Substituted pyridines as irreversible inhibitors of menin-MLL interaction
Inventors
Butler, Thomas • Palmer, Jim • Upasani, Ravi • Welsch, Matthew • Vempati, Sridhar • Kelly, Brendan • Painter, Edward
Assignees
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Publication Number
US-12116371-B2
Publication Date
2024-10-15
Expiration Date
Abstract
Disclosed herein are heterocyclic compounds that inhibit the binding of menin and MLL or MLL fusion proteins. Also described are specific irreversible inhibitors of menin-MLL interaction. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the menin-MLL irreversible inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, leukemia and other diseases or conditions dependent on menin-MLL interaction.
Core Innovation
The invention relates to inhibitor compounds represented by structural formulas corresponding to Formula (I) through Formula (XLIIIc), including specific examples such as Formula (XIIIa–XIIIc) and Formula (XLIIIa–XLIIIc). The disclosed compounds are provided as pharmaceutically acceptable salts, and stereoisomer forms are referenced in the claim set. The compounds inhibit the menin–MLL interaction and are described in the context of menin-MLL inhibition.
The disclosure provides structural embodiments for multiple labeled chemical formulae and variable substituent classes, including R7, R2, and R6a/R6b/R6c, with heteroaryl options, morpholinyl, substituted or unsubstituted pyridyl/pyrimidyl rings, and other heteroaryl ring options. It also includes pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, solvates, hydrates, polymorphs, amorphous forms, nano and milled forms, isotopically labeled compounds including deuterium derivatives, and prodrug forms metabolized in vivo to active derivatives.
The document further includes pharmaceutically acceptable carriers and excipients, multiple administration routes, pharmaceutical compositions, and therapeutic use for inhibiting menin-MLL activity. Biological evaluation is described with cell-based proliferation/inhibition testing in MLL-rearranged cell lines and IC50 measurement approaches, and the disclosure reports improved potency, high menin active-site occupancy, and in vivo dosing in rats at low doses.
Claims Coverage
The independent claims cover compound definitions by labeled formula, including formula (XVI) and another formula shown in claim 8, each optionally as pharmaceutically acceptable salts, and for formula (XVI) also as stereoisomers. Across the claims, there are 5 main inventive features: compound definition, pharmaceutically acceptable salt/stereoisomer coverage, pharmaceutical composition with a pharmaceutically acceptable carrier and therapeutically effective amount, and methods of administering the compound to inhibit menin-MLL activity with narrowed patient indications for cancer and diabetes types.
Compound defined by formula (XVI)
A compound according to formula (XVI), or a pharmaceutically acceptable salt or stereoisomer thereof.
Compound defined by formula shown in claim 8
A compound that is the formula shown in claim 8, or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition with carrier and therapeutically effective amount
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or stereoisomer thereof as applicable.
Therapeutic administration to inhibit menin-MLL activity
A method for inhibiting menin-MLL activity in a patient by administering a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt or stereoisomer thereof as applicable.
Cancer or diabetes indication narrowing
The method applies to cancer selected from an enumerated group including acute lymphoblastic leukemia, acute myeloid leukemia, childhood medulloblastoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, glioblastoma, liver cancer, myelodysplastic syndrome, pancreatic cancer, prostate cancer, renal cell carcinoma, and triple negative breast cancer, or to diabetes that is either type 1 diabetes or type 2 diabetes.
Overall claim coverage centers on specific formula-defined compounds, together with pharmaceutically acceptable salts and, for formula (XVI), stereoisomers. The dependent claim features further cover pharmaceutical compositions and therapeutic methods that inhibit menin-MLL activity by administering the compounds, with indications narrowed to enumerated cancers or to type 1 or type 2 diabetes.
Stated Advantages
Inhibits the menin–MLL interaction.
Improved potency as indicated by IC50 values as low as <1 nM or <0.1 nM.
High menin active-site occupancy reported as >50/70/90%.
Achieves the reported activity at low in vivo doses in rats, including ≤5 mg/kg and ≤3 mg/kg.
Provides pharmaceutical composition formulations comprising a pharmaceutically acceptable carrier and a therapeutically effective amount.
Documented Applications
Treating autoimmune/heteroimmune conditions including rheumatoid arthritis and lupus.
Treating inflammatory diseases.
Treating cancer, including acute lymphoblastic leukemia, acute myeloid leukemia, childhood medulloblastoma, chronic lymphocytic leukemia, diffuse large B cell lymphoma, follicular lymphoma, glioblastoma, liver cancer, myelodysplastic syndrome, pancreatic cancer, prostate cancer, renal cell carcinoma, triple negative breast cancer, and other listed cancer types.
Treating diabetes, including type 1 diabetes and type 2 diabetes.
Treating mastocytosis.
Treating osteoporosis and bone resorption disorders.
Use as a pharmaceutical composition for administration via oral, parenteral, buccal, nasal, topical, and rectal routes.
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