Bicyclic piperazinones and their therapeutic use

Abstract

Provided herein is a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein Z 1 Z 2 Z 3 R 1 R 2 R 3 and n are as defined herein. Also provided herein is a pharmaceutically acceptable composition comprising the compound of formula (I), or a pharmaceutically acceptable salt thereof. Also provided herein is a method of using the compound of formula (I), or a pharmaceutically acceptable salt thereof, for treating various diseases, disorders, and conditions responsive to modulation of the contractility of skeletal muscle sarcomeres. TIFF2025517635000297.tif42165

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 338,375, filed May 4, 2022, the contents of which are hereby incorporated by reference in their entirety for all purposes.

[0002] Provided herein are bicyclic piperazinone compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds and pharmaceutical compositions for treating various diseases, disorders, and conditions responsive to modulation of the contractility of the skeletal muscle sarcomere.

Background Art

[0003] The cytoskeletons of skeletal muscle cells and cardiomyocytes are unique compared to all other cells, consisting of an array of cytoskeletal proteins called sarcomeres that are closely packed in a crystal - like arrangement. The sarcomere is beautifully organized as an array where thin filaments and thick filaments intermesh with each other. The thick filaments are composed of myosin, a motor protein involved in converting the chemical energy of ATP hydrolysis into force and directed movement. The thin filaments consist of actin monomers arranged in a helical array. There are four regulatory proteins that bind to the actin filaments, and contraction is regulated by calcium ions. Muscle contraction is initiated by an influx of calcium ions into the cell, and the thick and thin filaments slide past each other as the interaction between the myosin motor domain and the thin actin filaments is repeatedly driven.

[0004] Of the 13 different myosins in human cells, the myosin II class is involved in the contraction of skeletal muscle, cardiac muscle, and smooth muscle. Myosins of this class are significantly different in amino acid composition and overall structure from the other 12 different classes of myosins. Myosin II forms a homodimer, with two globular head domains linked together by a long α-helical coiled-coil tail, forming the core of the thick filaments of the sarcomere. The globular head has a catalytic domain where myosin's actin binding and ATPase activity occur. When binding to the actin filament, the release of phosphate (see: from ADP-Pi to ADP) signals a change in the structural conformation of the catalytic domain, in response to which the orientation of the light chain-binding lever arm domain extending from the globular head changes. This movement is called the power stroke. The change in the orientation of this myosin head relative to actin causes the thick filament (of which the myosin head is a part) to move relative to the thin actin filament to which the myosin head is bound. When the globular head is released from the actin filament (Ca 2+ regulated), and the catalytic domain and light chain return to their original conformation / orientation, the catalytic cycle involved in intracellular movement and muscle contraction is completed.

[0005] Tropomyosin and troponin mediate the calcium effect on the interaction between actin and myosin. The troponin complex consists of three polypeptide chains: troponin C that binds calcium ions, troponin I that binds actin, and troponin T that binds tropomyosin. The skeletal muscle troponin-tropomyosin complex controls the myosin binding sites that span multiple actin units at once.

[0006] Troponin, which is a complex of the above three polypeptides, is an accessory protein closely associated with actin filaments in vertebrate muscles. The troponin complex acts together with muscle form tropomyosin to regulate Ca 2+It mediates the myosin ATPase activity that is dependent thereon, thereby controlling muscle contraction. Troponin polypeptides T, I, and C are named according to their tropomyosin-binding activity, tropomyosin-inhibiting activity, and calcium-binding activity, respectively. Troponin T is thought to bind to tropomyosin and play a role in positioning the troponin complex on the thin filaments of muscle. Troponin I binds to actin, and the complex formed by troponin I and troponin T and tropomyosin inhibits the interaction between actin and myosin. Skeletal muscle troponin C can bind up to four calcium molecules. Studies have shown that when the calcium level in muscle increases, troponin C exposes the binding site for troponin I and pulls troponin I away from actin. This also causes the position of tropomyosin molecules to move, exposing the myosin-binding site on actin and stimulating myosin ATPase activity.

[0007] Human skeletal muscle consists of various types of contractile fibers, is classified by the type of myosin, and is called either slow fibers or fast fibers. Table 1 summarizes the various proteins that make up these types of muscle.

Table 1

[0008] In healthy humans, most skeletal muscles consist of both fast and slow muscle fibers, although the respective proportions vary depending on the type of muscle. Skeletal muscle slow fibers, often called type I fibers, are structurally similar to cardiac muscle and tend to be used more for fine control and postural control. These typically have a high oxidative capacity and are resistant to fatigue even with continued use. Skeletal muscle fast fibers, often called type II fibers, are classified into oxidative (IIa) fast fibers and glycolytic (IIx / d type) fast fibers. These muscle fibers have different myosin types but share many components, including troponin and tropomyosin regulatory proteins. Skeletal muscle fast fibers exert greater force than skeletal muscle slow fibers but tend to fatigue more quickly and are functionally useful for acute, large movements such as rising from a chair or righting a fall.

[0009] Muscle contraction and force generation are controlled via neural stimulation by stimulating motor neurons. Each motor neuron can stimulate a number (approximately 100 - 380) of muscle fibers as a whole, which is called a motor unit. When it is necessary to contract a muscle, the motor neuron sends a stimulus as a nerve impulse (action potential) from the brainstem or spinal cord to each fiber within the motor unit. The contact area between the nerve and the muscle fiber is a special synapse called the neuromuscular junction (NMJ). Here, the action potential due to depolarization of the membrane in the nerve is converted into an impulse within the muscle fiber via the release of the neurotransmitter acetylcholine (ACh). ACh induces a second action potential within the muscle, which rapidly spreads along the fiber and into invaginations in the membrane called T-tubules. The T-tubules are physically connected via the dihydropyridine receptor (DHPR) to the Ca 2+ storage sites within the sarcoplasmic reticulum (SR) of the muscle. Stimulation of the DHPR activates the ryanodine receptor, a second Ca 2+ channel, to induce the release of Ca 2+ from the storage sites within the SR into the muscle cytoplasm, where it can interact with the troponin complex to initiate muscle contraction. When muscle stimulation ceases, calcium is removed by an ATP-dependent Ca 2+It is rapidly returned to the SR via the sarcoplasmic reticulum Ca 2+ -ATPase (SERCA), a pump.

[0010] Currently, most neuromuscular diseases have limited or no treatment. Therefore, the development of new compounds that regulate the contractility of skeletal muscle is needed. There is still a need for agents that utilize new mechanisms of action and can provide good results in terms of symptom relief, safety, and patient mortality in both the short and long term and have an improved therapeutic index.

Summary of the Invention

[0011] The present invention provides a pharmaceutical composition, particularly a compound that is expected to be used as an active ingredient of a pharmaceutical composition for preventing or treating a disease or condition that responds to the regulation of the contractility of the skeletal muscle sarcomere. The regulation of the skeletal muscle sarcomere can be, for example, by the regulation of the troponin complex of the skeletal muscle fast-twitch sarcomere via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, as well as fragments and isoforms thereof.

[0012] In one aspect, provided herein is a compound of formula (I):

Chemical formula

[0013] In another aspect, provided herein is a compound of formula (II):

Chemical formula

[0014] In another aspect, provided herein is a compound of formula (II-a):

Chemical formula

[0015] In another aspect, provided herein is a compound selected from Table 2, or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, provided herein is a method for treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, states of muscle wasting, muscular myopathy, muscle atrophy, muscle fatigue, and frailty in a subject, the method comprising administering to the subject an effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.

[0017] In another aspect, provided herein is a method for treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject, the method comprising administering to the subject an effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, provided herein is a method for treating a disease or condition in a subject selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke, the method comprising administering to the subject an effective amount of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof.

[0019] In another aspect, provided herein is the use of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition in a subject selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, states of muscle wasting, muscle myopathy, muscle atrophy, muscle fatigue, and frailty.

[0020] In another aspect, provided herein is the use of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition in a subject selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscle myopathy.

[0021] In another aspect, provided herein is the use of one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition in a subject selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke.

[0022] In another aspect, provided herein is one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, states of muscle wasting, muscle myopathy, muscle atrophy, muscle fatigue, and frailty in a subject.

[0023] In another aspect, provided herein is one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscle myopathy in a subject.

[0024] In another aspect, provided herein is one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting resulting from chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke in a subject.

[0025] Unless otherwise specified, when a symbol in a formula herein is also used in another formula, the same symbol indicates the same meaning. When the same symbol is used more than once in a given formula, each instance of the symbol in the formula represents a chemically moiety that is independently selected, and it should be understood that all instances of the symbol in the formula do not necessarily represent the same chemical moiety.

[0026] In a further aspect, the present invention relates to a pharmaceutical composition comprising one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, for preventing or treating various diseases, disorders, and conditions that respond to the regulation of the contractility of skeletal muscle sarcomeres.

[0027] In some embodiments, the present invention uses one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to treat frailty associated with aging (referred to as sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies including polymyositis, muscular dystrophy (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), long-term bed rest, immobilization / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-traumatic, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral artery disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; recovery after anesthesia or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); muscle weakness due to mechanical ventilation; or demyelinating diseases including spinocerebellar ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing.

[0028] Further embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and through practice of the present disclosure.

[0029] For the sake of brevity, the disclosures of the publications cited herein, including patents, are incorporated herein by reference.

Mode for Carrying Out the Invention

[0030] Definition As used herein, the following words and phrases are generally intended to have the following meanings, unless otherwise indicated in the context in which they are used.

[0031] Throughout this application, unless the context indicates otherwise, references to a compound of formula (I) include all subgroups of formula (I) as defined herein, such as formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), and all substructures, subgenera, preferences, embodiments, examples, and specific compounds defined and / or described herein. References to a compound of formula (I) and its subgroups, such as formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), include its ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, and / or isotopes. In some embodiments, references to a compound of formula (I) and its subgroups, such as formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), include its polymorphs, solvates, co-crystals, isomers, and / or tautomers. In some embodiments, references to a compound of formula (I) and its subgroups, such as (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), include its polymorphs, solvates, and / or co-crystals. In some embodiments, references to a compound of formula (I) and its subgroups, such as formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), include its isomers, tautomers and / or oxides. In some embodiments, references to a compound of formula (I) and its subgroups, such as formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), include its solvates. Similarly, the term "salt" includes solvates of salts of the compound.

[0032] "Alkyl" includes straight-chain and branched carbon chains having the indicated number of carbon atoms, e.g., from 1 to 20 carbon atoms, or from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms. For example, C 1-6 Alkyl includes both straight-chain alkyl and branched-chain alkyl having from 1 to 6 carbon atoms. When an alkyl residue having a specific number of carbons is specified, all branched-chain and straight-chain versions having that number of carbons are intended to be included. Thus, for example, "propyl" includes n-propyl and isopropyl, and "butyl" includes n-butyl, sec-butyl, isobutyl, and t-butyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.

[0033] When a range of values is specified (e.g., C 1-6 alkyl), each value within that range, and all ranges therebetween, are included. For example, "C 1-6 alkyl" includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 2-6 , C 3-6 , C 4-6 , C 5-6 , C 1-5 , C 2-5 , C 3-5 , C 4-5 , C 1-4 , C 2-4 , C 3-4 , C 1-3 , C 2-3 , and C 1-2 alkyl.

[0034] "Alkenyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8, or 2 to 6 carbon atoms) and at least one carbon-carbon double bond. This group may be in either the cis or trans configuration (Z or E configuration) with respect to the double bond(s). Alkenyl groups include, but are not limited to, ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl), and butenyl (e.g., but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl).

[0035] "Alkynyl" refers to an unsaturated branched or straight-chain alkyl group having the indicated number of carbon atoms (e.g., 2 to 8 or 2 to 6 carbon atoms) and at least one carbon-carbon triple bond. Alkynyl groups include, but are not limited to, ethynyl, propynyl (e.g., prop-1-yn-1-yl, prop-2-yn-1-yl), and butynyl (e.g., but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl).

[0036] "Cycloalkyl" refers to a non-aromatic, fully saturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. The cycloalkyl group can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, as well as bridged, cage-like, and spirocyclic ring groups (e.g., norbornane, bicyclo[2.2.2]octane, spiro[3.3]heptane). In addition, one of the rings in a polycyclic cycloalkyl group can be aromatic as long as the polycyclic cycloalkyl group is attached to the parent structure via a non-aromatic carbon. For example, the 1,2,3,4-tetrahydronaphthalen-1-yl group (this moiety is attached to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,2,3,4-tetrahydronaphthalen-5-yl (this moiety is attached to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. Examples of polycyclic cycloalkyl groups consisting of cycloalkyl groups fused to an aromatic ring are described below.

[0037] "Cycloalkenyl" refers to a non-aromatic, partially unsaturated carbocyclic ring having the indicated number of carbon atoms, e.g., 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. The cycloalkenyl group can be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl, as well as bridged, cage-like, and spirocyclic ring groups (e.g., norbornene, bicyclo[2.2.2]octene, spiro[3.3]heptene). In addition, one of the rings in a polycyclic cycloalkyl group can be aromatic as long as the polycyclic cycloalkyl group is attached to the parent structure via a non-aromatic carbon. For example, the 1,4-dihydronaphthalen-1-yl group (this moiety is attached to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1,4-dihydronaphthalen-5-yl (this moiety is attached to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group.

[0038] "Aryl" refers to an aromatic carbocyclic ring having the indicated number of carbon atoms, e.g., 6 to 12 or 6 to 10 carbon atoms. The aryl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). In some cases, both rings of the polycyclic aryl group are aromatic (e.g., naphthyl). In other cases, the polycyclic aryl group may contain a non-aromatic ring fused to the aromatic ring, provided that the polycyclic aryl group is attached to the parent structure through an atom in the aromatic ring. Thus, the 1,2,3,4-tetrahydronaphthalen-5-yl group (this moiety is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, but 1,2,3,4-tetrahydronaphthalen-1-yl (this moiety is attached to the parent structure through a non-aromatic carbon atom) is not considered an aryl group. Similarly, the 1,2,3,4-tetrahydroquinolin-8-yl group (this moiety is attached to the parent structure through an aromatic carbon atom) is considered an aryl group, but the 1,2,3,4-tetrahydroquinolin-1-yl group (this moiety is attached to the parent structure through a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" does not include or overlap with "heteroaryl" as defined herein, regardless of the point of attachment (e.g., both quinolin-5-yl and quinolin-2-yl are heteroaryl groups). In some cases, aryl is phenyl or naphthyl. In certain cases, aryl is phenyl. Further examples of aryl groups containing an aromatic carbocyclic ring fused to a non-aromatic ring are described below.

[0039] "Heteroaryl" refers to an aromatic ring containing a specified number of atoms, composed of one or more heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms) selected from N, O, and S and the remaining ring atoms being carbon (e.g., a 5- to 12-membered ring, or a 5- to 10-membered heteroaryl). The heteroaryl group does not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the heteroaryl group is 1 or less. Unless otherwise stated, the heteroaryl group may be attached to the parent structure by a carbon or nitrogen atom as valence permits. For example, "pyridyl" includes 2-pyridyl group, 3-pyridyl group, and 4-pyridyl group, and "pyrrolyl" includes 1-pyrrolyl group, 2-pyrrolyl group, and 3-pyrrolyl group.

[0040] In some cases, the heteroaryl group is monocyclic. Examples include pyrrole, pyrazole, imidazole, triazole (e.g., 1,2,3-triazole, 1,2,4-triazole, 1,2,4-triazole), tetrazole, furan, isoxazole, oxazole, oxadiazole (e.g., 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiadiazole (e.g., 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (e.g., 1,2,4-triazine, 1,3,5-triazine) and tetrazine.

