Pyridazinone compounds and uses thereof

Abstract

Disclosed herein are 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-alpha.

Description

[0001] Cross-referencing

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 756,539, filed November 6, 2018, which is incorporated herein by reference in its entirety. Background Technology

[0003] Skeletal muscle is the largest organ system in the human body, with two main functions. The first is force generation to enable muscle contraction, movement, and posture maintenance; the second is the metabolism of glucose, fatty acids, and amino acids. Skeletal muscle contraction during daily activities and exercise is naturally associated with muscle stress, breakdown, and remodeling, which are crucial for muscle adaptation. In individuals with neuromuscular conditions such as Duchenne muscular dystrophy (DMD), muscle contraction leads to a series of amplified muscle breakdowns that the body struggles to repair. Ultimately, as patients age, pathophysiological processes develop, resulting in excessive inflammation, fibrosis, and fat deposits in the muscles, foreshadowing a rapid decline in bodily function and ultimately death.

[0004] DMD is a genetic disorder affecting skeletal muscle, characterized by progressive muscle degeneration and weakness. Treatments to reduce muscle breakdown in patients with neuromuscular conditions such as DMD remain necessary. Summary of the Invention

[0005] This disclosure provides compounds for treating diseases and their salts. In some aspects, this disclosure provides compounds of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), (II), (III), and (III'), pharmaceutical compositions thereof, and methods for treating diseases.

[0006] In some respects, this article discloses compounds represented by formula (I') or pharmaceutically acceptable salts thereof:

[0007]

[0008] Or its salt, wherein:

[0009] Each X is independently selected from C(R) 3 ), N and N + (-O - ), wherein at least one X is N or N + (-O - );

[0010] A is selected from -O- and -NR 4 -、-CR 5 R 6 -、-C(O)-、-S-、-S(O)- and -S(O)2-;

[0011] R 1 Selected from:

[0012] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0013] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 The alkynyl group is replaced by a substituent, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 9 Replaced; or

[0014] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced;

[0015] R 25 Selected from:

[0016] Hydrogen and C 1-6 Alkyl; or

[0017] R 25 With R 2 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0018] R 2 Selected from:

[0019] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 A carbocyclic ring and 3 to 10-membered heterocycles, each 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 ), –CN, C 1-6 Alkyl and C 3-10 Carbon ring, wherein the C 1-6 Alkyl and C 3-10 The carbon ring is optionally composed of one or more elements independently selected from halogens, -OR 10 -SR10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0020] R 2 With R 25 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

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

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

[0023] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2. Substitution with -NO2 and -CN substituents; or

[0024] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0025] R 4 Selected from:

[0026] Hydrogen; and

[0027] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0028] R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced;

[0029] R 7 and R 8 Each is selected independently from:

[0030] Halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN;

[0031] Each R 9 Selected independently 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 2-3Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used;

[0034] Each R 10 Selected independently from:

[0035] Hydrogen; and

[0036] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0037] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

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

[0039] In some respects, this disclosure provides compounds represented by formula (II'):

[0040]

[0041] Or its salt, wherein:

[0042] T is selected from -O-, -NR 14 -、-CR 15 R 16 -、-C(O)-、-S-、-S(O)- and -S(O)2;

[0043] R 11 Selected from acetyl and C 1-5 Halogenated alkyl groups;

[0044] R 125 Selected from:

[0045] Hydrogen and C 1-6 Alkyl; or

[0046] R 125 With R 12 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0047] R 12 Selected from:

[0048] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 20 -SR 10 -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 Substituents of -CN and -CN; and

[0049] C1 alkyl, which is C 3-10 The carbon ring or a 3- to 10-membered heterocyclic ring is substituted, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 19 Replaced; and

[0050] C 3-10 Carbon rings, which are optionally composed of one or more R 19 Replace; or

[0051] R 12 With R 125 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0052] R 14 Selected from:

[0053] Hydrogen; and

[0054] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 2. Substitution of -NO2 and -CN groups;

[0055] R 15 and R 16 Each selected from:

[0056] Hydrogen, halogen, -OR 20 -SR 20 -N(R) 20 2. -NO2 and -CN; and

[0057] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0058] R 17 and R 18 Each selected from:

[0059] Halogen, -OR 20 -SR 20 -N(R) 20 )2, -CN, -CHF2, -CF3 and -CH2F; and

[0060] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0061] Each R 19 Selected independently from:

[0062] 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

[0063] C 1-3 Alkyl, C2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN; and

[0064] C 3-10 A carbon ring, optionally composed of one or more elements independently selected from halogens, -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 Substituents of ) and –CN are substituted;

[0065] Each R 20 Selected independently from:

[0066] Hydrogen; and

[0067] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0068] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0069] w is 0, 1, or 2; and z is 0, 1, or 2.

[0070] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) and a pharmaceutically acceptable excipient.

[0071] In some embodiments, this disclosure provides pyridazolone compounds or salts thereof for treating diseases and / or inhibiting myosin II. Methods of administering pyridazolone compounds or salts thereof discussed herein, such as compounds or salts of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be used to treat neuromuscular conditions and movement disorders.

