Pyridazinone compounds for 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, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Skeletal muscle is the largest organ system in the human body, serving two primary purposes. The first is the generation of force, which enables muscle contraction, locomotor activity, and postural maintenance; the second is the metabolism of glucose, fatty acids, and amino acids. Skeletal muscle contraction during daily activities and exercise naturally leads to muscle stress, breakdown, and remodeling, which are important for muscle adaptation. In individuals with neuromuscular conditions (e.g., Duchenne muscular dystrophy (DMD)), muscle contraction results in successive rounds of amplified muscle breakdown, which the body struggles to repair. Ultimately, as patients age, pathophysiological processes emerge that result in excessive inflammation, fibrosis, and the accumulation of fat deposits in muscle, presaging 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 breakdown in patients with neuromuscular conditions (e.g., DMD). Summary of the Invention [Means for solving the problem]

[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 to treat or prevent 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 embodiments, a method for treating a movement disorder can include administering a compound or salt of any one of Formulas (I), (IIA), (IIB), or (IIC) to inhibit skeletal muscle myosin II. The movement disorder can include muscle spasms. In some embodiments, the muscle spasms can be selected from spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or 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 embodiments, the present disclosure provides a compound represented by formula (IIA): [ka] or a salt thereof, wherein: R 11 teeth, hydrogen, C 1~6 Alkyl, C2~6 Alkenyl, C 2~6 alkynyl, (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 , -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 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 15 each replaced as necessary), 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(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, C2~6 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 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 R 12 is R 15 cyclobutyl optionally substituted with one or more substituents independently selected from 17 ethyl optionally substituted with one or more substituents independently selected from R 15 are respectively, 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 C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 alkynyl, (each of which is a halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R16 , -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), optionally substituted with one or more substituents independently selected from are independently selected from R 16 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycles and 3- to 10-membered heterocycles C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from R 17 are 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.

[0008] In certain embodiments, the present disclosure provides a compound represented by formula (IIB): [ka] or a salt thereof, wherein: X 21 and X 22 is N and C(R 23 ) are independently selected from X 21 and X 22 at least one of is N, X 23 is selected from S and O; R 21 teeth, hydrogen, 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 , -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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10Carbocycles 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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, 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 23 teeth, 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 C optionally substituted with one or more substituents independently selected from -NO and -CN 1~3 Alkyl is selected from R 25 are respectively, 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 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 ) and —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 26 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6alkyl), C 3~10 optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 10-membered heterocycle, and C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from

[0009] In certain embodiments, the present disclosure provides a compound represented by formula (IIC): [ka] or a salt thereof, wherein: R 31 teeth, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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)R36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is 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)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 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 35 (each replaced as necessary) is selected from R 32 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6alkynyl, (each of which is a 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 a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is 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)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 3~10optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 (each replaced as necessary) is selected from R 35 are respectively, 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 a 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(R36 ) and —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 36 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycle and 3- to 10-membered heterocycle; and C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from

[0010] In certain embodiments, the present disclosure provides a method of treating activity-induced muscle damage, comprising administering to a subject in need thereof a compound represented by formula (I): [ka] or a salt thereof, wherein: A ring is R 1a 5-membered heteroaromatic ring optionally substituted with one or more substituents independently selected from X is N or CH; R 1 are respectively, 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 ) and -CN; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle,3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 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 5 (each replaced as necessary) are independently selected from R 2 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R 6 )2, -N(R 6 )C(O)R6 , -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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 , each replaced as necessary), C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each replaced as necessary), and -C(O)NR 7 R8 is selected from R 4 are halogen, -OR 6 , -SR 6 , -N(R 6 )2, -NO2, -CN and C 1~6 Alkyl (halogen, -OR 6 , -SR 6 , -N(R 6 ) optionally substituted with one or more substituents independently selected from -NO and -CN; R 5 are respectively, 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 a 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 ) and —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 6 are respectively, hydrogen; and C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycle and 3- to 10-membered heterocycle; and C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from R 7 is hydrogen and C 1~6 Alkyl (halogen, -OR 6 , -SR 6 , -N(R 6) optionally substituted with one or more substituents independently selected from -N, -NO, and -CN; R 8 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 , each replaced as necessary), C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 (each replaced as necessary) is selected from p is 0, 1 or 2.

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

[0012] In certain embodiments, the disclosure provides a method of treating a movement disorder, comprising administering to a subject in need thereof a compound or salt of any one of Formula (I), (IIA), (IIB) or (IIC). In certain embodiments, the disclosure provides a method of treating a disease disorder, 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 selected from the group consisting of 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 traumatic event, e.g., stroke, traumatic brain injury, or encephalopathy. 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 CMD, Fukuyama CMD, myo-oculo-encephalopathies (MEB), stiff spine syndrome, Ullrich CMD, Walker-Warburg syndrome (WWS), congenital myopathy, distal myopathy, endocrine myopathy, inflammatory myopathy, metabolic myopathy, myofibrillar myopathy (MFM), scapuloperoneal myopathy, and cardiomyopathy.

[0013] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of any one of formula (IIA), (IIB), or (IIC), or a pharmaceutically acceptable excipient. References

[0014] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference 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 invention are set forth with particularity 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 and accompanying drawings (also referred to herein as "Figure" and "FIG.") that illustrate illustrative embodiments, and in which the principles of the invention are utilized. [Brief explanation of the drawings]

[0016] [Figure 1] Figure 1 illustrates the hypercontraction-induced injury that precedes the inflammation and irreversible fibrosis that characterize the pathology of late-stage DMD.

[0017] [Figure 2] Figure 2 illustrates that N-benzyl-p-tolyl-sulfonamide (BTS), an inhibitor of fast-twitch skeletal muscle myosin, protects muscle from pathological muscle disorganization in embryos derived from a zebrafish model of DMD.

[0018] [Figure 3] FIG. 3 illustrates a comparison of creatine kinase, fast troponin, and slow troponin in healthy volunteers, patients with BMD, and patients with DMD.

[0019] [Figure 4] FIG. 4 illustrates a comparison of creatine kinase, fast troponin, and slow troponin in patients with BMD and patients with DMD with respect to age.

[0020] [Figure 5] FIG. 5 illustrates a comparison of creatine kinase, fast troponin, and slow troponin in patients with BMD and DMD with respect to disease progression.

[0021] [Figure 6]FIG. 6 illustrates a comparison of blood levels of creatine kinase, fast troponin, and myoglobin in subjects with BMD, LGMD, and McArdle's disease before and after exercise.

[0022] [Figure 7] FIG. 7 illustrates a comparison of blood levels of creatine kinase in subjects with BMD, LGMD, and McArdle's disease before and after exercise.

[0023] [Figure 8] FIG. 8 illustrates a comparison of myoglobin blood levels in subjects with BMD, LGMD, and McArdle's disease before and after exercise. DETAILED DESCRIPTION OF THE INVENTION

[0024] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions may now occur to those skilled in the art without departing from the invention. It should be understood that various modifications to the embodiments of the invention described herein may be used in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby. (Detailed explanation)

[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 muscle is primarily composed of two types of fibers: slow-twitch fibers (i.e., type I) and fast-twitch fibers (i.e., type II). Within each muscle, the two types of fibers are arranged in a mosaic-like arrangement, with differences in the composition of fiber types in different muscles and at different times during growth and development. Slow-twitch fibers have superior aerobic energy-generating capacity. Slow-twitch fibers have a slower contraction rate but are more fatigue-resistant. Slow-twitch fibers typically have higher concentrations of mitochondria and myoglobin than fast-twitch fibers and are surrounded by more capillaries than fast-twitch fibers. Due to lower myosin ATPase activity, slow-twitch fibers contract at a lower rate and generate lower power compared to fast-twitch fibers, but they can maintain contractile function for longer periods, for example, in stabilization, postural control, and endurance exercise.

[0027] Fast-twitch muscle fibers in humans are further divided into two major fiber types depending on the specific skeletal fast-twitch myosin they express (type IIA, type IIx / d). A third type of fast-twitch muscle fiber (type IIB) exists in other mammals but is rarely identified in human muscle. Fast-twitch muscle fibers have superior anaerobic energy-generating capacity and can generate large amounts of tension over short periods of time. Typically, fast-twitch muscle fibers have lower concentrations of mitochondria, myoglobin, and capillaries compared to slow-twitch muscle fibers, and therefore can fatigue more quickly. Fast-twitch muscle fibers generate the force required for power and resistance activities more quickly.

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

[0029] Contraction of skeletal muscle leads to muscle damage in subjects with neuromuscular diseases (e.g., DMD), and this damage appears to be more pronounced in fast-twitch fibers. In dystrophic mouse models, rapid muscle loss after lengthening injury is observed more frequently in fast-twitch fibers, primarily type II fibers, compared with slow-twitch fibers, primarily type I fibers. It has also been shown that the degree of rapid muscle loss and tissue damage in dystrophic mouse models is proportional to the peak muscle force generated during the lengthening injury. The excessive contraction-induced injury that precedes the inflammation and irreversible fibrosis that characterize the pathology of late-stage DMD is shown in Figure 1 [Revised figure: Claflin and Brooks, Am J Brooks, Physiol Cell, 2008]. Contraction-induced muscle damage in these patients could potentially be reduced by limiting the peak force generation in type II fibers and increasing reliance on healthier type I fibers. N-benzyl-p-tolyl-sulfonamide (BTS) is an inhibitor of skeletal fast fiber myosin and has been shown to protect muscle from pathological muscle disorganization in embryos from a zebrafish model of DMD, as shown in Figure 2 [Source: Li and Arner, PLoSONE, 2015].

[0030] Inhibitors of skeletal muscle myosin that are not selective for type II fibers can result in excessive and unwanted inhibition of skeletal muscle contraction, including respiratory function, 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 a treatment option for Becker muscular dystrophy (BMD), Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy (LGMD), McArdle disease, and other neuromuscular conditions. Targeted inhibition of type II skeletal muscle myosin can reduce skeletal muscle contraction while minimizing the impact on a subject's daily activities.

[0031] When healthy muscles are subjected to excessive, unaccustomed exercise, they exhibit pain and a persistent decrease in strength and range of motion. Proteins also leak into the circulation from damaged muscle fibers, including creatine kinase (CK), lactate dehydrogenase, and myoglobin. These biomarkers are not specific to fast- or slow-twitch muscle fibers and therefore do not provide detailed information regarding differences in the fiber response to injury. Troponin I (TNNI) is a component of the troponin complex that controls calcium-mediated initiation of muscle contraction. It differs in that different isoforms exist for each type of striated muscle: TNNI1 in slow skeletal muscle, TNNI2 in fast skeletal muscle, and TNNI3 in cardiac muscle. Using selective enzyme-linked immunosorbent assays (ELISAs), it has been demonstrated that TNNI2, but not TNNI1, is elevated in the circulation after injurious exercise, even under extreme conditions.

[0032] DMD and BMD are caused by the absence (DMD) or shortening (BMD) of dystrophin protein 5. Dystrophin provides a structural link between the actin cytoskeleton and the basement membrane via the dystrophin-glycoprotein complex. When dystrophin is absent or truncated, muscle contraction increases muscle stress and injury during normal use. Although DMD muscles are much more susceptible to injury than BMD or healthy muscles, fast-twitch fibers appear to be more susceptible than slow-twitch fibers, with young DMD patients showing histological evidence of destruction of fast-twitch fibers and early loss of type IIx fibers. Example 10 demonstrates the relative susceptibility of these fibers to leakage of muscle contents such as troponin, creatine kinase, or myoglobin. In some embodiments, the present disclosure provides selective inhibitors of fast-fiber skeletal muscle myosin as a treatment option for DMD, BMD, McArdle 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 claims, the singular forms "a," "an," and "the" include plural references 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, is meant to include groups containing x to y carbons in the chain. For example, the term "C 1~6 "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups including straight-chain alkyl and branched-chain alkyl groups containing from 1 to 6 carbons.

[0036] The term “C x~y alkenyl" and "C x~y "Alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.

[0037] The term "carbocycle," as used herein, refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 12-membered spiro-bicyclic rings, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocycle 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. Bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as valences permit. Bicyclic carbocycles further include spiro-bicyclic rings, such as spiropentane. Bicyclic carbocycles include any combination of ring sizes such as a 3-3 spiro ring system, a 4-4 spiro ring system, a 4-5 fused ring system, a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, a 5-7 fused ring system, a 6-7 fused ring system, a 5-8 fused ring system, and a 6-8 fused ring system. Exemplary carbocycles 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. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon, and contains 5 to 18 carbon atoms, where at least one ring in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel's rule. 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. Cycloalkyl can include monocyclic and polycyclic rings, such as 3-10 membered monocyclic rings, 5-12 membered bicyclic rings, 5-12 membered spiro bicyclic rings, and 5-12 membered bridged rings. In certain embodiments, cycloalkyls contain 3-10 carbon atoms. In other embodiments, cycloalkyls contain 5-7 carbon atoms. A cycloalkyl can be attached to the remainder 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, wherein each atom of the ring is carbon and at least one double bond exists 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. A cycloalkenyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0041] The term "halo," or alternatively "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, that is substituted with one or more halo groups, e.g., trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl group is optionally further substituted as described herein.

