.

22. The ATM and DNA-PK dual inhibitor is a compound of formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof; During the ceremony, Y is CHR ５ or NR ６ and Z is CH, CR ３ , or N, n is 0, 1, 2, or 3; R １ is -O-L-N(R ７ ) ２ or an optionally substituted 4-membered saturated N-heterocyclyl; R ２ is C １ ~ ３ is alkyl, Each R ３ are independently halogen or optionally substituted C １～３ is alkyl, R ４ is optionally substituted alkyl; R ５ is hydrogen, optionally substituted C １～３ alkyl, or benzyloxy; R ６ is an optionally substituted C １～３ is alkyl, Each R ７ are independently H or optionally substituted C １～３ is alkyl, 22. The method of any one of claims 1 to 21, wherein L is optionally substituted ethylene.

23. The ATM and DNA-PK dual inhibitor is a compound of formula (IA): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

24. The ATM and DNA-PK dual inhibitor is a compound of formula (IB): 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

25. The ATM and DNA-PK dual inhibitor is 【Chemistry 4】 22. The method of any one of claims 1 to 21, wherein the compound is selected from the group consisting of:

26. The ATM and DNA-PK dual inhibitor is a compound of the following structure: 【Transformation 5】 or a pharmaceutically acceptable salt thereof.

27. The ATM and DNA-PK dual inhibitor is a compound of the following structure: 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

28. The ATM and DNA-PK dual inhibitor is a compound of the following structure: 【Transformation 7】 or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 1 to 28, wherein the subject is undergoing radiation therapy.

30. 30. The method of claim 29, wherein the radiation therapy comprises external, internal, brachytherapy, or whole-body exposure.

31. 31. The method of claim 29 or 30, wherein the radiation therapy comprises an antibody-radionuclide conjugate.

32. The method of any one of claims 29 to 31, wherein the inhibitor is administered to the subject simultaneously with the radiation therapy.

33. The method of any one of claims 29 to 31, wherein the inhibitor is administered to the subject prior to radiation therapy.

34. The method of any one of claims 29 to 31, wherein the inhibitor is administered to the subject after radiation therapy.

35. 35. The method of any one of claims 1 to 34, wherein the cancer is brain cancer, bladder cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gastrointestinal stromal tumor, gastric cancer, head and neck cancer, buccal cancer, oral cancer, hepatocellular carcinoma, lung cancer, melanoma, Merkel cell carcinoma, mesothelioma, nasopharyngeal cancer, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, salivary gland cancer, sarcoma, testicular cancer, urothelial cancer, vulvar cancer, or Wilms' tumor.

36. 35. The method of any one of claims 1 to 34, wherein the cancer is breast cancer, lung cancer, head and neck cancer, pancreatic cancer, rectal cancer, glioblastoma, hepatocellular carcinoma, cholangiocarcinoma, metastatic liver lesion, melanoma, osteosarcoma, soft tissue sarcoma, endometrial cancer, cervical cancer, prostate cancer, or Merkel cell carcinoma.

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