Pyridazinone compounds and uses thereof

Abstract

Disclosed herein are substituted pyridazinone compounds, conjugates, and pharmaceutical compositions for use in the treatment of neuromuscular diseases such as Duchenne muscular dystrophy (DMD). The disclosed compounds are useful, inter alia, for treating DMD and regulating inflammatory inhibitors IL-1, IL-6, or TNF-. The present disclosure generally relates to substituted pyridazinone compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), or (IIa), or salts thereof, and pharmaceutical compositions thereof. The substituted pyridazinone compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), or (IIa) disclosed herein can be used to treat or prevent neuromuscular diseases.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 62 / 756,552, filed November 6, 2018, 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 a substituted pyridazinone compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), or (IIa), or a salt thereof, and pharmaceutical compositions thereof. The substituted pyridazinone compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), or (IIa) disclosed herein can be used to treat or prevent neuromuscular diseases. In some embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), or (IIa) is an inhibitor of skeletal muscle contraction. In some embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), or (IIa) is an inhibitor of myosin. In some embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), or (IIa) is an inhibitor of skeletal myosin II.

[0005] In certain embodiments, the present disclosure provides a method for treating activity-induced muscle damage, comprising administering to a subject in need thereof a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'). In certain embodiments, the subject in need thereof has a neuromuscular condition or movement disorder. Examples of neuromuscular conditions include 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. In some embodiments, the movement disorder comprises muscle spasms. In some embodiments, the muscle spasms may be selected from multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or spasticity associated with an injury or traumatic event, such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis.

[0006] The present disclosure provides compounds and salts thereof for use in the treatment of diseases. In certain aspects, the present disclosure provides compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (II'), or (IIa), pharmaceutical compositions thereof, and methods of use in the treatment of diseases.

[0007] In certain embodiments, the present disclosure provides a compound of formula (I): [ka] or a salt thereof, wherein Each X is C(R 3 ), N, and N + (-O - ), wherein at least one X is N or N + (-O - ) and A is -O-, -NR 4 -, -CR 5 R 6 selected from -, -C(O)-, -S-, -S(O)-, and -S(O)-; R 1 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10, -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 each substituted as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from Selected from or R 1 is R 3 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 5 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 or R, where appropriate.1 is R 4 together with one or more R 9 , where necessary, A is -NR 4 -If R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further increased by -N(R 10 )2 and -OR 10 is selected from Each R 2 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, and -CN; C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10, -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and C optionally substituted with one or more substituents independently selected from —CN 3~10 carbocyclic ring are independently selected from R 3 , R 5 , and R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl or R 3 is R 1 Together with 5~10form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 5 is R 1 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 , substituted as necessary with R 4 teeth, hydrogen; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from, or R 4 is R 1 together with one or more R 9 forming an optionally substituted 3- to 10-membered heterocycle, R 7 and R 8 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and halogens, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 2~6 Alkyl are independently selected from Each R 9 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 10 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are halogen, -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 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 n is 0, 1, or 2; p is 0, 1, or 2; q is 1, 2, 3, 4, or 5; R 1 When is other than -CH3, q is further selected from 0.

[0008] In certain embodiments, the present disclosure provides a compound of formula (II): [ka] or a salt thereof, wherein T is -O-, -NR 14 -, -CR 15 R 16 -, -C(O)-, -S-, -S(O)-, and -S(O)-; R 11 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 20 , -SR 20, -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -CN, C 3~5 and substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 where appropriate, and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and —CN), optionally substituted with one or more substituents independently selected from Selected from or R 11 is R15 Together with 3~10 Forms a carbocyclic ring, and the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 19 or R, where appropriate. 11 is R 14 together with one or more R 19 , substituted as necessary with T is -NR 14 -If R 11 is further selected from hydrogen, and when T is -C(O)-, R 11 is further increased by -N(R 20 )2 and -OR 20 is selected from Each R 12 teeth, Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, and -CN; Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -C(O)OR 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -OC(O)R 20, -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and C optionally substituted with one or more substituents independently selected from —CN 1~3 alkyl; and Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and C optionally substituted with one or more substituents independently selected from —CN 3~10 carbocyclic ring are independently selected from R 14 teeth, hydrogen; and Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 Alkyl are independently selected from, or R 14 is R 11 together with one or more R 19 forming an optionally substituted 3- to 5-membered heterocycle, R 15 is R 11 together with one or more R 19 Saturated C optionally substituted with3~10 forming a carbocyclic ring or a 3- to 10-membered heterocyclic ring, R 16 teeth, Hydrogen, halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, and halogens, -OR 20 , -SR 20 , -N(R 20 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from R 18 teeth, Halogen, -SR 20 , -N(R 20 )2, -NO2, and halogens, -OR 20 , -SR 20 , -N(R 20 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 2~6 Alkyl are independently selected from R 19 teeth, Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 20 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and 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, C2~6 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 z is 0, 1, or 2; v is 1, 2, 3, 4, or 5.

[0009] In certain aspects, 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 (III): [ka] or a salt thereof, wherein: Each Y is C(R 3 ), N, and N + (-O - ), and A is absent, -O-, or -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)-, and -S(O)-; R 1 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10, -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 each substituted as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from Selected from or R 1 is R 3 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 5 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 4 together with one or more R 9 , where necessary, A is -NR 4 -If R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further increased by -N(R 10 )2 and -OR 10 is selected from If A is absent, then R 1 In addition, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2 and -CN; Each R 2 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, and -CN; C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10), and C optionally substituted with one or more substituents independently selected from —CN 3~10 carbocyclic ring are independently selected from R 3 , R 5 , and R 6 are respectively, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from, or R 3 is R 1 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 5 is R 1 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 , substituted as necessary with R 4 teeth, hydrogen; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from, or R 4 is R 1 together with one or more R9 forming an optionally substituted 3- to 10-membered heterocycle, R 7 and R 8 are respectively, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and halogens, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 2~6 Alkyl are independently selected from Each R 9 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 10 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and 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 Carbocyclic rings, 3- to 10-membered heterocyclic rings, and C 1~6 and optionally substituted with one or more substituents independently selected from haloalkyl. are independently selected from R 30 and R 31 is R10 or R 30 and R 31 Let's get together and C 3~7 Forms a carbocyclic or 3- to 7-membered heterocyclic ring, wherein C 3~7 Carbocyclic and 3- to 7-membered heterocyclic rings are represented by R 9 and optionally substituted with one or more substituents independently selected from n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, or 5.

[0010] In certain aspects, the disclosure provides methods of treating a neuromuscular condition, 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 Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II') or (IIa).

[0011] In certain aspects, the present 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 Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II') or (IIa).

[0012] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II') or (IIa) and a pharmaceutically acceptable excipient. References

[0013] 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.

[0014] 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. In an embodiment of the present invention, for example, the following items are provided: (Item 1) Formula (I) [ka] or a salt thereof, or a pharmaceutically acceptable salt thereof [wherein: Each X is C(R 3 ), N, and N + (-O - ), wherein at least one X is N or N + (-O - ) and A is -O-, -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)-, and -S(O) 2 - selected from R 1 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10) 2 , -OC(O)N(R 10 ) 2 , -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), -CN, C 3~10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 each substituted as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from Selected from or R1 is R 3 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 5 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 4 together with one or more R 9 , where necessary, A is -NR 4 -If R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further increased by -N(R 10 ) 2 AND -OR 10 is selected from Each R 2 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , and -CN; C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and —CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R 10 、 -N(R10 )C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and C optionally substituted with one or more substituents independently selected from —CN 3~10 carbocyclic ring are independently selected from R 3 、R 5 , and R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 , and -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1~6 alkyl; R 3 is R 1 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 5 is R 1 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C3~10 A carbocycle may be formed by one or more R 9 , substituted as necessary with R 4 teeth, hydrogen; and Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 1~6 independently selected from alkyl, or R 4 is R 1 together with one or more R 9 forming an optionally substituted 3- to 10-membered heterocycle, R 7 and R 8 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 , -CN, -CHF 2 , -CF 3 , -CH 2 F, as well as halogens, -OR 10 , -SR 10 , -N(R 10 ) 2 , -NO 2 C optionally substituted with one or more substituents independently selected from -CN, 2~6 Alkyl are independently selected from Each R 9 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R10 ) 2 , -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O) 2 R 10 , -NO 2 , =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 ) 2 , -C(O)R 10 , -C(O)N(R 10 ) 2 , -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 ) 2 , -OC(O)N(R 10 ) 2 , -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O) 2 R10 , -NO 2 , =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 10 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are halogen, -CN, -OH, -SH, -NO 2 , -NH 2 , =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 Carbocyclic and 3- to 10-membered heterocyclic rings (which are substituted with halogen, -CN, -OH, -SH, -NO, respectively) 2 , -NH 2 , =O, =S, -OC 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 n is 0, 1, or 2; p is 0, 1, or 2; q is 1, 2, 3, 4, or 5; R 1 Ga-CH 3 otherwise, q is further selected from 0]. (Item 2) The compound of formula (I) is of formula (Ia) or formula (Ib)

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[0015] [Figure 1] Figure 1 shows the hypercontraction-induced injury that precedes the inflammation and irreversible fibrosis that characterize the pathology of late-stage DMD.

[0016] [Figure 2] Figure 2 shows that N-benzyl-p-tolyl-sulfonamide (BTS), an inhibitor of fast-twitch skeletal muscle myosin, protects muscle from pathological muscle disorganization in embryonic zebrafish models of DMD.

[0017] [Figure 3] FIG. 3 shows the reduction in pre-injury force at 100 Hz using an exemplary compound of the present disclosure, Compound 5.

[0018] [Figure 4] FIG. 4 shows post-injury force reduction at 175 Hz using an exemplary compound of the present disclosure, Compound 5.

[0019] [Figure 5] FIG. 5 shows the reduction in force during extension using an exemplary compound of the present disclosure, Compound 5.

[0020] [Figure 6] FIG. 6 shows TA mass increase after injury using an exemplary compound of the present disclosure, Compound 5. DETAILED DESCRIPTION OF THE INVENTION

[0021] 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.

[0022] Detailed Description 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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].

[0027] Inhibitors of skeletal muscle myosin that are not selective for type II fibers may result in 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 being bound by a particular mechanistic theory, the present disclosure provides selective inhibitors of fast-twitch fiber skeletal muscle myosin as a treatment option for DMD 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. definition

[0028] 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.

[0029] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] The term "cycloalkenyl" refers to a saturated ring in which each atom of the ring is carbon and at least one double bond exists between two carbon atoms of the ring. 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, cycloalkenyls contain 5 to 7 carbon atoms. A cycloalkenyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0036] The term "halo," or alternatively "halogen" or "halide," means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0037] 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.

[0038] 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 spirocycles, and 5- to 12-membered bridged rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, 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 rings, for example, 2-oxa-6-azaspiro[3.3]heptane.

[0039] 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).

[0040] 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.

[0041] 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.

[0042] 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 substituted atom and the 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.

[0043] 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.

[0044] 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)".

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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

[0050] The following is a discussion of compounds and salts thereof that may be used in the methods of the present disclosure. The compounds and salts are set forth in formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), and (III).

[0051] In certain embodiments, the present specification provides a compound of formula (I): [ka] or a salt thereof, or a pharmaceutically acceptable salt thereof, wherein: Each X is C(R 3 ), N, and N + (-O - ), wherein at least one X is N or N + (-O - ) and A is -O-, -NR 4 -, -CR 5 R 6 selected from -, -C(O)-, -S-, -S(O)-, and -S(O)-; R 1 teeth, C 1~6Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 each substituted as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10), -CN, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 substituted with one or more substituents independently selected from carbocycle, and 3- to 10-membered heterocycle, wherein 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 9 (each replaced as necessary) Selected from or R 1 is R 3 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 5 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 4 together with one or more R 9 , substituted as necessary with A is -NR 4 -If R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further increased by -N(R 10 )2 and -OR 10 is selected from Each R 2 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10)2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, and -CN; C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10)C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -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 carbocycle and 3- to 10-membered heterocycle 3~10 Carbocyclic ring (where 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 9 (each replaced as necessary) are independently selected from R 3 , R 5 , and R 6 teeth, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 Alkyl or R 3 is R 1 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 5 is R 1 Together with 3~10forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 , where necessary, R 4 teeth, hydrogen; and Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 Alkyl are independently selected from, or R 4 is R 1 together with one or more R 9 forming an optionally substituted 3- to 10-membered heterocycle, R 7 and R 8 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and halogens, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 2~6 Alkyl are each independently selected from Each R 9 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10, -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 10 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and 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 Carbocycles, 3- to 10-membered heterocycles, and haloalkyl (e.g., C 1~6 haloalkyl) are independently selected from n is 0, 1, or 2; p is 0, 1, or 2; q is 1, 2, 3, 4, or 5; R 1 When is other than -CH3, q is further selected from 0.

[0052] In certain embodiments, for a compound or salt of formula (I): R 1 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R10 ), -CN, C 3~10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 each substituted as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN), Selected from or R 1 is R 3 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 5 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 4together with one or more R 9 , where necessary, A is -NR 4 -If R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further increased by -N(R 10 )2 and -OR 10 is selected from Each R 2 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, and -CN; C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10, -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and C optionally substituted with one or more substituents independently selected from —CN 3~10 carbocyclic ring are independently selected from Each R 10 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and 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

[0053] In certain embodiments, for a compound or salt of Formula (I), each X is C(R 3 ) and N, and at least one X is N. In some embodiments, one X is N and one X is C(R 3 In some embodiments, one X is N + (-O - ), while X is C(R 3 In some embodiments, each X is N. In some embodiments, one X is N and one X is N + (-O - )

[0054] In certain embodiments, for compounds or salts of Formula (I), each X can further be C(R 3 ) is selected.

