Pyridazinone compounds and their uses

Abstract

The present disclosure relates to substituted pyridazinone compounds, conjugates, and pharmaceutical compositions for treating neuromuscular diseases such as Duchenne muscular dystrophy (DMD). The disclosed compounds are particularly useful for treating DMD and modulating the inflammatory inhibitors IL-1, IL-6, or TNF-α.

Description

[0001] Cross-reference

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 756,553, filed on Nov. 6, 2018, which is hereby incorporated by reference in its entirety. BACKGROUND OF THE INVENTION

[0003] Skeletal muscle is the largest organ system in the human body and has two main functions. The first is force generation for 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 result in successive rounds of amplified muscle breakdown that are difficult for the body to repair. Eventually, as the patient ages, pathophysiological processes occur that lead to excessive inflammation, fibrosis, and accumulation of fat deposits in the muscle, portending a precipitous decline in physical function and leading to death.

[0004] DMD is a genetic disease that affects skeletal muscle and is characterized by progressive muscle degeneration and weakness. There is still a need for treatments that reduce muscle breakdown in patients with neuromuscular conditions such as DMD. SUMMARY OF THE INVENTION

[0005] 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 compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), or (IIa) are inhibitors of skeletal muscle contraction. In some embodiments, the compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), or (IIa) are inhibitors of myosin. In some embodiments, the compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), or (IIa) are inhibitors of skeletal muscle myosin II.

[0006] In some aspects, methods of treating movement disorders can include administering a compound or salt of any one 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 includes muscle spasticity. In some embodiments, the muscle spasticity can be selected from spasticity 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 or amyotrophic lateral sclerosis.

[0007] The present disclosure provides compounds and their salts for 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.

[0008] In certain aspects, the present disclosure provides a compound represented by formula (I):

[0009]

[0010] or a salt thereof, wherein:

[0011] Each X is independently selected from C(R 3 ), N and N + (-O - ) where at least one X is N or N + (-O - );

[0012] A is selected from -O-, -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-;

[0013] R 1 is selected from:

[0014] C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each of which is optionally substituted with 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 carbocyclic ring and 3- to 10-membered heterocyclic ring substituted by substituents, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 ; and

[0015] C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, 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 substituted by substituents, wherein C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted by one or more R 9 ; or

[0016] R 1 together with R 3 forms a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein said 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring is optionally substituted by one or more R 9 ; or R1 together with R 5 forms a 3- to 10-membered heterocycle or a C 3-10 carbocycle, wherein the 3- to 10-membered heterocycle or C 3-10 carbocycle is optionally substituted by one or more R 9 ; or R 1 together with R 4 forms a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted by one or more R 9 ;

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

[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, the substituent on the nitrogen atom of pyridyl or pyrimidinyl is optionally further selected from –O - ;

[0019] C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein each 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(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 carbocyclic ring and 3 to 10

[0020] membered heterocyclic ring substituents, wherein said C 3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring are each optionally substituted by one or more R 9 ; and

[0021] C 3-10 carbocyclic ring and 3 to 10 membered heterocyclic ring, each of which is optionally substituted by one or more R 9 ;

[0022] R 3 , R 5 and R 6 are each independently selected from:

[0023] hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and –CN; and

[0024] C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; or

[0025] R 3 and 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 carbocyclic ring is optionally substituted by one or more R 9 ; or R 5 and 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 carbocyclic ring is optionally substituted by one or more R 9 ;

[0026] R 4 is independently selected from:

[0027] Hydrogen; and

[0028] C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; or R 4 together with R 1 forms a 3- to 10-membered heterocycle, optionally substituted by one or more R 9 ;

[0029] R 7 and R 8 are independently selected from:

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

[0031] Each R 9 is 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 substituents;

[0034] Each R 10 is 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 substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O - C 1-6 alkyl, -S - C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, 3 - to 10 - membered heterocycle; and

[0037] C 3-10 carbocycle and 3 - to 10 - membered heterocycle, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O - C 1-6 alkyl, -S - C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3 - to 10 - membered heterocycle and C 1-6 haloalkyl;

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

[0039] p is 0, 1 or 2.

[0040] In some aspects, the present disclosure provides a compound 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 is selected from:

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

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

[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 a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is 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 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 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, where the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 ; and

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

[0050] R 14 is selected from:

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

[0052] Each R 15 and R 16 is 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 substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2 and -CN;

[0054] Each R 17 and R 18 is 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 substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2 and -CN;

[0056] Each R 19 is 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 ) and -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 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 substituents;

[0059] Each R 20 is 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 substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle; and

[0062] C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle and haloalkyl;

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

[0064] z is 0, 1 or 2.

[0065] In some aspects, the present disclosure provides a method for treating activity-induced muscle injury, which comprises administering to a subject in need a compound or a 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-;

[0070] R 1 is selected from:

[0071] C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each of 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 ), -CN, C 3-10 carbocyclic ring and substituents of 3- to 10-membered heterocyclic rings, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic rings are each optionally substituted by one or more R 9 ; and

[0072] C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic rings, 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 substituents; or

[0073] R 1 together with R 3 forms a 5- to 10-membered heterocycle or a C 5-10 carbocycle, wherein the 5- to 10-membered heterocycle or C 5-10 carbocycle is optionally substituted with one or more R 9 ; or R 1 together with R 5 forms a 3- to 10-membered heterocycle or a saturated C 3-10 carbocycle, wherein the 3- to 10-membered heterocycle or saturated C 3-10 carbocycle is optionally substituted with one or more R 9 ; or R 1 together with R 4 forms a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more R 9 ; and

[0074] when A is -NR 4 -, R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further selected from -N(R 10 )2 and -OR 10 ;

[0075] when A is absent, R 1 is further selected from halogen, -OR 10 、 -SR 10 、 -N(R 10 )2, -C(O)R 10 、 -C(O)N(R 10 )2, -N(R10 )C(O)R 10 、 -N(R 10 )C(O)N(R 10 )2、 -OC(O)N(R 10 )2、 -N(R 10 )C(O)OR 10 、 -C(O)OR 10 、 -OC(O)R 10 、 -S(O)R 10 、 -S(O)2R 10 、 -NO2 and –CN;

[0076] R 2 is a heteroaryl optionally substituted with one or more substituents independently selected from:

[0077] 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, the substituent on the nitrogen atom of the pyridyl or pyrimidinyl is optionally further selected from –O - ;

[0078] C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each of which is optionally substituted with 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 )、-CN、C 3-10 carbon rings and 3- to 10-membered heterocycles, which are each optionally substituted by one or more substituents R 3-10 wherein said carbon rings and 3- to 10-membered heterocycles are each optionally substituted by one or more R 9 substituted; and

[0079] C 3-10 carbon rings and 3- to 10-membered heterocycles, each of which is optionally substituted by one or more R 9 substituted;

[0080] Each R 3 、R 5 and R 6 is independently selected from:

[0081] 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 substituents independently selected from halogen, -OR 10 、-SR 10 、-

[0082] N(R 10 )2、-NO2 and -CN; or

[0083] R 3 and R 1 together form a 5- to 10-membered heterocycle or C 5-10 carbon ring, wherein said 5- to 10-membered heterocycle or C 5-10 carbon ring is optionally substituted by one or more R 9 substituted; R 5 and R 1 together form a 3- to 10-membered heterocycle or C 3-10 carbon ring, wherein said 3- to 10-membered heterocycle or C 3-10 carbon ring is optionally substituted by one or more R 9 substituted;

[0084] R 4 is independently selected from:

[0085] hydrogen; and

[0086] C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; or R 4 and R 1 together form a 3- to 10-membered heterocycle, optionally substituted with one or more R 9 ;

[0087] Each R 7 and R 8 is independently selected from

[0088] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN and C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN;

[0089] Each R 9 is independently selected from

[0090] 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

[0091] C 1-3 alkyl, C 2-3 alkenyl, C 2-3An alkynyl group, each of which is optionally substituted with 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;

[0092] Each R 10 is independently selected from

[0093] hydrogen; and

[0094] C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle; and

[0095] C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle and haloalkyl;

[0096] R 30 and R 31 are independently selected from R 10 or R 30 and R 31 together form C 3-7 a carbocyclic ring, wherein said 3- to 7-membered heterocyclic ring, wherein C 3-7 the carbocyclic ring and the 3- to 7-membered heterocyclic ring are optionally substituted by R 9 substituted;

[0097] n is 0, 1 or 2; and

[0098] p is 0, 1 or 2.

[0099] In certain aspects, the present disclosure provides a method for treating a neuromuscular condition or treating activity-induced muscle injury or inhibiting muscle myosin II, comprising administering to a subject in need thereof a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II) and (IIa).

[0100] In certain aspects, the present disclosure provides a method for treating a movement disorder, comprising administering to a subject in need thereof a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II) and (IIa).

[0101] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II) and (IIa) and a pharmaceutically acceptable excipient.

[0102] Incorporated by reference

[0103] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the 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

[0104] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the invention will be obtained from the following detailed description, which sets forth illustrative embodiments of the principles of the invention, and the accompanying drawings (also referred to herein as "FIGURES"), in which:

[0105] Figure 1 depicts injury induced by overcontraction, which precedes inflammation and irreversible fibrosis, which are characteristic of late-stage DMD pathology;

[0106] Figure 2Depicts N-benzyl-p-toluenesulfonamide (BTS), an inhibitor of fast-fiber skeletal muscle myosin, which has been shown to protect muscles from pathological muscle disorders in DMD zebrafish model embryos;

[0107] Figure 3 Depicts the pre-injury force reduction at 100 Hz for various compounds of the present disclosure;

[0108] Figure 4 Depicts the post-injury force reduction at 175 Hz for various compounds of the present disclosure;

[0109] Figure 5 Depicts the intermediate extension force decline for various compounds of the present disclosure;

[0110] Figure 6 Depicts the post-injury TA mass increase for various compounds of the present disclosure. Detailed Description

[0111] Although the 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. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The scope of the invention is intended to be defined by the appended claims, which thus cover the methods and structures within the scope of these claims and their equivalents.

[0112] In certain aspects, the present disclosure provides methods for treating neuromuscular diseases by selectively inhibiting skeletal muscle fast-twitch fiber myosin. In particular, the methods of the present disclosure can be used to treat DMD and other neuromuscular diseases.

[0113] Skeletal muscle is mainly composed of two types of fibers, slow-twitch muscle fibers (i.e., type I) and fast-twitch muscle fibers (i.e., type II). In each muscle, the two types of fibers are arranged in a mosaic pattern, and the fiber type composition varies in different muscles and at different points in growth and development. Slow-twitch muscle fibers have excellent aerobic energy production capabilities. Slow-twitch muscle fibers have a low contraction rate but a high fatigue tolerance. Slow-twitch muscle fibers generally have a higher concentration of mitochondria and myoglobin than fast-twitch muscle fibers and are surrounded by more capillaries compared to fast-twitch muscle fibers. Due to the lower myosin ATPase activity, slow-twitch muscle fibers contract more slowly and produce less energy compared to fast-twitch muscle fibers, but they are able to maintain contraction function for a longer period of time, such as in steady-state, postural control, and endurance exercises.

[0114] Based on the specific skeletal muscle fast myosin they express, human fast-twitch muscle fibers can be further divided into two main fiber types (type IIa, type IIx / d). 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 can generate a large amount of tension in a short period of time. Generally, compared with slow-twitch muscle fibers, fast-twitch muscle fibers have lower concentrations of mitochondria, myoglobin, and capillaries, and thus can fatigue more quickly. Fast-twitch muscle fibers generate the faster forces required for power and resistance activities.

[0115] The ratio of type I and type II can vary among different individuals. For example, in non-athletic individuals, each muscle fiber type can account for nearly 50%. Power athletes may have a higher proportion of fast-twitch muscle fibers. For example, in sprinters, 70 - 75% are type II. Endurance athletes may have a higher proportion of slow-twitch muscle fibers. For example, the proportion of slow-twitch muscle fibers in long-distance runners is 70 - 80%. The ratio of type I and type II fibers can also vary according to the age of the individual. The proportion of type II fibers (especially type IIx) can decrease with increasing age of the individual, resulting in a loss of lean muscle mass.

[0116] The contractile action of skeletal muscle causes muscle damage in subjects with neuromuscular diseases (such as DMD), and this damage seems to be more prevalent in fast-twitch muscle fibers. It has been observed that in a malnourished mouse model, the acute force decline after strain in a model mainly composed of fast type II fibers is greater than that in a model mainly composed of slow type I fibers (i.e., soleus muscle). It has also been demonstrated in a malnourished mouse model that the degree of acute force decline and histological damage is proportional to the peak force development during strain. Figure 1 Shows the damage caused by overcontraction, which occurs before the inflammation and irreversible fibrosis characteristic of late DMD pathology. [Figure adapted from: Claflin and Brooks, Am J Brooks, Physiol Cell, 2008]. By restricting the peak force generation of type II fibers and possibly increasing the dependence on healthier type I fibers, contraction-induced muscle damage in these patients can be reduced. N-benzyl-p-toluenesulfonamide (BTS) is an inhibitor of skeletal muscle fast myosin, as Figure 2 shown, in embryos from a DMD zebrafish model, it has been shown to protect muscles from pathological muscle disorders. [Source: Li and Arner, PLoSONE, 2015].

[0117] Skeletal muscle myosin inhibitors that lack selectivity for type II fibers may cause excessive inhibition of skeletal muscle contraction, including respiratory function and unwanted inhibition of cardiac activity, because the heart shares multiple structural components (such as type I myosin) with type I skeletal muscle fibers. Without wishing to be bound by a particular mechanical 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.

[0118] Definitions

[0119] 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, unless otherwise defined.

[0120] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0121] The term "C x-y " or "C x -C y ", when used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, is intended to include groups having x to y carbons in the chain. For example, the term "C 1-6 alkyl" refers to a saturated hydrocarbon group, substituted or unsubstituted, including straight-chain and branched-chain alkyl groups having 1 to 6 carbons.

[0122] The terms "C x-y alkenyl" and "C x-y alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups that are similar in length and possible substitution to the alkyl groups described above, but contain at least one double bond or triple bond, respectively.

[0123] As used herein, the term "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each ring atom is carbon. Carbocyclic rings include 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. Each ring of a bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as a phenyl group, may be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Where valence allows, bicyclic carbocyclic rings include any combination of saturated, unsaturated, and aromatic bicyclic rings. Bicyclic carbocyclic rings also include spirobicyclic rings such as spiropentane. Bicyclic carbocyclic rings include any combination of ring sizes, such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[1.1.1]pentyl.

[0124] The term "aryl" refers to an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon and 5 to 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 Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene.

[0125] The term "cycloalkyl" refers to a saturated ring in which each ring atom is carbon. Cycloalkyls may 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, cycloalkyls contain 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain 5 to 7 carbon atoms. Cycloalkyls may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic carbocyclic groups include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptyl), decahydronaphthyl, 7,7-dimethylbicyclo[2.2.1]heptyl, bicyclo[1.1.1]pentyl, and the like.

[0126] The term "cycloalkenyl" refers to a saturated ring in which each ring atom is carbon and there is at least one double bond between two ring carbons. Cycloalkenyls may 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 some other embodiments, cycloalkenyls contain 5 to 7 carbon atoms. Cycloalkenyls may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0127] The term "halo", "halogen", or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0128] The term "haloalkyl" refers to an alkyl group as defined above substituted by one or more halo groups, e.g., trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl group is optionally further substituted as described herein.

[0129] 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- to 10-membered monocyclic, 6- to 12-membered bicyclic, 5- to 12-membered spirobicyclic, and 5- to 12-membered bridged rings. Where valence permits, bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclics. In an exemplary embodiment, an aromatic ring, such as pyridyl, may be fused to a saturated or unsaturated ring such as cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles also include spirobicycles, e.g., 5- to 12-membered spirobicycles, such as 2-oxa-6-azaspiro[3.3]heptane.

[0130] 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, 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 Hückel theory. Heteroaryl includes 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 is attached to the remainder of the molecule through any atom in the ring. Examples of heteroaryl include, but are not limited to, azido group, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benz[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxo groups, benzoxazinyl, 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-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indazinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoaza groups, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl and thiophenyl (i.e., thienyl).

[0131] 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 monocyclic, 6- to 12-membered bicyclic, 5- to 12-membered spirobicyclic, 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 the valence allows, the heterocycloalkyl is attached to the remainder of the molecule through any atom of the heterocycloalkyl, such as any carbon or nitrogen atom of the heterocycloalkyl. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thieno[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thioxomorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl.

[0132] 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 carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic, 6- to 12-membered bicyclic, and 5- to 12-membered bridged rings. In other embodiments, the heterocycloalkenyl contains 5 to 7 carbon atoms. The heterocycloalkenyl can be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0133] The term "substituted" refers to a moiety having a substituent replacing hydrogen on one or more carbons or replaceable heteroatoms (e.g., NH or NH2) of a compound. It is understood that "substitution" or "substituted with" includes the implicit condition that the substitution is in accordance with the possible valences of the substituted atom and the substituent, and that the substitution results in 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 moiety in which two hydrogen atoms on the same carbon atom are replaced by substituents, 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 organic compounds. Broadly speaking, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, the permissible substituents can be one or more and can be the same or different.

[0134] In some embodiments, the substituent can include any of the substituents described herein, such as: halogen, hydroxy, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximino (=N-OH), hydrazino (=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O)t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which may optionally be substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), oxime(=N-OH), hydrazino(=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(Ra )2 (where t is 1 or 2); wherein each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, and each R a is optionally substituted, when valency permits, by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), oximino(=N-OH), hydrazino(=N-NH2), -R b -OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R c -C(O)N(R a )2、-R b -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (where t is 1 or 2)、-R b -S(O) t R a (where t is 1 or 2)、-R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and each R b is independently selected from a direct bond, or a straight or branched alkylene, alkenylene or alkynylene chain, and each R cis a straight-chain or branched alkylene, alkenylene or alkynylene chain.

[0135] A double bond with an oxygen atom, such as an oxo group, is represented herein as "=O" and "(O)". A double bond with a nitrogen atom is represented as "=NR" and "(NR)". A double bond with a sulfur atom is represented as "=S" and "(S)".

[0136] As used herein, the phrases "parenteral administration" and "parenterally administering" refer to modes of administration other than enteral and topical administration, typically by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0137] The phrase "pharmaceutically acceptable" is used herein to denote those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications and are commensurate with a reasonable benefit / risk ratio.

[0138] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein 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, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and 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) buffering agents, 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 solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0139] 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 from inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic bases 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, etc. Organic bases from which salts can be derived include, for example, primary amines, secondary amines and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc., specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts.

