Therapeutic compounds and compositions
Inventors
Chenard, Bertrand L. • Xu, Yuelian • Stassen, Frans L. • Hayward, Neil J. • TENG, ZHIYAO
Assignees
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Publication Number
US-12152014-B2
Publication Date
2024-11-26
Expiration Date
Abstract
The present invention provides compounds that inhibit Factor XIa or kallikrein and pharmaceutically acceptable salts thereof and compositions thereof. The present invention also provides methods of using these compounds and compositions.
Core Innovation
The invention relates to methods of treating or reducing the risk of thromboembolic disorder and atrial fibrillation in a subject in need thereof by administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof. The compounds are defined by substituent variables R1, Ra, Rb, R2, R3, R4, R5, R6, R8, R9, R10, Rx, m, and n, with optional pyridyl N-oxide formation when Rx is —O.
The formula scope includes R2 as optionally substituted 5-membered heteroaryl or optionally substituted 5-membered heterocyclyl, R3 as hydrogen, C1-6 alkyl, or C1-6 haloalkyl, and R4 and R5 as alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl with optional substitutions by halo, C1-6 alkyl, C1-6 haloalkyl, cyano, or —OR6. The parameters m and n are defined as m = 0, 1, 2, or 3 and n = 0 or 1, with the condition that if n is 0 then R5 is hydrogen and R4 is absent.
The disclosure also describes embodiments with 4-oxoazetidine-1,2-dicarboxamide cores, (2S,3R) stereochemistry, substituted aminopyridylmethyl groups, and heteroaryl or aryl substituents including imidazole, pyrazole, fluoro, difluoro, chloro, methyl, dimethyl, trifluoromethoxy, and oxane variants.
Claims Coverage
Two independent method claims are present, one directed to thromboembolic disorder and one directed to atrial fibrillation. Both claims cover administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and the inventive scope is defined by the same set of structural constraints on Formula (II), including optional pyridyl N-oxide formation and the m/n limitations.
Treating thromboembolic disorder using Formula (II) compounds
A method of treating or reducing the risk of a thromboembolic disorder in a subject by administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, where the compound is defined by the stated R-group constraints and optional pyridyl N-oxide formation when Rx is —O.
Treating atrial fibrillation using Formula (II) compounds
A method of treating or reducing the risk of atrial fibrillation in a subject by administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, where the compound is defined by the stated R-group constraints and optional pyridyl N-oxide formation when Rx is —O.
Across both independent claims, the claim coverage centers on administering Formula (II) compounds, or pharmaceutically acceptable salts, under extensive R-group definitions and optional pyridyl N-oxide formation, for either thromboembolic disorder or atrial fibrillation.
Stated Advantages
Treating or reducing the risk of a thromboembolic disorder.
Treating or reducing the risk of atrial fibrillation.
Documented Applications
Treating or reducing the risk of a thromboembolic disorder in a subject in need thereof.
Treating or reducing the risk of atrial fibrillation in a subject in need thereof.
Thromboembolic disorder treatment or risk reduction, including arterial and venous thromboembolic conditions and thrombosis arising from blood exposure to artificial surfaces such as prosthetic valves or implants, indwelling catheters, stents, cardiopulmonary bypass, hemodialysis, or other procedures.
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