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-12275739-B2
Publication Date
2025-04-15
Expiration Date
Abstract
Disclosed herein are heterocyclic compounds that inhibit the binding of menin and MLL or MLL fusion proteins. Also described are specific 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 a method for treating diabetes by administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. The treatment is directed to alleviating, abating, ameliorating, inhibiting, arresting the development of, relieving, causing regression of, or stopping the symptoms of diabetes.
The compound of formula (I) is defined through substituent and ring/heteroatom variables including A being O or N(R6a), Cy being defined by heterocycle and aryl or heteroaryl patterns, and X and Y constrained such that none of X and Y is —NR3a—, with the other being —C(R3b)2—, —NR3b—, or —O—. The definition further includes ranges for n and independently selected substituent options for R1, R2, R3a, R3b, R4, and R6a, with ring closure where two R groups on the same nitrogen are taken together with intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring.
The disclosed subject matter also describes pharmaceutical composition options for compounds of formula (I)-(XXIIIh), including parenteral, oral, sublingual lozenge, inhalation, rectal gel, topical gel, and ophthalmic solution. Additional disclosed therapeutic concepts include menin-MLL interaction inhibition and combination-therapy concepts in treatment regimens.
Claims Coverage
The provided claims center on one independent claim directed to treating diabetes 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 are the defined formula (I) compound structure and the diabetes symptom-treatment outcome, with dependent claims narrowing compound subsets and, in the provided text, Type 2 diabetes mellitus.
Diabetes treatment by administering formula (I) compound
A method for treating diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the treating consists of alleviating, abating, ameliorating, inhibiting, arresting the development of, relieving, causing regression of, or stopping the symptoms of the diabetes.
Defined formula (I) structure and heteroatom/ring constraints
The formula (I) compound is defined by A being O or N(R6a), Cy being defined by ring and heteroaryl patterns, X and Y being constrained so that none is —NR3a— and the other is —C(R3b)2—, —NR3b—, or —O—, with R1, R2, R3a, R3b, R4, R6a, and n taking the recited option sets.
Type 2 diabetes mellitus limitation
Dependent claim text narrows the method to treating diabetes that is Type 2 diabetes mellitus.
The claim coverage is directed to administering a defined formula (I) compound, or salt or composition, to treat diabetes by symptom alleviation or regression, with the compound scope defined by extensive ring, heteroatom, and substituent limitations and with a dependent limitation to Type 2 diabetes mellitus.
Stated Advantages
Alleviating, abating, ameliorating, inhibiting, arresting the development of, relieving, causing regression of, or stopping the symptoms of diabetes.
Improved menin-MLL potency, including IC50 <1 nM or <0.1 nM.
High active-site occupancy, stated as greater than 50% to 90%.
High activity at low in vivo doses stated as <5 mg/kg.
Documented Applications
Treating diabetes in a patient in need thereof by administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or pharmaceutical composition thereof.
Type 2 diabetes mellitus treatment using a compound according to the method of claim 1.
Parenteral, oral, sublingual lozenge, inhalation, rectal gel, topical gel, and ophthalmic solution formulations for compounds of formula (I)-(XXIIIh).
Therapeutic treatment indications for autoimmune/inflammatory conditions and cancer, including rheumatoid arthritis, lupus, B-cell proliferative disorder, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, AML, ALL, mastocytosis, osteoporosis, bone resorption disorders, and inflammatory disease.
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