DNA-PK inhibitors

1. A method of treating breast cancer, colorectal cancer, gastric-esophageal cancer, fibrosarcoma, glioblastoma, hepatocellular cancer, head and neck cancer, melanoma, lung cancer, pancreatic cancer, or prostate cancer in a patient, comprising administering a compound represented by Structural Formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

Q is N or CH;

R 1 is hydrogen, CH 3 , or CH 2 CH 3 , or R 1 and the carbon to which it is bound form a C═CH 2 group;

Ring A is a ring system selected from

R A1 is hydrogen, halogen, C 1-4 alkyl, C 0-4 alkyl-C 3-6 cycloalkyl, C 0-4 alkyl-OR A1a , C 0-4 alkyl-SR A1a , C 0-4 alkyl-C(O)N(R A1a ) 2 , C 0-4 alkyl-CN, C 0-4 alkyl-S(O)—C 1-4 alkyl, C 0-4 alkyl-S(O) 2 —C 1-4 alkyl, C 0-4 alkyl-C(O)OR A1b , C 0-4 alkyl-C(O)C 1-4 alkyl, C 0-4 alkyl-N(R A1b )C(O)R A1a , C 0-4 alkyl-N(R A1b )S(O) 2 R A1a , C 0-4 alkyl-N(R A1a ) 2 , C 0-4 alkyl-N(R A1b )(3-6 membered-cycloalkyl), C 0-4 alkyl-N(R A1b )(4-6 membered-heterocyclyl), N(R A1b )C 2-4 alkyl-N(R A1a ) 2 , N(R A1b )C 2-4 alkyl-OR A1a , N(R A1b )C 1-4 alkyl-(5-10 membered heteroaryl), N(R A1b )C 1-4 alkyl-(4-6 membered heterocyclyl), N(R A1b )C 2-4 alkyl-N(R A1b )C(O)R A1a , C 0-4 alkyl-N(R A1b )C(O)C 1-4 alkyl, C 0-4 alkyl-N(R A1b )C(O)OC 1-4 alkyl, C 0-4 alkyl-(phenyl), C 0-4 alkyl-(3-10 membered-heterocyclyl), C 0-4 alkyl-C(O)-(4-6 membered-heterocyclyl), C 0-4 alkyl-O—C 0-4 alkyl-(4-6 membered-heterocyclyl), C 0-4 alkyl-(5-6 membered-heteroaryl), C 0-4 alkyl-C(O)-(5-6 membered-heteroaryl), 4alkyl-(5-6 membered-heteroaryl), C 0-4 alkyl-N(R A1a )(4-6 membered-heterocyclyl), or C 0-4 alkyl-N(R A1b)( 5-6 membered-heteroaryl), wherein each of said R A1 heterocyclyl is a ring system selected from aziridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 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 R A1 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 R A1 alkyl, cycloalkyl, phenyl, heterocyclyl, and heteroaryl groups is optionally substituted with up to three F atoms, up to two C 1-2 alkyl groups, a C 3-6 cycloalkyl group, a phenyl group, a benzyl group, an alkenyl-C 0-2 alkyl group, an alkynyl-C 0-2 alkyl group, up to two C 0-2 alkyl-OR A1b groups, a C 0-2 alkyl-N(R A1b ) 2 group, a SC 1-4 alkyl group, a S(O) 2 C 1-4 alkyl group, a C(O)R A1b group, a C(O)OR A1b group, a C(O)N(R A1b ) 2 group, a —CN group, or a C 4-6 heterocyclic ring system selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, and morpholinyl;

each R A1a is, independently, hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl, C 5-6 heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, or two R A1a 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 R A1a alkyl, cycloalkyl, heterocyclyl, and heteroaryl groups is optionally substituted with up to three F atoms, up to two C 1-2 alkyl groups, a C 3-6 cycloalkyl group, up to two C 0-2 alkyl-OR A1b groups, a C 0-2 alkyl-N(R A1b ) 2 group, a SC 1-4 alkyl group, a C(O)R A1b group, a C(O)OR A1b group, a C(O)N(R A1b ) 2 group, or a —CN group;

each R A1b is, independently, hydrogen, C 1-2 alkyl, or C 3-4 cycloalkyl;

R A2 is hydrogen, C 1-4 alkyl, C 0-4 alkyl-C 3-6 cycloalkyl, C 0-2 alkyl-(4-6 membered)heterocyclyl, C 2-4 alkyl-OR A2a , C 0-2 alkyl-C(O)N(R A2a ) 2 , C 0-2 alkyl-S(O) 2 —C 1-4 alkyl, C 0-2 alkyl-C(O)OC 1-4 alkyl, or C 0-2 alkyl-C(O)-(4-6 membered)heterocyclyl, wherein each of said heterocyclyl is selected from oxetanyl, tetrahydropyranyl, tetrahydrofuranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl, piperazinyl, piperazinonyl, and 1,1-dioxothietanyl, and each of said R A2 groups except hydrogen is optionally substituted with up to three F atoms, up to two C 1-2 alkyl groups, a C 3-6 cycloalkyl group, an alkenyl-C 0-2 alkyl group, an alkynyl-C 0-2 alkyl group, up to two OR A2b groups, a C 0-2 alkyl-N(R A2b ) 2 group, a SC 1-4 alkyl group, a S(O) 2 C 1-4 alkyl group, a C(O)R A2b group, a C(O)OR A2b group, a C(O)N(R A2b ) 2 group, or a —CN group;

each R A2a is, independently, hydrogen, C 1-4 alkyl, a C 5-6 heteroaryl selected from imidazolyl, triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl, or two R A2a 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 R A2b is, independently, hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl;

