5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention pertains to certain pyridyl-amino-pyrazine carbonitrile compounds that, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or thymidylate synthase (TS) inhibitor; (d) a microtubule targeted agent; and (e) ionizing radiation.
1. A compound of the following formula, or a pharmaceutically acceptable salt thereof:
wherein:
—R B3 is independently:
each —R B3A is independently —H or saturated aliphatic C 1-3 alkyl;
—R A4 is independently —NHR A4A , —NR A4A 2 , or —OR A4A ;
each —R A4A is independently saturated aliphatic C 1-3 alkyl;
—R A5 is independently —R A5A , —R A5B , —R A5C , —R A5D , —R A5E , or —R A5F ;
—R A5A is independently:
—R A5AA is saturated aliphatic C 1-3 alkyl;
—R A5B is —CF 3 ;
—R A5C is independently —F, —Cl, —Br, or —I;
—R A5D is independently —C≡CH, —C≡C—R A5DA , or —C≡C—R A5DB —OH;
—R A5DA is saturated aliphatic C 1-4 alkyl;
—R A5DB is saturated aliphatic C 1-4 alkylene;
—R A5E is independently saturated C 3-6 cycloalkyl;
—R A5F is —C(═O)O—R A5FA ; and
—R A5FA is saturated aliphatic C 1-3 alkyl.
2. The compound according to claim 1 , wherein —R B3 is:
3. The compound according to claim 1 , wherein —R B3 is:
4. The compound according to claim 1 , wherein —R B3A is —H or -Me.
5. The compound according to claim 2 , wherein —R B3A is -Me.
6. The compound according to claim 3 , wherein —R B3A is —H or -Me.
7. The compound according to claim 4 , wherein —R A4 is independently —NHR A4A or —NR A4A 2 ; wherein each —R A4A is independently -Me or -Et.
8. The compound according to claim 5 , wherein —R A4 is independently —NHR A4A or —NR A4A 2 ; wherein each —R A4A is independently -Me or -Et.
9. The compound according to claim 6 , wherein —R A4 is independently —NHR A4A or —NR A4A 2 ; wherein each —R A4A is independently -Me or -Et.
10. The compound according to claim 4 , wherein —R A4 is —OR A4A ; wherein each —R A4A is independently -Me or -Et.
11. The compound according to claim 5 , wherein —R A4 is —OR A4A ; wherein each —R A4A is independently -Me or -Et.
12. The compound according to claim 6 , wherein —R A4 is —OR A4A ; wherein each —R A4A is independently -Me or -Et.
13. The compound according to claim 1 , wherein —R A5 is —R A5A .
14. The compound according to claim 2 , wherein —R A5 is —R A5A .
15. The compound according to claim 3 , wherein —R A5 is —R A5A .
16. The compound according to claim 4 , wherein —R A5 is —R A5A .
17. The compound according to claim 5 , wherein —R A5 is —R A5A .
18. The compound according to claim 6 , wherein —R A5 is —R A5A .
19. The compound according to claim 7 wherein —R A5 is —R A5A .
20. The compound according to claim 8 , wherein —R A5 is —R A5A .
21. The compound according to claim 9 , wherein —R A5 is —R A5A .
22. The compound according to claim 10 , wherein —R A5 is —R A5A .
23. The compound according to claim 11 , wherein —R A5 is —R A5A .
24. The compound according to claim 12 , wherein —R A5 is —R A5A .
25. The compound according to claim 1 , which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
26. The compound according to claim 1 , which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
27. The compound according to claim 1 , which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
28. The compound according to claim 1 , which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:
29. The compound according to claim 1 , which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
30. The compound according to claim 1 , which is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
31. The compound according to claim 1 , which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:
32. The compound according to claim 1 , which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:
33. The compound according to claim 1 , which is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:
34. The compound according to claim 1 , which is a compound of one of the following formulae, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
35. The compound according to claim 1 , which is a compound one of the following formulae, or a pharmaceutically acceptable salt thereof:
36. A compound of the following formula, or a pharmaceutically acceptable salt thereof:
37. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.
38. A method of preparing a pharmaceutical composition comprising the step of admixing a compound according to claim 1 , and a pharmaceutically acceptable carrier or diluent.
39. A method of treatment of neuroblastoma and colon cancer comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to claim 1 .