Pyridazinone compounds and uses thereof

Abstract

Disclosed herein are substituted pyridazinone compounds, conjugates, and pharmaceutical compositions for the treatment of neuromuscular diseases, such as Duchenne muscular dystrophy (DMD). The disclosed compounds are useful, inter alia, in the treatment of DMD and in the modulation of inflammatory inhibitors IL-1, IL-6 or TNF-alpha.

Description

[0001] This application is a divisional application of the Chinese patent application with an application date of November 6, 2019, application number 201980088114.7, and invention name “Pyridazinone compounds and their uses” (the corresponding PCT application with an application date of November 6, 2019, application number PCT / US2019 / 060157).

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 756,553, filed November 6, 2018, which is incorporated herein by reference in its entirety. Background Art

[0004] Skeletal muscle is the largest organ system in the human body and has two primary roles. The first is force production to enable muscle contraction, movement, and posture maintenance; the second is glucose, fatty acid, and amino acid metabolism. Skeletal muscle contractions during daily activities and exercise are naturally associated with muscle stress, breakdown, and remodeling, which are essential for muscle adaptation. In individuals with neuromuscular conditions such as Duchenne muscular dystrophy (DMD), muscle contractions lead to continuous rounds of amplified muscle breakdown that the body struggles to repair. Ultimately, as patients age, a pathophysiological process occurs that leads to excessive inflammation, fibrosis, and accumulation of fatty deposits in the muscles, heralding a dramatic decline in physical function and leading to death.

[0005] DMD is a genetic disease 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 such as DMD. Summary of the Invention

[0006] The present disclosure generally relates to substituted pyridazinone compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), or (IIa) and pharmaceutical compositions thereof. The substituted pyridazinone compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (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), or (IIa) is an inhibitor of skeletal muscle contraction. In some embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), or (IIa) is an inhibitor of myosin. In some embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), or (IIa) is an inhibitor of skeletal muscle myosin II.

[0007] In some aspects, a method of treating a movement disorder may comprise administering a compound or salt of any of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') to inhibit skeletal muscle myosin II. In some embodiments, the movement disorder comprises muscle spasms. In some embodiments, the muscle spasms may be selected from spasms associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury, or traumatic events such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis.

[0008] The present disclosure provides compounds and salts thereof for use in treating diseases. In certain aspects, the present disclosure provides compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (II) or (IIa), pharmaceutical compositions thereof, and methods for treating diseases.

[0009] In certain aspects, the present disclosure provides compounds represented by formula (I):

[0010]

[0011] or a salt thereof, wherein:

[0012] Each X is independently selected from C(R 3 ), N and N + (-O - ) wherein at least one X is N or N + (-O - ); A is selected from -O-, -NR 4 -、-CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-;

[0013] R 1 Selected from:

[0014] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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)R10 、-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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0015] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 and C 2-6 Alkynyl is substituted by a substituent, wherein C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replaced; or

[0016] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced by;

[0017] R 2 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following:

[0018] 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 when R 2 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0019] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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(R10 )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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0020] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally replaced by one or more R 9 replaced by;

[0021] R 3 、R 5 and R 6 Each independently selected from:

[0022] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, and –CN; and

[0023] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or

[0024] R 3 With R 1 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced; or

[0025] R 5 With R 1 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by;

[0026] R 4 Independently selected from:

[0027] hydrogen; and

[0028] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 replaced by;

[0029] R 7 and R 8 Independently selected from:

[0030] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents;

[0031] Each R 9 Independently selected from:

[0032] 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

[0033] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from halogen, -OR10 、-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;

[0034] Each R 10 Independently selected from:

[0035] hydrogen; and

[0036] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0037] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, 3- to 10-membered heterocyclic and C 1-6 substituted by a haloalkyl substituent;

[0038] n is 0, 1, or 2; and

[0039] p is 0, 1 or 2.

[0040] In certain aspects, the present disclosure provides compounds represented by formula (II):

[0041]

[0042] or a salt thereof, wherein:

[0043] T is selected from -O-, -NR 14 -、-CR 15 R 16 -, -C(O)-, -S-, -S(O)-, and -S(O)2;

[0044] R 11 Selected from:

[0045] C 1-5 Haloalkyl, optionally further substituted with one or more substituents independently selected from: -OR 20 、-SR 20 、-N(R 20 )2, -NO2, =O, =S, -CN, C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced by;

[0046] R 12 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following:

[0047] 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; and when R12 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0048] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced; and

[0049] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more -R 19 replace;

[0050] R 14 Selected from:

[0051] Hydrogen and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0052] Each R 15 and R 16 Independently selected from:

[0053] Hydrogen, halogen, -OR 20 、-SR 20 、-N(R20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0054] Each R 17 and R 18 Independently selected from:

[0055] Halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0056] Each R 19 Independently selected from:

[0057] 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; and

[0058] C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0059] Each R 20 Independently selected from:

[0060] hydrogen; and

[0061] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0062] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents;

[0063] w is 0, 1, or 2; and

[0064] z is 0, 1 or 2.

[0065] 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 or salt of formula (III'):

[0066]

[0067] or a salt thereof, wherein:

[0068] Each Y is independently selected from C(R 3 ), N and N + (-O - );

[0069] A is absent or selected from -O-, -NR 4 -、-CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-; R 1 Selected from:

[0070] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0071] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R10 )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; or

[0072] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or a saturated C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or saturated C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced; and

[0073] When A is -NR 4 -, R 1 Additionally selected from hydrogen, and when A is -C(O)-, R 1 Additionally selected from -N(R 10 )2 and -OR 10 ;

[0074] When A does not exist, R 1 Further selected from 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 and –CN;

[0075] R 2 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following:

[0076] 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 when R 2 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of the pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0077] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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(R10 )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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0078] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally replaced by one or more R 9 replaced by;

[0079] Each R 3 、R 5 and R 6 Independently selected from:

[0080] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or

[0081] R 3 With R 1 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 Replaced by; R 5 With R 1 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by;

[0082] R 4 Independently selected from:

[0083] hydrogen; and

[0084] C 1-6Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 replaced by;

[0085] Each R 7 and R 8 Independently selected from

[0086] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents;

[0087] Each R 9 Independently selected from

[0088] 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; and

[0089] C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R10 )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;

[0090] Each R 10 Independently selected from

[0091] hydrogen; and

[0092] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0093] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents;

[0094] R 30 and R 31 Independently selected from R 10 or R30 and R 31 Together they form C 3-7 carbocyclic ring, wherein the 3 to 7 membered heterocyclic ring, wherein C 3-7 The carbocyclic and 3- to 7-membered heterocyclic rings are optionally replaced by R 9 is substituted; n is 0, 1 or 2; and p is 0, 1 or 2.

[0095] In certain aspects, the present disclosure provides a method of treating a neuromuscular condition or treating activity-induced muscle damage or inhibiting muscle myosin II, comprising administering to a subject in need thereof a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II) and (IIa).

[0096] 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 Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), and (IIa).

[0097] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II) and (IIa) and a pharmaceutically acceptable excipient.

[0098] Incorporation by reference

[0099] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0100] The novel features of the present 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 of illustrative embodiments utilizing the principles of the present invention and the accompanying drawings (also referred to herein as "Figures"), in which:

[0101] Figure 1 Delineating hypercontraction-induced damage that precedes inflammation and irreversible fibrosis, hallmarks of advanced DMD pathology;

[0102] Figure 2 Describes N-benzyl-p-tolyl-sulfonamide (BTS), an inhibitor of fast-fiber skeletal muscle myosin, which has been shown to protect muscle from pathological muscle disorders in DMD zebrafish model embryos;

[0103] Figure 3Depicted are the reduction in pre-injury force at 100 Hz for various compounds of the present disclosure;

[0104] Figure 4 Depicted are post-injury force reduction at 175 Hz for various compounds of the present disclosure;

[0105] Figure 5 Depicted are the intermediate elongation force decreases for various compounds of the present disclosure;

[0106] Figure 6 Post-injury TA mass increase is depicted for various compounds of the present disclosure. DETAILED DESCRIPTION

[0107] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Without departing from the present invention, those skilled in the art will now appreciate that many variations, changes, and substitutions may be employed in implementing the present invention. It is to be understood that various alternatives to the embodiments of the present invention described herein may be employed. It is intended that the scope of the present invention be defined by the appended claims, and that methods and structures and their equivalents within the scope of these claims be encompassed thereby.

[0108] In certain aspects, the present disclosure provides methods for treating neuromuscular diseases by selectively inhibiting skeletal muscle fast twitch myosin. In particular, the methods of the present disclosure can be used to treat DMD and other neuromuscular diseases.

[0109] 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 pattern, with the composition of fiber types varying in different muscles and at different points in growth and development. Slow-twitch fibers have excellent aerobic energy production capabilities. Slow-twitch fibers have a low rate of contraction but a high tolerance to fatigue. 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 more slowly and produce less energy than fast-twitch fibers, but they are able to maintain contractile function for longer periods of time, such as during stabilization, postural control, and endurance exercise.

[0110] Human fast-twitch muscle fibers can be further divided into two major fiber types (type IIa and type IIx / d) based on the specific skeletal muscle fast-twitch myosin proteins they express. A third type of fast-twitch fiber (type IIb) exists in other mammals but is rarely found in human muscle. Fast-twitch muscle fibers have excellent anaerobic energy production capabilities and are able to generate large amounts of force in a short period of time. Generally, fast-twitch muscle fibers have lower mitochondrial, myoglobin, and capillary concentrations than slow-twitch muscle fibers and therefore fatigue more quickly. Fast-twitch muscle fibers generate force and the faster forces required for resistance activities.

[0111] The ratio of type I to type II fibers can vary between individuals. For example, a non-athletic individual may have approximately 50% of each type of muscle fiber. Power athletes may have a higher proportion of fast-twitch muscle fibers, for example, 70-75% type II in sprinters. Endurance athletes may have a higher proportion of slow-twitch muscle fibers, for example, 70-80% in long-distance runners. The ratio of type I to type II fibers can also vary depending on the age of the individual. The proportion of type II fibers (particularly type IIx) can decrease as the individual ages, leading to a loss of lean muscle mass.

[0112] The contractile action of skeletal muscle leads to muscle damage in subjects with neuromuscular diseases (e.g., DMD), and this damage appears to be more prevalent in fast-twitch muscle fibers. It has been observed that in a malnourished mouse model, the acute force drop after strain in a model that is primarily fast type II fiber muscle is greater than in a model that is primarily slow type I fiber muscle (i.e., soleus muscle). It has also been demonstrated that in a malnourished mouse model, the degree of acute force drop and histological damage is directly proportional to the peak force development during strain. Figure 1 Figure 1 shows the damage caused by excessive contraction, which precedes the inflammation and irreversible fibrosis that are characteristic of late-stage DMD pathology. [Figure adapted from: Claflin and Brooks, Am J Brooks, Physiol Cell, 2008]. By limiting the peak force production of type II fibers and potentially increasing reliance on healthier type I fibers, contraction-induced muscle damage in these patients may be reduced. N-Benzyl-p-Toluenesulfonamide (BTS) is an inhibitor of skeletal muscle fast twitch myosin, such as Figure 2 It has been shown to protect muscles from pathological muscle disorders in embryos from a zebrafish model of DMD [Source: Li and Arner, PLoS ONE, 2015].

[0113] Skeletal muscle myosin inhibitors that are not selective for type II fibers may lead to excessive inhibition of skeletal muscle contraction, including respiratory function and undesirable inhibition of cardiac activity, because the heart shares multiple structural components (e.g., type I myosin) with type I skeletal muscle fibers. Although not wishing to be bound by a particular mechanistic theory, the present disclosure provides selective inhibitors of skeletal muscle fast twitch fiber myosin as a treatment option for DMD and other neuromuscular diseases. Targeted inhibition of type II skeletal muscle myosin can reduce skeletal muscle contraction while minimizing the impact on the subject's daily activities.

[0114] definition

[0115] Unless defined otherwise, 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.

[0116] As used in this specification and the claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0117] The term "C x-y ” or “C x -C y " when used with a chemical moiety such as alkyl, alkenyl, or alkynyl, is intended to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched-chain alkyl groups containing 1 to 6 carbon atoms.

[0118] The term "C x-y Alkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group analogous in length and possible substitution to the alkyls described above, but containing at least one double or triple bond, respectively.

[0119] As used herein, the term "carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each ring atom is carbon. Carbocycles include 3-10 membered monocycles, 5-12 membered bicyclic rings, 5-12 membered spirobicyclic rings, and 5-12 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 a phenyl ring, can be fused with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings. Bicyclic carbocycles also include spirobicyclic rings, such as spiropentanes. Bicyclic carbocycles include any combination of ring sizes, such as a 3-3 spirocyclic system, a 4-4 spirocyclic 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.

[0120] The term "aryl" refers to an aromatic monocyclic or polycyclic hydrocarbon ring system. An aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and 5-18 carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0121] The term "cycloalkyl" refers to a saturated ring in which each ring atom is carbon. Cycloalkyl groups can include monocyclic and polycyclic rings, such as 3 to 10-membered monocyclic rings, 5 to 12-membered bicyclic rings, 5 to 12-membered spirobicyclic rings, and 5 to 12-membered bridged rings. In certain embodiments, the cycloalkyl group comprises 3 to 10 carbon atoms. In other embodiments, the cycloalkyl group comprises 5 to 7 carbon atoms. The cycloalkyl group can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic carbocyclyl groups include, for example, adamantyl, spiropentanyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentanyl, etc.

[0122] The term "cycloalkenyl" refers to a saturated ring in which each ring atom is carbon and has at least one double bond between two ring carbons. Cycloalkenyl groups can include monocyclic and polycyclic rings, such as 3 to 10 membered monocycles, 6 to 12 membered bicyclic rings, and 5 to 12 membered bridged rings. In other embodiments, the cycloalkenyl group comprises 5 to 7 carbon atoms. The cycloalkenyl group can be attached to the rest of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0123] The term "halo" or "halogen" or "halide" means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro or bromo.

[0124] The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups, for example, 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.

[0125] As used herein, the term "heterocycle" 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 3-10 membered monocycles, 6-12 membered bicyclic rings, 5-12 membered spirobicyclic rings, and 5-12 membered bridged rings. Where valence permits, bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings. In exemplary embodiments, aromatic rings, such as pyridyl, may be fused to saturated or unsaturated rings 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 also include spiro bicycles, for example 5- to 12-membered spiro bicycles, such as 2-oxa-6-azaspiro[3.3]heptane.

[0126] The term "heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic or tetracyclic ring system in which at least one ring is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is connected to the rest of the molecule through any atom in the ring. Examples of heteroaryls include, but are not limited to, aza benzo[b][1,4]dioxolane, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolane benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolanyl, 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-dihydro Benzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furano[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, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methan-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepine yl, 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, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl oxazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).

[0127] The term "heterocycloalkyl" refers to a saturated ring having carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl can include monocyclic and polycyclic rings, such as 3 to 10-membered monocycles, 6 to 12-membered bicyclics, 5 to 12-membered spirobicyclics, and 5 to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. As long as valence permits, the heterocycloalkyl group is attached to the rest of the molecule through any atom of the heterocycloalkyl group, such as any carbon or nitrogen atom of the heterocycloalkyl group. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl.

[0128] The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom, and having at least one double bond between two ring carbon atoms. Heterocycloalkenyl groups do not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl groups 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, the heterocycloalkenyl group contains 5 to 7 carbon atoms. The heterocycloalkenyl group can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazol), isothiazolin (dihydroisothiazole), oxadiazolin (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0129] The term "substituted" refers to a portion of a substituent having a hydrogen replacement group on one or more carbons or substitutable heteroatoms (e.g., NH or NH2) of a compound. It should be understood that "substituted" or "substituted with ... " include implicit conditions, i.e., the substitution is based on the possible valence of the substituted atom and the substituent, and the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. In certain embodiments, substitution refers to a portion in which two hydrogen atoms are substituted by a substituent on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thio group. As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For suitable organic compounds, permissible substituents can be one or more and are identical or different.

[0130] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thio (=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 (wherein 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 optionally replaced by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=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(Ra )2 (wherein t is 1 or 2) substituted; wherein each R a are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, wherein each R a Where valence permits, the alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=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 (wherein t is 1 or 2); and wherein each R b are independently selected from a direct bond, or a straight or branched alkylene, alkenylene or alkynylene chain, and each R cis a straight or branched alkylene, alkenylene or alkynylene chain.

[0131] Double bonds to oxygen atoms, such as oxo groups, are represented herein as "=O" and "(O)." Double bonds to nitrogen atoms are represented as "=NR" and "(NR)." Double bonds to sulfur atoms are represented as "=S" and "(S)."

[0132] As used herein, the phrases "parenteral administration" and "parenteral administration" refer to modes of administration other than enteral and topical administration, usually by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0133] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0134] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and tantalum oil. Soybean oil; (10) diols such as propylene glycol; (11) polyols such as glycerol, 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) ethanol; (20) phosphate buffer solution; and (21) other nontoxic compatible substances used in pharmaceutical preparations.

[0135] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counterions 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 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.

[0136] As used herein, "treatment" or "treating" refers to a method for obtaining a beneficial or desired result (including but not limited to a therapeutic benefit and / or a prophylactic benefit) with respect to a disease, disorder, or medical condition. A therapeutic benefit may include, for example, the eradication or improvement of the underlying disease being treated. Additionally, a therapeutic benefit may include, for example, the eradication or improvement of one or more physiological symptoms associated with the underlying disorder, such that an improvement is observed in the subject, even though the subject may still be suffering from the underlying disorder. In certain embodiments, for prophylactic benefit, a composition is administered to a subject at risk of developing a particular disease or to a subject who reports one or more physiological symptoms of a disease, even though a diagnosis of the disease may not yet have been made. Treatment by administering the compounds described herein does not require the involvement of a medical professional.

[0137] Compound

[0138] The following is a discussion of compounds and salts thereof that can be used in the methods of the present disclosure. In certain embodiments, the compounds and salts are described in Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II) and (IIa).

[0139] In one aspect, disclosed herein are compounds represented by formula (I):

[0140]

[0141] or a salt thereof, wherein:

[0142] Each X is independently selected from C(R 3 ), N and N + (-O- ), wherein at least one X is N or N + (-O - ); A is selected from -O-, -NR 4 -、-CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-;

[0143] R 1 Selected from:

[0144] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0145] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 and C 2-6 Alkynyl is substituted by a substituent, wherein C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replaced; or

[0146] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 Replaced by; R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced by;

[0147] R 2 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following:

[0148] 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)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and when R 2 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of the pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0149] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0150] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally replaced by one or more R 9 replaced by;

[0151] Each R 3 、R 5 and R 6 Independently selected from:

[0152] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or

[0153] R 3 With R 1 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 Replaced by; R 5 With R 1 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by;

[0154] R 4 Independently selected from:

[0155] hydrogen; and

[0156] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 replaced by;

[0157] R 7 and R 8 Independently selected from:

[0158] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents;

[0159] Each R 9 Independently selected from:

[0160] 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 ), -CN; and

[0161] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0162] Each R 10 Independently selected from:

[0163] hydrogen; and

[0164] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0165] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, 3- to 10-membered heterocyclic and C 1-6 substituted by a haloalkyl substituent;

[0166] n is 0, 1 or 2; and p is 0, 1 or 2.

[0167] In certain embodiments, for compounds or salts of Formula (I), each X is independently selected from C(R 3 ) and N, wherein 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 - ) and one 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 - ).

[0168] In certain embodiments, for compounds or salts of Formula (I), each X is further selected from C(R 3 ).

[0169] In some embodiments, the compound of formula (I) or a salt thereof is represented by formula (Ia):

[0170]

[0171] In some embodiments, the compound of formula (I) or a salt thereof is represented by formula (Ib):

[0172]

[0173] In some embodiments, the compound of formula (I) or a salt thereof is represented by formula (Ic):

[0174]

[0175] In some embodiments, the compound of formula (I) or a salt thereof is represented by formula (Id):

[0176]

[0177] In certain embodiments, the compound of Formula (I) is represented by Formula (Ia) or Formula (Ib):

[0178]

[0179] In certain embodiments, the compound of Formula (I) is represented by Formula (Ic) or Formula (Id):

[0180]

[0181] In certain embodiments, the compound of Formula (I) is represented by Formula (Ia) or Formula (Ic):

[0182]

[0183] In certain embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), A is selected from -O-, -NR 4 -,-CR 5 R 6 - and -C(O)-. In some embodiments, A is selected from -O- and -NR 4 In some embodiments, A is -O-.

[0184] In certain embodiments, for the compound or salt of any of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from:

[0185] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0186] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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; or

[0187] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9replaced.

[0188] In certain embodiments, for the compound or salt of any of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from:

[0189] C 1-5 Alkyl, which is optionally substituted by one or more independently selected from 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 、-CN、C 3-7 The substituents are substituted by carbocyclic and 3 to 7 membered heterocyclic groups, wherein the C 3-7 The carbocyclic ring and the 3- to 7-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0190] C 3-7 Carbocyclic ring, which is optionally substituted by one or more independently selected from 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 、-CN、C 1-6 Alkyl and C 1-6 is substituted by a haloalkyl substituent; or

[0191] or R 1 With R 4 Together form a 3 to 6 membered heterocyclic ring, wherein the 3 to 6 membered heterocyclic ring is optionally replaced by one or more R 9 replaced.