[0043] The term "heterocycle," 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. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spiro-bicyclic rings, and 5- to 12-membered bridged rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, as long as valences permit. 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 heterocycles 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 heterocycles further include spiro bicyclic rings, such as 5-12 membered spiro bicycles, for example, 2-oxa-6-azaspiro[3.3]heptane.

[0044] The term "heteroaryl" refers to a group derived from a 5-18-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 ring in the ring system is aromatic, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel's rule. Heteroaryl includes fused or bridged ring systems. The heteroatoms of a heteroaryl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[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-Hexahydrocycloocta[d]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- Oxoazepinyl, 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]pyri 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-cyclohexyl Examples include 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 containing 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 spiro-bicyclic rings, and 5- to 12-membered bridged rings. The heteroatoms of a heterocycloalkyl group are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. A heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl, e.g., any carbon or nitrogen atom of the heterocycloalkyl, if valence permits. 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 containing carbon atoms and at least one heteroatom, with at least one double bond 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, heterocycloalkenyls contain 5 to 7 ring atoms. Heterocycloalkenyls can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazolinone (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 moieties having substituents replacing a hydrogen on one or more carbon or substitutable heteroatoms (e.g., NH or NH) of a compound. It is understood that "substituted" or "substituted with" includes the implicit proviso that such substitution, subject to the allowed valencies of the replaced atom and substituent, results in a stable compound (i.e., a compound that does not spontaneously undergo modification, such as by rearrangement, cyclization, elimination, etc.). In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom (e.g., replacing the two hydrogen atoms on one carbon with oxo, imino, or thioxo groups). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0048] In some embodiments, substituents may include, for example, any of the following substituents described herein: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), -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 -ORc -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); where each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a is, if valence allows, 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(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 wherein each R b is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene, or alkynylene chain.

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

[0050] The phrases "parenteral administration" and "administered parenterally," as used herein, mean modes of administration other than enteral and local administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0051] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, 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 harmful 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and the like. 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) buffers, 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, and (21) other non-toxic, compatible substances used in pharmaceutical formulations.

[0053] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. 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 with inorganic and organic bases. 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. 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, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0054] As used herein, "treatment" or "treating" refers to an approach for obtaining a beneficial or desired result with respect to a disease, disorder, or medical condition, including, but not limited to, therapeutic benefit and / or prophylactic benefit. Therapeutic benefit can include, for example, eradication or alleviation of the underlying disorder being treated. Therapeutic benefit can also include, for example, eradication or alleviation of one or more physiological symptoms associated with the underlying disorder, such that the subject experiences improvement, even though the subject may still suffer from the underlying disorder. In certain embodiments, compositions are administered for prophylactic benefit to subjects at risk of developing a particular disease or who complain of one or more physical symptoms of a disease, even if the disease may not have been diagnosed. Treatment by administration of the compounds 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 set forth in formula (IIA), (IIB), or (IIC).

[0056] In one embodiment, the compound represented by formula (IIA): [ka] or a salt thereof, wherein: R 11 teeth, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (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 , -C(O)OR 16 , -OC(O)R16 , -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 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 15 each replaced as necessary), 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(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 is R 17 and optionally substituted with one or more substituents independently selected from C 3~10Carbocyclic 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 R 12 is R 15 cyclobutyl optionally substituted with one or more substituents independently selected from 17 ethyl optionally substituted with one or more substituents independently selected from R 15 are respectively, 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 C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 alkynyl, (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 ) and —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 16 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycles and 3- to 10-membered heterocycles C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from R 17 are 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.

[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 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.

[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 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 3~10 Carbocyclic ring, C 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.

[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 1~3optionally substituted with one or more substituents independently selected from alkyl (optionally substituted with one or more substituents independently selected from halogen);

[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, —OCF 3 , —OCHF 2 , and —CF 3 .

[0064] In certain embodiments, for a compound or salt of Formula (IIA), R 11 teeth, [ka] is selected from.

[0065] In certain embodiments, for a compound or salt of Formula (IIA), R 11 teeth, [ka] is selected from.

[0066] In certain embodiments, for a compound or salt of Formula (IIA), R 12 teeth, 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 C optionally substituted with one or more substituents independently selected from -NO and -CN 1~3 Alkyl and cyclobutyl optionally substituted with one or more substituents independently selected from:

[0067] 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 , ethyl optionally substituted with -NO2 and -CN.

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

[0069] In certain embodiments, for a 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 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 ) and —CN).

[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 (halogen, -OR 16 , -N(R 16 ) optionally substituted with one or more substituents independently selected from —NO 2 , ═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 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, each of which is selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, and —OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 It is optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles.

[0074] In certain embodiments, for a compound or salt of Formula (IIA), R 16 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl.

[0075] In certain embodiments, for a compound or salt of Formula (IIA), R 16 is C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl.

[0076] In certain embodiments, for a compound or salt of Formula (IIA), R 16 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 C optionally substituted with one or more substituents independently selected from alkyl and haloalkyl 3~10 It is a carbocyclic ring.

[0077] In certain embodiments, for a compound or salt of Formula (IIA), R 16 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 is a 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl and haloalkyl.

[0078] In certain embodiments, for a compound or salt of Formula (IIA), R 17 is 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 a halogen.

[0080] In one embodiment, the compound represented by formula (IIA): [ka] or a salt thereof, wherein: R 11 teeth, hydrogen, C 1~6 Alkyl (halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -NO2, =O, =S, =N(R 16 ), -CN, C 3~10 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 15 each substituted as necessary); 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 , -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 (each replaced as necessary) is selected from R 12 is R 15 cyclobutyl optionally substituted with one or more substituents independently selected from 17 ethyl optionally substituted with one or more substituents independently selected from R 15 are respectively, Halogen, -OR 16, -SR 16 , -N(R 16 )2, -NO2, =O, =S, =N(R 16 ) and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 alkynyl, (each of which is a halogen, -OR 16 , -SR 16 , -N(R 16 )2, -C(O)R 16 , -NO2, =O, =S, =N(R 16 ) and —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 16 are respectively, hydrogen, Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), 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 3~3 Carbocycles and 5- to 9-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from R 17are each independently selected from halogen, —OH, —OMe, —SH, —NH 2 , —NO 2 , ═O, ═S, and —CN.

[0081] In one embodiment, the compound represented by formula (IIA): [ka] or a salt thereof, wherein: R 11 teeth, C 1~6 Alkyl (halogen, -OR 16 , -CN, C 3~10 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 15 each substituted as necessary); and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 16 , -NO2, -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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 15 (each replaced as necessary) is selected from R 12 is selected from cyclobutyl and ethyl; R 15 are respectively, Halogen, -OR 16 and -CN; and Halogen, -OR 16 , -SR 16 and C optionally substituted with one or more substituents independently selected from -CN. 1~3 Alkyl are independently selected from R16 are respectively, hydrogen, Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), 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 3~6 Carbocycles and 5- to 9-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from

[0082] In certain embodiments, the compound or salt of Formula (IIA) is [ka] and any one of salts thereof.

[0083] In certain embodiments, the compound or salt of Formula (IIA) is [ka] and any one of salts thereof.

[0084] In one embodiment, the compound represented by formula (IIB): [ka] or a salt thereof, wherein: X 21 and X 22 is N and C(R 23 ) are independently selected from X 21 and X 22 at least one of is N, X 23 is selected from S and O; R 21 teeth, hydrogen, 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 , -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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, 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 23 teeth, 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 C optionally substituted with one or more substituents independently selected from -NO and -CN 1~3 Alkyl is selected from R 25 are respectively, 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 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(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 —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 26 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycle, a 3- to 10-membered heterocycle, and C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from

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

[0086] In certain embodiments, for a compound or salt of Formula (IIB), R 21 is replaced as necessary by C 1~6It is selected from alkyl, optionally substituted carbocycle and optionally substituted heteroaryl.

[0087] In certain embodiments, for a compound or salt of Formula (IIB), R 21 is replaced as necessary by C 1~3 Alkyl, optionally substituted C 3~6 selected from carbocycle and optionally substituted 5- or 6-membered heteroaryl; C 1~3 Substituents on alkyl are 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, C 3~6 Substituents on the carbocycle and 5- or 6-membered heteroaryl are 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 (one or more R 25 and optionally substituted with

[0088] In certain embodiments, for a compound or salt of Formula (IIB), R 21 is replaced as necessary by C 1~3 Alkyl, optionally substituted C 3~6 selected from carbocycle and optionally substituted 5- or 6-membered heteroaryl; C 1~3 Alkyl, C 3~6 Substituents on the carbocycle and 6-membered heteroaryl include halogen, -OR 26 , -N(R 26)2, —NO2 and —CN.

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

[0090] In certain embodiments, for a compound or salt of Formula (IIB), R 21 is -CH3 [ka] is selected from.

[0091] In certain embodiments, for a compound or salt of Formula (IIB), R 22 teeth, 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 and 3- to 10-membered heterocyclic rings (C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 C optionally substituted with one or more substituents independently selected from 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 and 3- to 10-membered heterocyclic rings (C 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 C optionally substituted with one or more substituents independently selected from 3~6 carbocyclic ring is selected from.

[0092] In certain embodiments, for a compound or salt of Formula (IIB), R 22 teeth, Halogen and phenyl (one or more R 25 C optionally substituted with one or more substituents independently selected from 1~3 alkyl; and Halogen, C 1~6 Alkyl, C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (C 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 C optionally substituted with one or more substituents independently selected from 3~6 carbocyclic ring is selected from.

[0093] In certain embodiments, for a compound or salt of Formula (IIB), R 22 teeth, C 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 alkyl; and Halogen, C 1~6 Alkyl, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 3~6 carbocyclic ring is selected from.

[0094] In certain embodiments, for a compound or salt of Formula (IIB), R 22 is C 1~3 Alkyl and C 3~6 carbocycles (optionally substituted with one or more halogens).

[0095] In certain embodiments, for a compound or salt of Formula (IIB), R 22 is -CH2CH3 [ka] is selected from.

[0096] In certain embodiments, for a compound or salt of Formula (IIB), R 23 is selected from hydrogen, —OMe, —OH, —NH 2 , —COOH, —NO 2 and —CN.

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

[0098] In certain embodiments, for a 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 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.

[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 (halogen, -OR 26 , -N(R 26 ) optionally substituted with one or more substituents independently selected from —NO 2 , ═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, each of which is selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, and —OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 It is optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles.

[0103] In certain embodiments, for a compound or salt of Formula (IIB), R 26 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl.

[0104] In certain embodiments, for a compound or salt of Formula (IIB), R 26 is C 3~10 Carbocycles and 3- to 10-membered heterocycles are selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, and -OC, respectively. 1~6 Alkyl, -SC 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 It is optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl.

[0105] In certain embodiments, for a compound or salt of Formula (IIB), R 26 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 C optionally substituted with one or more substituents independently selected from alkyl and haloalkyl 3~10 It is a carbocyclic ring.

[0106] In certain embodiments, for a compound or salt of Formula (IIB), R 26 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 is a 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl and haloalkyl.

[0107] In one embodiment, the compound represented by formula (IIB): [ka] or a salt thereof, wherein: X 21 and X 22 is N and C(R 23 ) are independently selected from X 21 and X 22 at least one of is N, X 23 is selected from S and O; R 21 is replaced as necessary by C 1~3 selected from alkyl, optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl; C 1~3Substituents on alkyl are 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 the phenyl 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 (one or more R 25 , optionally replaced by R 22 teeth, 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 and 3- to 10-membered heterocyclic rings (C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 C optionally substituted with one or more substituents independently selected from 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)R26 , -NO2, -CN, C 1~6 Alkyl, C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (C 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 C optionally substituted with one or more substituents independently selected from 3~6 carbocyclic ring is selected from R 23 is selected from hydrogen, -OMe, -OH, -NH2, -COOH, -NO2 and -CN; R 25 are halogen, -OR 26 , -N(R 26 )2, =O, -CN and C 1~3 Alkyl (halogen, -OR 26 , -N(R 26 ) optionally substituted with one or more substituents independently selected from —NO, ═O, and —CN; R 26 are hydrogen and C 1~6 Alkyl, C 3~10 and a 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —CN, —OH, —SH, —NO2, and —NH2.

