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 method for treating cancer in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of 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 three- to six-membered heterocycloalkyl;
each 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 method for treating cancer in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) 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 three- to six-membered heterocycloalkyl;
each 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. A method for treating cancer in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of 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 three- to six-membered heterocycloalkyl;
each 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.
4. The method of claim 3 , wherein the cancer is an anaplastic lymphoma kinase (ALK) positive cancer.
5. The method of claim 4 , wherein the ALK positive cancer has a G1202R mutation.
6. The method of claim 3 , wherein the cancer is a ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) positive cancer.
7. The method of claim 6 , wherein the ROS1 positive cancer has a G2032R mutation.
8. The method of claim 3 , wherein the cancer is selected from the group consisting of angiosarcoma, bile duct cancer, breast cancer, colon cancer, colorectal cancer, epithelioid hemangioendothelioma, esophageal cancer, gastric cancer, glioblastoma, an inflammatory myofibroblastic tumor (IMT), kidney cancer, lung cancer, melanoma, neuroblastoma, ovarian cancer, a spitzoid tumor, and thyroid cancer.
9. The method of claim 8 , wherein the cancer is lung cancer.
10. The method of claim 9 , wherein the lung cancer is non-small cell lung cancer.
11. The method of claim 3 , wherein the cancer is a solid tumor.
12. The method of claim 3 , 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.
13. The method of claim 12 , wherein each R 3 is H, F, Cl, CN, CH 3 , or CH 2 CH 3 .
14. The method of claim 13 , wherein R 4 is F.
15. The method of claim 14 , wherein R 5 is H.
16. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
24. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
25. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
26. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
27. The method of claim 3 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
28. A method for treating cancer in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising (i) a pharmaceutically acceptable carrier or excipient, and (ii) 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 three- to six-membered heterocycloalkyl;
each 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.
29. The method of claim 28 , wherein the cancer is an anaplastic lymphoma kinase (ALK) positive cancer.
30. The method of claim 29 , wherein the ALK positive cancer has a G1202R mutation.
31. The method of claim 28 , wherein the cancer is a ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) positive cancer.
32. The method of claim 31 , wherein the ROS1 positive cancer has a G2032R mutation.
33. The method of claim 28 , wherein the cancer is selected from the group consisting of angiosarcoma, bile duct cancer, breast cancer, colon cancer, colorectal cancer, epithelioid hemangioendothelioma, esophageal cancer, gastric cancer, glioblastoma, an inflammatory myofibroblastic tumor (IMT), kidney cancer, lung cancer, melanoma, neuroblastoma, ovarian cancer, a spitzoid tumor, and thyroid cancer.
34. The method of claim 33 , wherein the cancer is lung cancer.
35. The method of claim 34 , wherein the lung cancer is non-small cell lung cancer.
36. The method of claim 28 , wherein the cancer is a solid tumor.
37. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
38. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
39. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
40. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
41. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
42. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
43. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
44. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
45. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
46. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
47. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
48. The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.