[0192] In certain embodiments, for the compound or salt of any of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from:

[0193] C 1-5 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、C 3-5 The substituents are substituted by carbocyclic and 3 to 5 membered heterocyclic groups, wherein the C 3-5 The carbocyclic ring and the 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9replaced by;

[0194] C4-C6 saturated carbocyclic ring; or

[0195] R 1 With R 4 together forming optionally one or more R 9 a substituted 5-membered saturated heterocyclic ring;

[0196] where R 9 independently selected from halogen, -OR 10 、-N(R 10 )2, -NO2, =O, -CN;

[0197] and C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-N(R 10 )2, -NO2, =O and -CN substituents.

[0198] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 1 Selected from -CHF2, -CH(CH3)2, -CH2CH(CH3)2, -CH2CF(CH3)2, -CH2CF3, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2OCF3, -CH2C(CH3)2OCH3, -CH2 SCH3, -CH2CH2SCH3, -CH2CH(CH3)SCH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CF2CH3, -CH2C(CH3)3, -CH2CH(CH3)2 or R 1 With R 4 Together they form a 5-membered saturated heterocyclic ring substituted with -CH3 or -CF3.

[0199] In some embodiments, R 1 Selected from C 1-5 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、C 3-5 The substituents are substituted by carbocyclic and 3 to 5 membered heterocyclic groups, wherein the C 3-5 The carbocyclic ring and the 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced.

[0200] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 1 C 1-6 Alkyl, which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 is C substituted by one or more substituents independently selected from the following 1-6 Alkyl: 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 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 is C substituted by one or more substituents independently selected from the following 1-6 Alkyl: 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 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 Selected from C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, =O, =S, =N(R 10 ),-CN, C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced.

[0201] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 1 is C substituted by one or more substituents independently selected from the following 1-3 Alkyl: halogen, -OR 10 、-N(R 10 )2、-NO2、=O、-CN、C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 is a C substituted by one or more halogen substituents 1-3 In some embodiments, R 1 C 1-3 In some embodiments, R 1In some embodiments, R 1 C 3-10 Carbocyclic ring, which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, 3- to 10-membered heterocyclic and C 1-6 In some embodiments, R 1 Selected from C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 Selected from -CHF2, -CH2CF3, -CH2CH2OCF3, -CH3, -CH2CH3, -CH2CH2CH3 and -CH2CH2OCH3, In some embodiments, R 1 Selected from -CHF2, -CH(CH3)2, -CH2CH(CH3)2, -CH2CF(CH3)2, -CH2CF3, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2OCF3, -CH2C(CH3)2OCH3, -CH2 SCH3, -CH2CH2SCH3, -CH2CH(CH3)SCH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CF2CH3, -CH2C(CH3)3, -CH2CH(CH3)2, In some embodiments, R 1 It is -CH2CF3.

[0202] In some embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 1 With R 4 Together form a 3 to 6 membered heterocyclic ring, wherein the 3 to 6 membered heterocyclic ring is optionally replaced by one or more R 9 In some embodiments, R1 With R 4 together forming optionally one or more R 9 In some embodiments, R 1 With R 4 together to form optionally one or more selected from C 1-3 Alkyl and C 1-3 A 5-membered saturated heterocyclic ring substituted with a haloalkyl substituent.

[0203] In certain embodiments, for the compound or salt of any of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 is selected from optionally substituted C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl and spiropentyl, any one of which is optionally substituted. 1 is selected from alkyl, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may be optionally substituted. 1 is selected from optionally substituted saturated C4-C6 cycloalkyl. 1 Selected from: In certain embodiments, R 1 Selected from: In certain embodiments, R 1 Selected from optionally substituted In some embodiments, R 1 for

[0204] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 In some embodiments, R 1 With R 3 Together they form C 5-10 Carbocyclic or 5- to 10-membered heterocyclic rings, such as C 5-6 Carbocyclic or 5- to 6-membered heterocyclic rings, for example:

[0205]

[0206] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 1With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 In some embodiments, R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbon rings, such as:

[0207]

[0208] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 In some embodiments, R 1 With R 4 Together they form a 3- to 10-membered heterocyclic ring, for example:

[0209]

[0210] In some embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 1 Each R 9 independently selected from halogen, -OR 10 、-N(R 10 )2, -NO2, =O, -CN; and C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-N(R 10 )2, -NO2, =O and -CN. In some embodiments, R 1 Each R 9 independently selected from halogen and -OR 10 ; and C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen and -OR 10 In some embodiments, R 1 Each R 9 Independently selected from -CH3, -CF3 and =O.

[0211] In some embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2is an optionally substituted 5-membered heteroaryl, 6-membered heteroaryl, or 9-membered bicyclic heterocycle. 2 is an optionally substituted 5-membered heteroaryl. In certain embodiments, R 2 is an optionally substituted 5-membered heteroaryl group having at least one endocyclic nitrogen or oxygen atom in the 5-membered heteroaryl group, for example, oxazole, isoxazole, thiazole, pyrrole, pyrazole, furan, diazole, triazole, imidazole, oxadiazole, thiadiazole, isoxazole, isothiazole, and tetrazole. In certain embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 Selected from: Any of which is optionally substituted. In some embodiments, R 2 Selected from: Any of which is optionally substituted. In some embodiments, R 2 Selected from: Any of which is optionally substituted. In some embodiments, R 2 Selected from: Any of which is optionally substituted.

[0212] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 is selected from optionally substituted 5 or 6 membered monocyclic heteroaryl and optionally substituted 9 membered bicyclic heteroaryl. 2 is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, isothiazole, tetrazole, pyrazole, pyrrole, furan, imidazole, oxadiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazine, benzoxazole, benzothiazole, benzimidazole, indole, indazole, and imidazopyridine, any of which is optionally substituted. In some embodiments, R 2 is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, tetrazole, pyrazole, oxadiazole, thiazole, pyridine, pyridazine, pyrazine, benzoxazole, indazole and imidazopyridine, any of which is optionally substituted. 2 In R 2 is unsubstituted at any ortho position relative to the point of attachment to the rest of the molecule. 2 In R 2 In some embodiments, R 2is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, tetrazole, pyrazole, oxadiazole, thiazole, isoxazole, thiadiazole, any one of which is optionally substituted. 2 is selected from isoxazole, oxazole, thiadiazole, pyrazole, oxadiazole, thiazole, isoxazole, thiadiazole, any one of which is optionally substituted.

[0213] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 The substituents on 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents; and optionally substituted C 3-10 In some embodiments, R 2 is a heteroaryl, for example, a 5-membered heteroaryl, which is optionally substituted with one or more selected from halogen, -OR 10 and -N(R 10 )2 is substituted by a substituent; C 1-4 Alkyl, optionally substituted with one or more substituents independently selected from halogen; and optionally substituted C 3-10 Carbocycle, for example, optionally substituted phenyl or optionally substituted cycloalkyl such as cyclopropyl.

[0214] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 Selected from:

[0215] Any of which is optionally substituted. In some embodiments, R 2 Selected from: Any of which is optionally substituted. In some embodiments, R 2 Selected from: Any of which is optionally substituted.

[0216] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 In some embodiments, R 2 Can be selected from 6-membered heteroaryl groups such as pyridine, pyridazine, pyrimidine, pyrazine, triazine and N-oxides thereof. 2 is selected from the group consisting of optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl N-oxide, and optionally substituted pyrimidinyl N-oxide. 2 In certain embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 is a 6-membered heteroaryl, for example, pyridinyl or pyrimidinyl, which is optionally substituted by halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; optionally one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituted C 1-6 Alkyl; and optionally substituted C 3-10 In certain embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 is a 6-membered heteroaryl group, for example, pyridyl or pyrimidinyl, which is optionally substituted by halogen, -OR 10 ,-SR 10 and -N(R 10 )2 is replaced, and C 1-4 Alkyl, which is optionally substituted by one or more independently selected from halogen and -OR 10 In some embodiments, R 2 Selected from:

[0217] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 is selected from the group consisting of optionally substituted pyridine, optionally substituted pyrazine, optionally substituted pyridazine, and optionally substituted pyrimidine. 2 Selected from Any of which is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 , -CN and the substituents on the nitrogen atom of the pyridyl group are optionally selected from -O - ; and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen and -OR 10 In some embodiments, R 2 Selected from:

[0218] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 In some embodiments, R 2 is selected from an optionally substituted 9-membered bicyclic heteroaryl, for example, an optionally substituted benzoxazole, benzothiazole or benzimidazole. In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 is a 9-membered bicyclic heteroaryl, for example, benzoxazole, which is optionally substituted by halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents; and optionally substituted C 3-10 In some embodiments, R 2 In some embodiments, R 2 Selected from:

[0219] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 In some embodiments, R 2 is selected from benzoxazole, benzothiazole, benzimidazole, indole, indazole and imidazopyridine, any of which is optionally substituted. 2 is selected from benzoxazole, benzothiazole, indole, indazole and imidazopyridine, any of which is optionally substituted. 2is selected from benzoxazole, indazole and imidazopyridine, any of which is optionally substituted. 2 In some embodiments, R 2 Selected from: wherein any one of them is optionally replaced by one or more independently selected from halogen, -OR 10 、-SR 10 In some embodiments, R 2 Selected from:

[0220] In some embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), when R 2 When the heteroaryl ring is substituted at one or both ortho positions relative to the point of attachment to the rest of the molecule, R 2 Each ortho substituent on 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN. In some embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), when R 2 When the heteroaryl ring is substituted at one or both ortho positions relative to the point of attachment to the rest of the molecule, R 2 Each ortho substituent on the 1-3 Alkyl, optionally substituted with one or more substituents independently selected from halogen.

[0221] In some embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 The heteroaryl ring is unsubstituted at any ortho position relative to the point of attachment to the rest of the molecule. In some embodiments, for the compound or salt of any of Formula (I), (Ia), (Ib), (Ic), (Id), R 2 The heteroaryl ring is not substituted with a heterocycle or carbocycle at any ortho position relative to the point of attachment to the rest of the molecule.

[0222] In certain embodiments, for compounds or salts of Formula (I), each R 3 Selected from hydrogen, halogen, -OR10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN. In some embodiments, R 3 With R 1 Together form a 5- to 6-membered heterocyclic ring or C 5-6 Carbocyclic ring, wherein the 5- to 6-membered heterocyclic ring or C 5-6 The carbocyclic ring is optionally substituted with one or more R 9 In some embodiments, R 3 For hydrogen.

[0223] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), R 4 are independently selected from hydrogen; and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 In some embodiments, R 4 For hydrogen.

[0224] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), each R 5 and R 6 are independently selected from hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents.

[0225] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), each R 7 and R 8 independently selected from halogen, -OR10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 In certain embodiments, for the compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), each R 7 and R 8 independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-NO2、-CN、-CHF2、-CF3、-CH2F and C 2-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents.

[0226] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), each R 9 independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, =O, =S, -CN; and C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN. In some embodiments, R 9 In some embodiments, R 9 For unsubstituted C 1-3 In some embodiments, R 9 =0. In some embodiments, R 9 In some embodiments, R 9 is C substituted by one or more fluorine substituents 1-3 alkyl.

[0227] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), (Id), each R10 are independently selected from hydrogen; and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 The alkyl group is substituted by a carbocyclic ring, a 3- to 10-membered heterocyclic ring, and a haloalkyl group.

[0228] In certain embodiments, for the compound or salt of any of Formula (I), (Ia), (Ib), (Ic), (Id), n is 0.

[0229] In certain embodiments, for the compound or salt of any of Formula (I), (Ia), (Ib), (Ic), (Id), p is 0.

[0230] In one aspect, disclosed herein are compounds represented by Formula (Ie):

[0231]

[0232] or a salt thereof, wherein:

[0233] X is independently selected from C(R 3 ) and N;

[0234] R 1 Selected from

[0235] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OH, -SH, -NH2, -NO2, -CN, C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced by;

[0236] R 2is heteroaryl, for example, a 5-, 6- or 9-membered heteroaryl, which is optionally substituted with one or more substituents independently selected from

[0237] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN;

[0238] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN substituents; and optionally substituted with one or more R 9 Substituted C 3-10 carbon ring;

[0239] Each R 9 Independently selected from

[0240] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN; and

[0241] C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; and

[0242] Each R 10 Independently selected from

[0243] hydrogen; and

[0244] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl) substituent.

[0245] In certain embodiments, for the compound or salt of any of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 -A is further selected from hydrogen. For example, the compounds of the present disclosure can be represented as:

[0246] or a salt thereof.

[0247] In certain embodiments, for the compound or salt of formula (I):

[0248] Each X is N or N + (-O - ), preferably each X is N;

[0249] A is selected from -O-, -NR 4 -or-CR 5 R 6 -, preferably A is -O-;

[0250] R 1 Selected from C 1-5 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、C 3-5 The substituents are substituted by carbocyclic and 3 to 5 membered heterocyclic groups, wherein the C 3-5 The carbocyclic ring and the 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 substituted, preferably R 1 Selected from C 1-3 alkyl, optionally substituted with one or more substituents independently selected from halogen;

[0251] R 2 is selected from optionally substituted 5- or 6-membered monocyclic heteroaryl and optionally substituted 9-membered bicyclic heteroaryl,

[0252] Preferably R 2 is selected from optionally substituted 6-membered heteroaryl, wherein R 2 The substituents on 10 、-SR 10 、-CN、C 1-3 Alkyl and C 1-3 alkyl halide;

[0253] R 7 and R 8 independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-3 alkyl, optionally substituted with one or more substituents independently selected from halogen;

[0254] n is 0 or 1; and

[0255] p is 0 or 1.

[0256] In certain embodiments, the compounds of the present disclosure are selected from the compounds of Table 1 or salts thereof.

[0257] In one aspect, disclosed herein are compounds represented by formula (II):

[0258]

[0259] or a salt thereof, wherein:

[0260] T is selected from -O-, -NR 14 -、-CR 15 R 16 -, -C(O)-, -S-, -S(O)-, and -S(O)2;

[0261] R 11 Selected from:

[0262] C 1-5 haloalkyl, optionally further substituted with one or more substituents independently selected from: -OR 20 、-SR 20 、-N(R 20 )2, -NO2, =O, =S, -CN, C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced by;

[0263] R 12 is heteroaryl, which is optionally substituted by one or more substituents independently selected from 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; and when R 12 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of the pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0264] C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced; and

[0265] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more -R 19 replace;

[0266] Each R 15 and R 16 are independently selected from hydrogen, halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0267] R 14 independently selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0268] Each R 17 and R 18 Independently selected from:

[0269] Halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0270] Each R 19 Independently selected from:

[0271] 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; and

[0272] C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0273] Each R 20 Independently selected from:

[0274] hydrogen; and

[0275] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0276] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents;

[0277] w is 0, 1, or 2; and z is 0, 1, or 2.

[0278] In certain embodiments, for compounds or salts of formula (II), T is selected from -O-, -NR 14 -and-CR 15 R 16 -. In some embodiments, T is -O-.

[0279] In certain embodiments, for compounds or salts of formula (II), R 11 is selected from C optionally further substituted by one or more substituents independently selected from1-5 Haloalkyl: -OH, -SH, -NH2, -NO2, =O, =S, -CN, C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 In some embodiments, R 11 is selected from C optionally further substituted by one or more substituents independently selected from 1-3 Haloalkyl: -OR 20 、-SR 20 、-N(R 20 )2、=O、-CN、C 3-10 In certain embodiments, R 11 is a C substituted by one or more halogen substituents 1-3 In some embodiments, R 11 It is -CHF2 or -CH2CF3.

[0280] In certain embodiments, for the compound or salt of any one of Formula (II), R 11 is selected from optionally substituted C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl and spiropentyl, any one of which is optionally substituted. 11 is selected from alkyl, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may be optionally substituted. 11 Selected from: In certain embodiments, R 11 Selected from: In certain embodiments, R 11 Selected from optionally substituted

[0281] In some embodiments, for compounds of formula (II), R 12 is an optionally substituted 5-membered heteroaryl, 6-membered heteroaryl, or 9-membered bicyclic heterocycle. 12 is an optionally substituted 5-membered heteroaryl. In certain embodiments, R 12 is an optionally substituted 5-membered heteroaryl group, wherein at least one of the 5-membered heteroaryl groups is an internal nitrogen or oxygen atom, for example, oxazole, thiazole, pyrrole, pyrazole, furan, diazole, triazole, imidazole, oxadiazole, thiadiazole, isoxazole, isothiazole and tetrazole. In certain embodiments, for compounds or salts of formula (II), R 12 Selected from: Any of which is optionally substituted. In some embodiments, R 12 Selected from: Any of which is optionally substituted. In some embodiments, R 12 Selected from: Any of which is optionally substituted. In some embodiments, R 12 Selected from: Any of which is optionally substituted. In some embodiments, R 12 Selected from:

[0282] In some embodiments, R 12 is selected from optionally substituted 5 or 6 membered monocyclic heteroaryl and optionally substituted 9 membered bicyclic heteroaryl. 12 is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, isothiazole, tetrazole, pyrazole, pyrrole, furan, imidazole, oxadiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazine, benzoxazole, benzothiazole, benzimidazole, indole, indazole and imidazopyridine, any of which is optionally substituted. In some embodiments, R 12 is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, pyrazole, imidazole, oxadiazole, thiazole, pyridine, pyrimidine, benzoxazole, benzimidazole, any of which is optionally substituted. 12 is selected from the group consisting of isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole, thiazole, pyridine, and benzoxazole, any of which is optionally substituted. 12 In R 12 is unsubstituted at any ortho position relative to the point of attachment to the rest of the molecule. 12 In R 12 In some embodiments, R 12 is selected from the group consisting of isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole, and thiazole, any of which is optionally substituted.

[0283] In certain embodiments, for compounds of formula (II), R 12 The substituents on 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN; C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20、-SR 10 、-N(R 20 )2, -NO2 and -CN substituents; and optionally substituted C 3-10 In some embodiments, R 2 is a heteroaryl, for example, a 5-membered heteroaryl, which is optionally substituted with one or more selected from halogen, -OR 10 and -N(R 20 )2 is substituted by a substituent; C 1-4 Alkyl, optionally substituted with one or more substituents independently selected from halogen; and optionally substituted C 3-10 Carbocycle, for example, optionally substituted phenyl or optionally substituted cycloalkyl such as cyclopropyl.

[0284] In certain embodiments, for compounds or salts of formula (II), R 12 Selected from: Any of which is optionally substituted. In some embodiments, R 12 Selected from: Any of which is optionally substituted.

[0285] In certain embodiments, for compounds or salts of formula (II), R 12 In some embodiments, R 12 Can be selected from 6-membered heteroaryl groups such as pyridine, pyridazine, pyrimidine, pyrazine, triazine and N-oxides thereof. 12 is selected from the group consisting of optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl N-oxide, and optionally substituted pyrimidinyl N-oxide. 12 is selected from optionally substituted pyridinyl and optionally substituted pyrimidinyl. In certain embodiments, for the compound or salt of formula (II), R 12 is a 6-membered heteroaryl, for example, pyridinyl or pyrimidinyl, which is optionally substituted with halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN; C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents; and optionally substituted C 3-10 In certain embodiments, for the compound or salt of formula (II), R12 is a 6-membered heteroaryl, for example, pyridinyl or pyrimidinyl, which is optionally substituted with halogen, -OR 20 、-SR 20 and -N(R 20 )2; and C 1-4 Alkyl, which is optionally substituted by one or more independently selected from halogen and -OR 20 In some embodiments, R 12 Selected from:

[0286] In some embodiments, R 12 is selected from pyridine and pyrimidine, any of which is optionally substituted. 12 Selected from: Any of which is optionally substituted.

[0287] In some embodiments, R 12 In some embodiments, R 12 Optionally substituted

[0288] In certain embodiments, for compounds or salts of formula (II), R 12 In some embodiments, R 12 is selected from an optionally substituted 9-membered bicyclic heteroaryl, for example, an optionally substituted benzoxazole, benzothiazole or benzimidazole. In certain embodiments, for the compound or salt of formula (II), R 12 is a 9-membered bicyclic heteroaryl, for example, benzoxazole, which is optionally substituted by halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN; C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents; and optionally substituted C 3-10 In some embodiments, R 12 In some embodiments, R 12 Selected from

[0289] In some embodiments, for the compound or salt of formula (II), when R 12 When the heteroaryl ring is substituted at one or both ortho positions relative to the point of attachment to the rest of the molecule, R12 Each ortho substituent on 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN. In some embodiments, for the compound or salt of formula (II), when R 12 When the heteroaryl ring is substituted at one or both ortho positions relative to the point of attachment to the rest of the molecule, R 12 Each ortho substituent on the 1-3 Alkyl, optionally substituted with one or more substituents independently selected from halogen.

[0290] In some embodiments, for the compound or salt of formula (II), R 12 The heteroaryl ring is unsubstituted at any ortho position relative to the point of attachment to the rest of the molecule. In some embodiments, for compounds or salts of formula (II), R 12 The heteroaryl ring is not substituted with a heterocycle or carbocycle at any ortho position relative to the point of attachment to the rest of the molecule.

[0291] In certain embodiments, for compounds of formula (II), R 14 are independently selected from hydrogen; and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN. In some embodiments, R 14 For hydrogen.

[0292] In certain embodiments, for compounds of formula (II), each R 15 and R 16 are independently selected from hydrogen, halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents.

[0293] In certain embodiments, for compounds of formula (II), each R 17 and R 18 independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2、-NO2、-CN、-CHF2、-CF3、-CH2F and C 2-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 ) 2, -NO 2 and -CN. In certain embodiments, for the compound of formula (II), each R 17 and R 18 independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents.

[0294] In certain embodiments, for compounds of formula (II), each R 19 independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, =O, =S, -CN; and C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN. In some embodiments, R 19 In some embodiments, R 19 For unsubstituted C 1-3 In some embodiments, R 19 =0. In some embodiments, R 19 In some embodiments, R 19 is C substituted by one or more fluorine substituents 1-3 alkyl.