[0072] This disclosure also provides methods for inhibiting myosin II and / or for treating diseases such as neuromuscular diseases or movement disorders, including administering a compound of formula (III') to a subject in need:

[0073]

[0074] Or its salt, wherein:

[0075] Each Y is independently selected from C(R) 3 ), N and N + (-O- );

[0076] A does not exist or is selected from -O- or -NR. 4 -、-CR 5 R 6 -、-C(O)-、-S-、-S(O)- and -S(O)2-;

[0077] R 1 Selected from:

[0078] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0079] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 -CN, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is replaced by a substituent, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 9 Replaced; or

[0080] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; and

[0081] When A does not exist, R 1 Additionally, it is selected from H and halogens;

[0082] R 25 Selected from:

[0083] Hydrogen and C 1-6 Alkyl; or

[0084] R 25 With R 2 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0085] R 2 Selected from:

[0086] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0087] C 3-10 A carbocyclic ring and 3 to 10-membered heterocycles, each 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)OR10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), –CN, C 1-6 Alkyl and C 3-10 Carbon ring, wherein the C 1-6 Alkyl and C 3-10 The carbon ring is optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0088] R 2 With R 25 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0089] R 3 R 5 and R 6 Each is selected independently from:

[0090] Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and

[0091] C 1-6 Alkyl, optionally substituted with one or more substituents independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; or

[0092] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0093] R 4 Selected from:

[0094] Hydrogen; and

[0095] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2. Substitution with -NO2 and -CN substituents; or

[0096] R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced;

[0097] R 7 and R 8 Each is selected independently from:

[0098] Halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN;

[0099] Each R 9 Selected independently from:

[0100] 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

[0101] C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used;

[0102] Each R 10 Selected independently from:

[0103] Hydrogen; and

[0104] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0105] C 3-10A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0106] n is 0, 1, or 2; and

[0107] p is 0, 1, or 2.

[0108] In some embodiments, this disclosure provides a method for treating neuromuscular conditions or movement disorders, comprising administering to a subject in need a compound or salt of any one of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), (II), (III'), (III), or (IIIa). In some embodiments, the neuromuscular condition is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome.

[0109] In some embodiments, this disclosure provides a method for inhibiting myosin II, comprising administering to a subject in need a compound or salt of any one of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), (II), (III'), (III), or (IIIa).

[0110] Incorporation

[0111] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually cited and incorporated herein by reference. Attached Figure Description

[0112] The novel features of the invention are set forth in the appended claims. A better understanding of the features and advantages of the invention will be gained by referring to the following detailed description of illustrative embodiments utilizing the principles of the invention, along with the accompanying drawings (also referred to herein as “Figures”):

[0113] Figure 1 The damage induced by excessive contraction is described, which precedes inflammation and irreversible fibrosis, the latter being a characteristic of late-stage DMD pathology.

[0114] Figure 2 N-Benzyl-p-Tolyl-Sulfonamide (BTS), an inhibitor of fast-fiber skeletal muscle myosin, has been shown to protect muscles from pathological muscle disorder in DMD zebrafish model embryos.

[0115] Figure 3 The reduction in pre-damage force at 100 Hz is described for various compounds of this disclosure;

[0116] Figure 4 The damage reduction at 175 Hz is described for various compounds of this disclosure;

[0117] Figure 5 The decrease in intermediate elongation force is described for various compounds of this disclosure;

[0118] Figure 6 The increase in TA mass following damage to various compounds of this disclosure is described. Detailed Implementation

[0119] While preferred embodiments of the 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, modifications, 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 carrying out the invention. The scope of the invention is intended to be defined by the appended claims, thereby encompassing the methods and structures and their equivalents within the scope of those claims.

[0120] In some respects, this disclosure provides a method for treating neuromuscular diseases by selectively inhibiting skeletal muscle fast-twitch fibromyosin. In particular, the methods of this disclosure can be used to treat DMD and other neuromuscular diseases.

[0121] Skeletal muscle is primarily composed of two types of fibers: slow-twitch fibers (Type I) and fast-twitch fibers (Type II). In each muscle, these two types of fibers are arranged in a mosaic pattern, and the composition varies between different muscles and at different points in growth and development. Slow-twitch fibers have excellent aerobic energy production capacity. They have a low contraction rate but high fatigue tolerance. Slow-twitch fibers typically have higher mitochondrial and myoglobin concentrations than fast-twitch fibers and are surrounded by more capillaries. Due to lower myosin ATPase activity, slow-twitch fibers contract more slowly and produce less energy compared to fast-twitch fibers, but they can maintain contractile function for longer periods, such as in stability, postural control, and endurance training.

[0122] Based on the specific skeletal muscle fast-twitch myosin it expresses, human fast-twitch muscle fibers can be further divided into two main fiber types (Type IIa and Type IIx / d). Type III fast-twitch fibers (Type IIb) exist in other mammals but are rarely found in human muscles. Fast-twitch muscle fibers possess excellent anaerobic energy production capabilities and can generate significant amounts of tension in a short time. Typically, compared to slow-twitch muscle fibers, fast-twitch fibers have lower concentrations of mitochondria, myoglobin, and capillaries, thus fatigueing more quickly. Fast-twitch muscle fibers generate the force required to resist activity more rapidly.