[0041] In some cases, both rings of the polycyclic heteroaryl group are aromatic. Examples include indole, isoindole, indazole, benzimidazole, benzotriazole, benzofuran, benzoxazole, benzisoxazole, benzoxadiazole, benzothiophene, benzothiazole, benzisothiazole, benzothiadiazole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine, 3H-imidazo[4,5-b]pyridine, 3H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[3,2-b]pyridine, 1H-pyrazolo[4,3-b]pyridine, 1H-imidazo[4,5-b]pyridine, 1H-[1,2,3]triazolo[4,5-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrazolo[3,4-c]pyridine, 3H-imidazo[4,5-c]pyridine, 3H-[1,2,3]triazolo[4,5-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, 1H-pyrazolo[4,3-c]pyridine, 1H-imidazo[4,5-c]pyridine, 1H-[1,2,3]triazolo[4,5-c]pyridine, furo[2,3-b]pyridine, oxazolo[5,4-b]pyridine, isoxazolo[5,4-b]pyridine, [1,2,3]oxadiazolo[5,4-b]pyridine, furo[3,2-b]pyridine, oxazolo[4,5-b]pyridine, isoxazolo[4,5-b]pyridine, [1,2,3]oxadiazolo[4,5-b]pyridine, furo[2,3-c]pyridine, oxazolo[5,4-c]pyridine, isoxazolo[5,4-c]pyridine, [1,2,3]oxadiazolo[5,4-c]pyridine, furo[3,2-c]pyridine, oxazolo[4,5-c]pyridine, isoxazolo[4,5-c]pyridine, [1,2,3]oxadiazolo[4,5-c]pyridine, thieno[2,3-b]pyridine, thiazolo[5,4-b]pyridine, isothiazolo[5,4-b]pyridine, [1,2,3]thiadiazolo[5,4-b]pyridine, thieno[3,2-b]pyridine, thiazolo[4,5-b]pyridine, isothiazolo[4,5-b]pyridine, [1,2,3]thiadiazolo[4,5-b]pyridine, thieno[2,3-c]pyridine, thiazolo[5,4-c]pyridine, isothiazolo[5,4-c]pyridine, [1,2,3] Thiadiazolo[5,4-c]pyridine, thieno[3,2-c]pyridine, thiazolo[4,5-c]pyridine, isothiazolo[4,5-c]pyridine, [1,2,3]thiadiazolo[4,5-c]pyridine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, naphthyridine (e.g., 1,8-naphthyridine, 1,7-naphthyridine, 1,6-naphthyridine, 1,5-naphthyridine, 2,7-naphthyridine, 2,6-naphthyridine), imidazo[1,2-a]pyridine, 1H-pyrazolo[3,4-d]thiazole, 1H-pyrazolo[4,3-d]thiazole and imidazo[2,1-b]thiazole are mentioned.,

[0042] In other cases, provided that the polycyclic heteroaryl group is bonded to the parent structure through an atom in the aromatic ring, the polycyclic heteroaryl group may include a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to the heteroaryl ring. For example, the 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl group (this moiety is bonded to the parent structure through an aromatic carbon atom) is regarded as a heteroaryl group, but 4,5,6,7-tetrahydrobenzo[d]thiazol-5-yl (this moiety is bonded to the parent structure through a non-aromatic carbon atom) is not regarded as a heteroaryl group. Examples of polycyclic heteroaryl groups consisting of heteroaryl rings fused to non-aromatic rings are described below.,

[0043] "Heterocyclyl" includes the heterocycloalkyl moiety and the heterocycloalkenyl moiety defined below.,

[0044] "Heterocycloalkyl" refers to a non-aromatic, fully saturated ring having the indicated number of atoms, composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms) and the remaining ring atoms being carbon (e.g., 3- to 10-membered, or 3- to 7-membered heterocycloalkyl). The heterocycloalkyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkyl groups include oxiranyl, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Examples include thiomorpholine S-oxide and thiomorpholine S,S-dioxide. Examples of spirocyclic heterocycloalkyl groups include azaspiro[3.3]heptane, diazaspiro[3.3]heptane, diazaspiro[3.4]octane, and diazaspiro[3.5]nonane. Further, provided that one ring of a polycyclic heterocycloalkyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom, one ring of the polycyclic heterocycloalkyl group may be aromatic (e.g., aryl or heteroaryl). For example, the 1,2,3,4-tetrahydroquinolin-1-yl group (this moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is regarded as a heterocycloalkyl group, but the 1,2,3,4-tetrahydroquinolin-8-yl group (this moiety is bonded to the parent structure via an aromatic carbon atom) is not regarded as a heterocycloalkyl group. Examples of polycyclic heterocycloalkyl groups consisting of heterocycloalkyl groups fused to an aromatic ring are described below.

[0045] "Heterocycloalkenyl" refers to a non-aromatic ring having a specified number of atoms (e.g., 3 to 10, or a 3- to 7-membered heterocycloalkyl) composed of one or more heteroatoms selected from N, O, and S (e.g., 1, 2, 3, or 4 heteroatoms), with the remaining ring atoms being carbon, and having at least one double bond derived by removing one molecule of hydrogen from adjacent carbon atoms, adjacent nitrogen atoms, or adjacent carbon and nitrogen atoms of the corresponding heterocycloalkyl. The heterocycloalkenyl group may be monocyclic or polycyclic (e.g., bicyclic, tricyclic). Examples of heterocycloalkenyl groups include dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydrothiophenyl (e.g., 2,3-dihydrothiophenyl, 2,5-dihydrothiophenyl), dihydropyrrolyl (e.g., 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl), dihydroimidazolyl (e.g., 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl), pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl), tetrahydro-pyridinyl (e.g., 1,2,3,4-tetrahydro-pyridinyl, 1,2,3,6-tetrahydro-pyridinyl), and dihydropyridine (e.g., 1,2-dihydropyridine, 1,4-dihydropyridine). In addition, provided that a polycyclic heterocycloalkenyl group is bonded to the parent structure via a non-aromatic carbon or nitrogen atom, one ring of the polycyclic heterocycloalkenyl group may be aromatic (e.g., aryl or heteroaryl). For example, the 1,2-dihydroquinolin-1-yl group (this moiety is bonded to the parent structure via a non-aromatic nitrogen atom) is regarded as a heterocycloalkenyl group, while the 1,2-dihydroquinolin-8-yl group (this moiety is bonded to the parent structure via an aromatic carbon atom) is not regarded as a heterocycloalkenyl group. Examples of polycyclic heterocycloalkenyl groups composed of heterocycloalkenyl groups fused to an aromatic ring are described below.

[0046] Examples of polycyclic rings consisting of an aromatic ring (e.g., aryl or heteroaryl) fused to a non-aromatic ring (e.g., cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) include indenyl, 2,3-dihydro-1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, benzo[1,3]dioxolyl, tetrahydroquinolinyl, 2,3-dihydrobenzo[1,4]dioxinyl, indolinyl, isoindolinyl, 2,3-dihydro-1H-indazolyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 1,3-dihydrobenzo[c]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, 2,3-dihydrobenzo[d]oxazolyl, 2,3-dihydrobenzo[b]thiophenyl, 1,3-dihydrobenzo[c]thiophenyl, 1,3-dihydrobenzo[c]isothiazolyl, 2,3-dihydrobenzo[d]isothiazolyl, 2,3-dihydrobenzo[d]thiazolyl, 5,6-dihydro-4H-cyclopenta[d]thiazolyl, 4,5,6,7-tetrahydrobenzo[d]thiazolyl, 5,6-dihydro-4H-pyrrolo[3,4-d]thiazolyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, indolin-2-one, indolin-3-one, isoindolin-1-one, 1,2-dihydroindazol-3-one, 1H-benzo[d]imidazol-2(3H)-one, benzofuran-2(3H)-one, benzofuran-3(2H)-one, isobenzofuran-1(3H)-one, benzo[c]isoxazol-3(1H)-one, benzo[d]isoxazol-3(2H)-one, benzo[d]oxazol-2(3H)-one, benzo[b]thiophen-2(3H)-one, benzo[b]thiophen-3(2H)-one, benzo[c]thiophen-1(3H)-one, benzo[c]isothiazol-3(1H)-one, benzo[d]isothiazol-3(2H)-one, benzo[d]thiazol-2(3H)-one, 4,5-dihydropyrrolo[3,4-d]thiazol-6-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, quinolin-4(3H)-one, quinazolin-4(3H)-one, quinazolin-2,4(1H,3H)-diones, quinoxalin-2(1H)-one, quinoxalin-2,3(1H,4H)-dione, cinnolin-4(3H)-one, pyridin-2(1H)-one, pyrimidin-2(1H)-one, pyrimidin-4(3H)-one, pyridazin-3(2H)-one, 1H-pyrrolo[3,2-b]pyridin-2(3H)-one, 1H-pyrrolo[3,2-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-c]pyridin-2(3H)-one, 1H-pyrrolo[2,3-b]pyridin-2(3H)-one, 1,2-dihydropyrazolo[3,4-d]thiazol-3-one, and 4,5-dihydropyrrolo[3,4-d]thiazol-6-one. As described herein, whether each ring is considered an aryl group, heteroaryl group, cycloalkyl group, cycloalkenyl group, heterocycloalkyl group, or heterocycloalkenyl group depends on which atom the moiety is attached to the parent structure through.,

[0047] "Halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0048] "Cyclic" refers to a moiety that is a ring member and includes, but is not limited to, a cycloalkyl ring, cycloalkenyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring. For example, when a heteroaryl ring is described as "containing two or more cyclic heteroatoms", two or more of the ring members of the heteroaryl ring are heteroatoms.

[0049] Unless otherwise indicated, all compounds disclosed and / or described in this specification include all possible enantiomers, diastereomers, meso isomers, and other stereoisomeric forms, including their racemic mixtures, optically pure forms, and intermediate mixtures. Enantiomers, diastereomers, meso isomers, and other stereoisomeric forms can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Unless otherwise specified, if a compound disclosed and / or described in this specification contains an olefinic double bond or other geometrically asymmetric center, both the E isomer and the Z isomer are intended to be included in the compound. If a compound described in this specification contains a tautomerizable moiety, all possible tautomers are intended to be included in the compound unless otherwise specified.

[0050] "Protecting group" has the meaning customarily associated with it in organic synthesis, i.e., a group that selectively blocks one or more reactive sites in a polyfunctional compound so that a chemical reaction can be selectively carried out at another unprotected reactive site, and that can be readily removed after the selective reaction is complete. Various protecting groups are disclosed, for example, in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999). For example, a "hydroxy-protected form" contains at least one hydroxy group protected by a hydroxy protecting group. Similarly, amines and other reactive groups can be protected in the same way.

[0051] The term "pharmaceutically acceptable salt" refers to any salt of a compound herein that is known to be non-toxic and is commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salts of the compounds retain the biological effectiveness of the compounds described herein and are not undesirable biologically or otherwise. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Examples of inorganic acids from which the salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids from which the salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases from which the salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of organic bases from which the salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0052] When the compounds described in this specification are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, when the compound is a free base, addition salts, particularly pharmaceutically acceptable addition salts, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19). Those skilled in the art will recognize the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0053] "Solvates" are formed by the interaction of a solvent with a compound. Suitable solvents include, for example, water and alcohols (e.g., ethanol). Solvates include hydrates having any ratio of the compound and water, such as monohydrates, dihydrates, and hemihydrates.

[0054] The term "substituted" means that the specified group or moiety has one or more substituents including, but not limited to, substituents such as alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, amino, aminoacyl, aminocarbonylamino, aminocarbonyl-oxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, aryloxy, cyano, azide, halo, hydroxyl, nitro, carboxyl, thiol, thioalkyl, cycloalkyl, cycloalkenyl, alkyl, alkenyl, alkynyl, heterocycloalkyl, heterocycloalkenyl, aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy, etc. The term "unsubstituted" means that the specified group has no substituents. When the term "substituted" is used to describe a structural system, substitution is meant to occur at any valence-allowable position of that system. It is understood that when a group or moiety bears multiple substituents, the substituents may be the same or different from each other. In some embodiments, a substituted group or moiety bears from 1 to 5 substituents. In some embodiments, a substituted group or moiety bears 1 substituent. In some embodiments, a substituted group or moiety bears 2 substituents. In some embodiments, a substituted group or moiety bears 3 substituents. In some embodiments, a substituted group or moiety bears 4 substituents. In some embodiments, a substituted group or moiety has 5 substituents.

[0055] "Optional" or "optionally" means that the event or situation described thereafter may or may not occur, and the description is meant to include cases where the event or situation occurs and cases where it does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. With respect to any group containing one or more substituents, it is understood by those skilled in the art that such a group is not intended to introduce any substitutions or substitution patterns that are sterically impracticable, synthetically inaccessible, and / or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0056] The compounds disclosed and / or described herein are in enriched isotopic forms, for example, 2 H, 3 H, 11 C, 13 C and / or 14It may be enriched in the content of C. In one embodiment, the compound contains at least one deuterium atom. Such deuterated forms can be prepared, for example, by the means described in U.S. Patent Nos. 5,846,514 and 6,334,997. Such deuterated compounds can improve the efficacy of the compounds disclosed and / or described herein and increase the duration of action. Deuterium-substituted compounds can be synthesized using various methods, such as those described in Dean, D., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development, Curr. Pharm. Des., 2000; 6(10), Kabalka, G. et al., The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21, and Evans, E., Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0057] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. The use thereof in pharmaceutical compositions is contemplated, except where any conventional medium or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the pharmaceutical compositions.

[0058] The terms "patient", "individual", and "subject" refer to an animal such as a mammal, bird, or fish. In some embodiments, the patient or subject is a mammal. Mammals include, for example, mice, rats, dogs, cats, pigs, sheep, horses, cows, and humans. In some embodiments, the patient or subject is a human, for example, one who was or is the subject of treatment, observation, or experiment. The compounds, compositions, and methods described herein may be useful in both human therapy and veterinary applications.

[0059] As used herein, the term "therapeutic" refers to the ability to treat a condition, disorder, or disease described herein, such as, but not limited to, a condition, disorder, or disease responsive to modulation of the contractility of the skeletal muscle sarcomere. As used herein, "modulation" refers to a change in activity relative to the activity in the absence of a chemical substance, as a direct or indirect response to the chemical substance described herein. This change may be an increase or a decrease in activity and may be due to a direct interaction of the chemical substance with the target or to an interaction of the chemical substance with one or more other factors that in turn affect the activity of the target. For example, the presence of a chemical substance may increase or decrease target activity by, for example, binding directly to the target, increasing or decreasing (directly or indirectly) target activity by another factor, or increasing or decreasing (directly or indirectly) the amount of target present in a cell or organism.

[0060] The terms "therapeutically effective amount" or "effective amount" refer to an amount of a compound disclosed and / or described herein that, when administered to a patient in need of the treatment defined herein, is sufficient to affect such treatment. A therapeutically effective amount of a compound can be an amount sufficient to treat a disease, disorder, or condition described herein, such as, but not limited to, a condition, disorder, or disease responsive to the regulation of the contractility of the skeletal muscle sarcomere. A therapeutically effective amount will vary, for example, depending on the subject and condition being treated, the weight and age of the subject, the severity of the condition, the particular compound, the dosing regimen to be followed, the timing of administration, and the mode of administration, all of which can be readily determined by one of ordinary skill in the art. A therapeutically effective amount can be confirmed experimentally, for example, by assessing the blood concentration of the chemical substance, or theoretically, by calculating bioavailability.

[0061] "Treatment" (and related terms such as "treat," "treated," "treating," etc.) includes one or more of inhibiting a disease or disorder, delaying or preventing the occurrence of clinical symptoms of a disease or disorder, and / or alleviating a disease or disorder (i.e., causing remission or regression of clinical symptoms). The term encompasses both complete and partial reduction or prevention of a condition or disorder and complete or partial reduction of clinical symptoms of a disease or disorder. Thus, the compounds described and / or disclosed herein can prevent the worsening of an existing disease or disorder, assist in the management of a disease or disorder, or reduce or eliminate a disease or disorder.

