C40-, C28-, and C-32-linked rapamycin analogs as mTOR inhibitors
Inventors
Burnett, G. Leslie • Aggen, James Bradley • Pitzen, Jennifer
Assignees
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Publication Number
US-12048749-B2
Publication Date
2024-07-30
Expiration Date
Abstract
The present disclosure relates to mTOR inhibitors. Specifically, the embodiments are directed to compounds and compositions inhibiting mTOR, methods of treating diseases mediated by mTOR, and methods of synthesizing these compounds.
Core Innovation
The invention relates to mTOR inhibitor chemical entities and rapalog-based bifunctional rapalogs defined by Formula I, Formula Ia, Formula Ib, Formula Ic, Formula II, and Formula IIb, together with representative exemplars, monomers, intermediates, and large-molecule examples. The disclosure includes structural definitions for variables including A1, A2, B, B1, L1, L2, L3, R3-R8, R28, R32, R40, Z1, W, W1, G, G1/G2, Q, and related linker and ring motifs, and states that the compounds may be present as pharmaceutically acceptable salts, tautomers, and stereoisomers.
The described subject matter also includes specific chemical series such as Series 1-8 bifunctional rapalogs, Series 1 bivalent rapamycin products, Series 3 bivalent analogs, Series 6 and further Series 7-8 bivalent analogs, and mTOR-targeting bifunctional rapalog series entities. The content describes mTOR inhibitor compounds, pyrazolo[3,4-d]pyrimidine-based inhibitor monomers, rapamycin-derived intermediates, and bivalent analog constructs, together with stereoisomeric and tautomeric forms and pharmaceutically acceptable salts.
The disclosures further state that the compounds and compositions are useful in mTOR-mediated disease treatment, prevention, and risk reduction in subjects in need thereof, including cancer and immune-mediated diseases. Additional therapeutic framing includes autoimmune disease, inflammatory disease, neurodegenerative disease, metabolic disease, fungal infection, cardiovascular disease, transplant rejection, aging-related conditions, and immunosenescence-related phenomena.
Claims Coverage
The consolidated claim coverage centers on independent method claims for treating specified cancers by administering a therapeutically effective amount of a compound or composition defined by multiple formula options, including stereoisomers, tautomers, and an oxepane isomer, and compositions comprising mixtures of such forms. The inventive coverage repeatedly combines cancer selection, therapeutic administration, and structural/formulation scope, with the formulas spanning rapamycin-related and mTOR inhibitor-related embodiments.
Treating specified cancers by administering a therapeutically effective amount of a formula-defined compound or composition
A method of treating a cancer selected from head and neck cancers, lung cancer, liver cancer, ovarian cancer, prostate cancer, pancreatic cancers, endometrial cancer, vulva cancer, intestinal or rectal cancer, bile duct cancer, and thyroid cancer in a subject in need thereof, comprising administering a therapeutically effective amount of either a compound or a composition selected from multiple formula-defined options.
Formula-defined compound including stereoisomer, tautomer, and oxepane isomer forms
The administered compound is selected from formula options that include a stereoisomer thereof, a tautomer thereof, and an oxepane isomer thereof, with dependent refinements specifying particular depicted compounds or related form variants.
Composition comprising mixtures of depicted compound forms
The administered composition comprises a mixture of depicted compound forms and a stereoisomer or tautomer thereof, including compositions comprising mixtures of the chemical structures shown in the images and their stereoisomeric or tautomeric counterparts.
Overall, the claim set is directed to cancer treatment by administering therapeutically effective amounts of structurally defined compounds or compositions, with the main limitations being the listed cancer types, the formula-based chemical scope, and the inclusion of stereoisomeric, tautomeric, oxepane isomer, and mixture-defined forms.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating cancer selected from the group consisting of head and neck cancers, lung cancer, liver cancer, ovarian cancer, prostate cancer, pancreatic cancers, endometrial cancer, vulva cancer, intestinal or rectal cancer, bile duct cancer, and thyroid cancer in a subject in need thereof.
Treatment, prevention, or reducing risk of an mTOR-mediated disease in a subject in need thereof.
Therapeutic use in cancer and immune-mediated diseases, including autoimmune disease, inflammatory disease, neurodegenerative disease, metabolic disease, fungal infection, cardiovascular disease, transplant rejection, and aging-related conditions.
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