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-11981644-B2
Publication Date
2024-05-14
Expiration Date
Abstract
Provided herein are compounds of formula (1): 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 invention relates to compounds of formula (I), including pharmaceutically acceptable salts, stereoisomers, and tautomers thereof, defined by X1 and X2, each independently being N or C-Rx, and by substituent variables R1, R2, R3, and R4. The disclosed compounds are stereochemically defined small-molecule structures within a benzo[e][1,4]diazepine scaffold, including benzo[e][1,4]diazepin-2-one and tetrahydro-4H-benzo[e][1,4]diazepine variants.
The structural concept centers on substitution at the carbonyl or carboxamide position and related side chains, including C(O)-Rh motifs and alternative R2 classes such as alkyl, cycloalkenyl, heteroaryl, heterocyclyl, amidinyl, sulfonyl, and cyano. The disclosed substituent set includes amino- and hydroxy-functionalized substituents, cyclic amide- and urea-like substituents, and heteroaryl carbonyls, together with benzo[e][1,4]diazepine carboxamide, carboximidamide, amide, sulfonamide, and nitrile variants.
The document also describes compounds of formula (I) with extensive examples across multiple numbered compounds and related fused diazepine analogs, including bicyclic 1,4-diazepanone derivatives, pyrido[3,4-e][1,4]diazepine derivatives, pyrimido[5,4-e][1,4]diazepine derivatives, pyrido[3,2-e][1,4]diazepine derivatives, and benzo[f]imidazo[1,5-d][1,4]diazepin-6-one analogs. Therapeutic framing is present for compounds responsive to modulation of skeletal sarcomere contractility, including troponin/tropomyosin and skeletal muscle myosin/actin pathways.
The document also describes pharmaceutical compositions comprising the compounds together with pharmaceutically acceptable carriers, and crystalline forms of a particular example compound, including Form I and Form II. Multiple named compound examples and solid-form variants are provided across the disclosed compound families.
Claims Coverage
The provided claim content centers on one compound-of-formula (I) genus, with extensive structural definitions for X1, X2, R1, R2, R3, and R4, and with a pharmaceutical composition claim limited by administration routes. Across the input items, the claim coverage consistently emphasizes the same inventive features: the formula (I) scaffold, the C(O)-Rh branch at R2, alternative R2 classes, and the option for R2 and R3 to form a heterocyclyl or heteroaryl ring.
Compound of formula (I) with defined X1 and X2
A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein X1 and X2 are each independently N or C-Rx.
R1 substituent classes and size ranges
R1 is defined by size-restricted classes including C3-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, or C3-10 cycloalkenyl.
C(O)-Rh side-chain substituent definition
R2 includes a C(O)-Rh option, wherein Rh is amino optionally substituted with one or more Rg, or C1-12 alkyl optionally substituted with one or more Rn.
Alternative R2 substituent classes
R2 is alternatively C1-12 alkyl, C3-10 cycloalkenyl, 5-20 membered heteroaryl, 3-15 membered heterocyclyl, amidinyl, sulfonyl, or cyano.
R2 and R3 taken together to form ring systems
R2 and R3 are taken together with the atoms to which they are attached to form a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl comprising two or more annular heteroatoms, optionally substituted with oxo or OH.
R3 and R4 constrained end substituents
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.
Pharmaceutical composition with specified administration routes
A pharmaceutical composition comprising the compound and a pharmaceutical carrier, wherein the composition is administered via one or more specified routes including oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration.
The claim coverage is centered on compounds of formula (I) with defined X1/X2 positions, size-limited R1 classes, and an extensive R2 framework that includes C(O)-Rh, alternative alkyl/cycloalkenyl/heteroaryl/heterocyclyl/amidinyl/sulfonyl/cyano options, plus a ring-forming relationship between R2 and R3 and constrained R3/R4 definitions. A dependent composition claim further specifies administration routes.
Stated Advantages
Crystalline Form I and Form II are characterized with improved bioavailability, stability, and manufacturability.
Solvent-loss and solid-state behavior are described for Form I and Form II, supporting distinct stability characteristics.
Documented Applications
Treating diseases responsive to modulation of skeletal sarcomere contractility, including modulation associated with troponin/tropomyosin and skeletal muscle myosin/actin pathways, with disease areas including sarcopenia, cachexia, neuromuscular and CNS disorders, muscle myopathies, rehab deficits, peripheral vascular disease, and pelvic floor dysfunction.
Use in pharmaceutical compositions comprising the compounds for administration via oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular routes.
Therapeutic modulation of skeletal sarcomere contractility through the fast skeletal muscle troponin complex for treating sarcopenia, cachexia, and neuromuscular disorders.
Pharmaceutical use of crystalline Form I and Form II in compositions with pharmaceutically acceptable excipients.
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