[0108] In one embodiment, the compound represented by formula (IIB): [ka] or a salt thereof, wherein: X 21 and X 22 is N and C(R 23 ) are independently selected from X 21 and X 22 at least one of is N, X 23 is selected from S and O; R 21 is C 1~3 and optionally substituted 6-membered heteroaryl, wherein the substituents on the phenyl and 6-membered heteroaryl are selected from halogen, -OR 26 , -N(R 26 )2, -NO2 and -CN; R 22 teeth, C 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 alkyl; and Halogen, C 1~6 Alkyl, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 3~6 carbocyclic ring is selected from R 23 is hydrogen, R 25 are halogens, -OH, -NH2, =O, -CN and C, respectively. 1~3 alkyl (optionally substituted with one or more substituents independently selected from halogen, —OH, —NH, —NO, ═O, and —CN); R 26 are hydrogen and C 1~6 alkyl (optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2 and -NH2).

[0109] In certain embodiments, the compound or salt of Formula (IIB) is [ka] and any one of salts thereof.

[0110] In one embodiment, the compound represented by formula (IIC): [ka] or a salt thereof, wherein: R 31 teeth, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is 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(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 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 35 (each replaced as necessary) is selected from R 32 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 a carbocycle and a 3- to 10-membered heterocycle, 3~10Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is 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)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 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 (each replaced as necessary) is selected from R 35 are respectively, 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 a 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), optionally substituted with one or more substituents independently selected from are independently selected from R 36 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycle and 3- to 10-membered heterocycle; and C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively)1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from

[0111] In certain embodiments, for a compound or salt of Formula (IIC), R 31 is replaced as necessary by C 1~6 It is selected from alkyl, optionally substituted aryl and optionally substituted heteroaryl.

[0112] In certain embodiments, for a compound or salt of Formula (IIC), R 31 is replaced as necessary by C 1~3 selected from alkyl, optionally substituted phenyl and optionally substituted 5- or 6-membered heteroaryl; C 1~3 Substituents on 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, and the substituents on the phenyl and 5- or 6-membered heteroaryl are selected from 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 and optionally substituted with

[0113] In certain embodiments, for a compound or salt of Formula (IIC), R 31 is C 1~3 and optionally substituted 6-membered heteroaryl, wherein 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 C 1~3 It is selected from alkyl, substituted phenyl and optionally substituted pyridyl, the substituents on the phenyl and pyridyl being selected from halogen, -OH, -NH2, -NO2 and -CN.

[0115] In certain embodiments, for a compound or salt of Formula (IIC), R 32 teeth, 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 and 3- to 10-membered heterocyclic rings (C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 C optionally substituted with one or more substituents independently selected from 1~6 alkyl; 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 and 3- to 10-membered heterocyclic rings (C 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 C optionally substituted with one or more substituents independently selected from 3~6 carbocyclic ring is selected from.

[0116] In certain embodiments, for a compound or salt of Formula (IIC), R 32 teeth, Halogen and phenyl (one or more R 35 C optionally substituted with one or more substituents independently selected from 1~3 alkyl; and Halogen, C 1~6 Alkyl, C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (C 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 C optionally substituted with one or more substituents independently selected from 3~6 carbocyclic ring is selected from.

[0117] In certain embodiments, for a compound or salt of Formula (IIC), R 32 is 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 It is alkyl.

[0118] In certain embodiments, for a compound or salt of Formula (IIC), R 32is C 1~3 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 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)OR36 , -OC(O)R 36 , -S(O)R 36 , -S(O)2R 36 , -NO2, =O, =S, =N(R 36 ) and —CN.

[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 (halogen, -OR 36 , -N(R 36 ) optionally substituted with one or more substituents independently selected from —NO 2 , ═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 selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, and —OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 It is optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles.

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

[0126] In certain embodiments, for a compound or salt of Formula (IIC), R 36 is C 3~10 Carbocycles and 3- to 10-membered heterocycles are selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, and -OC, respectively. 1~6 Alkyl, -SC 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 It is optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl.

[0127] In certain embodiments, for a compound or salt of Formula (IIC), R 36 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 C optionally substituted with one or more substituents independently selected from alkyl and haloalkyl 3~10 It is a carbocyclic ring.

[0128] In certain embodiments, for a compound or salt of Formula (IIC), R 36 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 It is 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 [ka] or a salt thereof.

[0130] In some embodiments, the compound represented by formula (III): [ka] or a salt thereof, wherein: R 41 is selected from phenyl and pyridyl, which are each selected from halogen, —OH, —SH, —NH, —CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxides and C 1~6 optionally substituted with one or more substituents independently selected from haloalkoxides; R 42 are halogens, -OH, -SH, -NH2, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxides and C 1~6 is a 5- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from haloalkoxides.

[0131] In certain embodiments, the compound or salt of Formula (III) is [ka] [ka] and any one of salts thereof.

[0132] In certain embodiments, the compound or salt of Formula (III) is [ka] [ka] and any one of salts thereof.

[0133] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in Z- or E-forms (or cis- or trans-forms). Additionally, 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] "Tautomer" refers to a molecule capable of proton shift from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In environments where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include: [ka] Examples include:

[0135] The compounds disclosed herein may, in some embodiments, be, for example, 2 H, 3 H, 11 C. 13 C and / or 14The compound is used in different enriched isotopic forms, enriched in C content. In a specific embodiment, 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, compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds in which hydrogen is replaced by deuterium or tritium, or carbon is replaced by 13 C- or 14 Compounds having the present structures except for the substitution of C-enriched carbons are within the scope of this disclosure.

[0137] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, 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 All isotopic substitutions with I are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0138] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 is replaced with an H atom. 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 described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery. 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 amenable to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Many deuterium-containing reagents and components 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, pharmaceutically acceptable salts of these compounds, and active metabolites, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

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

[0143] The compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms in some cases. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, as well as appropriate 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 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 may 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. Furthermore, the compounds described herein can exist in unsolvated forms as well as 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, a compound or a salt of a 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 pharmaceuticals of the present disclosure under physiological conditions. One method for creating a prodrug is to include one or more selected moieties that undergo hydrolysis under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, such as a specific 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] Prodrug forms of the compounds described herein that are metabolized in vivo to produce the compounds as described herein are included within the scope of the claims. In some cases, some of the compounds described herein may 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 some situations. For example, a prodrug may be available by oral administration, whereas the parent drug is not. Prodrugs can help enhance the cellular permeability of a compound relative to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs can be designed as reversible drug derivatives to enhance drug transport to site-specific tissues or to be used as modifiers to increase drug retention within cells.

[0148] In some embodiments, the design of the prodrug increases the lipophilicity of the pharmaceutical. In some embodiments, the design of the prodrug increases the effective water solubility. For example, see 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 ACS Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (all such disclosures are incorporated herein by reference). According to another embodiment, the present disclosure provides a method for producing 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 chemistry variants and methodologies useful for synthesizing 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 administering the compounds or salts of Formula (I), (IIA), (IIB), (IIC), or (III) discussed herein can be used to inhibit muscle myosin II. In some embodiments, the compounds and their salts can be used to treat activity-induced muscle damage. In some embodiments, the compounds can be used to treat neuromuscular conditions and movement disorders (such as spasticity).

[0151] The method of administering the compound or salt 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, tendonitis and carpal tunnel syndrome.Examples of movement disorders include, but are not limited to, muscle spasticity disorders, or spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury or traumatic events (such as 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 myosin II, skeletal troponin C, skeletal troponin I, skeletal tropomyosin, skeletal troponin T, skeletal regulatory light chain, skeletal myosin-binding protein C, or skeletal actin. In some embodiments, the neuromuscular condition and movement disorder is selected from muscular dystrophies and myopathies. In some embodiments, muscular dystrophies are diseases in which genetic abnormalities (mutations) interfere with the production of proteins necessary to form healthy muscles, 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, the congenital muscular dystrophy (CMD) is selected from Bethlem CMD, Fukuyama CMD, muscle-eye-brain disease (MEB), stiff spine syndrome, Ullrich CMD, and Walker-Warburg syndrome (WWS). In some embodiments, the myopathy is a muscle disease not caused by neuropathy. Myopathy causes muscles to weaken or shrink (atrophy).In some embodiments, the myopathy is selected from congenital myopathy, distal myopathy, endocrine myopathy, inflammatory myopathy, metabolic myopathy, myofibrillar myopathy (MFM), scapuloperoneal myopathy, and cardiomyopathies. In some embodiments, the congenital myopathy is selected from cap myopathy, centronuclear myopathy, congenital myopathy with fiber type imbalance, core myopathy, central core disease, multiminicore myopathy, myosin storage myopathy, myotubular myopathy, and nemaline myopathy. In some embodiments, the distal myopathy is selected from gne myopathy / Nonaka myopathy / hereditary inclusion body myopathy (HIBM), Laing distal myopathy, Markesbery-Griggs late-onset distal myopathy, Miyoshi myopathy, Udd myopathy / tibial muscular dystrophy, VCP myopathy / IBMPFD, distal vocal cord and pharyngeal myopathy, and Welander 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 (Her 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 takotsubo cardiomyopathy, myocarditis, eosinophilic myocarditis, and ischemic cardiomyopathy. In some embodiments, the extrinsic cardiomyopathy is selected from metabolic cardiomyopathy, endomyocardial cardiomyopathy, endocrine cardiomyopathy, and cardiofacial cardiomyopathy. In some embodiments, the metabolic cardiomyopathy is selected from Fabry disease and hemochromatosis. In some embodiments, the endocrine cardiomyopathy is selected from endomyocardial fibrosis and hypereosinophilic syndrome. In some embodiments, the endocrine cardiomyopathy is selected from diabetes mellitus, hyperthyroidism, and acromegaly. In some embodiments, the cardiofacial cardiomyopathy is Noonan syndrome.

[0152] Disclosed herein, in some embodiments, are methods of treating neuromuscular and movement disorders by administering a compound or salt of Formula (I), (IIA), (IIB), or (IIC). In some embodiments, a compound or salt of Formula (I); [ka] Disclosed herein are methods for treating neuromuscular and movement disorders by administration of a compound of formula (I) or a salt thereof, wherein: A ring is R 1 a 5-membered heteroaromatic ring optionally substituted with one or more substituents independently selected from X is N or CH; R 1 are respectively, 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 a 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 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 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 5 (each replaced as necessary) are independently selected from R 2 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5, each replaced as necessary), C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each replaced as necessary), and -C(O)NR 7 R 8 is selected from R 4 are halogen, -OR 6 , -SR 6 , -N(R 6 )2, -NO2, -CN and C 1~6 Alkyl (halogen, -OR 6 , -SR 6 , -N(R 6 ) optionally substituted with one or more substituents independently selected from -NO and -CN; R 5 are respectively, 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 a 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), optionally substituted with one or more substituents independently selected from are independently selected from R 6 are respectively, hydrogen; and C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycle and 3- to 10-membered heterocycle; and C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from R 7 is hydrogen and C 1~6 Alkyl (halogen, -OR 6 , -SR 6 , -N(R 6 ) optionally substituted with one or more substituents independently selected from -N, -NO, and -CN; R 8 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 , each replaced as necessary), C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 (each replaced as necessary) is selected from p is 0, 1 or 2.

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

[0154] In certain embodiments, for compounds or salts of Formula (I), the A ring is 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 a 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 selected from R 1 and optionally substituted with one or more substituents independently selected from:

[0156] In certain embodiments, for a compound or salt of Formula (I), the A ring is selected from thiophene, oxadiazole, oxazole, thiadiazole, triazole, pyrazole, and thiazole, each of which is selected from R 1 and optionally substituted with one or more substituents independently selected from:

[0157] In certain embodiments, for a compound or salt of Formula (I), the A ring is: [ka] are selected from, each of which is R 1 and optionally substituted with one or more substituents independently selected from:

[0158] In certain embodiments, for a compound or salt of Formula (I), the A ring is: [ka] are selected from, each of which is R 1 and optionally substituted with one or more substituents independently selected from:

[0159] In certain embodiments, for a compound or salt of Formula (I), the A ring is: [ka] is selected from.

[0160] In certain embodiments, for a compound or salt of Formula (I), the A ring is: [ka] is selected from.

[0161] In certain embodiments, for compounds or salts of Formula (I), X is N. In certain embodiments, for compounds or salts of Formula (I), X is CH.

[0162] In certain embodiments, for a compound or salt of Formula (I), R 1 teeth, Halogen, -OR 6 , -CN, C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 C optionally substituted with one or more substituents independently selected from 1~6 alkyl; and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -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, C 3~10Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 (each replaced as necessary) is selected from.

[0163] In certain embodiments, for a compound or salt of Formula (I), R 1 teeth, Halogen, -OR 6 and C optionally substituted with one or more substituents independently selected from -CN. 1~6 alkyl; and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , - and C 1~6 Alkyl (one or more R 5 and optionally substituted with one or more substituents independently selected from is selected from.

