Inhibitors of cyclin dependent kinase 7 (CDK7)
The present invention provides, inter alia, compounds having the structures of formulas described herein; pharmaceutically acceptable salts, solvates, hydrates, tautomers, and isotopic forms thereof; and compositions (e.g., pharmaceutical compositions and kits) containing one or more of the foregoing. Also provided are methods of administering and uses involving the compounds and/or pharmaceutical compositions for treating or preventing disease. The disease can be a proliferative disease, such as a cancer (e.g., a blood cancer (e.g., a leukemia or lymphoma), a brain cancer, a breast cancer, melanoma, multiple myeloma, or an ovarian cancer) a benign neoplasm, pathologic angiogenesis, or a fibrotic disease. While no aspect of the invention is limited by the biological events that may transpire, administering a compound or other composition described herein may selectively inhibit the aberrant expression or activity of cyclin-dependent kinase 7 (CDK7) and, thereby, induce cellular apoptosis and/or inhibit the transcription of disease-related genes in the patient (or in a biological sample).
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
ring A is
ring B is
wherein each of R 2 , R 3 , R 4 and R 5 are, independently, hydrogen or —CH 3 ;
X and Y are, independently, N or CH;
R 1 is hydrogen or fluoro; and
the compound is other than:
2. The compound of claim 1 , wherein ring A is
3. The compound of claim 1 , wherein ring B is
4. The compound of claim 3 , wherein ring B is
5. The compound of claim 1 , wherein X is CH and Y is CH.
6. The compound of claim 1 , wherein X is N.
7. A compound of Formula II:
or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, wherein:
ring A is
and
R 1 is hydrogen or fluoro.
8. A compound selected from any one of the compounds set forth below or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof:
9. A compound selected from any one of the compounds set forth below or a pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof:
10. A pharmaceutical composition comprising a compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof; and a pharmaceutically acceptable excipient.
11. A method of treating a patient suffering from a disease associated with aberrant activity of CDK7, the method comprising a step of administering to the patient a therapeutically effective amount of the compound of claim 1 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, optionally within a pharmaceutical composition.
12. The method of claim 11 , wherein the disease is a proliferative disease, an infectious disease, or a disease caused by or associated with expanded repeats of simple nucleotide tracts.
13. The method of claim 12 , wherein the proliferative disease is a cancer.
14. The method of claim 13 , wherein the cancer is a blood cancer, a bone cancer, a brain cancer, a breast cancer, a lung cancer, melanoma, or an ovarian cancer.
15. The method of claim 11 , further comprising a step of administering to the patient one or more second agents, wherein the second agent is an anti-proliferative agent, an anti-cancer agent, an immunosuppressant agent, or a pain-relieving agent.
16. A pharmaceutical composition comprising a compound of claim 7 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof; and a pharmaceutically acceptable excipient.
17. A method of treating a patient suffering from a disease associated with aberrant activity of CDK7, the method comprising a step of administering to the patient a therapeutically effective amount of the compound of claim 7 or the pharmaceutically acceptable salt, stereoisomer, or isotopic form thereof, optionally within a pharmaceutical composition.
18. The method of claim 17 , wherein the disease is a proliferative disease, an infectious disease, or a disease caused by or associated with expanded repeats of simple nucleotide tracts.
19. The method of claim 18 , wherein the proliferative disease is a cancer.
20. The method of claim 17 , further comprising a step of administering to the patient one or more second agents, wherein the second agent is an anti-proliferative agent, an anti-cancer agent, an immunosuppressant agent, or a pain-relieving agent.