[0295] In certain embodiments, for compounds of formula (II), each R20 are independently selected from hydrogen; and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 In some embodiments, R 20 is C substituted by a 4- to 6-membered heterocyclic ring 1-2 In some embodiments, R 20 For hydrogen.

[0296] In certain embodiments, for compounds of Formula (II), w is 0.

[0297] In certain embodiments, for compounds of formula (II), z is 0.

[0298] In one aspect, disclosed herein are compounds represented by formula (IIa)

[0299]

[0300] or a salt thereof, wherein

[0301] R 11 Selected from:

[0302] C 1-5 Haloalkyl, optionally further substituted by one or more substituents independently selected from the group consisting of: -OH, -SH, -NH2, -NO2, -CN, C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced by;

[0303] R 12is heteroaryl, for example, 5-, 6-, or 9-membered heteroaryl, which is optionally substituted with one or more substituents independently selected from:

[0304] Halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN; and optionally one or more -R 19 Substituted C 3-10 carbon ring;

[0305] Each R 19 Independently selected from:

[0306] Halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN; and

[0307] C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN; and

[0308] Each R 20 Independently selected from:

[0309] hydrogen; and

[0310] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C 1-6 Alkyl)2 and -NH(C 1-6 alkyl) substituent.

[0311] In certain embodiments, for the compound or salt of any one of Formula (II), R 11 -T is further selected from hydrogen. For example, the compounds of the present disclosure can be represented as: or a salt thereof.

[0312] In certain embodiments, the compounds of the present disclosure are selected from the compounds of Table 2 or salts thereof.

[0313] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z- or E-form (or cis- or trans-form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are also intended to include all Z-, E- and tautomeric forms.

[0314] "Tautomers" refer to molecules in which it is possible for a proton to move from one atom of a molecule to another atom of the same molecule. In certain embodiments, the compounds presented herein exist as tautomers. Where tautomerism is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0315]

[0316] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, e.g., 2 H. 3 H. 11 C. 13 C and / or 14 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. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of the drug.

[0317] Unless otherwise indicated, the compounds described herein are intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, in addition to the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C- or 14 Compounds having the present structures other than C-enriched carbon substitutions are also within the scope of the present disclosure.

[0318] 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, isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C) Label the compound. 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, 125 Isotopic substitutions 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.

[0319] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 The synthesis methods of deuterium-containing compounds are known in the art, and include the following synthesis methods as non-limiting examples only.

[0320] Deuterium substituted compounds are synthesized using various methods, such as those described in: Dean, Dennis C. ed. 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.

[0321] Deuterated starting materials are readily available and are amenable to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0322] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs and amorphous forms of the compounds, and mixtures thereof.

[0323] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure having sufficiently acidic, sufficiently basic, or both functional groups can react with any of a variety of inorganic bases, inorganic acids, and organic acids to form salts. Alternatively, inherently charged compounds, such as compounds with quaternary nitrogen, can form salts with suitable counterions, such as halides, such as bromides, chlorides, or fluorides, particularly bromides.

[0324] In some cases, the compounds described herein may exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and suitable mixtures thereof. Separation of stereoisomers can be performed 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). Stereoisomers can also be obtained by stereoselective synthesis.

[0325] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. In addition, the compounds described herein may exist in unsolvated forms as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0326] In certain embodiments, the compound or the salt of the compound can be a prodrug, for example, wherein the hydroxyl group in the parent compound is presented in the form of an ester or carbonate, or the carboxylic acid present in the parent compound is presented in the form of an ester. The term "prodrug" is intended to encompass compounds that are converted to the disclosed medicament under physiological conditions. A method for preparing a prodrug includes one or more selected parts that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal, for example, by the specific target cell conversion in the host animal. For example, esters or carbonates (for example, esters of alcohol or carboxylic acid or esters of carbonate and phosphoric acid) are preferred prodrugs of the present disclosure.

[0327] Prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce the compounds described herein, are included within the scope of the claims. In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0328] Prodrugs are generally useful because, in some cases, prodrugs may be easier to use than the parent drug. For example, they can be bioavailable by oral administration, but the parent drug cannot. Prodrugs can help enhance the cell permeability of the compound relative to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs can be designed as reversible drug derivatives, used as modifiers to enhance the transport of drugs to site-specific tissues or increase the intracellular retention of drugs.

[0329] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective aqueous solubility. See, e.g., 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, ACS Symposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which disclosures are incorporated herein. According to another embodiment, the present disclosure provides methods for preparing the compounds defined above. These compounds can be synthesized using conventional techniques. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0330] 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 PGM Wuts, Protective Groups in Organic Synthesis, 2nd 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).

[0331] Therapeutic applications

[0332] The methods of administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (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 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb-girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome. Examples of movement disorders include, but are not limited to, muscle spasticity disorders, spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury, or traumatic events such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis. Also included are other conditions that may respond to inhibition of skeletal myosin II, skeletal troponin C, skeletal troponin I, skeletal tropomyosin, skeletal troponin T, skeletal regulatory light chains, skeletal myosin binding protein C, or skeletal actin.

[0333] In some embodiments, disclosed herein are methods of treating neuromuscular and movement disorders by administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), or (IIa). In some embodiments, disclosed herein are methods of treating neuromuscular and movement disorders by administering a compound or salt of Formula (III):

[0334]

[0335] or a salt thereof, wherein:

[0336] Each Y is independently selected from C(R 3 ), N and N + (-O - );

[0337] A is selected from -O-, -NR 4 -、-CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-;

[0338] R 1 Selected from:

[0339] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0340] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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; or

[0341] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced by;

[0342] R 2 is heteroaryl, which is optionally substituted by one or more substituents independently selected from 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 when R 2 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of the pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0343] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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)2R 10 , -NO2, =O, =S, =N(R 10 ),-CN, C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0344] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally replaced by one or more R 9 replaced by;

[0345] Each R 3 、R 5 and R 6 Independently selected from:

[0346] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or

[0347] R 3 With R 1 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 Replaced by; R 5 With R 1 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by;

[0348] R 4 Independently selected from:

[0349] hydrogen; and

[0350] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10)2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 replaced by;

[0351] Each R 7 and R 8 Independently selected from:

[0352] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents;

[0353] Each R 9 Independently selected from:

[0354] 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; and

[0355] C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0356] Each R 10 Independently selected from:

[0357] hydrogen; and

[0358] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0359] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents;

[0360] n is 0, 1, or 2; and

[0361] p is 0, 1 or 2.

[0362] In certain embodiments, the present disclosure provides a method of treating activity-induced muscle damage comprising administering to a subject in need thereof a compound or salt of formula (III'):

[0363]

[0364] or a salt thereof, wherein:

[0365] Each Y is independently selected from C(R 3 ), N and N + (-O - );

[0366] A is absent or selected from -O-, -NR 4 -、-CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-; R 1 Selected from:

[0367] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0368] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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; or

[0369] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or a saturated C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or saturated C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced; and

[0370] When A is -NR 4 -, R 1 Additionally selected from hydrogen, and when A is -C(O)-, R 1 Additionally selected from -N(R 10 )2 and -OR 10 ;

[0371] When A does not exist, R 1 Further selected from 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;

[0372] R 2 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following:

[0373] 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 when R 2 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of the pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0374] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 ),-CN, C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0375] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally replaced by one or more R 9 replaced by;

[0376] Each R 3 、R 5 and R 6 Independently selected from:

[0377] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or

[0378] R 3 With R 1 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 Replaced by; R 5 With R 1 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by;

[0379] R 4 Independently selected from:

[0380] hydrogen; and

[0381] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10)2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 replaced by;

[0382] Each R 7 and R 8 Independently selected from

[0383] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents;

[0384] Each R 9 Independently selected from

[0385] 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; and

[0386] C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0387] Each R 10 Independently selected from

[0388] hydrogen; and

[0389] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0390] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents;

[0391] R 30 and R 31 Independently selected from R 10 or R 30 and R 31 Together they form C 3-7 carbocyclic ring, wherein the 3 to 7 membered heterocyclic ring, wherein C 3-7The carbocyclic and 3- to 7-membered heterocyclic rings are optionally replaced by R 9 replace;

[0392] n is 0, 1, or 2; and

[0393] p is 0, 1 or 2.

[0394] In certain embodiments, for compounds or salts of Formula (III) or (III'), each Y is independently selected from C(R 3 ) and N wherein 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 - ) and one 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 the compound or salt of Formula (III) or (III'), each Y is further selected from C(R 3 ).

[0395] In certain embodiments, for compounds or salts of formula (III) or (III'), A is selected from -O-, -NR 4 -,-CR 5 R 6 - and -C(O)-. In some embodiments, A is selected from -O- and -NR 4 In some embodiments, A is -O-.

[0396] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 1 C 1-6 Alkyl, which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 is C substituted by one or more substituents independently selected from the following 1-6 Alkyl: 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 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 is C substituted by one or more substituents independently selected from the following 1-6 Alkyl: 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 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R1 Selected from C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, =O, =S, =N(R 10 ),-CN, C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 is C substituted by one or more substituents independently selected from the following 1-3 Alkyl: halogen, -OR 10 ,-N(R 10 )2,-NO2,=O,-CN,C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 In some embodiments, R 1 is a C substituted by one or more halogen substituents 1-3 In some embodiments, R 1 C 1-3 In some embodiments, R 1 Selected from -CHF2 and -CH2CF3.

[0397] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 1 is selected from optionally substituted C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl and spiropentyl, any one of which is optionally substituted. 1 is selected from alkyl, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may be optionally substituted. 1 Selected from: In certain embodiments, R 1 Selected from optionally substituted

[0398] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R9 In some embodiments, R 1 With R 3 Together they form C 5-10 Carbocyclic or 5- to 10-membered heterocyclic rings, such as C 5-6 Carbocyclic or 5- to 6-membered heterocyclic rings, for example:

[0399]

[0400] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 In some embodiments, R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbon rings, such as:

[0401]

[0402] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 In some embodiments, R 1 With R 4 Together they form a 3- to 10-membered heterocyclic ring, for example:

[0403]

[0404] In some embodiments, for the compound or salt of Formula (III) or (III'), R 2 is an optionally substituted 5-membered heteroaryl, 6-membered heteroaryl, or 9-membered bicyclic heterocycle. 2 is an optionally substituted 5-membered heteroaryl. In certain embodiments, R 2 is an optionally substituted 5-membered heteroaryl group, wherein at least one of the endocyclic nitrogen or oxygen atoms of the 5-membered heteroaryl group is, for example, oxazole, isoxazole, thiazole, pyrrole, pyrazole, furan, diazole, triazole, imidazole, oxadiazole, thiadiazole, isoxazole, isothiazole and tetrazole. In certain embodiments, for compounds or salts of formula (III) or (III'), R 2 Selected from: Any of which is optionally substituted. In some embodiments, R 2 Selected from: Any of which is optionally substituted. In some embodiments, R 2 Selected from: Any of which is optionally substituted.

[0405] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 2 The substituents on 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents; and optionally substituted C 3-10 In some embodiments, R 2 is a heteroaryl, for example, a 5-membered heteroaryl, which is optionally substituted with one or more selected from halogen, -OR 10 and -N(R 10 )2 is substituted by a substituent; C 1-4 Alkyl, optionally substituted with one or more substituents independently selected from halogen; and optionally substituted C 3-10 Carbocycle, for example, optionally substituted phenyl or optionally substituted cycloalkyl such as cyclopropyl.

[0406] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 2 Selected from:

[0407]

[0408] Any of which is optionally substituted. In some embodiments, R 2 Selected from:

[0409] Any of which is optionally substituted.

[0410] In certain embodiments, for a compound or salt of Formula (III) or (III'), R 2 In some embodiments, R 2Can be selected from 6-membered heteroaryl groups such as pyridine, pyridazine, pyrimidine, pyrazine, triazine and N-oxides thereof. 2 is selected from the group consisting of optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl N-oxide, and optionally substituted pyrimidinyl N-oxide. 2 is selected from optionally substituted pyridinyl and optionally substituted pyrimidinyl. In certain embodiments, for the compound or salt of formula (III) or (III'), R 2 is a 6-membered heteroaryl, for example, pyridyl or pyrimidinyl, optionally substituted by halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents; and optionally substituted C 3-10 In certain embodiments, for the compound or salt of formula (III) or (III'), R 2 is a 6-membered heteroaryl, for example, pyridinyl or pyrimidinyl, which is optionally substituted with halogen, -OR 10 、-SR 10 and -N(R 10 )2; and C 1-4 Alkyl, which is optionally substituted by one or more independently selected from halogen and -OR 10 In some embodiments, R 2 Selected from:

[0411] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 2 In some embodiments, R 2 is selected from an optionally substituted 9-membered bicyclic heteroaryl, for example, an optionally substituted benzoxazole, benzothiazole or benzimidazole. In certain embodiments, for a compound or salt of formula (III) or (III'), R 2 is a 9-membered bicyclic heteroaryl, for example, benzoxazole, which is optionally substituted with halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR10 、-N(R 10 )2, -NO2 and -CN substituents; and optionally substituted C 3-10 In some embodiments, R 2 In some embodiments, R 2 Selected from:

[0412] In certain embodiments, for the compound or salt of Formula (III) or (III'), each R 3 Selected from hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN. In some embodiments, R 3 With R 1 Together form a 5- to 6-membered heterocyclic ring or C 5-6 Carbocyclic ring, wherein the 5- to 6-membered heterocyclic ring or C 5-6 The carbocyclic ring is optionally substituted with one or more R 9 In some embodiments, R 3 For hydrogen.

[0413] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 4 are independently selected from hydrogen; and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 In some embodiments, R 4 For hydrogen.

[0414] In certain embodiments, for the compound or salt of Formula (III) or (III'), each R 5 and R 6 are independently selected from hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents.

[0415] In certain embodiments, for a compound or salt of Formula (III) or (III'), each R 7 and R 8 independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 In certain embodiments, for compounds or salts of formula (III) or (III'), each R 7 and R 8 independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-NO2、-CN、-CHF2、-CF3、-CH2F and C 2-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents.

[0416] In certain embodiments, for the compound or salt of Formula (III) or (III'), each R 9 independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, =O, =S, -CN; and C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN. In some embodiments, R 9 In some embodiments, R 9 For unsubstituted C 1-3 In some embodiments, R 9=0. In some embodiments, R 9 In some embodiments, R 9 is C substituted by one or more fluorine substituents 1-3 alkyl.

[0417] In certain embodiments, for the compound or salt of Formula (III) or (III'), each R 10 are independently selected from hydrogen; and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 The alkyl group is substituted by a carbocyclic ring, a 3- to 10-membered heterocyclic ring, and a haloalkyl group.

[0418] In certain embodiments, for the compound or salt of Formula (III) or (III'), n is 0.

[0419] In certain embodiments, for the compound or salt of Formula (III) or (III'), p is 0.

[0420] In certain embodiments, for the compound or salt of Formula (III) or (III'), R 1 -A is further selected from hydrogen. For example, the compounds of the present disclosure are represented by: or a salt thereof.

[0421] Methods for treating neuromuscular and movement disorders by reducing skeletal muscle contraction are presented herein. Treatment of subjects with neuromuscular and movement disorders with selective skeletal muscle fast twitch (type II) myosin inhibitors of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can reduce muscle breakdown by preventing excessive, uncoordinated muscle contractions, thereby reducing muscle damage. Furthermore, the methods of the present disclosure can reduce muscle damage while minimizing the impact on the subject's physical function. Function can be maintained by limiting the level of destructive force generated in type II fibers or by increasing reliance on healthier type I fibers. By inhibiting skeletal muscle myosin II, skeletal muscle contraction or uncoordinated muscle contracture can be reduced. In certain embodiments, the skeletal muscle myosin II inhibitor is a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') disclosed herein.

[0422] In some embodiments, disclosed herein is a method of inhibiting muscle myosin II, comprising administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') to a subject in need thereof. In some embodiments, the compound or salt does not significantly inhibit myocardial contraction. In some embodiments, wherein the compound or salt does not significantly inhibit myocardial contraction. In some embodiments, the compound or salt reduces myocardial force by less than 10%.

[0423] In some aspects, a method of treating a neuromuscular condition or movement disorder may comprise administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') to inhibit skeletal muscle contraction. In some embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (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.

[0424] Before and after treatment with a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III'), the subject's activities of daily living (ADL) or habitual physical activity can be monitored. ADL or habitual physical activity depends on the subject and may range from simple walking to extensive exercise, depending on the subject's ability and routine. Treatment options and dosages of the skeletal muscle contraction inhibitors discussed herein can be personalized for the subject so that ADL and habitual physical activity remain unchanged.

[0425] In some aspects, methods of treating a neuromuscular disease or movement disorder can comprise administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') to inhibit skeletal muscle contraction. The amount of the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') administered can be an amount relative to that required to reduce skeletal muscle contraction by 50%. The amount of the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') administered can be less than the amount required to reduce skeletal muscle contraction by 50% relative to the subject's pre-treatment skeletal muscle contractility. The compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') is administered in an amount that reduces skeletal muscle contraction by 5% to 45% relative to the subject's pre-treatment skeletal muscle contractility. In some cases, the amount of compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') administered 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 contractility. In certain embodiments, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') may be administered in an amount that reduces skeletal muscle contraction by 1% to 50% relative to the subject's pre-treatment skeletal muscle contractile capacity.

[0426] In some aspects, a method of treating a neuromuscular disease or movement disorder can comprise administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') to inhibit type I skeletal muscle contraction. The amount of the inhibitor of type I skeletal muscle contraction administered can be an amount relative to the amount required to reduce type I skeletal muscle contraction by 20%. The amount of the inhibitor of type I skeletal muscle contraction administered can be less than the amount required to reduce type I skeletal muscle contraction by 20% relative to the subject's pre-treatment type I skeletal muscle contractile capacity. 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 pre-treatment type I skeletal muscle contractile capacity. In some cases, the amount of the inhibitor administered can reduce 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 contractile 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 contractile capacity.

[0427] In some aspects, methods of treating neuromuscular diseases or movement disorders may comprise administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III')

[0428] or salt to inhibit type II skeletal muscle contraction. The amount of the inhibitor of type II skeletal muscle contraction administered may be an amount relative to that required to reduce type II skeletal muscle contraction by 90%. The amount of the inhibitor of type II skeletal muscle contraction administered may be 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 contractile capacity. The inhibitor of type II skeletal muscle contraction may be administered in an amount that reduces type II skeletal muscle contraction by 5% to 75% relative to the subject's pre-treatment type II skeletal muscle contractile capacity. In some cases, the amount of the inhibitor administered may reduce type II skeletal muscle contraction by less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85% or even less than 90% relative to the subject's pre-treatment type II skeletal muscle contractile 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 contractile capacity.

[0429] In some aspects, methods of treating contraction-induced damage in skeletal muscle fibers can comprise administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') to inhibit skeletal muscle contraction and / or skeletal muscle myosin II. In certain embodiments, the inhibitor does not significantly inhibit cardiac muscle contraction.

[0430] In some aspects, methods of treating metabolic myopathies such as McCardle syndrome may comprise administering a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (lla), (III), or (III').

[0431] In certain embodiments, the damage caused by contraction in skeletal muscle fibers is from involuntary skeletal muscle contraction. Involuntary skeletal muscle contraction may be associated with neuromuscular disease or spasticity-related diseases. In certain embodiments, the damage caused by contraction in skeletal muscle fibers may be from voluntary skeletal muscle contraction, such as sports.

[0432] In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') is administered to a subject to modulate one or more biomarkers associated with muscle contraction. Examples of biomarkers include, but are not limited to, creatinine kinase (CK), troponin T (TnT), troponin C (TnC), troponin I (TnI), pyruvate kinase (PK), lactate dehydrogenase (LDH), myoglobin, subtypes of TnI (e.g., myocardial, slow skeletal muscle, fast skeletal muscle TnI) and inflammatory markers (IL-1, IL-6, IL-4, TNF-α). Biomarkers can also include measures of muscle inflammation, such as edema. Relative to the pre-treatment level of the biomarker, after administration of the inhibitor, the level of the biomarker described herein may increase. Alternatively, relative to the pre-treatment level of the biomarker, after administration of the inhibitor, the level of the biomarker may decrease. Modulation of one or more biomarkers with the inhibitors described herein can be indicative of treatment for a neuromuscular disease, such as those described herein.

[0433] Compared to when the subject is inactive (e.g., sleeping), the CK level of the subject increases when active, and therefore CK is a potential measure for assessing the breakdown of skeletal muscle caused by skeletal muscle contraction. In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can be administered to a subject before mild, moderate or vigorous activity to reduce or prevent the breakdown of skeletal muscle due to activity. Moderate to vigorous activity may depend on the ability of the subject and may include physical exercise that can increase the heart rate by at least 20% or more, such as about 50% or more, relative to the subject's resting heart rate. Examples of moderate to vigorous activity include walking, running, weightlifting, cycling, swimming, hiking, etc.

