Inhibitors of cyclin-dependent kinase 7 (CDK7)
The present invention provides various compositions, including compounds of Formula (I) or (Ia), or a species thereof, and pharmaceutically acceptable salts, solvates (e.g., hydrates), stereoisomer, tautomers, isotopic and other specified forms thereof. Also provided are methods (or uses) and kits involving the compounds or pharmaceutically acceptable compositions containing them for treating or preventing a disease (e.g., a proliferative disease such as cancer) in a subject. Administration of a compound or pharmaceutical composition described herein is expected to inhibit cyclin-dependent kinase 7 (CDK7), and thereby, induce apoptosis in tumor cells in the subject.
1. A compound of structural Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl or ethyl;
R 2 is methyl or ethyl;
R 3 is 5-methylpiperidin-3-yl, 5,5-dimethylpiperidin-3-yl, 6-methylpiperidin-3-yl, or 6,6-dimethylpiperidin-3-yl, wherein one or more hydrogen atoms in R 3 is optionally replaced by deuterium; and
R 4 is —CF 3 or chloro.
2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein (i) R 1 is methyl and R 2 is methyl or (ii) R 1 is methyl and R 2 is ethyl.
3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 4 is —CF 3 .
4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 4 is chloro.
5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 3 is 5-methylpiperidin-3-yl.
6. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 3 is 5,5-dimethylpiperidin-3-yl.
7. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 3 is 6-methylpiperidin-3-yl.
8. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 3 is 6,6-dimethylpiperidin-3-yl.
9. The compound of claim 1 , having structural Formula (Ia):
or the pharmaceutically acceptable salt thereof, wherein R 3 is
10. The compound of claim 9 or the pharmaceutically acceptable salt thereof, wherein (i) R 1 is methyl and R 2 is methyl or (ii) R 1 is methyl and R 2 is ethyl.
11. The compound of claim 9 or the pharmaceutically acceptable salt thereof, wherein R 4 is —CF 3 .
12. The compound of claim 9 or the pharmaceutically acceptable salt thereof, wherein R 4 is chloro.
13. The compound of claim 9 , wherein the compound is:
or is a pharmaceutically acceptable salt of any one of the foregoing compounds.
14. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein one or more hydrogen atoms in R 3 is replaced with deuterium.
15. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein none of the hydrogen atoms in R 3 are replaced with deuterium.
16. The compound of claim 1 , wherein the compound is in the form of the pharmaceutically acceptable salt.
17. The compound of claim 16 , wherein the pharmaceutically acceptable salt is an acid addition salt.
18. The compound of claim 4 , wherein the acid addition salt is formed with lactic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid.
19. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19 , wherein the composition is formulated for oral administration.
21. The pharmaceutical composition of claim 19 , wherein the composition is formulated as an aqueous or non-aqueous solution or suspension.
22. The pharmaceutical composition of claim 19 , wherein the composition is formulated as a tablet or capsule.
23. The pharmaceutical composition of claim 19 , wherein the composition is formulated in unit dosage form.
24. The pharmaceutical composition of claim 19 , wherein the pharmaceutically acceptable carrier comprises an inert diluent, a dispersing or granulating agent, a surface active agent or emulsifier, a disintegrating agent, a binding agent, a preservative, a buffering agent, or an emulsifier.
25. The pharmaceutical composition of claim 19 , wherein the pharmaceutically acceptable carrier comprises a cellulose-based substance.
26. The pharmaceutical composition of claim 19 , wherein the pharmaceutically acceptable carrier comprises lactose and/or corn starch.
27. The pharmaceutical composition of claim 19 , wherein the pharmaceutically acceptable carrier is a sterile liquid.