Substituted imidazo[1,2-B]pyridazines as protein kinase inhibitors
Inventors
Xu, Yong • Brenning, Benjamin Gary • Kultgen, Steven G. • Liu, Xiaohui • Saunders, Michael David • Ho, Koc-Kan
Assignees
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Publication Number
US-10392392-B2
Publication Date
2019-08-27
Expiration Date
Abstract
The present invention provides substituted imidazo[1,2-b]pyridazines that are useful as protein kinase inhibitors and have one of the following structures (I), (II) or (III): or a stereoisomer, prodrug, tautomer or pharmaceutically acceptable salt thereof, wherein R, R1, R2 and X are as defined herein. For example, a compound having the following structure: Compositions and methods for using the same in the treatment of cancer, autoimmune, inflammatory and other Pim kinase-associated conditions are also disclosed.
Core Innovation
The invention relates to substituted imidazo[1,2-b]pyridazines and related compound families as protein kinase inhibitors, including Pim kinase. The disclosed compounds are defined by general chemical scaffold structures (I), (II), and (III) with variable substituents and related variants, together with permissible structural forms such as stereoisomers, prodrugs, tautomers, and pharmaceutically acceptable salts. The disclosure also emphasizes substituted aryl groups, heterocycle and sulfone/sulfoxide-like motifs, and pharmacologically relevant salt forms.
The specification includes related structure variants such as (I-A), (II-A), (I-B), (II-B), (I-C), (II-C), (III-C), (III-Cc), (III-D), (III-Da), and (III-Db), with extensive substituent definitions and linker options using variables such as X, W, m, y, and z. Alternative groups include O, S, SO, SO2, OCF3, CF3, Cl, F, hydroxyl, methoxy, cyano, halo, and phenyl-related motifs. The examples include substituted phenyl and heteroaryl groups with halo, cyano, CF3, OCF3, OCHF2, OCH3, hydroxyl, amino, nitro, amide, sulfonamide, piperidine, piperazine, tetrahydropyranyl, tetrahydrothiopyranyl, morpholine, piperidinol, aminomethyl, methanesulfonamide, and cyclohexanol-related variants.
Illustrative examples are provided across multiple tables and example series, including compounds identified as 8-1 to 8-45, 8-70 to 8-93, 8-101 to 8-113, and specific structures such as 8-31. The disclosure links the defined chemical structures to therapeutic activity and safety criteria, including hERG IC50 thresholds in some embodiments, and includes analytical characterization such as 1H NMR, MS, TLC/LCMS, isolation/purification, and ES+ data.
Claims Coverage
The independent claims cover defined compound structures, pharmaceutically acceptable salt forms, and therapeutic methods using the compounds or salts for four disease areas. Across the claims, the inventive features are the defined compound scaffolds and salt forms, together with administration of therapeutically effective amounts for solid tumors, hematological cancers, fibrosis, and autoimmune disorders, including psoriasis in one dependent refinement.
Defined compound structure
A compound having the following structure, including claim families based on structures (I), (II), and related variants.
Pharmaceutically acceptable salt forms
A pharmaceutically acceptable salt of a compound having the following structure, including acid addition salt and hydrochloric acid salt refinements.
Treating a solid tumor by administering the compound
A method for treating a solid tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having the following structure or a pharmaceutically acceptable salt thereof.
Treating a hematological cancer by administering the compound
A method for treating a hematological cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having the following structure or a pharmaceutically acceptable salt thereof.
Treating fibrosis by administering the compound
A method for treating fibrosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having the following structure or a pharmaceutically acceptable salt thereof.
Treating an autoimmune disorder by administering the compound
A method for treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having the following structure or a pharmaceutically acceptable salt thereof.
The claim coverage centers on defined compound scaffolds and their pharmaceutically acceptable salt forms, and extends to therapeutic administration methods for solid tumors, hematological cancers, fibrosis, and autoimmune disorders. Dependent refinements include hydrochloric acid salt forms, disease subsets, and, in some disclosures, additional co-administered therapeutic agent classes.
Stated Advantages
Treat or prevent Pim kinase-mediated cancers.
Treat solid tumors.
Treat hematological cancers.
Treat fibrosis.
Treat autoimmune disorders.
Provides hERG activity guidance, including embodiments with hERG IC50 values such as 10 μM, 30 μM, and ≤10 μM.
Documented Applications
Treatment of cancer, including solid tumor and hematological cancer, with representative compounds evaluated in cell-based, tumor, and hematological cancer screening assays.
Treatment of inflammatory bowel disease and autoimmune/inflammatory conditions, including osteoarthritis, rheumatoid arthritis, pain, respiratory disorders, and skin disorders.
Treatment of fibrosis.
Treatment of autoimmune disorder including psoriasis.
Treating a solid tumor in a subject, including various listed solid-tumor cancer types and categories such as soft-tissue sarcoma and bone cancer.
Treating a hematological cancer in a subject, including Hodgkin's disease, non-Hodgkin's lymphoma, acute leukemia, or chronic leukemia.
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