Pyridazinone compounds for the treatment of neuromuscular diseases

Abstract

To provide pyridazinone compounds for treatment of neuromuscular diseases.SOLUTION: Disclosed herein are substituted pyridazinone compounds, conjugates and pharmaceutical compositions for use in treatment of neuromuscular diseases, such as Duchenne Muscular Dystrophy (DMD). The disclosed compounds are useful, among other things, in treating DMD and modulating inflammatory inhibitors IL-1, IL-6 or TNF-α. DMD is a genetic disorder affecting skeletal muscle and is characterized by progressive muscle degeneration and weakness. There remains a need for treatments that reduce muscle breakdown in patients with neuromuscular conditions such as DMD.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 63 / 024,439, filed May 13, 2020, the entire disclosure of which is incorporated herein by reference.

Background Art

[0002] Skeletal muscle is the largest organ system in the human body and serves two major purposes. The first is the generation of force that enables muscle contraction, voluntary movement, and posture maintenance; the second is the metabolism of glucose, fatty acids, and amino acids. Contraction of skeletal muscle during daily activities and exercise naturally leads to muscle stress, damage, and remodeling, which are important for muscle adaptation. In individuals with neuromuscular conditions (e.g., Duchenne muscular dystrophy (DMD)), muscle contraction results in amplified rounds of muscle damage that the body struggles to repair. Eventually, as the patient ages, pathophysiological processes emerge that lead to the accumulation of excessive inflammation, fibrosis, and fat deposition in the muscle, portending a rapid decline in physical function and contributing to mortality.

[0003] DMD is a genetic disorder that affects skeletal muscle and is characterized by progressive muscle degeneration and weakness. There remains a need for treatments that reduce muscle damage in patients with neuromuscular conditions (e.g., DMD).

Summary of the Invention

Means for Solving the Problems

[0004] The present disclosure generally relates to substituted pyridazinone compounds of formula (IIA), (IIB) or (IIC), or salts thereof, and pharmaceutical compositions thereof. The substituted pyridazinone compounds or salts of formula (IIA), (IIB) or (IIC) disclosed herein can be used for the treatment or prevention of neuromuscular diseases. In some embodiments, the compounds or salts of formula (IIA), (IIB) or (IIC) are inhibitors of skeletal muscle contraction. In some embodiments, the compounds or salts of formula (IIA), (IIB) or (IIC) are inhibitors of myosin. In some embodiments, the compounds or salts of formula (IIA), (IIB) or (IIC) are inhibitors of skeletal muscle myosin II.

[0005] In some aspects, a method of treating a movement disorder may include administering a compound or salt of any one of formula (I), (IIA), (IIB) or (IIC) to inhibit skeletal muscle myosin II. The movement disorder includes muscle spasm. In some embodiments, the muscle spasm may be selected from multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or spasm associated with an injury or traumatic event, such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis.

[0006] The present disclosure provides compounds and salts thereof for use in the treatment of diseases. In certain aspects, the present disclosure provides compounds or salts of formula (IIA), (IIB) or (IIC), pharmaceutical compositions thereof, and methods of use in the treatment of diseases.

[0007] In certain aspects, the present disclosure provides a compound represented by formula (IIA):

Chemical formula

[0008] In certain embodiments, the disclosure provides a compound represented by formula (IIB): [Chemical Formula] or a salt thereof, wherein X 21 and X 22 are each independently selected from N and C(R 23 ), and at least one of X 21 and X 22 is N, X 23 is selected from S and O, R 21 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of which is independently halogen, -OR 26 -SR 26 -N(R 26 )2, -C(O)R 26 -C(O)N(R 26 )2, -N(R 26)C(O)R 26 、 -C(O)OR 26 、 -OC(O)R 26 、 -N(R 26 )C(O)N(R 26 )2、 -OC(O)N(R 26 )2、 -N(R 26 )C(O)OR 26 、 -S(O)R 26 、 -S(O)2R 26 、 -NO2、 =O、 =S、 =N(R 26 )、 -CN、 C 3~10 Optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring, said C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 25 ), and C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (each of these is halogen, -OR 26 、 -SR 26 、 -N(R 26 )2、 -C(O)R 26 、 -C(O)N(R 26 )2、 -N(R 26 )C(O)R 26 、 -N(R 26 )C(O)N(R 26 )2、 -OC(O)N(R 26 )2、 -N(R 26 )C(O)OR 26 、 -C(O)OR 26 、 -OC(O)R 26 、 -S(O)R 26 、 -S(O)2R 26 、 -NO2、 =O、 =S、 =N(R 26 )、 -CN、 C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 Optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10The carbon ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more Rs 25 (each being optionally substituted with one or more substituents independently selected from) selected from R 22 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of which is halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -C(O)OR 26 , -OC(O)R 26 , -S(O)R 26 , -S(O)2R 26 , -NO2, =O, =S, =N(R 26 ), -CN, C 3~10 carbon ring and 3- to 10-membered heterocyclic ring, each optionally substituted with one or more substituents independently selected from the above, and the C 3~10 carbon ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more Rs 25 (each being optionally substituted with one or more substituents), and C 3~10 carbon ring and 3- to 10-membered heterocyclic ring (each of which is halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -C(O)OR26 、 -OC(O)R 26 、 -S(O)R 26 、 -S(O)₂R 26 、 -NO₂、 =O、 =S、 =N(R 26 )、 -CN、 C 1~6 alkyl, C 3~10 optionally substituted with one or more substituents independently selected from carbocycles and 3 - to 10 - membered heterocycles, C 1~6 alkyl, C 3~10 carbocycles and 3 - to 10 - membered heterocycles are each optionally substituted with one or more R 25 ) selected from R 23 is hydrogen, halogen, -OR 26 、 -SR 26 、 -N(R 26 )₂、 -C(O)R 26 、 -C(O)N(R 26 )₂、 -N(R 26 )C(O)R 26 、 -C(O)OR 26 、 -OC(O)R 26 、 -NO₂ and -CN; and halogen, -OR 26 、 -SR 26 、 -N(R 26 )₂、 -C(O)R 26 、 -C(O)N(R 26 )₂、 -N(R 26 )C(O)R 26 、 -C(O)OR 26 、 -OC(O)R 26 、 -NO₂ and -CN, optionally substituted with one or more substituents independently selected from 1~3 alkyl selected from R 25 are each halogen, -OR 26 、 -SR 26 、 -N(R 26 )₂、 -C(O)R 26 、 -C(O)N(R 26 )₂、 -N(R 26)C(O)R 26 、 -N(R 26 )C(O)N(R 26 )2、 -OC(O)N(R 26 )2、 -N(R 26 )C(O)OR 26 、 -C(O)OR 26 、 -OC(O)R 26 、 -S(O)R 26 、 -S(O)2R 26 、 -NO2、 =O、 =S、 =N(R 26 )、 -CN; and C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl, (each of these is independently halogen, -OR 26 、 -SR 26 、 -N(R 26 )2、 -C(O)R 26 、 -C(O)N(R 26 )2、 -N(R 26 )C(O)R 26 、 -N(R 26 )C(O)N(R 26 )2、 -OC(O)N(R 26 )2、 -N(R 26 )C(O)OR 26 、 -C(O)OR 26 、 -OC(O)R 26 、 -S(O)R 26 、 -S(O)2R 26 、 -NO2、 =O、 =S、 =N(R 26 ) and -CN, independently selected, and optionally substituted with one or more substituents) independently selected from R 26 each represents hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of these is independently halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O - C 1~6 alkyl, -S - C 1~6 alkyl, -N(C 1~6 alkyl)2、 -NH(C 1~6(alkyl), C 3~10 optionally substituted with one or more substituents independently selected from a carbocyclic ring, a 3- to 10-membered heterocyclic ring), and C 3~10 a carbocyclic ring and a 3- to 10-membered heterocyclic ring (each of which is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 optionally substituted with one or more substituents independently selected from a carbocyclic ring, a 3- to 10-membered heterocyclic ring, and haloalkyl) is independently selected from.

[0009] In certain embodiments, the present disclosure provides a compound represented by formula (IIC):

Chemical formula

[0010] In certain embodiments, the present disclosure provides a method of treating activity-induced muscle injury, the method comprising administering to a subject in need thereof a compound or salt of formula (I)

Chemical formula

[0011] In certain embodiments, the present disclosure provides a method of treating a neuromuscular condition, or treating activity-induced muscle injury, or inhibiting muscle myosin II, the method comprising administering to a subject in need thereof a compound or salt of any one of formulas (I), (IIA), (IIB) or (IIC).

[0012] In certain aspects, the present disclosure provides a method of treating a movement disorder, the method comprising administering to a subject in need thereof a compound or salt of any one of formulas (I), (IIA), (IIB) or (IIC). In certain aspects, the present disclosure provides a method of treating a disease disorder, the method comprising administering to a subject in need thereof a compound or salt of any one of formulas (I), (IIA), (IIB) or (IIC), wherein the disease is Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), myotonic dystrophy type 1, myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), limb-girdle muscular dystrophy (LGMD), tendinitis, carpal tunnel syndrome, multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or an injury, or a traumatic event, for example, a stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, amyotrophic lateral sclerosis, congenital muscular dystrophy (CMD), Emery-Dreifuss muscular dystrophy (EDMD), facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), congenital muscular dystrophy (CMD), Bethlem myopathy, Fukuyama type CMD, muscle-eye-brain disease (MEB), rigid spine syndrome, Ullrich congenital muscular dystrophy, Walker-Warburg syndrome (WWS), congenital myopathy, distal myopathy, endocrine myopathy, inflammatory myopathy, metabolic myopathy, myofibrillar myopathy (MFM), scapuloperoneal myopathy, and cardiomyopathy.

[0013] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of any one of formulas (IIA), (IIB) or (IIC), or a pharmaceutically acceptable excipient. Incorporation by reference

[0014] All publications, patents, and patent applications mentioned herein are hereby incorporated by reference into this specification to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0015] The novel features of the present invention are set forth in detail in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description which illustrates exemplary embodiments and to the accompanying drawings (also referred to herein as "FIG." and "Figure") in which the principles of the invention are utilized.

Brief Description of the Drawings

[0016]

Figure 1

[0017]

Figure 2

[0018]

Figure 3

[0019]

Figure 4

[0020]

Figure 5

[0021]

Figure 6

[0022]

Figure 7

[0023]

Figure 8

[0024] Preferred embodiments of the invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions can now be envisaged by those skilled in the art without departing from the invention. It should be understood that various changes to the embodiments of the invention described herein can be made in practicing the invention. The following claims are intended to define the scope of the invention, and it is intended that methods and structures within the scope of these claims and their equivalents be covered by these claims. (Detailed Description)

[0025] In certain aspects, the present disclosure provides methods for treating neuromuscular conditions through the selective inhibition of fast-twitch skeletal muscle myosin. In particular, the methods of the present disclosure can be used in the treatment of DMD and other neuromuscular conditions.

[0026] Skeletal muscles are mainly composed of two types of fibers, slow-twitch fibers (i.e., type I) and fast-twitch fibers (i.e., type II). In each muscle, these two types of fibers are arranged in a mosaic-like pattern, with differences in fiber type composition at various times in various muscles, as well as in growth and development. Slow-twitch fibers have excellent aerobic energy generation ability. Although the contraction speed of slow-twitch fibers is slow, their fatigue resistance is high. Typically, slow-twitch fibers have a higher concentration of mitochondria and myoglobin than fast-twitch fibers and are surrounded by more capillaries than fast-twitch fibers. Due to their lower myosin ATPase activity, slow-twitch fibers contract at a lower speed and produce a lower work rate compared to fast-twitch fibers, but they can maintain their contraction function over a longer period, for example, in stabilization, postural control, and endurance exercise.

[0027] Fast-twitch fibers in humans are further divided into two main fiber types depending on the specific skeletal muscle fast myosin (IIA type, IIx / d type) they express. A third type of fast-twitch fiber (type IIB) exists in other mammals but is rarely identified in human muscle. Fast-twitch fibers have excellent anaerobic energy generation ability and can generate a large amount of tension over a short period. Typically, fast-twitch fibers have a lower concentration of mitochondria, myoglobin, and capillaries compared to slow-twitch fibers, so they can fatigue more quickly. Fast muscles generate the force required for power and resistance activities more quickly.

[0028] The ratios of type I and type II can vary among individuals. For example, non-athlete individuals may have approximately 50% of each muscle fiber type. Power athletes have a higher proportion of fast-twitch fibers. For example, sprinters may have 70 - 75% type II. Endurance athletes have a higher proportion of slow-twitch fibers. For example, long-distance runners may have 70 - 80%. The ratios of type I fibers and type II fibers can also vary depending on the age of the individual. The proportion of type II fibers, especially type IIx fibers, may decrease as the individual ages, resulting in a decrease in fat-free muscle mass.

[0029] The contractile action of skeletal muscle results in muscle damage in subjects with neuromuscular diseases (e.g., DMD), and this damage appears to be more prominent in fast-twitch fibers. In the dystrophic mouse model, a rapid decline in muscle force after a lengthening injury is observed to be greater in fast-twitch muscles of type II fibers compared to slow-twitch muscles of type I fibers. It has also been shown that the degree of rapid muscle force decline and tissue damage in the dystrophic mouse model is proportional to the peak muscle force that occurs during the lengthening injury. The excessive contraction-induced injury that occurs prior to the inflammation and irreversible fibrosis that characterize late-stage DMD is shown in FIG. 1 [Revised figure: Claflin and Brooks, Am J Brooks, Physiol Cell, 2008]. Contractile-induced muscle injury in these patients may be reduced, perhaps by limiting the peak muscle force generation in type II fibers and increasing the dependence on healthier type I fibers. N-benzyl-p-tolyl-sulfonamide (BTS) is an inhibitor of skeletal muscle fast-twitch fiber myosin and has been shown to protect muscle from pathological muscle disruption in embryos from a zebrafish model of DMD as shown in FIG. 2 [Source: Li and Arner, PLoSONE, 2015].

[0030] Inhibitors of skeletal muscle myosin that are not selective for type II fibers can lead to excessive and unwanted inhibition of skeletal muscle contraction, including respiratory function. This is because the heart shares some structural components (e.g., type I myosin) with type I skeletal muscle fibers. Without wishing to be bound by a particular mechanistic theory, the present disclosure provides selective inhibitors of fast-twitch fiber skeletal muscle myosin as treatment options for Becker muscular dystrophy (BMD), Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), McArdle's disease, and other neuromuscular conditions. Targeted inhibition of type II skeletal muscle myosin can reduce skeletal muscle contraction while minimizing the impact on the subject's daily activities.

[0031] When healthy muscle is subjected to excessive unfamiliar exercise, the muscle exhibits pain and a persistent decrease in the intensity and range of movement. Proteins also leak into the bloodstream from damaged muscle fibers, including creatine kinase (CK), lactate dehydrogenase, and myoglobin. These biomarkers are not specific to fast or slow muscle fibers and thus do not provide details regarding differences in fiber responses to injury. Troponin I (TNNI) is a component of the troponin complex that controls the initiation of muscle contraction by calcium. It differs in that there are different isoforms for each type of striated muscle: TNNI1 in slow skeletal muscle, TNNI2 in fast skeletal muscle, and TNNI3 in cardiac muscle. Using a selective enzyme-linked immunosorbent assay (ELISA), it has been demonstrated that even under extreme conditions, TNNI2, rather than TNNI1, increases in the bloodstream after harmful exercise.

[0032] DMD and BMD are caused by the absence (DMD) or shortening (BMD) of the dystrophin protein. Dystrophin provides a structural link between the actin cytoskeleton and the basement membrane via the dystrophin-glycoprotein complex. In the absence or disruption of dystrophin, muscle contraction leads to increased muscle stress and injury with normal use. The susceptibility to injury is much higher in DMD muscle than in BMD or healthy muscle, although fast muscle fibers appear to be more affected than slow muscle fibers, and young DMD patients show histological evidence of destruction of fast muscle fibers and early loss of type IIx fibers. Example 10 shows the relative susceptibility of these fibers to leak muscle constituents such as troponin, creatine kinase, or myoglobin. In some embodiments, the present disclosure provides selective inhibitors of fast fiber skeletal muscle myosin as treatment options for DMD, BMD, McArdle's disease, or limb-girdle muscular dystrophy. (Definition)

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0034] As used in this specification and the claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0035] The term "C x~y " or "C x ~C y ", when used with a chemical moiety such as alkyl, alkenyl, or alkynyl, means a group containing x to y carbon atoms in the chain. For example, the term "C 1~6 alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing 1 to 6 carbon atoms in a straight or branched chain.

[0036] The terms "C x~y alkenyl" and "C x~y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups that are similar in length and possible substitution to the alkyl described above, but contain at least one double bond or triple bond, respectively.

[0037] As used herein, the term "carbocyclic ring" refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Examples of carbocyclic rings include monocyclic rings having 3 to 10 members, bicyclic rings having 5 to 12 members, spiro bicyclic rings having 5 to 12 members, and bridged rings having 5 to 12 members. Each ring of the bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. The bicyclic carbocyclic ring includes any combination of saturated, unsaturated and aromatic bicyclic rings as long as the valence allows. The bicyclic carbocyclic ring further includes spiro bicyclic rings, such as spiropentane. The bicyclic carbocyclic ring includes any combination of ring sizes such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentanyl.

[0038] The term "aryl" refers to an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system. The aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon, contains 5 to 18 carbon atoms, and at least one of the rings in the ring system is aromatic, i.e., contains a cyclic delocalized (4n + 2)π - electron system according to Hückel's rule. Examples of ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0039] The term "cycloalkyl" refers to a saturated ring in which each atom of the ring is carbon. Cycloalkyls can include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spirobicycles, and 5- to 12-membered bridged rings. In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl groups include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptanyl), decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, and the like.

[0040] The term "cycloalkenyl" refers to an unsaturated ring in which each atom of the ring is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl can include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, cycloalkenyl contains 5 to 7 carbon atoms. Cycloalkenyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0041] The term "halo", or "halogen" or "halide", means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0042] The term "haloalkyl" refers to an alkyl group as defined above, substituted by one or more halo groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the haloalkyl group is further optionally substituted as described herein.

[0043] The term "heterocyclic ring" as used herein refers to a saturated, unsaturated or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocyclic rings include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. Bicyclic heterocyclic rings include any combination of saturated, unsaturated and aromatic bicyclic rings as long as the valency permits. In an exemplary embodiment, an aromatic ring, such as pyridyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. Bicyclic heterocyclic rings include any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocyclic rings further include spirobicyclic rings, such as 5- to 12-membered spirobicyclic rings, such as 2-oxa-6-azaspiro[3.3]heptane.

[0044] The term "heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n + 2)π-electron system in accordance with Hückel's rule. Examples of heteroaryl include fused ring systems or bridged ring systems. The heteroatoms of the heteroaryl group are oxidized as necessary. One or more nitrogen atoms, if present, are quaternized as necessary. Heteroaryl is attached to the remainder of the molecule via any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10 - hexahydrocyclooct[a]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8 - methano - 5,6,7,8 - tetrahydroquinazolinyl, naphthyridinyl, 1,6 - naphthyridinonyl, oxadiazolyl, 2 - oxazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a - octahydrobenzo[h]quinazolinyl, 1 - phenyl - 1H - pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4 - d]pyrimidinyl, pyridinyl, pyrido[3,2 - d]pyrimidinyl, pyrido[3,4 - d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8 - tetrahydroquinazolinyl, 5,6,7,8 - tetrahydrobenzo[4,5]thieno[2,3 - d]pyrimidinyl, 6,7,8,9 - tetrahydro - 5H - cyclohepta[4,5]thieno[2,3 - d]pyrimidinyl, 5,6,7,8 - tetrahydropyrido[4,5 - c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3 - d]pyrimidinyl, thieno[3,2 - d]pyrimidinyl, thieno[2,3 - c]pyridinyl, and thiophenyl (i.e., thienyl).

