Substituted Imidazo[1,2-a]-pyridines as IRAK 1/4 and FLT3 inhibitors
Inventors
STARCZYNOWSKI, Daniel T. • Thomas, Craig J. • RHYASEN, Garrett • MELGAR, Katelyn • WALKER, Morgan MacKenzie • Jiang, Jian-Kang
Assignees
Cincinnati Childrens Hospital Medical Center • US Department of Health and Human Services
Publication Number
US-11542261-B2
Publication Date
2023-01-03
Expiration Date
2037-08-16
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Abstract
Some embodiments of the invention include inventive compounds (e.g., compounds of Formula (I)) and compositions (e.g., pharmaceutical compositions) which can be used for treating, for example, certain diseases. Some embodiments include methods of using the inventive compound (e.g., in compositions or in pharmaceutical compositions) for administering and treating (e.g., diseases such as head and neck squamous cell carcinoma (HNSCC), cancer, blood disorders, etc.). Additional embodiments provide synergistic combinations of a BCL2 inhibitor with an IRAK inhibiting compound, and methods of using same.
Core Innovation
The invention relates to substituted imidazo[1,2-a]-pyridines compounds of Formula (I) and compositions, including pharmaceutical compositions, useful for treating diseases responsive to inhibition of interleukin-1 receptor-associated kinase (IRAK) and FMS-Like Tyrosine kinase 3 (FLT3). The compounds inhibit the activity of one or both of FLT3 and its mutations and optionally inhibit IRAK1 and/or IRAK4. The invention also includes methods for treating diseases such as cancer, blood disorders, and specifically acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and other related conditions using these compounds alone or in combinations.
The problem addressed by the invention concerns known cancer treatments, especially for AML and blood disorders such as MDS, which are inadequate. Existing compounds like Quizartinib and Cremolanib fail to result in complete remission or partial remission consistently and may lead to mutations that produce resistance to inhibitors. The inventive compounds aim to overcome these deficiencies by effectively targeting FLT3 and IRAK kinases and by preventing resistance mechanisms associated with current treatments.
Additional embodiments include synergistic combinations of a BCL2 inhibitor with an IRAK inhibiting compound to enhance therapeutic outcomes. The invention encompasses the synthesis of these compounds, pharmaceutical compositions containing them, and methods of administration to animals or humans through various routes. Synergistic effects of IRAK inhibitors with apoptotic modulators such as venetoclax are also described, providing enhanced potency and overcoming resistance in FLT3-ITD AML cells.
Claims Coverage
The patent includes multiple independent claims focusing on therapeutic methods involving BCL2 inhibitors and IRAK inhibiting compounds of Formula (I), as well as compositions containing these compounds. The main inventive features are extracted below.
Combination treatment with BCL2 inhibitors and IRAK inhibitors
A method of treating diseases or disorders responsive to IRAK inhibition by administering to an individual (i) a composition comprising a BCL2 inhibitor selected from a specified group including venetoclax and other apoptosis modulators, and (ii) a composition comprising an IRAK inhibiting compound of Formula (I). The administration can be coformulated or coadministered.
Specific chemical structures and substitutions of IRAK inhibiting compounds
The IRAK inhibiting compounds are substituted imidazo[1,2-a]pyridines of Formula (I) with defined substituents R1 to R8 and parameters m, n, and Y. The claims specify particular groups for these substituents, including hydrogen, halogens, alkyl, alkoxy, cyano, nitro, morpholinyl, and diverse heterocycles, among others, with options for substitution patterns.
Dosage ranges for IRAK inhibiting compounds
The amount of the IRAK inhibiting compound of Formula (I) in the composition is specified to be in the range of 0.005 mg/kg to 50 mg/kg body weight for treatment of an individual.
Specific substituents and structural aspects for maximizing efficacy
Claims define preferred substituents such as R1 being Cl, CH3, OCH3, or OCH2CH2-morpholinyl; R2 including Cl, CN, methyl, ethynyl, and various heterocycles; R3 as H or substituted methoxy; and defined groups for R4, R5, R6, R7, R8, Y, and the integers m and n. These structural features contribute to the activity and selectivity of the compounds.
The claims cover therapeutic methods using compositions comprising combinations of BCL2 inhibitors and IRAK inhibiting compounds defined by specific chemical structures of Formula (I), including dosage ranges, compound substituents, and preferred embodiments. They focus on enhancing treatment efficacy for diseases responsive to IRAK inhibition through selective kinase targeting and synergistic drug combinations.
Stated Advantages
The compounds effectively treat diseases such as AML and MDS which are inadequately treated by current compounds.
The compounds inhibit both FLT3 and IRAK kinases, including resistant mutations, improving potential treatment outcomes.
The compounds can prevent compensatory activation of IRAK that occurs with FLT3 inhibitor treatment, thus potentially reducing resistance.
Combination of IRAK inhibitors with BCL2 inhibitors produces synergistic effects, allowing increased efficacy at lower doses, potentially reducing toxicity.
Compounds demonstrate good pharmacokinetic properties including stability, plasma exposure, and oral or intraperitoneal bioavailability.
The compounds show selectivity for diseased cells over normal cells, suggesting favorable toxicity profiles.
The compounds can inhibit colony formation and viability of malignant cells including FLT3-ITD AML and MDS cells.
Some compounds prevent the emergence of resistant AML cells following treatment.
In vivo efficacy demonstrated by prolonged survival in xenograft mouse models of FLT3-ITD AML.
Documented Applications
Treatment of head and neck squamous cell carcinoma (HNSCC).
Treatment of cancer including acute myeloid leukemia (AML), lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, and other malignancies.
Treatment of blood disorders such as myelodysplastic syndromes (MDS), including various mutational subtypes of MDS.
Prevention or amelioration of future AML or MDS in animals susceptible to these diseases.
Treatment of diseases responsive to IRAK inhibition, optionally in combination with BCL2 inhibitors.
Use as adjuvant therapies in combination with chemotherapy, radiation, immunotherapy, or other treatments.
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