Heteroaromatic macrocyclic ether chemotherapeutic agents
Inventors
Horan, Joshua Courtney • Tang, Xinxing • MENTE, SCOT RICHARD • Pelish, Henry Efrem • Shair, Matthew D. • Tangpeerachaikul, Anupong
Assignees
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Publication Number
US-12275742-B2
Publication Date
2025-04-15
Expiration Date
Abstract
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.
Core Innovation
The invention relates to treating a ROS1 or ALK positive cancer by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), including an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof. The Formula (I) scaffold is defined by Q, Z, X, Y, and substituent groups R1 through R5, with Q as CH, Z as CR5, and X and Y as 5-membered heteroarylene groups selected from defined groups with indicated attachment points. R1 is selected from H, methyl, and hydroxymethyl, each instance of R2 and R3 is independently selected from enumerated substituent groups, and each of R4 and R5 is independently H or F.
A related embodiment provides a method of treating ROS1 or ALK positive cancer using a pharmaceutical composition comprising (i) a compound of Formula (I), including enantiomers, mixtures of enantiomers, tautomers, or pharmaceutically acceptable salts thereof, and (ii) a pharmaceutically acceptable carrier or excipient. The same structural definitions for Q, Z, X, Y, and R1 through R5 are imposed for the active compound in the composition. The dependent coverage further narrows the active compound to a compound of Formula (I-B) or a pharmaceutically acceptable salt thereof.
The treated cancers are specified as lung cancer, glioblastoma, inflammatory myofibroblastic tumor (IMT), bile duct cancer, ovarian cancer, gastric cancer, colorectal cancer, angiosarcoma, melanoma, epithelioid hemangioendothelioma, esophageal cancer, kidney cancer, breast cancer, colon cancer, thyroid cancer, spitzoid tumor, or neuroblastoma. The disclosure also describes ROS1- or ALK-driven contexts, including tumors with ROS1/ALK fusions and point mutations, and identifies resistance scenarios including ROS1 G2032R.
Claims Coverage
The consolidated independent claim coverage comprises two treatment methods for ROS1 or ALK positive cancer, with 2 inventive feature groupings: direct administration of a Formula (I) compound and administration of a pharmaceutical composition containing a Formula (I) compound plus a pharmaceutically acceptable carrier or excipient. Both claim groupings use the same Formula (I) scaffold constraints for Q, Z, X, Y, and R1 through R5, and dependent refinement narrows at least one embodiment to Formula (I-B).
Treating ROS1 or ALK positive cancer with Formula (I) compound
A method of treating a ROS1 or ALK positive cancer by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), including an enantiomer, a mixture of enantiomers, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q is CH, Z is CR5, X is a 5-membered heteroarylene selected from defined groups with indicated attachment points, Y is a 5-membered heteroarylene selected from defined groups with indicated attachment points, R1 is selected from H, methyl, and hydroxymethyl, each instance of R2 is independently selected from an enumerated group, each instance of R3 is independently selected from an enumerated group, and each of R4 and R5 is independently H or F.
Treating ROS1 or ALK positive cancer with a pharmaceutical composition containing Formula (I)
A method of treating a ROS1 or ALK positive cancer by administering to a subject in need thereof a pharmaceutical composition comprising (i) a compound of Formula (I), including an enantiomer, a mixture of enantiomers, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutically acceptable carrier or excipient, wherein Q is CH, Z is CR5, X is a 5-membered heteroarylene selected from defined groups with indicated attachment points, Y is a 5-membered heteroarylene selected from defined groups with indicated attachment points, R1 is selected from H, methyl, and hydroxymethyl, each instance of R2 is independently selected from an enumerated group, each instance of R3 is independently selected from an enumerated group, and each of R4 and R5 is independently H or F.
Narrowing the active compound to Formula (I-B)
A dependent refinement in which the active compound is a compound of Formula (I-B) or a pharmaceutically acceptable salt thereof.
The claim coverage is centered on treating ROS1 or ALK positive cancers by administering either a therapeutically effective amount of a Formula (I) compound or a pharmaceutical composition containing a Formula (I) compound with a carrier or excipient. The inventive scope is defined by the same structural parameters across the independent claims, and dependent coverage narrows one embodiment to Formula (I-B).
Stated Advantages
Reduced TRK-related CNS adverse events via ROS1/ALK selectivity over TRK.
Documented Applications
Treating ROS1 or ALK positive lung cancer.
Treating ROS1 or ALK positive glioblastoma.
Treating ROS1 or ALK positive inflammatory myofibroblastic tumor (IMT).
Treating ROS1 or ALK positive bile duct cancer.
Treating ROS1 or ALK positive ovarian cancer.
Treating ROS1 or ALK positive gastric cancer.
Treating ROS1 or ALK positive colorectal cancer.
Treating ROS1 or ALK positive angiosarcoma.
Treating ROS1 or ALK positive melanoma.
Treating ROS1 or ALK positive epithelioid hemangioendothelioma.
Treating ROS1 or ALK positive esophageal cancer.
Treating ROS1 or ALK positive kidney cancer.
Treating ROS1 or ALK positive breast cancer.
Treating ROS1 or ALK positive colon cancer.
Treating ROS1 or ALK positive thyroid cancer.
Treating ROS1 or ALK positive spitzoid tumor.
Treating ROS1 or ALK positive neuroblastoma.
Treating cancers driven by ROS1 and/or ALK, including tumors with ROS1/ALK fusions and point mutations, with attention to CNS metastases and resistance scenarios.
Combination therapy concepts for ROS1/ALK positive cancers using other anticancer agents, immuno-oncology agents, and TKIs.
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