Macrocyclic compounds for treating disease
Inventors
ROGERS, Evan W. • CUI, Jingrong J. • Zhai, Dayong • Zhang, Han • Ung, Jane • Deng, Wei • WHITTEN, JEFFREY
Assignees
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Publication Number
US-11286265-B2
Publication Date
2022-03-29
Expiration Date
Abstract
The present disclosure relates to certain macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat disease, such as cancer.
Core Innovation
The disclosure defines families of compounds by depicted chemical structures and includes pharmaceutically acceptable salts thereof. The compounds include fluorinated spiro/bridged fused heterocyclic compounds, closely related substituted heteroaromatic compounds, fluorinated bicyclic heteroaromatic compounds, macrocyclic derivative chemotypes, and benzo-fused heterocyclic carboxamide-containing compounds, with multiple specific structural embodiments shown in chemical figures.
The structures are described with variable definitions for substituents and ring systems, including M, M1, X, R1 through R10, Y, Z1 through Z6, and related parameters, together with allowed atom types and structural motifs such as O, S, S(O), and S(O)2. The disclosed subject matter includes stereochemically defined variations such as 3aR/21aS and 3aS/21aR, mono-, di-, and tri-fluoro substitution patterns, and additional substituent variations including methyl, hydroxy, and an acetyl substituent.
The document additionally describes pharmaceutical compositions including the compounds or their pharmaceutically acceptable salts together with diluents, carriers, or excipients. It further states therapeutic use in treating disease such as cancer, including treating cancer by inhibiting RET or SRC, ameliorating cancer in a human, and using the compound to treat thyroid cancer.
Claims Coverage
The consolidated claim coverage includes structurally defined compounds and pharmaceutically acceptable salts, with dependent coverage extending to pharmaceutical compositions and therapeutic methods. Across the input items, the inventive features repeatedly include the compound structure, pharmaceutical composition with diluent, carrier, or excipient, and cancer-related administration, including thyroid cancer and other specified cancers.
Structure-defined compound and pharmaceutically acceptable salt
A compound having a depicted chemical structure or a pharmaceutically acceptable salt thereof.
Macrocyclic derivative compound structure
A compound having a depicted macrocyclic derivative structure or a pharmaceutically acceptable salt thereof.
Depicted benzo-fused heterocyclic carboxamide-containing compound structure
A compound having a depicted benzo-fused heterocyclic carboxamide-containing structure or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with diluent, carrier, or excipient
A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof together with a diluent, carrier, or excipient.
Method of administering an effective amount to ameliorate cancer
A method of ameliorating cancer in a human by administering an effective amount of the compound or pharmaceutically acceptable salt thereof.
Cancer-type limitation including thyroid cancer
The method further limits the cancer to specified cancer types, including thyroid cancer.
Overall, the claims center on structurally defined compounds and their pharmaceutically acceptable salts, with dependent coverage extending to pharmaceutical compositions and cancer-amelioration methods, including thyroid cancer and other specified cancers.
Stated Advantages
Treating cancer by inhibiting RET or SRC via contacting kinase-containing cells.
Ameliorating cancer by administering an effective amount of the compound or a pharmaceutically acceptable salt.
Documented Applications
Biochemical kinase assay inhibition activity against RET variants and related kinases.
Cell proliferation/inhibition data with immunoblotting and cell-based assays.
In vivo xenograft efficacy in RET-driven tumor models, including tumor growth inhibition and tumor regression.
Treating cancer by inhibiting RET or SRC via contacting kinase-containing cells.
A method for ameliorating cancer in a human by administering an effective amount of a compound of the structure, with cancers selected from named cancer types including thyroid, lung, colon, breast, prostate, hepatocellular carcinoma, and head and neck cancer.
A method for using the compound to treat thyroid cancer.
Pharmaceutical compositions including the compound or pharmaceutically acceptable salt with diluents, carriers, or excipients.
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