[0062] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include the plural unless the context clearly dictates otherwise.

[0063] As used herein, unless otherwise specified, the terms "about" and "approximately" when used in connection with the dosage, amount, or weight percent of the components of a composition or dosage form mean a dosage, amount, or weight percent that will provide a pharmacological effect equivalent to that obtained from the recited dosage, amount, or weight percent. Specifically, the terms "about" and "approximately" when used in this context are intended to cover a dosage, amount, or weight percent within 5% of the recited dosage, amount, or weight percent.

[0064] Compound Compounds and their salts (e.g., pharmaceutically acceptable salts) are detailed herein, including in the summary and the appended claims. Also provided are all uses of the compounds described herein, including any geometric isomers (cis / trans), E / Z isomers, enantiomers, diastereomers, and any mixtures thereof in any ratio, including racemic mixtures, salts, and solvates, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.

[0065] In one aspect, provided herein is a compound of formula (I):

Chemical formula

[0066] In some embodiments, provided herein is a compound of formula (II):

Chemical formula

[0067] In some embodiments of the compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, Z 1 Z 2 and Z 3 one, two, or three of are CH or CR 3 . In some embodiments, Z 1 Z 2 and Z 3 are each independently CH or CR 3 . In some embodiments, Z 1 is N, and Z 2 and Z 3 are each independently CH or CR 3 . In some embodiments, Z 2 is N, and Z 1 and Z 3 are each independently CH or CR 3 . In some embodiments, Z 1 and Z 2 are each independently CH or CR 3 , and Z 3 is N. In some embodiments, Z 1 is CH or CR 3 , and Z 2 and Z 3 are each N.

[0068] In some embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-a), (I-b), (I-c), (I-d), or (I-e):

Chemical formula

[0069] In some embodiments, provided herein is a compound of formula (I-a):

Chemical formula

[0070] In some embodiments, provided herein is a compound of formula (I-b):

Chemical formula

[0071] In some embodiments, provided herein is a compound of formula (I-c):

Chemical formula

[0072] In some embodiments, provided herein is a compound of formula (I-d): [Chemical] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and n are as defined for the compound of formula (I), or any variation or embodiment thereof.

[0073] In some embodiments, provided herein is a compound of formula (I-e): [Chemical] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and n are as defined for the compound of formula (I), or any variation or embodiment thereof.

[0074] In some embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein the compound is (II-a), (II-b), (II-c), (II-d), or (II-e): [Chemical] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and n are as defined for the compound of formula (I), or any variation or embodiment thereof.

[0075] In some embodiments, provided herein is a compound of formula (II-a): [Chemical] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , and n are as defined for the compound of formula (I), or any variation or embodiment thereof.

[0076] In some embodiments, provided herein is a compound of formula (II-b):

Chemical formula

[0077] In some embodiments, provided herein is a compound of formula (II-c):

Chemical formula

[0078] In some embodiments, provided herein is a compound of formula (II-d):

Chemical formula

[0079] In some embodiments, provided herein is a compound of formula (II-e):

Chemical formula

[0080] In some embodiments of a compound of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a pharmaceutically acceptable salt thereof, R 1 is propyl or butyl. In some embodiments, R 1 is propan-1-yl, propan-2-yl, butan-1-yl, butan-2-yl, or 2-methylpropan-1-yl. In some embodiments, R 1 is propan-1-yl, propan-2-yl, butan-2-yl, or 2-methylpropan-1-yl. In some embodiments, R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0081] In some embodiments of the compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a pharmaceutically acceptable salt thereof, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0082] In embodiments of the compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a pharmaceutically acceptable salt thereof, each R 3 is independently halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 12 -cycloalkyl, or 3- to 12-membered heterocycloalkyl. In other embodiments, each R 3 is independently halogen or C 3 -C 12 -cycloalkyl. In other embodiments, each R 3 is independently halogen or C 3 -C 6 -cycloalkyl. In some embodiments, each R 3 is independently halogen. In some embodiments, each R 3 is independently fluoro, chloro, or bromo. In certain embodiments, each R 3 is fluoro. In other embodiments, each R 3 is chloro. In another embodiment, each R 3 is bromo. In some embodiments, each R3 is independently C 3 -C 12 -cycloalkyl. In some embodiments, each R 3 is independently C 3 -C 6 -cycloalkyl. In one embodiment, each R 3 is cyclopropyl. In another embodiment, each R 3 is cyclobutyl. In one embodiment, each R 3 is cyclopentyl. In one embodiment, each R 3 is cyclohexyl.

[0083] In embodiments of the compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or pharmaceutically acceptable salts thereof, n is 1 and R 3 is halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkoxy, C 3 -C 12 -cycloalkyl, or 3- to 12-membered heterocycloalkyl. In other embodiments, n is 1 and R 3 is halogen or C 3 -C 12 -cycloalkyl. In other embodiments, n is 1 and R 3 is halogen or C 3 -C 6 -cycloalkyl. In some embodiments, n is 1 and R 3 is halogen. In some embodiments, n is 1 and R 3 is fluoro, chloro, or bromo. In certain embodiments, n is 1 and R 3 is fluoro. In other embodiments, n is 1 and R 3is chloro. In another embodiment, n is 1 and R 3 is bromo. In some embodiments, n is 1 and R 3 is C 3 -C 12 -cycloalkyl. In some embodiments, n is 1 and R 3 is C 3 -C 6 -cycloalkyl. In one embodiment, n is 1 and R 3 is cyclopropyl. In another embodiment, n is 1 and R 3 is cyclobutyl. In one embodiment, n is 1 and R 3 is cyclopentyl. In one embodiment, n is 1 and R 3 is cyclohexyl.

[0084] In some embodiments of the compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a pharmaceutically acceptable salt thereof, R 2 is -C(=O)R 4 , -C(=O)-(CH 2 ) p -R 5 , -C(=O)NR 6 R 7 , or -C(=O)OCH 3 . In some embodiments, R 2 is -C(=O)R 4 . In some embodiments, R 2 is -C(=O)-(CH 2 ) p -R 5 . In some embodiments, R 2 is -C(=O)NR 6 R 7 . In some embodiments, R 2 is -C(=O)OCH 3 .

[0085] In some embodiments of the compound of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a pharmaceutically acceptable salt thereof, R 2 is -C(=O)R 4 wherein R 4 is C 4A optionally substituted with from 1 to 5 R 6 -C 12 -aryl, 5- to 12-membered heteroaryl optionally substituted with from 1 to 5 R 4B , C 4C optionally substituted with from 1 to 5 R 3 -C 12 -cycloalkyl, 4- to 12-membered heterocycloalkyl optionally substituted with from 1 to 5 R 4D , or 4- to 12-membered heterocycloalkenyl optionally substituted with from 1 to 5 R 4E . In some embodiments, R 2 is -C(=O)R 4 wherein R 4 is C 4A optionally substituted with from 1 to 5 R 6 -C 12 -aryl, 5- to 12-membered heteroaryl optionally substituted with from 1 to 5 R 4B , 4- to 12-membered heterocycloalkyl optionally substituted with from 1 to 5 R 4D , or 4- to 12-membered heterocycloalkenyl optionally substituted with from 1 to 5 R 4E .

[0086] In some embodiments, R 2 is -C(=O)R 4 wherein R 4 is unsubstituted C 6 -C 12 -aryl. In some embodiments, R 4 is C 4A -C 6 -aryl substituted with from 1 to 5 R 12 . In some embodiments, R 4is unsubstituted phenyl. In some embodiments, R 4 is phenyl substituted with 1 to 5 R 4A s. In some embodiments, R 4 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0087] In some embodiments, R 2 is -C(=O)R 4 and R 4 is unsubstituted 5- to 12-membered heteroaryl. In some embodiments, R 4 is 5- to 12-membered heteroaryl substituted with 1 to 5 R 4B . In some embodiments, R 4 is pyridinyl, pyrrolyl, pyrazolyl, isoxazolyl, thiazolyl, pyrrolopyridyl, imidazopyridyl, pyrrolopyrimidyl, pyrazolopyridyl, or pyrrolidinyl, each of which is optionally substituted with 1 to 5 R 4B . In some embodiments, R 4 is

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0088] In some embodiments, R 2 is -C(=O)R 4 wherein R 4 is unsubstituted 4- to 12-membered heterocycloalkyl. In some embodiments, R 4 is 4- to 12-membered heterocycloalkyl substituted with 1 to 5 R 4D In some embodiments, R 4 is indolinyl, azetidinyl, or piperidinyl, each of which is optionally substituted with 1 to 5 R 4D In some embodiments, R 4 is

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0089] In some embodiments, R 2 is -C(=O)R 4 where R 4 is unsubstituted 4- to 12-membered heterocycloalkenyl. In some embodiments, R 4 is 4- to 12-membered heterocycloalkenyl substituted with 1 to 5 R 4E . In some embodiments, R 4 is pyridonyl. In some embodiments, R 4 is

Chemical formula

[0090] In some embodiments of the compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a pharmaceutically acceptable salt thereof, R 2 is -C(=O)-(CH 2 ) p -R 5 wherein R 5 is OH, C 1 -C 6 -Alkoxy, C 1 -C 6 -Haloalkoxy, C 3 -C 12 Cycloalkyl, 3- to 12-membered heterocycloalkyl, or C 6 -C 12 -Aryl. In some embodiments, R 5 is OH or C 6 -C 12 -Aryl. In some embodiments, R 5 is OH. In some embodiments, R 5 is C 6 -C 12 -Aryl. In some embodiments, R 5is phenyl. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0091] In some embodiments of the compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a pharmaceutically acceptable salt thereof, R 2 is -C(=O)NR 6 R 7 wherein R 6 and R 7 , independently of one another, are H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 8 optionally substituted with 1 to 5 R 3 -C 12 -cycloalkyl, 4- to 12-membered heterocycloalkyl optionally substituted with 1 to 5 R 8 , 5- to 12-membered heteroaryl optionally substituted with 1 to 5 R 8 , C 6 -C 12 -aryl, C 8 -C 1 -alkylene-OH, C 6 -C 1 -alkylene-(C 6 -C 3 -cycloalkyl), C 12 , C 1 -C 6 -alkylene-(4- to 12-membered heterocycloalkyl), C 1 -C 6 -alkylene-(C 6 -C 12 -aryl), or C 1 -C 6 -alkylene-(5- to 12-membered heteroaryl). In some embodiments, R 6 and R7 are, independently of each other, H, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 3 -C 12 cycloalkyl, 1 to 5 R 8 optionally substituted C 6 -C 12 -aryl, 1 to 5 R 8 optionally substituted 5- to 12-membered heteroaryl, C 1 -C 6 -alkylene-OH, C 1 -C 6 -alkylene-(C 3 -C 12 cycloalkyl), C 1 -C 6 -alkylene-(C 6 -C 12 -aryl), and C 1 -C 6 -alkylene-(5- to 12-membered heteroaryl). In some embodiments, R 6 is H, and R 7 is H. In some embodiments, R 6 is H, and R 7 is C 1 -C 6 -alkyl. In some embodiments, R 6 is H, and R 7 is methyl. In some embodiments, R 6 is H, and R 7 is ethyl. In some embodiments, R 6 is H, and R 7 is C 1 -C 6 -haloalkyl. In some embodiments, R 6 is H, and R 7 is, and R 7 is

Chemical formula

Chemical formula

[0092] In some embodiments, R 6 is H, R 7 is C optionally substituted with 1 to 5 R 8 -C 3 -C 12 -cycloalkyl. In some embodiments, R 6 is H, R 7 is unsubstituted cyclohexyl. In some embodiments, R 6 is H, R 7 is cyclobutyl substituted with 1 R 8 . In some embodiments, R 6 is H, R 7 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

[0093] In some embodiments of the compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or pharmaceutically acceptable salts thereof, R 2 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0094] In one aspect, provided herein is a compound of the following formula:

Chemical formula

[0095] In another aspect, provided herein is a compound of the following formula:

Chemical formula

[0096] In another aspect, provided herein is a compound of the following formula:

Chemical formula

[0097] In some embodiments of the compound of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a pharmaceutically acceptable salt thereof, the compound is not 4-(3-methylbenzoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one, 4-(2-chlorobenzoyl)-3-isobutyl-3,4-dihydroquinoxalin-2(1H)-one, or 4-(4-(tert-butyl)benzoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one.

[0098] In some embodiments, provided herein is a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 2. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11]

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

[0099] In some variations, any of the compounds described herein, for example, a compound of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e) or any variation thereof, or a compound in Table 2 may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In some of other variations, the compound is deuterated at multiple sites. The deuterated compound can be prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compound. Other methods known in the art can be used to replace a hydrogen atom with a deuterium atom.

[0100] In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

[0101] In one aspect, provided herein is a compound selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

[0102] In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the group consisting of Compounds 1-133, or a pharmaceutically acceptable salt thereof.

[0103] In one aspect, provided herein is a compound selected from the group consisting of Compounds 1-133, or a pharmaceutically acceptable salt thereof.