[0055] In some embodiments, the compound of formula (I) or salt thereof has the formula (Ia): [ka] is expressed by

[0056] In some embodiments, the compound of formula (I) or salt thereof has the formula (Ib): [ka] is expressed by

[0057] In some embodiments, the compound of formula (I) or salt thereof has the formula (Ic): [ka] is expressed by

[0058] In some embodiments, the compound of formula (I) or salt thereof has the formula (Id): [ka] is expressed by

[0059] In some embodiments, the compound of formula (I) or salt thereof has the formula (Ia) or (Ib): [ka] is expressed by

[0060] In some embodiments, the compound of formula (I) or salt thereof has the formula (Ic) or (Id): [ka] is expressed by

[0061] In some embodiments, the compound of formula (I) or salt thereof has the formula (Ia) or (Ic): [ka] is expressed by

[0062] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), A is —O—, —NR 4 -, -CR 5 R 6 In some embodiments, A is selected from -O- and -NR 4In some embodiments, A is selected from: In some embodiments, A is -O-. In some embodiments, A is -C(O)-. In some embodiments, A is -NR 4 -, for example, -NH-.

[0063] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -C(O)OR 10 , -OC(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 C 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 9 In some embodiments, R 1 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -C(O)OR 10 , -OC(O)R 10 , -N(R 10 )C(O)N(R10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R 1 is halogen, -OR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -C(O)OR 10 , -OC(O)R 10 , -NO2, =O, =N(R 10 ), -CN, C 3~10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R 1 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~3 alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R1 is halogen, -OR 10 , -N(R 10 )2, -NO2, =O, -CN, C 3~10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~3 alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R 1 is a C substituted with one or more halogen substituents 1~3 In some embodiments, R 1 is C 1~3 In some embodiments, R 1 is selected from -CHF, -CHF, -CF, -CHCHF, CHCHF, or -CHCF. 1 is CHCN. In some embodiments, R 1 is not unsubstituted methyl. In some embodiments, R 1 is -NH2. In some embodiments, when A is -C(O)-, R 1 is -NH2. In some embodiments, R 1 -OR 10 C replaced with 1~3 alkyl, and R 10 is C substituted with one or more halogens 1~3 In some embodiments, R 1 is -CH2CH2-OR 10 and R 10 is -CHF2 or -CH3. In some embodiments, R 1 is C substituted with =O 1~3 In some embodiments, R 1 is —C(O)—CH. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is C 3~10selected from carbocycles and 3- to 10-membered heterocycles, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R 1 is C 3~10 In some embodiments, R 1 is C 3~5 In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is a C substituted with a 4- to 6-membered heterocycle 1~3 alkyl, and the 4- to 6-membered heterocycle is one or more R 9 In some embodiments, R 1 teeth, [ka] and methyl substituted with a 4- to 6-membered heterocycle selected from:

[0064] In certain embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (Ic) or (Id), R 1 is halogen, -OR 10 , and one or more R 9 a 3- to 6-membered heterocycle optionally substituted with, and one or more R 9 C substituted as needed 3~5 C optionally substituted with one or more substituents independently selected from carbocycle 1~3 alkyl.

[0065] In certain embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (Ic) or (Id), R 1 is halogen, -OR 10 , and one or more R 9 a 3- to 6-membered heterocycle optionally substituted with, and one or more R 9 C substituted as needed 3~5C optionally substituted with one or more substituents independently selected from carbocycle 1~3 alkyl, and each R 9 But C 1~3 Alkyl, C 1~3 haloalkyl, and halogen.

[0066] In certain embodiments, for a compound or salt of Formula (I), (Ia), (Ib), (Ic) or (Id), R 1 are -CH3, -CF3, -CH2F, -CHF2, and -CH2CHF 2、 -CH2CF3, -C(=O)CH3, [ka] is selected from.

[0067] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 is selected from optionally substituted C-C cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiropentyl, any of which is optionally substituted. In certain embodiments, R 1 is selected from alkyl, e.g., methyl, ethyl, propyl, iso-propyl, t-butyl, iso-butyl, sec-butyl, any of which may be optionally substituted. In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 teeth, [ka] In certain embodiments, R 1 is replaced as necessary [ka] In some embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic) or (Id), R 1 is selected from optionally substituted C3 cycloalkyl.

[0068] In certain embodiments, for a compound or salt of Formula (I), R 1 is R 3 Together with 5~10 Forms a carbocyclic ring, 5-10 membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 In some embodiments, R 1 is R 3 Together with C 5~6 C such as carbocyclic rings and 5-6 membered heterocyclic rings 5~10 Forms a carbocyclic ring or a 5- to 10-membered heterocyclic ring, for example, [ka] is.

[0069] In certain embodiments, for a compound or salt of Formula (I), R 1 is R 5 Together with 3~10 Forms a carbocyclic ring, 3-10 membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 In some embodiments, R 1 is R 5 Together with 3~10 Forms a carbocyclic ring, e.g. [ka] is.

[0070] In certain embodiments, for a compound or salt of Formula (I), R 1 is R4 and together form a 3- to 10-membered heterocyclic ring, and the 3- to 10-membered heterocyclic ring is 9 In some embodiments, R 1 is R 4 together with the above to form a 3- to 10-membered heterocycle, for example, [ka] is.

[0071] In some embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic) or (Id), R 1 is R 4 together with one or more R 9 has been substituted as necessary.

[0072] In some embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic) or (Id), R 4 R who joined 1 The 3- to 10-membered heterocycle formed from is selected from a 4-, 5-, 6-, or 7-membered ring, any of which may be joined by one or more R 9 has been substituted as necessary.

[0073] In some embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic) or (Id), R 4 R who joined 1 The 3- to 10-membered heterocyclic ring formed from [ka] and any of them may be selected from one or more R 9 has been substituted as necessary.

[0074] In some embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic) or (Id), R 4 R who joined 1 The 3- to 10-membered heterocycle formed from [ka] is selected from.

[0075] In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is in either or both of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, each R 2 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and halogens, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~3 In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), and (Id), R 2 is in either or both of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, each R 2 is a C optionally substituted with one or more substituents independently selected from halogen, -OH, -OCH3, -OCF3, and halogen; 1~3 alkyl.

[0076] In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is in one of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, R 2is not selected from a carbocycle or a heterocycle. In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is not present in any of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule.

[0077] In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), each R 2 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and halogens, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~3 In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), and (Id), each R 2 is selected from -Cl, -F, and -OH.

[0078] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), R 2 is C 3~6 Cycloalkyl, for example, is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiropentyl, any of which is optionally substituted. In certain embodiments, R 2 teeth, [ka] is.

[0079] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), q is 0, 1, or 2. In certain embodiments, q is 0.

[0080] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), each R 3 is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and halogens, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is R 1 Together with 5~6 Forms a carbocyclic ring, 5-6 membered heterocyclic ring or C 5~6 A carbocycle may be formed by one or more R 9 In some embodiments, R 3 is R 1 together with [ka] is.

[0081] In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), R 4 represents hydrogen, as well as halogens, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 alkyl, or R 4 is R 1 together with one or more R 9In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4 is R 1 together with one or more R 9 and R 9 is selected from methyl, —CH2F, —CHF2, —CF3, —F, —OCF3, and —OCHF2.

[0082] In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), each R 5 and R 6 is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and halogens, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R 1 is R 5 Together with 3~10 In some embodiments, R 1 is R 5 together to form a cyclopropyl ring.

[0083] In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), each R 7 and R 8 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and halogens, -OR 10 , -SR10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 2~6 alkyl.

[0084] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), each R 9 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, -CN; and halogens, -OR 10 , -SR 10 , -N(R 10 each optionally substituted with one or more substituents independently selected from —C, —NO, and —CN; 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 In some embodiments, R 9 is halogen. In some embodiments, R 9 is -F. In some embodiments, R 9 is C 1~3 In some embodiments, R 9 is a C substituted with one or more fluorine substituents 1~3 In some embodiments, R 9 is —CHF, —CHF, or —CF. In some embodiments, R 9 is the unsubstituted C 1~3 In some embodiments, R 9 is methyl. In some embodiments, R 9 -OR 10 In some embodiments, R 9 -OR 10 and R 10 is C 1~3 In some embodiments, R 9 -OR10 and R 10 is —CHF, —CHF, or —CF. In some embodiments, two R 9 The groups together form one or more R 10 3- to 10-membered heterocycle optionally substituted with C 3~10 In some embodiments, two R 9 The groups taken together form a spirocyclic C substituted with one or more fluorine substituents. 3~5 In some embodiments, two R 9 The groups together form a spirocyclic cyclobutane substituted with two fluorine substituents.

[0085] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), each R 10 is 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 carbocycle, 3- to 10-membered heterocycle 1~6 Alkyl; and 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 Alkyl, C 3~10 C, each optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl 3~10 In some embodiments, R 10 is -F.

[0086] In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), n is 0.

[0087] In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), p is 0.

[0088] In certain embodiments, the compound of Formula (I) has the formula (Ie): [ka] or a salt thereof, wherein: A is -O-, -NR 4 -, -CR 5 R 6 -, and -C(O)-; X is C(R 3 ) and N are independently selected; R 1 teeth, Halogen, -OR 10 , -N(R 10 )2, -C(O)R 10 , -CN, C 3~6 Carbocyclic rings and 4- to 6-membered heterocyclic rings (where C 3~6 Carbocycles and 4- to 6-membered heterocycles may be formed by one or more R 9 C optionally substituted with one or more substituents independently selected from 1~6 alkyl, and C 3~6 carbocyclic ring Selected from or R 1 is R 3 together with one or more R 9 or R 1 is R 5 Together with this, saturated C 3~5 Form a carbocyclic ring or R 1 is R 4 together with one or more R9 forming an optionally substituted 4- to 6-membered heterocycle, When A is -C(O)-, R 1 is further increased by -N(R 10 )2 and -OR 10 is selected from Each R 2 is halogen and halogen, -OR 10 , -SR 10 , -N(R 10 ) 2、 independently selected from -NO2, -CN, Each R 9 is halogen, -OR 10 , -SR 10 , -N(R 10 ) 2、 -NO2, -CN, and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~3 Alkyl are independently selected from The Two R's 9 The groups together form one or more R 10 4-6 membered heterocycle optionally substituted with or C 3~6 Forms a carbocyclic ring, 4-6 membered heterocyclic ring or C 3~6 the carbocycle is optionally spirocyclic; Each R 10 teeth, hydrogen; and Halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1~6 Alkyl, -N(C 1~6 alkyl)2, and -NH(C 1~6 C optionally substituted with one or more substituents independently selected from 1~6 Alkyl are independently selected from

[0089] In certain embodiments, for a compound or salt of Formula (Ie), each R 9teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 ) 2、 -NO2, -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~3 Alkyl are independently selected from

[0090] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 -A is further selected from hydrogen. For example, compounds of the present disclosure include [ka] or a salt thereof, and R 7 , R 2 , X, p, q, and n are as previously described for Formula (I). In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 -A is further selected from halogen and C1-C3 alkyl, e.g., C2-C3 alkyl. In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 -A is further selected from halogen.

[0091] In certain embodiments, the compound of the present disclosure is selected from the compounds in Table 1 or a salt thereof.

[0092] In certain embodiments, the present specification provides a compound of formula (II'): [ka] or a salt thereof, wherein: T is -O-, -NR 14 -, -CR 15 R 16 selected from -, -C(O)-, -S-, -S(O)-, and -S(O)-; R 11 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -CN, C 3~10 and substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 19 where appropriate, and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20)2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and —CN), optionally substituted with one or more substituents independently selected from Selected from or R 11 is R 17 Together with 5~10 forming a carbocyclic ring, and 5~10 A carbocycle may be formed by one or more R 19 or R, where appropriate. 11 is R 15 Together with 3~10 Forms a carbocyclic ring, and the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 19 or R, where appropriate. 11 is R 14 together with one or more R 19 , where necessary, T is -NR 14 -If R 11 is further selected from hydrogen, and when T is -C(O)-, R 11 is further increased by -N(R 20 )2 and -OR 20 is selected from Each R 12 teeth, Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, -CN; C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -C(O)OR 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and —CN; and Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20, -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and C optionally substituted with one or more substituents independently selected from —CN 3~10 carbocyclic ring are independently selected from R 14 teeth, hydrogen; and Halogen, -OR 20 , -SR 20 , -N(R 20 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from, or R 14 is R 11 together with one or more R 19 forming an optionally substituted 3- to 10-membered heterocycle, R 15 and R 16 teeth, Hydrogen, halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, and halogens, -OR 20 , -SR 20 , -N(R 20 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from or R 15 is R 11 together with one or more R 19 Saturated C optionally substituted with 3~10 forming a carbocyclic ring or a 3- to 10-membered heterocyclic ring, R 17 and R 18 are respectively, Halogen, -SR 20 , -N(R 20 )2, -NO2, -CN, and halogens, -OR 20 , -SR20 , -N(R 20 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 Alkyl are independently selected from, or R 17 is R 11 together with one or more R 19 C, substituted as needed 5~10 forming a carbocyclic ring or a 5- to 10-membered heterocyclic ring, R 19 teeth, Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 20 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and 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 w is 0, 1, or 2; z is 0, 1, or 2; v is 1, 2, 3, 4, or 5, and R 11 When is other than -CH3, v is further selected from 0.