[0123] The ratio of Type I to Type II fibers can vary among individuals. For example, in non-athletic individuals, each type of muscle fiber may account for approximately 50%. Strength athletes may have a higher proportion of fast-twitch muscle fibers; for example, 70-75% of sprinters are Type II. Endurance athletes may have a higher proportion of slow-twitch muscle fibers; for example, 70-80% of long-distance runners are slow-twitch. The ratio of Type I to Type II fibers can also vary with age. The proportion of Type II fibers (especially Type IIx) can decrease with age, leading to a loss of lean muscle mass.

[0124] The contraction of skeletal muscle leads to muscle damage in subjects with neuromuscular diseases (such as DMD), and this damage appears to be more prevalent in fast-twitch muscle fibers. It has been observed that in malnourished mouse models, the acute force reduction after strain is greater in models primarily composed of fast-twitch type II muscle fibers than in models primarily composed of slow-twitch type I muscle fibers (i.e., soleus muscle). It has also been demonstrated that in malnourished mouse models, the degree of acute force reduction and histological damage is proportional to the peak force developed during the strain. Figure 1This shows damage caused by excessive contraction, which occurs prior to the inflammation and irreversible fibrosis characteristic of late-stage DMD pathology. [Figure adapted from: Claflin and Brooks, Am J Brooks, Physiol Cell, 2008]. Contraction-induced muscle damage in these patients can be reduced by limiting peak force generation in type II fibers and potentially increasing dependence on healthier type I fibers. N-Benzyl-p-toluenesulfonamide (BTS) is an inhibitor of myosin in skeletal muscle fast-twitch fibroblasts, such as... Figure 2 As shown, it has been shown to protect muscles from pathological muscle disorders in embryos from a DMD zebrafish model. [Source: Li and Arner, PLoSONE, 2015].

[0125] Inhibitors of skeletal muscle myosin that are non-selective for type II skeletal muscle fibers may lead to excessive inhibition of skeletal muscle contraction, including respiratory function and undesirable inhibition of cardiac activity, since the heart shares multiple structural components (e.g., type I myosin) with type I skeletal muscle fibers. While not wishing to be bound by a specific mechanistic theory, this disclosure provides selective inhibitors of myosin in skeletal muscle fast-twitch fibroblasts as a treatment option for DMD and other neuromuscular disorders. Targeted inhibition of type II skeletal muscle myosin can reduce skeletal muscle contraction while minimizing the impact on the subject's daily activities.

[0126] definition

[0127] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0128] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” as used in this specification and claims include plural indicators.

[0129] Term "C" x-y "or "C x -C y "When used with chemical moieties such as alkyl, alkenyl, or alkynyl, it is intended to include groups containing x to y carbons in the chain. For example, the term 'C'..." 1-6 "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups containing 1 to 6 carbons.

[0130] Term "C" x-y "Alkenyl" and "C" x-y "Alkyne" refers to substituted or unsubstituted unsaturated aliphatic groups that are similar in length and possible substitutions to the alkyl groups mentioned above, but each contains at least one double or triple bond.

[0131] 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 exemplary embodiments, an aromatic ring, such as a phenyl ring, may be fused with a saturated or unsaturated ring such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, 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 spirocyclic systems, 4-4 spirocyclic 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.

[0132] The term "aryl" refers to an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system. An aromatic monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and carbon atoms, totaling 5-18 carbon atoms, wherein at least one ring in the system is aromatic, that is, according to Hückel's theory, it contains a cyclic, delocalized (4n+2)π–electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene.

[0133] The term "cycloalkyl" refers to a saturated ring in which each ring atom is a carbon atom. Cycloalkyl groups can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, spirobicyclic rings, and 5- to 12-membered bridged rings. In some embodiments, the cycloalkyl group contains 3 to 10 carbon atoms. In other embodiments, the cycloalkyl group contains 5 to 7 carbon atoms. The cycloalkyl group can be attached to the rest of the molecule via a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic carbocyclic groups include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclic [2.2.1]heptyl), decahydronaphthyl, 7,7-dimethylbicyclic [2.2.1]heptyl, bicyclic [1.1.1]pentyl, etc.

[0134] 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. Cycloalkenyl groups can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In some other embodiments, the cycloalkenyl group contains 5 to 7 carbon atoms. The cycloalkenyl group can be attached to the rest of the molecule via single bonds. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0135] The terms "halogenated," "halogen," or "halide" refer to fluorination, chlorination, bromination, or iodination. In some embodiments, halogenation is fluorination, chlorination, or bromination.

[0136] The term "haloalkyl" refers to an alkyl group as defined above that is substituted with one or more halogroups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-chloromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the haloalkyl group may optionally be further substituted as described herein.

[0137] 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 rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. Where valence permits, bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings. In exemplary embodiments, an aromatic ring, such as a pyridyl group, may be fused with 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, such as 5- to 12-membered spirobicycles, such as 2-oxa-6-azaspiro[3.3]heptane.