[0140] As used herein, "treating" or "treatment" refers to a method for obtaining a beneficial or desired result (including, but not limited to, therapeutic benefit and / or prophylactic benefit) with respect to a disease, disorder or medical condition. Therapeutic benefit may include, for example, eradication or amelioration of an underlying disease being treated. Additionally, therapeutic benefit may include, for example, eradication or amelioration of one or more physiological symptoms associated with the underlying disorder such that improvement is observed in a subject, even though the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease or a subject reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not yet have been made. Treatment by administration of the compounds described herein does not require the involvement of a medical professional.

[0141] Compound

[0142] The following is a discussion of compounds and their salts that can be used in the methods of the present disclosure. In certain embodiments, the compounds and salts are described in Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II) and (IIa).

[0143] In one aspect, compounds represented by Formula (I) are disclosed herein:

[0144]

[0145] or salts thereof, wherein:

[0146] Each X is independently selected from C(R 3 )、N and N + (-O- ), where at least one X is N or N + (-O - );

[0147] A is selected from -O-, -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)- and -S(O)2-;

[0148] R 1 is selected from:

[0149] C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of 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 , -C(O)OR 10 , -OC(O)R 10 , -N(R 10 )C(O)N(R 10 ), -OC(O)N(R 10 ), -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 ring and substituents of 3- to 10-membered heterocyclic rings, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 ; and

[0150] C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of 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 ), -CN, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are substituted by substituents, where C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl are each optionally substituted by one or more R 9 ; or

[0151] R 1 together with R 3 forms a 5- to 10-membered heterocycle or a C 5-10 carbocycle, where the 5- to 10-membered heterocycle or C 5-10 carbocycle is optionally substituted by one or more R 9 ; R 1 together with R 5 forms a 3- to 10-membered heterocycle or a C 3-10 carbocycle, where the 3- to 10-membered heterocycle or C 3-10 carbocycle is optionally substituted by one or more R 9 ; or R 1 together with R 4 forms a 3- to 10-membered heterocycle, where the 3- to 10-membered heterocycle is optionally substituted by one or more R 9 ;

[0152] R 2 is a heteroaryl optionally substituted by one or more substituents independently selected from:

[0153] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR10 、 -OC(O)R 10 、 -S(O)R 10 、 -S(O)2R 10 、 -NO2, =O, =S, =N(R 10 ) and -CN; and when R 2 is a pyridyl or pyrimidinyl group, the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O - ;

[0154] 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 carbocyclic ring and substituents of 3 - to 10 - membered heterocyclic rings, wherein said C 3-10 carbocyclic ring and 3 - to 10 - membered heterocyclic ring are each optionally substituted by one or more R 9 ; and

[0155] C 3-10 carbocyclic ring and 3 - to 10 - membered heterocyclic ring, each of which is optionally substituted by one or more R 9 ;

[0156] Each R 3 , R 5 and R 6 is independently selected from:

[0157] hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN and C 1-6An alkyl group, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; or

[0158] R 3 together with R 1 forms a 5- to 10-membered heterocycle or a C 5-10 carbocycle, wherein the 5- to 10-membered heterocycle or C 5-10 carbocycle is optionally substituted by one or more R 9 ; R 5 together with R 1 forms a 3- to 10-membered heterocycle or a C 3-10 carbocycle, wherein the 3- to 10-membered heterocycle or C 3-10 carbocycle is optionally substituted by one or more R 9 ;

[0159] R 4 is independently selected from:

[0160] hydrogen; and

[0161] C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; or R 4 together with R 1 forms a 3- to 10-membered heterocycle, which is optionally substituted by one or more R 9 ;

[0162] R 7 and R 8 are independently selected from:

[0163] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN and C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN;

[0164] Each R 9 is independently selected from:

[0165] 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 ), -CN; and

[0166] C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl, each of 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;

[0167] Each R 10 is independently selected from:

[0168] hydrogen; and

[0169] C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 substituted by substituents of a carbocyclic ring, a 3- to 10-membered heterocyclic ring; and

[0170] C 3-10 a carbocyclic ring and a 3- to 10-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 a carbocyclic ring, a 3- to 10-membered heterocyclic ring and C 1-6 substituted by substituents of haloalkyl;

[0171] n is 0, 1 or 2; and

[0172] p is 0, 1 or 2.

[0173] In certain embodiments, for a compound or salt of formula (I), each X is independently selected from C(R 3 ) and N, where 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 - ).

[0174] In certain embodiments, for a compound or salt of formula (I), each X is further selected from C(R 3 ).

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

[0176]

[0177] In some embodiments, the compound or its salt of formula (I) is represented by formula (Ib):

[0178]

[0179] In some embodiments, the compound of formula (I) or a salt thereof is represented by formula (Ic):

[0180]

[0181] In some embodiments, the compound of formula (I) or a salt thereof is represented by formula (Id):

[0182]

[0183] In certain embodiments, the compound of formula (I) is represented by formula (Ia) or formula (Ib):

[0184]

[0185] In certain embodiments, the compound of formula (I) is represented by formula (Ic) or formula (Id):

[0186]

[0187] In certain embodiments, the compound of formula (I) is represented by formula (Ia) or formula (Ic):

[0188]

[0189] 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-.

[0190] In certain embodiments, for the compound or salt of any one of formula (I), (Ia), (Ib), (Ic) or (Id), R 1 is selected from:

[0191] C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, wherein each is optionally substituted with 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 carbocyclic ring and 3- to 10-membered heterocyclic ring which are substituted by substituents, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 ; and

[0192] C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein each 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

[0193] R 1 together with R 3 forms a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein said 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring is optionally substituted by one or more R 9 ; or R 1 together with R 5 forms a 3- to 10-membered heterocyclic ring or C 3-10 carbocyclic ring, wherein said 3- to 10-membered heterocyclic ring or C 3-10 carbocyclic ring is optionally substituted by one or more R 9 ; or R 1 together with R 4Together form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more R 9 substituents.

[0194] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic) or (Id), R 1 is selected from:

[0195] C 1-5 alkyl, which is optionally substituted with 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 , -CN, C 3-7 substituents of a carbocycle and a 3- to 7-membered heterocycle, wherein the C 3-7 carbocycle and the 3- to 7-membered heterocycle are each optionally substituted with one or more R 9 substituents; and

[0196] C 3-7 carbocycle, which is optionally substituted with 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 , -CN, C 1-6 alkyl and C 1-6 haloalkyl substituents; or

[0197] or R 1 together with R 4 forms a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally substituted with one or more R 9 substituents.

[0198] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic) or (Id), R 1 is selected from:

[0199] C 1-5 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , C 3-5 substituents of a carbocycle and a 3- to 5-membered heterocycle, wherein the C3-5 The carbocyclic ring and 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 ;

[0200] a C4-C6 saturated carbocyclic ring; or

[0201] R 1 together with R 4 forms a 5-membered saturated heterocyclic ring optionally substituted by one or more R 9 ;

[0202] wherein R 9 is 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 substituents independently selected from halogen, -OR 10 , -N(R 10 )2, -NO2, =O and -CN.

[0203] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 1 is selected from -CHF2, -CH(CH3)2, -CH2CH(CH3)2, -CH2CF(CH3)2, -CH2CF3, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2OCF3, -CH2C(CH3)2OCH3, -CH2SCH3, -CH2CH2SCH3, -CH2CH(CH3)SCH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CF2CH3, -CH2C(CH3)3, -CH2CH(CH3)2 or R 1 together with R 4 forms a 5-membered saturated heterocyclic ring substituted by -CH3 or -CF3.

[0204] In some embodiments, R 1 is selected from C 1-5 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , C 3-5 carbocyclic ring and substituents of 3- to 5-membered heterocyclic rings, wherein the C 3-5 carbocyclic ring and 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 .

[0205] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 1 is C 1-6 alkyl, which is optionally substituted with 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 , -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 ring and 3- to 10-membered heterocyclic ring substituents, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 9 . In some embodiments, R 1 is C 1-6 alkyl substituted with 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 , -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 ring and 3- to 10-membered heterocyclic ring, 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 a C 1-6 alkyl group substituted by one or more substituents independently selected from the following: 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 ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 . In some embodiments, R 1 is selected from C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring substituents, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 .

[0206] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 1 is a C 1-3 alkyl group substituted by one or more substituents independently selected from the following: halogen, -OR 10 , -N(R 10 )2, -NO2, =O, -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 . In some embodiments, R 1 is a C 1-3 alkyl group substituted by one or more halogen substituents. In some embodiments, R 1 is C 1-3 fluoroalkyl. In some embodiments, R 1Selected from -CHF2 and -CH2CF3. In some embodiments, R 1 is C 3-10 a carbocycle, which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, a 3- to 10-membered heterocycle, and C 1-6 haloalkyl. In some embodiments, R 1 is selected from C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , C 3-10 carbocycle, and a 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and the 3- to 10-membered heterocycle are each optionally substituted by one or more R 9 . In some embodiments, R 1 is selected from -CHF2, -CH2CF3, -CH2CH2OCF3, -CH3, -CH2CH3, -CH2CH2CH3, and -CH2CH2OCH3, In some embodiments, R 1 is selected from -CHF2, -CH(CH3)2, -CH2CH(CH3)2, -CH2CF(CH3)2, -CH2CF3, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2OCF3, -CH2C(CH3)2OCH3, -CH2SCH3, -CH2CH2SCH3, -CH2CH(CH3)SCH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CF2CH3, -CH2C(CH3)3, -CH2CH(CH3)2, In some embodiments, R 1 is -CH2CF3.

[0207] In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 1 and R 4 together form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally substituted by one or more R 9 . In some embodiments, R1 together with R 4 forms an optionally 1- or more R 9 substituted 5-membered saturated heterocycle. In some embodiments, R 1 together with R 4 forms an optionally 1- or more substituents selected from C 1-3 alkyl and C 1-3 haloalkyl substituted 5-membered saturated heterocycle.

[0208] In certain embodiments, for a compound or salt of any one of formulas (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. In certain embodiments, R 1 is selected from alkyl, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any one of which may be optionally substituted. In some embodiments, R 1 is selected from optionally substituted saturated C4-C6 cycloalkyl. In certain embodiments, R 1 is selected from: In certain embodiments, R 1 is selected from: In certain embodiments, R 1 is selected from optionally substituted In some embodiments, R 1 is

[0209] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 1 together with R 3 forms a 5- to 10-membered heterocycle or C 5-10 carbocycle, wherein the 5- to 10-membered heterocycle or C 5-10 carbocycle is optionally 1- or more R 9 substituted. In some embodiments, R 1 together with R 3 forms a C 5-10 carbocycle or 5- to 10-membered heterocycle, such as a C 5-6 carbocycle or 5- to 6-membered heterocycle, for example:

[0210]

[0211] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 1 together with R 5Together form a 3- to 10-membered heterocycle or a C 3-10 carbocycle, wherein the 3- to 10-membered heterocycle or C 3-10 carbocycle is optionally substituted by one or more R 9 . In some embodiments, R 1 and R 5 together form a 3- to 10-membered heterocycle or a C 3-10 carbocycle, for example:

[0212]

[0213] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 1 and R 4 together form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted by one or more R 9 . In some embodiments, R 1 and R 4 together form a 3- to 10-membered heterocycle, for example:

[0214]

[0215] In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), each R 1 is independently selected from halogen, -OR 9 , -N(R 10 )(R 10 ), -NO2, =O, -CN; and C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -N(R 10 )(R 1 ), -NO2, =O and -CN. In some embodiments, each R 9 is independently selected from halogen and -OR 10 ; and C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen and -OR 10 . In some embodiments, each R 1 is independently selected from -CH3, -CF3 and =O. 9 In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R

[0216] is an optionally substituted 5-membered heteroaryl, 6-membered heteroaryl or 9-membered bicyclic heterocycle. In some embodiments, R 2 ​2 is an optionally substituted 5 - membered heteroaryl. In certain embodiments, R 2 is an optionally substituted 5 - membered heteroaryl and has at least one inner ring nitrogen or oxygen atom in said 5 - membered heteroaryl, for example, oxazole, isoxazole, thiazole, pyrrole, pyrazole, furan, dioxazole, triazole, imidazole, oxadiazole, thiadiazole, isoxazole, isothiazole, and tetrazole. In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is selected from:

[0217] any one of which is optionally substituted. In some embodiments, R 2 is selected from:

[0218] any one of which is optionally substituted. In some embodiments, R 2 is selected from:

[0219] any one of which is optionally substituted. In some embodiments, R 2 is selected from: any one of which is optionally substituted.

[0220] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is selected from an optionally substituted 5 - or 6 - membered monocyclic heteroaryl and an optionally substituted 9 - membered bicyclic heteroaryl. In some embodiments, R 2 is selected from 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 one of which is optionally substituted. In some embodiments, R 2 is selected from isoxazole, oxazole, thiadiazole, triazole, tetrazole, pyrazole, oxadiazole, thiazole, pyridine, pyridazine, pyrazine, benzoxazole, indazole, and imidazopyridine, any one of which is optionally substituted. In some embodiments, R 2 at any ortho - position relative to the point of attachment to the rest of the molecule on R 2 is unsubstituted. In some embodiments, R 2 at any ortho - position on R 2 is not substituted by a carbocyclic or heterocyclic ring. In some embodiments, R2 Selected from isoxazole, oxazole, thiadiazole, triazole, tetrazole, pyrazole, oxadiazole, thiazole, isoxazole, thiadiazole, any one of which is optionally substituted. In some embodiments, R 2 Selected from isoxazole, oxazole, thiadiazole, pyrazole, oxadiazole, thiazole, isoxazole, thiadiazole, any one of which is optionally substituted.

[0221] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2 The substituents on are independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; and optionally substituted C 3-10 carbocycle. In some embodiments, R 2 is heteroaryl, for example, a 5-membered heteroaryl, which is optionally substituted by one or more substituents selected from halogen, -OR 10 and -N(R 10 )2; C 1-4 alkyl, which is optionally substituted by 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.

[0222] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is selected from:

[0223]

[0224] Any one of which is optionally substituted. In some embodiments, R 2 is selected from:

[0225] Any one of which is optionally substituted. In some embodiments, R 2 is selected from:

[0226] Any one of them is optionally substituted.

[0227] In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is selected from optionally substituted 6-membered heteroaryl. In some embodiments, R 2 may be selected from 6-membered heteroaryl such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, and their N-oxides. In some embodiments, R 2 is selected from optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl N-oxide, and optionally substituted pyrimidinyl N-oxide. In some embodiments, R 2 is selected from optionally substituted pyridinyl and optionally substituted pyrimidinyl. In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is 6-membered heteroaryl, for example, pyridinyl or pyrimidinyl, which is optionally substituted with the following groups: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; optionally substituted C 10 alkyl by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 1-6 )2, -NO2, and -CN; and optionally substituted C 3-10 carbocycle. In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is 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 with one or more substituents independently selected from halogen and -OR 10 . In some embodiments, R 2 is selected from:

[0228] In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), (Id), R 2Selected from optionally substituted pyridine, optionally substituted pyrazine, optionally substituted pyridazine, and optionally substituted pyrimidine. In some embodiments, R 2 is selected from any one of which is optionally substituted by one or more substituents independently selected from the following: halogen, -OR 10 , -SR 10 , -CN, and the substituent on the nitrogen atom of pyridyl is optionally selected from –O - ; and C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen and -OR 10 . In some embodiments, R 2 is selected from:

[0229]

[0230] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is selected from optionally substituted bicyclic heteroaryl. In some embodiments, R 2 is selected from optionally substituted 9-membered bicyclic heteroaryl, for example, optionally substituted benzoxazole, benzothiazole, or benzimidazole. In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is a 9-membered bicyclic heteroaryl, for example, benzoxazole, which is optionally substituted by the following groups: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and optionally substituted C 3-10 carbocycle. In some embodiments, R 2 is selected from optionally substituted benzoxazole. In some embodiments, R 2 is selected from:

[0231] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is selected from optionally substituted 9-membered bicyclic heteroaryl. In some embodiments, R 2Selected from benzoxazole, benzothiazole, benzimidazole, indole, indazole and imidazopyridine, any one of which is optionally substituted. In some embodiments, R 2 Selected from benzoxazole, benzothiazole, indole, indazole and imidazopyridine, any one of which is optionally substituted. In some embodiments, R 2 Selected from benzoxazole, indazole and imidazopyridine, any one of which is optionally substituted. In some embodiments, R 2 Selected from optionally substituted benzoxazole.

[0232] In some embodiments, R 2 Selected from: Any one of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 and -CN. In some embodiments, R 2 Selected from:

[0233] In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), when R 2 is substituted at one or two ortho positions of the heteroaryl ring relative to the point of attachment to the rest of the molecule, each ortho substituent on R 2 is independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN and C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN. In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), when R 2 is substituted at one or two ortho positions of the heteroaryl ring relative to the point of attachment to the rest of the molecule, each ortho substituent on R 2 is independently selected from halogen, –OH, -OCH3, -OCF3 and C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen.

[0234] In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2It is unsubstituted at any ortho position of the heteroaryl ring relative to the point of attachment to the rest of the molecule. In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 2 is not substituted by a heterocyclic or carbocyclic ring at any ortho position of the heteroaryl ring relative to the point of attachment to the rest of the molecule.

[0235] In certain embodiments, for a compound or salt of formula (I), each R 3 is 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 substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN. In some embodiments, R 3 and R 1 together form a 5- to 6-membered heterocyclic or C 5-6 carbocyclic ring, wherein the 5- to 6-membered heterocyclic or C 5-6 carbocyclic ring is optionally substituted by one or more R 9 . In some embodiments, R 3 is hydrogen.

[0236] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), R 4 is independently selected from hydrogen; and C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; or R 4 and R 1 together form a 3- to 10-membered heterocyclic ring, which is optionally substituted by one or more R 9 . In some embodiments, R 4 is hydrogen.

[0237] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), each R 5 and R 6 is independently selected from hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and C 1-6An alkyl group, optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN.

[0238] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), each R 7 and R 8 is independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN. In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), each R 7 and R 8 is independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and C 2-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN.

[0239] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), each R 9 is 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, where each is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN. In some embodiments, R 9 is halogen. In some embodiments, R 9is an unsubstituted C 1-3 alkyl. In some embodiments, R 9 is ═O. In some embodiments, R 9 is haloalkyl. In some embodiments, R 9 is a C 1-3 alkyl substituted with one or more fluorine substituents.

[0240] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), each R 10 is independently selected from hydrogen; and C 1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, ═O, ═S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, ═O, ═S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and haloalkyl.

[0241] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), n is 0.

[0242] In certain embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), (Id), p is 0.