[0093] In certain embodiments, the present specification provides a compound of formula (II): [ka] or a salt thereof, wherein: T is -O-, -NR 14 -, -CR 15 R 16 selected from -, -C(O)-, -S-, -S(O)-, and -S(O)-; R 11 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -CN, C 3~5 and substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein 3~5 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 19 where appropriate, and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and —CN), optionally substituted with one or more substituents independently selected from Selected from or R 11 is R 15 Together with 3~10 Forms a carbocyclic ring, and the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 19 or R, where appropriate. 11 is R 14 together with one or more R 19 , where necessary, T is -NR 14 -If R 11 is further selected from hydrogen, and when T is -C(O)-, R 11 is further increased by -N(R 20 )2 and -OR 20 is selected from Each R 12 teeth, Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20)2, C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, -CN; Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -C(O)OR 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and C optionally substituted with one or more substituents independently selected from —CN 1~3 alkyl; and Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and C optionally substituted with one or more substituents independently selected from —CN 3~10 carbocyclic ring are independently selected from R 14 teeth, hydrogen; and Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 Alkyl are independently selected from, or R 14 is R 11 together with one or more R 19 forming an optionally substituted 3- to 10-membered heterocycle, R 15 is R 11 together with one or more R 19 Saturated C optionally substituted with 3~10 forming a carbocyclic ring or a 3- to 10-membered heterocyclic ring, R 16 teeth, Hydrogen, halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, and halogens, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 Alkyl are independently selected from R 18 teeth, Halogen, -SR 20 , -N(R 20 )2, -NO2, and halogens, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 2~6 Alkyl are independently selected from R 19 teeth, Halogen, -OR20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 20 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and C2~6 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 z is 0, 1, or 2; v is 1, 2, 3, 4, or 5.

[0094] In certain embodiments, for a compound or salt of Formula (II) or (II'), T is -O-, -NR 14 -, -CR 15 R 16 In some embodiments, T is selected from -O- and -NR 14 In some embodiments, T is selected from: In some embodiments, T is -O-. In some embodiments, T is -C(O)-. In some embodiments, T is -NR 14 -, for example, -NH-.

[0095] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), R11 is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -C(O)OR 20 , -OC(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -CN, C 3~5 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~6 alkyl, C 3~5 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 19 In some embodiments, R 11 is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -C(O)OR 20 , -OC(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -CN, C 3~5C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl, C 3~5 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 19 In some embodiments, R 11 is halogen, -OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 、 -C(O)OR 20 , -OC(O)R 20 , -NO2, =O, =N(R 20 ), -CN, C 3~5 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl, C 3~5 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 19 In some embodiments, R 11 is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, =O, =S, =N(R 20 ), -CN, C 3~5 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~3 alkyl, C 3~5 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 19 In some embodiments, R 11 is halogen, -OR 20 , -N(R 20 )2, -NO2, =O, -CN, C 3~5 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~3 alkyl, C 3~5Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 19 In some embodiments, R 11 is a C substituted with one or more halogen substituents 1~3 In some embodiments, R 11 is C 1~3 In some embodiments, R 11 is selected from -CHF, -CHF, -CF, -CHCHF, CHCHF, or -CHCF. 11 is CHCN. In some embodiments, R 11 is not unsubstituted methyl. In some embodiments, R 11 is -NH2. In some embodiments, when A is -C(O)-, R 11 is -NH2. In some embodiments, R 11 -OR 20 C replaced with 1~3 alkyl, and R 20 is C substituted with one or more halogens 1~3 In some embodiments, R 11 is -CH2CH2-OR 20 and R 20 is -CHF2 or -CH3. In some embodiments, R 11 is C substituted with =O 1~3 In some embodiments, R 11 is —C(O)—CH. In some embodiments, R 11 is -CH3. In some embodiments, R 11 is C 3~5 selected from carbocycles and 3- to 10-membered heterocycles, 3~5 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 19 In some embodiments, R 11 is C 3~5In some embodiments, R 11 is cyclopropyl. In some embodiments, R 11 is a C substituted with a 4- to 6-membered heterocycle 1~3 alkyl, and the 4- to 6-membered heterocycle is one or more R 19 In some embodiments, R 11 teeth, [ka] and methyl substituted with a 4- to 6-membered heterocycle selected from:

[0096] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), R 11 is selected from optionally substituted C-C cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiropentyl, any of which is optionally substituted. In certain embodiments, R 11 is selected from alkyl, e.g., methyl, ethyl, propyl, iso-propyl, t-butyl, iso-butyl, sec-butyl, any of which may be optionally substituted. In certain embodiments, R 11 teeth, [ka] In certain embodiments, R 11 teeth, [ka] In certain embodiments, R 11 is replaced as necessary [ka] is selected from.

[0097] In certain embodiments, for a compound or salt of Formula (II) or (II'), R11 is R 17 Together with 5~10 Forms a carbocyclic ring, 5-10 membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 19 In some embodiments, R 11 is R 17 Together with C 5~6 C such as carbocyclic rings and 5-6 membered heterocyclic rings 5~10 Forms a carbocyclic ring or a 5- to 10-membered heterocyclic ring, for example, [ka] is.

[0098] In certain embodiments, for a compound or salt of Formula (II) or (II'), R 11 is R 15 Together with 3~10 Forms a carbocyclic ring, 3-10 membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 19 In some embodiments, R 11 is R 15 Together with 3~10 Forms a carbocyclic ring, e.g. [ka] is.

[0099] In certain embodiments, for a compound or salt of Formula (II) or (II'), R 11 is R 14 and together form a 3- to 10-membered heterocyclic ring, and the 3- to 10-membered heterocyclic ring is 19 In some embodiments, R 11 is R 14 together with the above to form a 3- to 10-membered heterocycle, for example, [ka] is.

[0100] In some embodiments, for a compound or salt of any one of Formula (II) or (II'), each R 12 is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, and halogens, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~3 In some embodiments, each R 12 is selected from -Cl, -F, and -OH.

[0101] In certain embodiments, for a compound or salt of Formula (II) or (II'), R 12 is C 3~6 Cycloalkyl, for example, is selected from cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiropentyl, any of which is optionally substituted. In certain embodiments, R 12 teeth, [ka] is.

[0102] In certain embodiments, v is 0, 1, or 2. In certain embodiments, v is 0.

[0103] In some embodiments, for a compound or salt of any one of Formula (II) or (II'), R 12 is in either or both of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, each R 12 is halogen, -OR 20 , -SR 20 , -N(R 20)2, -NO2, -CN, and halogens, -OR 20 , -SR 20 , -N(R 20 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~3 In some embodiments, for a compound or salt of any one of Formula (II) or (II'), R 12 is in either or both of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, each R 12 is a C optionally substituted with one or more substituents independently selected from halogen, -OH, -OCH3, -OCF3, and halogen; 1~3 alkyl.

[0104] In some embodiments, for a compound or salt of either Formula (II) or (II'), R 12 is in one of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, R 12 is not selected from a carbocycle or a heterocycle. In some embodiments, for a compound or salt of any one of formula (II) or (II'), R 12 is not present in any of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule.

[0105] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), R 14 represents hydrogen, as well as halogens, -OR 20 , -SR 20 , -N(R 20 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 alkyl, or R 14 is R 11 together with one or more R 19 In some embodiments, R 14is hydrogen. In some embodiments, R 14 is methyl. In some embodiments, R 14 is R 11 together with one or more R 19 and R 19 is selected from methyl, —CH2F, —CHF2, —CF3, —F, —OCF3, and —OCHF2.

[0106] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), each R 15 and R 16 is hydrogen, halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, and halogens, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R 11 is R 15 Together with 3~10 In some embodiments, R 11 is R 15 together to form a cyclopropyl ring.

[0107] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), each R 17 is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and halogens, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 2~6alkyl.

[0108] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), each R 18 is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CHF2, -CF3, -CH2F, as well as halogens, -OR 20 , -SR 20 , -N(R 20 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 2~6 alkyl.

[0109] In some embodiments, for a compound or salt of any one of Formula (II) or (II'), R 17 is R 11 Together with 5~6 Forms a carbocyclic ring, 5-6 membered heterocyclic ring or C 5~6 A carbocycle may be formed by one or more R 19 In some embodiments, R 17 is R 11 together with [ka] is.

[0110] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), each R 19 is halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, =O, =S, -CN; and halogens, -OR 20 , -SR 20 , -N(R 20each optionally substituted with one or more substituents independently selected from —C, —NO, and —CN; 1~3 Alkyl, C 2~3 Alkenyl, C 2~3 In some embodiments, R 19 is halogen. In some embodiments, R 19 is -F. In some embodiments, R 19 is C 1~3 In some embodiments, R 19 is a C substituted with one or more fluorine substituents 1~3 In some embodiments, R 19 is —CHF, —CHF, or —CF. In some embodiments, R 19 is the unsubstituted C 1~3 In some embodiments, R 19 is methyl. In some embodiments, R 19 -OR 20 In some embodiments, R 19 -OR 20 and R 20 is haloalkyl. In some embodiments, R 19 -OR 20 and R 20 is —CHF, —CHF, or —CF. In some embodiments, two R 19 The groups together form one or more R 20 3- to 10-membered heterocycle optionally substituted with C 3~10 In some embodiments, two R 19 The groups taken together form a spirocyclic C substituted with one or more fluorine substituents. 3~5 In some embodiments, two R 19 The groups together form a spirocyclic cyclobutane substituted with two fluorine substituents.

[0111] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), each R 20 is 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 carbocycle, 3- to 10-membered heterocycle 1~6 Alkyl; and 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 Alkyl, C 3~10 C, each optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl 3~10 In some embodiments, R 20 is -F.

[0112] In certain embodiments, for compounds of Formula (II), w is 0.

[0113] In certain embodiments, z is 0 for compounds of Formula (II) or (II').

[0114] In certain embodiments, v is 1 or 2 for compounds of Formula (II) or (II').

[0115] In certain embodiments, the compound of Formula (II) has the formula (IIa): [ka] or a salt thereof, wherein: A is -O-, -NR 14-, -CR 15 R 16 -, and -C(O)-; R 11 teeth, Halogen, -OR 20 , -N(R 20 )2, -C(O)R 20 , -CN, C 3~6 Carbocyclic rings and 4- to 6-membered heterocyclic rings (where C 3~6 Carbocycles and 4- to 6-membered heterocycles may be formed by one or more R 9 C optionally substituted with one or more substituents independently selected from 1~6 alkyl, and C 3~6 carbocyclic ring Selected from or R 11 is R 13 together with one or more R 19 or R 11 is R 15 Together with this, saturated C 3~5 forming a carbocyclic ring, or R 11 is R 14 together with one or more R 19 forming an optionally substituted 4- to 6-membered heterocycle, When A is -C(O)-, R 11 is further increased by -N(R 20 )2 and -OR 20 is selected from Each R 12 is halogen and halogen, -OR 20 , -SR 20 , -N(R 20 ) 2、 independently selected from -NO2, -CN, R 17 is R 11 together with one or more R 19 forming an optionally substituted 5- to 10-membered heterocycle, Each R 19 is halogen, -OR 20, -SR 20 , -N(R 20 ) 2、 -NO2, -CN, and Halogen, -OR 20 , -SR 20 , -N(R 20 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~3 Alkyl are independently selected from The Two R's 19 The groups together form one or more R 20 4-6 membered heterocycle optionally substituted with or C 3~6 Forms a carbocyclic ring, 4-6 membered heterocyclic ring or C 3~6 the carbocycle is optionally spirocyclic; Each R 20 teeth, hydrogen; and Halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1~6 Alkyl, -N(C 1~6 alkyl)2, and -NH(C 1~6 C optionally substituted with one or more substituents independently selected from 1~6 Alkyl are independently selected from w is 0 or 1, v is 1 or 2.

[0116] In certain embodiments, w is 0 for a compound or salt of Formula (II') or (IIa).

[0117] In certain embodiments, for a compound or salt of any one of Formula (II), (II'), or (IIa), R 11 -T is further selected from hydrogen. For example, the compound of formula (II') is [ka] or a salt thereof, wherein R 17 , R 18, R 12 , w, z and v are as described for formula (II').

[0118] In certain embodiments, the compound of the present disclosure is selected from the compounds in Table 2 or salts thereof.

[0119] 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.

[0120] "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:

[0121] The compounds disclosed herein may, in some embodiments, be, for example, 2 H, 3 H, 11 C. 13 C and / or 14 The 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.

[0122] 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.

[0123] 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, 37 Cl, 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.

[0124] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2is 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:

[0125] Deuterium-substituted compounds are synthesized using a variety of methods, such as those described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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 cell 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.

[0134] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent. In some embodiments, the prodrug design increases the effective water solubility. For example, Fedorak et al., Am. J. Physiol., 269:G210-218 (1995), McLoed et al., Gastroenterol, 106:405-413 (1994), Hochhaus et al., Biomed. Chrom., 6:283-286 (1992), J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987), J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988), Sinkula et al., J. Pharm. Sci., 64:181-210 (1975), T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series; and Edward See B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987 (the entire disclosure of which is 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.

[0135] Synthetic chemistry transformations 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 application

[0136] The administration method of the compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II') or (IIa) 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 (e.g., stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis).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 are also included.