[0434] In certain embodiments, a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') is administered before, during, or after moderate or vigorous activity to reduce or prevent the breakdown of skeletal muscle due to activity. A compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can reduce CK levels in a subject relative to an untreated subject performing the same activity. CK levels can be measured in the subject's peripheral blood during or after the activity. Administration of the inhibitors described herein can reduce CK levels in an active subject by 5% to 90% relative to an untreated subject performing the same activity, thereby reducing or preventing the breakdown of skeletal muscle due to activity. Administration of the inhibitors described herein can regulate CK levels by about 5% to about 90% relative to an untreated subject performing the same activity, thereby reducing or preventing the breakdown of skeletal muscle due to activity. Administration of the inhibitors described herein can reduce CK levels by at least about 5% relative to untreated subjects performing the same activity, thereby reducing or preventing skeletal muscle breakdown due to activity. Administration of the inhibitors described herein can regulate CK levels by up to about 90% relative to untreated subjects performing the same activity. Administration of the inhibitors described herein can reduce 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%, From about 25% to about 85%, from about 25% to about 90%, from about 35% to about 45%, from about 35% to about 55%, from about 35% to about 65%, from about 35% to about 75%, from about 35% to about 85%, from about 35% to about 90%, from about 45% to about 55%, from about 45% to about 65%, from about 45% to about 75%, from about 45% to about 85%, from about 45% to about 90%, from about 55% to about 65%, from about 55% to about 75%, from about 55% to about 85%, from about 55% to about 90%, from about 65% to about 75%, from about 65% to about 85%, from about 65% to about 90%, from about 75% to about 85%, from about 75% to about 90%, or from about 85% to about 90%, thereby reducing or preventing the breakdown of skeletal muscle due to activity.Administration of the inhibitors described herein can modulate 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 performing the same activity, thereby reducing or preventing the breakdown of skeletal muscle due to activity.

[0435] Administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') to a subject can modulate the level of inflammatory markers, 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 inflammatory markers can be measured in the peripheral blood of the subject. Examples of inflammatory markers can include, but are not limited to, IL-1, IL-6, and TNF-α. Inflammatory markers can also be in the form of conditions such as edema, which can be measured using magnetic resonance imaging. The level of inflammatory markers in the peripheral blood can be increased after administration of an inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Alternatively, the level of inflammatory markers in the peripheral blood can be decreased after administration of an inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Administration of an inhibitor as described herein can modulate the level of an inflammatory marker by 5% to 90% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the level of an inflammatory marker can be modulated by about 5% to about 90% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the level of an inflammatory marker can be modulated by at least about 5% relative to the subject's pre-treatment level of the inflammatory marker. In some cases, the level of an inflammatory marker can 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 an inflammatory marker may be adjusted relative to the subject's pre-treatment level of the inflammatory marker 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%, From about 25% to about 75%, from about 25% to about 85%, from about 25% to about 90%, from about 35% to about 45%, from about 35% to about 55%, from about 35% to about 65%, from about 35% to about 75%, from about 35% to about 85%, from about 35% to about 90%, from about 45% to about 55%, from about 45% to about 65%, from about 45% to about 75%, from about 45% to about 85%, from about 45% to about 90%, from about 55% to about 65%, from about 55% to about 75%, from about 55% to about 85%, from about 55% to about 90%, from about 65% to about 75%, from about 65% to about 85%, from about 65% to about 90%, from about 75% to about 85%, from about 75% to about 90%, or from about 85% to about 90%.In some cases, the level of an inflammatory marker can 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.

[0436] Administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') to a subject can modulate the level of circulating skeletal muscle fast-muscle troponin I (fS-TnI). The level of fS-TnI can be measured in peripheral blood. The level of fS-TnI in the peripheral blood can be increased after administration of the inhibitor relative to the pre-treatment level of fS-TnI in the subject. Alternatively, the level of fS-TnI in the peripheral blood can be decreased after administration of the inhibitor relative to the pre-treatment level of fS-TnI in the subject. Administration of the inhibitors described herein can modulate the level of fS-TnI by 5% to 90% relative to the pre-treatment level of fS-TnI in the subject. In some cases, the level of fS-TnI can be modulated by at least about 5% relative to the pre-treatment level of fS-TnI in the subject. In some cases, the level of fS-TnI can be adjusted by up to about 90% relative to the subject's pre-treatment level of fS-TnI. In some cases, the level of fS-TnI can be adjusted by about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, , about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 65%, about 45% to about 75%, about 45% to about 85%, about 45% to about 90%, about 55% to about 65%, about 55% to about 75%, about 55% to about 85%, about 55% to about 90%, about 65% to about 75%, about 65% to about 85%, about 65% to about 90%, about 75% to about 85%, about 75% to about 90%, or about 85% to about 90%. In some cases, the level of fS-TnI can 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 fS-TnI.

[0437] 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), (IIa), (III) or (III'). Inhibiting skeletal muscle contraction may not inhibit some isoforms of troponin, such as cardiac troponin I (cTnI) or skeletal slow muscle troponin I (ssTnI). In some cases, inhibiting skeletal muscle contraction may not significantly inhibit cTnI or ssTnI. As used herein, with respect to cTnI or ssTnI, the term "not significantly" refers to a decrease in cTnI or ssTnI of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5% or even less than 0.1% relative to cTnI or ssTnI before administration of the inhibitor.

[0438] Administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can reduce involuntary muscle contractions. Relative to involuntary muscle contractions before administration of the inhibitor, involuntary muscle contractions can be reduced by 20% to 90%. In some cases, involuntary muscle contractions can be reduced by at least about 20% relative to involuntary muscle contractions before treatment. In some cases, involuntary muscle contractions can be reduced by up to about 90% relative to involuntary muscle contractions before treatment. In some cases, involuntary muscle contractions may be reduced by about 20% to about 25%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 20% to about 85%, about 20% to about 90%, about 25% to about 30%, about 25% to about 40%, about 25% to about 50%, about 25% to about 70%, about 25% to about 75%, about 25% to about 80%, about 25% to about 85%, about 25% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 70%, about 30% to about 75%, From about 30% to about 80%, from about 30% to about 85%, from about 30% to about 90%, from about 40% to about 50%, from about 40% to about 70%, from about 40% to about 75%, from about 40% to about 80%, from about 40% to about 85%, from about 40% to about 90%, from about 50% to about 70%, from about 50% to about 75%, from about 50% to about 80%, from about 50% to about 85%, from about 50% to about 90%, from about 70% to about 75%, from about 70% to about 80%, from about 70% to about 85%, from about 70% to about 90%, from about 75% to about 80%, from about 75% to about 85%, from about 75% to about 90%, from about 80% to about 85%, from about 80% to about 90%, or from about 85% to about 90%. In some cases, involuntary muscle contractions can be reduced by about 20%, about 25%, about 30%, about 40%, about 50%, about 70%, about 75%, about 80%, about 85%, or about 90% relative to involuntary muscle contractions before treatment.

[0439] The compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can be used to improve a subject's activities of daily living (ADL) or habitual physical activity because mature, fully functional intact muscle can be restored. Examples of ADL or habitual activities include, but are not limited to, stair climbing, time to get up from bed, regular getting up from a chair, habitual walking speed, North Star dynamic assessment, incremental / endurance round-trip walking, and 6-minute walk distance test. The level or ability of ADL or habitual physical activity can be measured before and after administration of a skeletal muscle inhibitor. Inhibiting skeletal muscle contraction may not affect ADL or habitual physical activity. In some cases, inhibiting skeletal muscle contraction may not significantly affect ADL or habitual physical activity. As used herein, with respect to ADL or habitual physical activity, the term non-significant means that the level of ADL or habitual activity is reduced by less than 20%, less than 15%, less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1%, relative to the ADL or habitual physical activity before administration of the inhibitor. Skeletal muscle contraction or force can be measured in a subject before and after administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (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), (IIa), (III), or (III'). The dose of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can be adjusted by about 5% to 50% relative to a dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dose of a skeletal muscle contraction inhibitor can be adjusted by at least about 5% relative to a dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dose of a skeletal muscle contraction inhibitor can be adjusted by up to about 50% relative to a dose that reduces type II skeletal muscle contraction by 90%.In some instances, the dose of a skeletal muscle contraction inhibitor can be adjusted by 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 20%, about 15% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 5 ... From about 1% to about 25%, from about 15% to about 30%, from about 15% to about 35%, from about 15% to about 40%, from about 15% to about 50%, from about 20% to about 25%, from about 20% to about 30%, from about 20% to about 35%, from about 20% to about 40%, from about 20% to about 50%, from about 25% to about 30%, from about 25% to about 35%, from about 25% to about 40%, from about 25% to about 50%, from about 30% to about 35%, from about 30% to about 40%, from about 30% to about 50%, from about 35% to about 40%, from about 35% to about 50%, or from about 40% to about 50%. In some cases, the dose of the skeletal muscle contraction inhibitor can be adjusted by about 10%, about 12%, about 15%, about 18%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%, relative to a dose that reduces type II skeletal muscle contraction by 90%. Skeletal muscle contraction can be measured before and after administration of the skeletal muscle contraction inhibitor by muscle force testing using surface electrodes after nerve stimulation (e.g., plantar flexion after peroneal nerve stimulation of the leg), isolated limb measurement, heart rate monitor or activity monitor, or its equivalent.

[0440] The subject's myocardial force or myocardial contraction can be measured before and after administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III'). Inhibiting skeletal muscle contraction may not inhibit myocardial contraction or myocardial force. In some embodiments, inhibiting skeletal muscle contraction may not significantly inhibit myocardial contraction. In certain embodiments regarding myocardial contraction, the term "not significantly" refers to a decrease in myocardial force of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5% or even less than 0.1% relative to the myocardial force before administration of the inhibitor. The subject's myocardial force or myocardial contraction after administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') may be within 0.1% to 10% of the myocardial force or myocardial contraction before administration of the inhibitor. In some embodiments, administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can inhibit skeletal muscle contraction and myocardial contraction or myocardial force. In some embodiments, myocardial force is reduced by more than 0.1%, more than 0.5%, more than 1%, more than 2%, more than 4%, more than 6%, more than 8% or more than 10%. In some embodiments, the reduction in skeletal muscle contraction and myocardial contraction is described by a ratio to one another. For example, in some embodiments, the ratio of the reduction in skeletal muscle contraction to the reduction in myocardial contraction is from about 1:1 to about 100:1, from about 2:1 to about 50:1, from about 3:1 to about 40:1, from about 4:1 to about 30:1, from about 5:1 to about 20:1, from about 7:1 to about 15:1 or from about 8:1 to about 12:1. Myocardial force or myocardial contraction can be measured using echocardiography (fractional shortening) or other equivalent tests.

[0441] 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), (IIa), (III) or (III'). Administration may not suppress the tidal volume in the lungs. In some cases, administration may not significantly suppress the tidal volume in the lungs. In certain embodiments regarding tidal volume in the lungs, the term "not significantly" refers to a decrease in tidal volume in the lungs of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5% or even less than 0.1% relative to the tidal volume in the lungs before administration of the inhibitor. The tidal volume in the lungs of a subject can be measured using a forced expiratory volume in one second test (FEV1) or a forced vital capacity test (FVC) or their equivalents.

[0442] Smooth muscle contraction can be measured in a subject before and after administration of a skeletal muscle contraction inhibitor. Inhibiting skeletal muscle contraction may not inhibit smooth muscle contraction. In some cases, inhibiting skeletal muscle contraction may not significantly inhibit smooth muscle contraction. As used herein, with respect to smooth muscle contraction, the term "not significantly" means that the smooth muscle contraction 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 smooth muscle contraction before administration of the inhibitor. Smooth muscle contraction in a subject can be assessed by measuring the subject's blood pressure.

[0443] Neuromuscular coupling can be measured in a subject before and after administration of a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III'). Inhibiting skeletal muscle contraction with an inhibitor as described herein may not impair neural transmission, neurotransmitter release, or electrical depolarization of skeletal muscle in the subject. In some cases, inhibiting skeletal muscle contraction may not significantly impair neuromuscular coupling in the subject. As used herein, with respect to neuromuscular coupling, the term "not significantly" means that the level of neuromuscular coupling in the subject 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 neurally induced electrical depolarization of skeletal muscle using surface or needle electrodes and recording the electrical activity of skeletal muscle following electrical or voluntary stimulation using electromyography (EMG).

[0444] In some aspects, a method of treating a neuromuscular disease or movement disorder can comprise administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III'), wherein the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') inhibits myosin ATPase activity, native skeletal muscle myofibrillar ATPase (calcium regulated), or reconstituted S1 with actin, tropomyosin, and troponin. In vitro assays can be used to test the effect of a test compound or inhibitor on myosin ATPase activity. Test compounds can be screened to assess their inhibitory activity on muscle contraction. Inhibitory activity can be determined using an absorbance assay to determine actin-activated ATPase activity. Rabbit muscle myosin subfragment 1 (S1) can be mixed with polymerized actin and dispensed into wells of a nucleotide-free assay plate. The test compound can then be added to the wells using a needle array. The reaction can be initiated with MgATP. ATP consumption in a test container over a defined time period can be compared to ATP consumption in a control container. The defined time period can be 5 to 20 minutes. ATP consumption can be determined by direct or indirect assays. Test compounds that reproducibly and strongly inhibit myosin S1 ATPase activity can be further evaluated in a dose-response assay to determine the compound's IC50 in vitro on dissected muscle. This assay indirectly measures ATPase activity by coupling myosin to pyruvate kinase and lactate dehydrogenase, providing an absorbance detection method at 340 nm based on the conversion of NADH to NAD+ driven by ADP accumulation. In some cases, the test compound can be selected as a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') if ATP consumption in the test container is reduced by at least 20% compared to the control container. In a kinetic assay, a test compound can be selected when the inhibition of NAD+ production is enhanced by at least 20%.

[0445] In an in vitro assay, the selected inhibitor or test compound may not inhibit cardiac myosin S1 ATPase. In some cases, when the test compound or compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') is tested in an in vitro assay, cardiac myosin S1 ATPase or cardiac fibrils or reconstitution 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%.

[0446] Test compounds for skeletal muscle contraction can be tested on stripped fibers. Single skeletal muscle fibers that have been treated to remove membranes and allow for direct activation of contraction following calcium administration can be used. An inhibitor compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can inhibit contraction of a single skeletal muscle fiber by about 5% to about 90% relative to pre-treatment values ​​or untreated control single skeletal muscle. The inhibitor can inhibit contraction of a single skeletal muscle fiber by at least about 5% relative to pre-treatment values ​​or untreated control single skeletal muscle fibers. The inhibitor can inhibit contraction of a single skeletal muscle fiber by up to about 90% relative to pre-treatment values ​​or untreated control single skeletal muscle fibers. The inhibitor may inhibit the contraction of individual 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%, about 20% 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 From about 20% to about 70%, from about 20% to about 80%, from about 20% to about 90%, from about 30% to about 40%, from about 30% to about 50%, from about 30% to about 60%, from about 30% to about 70%, from about 30% to about 80%, from about 30% to about 90%, from about 40% to about 50%, from about 40% to about 60%, from about 40% to about 70%, from about 40% to about 80%, from about 40% to about 90%, from about 50% to about 60%, from about 50% to about 70%, from about 50% to about 80%, from about 50% to about 90%, from about 60% to about 70%, from about 60% to about 80%, from about 60% to about 90%, from about 70% to about 80%, from about 70% to about 90%, or from about 80% to about 90%. The inhibitor can inhibit the contraction of individual skeletal muscle fibers 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 untreated control individual skeletal muscle fibers.

[0447] An inhibitor compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can inhibit contraction of a single skeletal muscle by about 5% to about 90% relative to pre-treatment values ​​or an untreated control single skeletal muscle. An inhibitor can inhibit contraction of a single skeletal muscle by at least about 5% relative to pre-treatment values ​​or an untreated control single skeletal muscle. An inhibitor can inhibit contraction of a single skeletal muscle by up to about 90% relative to pre-treatment values ​​or an untreated control single skeletal muscle. The inhibitor can inhibit the contraction of a single skeletal muscle by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60% , about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90%. The inhibitor can inhibit the contraction of a single skeletal muscle by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to the pre-treatment capacity or an untreated control single skeletal muscle.

[0448] The effect of a test compound on slow type I skeletal muscle fibers, cardiac muscle bundles, or lung muscle fibers can be evaluated. A test compound or inhibitor compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can be selected so that it does not significantly modulate the function of slow type I skeletal muscle fibers, cardiac muscle bundles, or lung muscle fibers and is specific for type II skeletal muscle. As used herein, the term "significantly modulates" can refer to a decrease in the contractile ability of a muscle after administration of the inhibitor relative to the muscle force / contraction before administration of the inhibitor 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%.

[0449] In some aspects, a method of treating a neuromuscular disease or movement disorder can comprise administering a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') to a subject in need thereof, wherein the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') reduces skeletal muscle contraction by 5% to 90% in an in vitro assay. The in vitro assay can be a mouse model. The mouse model can be a malnourished mouse model, such as an mdx mouse. The mdx mouse has a point mutation in the dystrophin gene that changes the amino acid encoding glutamine to threonine, thereby generating a nonfunctional dystrophin protein, leading to DMD with muscle damage and increased muscle weakness. The extensor digitorum longus muscle can be dissected from the mdx mouse and mounted on a lever arm. The muscle can be bathed in oxygenated Kreb's solution to preserve muscle function. A test compound or a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can be applied to the muscle. An isometric (fixed length) contraction step can then be performed, in which the muscle is stimulated with a series of electrical pulses. An eccentric (lengthening) contraction step can be performed, in which the muscle is stretched to 10%, 15%, 20%, 25% or 30% greater than its resting length while relaxing or being stimulated with electrical pulses. In some embodiments, the eccentric contraction step is repeated 2 to 50 times. In some embodiments, the eccentric contraction step is repeated 2 to 40 times. In some embodiments, the eccentric contraction step is repeated 2 to 30 times. In some embodiments, the eccentric contraction step is repeated 2 to 20 times. In some embodiments, the eccentric contraction step is repeated 2 to 10 times. In some embodiments, the eccentric contraction step is repeated 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 times to cause muscle fiber damage. In some embodiments, the electric pulses may have a frequency of about 1 Hz to about 500 Hz. In some embodiments, the electric pulses may have a frequency of about 1 Hz to about 400 Hz. In some embodiments, the electric pulses may have a frequency of about 1 Hz to about 300 Hz. In some embodiments, the electric pulses may have a frequency of about 1 Hz to about 200 Hz. In some embodiments, the electric pulses may have a frequency of about 1 Hz to about 100 Hz. The electric pulses may have a frequency of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 Hz. A series of electric pulses may include single pulses of different frequencies. For each pulse, the time period of each pulse in the series of electric pulses may be between 0.1 seconds and 0.5 seconds.The duration of each pulse can be 0.1, 0.2, 0.3, 0.35, 0.4 or 0.5 seconds. After isometric or eccentric contraction, incubation of the muscle in active orange can also measure sarcolemmal damage. Active orange is a fluorescent dye that is absorbed by muscle fibers with membrane damage. The number or proportion of dye-positive fibers can then be quantified by histology. When the test force decreases and / or the proportion of dye-positive fibers is at least 20% less than the control force decrease and / or dye absorption, the test compound can be selected as a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III').

[0450] The force generated by the muscle can be measured using a set of isometric or eccentric contractions. The change in force generated by the muscle before and after a set of isometric or eccentric contractions can be calculated as the test force drop and compared to the change in force generated by muscle contraction from the first pulse to the last pulse in a control sample not exposed to the test compound (control force drop). The force drop can be used as a proxy for muscle damage, and a test compound or inhibitor compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can be selected when the test force drop is at least 20% less than the control force drop.

[0451] pharmaceutical preparations

[0452] The compositions and methods described herein can be considered useful as pharmaceutical compositions for administration to a subject in need thereof. The pharmaceutical compositions can comprise at least a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') as described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents, and / or thickening agents.

[0453] Pharmaceutical compositions of the compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can be formulated using one or more physiologically acceptable carriers comprising excipients and adjuvants. The formulation can be modified depending on the chosen route of administration. Pharmaceutical compositions comprising the compound, salt or conjugate can be manufactured by, for example, lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or embedding the conjugate. Pharmaceutical compositions can also comprise the compound, salt or conjugate in free base form or in pharmaceutically acceptable salt form.

[0454] Methods for formulating a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') may comprise formulating any compound, salt or conjugate with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semisolid or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in some aspects, solid compositions further comprise non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers and other pharmaceutically acceptable additives. Alternatively, the compound, salt or conjugate may be lyophilized or in powder form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, prior to use.

[0455] Pharmaceutical compositions of compounds or salts of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') may comprise at least one active ingredient (e.g., a compound, salt, or conjugate and another pharmaceutical agent). The active ingredient may be encapsulated in microcapsules (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or macroemulsions.

[0456] The compositions and formulations can be sterilized. Sterilization can be accomplished by sterile filtration.

[0457] Compositions comprising a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can be formulated for administration as an injection. Non-limiting examples of injection formulations may include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles may include, but are not limited to, lipophilic solvents or vehicles, such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. The suspension may also contain a suitable stabilizer. The injection may be formulated for bolus injection or continuous infusion. Alternatively, the composition may be lyophilized or in powder form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, prior to use.

[0458] For parenteral administration, the compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can be formulated into a unit dose injectable form (e.g., solution, suspension, emulsion) together with a pharmaceutically acceptable parenteral vehicle. Such a vehicle can be inherently non-toxic and non-therapeutic. The vehicle 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 a small amount of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0459] In one embodiment, the present invention relates to methods and compositions of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') formulated for oral delivery to a subject in need thereof. In one embodiment, the compositions are formulated so that one or more pharmaceutically active agents are delivered to the subject through the mucosal layer in the mouth or esophagus. In another embodiment, the compositions are formulated so that one or more pharmaceutically active agents are delivered to the subject through the mucosal layer in the stomach and / or intestine.

[0460] In one embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (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 barrier coatings, enteric coatings, osmotic devices, multiparticulate devices, and combinations thereof. The composition may also contain a non-release controlling excipient.

