Amino-triazolopyridine compounds and their use in treating cancer
The specification generally relates to compounds of Formula (I): and pharmaceutically acceptable salts thereof, where R 1 and R 2 have any of the meanings defined herein. The specification also relates to the use of such compounds and salts thereof to treat or prevent DNA-PK mediated disease, including cancer. The specification further relates to pharmaceutical compositions comprising such compounds and salts; kits comprising such compounds and salts; methods of manufacture of such compounds and salts; intermediates useful in the manufacture of such compounds and salts; and to methods of treating DNA-PK mediated disease, including cancer, using such compounds and salts.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, where:
R 1 is a cyclohexyl, tetrahydrofuranyl or oxanyl ring, each of which is optionally substituted by one or more groups selected from hydroxyl, methoxy and methyl; and
R 2 is hydrogen or methyl.
2. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 1 is oxanyl.
3. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 2 , wherein R 1 is oxan-4-yl.
4. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 1 is cyclohexyl.
5. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 1 is 1-hydroxy-1-methyl-cyclohex-4-yl.
6. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein R 2 is hydrogen.
7. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is selected from the group consisting of:
9-((1r,4r)-4-hydroxycyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo [1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one;
9-((1s,4s)-4-hydroxycyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo [1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one;
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
2-((2,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7-methyl-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
9-((1s,4s)-4-methoxycyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo [1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one;
9-((1r,4r)-4-methoxycyclohexyl)-7-methyl-2-((7-methyl- [1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one;
(S)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-3-yl)-7,9-dihydro-8H-purin-8-one;
(R)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-3-yl)-7,9-dihydro-8H-purin-8-one;
9-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one;
9-((1s,4s)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo [1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one;
(S)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydrofuran-3-yl)-7,9-dihydro-8H-purin-8-one;
9-((1s,4s)-4-hydroxy-1-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one; and
9-cyclohexyl-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin -8-one.
8. The compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , wherein the compound is selected from the group consisting of:
7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one;
9-((1r,4r)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one; and
9-((1s, 4s)-4-hydroxy-4-methylcyclohexyl)-7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-7,9-dihydro-8H-purin-8-one.
9. A pharmaceutical composition which comprises a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1 , and at least one pharmaceutically acceptable diluent or carrier.
10. 7-Methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one.
11. A pharmaceutically acceptable salt of 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one.
12. A pharmaceutical composition which comprises 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro -2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
13. The pharmaceutical composition according to claim 12 , wherein the composition comprises 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one.
14. The pharmaceutical composition according to claim 12 , wherein the composition comprises a pharmaceutically acceptable salt of 7-methyl-2-((7-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)amino)-9-(tetrahydro-2H-pyran-4-yl)-7,9-dihydro-8H-purin-8-one.