[0164] In certain embodiments, for a compound or salt of Formula (I), R 1 teeth, C 1~6 alkyl; and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , - and C 1~6 Alkyl (one or more R 5 and optionally substituted with one or more substituents independently selected from is selected from.

[0165] In certain embodiments, for a compound or salt of Formula (I), R 1 is halogen or -OR 6 C, substituted as needed 1~6 Alkyl; and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , - and C 1~6 Alkyl (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 and 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 a compound or salt of Formula (I), R 2 is halogen, -OR 6 , -SR 6 , -N(R 6 )2, -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, wherein C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 are substituted as necessary.

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

[0173] In certain embodiments, for a compound or salt of Formula (I), R 2 is C 3~10 a carbocycle and a 3- to 10-membered heterocycle, each of which is selected from halogen, -OR 6 , -SR 6 , -N(R 6 )2, 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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 are substituted as necessary.

[0174] In certain embodiments, for a 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 alkynyl, each of which is 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.

[0183] In certain embodiments, for a compound or salt of Formula (I), R 5 is halogen, -OR 6 , -N(R 6 )2, =O, -CN and C 1~3 Alkyl (halogen, -OR 6 , -N(R 6 ) optionally substituted with one or more substituents independently selected from —NO 2 , ═O, and —CN.

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

[0185] In certain embodiments, for a 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 selected from halogen, —CN, —OH, —SH, —NO 2 , —NH 2 , ═O, ═S, and —OC 1~6Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 It is optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles.

[0186] In certain embodiments, for a compound or salt of Formula (I), R 6 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl.

[0187] In certain embodiments, for a compound or salt of Formula (I), R 6 teeth, C 3~10 Carbocycles and 3- to 10-membered heterocycles are selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, and -OC, respectively. 1~6 Alkyl, -SC 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 It is optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl.

[0188] In certain embodiments, for a compound or salt of Formula (I), R 6 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 C 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 a compound or salt of Formula (I), R 6 are halogens, -CN, -OH, -SH, -NO2, -NH2, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 and phenyl optionally substituted with one or more substituents independently selected from alkyl and haloalkyl.

[0190] In certain embodiments, for a 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 a compound or salt of Formula (I), R 6 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 is a 3- to 10-membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl and haloalkyl.

[0192] In certain embodiments, for a compound or salt of Formula (I), R 6 are halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 It is a 5-6 membered heterocyclic ring optionally substituted with one or more substituents independently selected from alkyl and haloalkyl.

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

[0194] In certain embodiments, for a 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 a compound or salt of Formula (I), R 7 is hydrogen and C 1~3 alkyl.

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

[0197] In certain embodiments, for a compound or salt of Formula (I), R 8 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a halogen, -OR 6 , -SR6 , -N(R 6 )2, -CN, C 3~10 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each substituted as necessary); and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -SR 6 , -N(R 6 )2, -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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 (each replaced as necessary) is selected from.

[0198] In certain embodiments, for a compound or salt of Formula (I), R 8 is halogen, -OR 6 , -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, wherein C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 are substituted as necessary.

[0199] In certain embodiments, for a 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 are optionally substituted with one or more of 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 C 3~10 a carbocycle and a 3- to 10-membered heterocycle, each of which is selected from halogen, -OR 6 , -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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 are substituted as necessary.

[0201] In certain embodiments, for a compound or salt of Formula (I), R 8 is C 3~6 a carbocycle and a 5- to 9-membered heterocycle, each of which is selected from halogen, -OR 6 , -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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 are substituted as necessary.

[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 may be selected from one or more R 5 will be substituted as necessary.

[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 selected from one or more R 5 will be substituted as necessary.

[0204] 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, each of which is optionally substituted with one or more of halogen, —CN, —OH, —OCH, —CF, —CHF, or —CHF.

[0205] In some embodiments, a compound or salt of formula (I); [ka] Disclosed herein are methods for treating neuromuscular and movement disorders by administration of a compound of formula (I) or a salt thereof, wherein: The A ring is selected from thiophene, oxadiazole, thiadiazole, thiazole, oxazole, pyrazole, imidazole, triazole, pyrrole, tetrazole, and furan, each of which is selected from R 1 and optionally substituted with one or more substituents independently selected from X is N or CH; R 1 are respectively, Halogen, -OR 6 , -CN, C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 C optionally substituted with one or more substituents independently selected from 1~6 alkyl; and C 3~10Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 (each replaced as necessary) are independently selected from R 2 teeth, Halogen, -OR 6 , -SR 6 , -N(R 6 )2, -CN, C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 C optionally substituted with one or more substituents independently selected from 1~6 alkyl; C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -SR 6 , -N(R 6 )2, 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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each substituted as necessary); and -C(O)NR 7 R 8 is selected from R 4 are halogens, -OH, -OMe, -SH, -NH2, -NO2, -CN and C, respectively. 1~6alkyl (optionally substituted with one or more substituents independently selected from halogen, —OH, —OMe, —SH, —N(H)2, —NO2, and —CN); R 5 are respectively, Halogen, -OR 6 , -SR 6 , -N(R 6 )2, -NO2, =O, =S and -CN; and Halogen, -OR 6 , -SR 6 , -N(R 6 )2, C optionally substituted with one or more substituents independently selected from ═O, ═S, and —CN 1~3 Alkyl are independently selected from R 6 are respectively, hydrogen, Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), 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 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from R 7is hydrogen and C 1~6 alkyl (optionally substituted with one or more substituents independently selected from halogen, —OH, —SH, —NH, —NO, and —CN); R 8 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a halogen, -OR 6 , -SR 6 , -N(R 6 )2, -CN, C 3~10 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each substituted as necessary); and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -SR 6 , -N(R 6 )2, -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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 (each replaced as necessary) is selected from p is 0.

[0206] In some embodiments, a compound or salt of formula (I); [ka] Disclosed herein are methods for treating neuromuscular and movement disorders by administration of a compound of formula (I) or a salt thereof, wherein: The A ring is [ka] is selected from X is N or CH; R 1 are respectively, Halogen, -OR 6 and C optionally substituted with one or more substituents independently selected from -CN. 1~6 alkyl; and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , - and C 1~6 Alkyl (one or more R 5 and optionally substituted with one or more substituents independently selected from are independently selected from 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 1~6 Haloalkyl, C 1~6 Alkoxide, C 1~6 Haloalkoxide, 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 R 4 are each independently selected from halogen, —OH, —OMe, —SH, —NH, —NO, and —CN; R 5 are halogens, -OH, -OMe, -NH2, =O, -CN and C, respectively. 1~3alkyl (optionally substituted with one or more substituents independently selected from halogen, —OH, —OMe, —NH, —NO, ═O, and —CN); R 6 are respectively, hydrogen, Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl; Halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -N(C 1~6 alkyl)2, -NH(C 1~6 alkyl), C 1~6 C optionally substituted with one or more substituents independently selected from alkyl and haloalkyl 3~10 carbocyclic ring are independently selected from R 7 is hydrogen and C 1~3 alkyl (optionally substituted with one or more substituents independently selected from halogen, —OH, —SH, —NH, —NO, and —CN); R 8 teeth, 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, wherein phenyl or pyridyl is optionally substituted with halogen, —CH3, —OH, —OCH3, —CF3, —CHF2, or —CH2F; and 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 of halogen, —CN, —OH, —OCH3, —CF3, —CHF2, or —CH2F; is selected from p is 0.

[0207] In certain embodiments, the compound or salt of Formula (I) is [ka] [ka] [ka] [ka] [ka] and any one of salts thereof.

[0208] In certain embodiments, the compound or salt of Formula (I) is [ka] [ka] [ka] [ka] and any one of salts thereof.

[0209] Methods for treating neuromuscular and movement disorders by reducing skeletal muscle contraction are presented herein. Treating subjects with neuromuscular and movement disorders with a selective fast-twitch skeletal (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 contractions, resulting in less muscle damage. Furthermore, the disclosed method can reduce muscle damage while minimizing the impact on physical function in the subject. Preservation of function can occur by both limiting the level of damage caused by muscle force generation in type II fibers and increasing reliance on healthier type I fibers. The reduction of skeletal muscle contraction or uncoordinated muscle contraction can be reduced by inhibiting skeletal myosin II. In certain embodiments, the skeletal myosin II inhibitor is a compound or salt of Formula (I), (IIA), (IIB), or (IIC) disclosed herein.

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

[0211] In some aspects, methods of treating neuromuscular conditions or movement disorders 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, hi 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 the 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 ability and daily routine.The treatment options and dosage of the skeletal muscle contraction inhibitor discussed herein can be individualized for each subject, so that its ADL and habitual physical activity remain unchanged.

[0213] In some aspects, a method for 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. 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 subject's pre-treatment skeletal muscle contraction capacity. 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 subject's pre-treatment skeletal muscle contraction capacity. In some cases, a 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 subject's pre-treatment skeletal muscle contraction capacity. In certain embodiments, a 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 subject's pre-treatment skeletal muscle contraction capacity.

[0214] In some aspects, a method for treating a neuromuscular condition or movement disorder can 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 can 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 can be administered in an amount less than the amount required to reduce type I skeletal muscle contraction by 20% relative to the subject's type I skeletal muscle contraction capacity before treatment. The inhibitor of type I skeletal muscle contraction can be administered in an amount that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the subject's type I skeletal muscle contraction capacity before 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 subject's pre-treatment type I skeletal muscle contraction capacity. 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 subject's pre-treatment type I skeletal muscle contraction capacity.

[0215] In some aspects, a method for 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 capacity. 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 capacity. In some cases, the inhibitor may be administered in an amount that reduces type II skeletal muscle contraction by less than 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or even less than 90% relative to the subject's pre-treatment type II skeletal muscle contraction capacity. 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 capacity.

[0216] In some aspects, methods of treating contraction-induced injury in skeletal muscle fibers can include administering a compound or salt of Formula (I), (IIA), (IIB), or (IIC) to inhibit skeletal muscle contraction and / or skeletal myosin II. In certain embodiments, the inhibitor does not appreciably inhibit cardiac muscle contraction.

[0217] In some aspects, a method of treating metabolic myopathy, such as McArdle Syndrome, can 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 fiber results from involuntary skeletal muscle contractions. The involuntary skeletal muscle contractions may be associated with a neuromuscular condition or a disease related to spasticity. In certain embodiments, the contraction-induced injury in the skeletal muscle fiber results 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 may also include measurements of muscle inflammation, such as edema. The level of a biomarker described herein may increase after administration of the inhibitor relative to the pre-treatment level of the biomarker. Alternatively, the level of a biomarker may decrease after administration of the inhibitor relative to the pre-treatment level of the biomarker. Modulation of one or more biomarkers with the inhibitors described herein can be indicative of treatment of a neuromuscular condition (eg, those described herein).

[0220] Since the level of CK in a subject increases when the subject is active compared to when the subject is inactive (e.g., sleeping), CK is a potential measurement indicator for assessing skeletal muscle breakdown caused by skeletal muscle contraction.In some embodiments, a compound or salt of formula (I), (IIA), (IIB) or (IIC) can be administered to a subject before light, moderate or vigorous activity to reduce or prevent skeletal muscle breakdown resulting from activity.Moderate to vigorous activity may depend on the subject's ability and may include physical exercise that increases heart rate by at least 20% or more (e.g., about 50% or more) compared to the subject's resting heart rate.Examples of moderate to vigorous activity include walking, running, weightlifting, cycling, swimming, hiking, etc.

[0221] In certain embodiments, a compound or salt of Formula (I), (IIA), (IIB), or (IIC) is administered before, during, or after moderate or vigorous activity to reduce or prevent skeletal muscle breakdown resulting from the activity. A compound or salt of Formula (I), (IIA), (IIB), or (IIC) can reduce CK levels in a subject relative to an untreated subject engaging in the same activity. CK levels can be measured in the subject's peripheral blood during or after the activity. Administration of an inhibitor described herein can reduce CK levels in an active subject by 5% to 90% relative to an untreated subject engaging in the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from the activity. Administration of an inhibitor described herein can adjust CK levels by about 5% to about 90% relative to an untreated subject engaging in the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from the activity. Administration of the inhibitors described herein can reduce the CK levels 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 regulate the CK levels by up to about 90% relative to an untreated subject performing the same activity.Administration of an inhibitor described herein may increase CK levels 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 3 ...90%, about 35% to about 90%, about 35% to about 90%, about 35% to about 90%, about 35% to about 90%, about 35% to about 90%, about 35% to about 90%, about 35% to about 90%, about 35% to about 90%, about 35% to about 90%, about 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%, thereby reducing or preventing skeletal muscle breakdown resulting from the activity. Administration of the inhibitors described herein may modulate the CK levels by about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% relative to an untreated subject engaging in the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from the activity.

