DNA-PK inhibitors

1. A compound represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein

Ring A is an aromatic ring system selected from

Ring B is a ring system selected from

wherein Ring B is optionally substituted with one or more substituents selected from the group consisting of —F, —OH, and C 1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —OH, and —OC 1-2 alkyl;

Ring C is a C 4-6 cycloalkyl, 5-6-membered heteroaryl, or phenyl group, wherein Ring C is optionally further substituted with one or more substituents selected from the group consisting of halogen, C 1-2 alkyl, —OH, and —OC 1-2 alkyl;

X is —NH—, —O—, —OC 1-4 alkyl-, —S—, or —CH 2 —;

each of R 1 and R 2 is, independently, hydrogen, —C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 ,

—NHC(O)OR 4 , —NHC(O)NHR 4 , —NHS(O) 2 R 4 , —NHR 4 , —C 1-4 alkyl-NHR 4 , —OR 4 , or R 7 wherein R 1 and R 2 cannot simultaneously be hydrogen;

each R 3 independently is hydrogen, —C 1-4 alkyl,

halogen, —OC 1-2 alkyl, —C(O)OH, —C(O)OC 1-2 alkyl, —CN, —C(O)NHC 1-2 alkyl, —C(O)NH 2 , C 3-4 cycloalkyl, or —NRR′, wherein each of said R 3 alkyl and cycloalkyl independently is optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —OH and —OC 1-2 alkyl;

each R 4 independently is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 5-10-membered heteroaryl, or 4-10-membered heterocyclyl, wherein each of said R 4 groups is optionally and independently substituted with one or more substituents selected from the group consisting of —Br, —Cl, —F, C 1-4 alkyl, CN, NO 2 , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(Co 1-4 alkyl-C 3-5 cycloalkyl), CH 2 OR 5 , C 0-4 alkyl-C(O)R 5 , C 0-4 alkyl-C(O)N(R 5 ) 2 , C 0-4 alkyl-C(O)OR 5 , C 0-4 alkyl-NHC(O)R 5 , C 0-4 alkyl-N(R 5 ) 2 , 5-6 membered heterocyclyl, —O(C 1-4 alkyl)OR 5 , —OR 5 , and oxo, and wherein each of said optional R 4 substituents is optionally and independently substituted with one or more substituents selected from the group consisting of —F, —Cl, C 1-4 alkyl, —OH, —OC 1-4 alkyl, —SC 1-4 alkyl, —C(O)C 1-4 alkyl, —C(O)OC 1-4 alkyl, and —C(O)OC 0-4 alkyl-C 3-5 cycloalkyl; and

each R 5 independently is hydrogen, C 1-4 alkyl, phenyl, 5-6-membered heteroaryl, or 4-7-membered heterocyclyl, wherein each R 5 is optionally and independently substituted with one or more substituents selected from the group consisting of —F, —Cl, C 1-2 alkyl, —CH 2 OH,

—CN, —OH, —OC 1-2 alkyl, 5-6-membered heteroaryl, and 4-7 membered heterocyclyl, or two R 5 groups together with the intervening nitrogen atom optionally form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring; and

R 6 is hydrogen or C 1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of —F, —Cl, —CH 2 OH, —CN, —OH, and —OC 1-2 alkyl;

R 7 is 6-10-membered aryl, 5-10-membered heteroaryl, or 4-7-membered heterocyclyl, each of which is optionally and independently substituted with one or more substituents selected from the group consisting of —F, —Cl,

C 1-2 alkyl, —CH 2 OH, —CN, and —OR; and

each of R and R′ independently is hydrogen or C 1-4 alkyl, or R and R′ together with the nitrogen atom to which they are attached optionally form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring.

2. The compound of claim 1 , wherein said aryl group for R 4 is optionally substituted and selected from phenyl or naphthalene; the heteroaryl group for R 4 is optionally substituted and selected from a pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, furopyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinolone, furopyrimidine, pyrrolopyrimidine, benzimidazole, benzothiazole, or benzoxazole; and said heterocyclyl group for R 4 is optionally substituted and selected from a tetrahydrofuran, oxetane, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropyridopyrimidine, dihydropyridopyrimidine, dihydrofuropyridine, dihydropyridopyridine, tetrahydropteridine, or isoindoline-1,3-dione.

3. The compound of claim 1 , wherein said heterocyclic group for the R 4 substituents is optionally substituted and selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine, piperazine, furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole or tetrazole.

4. The compound of claim 1 , wherein said heteroaryl group for R 5 is optionally substituted and selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, and wherein said heterocyclyl group for R 5 is optionally substituted and selected from oxetane, tetrahydrofuran, or tetrahydropyran.

5. The compound of claim 1 , wherein Ring C is optionally substituted C 4-6 cycloalkyl or optionally substituted 5-6 membered heteroaryl.

6. The compound of claim 1 , wherein X is —O— or —NH—.

7. The compound of claim 1 , wherein

B is optionally substituted and selected from

8. The compound of claim 1 , wherein each R 3 independently is hydrogen, —C 1-4 alkyl, halogen, —OC 1-2 alkyl, —CN, —C 3-4 cycloalkyl, or —NRR′, wherein each of said R 3 alkyl and cycloalkyl independently is optionally substituted.

9. The compound of claim 1 , wherein

each R 4 independently is hydrogen or an optionally substituted group selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, or phenyl.

10. The compound of claim 1 , wherein each R 4 independently is an optionally substituted group selected from a pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, furopyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinolone, furopyrimidine, pyrrolopyrimidine, benzimidazole, benzothiazole, benzoxazole, tetrahydrofuran, oxetane, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropyridopyrimidine, dihydropyridopyrimidine, dihydrofuropyridine, dihydropyridopyridine, tetrahydropteridine, or isoindoline-1,3-dione.

11. The compound of claim 1 , wherein each R 4 independently is an optionally substituted group selected from imidazole, pyrazole, pyrimidine, furopyrimidine, oxetane or dihydrofuropyrimidine.

12. The compound of claim 1 , wherein each R 4 independently is hydrogen or an optionally substituted group selected from C 1-4 alkyl,

or a ring group selected from C 3-5 cycloalkyl, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, tetrahydrofuran, oxetane, tetrahydropyran, dihydroisoxazole, or phenyl, wherein

X 1 is Nor CR 4d ;

X 2 is N or CR 4c , wherein X 1 and X 2 cannot simultaneously be N;

each of R 4a , R 4b , and R 4c independently is hydrogen, F, Cl, Br, CN, NO 2 , C 1-4 alkyl,

C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), a heterocyclic group selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, or piperazine, or a heteroaryl group selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, or tetrazole; or R 4c and R 4a , or R 4c and R 4b , together with the intervening atoms, optionally form a dihydrofuran, dihydropyran, or tetrahydropiperidine heterocyclic ring group;

R 4d independently is hydrogen, F, Cl, Br, CN, NO 2 , C 1-4 alkyl, C 0-4 alkyl-O—C 1-4 alkyl,

C 2-4 alkenyl, C 2-4 alkynyl, 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 each of the R 4 ring groups is optionally and independently substituted with one or more substituents selected from the group consisting of F, Cl, Br, CN, NO 2 , C 1-4 alkyl, C 0-4 alkyl-C 3-5 cycloalkyl, C 0-4 alkyl-O—C 1-4 alkyl, C 0-4 alkyl-O—C 0-4 alkyl-C 3-5 cycloalkyl,

C 2-4 alkenyl, C 2-4 alkynyl, C(O)OC 1-4 alkyl, C(O)OC 0-4 alkyl-C 3-5 cycloalkyl, C(O)NH 2 , C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , C(O)NH(C 0-4 alkyl-C 3-5 cycloalkyl), a heterocyclic group selected from oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, or piperazine, and a heteroaryl group selected from furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, or tetrazole;

each of said heterocyclic and heteroaryl groups for R 4a , R 4b and R 4c , and for the substituents of R 4 is optionally and independently substituted with one or more substituents selected from the group consisting of —F, C 1-4 alkyl, —OH, —C(O)C 1-4 alkyl, —C(O)OC 1-4 alkyl, or —C(O)OC 0-4 alkyl-C 3-5 cycloalkyl; and wherein each of said alkyl and cycloalkyl groups for R 4a , R 4b and R 4c , and for the substituents of R 4 is optionally and independently substituted with one or more substituents selected from the group consisting of —F and —OH.

13. The compound of claim 1 , wherein each R 4 independently is C 1-4 alkyl or a ring group selected from C 3-5 cycloalkyl, pyrazole, imidazole, oxetane,

wherein said R 4 C 1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of —Br, —Cl, —F, and —O(C 1-4 alkyl), and wherein each of said R 4 ring groups is optionally and independently substituted with one or more substituents selected from the group consisting of —Br, —Cl, —F, C 1-4 alkyl, —CN, —O(C 1-4 alkyl), C 3-6 cycloalkyl, C 0-4 alkyl-O—C 1-4 alkyl, C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , and a piperazine, wherein each of said optional R 4 substituents is optionally and independently substituted with one or more substitutents selected from the group consisting of —F, C 1-4 alkyl, —OH, and —OC 1-4 alkyl.

14. The compound of claim 13 , wherein said R 4 C 1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of —F and —O(C 1-4 alkyl), and wherein each of said R 4 ring groups is optionally and independently substituted with one or more substituents selected from the group consisting of C 1-4 alkyl, —O(C 1-4 alkyl), C 0-4 alkyl-O—C 1-4 alkyl, C(O)NHC 1-4 alkyl, C(O)N(C 1-4 alkyl) 2 , and a piperazine, wherein each of said optional R 4 substituents is optionally substituted with one or more C 1-4 alkyl.

15. The compound of claim 1 , wherein each of R 1 and R 2 independently is hydrogen, —C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —C 0-4 alkyl-NHR 4 , —OR 4 , or R 7 .

16. The compound of claim 1 , wherein R 7 is optionally substituted and selected from a pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, furopyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinolone, furopyrimidine, pyrrolopyrimidine, benzimidazole, benzothiazole, benzoxazole, tetrahydrofuran, oxetane, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropyridopyrimidine, dihydropyridopyrimidine, dihydrofuropyridine, dihydropyridopyridine, tetrahydropteridine, or isoindoline-1,3-dione.

17. The compound of claim 16 , wherein R 7 is optionally substituted and selected from a pyrimidine, imidazole, pyrazole, thiazole, furopyrimidine, pyrrolopyrimidine, benzimidazole, benzothiazole, benzoxazole, oxetane, dihydrofuropyrimidine, or isoindoline-1,3-dione.

18. The compound of claim 17 , wherein R 7 is optionally substituted and selected from a pyrimidine, pyrazole, furopyrimidine, thiazole, or isoindoline-1,3-dione.

19. The compound of claim 1 , wherein X is —O—.

20. The compound of claim 1 , wherein Ring C is optionally substituted C 4-6 cycloalkyl.

21. The compound of claim 20 , wherein Ring C is optionally substituted cyclohexane.

22. The compound of claim 1 , represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein

R 1 is —C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 , —NHS(O) 2 R 4 , —C 0-4 alkyl-NHR 4 , —OR 4 , or R 7 ; and

R 2 is hydrogen.

23. The compound of claim 1 , represented by the following formula:

(III-B-1), or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23 , wherein each R 1 independently is

—C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —C 1-4 alkyl-NHR 4 , —NHR 4 , —OR 4 , or R 7 .

25. The compound of claim 24 , wherein R 1 is —C 1-4 alkyl-NHR 4 , —NHR 4 , or —OR 4 .

26. The compound of claim 1 , represented by following formula:

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 26 , wherein each R 1 independently is

—C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —C 0-4 alkyl-NHR 4 , —OR 4 , or R 7 .

28. The compound of claim 1 , wherein

each R 3 independently is hydrogen, methyl, —Cl, —OCH 3 , —CN, cyclopropyl, —NHCH 3 , or —N(CH 3 ) 2 ; and

R 6 is hydrogen or methyl.

29. The compound of claim 1 , wherein Ring C is optionally substituted 5-6 membered heteroaryl.

30. The compound of claim 1 , wherein

is optionally substituted

31. The compound of claim 1 , wherein Ring C is optionally substituted phenyl.

32. The compound of claim 1 , wherein X is —OC 1-4 alkyl-.

33. The compound of claim 32 , represented by the following formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is hydrogen, —C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 , —NHS(O) 2 R 4 , —C 0-4 alkyl-NHR 4 , —OR 4 , or R 7 .

34. The compound of claim 31 , wherein

is optionally substituted

35. The compound of claim 31 , represented by the following formula:

or a pharmaceutically acceptable salt thereof.

36. The compound of claim 35 , wherein

R 3 is hydrogen, methyl, cyclopropyl, —F, —Cl, —OC 1-2 alkyl, —NRR′, or —CN, wherein each of said R 3 alkyl is optionally substituted with one or more substituents selected from the group consisting of —F, —OH, and —O(C 1-2 alkyl);

each R 4 independently is optionally substituted C 1-4 alkyl optionally substituted with one or more substituents selected from the group consisting of —F, —OH, and —O(C 1-2 alkyl);

R and R′ are each and independently hydrogen or C 1-2 alkyl.

37. The compound of claim 36 , wherein

each R 3 independently is hydrogen, methyl, —Cl, —OCH 3 , —CN, cyclopropyl, —NHCH 3 , or —N(CH 3 ) 2 ; and

R 6 is hydrogen or methyl.

38. A compound selected from the list of compounds in Tables 1 and 2, or a pharmaceutically acceptable salt thereof.

39. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

40. A method of sensitizing a cell to a therapeutic agent or a disease state that induces a DNA lesion comprising the step of contacting the cell with the compound of claim 1 , or a pharmaceutical composition comprising said compound.

41. A method of potentiating a therapeutic regimen for the treatment of cancer in a patient comprising the step of administering to said patient an effective amount of the compound of claim 1 , or a pharmaceutical composition comprising said compound.

42. A method of treating cancer or inhibiting cancer cell growth in a patient comprising administering to said patient an effective amount of the compound of claim 1 , or a pharmaceutical composition comprising said compound, either alone or in combination with one or more additional therapeutic agent.

43. A method of preparing a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the method comprises:

reacting Compound (X-1) with Compound (Y-1) to form a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

L 1 of Compound (X-1) is a halogen, toluenesulfonate, methanesulfonate or trifluoromethanesulfonate, and the other variables of Compound (X-1) are each and independently as described in claim 1 ; and

Compound (Y-1) is

wherein R a is —H or two R a , together with the oxygen atom to which they are attached, form a dioxane ring optionally substituted with one or more C 1-2 alkyl.

44. A method of preparing a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 , —NHS(O) 2 R 4 , —NHR 4 , or —OR 4 ; and the other variables of Formula (I) are each and independently as described in claim 1 ; and wherein the method comprises:

reacting Compound (X-2) with Compound (Y-2) to form a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

Q 1 of Compound (X-2) is —NH 2 or —OH, and the other variables of Compound (X-2) are each and independently as described in claim 1 ; and

Compound (Y-2) is R 4 —C(O)-L 2 , R 4 —O—C(O)-L 2 , NHR 4 —C(O)-L 2 , R 4 S(O) 2 -L 2 , R 4 -L 2 , R 4 C(O)OR b , or R 4 —N═C═O, wherein each R 4 is as described in claim 1 , L 2 is a halogen, toluenesulfonate, methanesulfonate or trifluoromethanesulfonate, and R b is C 1-4 alkyl.

45. A method of preparing a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —NH— or —O—, and the other variables of Formula (I) are each and independently as described in claim 1 , and wherein the method comprises:

(i) reacting Compound (X-3) with Compound (Y-3) to form a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

 or

(ii) reacting Compound X-4 with Compound Y-4 to form a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein L 3 is a halogen; L 4 is a halogen, toluenesulfonate, methanesulfonate, or trifluoromethanesulfonate, and wherein the variables of each of Compounds (X-3), (X-4), (Y-3), and (Y-4) are each and independently as described in claim 1 .

46. A method of preparing a compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein

R 1 is —C(O)NHR 4 , —C(O)OR 4 , —NHC(O)R 4 , —NHC(O)OR 4 , —NHC(O)NHR 4 , —NHS(O) 2 R 4 , —NHR 4 ,

—C 1-4 alkyl-NHR 4 , —OR 4 , or R 7 ; R 2 is hydrogen; each of R 4 independently is 5-10 membered heteroaryl substituted with —OR 5 ; R 7 independently is 5-10 membered heteroaryl substituted with —OR; R, R 5 , and the other variables of formula (I) are each and independently as described in claim 1 , provided that both R and R 5 are not hydrogen, and wherein the method comprises:

reacting Compound (X-5) with R 5 OH or ROH to form a compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

Q 2 is a bond, —C(O)NH—, —C(O)O—, —NHC(O)—, —NHC(O)O—, —NHC(O)NH—, —NHS(O) 2 —, —NH—, —C 1-4 alkyl-NH—, or —O—,

Ring D is 5-10-membered heteroaryl;

L 5 is a halogen; and

R of ROH, R 5 of R 5 OH, and the other variables of Compound (X-5) are each and independently as described in claim 1 , provided that both R and R 5 are not hydrogen.

47. A method of preparing a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is —O—, and the other variables of Formula (I) are each and independently as described in claim 1 , and wherein the method comprises:

wherein L 6 is —OH; L 7 is —OH; and the remaining variables of each of Compounds (X-6), and (Y-6) are each and independently as described in claim 1 .

48. A kit or composition for editing one or more target genomic regions, comprising:

a genome editing system; and

a compound of claim 1 or a pharmaceutically acceptable salt thereof.