[0104] In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of: 4-(6-Chloronicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 6-Chloro-4-(6-chloronicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-Methylnicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 5-Bromo-4-(6-chloronicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-Chloronicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-Fluoro-nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 5-Cyclopropyl-4-(6-methylnicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; N-(6-Methylpyridin-3-yl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-Propyl-4-(1H-pyrrole-2-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 4-Benzoyl-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-Isonicotinoyl-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-Nicotinoyl-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(1-Methyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(3-Methylisoxazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 3-Propyl-4-(thiophene-2-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 4-(5-Methylnicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(3-Fluorobenzoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(5-Fluoronicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(3-Phenylpropanoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(5-Chloronicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(3,4-Difluorobenzoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; N-(5-(3-Oxo-2-propyl-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)pyridin-2-yl)acetamide; 4-(6-(1H-Pyrrol-1-yl)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Difluoromethoxy)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 3-Propyl-4-(6-(trifluoromethoxy)nicotinoyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-Propyl-4-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-Aminonicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Dimethylamino)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Piperidin-1-yl)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(1-Ethyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(1-(Cyclopropylmethyl)-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(1-Cyclobutyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Ethyl(methyl)amino)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 3-Propyl-4-(6-((2,2,2-trifluoroethyl)amino)nicotinoyl)-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Azepan-1-yl)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Benzylamino)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Cyclopropyl(methyl)amino)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(3-Fluoroazetidin-1-yl)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Benzyl(methyl)amino)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(3-Methoxyazetidin-1-yl)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(3-Fluoropyrrolidin-1-yl)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(3,3-Difluoroazetidin-1-yl)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(3,3-Difluoropyrrolidin-1-yl)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-(Methyl(3,3,3-trifluoropropyl)amino)nicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(1,3-Dimethyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; N-Cyclohexyl-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-Oxo-2-propyl-N-(pyridin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-Oxo-2-propyl-N-(pyridin-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; N-Benzyl-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-Oxo-N-(1-phenylethyl)-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; N-(Cyclohexylmethyl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; 4-(Indoline-1-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; N-(2-Methoxyphenyl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; N-(3-Methoxyphenyl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; N-(4-Methoxyphenyl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; N-(2-Fluorophenyl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; N-(3-Fluorophenyl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; N-(4-Fluorophenyl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; N-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-2-propyl-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-Oxo-2-propyl-N-(o-tolyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-Oxo-2-propyl-N-(m-tolyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-Oxo-2-propyl-N-(p-tolyl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-(sec-Butyl)-4-(1-methyl-1H-pyrazole-4-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 6-Chloro-4-(1-methyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(Imidazo[1,5-a]pyridine-6-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(Imidazo[1,5-a]pyridine-7-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 4-(1-(2-Hydroxyethyl)-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 3-Isobutyl-4-(1-methyl-1H-pyrazole-4-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 5-Bromo-4-(1-methyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 3-Propyl-4-(pyrrolo[1,2-c]pyrimidine-3-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-Propyl-4-(1H-pyrazole-4-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-butyl)-4-(1H-pyrazole-4-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-propyl-4-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-aminonicotinoyl)-3-(sec-butyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-butyl)-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 4-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one; 3-isopropyl-4-(1-methyl-1H-pyrazole-4-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-butyl)-4-(1-(2-hydroxyethyl)-1H-pyrazole-4-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-butyl)-4-(1H-pyrazole-3-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 2-(4-(2-(sec-butyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-1-carbonyl)-1H-pyrazol-1-yl)acetamide; 3-isopropyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 4-(6-aminonicotinoyl)-3-isopropyl-3,4-dihydroquinoxalin-2(1H)-one; 3-isopropyl-4-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 4-(1-cyclopropyl-1H-pyrazole-4-carbonyl)-3-isopropyl-3,4-dihydroquinoxalin-2(1H)-one; 3-Isopropyl-4-(6-oxo-1,6-dihydropyridine-3-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-Isopropyl-4-(1H-pyrazole-4-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-Isopropyl-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one; 2-Isopropyl-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one; 2-(sec-Butyl)-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one; 2-(sec-Butyl)-1-(6-oxo-1,6-dihydropyridine-3-carbonyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one; 2-(sec-Butyl)-1-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one; 3-(sec-Butyl)-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one; 3-(sec-Butyl)-4-(1-methyl-1H-pyrazole-4-carbonyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one; 7-(sec-Butyl)-8-(1-methyl-1H-pyrazole-4-carbonyl)-7,8-dihydropteridin-6(5H)-one; 2-(sec-Butyl)-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one; 2-Isobutyl-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one; 1-benzoyl-2-(sec-butyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one; 2-(sec-butyl)-1-(3-methylbenzoyl)-1,4-dihydropyrido[3,4-b]pyrazin-3(2H)-one; 2-(sec-butyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-butyl)-5-fluoro-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-(sec-butyl)-4-(3-hydroxyazetidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 2-(sec-butyl)-N-methyl-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-butyl)-N-ethyl-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-(sec-butyl)-4-(pyrrolidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 2-(sec-butyl)-N-(2-hydroxyethyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-(sec-butyl)-4-(3-hydroxypyrrolidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-butyl)-4-(3-(hydroxymethyl)pyrrolidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-butyl)-4-(3-(hydroxymethyl)pyrrolidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-butyl)-4-(2-hydroxyacetyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-butyl)-4-(3-hydroxypropanoyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-Butyl)-4-(3-(hydroxymethyl)azetidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-Butyl)-4-(3-fluoroazetidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 2-(sec-Butyl)-7-fluoro-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-(sec-Butyl)-4-(3-hydroxypiperidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 2-(sec-Butyl)-N-(3-hydroxypropyl)-N-methyl-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 3-(sec-Butyl)-4-(3-(hydroxymethyl)piperidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-Butyl)-4-(3,3-difluoroazetidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-Butyl)-4-(4-hydroxypiperidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; N-(1-(2-(sec-Butyl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-1-carbonyl)azetidin-3-yl)acetamide; 3-(sec-Butyl)-4-(3-fluoropyrrolidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 3-(sec-Butyl)-4-(3-hydroxy-3-methylazetidine-1-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one; 2-(sec-Butyl)-N-(oxetan-3-yl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-Butyl)-N-(2,2-difluoroethyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-Butyl)-N-(2,2-difluoroethyl)-N-methyl-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; Methyl 2-(sec-butyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxylate; 2-(sec-Butyl)-3-oxo-N-(pyrrolidin-3-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-Butyl)-N-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-Butyl)-3-oxo-N-(2-oxaspiro[3.3]heptan-6-yl)-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-Butyl)-N-(1-methylpyrrolidin-3-yl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-Butyl)-N-(1-(2-hydroxyethyl)piperidin-4-yl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-Butyl)-N-(2-hydroxyethyl)-N-methyl-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; 2-(sec-Butyl)-N-(3-hydroxycyclobutyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; and 2-(sec-Butyl)-N-(3-hydroxycyclobutyl)-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide; Or a pharmaceutically acceptable salt thereof. Also provided are all stereoisomers, in any ratio, including geometric isomers (e.g., cis / trans isomers or E / Z isomers), enantiomers, diastereomers, of the compounds described herein, or mixtures thereof including racemic mixtures.

[0105] The formulas shown in this specification, such as formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), are all intended to represent compounds having the structure shown by the structural formula and specific variations or forms. In particular, compounds of any of the formulas shown in this specification may have asymmetric centers and, therefore, may exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, as well as mixtures thereof in any ratio, are considered to be within the scope of that formula. Thus, any of the formulas shown in this specification is intended to represent racemates, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. When the compounds in Table 2 are shown in a specific stereochemical configuration, any alternative stereochemical configuration of that compound, as well as mixtures of the stereoisomers of the compound in any ratio, are also provided herein. For example, if the compound in Table 2 has a stereocenter in the "S" stereochemical configuration, the enantiomer of that compound with the stereocenter in the "R" stereochemical configuration is also provided herein. Similarly, if the compound in Table 2 has a stereocenter in the "R" configuration, the enantiomer of that compound with the stereocenter in the "S" stereochemical configuration is also provided herein. Also provided are mixtures of compounds having both the "S" and "R" stereochemical configurations. Further, if the compounds in Table 2 have more than one stereocenter, any enantiomer or diastereomer of that compound is also provided. For example, if the compound in Table 2 contains a first stereocenter and a second stereocenter having stereochemical configurations that are "R" and "R", respectively, the stereoisomers of that compound having first and second stereocenters with stereochemical configurations that are "S" and "S", respectively, "S" and "R", respectively, and "R" and "S", respectively, are also provided.In addition, when the compounds in Table 2 each contain a first stereocenter and a second stereocenter having a stereochemical configuration of "S" and "S", stereoisomers of the compound having a stereochemical configuration of "R" and "R", a stereochemical configuration of "S" and "R", and a stereochemical configuration of "R" and "S" for the first and second stereocenters, respectively, are also provided. Further, when the compounds in Table 2 each contain a first stereocenter and a second stereocenter having a stereochemical configuration of "S" and "R", stereoisomers of the compound having a stereochemical configuration of "R" and "S", a stereochemical configuration of "R" and "R", and a stereochemical configuration of "S" and "S" for the first and second stereocenters, respectively, are also provided. Similarly, when the compounds in Table 2 each contain a first stereocenter and a second stereocenter having a stereochemical configuration of "R" and "S", stereoisomers of the compound having a stereochemical configuration of "S" and "R", a stereochemical configuration of "R" and "R", and a stereochemical configuration of "S" and "S" for the first and second stereocenters, respectively, are also provided. Furthermore, certain structures can exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. Additionally, all of the formulas shown herein are intended to refer to any one of the hydrates, solvates, and amorphous and crystalline forms of such compounds, as well as mixtures thereof, even if such forms are not explicitly indicated. In some embodiments, the solvent is water and the solvate is a hydrate.

[0106] Representative examples of the compounds detailed herein, including intermediates and final compounds, are shown anywhere in the tables and in this specification. In one aspect, it is understood that any compound, including intermediate compounds that can be isolated and administered to an individual or subject where applicable, can be used in the methods detailed herein.

[0107] The compounds shown in this specification may exist as salts even if the salts are not indicated, and as will be well understood by those skilled in the art, the compositions and methods provided herein are understood to include all salts and solvates of the compounds shown herein, as well as the non-salt and non-solvate forms of the compounds. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0108] In one variation, the compounds of this specification are synthetic compounds prepared for administration to an individual or subject. In another variation, a composition is provided that includes the compound in substantially pure form. In another variation, a pharmaceutical composition is provided that includes the compound detailed herein and a pharmaceutically acceptable carrier. In another variation, a method of administering the compound is provided. The purified form, pharmaceutical composition, and method of administering the compound are suitable for any of the compounds or forms thereof detailed herein.

[0109] The Z provided herein 1 、Z 2 、Z 3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 4A 、R 4B 、R 4C 、R 4D 、R 4E 、R 4B1 、Any variation or embodiment of n and p is Z 1 、Z 2 、Z 3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 4A 、R 4B 、R 4C 、R 4D 、R 4E 、R4B1 It can be combined with any variation or embodiment of n and p, and each and every combination is the same as if it were individually and specifically recited.

[0110] Other embodiments will be apparent to those skilled in the art from the following detailed description.

[0111] As used herein, when any variable occurs multiple times in a chemical formula, its definition at each occurrence is independent of its definition at any other occurrence.

[0112] Formula (I) includes its sub-formulas. For example, formula (I) includes compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or pharmaceutically acceptable salts thereof.

[0113] The names of Compounds 1 to 133 provided in this specification shown in Table 2 and Examples 1 to 12 are those provided by ChemDraw Professional 18.2.0.48. Those skilled in the art will understand that compounds can be named or identified using various naming systems and symbols that are generally recognized. By way of example, a compound may be named or identified by its common name, systematic name, or non-systematic name. Naming systems and symbols generally recognized in the chemical arts include, for example, Chemical Abstract Service (CAS), ChemBioDraw Ultra, and International Union of Pure and Applied Chemistry (IUPAC).

[0114] Composition Also provided are compositions such as the compounds disclosed and / or described herein, and pharmaceutical compositions comprising one or more additional agents, pharmaceuticals, adjuvants, carriers, excipients, etc. Suitable agents and pharmaceuticals include those described herein. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient or adjuvant and at least one chemical substance described herein. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, and magnesium carbonate. In some embodiments, provided are compositions such as pharmaceutical compositions containing one or more of the compounds described herein, or pharmaceutically acceptable salts thereof.

[0115] In some embodiments, provided are pharmaceutically acceptable compositions comprising a compound of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof. In some aspects, the composition may contain synthetic intermediates that can be used in the preparation of the compounds described herein. The compositions described herein may optionally contain any other suitable active or inactive agent.

[0116] Any of the compositions described herein may be sterile or may contain sterile components. Sterilization can be achieved by methods known in the art. Any of the compositions described herein may contain one or more compounds or conjugates that are substantially pure.

[0117] Also provided is a packaged pharmaceutical composition comprising the pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease or condition described herein.

[0118] Method of Use The compounds and compositions described in detail herein, for example, pharmaceutical compositions comprising a compound of any of the formulas provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment provided herein.

[0119] Furthermore, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), for example, a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Furthermore, the present invention relates to a pharmaceutical composition for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal muscle sarcomere in a subject, for example, via one or more of skeletal muscle fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, and modulation of the troponin complex of the skeletal muscle fast sarcomere. Furthermore, the present invention relates to an agent for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal muscle sarcomere in a subject, for example, via one or more of skeletal muscle fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, and modulation of the troponin complex of the skeletal muscle fast sarcomere, comprising a compound of formula (I), for example, a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0120] Furthermore, the present invention relates to a pharmaceutical composition for treating a disease or condition responsive to modulation of the contractility of the skeletal muscle sarcomere in a subject, for example, modulation of the troponin complex of the skeletal muscle fast-twitch sarcomere via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising a compound of formula (I), for example, a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to an agent for treating a disease or condition responsive to modulation of the contractility of the skeletal muscle sarcomere in a subject, for example, modulation of the troponin complex of the skeletal muscle fast-twitch sarcomere via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, comprising a compound of formula (I), for example, a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0121] Furthermore, the present invention relates to the use of a compound of formula (I), for example, a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for preventing or treating a disease or condition responsive to modulation of the contractility of the skeletal muscle sarcomere in a subject, for example, modulation of the troponin complex of the skeletal muscle fast-twitch sarcomere via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0122] Furthermore, the present invention relates to the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating a disease or condition responsive to modulation of the contractility of skeletal muscle sarcomeres in a subject, e.g., modulation of the troponin complex of skeletal muscle fast-twitch sarcomeres via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0123] In one aspect, provided herein is the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for preventing or treating a disease or condition responsive to modulation of the contractility of skeletal muscle sarcomeres in a subject, e.g., modulation of the troponin complex of skeletal muscle fast-twitch sarcomeres via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0124] In one aspect, provided herein is the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating a disease or condition responsive to modulation of the contractility of skeletal muscle sarcomeres in a subject, e.g., modulation of the troponin complex of skeletal muscle fast-twitch sarcomeres via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0125] In one aspect, provided herein are compounds of formula (I), such as compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or compounds of Table 2, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the prevention or treatment of a disease or condition responsive to modulation of the contractility of skeletal muscle sarcomeres in a subject, e.g., via modulation of one or more of skeletal muscle fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, of the troponin complex of skeletal muscle fast sarcomeres.

[0126] In one aspect, provided herein are compounds of formula (I), such as compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or compounds of Table 2, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for use in the treatment of a disease or condition responsive to modulation of the contractility of skeletal muscle sarcomeres in a subject, e.g., via modulation of one or more of skeletal muscle fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, of the troponin complex of skeletal muscle fast sarcomeres.

[0127] In one aspect, provided herein is a method for preventing or treating a disease or condition responsive to modulation of the contractility of skeletal muscle sarcomeres in a subject, e.g., modulation of the troponin complex of skeletal muscle fast-twitch sarcomeres via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), e.g., a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof. Further, the "subject" is a human or non-human animal in need of prevention or treatment, and in one embodiment, is a human in need of prevention or treatment.

[0128] In one aspect, provided herein is a method for treating a disease or condition responsive to modulation of the contractility of skeletal muscle sarcomeres in a subject, e.g., modulation of the troponin complex of skeletal muscle fast-twitch sarcomeres via one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), e.g., a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof. Further, the "subject" is a human or non-human animal in need of prevention or treatment, and in one embodiment, is a human in need of prevention or treatment.

[0129] In one aspect, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Such pharmaceutical therapy may be related to a disease or condition responsive to the regulation of the contractility of the skeletal muscle sarcomere, for example, via the regulation of the troponin complex of the skeletal muscle fast-twitch sarcomere through one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0130] In one aspect, a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, regulates the contractility of the skeletal muscle sarcomere. Specifically, the compound regulates the troponin complex of the skeletal muscle fast-twitch sarcomere through one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, "regulate" means either an increase or a decrease in activity. In some cases, a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, enhances (i.e., increases the activity of) one or more of skeletal muscle fast-twitch myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof.

[0131] In another aspect, provided herein are compounds of formula (I), for example, compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or compounds of Table 2, or pharmaceutically acceptable salts thereof, which inhibit (i.e., reduce the activity of) one or more of skeletal muscle fast myosin, actin, tropomyosin, troponin C, troponin I, and troponin T, and fragments and isoforms thereof. As used in this context, "activation of skeletal muscle fast muscle fibers such as myofibrils" means amplifying the response of skeletal muscle fast muscle fibers (such as myofibrils) to stimulation / Ca 2+ and means amplifying the response of skeletal muscle fast muscle fibers (such as myofibrils) to stimulation / Ca

[0132] In some aspects, provided herein is a method for preventing or treating frailty associated with aging (referred to as sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies including polymyositis, muscular dystrophy (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), long-term bed rest, immobilization / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-traumatic, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral artery disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; recovery after anesthesia or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); muscle weakness due to mechanical ventilation; or demyelinating diseases including spinocerebellar ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing, the method comprising administering to the subject an effective amount of a compound of formula (I), e.g., a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a compound of formula (I), e.g., a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0133] In some aspects, provided herein is a method of treating in a subject frailty associated with aging (referred to as sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies including polymyositis, muscular dystrophy (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), long-term bed rest, immobilization / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-traumatic, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; recovery after anesthesia or reversal of neuromuscular block; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); muscle weakness due to mechanical ventilation; or a demyelinating disease including spinocerebellar ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing, the method comprising administering to the subject an effective amount of a compound of formula (I), e.g., a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or an effective amount of a pharmaceutical composition comprising a compound of formula (I), e.g., a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0134] In some aspects, provided herein is a method for preventing or treating in a subject a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy, muscle fatigue, and frailty, the method comprising administering to the subject an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0135] In some aspects, provided herein is a method for treating in a subject a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy, muscle fatigue, and frailty, the method comprising administering to the subject an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0136] In some aspects, provided herein is a method for preventing or treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0137] In some aspects, provided herein is a method for treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject, the method comprising administering to the subject an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, provided herein is a method for preventing or treating in a subject a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting resulting from chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke, the method comprising administering to the subject an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments, provided herein is a method for treating in a subject a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting resulting from chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke, the method comprising administering to the subject an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising an effective amount of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof.

