Heteroaromatic macrocyclic ether chemotherapeutic agents
Disclosed are heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof. Also disclosed are methods of treating or preventing cancer using the heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions thereof.
1. A compound of Formula (I), or an enantiomer, a mixture of enantiomers, or a tautomer thereof, or a pharmaceutically acceptable salt thereof:
wherein
Q is CH;
Z is CR 5 ;
X is a 5-membered heteroarylene selected from the group consisting of
wherein * indicates the point of attachment of X to the methylene group bonded to X and Y;
Y is a 5- membered heteroarylene selected from the group consisting of
wherein * indicates the point of attachment of Y to the methylene group bonded to X and Y;
R 1 is selected from the group consisting of H, methyl, and hydroxymethyl;
each instance of R 2 is independently selected from the group consisting of H, CN, halo, C 1-4 alkoxy, C 1-4 alkyl, halo-C 1-4 alkyl, C 3-4 cycloalkylmethyl, C 3-6 cycloalkyl, and C 3-6 heterocyclyl;
each instance of R 3 is independently selected from the group consisting of H, halo, CN, C 1-4 alkoxy, halo-C 1-4 alkyl, and C 1-4 alkyl; and
each of R 4 and R 5 is independently H or F.
2. The compound of claim 1 , which is a compound of Formula (I-B):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each instance of R 2 is independently selected from the group consisting of H, chloro, fluoro, CN, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl, and oxetanyl.
4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein each instance of R 3 is independently selected from the group consisting of H, fluoro, chloro, bromo, CN, methoxy, difluoromethyl, trifluoromethyl, methyl, and ethyl.
5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 4 is F.
6. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
7. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 2 , which is:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
19. A pharmaceutical composition, comprising the compound of claim 6 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
20. A pharmaceutical composition, comprising the compound of claim 7 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
21. A pharmaceutical composition, comprising the compound of claim 8 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
22. A pharmaceutical composition, comprising the compound of claim 9 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
23. A pharmaceutical composition, comprising the compound of claim 10 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
24. A pharmaceutical composition, comprising the compound of claim 11 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
25. A pharmaceutical composition, comprising the compound of claim 12 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
26. A pharmaceutical composition, comprising the compound of claim 13 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
27. A pharmaceutical composition, comprising the compound of claim 14 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
28. A pharmaceutical composition, comprising the compound of claim 15 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
29. A pharmaceutical composition, comprising the compound of claim 16 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
30. A pharmaceutical composition, comprising the compound of claim 17 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
31. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 5 is H.