Substituted heterocyclyl derivatives as CDK inhibitors
The present invention provides substituted heterocyclylderivatives of formula (I), which are therapeutically useful, particularly as selective transcriptional CDK inhibitors including CDK7, CDK9, CDK12, CDK13 and CDK18, more particularly transcriptional CDK7 inhibitors. These compounds are useful in the treatment and prevention of diseases and/or disorders associated with selective transcriptional CDKs in a mammal. The present invention also provides preparation of the compounds and pharmaceutical formulations comprising at least one of the substituted heterocyclyl derivatives of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.
1. A compound having the structure:
or a pharmaceutically acceptable salt, or an enantiomer thereof.
2. A compound having the structure:
or a pharmaceutically acceptable salt, or an enantiomer thereof.
3. The compound of claim 2 , which is (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or an enantiomer thereof.
4. A compound having the structure:
or a pharmaceutically acceptable salt, or an enantiomer thereof.
5. The compound of claim 1 , which is (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or an enantiomer thereof.
6. The compound of claim 1 , which is (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , which is an enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , which is an enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.
9. The compound of claim 1 , which is (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.
10. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
11. A pharmaceutical composition comprising the compound of claim 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
12. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable carrier or excipient.
13. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable carrier or excipient.
14. A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable carrier or excipient.
15. The compound of claim 2 , which is (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt thereof.
16. The compound of claim 2 , which is the (S)-enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt thereof.
17. The compound of claim 2 , which is the (R)-enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)-phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising the compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
19. A pharmaceutical composition comprising the compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
20. A pharmaceutical composition comprising the compound of claim 15 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
21. A pharmaceutical composition comprising the compound of claim 16 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
22. A pharmaceutical composition comprising the compound of claim 17 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
23. The compound of claim 4 , which is (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide or a pharmaceutically acceptable salt thereof.
24. The compound of claim 4 , which is (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide or an enantiomer thereof.
25. The compound of claim 4 , which is the (S)-enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide or a pharmaceutically acceptable salt thereof.
26. The compound of claim 4 , which is the (R)-enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)pyridin-2-yl)-4-(pyrrolidin-1-yl)but-2-enamide or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising the compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
28. A pharmaceutical composition comprising the compound of claim 23 and a pharmaceutically acceptable carrier or excipient.
29. A pharmaceutical composition comprising the compound of claim 25 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
30. A pharmaceutical composition comprising the compound of claim 26 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.