Heteroaromatic macrocyclic ether chemotherapeutic agents
Disclosed are heterocyclic heteroaromatic macrocyclic ether compounds of Formula (I): pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof. The disclosure further relates to 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 a pharmaceutically acceptable salt, enantiomer, or tautomer thereof,
wherein:
Q is CH;
Z is CR 5 ;
X is:
wherein:
* indicates the point of attachment of X to the —CH 2 — group bonded to Y;
Y is:
wherein:
* indicates the point of attachment of Y to the —CH 2 — group bonded to X;
R 1 is H, CH 3 , or CH 2 OH;
each R 2 is independently H, halo, C 1-4 alkyl, C 1-4 haloalkyl, CH 2 —C 3-4 cycloalkyl, OC 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 heterocycloalkyl;
R 3 is H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, or OC 1-4 alkyl;
R 4 is H or F; and
R 5 is H or F.
2. A compound of Formula (I-B):
or a pharmaceutically acceptable salt thereof,
wherein:
Q is CH;
Z is CR 5 ;
X is:
wherein:
* indicates the point of attachment of X to the —CH 2 — group bonded to Y;
Y is:
wherein:
* indicates the point of attachment of Y to the —CH 2 — group bonded to X;
R 1 is H, CH 3 , or CH 2 OH;
each R 2 is independently H, halo, C 1-4 alkyl, C 1-4 haloalkyl, CH 2 —C 3-4 cycloalkyl, OC 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 heterocycloalkyl;
R 3 is H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, or OC 1-4 alkyl;
R 4 is H or F; and
R 5 is H or F.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently H, Cl, CH 3 , CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , CHF 2 , CF 3 , CH 2 CH 2 F, CH 2 CHF 2 , CH 2 -cyclopropyl, OCH 3 , cyclopropyl, cyclobutyl, or oxetanyl.
4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, F, Cl, CN, CH 3 , or H 2 CH 3 .
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 4 is F.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
7. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 2 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 7 , or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 8 , or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 9 , or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 10 , or a pharmaceutically acceptable salt thereof.
23. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 11 , or a pharmaceutically acceptable salt thereof.
24. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 12 , or a pharmaceutically acceptable salt thereof.
25. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 13 , or a pharmaceutically acceptable salt thereof.
26. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 14 , or a pharmaceutically acceptable salt thereof.
27. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 15 , or a pharmaceutically acceptable salt thereof.
28. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 16 , or a pharmaceutically acceptable salt thereof.
29. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 17 , or a pharmaceutically acceptable salt thereof.
30. A pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) the compound of claim 18 , or a pharmaceutically acceptable salt thereof.