[0243] In one aspect, compounds represented by formula (Ie) are disclosed herein:

[0244]

[0245] or a salt thereof, wherein:

[0246] X is independently selected from C(R 3 ) and N;

[0247] R 1 is selected from

[0248] C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, -OH, -SH, -NH2, -NO2, -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 ;

[0249] R 2 is heteroaryl, for example, a 5-, 6- or 9-membered heteroaryl, optionally substituted by one or more substituents independently selected from the following

[0250] halogen, -OR 10 -SR 10 -N(R 10 )2, -NO2 and -CN; C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, -OR 10 -SR 10 -N(R 10 )2, -NO2, -CN; and

[0251] optionally substituted by one or more R 9 substituted C 3-10 carbocyclic ring;

[0252] each R 9 is independently selected from

[0253] halogen, -OR 10 -SR 10 -N(R 10 )2, -NO2, -CN; and

[0254] C 1-3 alkyl, optionally substituted by one or more substituents independently selected from halogen, -OR 10 -SR 10 -N(R 10 )2, -NO2 and -CN; and

[0255] each R 10 is independently selected from

[0256] hydrogen; and

[0257] C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, -O-C 1-6 alkyl, -N(C 1-6 alkyl)2 and -NH(C1-6 substituted by a substituent of (alkyl).

[0258] In certain embodiments, for a compound or salt of any one of Formulas (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: or a salt thereof.

[0259] In certain embodiments, for a compound or salt of Formula (I):

[0260] each X is N or N + (-O - ), preferably each X is N;

[0261] A is selected from -O-, -NR 4 -, or -CR 5 R 6 -, preferably A is –O-;

[0262] R 1 is selected from C 1-5 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , C 3-5 carbocyclic ring and 3- to 5-membered heterocyclic ring, wherein the C 3-5 carbocyclic ring and 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 , preferably R 1 is selected from C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen;

[0263] R 2 is selected from optionally substituted 5- or 6-membered monocyclic heteroaryl and optionally substituted 9-membered bicyclic heteroaryl, preferably R 2 is selected from optionally substituted 6-membered heteroaryl, wherein the substituents on R 2 are independently selected from halogen, -OR 10 , -SR 10 , -CN, C 1-3 alkyl and C 1-3 haloalkyl;

[0264] R 7 and R 8 are independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN and C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen; n is 0 or 1; and

[0265] p is 0 or 1.

[0266] In certain embodiments, the compounds of the present disclosure are selected from the compounds of Table 1 or salts thereof.

[0267] In one aspect, compounds represented by Formula (II) are disclosed herein:

[0268]

[0269] or salts thereof, wherein:

[0270] T is selected from -O-, -NR 14 -, -CR 15 R 16 -, -C(O)-, -S-, -S(O)- and -S(O)2;

[0271] R 11 is selected from:

[0272] C 1-5 haloalkyl, which is optionally further substituted by one or more substituents independently selected from: -OR 20 , -SR 20 , -N(R 20 )2, -NO2, =O, =S, -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 ;

[0273] 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, the substituent on the nitrogen atom of the pyridyl or pyrimidinyl is optionally further selected from –O - ;

[0274] C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of 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 ), -CN, C 3-10 carbocyclic ring and the substituents of 3- to 10-membered heterocyclic rings, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 19 ; and

[0275] C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of which is optionally substituted by one or more -R 19 ;

[0276] Each R 15 and R 16 is 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 substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2 and -CN;

[0277] R 14 is independently selected from hydrogen and C 1-6An alkyl group, optionally substituted by one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2 and -CN;

[0278] Each R 17 and R 18 is independently selected from:

[0279] Halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN and C 1-6 An alkyl group, optionally substituted by one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2 and -CN;

[0280] Each R 19 is independently selected from:

[0281] 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

[0282] C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, each of 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 substituents;

[0283] Each R 20 is independently selected from:

[0284] hydrogen; and

[0285] C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle; and

[0286] C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle and haloalkyl;

[0287] w is 0, 1 or 2; and

[0288] z is 0, 1 or 2.

[0289] In certain embodiments, for the compounds or salts of formula (II), T is selected from -O-, -NR 14 -, and -CR15 R 16 -。In some embodiments, T is -O-.

[0290] In certain embodiments, for the compound or salt of formula (II), R 11 is selected from C optionally further substituted with one or more substituents independently selected from the following 1-5 haloalkyl: -OH, -SH, -NH2, -NO2, =O, =S, -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 19 . In some embodiments, R 11 is selected from C optionally further substituted with one or more substituents independently selected from the following 1-3 haloalkyl: -OR 20 , -SR 20 , -N(R 20 )2, =O, -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring. In certain embodiments, R 11 is C alkyl substituted with one or more halogen substituents 1-3 . In some embodiments, R 11 is -CHF2 or -CH2CF3.

[0291] 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. In certain embodiments, R 11 is selected from alkyl, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any one of which may be optionally substituted. In certain embodiments, R 11 is selected from: In certain embodiments, R 11 is selected from: In certain embodiments, R 11 is selected from optionally substituted

[0292] In some embodiments, for the compound of formula (II), R 12 is optionally substituted 5-membered heteroaryl, 6-membered heteroaryl or 9-membered bicyclic heterocycle. In some embodiments, R 12 is optionally substituted 5-membered heteroaryl. In certain embodiments, R 12is an optionally substituted 5-membered heteroaryl, and at least one of the inner ring nitrogen or oxygen atoms in the 5-membered heteroaryl, for example, oxazole, thiazole, pyrrole, pyrazole, furan, dioxazole, triazole, imidazole, oxadiazole, thiadiazole, isoxazole, isothiazole, and tetrazole. In certain embodiments, for the compound or salt of formula (II), R 12 is selected from:

[0293] any one of which is optionally substituted. In some embodiments, R 12 is selected from:

[0294] any one of which is optionally substituted. In some embodiments, R 12 is selected from:

[0295] any one of which is optionally substituted. In some embodiments, R 12 is selected from:

[0296] any one of which is optionally substituted. In some embodiments, R 12 is selected from:

[0297] In some embodiments, R 12 is selected from an optionally substituted 5- or 6-membered monocyclic heteroaryl and an optionally substituted 9-membered bicyclic heteroaryl. In some embodiments, R 12 is selected from 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 one of which is optionally substituted. In some embodiments, R 12 is selected from isoxazole, oxazole, thiadiazole, triazole, pyrazole, imidazole, oxadiazole, thiazole, pyridine, pyrimidine, benzoxazole, benzimidazole, any one of which is optionally substituted. In some embodiments, R 12 is selected from isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole, thiazole, pyridine, benzoxazole, any one of which is optionally substituted. In some embodiments, R 12 wherein in R 12is unsubstituted at any ortho position relative to the point of attachment to the remainder of the molecule. In some embodiments, R 12 at any ortho position of R 12 is not substituted by a carbocyclic or heterocyclic ring. In some embodiments, R 12 is selected from isoxazole, oxazole, thiadiazole, oxadiazole, pyrazole, tetrazole, and thiazole, any of which is optionally substituted.

[0298] In certain embodiments, for the compounds of formula (II), the substituents on R 12 are independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 ) 2、 -NO2 and -CN; C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 20 , -SR 10 , -N(R 20 )2, -NO2 and -CN; and optionally substituted C 3-10 carbocycle. In some embodiments, R 2 is heteroaryl, for example, 5-membered heteroaryl, which is optionally substituted by one or more substituents selected from halogen, -OR 10 and -N(R 20 )2; C 1-4 alkyl, which is optionally substituted by 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.

[0299] In certain embodiments, for the compounds or salts of formula (II), R 12 is selected from:

[0300] any of which is optionally substituted. In some embodiments, R 12 is selected from: any of which is optionally substituted.

[0301] In certain embodiments, for the compounds or salts of formula (II), R 12 is selected from optionally substituted 6-membered heteroaryl. In some embodiments, R 12may be selected from 6-membered heteroaryls such as pyridine, pyridazine, pyrimidine, pyrazine, triazine, and their N-oxides. In some embodiments, R 12 is selected from optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyridyl N-oxide, and optionally substituted pyrimidinyl N-oxide. In some embodiments, R 12 is selected from optionally substituted pyridyl and optionally substituted pyrimidinyl. In certain embodiments, for a compound or salt of formula (II), R 12 is a 6-membered heteroaryl, for example, pyridyl or pyrimidinyl, 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 substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN; and optionally substituted C 3-10 carbocycle. In certain embodiments, for a compound or salt of formula (II), R 12 is a 6-membered heteroaryl, for example, pyridyl or pyrimidinyl, which is optionally substituted by halogen, -OR 20 , -SR 20 , and -N(R 20 )2; and C 1-4 alkyl, which is optionally substituted by one or more substituents independently selected from halogen and –OR 20 . In some embodiments, R 12 is selected from:

[0302] In some embodiments, R 12 is selected from pyridine and pyrimidine, either of which is optionally substituted. In some embodiments, R 12 is selected from: either of which is optionally substituted.

[0303] In some embodiments, R 12 is selected from optionally substituted benzoxazole. In some embodiments, R 12 is optionally substituted

[0304] In certain embodiments, for a compound or salt of formula (II), R 12 is selected from optionally substituted bicyclic heteroaryl. In some embodiments, R 12Selected from optionally substituted 9-membered bicyclic heteroaryl, for example, optionally substituted benzoxazole, benzothiazole or benzimidazole. In certain embodiments, for the compound or salt of formula (II), R 12 is 9-membered bicyclic heteroaryl, for example, benzoxazole, which is optionally substituted with the following groups: halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2 and -CN; C 1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2 and -CN; and optionally substituted C 3-10 carbocycle. In some embodiments, R 12 is selected from optionally substituted benzoxazole. In some embodiments, R 12 is selected from

[0305] In some embodiments, for the compound or salt of formula (II), when R 12 is substituted at one or two ortho positions of the heteroaryl ring relative to the point of attachment to the rest of the molecule, each ortho substituent on R 12 is independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN and C 1-3 alkyl, which is optionally substituted with one or more substituents 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 is substituted at one or two ortho positions of the heteroaryl ring relative to the point of attachment to the rest of the molecule, each ortho substituent on R 12 is independently selected from halogen, –OH, -OCH3, -OCF3 and C 1-3 alkyl, which is optionally substituted with one or more substituents independently selected from halogen.

[0306] In some embodiments, for the compound or salt of formula (II), R 12 is not substituted at any ortho position of the heteroaryl ring relative to the point of attachment to the rest of the molecule. In some embodiments, for the compound or salt of formula (II), R 12 is not substituted with a heterocycle or carbocycle at any ortho position of the heteroaryl ring relative to the point of attachment to the rest of the molecule.

[0307] In certain embodiments, for a compound of formula (II), R 14 is independently selected from hydrogen; and C 1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN. In some embodiments, R 14 is hydrogen.

[0308] In certain embodiments, for a compound of formula (II), each R 15 and R 16 is independently selected from hydrogen, halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, and C 1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN.

[0309] In certain embodiments, for a compound of formula (II), each R 17 and R 18 is 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 with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN. In certain embodiments, for a compound of formula (II), each R 17 and R 18 is independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, and C 1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN.

[0310] In certain embodiments, for the compounds of formula (II), each R 19 is 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, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN. In some embodiments, R 19 is halogen. In some embodiments, R 19 is unsubstituted C 1-3 alkyl. In some embodiments, R 19 is =O. In some embodiments, R 19 is haloalkyl. In some embodiments, R 19 is C 1-3 alkyl substituted with one or more fluorine substituents.

[0311] In certain embodiments, for the compounds of formula (II), each R 20 is independently selected from hydrogen; and C 1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle; and C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein each is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 3-10 carbocycle, 3- to 10-membered heterocycle and haloalkyl. In some embodiments, R 20 is C 1-2 alkyl substituted with a 4- to 6-membered heterocycle. In some embodiments, R 20 is hydrogen.

[0312] In certain embodiments, for a compound of formula (II), w is 0.

[0313] In certain embodiments, for a compound of formula (II), z is 0.

[0314] In one aspect, the present disclosure provides a compound represented by formula (IIa)

[0315]

[0316] or a salt thereof, wherein

[0317] R 11 is selected from:

[0318] C 1-5 haloalkyl, which is optionally further substituted with one or more substituents independently selected from: -OH, -SH, -NH2, -NO2, -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted with one or more R 19 ;

[0319] R 12 is heteroaryl, for example, 5-, 6- or 9-membered heteroaryl, which is optionally substituted with one or more substituents independently selected from:

[0320] halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN; and

[0321] C 19 carbocyclic ring optionally substituted with one or more -R 3-10 ;

[0322] each R 19 is independently selected from:

[0323] halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN; and

[0324] C 1-3 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2 and -CN; and

[0325] each R 20 is independently selected from:

[0326] hydrogen; and

[0327] C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, ═O, ═S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2 and -NH(C 1-6 alkyl). In certain embodiments, for a compound or salt of any 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.

[0328] In certain embodiments, the compounds of the present disclosure are selected from the compounds of Table 2 or a salt thereof.

[0329] A chemical entity having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in the Z- or E-form (or cis- or trans-form). 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.

[0330] "Tautomers" refer to molecules in which the movement of a proton from one atom of the molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In cases where tautomerism can occur, there will be a chemical equilibrium of tautomers. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0331]

[0332] In some embodiments, the compounds disclosed herein are used in different enriched isotope forms, for example, in forms enriched in 2 H, 3 H, 11 C, 13 C and / or 14 C content. In one particular 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.

[0333] Unless otherwise indicated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure except that hydrogen is replaced by deuterium or tritium or carbon is replaced by 13 C- or 14 C-enriched carbon are also within the scope of the present disclosure.

[0334] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that make up such compounds. For example, isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C) can be used to label compounds. Substitution with 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 I is contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0335] In certain embodiments, some or all of the 1 H atoms of the compounds disclosed herein are replaced by 2 H atoms. Methods for synthesizing deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0336] A variety of methods are used to synthesize deuterium-substituted compounds, such methods being described, for example, 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, Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0337] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0338] 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 polymophs, and amorphous forms of the compounds, as well as mixtures thereof.

[0339] This disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of this disclosure having sufficient acidity, sufficient basicity, 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 bearing a quaternary nitrogen, can form salts with suitable counterions, such as halides, e.g., bromide, chloride, or fluoride, particularly bromide.

[0340] 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 their appropriate mixtures. Separation of stereoisomers can be carried out by chromatography or by forming diastereomers and separating them by recrystallization or chromatography or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0341] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, the active metabolites of these compounds having the same type of activity are also included within the scope of the present disclosure. Additionally, the compounds described herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and other solvents. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0342] In certain embodiments, the compound or a salt of the compound may be a prodrug, for example, wherein a hydroxyl group in the parent compound is presented in the form of an ester or a carbonate, or a carboxylic acid present in the parent compound is presented in the form of an ester. The term “prodrug” is intended to cover compounds that are converted into the agents disclosed herein under physiological conditions. A method for preparing a prodrug includes one or more selected moieties that are hydrolyzed under physiological conditions to expose the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal, for example, by specific target cells in the host animal. For example, esters or carbonates (such as esters of alcohols or carboxylic acids and carbonates and esters of phosphoric acid) are preferred prodrugs of the present disclosure.

[0343] Prodrug forms of the compounds described herein, wherein the prodrug metabolizes in vivo to produce the compounds set forth herein, are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0344] Prodrugs are often useful because in some cases, a prodrug may be more readily administered than the parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs can help enhance the cellular permeability of a compound relative to the parent drug. Prodrugs may also have improved solubility in a pharmaceutical composition compared to the parent drug. Prodrugs can be designed as reversible drug derivatives that serve as modifiers to enhance the transport of a drug to a site-specific tissue or increase the residence time of a drug within a cell.

[0345] In some embodiments, the prodrug is designed to increase the lipophilicity of the agent. In some embodiments, the prodrug is designed to increase the effective water 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, A.C.S. Symposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, the disclosures of which are incorporated herein by reference. 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.

[0346] Synthetic chemical transformations and methodologies useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 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).

[0347] Therapeutic applications

[0348] The methods of administering the compounds or salts 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 type 1, myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb-girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome. Examples of movement disorders include, but are not limited to, muscle spasm 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 chain, skeletal myosin-binding protein C, or skeletal actin.

[0349] In some embodiments, methods of treating neuromuscular and movement disorders by administering a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), or (IIa) are disclosed herein. In some embodiments, methods of treating neuromuscular and movement disorders by administering a compound or salt of formula (III) are disclosed herein:

[0350]

[0351] or a salt thereof, wherein:

[0352] Each Y is independently selected from C(R 3 ), N, and N +(-O - );

[0353] A is selected from -O-, -NR 4 -, -CR 5 R 6 (-), -C(O)-, -S-, -S(O)- and -S(O)2-;

[0354] R 1 is selected from:

[0355] C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of 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 (-), -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 ring and substituents of 3- to 10-membered heterocyclic rings, wherein each of the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring is optionally substituted by one or more R 9 ; and

[0356] C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of 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(R10 )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 substituents; or

[0357] R 1 together with R 3 forms a 5 - to 10 - membered heterocycle or a C 5-10 carbocycle, wherein the 5 - to 10 - membered heterocycle or C 5-10 carbocycle is optionally substituted by one or more R 9 ; or R 1 together with R 5 forms a 3 - to 10 - membered heterocycle or a C 3-10 carbocycle, wherein the 3 - to 10 - membered heterocycle or C 3-10 carbocycle is optionally substituted by one or more R 9 ; or R 1 together with R 4 forms a 3 - to 10 - membered heterocycle, wherein the 3 - to 10 - membered heterocycle is optionally substituted by one or more R 9 ;

[0358] R 2 is a heteroaryl, which is optionally substituted by one or more substituents independently selected from the following: 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 a pyridyl or pyrimidinyl, the substituent on the nitrogen atom of the pyridyl or pyrimidinyl is optionally further selected from -O - ;

[0359] C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of 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 ), -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring substituents, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 ; and

[0360] C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of which is optionally substituted by one or more R 9 ;

[0361] Each R 3 , R 5 and R 6 are independently selected from:

[0362] 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 substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; or

[0363] R 3 and R 1 together form a 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring, wherein said 5- to 10-membered heterocyclic ring or C 5-10The carbocyclic ring is optionally substituted by one or more R 9 ; R 5 together with R 1 forms a 3- to 10-membered heterocyclic ring or a C 3-10 carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or the C 3-10 carbocyclic ring is optionally substituted by one or more R 9 ;

[0364] R 4 is independently selected from:

[0365] hydrogen; and

[0366] C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; or R 4 together with R 1 forms a 3- to 10-membered heterocyclic ring, which is optionally substituted by one or more R 9 ;

[0367] Each R 7 and R 8 is independently selected from:

[0368] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN and C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN;

[0369] Each R 9 is independently selected from:

[0370] 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

[0371] C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, each of 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 , -

[0372] S(O)₂R 10 , -NO₂, =O, =S, =N(R 10 ) and -CN;

[0373] Each R 10 is independently selected from:

[0374] hydrogen; and

[0375] C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO₂, -NH₂, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)₂, -NH(C 1-6 alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle; and

[0376] C 3-10Carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic rings, 3- to 10-membered heterocyclic rings, and haloalkyl;

[0377] n is 0, 1, or 2; and

[0378] p is 0, 1, or 2.