[0045] The term "heterocycloalkyl" refers to a saturated ring having carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyls can include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. The heteroatoms of the heterocycloalkyl group are oxidized as necessary. One or more nitrogen atoms, if present, are quaternized as necessary. Heterocycloalkyl binds to the remainder of the molecule through any atom of the heterocycloalkyl, such as any carbon or nitrogen atom of the heterocycloalkyl, provided the valence allows. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl.

[0046] The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom, with at least one double bond existing between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl can include monocyclic and polycyclic rings such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, heterocycloalkenyl contains 5 to 7 ring atoms. Heterocycloalkenyl can be bonded to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0047] The term "substituted" refers to a moiety having a substituent that replaces hydrogen on one or more carbons or replaceable heteroatoms (e.g., NH or NH2) of a compound. It is understood that "substituted" or "substituted with" implies the condition that such substitution occurs in accordance with the allowed valence of the atom being substituted and its substituent and results in a stable compound (i.e., a compound that does not undergo spontaneous transformation such as rearrangement, cyclization, elimination, etc.). In certain embodiments, substituted refers to a moiety having a substituent that replaces two hydrogen atoms on the same carbon atom (e.g., replacing those two hydrogen atoms on one carbon with an oxo, imino, or thioxo group). As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad aspect, such permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. The permissible substituents can be one or more and can be the same or different for a suitable organic compound.

[0048] In some embodiments, the substituent can include, for example, any of the following substituents described herein: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (—CN), nitro (—NO2), imino (=N—H), oximo (=N—OH), hydrazino (=N—NH2), —R b —OR a , —R b —OC(O)—R a , —R b —OC(O)—OR a , —R b —OC(O)—N(R a )2, —R b —N(R a )2, —R b —C(O)R a , —R b —C(O)OR a , —R b —C(O)N(R a )2, —R b —O—Rc -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(Ra ) 2, -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) may be optionally substituted; where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where each R a is, if the valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), oxime(=N-OH), hydrazine(=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c-C(O)N(R a )2, -R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2(where t is 1 or 2) may be optionally substituted; and where each R b is independently selected from a direct bond, or a linear or branched alkylene, alkenylene, or alkynylene chain, and each R c is a linear or branched alkylene, alkenylene, or alkynylene chain.

[0049] A double bond with an oxygen atom, such as an oxo group, is represented herein as both "=O" and "(O)". A double bond with a nitrogen atom is represented as both "=NR" and "(NR)". A double bond with a sulfur atom is represented as both "=S" and "(S)".

[0050] The terms "parenteral administration" and "administered parenterally", as used herein, mean a method of administration other than enteral and typically local administration by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0051] The phrase "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0052] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sesame oil, coconut oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0053] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions well-known in the art. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Examples of organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., for example specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0054] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a prophylactic benefit, with respect to a disease, disorder, or medical condition. A therapeutic benefit may include, for example, eradication or alleviation of the underlying disorder being treated. Additionally, a therapeutic benefit may include, for example, eradication or alleviation of one or more of the physiological symptoms associated with the underlying disorder, even if the subject may still be afflicted with the underlying disorder, such that an improvement is observed in the subject. In certain embodiments, the composition is administered for a prophylactic benefit to a subject at risk of developing a particular disease, or a subject complaining of one or more of the physical symptoms of a disease, even if the disease has not been diagnosed. Treatment by administration of a compound described herein does not require the involvement of a medical professional. (Compound)

[0055] The following is a discussion of compounds and salts thereof that can be used in the methods of the present disclosure. In certain embodiments, the compounds and salts are those described by formula (IIA), (IIB), or (IIC).

[0056] In one aspect, a compound represented by formula (IIA):

Chemical formula

[0057] In certain embodiments, for a compound or salt of Formula (IIA), R 11 teeth, hydrogen, Halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)N(R 16 )2, -OC(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl; and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )C(O)N(R16 )2, -OC(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), -CN, C 1~6 Alkyl, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl is R 17 and optionally substituted with one or more substituents independently selected from C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings are represented by R 15 each optionally substituted with one or more substituents independently selected from is selected from.

[0058] In certain embodiments, for a compound or salt of Formula (IIA), R 11 is C 3~10 a carbocycle and a 3- to 10-membered heterocycle, each of which is selected from halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )C(O)N(R 16 )2, -OC(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~10 Optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 The carbocycles and 3- to 10-membered heterocycles are each optionally substituted with one or more R 15 .

[0059] In certain embodiments, for a compound or salt of formula (IIA), R 11 is halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )C(O)N(R 16 )2, -OC(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, C 3~10 Is a carbocycle, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 The carbocycles and 3- to 10-membered heterocycles are each optionally substituted with one or more R 15 .

[0060] In certain embodiments, for a compound or salt of formula (IIA), R 11are 3- to 10-membered heterocycles, each of which is a halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )C(O)N(R 16 )2, -OC(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ), -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 15 are substituted as necessary.

[0061] In certain embodiments, for a compound or salt of Formula (IIA), R 11 is selected from cycloalkyl, aryl, and heteroaryl, each of which is R 15 and optionally substituted with one or more substituents independently selected from:

[0062] In certain embodiments, for a compound or salt of Formula (IIA), R 11 is selected from phenyl, pyridyl and cyclopropyl, each of which is selected from halogen, -OR 16 and C 1~3is independently selected from one or more substituents (optionally substituted with one or more substituents independently selected from halogen) of alkyl (optionally substituted).

[0063] In certain embodiments, for a compound or salt of formula (IIA), R 11 is selected from phenyl, 3-pyridyl and cyclopropyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OMe, -OCF3, -OCHF2 and -CF3.

[0064] In certain embodiments, for a compound or salt of formula (IIA), R 11 is

Chemical formula

[0065] In certain embodiments, for a compound or salt of formula (IIA), R 11 is

Chemical formula

[0066] In certain embodiments, for a compound or salt of formula (IIA), R 12 is halogen, -OR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -NO2 and -CN; and halogen, -OR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16) 2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -NO2 and -CN, optionally substituted with one or more substituents independently selected from C 1~3 alkyl optionally substituted with one or more substituents independently selected from cyclobutyl.

[0067] In certain embodiments, for the compound or salt of formula (IIA), R 12 is halogen, -OR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -C(O)OR 16 , -OC(O)R 16 , -NO2 and -CN, optionally substituted ethyl.

[0068] In certain embodiments, for the compound or salt of formula (IIA), R 12 is selected from ethyl and cyclobutyl.

[0069] In certain embodiments, for the compound or salt of formula (IIA), R 15 is halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )C(O)N(R 16 )2, -OC(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16, -NO2, =O, =S, =N(R 16 ) and -CN.

[0070] In certain embodiments, for a compound or salt of formula (IIA), R 15 is C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl, each of which is independently selected from halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -C(O)N(R 16 )2, -N(R 16 )C(O)R 16 , -N(R 16 )C(O)N(R 16 )2, -OC(O)N(R 16 )2, -N(R 16 )C(O)OR 16 , -C(O)OR 16 , -OC(O)R 16 , -S(O)R 16 , -S(O)2R 16 , -NO2, =O, =S, =N(R 16 ) and -CN, and is optionally substituted with one or more substituents independently selected therefrom).

[0071] In certain embodiments, for a compound or salt of formula (IIA), R 15 is halogen, -OR 16 , -N(R 16 )2, =O, -CN and C 1~3 alkyl (optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 )2, -NO2, =O and -CN).

[0072] In certain embodiments, for a compound or salt of formula (IIA), R 16 is hydrogen.

[0073] In certain embodiments, for a compound or salt of formula (IIA), R 16 is selected from C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring.

[0074] In certain embodiments, for a compound or salt of formula (IIA), R 16 is selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 alkyl optionally substituted with one or more substituents independently selected from carbocyclic ring and 3- to 10-membered heterocyclic ring. 1~6 is selected from alkyl.

[0075] In certain embodiments, for a compound or salt of formula (IIA), R 16 is selected from C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic ring, 3- to 10-membered heterocyclic ring and haloalkyl).

[0076] In certain embodiments, for a compound or salt of formula (IIA), R 16 is one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl and haloalkyl, and is an optionally substituted C 3~10 carbocycle.

[0077] In certain embodiments, for a compound or salt of formula (IIA), R 16 is one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl and haloalkyl, and is an optionally substituted 3- to 10-membered heterocycle.

[0078] In certain embodiments, for a compound or salt of formula (IIA), R 17 is selected from halogen, -OR 16 , -SR 16 , -N(R 16 )2, -NO2, =O, =S, and -CN.

[0079] In certain embodiments, for a compound or salt of formula (IIA), R 17 is halogen.

[0080] In one aspect, a compound represented by formula (IIA):

Chemical formula

[0081] In one aspect, a compound represented by formula (IIA):

Chemical formula

[0082] In certain embodiments, the compound or salt of formula (IIA) is

Chemical formula

[0083] In certain embodiments, the compound or salt of formula (IIA) is

Chemical formula

[0084] In one aspect, a compound represented by formula (IIB): [Chemical formula] or a salt thereof is disclosed herein, wherein X 21 and X 22 are independently selected from N and C(R 23 ), and at least one of X 21 and X 22 is N, X 23 is selected from S and O, R 21 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of which is independently substituted with one or more substituents selected from halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -C(O)OR 26 , -OC(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -S(O)R 26 , -S(O)2R 26 , -NO2, =O, =S, =N(R 26 ), -CN, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of which is optionally substituted with one or more substituents independently selected therefrom, and the C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 25 ), and C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (each of which is independently halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -C(O)OR 26 , -OC(O)R 26 , -S(O)R 26 , -S(O)2R 26 , -NO2, =O, =S, =N(R 26 ), -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 (each replaced as necessary) is selected from R 22 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -C(O)OR 26 , -OC(O)R 26 , -S(O)R 26 , -S(O)2R 26, -NO2, =O, =S, =N(R 26 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring, wherein said C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 25 ), and C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (each of which is halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -C(O)OR 26 , -OC(O)R 26 , -S(O)R 26 , -S(O)₂R 26 , -NO2, =O, =S, =N(R 26 ), -CN, C 1~6 alkyl, C 3~10 optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring, C 1~6 alkyl, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 25 ), selected from R 23 is hydrogen, halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -C(O)OR 26, -OC(O)R 26 , -NO2 and -CN; and halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -C(O)OR 26 , -OC(O)R 26 , -NO2 and -CN, optionally substituted with one or more substituents independently selected from 1~3 C alkyl selected from, R 25 each is halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -C(O)OR 26 , -OC(O)R 26 , -S(O)R 26 , -S(O)2R 26 , -NO2, =O, =S, =N(R 26 ), -CN; and C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl, (each of these is halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R26 ) 2, -N(R 26 )C(O)OR 26 , -C(O)OR 26 , -OC(O)R 26 , -S(O)R 26 , -S(O)2R 26 , -NO2, =O, =S, =N(R 26 ) and optionally substituted with one or more substituents independently selected from -CN) independently selected from, R 26 each is, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of which is independently halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 carbocyclic, one or more substituents independently selected from 3- to 10-membered heterocycles, optionally substituted), and C 3~10 carbocyclic and 3- to 10-membered heterocycles (each of which is independently halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocyclic, 3- to 10-membered heterocycles and haloalkyl, optionally substituted with one or more substituents independently selected from) independently selected from.

[0085] In certain embodiments, for the compound or salt of formula (IIB), X 23 is O. In certain embodiments, X 23is S. In certain embodiments, for a compound or salt of formula (IIB), X 21 is N, and X 22 is CR 23 In certain embodiments, for a compound or salt of formula (IIB), X 22 is N, and X 21 is CR 23 In certain embodiments, for a compound or salt of formula (IIB), X 22 is N, and X 21 is N. In certain embodiments, for a compound or salt of formula (IIB), X 23 is O, X 21 is N, and X 22 is N. In certain embodiments, for a compound or salt of formula (IIB), X 23 is O, X 21 is CR 23 and X 22 is N. In certain embodiments, for a compound or salt of formula (IIB), X 23 is O, X 21 is N, and X 22 is CR 23 In certain embodiments, for a compound or salt of formula (IIB), X 23 is S, X 21 is N, and X 22 is N. In certain embodiments, for a compound or salt of formula (IIB), X 23 is S, X 21 is CR 23 and X 22 is N. In certain embodiments, for a compound or salt of formula (IIB), X 23 is S, X 21 is N, and X 22 is CR 23 In certain embodiments, for a compound or salt of formula (IIB), R

[0086] is optionally substituted C 21 is optionally substituted C 1~6It is selected from alkyl, optionally substituted carbocyclic ring, and optionally substituted heteroaryl.

[0087] In certain embodiments, for the compound or salt of formula (IIB), R 21 is optionally substituted C 1~3 alkyl, optionally substituted C 3~6 carbocyclic ring, and optionally substituted 5- or 6-membered heteroaryl, and the substituents on C 1~3 alkyl are selected from halogen, -OR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -C(O)OR 26 , -OC(O)R 26 , -NO2 and -CN, and the substituents on C 3~6 carbocyclic ring and 5- or 6-membered heteroaryl are selected from halogen, -OR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -C(O)OR 26 , -OC(O)R 26 , -NO2, -CN and C 1~6 alkyl (optionally substituted with one or more R 25 ). [[ID=**51]] [[ID=**52]]

[0088] [[ID=**53]] In certain embodiments, for the compound or salt of formula (IIB), R 21 is optionally substituted C 1~3 alkyl, optionally substituted C 3~6 carbocyclic ring, and optionally substituted 5- or 6-membered heteroaryl, and the substituents on C 1~3 alkyl, C 3~6 carbocyclic ring, and 6-membered heteroaryl are halogen, -OR 26 , -N(R 26)2. It is selected from -NO2 and -CN.

[0089] In certain embodiments, for the compound or salt of formula (IIB), R 21 is selected from C 1~3 alkyl, substituted phenyl, C5 carbocyclic ring and optionally substituted pyridyl, and the substituents on phenyl and pyridyl are selected from halogen, -OH, -NH2, -NO2 and -CN.

[0090] In certain embodiments, for the compound or salt of formula (IIB), R 21 is -CH3

Chemical formula

[0091] In certain embodiments, for the compound or salt of formula (IIB), R 22 is halogen, -OR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -C(O)OR 26 , -OC(O)R 26 , -NO2, -CN, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 25 ) and are optionally substituted with one or more substituents independently selected from C 1~6 alkyl; and halogen, -OR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -C(O)OR 26 , -OC(O)R 26, -NO2, -CN, C 1~6 alkyl, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (C 1~6 alkyl, C 3~10 The carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from 25 one or more substituents optionally substituted with one or more R 3~6 carbocyclic ring selected from.

[0092] In certain embodiments, for the compound or salt of formula (IIB), R 22 is halogen and phenyl (optionally substituted with one or more substituents independently selected from one or more R 25 optionally substituted with one or more substituents independently selected from 1~3 alkyl; and halogen, C 1~6 alkyl, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (C 1~6 alkyl, C 3~10 The carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from 25 one or more substituents optionally substituted with one or more R 3~6 carbocyclic ring selected from.

[0093] In certain embodiments, for the compound or salt of formula (IIB), R 22 is halogen and phenyl (optionally substituted with one or more substituents independently selected from one or more substituents independently selected from halogen) optionally substituted with one or more substituents independently selected from 1~3 alkyl; and halogen, C 1~6 alkyl, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from 3~6 carbocyclic ring selected from.

[0094] In certain embodiments, for the compound or salt of formula (IIB), R 22 is selected from C 1~3 alkyl and C 3~6 carbocyclic ring (optionally substituted with one or more halogens).

[0095] In certain embodiments, for the compound or salt of formula (IIB), R 22 is -CH2CH3

Chemical formula

[0096] In certain embodiments, for the compound or salt of formula (IIB), R 23 is selected from hydrogen, -OMe, -OH, -NH2, -COOH, -NO2, and -CN.

[0097] In certain embodiments, for the compound or salt of formula (IIB), R 23 is hydrogen.

[0098] In certain embodiments, for the compound or salt of formula (IIB), R 25 is halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -C(O)OR 26 , -OC(O)R 26 , -S(O)R 26 , -S(O)2R 26 , -NO2, =O, =S, =N(R 26) and -CN.

[0099] In certain embodiments, for a compound or salt of formula (IIB), R 25 is C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl, each of which is independently selected from halogen, -OR 26 , -SR 26 , -N(R 26 )2, -C(O)R 26 , -C(O)N(R 26 )2, -N(R 26 )C(O)R 26 , -N(R 26 )C(O)N(R 26 )2, -OC(O)N(R 26 )2, -N(R 26 )C(O)OR 26 , -C(O)OR 26 , -OC(O)R 26 , -S(O)R 26 , -S(O)2R 26 , -NO2, =O, =S, =N(R 26 ) and -CN, and is optionally substituted with one or more substituents independently selected from.

[0100] In certain embodiments, for a compound or salt of formula (IIB), R 25 is halogen, -OR 26 , -N(R 26 )2, =O, -CN and C 1~3 alkyl (optionally substituted with one or more substituents independently selected from halogen, -OR 26 , -N(R 26 )2, -NO2, =O and -CN).

[0101] In certain embodiments, for a compound or salt of formula (IIB), R 26 is hydrogen.

[0102] In certain embodiments, for a compound or salt of formula (IIB), R26 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, and each of these is independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 carbon ring and one or more substituents independently selected from 3- to 10-membered heterocyclic rings, and is optionally substituted with one or more substituents thus selected.

[0103] In certain embodiments, for the compound or salt of formula (IIB), R 26 is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 carbon ring and one or more substituents independently selected from 3- to 10-membered heterocyclic rings, and is optionally substituted with one or more substituents thus selected, C 1~6 is selected from alkyl.

[0104] In certain embodiments, for the compound or salt of formula (IIB), R 26 is C 3~10 selected from carbon rings and 3- to 10-membered heterocyclic rings, and each of these is independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbon ring, 3- to 10-membered heterocyclic ring and haloalkyl, and is optionally substituted with one or more substituents independently selected therefrom.

[0105] In certain embodiments, for a compound or salt of formula (IIB), R 26 is one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl and haloalkyl, and is an optionally substituted C 3~10 carbocycle.

[0106] In certain embodiments, for a compound or salt of formula (IIB), R 26 is one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl and haloalkyl, and is an optionally substituted 3- to 10-membered heterocycle.

