DNA-PK inhibitors
The invention relates to the use of compounds of formula (I) and isomers, salts, solvates, chemically protected forms, and prodrugs thereof, in the preparation of a medicament for inhibiting the activity of DNA-PK, wherein R 1 and R 2 are independently hydrogen, an optionally substituted C 1-7 alkyl group, C 3-20 heterocyclyl group, or C 5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms; X and Y are selected from CR 4 and O, O and CR′ 4 and NR″ 4 and N, where the unsaturation is in the appropriate place in the ring, and where one of R 3 and R 4 or R′ 4 is an optionally substituted C 3-20 heteroaryl or C 5-20 aryl group, and the other of R 3 and R 4 or R′ 4 is H, or R 3 and R 4 or R″ 4 together are -A-B—, which collectively represent a fused optionally substituted aromatic ring. The compounds also selectively inhibit the activity of DNA-PK compared to PI 3-kinase and/or ATM.
1. A compound of formula Ia:
or an isomer, salt, chemically protected for or prodrug thereof, wherein:
R 1 and R 2 are independently hydrogen, an optionally substituted C 1-7 alkyl group, C 3-20 heterocyclyl group, or C 5-20 aryl group, or may together form, along with the nitrogen atom to which they are attached, an optionally substituted heterocyclic ring having from 4 to 8 ring atoms;
R 3 and R 4 together are -A-B-, which collectively represent a fused benzene ring, substituted at the 8-position with an optionally substituted tricylic C 3-20 heterocyclic group or at the 6-, 7- or 8-position with a phenyl group substituted by phenyl.
2. A compound according to claim 1 , wherein R 1 and R 2 together with the nitrogen atom to which they are attached form a morpholino group.
3. A compound according to claim 1 , wherein the optionally substituted tricyclic C 3-20 heterocyclic group is an optionally substituted monovalent moiety obtained by removing a hydrogen atom from a ring atom of a compound selected from the group consisting of thioxanthene, xanthene, dibenzofuran and dibenzothiophene.
4. A compound according to claim 3 , wherein the optionally substituted C 3-20 heterocyclic group is an optionally substituted monovalent moiety obtained by removing a hydrogen atom from a ring atom of a compound selected from the group consisting of dibenzofuran and dibenzothiophene.
5. A compound according to claim 3 of formula
6. A pharmaceutical composition comprising a compound as defined in claim 1 , and a pharmaceutically acceptable carrier or diluent.
7. A compound according to claim 1 of formula:
8. A method of potentiating tumour cells for treatment with ionising radiation or chemotherapeutic agents comprising administering a therapeutically-effective amount of the compound of claim 1 .
9. A method of inhibiting DNA-PK in vitro, comprising contacting a cell with an effective amount of the compound of claim 1 .