[0222] Administration of a compound or salt of Formula (I), (IIA), (IIB), or (IIC) to a subject may modulate the level of an inflammatory marker (e.g., reduce the level of one or more inflammatory markers) relative to an untreated subject or a subject prior to treatment. The level of the inflammatory marker may be measured in the subject's peripheral blood. Examples of inflammatory markers may include, but are not limited to, IL-1, IL-6, and TNF-α. The inflammatory marker may 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 may increase after administration of the inhibitor relative to the subject's pre-treatment level of the inflammatory marker. Alternatively, the level of the inflammatory marker in the peripheral blood may decrease after administration of the inhibitor relative to the subject's pre-treatment level of the inflammatory marker. Administration of an inhibitor described herein may modulate the level of the inflammatory marker by 5% to 90% relative to the subject's pre-treatment level of the inflammatory marker. In some cases, the inflammatory marker level may be modulated by about 5% to about 90% relative to the subject's pre-treatment level of the inflammatory marker. In some cases, the inflammatory marker level may be modulated by at least about 5% relative to the subject's pre-treatment level of the inflammatory marker. In some cases, the inflammatory marker level may be modulated by up to about 90% relative to the subject's pre-treatment level of the inflammatory marker.In some cases, the level of the inflammatory marker is 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 90%, or about 35% of the pre-treatment level of the inflammatory marker in the subject. It may be adjusted to 5% 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%. In some cases, the inflammatory marker level may be modulated by about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% relative to the subject's pre-treatment level of the inflammatory marker.

[0223] Administration of a compound or salt of Formula (I), (IIA), (IIB), or (IIC) to a subject can modulate the level of circulating fast skeletal troponin I (fS-TnI). 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 subject's pre-treatment level of fS-TnI. Alternatively, the fS-TnI level in the peripheral blood can decrease after administration of the inhibitor relative to the subject's pre-treatment level of fS-TnI. Administration of an inhibitor described herein can modulate the fS-TnI level by 5% to 90% relative to the subject's pre-treatment level of fS-TnI. In some cases, the fS-TnI level can be modulated by at least about 5% relative to the subject's pre-treatment level of fS-TnI. In some cases, fS-TnI levels can be modulated by up to about 90% relative to the subject's pre-treatment levels of fS-TnI. In some cases, the fS-TnI level is 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 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 35% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 85%, about 35% to about 90 ... It may be adjusted to 5% 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%.In some cases, the fS-TnI level may be modulated by about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% of the subject's pre-treatment level of fS-TnI.

[0224] Troponin isoforms 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 troponin I (ssTnI)). In some cases, inhibition of skeletal muscle contraction may not appreciably inhibit cTnI or ssTnI. When used herein with respect to cTnI or ssTnI, the phrase "not appreciably" refers to cTnI or ssTnI 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 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. Involuntary muscle contractions can be reduced by 20% to 90% compared to involuntary muscle contractions before administration of the inhibitor. In some cases, involuntary muscle contractions can be reduced by at least about 20% compared to involuntary muscle contractions before treatment. In some cases, involuntary muscle contractions can be reduced by up to about 90% compared to involuntary muscle contractions before treatment. In some cases, the involuntary muscle contractions may be 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 35%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 35% to about 55%, about 35% to about 60%, about 35% to about 65%, about 35% to about 70%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 35% to about 40%, about 35% to about 5 ... The reduction may be 0% 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%. In some cases, involuntary muscle contractions may 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 involuntary muscle contractions before 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 activity in subjects, since mature, functional, uninjured muscles can be restored. Examples of ADL or habitual activity include, but are not limited to, stair climbing, stand-up, timed chair rise, habitual walking speed, North Star Gait Assessment, incremental load / constant load shuttle walk, and 6-minute walk distance test. The level or capacity of ADL or habitual physical activity can be measured before and after administration of a skeletal muscle inhibitor. Inhibition of skeletal muscle contraction may not affect ADL or habitual physical activity. In some cases, inhibition of skeletal muscle contraction may not appreciably affect ADL or habitual physical activity. When 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% compared to the ADL or habitual activity level prior to administration of the inhibitor. Skeletal muscle contraction or strength in a subject can be measured before and after administration of a compound or salt of Formula (I), (IIA), (IIB), or (IIC). Such measurements can be performed to generate a dose-response curve for a compound or salt of Formula (I), (IIA), (IIB), or (IIC). The dosage of a compound or salt of Formula (I), (IIA), (IIB), or (IIC) can be adjusted by about 5% to 50% to achieve a dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dosage of the skeletal muscle contraction inhibitor can be adjusted by at least about 5% relative to the dose that reduces type II skeletal muscle contractions by 90%. In some cases, the dosage of the skeletal muscle contraction inhibitor can be adjusted by up to about 50% relative to the dose that reduces type II skeletal muscle contractions by 90%.In some cases, the dosage of the skeletal muscle contraction inhibitor is 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 It can be adjusted 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%. 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 dose that reduces type II skeletal muscle contractions by 90%. Skeletal muscle contractions can be measured before and after administration of the skeletal muscle contraction inhibitor by muscle strength testing after nerve stimulation using surface electrodes (e.g., plantar flexion after peroneal nerve stimulation in the leg), isometric limb assays, heart rate monitors or activity monitors, or equivalents thereof.

[0227] The subject's myocardial strength or contractility 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 strength. In some embodiments, inhibition of skeletal muscle contraction may not appreciably inhibit myocardial contraction. In certain embodiments relating to myocardial contraction, the phrase "not appreciably" refers to myocardial strength being 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 strength before administration of the inhibitor. The subject's myocardial strength or contractility after administration of a compound or salt of Formula (I), (IIA), (IIB), or (IIC) may be within 0.1% to 10% of the myocardial contractility or myocardial 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 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 in skeletal muscle contraction and myocardial contraction is described by a ratio of each other. For example, in some embodiments, the ratio of reduction in skeletal muscle contraction to reduction in myocardial contraction is about 1:1 to about 100:1, about 2:1 to about 50:1, about 3:1 to about 40:1, about 4:1 to about 30:1, about 5:1 to about 20:1, about 7:1 to about 15:1, or about 8:1 to about 12:1. Myocardial force or contraction can be measured using echocardiography (left ventricular fractional shortening) 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 appreciably inhibit the tidal volume in the lungs. In certain embodiments relating to the tidal volume in the lungs, the phrase "not appreciably" 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 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 forced expiratory volume in one second (FEV1) or forced vital capacity (FVC), or equivalent tests.

[0229] The smooth muscle contraction in a subject can be measured before and after administration of a skeletal muscle contraction inhibitor.The 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 appreciably.When used herein with respect to smooth muscle contraction, the phrase "not appreciably" refers to 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.The 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 an inhibitor described herein may not impair nerve conduction, neurotransmitter release, or depolarization of skeletal muscle in a subject. In some cases, inhibition of skeletal muscle contraction may not appreciably impair neuromuscular coupling in a subject. When used herein with respect to neuromuscular coupling, the term "not appreciably" refers to a level of neuromuscular coupling in a 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 assessed by measuring nerve-induced depolarization of skeletal muscle with electromyography (EMG) using surface or needle electrodes, recording the electrical activity generated by skeletal muscle after electrical or voluntary stimulation.

[0231] In some aspects, a method for treating a neuromuscular condition or movement disorder can include 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) inhibits 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 test compounds or inhibitors on the myosin ATPase activity. Test compounds can be screened to assess 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 nucleotides. Test compounds can then be added to the wells along with the pin array. The reaction can be initiated with MgATP. The amount of ATP consumption in the test vessel over a defined period of time can be compared with the amount of ATP consumption in a control vessel. The defined period can be 5 to 20 minutes. The ATP consumption can be determined by a direct or indirect assay. Test compounds that reproducibly and potently inhibit the myosin S1 ATPase activity can be further evaluated in an ex vivo dose-response assay on dissected muscle to determine the compound's IC50. The assay can measure ATPase activity indirectly by coupling the myosin to pyruvate kinase and lactate dehydrogenase and providing absorbance detection at 340 nm based on the conversion of NADH to NAD+ driven by ADP accumulation. In some cases, the test compound can be selected as a compound or salt of Formula (I), (IIA), (IIB), or (IIC) if ATP consumption is reduced by at least 20% in the test vessel compared to the control vessel. A test compound can be selected if it inhibits NAD+ production by at least 20% in a kinetic assay.

[0232] The selected inhibitor or test compound may not inhibit cardiac myosin S1 ATPase in an in vitro assay. ATPase or cardiac myofibril or remodeling 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 a 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 skinned fibers. Single skeletal muscle fibers that have been treated to remove the membrane and allow direct activation of contraction after calcium administration can be used. Inhibitor compounds or salts of Formula (I), (IIA), (IIB), or (IIC) can inhibit contraction of single skeletal muscle fibers by about 5% to about 90% relative to pre-treatment values ​​or untreated control single skeletal muscle fibers. Inhibitors can inhibit contraction of single skeletal muscle fibers by at least about 5% relative to pre-treatment values ​​or untreated control single skeletal muscle fibers. Inhibitors can inhibit contraction of single skeletal muscle fibers by up to about 90% relative to pre-treatment values ​​or untreated control single skeletal muscle fibers. The inhibitor reduces the contraction of single skeletal muscle fibers 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%, or about 20% to about 60% of the capacity before treatment or of an untreated control single skeletal muscle fiber. , 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%. The inhibitor may inhibit 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 capacity or to the single skeletal muscle fiber of an untreated control.

[0234] The inhibitor compounds or salts of Formula (I), (IIA), (IIB), or (IIC) may inhibit the contraction of a single skeletal muscle by about 5% to about 90% relative to pre-treatment values ​​or a single skeletal muscle of an untreated control. The inhibitors may inhibit the contraction of a single skeletal muscle by at least about 5% relative to pre-treatment values ​​or a single skeletal muscle of an untreated control. The inhibitors may inhibit the contraction of a single skeletal muscle by up to about 90% relative to pre-treatment values ​​or a single skeletal muscle of an untreated control. The inhibitor reduces the contractility 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 25% or more relative to the capacity before treatment or to the capacity of an untreated control single skeletal muscle. 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%. The inhibitor may inhibit 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 pre-treatment capacity or a single skeletal muscle of an untreated control.

[0235] The effect of test compound on slow-twitch type I skeletal muscle fiber, cardiac muscle bundle or pulmonary muscle fiber can be evaluated.Test compound or inhibitor compound or salt of formula (I), (IIA), (IIB) or (IIC) can be selected so that it does not appreciably regulate the function of slow-twitch type I skeletal muscle fiber, cardiac muscle bundle or pulmonary muscle fiber, and is specific to type II skeletal muscle.As used herein, the term "appreciably regulate" can refer to the contractile ability of muscle after administration of the inhibitor being 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 muscle force / contraction before administration of the inhibitor.

[0236] In some aspects, a method for treating a neuromuscular condition or movement disorder can include 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) reduces 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., an mdx mouse). The mdx mouse has a point mutation in its dystrophin gene, changing the encoding amino acid from glutamine to threonine, producing a nonfunctional dystrophin protein and resulting in DMD, which exhibits increased muscle damage and weakness. The extensor digitorum longus muscle can be dissected from an mdx mouse and mounted on a lever arm. The muscle can be immersed in 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. An isometric (fixed length) contraction step can then be performed, in which the muscle is stimulated with a series of electrical pulses. An unusual (eccentric) contraction step can then be performed, in which the muscle is stretched 10%, 15%, 20%, 25%, or 30% longer than its resting length and either relaxed or stimulated with electrical pulses. 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 abnormal contraction step is repeated 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times to cause muscle fiber injury. In some embodiments, the electrical pulses may have a frequency of about 1 Hz to about 500 Hz. In some embodiments, the electrical pulses may have a frequency of about 1 Hz to about 400 Hz.In some embodiments, the electrical pulses may have a frequency of about 1 Hz to about 300 Hz. In some embodiments, the electrical pulses may have a frequency of about 1 Hz to about 200 Hz. In some embodiments, the electrical pulses may have a frequency of about 1 Hz to about 100 Hz. The electrical pulses may 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 train of electrical pulses may be composed of individual pulses at various frequencies. The duration of each pulse in the train may be between 0.1 seconds and 0.5 seconds for each pulse. The time for each pulse can be 0.1 seconds, 0.2 seconds, 0.3 seconds, 0.35 seconds, 0.4 seconds, or 0.5 seconds. Muscle membrane damage can also be measured by incubating the muscle in procion orange after its isometric or non-conventional contraction. Procion orange is a fluorescent dye that is taken up by muscle fibers with injured membranes. The number or percentage of dye-positive fibers can then be quantified by histology. If the test muscle's loss of force and / or the percentage of dye-positive fibers can be at least 20% less than the control's loss of force 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 non-conventional contraction set, the muscle force generated by the muscle can be measured. The change in force generated by the muscle before and after the isometric or non-conventional contraction set can be calculated as the test muscle force decline. This calculation can be compared to the change in force generated by the muscle contraction from the first pulse to the last pulse in a control sample without exposure to the test compound (control muscle force decline). Muscle force decline can be used as a surrogate for muscle injury, and a test compound or inhibitor compound or salt of formula (I), (IIA), (IIB) or (IIC) can be selected if the test muscle force decline is at least 20% less than the control muscle force decline. (Pharmaceutical preparations)

[0238] The compositions and methods described herein may be considered useful as pharmaceutical compositions for administration to a subject in need thereof. The pharmaceutical compositions may include 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, dispersing agents, suspending agents, and / or thickening agents.

