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-11254667-B2
Publication Date
2022-02-22
Expiration Date
2037-08-16
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Some embodiments of the invention include inventive compounds (e.g., compounds of Formula (I)). Other embodiments include compositions (e.g., pharmaceutical compositions) comprising the inventive compound. Still other embodiments of the invention include compositions (e.g., pharmaceutical compositions) for treating, for example, certain diseases using the inventive compounds. 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 cancer or blood disorders). Further embodiments include methods for making the inventive compounds. Additional embodiments of the invention are also discussed herein.
Core Innovation
The invention provides substituted imidazo[1,2-a]pyridine compounds of Formula (I) that act as inhibitors of IRAK1/4 and FLT3 kinases. These compounds, including their salts, optical and geometric isomers, and derivatives, can be used in pharmaceutical compositions for treating diseases such as cancer and blood disorders. The invention also includes methods of using and making these compounds.
The problem addressed is the inadequacy of existing treatments for cancers like Acute Myeloid Leukemia (AML) and blood disorders such as Myelodysplastic syndromes (MDS). Current compounds (e.g., Quizartinib and Cremolanib) sometimes fail to achieve complete or partial remission and can lead to mutations resistant to inhibitors. The inventive compounds aim to overcome these deficiencies by effectively inhibiting FLT3 and IRAK kinases, which play roles in these diseases.
Claims Coverage
The claims mainly cover a substituted imidazo[1,2-a]pyridine compound of Formula (I) and its pharmaceutically acceptable salts or stereoisomers, compositions containing these compounds, methods of inhibiting kinase activity, and methods for treating diseases using these compounds.
Substituted imidazo[1,2-a]pyridine compounds with specific substituents
The compounds of Formula (I) feature substituents at positions R1 to R8 with detailed possible groups such as halogens, alkyl, alkoxy, cyano, nitro, and various heterocyclic groups. Y can be specified nitrogenous groups. The compounds encompass specific stereoisomers and pharmaceutically acceptable salts.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions include the inventive compounds or their salts/stereoisomers combined with pharmaceutically acceptable carriers or formulary ingredients, with compound content ranging from about 0.0001% to about 99% by weight.
Method of inhibiting kinase activity by administering the composition
Methods involve administering the pharmaceutical compositions to humans to inhibit kinases such as FLT3, IRAK1, IRAK4, and others relevant to disease pathology.
Method for treating diseases with the compositions
The compositions are administered for treating diseases including blood disorders, cancers, leukemia, lymphoma, and myelodysplastic syndrome, with specified administration routes and dosage ranges (0.005 to 50 mg/kg body weight).
Methods for preparation of the compounds
Stepwise chemical synthetic methods are claimed involving reactions of precursor compounds (Formulas II, III, IV, V, VI, VII, VIII) leading to the compounds of Formula (I), employing reactions such as direct arylation, Buchwald-Hartwig amination, Suzuki-Miyaura coupling, and deprotection steps.
Overall, the claims cover novel substituted imidazo[1,2-a]pyridines with detailed substituents, their pharmaceutical compositions, methods of use in inhibiting kinases and treating diseases such as AML and MDS, and methods for synthesizing these compounds.
Stated Advantages
Some compounds exhibit superior potency compared to existing treatments such as quizartinib, with sub-nanomolar IC50 values for FLT3 and IRAK4 inhibition.
The compounds can inhibit compensatory activation of IRAK1/4 that occurs with FLT3 inhibition, potentially overcoming resistance.
They synergize FLT3 and IRAK inhibition leading to enhanced suppression of FLT3-ITD AML cells.
The compounds are selective, showing little inhibitory activity against unrelated cell lines, indicating low off-target toxicity.
Certain compounds demonstrate effectiveness in in vivo AML xenograft models, extending survival.
Compounds effectively inhibit colony formation and viability of MDSL MDS-derived cells, indicating utility in MDS treatment.
Documented Applications
Treatment of cancers including acute myeloid leukemia (AML), lymphoma, leukemia, bone marrow cancer, non-Hodgkin lymphoma, Waldenstrom's macroglobulinemia, and other solid and blood cancers.
Treatment of blood disorders, particularly myelodysplastic syndromes (MDS), including those with splicing factor mutations or mutations in isocitrate dehydrogenase 1 and 2.
Pharmaceutical compositions for administration via oral, parenteral, subcutaneous, intravenous, intradermal, topical, mucosal, intranasal, sublingual, or intramuscular routes.
Use as single-agent or in combination, including use in synergy with other kinase inhibitors and in adjuvant cancer therapy settings.
Interested in licensing this patent?