[0379] In certain embodiments, the present disclosure provides a method for treating activity-induced muscle injury, which comprises administering to a subject in need a compound or salt of formula (III’):

[0380]

[0381] or a salt thereof, wherein:

[0382] Each Y is independently selected from C(R 3 ), N, and N + (-O - );

[0383] A is absent or selected from -O-, -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)-, and -S(O)2-;

[0384] R 1 is selected from:

[0385] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with 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 ), -CN, C 3-10 carbon ring and 3- to 10-membered heterocyclic ring, which are each optionally substituted by one or more R 3-10 ; and 9 ; and

[0386] C 3-10 carbon ring and 3- to 10-membered heterocyclic ring, 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 substituents; or

[0387] R 1 together with R 3 forms a 5- to 10-membered heterocyclic ring or a C 5-10 carbon ring, where the 5- to 10-membered heterocyclic ring or C 5-10 carbon ring is optionally substituted by one or more R 9 ; or R 1 together with R 5 forms a 3- to 10-membered heterocyclic ring or a saturated C 3-10 carbon ring, where the 3- to 10-membered heterocyclic ring or saturated C 3-10 carbon ring is optionally substituted by one or more R 9 ; or R 1 together with R 4Together form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted by one or more R 9 ; and

[0388] When A is -NR 4 -, R 1 is further selected from hydrogen, and when A is -C(O)-, R 1 is further selected from -N(R 10 )2 and -OR 10 ;

[0389] When A is absent, R 1 is 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;

[0390] R 2 is a heteroaryl optionally substituted by one or more substituents independently selected from:

[0391] 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 a pyridyl or pyrimidinyl group, the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O - ;

[0392] 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 carbocyclic ring and substituents of 3- to 10-membered heterocyclic rings, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 ; and

[0393] C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of which is optionally substituted by one or more R 9 ;

[0394] Each R 3 , R 5 and R 6 is independently selected from:

[0395] 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. Substituted by substituents of -NO2 and -CN; or

[0396] R 3 Together with R 1 forms a 5- to 10-membered heterocycle or C 5-10 carbocycle, wherein the 5- to 10-membered heterocycle or C 5-10 carbocycle is optionally substituted by one or more R 9 ; R 5 Together with R 1 forms a 3- to 10-membered heterocycle or C 3-10 carbocycle, wherein the 3- to 10-membered heterocycle or C 3-10 carbocycle is optionally substituted by one or more R 9 ;

[0397] R 4 is independently selected from:

[0398] hydrogen; and

[0399] C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; or R 4 Together with R 1 forms a 3- to 10-membered heterocycle, which is optionally substituted by one or more R 9 ;

[0400] Each R 7 and R 8 is independently selected from

[0401] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN and C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN;

[0402] Each R 9 is independently selected from

[0403] 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

[0404] 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 substituents;

[0405] Each R 10 Independently selected from

[0406] Hydrogen; and

[0407] 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), C3-10 substituted by substituents on a carbocyclic ring or a 3- to 10-membered heterocyclic ring; and

[0408] C 3-10 a carbocyclic ring and a 3- to 10-membered heterocyclic ring, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 a carbocyclic ring, a 3- to 10-membered heterocyclic ring and a haloalkyl;

[0409] R 30 and R 31 are independently selected from R 10 or R 30 and R 31 together form a C 3-7 carbocyclic ring, wherein the 3- to 7-membered heterocyclic ring, wherein C 3-7 the carbocyclic ring and the 3- to 7-membered heterocyclic ring are optionally substituted by R 9 substituted;

[0410] n is 0, 1 or 2; and

[0411] p is 0, 1 or 2.

[0412] In certain embodiments, for a compound or salt of formula (III) or (III’), each Y is independently selected from C(R 3 ) and N, where 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 a compound or salt of formula (III) or (III’), each Y is further selected from C(R 3 ).

[0413] In certain embodiments, for a compound or salt 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-.

[0414] In certain embodiments, for a compound or salt of formula (III) or (III’), R 1 is C 1-6 alkyl, 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 , -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 substituents, wherein said C 3-10 carbocyclic and 3- to 10-membered heterocyclic are each optionally substituted by one or more R 9 . In some embodiments, R 1 is C 1-6 alkyl 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 、 -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 carbocyclic rings and 3- to 10-membered heterocyclic rings, wherein said C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 9 . In some embodiments, R 1 is a C 1-6 alkyl group substituted with one or more substituents independently selected from the following: 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 rings and 3- to 10-membered heterocyclic rings, wherein said C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 9 . In some embodiments, R 1 is selected from C 1-3 alkyl groups, which are optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, wherein said C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 9 . In some embodiments, R 1 is a C 1-3 alkyl group substituted with one or more substituents independently selected from the following: halogen, -OR 10 , -N(R 10 )2, -NO2, =O, -CN, C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, wherein said C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 9 . In some embodiments, R 1 is a C 1-3 alkyl group substituted with one or more halogen substituents. In some embodiments, R 1 is C 1-3fluoroalkyl. In some embodiments, R 1 is selected from -CHF2 and -CH2CF3.

[0415] In certain embodiments, for a compound or salt of formula (III) or (III’), R 1 is selected from optionally substituted C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiropentyl, any of which is optionally substituted. In certain embodiments, R 1 is selected from alkyl, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may be optionally substituted. In certain embodiments, R 1 is selected from: In certain embodiments, R 1 is selected from optionally substituted

[0416] In certain embodiments, for a compound or salt of formula (III) or (III’), R 1 together with R 3 forms a 5- to 10-membered heterocycle or a C 5-10 carbocycle, wherein the 5- to 10-membered heterocycle or C 5-10 carbocycle is optionally substituted by one or more R 9 In some embodiments, R 1 together with R 3 forms a C 5-10 carbocycle or a 5- to 10-membered heterocycle, such as a C 5-6 carbocycle or a 5- to 6-membered heterocycle, for example:

[0417]

[0418] In certain embodiments, for a compound or salt of formula (III) or (III’), R 1 together with R 5 forms a 3- to 10-membered heterocycle or a C 3-10 carbocycle, wherein the 3- to 10-membered heterocycle or C 3-10 carbocycle is optionally substituted by one or more R 9 In some embodiments, R 1 together with R 5 forms a 3- to 10-membered heterocycle or a C 3-10 carbocycle, for example:

[0419]

[0420] In certain embodiments, for a compound or salt of formula (III) or (III’), R 1 together with R 4Together form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted by one or more R 9 substituents. In some embodiments, R 1 and R 4 together form a 3- to 10-membered heterocycle, such as:

[0421]

[0422] In some embodiments, for the compounds or salts of formula (III) or (III’), R 2 is an optionally substituted 5-membered heteroaryl, 6-membered heteroaryl or 9-membered bicyclic heterocycle. In some embodiments, R 2 is an optionally substituted 5-membered heteroaryl. In certain embodiments, R 2 is an optionally substituted 5-membered heteroaryl, and at least one inner ring nitrogen or oxygen atom in the 5-membered heteroaryl, for example, oxazole, isoxazole, thiazole, pyrrole, pyrazole, furan, dioxazole, triazole, imidazole, oxadiazole, thiadiazole, isoxazole, isothiazole and tetrazole. In certain embodiments, for the compounds or salts of formula (III) or (III’), R 2 is selected from: Any one of which is optionally substituted. In some embodiments, R 2 is selected from:

[0423] Any one of which is optionally substituted. In some embodiments, R 2 is selected from: Any one of which is optionally substituted.

[0424] In certain embodiments, for the compounds or salts of formula (III) or (III’), the substituents on R 2 are independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; and an optionally substituted C 3-10 carbocycle. In some embodiments, R2 is a heteroaryl, for example, a 5-membered heteroaryl, which is optionally substituted with one or more substituents selected from halogen, -OR 10 and -N(R 10 )2; C 1-4 alkyl, which is 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.

[0425] In certain embodiments, for a compound or salt of formula (III) or (III’), R 2 is selected from:

[0426] any one of which is optionally substituted. In some embodiments, R 2 is selected from: any one of which is optionally substituted.

[0427] In certain embodiments, for a compound or salt of formula (III) or (III’), R 2 is selected from optionally substituted 6-membered heteroaryl. In some embodiments, R 2 may be selected from 6-membered heteroaryl such as pyridine, pyridazine, pyrimidine, pyrazine, triazine and their N-oxides. In some embodiments, R 2 is selected from optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyridyl N-oxide and optionally substituted pyrimidinyl N-oxide. In some embodiments, R 2 is selected from optionally substituted pyridyl and optionally substituted pyrimidinyl. In certain embodiments, for a compound or salt of formula (III) or (III’), R 2 is a 6-membered heteroaryl, for example, pyridyl or pyrimidinyl, optionally substituted with the following groups: halogen, -OR 10 , -SR 10 , -N(R 10 ) 2、 -NO2 and -CN; C 1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; and optionally substituted C 3-10Carbocyclic ring. In certain embodiments, for a compound or salt of formula (III) or (III’), R 2 is a 6-membered heteroaryl, e.g., pyridyl or pyrimidinyl, optionally substituted with halogen, -OR 10 , -SR 10 and -N(R 10 )2; and C 1-4 alkyl, optionally substituted with one or more substituents independently selected from halogen and -OR 10 . In some embodiments, R 2 is selected from:

[0428] In certain embodiments, for a compound or salt of formula (III) or (III’), R 2 is selected from optionally substituted bicyclic heteroaryl. In some embodiments, R 2 is selected from optionally substituted 9-membered bicyclic heteroaryl, e.g., 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, e.g., benzoxazole, optionally substituted with halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN; and optionally substituted C 3-10 carbocyclic ring. In some embodiments, R 2 is selected from optionally substituted benzoxazole. In some embodiments, R 2 is selected from:

[0429] In certain embodiments, for a compound or salt of formula (III) or (III’), each R 3 is selected from hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN and C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2 and -CN. In some embodiments, R3 Together with R 1 forms a 5- to 6-membered heterocycle or a C 5-6 carbocycle, wherein the 5- to 6-membered heterocycle or C 5-6 carbocycle is optionally substituted by one or more R 9 . In some embodiments, R 3 is hydrogen.

[0430] In certain embodiments, for a compound or salt of formula (III) or (III’), R 4 is independently selected from hydrogen; and C 1-6 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; or R 4 together with R 1 forms a 3- to 10-membered heterocycle, which is optionally substituted by one or more R 9 . In some embodiments, R 4 is hydrogen.

[0431] In certain embodiments, for a compound or salt of formula (III) or (III’), each R 5 and R 6 is 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 substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN.

[0432] In certain embodiments, for a compound or salt of formula (III) or (III’), each R 7 and R 8 is 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 substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN. In certain embodiments, for a compound or salt of formula (III) or (III’), each R 7 and R8 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 with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN.

[0433] In certain embodiments, for a compound or salt of formula (III) or (III’), each R 9 is 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, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN. In some embodiments, R 9 is halogen. In some embodiments, R 9 is unsubstituted C 1-3 alkyl. In some embodiments, R 9 is =O. In some embodiments, R 9 is haloalkyl. In some embodiments, R 9 is C 1-3 alkyl substituted with one or more fluorine substituents.

[0434] In certain embodiments, for a compound or salt of formula (III) or (III’), each R 10 is independently selected from hydrogen; and C 1-6 alkyl, which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, 3- to 10-membered heterocycle; and C 3-10Carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 3-10 carbocyclic rings, 3- to 10-membered heterocyclic rings, and haloalkyl.

[0435] In certain embodiments, for the compounds or salts of formula (III) or (III’), n is 0.

[0436] In certain embodiments, for the compounds or salts of formula (III) or (III’), p is 0.

[0437] In certain embodiments, for the compounds or salts of formula (III) or (III’), R 1 -A is further selected from hydrogen. For example, the compounds of the present disclosure are represented as: or a salt thereof.

[0438] Methods for treating neuromuscular and motor disorders by reducing skeletal muscle contraction are provided herein. Treating a subject having a neuromuscular and motor disorder with a selective skeletal muscle fast-twitch (type II) myosin inhibitor 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 and uncoordinated muscle contractions, thereby reducing muscle damage. In addition, the methods of the present disclosure can reduce muscle damage while minimizing the impact on the body functions of the subject. Preservation of function can be achieved either by limiting the level of destructive forces generated in type II fibers or by increasing the reliance on the 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.

[0439] In some embodiments, a method of inhibiting muscle myosin II is disclosed herein, which comprises administering to a subject in need thereof a compound or a salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’). 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%.

[0440] In some aspects, a method of treating a neuromuscular condition or a movement disorder may comprise administering a compound or a 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.

[0441] Before and after treatment with a compound or a salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’), the activities of daily living (ADL) or habitual physical activity of the subject can be monitored. The ADL or habitual physical activity depends on the subject and can range from simple walking to extensive exercise according to the subject's ability and routine. The treatment options and dosages of the skeletal muscle contraction inhibitors discussed herein can be personalized for the subject such that the ADL and habitual physical activity remain unchanged.

[0442] In some aspects, a method of treating a neuromuscular disease or a movement disorder can include administering a compound or a salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) to inhibit skeletal muscle contraction. The dosage of the compound or the salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be relative to the amount required to reduce skeletal muscle contraction by 50%. The dosage of the compound or the salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be less than the amount required to reduce skeletal muscle contraction by 50% relative to the pre-treatment skeletal muscle contraction ability of the subject. The compound or the 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 pre-treatment skeletal muscle contraction ability of the subject. In some cases, relative to the pre-treatment skeletal muscle contraction ability of the subject, the dosage of the compound or the salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can reduce 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%. In certain embodiments, the compound or the salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be administered in an amount that reduces skeletal muscle contraction by 1% to 50% relative to the pre-treatment skeletal muscle contraction ability of the subject.

[0443] In some aspects, a method of treating a neuromuscular disease or a movement disorder can include administering a compound or a salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) to inhibit type I skeletal muscle contraction. The dosage of the type I skeletal muscle contraction inhibitor can be relative to the amount required to reduce type I skeletal muscle contraction by 20%. The dosage of the type I skeletal muscle contraction inhibitor can be less than the amount required to reduce type I skeletal muscle contraction by 20% relative to the pre-treatment type I skeletal muscle contraction ability of the subject. The type I skeletal muscle contraction inhibitor can be administered in an amount that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the pre-treatment type I skeletal muscle contraction ability of the subject. In some cases, relative to the pre-treatment type I skeletal muscle contraction ability of the subject, the dosage of the inhibitor 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%. In certain embodiments, the inhibitor can be administered in an amount that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the pre-treatment type I skeletal muscle contraction ability of the subject.

[0444] In some aspects, a method of treating a neuromuscular disease or a movement disorder can include administering a compound or a salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) to inhibit type II skeletal muscle contraction. The dosage of the type II skeletal muscle contraction inhibitor can be relative to the amount required to reduce type II skeletal muscle contraction by 90%. The dosage of the type II skeletal muscle contraction inhibitor can be less than the amount required to reduce type II skeletal muscle contraction by 90% relative to the pre-treatment type II skeletal muscle contraction ability of the subject. The type II skeletal muscle contraction inhibitor can be administered in an amount that reduces type II skeletal muscle contraction by 5% to 75% relative to the pre-treatment type II skeletal muscle contraction ability of the subject. In some cases, relative to the pre-treatment type II skeletal muscle contraction ability of the subject, the dosage of the inhibitor can 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%. In certain embodiments, the inhibitor can be administered in an amount that reduces type II skeletal muscle contraction by 1% to 50% relative to the pre-treatment type II skeletal muscle contraction ability of the subject.

[0445] In some aspects, methods of treating contraction-induced injury in skeletal muscle fibers can include administering a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (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.

[0446] In some aspects, methods of treating metabolic myopathies such as McArdle syndrome can include administering a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III’).

[0447] In certain embodiments, contraction-induced injury in skeletal muscle fibers results from involuntary skeletal muscle contraction. Involuntary skeletal muscle contraction may be associated with neuromuscular diseases or spasticity-related disorders. In certain embodiments, contraction-induced injury in skeletal muscle fibers may result from voluntary skeletal muscle contraction, such as in sports.

[0448] In certain embodiments, administering a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III’) to a subject modulates one or more biomarkers associated with muscle contraction. Examples of biomarkers include, but are not limited to, creatine kinase (CK), troponin T (TnT), troponin C (TnC), troponin I (TnI), pyruvate kinase (PK), lactate dehydrogenase (LDH), myoglobin, isoforms of TnI (e.g., cardiac, slow skeletal muscle, fast skeletal muscle TnI), and inflammatory markers (IL-1, IL-6, IL-4, TNF-α). Biomarkers can also include a measure of muscle inflammation, such as edema. Relative to the pre-treatment levels of the biomarker, the levels of the biomarkers described herein can increase after administration of the inhibitor. Alternatively, relative to the pre-treatment levels of the biomarker, the levels of the biomarker can decrease after administration of the inhibitor. Modulation of one or more biomarkers with the inhibitors described herein can indicate treatment of a neuromuscular disease such as those described herein.

[0449] Compared to when the subject is inactive (e.g., sleeping), the CK level in the subject increases during activity. Thus, CK is a potential metric for assessing skeletal muscle breakdown 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 the subject before mild, moderate, or intense activity to reduce or prevent skeletal muscle breakdown due to activity. Moderate to intense activity may depend on the subject's ability 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 intense activity include walking, running, weightlifting, cycling, swimming, hiking, etc.

[0450] 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 strenuous activity to reduce or prevent breakdown of skeletal muscle due to the activity. Relative to an untreated subject performing the same activity, a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can reduce the CK level in the subject. The CK level can be measured in the peripheral blood of the subject during or after the activity. Relative to an untreated subject performing the same activity, administration of the inhibitor described herein can reduce the CK level in an active subject by 5% to 90%, thereby reducing or preventing breakdown of skeletal muscle due to the activity. Relative to an untreated subject performing the same activity, administration of the inhibitor described herein can modulate the CK level by about 5% to about 90%, thereby reducing or preventing breakdown of skeletal muscle due to the activity. Relative to an untreated subject performing the same activity, administration of the inhibitor described herein can reduce the CK level by at least about 5%, thereby reducing or preventing breakdown of skeletal muscle due to the activity. Relative to an untreated subject performing the same activity, administration of the inhibitor described herein can modulate the CK level by up to about 90%. Relative to an untreated subject performing the same activity, administration of the inhibitor described herein can reduce the CK level by about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 65%, about 45% to about 75%, about 45% to about 85%, about 45% to about 90%, about 55% to about 65%, about 55% to about 75%, about 55% to about 85%, about 55% to about 90%, about 65% to about 75%, about 65% to about 85%, about 65% to about 90%, about 75% to about 85%, about 75% to about 90% or about 85% to about 90%, thereby reducing or preventing breakdown of skeletal muscle due to the 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 untreated subjects performing the same activity, thereby reducing or preventing skeletal muscle breakdown due to activity.