[0239] Pharmaceutical compositions containing compounds or salts 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 depending on the selected route of administration. Pharmaceutical compositions containing compounds, salts, or conjugates can be prepared, for example, by lyophilizing, mixing, dissolving, emulsifying, encapsulating, or entrapping the compound, salt, or conjugate. Pharmaceutical compositions can also contain compounds, salts, or conjugates in free base form or in pharmaceutically acceptable salt form.

[0240] Methods for formulating a compound or salt of Formula (I), (IIA), (IIB), or (IIC) can include formulating the compound, salt, or conjugate with 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 compositions further contain 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 with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0241] Pharmaceutical compositions containing a compound or salt of Formula (I), (IIA), (IIB), or (IIC) can contain at least one active ingredient (e.g., a compound, salt, or conjugate and another agent). The active ingredient can be entrapped in, for example, microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methylmethacylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions prepared by coacervation techniques or interfacial polymerization.

[0242] The compositions and formulations may be sterilized, which may be achieved by filtration via sterile filtration.

[0243] Compositions containing compounds or salts of formula (I), (IIA), (IIB) or (IIC) can be formulated for administration as injections. Non-limiting examples of formulations for injections 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. Injections can be formulated for bolus injection or continuous infusion. Alternatively, the composition can be lyophilized or in powder form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0244] For parenteral administration, the compound or salt of formula (I), (IIA), (IIB) or (IIC) can be formulated into an injectable unit dosage form (e.g., solution, suspension, emulsion) in combination with a pharmaceutically acceptable parenteral vehicle. Such vehicles can be inherently non-toxic and non-therapeutic. Vehicles can be water, saline, Ringer's solution, dextrose 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. Vehicles can contain small amounts of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0245] In one embodiment, the present 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 compositions are formulated to deliver one or more pharmaceutically active agents to a subject through the mucosal layers in the mouth or esophagus. In another embodiment, the compositions are formulated to deliver one or more pharmaceutically active agents to a subject through the mucosal layers 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, multiparticulate devices, and combinations thereof. The composition may also include non-controlled release excipients.

[0247] In another embodiment, the composition of Formula (I), (IIA), (IIB), or (IIC) is provided in an enteric-coated dosage form. These enteric-coated dosage forms may 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 may further comprise 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 may further comprise glycerol monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, spherical sugar, talc, or triethyl citrate.

[0248] In another embodiment, the composition of Formula (I), (IIA), (IIB), or (IIC) is an enteric-coated controlled-release tablet for oral administration. The composition can further include 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 the 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 (for example, films or microcapsules).Examples of sustained-release matrices can include polyester, hydrogel (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide, 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 lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0250] Pharmaceutical formulations 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. The formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers can be non-toxic to recipients at the dosages and concentrations used. Acceptable carriers, excipients, and / or stabilizers may include buffers, 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 dextrins; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium ions; metal complexes; and / or non-ionic surfactants or polyethylene glycol.

[0251] In another embodiment, the compositions of Formula (I), (IIA), (IIB) or (IIC) may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, 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 compositions of Formula (I), (IIA), (IIB), or (IIC) are provided in effervescent dosage forms. These effervescent dosage forms may also contain non-controlled release excipients.

[0253] In another embodiment, the compositions of Formula (I), (IIA), (IIB), or (IIC) can be provided in a dosage form having at least one component capable of promoting immediate release of the active agent and at least one component capable of promoting controlled release of the active agent. In a further embodiment, the dosage form can be capable of discontinuous release of the compound in at least two consecutive pulses separated in time by 0.1 to 24 hours. The compositions can include one or more controlled-release and non-controlled-release excipients, such as excipients as swellable materials suitable for disruptable semipermeable membranes.

[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 layered material of a gastric juice-resistant polymer that has been partially neutralized with alkali, encapsulated in an intermediate reactive 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 or multi-dosage form. As used herein, a unit-dosage form refers to an individually packaged, physically discrete unit suitable for administration to a human or non-human animal subject. Each unit dose can contain a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, in combination with the necessary pharmaceutical carriers or excipients. Examples of unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, a unit-dosage form can be administered separately or in multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container, which can be administered in segregated unit-dosage form. 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, a multiple-dosage form contains different pharmaceutically active agents.

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

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

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

[0259] The components of the combination can be administered to a patient simultaneously or sequentially.It is understood that the components are in the same pharmaceutically acceptable carrier and therefore are administered simultaneously.Alternatively, the active ingredients can be in separate pharmaceutical carriers, such as conventional oral dosage forms, and they can be administered simultaneously or sequentially.

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

[0261] In some embodiments, the compounds or salts of the present disclosure are used in combination with gene therapy.In some embodiments, the compounds or salts of the present disclosure are used in combination with adeno-associated viruses (AAV) containing genes encoding replacement proteins, such as dystrophin, or truncated versions thereof, such as microdystrophin.In some embodiments, the compounds or salts of the present disclosure are administered in combination with vamorolone. [Example]

[0262] Having now generally described the invention, it will be more readily understood by reference to the following examples, which are included merely to illustrate certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0263] The following synthetic schemes are provided for illustrative purposes without limitation. The following examples illustrate various methods for making the compounds described herein. It is understood that those skilled in the art can make these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art can make the compounds in a similar manner to the following by using appropriate starting materials and modifying the synthetic route if necessary. In general, starting materials and reagents can be obtained from commercial suppliers, or can be synthesized according to sources known to those skilled in the art, or can be 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) [ka] 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) was 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 resulting 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 (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), brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by reverse-phase Combi-flash chromatography to give 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) was added dropwise CsCO (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 NHCl (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. The crude product was purified by preparative TLC to give 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 hours. 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, 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] Example 2 2-(3-(4-(3-chlorophenyl)thiazol-2-yl)-6-oxopyridazin-1(6H)-yl)-N-ethylacetamide (Compound 81) [ka] Step 1: 2-(3-cyano-6-oxopyridazin-1-yl)-N-ethylacetamide

[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) was added Zn(CN) (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 HO (30 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 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 HO (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. The crude product was purified by silica gel column chromatography to give 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 hours. The reaction was diluted by adding HO (20 mL) at 0° C. 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 preparative HPLC to afford 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) [ka] Step 1: 2-Bromo-5-(3-chlorophenyl)-1,3-thiazole

[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 CBr (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 aqueous NH4Cl (aqueous) (20 mL) at 0° C. 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 to give 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) was added hexamethyldistannane (2.52 g, 7.69 mmol) and Pd(dppf)Cl (281.32 mg, 0.38 mmol). The reaction was stirred at 100° C. under an argon atmosphere for 1 hour. The resulting mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography to give 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) was added Pd(dppf)Cl (212.70 mg, 0.29 mmol) and 2-bromo-5-(3-chlorophenyl)-1,3-thiazole (319.25 mg, 1.16 mmol). The reaction was stirred at 100° C. under an argon atmosphere for 3 hours. The reaction was quenched by adding HO (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 NaSO, and concentrated under reduced pressure. The crude product was first purified by silica gel column chromatography and then further purified by preparative HPLC to afford 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) [ka] Step 1: 3-Chlorobenzohydrazide

[0275] To 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 hours. The precipitated solid was collected by filtration and washed with ACN (3×3 mL) to give the title compound 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) was 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 hours. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with ACN (3×3 mL) to give the title compound 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 POCl (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 to give the title compound 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) was 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 hours. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration. The crude product was purified by preparative HPLC to give the title compound as a white solid (30 mg, 18.82%). 1 H 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 minutes;M S m / z: 365 [M+H] + .

[0279] The following compounds were synthesized according to Example 4: [Table B] Example 5 2-[3-[5-(3-chlorophenyl)-1,3-oxazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide (Compound 27) [ka] Step 1: 2-[3-[5-(3-chlorophenyl)-1,3-oxazol-2-yl]-6-oxopyridazin-1-yl]-N-ethylacetamide

[0280] To a stirred solution of 5-(3-chlorophenyl)-1,3-oxazole (200.00 mg, 1.11 mmol) in DMA (2.00 mL) was 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 at 120 °C for 1 h under microwave irradiation conditions. The reaction was diluted by adding HO (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 minutes 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) [ka] Step 1: 1-[(ethylcarbamoyl)methyl]-6-oxopyridazine-3-carboxamide

[0281] A solution of 2-(3-cyano-6-oxopyridazin-1-yl)-N-ethylacetamide (200.00 mg, 0.10 mmol) in sulfuric acid (2.0 mL) was stirred at 50° C. for 1 hour. The pH of the 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. The crude product was purified by silica gel column chromatography to give 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) was added 2-bromo-1-(3-chlorophenyl)ethanone (114.55 mg, 0.25 mmol). The reaction mixture was stirred at 120° C. for 2 days. The reaction was diluted by adding HO (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 preparative HPLC to afford 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) [ka] Step 1: M-Chlorobenzoylhydrazine

[0283] To a stirred solution of methyl 3-chlorobenzoate (600.00 mg, 3.53 mmol) in methanol (5.00 mL) was added hydrazine monohydrate (1.0 mL). The resulting solution was stirred at 70° C. for 1 hour. 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) was added HATU (1.23 g, 3.22 mmol), DIEA (568.19 mg, 4.396 mmol, 1.5 equiv.), and M-chlorobenzoylhydrazine (500.00 mg, 2.93 mmol). The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with ACN (2×2 mL) to give the title compound 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) was added KCO (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 hour. The reaction was diluted by adding HO (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 to give the title compound 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] To 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 added bis(4-methoxyphenyl)-1,3,2lambda 5,4lambda 5-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 hours. The reaction was diluted by adding HO (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 to afford 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] To 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 added ethylamine (1 mL, 0.66 mmol) in EtOH (35%). The resulting solution was stirred at 70° C. for 1 hour. The residue was filtered to give 35 mg of a white solid. The crude product was recrystallized from MeOH (1.00 mL) to give 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) [ka] Step 1: 6-oxo-1H-pyridazine-3-carboxylate methyl

[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 x 30 mL). The combined organic layers were washed with water (2 x 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 hours. The reaction mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with ACN (2×2 mL) to give the title compound 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) was 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 hours. The reaction was diluted by adding HO (12.0 mL). The precipitated solid was collected by filtration and washed with ACN (2 × 2 mL) to give the title compound 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 hour. The reaction mixture was cooled to room temperature. The reaction was diluted by adding HO (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 NaSO. 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 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) was added CHI (194.77 mg, 1.37 mmol) and KCO (316.08 mg, 2.29 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted by adding HO (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 to give 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 hours. The reaction mixture was cooled to room temperature. The reaction was diluted by adding HO (20 mL). The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 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) was added HO (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 HO (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 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) was 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 hours. The reaction was diluted by adding HO (20 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 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) was 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 give 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 myofibrillar ATPase assay

[0298] Overview: Myosin ATPase activity was assessed using a coupled reaction system in which ADP generated by myosin ATPase function was coupled to the loss of NADH by the pyruvate kinase / lactate dehydrogenase (PK-LDH) system. Myosin ATPase activity produced ADP, which was used as a substrate for PK to generate pyruvate and regenerate ATP. Pyruvate was then used as a substrate for LDH to oxidize NADH to NAD+. The reaction rate was monitored using absorbance at 340 nm via the time-dependent loss of NADH. Inhibition of ATPase activity by the assayed compounds was indicated by a reduced rate of NADH loss relative to vehicle-treated controls over the experimental time frame. To assess the selectivity of compounds assayed for skeletal myofibrils, the compounds were counterscreened in cardiac myofibrils.