[0461] In another embodiment, the composition of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') is provided in an enteric-coated dosage form. These enteric-coated dosage forms may also include 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 include cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric-coated pellets, as a controlled-release capsule for oral administration. The composition may further include glyceryl monostearate 40-50, hydroxypropyl cellulose, pyridazine, magnesium stearate, C-type methacrylic acid copolymer, polysorbate 80, sugar spheres, talc and triethyl citrate.

[0462] In another embodiment, the composition of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') is an enteric-coated controlled-release tablet for oral administration. The composition may further comprise palm wax, crospovidone, diacetylated monoglyceride, ethyl cellulose, hydroxypropyl cellulose, pyridazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide and yellow ferric oxide.

[0463] Sustained release articles comprising a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can also be prepared. Examples of sustained release articles 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 include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymers of L-glutamic acid and ethyl L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPO. TM (ie, injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

[0464] Pharmaceutical formulations comprising a compound or salt of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (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 non-toxic to the recipient at the dosages and concentrations employed. Acceptable carriers, excipients and / or stabilizers can 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; metal complexes; and / or nonionic surfactants or polyethylene glycol.

[0465] In another embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') may further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide and triethyl citrate.

[0466] In another embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III) or (III') is provided in an effervescent dosage form. These effervescent dosage forms may also contain non-release controlling excipients.

[0467] In another embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can be provided in a dosage form having at least one component that promotes immediate release of the active agent and at least one component that promotes controlled release of the active agent. In a further embodiment, the dosage form may be capable of providing discontinuous release of the compound in the form of at least two consecutive pulses separated in time by 0.1 to 24 hours. The composition may contain one or more release-controlling and non-release-controlling excipients, such as those suitable for rupturable semipermeable membranes and excipients that are swellable substances.

[0468] In another embodiment, the composition of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') is provided in a dosage form for oral administration to a subject in need thereof, comprising one or more pharmaceutically acceptable excipients or carriers encapsulated in a middle reactive layer comprising a gastric juice-resistant polymeric layered material that is partially neutralized with a base and has cation exchange capacity and a gastric juice-resistant outer layer.

[0469] In some embodiments, the compositions of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') provided herein can be in unit dose form or multiple dose form. As used herein, unit dose form refers to physically discrete units suitable for administration to human subjects or non-human animal subjects and individually packaged. Each unit dose can contain a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect and a desired pharmaceutical carrier or excipient. Examples of unit dose forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, the unit dose form can be divided into several portions or multiple administrations. Multiple dose forms are multiple identical unit dose forms packaged in a single container so that they can be administered in separate unit dose forms. Examples of multiple dose forms include, but are not limited to, vials, bottles, or pint or gallon bottles containing tablets or capsules. In another embodiment, the multiple dose form contains different pharmaceutically active agents.

[0470] In some embodiments, the compositions of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III') can also be formulated as modified release dosage forms, including immediate release, delayed release, extended release, extended release, sustained release, pulsed release, controlled release, prolonged release, accelerated release, fast 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, the entire contents of which are incorporated herein by reference).

[0471] Combination therapy

[0472] This article also relates to conjoint therapy, for example, co-administering the disclosed compounds and additional active agents as part of a specific treatment regimen intended to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effects of the conjoint therapy include, but are not limited to, the pharmacokinetic or pharmacodynamic co-actions produced by the combination of therapeutic agents. The conjoint administration of these therapeutic agents is typically carried out over a limited time period (typically hours, days, weeks, months, or years, depending on the selected combination). Conjoint therapy is intended to encompass the administration of multiple therapeutic agents in a sequential manner, i.e., wherein the various therapeutic agents are administered at different times, as well as the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0473] For example, substantially simultaneous administration is achieved by administering to the subject a single formulation or composition (e.g., a tablet or capsule of various therapeutic agents in a fixed ratio) or multiple single formulations (e.g., capsules). The sequential administration or substantially simultaneous administration of the various therapeutic agents is achieved by any appropriate route, including but not limited to oral routes, intravenous routes, intramuscular routes, and direct absorption by mucosal tissue. The therapeutic agents are administered by the same route or by different routes. For example, the first therapeutic agent in a selected combination is administered by intravenous injection, while the other therapeutic agents in the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally, or all therapeutic agents are administered by intravenous injection.

[0474] The components of the combination are administered to the patient simultaneously or sequentially. It should be understood that these components are present in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers that are administered simultaneously or sequentially, such as conventional oral dosage forms.

[0475] In certain embodiments, the compounds or salts of the present disclosure can be co-administered with oral corticosteroids. In certain embodiments, the compounds or salts of the present disclosure are co-administered with deflazacort. In certain embodiments, the compounds or salts of the present disclosure are co-administered with prednisone. In certain embodiments, the compounds or salts of the present disclosure are co-administered with morpholino antisense oligomers. In certain embodiments, the compounds or salts of the present disclosure are co-administered with exon skipping therapy. In certain embodiments, the additional therapeutic agent is eteplirsen or ataluren.

[0476] In certain embodiments, the compounds or salts of the present disclosure are used in combination with gene therapy. In certain embodiments, the compounds or salts of the present disclosure are used in combination with adeno-associated viruses (AAVs) comprising genes encoding alternative proteins (e.g., dystrophin) or truncated forms thereof (e.g., microdystrophin). In certain embodiments, the compounds or salts of the present disclosure are administered in combination with vamorolone.

[0477] The present invention provides embodiments including but not limited to the following:

[0478] 1. A compound represented by formula (I):

[0479]

[0480] or a salt thereof, wherein:

[0481] Each X is independently selected from C(R 3 ), N and N + (-O - ) wherein at least one X is N or N + (-O - ); A is selected from -O-, -NR 4 -、-CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-;

[0482] R 1 Selected from:

[0483] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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(R10 ),-CN, C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0484] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 and C 2-6 Alkynyl is substituted by a substituent, wherein C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Each alkynyl group is optionally substituted by one or more R 9 replaced; or

[0485] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced; or

[0486] R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced by;

[0487] R 2 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following:

[0488] 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 when R 2 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of the pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0489] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0490] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally replaced by one or more R 9 replaced by;

[0491] R 3 、R 5 and R 6 Each independently selected from:

[0492] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, and –CN; and

[0493] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or

[0494] R 3 With R 1 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced; or

[0495] R 5 With R 1 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by;

[0496] R 4 Independently selected from:

[0497] hydrogen; and

[0498] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10)2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 replaced by;

[0499] R 7 and R 8 Independently selected from:

[0500] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents;

[0501] Each R 9 Independently selected from:

[0502] 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

[0503] C 1-3 Alkyl, C 2-3 Alkenyl and C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0504] Each R 10 Independently selected from:

[0505] hydrogen; and

[0506] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0507] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, 3- to 10-membered heterocyclic and C 1-6 substituted by a haloalkyl substituent;

[0508] n is 0, 1, or 2; and

[0509] p is 0, 1 or 2.

[0510] 2. The compound or salt according to embodiment 1, wherein R 1 Selected from:

[0511] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0512] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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; or

[0513] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced; or

[0514] R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced.

[0515] 3. The compound or salt according to embodiment 1 or 2, wherein the compound of formula (I) is represented by formula (Ia) or formula (Ib):

[0516]

[0517] 4. The compound or salt according to embodiment 3, wherein the compound of formula (I) is represented by formula (Ia):

[0518]

[0519] 5. The compound or salt according to embodiment 1 or 2, wherein the compound of formula (I) is represented by formula (Ic) or formula (Id):

[0520]

[0521] 6. The compound or salt according to embodiment 5, wherein the compound of formula (I) is represented by formula (Ic):

[0522]

[0523] 7. A compound or salt according to any one of embodiments 1 to 6, wherein A is selected from -O-, -S- and -NR 4 -.

[0524] 8. The compound or salt of embodiment 7, wherein A is -O-.

[0525] 9. The compound or salt according to embodiment 7, wherein A is -NR 4 -.

[0526] 10. The compound or salt according to any one of embodiments 1 to 9, wherein R 1 Selected from:

[0527] C 1-5 Alkyl, which is optionally substituted by one or more independently selected from 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 、-CN、C 3-7 The substituents are substituted by carbocyclic and 3 to 7 membered heterocyclic groups, wherein the C 3-7 The carbocyclic ring and the 3- to 7-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0528] C 3-7 Carbocyclic ring, which is optionally substituted by one or more independently selected from 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 、-CN、C 1-6 Alkyl and C 1-6 is substituted by a haloalkyl substituent; or

[0529] R 1 With R 4 Together form a 3 to 6 membered heterocyclic ring, wherein the 3 to 6 membered heterocyclic ring is optionally replaced by one or more R 9 replaced.

[0530] 11. The compound or salt according to embodiment 10, wherein R 1 Selected from:

[0531] C 1-5 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、C 3-5 The substituents are substituted by carbocyclic and 3 to 5 membered heterocyclic groups, wherein the C 3-5 carbon

[0532] The ring and the 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced by;

[0533] C4-C6 saturated carbocyclic ring; or

[0534] R 1 With R 4 together forming optionally one or more R 9 a substituted 5-membered saturated heterocyclic ring;

[0535] where R 9 independently selected from halogen, -OR 10 、-N(R 10 )2, -NO2, =O, -CN;

[0536] and C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-N(R 10 )2, -NO2, =O and -CN substituents.

[0537] 12. The compound or salt according to embodiment 10, wherein R 1 Selected from:

[0538] -CHF2, -CH(CH3)2, -CH2CH(CH3)2, -CH2CF(CH3)2, -CH2CF3, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2OCF3, -CH2C(CH3)2OCH3, -CH2S CH3, -CH2CH2SCH3, -CH2CH(CH3)SCH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CF2CH3, -CH2C(CH3)3, -CH2CH(CH3)2, or R 1 With R 4 Together they form a 5-membered saturated heterocyclic ring substituted with -CH3 or -CF3.

[0539] 13. A compound or salt according to any one of embodiments 1 to 9, wherein R 1 Selected from C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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(R10 )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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced.

[0540] 14. The compound or salt according to embodiment 13, wherein R 1 Selected from C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, =O, =S, =N(R 10 ),-CN, C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced.

[0541] 15. The compound or salt according to embodiment 14, wherein R 1 Selected from C 1-5 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、C 3-5 The substituents are substituted by carbocyclic and 3 to 5 membered heterocyclic groups, wherein the C 3-5 The carbocyclic ring and the 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced.

[0542] 16. The compound or salt according to embodiment 15, wherein R 1 Selected from C 1-3 Alkyl, optionally substituted with one or more substituents independently selected from halogen.

[0543] 17. The compound or salt according to embodiment 15, wherein R 1Selected from -CHF2, -CH(CH3)2, -CH2CH(CH3)2, -CH2CF(CH3)2, -CH2CF3, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2OCF3, -CH2C(CH3)2OCH3, -CH2 SCH3, -CH2CH2SCH3, -CH2CH(CH3)SCH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CF2CH3, -CH2C(CH3)3, -CH2CH(CH3)2,

[0544] 18. The compound or salt according to embodiment 17, wherein R 1 Selected from: -CHF2 and -CH2CF3.

[0545] 19. The compound or salt according to embodiment 18, wherein R 1 It is -CH2CF3.

[0546] 20. The compound or salt according to any one of embodiments 1 to 9, wherein R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced.

[0547] 21. The compound or salt according to embodiment 20, wherein R 1 With R 4 Together form a 3 to 6 membered heterocyclic ring, wherein the 3 to 6 membered heterocyclic ring is optionally replaced by one or more R 9 replaced.

[0548] 22. The compound or salt according to embodiment 21, wherein R 1 With R 4 together forming optionally one or more R 9 substituted 5-membered saturated heterocyclic ring.

[0549] 23. The compound or salt according to embodiment 20, wherein R 1 With R 4 together to form optionally one or more selected from C 1-3 Alkyl and C 1-3 A 5-membered saturated heterocyclic ring substituted with a haloalkyl substituent.

[0550] 24. The compound or salt of embodiment 20, wherein the compound is represented by:

[0551]

[0552] 25. A compound or salt according to any one of embodiments 1 to 11, 13 to 16, 20 to 22 or 24, wherein R 1 Each R 9 independently selected from halogen, -OR 10 、-N(R 10 )2, -NO2, =O, -CN; and C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-N(R 10 )2, -NO2, =O and -CN substituents.

[0553] 26. The compound or salt according to embodiment 25, wherein R 1 Each R 9 independently selected from halogen and -OR 10 ; and C 1-3 Alkyl, which is optionally substituted by one or more independently selected from halogen and -OR 10 substituted by a substituent.

[0554] 27. The compound or salt according to embodiment 26, wherein R 1 Each R 9 Independently selected from -CH3, -CF3 and =O.

[0555] 28. A compound or salt according to any one of embodiments 1 to 9, wherein R 1 C 3-10 Carbocyclic ring, which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, 3- to 10-membered heterocyclic and C 1-6 The alkyl group is substituted by a haloalkyl substituent.

[0556] 29. The compound or salt according to embodiment 28, wherein R 1 is selected from optionally substituted C4-C6 cycloalkyl.

[0557] 30. The compound or salt according to embodiment 29, wherein R 1 is selected from optionally substituted saturated C4-C6 cycloalkyl.

[0558] 31. The compound or salt according to embodiment 30, wherein R 1 Selected from

[0559] 32. The compound or salt according to embodiment 31, wherein R 1 for

[0560] 33. A compound or salt according to any one of embodiments 1 to 32, wherein R 2 is selected from optionally substituted 5- or 6-membered monocyclic heteroaryl and optionally substituted 9-membered bicyclic heteroaryl.

[0561] 34. The compound or salt according to embodiment 33, wherein R 2 is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, isothiazole, tetrazole, pyrazole, pyrrole, furan, imidazole, oxadiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazine, benzoxazole, benzothiazole, benzimidazole, indole, indazole and imidazopyridine, any of which is optionally substituted.

[0562] 35. The compound or salt according to embodiment 34, wherein R 2 is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, tetrazole, pyrazole, oxadiazole, thiazole, pyridine, pyridazine, pyrazine, benzoxazole, indazole and imidazopyridine, any of which is optionally substituted.

[0563] 36. A compound or salt according to any one of embodiments 1 to 35, wherein R 2 In R 2 The amino acid residue is unsubstituted at any ortho position relative to the point of attachment to the rest of the molecule.

[0564] 37. A compound or salt according to any one of embodiments 1 to 35, wherein R 2 In R 2 Any ortho position on the alkylene group is not substituted by a carbocyclic or heterocyclic ring.

[0565] 38. A compound or salt according to any one of embodiments 33, 36 or 37, wherein R 2 is selected from optionally substituted 5-membered heteroaryl.

[0566] 39. The compound or salt according to embodiment 38, wherein R 2 is selected from isoxazole, oxazole, thiadiazole, triazole, tetrazole, pyrazole, oxadiazole, thiazole, isoxazole, thiadiazole, any one of which is optionally substituted.

[0567] 40. The compound or salt according to embodiment 39, wherein R2 is selected from isoxazole, oxazole, thiadiazole, pyrazole, oxadiazole, thiazole, isoxazole, thiadiazole, any one of which is optionally substituted.

[0568] 41. The compound or salt according to embodiment 38, wherein R 2 Selected from: Any of which is optionally substituted.

[0569] 42. The compound or salt according to embodiment 41, wherein R 2 Selected from: Any of which is optionally substituted.

[0570] 43. The compound or salt according to embodiment 41, wherein R 2 Selected from: Any of which is optionally substituted.

[0571] 44. The compound or salt according to embodiment 38, wherein R 2 Selected from:

[0572]

[0573] 45. The compound or salt according to embodiment 38, wherein R 2 Selected from:

[0574]

[0575] 46. ​​The compound or salt according to any one of embodiments 33, 36 or 37, wherein R 2 is selected from optionally substituted 6-membered heteroaryl.

[0576] 47. The compound or salt according to embodiment 46, wherein R 2 is selected from the group consisting of optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyridine N-oxide, optionally substituted pyridazine and optionally substituted pyrimidine N-oxide.

[0577] 48. The compound or salt according to embodiment 46, wherein R 2 is selected from the group consisting of optionally substituted pyridine, optionally substituted pyrazine, optionally substituted pyridazine and optionally substituted pyrimidine.

[0578] 49. The compound or salt according to embodiment 48, wherein R 2 Selected from Any of which is optionally substituted with one or more substituents independently selected from:

[0579] Halogen, -OR 10 、-SR 10 , -CN and the substituents on the nitrogen atom of the pyridyl group are optionally selected from -O - ;as well as

[0580] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen and -OR 10 substituted by a substituent.

[0581] 50. The compound or salt according to embodiment 47, wherein R 2 Selected from: Any of which is optionally substituted.

[0582] 51. The compound or salt according to embodiment 46, wherein R 2 Selected from:

[0583] 52. A compound or salt according to any one of embodiments 1 to 32, wherein R 2 is selected from optionally substituted bicyclic heteroaryl.

[0584] 53. A compound or salt according to any one of embodiments 33, 36 or 37, wherein R 2 is selected from optionally substituted 9-membered bicyclic heteroaryl.

[0585] 54. The compound or salt according to embodiment 53, wherein R 2 Selected from benzoxazole, benzothiazole, benzimidazole, indole, indazole and imidazopyridine, any of which is optionally substituted.

[0586] 55. The compound or salt according to embodiment 53, wherein R 2 is selected from benzoxazole, benzothiazole, indole, indazole and imidazopyridine, any of which is optionally substituted.

[0587] 56. The compound or salt according to embodiment 53, wherein R 2 is selected from benzoxazole, indazole, and imidazopyridine, any of which is optionally substituted.

[0588] 57. The compound or salt according to embodiment 56, wherein R2 is selected from optionally substituted benzoxazoles.

[0589] 58. The compound or salt according to embodiment 56, wherein R 2 Selected from: Any of which is optionally replaced by one or more independently selected from halogen, -OR 10 、-SR 10 and -CN substituents.

[0590] 59. The compound or salt according to embodiment 52, wherein R 2 Selected from: Any of which is optionally substituted.

[0591] 60. The compound or salt according to embodiment 58, wherein R 2 Selected from:

[0592] 61. The compound or salt of any one of embodiments 1 to 60, wherein n is 0.

[0593] 62. The compound or salt of any one of embodiments 1 to 61, wherein p is 0.

[0594] 63. The compound or salt according to embodiment 1, which is selected from:

[0595]

[0596]

[0597]

[0598]

[0599]

[0600] 64. The compound or salt according to embodiment 1, which is selected from:

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607] 65. Compounds represented by formula (II):

[0608]

[0609] or a salt thereof, wherein,

[0610] T is selected from -O-, -NR 14 -、-CR 15 R 16 -, -C(O)-, -S-, -S(O)-, and -S(O)2;

[0611] R 11 Selected from:

[0612] C 1-5 haloalkyl, optionally further substituted with one or more substituents independently selected from: -OR 20 、-SR 20 、-N(R 20 )2, -NO2, =O, =S, -CN, C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced by;

[0613] R 12 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following:

[0614] 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; and when R 12 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0615] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced; and

[0616] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more -R 19 replace;

[0617] R 14 Selected from:

[0618] Hydrogen and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0619] Each R 15 and R 16 Independently selected from:

[0620] Hydrogen, halogen, -OR 20 、-SR20 、-N(R 20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0621] Each R 17 and R 18 Independently selected from:

[0622] Halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents;

[0623] Each R 19 Independently selected from:

[0624] 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; and

[0625] C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0626] Each R 20 Independently selected from:

[0627] hydrogen; and

[0628] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0629] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents;

[0630] w is 0, 1, or 2; and

[0631] z is 0, 1 or 2.

[0632] 66. The compound or salt of embodiment 65, wherein T is -O-.

[0633] 67. According to embodiment 65 or 66, wherein R 11 Selected from optionally further selected from one or more independently selected from -OR 20 、-SR 20 、-N(R 20 )2、=O、-CN、C 3-10 C substituted by carbocyclic and 3- to 10-membered heterocyclic substituents 1-3 Halogenated alkyl.

[0634] 68. The compound or salt according to embodiment 67, wherein R 11 Selected from -CHF2 and -CH2CF3.

[0635] 69. A compound or salt according to any one of embodiments 66 to 68, wherein R 12 is selected from optionally substituted 5- or 6-membered monocyclic heteroaryl and optionally substituted 9-membered bicyclic heteroaryl.

[0636] 70. The compound or salt according to embodiment 69, R 12 is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, isothiazole, tetrazole, pyrazole, pyrrole, furan, imidazole, oxadiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazine, benzoxazole, benzothiazole, benzimidazole, indole, indazole and imidazopyridine, any of which is optionally substituted.

[0637] 71. The compound or salt according to embodiment 70, wherein R 12 is selected from isoxazole, oxazole, thiadiazole, triazole, pyrazole, imidazole, oxadiazole, thiazole, pyridine, pyrimidine, benzoxazole, benzimidazole, any one of which is optionally substituted.

[0638] 72. The compound or salt according to embodiment 71, wherein R 12 is selected from isoxazole, oxazole, thiadiazole, oxadiazole, thiazole, pyridine, benzoxazole, any one of which is optionally substituted.

[0639] 73. A compound or salt according to any one of embodiments 66 to 72, wherein R 12 In R 12 The amino acid residue is unsubstituted at any ortho position relative to the point of attachment to the rest of the molecule.

[0640] 74. A compound or salt according to any one of embodiments 66 to 72, wherein R 12 In R 12 Any ortho position on the alkylene group is not substituted by a carbocyclic or heterocyclic ring.

[0641] 75. A compound or salt according to any one of embodiments 65 to 74, wherein R 12 is selected from optionally substituted 5-membered heteroaryl.