[0451] 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 levels of inflammatory markers, e.g., reduce the levels of one or more inflammatory markers relative to an untreated subject or a subject prior to treatment. The levels 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. The inflammatory marker can also be in the form of a condition such as edema, which can be measured using magnetic resonance imaging. The level of the inflammatory marker in the peripheral blood can increase after administration of an inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Alternatively, the level of the inflammatory marker in the peripheral blood can decrease after administration of an inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Administration of the inhibitors described herein can modulate the levels of inflammatory markers by 5% to 90% relative to the pre-treatment levels of the inflammatory markers in the subject. In some cases, the levels of inflammatory markers can be modulated by about 5% to about 90% relative to the pre-treatment levels of the inflammatory markers in the subject. In some cases, the levels of inflammatory markers can be modulated by at least about 5% relative to the pre-treatment levels of the inflammatory markers in the subject. In some cases, the levels of inflammatory markers can be modulated by at most about 90% relative to the pre-treatment levels of the inflammatory markers in the subject. In some cases, the levels of inflammatory markers can be modulated 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 an inflammatory marker can be adjusted 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 pre-treatment level of the inflammatory marker in a subject.

[0452] 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 troponin I (fS-TnI). The level of fS-TnI can be measured in peripheral blood. Relative to the pre-treatment level of fS-TnI in the subject, the level of fS-TnI in peripheral blood can increase after administration of an inhibitor. Alternatively, relative to the pre-treatment level of fS-TnI in the subject, the level of fS-TnI in peripheral blood can decrease after administration of an inhibitor. Administration of an inhibitor as 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 modulated by at most about 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 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 pre-treatment level of fS-TnI in the subject.

[0453] The isoforms of troponin 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 slow skeletal 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 means that the reduction of cTnI or ssTnI is 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.

[0454] Administration of a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III') can reduce involuntary muscle contractions. The involuntary muscle contractions can be reduced by 20% to 90% relative to the involuntary muscle contractions before administration of the inhibitor. In some cases, the involuntary muscle contractions can be reduced by at least about 20% relative to the involuntary muscle contractions before treatment. In some cases, the involuntary muscle contractions can be reduced by at most about 90% relative to the involuntary muscle contractions before treatment. In some cases, the involuntary muscle contractions can be reduced by about 20% to about 25%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 20% to about 85%, about 20% to about 90%, about 25% to about 30%, about 25% to about 40%, about 25% to about 50%, about 25% to about 70%, about 25% to about 75%, about 25% to about 80%, about 25% to about 85%, about 25% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 30% to about 85%, about 30% to about 90%, about 40% to about 50%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 40% to about 85%, about 40% to about 90%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 50% to about 85%, about 50% to about 90%, about 70% to about 75%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 75% to about 80%, about 75% to about 85%, about 75% to about 90%, about 80% to about 85%, about 80% to about 90% or about 85% to about 90%. In some cases, relative to the involuntary muscle contractions before treatment, the involuntary muscle contractions can be reduced by about 20%, about 25%, about 30%, about 40%, about 50%, about 70%, about 75%, about 80%, about 85% or about 90%.

[0455] Compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be used to improve the activities of daily living (ADL) or habitual physical activity of a subject because mature, functionally intact and undamaged muscles can be restored. Examples of ADL or habitual activities include, but are not limited to, climbing stairs, time to get out of bed, timed chair rises, habitual walking speed, North Star dynamic assessment, incremental / endurance shuttle walk, and 6-minute walk distance test. The level or ability of ADL or habitual physical activity can be measured before and after administration of 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 “not significantly” 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 in 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’). Such measurements can be made to generate a dose-response curve for the compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’). The dose of the 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 the 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 the 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 most about 50% relative to the dose that reduces type II skeletal muscle contraction by 90%.In some cases, the dose of the 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 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 50%, about 35% to about 40%, about 35% to about 50% or about 40% to about 50% relative to the dose that reduces type II skeletal muscle contraction by 90%. 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 the 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 equivalent means.

[0456] The myocardial force or myocardial contractility of a subject can be measured before and after administering 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 means that the myocardial force is reduced by less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5% or even less than 0.1% relative to the myocardial force before administering the inhibitor. The myocardial force or myocardial contractility of a subject after administering a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be within 0.1% to 10% of the myocardial contractility or myocardial force before administering the inhibitor. In some embodiments, administering 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, the myocardial force is reduced by more than 0.1%, more than 0.5%, more than 1%, more than 2%, more than 4%, more than 6%, more than 8% or more than 10%. In some embodiments, the reduction of skeletal muscle contraction and myocardial contraction is described by the ratio of one to the other. For example, in some embodiments, the ratio of the reduction of skeletal muscle contraction to the reduction of myocardial contraction is from about 1:1 to about 100:1, about 2:1 to about 50:1, about 3:1 to about 40:1, about 4:1 to about 30:1, about 5:1 to about 20:1, about 7:1 to about 15:1 or about 8:1 to about 12:1. Echocardiography (fractional shortening) or other equivalent tests can be used to measure myocardial force or myocardial contractility.

[0457] The tidal volume in the lungs of a subject can be measured before and after administering a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’). Administration may not inhibit the tidal volume in the lungs. In some cases, administration may not significantly inhibit the tidal volume in the lungs. In certain embodiments regarding the tidal volume in the lungs, the term not significantly means that the tidal volume in the lungs 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 tidal volume in the lungs before administering the inhibitor. The tidal volume in the lungs of a subject can be measured using the forced expiratory volume in one second test (FEV1) or the forced vital capacity test (FVC) or their equivalent tests.

[0458] Smooth muscle contractions of a subject can be measured 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. The smooth muscle contraction of the subject can be evaluated by measuring the blood pressure of the subject.

[0459] Neuromuscular coupling in a subject can be measured before and after administration of a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III’). Inhibiting skeletal muscle contraction with an inhibitor as described herein may not impair nerve conduction, neurotransmitter release, or electrical depolarization of the skeletal muscle of the subject. In some cases, inhibiting skeletal muscle contraction may not significantly impair the neuromuscular coupling of 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. The neuromuscular coupling of the subject can be evaluated by measuring the nerve-induced electrical depolarization of the skeletal muscle, which is carried out by using surface or needle electrodes and recording the electrical activity generated by the skeletal muscle after electrical or voluntary stimulation with electromyography (EMG).

[0460] In some aspects, methods of treating neuromuscular diseases or movement disorders can include 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’) can inhibit myosin ATPase activity, native skeletal muscle myofibril ATPase (calcium-regulated) or a reconstituted S1 having 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 evaluate their inhibitory activity on muscle contraction. Absorbance assays can be used to determine inhibitory activity 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. Then the test compound can be added to the wells using a pin array. The reaction can be initiated with MgATP. The ATP consumption in the test vessel over a defined time period can be compared with the ATP consumption in a control vessel. The defined time period can be from 5 minutes to 20 minutes. The ATP consumption can be determined by direct or indirect measurement. Test compounds that reproducibly and strongly inhibit myosin S1 ATPase activity can be further evaluated in a dose-response assay to determine the ex vivo IC50 of the compound on dissected muscle. The assay can indirectly measure ATPase activity by coupling myosin with pyruvate kinase and lactate dehydrogenase to provide a method of absorbance detection at 340 nm based on the conversion of NADH to NAD+ driven by ADP accumulation. In some cases, wherein if the ATP consumption in the test vessel is reduced by at least 20% compared to the control vessel, then the test compound can be selected as a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’). In a kinetic assay, a test compound can be selected when the inhibition of NAD+ generation is enhanced by at least 20%.

[0461] In an in vitro assay, a selected inhibitor or test compound may not inhibit cardiac myosin S1 ATPase. In some cases, when testing a test compound or a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) in an in vitro assay, the cardiac myosin S1 ATPase or cardiac myofibril or reconstituted system can 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%.

[0462] A test compound for testing skeletal muscle contraction can be tested on stripped fibers. Single skeletal muscle fibers that have been treated to remove the membrane and allow direct activation of contraction after calcium administration can be used. Relative to the pre-treatment value or an untreated control single skeletal muscle, an inhibitor compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can inhibit the contraction of a single skeletal muscle fiber by about 5% to about 90%. Relative to the pre-treatment value or an untreated control single skeletal muscle fiber, the inhibitor can inhibit the contraction of a single skeletal muscle fiber by at least about 5%. Relative to the pre-treatment value or an untreated control single skeletal muscle fiber, the inhibitor can inhibit the contraction of a single skeletal muscle fiber by at most about 90%. Relative to the pre-treatment ability or an untreated control single skeletal muscle fiber, the inhibitor can inhibit the contraction of a single skeletal muscle fiber by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90% or about 80% to about 90%. Relative to the pre-treatment ability or an untreated control single skeletal muscle fiber, the inhibitor can inhibit the contraction of a single skeletal muscle fiber by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% or about 90%.

[0463] Relative to the pre-treatment value or an untreated control single skeletal muscle, an inhibitor compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can inhibit the contraction of the single skeletal muscle by about 5% to about 90%. Relative to the pre-treatment value or an untreated control single skeletal muscle, the inhibitor can inhibit the contraction of the single skeletal muscle by at least about 5%. Relative to the pre-treatment value or an untreated control single skeletal muscle, the inhibitor can inhibit the contraction of the single skeletal muscle by at most about 90%. Relative to the pre-treatment ability or an untreated control single skeletal muscle, the inhibitor can inhibit the contraction of the single skeletal muscle by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90% or about 80% to about 90%. Relative to the pre-treatment ability or an untreated control single skeletal muscle, the inhibitor can inhibit the contraction of the 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%.

[0464] The effects of a test compound on slow type I skeletal muscle fibers, cardiac muscle bundles or pulmonary muscle fibers can be evaluated. A test compound or an inhibitor compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be selected such that it does not significantly modulate the function of slow type I skeletal muscle fibers, cardiac muscle bundles or pulmonary muscle fibers and is specific for type II skeletal muscle. As used herein, the term “significantly modulate” can mean that the contractile ability of the muscle 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 muscle force / contractility prior to administration of the inhibitor.

[0465] In some aspects, a method of treating a neuromuscular disease or movement disorder can include administering to a subject in need thereof a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III’), wherein the compound 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 used can be a mouse model. The mouse model used can be a dystrophic mouse model, such as an mdx mouse. The dystrophin gene of the mdx mouse has a point mutation that changes the amino acid encoding glutamine to threonine, thereby generating non-functional dystrophin, resulting in 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 immersed in oxygenated Krebs solution to maintain muscle function. A test compound or a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III), or (III’) can be applied to the muscle. Then an isometric (fixed length) contraction step can be performed, wherein the muscle is stimulated with a series of electrical pulses. An eccentric (lengthening) contraction step can be performed, wherein the muscle is stretched to 10%, 15%, 20%, 25%, or 30% greater than its resting length when relaxed or stimulated with an electrical pulse. 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 electrical pulses can have a frequency of about 1 Hz to about 500 Hz. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 400 Hz. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 300 Hz. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 200 Hz. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 100 Hz. The electrical pulses can 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 electrical pulses can include individual pulses of different frequencies. For each pulse, the period of each pulse in the series of electrical pulses can be between 0.1 second and 0.5 second.The time for each pulse can be 0.1, 0.2, 0.3, 0.35, 0.4 or 0.5 seconds. After isometric or eccentric contractions, incubation of the muscle in reactive orange can also measure sarcolemma damage. Reactive orange is a fluorescent dye that is taken up by muscle fibers with membrane damage. The number or proportion of dye-positive fibers can then be quantified by histology. When the test force decline and / or the proportion of dye-positive fibers is at least 20% less than the control force decline and / or dye uptake, the test compound can be selected as a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’).

[0466] Using a set of isometric or eccentric contractions, the force generated by the muscle can be measured. 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 decline and compared with the change in force generated by muscle contractions from the first pulse to the last pulse in a control sample not exposed to the test compound (control force decline). The force decline can be used as a representative of muscle damage, and when the test force decline is at least 20% less than the control force decline, the test compound or an inhibitor compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be selected.

[0467] Pharmaceutical preparation

[0468] The compositions and methods described herein can be considered to be useful as pharmaceutical compositions for administration to a subject in need. The pharmaceutical composition can comprise at least a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents and / or thickening agents.

[0469] The pharmaceutical composition of a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be formulated using one or more physiologically acceptable carriers, which include excipients and auxiliaries. The formulation can be modified according to the selected route of administration. The pharmaceutical composition comprising the compound, salt or conjugate can be manufactured by, for example, lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical composition can also comprise the compound, salt or conjugate in free base form or in pharmaceutically acceptable salt form.

[0470] A method for formulating a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) may include formulating any compound, salt or conjugate with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semi-solid or liquid composition. Solid compositions may include, for example, powders, tablets, dispersible granules and capsules, and in certain aspects, the solid compositions further contain non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffering agents 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.

[0471] A pharmaceutical composition of a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) may contain at least one active ingredient (e.g., a compound, salt or conjugate and other medicaments). The active ingredient may be encapsulated in, for example, microcapsules prepared by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or coarse emulsions.

[0472] The compositions and formulations may be sterilized. Sterilization may be accomplished by sterile filtration.

[0473] Compositions containing a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) may be formulated for administration as an injection. Non-limiting examples of injectable formulations may include sterile suspensions, solutions or emulsions in an oily or aqueous vehicle. 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 suitable stabilizers. The injection may be formulated for bolus 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.

[0474] For parenteral administration, a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can be formulated with a pharmaceutically acceptable parenteral vehicle into a unit dose injectable form (e.g., solution, suspension, emulsion). Such vehicles 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 minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0475] In one embodiment, the 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 composition is formulated to deliver one or more pharmaceutically active agents to the subject through the mucosal layer in the oral cavity or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to the subject through the mucosal layer in the stomach and / or intestine.

[0476] 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 can also contain non-release controlling excipients.

[0477] 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 can also contain non-release controlling excipients. In one embodiment, the composition is in the form of enteric coated granules as a controlled release capsule for oral administration. The composition can further contain cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, pyridazine, lactose, mannitol, or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric coated pellets as a controlled release capsule for oral administration. The composition can further contain 40 - 50 glyceryl monostearate, hydroxypropyl cellulose, pyridazine, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl citrate.

[0478] 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, ethylcellulose, hydroxypropylcellulose, phthalazine phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide and yellow ferric oxide.

[0479] 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, which can contain the compound, salt or conjugate, and these matrices can be in the form of shaped articles (e.g., membranes 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 (i.e., injectable microspheres composed of a lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

[0480] A pharmaceutical preparation 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 preparation can be a lyophilized preparation or an aqueous solution. The acceptable carrier, excipient and / or stabilizer can be non-toxic to the recipient at the doses 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 dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; counterions forming salts such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycols.

[0481] 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.

[0482] 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 comprise non-release controlling excipients.

[0483] In another embodiment, the composition of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) may 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 at least two consecutive pulses that are separated in time by from 0.1 to 24 hours. The composition may comprise one or more release controlling and non-release controlling excipients, such as excipients suitable for a rupturable semipermeable membrane and as swellable substances.

[0484] 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, which are encapsulated in an intermediate reactive layer containing an anti-gastric juice polymeric material, which is partially neutralized with a base and has cation exchange capacity and an anti-gastric juice outer layer.

[0485] 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 a physically discrete unit suitable for administration to a human subject or a non-human animal subject and individually packaged. Each unit dose may contain a predetermined amount of the active ingredient sufficient to produce the desired therapeutic effect, as well as the required 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 portions or administered in multiple doses. Multiple dose form is a plurality of identical unit dose forms packaged in a single container so that they can be administered in discrete unit dose forms. Examples of multiple dose forms include, but are not limited to, vials, bottles containing tablets or capsules, or pint bottles or gallon bottles. In another embodiment, the multiple dose form contains different pharmaceutical active agents.

[0486] In some embodiments, the compositions of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (III) or (III’) can also be formulated into modified release dosage forms, including immediate release, delayed release, extended release, sustained release, continuous release, pulsatile release, controlled release, prolonged, accelerated release and rapid release, targeted release, programmed release, and gastric retention dosage forms. These dosage forms can be prepared according to known methods and techniques (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126, the entire content of which is incorporated herein by reference).

[0487] Combination therapy

[0488] The present invention also relates to combination therapies, e.g., co-administering the disclosed compounds and additional active agents as part of a specific treatment regimen designed to provide beneficial effects from the combined action of these therapeutic agents. The beneficial effects of the combination therapies include, but are not limited to, pharmacokinetic or pharmacodynamic interactions resulting from the combination of the therapeutic agents. Co-administration of these therapeutic agents is generally carried out over a defined period of time (usually several hours, days, weeks, months or years depending on the selected combination). Combination therapies are intended to cover the administration of multiple therapeutic agents in a sequential manner, i.e., where the various therapeutic agents are administered at different times, as well as the administration of these therapeutic agents or at least two of them in a substantially simultaneous manner.

[0489] For example, substantially simultaneous administration is achieved by administering to a subject a single formulation or composition (e.g., a tablet or capsule having a fixed ratio of the various therapeutic agents) or multiple single formulations (e.g., capsules) of each therapeutic agent. Sequential or substantially simultaneous administration of the various therapeutic agents is achieved by any suitable route, including but not limited to oral, intravenous, intramuscular and direct absorption through mucosal tissue. The therapeutic agents are administered by the same route or 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. Or, for example, all therapeutic agents are administered orally, or all therapeutic agents are administered by intravenous injection.

[0490] The components of the combination are administered to a patient simultaneously or sequentially. It is understood that these components are present in the same pharmaceutically acceptable carrier and are thus administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers that are administered simultaneously or sequentially, such as in conventional oral dosage forms.

[0491] 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 therapies. In certain embodiments, the additional therapeutic agent is eteplirsen or ataluren.

[0492] In certain embodiments, the compounds or salts of the present disclosure are used in combination with gene therapy. In certain embodiments, the compounds or salts of the present disclosure are used in combination with an adeno-associated virus (AAV) comprising a gene encoding an alternative protein (e.g., dystrophin) or a truncated form thereof (e.g., microdystrophin). In certain embodiments, the compounds or salts of the present disclosure are co-administered with vamorolone.

[0493] Example

[0494] The present invention will now be described generally and will be more readily understood by reference to the following examples, which are included for the purpose of illustrating certain aspects and embodiments of the invention only and are not intended to limit the invention in any way.

[0495] 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 are capable of preparing 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 using suitable starting materials and modifying the synthetic routes as needed in a similar manner as described below. Generally, the starting materials and reagents are available from commercial suppliers or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0496] 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)

[0497]

[0498] 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)

[0499]

[0500] Step 1: Substitution of pyridine, pyrimidine or phenyl

[0501] 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 displacement. Isolation of the major product provides the corresponding 2-substituted pyrimidine.

[0502] Steps 2-3: Cross-coupling of pyridine, pyrimidine or phenyl with pyridone

[0503] The Suzuki reaction carried out 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 produced the biaryl core in good yield.