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

[0300] pCa buffer stock solution. 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 myofibrillar ATPase assay procedure: BSA, ATP, NADH, PEP, and DTT solutions were thawed at room temperature and then transferred to ice. Pelleted frozen myofibrils (approximately twice the required volume) were transferred to a sufficiently large tube and capped. Myofibrils were thawed by rolling in a water bath at room temperature for approximately 15 minutes and then chilled on ice. Buffers A and B were prepared as needed by adjusting the volume to fit the required number of wells and stored on ice. 0.5 μL of the compound to be assayed was added to wells of a 384-well plate. Buffers A and B were mixed by inversion immediately before use, and then 25 μL of each was dispensed using a Multidrop dispenser (first Buffer A, then Buffer B). The absorbance in the wells was measured at 340 nm using a kinetic protocol, reading wells every 1.5–2 minutes over a 1-hour period. Using either SoftMax Pro plate reader software or a spreadsheet program such as Excel, reaction rates were qualitatively assessed by subtracting the minimum absorbance value from the maximum for each well. Using GraphPad Prism 8.0, data were normalized by defining 100% activity as the absorbance change in the 1% DMSO vehicle wells and assigning 0% to no change in absorbance over the course of the experiment. Normalized data were fit to a four-parameter logistic model with a variable slope, constrained to have a base of 0 or greater. Compounds in Tables 1-3 were tested. Assay results can be found in Table 4 herein. A=IC 50 is less than or equal to 10 μM; B=IC 50 is greater than 10 μM and less than 100 μM; C = IC 50 is over 100 μM. Example 10 Comparison of biomarkers in muscular dystrophies

[0304] Frozen plasma samples from healthy volunteers (HVs) 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 50–100 μL working volumes and stored at −80°C to minimize freeze-thaw damage. Red-top serum vacutainer blood collection tubes containing silica act clot activator were used for blood collection. If subjects required MLPA testing, additional EDTA tubes were used for collection but were not used for any other analyses. After allowing serum tubes to clot for 30 minutes, they were processed by centrifugation at 1000–1300 × g for 10 minutes. The serum (upper layer) fluid was then pipetted from the vacutainer tubes, 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 shipped to Binghamton University, where they were stored at -80°C. Samples were collected between 2017 and 2019 and analyzed in 2019. Plasma samples from the Newcastle MRC Centre Biobank were collected from patients attending clinics at The John Walton Muscular Dystrophy Research Centre. Blood was drawn into a vacutainer, gently inverted 5–10 times to ensure adequate mixing of the blood and EDTA, and then centrifuged at 1,500 × g for 10 minutes. The upper plasma fraction was pipetted into a cryovial 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 conjugate reaction kit purchased from Pointe Scientific (Canton, MI). Plasma was diluted 25-fold with phosphate-buffered saline (PBS), and 2 μL of this solution 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). Reaction progress 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 completion of the reaction, pathlength correction values ​​were measured by near-IR absorbance at 900 nm and 975 nm. Raw absorbance data were processed in Microsoft Excel, with A340 > 2.5 excluded, and pathlength correction was performed using a system-specific K factor of 0.168. The time-corrected absorbance data were fitted to a linear model in GraphPad Prism (GraphPad Software, San Diego, CA) to obtain the reaction slope, which was compared to a standard curve of NADH (5–100 μM) to obtain the enzyme rate in U / L, where U is 1 μmol L -1 ·minute -1 It is defined as the amount of enzyme that results in a decrease in NADP. TNNI ELISA

[0306] Plasma concentrations of TNNI isoforms for slow and fast muscle 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 with α-TNNI2 monoclonal antibody (clone 7G2, OriGene, Inc., Rockville, MD) at a concentration of 6.4 μg / mL overnight at 4°C. Wells were blocked with 1% w / v nonfat dry milk in PBS for 30 minutes at 37°C, and then incubated with recombinant human TNNI2 as a sample or standard curve for 2 hours at 37°C. Wells were washed with PBS containing 0.1% Tween®-20 (PBS-T) and incubated with 1 μg / mL polyclonal α-TNNI2 antibody (PA5-76303, ThermoFisher, Inc.) for 90 minutes at 37°C. After washing with PBS-T, detection antibody (HRP-conjugated goat-α-rabbit IgG, 0.08 μg / mL, Pierce Biosciences) was added for 45 minutes at 37°C. HRP was visualized with Ultra-TMB colorimetric reagent (ThermoFisher), followed by quenching with 2N H2SO4 and measuring absorbance at 410 nm. The selectivity of these assays for fast versus slow TNNI has been previously confirmed using human muscle extracts.

[0307] These studies demonstrate the relationship between musculoskeletal biomarkers in the plasma of patients with DMD and BMD.

[0308] Figure 3. Patients with Becker muscular dystrophy (BMD) with healthy volunteers (circles) as controls. Creatine kinase (CK) enzyme activity (A), fast skeletal troponin I (TNNI1) (B), and slow skeletal TNNI2 (C) plasma concentrations were measured in samples from patients with Duchenne muscular dystrophy (DMD) (squares) and Duchenne muscular dystrophy (DMD) (triangles). In each panel, error bars represent the median + / - interquartile range. In panels B and C, samples with undetectable TNNI concentrations were assigned a value 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 with each other, a significant correlation was found between CK and fast TNNI2 (D), with an R of 0.67. There was no significant correlation between CK and slow TNNI1 (E) or 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. Creatine kinase enzyme activity (A), fast troponin I (TNNI2) (B), and slow troponin I (TNNI1) (C) concentrations in samples from patients with Duchenne muscular dystrophy (DMD) versus patient age. The same comparisons were made for Becker muscular dystrophy (BMD) in panels (D, E, and F) for CK, TNNI2, and TNNI1, respectively.

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

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

[0312] Figure 7. Comparison of pre- and post-exercise creatine kinase (CK) levels in healthy adults and subjects with BMD, LGMD, and McArdle's disease. Data are presented as mean + standard error. X-axis: 0 = pre-exercise, and 1, 2, 4, and 24 = hours after completion of exercise. It should be noted that this assay has a limit at 22,000 U / L, which is relative to McArdle's data.

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

[0314] In some embodiments, the compounds of the present disclosure are 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 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 listed in Table 3. The compounds in Table 3 were tested. IC 50 can be found in Table 4 herein. A=IC 50 is less than or equal to 10 μM; 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] Scaffold IC of the compounds of the present disclosure 50 The values ​​can be seen in Table 4. [Table 4-1] [Table 4-2]