[0137] In some embodiments, disclosed herein are methods for treating neuromuscular and movement disorders by administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), or (IIa). In some embodiments, disclosed herein are methods for treating neuromuscular and movement disorders by administering a compound or salt of Formula (III) [ka] or a salt thereof, wherein: Each Y is C(R 3 ), N, and N + (-O - ), and A is absent, -O-, or -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)-, and -S(O)-; R 1 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3~10and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 each substituted as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from Selected from or R 1 is R 3 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 5 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 4together with one or more R 9 , substituted as necessary with A is -NR 4 -If R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further increased by -N(R 10 )2 and -OR 10 is selected from If A is absent, then R 1 In addition, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2 and -CN; Each R 2 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10, -NO2, and -CN; C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and C optionally substituted with one or more substituents independently selected from —CN 3~10 carbocyclic ring are independently selected from R3 , R 5 , and R 6 are respectively, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from, or R 3 is R 1 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 5 is R 1 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 , substituted as necessary with R 4 teeth, hydrogen; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from, or R 4 is R 1 together with one or more R 9 forming an optionally substituted 3- to 10-membered heterocycle, R 7 and R 8 are respectively, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and halogens, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 2~6 Alkyl are independently selected from Each R 9 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10, -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 10 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and 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 30 and R 31 is R 10 or R 30 and R 31 Let's get together and C 3~7 Forms a carbocyclic or 3- to 7-membered heterocyclic ring, wherein C3~7 Carbocyclic and 3- to 7-membered heterocyclic rings are represented by R 9 and optionally substituted with one or more substituents independently selected from n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, or 5.

[0138] In some embodiments, the present disclosure provides a compound of formula (III'): [ka] or a salt thereof, wherein: Each Y is C(R 3 ), N, and N + (-O - ), and A is -O-, -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)-, and -S(O)-; R 1 teeth, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10, -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 each substituted as necessary), and C 3~10 Carbocyclic and 3- to 10-membered heterocyclic rings (each of which is substituted with halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from Selected from or R 1 is R 3 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 1 is R 5 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 or R, where appropriate.1 is R 4 together with one or more R 9 , substituted as necessary with A is -NR 4 -If R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further increased by -N(R 10 )2 and -OR 10 is selected from Each R 2 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from R 3 , R 5 , and R 6 are respectively, Hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from, or R 3 is R 1 Together with 5~10 form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 or R, where appropriate. 5 is R 1 Together with 3~10 forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 , substituted as necessary with R 4 teeth, hydrogen; and Halogen, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 Alkyl are independently selected from, or R 4 is R 1 together with one or more R 9 forming an optionally substituted 3- to 10-membered heterocycle, R 7 and R 8 are respectively, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and halogens, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 2~6 Alkyl are independently selected from Each R 9 teeth, Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1~3 Alkyl, C 2~3 Alkenyl, and C 2~3 Alkynyl (which are each halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and —CN), optionally substituted with one or more substituents independently selected from are independently selected from Each R 10 teeth, hydrogen; C 1~6 Alkyl, C 2~6 Alkenyl, and 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 n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, or 5.

[0139] In certain embodiments, for compounds or salts of Formula (III) or (III'), at least one Y is selected from the group consisting of N and N + (-O - In certain embodiments, for a compound or salt of formula (III) or (III'), one Y is N and the other is C(R 3 ), or each Y is N.

[0140] In certain embodiments, for a compound or salt of Formula (III) or (III′), each Y is C(R 3 ) and N, and at least one Y is N. In some embodiments, one Y is N and one Y is C(R 3 In some embodiments, one Y is N + (-O - ), while Y is C(R 3 In some embodiments, each Y is N. In some embodiments, one Y is N and one Y is N + (-O - In certain embodiments, for a compound or salt of formula (III) or (III'), each Y is C(R 3 )

[0141] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), A is -O-, -NR 4 -, -CR 5 R 6 In some embodiments, A is selected from -O- and -NR4 In some embodiments, A is selected from: In some embodiments, A is -O-. In some embodiments, A is -C(O)-. In some embodiments, A is -NR 4 -, for example, -NH-.

[0142] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), R 1 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -C(O)OR 10 , -OC(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 C 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 9 In some embodiments, R 1 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -C(O)OR 10 , -OC(O)R 10 , -N(R 10 )C(O)N(R10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 are substituted as necessary.

[0143] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), R 1 is halogen, -OR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 、 -C(O)OR 10 , -OC(O)R 10 , -NO2, =O, =N(R 10 ), -CN, C 3~10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~6 alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R 1 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, =N(R 10 ), -CN, C 3~10 C optionally substituted with one or more substituents independently selected from carbocycle and 3- to 10-membered heterocycle 1~3 alkyl, C 3~10Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R 1 is halogen, -OR 10 , -N(R 10 )2, -NO2, =O, -CN, C 3~10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1~3 alkyl, C 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R 1 is a C substituted with one or more halogen substituents 1~3 In some embodiments, R 1 is C 1~3 In some embodiments, R 1 is selected from -CHF, -CHF, -CF, -CHCHF, CHCHF, or -CHCF. 1 is CHCN. In some embodiments, R 1 is not unsubstituted methyl. In some embodiments, R 1 is -NH2. In some embodiments, when A is -C(O)-, R 1 is -NH2. In some embodiments, R 1 -OR 10 C replaced with 1~3 alkyl, and R 10 is C substituted with one or more halogens 1~3 In some embodiments, R 1 is -CH2CH2-OR 10 and R 10 is -CHF2 or -CH3. In some embodiments, R 1 is C substituted with =O 1~3 In some embodiments, R 1is —C(O)—CH. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is C 3~10 selected from carbocycles and 3- to 10-membered heterocycles, 3~10 Carbocycles and 3- to 10-membered heterocycles may be formed by one or more R 9 In some embodiments, R 1 is C 3~10 In some embodiments, R 1 is C 3~5 In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is a C substituted with a 4- to 6-membered heterocycle 1~3 alkyl, and the 4- to 6-membered heterocycle is one or more R 9 In some embodiments, R 1 teeth, [ka] and methyl substituted with a 4- to 6-membered heterocycle selected from:

[0144] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), R 1 is selected from optionally substituted C-C cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiropentyl, any of which is optionally substituted. In certain embodiments, R 1 is selected from alkyl, e.g., methyl, ethyl, propyl, iso-propyl, t-butyl, iso-butyl, sec-butyl, any of which may be optionally substituted. In certain embodiments, R 1 teeth, [ka] In certain embodiments, R1 is replaced as necessary [ka] is selected from.

[0145] In certain embodiments, for a compound or salt of Formula (III) or (III'), R 1 is R 3 Together with 5~10 Forms a carbocyclic ring, 5-10 membered heterocyclic ring or C 5~10 A carbocycle may be formed by one or more R 9 In some embodiments, R 1 is R 3 Together with C 5~6 C such as carbocyclic rings and 5-6 membered heterocyclic rings 5~10 Forms a carbocyclic ring or a 5- to 10-membered heterocyclic ring, for example, [ka] is.

[0146] In certain embodiments, for a compound or salt of Formula (III) or (III'), R 1 is R 5 Together with 3~10 Forms a carbocyclic ring, 3-10 membered heterocyclic ring or saturated C 3~10 A carbocycle may be formed by one or more R 9 In some embodiments, R 1 is R 5 Together with 3~10 Forms a carbocyclic ring, e.g. [ka] is.

[0147] In certain embodiments, for a compound or salt of Formula (III) or (III'), R 1 is R4 and together form a 3- to 10-membered heterocyclic ring, and the 3- to 10-membered heterocyclic ring is 9 In some embodiments, R 1 is R 4 together with the above to form a 3- to 10-membered heterocycle, for example, [ka] is.

[0148] In some embodiments, for a compound or salt of any one of Formula (III) or (III'), each R 2 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and halogens, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~3 In some embodiments, for a compound or salt of any one of Formula (III) or (III'), R 2 is selected from -Cl, -F, and -OH. In certain embodiments, q is 0, 1, or 2. In certain embodiments, q is 0.

[0149] In some embodiments, for a compound or salt of any one of formula (III) or (III'), R 2 is in either or both of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, each R 2 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and halogens, -OR 10 , -SR 10 , -N(R 10C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~3 In some embodiments, for a compound or salt of any one of Formula (III) or (III'), R 2 is in either or both of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, each R 2 is a C optionally substituted with one or more substituents independently selected from halogen, -OH, -OCH3, -OCF3, and halogen; 1~3 alkyl.

[0150] In some embodiments, for a compound or salt of either Formula (III) or (III'), R 2 is in one of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, R 2 is not selected from a carbocycle or a heterocycle. In some embodiments, for a compound or salt of any one of formula (III) or (III'), R 2 is not present in any of the ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule.

[0151] In certain embodiments, for a compound or salt of Formula (III) or (III'), each R 3 is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and halogens, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is R 1 Together with 5~6Forms a carbocyclic ring, 5-6 membered heterocyclic ring or C 5~6 A carbocycle may be formed by one or more R 9 In some embodiments, R 3 is R 1 together with [ka] is.

[0152] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), R 4 represents hydrogen, as well as halogens, -OR 10 , -SR 10 , -N(R 10 C optionally substituted with one or more substituents independently selected from —C, —NO, and —CN. 1~6 alkyl, or R 4 is R 1 together with one or more R 9 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4 is R 1 together with one or more R 9 and R 9 is selected from methyl, —CH2F, —CHF2, —CF3, —F, —OCF3, and —OCHF2.

[0153] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), each R 5 and R 6 is hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10)2, -NO2, -CN, and halogens, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 1~6 In some embodiments, R 1 is R 5 Together with 3~10 In some embodiments, R 1 is R 5 together to form a cyclopropyl ring.

[0154] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), each R 7 and R 8 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and halogens, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN, optionally substituted with one or more substituents independently selected from 2~6 alkyl.

[0155] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), each R 9 is halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, -CN; and halogens, -OR 10 , -SR 10 , -N(R 10 each optionally substituted with one or more substituents independently selected from —C, —NO, and —CN; 1~3 Alkyl, C 2~3 Alkenyl, C 2~3In some embodiments, R 9 is halogen. In some embodiments, R 9 is -F. In some embodiments, R 9 is C 1~3 In some embodiments, R 9 is a C substituted with one or more fluorine substituents 1~3 In some embodiments, R 9 is —CHF, —CHF, or —CF. In some embodiments, R 9 is the unsubstituted C 1~3 In some embodiments, R 9 is methyl. In some embodiments, R 9 -OR 10 In some embodiments, R 9 -OR 10 and R 10 is C 1~3 In some embodiments, R 9 -OR 10 and R 10 is —CHF, —CHF, or —CF. In some embodiments, two R 9 The groups together form one or more R 10 3- to 10-membered heterocycle optionally substituted with C 3~10 In some embodiments, two R 9 The groups taken together form a spirocyclic C substituted with one or more fluorine substituents. 3~5 In some embodiments, two R 9 The groups together form a spirocyclic cyclobutane substituted with two fluorine substituents.

[0156] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), each R 10 is hydrogen; halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC1~6 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 carbocycle, 3- to 10-membered heterocycle 1~6 Alkyl; and 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 Alkyl, C 3~10 C, each optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl 3~10 In some embodiments, R 10 is -F.

[0157] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), n is 0.

[0158] In certain embodiments, p is 0 for a compound or salt of any one of Formula (III) or (III').

[0159] In certain embodiments, for a compound or salt of any one of Formula (III) or (III'), R 1 -A is further selected from hydrogen. For example, the compound of formula (III) or (III') may further comprise: [ka] or a salt thereof.

[0160] A method for treating neuromuscular and movement disorders by reducing skeletal muscle contraction is provided 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can reduce muscle breakdown and cause less muscle damage by preventing excessive uncoordinated muscle contraction. Furthermore, the disclosed method can reduce muscle damage while minimizing the impact on physical function in subjects. 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 inhibitor of skeletal myosin II is a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') disclosed herein.

[0161] In some embodiments, disclosed herein are methods of inhibiting muscle myosin II, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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 reduces myocardial force by less than 10%.

[0162] In some aspects, a method for treating a neuromuscular condition or movement disorder may include administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') to inhibit skeletal muscle contraction. In some embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') does not significantly inhibit myocardial contraction. In some embodiments, myocardial contraction is inhibited by 20% or less. In some embodiments, myocardial contraction is inhibited by 15% or less. In some embodiments, myocardial contraction is inhibited by 10% or less. In some embodiments, myocardial contraction is inhibited by 9% or less. In some embodiments, myocardial contraction is inhibited by 8% or less. In some embodiments, myocardial contraction is inhibited by 7% or less. In some embodiments, myocardial contraction is inhibited by 6% or less. In some embodiments, myocardial contraction is inhibited by 5% or less. In some embodiments, myocardial contraction is inhibited by 4% or less. In some embodiments, myocardial contraction is inhibited by 3% or less. In some embodiments, myocardial contraction is inhibited by 2% or less. In some embodiments, myocardial contraction is inhibited by 1% or less.

[0163] 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III').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.

[0164] In some aspects, a method of treating a neuromuscular condition or movement disorder can include administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') to inhibit skeletal muscle contraction. The compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can be given in an amount relative to the amount required to reduce skeletal muscle contraction by 50%. The compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') may be administered in an amount less than that required to reduce skeletal muscle contraction by 50% relative to the subject's pre-treatment skeletal muscle contractile capacity. The compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') may be administered in an amount that reduces skeletal muscle contraction by 5% to 45% relative to the subject's pre-treatment skeletal muscle contractile capacity. In some cases, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can 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.