[0504] Step 4: Alkylation of the compound

[0505] The nitrogen was cleanly alkylated using various heteroaryl methyl bromides or heteroaryl methyl chlorides (e.g., 5-(chloromethyl)-3-ethylisoxazole) and an inorganic base in a polar aprotic solvent (e.g., DMF). Alternatively, the Mitsunobu method can be used to functionalize the nitrogen of pyridone. This requires a hydroxymethyl heteroaryl compound, triphenylphosphine, and a carbodiimide reagent (e.g., DEAD). Depending on the availability of the appropriate coupling partner, both alternative methods 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.

[0506] Example 3: 6-[2-[(3-Fluorooxetan-3-yl)methoxy]pyrimidin-5-yl]-2-[(5-phenyl-1,3,4-thiadiazol-2-yl)methyl]-2,3-dihydropyridazin-3-one (Compound 36)

[0507]

[0508] Step 1: 5-Bromo-2-((3-fluoroxetane-3-yl)methoxy)pyrimidine

[0509] Following Step 1 in Example 2, the title compound was obtained as a solid, 160 mg (58.8%). LC / MS (ESI): 263 [M+H] + 。

[0510] Steps 2 / 3: 6-(2-((3-fluoroxetane-3-yl)methoxy)pyrimidin-5-yl)pyridazin-3(2H)-one

[0511] Following Step 2 in Example 2, the title compound was obtained as a white solid (500 mg, 32.8%). LC / MS (ESI): 279 [M+H] + 。

[0512] Step 4: 6-[2-[(3-fluoroxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[(5-phenyl-1,3,4- thiadiazol-2-yl)methyl]-2,3-dihydropyridazin-3-one

[0513] To a stirred solution of 6-[2-[(3-fluoroxetane-3-yl)methoxy]pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (100 mg, 0.36 mmol) and (5-phenyltetrazol-1,3,4-thiadiazol-2-yl)methanol (69.0 mg, 0.36 mmol) in THF (1.5 mL) was added PPh3 (188 mg, 0.72 mmol) and DEAD (94.0 mg, 0.54 mmol). The reaction was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC to afford the title compound as a white solid (24 mg, 14.8%). 1 1H NMR (DMSO-d6, 300 MHz): δ 9.14 (s, 2H), 8.20 (d, J \ = 9.6 Hz, 1H), 8.00 - 7.97 (m, 2H), 7.59 - 7.53 (m, 3H), 7.26 (d, J \ = 9.9 Hz, 1H), 5.83 (s, 2H), 4.88 - 4.71 (m, 6H); LC / MS (ESI): 453 [M+H] + .

[0514] Example 4: 6-[2-[(3-Fluoroxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl]-2,3-dihydropyridazin-3-one (Compound 90)

[0515]

[0516] Step 1: 6-[2-[(3-fluoroxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[[3-(4-fluorophenyl)- 1,2,4-oxadiazol-5-yl]methyl]-2,3-dihydropyridazin-3-one

[0517] A solution of 6-[2-[(3-fluoroxetane-3-yl)methoxy]pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (100 mg, 0.036 mmol) in DMF (1 mL) was added Cs2CO3 (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 h. The resulting mixture was purified by preparative HPLC to afford the title compound as a white solid (10 mg, 6.1%). 1 1H NMR (CD3OD, 300 MHz): δ 9.13 (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]+ .

[0518] The following compounds were synthesized according to Example 4:

[0519]

[0520] Example 5: 6-(6-(Difluoromethoxy)pyridazin-3-yl)-2-((5-phenyl-1,3,4-thiadiazol-2-yl)methyl)pyridazin-3(2H)-one (Compound 22)

[0521]

[0522] Steps 1 / 2: 6-(6-(Difluoromethoxy)pyridazin-3-yl)pyridazin-3(2H)-one

[0523] The title compound as a white solid (3.5 g, 72.1%) was obtained according to Steps 1 and 2 in Example 2. LC / MS (ESI): 240 [M+H] + .

[0524] Step 3: Ethyl 2-(2-benzohydrazide)-2-oxoacetate

[0525] Ethyl oxalyl chloride (1.00 g, 7.32 mmol) was added to a solution of benzohydrazide (1.00 g, 7.35 mmol) in DCM (5.0 mL). The resulting mixture was stirred at 25 °C for 1 h. 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] + .

[0526] Step 4: Ethyl 5-phenyl-1,3,4-thiadiazole-2-carboxylate

[0527] A mixture of ethyl 2-(2-benzohydrazido)-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 h. The resulting mixture was concentrated in vacuo to give a residue, which was purified by silica gel chromatography (Flash 40 g, 20 - 50% EA:PE) to give the title compound as a white solid (390 mg, 81.9%). LC / MS (ESI): 235 [M+H] + .

[0528] Step 5: (5-Phenyl-1,3,4-thiadiazol-2-yl)methanol

[0529] 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 h. 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 as a white solid (300 mg, 83.1%). LC / MS (ESI): 193 [M+H] + 。

[0530] Step 6: 6-[2-[(3-fluoroxetane-3-yl)methoxy]pyrimidin-5-yl]-2-[(5-phenyl-1,3,4- thiadiazol-2-yl)methyl]-2,3-dihydropyridazin-3-one

[0531] The title compound as a white solid (38.8 mg, 22.5%) was obtained according to Step 4 in Example 8. 1 H NMR (DMSO-d6, 400 MHz): δ8.81 (d, J \ =2.4 Hz, 1H), 8.42 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 8.21 (d, J \ =10.0 Hz, 1H), 7.99 - 7.97 (m, 2H), 7.79 (t, J=73.2 Hz, 1H), 7.59 - 7.53 (m, 3H), 7.27 - 7.24 (m, 2H), 5.83 (s, 2H); LC / MS (ESI): 414 [M+H] + 。

[0532] The following compounds were synthesized according to Example 5 (by Mitsunobo or substitution):

[0533]

[0534]

[0535]

[0536] Example 6: 2-[(4-chlorophenyl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (Compound 1)

[0537]

[0538] Step 1: 5-Bromo-2-(2,2,2-trifluoroethoxy)pyrimidine

[0539] At room temperature, 2,2,2-trifluoroethanol (6.21 g, 0.025 mol, 1.20 equiv) and Cs2CO3 (25.27 g, 0.062 mol, 3.0 equiv) were added to a mixture of 5-bromo-2-chloropyrimidine (10 g, 0.021 mol, 1.0 equiv) in DMSO (10 mL). The reaction mixture was stirred at 70 °C for 2 h. The solution was diluted with water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed in vacuo. Purification by silica gel chromatography (Flash 300 g, 0-40% EtOAc: cyclohexane) afforded the title compound as a yellow oil (10.0 g, 94.08%). LC / MS (ESI): 257 [M+H] + 。

[0540] Step 2: [2-(2,2,2-Trifluoroethoxy)pyrimidin-5-yl]boronic acid

[0541] 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) were 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)Cl2 (1.42 g, 1.94 mmol, 0.1 equiv). The flask was purged and maintained with an inert nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 4 h and confirmed by LCMS. The reaction was used directly for the next step without workup.

[0542] Step 3: 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one

[0543] To a mixture of [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid (4.2 g, 18.93 mmol, 1.0 eq) in dioxane (40 mL) was added 6-bromo-2,3-dihydropyridazin-3-one (3.31 g, 18.916 mmol, 1.00 eq), Pd(dppf)Cl2 (0.69 g, 0.943 mmol, 0.05), K2CO3 (3.92 g, 28.387 mmol, 1.5 eq), and H2O (4 mL). The flask was purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred at 90 °C for 2 h. 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 removed in vacuo. Purification by silica gel chromatography (Flash 300 g, 50-100% EtOAc:cyclohexane) afforded the title compound as a brown solid (3.0 g, 58.24%). LC / MS (ESI): 273 [M+H] + .

[0544] Step 4: 2-[(5-Chloropyridin-3-yl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3- dihydropyridazin-3-one

[0545] 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 eq) in DMF (10 mL) at room temperature was added 1-(bromomethyl)-4-chloropyridine (0.82 g, 0.004 mmol, 1.0 eq) and Cs2CO3 (2.39 g, 0.007 mmol, 2.0 eq). The resulting solution was stirred at room temperature for 2 h. The residue was purified by preparative HPLC to afford a white solid (700 mg, 48%).

[0546] The following compounds were synthesized according to Example 6:

[0547]

[0548]

[0549]

[0550] Example 7: 6-[4-(Difluoromethoxy)phenyl]-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-2,3-dihydropyridazin-3-one (Compound 204)

[0551]

[0552] 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 equiv) in dioxane (20 mL) was added [4-(difluoromethoxy)phenyl]boronic acid (2.0 g, 10.64 mmol, 1.1 equiv), K2CO3 (4.0 g, 29.0 mmol, 3.0 equiv), Pd(dppf)Cl2 (707.51 mg, 0.97 mmol, 0.1 equiv) and H2O (2 mL). The reaction mixture was stirred at 90 °C for 4 h under an argon atmosphere.

[0553] The solution was diluted with water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed in vacuo. Purification by silica gel chromatography (Flash 300 g, 50 - 90% EtOAc: cyclohexane) afforded the title compound as an off-white solid (1.55 g, 67.30%). LC / MS (ESI): 239 [M+H] + 。

[0554] Step 2: 6-[4-(Difluoromethoxy)phenyl]-2-[(3-methyl-1,2-oxazol-5-yl)methyl]-2,3-dihydro pyridazin-3-one

[0555] 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 h. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate. The solution was diluted with water and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by preparative HPLC to give a white solid (76 mg, 54.31%). 1 1H NMR (400 MHz, DMSO-d6): δ 8.11 (d, J = 10.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 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] +

[0556] The following compounds were synthesized according to Example 7:

[0557]

[0558]

[0559]

[0560]

[0561] Example 8: 6'-(Bicyclo[1.1.1]pentan-1-ylamino)-1-(pyridazin-3-ylmethyl)-[3,3'-bipyridine]-6(1H)-one (Compound 71)

[0562]

[0563] Step 1: N-(Bicyclo[1.1.1]pentan-1-yl)-5-bromopyridin-2-amine

[0564] 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 Cs2CO3 (1.11 g, 3.409 mmol) in DMSO (3 mL) was stirred at 120 °C for 2 h. 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] +

[0565] Step 2: N-(Bicyclo[1.1.1]pentan-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)pyridazin-2-amine

[0566] 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 under an inert nitrogen atmosphere. 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 further workup.

[0567] 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

[0568] 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 to 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 nitrogen atmosphere. The resulting solution was stirred at 90 °C for 2 h. The solution was diluted with water and extracted with EtOAc (x3). 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 crude product. The crude product was purified by RP-HPLC to give a white solid. 1 1H NMR (DMSO-d6, 300 MHz): δ 8.54 (d, J = 2.1 Hz, 1H), 8.10 (t, J = 5.1 Hz, 1H), 8.00 (d, J = 9.9 Hz, 1H), 7.88 (dd, J1 = 8.7 Hz, J1 = 2.4 Hz 1H), 7.59 (s, 1H), 7.04 (d, J = 9.9 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.67 (s, 2H), 3.16 - 3.07 (m, 2H), 2.47 (s, 1H), 2.10 (s, 6H), 1.04 (t, J = 7.2 Hz, 3H); LC / MS R t = 0.848 min; MS m / z: 340 [M+H] +

[0569] The following compounds were synthesized according to Example 8:

[0570]

[0571]

[0572]

[0573]

[0574]

[0575] Example 9: 2-((5-Fluoropyridin-3-yl)methyl)-6-(2-(2-methoxyethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 70)

[0576]

[0577] Step 1: 2-((5-Fluoropyridin-3-yl)methyl)-6-(2-(2-methoxyethoxy)pyrimidin-5-yl)pyridazin-3 (2H)-one

[0578] To the stirred 2-((5-fluoropyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (100.00 mg, 0.272 mmol, 1.00 equiv) was added portionwise a solution of K2CO3 (112.89 mg, 0.817 mmol, 3 equiv) in 2-methoxy-ethanol (1 mL). 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 1H NMR (DMSO-d6, 400 MHz) δ 9.10 (s, 2H), 8.54 (d, J = 2.4 Hz, 2H), 8.12 (d, J = 10.0 Hz, 1H), 7.82–7.74 (m, 1H), 7.16 (d, J = 9.6 Hz, 1H), 5.40 (s, 2H), 4.52–4.45 (m, 2H), 3.73–3.66 (m, 2H), 3.31 (s, 3H). LC / MS: Rt = 0.810 min, MS m / z: 358 [M+H] + 。

[0579] The following compounds were synthesized according to Example 9:

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586] Example 10: 2-((5-(methylthio)pyridazin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 111)

[0587]

[0588] Step 1: Methyl 5-(methylthio)nicotinate

[0589] A solution / mixture of methyl 5-bromopyridine-3-carboxylate (216.00 mg, 1.000 mmol, 1.00 equiv) and sodium methanethiolate (70.08 mg, 1.000 mmol, 1.00 equiv) in DMF was stirred overnight under a nitrogen atmosphere at 80 °C. The reaction was monitored by LCMS. The mixture was cooled 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, 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 as a solid (150 mg, 81.88%).

[0590] Step 2: (5-(Methylthio)pyridazin-3-yl)methanol

[0591] Under a N2 atmosphere, LAH (63 mg, 1.64 mmol) was added portionwise to a solution of methyl 5-(methylthio)nicotinate (150 mg, 0.82 mmol) in THF (3 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 1.5 h. Then the reaction was 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 as a solid (100 mg, 78.7%).

[0592] Step 3: 3-(chloromethyl)-5-(methylthio)pyridine

[0593] A solution of (5-(methylthio)pyridazin-3-yl)methanol (100 mg, 0.64 mmol) and SOCl2 (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 could be detected by LCMS. The mixture was concentrated in vacuo and the crude product was used in the next step without further purification.

[0594] Step 4: 2-((5-(methylthio)pyridazin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5- yl)

[0595] pyridazin-3(2H)-one

[0596] To a stirred solution of 6-[2-[(3-fluoroxetane-3-yl)methoxy]pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (174 mg, 0.64 mmol) and 3-(chloromethyl)-5-(methylthio)pyridine (111 mg, 0.64 mmol) (177 mg, 1.28 mmol, 2 equiv) in DMF (2 mL) was added portionwise. The reaction was stirred at 25 °C for 2 h. The resulting mixture was extracted with EtOAc and water. The combined organic layers were washed with brine, 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 as a white solid (45 mg, 17.2%). 1 1H NMR (300 MHz, methanol-d4) δ 9.14 (s, 2H), 8.41 (dd, J = 12.9, 2.1 Hz, 2H), 8.06 (d, J = 9.6 Hz, 1H), 7.87 (t, J = 2.1 Hz, 1H), 7.16 (d, J = 9.9 Hz, 1H), 5.47 (s, 2H), 5.04 (q, J = 8.7 Hz, 2H), 2.55 (s, 3H). LC / MS Rt = 2.406 min; MS m / z: 410 [M+H] + 。

[0597] Example 11: 2-((3-Methylisoxazol-5-yl)methyl)-6-(2-(methylthio)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 65)

[0598]

[0599] Step 1: 6-(2-(methylthio)pyrimidin-5-yl)pyridazin-3(2H)-one

[0600] 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 sodium (methylthio) (231.72) in 3.307 mmol (mg, 3.307 mmol, 3.00 equiv) in DMF (3.00 mL) was stirred at 70 °C for 1 h. The reaction was quenched with a saturated solution. 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 flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous MeOH, 10% to 50% gradient, 10 min; 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 as a white solid (280 mg, 115.34%). MS m / z: 221 [M+H] +

[0601] Step 2: 2-((3-methylisoxazol-5-yl)methyl)-6-(2-(methylthio)pyrimidin-5-yl)pyridazin-3 (2H)-one

[0602] 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 K2CO3 (376.50 mg, 2.724 mmol, 3.00 equiv) in DMF (2.00 mL) was stirred at 25 °C for 2 h. The resulting mixture was diluted with EtOAc (50 mL) and washed with 2 x 10 mL of water. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous MeOH, 10% to 50% gradient, 10 min; detector, UV 254 nm. There was obtained 2-[(3-methyl-1,2-oxazol-5-yl)methyl]-6-[2-(methylsulfanyl)pyrimidin-5-yl]pyridazin-3-one as a white solid (52.3 mg, 17.70%). 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.15 (d, J = 9.6 Hz, 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 = 1.219 min; MS m / z: 316 [M+H] + 。

[0603] The following compounds were synthesized according to Example 11:

[0604]

[0605]

[0606] 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)

[0607]

[0608] Step 1: Ethyl 2-ethylthiazole-5-carboxylate

[0609] Ethyl 2-chloro-3-oxopropionate (2.00 g, 13.284 mmol, 1.00 equivalent), EtOH (20.00 mL), and propylthiourea (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 equivalents). The resulting solution was stirred at 80 °C for 16 hours. The mixture was cooled to 25 °C and filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. 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 as a pale yellow oil. MS m / z: 186 [M+H] +

[0610] Step 2: (2-Ethylthiazol-5-yl)methanol

[0611] At 0 °C, LiAlH4 (4.10 g, 107.968 mmol, 1.00 equivalent) was added portionwise to a solution of ethyl 2-ethyl-1,3-thiazole-5-carboxylate (20.00 g, 107.968 mmol, 1.00 equivalent) in THF (300.00 mL). The mixture was stirred at 0 °C for 1 hour, 4 g of Na2SO4·10H2O was added in portions, then 2 g of Na2SO4 was added. The mixture was stirred for 30 minutes and filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to give 15 g (97.02%) of a crude product as a pale yellow oil. MS m / z: 144 [M+H] +

[0612] Step 3: 5-(Chloromethyl)-2-ethylthiazole

[0613] To a solution of (2-ethyl-1,3-thiazol-5-yl)methanol (10.00 g, 69.832 mmol, 1.00 eq) in DCM (100.00 mL), SOCl2 (10.13 mL, 85.161 mmol, 2.00 eq) was added dropwise at 0 °C. The mixture was stirred for 1 h. The mixture was concentrated in vacuo, and the residue was dissolved in 100 mL of water. The pH was adjusted to 8 with saturated Na2CO3 solution, and then extracted with 3 × 100 mL of EA. The organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude product. Purification by silica gel column chromatography gave 6 g of a pale yellow oil (53.15%). MS m / z: 162 [M+H] +

[0614] Step 4: 2-((2-Ethylthiazol-5-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridaz in-3(2H)-one

[0615] 6-[2-(2,2,2-Trifluoroethoxy)pyrimidin-5-yl]-2H-pyridazin-3-one (10.00 g, 36.739 mmol, 1.00 eq) was placed in a 250-mL round-bottom flask, DMF (100.00 mL), 5-(chloromethyl)-2-ethyl-1,3-thiazole (7126.72 mg, 44.087 mmol, 1.20 eq), K2CO3 (15232.78 mg, 110.218 mmol, 3.00 eq). The resulting solution was stirred at 50 °C for 1 h. 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 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 2H), 8.12 (d, J = 9.6 Hz, 1H), 7.75 (s, 1H), 7.17 (d, J = 9.6 Hz, 1H), 5.48 (s, 2H), 5.12 (q, J = 8.8 Hz, 2H), 2.92 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H). LC / MS Rt = 1.873 min; MS m / z: 398 [M+H] + 。

[0616] Step 5: 2-((2-Ethylthiazol-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- in a nitrogen atmosphere at 25 °C, a solution of K2CO3 (104.34 mg, 0.755 mmol, 3.00 equiv) in DMF (100.00 mg, 0.252 mmol, 1.00 equivalent) was added portionwise. Propanol (302.46 mg, 5.033 mmol, 20.00 equiv) was added portionwise to the above mixture at 25 °C. The resulting mixture was stirred at 25 °C for an additional 4 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with hexane / EtOAc (1:1), to afford 2-[(2-ethyl-1,3-thiazol-5-yl)methyl]-6-(2-propoxypyrimidin-5-yl)pyridazin-3(2H)-one as a pale yellow solid (13.2 mg, 14.46%). 1 1H NMR (DMSO-d6, 300 MHz) δ 9.08 (s, 2H), 8.10 (d, J = 9.6 Hz, 1H), 7.75 (s, 1H), 7.16 (d, J = 9.6 Hz, 1H), 5.48 (s, 2H), 4.33 (t, J = 6.9 Hz, 2H), 2.93 (q, J = 7.5 Hz, 2H), 1.812 - 1.742 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H). LC / MS Rt = 1.349 min; MS m / z: 358 [M+H] + 。

[0617] The following compounds were synthesized according to Example 12:

[0618]

[0619]

[0620]

[0621] Example 13: 2-((5-fluoropyridin-3-yl)methyl)-6-(6-(2-methylpropoxy-2-D)pyridazin-3-yl)pyridazin-3(2H)-one (EDG-006364)

[0622]

[0623] Step 1: 5-Bromo-2-(2-methylpropoxy-2-d)pyrimidine

[0624] 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(2-2D)propan-1-ol (42.45 mg, 0.565 mmol, 1.00 equiv). The resulting solution was stirred at 0 °C for 1 h. The resulting mixture was concentrated. The residue was applied to a silica gel column with acetate / petroleum ether (1:4). This gave 110 mg (83.88%) of 5-bromo-2-[2-methyl(2-2H)propoxy]pyrimidine as a solid. MS m / z: 232 [M+H] +

[0625] Step 2: 2-(2-Methylpropoxy-2-d)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine

[0626] 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).