[0642] 76. The compound or salt according to embodiment 75, wherein R 12 is selected from the group consisting of isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole and thiazole, any of which is optionally substituted.

[0643] 77. The compound or salt according to embodiment 75, wherein R 12 Selected from: Any of which is optionally substituted.

[0644] 78. The compound or salt according to embodiment 75, wherein R 12 Selected from: Any of which is optionally substituted.

[0645] 79. The compound or salt according to embodiment 75, wherein R 12 Selected from: Any of which is optionally substituted.

[0646] 80. The compound or salt according to embodiment 79, wherein R 12 Selected from:

[0647]

[0648] 81. The compound or salt according to embodiment 75, wherein R 12 Selected from:

[0649]

[0650]

[0651] 82. A compound or salt according to any one of embodiments 65 to 74, wherein R 12 is selected from optionally substituted 6-membered heteroaryl.

[0652] 83. The compound or salt according to embodiment 82, wherein R 12 is selected from pyridine and pyrimidine, either of which is optionally substituted.

[0653] 84. The compound or salt according to embodiment 82, wherein R12 Selected from: Any of which is optionally substituted.

[0654] 85. The compound or salt according to embodiment 82, wherein R 12 is selected from optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl N-oxide, optionally substituted pyridazine and optionally substituted pyrimidinyl N-oxide.

[0655] 86. The compound or salt according to embodiment 85, wherein R 12 Selected from: Any of which is optionally substituted.

[0656] 87. A compound or salt according to any one of embodiments 65 to 74, wherein R 12 is selected from optionally substituted bicyclic heteroaryl.

[0657] 88. The compound or salt according to embodiment 87, wherein R 12 is selected from optionally substituted benzoxazoles.

[0658] 89. The compound or salt according to embodiment 88, wherein R 12 Optionally substituted

[0659] 90. The compound or salt according to embodiment 87, wherein R 12 Selected from: Any of which is optionally substituted.

[0660] 91. The compound or salt of any one of embodiments 65 to 90, wherein w is 0.

[0661] 92. The compound or salt of any one of embodiments 65 to 91, wherein z is 0.

[0662] 93. The compound or salt of embodiment 30, selected from:

[0663]

[0664]

[0665] 94. The compound or salt of embodiment 30, selected from:

[0666]

[0667]

[0668] 95. A method of treating activity-induced muscle damage comprising administering to a subject in need thereof a compound or salt of formula (III'):

[0669]

[0670] or a salt thereof, wherein:

[0671] Each Y is independently selected from C(R 3 ), N and N + (-O - );

[0672] A is absent or selected from -O-, -NR 4 -、-CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-; R 1 Selected from:

[0673] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0674] C 3-10carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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; or

[0675] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or a saturated C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or saturated C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced; and

[0676] When A is -NR 4 -, R 1 Additionally selected from hydrogen, and when A is -C(O)-, R 1 Additionally selected from -N(R 10 )2 and -OR 10 ;

[0677] When A does not exist, R 1 Further selected from 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;

[0678] R 2 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following:

[0679] 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 when R 2 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of the pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0680] C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R10 、-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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0681] C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally replaced by one or more R 9 replaced by;

[0682] Each R 3 、R 5 and R 6 Independently selected from:

[0683] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or

[0684] R 3 With R 1 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 Replaced by; R 5 With R 1 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by;

[0685] R 4 Independently selected from:

[0686] hydrogen; and

[0687] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 replaced by;

[0688] Each R 7 and R 8 Independently selected from:

[0689] Halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents;

[0690] Each R 9 Independently selected from:

[0691] 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; and

[0692] C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0693] Each R 10 Independently selected from:

[0694] hydrogen; and

[0695] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0696] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents;

[0697] R 30 and R 31 Independently selected from R 10 or R 30 and R 31 Together they form C 3-7 carbocyclic ring, wherein the 3 to 7 membered heterocyclic ring, wherein C 3-7 The carbocyclic and 3- to 7-membered heterocyclic rings are optionally replaced by R 9 substituted; n is 0, 1 or 2; and

[0698] p is 0, 1 or 2.

[0699] 96. A method of treating activity-induced muscle damage comprising administering to a subject in need thereof a compound or salt of formula (III):

[0700]

[0701] or a salt thereof, wherein:

[0702] Each Y is independently selected from C(R 3 ), N and N + (-O - );

[0703] A is selected from -O-, -NR 4 -、-CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-;

[0704] R 1 Selected from

[0705] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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)2R10 , -NO2, =O, =S, =N(R 10 ),-CN, C 3-10 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0706] C 3-10 carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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; or

[0707] R 1 With R 3 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 Replaced by; R 1 With R 5 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by; or R 1 With R 4 Together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally replaced by one or more R 9 replaced by;

[0708] R 2 is heteroaryl, which is optionally substituted by one or more substituents independently selected from the following

[0709] 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 when R 2 is pyridyl or pyrimidinyl, and the substituents on the nitrogen atom of the pyridyl or pyrimidinyl are optionally further selected from -O - ;

[0710] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 replaced; and

[0711] C3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally replaced by one or more R 9 replaced by;

[0712] Each R 3 、R 5 and R 6 Independently selected from

[0713] Hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or

[0714] R 3 With R 1 Together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 The carbocyclic ring is optionally substituted with one or more R 9 Replaced by; R 5 With R 1 Together form a 3- to 10-membered heterocyclic ring or C 3-10 Carbocyclic ring, wherein the 3 to 10 membered heterocyclic ring or C 3-10 The carbocyclic ring is optionally substituted with one or more R 9 replaced by;

[0715] R 4 Independently selected from

[0716] hydrogen; and

[0717] C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN; or R 4 With R 1 together to form a 3- to 10-membered heterocyclic ring, which is optionally replaced by one or more R 9 replaced by;

[0718] Each R 7 and R 8 Independently selected from

[0719] Halogen, -OR 10 、-SR 10 、-N(R 10)2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 10 、-SR 10 、-N(R 10 )2, -NO2 and -CN substituents;

[0720] Each R 9 Independently selected from

[0721] 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; and

[0722] C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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;

[0723] Each R 10 Independently selected from

[0724] hydrogen; and

[0725] C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and

[0726] C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents;

[0727] n is 0, 1 or 2; and p is 0, 1 or 2.

[0728] 97. The method according to embodiment 95 or 96, wherein at least one Y is N or N + (-O - ).

[0729] 98. The method of embodiment 97, wherein each Y is N.

[0730] 99. The method of any one of embodiments 96 to 98, wherein A is absent.

[0731] 100. A method of treating a neuromuscular condition comprising administering to a subject in need thereof a compound or salt of any one of embodiments 1 to 62.

[0732] 101. A method of treating activity-induced muscle damage comprising administering to a subject in need thereof a compound or salt of any one of embodiments 1 to 94.

[0733] 102. The method of any one of embodiments 95 to 101, wherein the compound or salt does not significantly inhibit myocardial contraction relative to an untreated control.

[0734] 103. The method of embodiment 102, wherein the compound or salt reduces myocardial force by less than 10% relative to an untreated control.

[0735] 104. The method of any one of embodiments 95 to 103, wherein the subject in need of treatment has a neuromuscular condition or movement disorder.

[0736] 105. The method of any one of embodiments 95 to 104, wherein the compound or salt is administered in an amount that reduces skeletal muscle contraction by 5% to 90% relative to the subject's pre-treatment skeletal muscle contractile capacity.

[0737] 106. The method of embodiment 104, wherein the neuromuscular condition is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb-girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome.

[0738] 107. The method of embodiment 106, wherein the neuromuscular condition is Duchenne muscular dystrophy.

[0739] 108. A method of treating a movement disorder comprising administering to a subject in need thereof a compound or salt of any one of embodiments 1 to 94.

[0740] 109. The method of embodiment 108, wherein the movement disorder comprises muscle spasm.

[0741] 110. The method of embodiment 109, wherein the muscle spasm is selected from spasms associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury, or a traumatic event such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, and amyotrophic lateral sclerosis.

[0742] 111. The method of embodiment 110, wherein the compound or salt is administered in an amount sufficient to reduce involuntary muscle contractions.

[0743] 112. The method of embodiment 111, wherein the compound or salt is administered in an amount sufficient to reduce involuntary muscle contractions by at least 10%.

[0744] 113. The method of any one of embodiments 95 to 112, wherein the method further comprises administering an additional therapeutic agent to the subject.

[0745] 114. The method of embodiment 113, wherein the additional therapeutic agent is a corticosteroid.

[0746] 115. The method of embodiment 114, wherein the corticosteroid is deflazacort or prednisone.

[0747] 116. The method of embodiment 113, wherein the additional therapeutic agent is vamorolone.

[0748] 117. The method of embodiment 113, wherein the additional therapeutic agent is gene therapy.

[0749] 118. The method of embodiment 117, wherein the gene therapy comprises a dystrophin gene or a variant or truncated form thereof.

[0750] 119. The method of embodiment 117, wherein the gene therapy comprises micro-dystrophin.

[0751] 120. The method of embodiment 113, wherein the additional therapeutic agent is eteplirsen.

[0752] 121. The method of embodiment 113, wherein the additional therapeutic agent is ataluren.

[0753] 122. A pharmaceutical composition comprising a compound or salt thereof according to any one of embodiments 1-94 and a pharmaceutically acceptable excipient.

[0754] Example

[0755] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0756] The following synthetic schemes are provided for illustration and not limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art will be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It should also be understood that those skilled in the art will be able to prepare in a similar manner as described below by using appropriate starting materials and modifying the synthetic routes as needed. Generally, starting materials and reagents can be obtained from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0757] Example 1. General Scheme - Synthesis of 2-((3-ethylisoxazol-5-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 36)

[0758]

[0759] Example 2. Exemplary Scheme - Synthesis of 2-((3-ethylisoxazol-5-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 36)

[0760]

[0761] Step 1: Substitution of pyridine, pyrimidine or phenyl

[0762] The bromofluoropyrimidine is combined with an alcohol (e.g., 2,2,2-trifluoroethanol), cesium carbonate, and an aprotic solvent (e.g., DMF). If necessary, the mixture is gently heated to increase the rate of fluorine exchange. Isolation of the major product provides the corresponding 2-substituted pyrimidine.

[0763] Step 2-3: Cross-coupling of pyridine, pyrimidine or phenyl with pyridone

[0764] 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 provide bisaryl cores in good yields.

[0765] Step 4: Alkylation of the compound

[0766] Nitrogen can be cleanly alkylated using various heteroarylmethyl bromides or heteroarylmethyl chlorides (e.g., 5-(chloromethyl)-3-ethylisoxazole) and an inorganic base in a polar aprotic solvent (e.g., DMF). Alternatively, the nitrogen of the pyridone can be functionalized using the Mitsunobu method. This requires a hydroxymethyl heteroaryl compound, triphenylphosphine, and a carbodiimide reagent (e.g., DEAD). Depending on the availability of the appropriate coupling partner, two alternatives are used to prepare the desired product. Examples 1 and 2 can be appropriately modified to prepare the compounds described in Tables 1 and 2 herein.

[0767] Example 3: 6-[2-[(3-fluorooxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[(5-phenyl-1,3,4-thiadiazol-2-yl)methyl]-2,3-dihydropyridazin-3-one (Compound 36)

[0768]

[0769] Step 1: 5-Bromo-2-((3-fluorooxetane-3-yl)methoxy)pyrimidine

[0770] According to Step 1 of Example 2, 160 mg (58.8%) of the title compound was obtained as a solid. LC / MS (ESI): 263 [M+H] + .

[0771] Step 2 / 3: 6-(2-((3-fluorooxetan-3-yl)methoxy)pyrimidin-5-yl)pyridazin-3(2H)-one

[0772] According to step 2 of Example 2, the title compound was obtained as a white solid (500 mg, 32.8%). LC / MS (ESI): 279 [M+H] + .

[0773] Step 4: 6-[2-[(3-fluorooxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[(5-phenyl-1,3,4- [2-thiadiazol-2-yl)methyl]-2,3-dihydropyridazin-3-one

[0774] To a stirred solution of 6-[2-[(3-fluorooxetane-3-yl)methoxy]pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (100 mg, 0.36 mmol) and (5-phenyl-1,3,4-thiadiazol-2-yl)methanol (69.0 mg, 0.36 mmol) in THF (1.5 mL) was added PPh (188 mg, 0.72 mmol) and DEAD (94.0 mg, 0.54 mmol). The reaction was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo to a residue that was purified by preparative HPLC to give the title compound (24 mg, 14.8%) as a white solid. 1 H NMR(DMSO-d6,300MHz): δ9.14(s,2H),8.20(d,J \ =9.6Hz,1H),8.00-7.97(m,2H),7.59-7.53(m,3H),7.26(d,J \ =9.9Hz,1H),5.83(s,2H),4.88-4.71(m,6H); LC / MS(ESI):453

[0775] [M+H] + .

[0776] Example 4: 6-[2-[(3-fluorooxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl]-2,3-dihydropyridazin-3-one (Compound 90)

[0777]

[0778] Step 1: 6-[2-[(3-fluorooxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[[3-(4-fluorophenyl)- 1,2,4-oxadiazol-5-yl]methyl]-2,3-dihydropyridazin-3-one

[0779] To a solution of 6-[2-[(3-fluorooxetane-3-yl)methoxy]pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (100 mg, 0.036 mmol) in DMF (1 mL) was added CsCO (351 mg, 0.11 mmol) and 5-(chloromethyl)-3-(4-fluorophenyl)-1,2,4-oxadiazole (76.4 mg, 0.036 mmol). The resulting mixture was stirred at 0°C for 1 hour. The resulting mixture was purified by preparative HPLC to give the title compound (10 mg, 6.1%) as a white solid. 1 H NMR (CD3OD, 300MHz): δ9.13 (s, 2H), 8.17-8.05 (m, 3H), 7.30-7.21 (m, 3H), 5.80 (s, 2H), 5.03-4.75 (m, 6H); LC / MS (ESI): 456 [M+H] + .

[0780] The following compounds were synthesized according to Example 4:

[0781]

[0782] Example 5: 6-(6-(difluoromethoxy)pyridazin-3-yl)-2-((5-phenyl-1,3,4-thiadiazol-2-yl)methyl)pyridazin-3(2H)-one (Compound 22)

[0783]

[0784] Step 1 / 2: 6-(6-(difluoromethoxy)pyridazin-3-yl)pyridazin-3(2H)-one

[0785] The title compound (3.5 g, 72.1%) was obtained as a white solid according to Steps 1 and 2 of Example 2. LC / MS (ESI): 240 [M+H] + .

[0786] Step 3: Ethyl 2-(2-benzoylhydrazide)-2-oxoacetate

[0787] To a solution of benzohydrazide (1.00 g, 7.35 mmol) in DCM (5.0 mL) was added ethyl oxalyl chloride (1.00 g, 7.32 mmol). The resulting mixture was stirred at 25 ° C for 1 hour. The reaction was concentrated to give a residue, which was purified by silica gel chromatography (Flash 40 g, 30-80% EA: PE) to give the title compound as a white solid (0.5 g, 28.8%). LC / MS (ESI): 237 [M + H] + .

[0788] Step 4: Ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate

[0789] A mixture of ethyl 2-(2-benzoylhydrazide)-2-oxoacetate (480 mg, 2.03 mmol) and Lawesson's reagent (1.49 g, 4.06 mmol) in toluene (5.0 mL) was stirred at 80° C. for 2 hours. The resulting mixture was concentrated under vacuum to give a residue, which was purified by silica gel chromatography (Flash 40 g, 20-50% EA:PE) to give the title compound (390 mg, 81.9%) as a white solid. LC / MS (ESI): 235 [M+H] + .

[0790] Step 5: (5-phenyl-1,3,4-thiadiazol-2-yl)methanol

[0791] To a solution of ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate (440 mg, 1.888 mmol) in MeOH (5.0 mL) was added NaBH4 (142 mg, 3.76 mmol). The resulting solution was stirred at 25 ° C for 1 hour. The resulting mixture was concentrated to give a residue, which was purified by silica gel chromatography (Flash 40 g, 50-80% EA: PE) to give the title compound (300 mg, 83.1%) as a white solid. LC / MS (ESI): 193 [M + H] + .

[0792] Step 6: 6-[2-[(3-fluorooxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[(5-phenyl-1,3,4- [2-thiadiazol-2-yl)methyl]-2,3-dihydropyridazin-3-one

[0793] The title compound (38.8 mg, 22.5%) was obtained as a white solid according to Step 4 of Example 8. 1 H NMR(DMSO-d6,400MHz): δ8.81(d,J \ =2.4Hz,1H),8.42(dd,J1=8.4Hz,J2=2.4Hz,1H),8.21(d,J \ =10.0Hz,1H),7.99-7.97(m,2H),7.79(t,J=73.2Hz,1H),7.59-7.53(m,3H),7.27-7.24(m,2H),5.83(s,2H); LC / MS(ESI):414[M+H] + .

[0794] The following compounds were synthesized according to Example 5 (by Mitsunobo or substitution):

[0795]

[0796]

[0797]

[0798] Example 6: 2-[(4-chlorophenyl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (Compound 1)

[0799]

[0800] Step 1: 5-Bromo-2-(2,2,2-trifluoroethoxy)pyrimidine

[0801] To a mixture of 5-bromo-2-chloropyrimidine (10 g, 0.021 mol, 1.0 equivalent) in DMSO (10 mL) was added 2,2,2-trifluoroethane-1-ol (6.21 g, 0.025 mol, 1.20 equivalents) and Cs2CO3 (25.27 g, 0.062 mol, 3.0 equivalents) at room temperature. The reaction mixture was stirred at 70 ° C for 2 hours. The solution was diluted with water and extracted with EtOAc (30 mL x3). The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed in vacuo. The title compound (10.0 g, 94.08%) was obtained as a yellow oil by silica gel chromatography (Flash 300 g, 0-40% EtOAc: cyclohexane). LC / MS (ESI): 257 [M+H] + .

[0802] Step 2: [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid

[0803] 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) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-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). The flask was purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at 80 °C for 4 h and confirmed by LCMS. The reaction was used directly in the next step without workup.

[0804] Step 3: 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one

[0805] 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) was added 6-bromo-2,3-dihydropyridazine-3-one (3.31 g, 18.916 mmol, 1.00 equiv), Pd(dppf)Cl2 (0.69 g, 0.943 mmol, 0.05), K2CO3 (3.92 g, 28.387 mmol, 1.5 equiv) and H2O (4 mL). A nitrogen inert atmosphere was purged into the flask and maintained. The resulting solution was stirred at 90 ° C for 2 hours. The solution was diluted with water and extracted with tOAc (30 mL x 3). The combined organics were washed with brine, dried over Na2SO4 and the solvent was removed in vacuo. Purification by silica gel chromatography (Flash 300 g, 50-100% EtOAc:cyclohexane) gave the title compound (3.0 g, 58.24%) as a brown solid. LC / MS (ESI): 273

[0806] [M+H] + .

[0807] Step 4: 2-[(5-chloropyridin-3-yl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3- Dihydropyridazin-3-one

[0808] 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-chloropyridine (0.82 g, 0.004 mmol, 1.0 equiv) and Cs2CO3 (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%).

[0809] The following compounds were synthesized according to Example 6:

[0810]

[0811]

[0812]

[0813] Example 7: 6-[4-(difluoromethoxy)phenyl]-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-2,3-dihydropyridazin-3-one (Compound 204)

[0814]

[0815] Step 1: 6-[4-(difluoromethoxy)phenyl]-2,3-dihydropyridazin-3-oneTo a mixture of 6-bromo-2,3-dihydropyridazin-3-one (1.69 g, 9.67 mmol, 1.0 eq) in dioxane (20 mL) was added [4-(difluoromethoxy)phenyl]boronic acid (2.0 g, 10.64 mmol, 1.1 eq), K2CO3 (4.0 g, 29.0 mmol, 3.0 eq), Pd(dppf)Cl2 (707.51 mg, 0.97 mmol, 0.1 eq) and H2O (2 mL). The reaction mixture was stirred at 90°C under an argon atmosphere for 4 hours.

[0816] The solution was diluted with water and extracted with EtOAc (30 mL x 3). The combined organics were washed with brine, dried over Na2SO4, and the solvent removed in vacuo. Purification by silica gel chromatography (Flash 300 g, 50-90% EtOAc:cyclohexane) gave the title compound as an off-white solid (1.55 g, 67.30%). LC / MS (ESI): 239 [M+H] + .