[0165] In some aspects, a method for treating a neuromuscular condition or movement disorder can include administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0166] In some aspects, a method for treating a neuromuscular condition or movement disorder can include administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') to inhibit type II skeletal muscle contraction. The inhibitor of type II skeletal muscle contraction can 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 can 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 can be administered in an amount that reduces type II skeletal muscle contraction by 5% to 90% 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.

[0167] In some aspects, methods of treating contraction-induced injury in skeletal muscle fibers can include administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') to inhibit skeletal muscle contraction and / or skeletal myosin II. In certain embodiments, the inhibitor does not appreciably inhibit cardiac muscle contraction.

[0168] 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.

[0169] In some aspects, a method of treating metabolic myopathy, e.g., McArdle syndrome, can include administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III').

[0170] In certain embodiments, administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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 levels of the biomarkers 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 be decreased 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 may indicate treatment of a neuromuscular condition (e.g., those described herein).

[0171] 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 evaluating skeletal muscle breakdown caused by skeletal muscle contraction. In some embodiments, a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') 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 the subject's 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.

[0172] In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III) can reduce CK levels in a subject relative to an untreated subject engaging in the same activity. The 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 the inhibitors described herein can modulate the CK levels by about 5% to about 90% relative to an untreated subject performing the same activity, thereby reducing or preventing skeletal muscle breakdown resulting from the activity. Administration of the inhibitors described herein can reduce the CK 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 modulate 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.

[0173] Administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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 peripheral blood of the subject. 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 pre-treatment level of the inflammatory marker in the subject. Alternatively, the level of the inflammatory marker in the peripheral blood may decrease after administration of the inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Administration of an inhibitor described herein may modulate inflammatory marker levels 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.

[0174] Administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') to a subject can modulate the level of circulating fast skeletal muscle troponin I (fS-TnI). The fS-TnI level can be measured in peripheral blood. The fS-TnI level in the peripheral blood can be increased 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 be decreased 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 levels may be modulated by at least about 5% relative to the subject's pre-treatment levels of fS-TnI. In some cases, the fS-TnI levels may 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.

[0175] Troponin isoforms can be measured in a subject before and after administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'). Inhibition of skeletal muscle contraction may not inhibit some troponin isoforms (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 prior to administration of the inhibitor.

[0176] Administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0177] The compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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 / 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 reduction in the level of ADL or habitual activity of 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 before 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'). Such measurements can be performed to generate a dose-response curve for a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'). The dosage of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can be adjusted by about 5% to 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 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 up to about 50% of 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 up to about 5% of 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 up to about 5% of the dose that reduces type II skeletal muscle contractions by 90%, such as 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.

[0178] The subject's myocardial strength or contractility can be measured before and after administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'). 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 prior to administration of the inhibitor. After administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'), a subject's myocardial strength or contraction may be within 0.1% to 10% of the myocardial contraction or force before administration of the inhibitor. In some embodiments, administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') may 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 the ratio of each other. For example, in some embodiments, the ratio of reduction in skeletal muscle contraction to reduction in cardiac muscle 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 strength or contractility can be measured using echocardiography (left ventricular fractional shortening) or other equivalent tests.

[0179] The tidal volume in the lungs of a subject can be measured before and after administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III'). 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.

[0180] 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.

[0181] Neuromuscular coupling in a subject can be measured before and after administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'). 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.

[0182] 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'), wherein the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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 the wells of a nucleotide-free assay plate. 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 consumed in the test vessel over a defined period can be compared to the amount of ATP consumed 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 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 indirectly measure ATPase activity by coupling the myosin to pyruvate kinase and lactate dehydrogenase, providing absorbance detection at 340 nm based on the conversion of NADH to NAD+ driven by ADP accumulation.In some cases, the test compound may be selected as a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') if ATP consumption is reduced by at least 20% in the test vessel compared to the control vessel. A test compound may be selected if it inhibits NAD production by at least 20% in a kinetic assay.

[0183] The selected inhibitor or test compound may not inhibit cardiac myosin S1 ATPase in an in vitro assay. In some cases, the cardiac myosin S1 ATPase or cardiac myofibril or reconstituted system may be inhibited by less than 10%, less than 8%, less than 5%, less than 3%, less than 2%, less than 1%, or less than 0.5% when the test compound or compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') is tested in an in vitro assay.

[0184] 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0185] The inhibitor compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') may inhibit 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 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 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.

[0186] The effect of test compound on slow-twitch type I skeletal muscle fibers, cardiac muscle bundles or pulmonary muscle fibers can be evaluated. Test compound or inhibitor compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') can be selected so that it does not appreciably regulate the function of slow-twitch type I skeletal muscle fibers, cardiac muscle bundles or pulmonary muscle fibers, 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.

[0187] 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'), wherein the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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., mdx mouse). The mdx mouse has a point mutation in its dystrophin gene, which changes the amino acid glutamine to threonine, producing a nonfunctional dystrophin protein and resulting in DMD, which is characterized by increased muscle damage and weakness. The extensor digitorum longus muscle can be dissected from the 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can be applied to the muscle. An isometric (fixed-length) contraction procedure can then be performed, in which the muscle is stimulated with a series of electrical pulses. An abnormal (eccentric) contraction step may be performed, in which the muscle is stretched 10%, 15%, 20%, 25%, or 30% longer than its resting length and then relaxed or stimulated with an electrical pulse. In some embodiments, the abnormal contraction step is repeated 2 to 50 times. In some embodiments, the abnormal contraction step is repeated 2 to 40 times. In some embodiments, the abnormal contraction step is repeated 2 to 30 times. In some embodiments, the abnormal contraction step is repeated 2 to 20 times. In some embodiments, the abnormal 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 induce 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, 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III').

[0188] The muscle force generated by the muscle can be measured using an isometric or non-conventional contraction set. 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can be selected if the test muscle force decline is at least 20% less than the control muscle force decline. Pharmaceutical preparations

[0189] 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), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') described herein, and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and / or thickening agents.

[0190] Pharmaceutical compositions containing compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0191] Methods for formulating a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0192] Pharmaceutical compositions containing a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0193] The compositions and formulations may be sterilized, which may be achieved by filtration via sterile filtration.

[0194] Compositions containing compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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 compositions can be lyophilized or in powder form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0195] For parenteral administration, the compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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. The vehicle can contain small amounts of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0196] In one embodiment, the present invention relates to methods and compositions of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0197] In one embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0198] In another embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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, hypromellose, 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, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, or triethyl citrate.

[0199] In another embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') is an enteric-coated controlled-release tablet for oral administration. The composition may further comprise carnauba wax, crospovidone, diacetylated monoglyceride, ethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, or yellow iron oxide.

[0200] Sustained-release preparations containing the compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') can also be prepared. Examples of sustained-release preparations can include semipermeable matrices of solid hydrophobic polymers that can contain the compound, salt or conjugate, and these matrices can be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained-release matrices can include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide, copolymers of L-glutamic acid and gamma-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 copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0201] Pharmaceutical formulations comprising a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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 nontoxic 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.

[0202] In another embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') can 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.

[0203] In another embodiment, the compositions of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') are provided in effervescent dosage forms. These effervescent dosage forms may also contain non-controlled release excipients.

[0204] In another embodiment, the compositions of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') 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.

[0205] In another embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') 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.

[0206] In some embodiments, the compositions of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') provided herein may be in unit-dosage or multiple-dosage form. A unit-dosage form, as used herein, refers to a physically discrete, individually packaged unit suitable for administration to a human or non-human animal subject. Each unit dose may 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 may be administered in separate doses or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container, which may 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, the multiple-dosage form comprises different pharmaceutically active agents.

[0207] In some embodiments, the compositions of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') 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

[0208] 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 therapeutic 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), as well as the administration of at least two of these therapeutic agents or therapeutic agents in a substantially simultaneous manner.

[0209] 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.

[0210] 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.

[0211] 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.

[0212] 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]

[0213] 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.

[0214] 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 of the present disclosure 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 General Scheme - Synthesis of 2-benzyl-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one [ka] Example 2 Exemplary Scheme - Synthesis of 2-benzyl-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one [ka]

[0215] Bromofluoropyrimidines were combined with alcohols (e.g., 2,2,2-trifluoroethanol), cesium carbonate, and aprotic solvents (e.g., DMF). If necessary, the mixture was gently heated to increase the rate of fluoro substitution. Isolation of the major product afforded the corresponding 2-substituted pyrimidine. Suzuki reactions at the C-4 bromo position using a palladium catalyst (e.g., [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a weak base (e.g., potassium acetate) in dioxane / water afforded biaryl cores in good yields. The nitrogen was cleanly alkylated using a wide variety of arylmethyl bromides or arylmethyl chlorides (e.g., benzyl chloride) and inorganic bases in polar aprotic solvents (e.g., DMF). Alternatively, the pyridizinone nitrogen could be functionalized using the Mitsunobu method. This required a hydroxymethylaryl compound (e.g., benzyl alcohol), triphenylphosphine, and a carbodiimide reagent (e.g., DEAD). Both options were utilized in the preparation of the desired product, depending on the availability of the appropriate coupling partner. Examples 1 and 2 can be modified appropriately to prepare the compounds set forth in Tables 1 and 2 herein. Example 3 Synthesis of 2-(3-fluorobenzyl)-6-(4-(methylthio)phenyl)pyridazin-3(2H)-one [ka] Step 1: 6-(4-(methylthio)phenyl)pyridazin-3(2H)-one

[0216] A mixture of 6-bromopyridazin-3(2H)-one (250 mg, 1.43 mmol), 4,4,5,5-tetramethyl-2-(4-(methylthio)phenyl)-1,3,2-dioxaborolane (357 mg, 1.43 mmol), Pd(dppf)Cl (104.5 mg, 0.143 mmol), and KCO (592 mg, 4.29 mmol) in dioxane (5.0 mL) / HO (0.5 mL) was stirred at 90 °C for 4 h under a N atmosphere. The reaction was concentrated in vacuo to give a residue that was purified by chromatography on silica gel (Flash 20 g, 30-80% EA:PE) to give the title compound as a yellow solid (250 mg, 80.2%). LC / MS (ESI): 219 [M+H] + . Step 2: 2-(3-fluorobenzyl)-6-(4-(methylthio)phenyl)pyridazin-3(2H)-one

[0217] To a stirred solution of 6-[4-(methylsulfanyl)phenyl]-2,3-dihydropyridazin-3-one (150 mg, 0.69 mmol) in DMF (2 mL) was added CsCO (672 mg, 2.06 mmol). 1-(Bromomethyl)-3-fluorobenzene (143 mg, 0.76 mmol) was then added. The resulting mixture was stirred at 25 °C for 2 hours. The reaction was filtered, and the filtrate was purified by preparative HPLC to give the title compound as a white solid (100 mg, 44.6%). 1 H NMR (DMSO-d6, 300MHz): δ 8.07 (d, J=9.6 Hz, 1H), 7.86-7.81 (m, 2H), 7.44-7.34 (m, 3H), 7.20-7.08 (m, 4H), 5.34 (s, 2H), 2.56 (s, 3H); LC / MS (ESI): 327 [M+H] + . Example 4 Synthesis of 2-(4-chlorobenzyl)-6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one [ka] Step 1: 6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0218] A mixture of 6-bromopyridazin-3(2H)-one (250 mg, 0.29 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (267 mg, 0.31 mmol), and KCO (400 mg, 2.90 mmol) in dioxane (1.0 mL) / HO (0.2 mL) under a N atmosphere was heated at 90 °C for 8 h. The reaction was concentrated in vacuo to give a residue that was purified by chromatography on silica gel (Flash 20 g, 30-80% EA:PE) to give the title compound as a white solid (150 mg, 76.3%). LC / MS (ESI): 221 [M+H] + . Step 2: 2-(4-chlorobenzyl)-6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0219] To a stirred solution of 6-(2-fluoro-4-methoxyphenyl)-2,3-dihydropyridazin-3-one (156 mg, 0.71 mmol) in DMF (2 mL) was added CsCO (692 mg, 2.13 mmol). Then, 1-(bromomethyl)-4-chlorobenzene (160 mg, 0.78 mmol) was added. The resulting mixture was stirred at 25 °C for 2 hours. LCMS showed the reaction was progressing smoothly. The reaction was filtered, and the filtrate was purified by preparative HPLC to give the title compound as a white solid (32.1 mg, 13.1%). 1 H NMR (DMSO-d6, 300MHz): δ 7.75 (dd, J1=9.6 Hz, J2=2.1 Hz, 1H), 7.59 (m, 1H), 7.43-7.36 (m, 4H), 7.07 (d, J=9.6 Hz, 1H), 6.98 (dd, J1=13.2 Hz, J2=2.4 Hz, 1H), 6.92 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 5.30 (s, 2H), 3.83 (s, 3H); LC / MS (ESI): 345 [M+H] + . Example 5 Synthesis of N-(4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)acetamide [ka] Step 1: 6-Bromo-2-(4-chlorobenzyl)pyridazin-3(2H)-one

[0220] To a stirred solution of 6-bromo-2,3-dihydropyridazin-3-one (600 mg, 3.43 mmol) in DMF (6 mL) was added CsCO (3.35 g, 10.29 mmol). Then, 1-(bromomethyl)-4-chlorobenzene (705 mg, 3.43 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was progressing smoothly. The reaction was quenched by adding saturated aqueous NHCl (5 mL) and then diluted with water (20 mL) and extracted twice with EA (25 mL). The combined EA phase was washed with water (20 mL), brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give the crude product. This was purified by chromatography on silica gel (Flash 40 g, 20-30% EA:PE) to give the title compound as a white solid (700 mg, 68.2%). LS / MS (ESI): 299 [M+H] + . Step 2: N-(4-(1-(4-chlorobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)acetamide

[0221] A mixture of 6-bromo-2-[(4-chlorophenyl)methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.67 mmol), (4-acetamidophenyl)boronic acid (132 mg, 0.73 mmol), KCO (277 mg, 2.00 mmol), and Pd(dppf)Cl (49 mg, 0.07 mmol) in dioxane (3 mL) containing HO (0.2 mL) was stirred at 90 °C for 3 h under a N atmosphere. The reaction mixture was purified by silica gel column chromatography and eluted with EA. The EA phase was then concentrated in vacuo to give the crude product, which was purified by preparative HPLC to give the title compound as a white solid (27.0 mg, 13.1%). 1 H NMR (DMSO-d6, 300MHz): δ 10.14(s, 1H), 8.05(d, J=9.9 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.44-7.37 (m, 4H), 7.08 (d, J=9.6 Hz, 1H), 5.31 (s, 2H), 2.07 (s, 3H); LC / MS (ESI): 354 [M+H] + .