[0107] In one aspect, a compound represented by formula (IIB):

Chemical formula

[0108] In one embodiment, a compound represented by formula (IIB):

Chemical formula

[0109] In certain embodiments, the compound or salt of formula (IIB) is

Chemical formula

[0110] In one aspect, a compound represented by formula (IIC): [Chemical Formula] or a salt thereof is disclosed herein, wherein R 31 is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, each of which is independently selected from halogen, -OR 36 , -SR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -C(O)OR 36 , -OC(O)R 36 , -N(R 36 )C(O)N(R 36 )2, -OC(O)N(R 36 )2, -N(R 36 )C(O)OR 36 , -S(O)R 36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ), -CN, C 3~10 carbocyclic ring and one or more substituents independently selected from 3- to 10-membered heterocyclic rings, optionally substituted, wherein the C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 35 ), and C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic rings (each of which is independently selected from halogen, -OR 36 , -SR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -N(R 36 )C(O)N(R 36 )2, -OC(O)N(R36 ) 2, -N(R 36 )C(O)OR 36 , -C(O)OR 36 , -OC(O)R 36 , -S(O)R 36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ), -CN, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 carbocycles and 3- to 10-membered heterocycles are each optionally substituted with one or more R 35 s) selected from R 32 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of which is halogen, -OR 36 , -SR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -N(R 36 )C(O)N(R 36 )2, -OC(O)N(R 36 )2, -N(R 36 )C(O)OR 36 , -C(O)OR 36 , -OC(O)R 36 , -S(O)R 36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, said C 3~10The carbon ring and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more Rs 35 (where appropriate), and C 3~10 The carbon ring and 3- to 10-membered heterocyclic rings (each of which is independently selected from halogen, -OR 36 , -SR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -N(R 36 )C(O)N(R 36 )2, -OC(O)N(R 36 )2, -N(R 36 )C(O)OR 36 , -C(O)OR 36 , -OC(O)R 36 , -S(O)R 36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ), -CN, C 1~6 alkyl, C 3~10 The carbon ring and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more substituents independently selected from C 1~6 alkyl, C 3~10 The carbon ring and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more Rs 35 )(where appropriate) selected from R 35 each is halogen, -OR 36 , -SR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -N(R 36 )C(O)N(R 36 )2, -OC(O)N(R 36 )2, -N(R 36 )C(O)OR 36 , -C(O)OR 36 , -OC(O)R 36, -S(O)R 36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ), and -CN; and C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl, (each of which is independently selected from halogen, -OR 36 , -SR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -N(R 36 )C(O)N(R 36 )2, -OC(O)N(R 36 )2, -N(R 36 )C(O)OR 36 , -C(O)OR 36 , -OC(O)R 36 , -S(O)R 36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ) and -CN, and is optionally substituted with one or more substituents independently selected from and is independently selected from R 36 each represents hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of which is independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 carbocyclic rings and 3- to 10-membered heterocyclic rings, and is optionally substituted with one or more substituents independently selected from); and C 3~10 carbocyclic rings and 3- to 10-membered heterocyclic rings (each of which is independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 a carbon ring, a 3- to 10-membered heterocyclic ring, and one or more substituents independently selected from haloalkyl, optionally substituted) independently selected from.

[0111] In certain embodiments, for the compound or salt of formula (IIC), R 31 is optionally substituted C 1~6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl selected from.

[0112] In certain embodiments, for the compound or salt of formula (IIC), R 31 is optionally substituted C 1~3 alkyl, optionally substituted phenyl, and optionally substituted 5- or 6-membered heteroaryl selected from, C 1~3 substituents on the alkyl are halogen, -OR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -C(O)OR 36 , -OC(O)R 36 , -NO2 and -CN selected from, and substituents on phenyl and 5- or 6-membered heteroaryl are halogen, -OR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -C(O)OR 36 , -OC(O)R 36 , -NO2, -CN and C 1~6Alkyl (one or more R 35 optionally substituted therein) is selected from.

[0113] In certain embodiments, for a compound or salt of formula (IIC), R 31 is selected from C 1~3 alkyl, substituted phenyl and optionally substituted 6-membered heteroaryl, and the substituents on the phenyl and 6-membered heteroaryl are selected from halogen, -OR 36 , -N(R 36 )2, -NO2 and -CN.

[0114] In certain embodiments, for a compound or salt of formula (IIC), R 31 is selected from C 1~3 alkyl, substituted phenyl and optionally substituted pyridyl, and the substituents on the phenyl and pyridyl are selected from halogen, -OH, -NH2, -NO2 and -CN.

[0115] In certain embodiments, for a compound or salt of formula (IIC), R 32 is halogen, -OR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -C(O)OR 36 , -OC(O)R 36 , -NO2, -CN, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 35 optionally substituted with substituents independently selected from), and C 1~6 alkyl optionally substituted with one or more substituents; and halogen, -OR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R36 )C(O)R 36 、 -C(O)OR 36 、 -OC(O)R 36 、 -NO2, -CN, C 1~6 alkyl, C 3~10 carbocyclic ring and 3 - to 10 - membered heterocyclic ring (C 1~6 alkyl, C 3~10 carbocyclic ring and 3 - to 10 - membered heterocyclic ring are each optionally substituted with one or more R 35 and are independently selected from one or more substituents optionally substituted with one or more substituents)C 3~6 carbocyclic ring selected from.

[0116] In certain embodiments, for the compound or salt of formula (IIC), R 32 is halogen and phenyl (optionally substituted with one or more R 35 and are independently selected from one or more substituents optionally substituted with one or more substituents)C 1~3 alkyl; and halogen, C 1~6 alkyl, C 3~10 carbocyclic ring and 3 - to 10 - membered heterocyclic ring (C 1~6 alkyl, C 3~10 carbocyclic ring and 3 - to 10 - membered heterocyclic ring are each optionally substituted with one or more R 35 and are independently selected from one or more substituents optionally substituted with one or more substituents)C 3~6 carbocyclic ring selected from.

[0117] In certain embodiments, for the compound or salt of formula (IIC), R 32 is alkyl optionally substituted with one or more substituents independently selected from halogen and phenyl (optionally substituted with one or more substituents independently selected from halogen). 1~3

[0118] In certain embodiments, for the compound or salt of formula (IIC), R 32 ​is C 1~3 selected from alkyl.

[0119] In certain embodiments, for a compound or salt of formula (IIC), R 32 is selected from -CH2CH3.

[0120] In certain embodiments, for a compound or salt of formula (IIC), R 35 is halogen, -OR 36 , -SR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -N(R 36 )C(O)N(R 36 )2, -OC(O)N(R 36 )2, -N(R 36 )C(O)OR 36 , -C(O)OR 36 , -OC(O)R 36 , -S(O)R 36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ) and -CN.

[0121] In certain embodiments, for a compound or salt of formula (IIC), R 35 is C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl, each of which is independently substituted with halogen, -OR 36 , -SR 36 , -N(R 36 )2, -C(O)R 36 , -C(O)N(R 36 )2, -N(R 36 )C(O)R 36 , -N(R 36 )C(O)N(R 36 )2, -OC(O)N(R 36 )2, -N(R 36 )C(O)OR 36 , -C(O)OR36 、 -OC(O)R 36 、 -S(O)R 36 、 -S(O)₂R 36 、 -NO₂、 =O、 =S、 =N(R 36 ) and -CN, and is optionally substituted with one or more substituents independently selected from

[0122] In certain embodiments, for a compound or salt of formula (IIC), R 35 is halogen, -OR 36 、 -N(R 36 )₂、 =O、 -CN and C 1~3 alkyl (optionally substituted with one or more substituents independently selected from halogen, -OR 36 、 -N(R 36 )₂、 -NO₂、 =O and -CN).

[0123] In certain embodiments, for a compound or salt of formula (IIC), R 36 is hydrogen.

[0124] In certain embodiments, for a compound or salt of formula (IIC), R 36 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO₂, -NH₂, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)₂、 -NH(C 1~6 alkyl), C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring.

[0125] In certain embodiments, for a compound or salt of formula (IIC), R 36 is halogen, -CN, -OH, -SH, -NO₂, -NH₂, =O, =S, -O-C 1~6 alkyl, -S-C 1~6Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 alkyl optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles. 1~6 is selected from alkyl.

[0126] In certain embodiments, for the compound or salt of formula (IIC), R 36 is selected from carbocycles and 3- to 10-membered heterocycles, each of which is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 3~10 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 alkyl optionally substituted with one or more substituents independently selected from carbocycles, 3- to 10-membered heterocycles and haloalkyl.

[0127] In certain embodiments, for the compound or salt of formula (IIC), R 36 is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl optionally substituted with one or more substituents independently selected from alkyl and haloalkyl. 3~10 is a carbocycle.

[0128] In certain embodiments, for the compound or salt of formula (IIC), R 36 is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C1~6 (alkyl)2, -NH(C 1~6 alkyl), C 1~6 A 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl and haloalkyl.

[0129] In certain embodiments, the compound or salt of formula (IIC) is

Chemical formula

[0130] In some embodiments, the compound represented by formula (III):

Chemical formula

[0131] In certain embodiments, the compound or salt of formula (III) is

Chemical formula

Chemical formula

[0132] In certain embodiments, the compound or salt of formula (III) is

Chemical formula

Chemical formula

[0133] A chemical entity having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in the Z- or E-form (or cis- or trans-form). Further, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0134] "Tautomers" refer to molecules in which a proton shift is possible from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In an environment where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers is determined by several factors including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibria include

Chemical formula

[0135] The compounds disclosed herein, in some embodiments, for example, 2 H, 3 H, 11 C, 13 C and / or 14It is used in different enriched isotopic forms with the content of C being enriched. In certain embodiments, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy and thus increase the duration of action of the drug.

[0136] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds that have the structure of the present invention except that hydrogen is replaced by deuterium or tritium, or carbon is replaced by 13 C- or 14 C-enriched carbon are within the scope of the present disclosure.

[0137] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes in one or more of the atoms that make up such compounds. For example, the compounds can be labeled with isotopes such as, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37Cl, 79 Br, 81 Br, and 125 Isotopic substitution with I is contemplated for all. All isotopic variants of the compounds of the present invention are included within the scope of the present invention whether radioactive or not.

[0138] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms are 2 Replaced by H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0139] Deuterium-substituted compounds are synthesized using a variety of methods such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp, George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21, and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0140] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. Many reagents and components containing deuterium are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0141] The compounds of the present invention also include crystalline and amorphous forms of compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof, pharmaceutically acceptable salts of these compounds, and active metabolites.

[0142] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficiently acidic, sufficiently basic, or both functional groups can react with several inorganic bases and either inorganic or organic acids to form salts. Alternatively, inherently charged compounds, such as compounds having a quaternary nitrogen, can form salts with suitable counterions, such as halide ions, for example bromide, chloride, or fluoride ions, particularly bromide ions.

[0143] The compounds described herein may, in some cases, exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and suitable mixtures thereof. Separation of stereoisomers can be carried out by chromatography or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, ”Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, incorporated herein by reference for the purposes of this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0144] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein can be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of the present disclosure. Further, the compounds described herein can exist in unsolvated forms and can also exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0145] In certain embodiments, the compound or a salt of the compound can be a prodrug, for example, where a hydroxyl in the parent compound is presented as an ester or carbonate, or a carboxylic acid present in the parent compound is presented as an ester. The term "prodrug" is intended to encompass compounds that are converted to the pharmaceutical agents of the present disclosure under physiological conditions. One method for making a prodrug is to include one or more selected moieties that undergo hydrolysis under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal, such as a particular target cell in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0146] As described herein, prodrug forms of the compounds described herein that are metabolized in vivo to produce the compounds are included in the claims. In some cases, some of the compounds described herein can be prodrugs for another derivative or active compound.

[0147] Prodrugs are often useful because they may be easier to administer than the parent drug in certain situations. For example, a prodrug may be available for oral administration while the parent is bio-unavailable by oral administration. A prodrug can help enhance the cellular permeability of a compound relative to the parent drug. A prodrug can also have improved solubility in a pharmaceutical composition over the parent drug. A prodrug can be designed as a reversible drug derivative for use as a modifier that enhances drug transport to a site-specific tissue or increases drug retention inside cells.

[0148] In some embodiments, the design of a prodrug increases the lipophilicity of a pharmaceutical. In some embodiments, the design of a prodrug increases effective water solubility. For example, Fedorak et al., Am. J. Physiol., 269:G210-218 (1995), McLoed et al., Gastroenterol, 106:405-413 (1994), Hochhaus et al., Biomed. Chrom., 6:283-286 (1992), J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987), J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988), Sinkula et al., J. Pharm. Sci., 64:181-210 (1975), T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the See A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (such disclosures are hereby incorporated by reference in their entirety). According to another embodiment, the present disclosure provides a method for generating the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0149] Synthetic chemical transformations and methodologies useful in the synthesis of the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989), T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991), L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994), and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). (Therapeutic Use)

[0150] The methods of administration of the compounds or salts of formula (I), (IIA), (IIB), (IIC) or (III) discussed herein can be used to inhibit myosin II. In some embodiments, the compounds and their salts can be used to treat exercise-induced muscle injury. In some embodiments, the compounds may be used to treat neuromuscular conditions and movement disorders (such as spasticity).

[0151] The methods of administration of the compounds or salts of formula (I), (IIA), (IIB), (IIC) or (III) discussed herein can be used to treat neuromuscular conditions and movement disorders. Examples of neuromuscular conditions include, but are not limited to, Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb-girdle muscular dystrophy, tendinitis and carpal tunnel syndrome. Examples of movement disorders include, but are not limited to, spastic disorders, or spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury, or traumatic events (e.g., stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis). Also included are other conditions that may respond to inhibition of skeletal muscle myosin II, skeletal muscle troponin C, skeletal muscle troponin I, skeletal muscle tropomyosin, skeletal muscle troponin T, skeletal muscle regulatory light chain, skeletal muscle myosin binding protein C or skeletal muscle actin. In some embodiments, the neuromuscular condition and movement disorder are selected from muscular dystrophy and myopathy. In some embodiments, muscular dystrophy is a disease in which a genetic abnormality (mutation) interferes with the production of proteins necessary for the formation of healthy muscle, causing progressive weakness and loss of muscle mass. In some embodiments, the muscular dystrophy is selected from Becker muscular dystrophy (BMD), congenital muscular dystrophy (CMD), Duchenne muscular dystrophy (DMD), Emery-Dreifuss muscular dystrophy (EDMD), facioscapulohumeral muscular dystrophy (FSHD), limb-girdle muscular dystrophy (LGMD), myotonic dystrophy (DM) and oculopharyngeal muscular dystrophy (OPMD). In some embodiments, congenital muscular dystrophy (CMD) is selected from Bethlem myopathy, Fukuyama type CMD, muscle-eye-brain disease (MEB), rigid spine syndrome, Ullrich type CMD and Walker-Warburg syndrome (WWS). In some embodiments, myopathy is a disease of muscle not caused by neuropathy. Myopathy weakens or contracts (atrophies) muscle.In some embodiments, the myopathy is selected from congenital myopathy, distal myopathy, endocrine myopathy, inflammatory myopathy, metabolic myopathy, myofibrillar myopathy (MFM), scapuloperoneal myopathy, and cardiomyopathy. In some embodiments, the congenital myopathy is selected from cap myopathy, centronuclear myopathy, congenital myopathy with fiber type disproportion, core myopathy, central core disease, multi-minicore myopathy, myosin storage myopathy, myotubular myopathy, and nemaline myopathy. In some embodiments, the distal myopathy is selected from gne myopathy / Nakamori myopathy / hereditary inclusion body myopathy (HIBM), Laing type distal myopathy, Markesbery-Griggs type late-onset distal myopathy, Miyoshi myopathy, Udd myopathy / tibial muscular dystrophy, VCP myopathy / IBMPFD, vocal cord and pharyngeal distal myopathy, and Welander type distal myopathy. In some embodiments, the endocrine myopathy is selected from hyperthyroid myopathy and hypothyroid myopathy. In some embodiments, the inflammatory myopathy is selected from dermatomyositis, inclusion body myositis, and polymyositis. In some embodiments, the metabolic myopathy is selected from von Gierk disease, Anderson disease, Fanconi-Bickel syndrome, aldolase A deficiency, acid maltase deficiency (Pompe disease), carnitine deficiency, carnitine palmitoyltransferase deficiency, debranching enzyme deficiency (Cori disease, Forbes disease), lactate dehydrogenase deficiency, myoadenylate deaminase deficiency, phosphofructokinase deficiency (Tarui disease), phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency (Hers disease), and phosphorylase deficiency (McArdle disease). In some embodiments, the cardiomyopathy is selected from intrinsic cardiomyopathy and extrinsic cardiomyopathy. In some embodiments, the intrinsic cardiomyopathy is selected from genetic myopathy and acquired myopathy. In some embodiments, the genetic myopathy is selected from hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ARVC), LV non-compaction, ion channelopathy, dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM).In some embodiments, the acquired myopathy is selected from tako-tsubo cardiomyopathy, myocarditis, eosinophilic myocarditis, and ischemic cardiomyopathy. In some embodiments, the extrinsic myopathy is selected from metabolic myopathy, endomyocardial myopathy, endocrine myopathy, and cardiofacial cardiomyopathy. In some embodiments, the metabolic myopathy is selected from Fabry disease and hemochromatosis. In some embodiments, the endocrine myopathy is selected from endomyocardial fibrosis and eosinophilia syndrome. In some embodiments, the endocrine myopathy is selected from diabetes, hyperthyroidism, and acromegaly. In some embodiments, the cardiofacial cardiomyopathy is Noonan syndrome.

