Method for treating cancer using a combination of dna-damaging agents and dna-pk inhibitors

A method of treating a proliferative disorder in a subject, the method comprising:

• administering to a subject in need thereof a DNA-damaging agent, wherein administration occurs two or more times per treatment cycle;
• and
• administering to the subject a DNA-PK inhibitor between about 8 and about 48 hours after administration of the DNA-damaging agent, wherein the DNA-damaging agent is a doxorubicin agent;
• wherein the proliferative disorder is a cancer selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colorectal cancer, breast cancer, hepatocellular carcinoma, endometrial cancer, and ovarian cancer;
• and
• wherein the DNA-PK inhibitor is represented by Formula (B-I):
• or a pharmaceutically acceptable salt thereof,
• wherein:
• Q is N or CH;
• R1 is hydrogen, CH3, or CH2CH3, or R1 and the carbon to which it is bound form a C═CH2 group;
• Ring A is a ring system selected from the group consisting of:
• RA1 is hydrogen, halogen, C1-4alkyl, C0-4alkyl-C3-6cycloalkyl, C0-4alkyl-ORA1a, C0-4alkyl-SRA1a, C0-4alkyl-C(O)N(RA1a)2, C0-4alkyl-CN, C0-4alkyl-S(O)—C1-4alkyl, C0-4alkyl-S(O)2—C1-4alkyl, C0-4alkyl-C(O)ORA1b, C0-4alkyl-C(O)C1-4alkyl, C0-4alkyl-N(RA1b)C(O)RA1a, C0-4alkyl-N(RA1b)S(O)2RA1a, C0-4alkyl-N(RA1a)2, C0-4alkyl-N(RA1b)(3-6 membered-cycloalkyl), C0-4alkyl-N(RA1b)(4-6 membered-heterocyclyl), N(RA1b)C2-4alkyl-N(RA1a)2, N(RA1b)C2-4alkyl-ORA1a, N(RA1b)C1-4alkyl-(5-10 membered heteroaryl), N(RA1b)C1-4alkyl-(4-6 membered heterocyclyl), N(RA1b)C2-4alkyl-N(RA1b)C(O)RA1a, C0-4alkyl-N(RA1b)C(O)C1-4alkyl, C0-4alkyl-N(RA1b)C(O)OC1-4alkyl, C0-4alkyl-(phenyl), C0-4alkyl-(3-10 membered-heterocyclyl), C0-4alkyl-C(O)-(4-6 membered-heterocyclyl), C0-4alkyl-O—C0-4alkyl-(4-6 membered-heterocyclyl), C0-4alkyl-(5-6 membered-heteroaryl), C0-4alkyl-C(O)-(5-6 membered-heteroaryl), C0-4alkyl-O—C0-4alkyl-(5-6 membered-heteroaryl), C0-4alkyl-N(RA1a)(4-6 membered-heterocyclyl), or C0-4alkyl-N(RA1b)(5-6 membered-heteroaryl), wherein each of said RA1 heterocyclyl is a ring system selected from aziridinyl, oxetanyl, tetrahydropyran, tetrahydrofuranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl, piperazinyl, piperazinonyl, tetrahydrothiophenedioxidyl, 1,1-dioxothietanyl, 2-oxa-6-azaspiro[3.4]octanyl, and isoindolinonyl wherein each of said RA1 heteroaryl is a ring system selected from furanyl, thiophenyl, imidazolyl, benzoimidazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, and tetrazolyl, and wherein each of said RA1 alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl groups is optionally substituted with up to three F atoms, up to two C1-2alkyl groups, a C3-6cycloalkyl group, a phenyl group, a benzyl group, an alkenyl-C0-2alkyl group, an alkynyl-C0-2alkyl group, up to two C0-2alkyl-ORA1b groups, a C0-2alkyl-N(RA1b)2 group, a SC1-4alkyl group, a S(O)2C1-4alkyl group, a C(O)RA1b group, a C(O)ORA1b group, a C(O)N(RA1b)2 group, a —CN group, or a C4-6heterocyclic ring system selected from oxetanyl, tetrahydrofuranyl, tetrahydropyran, piperidinyl, and morpholinyl;
• each RA1a is, independently, hydrogen, C1-4alkyl, C3-6cycloalkyl, C4-6heterocyclyl selected from oxetanyl, tetrahydrofuranyl, tetrahydropyran, pyrrolidinyl, and piperidinyl, C5-6heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, or two RA1a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, and morpholinyl, wherein each of said RA1a alkyl, cycloalkyl, heterocyclyl, and heteroaryl groups is optionally substituted with up to three F atoms, up to three 2H atoms, up to two C1-2alkyl groups, a C3-6cycloalkyl group, up to two C0-2alkyl-ORA1b groups, a C0-2alkyl-N(RA1b)2 group, a SC1-4alkyl group, a C(O)RA1b group, a C(O)ORA1b group, a C(O)N(RA1b)2 group, or a —CN group;