[0222] The following compounds were synthesized according to Example 5: [Table 7] Example 6 Synthesis of 2-[(4-chlorophenyl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one [ka] Step 1: 5-Bromo-2-(2,2,2-trifluoroethoxy)pyrimidine

[0223] To a mixture of 5-bromo-2-chloropyrimidine (10 g, 0.021 mol, 1.0 equiv.) in DMSO (10 mL) at room temperature, 2,2,2-trifluoroethan-1-ol (6.21 g, 0.025 mol, 1.20 equiv.) and Cs2CO3 (25.27 g, 0.062 mol, 3.0 equiv.) were added. The reaction mixture was stirred at 70 °C for 2 h. The solution was diluted with water and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was removed in vacuo. Purification by chromatography on silica gel (Flash 300 g, 0-40% EtOAc:cyclohexane) afforded the title compound as a yellow oil (10.0 g, 94.08%). LC / MS (ESI): 257 [M+H] + . Step 2: [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid

[0224] To a mixture of 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine (5.0 g, 19.45 mmol, 1.0 equiv.) in dioxane (40 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (7.41 g, 29.18 mmol, 1.5 equiv.), KOAc (5.73 g, 58.36 mmol, 3.0 equiv.), and Pd(dppf)Cl (1.42 g, 1.94 mmol, 0.1 equiv.) were added. The flask was purged with and maintained under an inert atmosphere of nitrogen. The reaction mixture was stirred at 80 °C for 4 hours and confirmed by LCMS. The reaction mixture was used directly in the next step without workup. Step 3: 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one

[0225] To a mixture of [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid (4.2 g, 18.93 mmol, 1.0 equiv.) in dioxane (40 mL), 6-bromo-2,3-dihydropyridazin-3-one (3.31 g, 18.916 mmol, 1.00 equiv.), Pd(dppf)Cl (0.69 g, 0.943 mmol, 0.05 equiv.), KCO (3.92 g, 28.387 mmol, 1.5 equiv.), and HO (4 mL) were added. The flask was purged with and maintained under an inert atmosphere of nitrogen. The resulting solution was stirred at 90 °C for 2 h. The solution was diluted with water and extracted with EtOAc (30 mL × 3). The combined organics were washed with brine, dried over NaSO, and the solvent was removed in vacuo. Purification by chromatography on silica gel (Flash 300 g, 50-100% EtOAc:cyclohexane) afforded the title compound as a brown solid (3.0 g, 58.24%). LC / MS (ESI): 273 [M+H] + . Step 4: 2-[(4-chlorophenyl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one

[0226] To a mixture of 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (1.0 g, 3.67 mmol, 1.0 equiv.) in DMF (10 mL) was added 1-(bromomethyl)-4-chlorobenzene (0.75 g, 0.004 mmol, 1.0 equiv.) and CsCO (2.39 g, 0.007 mmol, 2.0 equiv.) at room temperature. The resulting solution was stirred at room temperature for 2 hours. The residue was purified by preparative HPLC to give a white solid (700 mg, 48%). 1 H NMR (300 MHz, DMSO-d6): δ 9.16 (s, 2H), 8.13 (d, J = 9.9 Hz, 1H), 7.46-7.43 (m, 4H), 7.16 (d, J = 9.6 Hz, 1H), 5.33 (s, 2H), 5.12 (q, J = 9.0 Hz, 2H); LC / MS (ESI): 397 [M+H]+ .

[0227] The following compounds were synthesized according to Example 6: [Table 8-1] [Table 8-2] [Table 8-3] Example 7 Synthesis of 2-(4-chlorobenzyl)-6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one [ka] Step 1: 6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0228] A mixture of 6-bromopyridazin-3(2H)-one (250 mg, 0.29 mmol), (2-fluoro-4-methoxyphenyl)boronic acid (267 mg, 0.31 mmol), and KCO (400 mg, 2.90 mmol) in dioxane (1.0 mL) / HO (0.2 mL) under a N atmosphere was heated at 90 °C for 8 h. The reaction was concentrated in vacuo to give a residue that was purified by chromatography on silica gel (Flash 20 g, 30-80% EA:PE) to give the title compound as a white solid (150 mg, 76.3%). LC / MS (ESI): 221 [M+H] + . Step 2: 2-(4-chlorobenzyl)-6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0229] To a stirred solution of 6-(2-fluoro-4-methoxyphenyl)-2,3-dihydropyridazin-3-one (156 mg, 0.71 mmol) in DMF (2 mL) was added CsCO (692 mg, 2.13 mmol). Then, 1-(bromomethyl)-4-chlorobenzene (160 mg, 0.78 mmol) was added. The resulting mixture was stirred at 25 °C for 2 hours. LCMS showed the reaction was progressing smoothly. The reaction was filtered, and the filtrate was purified by preparative HPLC to give the title compound as a white solid (32.1 mg, 13.1%). 1 H NMR (DMSO-d6, 300MHz): δ 7.75 (dd, J1=9.6 Hz, J2=2.1 Hz, 1H), 7.59 (m, 1H), 7.43-7.36 (m, 4H), 7.07 (d, J=9.6 Hz, 1H), 6.98 (dd, J1=13.2 Hz, J2=2.4 Hz, 1H), 6.92 (dd, J1=8.7 Hz, J2=2.4 Hz, 1H), 5.30 (s, 2H), 3.83 (s, 3H); LC / MS (ESI): 345 [M+H] + . Example 8 Synthesis of 2-(1-phenylcyclopropyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one [ka] Step 1: 6-Hydroxy-2-(1-phenylcyclopropyl)pyridazin-3(2H)-one

[0230] To a mixture of (1-phenylcyclopropyl)hydrazine (400.00 mg, 2.699 mmol, 1.00 equiv) and maleic anhydride (291.11 mg, 2.969 mmol, 1.10 equiv) in HO (1.60 mL) was added concentrated HCl (0.40 mL). The resulting solution was stirred at 95 °C for 8 h. The reaction was monitored by LCMS. After cooling to room temperature, the resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in 250 mg (40.58%) of 6-hydroxy-2-(1-phenylcyclopropyl)pyridazin-3(2H)-one as a solid. Step 2: 6-Bromo-2-(1-phenylcyclopropyl)pyridazin-3(2H)-one

[0231] To a solution of 6-hydroxy-2-(1-phenylcyclopropyl)pyridazin-3-one (240.00 mg, 1.051 mmol, 1.00 equiv) in DCE (3.00 mL) was added phosphoryl bromide (904.33 mg, 3.154 mmol, 3.00 equiv) in several portions. The resulting solution was stirred at 85 °C for 16 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). This resulted in the production of 200 mg (65.33%) of 6-bromo-2-(1-phenylcyclopropyl)pyridazin-3-one as a yellow solid. Step 3: 2-(1-phenylcyclopropyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one

[0232] Following Example 8, the title compound was obtained as a white solid (84 mg, 31.5%). 1H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 2H), 8.12 (d, J = 9.6Hz, 1H), 7.33-7.14 (m, 3H), 7.13 (d, J = 9.9Hz, 3H), 5.13 (q, J = 9.0 Hz, 2H), 1.67-1.54 (m, 4H). LC / MS Rt=1.501min, MS m / z:389 [M+H] + Example 9 Synthesis of 2-(phenylmethyl-d2)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one [ka] Step 1: 2-(phenylmethyl-d2)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one

[0233] A mixture of 6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (100.00 mg, 0.367 mmol, 1.00 equiv), (bromomethyl-d2)benzene (63.58 mg, 0.367 mmol, 1.00 equiv), potassium carbonate (102.29 mg, 0.735 mmol, 2 equiv) in dimethylformamide (1.00 mL) was added to an 8 mL flask and stirred at 35 °C for 1 hour. The mixture was purified by preparative HPLC (0.05% NH3H2O-H2O / ACN, 5% to 55% gradient, 30 min) to give 2-(phenylmethyl-d2)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (80 mg, 59.77%) as an off-white solid. 1LC / MS Rt = 1.437 min; MS m / z: 386 [M+H] + . Example 10 Skeletal myofibrillar ATPase assay

[0234] Summary: Myosin ATPase activity is assessed using a coupled reaction system in which ADP generated by myosin ATPase function is coupled to the loss of NADH by the pyruvate kinase / lactate dehydrogenase (PK-LDH) system. Myosin ATPase activity generates ADP, which is used as a substrate by PK to generate pyruvate and regenerate ATP. Pyruvate is then used as a substrate by LDH to oxidize NADH to NAD+. The reaction rate is monitored using absorbance at 340 nm via the time-dependent loss of NADH. Inhibition of ATPase activity by the assayed compound is 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 are counterscreened in cardiac myofibrils.

[0235] Materials: The following stock solutions and reagents were used in the skeletal myofibrillar ATPase assay. [Table 9]

[0236] 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 10]

[0237] Buffer A and Buffer B. The buffers were stored on ice until use.

[0238] Preparation of buffers [Table 11] [Table 12]

[0239] 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 were transferred to a tube large enough to hold approximately twice the required volume and capped. Myofibrils were thawed by rolling in a water bath at room temperature for approximately 15 minutes and chilled on ice. Buffers A and B were prepared by adjusting the volume as needed for the required number of wells and stored on ice. 0.5 μL of the compound to be assayed was added to the well. 25 μL of buffer A was dispensed into the well, followed by 25 μL of buffer B. Wells were measured for absorbance at 340 nm using a kinetic protocol in which wells were read every 1.5–2 minutes for 45 minutes. Data slopes were approximated by subtracting the minimum absorbance value from the maximum for each well. This was accomplished using either SoftMax Pro software or a spreadsheet program such as Excel. Using GraphPad Prism 8.0, data were normalized by assigning a value of 100% to the 1% DMSO vehicle wells. Typically, the normalized 0% value was simply assigned a value of 0 (max-min). The normalized data was fit to a four-parameter logistic sigmoidal equation with the base constrained to be at or above 0. Compounds in Tables 1-4 were tested. The results of the assay can be seen in Table 5 herein. A=IC 50 is 10 μM or less; B=IC 50 is greater than 10 μM and less than 100 μM; C = IC 50 is greater than 100 μM. Example 11 Cardiomyofibrillar ATPase assay

[0240] Counterscreening was performed using frozen myofibril pellets obtained from cardiac tissue according to Example 10. The assay was performed in the same manner as above, with the notable exception that the final well concentration of myofibrils was 1.0 mg / mL and KCl was omitted from the formulation. The compounds in Tables 1-4 were tested and the results of the assays can be seen in Table 6 herein. A=IC 50 is 10 μM or less, and B=IC 50 is greater than 10 μM and less than 100 μM, and C=IC 50 is greater than 100 μM, and D=IC 50 is greater than 60 μM. Example 12 Tibialis anterior muscle assay

[0241] The skeletal muscles of patients with Duchenne muscular dystrophy (DMD) and mdx mice lack dystrophin and are more susceptible to contraction-induced injury than control muscles.Using two in situ stretches of the maximally activated tibialis anterior (TA) muscle, the susceptibility of limb muscles to injury in mdx mice after administration of the compounds disclosed herein was evaluated.Stretching was initiated from the plateau of isometric contraction, with a deformation of 20% relative to muscle fiber length.The magnitude of injury was assessed by the decrease in isometric force after 1 minute. animal

[0242] Mice ranging in age from 2 to 19 months were tested. Specific pathogen-free (SPF) C57BL control and mdx mice were purchased from Jackson Laboratories or bred in-house using purchased breeding pairs. All control mice were C57BL / 10J except for the 19-month-old mice, which were C57BL / 6. Unlike C57BL / 10J mice, C57BL / 6 mice can be purchased at advanced ages from the aging rodent colony maintained by the National Institute on Aging, so the use of C57BL / 6 mice was essential for the oldest age group. in situ preparation

[0243] Mice were anesthetized with an initial intraperitoneal injection of Avertin (tribromoethanol, 13–17 μl / g). Anesthesia was supplemented until no response to tactile stimulation was detected. This level of anesthesia was maintained throughout the experiment with additional doses of Avertin. The TA tendon was exposed by an incision at the ankle. The tendon was cut several millimeters distal to the end of the muscle. The tendon was tied as close as possible to the muscle attachment using 4.0 nylon suture, and the tendon was folded over and retied. The tendon and exposed muscle were kept moist by periodic application of isotonic saline. Mice were placed on a heated platform maintained at 37°C. The mouse's legs were fastened to the platform with cloth tape, and the knees were secured in a clamp between sharp screws. The muscle tendons were tightly attached to the lever arm of a servomotor. The servomotor controlled the muscle's position and monitored the force generated by the muscle. All data were displayed on a digital oscilloscope and stored on a computer.

