DNA-PK inhibitors
View Patent ↗Compounds of formula I: wherein A, B and D are respectively selected from the group consisting of: (i) CH, NH, C; (ii) CH, N, N; and (iii) CH, O, C; the dotted lines represent two double bonds in the appropriate locations; and where Z is selected from S, O, C(═O), CH 2 and NH are disclosed for use in inhibiting DNA-PK.
1. A compound of formula (I):
and isomers, salts, chemically protected forms, or prodrugs thereof, wherein, A, B and D are respectively selected from the group consisting of:
(i) CH, NH, C;
(ii) CH, N, N; and
(iii) CH, O, C;
the dotted lines represent two double bonds in the appropriate locations;
R N1 and R N2 are independently selected from hydrogen, an optionally substituted C 1-7 alkyl group, C 3-20 heterocyclyl group, or C 5-20 aryl group, or together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms;
if A, B, D are selected from groups (i), (ii) above, then Z is selected from the group consisting of S, O, C(═O), CH 2 and NH; and if A, B, D represent group (iii), then Z is selected from the group consisting of O, C(═O), CH 2 and NH;
R 4 is selected from the group consisting of H, OH, NO 2 , NH 2 and Q—Y—X where
Q is —NH—C(═O)— or —O—;
Y is an optionally substituted C 1-15 alkylene group;
X is selected from SR S1 or NR N3 R N4 , wherein,
R S1 , or R N3 and R N4 are independently selected from hydrogen, optionally substituted C 1-7 alkyl, C 5-20 aryl, or C 3-20 heterocyclyl groups, or R N3 and R N4 together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms;
if Q is —O—, then X may additionally be selected from —C(═O)—NR N5 R N6 , wherein R N5 and R N6 are independently selected from hydrogen, optionally substituted C 1-7 alkyl, C 5-20 aryl, or C 3-20 heterocyclyl groups, or R N5 and R N6 together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms and
if Q is —NH—C(═O)—, then —Y—X may additionally be selected from C 1-7 alkyl;
with the proviso that if A, B, D represent group (iii) and R N1 and R N2 together with the carbon atom to which they are bound form a morpholino group, R 4 cannot be H.
2. A compound according to claim 1 , wherein R 4 is Q-Y—X.
3. A compound according to claim 1 , wherein Q is —NH—C(═O)— and X is NR N3 R N4 .
4. A compound according to claim 1 , wherein Q is —O—, X is NR N3 R N4 , and Y is an optionally substituted C 1-3 alkylene group.
5. A compound according to claim 1 , wherein Z is selected from S and O, where appropriate.
6. A compound according to claim 1 , wherein R N1 and R N2 form, along with the nitrogen atom to which they are attached, a heterocyclic ring having from 4 to 8 atoms.
7. A compound according to claim 1 , wherein R N1 and R N2 form, along with the nitrogen atom to which they are attached, a group selected from morpholino and thiomorpholino.
8. A composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.
9. A method of inhibiting DNA-PK in vitro or in vivo, comprising contacting a cell with an effective amount of a compound according to claim 1 .