[0138] The term "heteroaryl" refers to a group derived from a 5- to 18-membered aromatic ring group comprising 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 comprises a cyclic, delocalized (4n+2)π–electron system according to Hückel theory. Heteroaryls include fused or bridged ring systems. The heteroatoms in the heteroaryl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heteroaryl group is connected to the rest of the molecule via any atom in the ring. Examples of heteroaryls include, but are not limited to, nitrogen-containing heteroaryls. 1,3-benzodioxolane, acridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxolane, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxolane Benz[b][1,4]oxazinyl, 1,4-benzodioxane, benzonaphthofuranyl, benzooxazolyl, benzodioxolanecycloyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothien[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, cenolinyl, cyclopent[d]pyrimidinyl, 6,7-dihydro-5H-cyclopent[4,5]thien[2,3-d]pyrimidinyl, 5,6-dihydro Benzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cenolinyl, 6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocyclooctano[d]pyridinyl, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indazinyl, isoxazolyl, 5,8-methylbridged-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazapyridine 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purineyl, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyridazinyl, pyrroleyl, quinazolinyl, quinoxalinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl Zolpidem, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptano[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyridino[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)).

[0139] The term "heterocyclic alkyl" refers to a saturated ring having a carbon atom and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocyclic alkyl groups can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, spirobicyclic rings, and 5- to 12-membered bridged rings. The heteroatom in the heterocyclic alkyl group is optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. Wherever valence permits, the heterocyclic alkyl group is attached to the remainder of the molecule through any atom of the heterocyclic alkyl group, such as any carbon or nitrogen atom of the heterocyclic alkyl group. Examples of heterocyclic alkyl groups include, but are not limited to, dioxolane, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl.

[0140] The term "heterocyclic alkenyl" refers to an unsaturated ring having a carbon atom and at least one heteroatom, and having at least one double bond between the two ring carbons. Heterocyclic alkenyls do not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocyclic alkenyls can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, the heterocyclic alkenyl contains 5 to 7 carbon atoms. The heterocyclic alkenyl can be attached to the rest of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrrolidone (dihydropyrrole), pyrazolinone (dihydropyrazole), imidazoline (dihydroimidazol), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazol), isothiazolinone (dihydroisothiazol), oxadiazolinone (dihydrooxadiazole), thiadiazolinone (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyrimidine, tetrahydropyrimidine, dihydropyridine, tetrahydropyrimidine, dihydropyridine, tetrahydropyridine, pyran, dihydropyran, thiaran, dihydrothiaran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0141] The term "substituted" refers to a portion of a compound having a substituent that replaces hydrogen atom on one or more carbon atoms or substituted heteroatoms (e.g., NH or NH2). It should be understood that "substituted" or "replaced with..." implies that the substitution is based on the possible valences of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. In some embodiments, substitution refers to a portion where two hydrogen atoms on the same carbon atom are replaced by a substituent, such as replacing two hydrogen atoms on a single carbon atom with an oxo, imino, or thio group. As used herein, the term "substituted" is intended to include all permissible substituents in an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For a suitable organic compound, permissible substituents can be one or more and can be the same or different.

[0142] In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O)t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, areneyl, arynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any one of which may optionally be replaced by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(Ra )2 (where t is 1 or 2) replace; where each R a Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a Where the valence permits, it may be optionally replaced by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) replace; and where each R b Independently selected from direct bonds, or straight-chain or branched alkylene, alkenylene, or ynylene chains, and each R cIt is a straight-chain or branched alkylene, alkenylene, or ynylene chain.

[0143] Double bonds with oxygen atoms, such as oxo groups, are represented in this document as “=O” and “(O)”. Double bonds with nitrogen atoms are represented as “=NR” and “(NR)”. Double bonds with sulfur atoms are represented as “=S” and “(S)”.

[0144] As used herein, the phrases “parenteral administration” and “prescription” refer to administration methods other than enteral and local administration, usually by injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-occipital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0145] This article uses the phrase "pharmaceutically acceptable" to refer to those compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0146] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein refers to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is harmless to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth gum powder; (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 so on. Soybean oil; (10) Diols, such as propylene glycol; (11) Polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and aluminum hydroxide; (15) Alginate; (16) Atherless water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethanol; (20) Phosphate buffer solution; and (21) Other non-toxic compatible substances used in pharmaceutical preparations.

[0147] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. 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, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0148] compound

[0149] The following is a discussion of compounds and their salts that can be used in the methods of this disclosure. The compounds and salts are described in formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), and (II).