[0318] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions may now occur to those skilled in the art without departing from the invention. It should be understood that various modifications to the embodiments of the invention described herein may be used in practicing the invention. It is intended that the following claims define the scope of the invention, and that methods and structures within the scope of these claims and their equivalents be covered thereby. The present invention provides, for example, the following items. (Item 1) Compounds represented by formula (IIA): [ka] or a salt thereof [wherein: R 11 teeth, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (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 , -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 3~10optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 15 each replaced as necessary), 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(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 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 R 12 is R 15 cyclobutyl optionally substituted with one or more substituents independently selected from 17ethyl optionally substituted with one or more substituents independently selected from R 15 are respectively, 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 C 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 alkynyl, (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 ) and —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 16 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycles and 3- to 10-membered heterocycles C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from R 17 are 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(R16 ) and -CN]. (Item 2) R 11 But 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 2~6 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 are each selected from the group consisting of one or more R 15 Item 1. A compound or salt according to item 1, each optionally substituted with (Item 3) R 11 are selected from cycloalkyl, aryl, and heteroaryl, each of which is R 15 3. The compound or salt according to item 2, optionally substituted with one or more substituents independently selected from: (Item 4) R 11 is selected from phenyl, pyridyl and cyclopropyl, each of which is selected from halogen, -OR 16, and C 1~3 Item 4. The compound or salt according to item 3, optionally substituted with one or more substituents independently selected from alkyl (optionally substituted with one or more substituents independently selected from halogen). (Item 5) R 11 but, [ka] 5. The compound or salt according to item 4, selected from: (Item 6) R 11 but, [ka] Item 6. The compound or salt according to item 5, selected from: (Item 7) R 12 but, 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 C optionally substituted with one or more substituents independently selected from -NO and -CN 1~3 Alkyl 7. The compound according to any one of items 1 to 6, wherein R is cyclobutyl optionally substituted with one or more substituents independently selected from: (Item 8) R 12 But 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 , ethyl optionally substituted with -NO2 and -CN. (Item 9) R 12 is ethyl or cyclobutyl. (Item 10) [ka] [ka] and any one of salts thereof. (Item 11) [ka] [ka] and any one of salts thereof. (Item 12) Compounds represented by formula (IIB): [ka] or a salt thereof [wherein: X 21 and X 22 is N and C(R 23 ) are independently selected from X 21 and X22 at least one of is N, X 23 is selected from S and O; R 21 teeth, hydrogen, 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 , -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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, 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 23 teeth, 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)R26 , -C(O)OR 26 , -OC(O)R 26 C optionally substituted with one or more substituents independently selected from -NO and -CN 1~3 Alkyl is selected from R 25 are respectively, 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 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) and —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 26 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycle, a 3- to 10-membered heterocycle, and C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from (Item 13) X 23 13. The compound or salt according to item 12, wherein (Item 14) X 23 Item 13. The compound or salt according to item 12, wherein is S. (Item 15) X 21 is N and X 22 is CR 23 or X 22 is N and X 21 is CR 2315. The compound or salt according to any one of items 12, 13 or 14, wherein (Item 16) CR 23 16. The compound or salt according to any one of items 12, 13, 14 or 15, wherein is CH. (Item 17) X 21 and X 22 15. The compound or salt according to any one of items 12, 13 or 14, wherein each is N. (Item 18) R 21 C, which is replaced as needed 1~6 18. The compound or salt according to any one of items 12 to 17, wherein the alkyl is selected from alkyl, optionally substituted aryl and optionally substituted heteroaryl. (Item 19) R 21 C, which is replaced as needed 1~3 Alkyl, optionally substituted C 3~6 selected from carbocycle and optionally substituted 5- or 6-membered heteroaryl; C 1~3 Substituents on alkyl are 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, C 3~6 Substituents on the carbocycle and 5- or 6-membered heteroaryl are 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 (one or more R 2519. The compound or salt according to item 18, wherein the compound or salt is selected from the group consisting of: (Item 20) R 21 But -CH3 [ka] 20. The compound or salt according to item 19, selected from: (Item 21) R 22 but, 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 rings and 3- to 10-membered heterocyclic rings (see above C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 C optionally substituted with one or more substituents independently selected from 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 and 3- to 10-membered heterocyclic rings (C 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 C optionally substituted with one or more substituents independently selected from 3~6 carbocyclic ring 21. The compound according to any one of items 12 to 20, selected from: (Item 22) R 22 but, Halogen and phenyl (one or more R 25 C optionally substituted with one or more substituents independently selected from 1~3 alkyl; and Halogen, C 1~6 Alkyl, C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (C 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 25 C optionally substituted with one or more substituents independently selected from 3~6 carbocyclic ring 22. The compound according to item 21, selected from: (Item 23) R 22 but, C 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 alkyl; and Halogen, C 1~6 Alkyl, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 3~6 23. The compound according to item 22, selected from carbocycles. (Item 24) R 22 But -CH2CH3 [ka] 24. The compound according to item 23, selected from: (Item 25) [ka] and any one of salts thereof. (Item 26) Compounds represented by formula (IIC): [ka] or a salt thereof [wherein: R 31 teeth, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is 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)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 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 35 (each replaced as necessary) is selected from R 32 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 3~10optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is 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)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 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 35 (each replaced as necessary) is selected from R 35 are respectively, 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 a 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), optionally substituted with one or more substituents independently selected from are independently selected from R 36 are respectively, hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycle and 3- to 10-membered heterocycle; and C 3~10Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from (Item 27) R 31 27. The compound or salt according to item 26, wherein is selected from optionally substituted aryl or heteroaryl. (Item 28) R 31 28. The compound or salt according to item 27, wherein is selected from optionally substituted phenyl. (Item 29) R 31 but, [ka] 29. The compound or salt according to item 28, wherein (Item 30) R 32 29. The compound or salt according to any one of items 26, 27 or 28, wherein is selected from optionally substituted C1-C6 alkyl. (Item 31) R 32 31. The compound or salt according to item 30, wherein is ethyl. (Item 32) [ka] or a salt thereof. (Item 33) 33. A pharmaceutical composition comprising the compound or salt according to any one of items 1 to 32. (Item 34) A method for treating a disease, comprising administering to a subject in need thereof a compound or salt according to any one of items 1 to 32. (Item 35) 33. A method of treating a neuromuscular condition, comprising administering to a subject in need thereof a compound or salt according to any one of items 1 to 32. (Item 36) 36. The method of item 34 or 35, wherein the neuromuscular condition is 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, tendonitis, and carpal tunnel syndrome. (Item 37) Item 38. The method of item 36, wherein the neuromuscular condition is Duchenne muscular dystrophy. 33. A method for treating a movement disorder, comprising administering to a subject in need thereof a compound or salt according to any one of items 1 to 32. (Item 39) 39. The method of claim 38, wherein the movement disorder comprises muscle spasticity. (Item 40) 40. The method of item 39, wherein the muscle spasticity is selected from spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or an injury or traumatic event such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis. (Item 41) 41. The method of claim 40, wherein the compound or salt is administered in an amount sufficient to reduce involuntary muscle contractions. (Item 42) 42. The method of claim 41, wherein the compound or salt is administered in an amount sufficient to reduce involuntary muscle contractions by at least 10%. (Item 43) 1. A method of treating a neuromuscular condition or movement disorder, comprising administering to a subject in need thereof a compound represented by formula (I): [ka] or a salt thereof, wherein: The A ring is R 1 a 5-membered heteroaromatic ring optionally substituted with one or more substituents independently selected from X is N or CH; R 1 are respectively, 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 ) and -CN; C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each replaced as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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 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 5 (each replaced as necessary) are independently selected from R 2 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 , each replaced as necessary), C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with 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, C1~6 Alkyl, C 3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each replaced as necessary), and -C(O)NR 7 R 8 is selected from R 4 are halogen, -OR 6 , -SR 6 , -N(R 6 )2, -NO2, -CN and, C 1~6 Alkyl (halogen, -OR 6 , -SR 6 , -N(R 6 ) optionally substituted with one or more substituents independently selected from -NO and -CN; R 5 are respectively, 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 a halogen, -OR 6 , -SR6 , -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), optionally substituted with one or more substituents independently selected from are independently selected from R 6 are respectively, hydrogen; and C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1~6 Alkyl, -SC 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 carbocycle and 3- to 10-membered heterocycle; and C 3~10 Carbocycles and 3- to 10-membered heterocycles (which are halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC, respectively) 1~6 Alkyl, -SC 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 3~10optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl are independently selected from R 7 is hydrogen and C 1~6 Alkyl (halogen, -OR 6 , -SR 6 , -N(R 6 ) optionally substituted with one or more substituents independently selected from -NO and -CN; R 8 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a 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 carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 , each replaced as necessary), C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -SR 6 , -N(R 6 )2, -C(O)R 6 , -C(O)N(R6 )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 carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 (each replaced as necessary) is selected from The method wherein p is 0, 1 or 2. (Item 44) The A ring is selected from thiophene, oxadiazole, thiadiazole, thiazole, oxazole, pyrazole, imidazole, triazole, pyrrole, tetrazole, and furan, each of which is selected from R 1 44. The method of claim 43, optionally substituted with one or more substituents independently selected from: (Item 45) The A ring is selected from thiophene, oxadiazole, oxazole, thiadiazole, triazole, pyrazole, and thiazole, each of which is selected from R 1 45. The method of claim 44, optionally substituted with one or more substituents independently selected from: (Item 46) wherein the A ring is [ka] are selected from, respectively, R1 46. ​​The method of claim 45, optionally substituted with one or more substituents independently selected from: (Item 47) wherein the A ring is [ka] are selected from, respectively, R 1 47. The method of claim 46, optionally substituted with one or more substituents independently selected from: (Item 48) wherein the A ring is [ka] 47. The method of claim 46, wherein the compound is selected from the group consisting of: (Item 49) wherein the A ring is [ka] Item 49. The method of item 48, wherein the compound is selected from the group consisting of: (Item 50) R 1 but, Halogen, -OR 6 , -CN, C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (see above C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 C optionally substituted with one or more substituents independently selected from 1~6 alkyl; and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5(each replaced as necessary) 50. The method according to any one of items 43 to 49, wherein the method is selected from the group consisting of: (Item 51) R 1 but, C 1~6 alkyl; and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , - and C 1~6 Alkyl (one or more R 5 and optionally substituted with one or more substituents independently selected from 51. The method of claim 50, wherein the (Item 52) R 1 is selected from methyl optionally substituted with one or more substituents independently selected from halogen, -OH, or -OCH3. (Item 53) R 1 However, pyridine, C 3~5 52. The method of any one of items 43 to 51, wherein the aryl group is selected from cycloalkyl and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —CH3, —CN, —OH, —OCH3, —OCF3, —CF3, —CHF2, —OCHF2 and cyclopropyl. (Item 54) 48. The method according to any one of items 43 to 47, wherein ring A is unsubstituted. (Item 55) R 2 but, Halogen, -OR 6 , -SR 6 , -N(R 6 )2, -CN, C 3~10 Carbocyclic rings and 3- to 10-membered heterocyclic rings (see above C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 C optionally substituted with one or more substituents independently selected from1~6 alkyl; C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -SR 6 , -N(R 6 )2, 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, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each substituted as necessary); and -C(O)NR 7 R 8 55. The method according to any one of items 43 to 54, wherein the method is selected from the group consisting of: (Item 56) R 2 But halogen, -OR 6 , -SR 6 , -N(R 6 )2, -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, wherein C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings are each independently selected from one or more R 5 56. The method of claim 55, wherein each of (Item 57) R 2 But halogen, -OR 6 , -SR 6 , -N(R 6 C optionally substituted with one or more substituents independently selected from —CN and —CN. 1~6 57. The method of claim 56, wherein the alkyl is selected from alkyl. (Item 58) R 2 But C 3~10 a carbocycle and a 3- to 10-membered heterocycle, each of which is selected from halogen, -OR 6 , -SR 6 , -N(R6 )2, 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, C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings are each independently selected from one or more R 5 56. The method of claim 55, wherein each of (Item 59) R 2 is 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 59. The method of claim 58, optionally substituted with one or more substituents independently selected from alkyl. (Item 60) R 2 But -C(O)NR 7 R 8 Item 57. The method according to Item 56, wherein (Item 61) R 8 but, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 alkynyl, (each of which is a halogen, -OR 6 , -SR 6 , -N(R 6 )2, -CN, C 3~10 optionally substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 each substituted as necessary); and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 6 , -SR 6 , -N(R 6 )2, -CN, C 1~6 Alkyl, C3~10 optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle; 1~6 Alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 5 (each replaced as necessary) Item 61. The method of item 60, wherein the method is selected from the group consisting of: (Item 62) R 8 But halogen, -OR 6 , -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, wherein C 3~10 Carbocycles and 3- to 10-membered heterocycles are each selected from the group consisting of one or more R 5 Item 62. The method of item 61, wherein each of the following is optionally substituted: (Item 63) 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, wherein said phenyl or pyridyl is optionally substituted with halogen, -CH3, -OH, -OCH3, -CF3, -CHF2 or -CH2F. (Item 64) R 8 But C 3~10 a carbocycle and a 3- to 10-membered heterocycle, each of which is selected from halogen, -OR 6 , -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, C 3~10 Carbocycles and 3- to 10-membered heterocycles are each selected from the group consisting of one or more R 5 Item 62. The method of item 61, wherein each of the following is optionally substituted: (Item 65) R 8is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxadiazole, thiadiazole, thiazole, oxazole, pyrazole, imidazole, triazole, pyrrole, and furan, each of which is selected from one or more R 5 65. The method of claim 64, optionally substituted with (Item 66) R 8 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, oxadiazole, thiadiazole, and thiazole, each of which is selected from one or more R 5 Item 66. The method of item 65, optionally substituted with (Item 67) 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. (Item 68) The compound is [ka] [ka] [ka] [ka] [ka] and any one of salts thereof. (Item 69) The compound is [ka] [ka] [ka] [ka] and any one of salts thereof. (Item 70) 70. The method of any one of items 43 to 69, wherein the disease is a neuromuscular condition. (Item 71) 71. The method of claim 70, wherein the neuromuscular condition is 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, tendonitis, and carpal tunnel syndrome. (Item 72) Item 73. The method of item 71, wherein the neuromuscular condition is Duchenne muscular dystrophy. A method for treating a movement disorder, comprising administering to a subject in need thereof a compound or salt according to any one of items 43 to 70. (Item 74) 74. The method of claim 73, wherein the movement disorder comprises muscle spasticity. (Item 75) 75. The method of item 74, wherein the muscle spasticity is selected from spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or an injury or traumatic event such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis. (Item 76) 74. The method of claim 73, wherein the compound or salt is administered in an amount sufficient to reduce involuntary muscle contractions. (Item 77) 77. The method of claim 76, wherein the compound or salt is administered in an amount sufficient to reduce involuntary muscle contractions by at least 10%.

Claims

1. A compound represented by formula (IIB): 【Chemistry 63】 or a salt thereof [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; R21 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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 , —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) 2 R 26 , —NO 2 , ═O, ═S, ═N(R 26 ), optionally substituted with one or more substituents independently selected from -CN, C 3-10 carbocycle, and 3-10 membered heterocycle, each of which is optionally substituted with one or more R 25 ; and C 3-10 carbocycles and 3-10 membered heterocycles (which are each 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) 2 R 26 , —NO 2 , ═O, ═S, ═N(R 26 ), —CN, C 1-6 optionally substituted with one or more substituents independently selected from alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, and 3-10 membered heterocycle, each of which is optionally substituted with one or more R 25 ; is selected from R22 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 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(R 26 ) 2 , —N(R 26 )C(O)OR 26 , —C(O)OR 26 , —OC(O)R 26 , —S(O)R 26 , —S(O) 2 R 26 , —NO 2 , ═O, ═S, ═N(R 26 ), optionally substituted with one or more substituents independently selected from -CN, C 3-10 carbocycle, and 3-10 membered heterocycle, each of which is optionally substituted with one or more R 25 ; and C 3-10 carbocycles and 3-10 membered heterocycles (which are each 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) 2 R 26 , —NO 2 , ═O, ═S, ═N(R 26 ), —CN, C 1-6 optionally substituted with one or more substituents independently selected from alkyl, C 3-10 carbocycle, and 3-10 membered heterocycle, each of which is optionally substituted with one or more R 25 ; is selected from R23 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 , -NO 2 and -CN; and C 1-3 alkyl optionally substituted with one or more substituents 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 , -C(O)OR 26 , -OC(O)R 26 , -NO 2 and -CN; is selected from 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) 2 R 26 , -NO 2 , =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(R 26 ) 2 , —N(R 26 )C(O)OR 26 , —C(O)OR 26 , —OC(O)R 26 , —S(O)R 26 , —S(O) 2 R 26 , —NO 2 , ═O, ═S, ═N(R 26 ) and -CN, are independently selected from R 26 is hydrogen, 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, -NO 2 , -NH 2 , ═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 carbocycle, 3-10 membered heterocycle; and C 3-10 carbocycle and 3-10 membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , ═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 carbocycle, 3-10 membered heterocycle, and haloalkyl; are selected independently.

2. The compound or salt according to claim 1, wherein X 23 is O.

3. The compound or salt according to claim 1, wherein X 23 is S.

4. The compound or salt according to any one of claims 1 to 3, wherein X 21 is N and X 22 is CR 23 , or X 22 is N and X 21 is CR 23 .

5. The compound or salt according to any one of claims 1 to 3, wherein CR 23 is CH.

6. The compound or salt according to claim 1, wherein X 21 and X 22 are each N.

7. The compound or salt of any one of claims 1 to 3, wherein R 21 is selected from optionally substituted C 1-6 alkyl, optionally substituted aryl and optionally substituted heteroaryl.

8. R 21 is selected from optionally substituted C 1-3 alkyl, optionally substituted C 3-6 carbocycle and optionally substituted 5- or 6-membered heteroaryl; substituents on said 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 , -NO 2 and -CN; and substituents on said C 3-6 carbocycle and said 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 8. The compound or salt of claim 7, wherein R is selected from: -N(R 26 )C(O)R 26 , -C(O)OR 26 , -OC(O)R 26 , -NO 2 , -CN and C 1-6 alkyl (optionally substituted by one or more R 25 ).

9. R 21 is -CH 3 【Chemistry 64】 9. The compound or salt of claim 8, selected from:

10. R 22 is C 1-6 alkyl optionally substituted with one or more substituents independently 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 , -NO 2 , -CN, C 3-10 carbocycle and 3-10 membered heterocycle, each of which is optionally substituted with one or more R 25 ; and C 3-6 carbocycle optionally substituted with one or more substituents independently 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 , -NO 2 , -CN, C 1-6 alkyl, C 3-10 carbocycle and 3-10 membered heterocycle, each of which is optionally substituted with one or more R 25 .

2. The compound or salt of claim 1, selected from:

11. R 22 is C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen and phenyl (optionally substituted with one or more R 25 ); and C 3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, C 3-10 carbocycle and 3-10 membered heterocycle, each of which is optionally substituted with one or more R 25 .

9. The compound of claim 8, selected from:

12. R 22 is C 1-3 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 a C 3-6 carbocycle optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, C 3-10 carbocycle, and a 3-10 membered heterocycle; 12. The compound of claim 11 selected from:

13. R 22 is -CH 2 CH 3 【Chemistry 65】 13. The compound of claim 12, selected from:

14. 【Chemical 66】 and any one of the salts thereof.

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

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

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

18. The composition of claim 16, wherein the composition is for use in treating 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, tendonitis, and carpal tunnel syndrome.

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

20. The composition described in claim 18, wherein the neuromuscular condition is Becker muscular dystrophy.

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

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

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

24. The composition described in claim 22, wherein the muscle spasms are selected from spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury, or a traumatic event.

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

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

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

Images