[0817] Step 2: 6-[4-(difluoromethoxy)phenyl]-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-2,3-dihydro Pyridazin-3-one

[0818] To a mixture of 6-[4-(difluoromethoxy)phenyl]-2,3-dihydropyridazin-3-one (100 mg, 0.42 mmol, 1.0 equiv) in DMF (2 mL) was added 5-(bromomethyl)-3-methyl-1,2-oxazole (81.28 mg, 0.462 mmol, 1.1 equiv) and Cs2CO3 (411.63 mg, 1.259 mmol, 3.0 equiv). The reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution. The solution was diluted with water and extracted with ethyl acetate (30 mL x 3). The combined organics were washed with brine, dried over Na2SO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to give a white solid (76 mg, 54.31%). 1 H NMR (400MHz, DMSO-d6): δ8.11(d,J=10.0Hz,1H),7.94(d,J=8.0Hz,2H),7.52-7.12(m,4H),6.34(s,1H),5.46(s,2H),2.21(s,3H); LC / MS(ESI):334[M+H] +

[0819] The following compounds were synthesized according to Example 7:

[0820]

[0821]

[0822]

[0823]

[0824] Example 8: 6'-(Bicyclo[1.1.1]pentan-1-ylamino)-1-(pyridazin-3-ylmethyl)-[3,3'-bipyridin]-6(1H)-one (Compound 71)

[0825]

[0826] Step 1: N-(bicyclo[1.1.1]pentan-1-yl)-5-bromopyridin-2-amine

[0827] A mixture of 5-bromo-2-fluoropyridine (200 mg, 1.136 mmol), bicyclo[1.1.1]pentan-1-amine (141.72 mg, 1.705 mmol), and CsCO (1.11 g, 3.409 mmol) in DMSO (3 mL) was stirred at 120° C. for 2 hours. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:2). This gave the title compound as a solid (40.48%). MS m / z: 239 [M+H] +

[0828] Step 2: N-(bicyclo[1.1.1]pentan-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) 2-Pentyl)pyridazin-2-amine

[0829] To a mixture of N-(bicyclo[1.1.1]pentan-1-yl)-5-bromopyridin-2-amine (110 mg, 0.46 mmol, 1.0 equiv) in dioxane (1.1 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (175 mg, 0.69 mmol, 1.5 equiv), KOAc (135 mg, 1.38 mmol, 3.0 equiv), and Pd(dppf)Cl2 (37 mg, 0.05 mmol, 0.1 equiv). The flask was purged and maintained with an inert atmosphere of nitrogen. The reaction mixture was stirred at 80°C for 4 hours and confirmed by LCMS. The reaction was used directly in the next step without workup.

[0830] Step 3: 2-[3-[6-([Bicyclo[1.1.1]pentan-1-yl]amino)pyridazin-3-yl]-6-oxo-1,6-dihydro Pyridazin-1-yl]-N-ethylacetamide

[0831] A mixture of N-(bicyclo[1.1.1]pentan-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazin-2-amine (131 mg, 0.46 mmol, 1.0 equiv) in dioxane (1.1 mL) was added 6-bromo-2-(pyridazin-3-ylmethyl)pyridazin-3(2H)-one (122 mg, 0.46 mmol, 1.00 equiv), Pd(dppf)Cl2 (23 mg, 0.03 mmol, 0.05 equiv), K2CO3 (95 mg, 0.69 mmol, 1.5 equiv), and H2O (0.1 mL). The flask was purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at 90°C for 2 hours. The solution was diluted with water and extracted with EtOAc (x3). The combined organics were washed with brine, dried over Na2SO4 and the solvent removed in vacuo. Purification by silica gel chromatography (Flash 300 g, 50-100% EtOAc: cyclohexane) gave the crude product. The crude product was purified by RP-HPLC to give a white solid. 1 H NMR (DMSO-d6, 300MHz): δ8.54 (d, J = 2.1Hz, 1H), 8.10 (t, J = 5.1Hz, 1H), 8.00 (d, J = 9.9Hz, 1H), 7.88 (dd,

[0832] J1=8.7Hz, J1=2.4Hz 1H),7.59(s,1H),7.04(d,J=9.9Hz,1H),6.59(d,J=8.7Hz,1H),4.67(s,2H),3.16-3.07(m,2H),2.47(s,1H),2.10(s,6H),

[0833] 1.04(t,J=7.2Hz,3H); LC / MS R t =0.848 min; MS m / z: 340 [M+H] +

[0834] The following compounds were synthesized according to Example 8:

[0835]

[0836]

[0837]

[0838]

[0839]

[0840] Example 9: 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2-methoxyethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 70)

[0841]

[0842] Step 1: 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2-methoxyethoxy)pyrimidin-5-yl)pyridazine-3-yl (2H)-Ketone

[0843] To a stirred solution of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (100.00 mL) was added portionwise a solution of KCO (112.89 mg, 0.817 mmol, 3 equiv) in 2-methoxy-ethanol (1 mL) (mg, 0.272 mmol, 1.00 equiv), and the solution was stirred at 70° C. for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC to give the title compound (35 mg, 35.97%) as a white solid. 1 H NMR(DMSO-d6,400MHz)δ9.10(s,2H),8.54(d,J=2.4Hz,2H),8.12(d,J=10.0Hz,1H),7.82–7.74(m,1H),7.16(d,J= 9.6Hz,1H),5.40(s,2H),4.52–4.45(m,2H),3.73–3.66(m,2H),3.31(s,3H).LC / MS:Rt=0.810min,MSm / z:358[M+H] + .

[0844] The following compounds were synthesized according to Example 9:

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851] Example 10: 2-((5-(methylthio)pyridazin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 111)

[0852]

[0853] Step 1: 5-(Methylthio)nicotinate

[0854] A solution / mixture of methyl 5-bromopyridine-3-carboxylate (216.00 mg, 1.000 mmol, 1.00 eq) and sodium thiomethoxide (70.08 mg, 1.000 mmol, 1.00 eq) in DMF was stirred overnight under a nitrogen atmosphere at 80 degrees Celsius. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was quenched with water at 0°C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc to give methyl 5-(methylthio)nicotinate (150 mg, 81.88%) as a solid.

[0855] Step 2: (5-(Methylthio)pyridazin-3-yl)methanol

[0856] Under N2 atmosphere, LAH (63 mg, 1.64 mmol) was added to a solution of methyl 5-(methylthio)nicotinate (150 mg, 0.82 mmol) in THF (3 mL) at 0 ° C in several batches. The resulting mixture was stirred at 25 ° C for 1.5 hours. The reaction was then quenched by adding 4 mL of water and 10 mL of EA was added to the mixture. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by silica gel chromatography to give the title compound (100 mg, 78.7%) as a solid.

[0857] Step 3: 3-(chloromethyl)-5-(methylthio)pyridine

[0858] A solution of (5-(methylthio)pyridazin-3-yl)methanol (100 mg, 0.64 mmol) and SOCl (152 mg, 1.29 mmol, 2.00 equiv) in DCM was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The desired product was detected by LCMS. The mixture was concentrated in vacuo and the crude product was used in the next step without further purification.

[0859] Step 4: 2-((5-(methylthio)pyridazin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidine-5-yl)- base)

[0860] Pyridazin-3(2H)-one

[0861] To a stirred mixture of 6-[2-[(3-fluorooxetane-3-yl)methoxy]pyrimidin-5-yl]-2,3-dihydro-pyridazin-3-one (174 mg, 0.64 mmol) and 3-(chloromethyl)-5-(methylthio)pyridine (111 mg, 0.64 mmol) (177 mg, 1.28 mmol, 2 equivalents) in DMF (2 mL) was added portionwise. The reaction was stirred at 25 ° C for 2 hours. The resulting mixture was extracted with EtOAc and water. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (45 mg, 17.2%) as a white solid. 1 H NMR (300MHz, methanol-d4) δ9.14(s,2H),8.41(dd,J=12.9,2.1Hz,2H),8.06(d,J=9.6Hz,1H),7.87( t,J=2.1Hz,1H),7.16(d,J=9.9Hz,1H),5.47(s,2H),5.04(q,J=8.7Hz,2H),2.55(s,3H).LC / MS Rt=2.406min; MSm / z:410[M+H] + .

[0862] Example 11: 2-((3-methylisoxazol-5-yl)methyl)-6-(2-(methylthio)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 65)

[0863]

[0864] Step 1: 6-(2-(methylthio)pyrimidin-5-yl)pyridazin-3(2H)-one

[0865] A solution / mixture of 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2H-pyridazin-3-one (300.00 mg, 1.102 mmol, 1.00 equiv) and (methylsulfanyl)sodium (231.72 g) was stirred at 70°C for 1 hour. The reaction was quenched with a saturated solution of NH4Cl (aq.) at 25°C. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with 5 x 10 mL of water. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeOH, 10% to 50% gradient over 10 minutes; detector, UV 254 nm. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (1:1) to give 6-[2-(methylsulfanyl)pyrimidin-5-yl]-2H-pyridazin-3-one (280 mg, 115.34%) as a white solid. MS m / z: 221

[0866] [M+H] +

[0867] Step 2: 2-((3-methylisoxazol-5-yl)methyl)-6-(2-(methylthio)pyrimidin-5-yl)pyridazine-3-yl (2H)-Ketone

[0868] A mixture of 6-[2-(methylsulfanyl)pyrimidin-5-yl]-2H-pyridazin-3-one (200.00 mg, 0.908 mmol, 1.00 equiv), 5-(bromomethyl)-3-methyl-1,2-oxazole (191.80 mg, 1.090 mmol, 1.20 equiv), and KCO (376.50 mg, 2.724 mmol, 3.00 equiv) in DMF (2.00 mL) was stirred at 25°C for 2 hours. The resulting mixture was diluted with EtOAc (50 mL) and washed with 2 x 10 mL of water. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeOH, 10% to 50% gradient over 10 minutes; detector, UV 254 nm. 2-[(3-methyl-1,2-oxazol-5-yl)methyl]-6-[2-(methylsulfanyl)pyrimidin-5-yl]pyridazin-3-one (52.3 mg, 17.70%) was obtained as a white solid. 1 H NMR(400MHz, DMSO-d6)δ9.09(s,2H),8.15(d,J=9.6Hz,1H),7.21-7.19(m,1H),6.39(s,1H),5.46(s,2H),2.58(s,3H),2.21(s,3H).LC / MS Rt=1.219min; MSm / z:316[M+H]+ .

[0869] The following compounds were synthesized according to Example 11:

[0870]

[0871]

[0872] Example 12: 2-((2-ethylthiazol-5-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 99) and 2-((2-ethylthiazol-5-yl)methyl)-6-(2-propoxypyrimidin-5-yl)pyridazin-3(2H)-one (Compound 112)

[0873]

[0874] Step 1: Ethyl 2-ethylthiazole-5-carboxylate

[0875] Ethyl 2-chloro-3-oxopropanoate (2.00 g, 13.284 mmol, 1.00 equiv), EtOH (20.00 mL), propylthioamide (1184.38 mg, 13.284 mmol, 1.00 MgSOv) were placed in a 100-mL round-bottom flask (7994.69 mg, 66.419 mmol, 5.00 equiv). The resulting solution was stirred at 80 ° C for 16 hours. The mixture was cooled to 25 ° C and filtered through celite, the filtrate was concentrated in vacuo, and the residue was applied to a silica gel column with ethyl acetate / petroleum ether (1: 1) to give 1 g (40.64%) of ethyl 2-ethyl-1,3-thiazole-5-carboxylate, which gave 1 g (40.64%) of ethyl 2-ethyl-1,3-thiazole-5-carboxylate as a light yellow oil. MSm / z: 186 [M + H] +

[0876] Step 2: (2-ethylthiazol-5-yl)methanol

[0877] To a solution of ethyl 2-ethyl-1,3-thiazole-5-carboxylate (20.00 g, 107.968 mmol, 1.00 equiv) in THF (300.00 mL) was added LiAlH4 (4.10 g, 107.968 mmol, equiv) at 0°C in 1.00-minute portions. The mixture was stirred at 0°C for 1 hour. 4 g Na2SO4, 10 H2O, and then 2 g Na2SO4 were added in portions. The mixture was stirred for 30 minutes and filtered through celite. The filtrate was concentrated in vacuo to give 15 g (97.02%) of the crude product as a pale yellow oil. MS m / z: 144 [M+H] +

[0878] Step 3: 5-(Chloromethyl)-2-ethylthiazole

[0879] To a solution of (2-ethyl-1,3-thiazol-5-yl)methanol (10.00 g, 69.832 mmol, 1.00 equiv) in DCM (100.00 mL) was added dropwise SOCl₂ (10.13 mL, 85.161 mmol, 2.00 equiv) at 0°C, and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo, and the residue was dissolved in 100 mL of water and adjusted to pH 8 with saturated Na₂CO₃ solution. The mixture was then extracted with 3×100 mL of EA. The organic layer was dried over Na₂SO₄ and concentrated in vacuo to afford the crude product. Purification on a silica gel column afforded 6 g (53.15%) of a light yellow oil. MS m / z: 162 [M+H] +

[0880] Step 4: 2-((2-ethylthiazol-5-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyrimidin Oxazin-3(2H)-one

[0881] 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2H-pyridazin-3-one (10.00 g, 36.739 mmol, 1.00 equiv) was placed in a 250-mL round-bottom flask along with DMF (100.00 mL), 5-(chloromethyl)-2-ethyl-1,3-thiazole (7126.72 mg, 44.087 mmol, 1.20 equiv), and KCO (15232.78 mg, 110.218 mmol, 3.00 equiv). The resulting solution was stirred at 50°C for 1 hour. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo to give the product, which was purified by Combiflsh (reverse phase: 0.05% ammonia / L) to give 5.1 g (34.93%) of 2-[(2-ethyl-1,3-thiazol-5-yl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]pyridazin-3-one as a white solid. 1 H NMR (400MHz, DMSO-d6): δ9.16(s,2H),8.12(d,J=9.6Hz,1H),7.75(s,1H),7.17(d,J=9.6Hz, 1H),5.48(s,2H),5.12(q,J=8.8Hz,2H),2.92(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H).LC / MS Rt=1.873min; MSm / z:398[M+H] + . Step 5: 2-((2-ethylthiazole- 5-yl)methyl)-6-(2-propoxypyrimidin-5-yl)pyridazin-3(2H)-oneTo a stirred solution of 2-[(2-ethyl-1,3-thiazol-5-yl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]pyridazine-3- was added a DMF solution (100.00 mg, 0.252 mmol, 1.00 equiv) of KCO (104.34 mg, 0.755 mmol, 3.00 equiv) in portions at 25°C under a nitrogen atmosphere. To the above mixture was added propanol (302.46 mg, 5.033 mmol, 20.00 equiv) in portions at 25°C. The resulting mixture was stirred at 25°C for another 4 hours. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and purified by filtration using hexane.

[0882] / EtOAc (1:1) to give 2-[(2-ethyl-1,3-thiazol-5-yl)methyl]-6-(2-propoxypyrimidin-5-yl)pyridazin-3-one (13.2 mg, 14.46%) as a light yellow solid. 1 H NMR(DMSO-d6,300MHz)δ9.08(s,2H),8.10(d,J=9.6Hz,1H),7.75(s,1H),7.16(d,J=9.6Hz,1H),5.48(s,2H),4.33 (t,J=6.9Hz,2H),2.93(q,J=7.5Hz,2H),1.812-1.742(m,2H),1.25(t,J=7.5Hz,3H),0.99(t,J=7.5Hz,3H).LC / MS Rt=1.349min; MSm / z:358[M+H] + .

[0883] The following compounds were synthesized according to Example 12:

[0884]

[0885]

[0886]

[0887] Example 13: 2-((5-fluoropyridin-3-yl)methyl)-6-(6-(2-methylpropoxy-2-D)pyridazin-3-yl)pyridazin-3(2H)-one (EDG-006364)

[0888]

[0889] Step 1: 5-Bromo-2-(2-methylpropoxy-2-d)pyrimidine

[0890] 5-Bromo-2-fluoropyrimidine (100.00 mg, 0.565 mmol, 1.00 equiv), THF (2.00 mL), NaH (20.34 mg, 0.848 mmol, 1.5 equiv), 2-methyl (2-2H) propan-1-ol (42.45 mg, 0.565 mmol, 1.00 equiv). The resulting solution was stirred at 0 ° C for 1 hour. The resulting mixture was concentrated. The residue was added to a silica gel column with acetate / petroleum ether (1:4). This produced 110 mg (83.88%) of 5-bromo-2-[2-methyl (2-2H) propoxy] pyrimidine as a solid. MS m / z: 232 [M + H] +

[0891] Step 2: 2-(2-methylpropoxy-2-d)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- 1-Methyl)pyridine

[0892] 5-Bromo-2-[2-methyl(2-2H)propoxy]pyrimidine (110.00 mg, 0.474 mmol, 1.00 equiv), bis(pinacolato)diboron (180.53 mg, 0.711 mmol, 1.50 equiv), dioxane (5.00 ml), KOAc (93.03 mg, 0.948 mmol, 2 equiv), Pd(dppf)Cl2 (34.68 mg, 0.047 mmol, 0.1 equiv) were added.

[0893] The resulting solution was stirred at 80°C for 2 hours and confirmed by LCMS. The reaction was used directly in the next step without work-up.

[0894] Step 3: 2-((5-fluoropyridin-3-yl)methyl)-6-(6-(2-methylpropoxy-2-d)pyridazin-3-yl)pyridazin-3 (2H)-Ketone

[0895] 2-[2-Methyl(2-2H)propoxy]pyrimidin-5-ylboronic acid (110.00 mg, 0.558 mmol, 1.00 equiv), 6-chloro-2-[(5-fluoropyridin-3-yl)methyl]pyridazin-3-one (133.79 mg, 0.558 mmol, 1.00 equiv), KCO (154.33 mg, 1.117 mmol, 2 equiv), dioxane (3.00 mL), HO (0.50 mg), and Pd(d(d))Cl (40.85 mg, 0.056 mmol, 0.1 equiv) were added. The resulting solution was stirred at 90° C. for 2 hours. The resulting mixture was concentrated. The residue was applied to a silica gel column with dichloromethane / methanol (20:1). This resulted in 100 mg (50.26%) of 2-[(5-fluoropyridin-3-yl)methyl]-6-[2-[2-methyl(2-2H)propoxy]pyrimidin-5-yl]pyridazin-3-one as a white solid. 1H NMR (400MHz, DMSO-d6) δ9.09 (s, 2H), 8.55-8.53 (m, 2H), 8.12 (d, J = 10.0Hz, 1H), 7.77 ( d,J=9.6Hz,1H),7.16(d,J=10.0Hz,1H),5.40(s,2H),4.15(s,2H),0.98(s,6H).LC / MS Rt=1.676min; MSm / z:357[M+H] +

[0896] Example 14: 2-((5-fluoropyridin-3-yl)methyl)-6-(2-propoxypyrimidin-5-yl)pyridazin-3(2H)-one (Compound 125)

[0897]

[0898] Step 1: N-cyclobutyl-2-[3-[2-(2-methylpropyloxy)pyrimidin-5-yl]-6-oxopyridazin-1-yl]acetyl amine

[0899] To a stirred solution of 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (1.98 g, 5.217 mmol, 1.00 equiv) in 2-methoxy-2-methylpropan-1-ol (20 mL) was added KCO (1.422 g, 10.435 mmol, 2.00 equiv) in portions, and the solution was stirred at 80 ° C for 4 hours. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give the title compound as a white solid.

[0900] The following compounds were synthesized according to Example 14:

[0901]

[0902]

[0903]

[0904]

[0905] Example 15: 2-((5-methoxypyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 128)

[0906]

[0907] Step 1: 2-((5-methoxypyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)

[0908] Pyridazin-3(2H)-one

[0909] 6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazine-3(2H)-one (2.00 g,

[0910] A mixture of methoxypyridine (1.43 g, 7.348 mmol, 1.00 equiv) and potassium carbonate (2.54 g, 18.370 mmol, 2.5 equiv) in dimethylformamide (20.00 mL) was added to a 40-mL flask and stirred at 60° C. for 48 hours. The mixture was purified by Pre-HPLC (0.05% NH 3 H 2 O-H 2 O / I, 5% to 55% gradient, 30 minutes) to give 2-((5-methoxy-pyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (1.3 g, 45.02%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ9.17 (s, 2H), 8.25-8.23 (m, 2H), 8.15 (d, J = 9.6Hz, 1H), 7.42-7. 41(m,1H),7.18(d,J=9.6Hz,1H),5.36(s,2H),5.12(q,J=9.0Hz,2H),3.82(s,3H).LC / MS Rt=1.301min; MSm / z:394

[0911] [M+H] + .