[0150] In some respects, this paper discloses compounds represented by formula (I)':

[0151]

[0152] Or its salt, wherein:

[0153] Each X is independently selected from C(R) 3 ), N and N + (-O - ), wherein at least one X is N or N + (-O - );

[0154] A is selected from -O- and -NR 4 -、-CR 5 R 6 -、-C(O)-、-S-、-S(O)- and -S(O)2-;

[0155] R 1 Selected from:

[0156] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0157] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 The alkynyl group is replaced by a substituent, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups.9 Replaced; or

[0158] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced;

[0159] R 25 Selected from:

[0160] Hydrogen and C 1-6 Alkyl; or

[0161] R 25 With R 2 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0162] R 2 Selected from:

[0163] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 A carbocyclic ring and 3 to 10-membered heterocycles, each 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 ), –CN, C 1-6 Alkyl and C 3-10 Carbon ring, wherein the C 1-6 Alkyl and C 3-10 The carbon ring is optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0164] R 2 With R 25Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0165] R 3 R 5 and R 6 Each is selected independently from:

[0166] Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and

[0167] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0168] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0169] R 4 Selected from:

[0170] Hydrogen; and

[0171] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10)2, replaced by substituents of -NO2 and -CN; or

[0172] R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced;

[0173] R 7 and R 8 Each is selected independently from:

[0174] Halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN;

[0175] Each R 9 Selected independently from:

[0176] 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

[0177] C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used;

[0178] Each R 10 Selected independently from:

[0179] Hydrogen; and

[0180] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0181] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0182] n is 0, 1, or 2; and

[0183] p is 0, 1, or 2.

[0184] In some respects, this document discloses compounds represented by formula (I) or pharmaceutically acceptable salts thereof:

[0185]

[0186] Or its salt, wherein:

[0187] Each X is independently selected from C(R) 3 ), N and N + (-O - ), wherein at least one X is N or N + (-O - );

[0188] A is selected from -O- and -NR 4 -、-CR 5 R 6 -、-C(O)-、-S-、-S(O)- and -S(O)2-;

[0189] R 1 Selected from:

[0190] C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0191] C 3-10Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN; or

[0192] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced;

[0193] R 2 Selected from:

[0194] C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0195] C 3-10 A carbocyclic ring and 3 to 10-membered heterocycles, each 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 C 1-6 Alkyl and C 3-10 Carbon rings, any one of which may optionally be independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN;

[0196] R 3 R 5 and R 6 Selected independently from:

[0197] Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0198] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0199] R 4 Selected from:

[0200] Hydrogen; and

[0201] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced;

[0202] Each R 7 and R 8 Selected independently from:

[0203] Halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN;

[0204] Each R9 Selected independently from:

[0205] 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

[0206] C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used;

[0207] Each R 10 Selected independently each time it appears.

[0208] Hydrogen; and

[0209] C 1-6 Alkyl, C2-6 alkenyl, C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in carbocyclic rings and 3- to 10-membered heterocycles; and

[0210] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0211] n is 0, 1, or 2; and

[0212] p is 0, 1, or 2.

[0213] In some embodiments, for compounds or salts of formula (I') or (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 implementations, an X is N. + (-O - And an X is C(R) 3 In some implementations, each X is N. In some implementations, one X is N, and another X is N. + (-O - ).

[0214] In some embodiments, for compounds or salts of formula (I') or (I), each X is further selected from C(R) 3 ).

[0215] In some embodiments, the compound of formula (I') or (I) is represented by formula (Ia) or formula (Ib):

[0216]

[0217] In some embodiments, compounds of formula (I') or (I) are represented by formula (Ic) or formula (Id):

[0218]

[0219] In some embodiments, compounds of formula (I') or (I) are represented by formula (Ia) or formula (Ic):

[0220]

[0221] In some embodiments, for compounds or salts of any one of formulas (I'), (I), (Ia), (Ib), (Ic), or (Id), A is selected from -S-, -O-, and -NR-. 4 -and-CHR 5 -, where R 4 For H or C 1-3 Alkyl; or R 4 and R 1 Together with the N atoms to which they are attached, they form 4 to 9-membered heterocycles, which are optionally bounded by one or more R atoms. 9 Replaced; and R 5 For H; or R 5 and R 1 Together with the atoms they are attached to, they form C 3-6 Carbon rings, which are optionally composed of one or more R 9 Replaced. In some implementations, A is selected from -O-, -NR. 4 -、-CR 5 R 6 - and -C(O)-. In some implementations, A is selected from -O- and -NR-. 4 In some implementations, A is -O-. In some implementations, A is -C(O)-. In some implementations, A is –NR. 4 -, such as –NH-. In some embodiments, A is selected from -CR 5 R 6 -, such as -CHR 5 -, such as -CH2-.

[0222] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from:

[0223] C 1-6 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OR 10 -SR 10 -N(R) 10)2, -NO2, =O, =S, =NH, =N(C 1-3 Alkyl), -CN, C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein the C 3-6 The carbon ring or 3- to 6-membered heterocycle is optionally separated by one or more R 9 Replaced; and

[0224] R 1 Selected from C 3-8 Carbon rings and 3- to 8-membered heterocycles containing 1 to 3 heteroatoms, wherein the C 3-8 The carbon ring and the 3- to 8-membered heterocycle are each optionally separated by one or more R 9 Replaced; or

[0225] R 1 With R 4 Together they form 4 to 9-membered heterocycles, which are optionally separated by one or more R 9 The 4- to 9-membered heterocycles are selected from monocyclic, bridged, and spirocyclic rings, optionally containing one or two additional heteroatoms; or

[0226] R 1 With R 5 Together they form C 3-6 cycloalkyl, which is optionally composed of one or more R 9 What it replaced.

