Substituted amines for treating cardiac diseases
Inventors
Matsunaga, Nobuyuki • Nakahata, Takashi • Tanaka, Yuta • TAKAHAGI, Hiroki • Miyamoto, Yasufumi • Okamoto, Rei • Yoshikawa, Takeshi • Terao, Yoshito • Yukawa, Takafumi • KAKEGAWA, Keiko • Nishikawa, Yoichi • Takagi, Terufumi • Takahashi, Masashi • Komandla, Mallareddy • Kwok, Lily • Miura, Joanne • Sabat, Mark • Scorah, Nicholas • TANIS, Paul • Tyhonas, John • Vu, Phong H. • Wang, Haixia • Wang, Xiaolun • Shirai, Junya • Okawa, Tomohiro • Shiokawa, Zenyu • Shibuya, Akito
Assignees
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Publication Number
US-10543212-B2
Publication Date
2020-01-28
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 compounds represented by formula (I) and related formulae (II-1A), (II-2), and (II-3), and to pharmaceutically acceptable salts thereof. The compounds are defined by structural ring systems designated as Ring A, Ring B, and Ring C, together with the linker option Z selected from —CH2—, —O—, —S—, —S(O)—, or —S(O2)—. The definitions include extensive substitution possibilities on Ring A, including benzene, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, thiazole, isothiazole, imidazole, isoxazole, thiadiazole, thiophene, and multiple other heterocyclic rings and cycloalkyl frameworks.
Ring A includes multiple alternative substitution regimes, including cases where a benzene ring is substituted by 0 to 3 substituents selected from defined group classes, or where two substituents on the benzene ring are bonded to each other to form a 5- or 6-membered monocyclic aromatic heterocycle, a 3- to 8-membered monocyclic non-aromatic heterocycle, or a C5-6 cycloalkene ring. The structural options also include fused, bridged, or spiro configurations, with substituents selected from alkoxy groups, halogenated alkoxy groups, alkyl groups, hydroxy, amino, halogen, cyano, carboxy, alkoxy-carbonyl, alkylsulfanyl, alkyl sulfonyl, carbamoyl, sulfamoyl, and aromatic or non-aromatic heterocyclic groups.
The partial content also describes specific pyrimidin-2-amine derivatives featuring chiral tetrazole-containing oxy substituents and substituted pyrazole rings. These examples include fluorinated ether substituents such as 2,2,2-trifluoroethoxy and 2,2-difluoroethoxy, as well as morpholinocyclohexyl, tetrahydro-2H-pyran-4-yl, oxetan-3-yl, 2-azaspiro[3.3]heptane, piperidyl, piperazinyl, azabicyclic, and benzonitrile or nicotinonitrile variants, with stereochemical descriptors such as (S), (1R,5S), and (trans).
Claims Coverage
The independent claims cover a broad compound family of formula (I), three narrower formula families (II-1A, II-2, and II-3), an enumerated group of specific pyrimidin-2-amine derivatives, and a therapeutic-use claim directed to calcium/calmodulin-dependent protein kinase II inhibition in a mammal. In total, five inventive feature groups are present across the independent claims.
Compound represented by formula (I)
A compound represented by the formula (I) with Ring A, Ring B, and Ring C defined by the specified ring types and substitution options, Z selected from —CH2—, —O—, —S—, —S(O)—, or —S(O2)—, Rz as a hydrogen atom, and R1, R2, and R3 selected from the specified substituent classes, including pharmaceutically acceptable salts thereof.
Compound represented by formula (II-1A)
A compound represented by the formula (II-1A) in which Rx1 is limited to C1-6 alkyl or halogenated C1-6 alkyl, substituted C1-6 alkoxy with defined substituent counts, oxygen-containing monocyclic non-aromatic heterocyclyloxy groups, C1-6 alkyl-carbonyl or halogenated C1-6 alkyl-carbonyl groups, or C3-10 cycloalkyl; Ry1 is cyano, halogen, or C1-6 alkyl or halogenated C1-6 alkyl; and Rz1 is a nitrogen-containing 3- to 8-membered monocyclic non-aromatic heterocyclic group substituted by 0 or 2 hydroxy and/or C1-6 alkyl substituents, with pharmaceutically acceptable salt forms.
Compound represented by formula (II-2)
A compound represented by the formula (II-2) in which Rx2 is limited to C1-6 alkyl or halogenated C1-6 alkyl, substituted C1-6 alkoxy with defined substituent counts, oxygen-containing monocyclic non-aromatic heterocyclyloxy groups, C1-6 alkyl-carbonyl or halogenated C1-6 alkyl-carbonyl groups, or C3-10 cycloalkyl; Ry2 is cyano, halogen, or C1-6 alkyl or halogenated C1-6 alkyl; and Rz2 is selected from defined C1-6 alkyl, C3-10 cycloalkyl, C1-6 alkoxy-carbonyl, C6-14 aryl, nitrogen-containing monocyclic aromatic heterocyclic, or oxygen-containing monocyclic non-aromatic heterocyclic groups, including cyano and deuterium options, with pharmaceutically acceptable salt forms.
Compound represented by formula (II-3)
A compound represented by the formula (II-3) in which Rx3 is limited to C1-6 alkyl or halogenated C1-6 alkyl, substituted C1-6 alkoxy with defined substituent counts, oxygen-containing monocyclic non-aromatic heterocyclyloxy groups, C1-6 alkyl-carbonyl or halogenated C1-6 alkyl-carbonyl groups, or C3-10 cycloalkyl; and Ry3 is cyano, halogen, or C1-6 alkyl or halogenated C1-6 alkyl, with pharmaceutically acceptable salt forms.
Enumerated pyrimidin-2-amine derivatives
A compound selected from a group consisting of multiple specifically named structures, each comprising a pyrimidin-2-amine core with a chiral tetrazole-containing oxy substituent and a substituted pyrazole ring bearing fluorinated ether substituents and named cyclic substituent frameworks such as morpholinocyclohexyl and 2-azaspiro[3.3]heptane, optionally as pharmaceutically acceptable salts.
Inhibiting calcium/calmodulin-dependent protein kinase II in a mammal
Inhibiting calcium/calmodulin-dependent protein kinase II in a mammal by administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
Overall, the independent claims define a broad formula (I) compound class with detailed ring and substituent constraints, three narrower formula-based compound families with restricted Rx/Ry/Rz substituent classes, an enumerated set of specific pyrimidin-2-amine derivatives, and a therapeutic-use claim directed to calcium/calmodulin-dependent protein kinase II inhibition in a mammal.
Stated Advantages
CaMKIIδ inhibition is reported with in vitro CaMKIIδ enzyme inhibition and TR-FRET binding assay results.
In vivo rat cardiac CaMKII inhibition is reported as a reduction rate of phospholamban Thr17 (P-PLN) after oral dosing.
Prophylaxis or treatment of cardiac diseases is described, including catecholaminergic polymorphic ventricular tachycardia (CPVT), postoperative atrial fibrillation, heart failure, and fatal arrhythmia.
Inhibiting calcium/calmodulin-dependent protein kinase II in a mammal.
Documented Applications
Inhibiting calcium/calmodulin-dependent protein kinase II in a mammal by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt.
Prophylaxis or treatment of cardiac diseases, including catecholaminergic polymorphic ventricular tachycardia (CPVT), postoperative atrial fibrillation, heart failure, and fatal arrhythmia.
Therapeutic use for inhibiting calcium/calmodulin-dependent protein kinase II in a mammal by administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof.
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