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 - 21 . (canceled)
22 . 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 a ring system selected from
Ring B is a ring system selected from
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, a 5-10-membered monocyclic or bicyclic heteroaryl ring selected from pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, or quinoline, or a 4-10-membered monocyclic or bicyclic heterocyclyl ring selected from 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, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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.
23 . 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 a compound having the formula:
wherein
Ring A is a ring system selected from
Ring B is a ring system selected from
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, a 5-10-membered monocyclic or bicyclic heteroaryl ring selected from pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole, pyridine, pyrimidine, pyrimidinone, pyrazine, pyridazine, or quinoline, or a 4-10-membered monocyclic or bicyclic heterocyclyl ring selected from 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, a 5-6-membered heteroaryl selected from imidazole, triazole, thiazole, pyridine, or pyrimidine, a 4-6-membered heterocyclyl selected from 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.