[0227] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from:

[0228] C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OC 1-3 Haloalkyl, -N(C) 1-3 Alkyl)2, C 4-6 Cycloalkyl groups and 4-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 The cycloalkyl or 4-membered saturated heterocycle is optionally substituted by 1 to 3 substituents, which are independently selected from halogens and C. 1-3 Alkyl groups; and

[0229] C 4-8 Saturated carbocyclic rings, aryl rings, and 4- to 6-membered saturated heterocycles containing one or two heteroatoms, wherein the C 4-8 The saturated carbocyclic ring, aryl group, and 4- to 6-membered saturated heterocycle are each optionally substituted by 1 to 3 substituents, which are independently selected from halogens, -OH, and -OC. 1-3 Alkyl, -OC 1-3Haloalkyl, -SH, -NH2, -NO2, =O, =S, =NH, -CN, C 1-3 Alkyl and C 1-3 Hydroxyalkyl; or

[0230] R 1 With R 4 Together they form 4 to 9-membered heterocycles selected from 4 to 6-membered monocyclic rings, 7 to 9-membered bridged rings, and 7-membered spirocyclic rings, each optionally containing one or two additional heteroatoms, and each optionally substituted with 1 to 3 substituents selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -NO2, =O, =S, =NH and -CN, wherein the C 1-3 The alkyl group may optionally be further substituted with a group selected from -OH, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl; or

[0231] R 1 With R 5 Together they form C 3-6 Cycloalkyl.

[0232] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from:

[0233] C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OC 1-3 Haloalkyl, C 4-6 Cycloalkyl groups and 4-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 The cycloalkyl or 4-membered saturated heterocycle is optionally substituted by 1 to 3 substituents, which are independently selected from halogens and C. 1-3 Alkyl groups; and

[0234] C 4-6 cycloalkyl, C 5-8 Bridged cycloalkyl groups, phenyl groups, and 4- to 6-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 cycloalkyl, C 5-8 The bridged cycloalkyl group, phenyl group, and 4- to 6-membered saturated heterocycle are each optionally substituted with 1 to 3 substituents, which are independently selected from halogens, -OH, and -OC. 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Alkyl and C1-3 Hydroxyalkyl; or

[0235] R 1 With R 4 Together they form 4 to 7-membered heterocycles selected from aziridine, pyrrolidine, piperidine, morpholine, spiro-aziridine, bridged piperidine, and bridged morpholine, each optionally bounded by 1 to 3 R groups. 9 The substitutions, wherein each of the spiro-azacyclobutane, bridged piperidine, and bridged morpholine optionally contains an additional heteroatom; and wherein each R 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and -OC 1-3 Halogenated alkyl groups, wherein the C 1-3 Alkyl groups may optionally be further divided by a -OC 1-3 Halogenated alkyl substitution; or

[0236] R 1 With R 5 Together they form C 3-6 Cycloalkyl.

[0237] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from -CH3, -CH(CH3)2, -CH2CH2CH3, -C(CH3)3, -CHF2, -CF3, -CH2CF3, CH2CH2CF3, -CH2CH2-O-CF3, Or R 1 and R 4 Together with the N atoms they are attached to, they form Or R 1 and R 5 Together with the atoms they are attached to, they form In some implementation schemes, R 1 Selected from -CH3, -CH2CH2CH3, -C(CH3)3, -CHF2, -CF3, -CH2CF3, CH2CH2CF3, -CH2CH2-O-CF3, Or R 1 and R 4 Together with the N atoms they are attached to, they form Or R 1 and R 5 Together with the atoms they are attached to, they form

