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) ionising radiation.
1. A method of treatment of lymphoma or leukemia comprising administering to a subject in need of treatment a therapeutically-effective amount of 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- 13 R A5FA ; and
—R A5FA is saturated aliphatic C 1-3 alkyl.
2. The method according to claim 1 , wherein —R B3 is:
3. The method according to claim 1 , wherein —R B3 is:
4. The method according to claim 1 , wherein —R B3A is —H or -Me.
5. The method according to claim 2 , wherein —R B3A is -Me.
6. The method according to claim 3 , wherein —R B3A is —H or -Me.
7. The method 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 method 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 method 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 method according to claim 4 , wherein —R A4 is —OR A4A ; wherein each —R A4A is independently -Me or -Et.
11. The method according to claim 5 , wherein —R A4 is —OR A4A ; wherein each —R A4A is independently -Me or -Et.
12. The method according to claim 6 , wherein —R A4 is —OR A4A ; wherein each —R A4A is independently -Me or -Et.
13. The method according to claim 1 , wherein —R A5 is —R A5A .
14. The method according to claim 2 , wherein —R A5 is —R A5A .
15. The method according to claim 3 , wherein —R A5 is —R A5A .
16. The method according to claim 4 , wherein —R A5 is —R A5A .
17. The method according to claim 5 , wherein —R A5 is —R A5A .
18. The method according to claim 6 , wherein —R A5 is —R A5A .
19. The method according to claim 7 wherein —R A5 is —R A5A .
20. The method according to claim 8 , wherein —R A5 is —R A5A .
21. The method according to claim 9 , wherein —R A5 is —R A5A .
22. The method according to claim 10 , wherein —R A5 is —R A5A .
23. The method according to claim 11 , wherein —R A5 is —R A5A .
24. The method according to claim 12 , wherein —R A5 is —R A5A .
25. The method according to claim 1 , wherein the compound is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
26. The method according to claim 1 , wherein the compound is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
27. The method according to claim 1 , wherein the compound is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
28. The method according to claim 1 , wherein the compound is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:
29. The method according to claim 1 , wherein the compound is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
30. The method according to claim 1 , wherein the compound is a compound of the following formula, or a pharmaceutically acceptable salt thereof:
31. The method according to claim 1 , wherein the compound is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:
32. The method according to claim 1 , wherein the compound is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:
33. The method according to claim 1 , wherein the compound is a compound of one of the following formulae, or a pharmaceutically acceptable salt thereof:
34. The method according to claim 1 , wherein the compound is a compound of one of the following formulae, or a pharmaceutically acceptable salt, hydrate, or solvate thereof:
35. The method according to claim 1 , wherein the compound is a compound one of the following formulae, or a pharmaceutically acceptable salt thereof:
36. A method of treatment of lymphoma or leukemia comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of the following formula, or a pharmaceutically acceptable salt thereof:
37. The method according to claim 1 , wherein the treatment further comprises administering to the subject one or more other agents selected from: (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) ionising radiation.
38. The method according to claim 36 , wherein the treatment further comprises administering to the subject one or more other agents selected from: (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) ionising radiation.