[0152] In some embodiments, methods for treating neuromuscular disorders and movement disorders by administration of a compound or salt of formula (I), (IIA), (IIB), or (IIC) are disclosed herein. In some embodiments, a compound or salt of formula (I); [Chemical formula] or a method for treating neuromuscular disorders and movement disorders by administration of a salt thereof is disclosed herein, wherein Ring A is selected from 5-membered heteroaromatic rings optionally substituted with one or more substituents independently selected from R 1 , X is N or CH, R 1 each is halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 )C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -N(R 6 )C(O)N(R 6 )2, -OC(O)N(R6 ) 2, -N(R 6 ) C(O)OR 6 , -S(O)R 6 , -S(O)2R 6 , -NO2, =O, =S, =N(R 6 ) and -CN; C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of which is halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 ) C(O)R 6 , -C(O)OR 6 , -OC(O)R 6 , -N(R 6 ) C(O)N(R 6 )2, -OC(O)N(R 6 )2, -N(R 6 ) C(O)OR 6 , -S(O)R 6 , -S(O)2R 6 , -NO2, =O, =S, =N(R 6 ), -CN, C 3~10 carbon ring and one or more substituents independently selected from 3- to 10-membered heterocyclic rings, optionally substituted, said C 3~10 carbon ring and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 5 ), and C 3~10 carbon ring and 3- to 10-membered heterocyclic rings (each of which is halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 ) C(O)R 6 , -N(R 6 ) C(O)N(R 6 )2, -OC(O)N(R 6 )2, -N(R 6 ) C(O)OR6 、 -C(O)OR 6 、 -OC(O)R 6 、 -S(O)R 6 、 -S(O)₂R 6 、 -NO₂、 =O、 =S、 =N(R 6 )、 -CN、 C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 the carbocycles and 3- to 10-membered heterocycles are each optionally substituted with one or more R 5 ) independently selected from, R 2 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, (each of these is halogen, -OR 6 、 -SR 6 、 -N(R 6 )₂、 -C(O)R 6 、 -C(O)N(R 6 )₂、 -N(R 6 )C(O)R 6 、 -N(R 6 )C(O)N(R 6 )₂、 -OC(O)N(R 6 )₂、 -N(R 6 )C(O)OR 6 、 -C(O)OR 6 、 -OC(O)R 6 、 -S(O)R 6 、 -S(O)₂R 6 、 -NO₂、 =O、 =S、 =N(R 6 )、 -CN、 C 3~10 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, said C 3~10 the carbocycles and 3- to 10-membered heterocycles are each optionally substituted with one or more R 5(each optionally replaced as necessary), C 3~10 a carbocyclic ring and a 3- to 10-membered heterocyclic ring (each of which is independently selected from halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 )C(O)R 6 , -N(R 6 )C(O)N(R 6 )2, -OC(O)N(R 6 )2, -N(R 6 )C(O)OR 6 , -C(O)OR 6 , -OC(O)R 6 , -S(O)R 6 , -S(O)2R 6 , -NO2, =O, =S, =N(R 6 ) and -CN, C 1~6 alkyl, C 3~10 a carbocyclic ring and a 3- to 10-membered heterocyclic ring, each independently selected from one or more substituents and optionally substituted, C 1~6 alkyl, C 3~10 a carbocyclic ring and a 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 5 ), and -C(O)NR 7 R 8 selected from R 4 is each independently selected from halogen, -OR 6 , -SR 6 , -N(R 6 )2, -NO2, -CN and C 1~6 alkyl (optionally substituted with one or more substituents independently selected from halogen, -OR 6 , -SR 6 , -N(R 6 )2, -NO2 and -CN), R 5 is each independently halogen, -OR 6 , -SR 6 ),, -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 )C(O)R 6 , -N(R 6 )C(O)N(R 6 )2, -OC(O)N(R 6 )2, -N(R 6 )C(O)OR 6 , -C(O)OR 6 , -OC(O)R 6 , -S(O)R 6 , -S(O)2R 6 , -NO2, =O, =S, =N(R 6 ) and -CN; and C 1~3 alkyl, C 2~3 alkenyl, C 2~3 alkynyl, (each of which is independently selected from halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 )C(O)R 6 , -N(R 6 )C(O)N(R 6 )2, -OC(O)N(R 6 )2, -N(R 6 )C(O)OR 6 , -C(O)OR 6 , -OC(O)R 6 , -S(O)R 6 , -S(O)2R 6 , -NO2, =O, =S, =N(R 6 ) and -CN and is optionally substituted with one or more substituents independently selected from and is independently selected from R 6 each represents hydrogen; and C 1~6 alkyl, C 2~6 alkenyl, C 2~6alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 a carbon ring and one or more substituents independently selected from 3- to 10-membered heterocyclic rings, optionally substituted); and C 3~10 a carbon ring and 3- to 10-membered heterocyclic rings (each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~10 a carbon ring, 3- to 10-membered heterocyclic rings and haloalkyl, optionally substituted with one or more substituents independently selected therefrom) independently selected from R 7 is hydrogen and C 1~6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR 6 , -SR 6 , -N(R 6 )2, -NO2 and -CN); and R 8 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 )C(O)R 6 , -N(R 6 )C(O)N(R 6) 2. -OC(O)N(R 6 ) 2. -N(R 6 ) C(O)OR 6 . -C(O)OR 6 . -OC(O)R 6 . -S(O)R 6 . -S(O)2R 6 . -NO2, =O, =S, =N(R 6 )、-CN、C 3~10 Optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring, said C 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 5 ), C 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring (each of which is halogen, -OR 6 , -SR 6 , -N(R 6 ) 2, -C(O)R 6 , -C(O)N(R 6 ) 2, -N(R 6 ) C(O)R 6 , -N(R 6 ) C(O)N(R 6 ) 2, -OC(O)N(R 6 ) 2, -N(R 6 ) C(O)OR 6 , -C(O)OR 6 , -OC(O)R 6 , -S(O)R 6 , -S(O)2R 6 , -NO2, =O, =S, =N(R 6 ), -CN, C 1~6 alkyl, C 3~10 Optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 3- to 10-membered heterocyclic ring, C 1~6 alkyl, C 3~10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 5 ), selected from, p is 0, 1 or 2.

[0153] In certain embodiments, for the compound or salt of formula (I), the A ring is a 5-membered unsubstituted heteroaromatic ring.

[0154] In certain embodiments, for the compound or salt of formula (I), the A ring is a 5-membered heteroaromatic ring substituted with one or more substituents independently selected from R 1 In certain embodiments, the A ring has two or more heteroatoms. In certain embodiments, the A ring has three heteroatoms.

[0155] In certain embodiments, for the compound or salt of formula (I), the A ring is selected from thiophene, oxadiazole, thiadiazole, thiazole, oxazole, pyrazole, imidazole, triazole, pyrrole, tetrazole, and furan, each of which is optionally substituted with one or more substituents independently selected from R 1 In certain embodiments, for the compound or salt of formula (I), the A ring is selected from thiophene, oxadiazole, oxazole, thiadiazole, triazole, pyrazole, and thiazole, each of which is optionally substituted with one or more substituents independently selected from R

[0156] In certain embodiments, for the compound or salt of formula (I), the A ring is selected from 1 In certain embodiments, for the compound or salt of formula (I), the A ring is selected from

[0157] In certain embodiments, for the compound or salt of formula (I), the A ring is

Chemical formula

[0158] In certain embodiments, for the compound or salt of formula (I), the A ring is

Chemical formula

[0159] In certain embodiments, for the compound or salt of formula (I), the A ring is

Chemical formula

[0160] In certain embodiments, for the compound or salt of formula (I), the A ring is

Chemical formula

[0161] In certain embodiments, for the compound or salt of formula (I), X is N. In certain embodiments, for the compound or salt of formula (I), X is CH.

[0162] In certain embodiments, for the compound or salt of formula (I), R 1 is halogen, -OR 6 , -CN, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (the carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents selected independently from R 3~10 and are each optionally substituted with one or more substituents independently selected from) C 5 alkyl; and 1~6 C C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring (each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 6 , -CN, C 1~6 alkyl, C 3~10 carbocyclic ring and 3- to 10-membered heterocyclic ring and is optionally substituted with one or more substituents independently selected from, C 1~6 alkyl, C 3~10The carbon ring and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 5 (s). are each independently selected from

[0163] In certain embodiments, for the compound or salt of formula (I), R 1 is halogen, -OR 6 and -CN, each independently selected from one or more substituents, and optionally substituted C 1~6 alkyl; and C 3~10 carbon ring and 3- to 10-membered heterocyclic rings (each of which is independently selected from halogen, -OR 6 , - and C 1~6 alkyl (optionally substituted with one or more R 5 (s))), and optionally substituted with one or more substituents selected from are each independently selected from

[0164] In certain embodiments, for the compound or salt of formula (I), R 1 is C 1~6 alkyl; and C 3~10 carbon ring and 3- to 10-membered heterocyclic rings (each of which is independently selected from halogen, -OR 6 , - and C 1~6 alkyl (optionally substituted with one or more R 5 (s))), and optionally substituted with one or more substituents selected from are each independently selected from

[0165] In certain embodiments, for the compound or salt of formula (I), R 1 is halogen or -OR 6 optionally substituted C 1~6 alkyl; and C 3~10 carbon ring and 3- to 10-membered heterocyclic rings (each of which is independently selected from halogen, -OR 6 , - and C 1~6 alkyl (optionally substituted with one or more R5 and optionally substituted with one or more substituents independently selected from:

[0166] In certain embodiments, for a compound or salt of Formula (I), R 1 is halogen and -OR 6 C optionally substituted with one or more substituents independently selected from 1~3 alkyl.

[0167] In certain embodiments, for a compound or salt of Formula (I), R 1 is selected from methyl optionally substituted with one or more substituents independently selected from halogen, —OH, —OC 6 H 5 and —OCH 3 .

[0168] In certain embodiments, for a compound or salt of Formula (I), R 1 is pyridine, C 3~5 cycloalkyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CH 3 , —CN, —OH, —OCH 3 , —OCF 3 , —CF 3 , —CHF 2 , —OCHF 2 and cyclopropyl.

[0169] In certain embodiments, for a compound or salt of Formula (I), R 1 is methyl [ka] [ka] is selected from.

[0170] In certain embodiments, for a compound or salt of Formula (I), R 1 is methyl [ka] is selected from.

[0171] In certain embodiments, for the compound or salt of formula (I), R 2 is halogen, -OR 6 -SR 6 -N(R 6 )2, -CN, C 3~10 alkyl optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, the C 1~6 alkyl is selected from, and the C 3~10 carbocycles and 3- to 10-membered heterocycles are each optionally substituted with one or more R 5 .

[0172] In certain embodiments, for the compound or salt of formula (I), R 2 is halogen, -OR 6 -SR 6 -N(R 6 )2 and -CN, and is selected from C 1~6 alkyl optionally substituted with one or more substituents independently selected therefrom.

[0173] In certain embodiments, for the compound or salt of formula (I), R 2 is selected from C 3~10 carbocycles and 3- to 10-membered heterocycles, each of which is halogen, -OR 6 -SR 6 -N(R 6 )2, CN, C 1~6 alkyl, C 3~10 alkyl optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, C 1~6 alkyl, C 3~10 carbocycles and 3- to 10-membered heterocycles are each optionally substituted with one or more R 5 .

[0174] In certain embodiments, for the compound or salt of formula (I), R 2is selected from phenyl, pyridyl, pyrimidyl, thiazole, oxadiazole and oxazole, each of which is selected from halogen, -OR 6 , -SR 6 , -N(R 6 )2, CN and C 1~6 and optionally substituted with one or more substituents independently selected from alkyl.

[0175] In certain embodiments, for a compound or salt of Formula (I), R 2 is ethyl, tert-pentyl, n-propyl, n-butyl, isopropyl, cyclobutyl, benzyl, [ka] is selected from.

[0176] In certain embodiments, for a compound or salt of Formula (I), R 2 teeth, [ka] is selected from.

[0177] In certain embodiments, for a compound or salt of Formula (I), R 2 teeth, C optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -NH and CN 1~6 alkyl; C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are substituted with halogen, -OH, -SH, -NH, -CN, C, 1~6 Alkyl, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; and -C(O)NR 7 R 8 is selected from.

[0178] In certain embodiments, for a compound or salt of Formula (I), R 2 is -C(O)NR 7 R 8 is.

[0179] In certain embodiments, for a compound or salt of Formula (I), R 4 are halogens, -OH, -OMe, -SH, -N(H)2, -NO2, -CN and C 1~6 alkyl (optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -SH, -N(H)2, -NO2 and -CN).

[0180] In certain embodiments, for a compound or salt of Formula (I), R 4 is selected from halogen, —OH, —OMe, —SH, —N(H) 2 , —NO 2 and —CN.

[0181] In certain embodiments, for a compound or salt of Formula (I), R 5 is halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 )C(O)R 6 , -N(R 6 )C(O)N(R 6 )2, -OC(O)N(R 6 )2, -N(R 6 )C(O)OR 6 , -C(O)OR 6 , -OC(O)R 6 , -S(O)R 6 , -S(O)2R 6 , -NO2, =O, =S, =N(R 6 ) and —CN.

[0182] In certain embodiments, for a compound or salt of Formula (I), R 5 is C 1~3 Alkyl, C2~3 Alkenyl, C 2~3 selected from alkynyl, each of which is halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 )C(O)R 6 , -N(R 6 )C(O)N(R 6 )2, -OC(O)N(R 6 )2, -N(R 6 )C(O)OR 6 , -C(O)OR 6 , -OC(O)R 6 , -S(O)R 6 , -S(O)2R 6 , -NO2, =O, =S, =N(R 6 ) and -CN, and is optionally substituted with one or more substituents independently selected from these.

[0183] In certain embodiments, for the compound or salt of formula (I), R 5 is halogen, -OR 6 , -N(R 6 )2, =O, -CN and C 1~3 alkyl (optionally substituted with one or more substituents independently selected from halogen, -OR 6 , -N(R 6 )2, -NO2, =O and -CN).

[0184] In certain embodiments, for the compound or salt of formula (I), R 6 is hydrogen.

[0185] In certain embodiments, for the compound or salt of formula (I), R 6 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, each of which is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6Alkyl, -S-C 1~6 Alkyl, -N(C 1~6 Alkyl)2, -NH(C 1~6 Alkyl), C 3~10 Optionally substituted with one or more substituents independently selected from carbocyclic rings and 3- to 10-membered heterocyclic rings.

[0186] In certain embodiments, for the compound or salt of formula (I), R 6 Is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 Alkyl, -S-C 1~6 Alkyl, -N(C 1~6 Alkyl)2, -NH(C 1~6 Alkyl), C 3~10 Optionally substituted with one or more substituents independently selected from carbocyclic rings and 3- to 10-membered heterocyclic rings. C 1~6 Selected from alkyl.

[0187] In certain embodiments, for the compound or salt of formula (I), R 6 Is C 3~10 Selected from carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 Alkyl, -S-C 1~6 Alkyl, -N(C 1~6 Alkyl)2, -NH(C 1~6 Alkyl), C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Optionally substituted with one or more substituents independently selected from carbocyclic rings, 3- to 10-membered heterocyclic rings and haloalkyl.

[0188] In certain embodiments, for the compound or salt of formula (I), R 6 Is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 Alkyl, -S-C 1~6Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 carbon ring optionally substituted with one or more substituents independently selected from alkyl and haloalkyl. 3~10 It is a carbocyclic ring.

[0189] In certain embodiments, for the compound or salt of formula (I), R 6 is phenyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl and haloalkyl.

[0190] In certain embodiments, for the compound or salt of formula (I), R 6 is phenyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2 and -NH2.

[0191] In certain embodiments, for the compound or salt of formula (I), R 6 is a 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 alkyl and haloalkyl.

[0192] In certain embodiments, for the compound or salt of formula (I), R 6 is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl and haloalkyl.

[0193] In certain embodiments, for the compound or salt of formula (I), R 6 is halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1~6 alkyl, -S-C 1~6 alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 a 5-membered heterocycle optionally substituted with one or more substituents independently selected from alkyl and haloalkyl.

[0194] In certain embodiments, for the compound or salt of formula (I), R 7 is hydrogen and C 1~6 alkyl (optionally substituted with one or more substituents independently selected from halogen, -OH, -SH, -NH2, -NO2 and -CN).

[0195] In certain embodiments, for the compound or salt of formula (I), R 7 is hydrogen and C 1~3 alkyl.

[0196] In certain embodiments, for the compound or salt of formula (I), R 7 is hydrogen.

[0197] In certain embodiments, for the compound or salt of formula (I), R 8 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, each of which is halogen, -OR 6 , -SR6 ,-N(R 6 )2, -CN, C 3~10 carbon ring and one or more substituents independently selected from 3- to 10-membered heterocyclic rings, optionally substituted, said C 3~10 carbon ring and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 5 ; and C 3~10 carbon ring and 3- to 10-membered heterocyclic rings (each of which is independently halogen, -OR 6 , -SR 6 , -N(R 6 )2, -CN, C 1~6 alkyl, C 3~10 carbon ring and one or more substituents independently selected from 3- to 10-membered heterocyclic rings, optionally substituted, C 1~6 alkyl, C 3~10 carbon ring and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 5 ); selected from.

[0198] In certain embodiments, for the compound or salt of formula (I), R 8 is selected from halogen, -OR 6 , -CN, C 3~10 alkyl optionally substituted with one or more substituents independently selected from carbon rings and 3- to 10-membered heterocyclic rings, said C 1~6 alkyl, and the C 3~10 carbon ring and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 5 .

[0199] In certain embodiments, for the compound or salt of formula (I), R 8 is selected from methyl, ethyl, propyl and butyl, each of which is optionally substituted with one or more of halogen, -OH, -CN, -OCH3, -CF3, -CHF2, -CH2F, phenyl or pyridyl, and phenyl or pyridyl is halogen, -CH 3、Optionally substituted with -OH, -OCH3, -CF3, -CHF2 or -CH2F.

[0200] In certain embodiments, for a compound or salt of formula (I), R 8 is selected from C 3~10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is independently selected from halogen, -OR 6 , -CN, C 1~6 alkyl, C 3~10 carbocyclic rings and 3- to 10-membered heterocyclic rings, independently selected from one or more substituents optionally substituted with C 1~6 alkyl, C 3~10 carbocyclic rings and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 5 .

[0201] In certain embodiments, for a compound or salt of formula (I), R 8 is selected from C 3~6 carbocyclic rings and 5- to 9-membered heterocyclic rings, each of which is independently selected from halogen, -OR 6 , -CN, C 1~6 alkyl, C 3~10 carbocyclic rings and 3- to 10-membered heterocyclic rings, independently selected from one or more substituents optionally substituted with C 1~6 alkyl, C 3~10 carbocyclic rings and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 5 .

[0202] In certain embodiments, for a compound or salt of formula (I), R 8 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxadiazole, thiadiazole, thiazole, oxazole, pyrazole, imidazole, triazole, pyrrole and furan, each of which is optionally substituted with one or more R 5 .

[0203] In certain embodiments, for a compound or salt of formula (I), R8 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxadiazole, thiadiazole, thiazole, each of which is optionally substituted with one or more R 5 as required.

[0204] In certain embodiments, for the compound or salt of formula (I), R 8 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxadiazole, thiadiazole, thiazole, each of which is optionally substituted with one or more of halogen, -CN, -OH, -OCH3, -CF3, -CHF2 or -CH2F as required.

[0205] In some embodiments, the compound or salt of formula (I);

Chemical formula

[0206] In some embodiments, a method of treating neuromuscular disorders and movement disorders by administering a compound of formula (I) or a salt;

Chemical formula

Chemical formula

[0207] In certain embodiments, the compound or salt of formula (I) is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0208] In certain embodiments, the compound or salt of formula (I) is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0209] Methods for treating neuromuscular and movement disorders by reducing skeletal muscle contraction are provided herein. Treatment of a subject having a neuromuscular and movement disorder with a selective fast skeletal muscle (type II) myosin inhibitor of a compound or salt of formula (I), (IIA), (IIB) or (IIC) can reduce muscle breakdown by preventing excessive uncoordinated muscle contraction, resulting in less muscle damage. Further, the methods of the present disclosure can reduce muscle damage while minimizing the impact on body function in a subject. Preservation of function can occur by both limiting the level of damage due to force generation in type II fibers and increasing dependence on healthier type I fibers. Reduction of skeletal muscle contraction or uncoordinated muscle contraction can be reduced by inhibition of skeletal muscle myosin II. In certain embodiments, the inhibitor of skeletal muscle myosin II is a compound or salt of formula (I), (IIA), (IIB) or (IIC) disclosed herein.

[0210] In some embodiments, provided herein is a method of inhibiting muscle myosin II, the method comprising administering to a subject in need thereof a compound or salt of formula (I), (IIA), (IIB) or (IIC). In some embodiments, the compound or salt does not inhibit myocardial contraction appreciably. In some embodiments, the compound or salt does not inhibit myocardial contraction appreciably. In some embodiments, the compound or salt reduces myocardial force by less than 10%.

[0211] In some situations, a method of treating a neuromuscular condition or movement disorder may include administering a compound or salt of formula (I), (IIA), (IIB) or (IIC) to inhibit skeletal muscle contraction. In some embodiments, the compound or salt of formula (I), (IIA), (IIB) or (IIC) does not significantly inhibit myocardial contraction. In some embodiments, myocardial contraction is inhibited by 20% or less. In some embodiments, myocardial contraction is inhibited by 15% or less. In some embodiments, myocardial contraction is inhibited by 10% or less. In some embodiments, myocardial contraction is inhibited by 9% or less. In some embodiments, myocardial contraction is inhibited by 8% or less. In some embodiments, myocardial contraction is inhibited by 7% or less. In some embodiments, myocardial contraction is inhibited by 6% or less. In some embodiments, myocardial contraction is inhibited by 5% or less. In some embodiments, myocardial contraction is inhibited by 4% or less. In some embodiments, myocardial contraction is inhibited by 3% or less. In some embodiments, myocardial contraction is inhibited by 2% or less. In some embodiments, myocardial contraction is inhibited by 1% or less.

[0212] The activities of daily living (ADL) or habitual physical activity of a subject can be monitored before and after treatment with a compound or salt of formula (I), (IIA), (IIB) or (IIC). ADL or habitual physical activity is subject-dependent and can range from simple walking to intensive exercise, depending on the subject's capabilities and routines. Treatment options and dosages of the skeletal muscle contraction inhibitors contemplated herein can be individualized to the subject such that their ADL and habitual physical activity remain unchanged.

