Aminopyrimidine compound
Inventors
Matsunaga, Nobuyuki • Miyamoto, Yasufumi • Shirai, Junya • Nakahata, Takashi • Shiokawa, Zenyu • Okawa, Tomohiro • Shibuya, Akito • MacCoss, Malcolm
Assignees
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Publication Number
US-11130752-B2
Publication Date
2021-09-28
Expiration Date
Abstract
The present invention provides a 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 specification, or a salt thereof.
Core Innovation
The invention relates to stereochemically defined substituted pyrimidine/benzonitrile compounds represented by formula (I) and selected compound sets, including pharmaceutically acceptable salts. The scaffold includes variable substituents A, R1, R2, R3, and R4, with R2 defined by oxygen-linked patterns and R4 as a morpholinyl group or a bridged morpholinyl group, while the selected members retain a benzonitrile/pyrimidinyl core with an (S)-1-(1H-tetrazol-1-yl)propan-2-yl oxy substituent and substituted pyrazolyl linkages.
Within the disclosed structures, the pyrazolyl-pyrimidinyl or pyrazolyl-amino pyrimidine framework varies by named ether and alkoxy side-chain motifs, including methoxypropoxy, ethoxypropoxy, methoxyethoxy, ethoxyethoxy, oxetan-3-yl, tetrahydro-2H-pyran-4-yl, and related hydroxyalkoxy or polyether variants. The set also includes stereochemically specified ring systems such as morpholinocyclohexyl and 3-oxa-8-azabicyclo[3.2.1]octane motifs, with explicit stereochemical assignments including (1r,4r), (2S,6R), (1R,5S), and (S) configurations.
The described members further include chlorophenyl or 4-chlorophenyl variants, pyrimidin-2-amine or pyrimidin-5-yl benzonitrile presentations, and at least one hydrochloride salt form. The structural disclosure emphasizes Markush-defined diversity around a common substituted pyrimidine/benzonitrile scaffold, with recurring tetrazolyl or triazolyl heterocycle references and constrained substituent families for the selected compounds.
Claims Coverage
The consolidated claim coverage includes broad formula (I) compounds and selected stereochemically defined compound sets, with one broad Markush claim family and one selected-member claim family. Across the covered claims, the main inventive features are the constrained substituent architecture at A, R1, R2, R3, and R4, together with the fixed (S)-1-(1H-tetrazol-1-yl)propan-2-yl oxy motif, substituted pyrazolyl connections, and specific stereochemically defined ring systems. In total, the covered inventive feature families are consolidated into six core features.
Formula (I) compound with constrained substituent architecture
A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, where A is CH or N; R1 is a C1-3 alkyl group; R2 is defined by specified O-X1-X2-O-(CH2-CH2-O)p-Y, O-X3-Z1, or O-X4-Z2 patterns; R3 is a cyano group or a halogen atom; and R4 is a morpholinyl group or a bridged morpholinyl group optionally substituted by 1 to 3 C1-6 alkyl groups.
Stereochemically defined (S)-1-(1H-tetrazol-1-yl)propan-2-yl oxy scaffold
Selected compounds include a 2-(((S)-1-(1H-tetrazol-1-yl)propan-2-yl)oxy) motif attached to the pyrimidine/benzonitrile scaffold.
Substituted pyrazolyl-pyrimidinyl or pyrazolyl-amino pyrimidine linkage
The claim sets cover compounds in which a substituted pyrazolyl group is linked to the pyrimidinyl portion, including amino-linked pyrazol-4-yl or pyrazol-3-yl connections.
Stereochemically specified cyclohexyl and bridged morpholine ring systems
The selected compounds include morpholinocyclohexyl variants and 3-oxa-8-azabicyclo[3.2.1]octane-related ring systems, with explicit stereochemistry such as (1r,4r), (2S,6R), and (1R,5S).
Variable ether and polyether side-chain motifs on the pyrazole unit
The pyrazolyl side chain includes named ether and polyether motifs such as ethoxyethoxy, methoxyethoxy, methoxypropoxy, ethoxypropoxy, hydroxyalkoxy variants, oxetan-3-yl and oxetan-3-ylmethoxy motifs, tetrahydro-2H-pyran-4-ylmethoxy motifs, and related ether-linked variations.
Pharmaceutically acceptable salt form including hydrochloride
At least one covered member is explicitly presented as a hydrochloride salt, and the claims also recite pharmaceutically acceptable salts.
Overall, the consolidated claims cover a Markush-defined pyrimidine/benzonitrile scaffold with restricted substituent families for R1, R2, R3, and morpholinyl or bridged morpholinyl R4, together with selected stereochemically defined members that retain the (S)-1-(1H-tetrazol-1-yl)propan-2-yl oxy motif, substituted pyrazolyl linkages, specific cyclohexyl or bridged morpholine ring systems, variable ether side chains, and at least one hydrochloride salt form.
Stated Advantages
Improved CaMKII inhibitory action.
Therapeutic usefulness.
In vitro TR-FRET CaMKIIδ inhibitory activity evaluation is disclosed.
In vivo rat cardiac CaMKII inhibition is disclosed via reduction of phospholamban (Thr17) phosphorylation.
Cytotoxicity assessment is disclosed using ATP reduction in HepG2 cells.
Therapeutic utility for cardiac diseases and related disorders is stated.
Prophylaxis and/or treatment of cardiac diseases via CaMKII inhibition.
Targets CaMKII for listed cardiac indications including catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, and fatal arrhythmia.
Documented Applications
Treatment or utility for cardiac diseases and related disorders.
Treatment or utility relating to catecholaminergic polymorphic ventricular tachycardia.
Treatment or utility relating to postoperative atrial fibrillation.
Treatment or utility relating to heart failure.
Treatment or utility relating to fatal arrhythmia.
PET tracer is included among the disclosed forms/concepts.
Medicinal use as a CaMKII inhibitor in mammals, including prophylaxis and/or treatment of cardiac diseases for catecholaminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, and fatal arrhythmia.
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