DNA-PK inhibitors
The present invention relates to compounds useful as inhibitors of DNA-PK. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
1. A method of sensitizing a cell to an agent that induces a DNA lesion comprising the step of contacting the cell with a compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein
Ring A is
Ring B is
wherein Ring B is optionally substituted with up to 4 fluorine atoms or up to two C 1-4 alkyl optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
X is NH or O;
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 , 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 3 is hydrogen, C 1-4 alkyl, fluoro, chloro, OC 1-2 alkyl, C(O)OH, C(O)OC 1-2 alkyl, CN, C(O)NHC 1-2 alkyl, or C(O)NH 2 , wherein each of said R 3 alkyl is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
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 Br, Cl, up to three fluorine atoms, up to three C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, an oxetane ring, a tetrahydrofuran ring, a dihydropyran ring, a tetrahydropyran ring, a pyrrolidine ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxadiazole ring, CN, CH 2 OR 5 , C(O)R 5 , C(O)N(R 5 ) 2 , C(O)OR 5 , NO 2 —NHC(O)R 5 , N(R 5 ) 2 , or up to two OR 5 , wherein each of said optional R 4 substituents is optionally substituted with up to 3 fluorine atoms, up to two C 1-4 alkyl groups, up to two OH groups, up to two OC 1-4 alkyl groups, or up to two SC 1-4 alkyl groups; and
each R 5 is, independently, hydrogen, C 1-4 alkyl, imidazole, triazole, thiazole, pyridine, pyrimidine, 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, a 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, wherein each of said rings is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
or a pharmaceutical composition comprising said compound, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein X is NH.
3. The method of claim 1 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 3 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
5. The method of claim 2 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
6. The method of claim 5 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
7. The method of claim 6 , wherein
R 3 is hydrogen, C 1-4 alkyl, fluoro, chloro, OC 1-2 alkyl, C(O)OH, C(O)OC 1-2 alkyl, CN, C(O)NHC 1-2 alkyl, or C(O)NH 2 , wherein each of said R 3 alkyl is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
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;
each of said R 4 groups is optionally substituted with Br, Cl, up to three fluorine atoms, up to three C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, an oxetane ring, a tetrahydrofuran ring, a dihydropyran ring, a tetrahydropyran ring, a pyrrolidine ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxadiazole ring, CN, CH 2 OR 5 , C(O)R 5 , C(O)N(R 5 ) 2 , C(O)OR 5 , NO 2 , NHC(O)R 5 , N(R 5 ) 2 , or up to two OR 5 , wherein each of said optional R 4 substituents is optionally substituted with up to 3 fluorine atoms, up to two C 1-4 alkyl groups, up to two OH groups, up to two OC 1-4 alkyl groups, or up to two SC 1-4 alkyl groups; and
each R 5 is, independently, hydrogen, C 1-4 alkyl, imidazole, triazole, thiazole, pyridine, pyrimidine, 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, 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, wherein each of said rings is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups.
8. The method of claim 6 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein X is O.
10. The method of claim 9 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 10 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 9 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
14. The method of claim 13 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
15. The method of claim 13 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof, wherein Y is O or NH.
16. The method of claim 13 , wherein the compound is of formula:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 16 , wherein
R 3 is hydrogen, C 1-4 alkyl, fluoro, chloro, OC 1-2 alkyl, C(O)OH, C(O)OC 1-2 alkyl, CN, C(O)NHC 1-2 alkyl, or C(O)NH 2 , wherein each of said R 3 alkyl is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups;
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;
each of said R 4 groups except hydrogen is optionally substituted with Br, Cl, up to three fluorine atoms, up to three C 1-4 alkyl, up to two C 0-4 alkyl-R 5 , up to two C 0-4 alkyl-O-C 0-4 alkyl-R 5 , C 2-4 alkenyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, CN NO 2 , C(O)R 5 , C(O)N(R 5 ) 2 , C(O)OC 0-4 alkyl-R 5 , NHC(O)R 5 , N(R 5 ) 2 , oxetane, azetidine tetrahydrofuran, dihydropyran, tetrahydropyran, pyrrolidine, pyrazole, triazole, tetrazole, or oxadiazole, wherein each of said optional R 4 substituents is optionally substituted with up to 3 fluorine atoms, up to two C 1-4 alkyl groups, up to two OH groups, up to two OC 1-4 alkyl groups, or up to two SC 1-4 alkyl groups; and
each R 5 is, independently, hydrogen, C 1-4 alkyl, C 3-5 cycloalkyl, imidazole, triazole, thiazole, pyridine, pyrimidine, 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, pyrrolidine, or triazole, or two R 5 groups together with an intervening nitrogen atom form a morpholine ring, azetidine ring, pyrrolidine ring, piperidine ring, or piperazine ring, wherein each of said rings is optionally substituted with up to 3 fluorine atoms, up to two OH, or up to two OC 1-2 alkyl groups.
18. The method of claim 1 , wherein
19. The method of claim 1 , wherein the compound of formula (I) is of formula:
or pharmaceutically acceptable salts thereof.