[0244] The TA muscle was stimulated with 0.2 ms pulses via two needle electrodes piercing the skin on either side of the peroneal nerve near the knee. The stimulation voltage and subsequently the muscle length (Lo) were adjusted for maximum isometric twitch force (Pt). While held at Lo, the muscle was stimulated with a frequency stepwise increase of 50 Hz from 150 Hz until maximum force (Po) was reached, typically at 250 Hz. A 1-2 min rest period was allowed between each tetanic contraction. Muscle length was measured with vernier calipers based on well-defined anatomical landmarks near the knee and ankle. Optimal fiber length was determined by multiplying Lo by the TA's Lf / Lo ratio of 0.6. Eccentric Contraction Protocol

[0245] Muscles were stimulated at 250 Hz (this frequency most often resulted in Po), and each muscle was exposed to two stretches in situ. To avoid fatigue, a protocol consisting of only two contractions was used. Stretching began from the plateau of isometric contraction at Lo. The time course of the protocol is shown in Figure 1. At time 0, stimulation began, and the muscle was held motionless for 100 ms to allow maximal activation. From the plateau of maximal isometric contraction, a length change of 20% Lf was imposed at a rate of 1 Lf / s (LC1). At the end of the stretch ramp, stimulation was stopped. The muscle was held at the stretched length for 100 ms and then returned to Lo at the same rate. A second eccentric contraction identical to the first was performed 10 min later (LC2). Maximum isometric force was measured 1 min later (p1 min) and then again every 5 min for 15 min. The force decline was calculated as the difference between the isometric force during LCl and the maximum isometric force measured at any given time and expressed as a percentage of the isometric force during LCl. Recovery over the 15 min period following the two eccentric contraction protocol was quantified as the difference between the isometric force measured at 15 min and the isometric force after the second eccentric contraction and expressed as a percentage of the initial Po.

[0246] The experimental protocol consisted of two muscle stretches during maximal activation, followed by maximal activation to measure the reduction in maximal isometric force (Po). Panel A shows the muscle length change of 20% deformation relative to fiber length (Lf), where 100% corresponds to the optimal muscle length (Lo) for force generation. The muscle was stretched at a rate of 2 Lf / s. Panel B demonstrates the reduction in Po after the two-stretch protocol in a representative mdx mouse. Each eccentric contraction was initiated from the plateau of the maximal isometric contraction. Ten minutes after the first eccentric contraction (LC1), the second eccentric contraction occurred (LC2). Maximum force during the isometric contraction was measured 10 minutes after LC2 (p1 min). The force reduction was calculated by dividing the difference between the Po during LC1 and the Po measured at any time after LC1 by the Po during LC1 and multiplying by 100%. The sutures were removed from the muscle, and the muscle was weighed. After removing the TA muscle, mice under deep anesthesia were euthanized by induction of pneumothorax. The total myofiber cross-sectional area (CSA) of the TA muscle was calculated by dividing the muscle mass by the product of Lf and the mammalian skeletal muscle density of 1.06 mg / mm. The ratio Po was calculated by dividing Po by CSA. The test results are shown in Figures 3-6.

[0247] Figure 3 shows the reduction in pre-injury force at 100 Hz for Compound 5 of the present disclosure. Force was measured in situ at 100 Hz in the TA muscle of mdx mice before and after oral administration of Compound 5. 100 Hz stimulation was applied every 10 minutes, and the change in force was recorded before the start of the unusual injury protocol. This metric indicates the relative ability of Compound 5 to reduce force in target tissues.

[0248] Figure 4 shows the reduction in force after injury at 175 Hz for Compound 5 of the present disclosure. Maximum force was measured in situ in the TA muscle at 175 Hz before and 10 minutes after two non-conventional (eccentric) contractions. In mdx mice, eccentric contractions result in an exaggerated force decrease. This measurement suggests the ability of Compound 5 to reduce the relative force decrease after non-conventional contractions. Figure 5 shows the force decrease during stretch for Compound 5 of the present disclosure. In situ injury of the TA muscle was induced via two maximal non-conventional contractions with 20% stretch, 10 minutes apart. This metric measures the relative decrease in force before stretch between the first and second contractions.

[0249] Figure 6 shows the TA mass increase after injury for Compound 5 of the present disclosure. The tensile injury of the TA muscle in mdx mice causes a delay in the increase in muscle weight after injury. This is likely due to the accumulation of fluid in the form of edema. Muscles (both injured and contralateral) were removed from the mice 1 hour after injury and weighed. The relative increase in weight of the injured muscle compared to the contralateral muscle was recorded. A reduction in this relative change indicates a reduction in edema after injury.

[0250] In some embodiments, the compounds of the disclosure are those in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

[0251] In some embodiments, the compounds of the disclosure are those in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0252] In certain embodiments, compounds for the methods described herein may be selected from commercially available compounds, including those shown in Table 3. The compounds in Tables 3 and 4 were tested. The results of the assays can be found in Table 6 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 50is 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]

[0253] In certain embodiments, the other compounds of the methods described herein include compounds in Table 4 or salts thereof. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0254] The compounds of the present disclosure have the backbone IC as shown in Table 5. 50 It has a value. [Table 5-1] [Table 5-2] [Table 5-3] 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.

[0255] Compounds of the present disclosure exhibit cardiac IC as shown in Table 6. 50 It has a value. [Table 6-1] [Table 6-2] [Table 6-3]

Claims

1. Formula (I) 【Chemical Formula 59】 or a salt thereof, or a pharma- ceutically acceptable salt thereof, Each X is C(R ３ ), N, and N ＋ (-O － ) independently selected from the group consisting of N and N ＋ (-O － ) and A is -O-, -NR ４ -, -CR ５ R ６ -, -C(O)-, -S-, -S(O)-, and -S(O) ２ - selected from R １ teeth, C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), -CN,C ３～１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３～１０ Carbocycles and 3- to 10-membered heterocycles are each independently selected from one or more R ９ each optionally substituted), and C ３～１０ Carbocycles and 3- to 10-membered heterocycles (each of which is substituted with halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN, or X is CR ３ If R １ is R ３ and together form a 5- to 10-membered heterocycle or C ５～１０ can form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C ５～１０ A carbocycle may be one or more R ９ with the appropriate replacement, or A is -CR ５ R ６ -, then R １ is R ５ Together with a 3- to 10-membered heterocyclic ring or a saturated C ３～１０ can form a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C ３～１０ A carbocycle may be one or more R ９ with the appropriate replacement, or A is -NR ４ -, then R １ is R ４ and together with each other may form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is selected from one or more R ９ with the appropriate replacement, or A is -NR ４ -, then R １ is further selected from hydrogen; or When A is -C(O)-, R １ is further -N(R １０ ) ２ and -OR １０ is selected from Each R ２ teeth, Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , and -CN; C １～３ Alkyl, C ２～３ Alkenyl, and C ２～３ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ and -CN; Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and —CN, optionally substituted with one or more substituents independently selected from ３～１０ Carbocycle are independently selected from R ３ , R ５ , and R ６ teeth, Hydrogen, halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ -CN; and Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ alkyl; or R ３ is R １ and together form a 5- to 10-membered heterocycle or C ５～１０ forming a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C ５～１０ A carbocycle may be one or more R ９ or R ５ is R １ Together with a 3- to 10-membered heterocyclic ring or a saturated C ３～１０ forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C ３～１０ A carbocycle may be one or more R ９ where appropriate, R ４ teeth, Hydrogen; and Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ independently selected from alkyl, R ４ is R １ together with one or more R ９ forming a 3- to 10-membered heterocycle optionally substituted with R ７ and R ８ teeth, Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ , -CN, -CHF ２ , -CF ３ , and -CH ２ F are each independently selected from Each R ９ teeth, Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN; and C １～３ Alkyl, C ２～３ Alkenyl, and C ２～３ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN, are independently selected from Each R １０ teeth, hydrogen; C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (which are 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 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 each substituted with 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 and optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl. are independently selected from n is 0, 1, or 2; p is 0, 1, or 2; q is 1, 2, 3, 4, or 5; R １ Ga-CH ３ When other than, q is further selected from 0.

2. The compound of formula (I) is represented by the formula (Ia) or (Ib) 【Chemistry 60】 2. The compound or salt of claim 1, represented by:

3. The compound of formula (I) has the formula (Ia) 【Chemistry 61】 3. The compound or salt of claim 2, represented by:

4. The compound of formula (I) is represented by the formula (Ic) or (Id): 【Chemistry 62】 2. The compound or salt of claim 1, represented by:

5. The compound of formula (I) has the formula (Ic) 【Chemistry 63】 2. The compound or salt of claim 1, represented by:

6. The compound or salt of claim 1, wherein A is -O-.

7. A is -NR ４ The compound or salt according to claim 1, wherein

8. R １ But, C １～３ alkyl, which is selected from halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ , =O, =S, =N(R １０ ), -CN,C ３～１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３～１０ Carbocycles and 3- to 10-membered heterocycles are each selected from the group consisting of one or more R ９ 2. The compound or salt of claim 1, each optionally substituted with:

9. R １ が、-CH ３ 、-CF ３ 、-CH ２ F、-CHF ２ 、-CH ２ CHF ２、 -CH ２ CF ３ 、-C(=O)CH ３ 、 【Chemistry 64】 9. The compound or salt of claim 8, selected from:

10. R １ But -CF ３ , -CHF ２ , and -CH ２ CF ３ 10. The compound or salt of claim 9, selected from:

11. R １ but, 【Chemistry 65】 2. The compound or salt of claim 1, selected from:

12. R １ But, R ４ together with R to R to R form a 3- to 10-membered heterocycle, wherein said 3- to 10-membered heterocycle is selected from one or more R ９ 2. The compound or salt of claim 1, optionally substituted with:

13. R ４ Together with R １ The 3- to 10-membered heterocycle formed from 【Chemistry 67】 13. The compound or salt of claim 12, selected from:

14. Each R ２ is halogen, -OH, -SH, -NH ２ , -NO ２ , -CN, as well as halogens, -OH, -SH, -NH ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～３ 2. The compound or salt of claim 1, wherein each is independently selected from alkyl.

15. Each R ２ The compound or salt of claim 14, wherein is -Cl.

16. R ２ but, 【Chemistry 68】 15. The compound or salt of claim 14,

17. 2. The compound or salt of claim 1, wherein n is 0.

18. 2. The compound or salt of claim 1, wherein p is 0.

19. 2. The compound or salt of claim 1, wherein q is 1 or 2. 【Request 20】 【Chemical 69-1】 【Chemistry 69-2】 【Chemistry 69-3】 2. The compound or salt of claim 1, selected from:

21. Formula (II) 【Chemistry 70】 or a salt thereof, or a pharma- ceutically acceptable salt thereof, T is -O-, -NR １４ -, -CR １５ R １６ -, -C(O)-, -S-, -S(O)-, and -S(O) ２ - selected from R １１ teeth, C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (each of which is halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ 、 -N(R ２０ ) C(O)N(R ２０ ) ２ , -OC(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , =O, =S, =N(R ２０ ), -CN,C ３～５ and substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３～１０ Carbocycles and 3- to 10-membered heterocycles are each independently selected from one or more R ９ where appropriate, And C ３～１０ Carbocycles and 3- to 10-membered heterocycles (each of which is substituted with halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ 、 -N(R ２０ ) C(O)N(R ２０ ) ２ , -OC(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , =O, =S, =N(R ２０ ), and -CN, or T is -CR １５ R １６ -, then R １１ is R １５ and together form a 3- to 10-membered heterocycle or ３～１０ can form a carbocyclic ring, and the 3- to 10-membered heterocyclic ring or saturated C ３～１０ A carbocycle may be one or more R １９ with the appropriate replacement, or T is -NR １４ -, then R １１ is R １４ and together with each other may form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is selected from one or more R １９ with the appropriate replacement, or When T is -C(O)-, R １１ is further -OR ２０ is selected from Each R １２ teeth, Halogen, -OH, -SH, -NH 2 , -NO ２ , -CN, as well as the halogens, -OH, -SH, -NH 2 , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～３ Alkyl are independently selected from R １４ teeth, Hydrogen; and Halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ independently selected from alkyl, R １４ is R １１ together with one or more R １９ forming an optionally substituted 3- to 5-membered heterocycle with R １５ is R １１ together with one or more R １９ Saturated C optionally substituted with ３～１０ forming a carbocyclic or 3- to 10-membered heterocyclic ring, R １６ teeth, Hydrogen, halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -NO ２ , -CN, and halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ Alkyl are independently selected from R １８ teeth, Halogen, -SR ２０ , -N(R ２０ ) ２ and -NO ２ are independently selected from R １９ teeth, Halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ 、 -N(R ２０ ) C(O)N(R ２０ ) ２ , -OC(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , ═O, ═S, and —CN; and C １～３ Alkyl, C ２～３ Alkenyl, and C ２～３ Alkynyl (each of which is halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ 、 -N(R ２０ ) C(O)N(R ２０ ) ２ , -OC(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , =O, =S, =N(R ２０ ), and -CN, are independently selected from Each R ２０ teeth, hydrogen; C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (which are halogen, -CN, -OH, -SH, -NO ２ , -NH ２ , =S, -O-C １～６ Alkyl, -S-C １～６ Alkyl, -N(C １～６ Alkyl) ２ , -NH(C １～６ Alkyl), C ３～１０ optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 10-membered heterocycle; and C ３～１０ Carbocycles and 3- to 10-membered heterocycles (which are each substituted with 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 and optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl. are independently selected from z is 0, 1, or 2; v is 1, 2, 3, 4, or 5.

