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

Biomea Fusion Inc

Abstract

Disclosed herein are heterocyclic compounds according to formula (I) having the structure that inhibit the binding of menin and MLL or MLL fusion proteins. Also described are specific irreversible inhibitors of menin-HLL interaction. Also disclosed are pharmaceutical compositions that include compounds according to formula (I). Methods of using the menin-HLL 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 menin-MLL interaction inhibitors and Menin-MLL irreversible covalent inhibitors that inhibit menin-MLL activity. The compounds are described as covalent inhibitors that form a covalent bond to a menin cysteine residue homologous to Cys329, and are also described for menin-MLL fusion proteins, often via a Michael acceptor moiety.

The compounds are defined by specific chemical structures, including Formula (I), Formula (XLIIa), and (XLIIIa-XLIIIc), and by broader groups of compound embodiments expressed through numbered formulas and variable-defined substituents. The disclosure includes pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically active metabolites, and pharmaceutically acceptable prodrugs, together with structurally defined scaffold families and representative compound structures.

The document further presents representative inventive small-molecule compounds with a common multi-ring scaffold, fused heteroaromatic rings, aromatic amide/urea-like linkers, and variable substituted heterocycles and/or cyclic amines. The disclosed compounds are described as inhibitors of menin-MLL interaction, including menin active-site targeting, improved menin-MLL potency, sub-nanomolar IC50 values, and high active-site occupancy at low in vivo doses.

The invention also provides pharmaceutical compositions comprising the compounds and describes therapeutic use for autoimmune, heteroimmune, inflammatory, and cancer indications. The therapeutic use includes rheumatoid arthritis, lupus, B-cell proliferative disorders, leukemia/lymphoma indications, myeloid leukemia, lymphoid leukemia, soft tissue tumors, glioblastoma, pancreatic tumor, renal cell cancer, mastocytosis, osteoporosis, bone resorption disorders, and thromboembolic disorders, with routes of administration including oral, parenteral, buccal, nasal, topical, and rectal.

Claims Coverage

The independent claim coverage is directed to compounds selected from defined groups of menin-MLL inhibitor structures and pharmaceutically acceptable salts thereof, with dependent claims narrowing the selection to specific named embodiments. Across the provided items, seven inventive features are identified, covering group selections and specific compounds.

Overall, the claim set covers selected compounds from defined chemical groups, consistently including pharmaceutically acceptable salts, and is narrowed in dependent claims to specific named embodiments such as Compound 6, Compound 10, and Compound 13.

Stated Advantages

Documented Applications