[0627] The resulting solution was stirred at 80 °C for 2 h and confirmed by LCMS. This reaction can be directly used for the next step without post-treatment.

[0628] Step 3: 2-((5-Fluoropyridin-3-yl)methyl)-6-(6-(2-methylpropoxy-2-d)pyridazin-3-yl)pyridazin-3 (2H)-one

[0629] 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), K2CO3 (154.33 mg, 1.117 mmol, 2 equiv), dioxane (3.00 mL), H2O (0.50 mg), Pd(d(d))Cl2 (40.85 mg, 0.056 mmol, 0.1 equiv). The resulting solution was stirred at 90 °C for 2 h. The resulting mixture was concentrated. The residue was applied to a silica gel column with dichloromethane / methanol (20:1). This gave 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. 11H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 2H), 8.55 - 8.53 (m, 2H), 8.12 (d, J = 10.0 Hz, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.16 (d, J = 10.0 Hz, 1H), 5.40 (s, 2H), 4.15 (s, 2H), 0.98 (s, 6H). LC / MS Rt = 1.676 min; MS m / z: 357 [M+H] +

[0630] Example 14: 2-((5-Fluoropyridin-3-yl)methyl)-6-(2-propoxypyrimidin-5-yl)pyridazin-3(2H)-one (Compound 125)

[0631]

[0632] Step 1: N-Cyclobutyl-2-[3-[2-(2-methylpropoxy)pyrimidin-5-yl]-6-oxopyridazin-1-yl]acet amide

[0633] To stirred 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 K2CO3 (1.422 g, 10.435 mmol, 2.00 equiv) portionwise and the solution was stirred at 80 °C for 4 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound as a white solid.

[0634] The following compounds were synthesized according to Example 14:

[0635]

[0636]

[0637]

[0638]

[0639] Example 15: 2-((5-Methoxypyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (Compound 128)

[0640]

[0641] Step 1: 2-((5-Methoxypyridin-3-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)

[0642] pyridazin-3(2H)-one

[0643] A mixture of 6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one (2.00 g, 7.348 mmol, 1.00 equiv), 3-(chloromethyl)-5-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 h. The mixture was purified by Pre-HPLC (0.05% NH₃·H₂O - H₂O / I, 5% to 55% gradient, 30 min) to give 2-((5-methoxypyridin-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 ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (s, 2H), 8.25 - 8.23 (m, 2H), 8.15 (d, J = 9.6 Hz, 1H), 7.42 - 7.41 (m, 1H), 7.18 (d, J = 9.6 Hz, 1H), 5.36 (s, 2H), 5.12 (q, J = 9.0 Hz, 2H), 3.82 (s, 3H). LC / MS Rt = 1.301 min; MS m / z: 394 [M+H] + 。

[0644] The following compounds were synthesized according to Example 15:

[0645]

[0646]

[0647]

[0648]

[0649]

[0650] 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)

[0651]

[0652] Step 1: Ethyl 2-ethylthiazole-5-carboxylate

[0653] Ethyl 2-chloro-3-oxopropionate (80.00 g, 0.531 mol, 1.00 equiv), EtOH (600.00 mL), propanethioamide (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 h. The mixture was cooled to 25 °C and filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1) to give 60.00 g (60.96%) of ethyl 2-ethyl-1,3-thiazole-5-carboxylate as a pale yellow oil. MS m / z: 186 [M+H] +

[0654] Step 2: (2-Ethylthiazol-5-yl)methanol

[0655] At 0 °C, LiAlH4 (4.10 g, 107.968 mmol, 1.00 equiv) was added portionwise 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). The mixture was stirred at 0 °C for 1 h, 4 g of Na2SO4·10H2O was added in portions, then 2 g of Na2SO4 was added, and the mixture was stirred for 30 min. It was filtered through diatomaceous earth, and the filtrate was concentrated in vacuo to give 15 g (97.02%) of a crude product as a pale yellow oil. MS m / z: 144 [M+H] +

[0656] Step 3: 5-(Chloromethyl)-2-ethylthiazole

[0657] SOCl2 (10.13 mL, 85.161 mmol, 2.00 equiv) was added dropwise 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) at 0 °C. The mixture was stirred for 1 h. The mixture was concentrated in vacuo, and the residue was dissolved in 100 mL of water. The pH was adjusted to 8 with saturated Na2CO3 solution, and then extracted with 3 × 100 mL of EA. The organic layer was dried over Na2SO4 and concentrated in vacuo to give a crude product, which was purified by silica gel column to give 6 g (53.15%) of a pale yellow oil. MS m / z: 162 [M+H]

[0658] [M+H] +

[0659] Step 4: 2-((2-Ethylthiazol-5-yl)methyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridaz in-3(2H)-one

[0660] 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, DMF (100.00 mL), 5-(chloromethyl)-2-ethyl-1,3-thiazole (7126.72 mg, 44.087 mmol, 1.20 equiv), K2CO3 (15232.78 mg, 110.218 mmol, 3.00 equiv). The resulting solution was stirred at 50 °C for 1 h. 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 (RP: 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 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 2H), 8.12 (d, J = 9.6 Hz, 1H), 7.75 (s, 1H), 7.17 (d, J = 9.6 Hz, 1H), 5.48 (s, 2H), 5.12 (q, J = 8.8 Hz, 2H), 2.92 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H). LC / MS Rt = 1.873 min; MS m / z: 398 [M+H] + . Step 5: 2-((2-Ethyl thiazol-5-yl)methyl)-6-(2-isobutoxypyrimidin-5-yl)pyridazin-3(2H)-one

[0661] To a stirred solution of 2-[(2-ethyl-1,3-thiazol-5-yl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]pyridazin-3-one in 2-methylpropan-1-ol (10 mL) (1.00 g, 2.516 mmol, 1.00 equiv) was added portionwise a solution of K2CO3 (0.70 mg, 5.033 mmol, 2.00 equiv) in 2-methylpropan-1-ol (10 mL) at 25 °C under a nitrogen atmosphere. The resulting mixture was slowly warmed to 70 °C and stirred for an additional 6 h. The resulting mixture was concentrated in vacuo. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous methanol, 10% to 90% gradient, 40 min; detector, UV 254 nm. 2-((2-Ethyl-thiazol-5-yl)methyl)-6-(2-isobutoxypyrimidin-5-yl)pyridazin-3(2H)-one (800 mg, 85.58%) was obtained as a grey solid. 11H NMR (300 MHz, DMSO-d6) δ 9.08 (s, 2H), 8.10 (d, J = 9.9 Hz, 1H), 7.75 (s, 1H), 7.16 (d, J = 9.9 Hz, 1H), 5.48 (s, 2H), 4.16 (d, J = 6.6 Hz, 2H), 2.93 (q, J = 7.5 Hz, 2H), 2.13 - 2.02 (m, 1H), 1.25 (t, J = 7.5 Hz, 3H), 0.99 (d, J = 6.7 Hz, 6H). LC / MS Rt = 1.462 min; MS m / z: 372 [M+H] + 。

[0662] The following compounds were synthesized according to Example 16:

[0663]

[0664]

[0665] Example 17: 5,6-(2,4-Dihydroxypyrimidin-5-yl)-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-one (Compound 353)

[0666]

[0667] 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 a nitrogen inert atmosphere. The resulting solution was stirred at 90 °C for 2 h. The solution was diluted with water and extracted with EtOAc (x3). The combined organics were washed with brine, dried over Na2SO4 and the solvent was removed in vacuo. Purification by silica gel chromatography gave the solid 6-(2,4-dimethoxypyrimidin-5-yl)-2-((5-fluoro-pyridin-3-yl)methyl)pyridazin-3(2H)-one (610 mg, 59.3%).

[0668] Step 2: 6-(2,4-Dihydroxypyrimidin-5-yl)-2-((5-fluoropyridin-3-yl)methyl)pyridazin-3(2H)-oneTo 6-(2,4-dimethoxypyrimidin-5-yl)-2-((5-fluoro-pyridin-3-yl)methyl)pyridazin-3(2H)-one (172 mg, 0.5 mmol, 1.0 equiv) was added a solution of 4 M HCl (8 mL) in MeOH (6 mL). The resulting solution was stirred at 90 °C for 2 h. 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 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 2H), 8.91 - 8.23 (m, 2H), 8.05 - 7.80 (m, 2H), 7.74 - 7.69 (m, 1H), 7.00 (d, J = 9.8 Hz, 1H), 5.34 (s, 2H). LC / MS Rt = 0.721 min; MS m / z: 316 [M+H] + 。

[0669] Example 18. Skeletal Muscle Myofibril ATPase Assay

[0670] Overview: Myosin ATPase activity was evaluated using a coupled reaction system in which ADP generated by the function of myosin ATPase was coupled to the disappearance of NADH via the pyruvate kinase / lactate dehydrogenase (PK-LDH) system. Myosin ATPase activity generates ADP, which serves as a substrate for PK to produce pyruvate and regenerate ATP. Then pyruvate is used as a substrate by LDH to oxidize NADH to NAD+. Using the absorbance at 340 nm, the reaction rate was monitored by the time-dependent disappearance of NADH. Inhibition of the ATPase activity by the tested compound was indicated by a decrease in the rate of NADH loss relative to the vehicle-treated control within the experimental time window. To evaluate the selectivity of the tested compound for skeletal muscle myofibrils, the compound was re-screened in cardiac myofibrils.

[0671] Materials: The following stock solutions and reagents were used in the skeletal muscle myofibril ATPase assay:

[0672]

[0673] Stock solution of pCa buffer. Combine PIPES, CaCl2, and EGTA solutions with 70 mL of water. Adjust the pH to 7.0 and adjust the final volume to 100 mL.

[0674]

[0675]

[0676] Buffer A and Buffer B. The buffers were stored on ice until use.

[0677] Buffer Preparation

[0678]

[0679] Skeletal Muscle Myofibril ATPase Assay Procedure: Thaw the BSA, ATP, NADH, PEP, and DTT solutions at room temperature and then transfer them to ice. Transfer the frozen myofibrils (about twice the required volume) to a tube large enough and cap it. Thaw the myofibrils by rolling in a water bath at room temperature for about 15 minutes and cool on ice. Buffers A and B are prepared by adjusting the volume according to the number of wells needed and stored on ice. Add 0.5 μL of the compound to be tested to the wells of a 384-well plate. Buffers A and B are mixed by inverting immediately before use and then 25 μL of each (Buffer A first, then Buffer B) is dispensed using a Multidrop dispenser. Measure the absorbance in the wells at 340 nm using a kinetic protocol, where the wells are read every 1.5 - 2 minutes for 1 hour. Qualitatively estimate the reaction rate by subtracting the minimum absorbance value from the maximum absorbance value in each well using SoftMax Pro plate reader software or a spreadsheet program such as Excel. Using GraphPad Prism 8.0, normalize the data, define 100% activity as the absorbance change activity in the 1% DMSO vehicle wells, and 0% as no change throughout the assay. Fit the normalized data to a variable slope four-parameter Logistic model with the bottom limit set to 0 or greater. The compounds in Tables 1 to 4 were tested and the measured results 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 100 μM.

[0680] Example 11. Cardiac Myofibril ATPase Assay

[0681] Following Example 10, a reverse screen was performed using frozen myofibril pellets obtained from cardiac tissue. The assay was conducted in the same manner as above, but with the following significant differences: the final well concentration of myofibrils was 1.0 mg / mL and KCl was omitted from the formulation.

[0682] The compounds in Tables 1 to 4 were tested and the measured results 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 60 μM.

[0683] Example 12. Anterior Tibialis Muscle Measurement

[0684] Skeletal muscles of Duchenne muscular dystrophy (DMD) patients and mdx mice lack dystrophin and are more susceptible to contraction-induced injury than control muscles. The susceptibility of mdx mice to limb muscle injury after administration of the compounds disclosed herein was evaluated using two segments of maximally activated anterior tibialis (TA) muscle in situ. The 20% stress segment relative to the muscle fiber length was started from the plateau of the isometric contraction. The degree of injury was evaluated by the deficit of isometric force after one minute.

[0685] Animal

[0686] Mice aged 2 - 19 months were tested. Specific pathogen-free (SPF) C57BL control and mdx mice were either purchased or bred in-house from mating pairs obtained from Jackson Laboratories. All control mice were of the C57BL / 10J strain except for the 19-month-old mice which were C57BL / 6. It was necessary to use C57BL / 6 mice for the oldest group because, unlike C57BL / 10J mice, C57BL / 6 mice can be purchased at an old age from the aging rodent colony maintained by the National Institute on Aging.

[0687] In-situ preparation

[0688] Mice were initially anesthetized by intraperitoneal injection of Avertin (tribromoethanol; 13 - 17 μl / g). The anesthesia was supplemented until no response to tactile stimulation was detected. This level of anesthesia was maintained throughout the experiment using additional doses of Avertin. The tendon of the TA was exposed through an incision at the ankle. The tendon was cut a few millimeters from the muscle end. The tendon was ligated with 4.0 nylon sutures as close as possible to the muscle attachment point, and the tendon was folded back on itself and ligated again. The tendon and the exposed muscle were kept moist by regular application of isotonic saline. The mice were placed on a heated platform maintained at 37°C. The feet of the mice were fixed to the platform with cloth straps, and the knees were fixed in a clamp between sharp screws. The tendon of the muscle was firmly 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.

[0689] The TA muscle was stimulated with 0.2-ms pulses through 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 the maximal isometric twitch force (Pt). With the muscle held at Lo, it was stimulated at increasing frequencies, stepping up from 150 Hz in 50-Hz increments until the maximal force (Po), typically 250 Hz, was reached. A 1- to 2-minute rest period 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 TA Lf / Lo ratio of 0.6.

[0690] Extended contraction protocol

[0691] Each muscle was stretched twice in situ, stimulating the muscle at 250 Hz, the frequency most often resulting in Po. A protocol consisting of only two contractions was used to avoid fatigue. The stretch started from the plateau of the Lo isometric contraction. At time 0, stimulation began and the muscle remained stationary for 100 ms to allow maximal activation. From the plateau of the maximal isometric contraction, a 20% Lf length change (LC1) was applied at a speed of 1 Lf / s. Stimulation 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. A second lengthening contraction (LC2) identical to the first was performed after 10 minutes. The maximal isometric force was measured 1 minute later and then again every 5 minutes for 15 minutes. Force deficit was calculated as the difference between the isometric force during LC1 and the maximal 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.

[0692] The experimental protocol included two muscle stretches during maximal activation, followed by maximal activation to measure the decrease in maximal isometric force (Po). The change in muscle length at 20% stress relative to fiber length (Lf) was measured, where 100% corresponded to the optimal muscle length (Lo) for force development. The muscle was stretched at a rate of 2Lf / s. The decrease in Po after two stretch protocols was measured in representative mdx mice. Each lengthening contraction started from the plateau of the maximal isometric contraction. The second lengthening contraction (LC2) occurred 10 minutes after the first lengthening contraction (LC1). The maximal force during the isometric contraction was measured 10 minutes after LC2 (t1 min). The force deficit was calculated by dividing the difference between Po during LC1 and Po measured at any time after LC1 by Po during LC1 and multiplying by 100%. The sutures were cut from the muscle, and the muscle was weighed. After removing the TA muscle, the deeply anesthetized mice were sacrificed by inducing pneumothorax. The total cross-sectional area (CSA) of the myofibers of the TA muscle was calculated by dividing the muscle mass by the product of Lf and 1.06 mg / mm3 (the density of mammalian skeletal muscle). The specific Po was calculated by dividing Po by the CSA. The test results are shown in Figures 3-6 。

[0693] Figure 3 shows the force decrease before injury at 100 Hz for the compounds of the present disclosure. The force in the TA muscle of mdx mice was measured in situ at 100 Hz before and after oral administration of the compound. Stimulation at 100 Hz was applied every 10 minutes, and the change in force was recorded before starting the eccentric injury protocol. This metric gives an indication of the relative ability of the compound to decrease force in the target tissue.

[0694] Figure 4 shows the post-injury force decrease at 175 Hz for the compounds of the present disclosure.

[0695] The maximal 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 exaggerated force drops. This measurement gives an indication of the relative ability of the compound to reduce the relative drop in force after eccentric contractions. Figure 5 shows the intermediate lengthening force decrease for the compounds of the present disclosure. In situ injury of the TA muscle was caused by two maximal eccentric contractions, each with a 20% lengthening, spaced 10 minutes apart. This metric measures the relative decrease in pre-lengthening force between the first and second contractions.

