Benzoxazole kinase inhibitors and methods of use
Inventors
Ren, Pingda • Liu, Yi • Wilson, Troy Edward • Li, Liansheng • Chan, Katrina
Assignees
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Publication Number
US-9345706-B2
Publication Date
2016-05-24
Expiration Date
Abstract
The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.
Core Innovation
The disclosure defines extensive structural scope for substituted chemical structures associated with multiple formulas, including Formula I′-A′, Formula I-A, Formula I-B, Formula I′-B′, Formula II-A-1, Formula II-B, Formula III, Formula IV-A, and Formula IV-B. It specifies allowable structures for substituent groups, including aryl, heteroaryl, alkyl, cycloalkyl, heterocyclyl, heteroalkyl, halo, hydroxy, CF3, OCF3, OR31, NR31R32, carbonyl-containing groups, nitro, cyano, sulfonyl or sulfone, phosphonate, thiocarbonyl motifs, and ring-closure rules in which R34 and R35 together with a nitrogen atom form 3–10 membered saturated or unsaturated rings.
The disclosure further provides variable definitions for X1, X2, X3, X4, L, E1, E2, W1, W2, k, j, R1–R5, M1, and related ring-forming heterocycles, including benzoxazolyl-associated scaffolds and aza-substituted benzoxazolyl variants. It also defines relationships among Formula I′-A′, Formula I′-B′, Formula III, Formula III-A, Formula III-B, Formula C, Formula A, Formula B, Formula D, Formula G-6, G-6-B, and G-6-A, with constraints such as no more than two adjacent ring nitrogen atoms and embodiments where X1 and X2 are N.
The compounds are described as kinase inhibitors intended to modulate mTOR, tyrosine kinases, and lipid kinases such as PI3K, with selective inhibition of mTOR signaling over PI3K. The disclosure states ATP-competitive binding to mTORC1 and/or mTORC2 and reduced Akt phosphorylation at S473 and T308 compared with rapamycin. The described biological effects include induction of apoptosis or cell cycle arrest following selective inhibition of mTOR signaling.
The document also describes synthetic relationships among named formulas and intermediates, including palladium-mediated coupling, boron-containing intermediates, conversion to target boronate or aryl-boron species using boron reagents, and scheme descriptions involving halogenation, nitration, reduction, cyanogen bromide conversion, and formation of heterocyclic cores from amine precursors. It also includes extensive structural constraints and reaction-scheme style transformations supporting the preparation of compounds within the defined formula sets.
Claims Coverage
The consolidated claim coverage reflects one independent claim set repeated across the inputs. The claim coverage centers on a pharmaceutical composition, with the core inventive feature being a therapeutically effective amount of the specified compound or pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.
Pharmaceutical composition with therapeutically effective amount of specified compound and carrier
A pharmaceutical composition comprising a therapeutically effective amount of the specified compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The provided claim content is limited to a pharmaceutical composition framework that combines a therapeutically effective amount of the specified compound, or its pharmaceutically acceptable salt, with a pharmaceutically acceptable carrier. No additional independent claim refinements are provided in the consolidated input.
Stated Advantages
Selective inhibition of mTOR signaling over PI3K.
Reduced Akt phosphorylation at S473/T308.
Induction of apoptosis or cell cycle arrest.
In vivo tumor growth inhibition.
Inhibits protein kinase(s), particularly mTOR, including mTORC1 and/or mTORC2, with selectivity versus type I PI3Ks.
Causes cell proliferation inhibition, apoptosis, and cell cycle arrest in neoplastic cells.
Documented Applications
Treating disorders by selective inhibition of mTOR signaling, with the patent content specifically noting cancer and other disease categories.
Anti-cancer application including potential combination with an anti-cancer agent such as rapamycin or Gleevec.
In vivo tumor models, including U87 glioblastoma xenograft and dosing/oral administration references.
Therapy contexts are mentioned in connection with mTOR inhibition and downstream effects in neoplastic cells.
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