[0213] In some aspects, a method of treating a neuromuscular condition or motor disorder may include administering a compound or salt of formula (I), (IIA), (IIB) or (IIC) to inhibit skeletal muscle contraction. The compound or salt of formula (I), (IIA), (IIB) or (IIC) may be administered in an amount relative to the amount required to reduce skeletal muscle contraction by 50%. The compound or salt of formula (I), (IIA), (IIB) or (IIC) may be administered in an amount less than the amount required to reduce skeletal muscle contraction by 50% relative to the skeletal muscle contraction ability of the subject prior to treatment. The compound or salt of formula (I), (IIA), (IIB) or (IIC) may be administered in an amount that reduces skeletal muscle contraction by 5% to 45% relative to the skeletal muscle contraction ability of the subject prior to treatment. In some cases, the compound or salt of formula (I), (IIA), (IIB) or (IIC) may be administered in an amount that reduces skeletal muscle contraction by less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or even less than 50% relative to the skeletal muscle contraction ability of the subject prior to treatment. In certain embodiments, the compound or salt of formula (I), (IIA), (IIB) or (IIC) may be administered in an amount that reduces skeletal muscle contraction by 1% to 50% relative to the skeletal muscle contraction ability of the subject prior to treatment.

[0214] In some aspects, a method of treating a neuromuscular condition or movement disorder may include administering a compound or salt of formula (I), (IIA), (IIB) or (IIC) to inhibit type I skeletal muscle contraction. The inhibitor of type I skeletal muscle contraction may be administered in an amount relative to the amount required to reduce type I skeletal muscle contraction by 20%. The inhibitor of type I skeletal muscle contraction may be administered in an amount less than the amount required to reduce type I skeletal muscle contraction by 20% relative to the type I skeletal muscle contraction ability of the subject prior to treatment. The inhibitor of type I skeletal muscle contraction may be administered in an amount that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the type I skeletal muscle contraction ability of the subject prior to treatment. In some cases, the inhibitor may be administered in an amount that reduces type I skeletal muscle contraction by less than 0.01%, less than 0.1%, less than 0.5%, less than 1%, less than 5%, less than 10%, less than 15%, or less than 20% relative to the type I skeletal muscle contraction ability of the subject prior to treatment. In certain embodiments, the inhibitor may be administered in an amount that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the type I skeletal muscle contraction ability of the subject prior to treatment.

[0215] In some aspects, a method of treating a neuromuscular condition or movement disorder may include administering a compound or salt of formula (I), (IIA), (IIB) or (IIC) to inhibit type II skeletal muscle contraction. The inhibitor of type II skeletal muscle contraction may be administered in an amount relative to the amount required to reduce type II skeletal muscle contraction by 90%. The inhibitor of type II skeletal muscle contraction may be administered in an amount less than the amount required to reduce type II skeletal muscle contraction by 90% relative to the subject's pre-treatment type II skeletal muscle contraction ability. The inhibitor of type II skeletal muscle contraction may be administered in an amount that reduces type II skeletal muscle contraction by 5% to 75% relative to the subject's pre-treatment type II skeletal muscle contraction ability. In some cases, the inhibitor may reduce type II skeletal muscle contraction by less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85% or even less than 90% relative to the subject's pre-treatment type II skeletal muscle contraction ability. In certain embodiments, the inhibitor may be administered in an amount that reduces type II skeletal muscle contraction by 1% to 50% relative to the subject's pre-treatment type II skeletal muscle contraction ability.

[0216] In some aspects, a method of treating contraction-induced injury in skeletal muscle fibers may include administering a compound or salt of formula (I), (IIA), (IIB) or (IIC) to inhibit skeletal muscle contraction and / or skeletal muscle myosin II. In certain embodiments, the inhibitor does not inhibit myocardial contraction to a detectable extent.

[0217] In some aspects, a method of treating a metabolic myopathy, such as McArdle's syndrome, may include administering a compound or salt of formula (I), (IIA), (IIB) or (IIC).

[0218] In certain embodiments, the contraction-induced injury in the skeletal muscle fibers is derived from involuntary skeletal muscle contractions. The involuntary skeletal muscle contractions can be associated with neuromuscular conditions or diseases associated with spasticity. In certain embodiments, the contraction-induced injury in the skeletal muscle fibers can be derived from voluntary skeletal muscle contractions, such as physical exercise.

[0219] In certain embodiments, administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC) to a subject modulates one or more biomarkers associated with muscle contraction. Examples of biomarkers include, but are not limited to, creatine kinase (CK), troponin T (TnT), troponin C (TnC), troponin I (TnI), pyruvate kinase (PK), lactate dehydrogenase (LDH), myoglobin, isoforms of TnI (e.g., cardiac muscle, slow skeletal muscle, fast skeletal muscle), and inflammatory markers (IL-1, IL-6, IL-4, TNF-α). Biomarkers can also include measurements of muscle inflammation, such as edema. The levels of the biomarkers described herein can increase after administration of the inhibitor relative to the pre-treatment levels of the biomarker. Alternatively, the levels of the biomarker can decrease after administration of the inhibitor relative to the pre-treatment levels of the biomarker. Modulation of one or more biomarkers with the inhibitors described herein can indicate treatment of a neuromuscular condition (e.g., those described herein).

[0220] The level of CK in a subject increases when the subject is active compared to when the subject is not active (e.g., sleeping), so CK is a potential measurement indicator for assessing skeletal muscle damage caused by skeletal muscle contraction. In certain embodiments, the compounds or salts of formula (I), (IIA), (IIB) or (IIC) can be administered to a subject to reduce or prevent skeletal muscle damage resulting from activity, prior to mild, moderate or intense activity. Moderate to intense activity can depend on the subject's ability and can include physical exercise that increases the heart rate by at least 20% or more (e.g., about 50% or more) relative to the subject's resting heart rate. Examples of moderate to intense activity include walking, running, weightlifting, cycling, swimming, hiking, and the like.

[0221] In certain embodiments, a compound or salt of formula (I), (IIA), (IIB), or (IIC) is administered to reduce or prevent skeletal muscle breakdown resulting from an activity, before, during, or after moderate or intense activity. A compound or salt of formula (I), (IIA), (IIB), or (IIC) can reduce the CK level of a subject relative to an untreated subject performing the same activity. The CK level can be measured in the peripheral blood of the subject during or after the activity. Administration of the inhibitors described herein can reduce the CK level of an active subject by 5% to 90% relative to an untreated subject performing the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from the activity. Administration of the inhibitors described herein can adjust the CK level to about 5% to about 90% relative to an untreated subject performing the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from the activity. Administration of the inhibitors described herein can reduce the CK level by at least about 5% relative to an untreated subject performing the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from the activity. Administration of the inhibitors described herein can adjust the CK level by up to about 90% relative to an untreated subject performing the same activity.Administration of the inhibitors described herein can reduce the CK level by about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 65%, about 45% to about 75%, about 45% to about 85%, about 45% to about 90%, about 55% to about 65%, about 55% to about 75%, about 55% to about 85%, about 55% to about 90%, about 65% to about 75%, about 65% to about 85%, about 65% to about 90%, about 75% to about 85%, about 75% to about 90%, or about 85% to about 90% relative to untreated subjects performing the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from that activity. Administration of the inhibitors described herein can adjust the CK level to about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% relative to untreated subjects performing the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from that activity.

[0222] Administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC) to a subject can modulate the level of an inflammatory marker (e.g., reduce the level of one or more inflammatory markers) relative to an untreated or pre-treated subject. The level of the inflammatory marker can be measured in the peripheral blood of the subject. Examples of inflammatory markers can include, but are not limited to, IL-1, IL-6 and TNF-α. The inflammatory marker can also be in the form of a condition (e.g., edema) that can be measured using magnetic resonance imaging. The level of the inflammatory marker in the peripheral blood can increase after administration of the inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Alternatively, the level of the inflammatory marker in the peripheral blood can decrease after administration of the inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Administration of the inhibitor described herein can modulate the inflammatory marker level from 5% to 90% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the inflammatory marker level can be modulated from about 5% to about 90% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the inflammatory marker level can be modulated by at least about 5% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the inflammatory marker level can be modulated up to about 90% maximum relative to the pre-treatment level of the inflammatory marker in the subject.In some cases, the inflammatory marker level can be adjusted to about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 65%, about 45% to about 75%, about 45% to about 85%, about 45% to about 90%, about 55% to about 65%, about 55% to about 75%, about 55% to about 85%, about 55% to about 90%, about 65% to about 75%, about 65% to about 85%, about 65% to about 90%, about 75% to about 85%, about 75% to about 90%, or about 85% to about 90% of the pre-treatment level of the inflammatory marker of the subject. In some cases, the inflammatory marker level can be adjusted to about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% of the pre-treatment level of the inflammatory marker of the subject.

[0223] Administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC) to a subject can regulate the level of fast skeletal muscle troponin I (fS-TnI) in the circulating skeletal muscle. The fS-TnI level can be measured in peripheral blood. The fS-TnI level in the peripheral blood can increase after administration of the inhibitor relative to the pre-treatment level of fS-TnI in the subject. Alternatively, the fS-TnI level in the peripheral blood can decrease after administration of the inhibitor relative to the pre-treatment level of fS-TnI in the subject. Administration of the inhibitor described herein can regulate the fS-TnI level from 5% to 90% relative to the pre-treatment level of fS-TnI in the subject. In some cases, the fS-TnI level can be regulated to at least about 5% relative to the pre-treatment level of fS-TnI in the subject. In some cases, the fS-TnI level can be regulated up to about 90% maximum relative to the pre-treatment level of fS-TnI in the subject. In some cases, the fS-TnI level can be from about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 65%, about 45% to about 75%, about 45% to about 85%, about 45% to about 90%, about 55% to about 65%, about 55% to about 75%, about 55% to about 85%, about 55% to about 90%, about 65% to about 75%, about 65% to about 85%, about 65% to about 90%, about 75% to about 85%, about 75% to about 90%, or about 85% to about 90% relative to the pre-treatment level of fS-TnI in the subject.In some cases, the fS-TnI level can be adjusted to about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% of the pre-treatment level of fS-TnI of the subject.

[0224] The isoforms of troponin can be measured in a subject before and after administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC). Inhibition of skeletal muscle contraction may not inhibit some isoforms of troponin (e.g., cardiac troponin I (cTnI) or slow skeletal muscle troponin I (ssTnI)). In some cases, inhibition of skeletal muscle contraction may not inhibit cTnI or ssTnI to a detectable extent. As used herein with respect to cTnI or ssTnI, the phrase "not to a detectable extent" means that cTnI or ssTnI is reduced by less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to cTnI or ssTnI before administration of the inhibitor.

[0225] Administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC) can reduce involuntary muscle contractions. The involuntary muscle contractions can be reduced by 20% to 90% relative to the involuntary muscle contractions prior to administration of the inhibitor. In some cases, the involuntary muscle contractions can be reduced by at least about 20% relative to the involuntary muscle contractions prior to treatment. In some cases, the involuntary muscle contractions can be reduced by up to about 90% relative to the involuntary muscle contractions prior to treatment. In some cases, the involuntary muscle contractions can be reduced by about 20% to about 25%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 20% to about 85%, about 20% to about 90%, about 25% to about 30%, about 25% to about 40%, about 25% to about 50%, about 25% to about 70%, about 25% to about 75%, about 25% to about 80%, about 25% to about 85%, about 25% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 30% to about 85%, about 30% to about 90%, about 40% to about 50%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 40% to about 85%, about 40% to about 90%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 50% to about 85%, about 50% to about 90%, about 70% to about 75%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 75% to about 80%, about 75% to about 85%, about 75% to about 90%, about 80% to about 85%, about 80% to about 90%, or about 85% to about 90% relative to the involuntary muscle contractions prior to treatment. In some cases, the involuntary muscle contractions can be reduced by about 20%, about 25%, about 30%, about 40%, about 50%, about 70%, about 75%, about 80%, about 85%, or about 90% relative to the involuntary muscle contractions prior to treatment.

[0226] The compounds or salts of formula (I), (IIA), (IIB) or (IIC) can be used to improve activities of daily living (ADL) or habitual physical activities in a subject, since mature, functional and uninjured muscle can be restored. Examples of ADL or habitual activities include, but are not limited to, ascending and descending stairs, rising from a standing position, timed chair rise, habitual walking speed, North Star walking assessment, incremental / constant load shuttle walk, and 6-minute walk distance test. The level or ability of ADL or habitual physical activity can be measured before and after administration of the skeletal muscle inhibitor. Inhibition of skeletal muscle contraction may not affect ADL or habitual physical activity. In some cases, the inhibition of skeletal muscle contraction may not appreciably affect ADL or habitual physical activity. As used herein with respect to ADL or habitual physical activity, the phrase "not appreciably" refers to a level of ADL or habitual activity that is reduced by less than 20%, less than 15%, less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to the ADL or habitual activity prior to administration of the inhibitor. Skeletal muscle contraction or muscle strength in a subject can be measured before and after administration of the compounds or salts of formula (I), (IIA), (IIB) or (IIC). Such measurements can be made to generate a dose-response curve for the compounds or salts of formula (I), (IIA), (IIB) or (IIC). The dosage of the compounds or salts of formula (I), (IIA), (IIB) or (IIC) can be adjusted from about 5% to 50% relative to the dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dosage of the skeletal muscle contraction inhibitor can be adjusted to at least about 5% relative to the dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dosage of the skeletal muscle contraction inhibitor can be adjusted to a maximum of about 50% relative to the dose that reduces type II skeletal muscle contraction by 90%.In some cases, the dosage of the skeletal muscle contraction inhibitor can be adjusted to about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 5% to about 40%, about 5% to about 50%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 50%, about 35% to about 40%, about 35% to about 50%, or about 40% to about 50% of the dosage that reduces type II skeletal muscle contraction by 90%. In some cases, the dosage of the skeletal muscle contraction inhibitor can be adjusted to about 10%, about 12%, about 15%, about 18%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% or about 50% of the dosage that reduces type II skeletal muscle contraction by 90%. Skeletal muscle contraction can be measured by a muscle strength test after nerve stimulation using surface electrodes (e.g., plantar flexion after peroneal nerve stimulation in the leg), an isometric limb assay, a heart rate monitor or an activity monitor, or an equivalent thereof, before and after administration of the skeletal muscle contraction inhibitor.

[0227] The muscle strength or myocardial contraction of a subject can be measured before and after administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC). Inhibition of skeletal muscle contraction may not inhibit myocardial contraction or myocardial muscle strength. In some embodiments, inhibition of skeletal muscle contraction may not inhibit myocardial contraction to a perceptible extent. In certain embodiments regarding myocardial contraction, the phrase, not to a perceptible extent, refers to a myocardial muscle strength that is reduced by less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to the myocardial muscle strength before administration of the inhibitor. The myocardial muscle strength or myocardial contraction of a subject after administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC) can be within 0.1% to 10% of the myocardial contraction or myocardial muscle strength before administration of the inhibitor. In some embodiments, administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC) can inhibit skeletal muscle contraction and myocardial contraction or myocardial force. In some embodiments, myocardial force is reduced by more than 0.1%, more than 0.5%, more than 1%, more than 2%, more than 4%, more than 6%, more than 8%, or more than 10%. In some embodiments, the reduction of skeletal muscle contraction and myocardial contraction is described by their ratio to each other. For example, in some embodiments, the ratio of the reduction of skeletal muscle contraction to the reduction in myocardial contraction is from about 1:1 to about 100:1, from about 2:1 to about 50:1, from about 3:1 to about 40:1, from about 4:1 to about 30:1, from about 5:1 to about 20:1, from about 7:1 to about 15:1, or from about 8:1 to about 12:1. Myocardial muscle strength or myocardial contraction can be measured using echocardiogram (left ventricular internal diameter shortening rate) or other equivalent tests.

[0228] The tidal volume in the lungs of a subject can be measured before and after administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC). Administration may not inhibit the tidal volume in the lungs. In some cases, administration may not inhibit the tidal volume in the lungs to a perceptible extent. In certain embodiments regarding the tidal volume in the lungs, the phrase "not to a perceptible extent" refers to a tidal volume in the lungs that is reduced by less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% compared to the tidal volume in the lungs before administration of the inhibitor. The tidal volume in the lungs of a subject can be measured using the forced expiratory volume in one second (FEV1) or the forced vital capacity (FVC), or a test equivalent thereto.

[0229] Smooth muscle contraction in a subject can be measured before and after administration of a skeletal muscle contraction inhibitor. Inhibition of skeletal muscle contraction may not inhibit smooth muscle contraction. In some cases, the inhibition of skeletal muscle contraction may not inhibit smooth muscle contraction to a perceptible extent. As used herein with respect to smooth muscle contraction, the phrase "not to a perceptible extent" refers to a smooth muscle contraction that is reduced by less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% compared to the smooth muscle contraction before administration of the inhibitor. Smooth muscle contraction in a subject can be evaluated by measuring the blood pressure of the subject.

[0230] Neuromuscular coupling in a subject can be measured before and after administration of a compound or salt of formula (I), (IIA), (IIB) or (IIC). Inhibition of skeletal muscle contraction with the inhibitors described herein may not disrupt nerve conduction, neurotransmitter release or depolarization in the skeletal muscle of a subject. In some cases, the inhibition of skeletal muscle contraction may not disrupt neuromuscular coupling in the subject to a perceptible extent. As used herein with respect to neuromuscular coupling, the term, not to a perceptible extent, refers to a level of neuromuscular coupling in the subject that is reduced by less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% relative to the level of neuromuscular coupling in the subject before administration of the inhibitor. Neuromuscular coupling in a subject can be evaluated by measuring the nerve-induced depolarization of skeletal muscle by recording the electrical activity generated by the skeletal muscle after electrical or voluntary stimulation with an electromyogram (EMG) using surface or needle electrodes.

[0231] In some aspects, a method of treating a neuromuscular condition or motor disorder comprises administering to a subject a compound or salt of formula (I), (IIA), (IIB) or (IIC), wherein the compound or salt of formula (I), (IIA), (IIB) or (IIC) may comprise inhibiting myosin ATPase activity, native skeletal muscle myofibrillar ATPase (calcium-regulated) or S1 reconstituted with actin, tropomyosin and troponin. In vitro assays can be used to test the effect of a test compound or inhibitor on its myosin ATPase activity. Test compounds can be screened to evaluate their muscle contraction inhibitory activity. Inhibitory activity can be measured using an absorbance assay to determine actin-activated ATPase activity. Rabbit muscle myosin subfragment 1 (S1) can be mixed with polymerized actin and dispensed into wells of an assay plate without nucleotide. The test compound can then be added to the wells along with a pin array. The reaction can be initiated with MgATP. The amount of ATP consumption over a defined period in the test vessel can be compared to the amount of ATP consumption in a control vessel. The defined period can be from 5 minutes to 20 minutes. The ATP consumption can be determined by a direct assay or an indirect assay. Test compounds that inhibit the myosin S1 ATPase activity reproducibly and potently can be further evaluated in a dose-response assay to determine the IC50 of the compound ex vivo on dissected muscle. The assay can indirectly measure ATPase activity by coupling the myosin to pyruvate kinase and lactate dehydrogenase to provide absorbance detection at 340 nm based on the conversion of NADH to NAD+ driven by ADP accumulation. In some cases, if the ATP consumption is reduced by at least 20% in the test vessel compared to the control vessel, the test compound can be selected as a compound or salt of formula (I), (IIA), (IIB) or (IIC). A test compound can be selected if it inhibits NAD+ production by at least 20% more in a kinetic assay.