[0696] Figure 6 shows the increase in TA mass after injury for the compounds of the present disclosure.

[0697] Extended injury to the TA muscle in mdx mice results in a delayed increase in muscle weight after injury. This may be due to the accumulation of fluid in the form of edema. Muscles (injured and contralateral) were removed from the mice 1 hour after injury and weighed. The relative increase in the weight of the injured muscle relative to the contralateral muscle was recorded. A decrease in this relative change indicates a reduction in edema after injury.

[0698] In some embodiments, the compounds of the present disclosure are shown in Table 1 below.

[0699] Table 1

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737] In some embodiments, the compounds of the present disclosure are as shown in Table 2 below.

[0738] Table 2

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748] In certain embodiments, the compounds of the methods described herein are optionally selected from commercially available compounds, including those described in Table 3. The compounds of Tables 3 and 4 were tested, and the IC 50 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 100 μM.

[0749] Table 3

[0750]

[0751]

[0752]

[0753] In certain embodiments, the compounds for the methods described herein include those in Table 4 or salts thereof.

[0754] Table 4

[0755]

[0756] The skeletal IC of the compounds of the present disclosure 50 values are presented in Table 5.

[0757] Table 5

[0758]

[0759]

[0760] 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.

[0761] Certain compounds of the present disclosure have cardiac IC as in Table 6 50 values.

[0762] Table 6

[0763]

[0764]

[0765] 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 is greater than 60 μM.

[0766] Although the 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. 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 alternatives 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 thereby cover the methods and structures and their equivalents falling within the scope of these claims.

Claims

1. A compound represented by formula (I): or a salt thereof, wherein: Each X is independently selected from C(R 3 ), and N, where at least one X is N; A is selected from -O-, -NR 4 -, -CR 5 R 6 - or -S-; R 1 Selected from: C 1-6 alkyl and C 2-6 alkenyl, each of which is optionally substituted with one or more independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -CN, C 3-10 carbocycle and 3 substituted by substituents of a 3- to 10-membered heterocycle, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocycle are each optionally substituted by one or more R 9 substituents; and C 3-10 a carbocyclic ring, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -CN, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl; or R 1 Together with R 3 forms a 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted by one or more R 9 ; or R 1 Together with R 4 forms a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted by one or more R 9 ; R 2 a 5- to 18-membered heteroaryl group having 2 to 17 carbon atoms and 1 to 6 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with one or more substituents independently selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and When R 2 is a pyridyl or pyrimidinyl group, the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from -O - ; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more R 9 substituted; R 3 、R 5 and R 6 each independently selected from: hydrogen; and C 1-6 alkyl; R 4 independently selected from: hydrogen; and C 1-6 alkyl; R 7 and R 8 are independently selected from: halogen, -OH, -OMe, -SH, -SMe, -NH2, -N(Me)2, - NO2, -CN and C 1-6 alkyl group; Each R 9 is independently selected from: halogen, -OR 10 , -SR 10 and -CN; and C 1-3 alkyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 and -CN; Each R 10 is independently selected from: hydrogen; and C 1-6 alkyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -CN, and -OH; n is 0 or 1; and p is 0 or 1.

2. The compound or its salt according to claim 1, wherein R 1 is selected from: C 1-6 alkyl and C 2-6 alkenyl, each of which is optionally substituted by one or more independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -CN, C 3-10 carbocyclic ring and 3 substituted by substituents of 3- to 10-membered heterocycles, wherein said C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 substituents; and C 3-10 a carbocyclic ring, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; or R 1 Together with R 3 forms a 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted by one or more R 9 ; or R 1 Together with R 4 forms a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted by one or more R 9 substituents.

3. The compound or a salt thereof according to claim 1 or 2, wherein the compound of formula (I) is represented by formula (Ia):

4. The compound or a salt thereof according to claim 3, wherein the compound of formula (I) is represented by formula (Ia):

5. The compound or a salt thereof according to claim 1 or 2, wherein the compound of formula (I) is represented by formula (Ic):

6. The compound or a salt thereof according to claim 5, wherein the compound of formula (I) is represented by formula (Ic’):

7. The compound or its salt according to claim 1 or 2, wherein A is selected from -O-, -S- and -NR 4 -.

8. The compound or a salt thereof according to claim 7, wherein A is -O-.

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

10. The compound or its salt according to claim 1, wherein R 1 is selected from: C 1-5 alkyl, which is optionally substituted with one or more independently selected from halogen, - OR 10 、 -SR 10 、 -N(R 10 )2、 -CN、 C 3-7 substituted by substituents of a carbocyclic ring and a 3- to 7-membered heterocyclic ring, wherein said C 3-7 carbocyclic ring and 3- to 7-membered heterocyclic ring are each optionally substituted by one or more R 9 ; and C 3-7 A carbocyclic ring, which is optionally substituted by one or more independently selected from halogen, - OR 10 、 -SR 10 、 -N(R 10 )2, -CN and C 1-6 substituted by a substituent of an alkyl group; or or R 1 Together with R 4 forms a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally substituted by one or more R 9 substituents.

11. The compound or its salt according to claim 10, wherein R 1 is selected from: C 1-5 An alkyl group, optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , C 3-5 carbocyclic ring and 3- to 5-membered heterocyclic ring, wherein said C 3-5 carbocyclic ring and 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 ; a C4-C6 saturated carbocyclic ring; or R 1 Together with R 4 forms an optionally one or more R 9 substituted 5-membered saturated heterocycle; wherein R 9 is independently selected from halogen, -OR 10 , and -CN; and C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 and -CN.

12. The compound or its salt according to claim 10, wherein R 1 is selected from: -CHF2, -CH(CH3)2, -CH2CH(CH3)2, -CH2CF(CH3)2, - CH2CF3, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2OCF3, - CH2C(CH3)2OCH3, -CH2SCH3, -CH2CH2SCH3, - CH2CH(CH3)SCH3, -CH3, -CH2CH3, -CH2CH2CH3, - CH(CH3)CH2CH3, -CH2CF2CH3, -CH2C(CH3)3, or R 1 together with R 4 forms a 5-membered saturated heterocycle substituted by -CH3 or -CF3.

13. The compound or its salt according to claim 1, wherein R 1 is selected from C 1-6 alkyl and C 2-6 alkenyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, and wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 .

14. The compound or its salt according to claim 13, wherein R 1 is selected from C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -CN, C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, wherein the C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring are each optionally substituted by one or more R 9 .

15. The compound or its salt according to claim 14, wherein R 1 is selected from C 1-5 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , C 3-5 carbocyclic ring and 3- to 5-membered heterocyclic ring, wherein the C 3-5 carbocyclic ring and 3- to 5-membered heterocyclic ring are each optionally substituted by one or more R 9 .

16. The compound or its salt according to claim 15, wherein R 1 is selected from C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen.

17. The compound or its salt according to claim 15, wherein R 1 is selected from -CHF2, -CH(CH3)2, -CH2CH(CH3)2, -CH2CF(CH3)2, -CH2CF3, -CH2CH2CF3, -CH2CH2OCH3, -CH2CH2OCF3, -CH2C(CH3)2OCH3, -CH2SCH3, -CH2CH2SCH3, -CH2CH(CH3)SCH3, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)CH2CH3, -CH2CF2CH3, -CH2C(CH3)3, 18. The compound or its salt according to claim 17, wherein R 1 is selected from: -CHF2 and -CH2CF3.

19. The compound or its salt according to claim 18, wherein R 1 is -CH2CF3.

20. The compound or its salt according to claim 1, wherein R 1 and R 4 together form a 3- to 10-membered heterocycle, and the 3- to 10-membered heterocycle is optionally substituted by one or more R 9 .

21. The compound or its salt according to claim 20, wherein R 1 together with R 4 forms a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally substituted by one or more R 9 .

22. The compound or its salt according to claim 21, wherein R 1 and R 4 together form a 5-membered saturated heterocycle optionally substituted by one or more R 9 substituents.

23. The compound or its salt according to claim 20, wherein R 1 together with R 4 forms a 5-membered saturated heterocycle optionally substituted with one or more substituents selected from C 1-3 alkyl and C 1-3 haloalkyl.

24. The compound or a salt thereof according to claim 20, wherein the compound is represented as:

25. The compound or its salt according to claim 1, wherein R 1 each R 9 is independently selected from halogen, -OR 10 , -CN; and C 1-3 alkyl, which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 and -CN.

26. The compound or its salt according to claim 25, wherein each R 1 is independently selected from halogen and -OR 9 ; and C 10 alkyl, which is optionally substituted by one or more substituents independently selected from halogen and -OR 1-3 10 10 .

27. The compound or its salt according to claim 26, wherein each R 1 of R 9 is independently selected from -CH3 and -CF3.

28. The compound or its salt according to claim 1, wherein R 1 is a C 3-10 carbocyclic ring, which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NH2, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 3-10 carbocyclic ring, 3- to 10-membered heterocyclic ring and C 1-6 haloalkyl.

29. The compound or its salt according to claim 28, wherein R 1 is selected from optionally substituted C4-C6 cycloalkyl, which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NH2, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 3-10 carbocycle, 3- to 10-membered heterocycle and C 1-6 haloalkyl.

30. The compound or its salt according to claim 29, wherein R 1 is selected from optionally substituted saturated C4-C6 cycloalkyl, which is optionally substituted by one or more substituents independently selected from halogen, -CN, -OH, -SH, -NH2, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 3-10 carbocycle, 3- to 10-membered heterocycle and C 1-6 haloalkyl.

31. The compound or its salt according to claim 30, wherein R 1 is selected from 32. The compound or its salt according to claim 31, wherein R 1 is 33. The compound or its salt according to claim 1, wherein R 2 is selected from 5- or 6-membered monocyclic heteroaryl groups and 9-membered bicyclic heteroaryl groups, and the 5- or 6-membered monocyclic heteroaryl groups and 9-membered bicyclic heteroaryl groups are each optionally substituted with substituents selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of which is optionally substituted with one or more R 9 substituted.

34. The compound or its salt according to claim 33, wherein R 2 is selected from 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 one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 groups.

35. The compound or its salt according to claim 34, wherein R 2 is selected from isoxazole, oxazole, thiadiazole, triazole, tetrazole, pyrazole, oxadiazole, thiazole, pyridine, pyridazine, pyrazine, benzoxazole, indazole and imidazopyridine, any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 groups.

36. The compound or its salt according to claim 1, wherein R 2 At any ortho position of R 2 is unsubstituted relative to the point of attachment to the rest of the molecule.

37. The compound or its salt according to claim 1, wherein R 2 At any ortho position on R 2 is not substituted by a carbocyclic or heterocyclic ring.

38. A compound or a salt thereof according to any one of claims 33, 36 or 37, wherein R 2 is selected from 5-membered heteroaryl optionally substituted with substituents selected from the following: Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 substituents.

39. The compound or its salt according to claim 38, wherein R 2 is selected from isoxazole, oxazole, thiadiazole, triazole, tetrazole, pyrazole, oxadiazole and thiazole, any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 substituents.

40. The compound or its salt according to claim 39, wherein R 2 is selected from isoxazole, oxazole, thiadiazole, pyrazole, oxadiazole and thiazole, any one of which is optionally substituted with a substituent selected from the following: Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of which is optionally substituted with one or more R 9 substituted.

41. The compound or its salt according to claim 38, wherein R 2 is selected from: Any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 substituents.

42. The compound or its salt according to claim 41, wherein R 2 is selected from: Any one of which is optionally substituted with a substituent selected from the following: Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 substituents.

43. The compound or its salt according to claim 41, wherein R 2 is selected from: Any one of which is optionally substituted with a substituent selected from the following: Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 substituents.

44. The compound or a salt thereof according to claim 38, wherein R 2 is selected from:

45. The compound or its salt according to claim 38, wherein R 2 is selected from:

46. A compound or a salt thereof according to any one of claims 33, 36 or 37, wherein R 2 is selected from optionally substituted 6-membered heteroaryl groups, optionally substituted with substituents selected from: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is pyridyl or pyrimidinyl, the substituent on the nitrogen atom of the pyridyl or pyrimidinyl is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 groups 47. The compound or a salt thereof according to claim 46, wherein R 2 is selected from pyridine, pyrimidine, pyridine N-oxide, pyridazine and pyrimidine N-oxide, any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more R 9 substituents.

48. The compound or its salt according to claim 46, wherein R 2 is selected from pyridine, pyrazine, pyridazine and pyrimidine, any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic ring and 3- to 10-membered heterocyclic ring, each of which is optionally substituted with one or more R 9 substituents.

49. The compound or its salt according to claim 48, wherein R 2 is selected from Any one of which is optionally substituted with one or more substituents independently selected from the following: halogen, -OR 10 , -SR 10 , -CN and the substituent on the nitrogen atom of pyridyl is optionally selected from –O - ; and C 1-6 alkyl, optionally substituted by one or more substituents independently selected from halogen and -OR 10 substituents.

50. The compound or its salt according to claim 47, wherein R 2 is selected from: Any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more R 9 substituents.

51. The compound or its salt according to claim 46, wherein R 2 is selected from:

52. The compound or its salt according to claim 1, wherein R 2 is selected from bicyclic heteroaryl optionally substituted with substituents selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 groups.

53. A compound or a salt thereof according to any one of claims 33, 36 or 37, wherein R 2 is selected from 9-membered bicyclic heteroaryl optionally substituted with substituents selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 groups.

54. The compound or its salt according to claim 53, wherein R 2 is selected from benzoxazole, benzothiazole, benzimidazole, indole, indazole and imidazopyridine, any one of which is optionally substituted with a substituent selected from the following: Halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more R 9 substituents.

55. The compound or its salt according to claim 53, wherein R 2 is selected from benzoxazole, benzothiazole, indole, indazole and imidazopyridine, any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic rings and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 substituents.

56. The compound or its salt according to claim 53, wherein R 2 is selected from benzoxazole, indazole and imidazopyridine, any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is a pyridyl or pyrimidinyl group, and the substituent on the nitrogen atom of the pyridyl or pyrimidinyl group is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted by one or more R 9 groups.

57. The compound or its salt according to claim 56, wherein R 2 is selected from benzoxazoles optionally substituted with substituents selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , - C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more R 9 substituents.

58. The compound or its salt according to claim 56, wherein R 2 is selected from: Any one of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 and -CN.

59. The compound or its salt according to claim 52, wherein R 2 is selected from: Any one of which is optionally substituted with a substituent selected from the following: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , and -CN; and when R 2 is pyridyl or pyrimidinyl, the substituent on the nitrogen atom of the pyridyl or pyrimidinyl is optionally further selected from –O-; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted by one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, and -CN; and C 3-10 carbocyclic and 3- to 10-membered heterocyclic rings, each of which is optionally substituted with one or more R 9 substituents.

60. The compound or its salt according to claim 58, wherein R 2 is selected from:

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

62. The compound or a salt thereof according to claim 1, wherein p is 0.

63. The compound or a salt thereof according to claim 1, which is selected from:

64. The compound or a salt thereof according to claim 1, which is selected from: The compound or its salt according to claim 1, which is selected from or its salt. The compound or its salt according to claim 1, which is selected from or its salt.

67. The compound of claim 1 or a salt thereof, which is selected from or a salt thereof. The compound of claim 1 or a salt thereof, which is selected from or a salt thereof. The compound of claim 1 or a salt thereof, which is selected from or a salt thereof.

70. The compound of claim 1 or a salt thereof, which is selected from or a salt thereof.

71. The compound or its salt according to claim 1, which is selected from or its salt. The compound or its salt according to claim 1, which is selected from or its salt. The compound or its salt according to claim 1, which is selected from or its salt. The compound of claim 1 or a salt thereof, which is selected from or a salt thereof.

75. Use of the compound or a salt thereof according to any one of claims 1 to 74 in the preparation of a medicament for treating a neuromuscular condition, a metabolic myopathy or a movement disorder in a subject in need thereof, wherein the neuromuscular condition is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb-girdle muscular dystrophy, tendinitis and carpal tunnel syndrome, wherein the metabolic myopathy is McArdle syndrome, and wherein the movement disorder is selected from muscle spasms associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury, traumatic event, stroke, hypoxia, meningitis, encephalitis, phenylketonuria or amyotrophic lateral sclerosis.

76. The use according to claim 75, wherein the movement disorder is selected from traumatic brain injury and spinal cord injury.

77. The use according to claim 75, wherein the compound or a salt thereof does not significantly inhibit myocardial contraction relative to an untreated control.

78. The use according to claim 77, wherein the compound or a salt thereof reduces myocardial force by less than 10% relative to an untreated control.

79. The use according to claim 75, wherein the subject has a neuromuscular condition or a movement disorder.

80. The use according to claim 75, wherein the compound or its salt is administered in an amount that reduces skeletal muscle contraction by 5% to 90% relative to the pre-treatment skeletal muscle contraction ability of the subject.

81. The use according to claim 75, wherein the neuromuscular condition is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, and limb-girdle muscular dystrophy.

82. The use according to claim 81, wherein the neuromuscular condition is Becker muscular dystrophy.

83. The use according to claim 81, wherein the neuromuscular condition is Duchenne muscular dystrophy.

84. The use according to claim 75, wherein the subject has a movement disorder, and wherein the movement disorder includes muscle spasm.

85. The use according to claim 84, wherein the muscle spasm is selected from spasms associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury, or traumatic event.

86. The use according to claim 84, wherein the muscle spasm is selected from spasms associated with stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, and amyotrophic lateral sclerosis.

87. The use according to claim 75, wherein the compound or its salt is administered in an amount sufficient to reduce involuntary muscle contraction.

88. The use according to claim 87, wherein the compound or its salt is administered in an amount sufficient to reduce involuntary muscle contraction by at least 10%.

89. The use according to claim 75, wherein the subject has a metabolic myopathy, and wherein the metabolic myopathy is McArdle syndrome.

90. The use according to claim 75, wherein the neuromuscular condition is selected from myotonic dystrophy type 1, myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, tendinitis, and carpal tunnel syndrome.

91. The use according to claim 75, wherein the use further comprises administering an additional therapeutic agent to the subject.

92. The use according to claim 91, wherein the additional therapeutic agent is a corticosteroid.

93. The use according to claim 92, wherein the corticosteroid is deflazacort or prednisone.

94. The use according to claim 91, wherein the additional therapeutic agent is vamorolone.

95. The use according to claim 91, wherein the additional therapeutic agent is gene therapy.

96. The use according to claim 95, wherein the gene therapy comprises the dystrophin gene or a variant or truncated form thereof.

97. The use according to claim 95, wherein the gene therapy comprises microdystrophin.

98. The use according to claim 91, wherein the additional therapeutic agent is eteplirsen.

99. The use according to claim 91, wherein the additional therapeutic agent is ataluren.

100. A pharmaceutical composition comprising the compound or its salt according to any one of claims 1-74 and a pharmaceutically acceptable excipient.

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