R A3 is hydrogen or C 1-2 alkyl;

each R A4 is, independently, deuterium, halogen, CN, C 1-4 alkyl, or OC 1-4 alkyl, wherein each R A4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC 1-2 alkyl, or two R A4 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

R B1 is hydrogen, C 1-4 alkyl, (CH 2 ) 0-1 C 3-6 cycloalkyl, C(O)C 1-2 alkyl, (CH 2 ) 0-1 -(4-6 membered)heterocyclyl ring wherein said heterocyclic ring is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, and pyrrolidinonyl, phenyl, benzyl, or (CH 2 ) 1-2 (5-6 membered)heteroaryl ring wherein said heteroaryl ring is selected from pyridinyl, imidazolyl, and pyrazolyl, and wherein each of said R B1 alkyl, cycloalkyl, phenyl, benzyl, heterocyclyl and heteroaryl groups is optionally substituted with up to 3 F atoms, up to two C 1-2 alkyl groups, two non-geminal OH groups, or one OC 1-2 alkyl;

R B2 is hydrogen, C 1-4 alkyl, or OC 1-4 alkyl;

each R B3 is, independently, hydrogen, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, CN, C(O)H, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)C 1-4 alkyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)NH(CH 2 ) 0-1 C 3-6 cycloalkyl, C(O)NHCH 2 oxetanyl, C(O)NHCH 2 tetrahydrofuranyl, C(O)NHCH 2 tetrahydropyranyl, C(O)NHphenyl, C(O)NHbenzyl, C(O)NHOH, C(O)NHOC 1-4 alkyl, C(O)NHO(CH 2 ) 0-1 C 3-6 cycloalkyl, C(O)NHO(CH 2 ) 0-1 oxetanyl, C(O)NHO(CH 2 ) 0-1 tetrahydrofuranyl, C(O)NHO(CH 2 ) 0-1 tetrahydropyranyl, C(O)NHOphenyl, C(O)NHObenzyl, NH 2 , NHC(O)C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, S(O)C 1-4 alkyl, or a 5-membered-heteroaryl ring system selected from furanyl, thiophenyl, imidazolyl, pyrrole, pyrazolyl, and oxadiazolyl, wherein each R B3 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 OC 1-2 alkyl, one NH 2 , one NHC 1-2 alkyl, one NHC(O)C 1-2 alkyl, or one N(C 1-2 alkyl) 2 ;

each R B4 is, independently, hydrogen, halogen, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , NHC(O)C 1-4 alkyl, C(O)OH, C(O)OC 1-4 alkyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , CN, a morpholinyl ring, or an imidazolyl ring, wherein each R B4 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC 1-2 alkyl;

R B5 is hydrogen, C 1-4 alkyl, C(O)C 1-4 alkyl, C(O)OC 1-4 alkyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, or C(O)N(C 1-4 alkyl) 2 , wherein said R B5 alkyl is optionally substituted with up to 3 F atoms, two non-geminal OH groups, or one OC 1-2 alkyl and

R B6 is F or C 1-2 alkyl, or two R B6 and an intervening carbon atom form a spirocyclopropyl or spirocyclobutyl ring,

or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt thereof, to said patient in a pharmaceutically acceptable amount.

2. The method of claim 1 , wherein the compound is represented by Structural Formula (III), or a pharmaceutically acceptable salt thereof:

wherein:

X is N or CR A5 ;

R A1 is F, C 1-4 alkyl, C 3-5 cycloalkyl, OC 1-4 alkyl, OC 1-4 alkyl-C 3-5 cycloalkyl, NH 2 , NHC 1-4 alkyl, NHC 0-4 alkyl-C 3-5 cycloalkyl, or C 0-4 alkyl-heterocyclyl, wherein said heterocyclic ring system is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and morpholinyl, and each of said alkyl, cycloalkyl, and heterocyclyl is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two non-geminal OH groups, or up to two OC 1-2 alkyl;

each R A4 is, independently, H or 2 H;

R A5 is hydrogen, F, C 1-4 alkyl, or OC 1-4 alkyl, wherein each of said alkyl is optionally substituted with up to three F atoms or up to three 2 H atoms;

R B3 is C(O)NHC 1-4 alkyl, wherein said alkyl is optionally substituted with up to three F atoms, up to three 2 H atoms, up to two non-geminal OH groups, or up to two OC 1-2 alkyl; and

each R B4 is, independently, hydrogen, deuterium, F, or C 1-4 alkyl.

3. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

4. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

5. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

6. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

7. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

8. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

9. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

10. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

11. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

12. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof:

13. The method of claim 1 , wherein the compound is represented by the following formula, or a pharmaceutically acceptable salt thereof: