Substituted benzooxadiazole DNA-PK inhibitors
Provided are compounds of Formula (I): wherein R 1 , R 2 , X, Ring A, Ring B, and Ring C are as defined herein. Compounds of Formula (I) are useful as inhibitors of DNA-PK. Also provided are pharmaceutical compositions comprising said compounds and methods of using the compounds and compositions in the treatment of various diseases, conditions, and disorders.
1. A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
Ring A is
Ring B is
wherein Ring B is optionally substituted with up to four fluorine atoms, up to two OH, or up to two C 1-4 alkyl which is optionally substituted with up to three fluorine atoms, up to two OH, or up to two —OC 1-2 alkyl groups;
Ring C is cyclohexane or cyclobutane;
X is —NH—, —O—, or —OC 1-4 alkyl-;
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 , —C 0-4 alkyl-NHR 4 , or —OR 4 , wherein R 1 and R 2 cannot simultaneously be hydrogen, and wherein R 1 and R 2 and the intervening carbon atom can form a dioxane or dioxolane ring;
R 4 is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-5 cycloalkyl, phenyl, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, quinoline, oxetane, tetrahydrofuran, tetrahydropyran, dihydroisoxazole, pyrimidine-2,4(1H,3H)-dione, dihydrofuropyrimidine, dihydropyranopyrimidine, dihydropyrrolopyrimidine, tetrahydropteridine, or tetrahydropyridopyrimidine, wherein each of said R 4 groups is optionally substituted with up to four Br, Cl, F, or C 1-4 alkyl; up to three 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(C 0-4 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 , oxetane, azetidine, tetrahydrofuran, dihydropyran, tetrahydropyran, morpholine, piperidine, pyrrolidine, piperazine, furan, oxazole, oxadiazole, pyrrole, pyrazole, triazole, oxadiazole, or tetrazole; or up to two OR 5 , wherein each of said optional R 4 substituents is optionally substituted with up to four fluorine atoms, up to two C 1-4 alkyl groups, up to two OH groups, up to two OC 1-4 alkyl groups, up to two SC 1-4 alkyl groups, a C(O)C 1-4 alkyl, a C(O)OC 1-4 alkyl, or a C(O)OC 0-4 alkyl-C 3-5 cycloalkyl; and
each R 5 is independently hydrogen, C 1-4 alkyl, imidazole, triazole, thiazole, pyridine, oxetane, tetrahydrofuran, or tetrahydropyran, and each R 5 group is optionally substituted with chloro, up to three fluorine atoms, up to two C 1-2 alkyl, CH 2 OH, CN, up to two OH, up to two OC 1-2 alkyl, spirooxetane, pyrrolidine, or triazole, or two R 5 groups together with the intervening nitrogen atom form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is cyclobutane.
3. The compound of claim 2 , represented by Formula (II), or a pharmaceutically acceptable salt thereof:
4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is cyclohexane.
6. The compound of claim 5 , represented by Formula (III), or a pharmaceutically acceptable salt thereof:
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein X is —NH—.
8. The compound of claim 7 , represented by Formula (III-A-2), or a pharmaceutically acceptable salt thereof:
9. The compound of claim 7 , represented by Formula (III-B-2), or a
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein
11. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R is —C 0-4 alkyl-NHR 4 or —OR 4 .
12. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein X is —O—.
13. The compound of claim 12 , represented by Formula (III-C-2), or a pharmaceutically acceptable salt thereof:
14. The compound of claim 12 , represented by Formula (III-D-2), or a pharmaceutically acceptable salt thereof:
15. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
16. The compound of claim 14 , or a pharmaceutically acceptable salt thereof, wherein is R 1 is —C 0-4 alkyl-NHR 4 or —OR 4 .
17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein is R 1 is —NHR 4 .
18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein is R 1 is —OR 4 .
19. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
20. A compound of the formula:
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of claim 20 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
22. A compound of the formula:
or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising a compound of claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.