• each RA1b is, independently, hydrogen, C1-2alkyl, or C3-4cycloalkyl;
• RA2 is hydrogen, C1-4alkyl, C0-4alkyl-C3-6cycloalkyl, C0-2alkyl-(4-6 membered)heterocyclyl, C2-4alkyl-ORA2a, C0-2alkyl-C(O)N(RA2a)2, C0-2alkyl-S(O)2—C1-4alkyl, C0-2alkyl-C(O)OC1-4alkyl, C0-2alkyl-C(O)-(4-6 membered)heterocyclyl, wherein each of said heterocyclyl is selected from oxetanyl, tetrahydropyran, tetrahydrofuranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl, piperazinyl, piperazinonyl, and 1,1-dioxothietanyl, and each of said RA2 groups except hydrogen is optionally substituted with up to three F atoms, up to two C1-2alkyl groups, a C3-6cycloalkyl group, an alkenyl-C0-2alkyl group, an alkynyl-C0-2alkyl group, up to two ORA2b groups, a C0-2alkyl-N(RA2b)2 group, a SC1-4alkyl group, a S(O)2C1-4alkyl group, a C(O)RA2b group, a C(O)ORA2b group, a C(O)N(RA2b)2 group, or a —CN group;
• each RA2a is, independently, hydrogen, C1-4alkyl, a C5-6heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, or two RA2a and an intervening nitrogen atom form a 3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, and morpholinyl;
• each RA2b is, independently, hydrogen, C1-4alkyl, or C3-4cycloalkyl;
• RA3 is hydrogen or C1-2alkyl;
• each RA4 is, independently, deuterium, halogen, CN, C1-4alkyl, or OC1-4alkyl, wherein each RA4alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC1-2alkyl, or two RA4 together with an intervening saturated carbon atom form a spiro-linked cyclopropyl or cyclobutyl ring;
• n is 0-3;
• Ring B is a ring system selected from the group consisting of:
• RB1 is hydrogen, C1-4alkyl, (CH2)0-1C3-6cycloalkyl, C(O)C1-2alkyl, (CH2)0-1-(4-6 membered)heterocyclyl ring wherein said heterocyclic ring is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyran, dioxanyl, dioxolanyl, and pyrrolidinonyl, or (CH2)1-2(5-6 membered)heteroaryl ring wherein said heteroaryl ring is selected from pyridinyl, imidazolyl, and pyrazolyl, and wherein each of said RB1 alkyl, cycloalkyl, phenyl, benzyl, heterocyclyl and heteroaryl groups is optionally substituted with up to 3 F atoms, up to two C1-2alkyl groups, two non-geminal OH groups, or one OC1-2alkyl;
• RB2 is hydrogen, C1-4alkyl, OC1-4alkyl;
• each RB3 is, independently, hydrogen, halogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, CN, C(O)H, C(O)C1-4alkyl, C(O)OC1-4alkyl, C(O)C1-4alkyl, C(O)NH2, C(O)NHC1-4alkyl, C(O)NH(CH2)0-1C3-6cycloalkyl, C(O)NHCH2oxetanyl, C(O)NHCH2tetrahydrofuranyl, C(O)NHCH2tetrahydropyranyl, C(O)NHphenyl, C(O)NHbenzyl, C(O)NHOH, C(O)NHOC1-4alkyl, C(O)NHO(CH2)0-1C3-6cycloalkyl, C(O)NHO(CH2)0-1oxetanyl, C(O)NHO(CH2)0-1tetrahydrofuranyl, C(O)NHO(CH2)0-1tetrahydropyranyl, C(O)NHOphenyl, C(O)NHObenzyl, NH2, NHC(O)C1-4alkyl, OC1-4alkyl, SC1-4alkyl, S(O)C1-4alkyl, or a 5-membered-heteroaryl ring system selected from furanyl, thiophenyl, imidazolyl, pyrrole, pyrazolyl, and oxadiazolyl, wherein each RB3 group except hydrogen or halogen is optionally substituted with Cl, up to three F atoms, up to two non-geminal OH groups, up to two OC1-2 alkyl, one NH2, one NHC1-2alkyl, one NHC(O)C1-2alkyl, or one N(C1-2alkyl)2;
• each RB4 is, independently, hydrogen, deuterium, halogen, C1-4alkyl, OC1-4alkyl, SC1-4alkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)2, NHC(O)C1-4alkyl, C(O)OH, C(O)OC1-4alkyl, C(O)NH2, C(O)NHC1-4alkyl, C(O)N(C1-4alkyl)2, CN, a morpholinyl ring, or an imidazolyl ring, wherein each RB4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC1-2alkyl;
• RB5 is hydrogen, C1-4alkyl, C(O)C1-4alkyl, C(O)OC1-4alkyl, C(O)NH2, C(O)NHC1-4alkyl, or C(O)N(C1-4alkyl)2, wherein said RB5 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC1-2alkyl and
• RB6 is F or C1-2alkyl, or two RB6 and an intervening carbon atom form a spirocyclopropyl or spirocyclobutyl ring.