Bicyclic 1,4-diazepanones and therapeutic uses thereof
Inventors
Morgan, Bradley P. • Evans, Chris • Lu, Pu-Ping • Yamasaki, Makoto • Wang, Wenyue • Collibee, Scott • Makino, Takuya • Tsuchiya, Kazuyuki • Kurosaki, Toshio • Yamaki, Susumu • Honjo, Eriko • KOIZUMI, Yuka • Katoh, Naoto • SEKIOKA, Ryuichi • Kuriwaki, Ikumi
Assignees
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Publication Number
US-12441691-B2
Publication Date
2025-10-14
Expiration Date
Abstract
Provided herein are compounds of formula (I): or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X1, X2, Ry, Rz, R1, R2, R3, and R4 are as defined herein. Also provided herein is a pharmaceutically acceptable composition comprising a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.Also provided herein are methods of using a compound of formula (I), or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, to treat various diseases, disorders, and conditions responsive to the modulation of the contractility of the skeletal sarcomere.
Core Innovation
The disclosure describes administering an effective amount of a compound of Formula (I), including pharmaceutically acceptable salts, stereoisomers, or tautomers, or a pharmaceutical composition comprising the compound and a pharmaceutical carrier, to treat a disease or condition in a subject. The treated conditions include peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, frailty, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, muscle wasting caused by heart failure, cancer, chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, post-stroke muscle dysfunction, facioscapulohumeral dystrophy, and Charcot-Marie-Tooth disease.
Formula (I) is defined by structural variables including X1 and X2, each independently N or C—Rx, with Rx, Ry, and Rz independently H, halo, C3-10 cycloalkyl, C3-10 cycloalkenyl, or C6-20 aryl. R1 is selected from C3-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or C3-10 cycloalkenyl, and Rw is C1-12 alkyl. R2 is defined through carbonyl-linked, alkyl, cycloalkenyl, heteroaryl, heterocyclyl, amidinyl, optionally substituted sulfonyl, and cyano options, including ring-forming combinations of R2 and R3 to form a 5- or 6-membered heterocyclyl or heteroaryl.
The disclosure also provides stereochemically defined benzo[e][1,4]diazepin-2-one and related derivatives, including compounds with an (S)-sec-butyl core and varied N-substituents or carbonyl-linked heterocycles. The examples include carboxamide, carboximidamide, sulfonamide, and related heteroaryl or heterocyclic substituents, with named structures illustrating pyrrolidine, piperidine, morpholine, azetidine, triazole, pyridine-like, and other carbonyl-containing motifs.
Claims Coverage
The consolidated independent claim coverage includes one independent method claim directed to treating a broad set of diseases or conditions by administering an effective amount of a Formula (I) compound, or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or a pharmaceutical composition comprising the foregoing. The claim is defined by multiple inventive feature groupings covering the treatment scope and the Formula (I) structural limitations.
Treating a listed disease or condition with a Formula (I) compound
A method for treating a disease or condition selected from the listed group by administering to a subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer, or a pharmaceutical composition comprising any of the foregoing and a pharmaceutical carrier.
Formula (I) core substituent definitions
X1 and X2 are each independently N or C—Rx; each Rx, Ry, and Rz is independently H, halo, C3-10 cycloalkyl, C3-10 cycloalkenyl, or C6-20 aryl; R1 is C3-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or C3-10 cycloalkenyl, wherein Rw is C1-12 alkyl.
R2 defined by multiple functional-group classes
R2 is selected from C(O)—Rh with Rh including amino optionally substituted with one or more Rq, and alternative classes including C1-12 alkyl, C3-10 cycloalkenyl, 5-20 membered heteroaryl, 3-15 membered heterocyclyl, amidinyl, optionally substituted sulfonyl, or cyano, including cases where R2 and R3 together form a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl.
R3 and R4 constraints
R3 is H, C1-12 alkyl, C(O)NH2, or C(O)—C1-12 alkoxy; and R4 is absent or is H, C1-12 alkyl, C(O)NH2, or C(O)—C1-12 alkoxy.
The independent claim is centered on a treatment method using a Formula (I) compound or pharmaceutical composition for a defined disease list, with claim scope controlled by explicit structural constraints on X1/X2, Rx/Ry/Rz, R1, R2, R3, and R4.
Stated Advantages
Bioavailability
Stability
Manufacturability
Documented Applications
Treating a disease or condition selected from the listed group including peripheral vascular disease, peripheral arterial disease, rehabilitation-related deficits, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, conditions of muscle wasting, muscular myopathies, muscle atrophy and fatigue, frailty, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, muscle wasting caused by heart failure, cancer, chronic kidney disease/dialysis, post-spinal cord injury (SCI) muscle dysfunction, post-stroke muscle dysfunction, facioscapulohumeral dystrophy, and Charcot-Marie-Tooth disease.
Treating diseases or conditions responsive to modulation of fast skeletal muscle sarcomere contractility, including frailty, sarcopenia, cachexia syndrome, ALS, SMA, myasthenia gravis, COPD, stress urinary incontinence (SUI), mixed urinary incontinence (MUI), and fecal incontinence.
Characterization of crystalline Form I of Compound 10 using XRPD, including peak positions and intensities.
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