[0140] In some aspects, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition for preventing or treating frailty associated with aging (referred to as sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies including polymyositis, muscular dystrophy (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), long-term bed rest, immobilization / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-traumatic, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; recovery after anesthesia or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); muscle weakness due to mechanical ventilation; or demyelinating diseases including spinocerebellar ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing.

[0141] In some aspects, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition for treating frailty associated with aging (referred to as sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies including polymyositis, muscular dystrophy (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), long-term bed rest, immobilization / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-traumatic, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral artery disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; recovery after anesthesia or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); muscle weakness due to mechanical ventilation; or demyelinating diseases including spinocerebellar ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing.

[0142] In some embodiments, provided herein is the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for preventing or treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy, muscle fatigue, and frailty in a subject.

[0143] In some embodiments, provided herein is the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscle myopathy, muscle atrophy, muscle fatigue, and frailty in a subject.

[0144] In some embodiments, provided herein is the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for preventing or treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscle myopathy in a subject.

[0145] In some embodiments, provided herein is the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject.

[0146] In some embodiments, provided herein is the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for preventing or treating a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke in a subject.

[0147] In some embodiments, provided herein is the use of a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical composition for treating a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke in a subject.

[0148] In some aspects, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of frailty associated with aging (referred to as sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies including polymyositis, muscular dystrophy (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), long-term bed rest, immobilization / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-traumatic, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral arterial disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; recovery after anesthesia or reversal of neuromuscular block; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); muscle weakness due to mechanical ventilation; or demyelinating diseases including spinocerebellar ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing.

[0149] In some aspects, provided herein is a compound of formula (I), for example a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of frailty associated with aging (referred to as sarcopenia); cachexia syndromes associated with diseases such as cancer, heart failure, chronic obstructive pulmonary disease (COPD), kidney disease, and chronic kidney disease / dialysis; diseases and disorders of the central nervous system (CNS); neuromuscular diseases such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and myasthenia gravis, peripheral neuropathy, Charcot-Marie-Tooth disease, Parkinson's disease, stroke, spinal cord injury, and motor unit disorders; muscle myopathies including polymyositis, muscular dystrophy (limb-girdle, facioscapulohumeral, oculopharyngeal), steroid myopathy, and mitochondrial myopathy; rehabilitation-related disorders: recovery from surgery (e.g., postoperative muscle weakness), long-term bed rest, immobilization / disuse atrophy, recovery after hip fracture, ICU neuromuscular disorders, post-traumatic, stroke rehabilitation; peripheral vascular disease (PVD) or peripheral artery disease (PAD) (e.g., claudication), metabolic syndrome, chronic fatigue syndrome, obesity, and frailty due to aging; recovery after anesthesia or reversal of neuromuscular blockade; obstructive sleep apnea; chronic fatigue syndrome; metabolic syndrome, metabolic / ischemic disorders, or claudication; obesity; pelvic floor muscle and urethral / anal sphincter dysfunction (e.g., urinary incontinence such as stress urinary incontinence (SUI) and mixed urinary incontinence (MUI), and fecal incontinence); muscle dysfunction after spinal cord injury (SCI); muscle weakness due to mechanical ventilation; or demyelinating diseases including spinocerebellar ataxia or multiple sclerosis, post-polio syndrome, or any combination of the foregoing.

[0150] In some embodiments, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscular myopathies, muscle atrophy, muscle fatigue, and frailty in a subject.

[0151] In some embodiments, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a disease or condition selected from the group consisting of peripheral vascular disease, peripheral arterial disease, rehabilitation-related disorders, metabolic syndrome, obesity, muscle weakness due to mechanical ventilation, chronic fatigue syndrome, neuromuscular disorders, muscle wasting conditions, muscular myopathies, muscle atrophy, muscle fatigue, and frailty in a subject.

[0152] In some embodiments, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathies in a subject.

[0153] In some embodiments, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy in a subject.

[0154] In some embodiments, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the prevention or treatment of a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke in a subject.

[0155] In some embodiments, provided herein is a compound of formula (I), such as a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or a compound of Table 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke in a subject.

[0156] Dosage The compounds and compositions disclosed and / or described herein are administered at therapeutically effective dosages, e.g., dosages sufficient to effect treatment of a medical condition. Dosage levels of the chemical substances described herein for human administration have not yet been optimized, but generally, the daily dosage is in the range of about 0.01 to 100 mg / kg body weight, and in some embodiments, about 0.05 to 10.0 mg / kg body weight, and in some embodiments, in the range of about 0.10 to 1.4 mg / kg body weight. Thus, when administered to a 70 kg human, the dosage range is, in some embodiments, about 0.7 to 7000 mg per day, and in some embodiments, about 3.5 to 700.0 mg per day, and in some embodiments, about 7 to 100.0 mg per day. The amount of the chemical substance administered depends, for example, on the subject and medical condition being treated, the severity of the disease, the mode and schedule of administration, as well as the judgment of the prescribing physician. For example, exemplary dosage ranges for oral administration are about 5 mg to about 500 mg per day, depending on the pharmacokinetics of the respective compound, and exemplary dosages for intravenous administration are about 5 mg to about 500 mg per day.

[0157] The daily dosage is the total amount administered in a day. The daily dosage can be administered daily, every other day, weekly, every two weeks, monthly, or at various intervals, without limitation. In some embodiments, the daily dosage is administered for a period ranging from one day to the lifetime of the subject. In some embodiments, the daily dosage is administered once a day. In some embodiments, the daily dosage is administered in multiple divided doses, such as two, three, or four divided doses. In some embodiments, the daily dosage is administered in two divided doses.

[0158] Administration of the compounds and compositions disclosed and / or described herein can be via any of the acceptable modes of administration of a therapeutic agent, including, but not limited to, oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular administration. In some embodiments, the compound or composition is administered orally or intravenously. In some embodiments, the compounds or compositions disclosed and / or described herein are administered orally.

[0159] Pharmaceutically acceptable compositions include solid, semi-solid, liquid, and aerosol dosage forms such as tablets, capsules, powders, solutions, suspensions, suppositories, and aerosols. The compounds disclosed and / or described herein can also be administered in dosage forms for sustained or controlled release (e.g., controlled release / sustained release pills, depot injections, osmotic pumps, or transdermal (including electrotransport) patches) for long-term timed administration and / or pulsed administration at a predetermined rate. In some embodiments, the composition is provided in unit dosage forms suitable for single administration of precise dosages.

[0160] The compounds disclosed and / or described in this specification may be administered alone or in combination with one or more conventional pharmaceutical carriers or excipients (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate). If desired, the pharmaceutical composition may contain small amounts of non-toxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents, etc. (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate). Generally, the pharmaceutical composition may contain the compounds disclosed and / or described in this specification in an amount of about 0.005% to 95% by weight, or about 0.5% to 50% by weight, depending on the intended mode of administration. The actual methods for preparing such dosage forms are known to those skilled in the art or will become apparent. See, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0161] In some embodiments, the composition takes the form of pills or tablets, and thus the composition may contain, together with the compounds disclosed and / or described in this specification, one or more of a diluent (e.g., lactose, sucrose, dicalcium phosphate), a lubricant (e.g., magnesium stearate), and / or a binder (e.g., starch, gum arabic, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives). Other solid dosage forms include powders encapsulated in gelatin capsules, marume, solutions or suspensions (e.g., in propylene carbonate, vegetable oils, or triglycerides).

[0162] A pharmaceutically administrable composition of a liquid can be prepared, for example, by dissolving, dispersing, or suspending a compound disclosed and / or described herein and an optional pharmaceutical additive in a carrier (such as water, physiological saline, aqueous dextrose, glycerol, glycol, ethanol, etc.) to form a solution or suspension. Injectable substances can be prepared in conventional forms as a liquid solution or suspension, as an emulsion, or in a solid form suitable for dissolving or suspending in a liquid before injection. The percentage of the compound contained in such a parenteral composition depends, for example, on the physical properties of the compound, the activity of the compound, and the needs of the subject. However, a percentage of the active ingredient from 0.01% to 10% in solution can be used, and can be higher if the composition is solid and later diluted to another concentration. In some embodiments, the composition contains from about 0.2% to 2% of the compound disclosed and / or described herein in solution.

[0163] The pharmaceutical composition of the compound disclosed and / or described herein can be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as an ultrafine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such cases, the particles of the pharmaceutical composition can have a diameter of less than 50 microns, or in some embodiments less than 10 microns.

[0164] Furthermore, the pharmaceutical composition can include the compound disclosed and / or described herein, as well as one or more additional agents, pharmaceuticals, adjuvants, etc. Suitable agents and pharmaceuticals include those described herein.

[0165] Kit Also provided are articles of manufacture and kits containing any of the compounds or pharmaceutical compositions provided herein. The article of manufacture can include a container having a label. Suitable containers include, for example, bottles, vials, and test tubes. The container can be formed from a variety of substances, such as glass or plastic. The container can hold the pharmaceutical composition provided herein. The label on the container can indicate that the pharmaceutical composition is to be used for preventing, treating, or suppressing the conditions described herein, and can also indicate instructions for any use, either in vivo or in vitro.

[0166] In one aspect, provided herein is a kit containing a compound or composition described herein and instructions for use. The kit can include instructions for use in the treatment of heart disease in an individual or subject in need thereof. The kit can additionally contain any materials or devices that can be used in the administration of the compound or composition, such as vials, syringes, or IV bags. The kit can also contain a sterile package.

[0167] Combination The compounds and compositions described and / or disclosed herein can be administered alone or in combination with other therapies and / or therapeutic agents useful in the treatment of the aforementioned disorders, diseases, or conditions.

[0168] General synthetic methods Compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e) are described herein by reference to exemplary synthetic schemes for their general preparation and the specific examples that follow. One of ordinary skill in the art will recognize that, in order to obtain the various compounds of this book, the starting materials can be suitably selected such that the ultimately desired substituents are retained through the reaction scheme, with or without appropriate protection, to give the desired product. Alternatively, it may be necessary or desirable to employ appropriate groups that are retained through the reaction scheme and can be optionally replaced with the ultimately desired substituents. In addition, one of ordinary skill in the art will recognize that protecting groups may be used to protect certain functional groups (e.g., amino, carboxy, or side chain groups) from the reaction conditions, and such groups are removed as appropriate under standard conditions. It is also understood that any of the steps shown in any of the following general schemes can be used in any combination and in any order that is chemically practicable to achieve the desired intermediates or the disclosed compounds. Unless otherwise specified, the variables are as defined above with respect to formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e).

[0169] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from a mixture of the corresponding enantiomers using any conventional procedure suitable for separating or resolving enantiomers. Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, such as a racemate, with a suitable chiral compound. The diastereomers can then be separated by any convenient means, such as crystallization, and the desired enantiomer recovered. In another resolution process, chiral high performance liquid chromatography may be used to separate the racemate. Alternatively, if desired, a specific enantiomer can also be obtained by using a suitable chiral intermediate in one of the desired processes.

[0170] Chromatography, recrystallization and other conventional separation procedures can also be used in intermediates or final products where it is desired to obtain a specific isomer of a compound or otherwise purify the product of a reaction.

[0171] General methods for preparing the compounds described herein are shown in the following exemplary methods. The variable groups in the schemes provided herein are defined as pertains to the compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (II), (II-a), (II-b), (II-c), (II-d), or (II-e), or any variation thereof. Other compounds described herein can be prepared by similar methods.

[0172] In some embodiments, the compounds provided herein can be synthesized according to Scheme I-A:

Chemical formula

[0173] In such an embodiment, there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (A-4) or a salt thereof with a compound of formula (A-5) or a salt thereof, wherein Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3 , and n are as defined for the compound of formula (I), and X is OH or halogen. In some embodiments, X is OH, and the step of reacting the compound of formula (A-4) or a salt thereof with the compound of formula (A-5) or a salt thereof is carried out in the presence of a coupling agent. In some embodiments, the coupling agent is 1-chloro-N,N,2-trimethylprop-1-en-1-amine. In some embodiments, X is halogen. In some embodiments, X is chloro. In some embodiments, the reaction between (A-4) and (A-5) is carried out in the presence of a base. In some embodiments, the base is DIPEA.

[0174] In some embodiments, the method further comprises preparing a compound of formula (A-5) or a salt thereof (wherein X is chloro) by reacting a compound of formula R 2 -OH with a chlorinating agent. In some embodiments, the chlorinating agent is 1-chloro-N,N,2-trimethylprop-1-en-1-amine. In some embodiments, the chlorinating agent is thionyl chloride.

[0175] In some embodiments, the method further comprises preparing a compound of formula (A-4) or a salt thereof by converting a compound of formula (A-3) or a salt thereof (wherein R is C 1 -C 6 -alkyl) to a compound of formula (A-4) or a salt thereof, wherein Z 1 , Z 2 , Z 3 , R 1 , R 2, R 3 , and n are as defined for the compounds of formula (I). In some embodiments, the step of converting a compound of formula (A-3) or a salt thereof to a compound of formula (A-4) or a salt thereof is carried out in the presence of iron and an acid. In some embodiments, the acid is ammonium chloride or acetic acid. In some embodiments, the acid is ammonium chloride. In some embodiments, the acid is acetic acid. In some embodiments, the step of converting a compound of formula (A-3) or a salt thereof to a compound of formula (A-4) or a salt thereof is carried out in the presence of a palladium catalyst. In some embodiments, the palladium catalyst is palladium on carbon or palladium hydroxide on carbon (Pearlman's catalyst), and the step of converting a compound of formula (A-3) or a salt thereof to a compound of formula (A-4) or a salt thereof is carried out in the presence of H 2 . In some embodiments, the palladium catalyst is palladium on carbon, and the step of converting a compound of formula (A-3) or a salt thereof to a compound of formula (A-4) or a salt thereof is carried out in the presence of H 2 . In some embodiments, the palladium catalyst is palladium hydroxide on carbon (Pearlman's catalyst), and the step of converting a compound of formula (A-3) or a salt thereof to a compound of formula (A-4) or a salt thereof is carried out in the presence of H 2 . In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0176] In some embodiments, the method further comprises preparing a compound of formula (A-3) or a salt thereof (wherein R is C 1 -C 6 -alkyl) by reacting a compound of formula (A-1) with a compound of formula (A-2) or a salt thereof, wherein Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3and n are as defined for the compound of formula (I). In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0177] In some embodiments, the method further comprises preparing a compound of formula (A-3) or a salt thereof by reacting a compound of formula (A-1) with the hydrochloride salt of a compound of formula (A-2) in the presence of a base, wherein Z 1 Z 2 Z 3 R 1 R 2 R 3 and n are as defined for the compound of formula (I). In some embodiments, the base is diisopropylamine or lutidine. In some embodiments, the base is diisopropylamine. In some embodiments, the base is lutidine. In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0178] In some embodiments, R 4 is -C(=O)NR 6 R 7 and the compound of formula (I), or a pharmaceutically acceptable salt thereof, is a compound of formula (A-8), or a pharmaceutically acceptable salt thereof, wherein Z 1 Z 2 Z 3 R 1 R 5 R 6 and n are as defined for the compound of formula (I). The compound of formula (A-8) or a pharmaceutically acceptable salt thereof can be prepared according to Scheme I-B:

Chemical formula

[0179] In such an embodiment, there is provided a method for preparing a compound of formula (A-8) or a pharmaceutically acceptable salt thereof by reacting a compound of formula (A-6) or a salt thereof with a compound of formula (A-7) or a salt thereof, wherein Z 1 Z 2 Z 3 R 1 R 5 R 6 and n are as defined for the compound of formula (I), or any variation or embodiment thereof).

