Cardiac sarcomere inhibitors
Inventors
Chuang, Chihyuan • Morgan, Bradley P. • VANDERWAL, Mark • Ashcraft, Luke W. • Lau, Kevin
Assignees
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Publication Number
US-12275741-B2
Publication Date
2025-04-15
Expiration Date
Abstract
Provided are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2A, R2B, R3, R4, and R5 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention relates to a method of preparing a compound of formula (1a-7) or a salt thereof. The method comprises reacting a compound of formula (1a-1) or a salt thereof with a compound of formula (1a-2) or a salt thereof to form a compound of formula (1a-3) or a salt thereof, and then converting the compound of formula (1a-3) or a salt thereof to the compound of formula (1a-7) or a salt thereof.
The method defines substituent selections for R1a as cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl. R2A and R2B are defined either as R2A being H or substituted or unsubstituted alkyl and R2B being substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl, or as R2A and R2B taken together with the carbon atom to which they are attached to form G1.
G1 is a substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkynyl, or heterocyclyl ring, each optionally fused to a phenyl ring. Alk2 is C1-C6 alkyl and Alk is C1-C6 alkyl. The disclosed content also describes piperazine-2,5-dione, diazaspiro, triazaspiro, and related substituted examples, including stereoisomeric compounds and fluorinated, pyridyl, benzonitrile, carboxamide, urea, and amide compounds.
Claims Coverage
The independent claim clm-00001 covers a two-stage method for preparing compounds of formula (1a-7) or salts thereof. The inventive features center on the reaction sequence from formula (1a-1) and formula (1a-2) to formula (1a-3), followed by conversion to formula (1a-7), together with structural limitations on R1a, R2A/R2B, G1, and Alk/Alk2.
Two-stage preparation via formula (1a-3) intermediate
Reacting a compound of formula (1a-1) or a salt thereof with a compound of formula (1a-2) or a salt thereof to form a compound of formula (1a-3) or a salt thereof, and converting the compound of formula (1a-3) or a salt thereof to the compound of formula (1a-7) or a salt thereof.
R1a substituent selection
R1a is selected from the group consisting of cyano, halo, substituted or unsubstituted alkoxy, substituted or unsubstituted alkyl, and substituted or unsubstituted heterocyclyl.
R2A and R2B definition including ring formation via G1
R2A and R2B are defined either as R2A being H or substituted or unsubstituted alkyl and R2B being substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl, or as R2A and R2B taken together with the carbon atom to which they are attached to form G1, wherein G1 is a substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkynyl, or heterocyclyl ring, each optionally fused to a phenyl ring.
Alk2 and Alk as C1-C6 alkyl
Alk2 is C1-C6 alkyl and Alk is C1-C6 alkyl.
The claim coverage is centered on the defined two-stage synthesis to reach formula (1a-7) from formulas (1a-1) and (1a-2) through formula (1a-3), with structural scope controlled by R1a, the R2A/R2B relationship including G1, and the C1-C6 alkyl limits for Alk2 and Alk.
Stated Advantages
Improved therapeutic index.
Reduced impact on relaxation.
Better pharmacokinetics.
Improved safety.
Documented Applications
Treating cardiac diseases, notably hypertrophic cardiomyopathy (HCM) and heart failure with preserved ejection fraction (HFpEF), including related conditions such as diastolic dysfunction and left ventricular outflow tract obstruction.
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