Cardiac sarcomere inhibitors
Inventors
Morgan, Bradley P. • Chuang, Chihyuan • Ashcraft, Luke W. • Ho, Justin • Garcia, Alfredo • Chandra, Aroop
Assignees
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Publication Number
US-12286437-B2
Publication Date
2025-04-29
Expiration Date
Abstract
Provided are compounds of Formula (I): or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1, R2, R3, and R4 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing. Also provided are methods of using a compound of Formula (I), or stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
Core Innovation
The invention provides heterocyclic compounds defined by Formula (I) and variants (I-A) through (I-D), including a 2,5,8-triazaspiro[3.5]nonane core, stereoisomers, tautomers, pharmaceutically acceptable salts, and deuterated compounds. The compounds are characterized by substituent parameters with defined ranges of structural options within the specified formulas, including benzyl, cyclohexyl, pyridazinyl, carboxamide, carbaldehyde, and 6,9-dione variants.
The compounds are disclosed as cardiac sarcomere inhibitors, including allosteric cardiac myosin inhibitors, for inhibiting the cardiac sarcomere by contacting the cardiac sarcomere with a Formula (I) compound or a pharmaceutically acceptable salt. The disclosure connects these compounds to treating heart disease in a subject in need thereof by administering a compound of a formula and pharmaceutically acceptable salt thereof.
The treated conditions are defined by heart disease type and by associations such as hypertrophic cardiomyopathy, secondary left ventricular wall thickening, small left ventricular cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, cardiac fibrosis, diastolic dysfunction, restrictive cardiomyopathy, left ventricular outflow tract obstruction, cardiac ischemia, coronary heart disease, hypertensive heart disease, congenital heart disease, diabetic heart disease, congestive heart failure, right heart failure, cardiorenal syndrome, and infiltrative cardiomyopathy. The disclosure also includes pharmaceutical compositions that include a compound of Formula (I) and one or more excipients.
Claims Coverage
The independent claims are directed to administering a compound of a formula, or a pharmaceutically acceptable salt, to treat heart disease and related cardiac disease or condition associations, and to contacting a cardiac sarcomere to inhibit it. Six independent claims are identified across the provided items, centered on treatment scope for specified cardiac indications and one mechanistic sarcomere inhibition method.
Treating heart disease by administering a formula compound
A method of treating a heart disease in a subject in need thereof, comprising administering to the subject a compound of formula or a pharmaceutically acceptable salt thereof.
Treating a disease or condition associated with hypertrophic cardiomyopathy by administering a formula compound
A method of treating a disease or condition associated with hypertrophic cardiomyopathy in a subject in need thereof, comprising administering to the subject a compound of formula or a pharmaceutically acceptable salt thereof.
Treating a disease or condition associated with secondary left ventricular wall thickening by administering a formula compound
A method of treating a disease or condition that is associated with secondary left ventricular wall thickening in a subject in need thereof, comprising administering to the subject a compound of formula or a pharmaceutically acceptable salt thereof.
Treating a disease or condition associated with specified cardiac phenotypes by administering a formula compound
A method of treating a disease or condition that is associated with small left ventricular cavity and cavity obliteration, hyperdynamic left ventricular contraction, myocardial ischemia, or cardiac fibrosis in a subject in need thereof, comprising administering to the subject a compound of formula or a pharmaceutically acceptable salt thereof.
Treating heart failure with preserved ejection fraction by administering a formula compound
A method of treating heart failure with preserved ejection fraction in a subject in need thereof, comprising administering to the subject a compound of formula or a pharmaceutically acceptable salt thereof.
Inhibiting a cardiac sarcomere by contacting the cardiac sarcomere with a formula compound
A method of inhibiting a cardiac sarcomere, comprising contacting the cardiac sarcomere with a compound of formula or a pharmaceutically acceptable salt thereof.
Across the independent claims, the core inventive concept is the use of a compound of a formula, including pharmaceutically acceptable salts, to treat defined cardiac diseases or conditions by administration or to inhibit a cardiac sarcomere by contacting. The independent claim families are distinguished by the associated cardiac phenotype or disease context.
Stated Advantages
Wider therapeutic index
Less impact on relaxation
Improved pharmacokinetics/safety
Possible once-daily dosing
Provides methods of treating heart disease, including hypertrophic cardiomyopathy and heart failure with preserved ejection fraction.
Provides methods for inhibiting a cardiac sarcomere.
Documented Applications
Treating heart diseases, including hypertrophic cardiomyopathy (obstructive and nonobstructive; sarcomeric and/or non-sarcomeric mutation-associated) and heart failure with preserved ejection fraction (HFpEF).
Treating diseases or conditions associated with hypertrophic cardiomyopathy, including Fabry's Disease, Danon Disease, mitochondrial cardiomyopathies, and Noonan Syndrome.
Treating a disease or condition associated with secondary left ventricular wall thickening, including hypertension, valvular heart diseases, aortic stenosis, Mitral valve regurgitation, metabolic syndromes, diabetes, obesity, end stage renal disease, scleroderma, sleep apnea, amyloidosis, Fabry's disease, Friedreich Ataxia, Danon disease, Noonan syndrome, and Pompe disease.
Treating diseases or conditions associated with diastolic dysfunction and restrictive cardiomyopathy.
Treating cardiac ischemia and coronary heart disease, including myocardial infarction and angina pectoris.
Treating left ventricular outflow tract obstruction.
Treating additional cardiometabolic and cardiac conditions such as cardiac remodeling, senescence, congestive heart failure, right heart failure, and cardiorenal syndrome.
Inhibiting the cardiac sarcomere by contacting it with a Formula (I) compound.
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