[0232] The selected inhibitor or test compound need not inhibit cardiac myosin S1 ATPase in an in vitro assay. In some cases, the cardiac myosin S1 ATPase, or cardiac myofibrils, or reconstituted system may be inhibited by less than 10%, less than 8%, less than 5%, less than 3%, less than 2%, less than 1%, or less than 0.5% when the test compound or a compound or salt of formula (I), (IIA), (IIB) or (IIC) is tested in an in vitro assay.

[0233] Test compounds for skeletal muscle contraction can be tested on demembranated fibers. A single skeletal muscle fiber that has been stripped of its membrane and treated to allow for direct activation of contraction after calcium administration can be used. An inhibitor compound or salt of formula (I), (IIA), (IIB) or (IIC) can inhibit the contraction of a single skeletal muscle fiber by about 5% to about 90% relative to the pre-treatment value or an untreated control single skeletal muscle fiber. The inhibitor can inhibit the contraction of a single skeletal muscle fiber by at least about 5% relative to the pre-treatment value or an untreated control single skeletal muscle fiber. The inhibitor can inhibit the contraction of a single skeletal muscle fiber by up to about 90% relative to the pre-treatment value or an untreated control single skeletal muscle fiber. The inhibitor can inhibit the contraction of a single skeletal muscle fiber by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90% relative to the pre-treatment value or an untreated control single skeletal muscle fiber. The inhibitor can inhibit the contraction of a single skeletal muscle fiber by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to the pre-treatment value or an untreated control single skeletal muscle fiber.

[0234] An inhibitor compound or salt of formula (I), (IIA), (IIB) or (IIC) can inhibit the contraction of a single skeletal muscle by about 5% to about 90% relative to the value before treatment or the single skeletal muscle of an untreated control. The inhibitor can inhibit the contraction of a single skeletal muscle by at least about 5% relative to the value before treatment or the single skeletal muscle of an untreated control. The inhibitor can inhibit the contraction of a single skeletal muscle by up to about 90% relative to the value before treatment or the single skeletal muscle of an untreated control. The inhibitor can inhibit the contraction of a single skeletal muscle by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90% relative to the ability before treatment or the single skeletal muscle of an untreated control. The inhibitor can inhibit the contraction of a single skeletal muscle by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to the ability before treatment or the single skeletal muscle of an untreated control.

[0235] The effect of a test compound on slow-twitch type I skeletal muscle fibers, myocardial bundles, or pulmonary muscle fibers can be evaluated. The test compound or an inhibitor compound or salt of formula (I), (IIA), (IIB), or (IIC) can be selected to not appreciably modulate the function of slow-twitch type I skeletal muscle fibers, myocardial bundles, or pulmonary muscle fibers and to be specific for type II skeletal muscle. As used herein, the term "not appreciably modulate" can refer to a reduction in the muscle's contractile ability after administration of the inhibitor of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to the muscle strength / contractility prior to administration of the inhibitor.

[0236] In some aspects, a method of treating a neuromuscular condition or motor disorder comprises administering to a subject in need thereof a compound or salt of formula (I), (IIA), (IIB) or (IIC), wherein the compound or salt of formula (I), (IIA), (IIB) or (IIC) can comprise a step of reducing skeletal muscle contraction by 5% to 90% in an ex vivo assay. The ex vivo assay used can be a mouse model. The mouse model used can be a dystrophic mouse model (e.g., mdx mouse). The mdx mouse has a point mutation in its dystrophin gene, the encoded amino acid is changed from glutamine to threonine, produces a non-functional dystrophin protein, and results in increased muscle damage and weakness in DMD. The extensor digitorum longus muscle can be dissected from the mdx mouse and mounted on a lever arm. The muscle can be immersed in an oxygenated Krebs solution to maintain muscle function. A test compound or a compound or salt of formula (I), (IIA), (IIB) or (IIC) can be applied to the muscle. Then, an isometric (fixed length) contraction step can be performed, where the muscle is stimulated with a series of electrical pulses. An unusual (extensive) contraction step can be performed, where the muscle is stretched 10%, 15%, 20%, 25%, or 30% longer than its resting length and allowed to relax or stimulated with an electrical pulse. In some embodiments, the unusual contraction step is repeated 2 to 50 times. In some embodiments, the unusual contraction step is repeated 2 to 40 times. In some embodiments, the unusual contraction step is repeated 2 to 30 times. In some embodiments, the unusual contraction step is repeated 2 to 20 times. In some embodiments, the unusual contraction step is repeated 2 to 10 times. In some embodiments, the unusual contraction step is repeated 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times to cause muscle fiber damage. In some embodiments, the electrical pulse can have a frequency of about 1 Hz to about 500 Hz. In some embodiments, the electrical pulse can have a frequency of about 1 Hz to about 400 Hz.In some embodiments, the electrical pulse can have a frequency of from about 1 Hz to about 300 Hz. In some embodiments, the electrical pulse can have a frequency of from about 1 Hz to about 200 Hz. In some embodiments, the electrical pulse can have a frequency of from about 1 Hz to about 100 Hz. The electrical pulse can have a frequency of about 50 Hz, 55 Hz, 60 Hz, 65 Hz, 70 Hz, 75 Hz, 80 Hz, 85 Hz, 90 Hz, 95 Hz, 100 Hz, 105 Hz, 110 Hz, 115 Hz, 120 Hz, 125 Hz, 130 Hz, 135 Hz, 140 Hz, 145 Hz, or 150 Hz. A series of electrical pulses can be composed of individual pulses of various frequencies. The duration of each pulse in the series of electrical pulses can be between 0.1 second and 0.5 second for each pulse. The time for each pulse can be 0.1 second, 0.2 second, 0.3 second, 0.35 second, 0.4 second, or 0.5 second. Muscle membrane damage can also be measured by incubating the muscle in propidium orange after its isometric or unusual contraction. Propidium orange is a fluorescent dye taken up by muscle fibers having damaged membranes. Then, the number or percentage of dye-positive fibers can be quantified by histology. If the reduction in the test muscle strength and / or the percentage of dye-positive fibers can be less than at least 20% of the reduction in the control muscle strength and / or dye uptake, the test compound can be selected as a compound or salt of formula (I), (IIA), (IIB) or (IIC).

[0237] Using an isometric or unusual contraction set, the muscle force generated by the muscle can be measured. The change in the force generated by the muscle before and after the isometric or unusual contraction set can be calculated as the reduction in the test muscle strength. The calculation can be compared with the change in the force generated by the muscle contraction from the first pulse to the last pulse in the control sample without exposure to the test compound (reduction in the control muscle strength). The reduction in muscle strength can be used as an alternative to muscle injury, and the test compound or an inhibitor compound or salt of formula (I), (IIA), (IIB) or (IIC) can be selected if the reduction in the test muscle strength is less than at least 20% of the reduction in the control muscle strength. (Pharmaceutical Preparation)

[0238] The compositions and methods described herein can be considered useful as pharmaceutical compositions for administration to a subject in need thereof. The pharmaceutical composition can comprise at least a compound or salt of formula (I), (IIA), (IIB) or (IIC) described herein, and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents, and / or thickening agents.

[0239] A pharmaceutical composition comprising a compound or salt of formula (I), (IIA), (IIB) or (IIC) can be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries. The formulation can be modified according to the selected route of administration. A pharmaceutical composition comprising a compound, salt or conjugate can be produced, for example, by lyophilizing, mixing, dissolving, emulsifying, encapsulating the compound, salt or conjugate, or capturing the conjugate. The pharmaceutical composition can also comprise a compound, salt or conjugate in free base form or in a pharmaceutically acceptable salt form.

[0240] A method for formulating a compound or salt of formula (I), (IIA), (IIB) or (IIC) can include formulating any of the compound, salt or conjugate using one or more inert pharmaceutically acceptable excipients or carriers to form a solid, semi-solid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, the solid composition further contains non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. Alternatively, the compound, salt or conjugate can be lyophilized or in powder form for reconstitution prior to use with a suitable vehicle such as pyrogen-free sterile water.

[0241] A pharmaceutical composition comprising a compound or salt of formula (I), (IIA), (IIB) or (IIC) may contain at least one active ingredient (e.g., a compound, salt or conjugate and other agents). The active ingredient can be encapsulated, for example, in microcapsules prepared by coacervation techniques or interfacial polymerization (e.g., hydroxyethylmethylcellulose or gelatin microcapsules and poly-(methylmethacrylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions.

[0242] The compositions and formulations can be sterilized. Sterilization can be achieved by filtration through sterile filtration.

[0243] Compositions comprising a compound or salt of formula (I), (IIA), (IIB) or (IIC) can be formulated for administration by injection. Non-limiting examples of formulations for injection can include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. The injection can be formulated for bolus injection or continuous infusion. Alternatively, the composition can be lyophilized or in powder form for reconstitution prior to use with a suitable vehicle such as sterile water free of pyrogens.

[0244] For parenteral administration, the compounds or salts of formula (I), (IIA), (IIB) or (IIC) can be formulated in injectable unit dosage forms (e.g., solutions, suspensions, emulsions) in conjunction with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently non-toxic and non-therapeutic. The vehicle can be water, physiological saline, Ringer's solution, glucose solution, and 5% human serum albumin. Non-aqueous vehicles, such as fixed oils and ethyl oleate, can also be used. Liposomes can be used as carriers. The vehicle can contain additives (e.g., buffers and preservatives) such as small amounts of substances that enhance isotonicity and chemical stability.

[0245] In one embodiment, the invention relates to methods and compositions of formula (I), (IIA), (IIB) or (IIC) formulated for oral delivery to a subject in need thereof. In one embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to the subject via the mucosal layer in the mouth or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to the subject via the mucosal layer in the stomach and / or intestine.

[0246] In one embodiment, the composition of formula (I), (IIA), (IIB) or (IIC) is provided in a modified release dosage form. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble separating layer coatings, enteric coatings, osmotic devices, multiple microparticle devices, and combinations thereof. The composition can also include non-release controlling excipients.

[0247] In another embodiment, the compositions of formula (I), (IIA), (IIB) or (IIC) are provided in enteric-coated dosage forms. These enteric-coated dosage forms can also contain non-release controlling excipients. In one embodiment, the composition is in the form of enteric-coated granules as a controlled release capsule for oral administration. The composition can further contain cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol, or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric-coated pellets as a controlled release capsule for oral administration. The composition can further contain 40-50 glycerol monostearate, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, spherical sugar, talc, or triethyl citrate.

[0248] In another embodiment, the compositions of formula (I), (IIA), (IIB) or (IIC) are enteric-coated controlled release tablets for oral administration. The composition can further contain carnauba wax, crospovidone, diacetylated monoglyceride, ethyl cellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow iron oxide.

[0249] Sustained-release preparations containing a compound or salt of formula (I), (IIA), (IIB) or (IIC) can also be prepared. Examples of sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides, copolymers of L-glutamic acid and γ-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as LUPRON DEPO™ (i.e., injectable microspheres composed of a lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0250] Pharmaceutical preparations containing a compound or salt of formula (I), (IIA), (IIB) or (IIC) can be prepared for storage by mixing the compound, salt or conjugate with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. This preparation can be a lyophilized preparation or an aqueous solution. The acceptable carrier, excipient, and / or stabilizer can be non-toxic to the recipient at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers can include buffering agents, such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives, polypeptides; proteins, such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions, such as sodium ions; metal complexes; and / or nonionic surfactants or polyethylene glycols.

[0251] In another embodiment, the composition of formula (I), (IIA), (IIB) or (IIC) can further comprise calcium stearate, crospovidone, hydroxypropylmethylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0252] In another embodiment, the composition of formula (I), (IIA), (IIB) or (IIC) is provided in a foaming dosage form. These foaming dosage forms can also contain non-release controlling excipients.

[0253] In another embodiment, the composition of formula (I), (IIA), (IIB) or (IIC) can be provided in a dosage form having at least one component that can promote immediate release of the active agent and at least one component that can promote controlled release of the active agent. In a further embodiment, the dosage form may be capable of discontinuously releasing the compound in the form of at least two consecutive pulses spaced in time from 0.1 hour to 24 hours. The composition can include one or more release controlling and non-release controlling excipients, such as an excipient as a swellable material suitable for a breakable semipermeable membrane.

[0254] In another embodiment, the composition of formula (I), (IIA), (IIB) or (IIC) is provided in a dosage form for oral administration to a subject, comprising a layer material of a gastric juice resistant polymer partially neutralized with an alkali, one or more pharmaceutically acceptable excipients or carriers encapsulated in an intermediate reaction layer having cation exchange capacity, and a gastric juice resistant outer layer.

[0255] In some embodiments, the compositions of formula (I), (IIA), (IIB) or (IIC) provided herein may be in unit dosage form or in multiple dosage forms. A unit dosage form, as used herein, refers to physically discrete units, individually packaged, suitable for administration to a human or non-human animal subject. Each unit dose can contain a predetermined amount of the active ingredient sufficient to produce the desired therapeutic effect, together with the necessary pharmaceutical carrier or excipient. Examples of unit dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, the unit dosage form can be administered in divided or multiple portions. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container, which can be administered in separate unit dosage forms. Examples of multiple dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons. In another embodiment, the multiple dosage form contains different pharmaceutically active agents.

[0256] In some embodiments, the compositions of formula (I), (IIA), (IIB) or (IIC) may also be formulated as modified release dosage forms including immediate release, delayed release, extended release, sustained release, pulsatile, controlled release, extended release, accelerated and rapid release, targeted release, programmed release, and intragastric retention forms. These dosage forms can be prepared according to known methods and techniques (see Remington: The Science and Practice of Pharmacy, supra, which is incorporated herein by reference in its entirety; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126). (Combination Therapy)

[0257] Also, in the present specification, for example, combination therapies are contemplated in which the disclosed compounds and additional therapeutic agents are co-administered as part of a particular treatment regimen intended to provide beneficial effects from the combined action of these active agents. Beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic interactions resulting from the combination of therapeutic agents. Administration of these therapeutic agents in the combination is typically carried out over a defined period (usually several hours, days, weeks, months or years, depending on the selected combination). The combination therapy is intended to include administration of multiple therapeutic agents in a sequential manner (i.e., here each therapeutic agent is administered at a different time point), and administration of these therapeutic agents or at least two of the therapeutic agents in a substantially simultaneous manner.

[0258] Substantially simultaneous administration is achieved by administering to the subject, for example, a single formulation or composition (e.g., a tablet or capsule) having each therapeutic agent in a fixed ratio, or by administering multiple single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is affected by any suitable route, including, but not limited to, oral, intravenous, intramuscular, and direct absorption through mucosal tissue. The therapeutic agents are administered by the same route or different routes. For example, the first therapeutic agent of a selected combination is administered by intravenous injection, while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.

[0259] The components of the combination are administered to the patient simultaneously or sequentially. The components are present in the same pharmaceutically acceptable carrier and are thus understood to be administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, which are administered simultaneously or sequentially.

[0260] In certain embodiments, the compounds or salts of the present disclosure can be administered in combination with oral corticosteroids. In certain embodiments, the compounds or salts of the present disclosure are administered in combination with deflazacort. In certain embodiments, the compounds or salts of the present disclosure are administered in combination with prednisone. In certain embodiments, the compounds or salts of the present disclosure are administered in combination with morpholino antisense oligomers. In certain embodiments, the compounds or salts of the present disclosure are administered in combination with exon skipping therapy. In certain embodiments, the additional therapeutic agent is eteplirsen or ataluren.

[0261] In certain embodiments, the compounds or salts of the present disclosure are used in combination with gene therapy. In certain embodiments, the compounds or salts of the present disclosure are used in combination with an adeno-associated virus (AAV) containing a gene encoding a substituted protein, such as dystrophin, or a shortened version thereof, such as microdystrophin. In certain embodiments, the compounds or salts of the present disclosure are administered in combination with vamorolone.

Examples

[0262] The present invention is generally described herein, and will be more readily understood by reference to the following examples, which are included for the purpose of merely exemplifying certain aspects and embodiments of the invention and are in no way intended to limit the invention.

[0263] The following synthetic schemes are provided for illustrative purposes without limitation. The following examples illustrate various methods for preparing the compounds described herein. It is understood by those skilled in the art that these compounds can be prepared by similar methods or by combining other methods known to those skilled in the art. It is also understood by those skilled in the art that they can be prepared in a similar manner as described below by using appropriate starting materials and modifying the synthetic route as necessary. Generally, starting materials and reagents can be obtained from commercial suppliers, synthesized according to sources known to those skilled in the art, or prepared as described herein. (Example 1) 2-[3-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-6-oxo-1,6-dihydropyridazin-1-yl]-N-ethylacetamide (Compound 15) [Chemical Structure] Step 1: 6-Oxo-1,6-dihydropyridazine-3-carboxylate

[0264] To a stirred solution of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (200 mg, 1.43 mmol) in DCM (10 mL) were added N-hydroxycyclopropanecarboximidamide (157.22 mg, 1.57 mmol), DIC (270.24 mg, 2.14 mmol) and HOBt (289.35 mg, 2.14 mmol). The resulting mixture was stirred at room temperature for 2 hours. The precipitated solid was collected by filtration and washed with THF (3×3 mL). The obtained solid was dried under vacuum to give the title compound as a white solid (290 mg, 91.42%). MS m / z: 223 [M+H] + . Step 2: 6-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydropyridazin-3-one

[0265] A solution of 6-oxo-1,6-dihydropyridazine-3-carboxylate (290 mg, 1.31 mmol) in pyridine (3 mL) was stirred at 103 °C overnight. The reaction was quenched by adding saturated aqueous NH4Cl solution (5 mL), then diluted with water (20 mL) and extracted twice with EA (25 mL). The combined EA phases were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and concentrated under vacuum to give the crude product. Purification of the crude product by reverse phase Combi-flash chromatography afforded the title compound as a yellow solid (220 mg, 82.3%). MS m / z: 205 [M+H] + 。 Step 3: Methyl 2-[3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-6-oxo-1,6-dihydropyridazin-1-yl]acetate

[0266] To a stirred solution of 6-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-2,3-dihydropyridazin-3-one (205 mg, 1.00 mmol) in DMF (5 mL) were added dropwise Cs2CO3 (654.23 mg, 2.00 mmol) and methyl 2-bromoacetate (153.58 mg, 1.00 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was quenched by adding saturated NH4Cl (aqueous) (10 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by preparative TLC afforded the title compound as a white solid (150 mg, 54.08%). MS m / z: 277 [M+H] + 。 Step 4: 2-[3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-6-oxo-1,6-dihydropyridazin-1-yl]-N-ethylacetamide

[0267] A solution of methyl 2-[3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-6-oxo-1,6-dihydro-pyridazin-1-yl]acetate (120 mg, 0.43 mmol) in 35% ethanamine in EtOH (5 mL) was stirred at 80 °C for 4 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound as a white solid (64.5 mg, 51.33%). 1 H NMR (300 MHz, methanol-d4): δ 8.09 (d, J = 9.9 Hz, 1H), 7.16 (d, J = 9.9 Hz, 1H), 4.93 (s, 2H), 3.29 (q, J = 7.2 Hz, 1H), 2.25-2.15 (m, 1H), 1.29-1.00 (m, 7H). LC / MS: R t = 1.782 min; MS m / z: 290 [M+H] + 。

[0268] The following compounds were synthesized according to Example 1.

