Benzimidazolone derived inhibitors of BCL6
Inventors
Bellenie, Benjamin Richard • Carter, Michael K. • CHEUNG, KWAI MING JACK • DAVIS, OWEN ALEXANDER • Hoelder, Swen • LLOYD, MATTHEW GARTH • Varela Rodriguez, Ana • Woodward, Hannah • Innocenti, Paolo
Assignees
Institute of Cancer Research Royal Cancer Hospital • Cancer Research Technology Ltd
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Publication Number
US-12110286-B2
Publication Date
2024-10-08
Expiration Date
Abstract
The present invention relates to compounds of Formula I that function as inhibitors of BCL6 (B-cell lymphoma 6) activity: wherein X1, X2, R1, R2 and R3 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which BCL6 activity is implicated.
Core Innovation
The invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, solvates, or hydrates thereof. The scaffold is defined by variable selections for X1, X2, R1, R2, and R3, with X1 and X2 selected from N or CRa/CRd and with R1 expressed as a group of the formula -L-Z, where L is absent or (1-2C)alkylene and Z is (1-6C)alkyl, (3-6C)cycloalkyl, or 4 to 7 membered heterocyclyl, optionally substituted by selected groups.
R2 is selected from defined substructures that include W1, W2, W3, ring A, and nested groups such as -Y2-L2-Z2, -Y3-Z3, and -Y5-Z5, together with linked or ring-forming possibilities. R3 is selected from Formula A, Formula B, or Formula C, with specified atom-type selections, substituent sets, and explicit nitrogen-count provisos for selected formulas.
The disclosure also includes benzimidazole-based intermediate compounds and related sulfonate, ester, and alkoxy alcohol derivatives, with LCMS, 1H NMR, and retention-time data reported for example intermediates. In the biological context provided, the compounds are associated with BCL6 inhibition/degradation, proliferation/cancer, and assay-based functional evaluation.
Claims Coverage
The consolidated claim coverage includes a broad Formula (I) compound claim, selected specific compounds where provided, a pharmaceutical composition claim, and a cancer-treatment claim. Across the provided items, the main inventive features center on X1/X2 selection, R1 as -L-Z, R2 defined through nested structural families, and R3 selected from Formula A, Formula B, or Formula C with nitrogen-count provisos.
Formula (I) compound with defined substituent variables
A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein X1 is selected from N or CRa; X2 is selected from N or CRd; R1 is a group of the formula -L-Z with L absent or (1-2C)alkylene and Z selected from (1-6C)alkyl, (3-6C)cycloalkyl, or 4 to 7 membered heterocyclyl, optionally substituted; and R2 is selected from defined formula options with W1, W2, W3, ring A, and nested substructures.
R3 selection from Formula A, Formula B, or Formula C
R3 is selected from a group of Formula A, a group of Formula B, or a group of Formula C, with defined selections for internal variables and substituent positions, including R9, R10, R11, and R12, and with optional groups such as -Y3-Z3 and -Y5-Z5.
Nitrogen-count proviso tied to Formula B and Formula C
When R3 is a group of Formula B, no more than two of Xc, Xd, and Xe are nitrogen; and when R3 is a group of Formula C, no more than three of Xf, Xg, Xh, Xi, and Xj are nitrogen.
Selected enumerated compounds
A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from specifically enumerated structures including benzimidazole-containing frameworks and related substituted compounds.
Pharmaceutical composition and cancer treatment
A pharmaceutical composition comprising a Formula (I) compound with a pharmaceutically acceptable carrier or excipient, and a method for treating cancer in a subject by administering a therapeutically effective amount of a Formula (I) compound or such composition.
The claim coverage is anchored by the Formula (I) scaffold and its extensive substituent definitions, especially the R2 and R3 substructures with linked or ring-forming options. Additional coverage includes selected specific compounds, a pharmaceutical composition, and a cancer-treatment method.
Stated Advantages
Supports BCL6 inhibition/degradation and proliferation/cancer therapeutic framing, with assay threshold reporting and observed biological activity.
Documented Applications
Therapeutic use for BCL6 inhibition/degradation and proliferation/cancer, including cancer indications listed as lymphomas (DLBCL, FL, BL, AITL), leukaemias (ALL, CML), multiple myeloma, and solid tumours (glioma, breast cancer, NSCLC, SCC).
HTRF assay measurement for potency/functional evaluation of the disclosed compounds.
nanoBRET assay measurement for potency/functional evaluation of the disclosed compounds.
Immunofluorescence-based BCL6 degradation assay reporting DC50 for potency/functional evaluation.
14-day cell proliferation assay used for potency/functional evaluation of the disclosed compounds.
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