[0238] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from C 1-6 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =NH, =N(C 1-3 Alkyl), -CN, C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein the C 3-6 The carbon ring or 3- to 6-membered heterocycle is optionally separated by one or more R 9 Replaced. In some implementations, R 1 Selected from C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OH, -OC. 1-3 Alkyl, -OC 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 4-6 Cycloalkyl groups and 4- to 6-membered saturated heterocycles containing one or two heteroatoms, wherein the C 4-6 The cycloalkyl group and the 4- to 6-membered saturated heterocycle are each optionally substituted with 1 to 3 substituents, which are independently selected from halogens and C. 1-3 Alkyl group. In some embodiments, R 1 Selected from C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OC 1-3 Haloalkyl, -N(C) 1-3 Alkyl)2, C 4-6 Cycloalkyl groups and 4-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 The cycloalkyl or 4-membered saturated heterocycle is optionally substituted by 1 to 3 substituents, which are independently selected from halogens and C. 1-3 Alkyl group. In some embodiments, R 1 Selected from C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OC 1-3 Haloalkyl, C 4-6 Cycloalkyl groups and 4-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 The cycloalkyl or 4-membered saturated heterocycle is optionally substituted by 1 to 3 substituents, which are independently selected from halogens and C. 1-3Alkyl group. In some embodiments, C 1-4 C on alkyl 4-6 The cycloalkyl substituent is cyclobutyl. In some embodiments, C 1-4 The four-membered saturated heterocyclic substituent on the alkyl group is an oxobutyryl group. In some embodiments, R 1 Selected from -CH3, -CH(CH3)2, -CH2CH2CH3, -C(CH3)3, -CHF2, -CF3, -CH2CF3, CH2CH2CF3, -CH2CH2-O-CF3, In some implementation schemes, R 1 Selected from -CH3, -CH2CH2CH3, -C(CH3)3, -CHF2, -CF3, CH2CF3, CH2CH2CF3, -CH2CH2-O-CF3, In some implementation schemes, R 1 Selected from C 3-8 Carbon rings and 3- to 8-membered heterocycles containing 1 to 3 heteroatoms, wherein the C 3-8 The carbon ring and the 3- to 8-membered heterocycle are each optionally separated by one or more R 9 Replaced. In some implementations, R 1 Selected from C 4-8 Saturated carbocyclic rings, aryl rings, and 4- to 6-membered saturated heterocycles containing one or two heteroatoms, wherein the C 4-8 The saturated carbide ring, aryl group, and 4- to 6-membered saturated heterocycle are each optionally separated by 1 to 3 R groups. 9 Replacement. In some implementations, R 1 Selected from C 4-6 cycloalkyl, C 5-8 Bridged cycloalkyl groups, phenyl groups, and 4- to 6-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 cycloalkyl, C 5-8 Bridged cycloalkyl, phenyl, and 4- to 6-membered saturated heterocycles are each optionally bounded by 1 to 3 R... 9 Replacement. In some implementations, R 1 Selected from Each can be randomly assigned to 1 to 3 Rs 9 Replacement. In some implementations, R 1 Selected from Each can be randomly assigned to 1 to 3 Rs 9 Replacement. In some implementations, each R 9 Independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10-CN and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected independently by one or more halogens, -OH, -OC. 1-3 Alkyl and -OC 1-3 The alkyl halogroups are substituted. In some embodiments, each R... 9 Independently selected from halogens, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -SH, -NH2, -NO2, =O, =S, =NH, -CN, C 1-3 Alkyl and C 1-3 Hydroxyalkyl. In some embodiments, each R 9 Independently selected from halogens, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Alkyl and C 1-3 Hydroxyalkyl. In some embodiments, each R 9 Independently selected from halogens, -OH, C 1-3 Alkyl and C 1-3 Hydroxyalkyl. In some embodiments, R 1 Selected from In some implementation schemes, R 1 Selected from

[0239] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 The substituted phenyl group, optionally replaced by one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10-C(O)N(R) 10 2, -NO2, -CN and C 1-6 Alkyl groups are substituted; and 4- to 6-membered heterocyclic alkyl groups are optionally replaced by one or more groups independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN and C 1-6 Alkyl groups are substituted.

[0240] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from C 1-3 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 The substituted phenyl group, optionally replaced by one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl groups are substituted; and 4- to 6-membered heterocyclic alkyl groups are optionally replaced by one or more groups independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl groups are substituted.

[0241] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from C 1-3 Alkyl groups, optionally substituted with one or more substituents independently selected from halogens; and 4- to 6-membered heterocyclic alkyl groups and phenyl groups, any one of which may optionally be substituted with one or more substituents independently selected from halogens and C. 1-3 Alkyl substituents. In some embodiments, R 1Selected from -CHF2, -CF3, -CH3, -CH2CH2CF3, -CH2CF3, p-fluorophenyl, p-chlorophenyl,

[0242] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), A is -NR. 4 -; and R 1 and R 4 Together with the N atoms to which they are attached, they form 4 to 9-membered heterocycles, which are optionally bounded by one or more R atoms. 9 The 4- to 9-membered heterocycle is selected from monocyclic, bridged, and spirocyclic rings, and optionally contains one or two additional heteroatoms. In some embodiments, R 1 and R 4 Together with the N atoms they are attached to, they form 4 to 9-membered heterocycles, selected from 4 to 6-membered monocycles, 7 to 9-membered bridged rings, and 7-membered spirocycles, each optionally containing one or two additional heteroatoms, and each optionally bounded by 1 to 3 R atoms. 9 Replacement. In some implementations, by R 1 and R 4 The resulting 4- to 9-membered heterocycles are optionally bounded by 1 to 3 R groups. 9 Replacement of 4- to 7-membered heterocyclic rings. In some embodiments, R... 1 and R 4 The 4- to 7-membered heterocycles are selected from aziridine, pyrrolidine, piperidine, morpholine, spiro-aziridine, bridged piperidine, and bridged morpholine, each optionally bound by 1 to 3 R groups. 9 The alternatives, wherein each of the spiro-azacyclobutane, bridged piperidine, and bridged morpholine optionally contains an additional heteroatom. In some embodiments, R 1 and R 4 Together with the N atoms they are attached to, they form 4 to 9-membered heterocycles, selected from... Each of these is arbitrarily divided by 1 to 3 Rs. 9 Replaced. In some implementations, R 1 and R 4 Together with the N atoms they are attached to, they form 4- to 7-membered heterocycles, selected from... Each of these is arbitrarily divided by 1 to 3 Rs. 9 Replaced. In some implementations, each R 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OR 10 -SR 10 -N(R) 10)2, -NO2, =O, =S, =N(R 10 ) and -CN, wherein the C 1-3 The alkyl group may optionally be further substituted with a group selected from -OH, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups. In some embodiments, each R... 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -NO2, =O, =S, =NH and -CN, wherein the C 1-3 The alkyl group may optionally be further substituted with a group selected from -OH, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups. In some embodiments, each R... 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl and =O, wherein the C 1-3 The alkyl group may optionally be further substituted with a group selected from -OH, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups. In some embodiments, each R... 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and -OC 1-3 Halogenated alkyl groups, wherein the C 1-3 Alkyl groups may optionally be further divided by a -OC 1-3 Halogenated alkyl substitution. In some embodiments, R 1 and R 4 Together with the N atoms they are attached to, they form 4 to 9-membered heterocycles, selected from... In some implementation schemes, R 1 and R 4 Together with the N atoms they are attached to, they form 4- to 7-membered heterocycles, selected from...