Table A-1

Table A-2

Table A-3

Table A-4

Table A-5

Table A-6

Chemical Structure

[0269] To a stirred solution of 2-(3-bromo-6-oxopyridazin-1-yl)-N-ethylacetamide (1.00 g, 0.38 mmol) in DMA (10.00 mL) were added Zn(CN)2 (496.70 mg, 0.42 mmol), Xantphos (222.47 mg, 0.038 mmol) and DIPEA (49.69 mg, 0.038 mmol). The resulting solution was stirred at 100 °C for 16 h. The reaction was diluted by adding H2O (30 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a yellow solid (499 mg, 63.07%). MS m / z: 207 [M+H] + 。 Step 2: 2-(3-Carbamothioyl-6-oxopyridazin-1-yl)-N-ethylacetamide

[0270] To a stirred solution of 2-(3-cyano-6-oxopyridazin-1-yl)-N-ethylacetamide (200.00 mg, 0.097 mmol) in EtOH (2.00 mL) was added P2S5 (431.17 mg, 0.19 mmol). The resulting solution was stirred at 80 °C for 3 h. The reaction was quenched by adding H2O (20 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a white solid (150 mg, 64.36%). MS m / z: 241 [M+H] + 。 Step 3: 2-(3-(4-(3-Chlorophenyl)thiazol-2-yl)-6-oxopyridazin-1(6H)-yl)-N-ethylacetamide

[0271] To a stirred solution of 2-(3-carbamothioyl-6-oxopyridazin-1-yl)-N-ethylacetamide (100.00 mg, 0.083 mmol) in ethanol (3.00 mL) was added 2-bromo-1-(3-chlorophenyl)ethanone (106.89 mg, 0.092 mmol). The resulting solution was stirred at 80 °C for 2 h. The reaction was diluted by adding H2O (20 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by preparative HPLC afforded the title compound as a white solid (50 mg, 32.05%). 1 H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H), 8.30 (d, J = 9.6 Hz, 1H), 8.22 (t, J = 5.2 Hz, 1H), 8.14 (t, J = 2.0 Hz, 1H), 8.04 (m, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.46 (m, 1H), 7.16 (d, J = 9.6 Hz, 1H), 4.74 (s, 2H), 3.13 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). LC / MS:R t = 2.571 min; MS m / z: 375 [M+H] + 。 (Example 3) 2-[3-[5-(3-Chlorophenyl)-1,3-thiazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide (Compound 25)

Chemical Structure

[0272] To a stirred solution of 5-(3-chlorophenyl)-1,3-thiazole (600.00 mg, 1.02 mmol) in THF (3.00 mL) was added LDA (492.75 mg, 1.53 mmol) and CBr4 (1525.42 mg, 1.533 mmol) at -78 °C. The resulting solution was stirred at -78 °C for 30 minutes and at room temperature for 1 hour. The reaction was quenched by adding saturated NH4Cl (aqueous) (20 mL) solution at 0 °C. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a yellow solid (800 mg, 95.02%). MS m / z: 274 [M+H] + 。 Step 2: N-Ethyl-2-[6-oxo-3-(trimethylstannyl)pyridazin-1-yl]acetamide

[0273] To a stirred solution of 2-(3-bromo-6-oxopyridazin-1-yl)-N-ethylacetamide (1.00 g, 3.85 mmol) in dioxane (5.00 mL) were added hexamethyldistannane (2.52 g, 7.69 mmol) and Pd(dppf)Cl2 (281.32 mg, 0.38 mmol). The reaction was stirred at 100 °C for 1 hour under an argon atmosphere. The resulting mixture was concentrated under vacuum. Purification of the crude product by silica gel column chromatography afforded the title compound as a yellow solid (800 mg, 60.49%). MS m / z: 346 [M+H] + 。 Step 3: 2-[3-[5-(3-chlorophenyl)-1,3-thiazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide

[0274] To a stirred solution of N-ethyl-2-[6-oxo-3-(trimethylstannyl)pyridazin-1-yl]acetamide (200.00 mg, 0.58 mmol) in dioxane (2.00 mL) were added Pd(dppf)Cl2 (212.70 mg, 0.29 mmol) and 2-bromo-5-(3-chlorophenyl)-1,3-thiazole (319.25 mg, 1.16 mmol). The reaction mixture was stirred at 100 °C for 3 h under an argon atmosphere. The reaction was quenched by adding H2O (20 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was first purified by silica gel column chromatography and then further purified by preparative HPLC to give the title compound as an off-white solid (17.1 mg, 7.85%). 1 H NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H), 8.20 (t, J = 5.6 Hz, 1H), 8.14 (d, J = 9.6 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H), 7.72 (dd, J = 7.2, 1.6 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.15 (d, J = 9.7 Hz, 1H), 4.73 (s, 2H), 3.20 - 3.08 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). LC / MS:R t = 2.576 min; MS m / z: 375 [M+H] + 。 (Example 4) 2-Benzyl-6-(5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)pyridazin-3(2H)-one (Compound 73)

Chemical Structure

[0275] A stirred solution of methyl 3-chlorobenzoate (3.00 g, 17.58 mmol) in MeOH (10.00 mL) was added hydrazine monohydrate (3.0 mL). The reaction mixture was stirred at 50 °C for 2 h. The precipitated solid was collected by filtration and washed with ACN (3 × 3 mL), and the title compound was obtained as an off-white solid (2.5 g, 83.33%). MS m / z: 171 [M+H] + 。 Step 2: N-(3-Chlorobenzoyl)-6-oxo-1H-pyridazine-3-carbohydrazide

[0276] To a stirred solution of 3-chlorobenzohydrazide (500.00 mg, 2.93 mmol) in DMF (5.00 mL) were added 6-oxo-1H-pyridazine-3-carboxylic acid (451.66 mg, 3.22 mmol), HATU (1.33 g, 3.52 mmol) and DIEA (1.14 g, 8.79 mmol). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with ACN (3 × 3 mL), and the title compound was obtained as a white solid (400 mg, 46.63%). MS m / z: 293 [M+H] + 。 Step 3: 6-[5-(3-Chlorophenyl)-1,3,4-oxadiazol-2-yl]-2H-pyridazin-3-one

[0277] To a stirred solution of N-(3-chlorobenzoyl)-6-oxo-1H-pyridazine-3-carbohydrazide (330 mg, 1.13 mmol) in toluene (3.00 mL) was added POCl3 (0.32 mL, 3.43 mmol). The reaction mixture was stirred at 100 °C overnight. The reaction was quenched by adding water (15 mL) at room temperature. The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, and the title compound was obtained as a brown solid (280 mg, 90.42%). MS m / z: 275 [M+H] + 。 Step 4: 2-Benzyl-6-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-one

[0278] To a stirred solution of 6-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2H-pyridazin-3-one (120.00 mg, 0.44 mmol) in DMF (2.0 mL) were added benzyl bromide (82.20 mg, 0.48 mmol) and K2CO3 (181.15 mg, 1.31 mmol). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration. Purification of the crude product by preparative HPLC gave the title compound as a white solid (30 mg, 18.82%). 1 1H NMR (400 MHz, DMSO-d6): δ 8.18 (d, J = 9.6 Hz, 1H), 8.12 - 8.03 (m, 2H), 7.79 - 7.76 (m, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 4.4 Hz, 4H), 7.79 - 7.71 (m, 1H), 7.24 (d, J = 9.6 Hz, 1H), 5.42 (s, 2H). LC / MS:R t = 2.443 min; M S m / z: 365 [M+H] + 。

[0279] The following compounds were synthesized according to Example 4.

Table B

Chem.

[0280] To a stirred solution of 5-(3-chlorophenyl)-1,3-oxazole (200.00 mg, 1.11 mmol) in DMA (2.00 mL) were added 2-(3-bromo-6-oxopyridazin-1-yl)-N-ethylacetamide (318.6 mg, 1.23 mmol), K2CO3 (384.76 mg, 2.78 mmol), PPh3 (58.42 mg, 0.22 mmol), CuI (127.25 mg, 0.67 mmol) and Pd(OAc)2 (25.00 mg, 0.011 mmol). The resulting reaction mixture was irradiated under microwave irradiation conditions at 120 °C for 1 hour. The reaction was diluted by adding H2O (20 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and then further purified by preparative HPLC to give the title compound as a white solid (35 mg, 8.76%). 1 H NMR (400 MHz, DMSO-d6): δ 8.21 (t, J = 5.4 Hz, 1H), 8.12 (d, J = 9.6 Hz, 1H), 8.07 (s, 1H), 7.91 (t, J = 2.0 Hz, 1H), 7.79 (d, J = 7.6, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.46-7.43 (m, 1H), 7.15 (d, J = 10.0 Hz, 1H), 4.79 (s, 2H), 3.15-3.10 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). LC / MS: R t = 1.389 min ; MS m / z: 359 [M+H] + . (Example 6) 2-[3-[4-(3-chlorophenyl)-1,3-oxazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide (Compound 30)

Chem.

[0281] A sulfuric acid (2.0 mL) solution of 2-(3-cyano-6-oxopyridazin-1-yl)-N-ethylacetamide (200.00 mg, 0.10 mmol) was stirred at 50 °C for 1 hour. The pH value of this solution was adjusted to 7 with NaOH (1 mol / L). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography gave the title compound as a white solid (150 mg, 68.97%). MS m / z: 225 [M+H] + 。 Step 2: 2-[3-[4-(3-chlorophenyl)-1,3-oxazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide

[0282] To a stirred solution of 1-[(ethylcarbamoyl)methyl]-6-oxopyridazine-3-carboxamide (100.00 mg, 0.22 mmol) in toluene (5.00 mL), 2-bromo-1-(3-chlorophenyl)ethanone (114.55 mg, 0.25 mmol) was added. The reaction mixture was stirred at 120 °C for 2 days. The reaction was diluted by adding H2O (20 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by preparative HPLC gave the title compound as a white solid (11.7 mg, 7.31%). 1 H NMR (400 MHz, DMSO-d6): δ 8.87 (s, 1H), 8.21 (t, J = 5.6 Hz, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H), 7.83 (d, J = 7.6, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.46 - 7.43 (m, 1H), 7.15 (d, J = 10.0 Hz, 1H), 4.77 (s, 2H), 3.15 - 3.10 (m, 2H), 1.05 (t, J = 7.2 Hz, 3H). LC / MS: R t = 1.399 min; MS m / z: 359 [M + H] + 。 (Example 7) 2 - [3 - [5 - (3 - Chlorophenyl)-1,3,4 - thiadiazol - 2 - yl]-6 - oxopyridazin - 1 - yl]-N - ethylacetamide (Compound 24)

Chemical Structure

[0283] Hydrazine monohydrate (1.0 mL) was added to a stirred solution of methyl 3 - chlorobenzoate (600.00 mg, 3.53 mmol) in methanol (5.00 mL). The resulting solution was stirred at 70 °C for 1 h. The precipitated solid was collected by filtration and washed with ACN (2 × 2 mL) to give the title compound as an off - white solid (550 mg, 91.67%). MS m / z: 171 [M + H] + 。 Step ②: 3 - Chloro - N - (6 - oxo - 1H - pyridazine - 3 - carbonyl)benzohydrazide

[0284] To a stirred solution of 6-oxo-1H-pyridazine-3-carboxylic acid (451.66 mg, 3.22 mmol) in DMF (8.00 mL) were added HATU (1.23 g, 3.22 mmol), DIEA (568.19 mg, 4.396 mmol, 1.5 equiv) and M-chlorobenzoyl hydrazine (500.00 mg, 2.93 mmol). The resulting solution was stirred at room temperature for 1 h. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with ACN (2×2 mL), and the title compound was obtained as a white solid (350 mg, 40.91%). MS m / z: 293 [M+H] + 。 Step 3: Methyl 2-(3-[[(3-chlorophenyl)formohydrazide]carbonyl]-6-oxopyridazin-1-yl)acetate

[0285] To a stirred solution of 3-chloro-N-(6-oxo-1H-pyridazine-3-carbonyl)benzohydrazide (175.00 mg, 0.601 mmol) in DMF (2.00 mL) were added K2CO3 (167.43 mg, 1.20 mmol) and methyl 2-bromoacetate (82.79 mg, 0.54 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction was diluted by the addition of H2O (20 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, and the title compound was obtained as a white solid (150 mg, 64.97%). MS m / z: 365 [M+H] + 。 Step 4: Methyl 2-[3-[5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-oxopyridazin-1-yl]acetate

[0286] A stirred solution of methyl 2-(3-[[(3-chlorophenyl)formohydrazide]carbonyl]-6-oxopyridazin-1-yl)acetate (130.00 mg, 0.36 mmol) in toluene (2.00 mL) was treated with bis(4-methoxyphenyl)-1,3,2λ5,4λ5-dithiadiphosphetane-2,4-dithione (288.31 mg, 0.71 mmol) and TEA (108.20 mg, 1.069 mmol). The resulting solution was stirred at 100 °C for 2 h. The reaction was diluted by the addition of H2O (20 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a white solid (50 mg, 36.73%). MS m / z: 363 [M+H] + 。 Step 5: 2-[3-[5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide

[0287] A stirred solution of methyl 2-[3-[5-(3-chlorophenyl)-1,3,4-thiadiazol-2-yl]-6-oxopyridazin-1-yl]acetate (47.42 mg, 0.131 mmol) in methanol (1.00 mL) was treated with ethylamine (1 mL, 0.66 mmol) in EtOH (35%). The resulting solution was stirred at 70 °C for 1 h. The residue was filtered to give 35 mg of a white solid. Recrystallization of the crude product from MeOH (1.00 mL) afforded the title compound as a white solid (25 mg, 48.47%). 1 H NMR (400 MHz, DMSO-d6): δ 8.26-8.21 (m, 2H), 8.13 (t, J = 2.0 Hz, 1H), 8.06-8.04 (m, 1H), 7.72-7.69 (m, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 10 Hz, 1H), 4.76 (s, 2H), 3.14 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H). LC / MS Rt = 1.16 min; MS m / z: 3 76 [M+H] + 。

[0288] The following compounds were synthesized according to Example 7. [Table C-1] [Table C-2] (Example 8) 2-[3-(5-[Bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-oxopyridazin-1-yl]-N-ethylacetamide (Compound 32) [Chemical formula] Step 1: Methyl 6-oxo-1H-pyridazine-3-carboxylate

[0289] To a stirred solution of 6-methoxypyridazine-3-carboxylic acid (1.50 g, 9.732 mmol) in MeOH (50.00 mL) was added H2SO4 (1.00 mL). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was cooled to room temperature. The reaction was diluted by adding H2O (200 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the title compound as a white solid (1.20 g, 73.33%). MS m / z: 155 [M+H] + 。 Step 2: 6-Oxo-1H-pyridazine-3-carbohydrazide

[0290] To a stirred solution of methyl 6-oxo-1H-pyridazine-3-carboxylate (800.00 mg, 5.19 mmol) in EtOH (5.00 mL) was added hydrazine monohydrate (1.0 mL). The reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with ACN (2 × 2 mL), and the title compound was obtained as a white solid (650 mg, 81.25%). MS m / z: 155 [M+H] + 。 Step 3: N’-[Bicyclo[1.1.1]pentane-1-carbonyl]-6-oxo-1H-pyridazine-3-carbohydrazide

[0291] To a stirred solution of 6-oxo-1H-pyridazine-3-carbohydrazide (500.00 mg, 3.24 mmol) in DMF (8.00 mL) were added bicyclo[1.1.1]pentane-1-carboxylic acid (363.30 mg, 3.24 mmol), PyBOP (2.19 g, 4.21 mmol) and DIPEA (1.26 g, 9.72 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction was diluted by the addition of H2O (12.0 mL). The precipitated solid was collected by filtration and washed with ACN (2 × 2 mL), and the title compound was obtained as a white solid (450 mg, 48.90%). MS m / z: 249 [M+H] + 。 Step 4: 6-(5-[Bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-2H-pyridazine-3-thione

[0292] To a stirred solution of N-[bicyclo[1.1.1]pentane-1-carbonyl]-6-oxo-1H-pyridazine-3-carbohydrazide (400.00 mg, 1.61 mmol) in toluene (5.00 mL) was added Lawesson's reagent (977.60 mg, 2.42 mmol). The reaction mixture was stirred at 60 °C for 1 h. The reaction mixture was cooled to room temperature. The reaction was diluted by the addition of H2O (30 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a yellow solid (300 mg, 75.59%). MS m / z: 263 [M+H] + 。 Step 5: 3-(5-[Bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-(methylsulfanyl)pyridazine

[0293] To a stirred solution of 6-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-2H-pyridazine-3-thione (300.00 mg, 1.14 mmol) in DMF (5.00 mL) were added CH3I (194.77 mg, 1.37 mmol) and K2CO3 (316.08 mg, 2.29 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted by the addition of H2O (20 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a yellow solid (260 mg, 82.27%). MS m / z: 277 [M+H] + 。 Step 6: 3-(5-[Bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-methanesulfonylpyridazine

[0294] To a stirred solution of 3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-(methylsulfanyl)pyridazine (280.00 mg, 1.01 mmol) in DCM (6.00 mL) was added M-CPBA (524.48 mg, 3.04 mmol). The reaction mixture was stirred at 40 °C for 2 h. The reaction mixture was cooled to room temperature. The reaction was diluted by adding H2O (20 mL). The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a pale yellow solid (260 mg, 83.22%). MS m / z: 309 [M+H] + 。 Step 7: 6-(5-[Bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-2H-pyridazin-3-one

[0295] To a stirred solution of 3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-methanesulfonylpyridazine (220.00 mg, 0.71 mmol) in THF (2.00 mL) were added H2O (1.00 mL) and KOH (160.11 mg, 2.85 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was cooled to room temperature. The reaction was diluted by adding H2O (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a pale yellow solid (160 mg, 91.06%). MS m / z: 247 [M+H] + 。 Step 8: Methyl 2-[3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-oxopyridazin-1-yl]acetate

[0296] To a stirred solution of 6-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-2H-pyridazin-3-one (150.00 mg, 0.61 mmol) in DMF (5.00 mL) were added methyl 2-bromoacetate (102.48 mg, 0.67 mmol) and K2CO3 (168.34 mg, 1.22 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted by adding H2O (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. Purification of the crude product by silica gel column chromatography afforded the title compound as a white solid (160 mg, 82.22%). MS m / z: 319 [M+H] + 。 Step 9: 2-[3-(5-[Bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-oxopyridazin-1-yl]-N-ethylacetamide

[0297] To a stirred solution of methyl 2-[3-(5-[bicyclo[1.1.1]pentan-1-yl]-1,3,4-thiadiazol-2-yl)-6-oxopyridazin-1-yl]acetate (160 mg, 0.50 mmol) in EtOH (4 mL) were added DMAP (6.14 mg, 0.05 mmol) and ethylamine (35%) in EtOH (1 mL). The reaction mixture was stirred at 70 °C overnight. The reaction mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with ACN (2 × 2 mL) to afford the title compound as a white solid (95.6 mg, 56.65%). 1 H NMR (300 MHz, DMSO-d6): δ 8.22-8.15 (m, 2H), 7.16 (d, J = 9.6 Hz, 1H), 4.71 (s, 2H), 3.16-3.07 (m, 2H), 2.64 (s, 1H), 2.29 (s, 6H), 1.04 (t, J = 7.2 Hz, 3H). LC / MS:R t = 1.325 min; MS m / z: 332 [M+H] + 。 (Example 9) Skeletal Muscle Myofibril ATPase Assay

[0298] Overview: Myosin ATPase activity was evaluated using a coupled reaction system in which ADP generated by the myosin ATPase function was coupled with the disappearance of NADH by the pyruvate kinase / lactate dehydrogenase (PK-LDH) system. Myosin ATPase activity generates ADP, which was used as a substrate for PK to generate pyruvate and regenerate ATP. Next, pyruvate was used as a substrate for LDH to oxidize NADH to NAD+. The reaction rate was monitored using the absorbance at 340 nm due to the time-dependent disappearance of NADH. Inhibition of ATPase activity by the assayed compound was indicated by a reduction in the rate of NADH loss relative to the vehicle-treated control over the experimental time frame. To evaluate the selectivity of the compound assayed on skeletal muscle myofibrils, the compound was counter-screened in cardiac myofibrils.