22. 22. The compound or salt of claim 21, wherein T is -O-.

23. T is -NR １４ The compound or salt of claim 21, wherein

24. R １１ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ 22. The compound or salt of claim 21, wherein said aryl group is selected from alkynyl, each of which is substituted with one or more halogen substituents.

25. R １１ is -cyclopropyl, -CH ２ CF ３ , -CH ２ CHF ２ , -CHF ２ , -CF ３ , -CH ２ CH ２ OCH ３ , -C(=O)CH ３ , -CH ２ C.N., 【Chemistry 71】 22. The compound or salt of claim 21 selected from:

26. R １１ is 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 C optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl. ３～１０ 22. The compound or salt of claim 21 which is a carbocyclic ring.

27. Each R １２ is halogen, -OH, -NH ２ , -NO ２ , -CN, as well as halogens, -OH, -NH ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～３ 22. The compound or salt of claim 21, wherein each is independently selected from alkyl.

28. Each R １２ The compound or salt of claim 21, wherein is -Cl.

29. R １２ but 【Chemical Formula 74】 22. The compound or salt of claim 21,

30. 22. The compound or salt of claim 21 , wherein z is 0.

31. 22. The compound or salt of claim 21 , wherein v is 1.

32. 【Catalog 75】 22. The compound or salt of claim 21 selected from: 【Request 33】 【Chemical 76】 22. The compound or salt of claim 21 selected from: 【Request 34】 【Chemical 70-1】 or a pharma- ceutically acceptable salt thereof, Each R １２ teeth, ハロゲン、-OR ２０ 、-SR ２０ 、-N(R ２０ ) ２ 、-C(O)R ２０ 、-C(O)N(R ２０ ) ２ 、-N(R ２０ )C(O)R ２０ 、 -N(R ２０ )C(O)N(R ２０ ) ２ 、-OC(O)N(R ２０ ) ２ 、-N(R ２０ )C(O)OR ２０ 、-C(O)OR ２０ 、-OC(O)R ２０ 、-S(O)R ２０ 、-S(O) ２ R ２０ 、-NO ２ 、-CN、 C １～３ Alkyl, C ２～３ Alkenyl, C ２～３ Alkynyl (each of which is halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ 、 -C(O)OR ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -OC(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , =O, =S, =N(R ２０ ), and -CN; Halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ 、 -N(R ２０ ) C(O)N(R ２０ ) ２ , -OC(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , =O, =S, =N(R ２０ ), and —CN, ３～１０ Carbocycle are independently selected from Each R １８ teeth, Halogen, -SR ２０ , -N(R ２０ ) ２ , -NO ２ , -CN, and halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ Alkyl or Each R １９ teeth, Halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ 、 -N(R ２０ ) C(O)N(R ２０ ) ２ , -OC(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , =O, =S, =N (R 20), and -CN; and C １～３ Alkyl, C ２～３ Alkenyl, and C ２～３ Alkynyl (each of which is halogen, -OR ２０ , -SR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)R ２０ 、 -N(R ２０ ) C(O)N(R ２０ ) ２ , -OC(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -S(O)R ２０ , -S(O) ２ R ２０ , -NO ２ , =O, =S, =N(R ２０ ), and -CN, are independently selected from Each R ２０ teeth, hydrogen; C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (which are 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 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 each substituted with 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 and optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl. are independently selected from z is 0, 1, or 2; v is 1, 2, 3, 4, or 5. 【Request 35】 【Chemical 70-2】 35. The compound or salt of claim 34, selected from:

36. A compound according to the present invention comprising a compound of formula (III) for treating a neuromuscular condition, a movement disorder, or a metabolic myopathy in a subject in need thereof. 【Chemical Formula 77】 or a salt thereof, wherein Each Y is C(R ３ ), N, and N ＋ (-O － ) are independently selected from A is absent, -O-, -NR ４ -, -CR ５ R ６ -, -C(O)-, -S-, -S(O)-, and -S(O) ２ - selected from R １ teeth, C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), -CN,C ３～１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３～１０ Carbocycles and 3- to 10-membered heterocycles are each independently selected from one or more R ９ each optionally substituted), and C ３～１０ Carbocycles and 3- to 10-membered heterocycles (each of which is substituted with halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN, or X is CR ３ If R １ is R ３ and together form a 5- to 10-membered heterocycle or C ５～１０ can form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C ５～１０ A carbocycle may be one or more R ９ with the appropriate replacement, or A is -CR ５ R ６ -, then R １ is R ５ Together with a 3- to 10-membered heterocyclic ring or a saturated C ３～１０ can form a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C ３～１０ A carbocycle may be one or more R ９ with the appropriate replacement, or A is -NR ４ -, then R １ is R ４ and together with each other may form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is selected from one or more R ９ with the appropriate replacement, or A is -NR ４ -, then R １ is further selected from hydrogen; or When A is -C(O)-, R １ is further -N(R １０ ) ２ and -OR １０ or If A is absent, then R １ may further include halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ , -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ and -CN; Each R ２ teeth, ハロゲン、-OR １０ 、-SR １０ 、-N(R １０ ) ２ 、-C(O)R １０ 、-N(R １０ )C(O)R １０ 、 -N(R １０ )C(O)N(R １０ ) ２ 、-OC(O)N(R １０ ) ２ 、-N(R １０ )C(O)OR １０ 、-C(O)OR １０ 、-OC(O)R １０ 、-S(O)R １０ 、-S(O) ２ R １０ 、-NO ２ 、および-CN; C １～３ Alkyl, C ２～３ Alkenyl, and C ２～３ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =S, =N(R １０ ), and -CN; Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and —CN, optionally substituted with one or more substituents independently selected from ３～１０ Carbocycle are independently selected from R ３ , R ５ , and R ６ are respectively: Hydrogen, halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ -CN; and Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ independently selected from alkyl, R ３ is R １ and together form a 5- to 10-membered heterocycle or C ５～１０ forming a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C ５～１０ A carbocycle may be one or more R ９ or R ５ is R １ Together with a 3- to 10-membered heterocyclic ring or a saturated C ３～１０ forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C ３～１０ A carbocycle may be one or more R ９ where appropriate, R ４ teeth, Hydrogen; and Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ independently selected from alkyl, R ４ is R １ together with one or more R ９ forming a 3- to 10-membered heterocycle optionally substituted with R ７ and R ８ are respectively: Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ , -CN, -CHF ２ , -CF ３ , -CH ２ F, as well as halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from ２～６ Alkyl are independently selected from Each R ９ teeth, Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN; and C １～３ Alkyl, C ２～３ Alkenyl, and C ２～３ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN, are independently selected from Each R １０ teeth, hydrogen; C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (which are 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 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 each substituted with 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 Carbocycles, 3- to 10-membered heterocycles, and C １～６ and optionally substituted with one or more substituents independently selected from haloalkyl. are independently selected from R ３０ and R ３１ is R １０ or R ３０ and R ３１ Let's get together and ３～７ Forms a carbocyclic or 3- to 7-membered heterocyclic ring, where C ３～７ Carbocycles and 3- to 7-membered heterocycles are represented by R ９ and optionally substituted with one or more substituents independently selected from n is 0, 1, or 2; p is 0, 1, or 2; q is 0, 1, 2, 3, 4, or 5; 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; and wherein the metabolic myopathy is McArdle's disease; and wherein the movement disorder comprises muscle spasms associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, cerebral palsy, injury, stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis; composition.

37. Each Y is C(R ３ ), N, and N ＋ (-O － ) are independently selected from A is -O-, -NR ４ -, -CR ５ R ６ -, -C(O)-, -S-, -S(O)-, and -S(O) ２ - selected from R １ but, C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), -CN,C ３～１０ and optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 10-membered heterocycle, wherein ３～１０ Carbocycles and 3- to 10-membered heterocycles are each independently selected from one or more R ９ each optionally substituted), and C ３～１０ Carbocycles and 3- to 10-membered heterocycles (each of which is substituted with halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN, or X is CR ３ If R １ But, R ３ and together form a 5- to 10-membered heterocycle or C ５～１０ can form a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C ５～１０ A carbocycle may be one or more R ９ with the appropriate replacement, or A is -CR ５ R ６ -, then R １ But, R ５ Together with a 3- to 10-membered heterocyclic ring or a saturated C ３～１０ can form a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C ３～１０ A carbocycle may be one or more R ９ with the appropriate replacement, or A is -NR ４ -, then R １ But, R ４ and together with each other may form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is selected from one or more R ９ with the appropriate replacement, or A is -NR ４ -, then R １ is further selected from hydrogen; or When A is -C(O)-, R １ is further -N(R １０ ) ２ and -OR １０ is selected from Each R ２ but, ハロゲン、-OR １０ 、-SR １０ 、-N(R １０ ) ２ 、-C(O)R １０ 、-N(R １０ )C(O)R １０ 、 -N(R １０ )C(O)N(R １０ ) ２ 、-OC(O)N(R １０ ) ２ 、-N(R １０ )C(O)OR １０ 、-C(O)OR １０ 、-OC(O)R １０ 、-S(O)R １０ 、-S(O) ２ R １０ 、-NO ２ 、および-CN; C １～３ Alkyl, C ２～３ Alkenyl, and C ２～３ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =S, =N(R １０ ), and -CN; Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and —CN, optionally substituted with one or more substituents independently selected from ３～１０ Carbocycle are independently selected from R ３ , R ５ , and R ６ are respectively, Hydrogen, halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ -CN; and Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ independently selected from alkyl, R ３ is R １ and together form a 5- to 10-membered heterocycle or C ５～１０ forming a carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C ５～１０ A carbocycle may be one or more R ９ or R ５ is R １ Together with a 3- to 10-membered heterocyclic ring or a saturated C ３～１０ forming a carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C ３～１０ A carbocycle may be one or more R ９ where appropriate, R ４ but, Hydrogen; and Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from １～６ independently selected from alkyl, R ４ is R １ together with one or more R ９ forming a 3- to 10-membered heterocycle optionally substituted with R ７ and R ８ are respectively, Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ , -CN, -CHF ２ , -CF ３ , -CH ２ F, as well as halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -NO ２ and -CN, optionally substituted with one or more substituents independently selected from ２～６ Alkyl are independently selected from Each R ９ but, Halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN; and C １～３ Alkyl, C ２～３ Alkenyl, and C ２～３ Alkynyl (each of which is halogen, -OR １０ , -SR １０ , -N(R １０ ) ２ , -C(O)R １０ , -C(O)N(R １０ ) ２ , -N(R １０ ) C(O)R １０ 、 -N(R １０ ) C(O)N(R １０ ) ２ , -OC(O)N(R １０ ) ２ , -N(R １０ ) C(O)OR １０ , -C(O)OR １０ , -OC(O)R １０ , -S(O)R １０ , -S(O) ２ R １０ , -NO ２ , =O, =S, =N(R １０ ), and -CN, are independently selected from Each R １０ but, hydrogen; C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ Alkynyl (which are 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 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 each substituted with 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 and optionally substituted with one or more substituents independently selected from carbocycle, 3- to 10-membered heterocycle, and haloalkyl. are independently selected from n is 0, 1, or 2; p is 0, 1, or 2; q is 1, 2, 3, 4, or 5; 37. The composition of claim 36.

38. 37. A composition for treating activity-induced muscle damage in a subject in need thereof comprising a compound or salt according to any one of claims 1, 21 or 34.

39. 37. A composition for inhibiting muscle myosin II comprising a compound or salt according to any one of claims 1, 21 or 34.

40. 40. The composition of claim 38 or claim 39, wherein the compound or salt does not appreciably inhibit myocardial contraction relative to an untreated control.

41. 40. The composition of claim 38 or claim 39 for the treatment of a subject having a neuromuscular condition or movement disorder.

42. 40. The composition of claim 38 or claim 39, 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.

43. 42. The composition of claim 41, wherein the neuromuscular condition is Duchenne muscular dystrophy.

44. 37. A composition for treating a movement disorder in a subject in need thereof comprising a compound or salt according to any one of claims 1, 21 or 34.

45. 42. The composition of claim 41, wherein the movement disorder comprises muscle spasticity.

46. 46. ​​The composition of claim 45, wherein the muscle spasms are selected from spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, cerebral palsy, injury, a traumatic event, such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, and amyotrophic lateral sclerosis.

47. 43. The composition of claim 42, wherein the compound or salt is administered in an amount sufficient to reduce involuntary muscle contractions.

48. 35. A pharmaceutical composition comprising a compound or salt according to any one of claims 1, 21 or 34 and a pharma- ceutically acceptable excipient.

49. 38. The composition of claim 36 or 37, further comprising an additional therapeutic agent.

50. 50. The composition of claim 49, wherein the additional therapeutic agent is a corticosteroid.

51. 50. The composition of claim 49, wherein the additional therapeutic agent is a gene therapy.

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