Substituted imidazo[1,2-b]pyridazines and [1,2,4]triazolo[4,3-b]pyridazines as CaMKII inhibitors
Inventors
Matsunaga, Nobuyuki • Shirai, Junya • Okawa, Tomohiro • Miyamoto, Yasufumi • Shiokawa, Zenyu • Nakahata, Takashi • Shibuya, Akito • Kawada, Akira • MacCoss, Malcolm
Assignees
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Publication Number
US-11795172-B2
Publication Date
2023-10-24
Expiration Date
Abstract
The present invention provides a fused heteroaryl compound having a CaMKII inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like.The present invention relates to a compound represented by the formula (I): wherein each symbol is as defined in the description, or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, defined by a fused heteroaryl structure with variable substituents X1–X6, Y1–Y4, Ring A1, Ring B1, V, and Z. The scaffold specifies V as —O— and Z as C1-6 alkylene, while Ring A1 and Ring B1 are aryl or heteroaryl rings that can be optionally substituted with multiple substituents selected from a large group of chemical functionalities.
The structural definition further constrains the compound by specifying R substituent options at positions X1, X6, Y1–Y4 and by including additional variables that define the substitution patterns, including hydrogen, halogen, or CN options, and various allowed ring and substituent types. The document additionally provides related compound scaffolds represented by formulas (I-1), (II), (II-1), (III), and (III-1), extending the fused heteroaryl CaMKII inhibitor concept beyond formula (I).
The invention also includes medicinal-product scope by defining pharmaceutically acceptable salts and medicaments that comprise the CaMKII inhibitor compounds. The listed cardiac disease indications include catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, and fatal arrhythmia. The disclosed structure space is supported by detailed substituent-definition sections and representative named compounds and partial structural subcomponents.
Claims Coverage
The partial content includes two independent claims. One independent claim broadly covers a fused heteroaryl CaMKII inhibitor scaffold defined by formula (I) with extensive structural variability, and the other independent claim covers selected compounds from a group of alternatives, including pharmaceutically acceptable salts.
Fused heteroaryl CaMKII inhibitor scaffold of formula (I)
A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein X1 is CR1X1 or N; X1 is H, halogen, or C1-6 alkyl; X6 is H; Y1 is CRY1 or N; Y2 is CRY2 or N; Y3 is CRY3 or N; Y4 is CRY4 or N; V is —O—; Z is C1-6 alkylene; Ring A1 is C6-14 aryl or heteroaryl optionally substituted; and Ring B1 is heteroaryl optionally substituted.
Selected compounds from a group of alternatives
A compound selected from the group consisting of [alternatives not reproduced in the partial content], or a pharmaceutically acceptable salt thereof.
Overall, the claims coverage in the provided text centers on a broad formula (I) fused heteroaryl CaMKII inhibitor scaffold (with V as —O— and Z as C1-6 alkylene, plus aryl/heteroaryl Ring A1 and Ring B1 with optional substitution) and a separate independent selection claim directed to compounds from a listed group of alternatives.
Stated Advantages
CaMKII inhibitory action for prophylaxis/treatment across a wide set of disease categories.
The claimed fused heteroaryl compounds are expected to treat or prevent cardiac diseases including CPVT and postoperative atrial fibrillation.
In the in vivo example, four tested compounds are reported to achieve a phospholamban Thr17 (P-PLN) phosphorylation reduction rate greater than 25%.
Documented Applications
Prophylaxis or treatment of cardiac diseases, including catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, and fatal arrhythmia.
In vitro CaMKIIδ binding TR-FRET assay evaluation of CaMKII inhibitory activity, including IC50-based activity ranks A–C.
In vivo rat cardiac CaMKII inhibition following oral dosing, assessed via reduction of phospholamban Thr17 (P-PLN) phosphorylation rate.
Capsule and tablet formulation examples are described for the compounds.
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