[0299] Materials: The following stock solutions and reagents were used in the skeletal muscle myofibril ATPase assay. [Table D]

[0300] Stock solution of pCa buffer. Combine PIPES, CaCl2 and EGTA solutions with 70 mL of water. Adjust the pH to 7.0 and bring the final volume to 100 mL. [Table E]

[0301] Buffer A and Buffer B. The buffers were stored on ice until use.

[0302] Preparation of Buffers [Table F-1]

Table F-2

[0303] Skeletal Muscle Fiber ATPase Assay Procedure: BSA, ATP, NADH, PEP, and DTT solutions were thawed at room temperature and then transferred to ice. Pelleted frozen muscle fibers (approximately twice the required volume) were transferred to a sufficiently large tube and capped. The muscle fibers were thawed by rolling in a water bath at room temperature for approximately 15 minutes and then cooled on ice. Buffer A and Buffer B were prepared by adjusting the volume according to the required number of wells as needed and stored on ice. 0.5 μL of the compound to be assayed was added to the wells of a 384-well plate. Buffer A and Buffer B were mixed by inverting immediately before use and then 25 μL of each was dispensed using a Multidrop dispenser (Buffer A first, then Buffer B). The absorbance in the wells was measured at 340 nm using a dynamic protocol of reading the wells every 1.5 - 2 minutes over a period of 1 hour. The reaction rate was qualitatively evaluated by subtracting the minimum absorbance value from the maximum value for each well using either SoftMax Pro plate reader software or a spreadsheet program such as Excel. Using GraphPad Prism 8.0, 100% activity was defined as the change in absorbance in the 1% DMSO vehicle well, and 0% was assigned to no change in absorbance over the course of the experiment to normalize the data. The normalized data was fit to a variable slope 4-parameter logistic model with the bottom constrained to 0 or above. The compounds in Tables 1 - 3 were tested. The results of the assay are shown in Table 4 of this specification. A = IC 50 is less than 10 μM or equivalent; B = IC 50 is greater than 10 μM and less than 100 μM; C = IC 50 is greater than 100 μM. (Example 10) Comparison of Biomarkers in Muscular Dystrophy

[0304] Frozen plasma samples from healthy volunteers (HV) were purchased from BioIVT (Westbury, NY). Plasma and serum from affected individuals were obtained from the Newcastle MRC Centre Biobank for Rare and Neuromuscular Diseases (Duchenne muscular dystrophy), and the Becker muscular dystrophy biomarker research unit at Binghamton University - SUNY (Becker muscular dystrophy). Upon receipt, all samples were aliquoted to a working volume of 50 - 100 μL and stored at -80 °C to minimize freeze - thaw damage. Red - top serum vacutainer tubes containing silica act coagulant were used for blood collection. When subjects required an MLPA test, EDTA tubes were added for their collection but were not used for any other analysis. After allowing the serum tubes to clot for 30 minutes, these tubes were centrifuged at 1000 - 1300 × g for 10 minutes. Next, the serum (upper layer) fluid was pipetted from the vacutainer tube, transferred to cryovials, and immediately frozen on dry ice for transport and later storage at -80 °C. Serum samples were frozen on dry ice and sent to Binghamton University for storage at -80 °C. Samples were collected between 2017 - 2019 and analyzed in 2019. Plasma samples from the Newcastle MRC Centre Biobank were collected from patients who visited the clinics of The John Walton Muscular Dystrophy Research Centre. Blood was drawn into vacutainers, gently inverted 5 - 10 times to ensure proper mixing of the blood and EDTA, and then centrifuged at 1,500 × g for 10 minutes. The upper plasma fraction was pipetted into cryovials and immediately stored at -80 °C. Samples were collected over a 9 - year period (2010 - 2019) and stored at -80 °C until analysis. Creatine kinase assay

[0305] Plasma CK activity was assayed using a coupled reaction kit purchased from Pointe Scientific (Canton, MI). Plasma was diluted 25-fold with phosphate buffered saline (PBS), and 2 μL of this was added to a 384-well plate. CK assay reagent (70 μL, 4:1 kit buffer A:buffer B) was added using a Multidrop Combi (ThermoFisher, Inc., Waltham, MA), and the progress of the reaction was monitored over approximately 20 - 30 minutes by absorbance at 340 nm for 30 minutes using a SpectraMax M3 plate reader (Molecular Devices, San Jose, CA). After the reaction ended, the path length correction value was measured by near-IR absorbance at 900 nm and 975 nm. The untreated absorbance data was processed in Microsoft Excel, points with A340 > 2.5 were excluded, and correction was performed for the path length using the system-specific K coefficient of 0.168. The corrected absorbance data against time was fitted to a linear model in GraphPad Prism (GraphPad Software, San Diego, CA) to obtain the slope of the reaction, and when this was compared with the standard curve of NADH (5 - 100 μM), the enzyme velocity in U / L was obtained, where U is defined as the amount of enzyme that results in a decrease in 1 μmol·L -1 ·min -1 of NADP. TNNI ELISA

[0306] The plasma concentrations of TNNI isoforms related to slow and fast muscles were measured by capture ELISA. The slow isoform (TNNI1) was measured using a commercially available test kit (LSF7068, LifeSpan Biosciences, Inc, Seattle, WA) according to the manufacturer's instructions. The fast isoform (TNNI2) was assayed as previously described. Briefly, high-binding ELISA plates were coated overnight at 4 °C with an α-TNNI2 monoclonal antibody (clone 7G2, OriGene, Inc., Rockville, MD) at a concentration of 6.4 μg / mL. Wells were blocked with 1% w / v non-fat dry milk in PBS for 30 min at 37 °C and then incubated for 2 h at 37 °C with samples or recombinant human TNNI2 as a standard curve. Wells were washed with PBS containing 0.1% Tween®-20 (PBS-T) and incubated for 90 min at 37 °C with a 1 μg / mL polyclonal α-TNNI2 antibody (PA5-76303, ThermoFisher, Inc.). After washing with PBS-T, a detection antibody (HRP-conjugated goat-α-rabbit IgG, 0.08 μg / mL, Pierce Biosciences) was added for 45 min at 37 °C, HRP was visualized with Ultra-TMB colorimetric reagent (ThermoFisher), and then quenched with 2N H2SO4 to measure absorbance at 410 nm. The selectivity of these assays for fast TNNI vs slow TNNI has been previously confirmed using human muscle extracts.

[0307] These studies have shown the relationship of skeletal muscle biomarkers in the plasma of DMD and BMD patients.

[0308] Figure 3. Becker muscular dystrophy (BMD) along with healthy volunteers (circles) as controls , in samples from healthy individuals (squares), Becker muscular dystrophy (BMD) patients (diamonds), and Duchenne muscular dystrophy (DMD) patients (triangles), the plasma concentrations of creatine kinase (CK) enzyme activity (A), fast skeletal troponin I (TNNI1) (B), and slow skeletal TNNI2 (C) were measured. In each panel, error bars represent the median + / - interquartile range. In panels B and C, samples showing undetectable TNNI concentrations were assigned values equal to the detection limit of the assay (0.1 ng / mL and 0.001 ng / mL for fast TNNI and slow TNNI, respectively). When compared to each other, a significant correlation was found between CK and fast TNNI2 (D), with an R2 of 0.67. No significant correlations were found between CK and slow TNNI1 (E), nor between fast TNNI2 and slow TNNI1 (F). In panels D - F, healthy samples are represented as black triangles, BMD as blue diamonds, and DMD as red circles. **** : p < 0.0001. All other comparisons were not significant.

[0309] Figure 4. Concentrations of creatine kinase enzyme activity (A), fast troponin I (TNNI2) (B), and slow troponin I (TNNI1) (C) against patient age in samples from Duchenne muscular dystrophy (DMD) patients. The same comparisons for Becker muscular dystrophy (BMD) were made in panels (D, E, and F) for CK, TNNI2, and TNNI1, respectively.

[0310] Figure 5. The walking status in the case of Duchenne muscular dystrophy (DMD) was compared with the plasma concentrations of creatine kinase (CK) enzyme activity (A), fast troponin I (TNNI2) (B), and slow troponin I (TNNI1) (C). The same comparisons were made for Becker muscular dystrophy (BMD) (D, E, and F). Patients were defined as "walking" unless they could be said to be completely reliant on a wheelchair for mobility. Bars represent the mean + / - standard error for the group. **** : p < 0.0001, ns: not significant.

[0311] Figure 6. Plasma fast troponin I (A), myoglobin (B) and creatine kinase (C) in healthy control subjects (Control), and subjects with McArdle's disease (McA) or Becker muscular dystrophy (BMD) after exercise. Data are presented as mean ± standard error. X-axis: 0 = before exercise, and 1, 2, 4, 24 and 48 = time after the end of exercise. Asterisks indicate significant (P < 0.05) differences compared to before exercise. N = 6 (McArdle), 4 (BMD) and 11 (healthy volunteers).

[0312] Figure 7. Comparison of creatine kinase (CK) levels before and after exercise in healthy adults, and subjects with BMD, LGMD and McArdle's disease. Data are presented as mean + standard error. X-axis: 0 = before exercise, and 1, 2, 4 and 24 = time after the end of exercise. Note that this assay is limited at 22,000 U / L, which is relevant to the McArdle data.

[0313] Figure 8. Comparison of myoglobin levels before and after exercise in healthy adults, and subjects with BMD, LGMD and McArdle's disease. Data are presented as mean + standard error. X-axis: 0 = before exercise, and 1, 2, 4 and 24 = time after the end of exercise.

[0314] In some embodiments, the compounds of the present disclosure are as shown in Table 1 below.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

[0315] In some embodiments, the compounds of the present disclosure are as shown in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3]

[0316] In certain embodiments, the compounds of the methods described herein may be selected from commercially available compounds, including those described in Table 3. The compounds in Table 3 were tested. IC 50 is shown in Table 4 herein. A = IC 50 is less than 10 μM or equivalent; B = IC 50 is greater than 10 μM and less than 100 μM; C = IC 50 is greater than 100 μM. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9]

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

[0317] The skeletal IC of the compounds of the present disclosure 50 values are shown in Table 4.

Table 4-1

Table 4-2

[0318] Preferred embodiments of the present invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, modifications, and substitutions can now be envisaged by those skilled in the art without departing from the present invention. It should be understood that various changes to the embodiments of the present invention described herein can be used in practicing the present invention. The following claims are intended to define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are intended to be covered by the claims. The present invention provides, for example, the following items. (Item 1) A compound represented by formula (IIA):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

**Claim 1**: A compound represented by formula (IIB): 【Chemical Formula 63】 or a salt thereof [wherein, X21 and X22 are independently selected from N and C(R23), and at least one of X21 and X22 is N, X23 is selected from S and O, R21 is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl (each of which is optionally substituted with one or more substituents independently selected from halogen, -OR26, -SR26, -N(R26)2, -C(O)R26, -C(O)N(R26)2, -N(R26)C(O)R26, -C(O)OR26, -OC(O)R26, -N(R26)C(O)N(R26)2, -OC(O)N(R26)2, -N(R26)C(O)OR26, -S(O)R26, -S(O)2R26, -NO2, =O, =S, =N(R26), -CN, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring, and the C3-10 carbocyclic ring and 3-10 membered heterocyclic ring are each optionally substituted with one or more R25), and C3-10 carbocyclic ring and 3-10 membered heterocyclic ring (each of which is optionally substituted with one or more substituents independently selected from halogen, -OR26, -SR26, -N(R26)2, -C(O)R26, -C(O)N(R26)2, -N(R26)C(O)R26, -N(R26)C(O)N(R26)2, -OC(O)N(R26)2, -N(R26)C(O)OR26, -C(O)OR26, -OC(O)R26, -S(O)R26, -S(O)2R26, -NO2, =O, =S, =N(R26), -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring, and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring are each optionally substituted with one or more R25)] is selected from R22 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR26, -SR26, -N(R26)2, -C(O)R26, -C(O)N(R26)2, -N(R26)C(O)R26, -N(R26)C(O)N(R26)2, -OC(O)N(R26)2, -N(R26)C(O)OR26, -C(O)OR26, -OC(O)R26, -S(O)R26, -S(O)2R26, -NO2, =O, =S, =N(R26), -CN, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring, and the C3-10 carbocyclic ring and 3-10 membered heterocyclic ring are each optionally substituted with one or more R25), and C3-10 carbocyclic ring and 3-10 membered heterocyclic ring, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR26, -SR26, -N(R26)2, -C(O)R26, -C(O)N(R26)2, -N(R26)C(O)R26, -N(R26)C(O)N(R26)2, -OC(O)N(R26)2, -N(R26)C(O)OR26, -C(O)OR26, -OC(O)R26, -S(O)R26, -S(O)2R26, -NO2, =O, =S, =N(R26), -CN, C1-6 alkyl, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring, and the C1-6 alkyl, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring are each optionally substituted with one or more R25) selected from R23 is hydrogen,[[]]END]] halogen, -OR26, -SR26, -N(R26)2, -C(O)R26, -C(O)N(R26)2, -N(R26)C(O)R26, -C(O)OR26, -OC(O)R26, -NO2 and -CN; and C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR26, -SR26, -N(R26)2, -C(O)R26, -C(O)N(R26)2, -N(R26)C(O)R26, -C(O)OR26, -OC(O)R26, -NO2 and -CN selected from each R25 halogen, -OR26, -SR26, -N(R26)2, -C(O)R26, -C(O)N(R26)2, -N(R26)C(O)R26, -N(R26)C(O)N(R26)2, -OC(O)N(R26)2, -N(R26)C(O)OR26, -C(O)OR26, -OC(O)R26, -S(O)R26, -S(O)2R26, -NO2, =O, =S, =N(R26), -CN; and C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR26, -SR26, -N(R26)2, -C(O)R26, -C(O)N(R26)2, -N(R26)C(O)R26, -N(R26)C(O)N(R26)2, -OC(O)N(R26)2, -N(R26)C(O)OR26, -C(O)OR26, -OC(O)R26, -S(O)R26, -S(O)2R26, -NO2, =O, =S, =N(R26) and -CN selected independently from each R26 hydrogen C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C3-10 carbocyclic ring, 3-10 membered heterocyclic ring, and C3-10 carbon rings and 3- to 10-membered heterocyclic rings (each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-6 alkyl, -S-C1-6 alkyl, -N(C1-6 alkyl)2, -NH(C1-6 alkyl), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbon rings, 3- to 10-membered heterocyclic rings, and haloalkyl). selected independently from]. The compound or salt according to claim 1, wherein X23 is O. The compound or salt according to claim 1, wherein X23 is S. The compound or salt according to any one of claims 1 to 3, wherein X21 is N and X22 is CR23, or X22 is N and X21 is CR23. The compound or salt according to any one of claims 1 to 3, wherein CR23 is CH. The compound or salt according to any one of claims 1 to 3, wherein X21 and X22 are each N. The compound or salt according to any one of claims 1 to 3, wherein R21 is selected from optionally substituted C1-6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl. **Claim 8**: R₂₁ is selected from C₁₋₃ alkyl optionally substituted, C₃₋₆ carbocyclic ring optionally substituted, and 5- or 6-membered heteroaryl optionally substituted; the substituents on the C₁₋₃ alkyl are selected from halogen, -OR₂₆, -N(R₂₆)₂, -C(O)R₂₆, -C(O)N(R₂₆)₂, -N(R₂₆)C(O)R₂₆, -C(O)OR₂₆, -OC(O)R₂₆, -NO₂, and -CN; the substituents on the C₃₋₆ carbocyclic ring and the 5- or 6-membered heteroaryl are selected from halogen, -OR₂₆, -N(R₂₆)₂, -C(O)R₂₆, -C(O)N(R₂₆)₂, -N(R₂₆)C(O)R₂₆, -C(O)OR₂₆, -OC(O)R₂₆, -NO₂, -CN, and C₁₋₆ alkyl (optionally substituted with one or more R₂₅); the compound or salt according to claim 7. **Claim 9**: R₂₁ is -CH₃ 【Chemical Formula 64】 selected from; the compound or salt according to claim 8. **Claim 10**: R₂₂ is C₁₋₆ alkyl optionally substituted with one or more substituents independently selected from halogen, -OR₂₆, -N(R₂₆)₂, -C(O)R₂₆, -C(O)N(R₂₆)₂, -N(R₂₆)C(O)R₂₆, -C(O)OR₂₆, -OC(O)R₂₆, -NO₂, -CN, C₃₋₁₀ carbocyclic ring, and 3- to 10-membered heterocyclic ring (the C₃₋₁₀ carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R₂₅); and C₃₋₆ carbocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR₂₆, -N(R₂₆)₂, -C(O)R₂₆, -C(O)N(R₂₆)₂, -N(R₂₆)C(O)R₂₆, -C(O)OR₂₆, -OC(O)R₂₆, -NO₂, -CN, C₁₋₆ alkyl, C₃₋₁₀ carbocyclic ring, and 3- to 10-membered heterocyclic ring (the C₁₋₆ alkyl, C₃₋₁₀ carbocyclic ring, and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R₂₅) The compound or salt according to claim 1, selected from

11. R22 is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen and phenyl (optionally substituted with one or more R25); and C3-6 carbocyclic ring optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring (C1-6 alkyl, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring are each optionally substituted with one or more R25) The compound according to claim 8, selected from

12. R22 is C1-3 alkyl optionally substituted with one or more substituents independently selected from halogen and phenyl (optionally substituted with one or more substituents independently selected from halogen); and C3-6 carbocyclic ring optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C3-10 carbocyclic ring and 3-10 membered heterocyclic ring The compound according to claim 11, selected from

13. R22 is -CH2CH3 【Chemical Formula 65】 The compound according to claim 12, selected from

14. 【Fig. 66】 And the compound according to claim 1, selected from any one of their salts.

15. A pharmaceutical composition comprising the compound or salt according to claim 1.

16. A composition or pharmaceutical composition for use in the treatment of activity-induced muscle injury, neuromuscular condition, metabolic myopathy or movement disorder, comprising the composition comprising the compound or salt according to claim 1 or the pharmaceutical composition according to claim 12.

17. A composition for treating a neuromuscular condition, comprising the compound or salt according to claim 1.

18. The composition according to claim 16, for use in the treatment of a neuromuscular condition selected from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb-girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome.

19. The composition according to claim 18, wherein the neuromuscular condition is Duchenne muscular dystrophy.

20. The composition according to claim 18, wherein the neuromuscular condition is Becker muscular dystrophy.

21. A composition for treating a movement disorder, the composition comprising the compound or salt according to claim 1.

22. The composition according to claim 21, for use in the treatment of a movement disorder comprising muscle spasticity associated with a traumatic event including multiple sclerosis; Parkinson's disease; Alzheimer's disease; cerebral palsy; or stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis.

23. The composition according to claim 16, wherein the metabolic myopathy is selected from McArdle's disease.

24. The composition according to claim 22, wherein the muscle spasticity is selected from multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or spasticity associated with an injury, or a traumatic event.

25. The composition according to claim 24, wherein the traumatic event includes stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria or amyotrophic lateral sclerosis.

26. The composition according to claim 24, wherein the composition is administered in an amount sufficient to reduce involuntary muscle contractions.

27. The composition according to claim 26, wherein the composition is administered in an amount sufficient to reduce involuntary muscle contractions by at least 10%.

Images