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-11845753-B2
Publication Date
2023-12-19
Expiration Date
Abstract
Disclosed herein are heterocyclic compounds that inhibit the binding of menin and MLL or MLL fusion proteins. Also described are specific inhibitors of menin-MLL interaction. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the menin-MLL 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 heterocyclic compounds of formula (I), including corresponding sub-formulas and primed variants, defined by variable selections for A, Cy, and the X/Y relationship, together with substituent definitions for R1, R2, R3/R3b, R4, R5a, R6a, R7, and the ring-size parameter n. The structures are characterized by A being O or N(R6a), and by Cy in which one of X and Y is NR3a and the other is C(R3b)2, NR3b, or O.
The disclosed subject matter concerns inhibition of menin-MLL interaction, including menin-MLL1 (KMT2A/MLL1) and MLL fusion proteins, and frames the approach in relation to KMT2/MLL function in chromatin and gene regulation. The compounds are described as interaction inhibitors associated with menin-MLL active-site occupancy and possible anti-tumor activity.
The invention concerns administration to a patient in need thereof of a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The method is directed to alleviating, abating or ameliorating symptoms, inhibiting disease or condition, arresting development, relieving disease or condition, causing regression, relieving a condition caused by the disease, or stopping symptoms, and it is linked to the listed disease and condition exemplars.
Claims Coverage
The independent claim coverage centers on a method for treating specified cancers and lymphoid malignancies by administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The inventive features primarily define the formula (I) scaffold through A, Cy, the X/Y relationship, and constrained substituent variables, with dependent refinements narrowing specific sub-formula options and substituent selections.
Therapeutic treatment with formula (I) compounds
A method for treating diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, lymphoid leukemia, acute lymphoblastic lymphoma, soft tissue tumor, glioblastoma, pancreatic tumor, or renal cell cancer by administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
A and Cy structural definition with X/Y linkage pattern
In formula (I), A is O or N(R6a), and Cy is defined such that one of X and Y is NR3a and the other is C(R3b)2, NR3b, or O.
Substituent-variable constraints for formula (I)
R1 is an optionally substituted group selected from C1-6 alkyl, C3-7 cycloalkyl, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms; R2 is H, C1-6 alkyl, C1-6 haloalkyl, halo, or CN; R3/R3b are independently H or C1-6 alkyl; R4 is independently H, halo, CN, OR, N(R)2, C(O)N(R)2, NRC(O)R, SO2R, C(O)R, or CO2R; R6a is H or C1-6 alkyl; and n is 1, 2, 3, or 4.
R7 cyclic substituent selection
R7 is an optionally substituted group selected from a 4-7 membered heterocycloalkyl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, phenyl, an 8-10 membered bicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
Dependent narrowing to selected sub-formulas and R7 options
Dependent claim refinements narrow the compound to selected sub-formulas and further constrain substituent choices, including specific R1 selections, the 4-7 membered heterocycloalkyl ring form of R7 substituted with Me, Et, or i-Pr, and specialization of R7 to morpholinyl.
Overall, the claims focus on a treatment method for the listed cancers and lymphoid malignancies using compounds of formula (I), with the core inventive coverage residing in the defined scaffold, the A and Cy/X/Y constraints, the variable substituent sets, and dependent narrowing to specific sub-formula and R7 selections.
Stated Advantages
Improved potency against menin-MLL as indicated by IC50 values below 1 nM, or below 0.1 nM.
High menin active-site occupancy above 50%, 70%, or 90%.
Activity at low in vivo dosages below 5 mg/kg, including ≤3 mg/kg in rats.
Inhibiting the disease or condition.
Arresting the development of the disease or condition.
Causing regression of the disease or condition.
Alleviating, abating or ameliorating symptoms and stopping symptoms of the disease or condition.
Relieving the disease or condition.
Relieving a condition caused by the disease or condition.
Ameliorating underlying metabolic causes of the disease or the symptoms.
Pharmaceutical compositions are provided in multiple parenteral dosage forms and additionally include topical and rectal formulation concepts.
Treatment concepts include prophylactic versus therapeutic use and chronic/continuous administration concepts with drug holidays, including combination therapy with other agents.
Documented Applications
Treating diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, lymphoid leukemia, acute lymphoblastic lymphoma, soft tissue tumor, glioblastoma, pancreatic tumor, or renal cell cancer by inhibiting menin-MLL interaction.
Treating immune or inflammatory indications by inhibiting menin-MLL interaction, including autoimmune disease such as rheumatoid arthritis and lupus, heteroimmune disease, mastocytosis, osteoporosis, and bone resorption disorders.
Menin (Menin-MLL) inhibition treatment concepts, including prophylactic versus therapeutic use, chronic/continuous administration concepts including drug holidays, and combination therapy.
Formulation use cases for pharmaceutical compositions including parenteral injection and additional topical and rectal formulation concepts.
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