[0180] In such an embodiment, the method further comprises preparing a compound of (A-6) or a salt thereof by reacting a compound of formula (A-4) with triphosgene and NH 3 / MeOH, wherein Z 1 Z 2 Z 3 R 1 and n are as defined for the compound of formula (I), or any variation or embodiment thereof).

[0181] In some embodiments, the compounds of formula (II) provided herein can be synthesized according to Scheme II-A:

Chemical formula

[0182] In such an embodiment, there is provided a method for preparing a compound of formula (II) or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (B-4) or a salt thereof with a compound of formula (B-5) or a salt thereof, wherein Z 1 Z 2 Z 3 R 1 R 2 R 3 and n are as defined for the compound of formula (II), and X is OH or halogen. In some embodiments, X is OH, and the step of reacting a compound of formula (B-4) or a salt thereof with a compound of formula (B-5) or a salt thereof is carried out in the presence of a coupling agent. In some embodiments, the coupling agent is 1-chloro-N,N,2-trimethylprop-1-en-1-amine. In some embodiments, X is halogen. In some embodiments, X is chloro. In some embodiments, the reaction between (B-4) and (B-5) is carried out in the presence of a base. In some embodiments, the base is DIPEA.

[0183] In some embodiments, the method further comprises preparing a compound of formula (B-5) or a salt thereof (wherein X is chloro) by reacting a compound of formula R 2 -OH with a chlorinating agent. In some embodiments, the chlorinating agent is 1-chloro-N,N,2-trimethylprop-1-en-1-amine. In some embodiments, the chlorinating agent is thionyl chloride.

[0184] In some embodiments, the method further comprises preparing a compound of formula (B-4) or a salt thereof by converting a compound of formula (B-3) or a salt thereof (wherein R is C 1 -C 6 -alkyl) to a compound of formula (B-4) or a salt thereof, wherein Z 1 Z 2 Z 3 R 1 R 2 R 3, and n is as defined for the compound of formula (II). In some embodiments, the step of converting a compound of formula (B-3) or a salt thereof to a compound of formula (B-4) or a salt thereof is carried out in the presence of iron and an acid. In some embodiments, the acid is ammonium chloride or acetic acid. In some embodiments, the acid is ammonium chloride. In some embodiments, the acid is acetic acid. In some embodiments, the step of converting a compound of formula (B-3) or a salt thereof to a compound of formula (B-4) or a salt thereof is carried out in the presence of a palladium catalyst. In some embodiments, the palladium catalyst is palladium on carbon or palladium hydroxide on carbon (Pearlman's catalyst), and the step of converting a compound of formula (B-3) or a salt thereof to a compound of formula (B-4) or a salt thereof is carried out in the presence of H 2 . In some embodiments, the palladium catalyst is palladium on carbon, and the step of converting a compound of formula (B-3) or a salt thereof to a compound of formula (B-4) or a salt thereof is carried out in the presence of H 2 . In some embodiments, the palladium catalyst is palladium hydroxide on carbon (Pearlman's catalyst), and the step of converting a compound of formula (B-3) or a salt thereof to a compound of formula (B-4) or a salt thereof is carried out in the presence of H 2 . In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0185] In some embodiments, the method further comprises preparing a compound of formula (B-3) or a salt thereof (wherein R is C 1 -C 6 -alkyl) by reacting a compound of formula (B-1) with a compound of formula (B-2) or a salt thereof, wherein Z 1 , Z 2 , Z 3 , R 1 , R 2 , R 3and n are as defined for the compound of formula (II). In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0186] In some embodiments, the method further comprises preparing a compound of formula (B-3) or a salt thereof by reacting a compound of formula (B-1) with the hydrochloride salt of a compound of formula (B-2) in the presence of a base, wherein Z 1 Z 2 Z 3 R 1 R 2 R 3 and n are as defined for the compound of formula (II). In some embodiments, the base is diisopropylamine or lutidine. In some embodiments, the base is diisopropylamine. In some embodiments, the base is lutidine. In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0187] In some embodiments, R 4 is -C(=O)NR 6 R 7 and the compound of formula (II), or a pharmaceutically acceptable salt thereof, is a compound of formula (B-8), or a pharmaceutically acceptable salt thereof, wherein Z 1 Z 2 Z 3 R 1 R 5 R 6 and n are as defined for the compound of formula (II). The compound of formula (B-8) or a pharmaceutically acceptable salt thereof can be prepared according to Scheme II-B:

Chemical formula

[0188] In such an embodiment, there is provided a method for preparing a compound of formula (B-8) or a pharmaceutically acceptable salt thereof by reacting a compound of formula (B-6) or a salt thereof with a compound of formula (B-7) or a salt thereof, wherein Z 1 , Z 2 , Z 3 , R 1 , R 5 , R 6 , and n are as defined for the compound of formula (II), or any variation or embodiment thereof.

[0189] In such an embodiment, the method further comprises preparing a compound of (B-6) or a salt thereof by reacting a compound of formula (B-4) with triphosgene and NH 3 / MeOH, wherein Z 1 , Z 2 , Z 3 , R 1 , and n are as defined for the compound of formula (II), or any variation or embodiment thereof.

[0190] In some embodiments, the compounds of formula (II-a) provided herein can be synthesized according to Scheme III-A: [Chemical formula] (wherein R 1 , R 2 , R 3 , and n are as defined for the compound of formula (II-a), or any variation or embodiment thereof).

[0191] In such an embodiment, there is provided a method for preparing a compound of formula (II-a) or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (C-4) or a salt thereof with a compound of formula (C-5) or a salt thereof, wherein R1 , R 2 , R 3 , and n are as defined for the compound of formula (II-a), and X is OH or halogen. In some embodiments, X is OH, and the step of reacting a compound of formula (C-4) or a salt thereof with a compound of formula (C-5) or a salt thereof is carried out in the presence of a coupling agent. In some embodiments, the coupling agent is 1-chloro-N,N,2-trimethylprop-1-en-1-amine. In some embodiments, X is halogen. In some embodiments, X is chloro. In some embodiments, the reaction between (C-4) and (C-5) is carried out in the presence of a base. In some embodiments, the base is DIPEA.

[0192] In some embodiments, the method further comprises preparing a compound of formula (C-5) or a salt thereof (wherein X is chloro) by reacting a compound of formula R 2 -OH with a chlorinating agent. In some embodiments, the chlorinating agent is 1-chloro-N,N,2-trimethylprop-1-en-1-amine. In some embodiments, the chlorinating agent is thionyl chloride.

[0193] In some embodiments, the method further comprises preparing a compound of formula (C-4) or a salt thereof by converting a compound of formula (C-3) or a salt thereof (wherein R is C 1 -C 6 -alkyl) into a compound of formula (C-4) or a salt thereof, wherein R 1 , R 2 , R 3, and n is as defined for the compound of formula (II-a). In some embodiments, the step of converting a compound of formula (C-3) or a salt thereof to a compound of formula (C-4) or a salt thereof is carried out in the presence of iron and an acid. In some embodiments, the acid is ammonium chloride or acetic acid. In some embodiments, the acid is ammonium chloride. In some embodiments, the acid is acetic acid. In some embodiments, the step of converting a compound of formula (C-3) or a salt thereof to a compound of formula (C-4) or a salt thereof is carried out in the presence of a palladium catalyst. In some embodiments, the palladium catalyst is palladium on carbon or palladium hydroxide on carbon (Pearlman's catalyst), and the step of converting a compound of formula (C-3) or a salt thereof to a compound of formula (C-4) or a salt thereof is carried out in the presence of H 2 is carried out in the presence of. In some embodiments, the palladium catalyst is palladium on carbon, and the step of converting a compound of formula (C-3) or a salt thereof to a compound of formula (C-4) or a salt thereof is carried out in the presence of H 2 is carried out in the presence of. In some embodiments, the palladium catalyst is palladium hydroxide on carbon (Pearlman's catalyst), and the step of converting a compound of formula (C-3) or a salt thereof to a compound of formula (C-4) or a salt thereof is carried out in the presence of H 2 is carried out in the presence of. In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0194] In some embodiments, the method further comprises preparing a compound of formula (C-3) or a salt thereof (wherein R is C 1 -C 6 -alkyl) by reacting a compound of formula (C-1) with a compound of formula (C-2) or a salt thereof, wherein R 1 , R 2 , R 3 , and n are as defined for the compound of formula (II-a). In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0195] In some embodiments, the method further comprises preparing a compound of formula (C-3) or a salt thereof by reacting a compound of formula (C-1) with a hydrochloride salt of a compound of formula (C-2) in the presence of a base, wherein R 1 、R 2 、R 3 、and n are as defined for the compound of formula (II-a). In some embodiments, the base is diisopropylamine or lutidine. In some embodiments, the base is diisopropylamine. In some embodiments, the base is lutidine. In some embodiments, R is methyl or ethyl. In some embodiments, R is methyl. In some embodiments, R is ethyl.

[0196] In some embodiments, R 4 is -C(=O)NR 6 R 7 and the compound of formula (II-a), or a pharmaceutically acceptable salt thereof, is a compound of formula (C-8), or a pharmaceutically acceptable salt thereof, wherein R 1 、R 5 、R 6 、and n are as defined for the compound of formula (II-a). The compound of formula (C-8) or a pharmaceutically acceptable salt thereof can be prepared according to Scheme III-B:

Chemical formula

[0197] In such embodiments, there is provided a method for preparing a compound of formula (C-8) or a pharmaceutically acceptable salt thereof by reacting a compound of formula (C-6) or a salt thereof with a compound of formula (B-7) or a salt thereof, wherein R 1 、R 5 、R6 and n are as defined for the compound of formula (II-a) or any variation or embodiment thereof.

[0198] In such embodiments, the method further comprises preparing a compound of formula (C-6) or a salt thereof by reacting a compound of formula (C-4) with triphosgene and NH 3 / MeOH, wherein Z 1 , Z 2 , Z 3 , R 1 and n are as defined for the compound of formula (II-a) or any variation or embodiment thereof.

[0199] Also provided herein are intermediate compounds or salts thereof for making a compound of formula (I) or any subformula thereof. In some embodiments, the intermediate compound is an intermediate compound shown in the general synthetic scheme above. In some embodiments, the intermediate compound is an intermediate compound shown in the Examples section below.

Examples

[0200] The following examples are provided to illustrate, but not limit, the compounds, compositions, uses, and methods provided herein. In some examples, the compounds and intermediates are prepared using the general methods described above.

[0201] Throughout the examples, the following abbreviations are used: DIPEA (N,N-diisopropylethylamine), LRMS (low resolution mass spectrometry), Ac (acetyl), Et (ethyl), Me (methyl), tBu (tert-butyl), APCI (atmospheric pressure chemical ionization), THF (tetrahydrofuran), DMAP (4-dimethylaminopyridine), DMF (dimethylformamide), DMSO (dimethyl sulfoxide), HPLC (high performance liquid chromatography), TEA (triethylamine), and ESI (electrospray ionization).

[0202] Example 1: Compound 64

Chem.

Chem.

[0203] Step 2: (S)-6-Chloro-3-propyl-3,4-dihydroquinoxalin-2(1H)-one. To a mixture of ethyl (S)-2-((5-chloro-2-nitrophenyl)amino)valerate (1.74 g, 5.8 mmol) in MeOH (20 mL) and water (10 mL) were added iron powder (2.26 g, 40.5 mmol) and NH 4 Cl (371 mg, 6.9 mmol) at room temperature. The reaction mixture was heated to 70 °C, stirred for 4 h, diluted with water and CHCl 3 , and filtered through a pad of celite. The filtrate was extracted with CHCl 3 , dried over MgSO 4 , concentrated, and purified using aminopropyl silica gel chromatography (0 - 50% EtOAc / hexane) to give (S)-6-chloro-3-propyl-3,4-dihydroquinoxalin-2(1H)-one (1.15 g, 88%) as a yellow solid.

Chem.

[0204] Step 3: (S)-6-Chloro-4-(1-methyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one. CH 2 Cl 2 (2 mL) of a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (130 mg, 1.0 mmol) was added to 1-chloro-N,N,2-trimethylprop-1-en-1-amine (145 μL, 1.1 mmol). After stirring at room temperature for 2 hours, (S)-6-chloro-3-propyl-3,4-dihydroquinoxalin-2(1H)-one (150 mg, 668 μmol) and pyridine (160 μL, 2.0 mmol) were added. The reaction mixture was stirred at room temperature overnight, then quenched with water and then diluted with CHCl 3 . The organic layer was separated, concentrated under reduced pressure, and purified using aminopropyl silica gel chromatography (0 - 5% MeOH / CHCl 3 ) to obtain (S)-6-chloro-4-(1-methyl-1H-pyrazole-4-carbonyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one (104 mg, 47%) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 10.87 (s, 1H), 7.90 (s, 1H), 7.26 (dd, J = 2.3, 8.6 Hz, 1H), 7.19 (s, 1H), 7.15 (d, J = 2.1 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 4.89 (dd, J = 5.9, 8.9 Hz, 1H), 3.81 (s, 3H), 1.51 - 1.43 (m, 1H), 1.40 - 1.22 (m, 3H), 0.90 - 0.84 (m, 3H). LRMS (ESI) m / z 333.2 [M + H] + .

[0205] Example 2: Synthesis of Compound 100

Chem.

[0206] Step 2: (S)-3-((S)-sec-Butyl)-8-fluoro-3,4-dihydroquinoxalin-2(1H)-one. To a mixture of (3-fluoro-2-nitrophenyl)-L-isoleucine methyl ester (1.7 g, 5.98 mmol) in ethanol (20 mL) was added 5% Pd / C (340 mg). The reaction was stirred under a hydrogen atmosphere for 2.5 days and then filtered through a Celite pad. The Celite pad was washed with ethanol (10 mL) and the combined organic filtrates were heated to 80 °C and stirred for 1 day. A solution of ammonium chloride (384 mg, 7.18 mmol) in H 2 2O (8.0 mL) was added and the mixture was heated to 80 °C and stirred for 1 day. HCl (1 M, 7.0 mL) was added to the mixture and the mixture was stirred at 80 °C for 2 days. The reaction mixture was then concentrated, diluted with chloroform, and neutralized with saturated sodium bicarbonate. The organic layer was separated, concentrated, and purified using silica gel chromatography (5 - 40% EtOAc / hexane), followed by aminopropyl silica gel chromatography (5 - 50% EtOAc / hexane) to give (S)-3-((S)-sec-butyl)-8-fluoro-3,4-dihydroquinoxalin-2(1H)-one (713 mg, 54%) as a pale yellow solid. [Chemical]

[0207] Step 3: (S)-2-((S)-sec-Butyl)-5-fluoro-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide. To a cooled solution of (S)-3-((S)-sec-butyl)-8-fluoro-3,4-dihydroquinoxalin-2(1H)-one (200 mg, 0.9 mmol) and DIPEA (462 μL, 2.7 mmol) in THF (2.0 mL) was added triphosgene (107 mg, 361 μmol). After stirring for 25 minutes, NH 3 / MeOH (7M, 770 μL, 5.4 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was then concentrated and diluted with CHCl 3 and H 2 O. The organic layer was separated, concentrated under reduced pressure, purified using silica gel chromatography (0 - 5% MeOH / CHCl 3 ), and triturated with isopropyl ether to give (S)-2-((S)-sec-butyl)-5-fluoro-3-oxo-3,4-dihydroquinoxaline-1(2H)-carboxamide (138 mg, 58%) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 7.28 - 7.24 (m, 1H), 7.05 - 7.01 (m, 2H), 6.49 (s, 2H), 4.50 (d, J = 10.4 Hz, 1H), 1.44 - 1.35 (m, 1H), 1.24 - 1.15 (m, 1H), 1.10 - 1.00 (m, 1H), 0.86 (d, J = 6.7 Hz, 3H), 0.73 (t, J = 7.4 Hz, 3H). LRMS (ESI) m / z 266.3 [M + H] + .