[0912] The following compounds were synthesized according to Example 15:

[0913]

[0914]

[0915]

[0916]

[0917]

[0918] Example 16: 2-((2-ethylthiazol-5-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 99) and 2-((2-ethylthiazol-5-yl)methyl)-6-(2-isobutoxypyrimidin-5-yl)pyridazin-3(2H)-one (Compound 124)

[0919]

[0920] Step 1: Ethyl 2-ethylthiazole-5-carboxylate

[0921] Ethyl 2-chloro-3-oxopropanoate (80.00 g, 0.531 mol, 1.00 equiv), EtOH (600.00 mL), propylthioamide (49.74 mg, 0.558 mol, 1.05 MgSO4 equiv) were placed in a 100 mL round-bottom flask (128.00 g, 1.062 mol, 2.00 equiv). The resulting solution was stirred at 80 ° C for 16 hours. The mixture was cooled to 25 ° C and filtered through celite, the filtrate was concentrated in vacuo, and the residue was applied to a silica gel column with ethyl acetate / petroleum ether (1: 1) to obtain 60.00 g (60.96%) of ethyl 2-ethyl-1,3-thiazole-5-carboxylate as a light yellow oil. MS m / z: 186 [M + H] +

[0922] Step 2: (2-ethylthiazol-5-yl)methanol

[0923] To a solution of ethyl 2-ethyl-1,3-thiazole-5-carboxylate (20.00 g, 107.968 mmol, 1.00 eq) in THF (300.00 mL) was added LiAlH4 (4.10 g, 107.968 mmol, eq) at 0°C. Each 1.00 portion was stirred at 0°C for 1 hour. 4 g Na2SO4 10H2O was added in portions, followed by 2 g Na2SO4. The mixture was stirred for 30 minutes, filtered through celite, and the filtrate was concentrated in vacuo to give 15 g (97.02%) of the crude product as a pale yellow oil. MS m / z: 144 [M+H] +

[0924] Step 3: 5-(Chloromethyl)-2-ethylthiazole

[0925] To a solution of (2-ethyl-1,3-thiazol-5-yl)methanol (10.00 g, 69.832 mmol, 1.00 equiv) in DCM (100.00 mL) was added SOCl₂ (10.13 mL, 85.161 mmol, 2.00 equiv) dropwise at 0°C, and the mixture was stirred for 1 hour. The mixture was concentrated in vacuo, and the residue was dissolved in 100 mL of water and adjusted to pH 8 with saturated Na₂CO₃ solution. The residue was then extracted with 3 x 100 mL of EA. The organic layer was dried over Na₂SO₄ and concentrated in vacuo to afford the crude product, which was purified on a silica gel column to afford 6 g (53.15%) of a light yellow oil. MS m / z: 162 [M+H] +

[0926] Step 4: 2-((2-ethylthiazol-5-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyrimidin Oxazin-3(2H)-one

[0927] 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2H-pyridazin-3-one (10.00 g, 36.739 mmol, 1.00 equiv) was placed in a 250-mL round-bottom flask along with DMF (100.00 mL), 5-(chloromethyl)-2-ethyl-1,3-thiazole (7126.72 mg, 44.087 mmol, 1.20 equiv), and KCO (15232.78 mg, 110.218 mmol, 3.00 equiv). The resulting solution was stirred at 50°C for 1 hour. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1). The collected fractions were combined and concentrated in vacuo to give the product, which was purified by Combiflsh (reverse phase: 0.05% ammonia / L) to give 5.1 g (34.93%) of 2-[(2-ethyl-1,3-thiazol-5-yl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]pyridazin-3-one as a white solid. 1 H NMR (400MHz, DMSO-d6): δ9.16(s,2H),8.12(d,J=9.6Hz,1H),7.75(s,1H),7.17(d,J=9.6Hz, 1H),5.48(s,2H),5.12(q,J=8.8Hz,2H),2.92(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H).LC / MS Rt=1.873min; MSm / z:398[M+H] + . Step 5: 2-(2-Ethylthiophene) oxazol-5-yl)methyl)-6-(2-isobutoxypyrimidin-5-yl)pyridazin-3(2H)-one

[0928] To a stirred solution of 2-[(2-ethyl-1,3-thiazol-5-yl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]pyridazine-3-ol was added portionwise at 25°C under a nitrogen atmosphere as a solution of KCO (0.70 mg, 5.033 mmol, 2.00 equiv) in 2-methylpropan-1-ol (10 mL) (1.00 g, 2.516 mmol, 1.00 equiv). The resulting mixture was slowly warmed to 70°C and stirred for an additional 6 hours. The resulting mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, methanol in water, 10% to 90% gradient over 40 minutes; detector, UV 254 nm. 2-((2-Ethyl-thiazol-5-yl)methyl)-6-(2-isobutoxypyrimidin-5-yl)pyridazin-3(2H)-one was obtained as a grey solid (800 mg, 85.58%). 1H NMR(300MHz,DMSO-d6)δ9.08(s,2H),8.10(d,J=9.9Hz,1H),7.75(s,1H),7.16(d,J=9.9Hz,1H),5.48(s,2H),4.1 6(d,J=6.6Hz,2H),2.93(q,J=7.5Hz,2H),2.13-2.02(m,1H),1.25(t,J=7.5Hz,3H),0.99(d,J=6.7Hz,6H).LC / MS Rt=1.462min; MSm / z:372[M+H] + .

[0929] The following compounds were synthesized according to Example 16:

[0930]

[0931]

[0932] Example 17: 5:6-(2,4-dihydropyrimidin-5-yl)-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one (Compound 353)

[0933]

[0934] Step 1: 6-(2,4-dimethoxypyrimidin-5-yl)-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one To a mixture of (2,4-dimethoxypyrimidin-5-yl)boronic acid (552 mg, 3 mmol, 1.0 equiv) in dioxane (5 mL) was added 6-chloro-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one (717 mg, 3 mmol, 1.00 equiv), Pd(dppf)Cl2 (110 mg, 0.15 mmol, 0.05 equiv), K2CO3 (621 mg, 4.5 mmol, 1.5 equiv), and water (0.5 mL). The flask was purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred at 90°C for 2 hours. The solution was diluted with water and extracted with EtOAc (x3). The combined organics were washed with brine, dried over Na2SO4, and the solvent removed in vacuo. Purification by silica gel chromatography gave 6-(2,4-dimethoxypyrimidin-5-yl)-2-((5-fluoro-pyridin-3-yl)methyl)pyridazin-3(2H)-one (610 mg, 59.3%) as a solid.

[0935] Step 2: 6-(2,4-dihydropyrimidin-5-yl)-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one

[0936] To 6-(2,4-dimethoxypyrimidin-5-yl)-2-((5-fluoro-pyridin-3-yl)methyl)pyridazin-3(2H)-one (172 mg, 0.5 mmol, 1.0 mL) was added 4 M HCl (8 mL) in MeOH (6 mL). The resulting solution was stirred at 90° C. for 2 hours. The mixture was concentrated under reduced pressure. The crude product was purified by RP-HPLC to give a white solid (28 mg, 17.8%). 1 H NMR (300MHz, DMSO-d6) δ11.46(s,2H),8.91-8.23(m,2H),8.05-7.80(m,2H),7.74-7.69(m,1H),7.00(d,J=9.8Hz,1H),5.34(s,2H).LC / MS Rt=0.721min; MS m / z:316[M+H] + .

[0937] Example 18. Skeletal muscle fibrillary ATPase assay

[0938] Overview: Myosin ATPase activity is assessed by using a coupled reaction system in which the generation of ADP by myosin ATPase function is coupled to the disappearance of NADH via the pyruvate kinase / lactate dehydrogenase (PK-LDH) system. Myosin ATPase activity produces ADP, which is used as a substrate for PK to produce pyruvate and regenerate ATP. Pyruvate is then used as a substrate by LDH to oxidize NADH to NAD+. The reaction rate is monitored by the time-dependent disappearance of NADH using absorbance at 340 nm. Inhibition of ATPase activity by the assayed compounds is indicated by a decrease in the rate of NADH loss within the experimental time window relative to the vehicle-treated control. To assess the selectivity of the assayed compounds for skeletal myofibrils, the compounds are counter-screened in cardiac myofibrils.

[0939] Materials: The following stock solutions and reagents were used in the skeletal myofibrillar ATPase assay:

[0940]

[0941]

[0942] Prepare a stock solution of pCa buffer. Combine the PIPES, CaCl2, and EGTA solutions with 70 mL of water. Adjust the pH to 7.0 and bring the final volume to 100 mL.

[0943]

[0944] Buffer A and Buffer B. Store buffers on ice until use.

[0945] Buffer preparation

[0946]

[0947] Skeletal Myofibril ATPase Assay Procedure: Thaw the BSA, ATP, NADH, PEP, and DTT solutions at room temperature and transfer to ice. Transfer the pelleted frozen myofibrils (approximately twice the required volume) to a sufficiently large tube and cap. Thaw the myofibrils by rolling in a water bath at room temperature for approximately 15 minutes and cool on ice. Buffers A and B are prepared by adjusting the volumes as needed based on the number of wells and stored on ice. Add 0.5 μL of the test compound to the wells of a 384-well plate. Buffer A and buffer B are mixed by inversion immediately before use, and then 25 μL each is dispensed using a Multidrop dispenser (buffer A first, then buffer B). The absorbance in the wells is measured at 340 nm using a kinetic protocol, with wells read every 1.5-2 minutes for 1 hour. Qualitatively estimate the reaction rate by subtracting the minimum absorbance value from the maximum value for each well using SoftMax Pro plate reader software or a spreadsheet program such as Excel. Data were normalized using GraphPad Prism 8.0, with 100% activity defined as the change in absorbance in the 1% DMSO vehicle wells and 0% defined as no change over the entire assay. Normalized data were fit to a variable slope four-parameter logistic model with the bottom constrained to 0 or greater. The compounds in Tables 1 to 4 were tested, and the results of the assays are presented in Table 5 herein. A = IC 50 Less than or equal to 10 μM; B = IC 50 Greater than 10 μM and less than 100 μM; C = IC 50 Greater than 100μM.

[0948] Example 11. Cardiac myofibril ATPase assay

[0949] Counterscreening was performed using frozen myofibril pellets obtained from cardiac tissue as in Example 10. The assay was performed in the same manner as described above with the following notable exceptions: the final well concentration of myofibrils was 1.0 mg / mL and KCl was omitted from the formulation.

[0950] The compounds of Tables 1 to 4 were tested and the results of the assay are presented in Table 6 herein. A = IC 50 Less than or equal to 10 μM; B = IC 50 Greater than 10 μM and less than 100 μM; C = IC 50 Greater than 100 μM; D = IC 50 Greater than 60μM.

[0951] Example 12. Tibialis anterior muscle assay

[0952] Skeletal muscle from Duchenne muscular dystrophy (DMD) patients and mdx mice lacks dystrophin and is more susceptible to contraction-induced injury than control muscle. The susceptibility of mdx mice to limb muscle injury following administration of compounds disclosed herein was assessed using two maximally activated tibialis anterior (TA) muscle segments in situ. A stress segment at 20% of the muscle fiber length was initiated from the plateau of isometric contraction. The extent of injury was assessed after one minute by the deficit in isometric force.

[0953] animal

[0954] Mice aged 2 to 19 months were tested. Specific pathogen-free (SPF) C57BL control and mdx mice were either purchased or bred in-house from mating pairs purchased from Jackson Laboratories. All control mice were of the C57BL / 10J strain, except for the 19-month-old mice, which were C57BL / 6. The use of C57BL / 6 mice for the oldest group was necessary because, unlike C57BL / 10J mice, C57BL / 6 mice can be purchased from the aged rodent colony maintained by the National Institute on Aging.

[0955] In situ preparation

[0956] Mice were anesthetized with an initial intraperitoneal injection of Avertin (tribromoethanol; 13-17 1 l / g). Anesthesia was supplemented until no response to tactile stimulation was detected. This level of anesthesia was maintained with additional doses of Avertin throughout the experiment. The tendon of the TA was exposed through an incision at the ankle. The tendon was cut a few millimeters from the end of the muscle. The tendon was tied as close to the muscle attachment point as possible with 4.0 nylon suture, and the tendon was folded back on itself and tied again. The tendon and exposed muscle were kept moist by regular application of isotonic saline. The mice were placed on a heated platform maintained at 37°C. The mouse's feet were secured to the platform with cloth straps, and the knees were fixed in clamps between sharp screws. The tendon of the muscle was securely tied to the lever arm of a servo motor. The servo motor controlled the position of the muscle and monitored the force generated by the muscle. All data were displayed on a digital oscilloscope and stored on a computer.

[0957] The TA muscle was stimulated with 0.2-ms pulses using two needle electrodes that penetrated the skin on either side of the peroneal nerve near the knee. The stimulation voltage and subsequent muscle length (Lo) were adjusted for maximum isometric twitch force (Pt). While maintained at Lo, the muscle was stimulated at increasing frequencies, starting from 150 Hz and increasing in steps of 50 Hz until maximum force (Po) was reached, typically 250 Hz. A rest period of 1 to 2 minutes was allowed between each tetanic contraction. Muscle length was measured with calipers based on well-defined anatomical landmarks near the knee and ankle. The optimal fiber length was determined by multiplying Lo by the TALf / Lo ratio of 0.6.

[0958] Extended contraction plan

[0959] Each muscle was stretched twice in situ, stimulating the muscle at 250 Hz, the frequency that most often results in Po. A protocol consisting of only two contractions was used to avoid fatigue. Stretching began with a plateau of isometric contraction at Lo. At time 0, stimulation was initiated and the muscle was held motionless for 100 ms to allow maximum activation. From the plateau of maximal isometric contraction, a length change of 20% Lf was applied at a speed of 1 Lf / s (LC1). Stimulation was stopped at the end of the stretch climb. The muscle was held at the stretched length for 100 ms and then returned to Lo at the same speed. Ten minutes later, a second lengthening contraction (LC2) identical to the first was performed. Maximum isometric force was measured after 1 minute and then again every 5 minutes for 15 minutes. Force deficit was calculated as the difference between the isometric force during LC1 and the maximum isometric force measured at any given time and expressed as a percentage of the isometric force during LC1. Recovery within 15 minutes after the two lengthening contraction protocol was quantified as the difference between the isometric force measured at 15 minutes and the isometric force after the second lengthening contraction and expressed as a percentage of the initial Po.

[0960] The experimental protocol includes two muscle stretches during maximum activation, followed by maximum activation to measure the decrease in maximum isometric force (Po). Figure A shows the change in muscle length at 20% stress relative to fiber length (Lf), where 100% corresponds to the optimal muscle length (Lo) for force development. The muscle was stretched at a speed of 2Lf / s. Figure B shows the decrease in Po after two stretching protocols in representative mdx mice. Each extension contraction starts from the platform of maximum isometric contraction. 10 minutes after the first extension contraction (LC1), the second extension contraction (LC2) occurs. The maximum force during isometric contraction is measured 10 minutes after LC2 (t1 min). The force deficit is 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 are cut from the muscles and the muscles are weighed. After removing the TA muscle, deeply anesthetized mice are killed by inducing pneumothorax. The total cross-sectional area (CSA) of TA muscle was calculated by dividing the muscle mass by the product of Lf and 1.06 mg / mm3 (density of mammalian skeletal muscle). The specific Po was calculated by dividing Po by CSA. Figure 3-6 .

[0961] Figure 3 The force reduction before injury at 100 Hz is shown for compounds of the present disclosure. Force in the TA muscle of mdx mice was measured in situ at 100 Hz before and after oral administration of the compound. 100 Hz stimulation was applied every 10 minutes, and the change in force was recorded before starting the centrifugal injury protocol. This metric provides an indication of the relative ability of the compound to reduce force in the target tissue.

[0962] Figure 4 Post-injury force reduction at 175 Hz is shown for compounds of the present disclosure.

[0963] The maximum force was measured in situ at 175 Hz in the TA muscle 10 minutes before and after two rounds of eccentric (lengthening) contractions. In mdx mice, lengthening contractions produce an exaggerated decrease in force. This measurement gives an indication of the ability of the compound to reduce the relative decrease in force after eccentric contractions. Figure 5 Figure 2 shows the decrease in intermediate extension force for compounds of the present disclosure. TA muscle in situ injury was induced by two maximal eccentric contractions, each with a 20% extension, separated by 10 minutes. This metric measures the relative decrease in pre-extension force between the first and second contractions.

[0964] Figure 6 Compounds of the present disclosure were shown to increase TA mass after injury.

[0965] Prolonged injury of the TA muscle in mdx mice resulted in a delayed increase in muscle weight after injury. This was likely due to fluid accumulation in the form of edema. Muscles (injured and contralateral) were removed from the mice 1 hour after injury and weighed. The relative increase in weight of the injured muscle relative to the contralateral muscle was recorded. A decrease in this relative change indicated a decrease in edema after injury.

[0966] In some embodiments, the compounds of the present disclosure are as shown in Table 1 below.

[0967] Table 1

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004] In some embodiments, the compounds of the present disclosure are as shown in Table 2 below.

[1005] Table 2

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015] In certain embodiments, the compounds of the methods described herein can be selected from commercially available compounds, including those described in Table 3. The compounds of Tables 3 and 4 were tested, and IC 50 The data are presented in Table 6 herein. A = IC 50 Less than or equal to 10 μM; B = IC 50 Greater than 10 μM and less than 100 μM; C = IC 50 Greater than 100μM.

[1016] Table 3

[1017]

[1018]

[1019]

[1020] In certain embodiments, compounds used in the methods described herein include those in Table 4 or salts thereof.

[1021] Table 4

[1022]

[1023]

[1024] Skeletal IC of the compounds of the present disclosure 50 The values ​​are presented in Table 5.

[1025] Table 5

[1026]

[1027]

[1028] A=IC 50 Less than or equal to 10 μM; B = IC 50 Greater than 10 μM and less than 100 μM; C = IC 50 Greater than 100μM.

[1029] Certain compounds of the present disclosure have cardiac IC values ​​as shown in Table 6. 50 value.

[1030] Table 6

[1031]

[1032]

[1033] A=IC50 Less than or equal to 10 μM; B = IC 50 Greater than 10 μM and less than 100 μM; C = IC 50 Greater than 100μM; D greater than 60μM.

[1034] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided as examples only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the present invention. It should be understood that various substitutions to the embodiments of the present invention described herein may be employed in practicing the present invention. The following claims are intended to define the scope of the present invention and thus encompass methods and structures within the scope of these claims and their equivalents.

Claims

1. A compound represented by formula (II): or a salt thereof, wherein: T is selected from -O-, -NR 14 -、-CR 15 R 16 -, -C(O)-, -S-, -S(O)-, and -S(O)2; R 11 Selected from: C 1-5 haloalkyl, optionally further substituted with one or more substituents independently selected from: -OR 20 、-SR 20 、-N(R 20 )2, -NO2, =O, =S, -CN, C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced by; R 12 is a heteroaryl group optionally substituted by one or more substituents independently selected from the following: 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; and when R 12 is pyridyl or pyrimidinyl, The substituents on the nitrogen atom of the pyridyl or pyrimidinyl group are optionally further selected from -O - ; C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 The substituents are substituted by carbocyclic and 3 to 10-membered heterocyclic groups, wherein the C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 replaced; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more -R 19 replace; R 14 Selected from: Hydrogen and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents; Each R 15 and R 16 Independently selected from: Hydrogen, halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-6 Alkyl, which is optionally substituted by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents; Each R 17 and R 18 Independently selected from: Halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2, -CN and C 1-6 alkyl, which are optionally replaced by one or more independently selected from halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NO2 and -CN substituents; Each R 19 Independently selected from: 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; and C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, each of which is optionally substituted by one or more independently selected from 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; Each R 20 Independently selected from: hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl, each of which is optionally substituted by one or more independently selected from 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 substituted by a carbocyclic or 3- to 10-membered heterocyclic substituent; and C 3-10 Carbocyclic and 3 to 10 membered heterocyclic rings, each of which is optionally substituted by one or more independently selected from 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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 substituted by carbocyclic, 3- to 10-membered heterocyclic, and haloalkyl substituents; w is 0, 1, or 2; and z is 0, 1 or 2.

2. The compound or salt according to claim 1, wherein T is -O-.

3. The method according to claim 1, wherein R 11 Selected from optionally further selected from one or more independently selected from -OR 20 、-SR 20 、-N(R 20 )2、=O、-CN、C 3-10 C substituted by carbocyclic and 3- to 10-membered heterocyclic substituents 1-3 Halogenated alkyl.

4. The compound or salt according to claim 1, wherein R 11 Selected from -CHF2 and -CH2CF3.

5. The compound or salt according to claim 1, wherein R 12 is selected from optionally substituted 5- or 6-membered monocyclic heteroaryl and optionally substituted 9-membered bicyclic heteroaryl.

6. The compound or salt according to claim 1, wherein R 12 is selected from the group consisting of isoxazole, oxazole, thiadiazole, triazole, isothiazole, tetrazole, pyrazole, pyrrole, furan, imidazole, oxadiazole, thiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazine, benzoxazole, benzothiazole, benzimidazole, indole, indazole and imidazopyridine, any of which is optionally substituted.

7. The compound or salt according to claim 1, wherein R 12 is selected from the group consisting of isoxazole, oxazole, thiadiazole, oxadiazole, thiazole, pyridine and benzoxazole, any of which is optionally substituted.

8. The compound or salt according to claim 1, wherein R 12 Selected from: Any of which is optionally substituted.

9. The compound or salt according to claim 1, wherein R 12 Selected from: Any of which is optionally substituted.

10. The compound or salt according to claim 1, wherein R 12 Selected from: Any of which is optionally substituted.

11. The compound or salt according to claim 1, wherein R 12 is selected from optionally substituted 6-membered heteroaryl.

12. The compound or salt according to claim 1, wherein R 12 is selected from pyridine and pyrimidine, either of which is optionally substituted.

13. The compound or salt according to claim 1, wherein R 12 Selected from: Any of which is optionally substituted.

14. The compound or salt according to claim 1, wherein R 12 is selected from optionally substituted bicyclic heteroaryl.

15. The compound or salt according to claim 1, wherein R 12 is selected from optionally substituted benzoxazoles.

16. The compound or salt according to claim 1, wherein R 12 Selected from: Any of which is optionally substituted.

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

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

19. The compound or salt according to claim 1, which is selected from:

20. The compound or salt according to claim 1, selected from: or a salt thereof.

21. Use of a compound according to any one of claims 1 to 20 or a salt thereof in the preparation of a medicament for treating neuromuscular conditions, activity-induced muscle damage or metabolic myopathy.

22. The use according to claim 21, wherein the neuromuscular condition is selected from the group consisting of Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb-girdle muscular dystrophy, tendinitis and carpal tunnel syndrome.

23. The use according to claim 22, wherein the neuromuscular condition is Duchenne muscular dystrophy.

24. The use according to claim 22, wherein the neuromuscular condition is Becker muscular dystrophy.

25. The use of claim 22, wherein the neuromuscular condition is limb-girdle muscular dystrophy.

26. Use of a compound or salt according to any one of claims 1 to 20 in the preparation of a medicament for the treatment of movement disorders.

27. The use according to claim 26, wherein the movement disorder is muscle spasm.

28. The use according to claim 27, wherein the muscle spasm is selected from the group consisting of spasms associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, cerebral palsy, stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria and amyotrophic lateral sclerosis.

29. Use of a compound or salt according to any one of claims 1 to 20 in the preparation of a medicament for the treatment of metabolic myopathy.

30. The use according to claim 29, wherein the metabolic myopathy is McCardle syndrome.

31. A pharmaceutical composition comprising the compound or salt of any one of claims 1 to 20 and a pharmaceutically acceptable excipient.

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