C26-linked rapamycin analogs as mTOR inhibitors
Inventors
Semko, Christopher Michael • Wang, Gang • Burnett, G. Leslie • Aggen, James Bradley • KISS, Gert • Cregg, James Joseph • Gliedt, Micah James Evans • Pitzen, Jennifer • Lee, Julie Chu-Li • Won, Walter • Thottumkara, Arun P. • Gill, Adrian Liam
Assignees
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Publication Number
US-12187746-B2
Publication Date
2025-01-07
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 a method of treating a disease or disorder in a subject suffering from or susceptible to developing a disease or disorder mediated by mTOR. The method comprises administering a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof.
The disease or disorder is selected to include cancer, immune-mediated disease, and additional listed conditions. Cancer includes brain and neurovascular tumors, head and neck cancers, breast cancer, lung cancer, mesothelioma, lymphoid cancer, stomach cancer, kidney cancer, renal carcinoma, liver cancer, ovarian cancer, testicular cancer, gastrointestinal cancer, prostate cancer, glioblastoma, skin cancer, melanoma, lymphoma, leukemia, gastrointestinal stromal tumors, and neuro-endocrine tumors.
Immune-mediated disease includes resistance by transplantation of named organs or tissues, graft-versus-host diseases brought about by medulla ossium transplantation, and rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, and glomerulonephritis. The additional conditions include sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, stroke, diminished life expectancy, impaired kidney function, age-related hearing loss, aging-related mobility disability, cognitive decline, age-related dementia, memory impairment, tendon stiffness, heart dysfunction, immunosenescence, obesity, and diabetes.
Formula Ia is defined by detailed structural variables and options, including R32, A3, R26, A1, A2, Q, X, X1, W, W1, G, G1, G2, L1, L2, L3, B, B1, R3, R4, R5, R6, R7, R8, Y, and integer ranges for n, o, p, q, and r. The structural definitions specify allowed ring systems, optional substitution patterns, and connectivity constraints for the administered compound.
Claims Coverage
One independent claim is present. It covers treatment of an mTOR-mediated disease or disorder by administering a therapeutically effective amount of a Formula Ia compound or specified derivative forms, with the disease/disorder scope and the compound structure both extensively defined.
mTOR-mediated disease treatment by administering Formula Ia
A method of treating a disease or disorder in a subject suffering from or susceptible to developing a disease or disorder mediated by mTOR, comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or oxepane isomer thereof.
Disease selection including cancer, immune-mediated disease, and additional listed conditions
The method wherein the disease or disorder is cancer selected from the listed cancer types; or an immune-mediated disease selected from the listed transplantation resistance conditions, graft-versus-host diseases, and named autoimmune diseases; or a disease or disorder selected from the listed additional conditions including sarcopenia and multiple aging-related and other disorders.
Formula Ia structural constraints for R32, A3, and R26
The administered Formula Ia compound is defined such that R32 is H, O, -OR3, or -N3; A3 is -[C(R3)2]n-, (C6-C10) arylene, cycloalkylene, heteroarylene, or heterocyclylene; and R26 is -A1-L1-A2-B, -A1-A2-B, or -L2-A1-L1-A2-L3, with A1 and A2 independently absent or independently selected as defined.
Ring and substituent constraints within Formula Ia
Each Q is independently 1 to 3 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; each X is independently absent or 1 to 2 rings selected from arylene, cycloalkylene, heteroarylene, and heterocyclylene; and X1, W, W1, G, G1, and G2 are independently absent or heteroarylene or heterocyclylene ring according to the claim. The heteroarylene, heterocyclylene, and arylene are optionally substituted with alkyl, hydroxyalkyl, haloalkyl, alkoxy, halogen, or hydroxyl.
Allowed substituent values and integer ranges for Formula Ia
Each R3 is independently H or (C1-C6)alkyl; each R4 is independently H, (C1-C6)alkyl, halogen, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, or (C6-C10) aryl with optional substitution; each R5, R6, R7, and R8 are independently H, (C1-C6)alkyl, -C(O)OR3, or -N(R3)2; each Y is independently C(R3)2 or a bond; and n, o, p, q, and r are within the recited integer ranges.
Claim coverage centers on an mTOR-mediated treatment method using a therapeutically effective amount of a Formula Ia compound, with explicit disease-category selection and extensive structural constraints on the administered compound. The inventive features are the enumerated therapeutic scope and the defined Formula Ia variable patterns.
Stated Advantages
Treating, preventing, or reducing risk of mTOR-mediated diseases or disorders.
Documented Applications
Treatment of cancer selected from multiple enumerated cancer types.
Treatment of immune-mediated diseases selected from transplant resistance categories, graft-versus-host diseases, and named autoimmune diseases.
Treatment of diseases or disorders selected from sarcopenia, aging-related mobility disability, heart dysfunction, immunosenescence, and other listed aging-related and non-oncology conditions.
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