[0208] The following compounds were prepared by a method similar to the method described for Compound 100. [Table 5]

[0209] Example 3: Synthesis of Compound 7

Chem.

Chem.

[0210] Step 2: (S)-5-Bromo-3-propyl-3,4-dihydroquinoxalin-2(1H)-one. To a mixture of ethyl (S)-2-((2-bromo-6-nitrophenyl)amino)valerate (1.65 g, 4.8 mmol) in MeOH (20 mL) and water (10 mL) were added iron powder (1.87 g, 33.5 mmol) and NH 4 Cl (310 mg, 5.8 mmol) at room temperature. The reaction mixture was heated to 70 °C and stirred for 4 h, then heated to 80 °C and stirred overnight. The reaction was cooled to room temperature, diluted with water and CHCl 3 and filtered through a pad of celite. The filtrate was extracted with CHCl 3 and dried over MgSO 4It was dried, concentrated, and purified using amino silica gel chromatography (0 - 50% EtOAc / hexane) to obtain (S)-5-bromo-3-propyl-3,4-dihydroquinoxalin-2(1H)-one (1.04 g, 81%) as a yellow solid.

Chemical formula

[0211] Step 3: (S)-5-Cyclopropyl-3-propyl-3,4-dihydroquinoxalin-2(1H)-one. To a mixture of (S)-5-bromo-3-propyl-3,4-dihydroquinoxalin-2(1H)-one (265 mg, 0.99 mmol) in toluene (3 mL) and water (800 mL), cyclopropylboronic acid (170 mg, 1.99 mmol), potassium phosphate (420 mg, 1.98 mmol), and tetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol) were added. The mixture was heated to 100 °C, stirred overnight, then cooled to room temperature and diluted with water. Ethyl acetate was added, the organic layer was separated, dried over MgSO 4 dried, concentrated, and purified using amino silica gel chromatography (0 - 50% EtOAc / hexane) and silica gel (0 - 50% EtOAc / hexane) to obtain (S)-5-cyclopropyl-3-propyl-3,4-dihydroquinoxalin-2(1H)-one (161 mg, 71%) as a yellow oil.

Chemical formula

[0212] Step 4: (S)-5-Cyclopropyl-4-(6-methylnicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one. To a solution of 6-methylnicotinic acid (188 mg, 1.4 mmol) in dichloroethane (1.6 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (182 μL, 1.4 mmol). The reaction mixture was stirred for 1 h, and then a solution of (S)-5-cyclopropyl-3-propyl-3,4-dihydroquinoxalin-2(1H)-one (158 mg, 0.7 mmol) in DCE (1.6 mL) and DIPEA (350 μL, 2.04 mmol) was added. The mixture was stirred overnight and then diluted with water and CHCl 3 . The organic layer was separated, concentrated, purified using aminopropyl silica gel chromatography (0 - 50% EtOAc / hexane) and reverse phase ODS silica gel chromatography (0 - 50% EtOH / H2O), and then triturated with acetonitrile to give (S)-5-cyclopropyl-4-(6-methylnicotinoyl)-3-propyl-3,4-dihydroquinoxalin-2(1H)-one (116 mg) as a colorless solid. LRMS (ESI) m / z 350.4 [M + H] + .

[0213] Example 4: Synthesis of Compound 69

Chemical Structure

[0214] The following compounds were prepared by a method similar to the method described for Compound 69 (standard protecting group strategies were employed for compounds with reactive heteroatoms).

Table 6-1

Table 6-2

Table 6-3

Table 6-4

[0215] Example 5: Synthesis of Compound 77

Chemical Structure

[0216] Example 6: Synthesis of Compound 63 [Chemical formula] To a solution of 1-methyl-1H-pyrazole-4-carboxylic acid (140 mg, 1.1 mmol) in dichloroethane (2 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (160 μL, 1.2 mmol). The reaction mixture was stirred at room temperature for 2 hours, CH2 Cl 2 (2.0 mL) and a solution of (S)-3-((S)-sec-butyl)-3,4-dihydroquinoxalin-2(1H)-one (150 mg, 0.7 mmol) in pyridine (178 μL, 2.2 mmol) were added. The mixture was stirred overnight at room temperature and then diluted with water and CHCl 3 . The organic layer was separated, concentrated, purified using aminopropyl silica gel chromatography (0 - 5% MeOH / CHCl3), and triturated with isopropyl ether / hexane to obtain (S)-3-((S)-sec-butyl)-4-(1-methyl-1H-pyrazole-4-carbonyl)-3,4-dihydroquinoxalin-2(1H)-one (130 mg, 57%) as a colorless solid. 1 1H NMR (500 MHz, DMSO-d6) δ 10.77 (s, 1H), 7.75 (s, 1H), 7.20 (dt, J = 1.3, 7.7 Hz, 1H), 7.05 (dd, J = 1.2, 8.0 Hz, 1H), 7.03 - 6.99 (m, 2H), 6.89 (dt, J = 1.2, 7.7 Hz, 1H), 4.68 (d, J = 10.1 Hz, 1H), 3.76 (s, 3H), 1.49 - 1.40 (m, 1H), 1.38 - 1.30 (m, 1H), 1.14 - 1.05 (m, 1H), 0.89 (d, J = 6.8 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H). LRMS (ESI) m / z 313.2 [M + H] + .

[0217] Example 7: Synthesis of Compound 81

Chemical Structure

[0218] Example 8: Synthesis of Compound 99

Chemical Structure

[0219] Example 9: Synthesis of Compound 132

Chemical Structure

[0220] The following compounds were prepared by a method similar to the method described for compound 132.

Table 7-1

Table 7-2

[0221] Example 10: Synthesis of Compound 92

Chem.

Chem.

[0222] Step 2: (S)-3-((S)-sec-Butyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one. Iron powder (9.4 g) was added to a stirred solution of (3-fluoro-2-nitrophenyl)-L-isoleucine methyl ester (9.00 g, 33.6 mmol) in AcOH (100 mL) at room temperature. After 2 h, the reaction was filtered through a pad of celite, concentrated, and azeotroped with cyclohexane (100 mL) and toluene (100 mL) to give (S)-3-((S)-sec-butyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one as a red solid.

Chem.

[0223] Step 3: (S)-3-((S)-sec-Butyl)-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one. Thionyl chloride (0.87 g, 7.3 mmol) was added to a stirred solution of 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (560 mg, 3.7 mmol), DMF (1 drop), and CH 2 Cl 2 (10 mL) at room temperature. After 2 h, the reaction was concentrated, and then NMP (5 mL), (S)-3-((S)-sec-butyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one (250 mg, 1.2 mmol), and DIPEA (0.48 g, 3.7 mmol) were added sequentially. The reaction was stirred for 2 h, quenched with MeOH (10 mL), and stirred for 5 min. The mixture was concentrated, filtered through a 0.4 μm syringe filter, and purified using reverse-phase HPLC (0 - 30% MeCN / H 2 O + 0.1% formic acid) to give 115 mg of (S)-3-((S)-sec-butyl)-4-(1-methyl-6-oxo-1,6-dihydropyridine-3-carbonyl)-3,4-dihydropyrido[2,3-b]pyrazin-2(1H)-one as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.90 (d, J = 2.6 Hz, 1H), 7.76 (dd, J = 4.9, 1.6 Hz, 1H), 7.33 (dd, J = 7.9, 1.6 Hz, 1H), 7.12 (dd, J = 8.0, 4.9 Hz, 1H), 6.86 (dd, J = 9.4, 2.6 Hz, 1H), 6.13 (d, J = 9.5 Hz, 1H), 4.78 (s, 1H), 3.44 (s, 3H), 1.58 - 1.32 (m, 2H), 1.31 - 1.02 (m, 2H), 0.86 (d, J = 6.7 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H). LRMS (APCI) m / z 341.0 [M + H]+ .

[0224] The following compounds were prepared by a method similar to the method described for Compound 92.

Table 8

[0225] Example 11: Synthesis of Compound 94

Chem.

Chem.

[0226] Step 2: (S)-7-((S)-sec-Butyl)-7,8-dihydropteridin-6(5H)-one. (2-Chloro-5-nitropyrimidin-4-yl)-L-isoleucine methyl ester, Pearlman's catalyst, and MeOH (50 mL) were mixed and stirred at room temperature under a hydrogen atmosphere (80 psi) for 4 hours. The reaction was then filtered through a pad of Celite and concentrated. Acetic acid was added and the mixture was heated to 100 °C and stirred for 2 hours. The reaction was then cooled to room temperature, concentrated, and 10% MeOH / CH 2 Cl 2It was suspended therein, filtered through a silica pad, and 1.5 g of (S)-7-((S)-sec-butyl)-7,8-dihydropteridin-6(5H)-one was obtained.

Chemical formula

[0227] Step 3: (S)-7-((S)-sec-butyl)-8-(1-methyl-1H-pyrazole-4-carbonyl)-7,8-dihydropteridin-6(5H)-one. Thionyl chloride (0.58 g, 4.8 mmol) was added to a stirred solution of 1-methyl-1H-pyrazole-4-carboxylic acid (0.46 g, 3.6 mmol), DMF (1 drop), and CH 2 Cl 2 (10 mL) at room temperature. After 2 hours, the reaction mixture was concentrated, and then NMP (2 mL), (S)-7-((S)-sec-butyl)-7,8-dihydropteridin-6(5H)-one (250 mg, 1.2 mmol), and DIPEA (0.8 g, 6.1 mmol) were added sequentially. The reaction mixture was stirred for 4 hours, quenched with methylamine / MeOH solution, and stirred for 5 minutes. The mixture was concentrated, filtered through a 0.4 μm syringe filter, and purified using reverse-phase HPLC (0 - 30% MeCN / H 2 O + 0.1% formic acid) to obtain 55 mg of (S)-7-((S)-sec-butyl)-8-(1-methyl-1H-pyrazole-4-carbonyl)-7,8-dihydropteridin-6(5H)-one as a white solid. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.26 (s, 1H), 7.72 (s, 1H), 7.25 (s, 1H), 4.73 (s, 1H), 3.74 (s, 3H), 1.50 (tq, J = 10.3, 4.2, 2.9 Hz, 2H), 1.14 (ddt, J = 15.9, 8.5, 4.3 Hz, 1H), 0.83 (d, J = 6.5 Hz, 3H), 0.78 (t, J = 7.2 Hz, 3H). LRMS (APCI) m / z 315.0 [M + H] + .

[0228] Compound 125 was prepared by using a similar method. [Table 9]

[0229] Example 12: Synthesis of Compound 95 [Chemical Structure] To a stirred solution of 1-methyl-1H-pyrazole-4-carbonyl chloride (0.63 g, 4.4 mmol) was added a mixture of (S)-2-((S)-sec-butyl)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (300 mg, 1.5 mmol), DIPEA (0.8 mL, 5.8 mmol), DMAP (18 mg, 0.1 mmol), and NMP (5 mL). The reaction was stirred at room temperature for 2 h, quenched with methylamine / MeOH, and stirred for 5 min. The mixture was concentrated, filtered through a 0.4 μm syringe filter, and purified using reverse-phase HPLC (0 - 30% MeCN / H 2 O + 0.1% formic acid) to give (S)-2-((S)-sec-butyl)-1-(1-methyl-1H-pyrazole-4-carbonyl)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one as a white solid. 1H NMR (400 MHz, methanol-d4) δ 8.09 (dd, J = 4.9, 1.4 Hz, 1H), 7.64 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.19 (s, 1H), 6.87 (dd, J = 8.0, 4.9 Hz, 1H), 4.79 (d, J = 9.6 Hz, 1H), 3.74 (s, 3H), 1.46 (dqd, J = 15.0, 7.5, 3.7 Hz, 1H), 1.35 (tdd, J = 9.7, 6.4, 3.2 Hz, 1H), 1.19 - 1.00 (m, 1H), 0.89 (d, J = 6.7 Hz, 3H), 0.75 (t, J = 7.4 Hz, 3H). LRMS (APCI) m / z 314.0 [M + H]+.

[0230] Example 13: Synthesis of Compounds 27 - 29 and 33 - 44

Chem.

Table 10

[0231] By reacting an appropriate fluoroaryl or fluoroheteroaryl intermediate with an appropriate amine, additional compounds were prepared by aromatic nucleophilic substitution reaction (S N Ar). The reaction can be carried out in an aprotic polar solvent such as NMP, DMSO, DMF, dioxane, THF, or without using a solvent at a high temperature, for example, above 100 °C, in the presence of a stoichiometric or excess amount of amine.

[0232] Biological Example 1 Assay Example 1: Preparation and Assay of Fast Muscle Myofibrils of Skeletal Muscle Preparation of skeletal muscle fast muscle fibers: Rabbit skeletal muscle fast muscle fibers were prepared based on the method of Herrmann et al. (Biochem. 32(28):7255 - 7263(1993)). The fast muscle fibers were prepared within 2 days after ordering from rabbit iliopsoas muscle purchased from Pel-Freez Biologicals (Arkansas) and stored on ice. The minced muscle was homogenized using an Omni-Macro homogenizer in 10 volumes of ice-cold "standard" buffer (50 mM Tris, pH 7.4, 0.1 M KOAc, 5 mM KCl, 2 mM dithiothreitol (DTT), 0.2 mM phenylmethylsulfonyl fluoride (PMSF), 10 μM leupeptin, 5 μM pepstatin, and 0.5 mM sodium azide) containing 5 mM ethylenediaminetetraacetic acid (EDTA) and 0.5% Triton X-100. The fast muscle fibers were recovered by low-speed centrifugation (3000 rpm for 10 minutes), washed twice with Triton X-100 containing buffer to ensure complete removal of cell membranes. After washing with Triton, the fast muscle fibers were washed three times with "standard" buffer containing 2 mM magnesium acetate. A final wash was performed with assay buffer (12 mM piperazine-1,4-bis(2-ethanesulfonic acid) (PIPES), pH 6.8, 60 mM KCl, 1 mM DTT), replaced with 10% sucrose, rapidly frozen in liquid nitrogen, and stored at -80°C.

[0233] Activation of fast skeletal muscle myofibrils: Fast muscle fiber activating factors were identified by measuring the enzyme activity of myofibril preparations using a commercially available PUMA (trademark) assay system (see, e.g., U.S. Pat. Nos. 6,410,254, 6,743,599, 7,202,051, and 7,378,254). The myofibril preparations consisted of rabbit skeletal muscle (approximately 90% fast muscle fibers) that had been mechanically homogenized and washed with a detergent (Triton X-100) to remove the cell membrane. This preparation retained all sarcomere components in their native structure, and enzyme activity was unchanged and calcium-regulated. Compounds were tested using a myofibril suspension and a calcium level (referred to as pCa25) sufficient to increase the enzyme activity of the myofibrils to 25% of its maximum value. Enzyme activity was followed through the pyruvate kinase and lactate dehydrogenase coupled enzyme system. This assay regenerates myosin-generated ADP to ATP by oxidizing NADH (which causes a change in absorbance at 340 nm). The buffer system was 12 mM PIPES, 2 mM MgCl 2 , 1 mM DTT (pH 6.8) (PM12 buffer). Data were reported as AC1.4, the concentration of the compound that increased enzyme activity by 40%. In Table 3, "exemplary compound" refers to the compound designated by the same number in Table 2.

Table 3-1

Table 3-2

[0234] Assay Example 2: Preparation of the isometric ankle plantarflexor muscle of a rat and muscle strength assay Female Sprague-Dawley rats were anesthetized with inhaled isoflurane (1 - 5%) to a stable state. A single incision was made in the middle of the right thigh to expose the sciatic nerve. To prevent co-contraction of the ankle dorsiflexor muscles, an additional incision was made lateral to the patella to isolate and cut the peroneal nerve. The rat was then placed in a temperature-maintained in situ muscle analysis apparatus (Aurora Scientific, Model 806C). The knee was fixed with a clamp between two sharp screws, and the foot was taped to a footplate attached to a force transducer (Aurora Scientific, Ontario, Canada). Stainless steel needle electrodes (0.10 mm) were hooked around the exposed sciatic nerve. With the ankle flexed at 90°, the contractile force of the isometric ankle plantarflexor muscle was evaluated. Electrical stimulation at 30 Hz (under maximum supramaximal voltage conditions) was applied to the nerve, and the resulting muscle force was recorded with a servomotor. The 30 Hz force response before administration was used as the baseline force. The 150 Hz force response before administration was used as the maximum isometric muscle force. The compound was formulated in polyethylene glycol 50% (PEG): Cavitron 16%: dimethylacetamide (DMA) 10% and administered by continuous intravenous infusion over a period of 60 minutes. The muscle force response to the compound was measured every 2 minutes over the administration period. The data were reported as the estimated EC 50 value. This is the concentration at which the muscle force is 50% of the maximum tension before administration. The EC 50 results are summarized in Table 4 below. In Table 4, "exemplary compound" refers to the compound indicated by the same number in Table 2.

Table 4

Claims

1. Compound of formula (I): 【Chemistry 251】 or a pharmaceutically acceptable salt thereof (in the formula, Z １ Z ２ , and Z ３ CH and CR are independent of each other. ３ , or N, however Z １ Z ２ , and Z ３ At least one of them is CH or CR ３ And, R １ is unsubstituted C ３ -C ４ alkyl, and R ２ is -C(=O)R ４ , -C(=O)-(CH ２ ) ｐ -R ５ , -C(=O)NR ６ R ７ , or -C(=O)OCH ３ And, Each R ３ These are, independently, halogen, C １ -C ６ - Alkyl, C １ -C ６ - Haroakil, C １ -C ６ - Alkoxy, C １ -C ６ - Haloacoxi, C ３ -C １２ - Cycloalkyl or 3-12 member heterocycloalkyl, R ４ These are 1 to 5 R's ４Ａ C replaced by arbitrary selection ６ -C １２ - Aryl, 1 to 5 R's ４Ｂ 5-12 member heteroaryls, 1-5 R, which are optionally substituted. ４Ｃ C replaced by arbitrary selection ３ -C １２ Cycloalkyl, 1 to 5 R ４Ｄ A 4-12 member heterocycloalkyl group or 1-5 R groups are optionally substituted. ４Ｅ These are 4- to 12-membered heterocycloalkenyls that have been optionally substituted, Each R ４Ａ is halo, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, OH, C １ -C ６ -alkoxy, C １ -C ６ -haloalkoxy, NH ２ , NH(C １ -C ６ -alkyl), N(C １ -C ６ -alkyl) ２ , NH(C １ -C ６ -haloalkyl), N(C １ -C ６ -alkyl)(C １ -C ６ -haloalkyl), N(C １ -C ６ -haloalkyl) ２ , NH(C １ -C ６ -alkylene-(C ６ -C １２ -aryl)), N(C １ -C ６ -alkyl)(C １ -C ６ -alkylene-(C ６ -C １２ -aryl)), N(C １ -C ６ -alkylene-(C ６ -C １２ -aryl)) ２ , NH(C ３ -C １２ cycloalkyl), N(C １ -C ６ -alkyl)(C ３ -C<舍 １２ cycloalkyl), N(C ３ -C １２ cycloalkyl) ２ , NHC(O)-C １ -C ６ -alkyl, C ４Ｂ１ optionally substituted by 1 to 5 R ３ -C １２ Cycloalkyl, 1 to 5 Rs ４Ｂ１ 4- to 12-membered heterocycloalkyl optionally substituted with ４Ｂ１ , C １ -C ６ -alkylene-OH, C １ -C ６ -alkylene-CONH ２ , C １ -C ６ -alkylene-(C ３ -C １２ cycloalkyl), C １ -C ６ -alkylene-(4- to 12-membered heterocycloalkyl), C ６ -C １２ -aryl, and 5- to 12-membered heteroaryl, independently selected from the group consisting of Each R ４Ｂ Hello, C １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, OH, C １ -C ６ - Alkoxy, C １ -C ６ - Haloalkoxy, NH ２ NH(C １ -C ６ -alkyl), N(C １ -C ６ -Alkyl) ２ NH(C １ -C ６ -Haloalkyl), N(C １ -C ６ -Alkyl) (C １ -C ６ -Haloalkyl), N(C １ -C ６ - Haloalkyl) ２ NH(C １ -C ６ -Alkilen- (C ６ -C １２ -Ayl)), N(C １ -C ６ -Alkyl) (C １ -C ６ -Alkilen- (C ６ -C １２ -Ayl)), N(C １ -C ６ -Alkilen- (C ６ -C １２ -Ail)) ２ NH(C ３ -C １２ Cycloalkyl), N (C １ -C ６ -Alkyl) (C ３ -C １２ Cycloalkyl), N (C ３ -C １２ Cycloalkyl) ２ NHC(O)-C １ -C ６ - Alkyl, 1 to 5 R ４Ｂ１ C replaced by arbitrary selection ３ -C １２ Cycloalkyl, 1 to 5 R ４Ｂ１ A 4- to 12-membered heterocycloalkyl group, C, which is optionally substituted. １ -C ６ -Alkylene-OH, C １ -C ６ -Alkilen-CONH ２ , C １ -C ６ -Alkilen- (C ３ -C １２ Cycloalkyl), C １ -C ６ -Alkylene- (4-12 member heterocycloalkyl) and 5-12 member heteroaryl are independently selected from the group consisting of these, Each R ４Ｂ１ Hello, C １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, OH, C １ -C ６ - Alkoxy, C １ -C ６ - Haloalkoxys and C １ -C ６ Independently selected from the group consisting of -alkylene-OH, Each R ４Ｃ Hello, C １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, OH, C １ -C ６ - Alkoxy, C １ -C ６ - Haloalkoxy, NHC(O)-C １ -C ６ - Alkyl and C １ -C ６ Independently selected from the group consisting of -alkylene-OH, Each R ４Ｄ Hello, C １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, OH, C １ -C ６ - Alkoxy, C １ -C ６ - Haloalkoxy, NHC(O)-C １ -C ６ - Alkyl and C １ -C ６ Independently selected from the group consisting of -alkylene-OH, Each R ４Ｅ , oxo, halo, C １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, OH, C １ -C ６ - Alkoxy, C １ -C ６ - Haloalkoxy, NHC(O)-C １ -C ６ - Alkyl and C １ -C ６ Independently selected from the group consisting of -alkylene-OH, R ５ is OH, C １ -C ６ - Alkoxy, C １ -C ６ - Haloalkoxy, C ３ -C １２ Cycloalkyl, 3-12 member heterocycloalkyl, or C ６ -C １２ - It is an allele, R ６ and R ７ H and C are independent of each other. １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, 1 to 5 R ８ C replaced by arbitrary selection ３ -C １２ Cycloalkyl, 1 to 5 R ８ A 4-12 member heterocycloalkyl group, 1-5 R groups, optionally substituted. ８ C replaced by arbitrary selection ６ -C １２ - Aryl, 1 to 5 R's ８ 5- to 12-membered heteroaryls, C, which are optionally substituted. １ -C ６ -Alkylene-OH, C １ -C ６ -Alkilen- (C ３ -C １２ Cycloalkyl), C １ -C ６ -Alkylene-(4-12 member heterocycloalkyl), C １ -C ６ -Alkilen- (C ６ -C １２ -Aaryl), and C １ -C ６ Selected from the group consisting of alkylenes (5-12 member heteroaryls), Each R ８ Hello, C １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, OH, C １ -C ６ - Alkoxy, C １ -C ６ -Alkylene-OH, and C １ -C ６ - Independently selected from the group consisting of haloalkoxys, n is 0, 1, 2, 3, or 4. p is 1, 2, or 3. However, the compound of formula (I) is not a compound selected from the group consisting of the following: 4-(3-methylbenzoyl)-3-propyl-3,4-dihydroquinoxaline-2(1H)-one, 4-(2-chlorobenzoyl)-3-isobutyl-3,4-dihydroquinoxaline-2(1H)-one, and 4-(4-(tert-butyl)benzoyl)-3-propyl-3,4-dihydroquinoxaline-2(1H)-one).

2. The compound of formula (I) is a compound of formula (I-a), (I-b), (I-c), (I-d), or (I-e): 【Chemistry 252】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) is the compound of formula (II): 【Chemistry 253】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound of formula (II) is a compound of formula (II-a), (II-b), (II-c), (II-d), or (II-e): 【Chemistry 254】 The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

5. The compound of formula (II) is the compound of formula (II-a): 【Chemistry 255】 The compound according to claim 3, or a pharmaceutically acceptable salt thereof.

6. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of propa-1-yl, propa-2-yl, buta-2-yl, and 2-methylpropa-1-yl.

7. R ３ However, halogen or C ３ -C １２ - The compound according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

8. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a halogen.

9. R ３ However, C ３ -C ６ - The compound according to claim 1, which is a cycloalkyl compound, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

11. R ２ However, -C(=O)R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R ４ However, 1 to 5 R ４Ａ C replaced by arbitrary selection ６ -C １２ - Aryl, 1 to 5 R's ４Ｂ 5- to 12-membered heteroaryls, C, which are optionally substituted. ３ -C １２ Cycloalkyl, 1 to 5 R ４Ｄ A 4-12 member heterocycloalkyl group or 1-5 R groups are optionally substituted. ４Ｅ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is a 4- to 12-membered heterocycloalkenyl optionally substituted with the compound according to claim 11.

13. R ４ However, 1 to 5 R ４Ａ C replaced by ６ -C １２ - It is aryl, R ４Ａ However, Halo or C １ -C ６ - The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

14. R ４ However, 1 to 5 R ４Ｂ It is a 5- to 12-membered heteroaryl substituted with R ４Ｂ But, hello, C １ -C ６ - Alkyl, C １ -C ６ - Haloalkoxy, NH ２ , N(C １ -C ６ -Alkyl) ２ NH(C １ -C ６ -Haloalkyl), N(C １ -C ６ -Alkyl) (C １ -C ６ -Haloalkyl), NH(C １ -C ６ -Alkilen- (C ６ -C １２ -Ayl)), N(C １ -C ６ -Alkyl) (C ３ -C １２ Cycloalkyl), NHC(O)-C １ -C ６ - Alkyl, C ３ -C １２ Cycloalkyl, 1 to 5 R ４Ｂ１ A 4- to 12-membered heterocycloalkyl group, C, which is optionally substituted. １ -C ６ -Alkylene-OH, C １ -C ６ -Alkilen-CONH ２ , C １ -C ６ -Alkilen- (C ３ -C １２ A compound according to claim 11, or a pharmaceutically acceptable salt thereof, selected from the group consisting of cycloalkyls and 5- to 12-membered heteroaryls.

15. R ４Ｂ However, 1 to 5 R ４Ｂ１ A 4- to 12-membered heterocycloalkyl group substituted with R ４Ｂ１ However, Halo or C １ -C ６ - The compound according to claim 14, or a pharmaceutically acceptable salt thereof, which is an alkoxy.

16. R ４ However, 1 to 5 R ４Ｄ A 4- to 12-membered heterocycloalkyl group substituted with R ４Ｄ But, hello, C １ -C ６ -Alkyl, OH, NHC(O)-C １ -C ６ - Alkyl and C １ -C ６ A compound according to claim 11, selected from the group consisting of -alkylene-OH, or a pharmaceutically acceptable salt thereof.

17. R ４ However, 1 to 5 R ４Ｅ A 4- to 12-membered heterocycloalkenyl substituted with R ４Ｅ However, oxo or C １ -C ６ - The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

18. R ２ However, -C(=O)-(CH ２ ) ｐ -R ５ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. R ５ However, OH or C ６ -C １２ - The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein the compound is an aryl compound.

20. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

21. R ２ However, -C(=O)NR ６ R ７ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

22. R ６ and R ７ However, H and C are independent of each other. １ -C ６ - Alkyl, C １ -C ６ - Haloalkyl, C ３ -C １２ Cycloalkyl, 1 to 5 R ８ C replaced by arbitrary selection ６ -C １２ - Aryl, 1 to 5 R's ８ 5- to 12-membered heteroaryls, C, which are optionally substituted. １ -C ６ -Alkylene-OH, C １ -C ６ -Alkilen- (C ３ -C １２ Cycloalkyl), C １ -C ６ -Alkilen- (C ６ -C １２ -Aaryl), and C １ -C ６ A compound according to claim 21, selected from the group consisting of alkylenes (5-12 membered heteroaryls), or a pharmaceutically acceptable salt thereof.

23. Each R ８ But, hello, C １ -C ６ - Alkyl, C １ -C ６ -Alkylene-OH, and C １ -C ６ - A compound according to claim 22, independently selected from the group consisting of alkoxys, or a pharmaceutically acceptable salt thereof.

24. R ２ is -C(=O)OCH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

25. A compound selected from the compounds in Table 2, or a pharmaceutically acceptable salt thereof.

26. A compound selected from the group consisting of compounds 1 to 133, or a pharmaceutically acceptable salt thereof.

27. Compounds with the following formula: 【Chemistry 256】 or a pharmaceutically acceptable salt thereof.

28. Compounds with the following formula: 【Chemistry 257】 or a pharmaceutically acceptable salt thereof.

29. Compounds with the following formula: 【Chemistry 258】 or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

31. The pharmaceutical composition according to claim 30, wherein the pharmaceutical composition is formulated for oral, sublingual, subcutaneous, parenteral, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, transvaginal, transrectal, or intraocular administration.

32. A pharmaceutical composition for use in treating a disease or condition selected from the group consisting of peripheral vascular disease, peripheral artery disease, rehabilitation-related disorders, metabolic syndrome, obesity, ventilator-induced muscle weakness, chronic fatigue syndrome, neuromuscular disorders, muscle wasting, muscle myopathy, muscle atrophy, muscle fatigue, and frailty, the pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition for use in treating a disease or condition selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), myasthenia gravis, and muscular myopathy, comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition for use in treating a disease or condition selected from the group consisting of stress urinary incontinence (SUI), mixed urinary incontinence (MUI), fecal incontinence, frailty, sarcopenia, chronic obstructive pulmonary disease (COPD), cachexia syndrome, heart failure, cancer, or muscle wasting due to chronic kidney disease / dialysis, muscle dysfunction after spinal cord injury (SCI), and muscle dysfunction after stroke, the pharmaceutical composition comprising a compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

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