[0243] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 With R 4 Together they form an optional combination of one or more R 9The 4- to 7-membered heterocycle is replaced. In some embodiments, the 4- to 7-membered heterocycle is selected from α-saturated heterocycles. In some embodiments, the 4- to 7-membered heterocycle is selected from α-monocyclic saturated heterocycles or spirocyclic saturated heterocycles, for example, Any one of them may be arbitrarily assigned to one or more R 9 Replaced. In some embodiments, the substituents on the 4- to 7-membered heterocycles are independently selected from halogens and C. 1-6 alkyl.

[0244] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 With R 4 Together they form 4- to 7-membered heterocycles, selected from:

[0245] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 Selected from optionally substituted C3-C6 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl, and spiropentyl, wherein any one of them is optionally substituted. In some embodiments, R 1 Selected from alkyl groups, such as methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may optionally be substituted. In some embodiments, R 1 Selected from: In some implementations, R 1 Selected from optional replacements

[0246] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), A is -CHR. 5 -; and R 1 and R 5 Together with the atoms they are attached to, they form C 3-6 Carbon rings, which are optionally composed of one or more R 9 Replaced. In some implementations, R 1 and R 5 Together with the atoms they are attached to, they form C 3-6 cycloalkyl, which is optionally composed of one or more R 9 Replaced. In some implementations, R 1 and R 5 Together with the atoms they are attached to, they form It is optionally controlled by one or more R 9 What it replaced.

[0247] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 2 Selected from:

[0248] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 The aryl group, -CN, and 5- to 6-membered heteroaryl group are substituted with substituents containing 1 to 3 heteroatoms, wherein the aryl group and the 5- to 6-membered heteroaryl group are each optionally replaced by one or more R groups. 9 Replaced; and

[0249] a saturated C 3-8 A carbon ring, optionally composed of one or more independently selected from halogens, C 1-3 Substituents of alkyl and aryl groups; or

[0250] R 2 and R 25 Together with the N atoms they are attached to, they form 4- to 6-membered rings, which are optionally bounded by one or more R atoms. 9 What it replaced.

[0251] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 2 Selected from:

[0252] C 1-5 Alkyl groups, optionally substituted with 1 to 3 substituents independently selected from: halogen, -NO2, =O, =S, =NH, -CN, aryl, and 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms, wherein each of the aryl and 5- to 6-membered heteroaryl groups is optionally substituted with 1 to 3 substituents independently selected from halogen and C 1-3 Alkyl groups; and

[0253] C 3-6 Monocyclic cycloalkyl, C 5-6 Bridged cycloalkyl and C 5-6 Spirocycloalkyl, wherein each is optionally substituted with 1 to 3 substituents, which are independently selected from halogens, C 1-3 Alkyl and phenyl; or

[0254] R 2 and R 25 Together with the N atoms they are attached to, they form 4 to 6-membered rings.

[0255] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 2 Selected from:

[0256] C 1-5 An alkyl group, optionally substituted with one to three substituents independently selected from: halogen, -CN, and phenyl, wherein the phenyl group is optionally substituted with one, two, or three halogens; and

[0257] C 3-4 cycloalkyl, Each can be chosen by C 1-3 Alkyl or phenyl substitution; or

[0258] R 2 and R 25 Together with the N atoms they are attached to, they form nitrogen-containing heterocyclic butyl groups.

[0259] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 2 Selected from ethyl, Or R 2 and R 25 Together with the N atoms they are attached to, they form In some implementation schemes, R 2 Selected from ethyl, Or R 2 and R 25 Together with the N atoms they are attached to, they form

[0260] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 2 C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 The aryl group, -CN, and 5- to 6-membered heteroaryl group are substituted with substituents containing 1 to 3 heteroatoms, wherein the aryl group and the 5- to 6-membered heteroaryl group are each optionally replaced by one or more R groups. 9 Replaced. In some implementations, R 2 C 1-5Alkyl groups, optionally substituted with 1 to 3 substituents independently selected from: halogen, -NO2, =O, =S, =NH, -CN, aryl, and 5 to 6-membered heteroaryl containing 1 to 3 heteroatoms, wherein each of the aryl and 5 to 6-membered heteroaryl groups is optionally substituted with 1 to 3 R groups. 9 Replacement. In some implementations, R 2 The aryl substituent is phenyl. In some embodiments, R 2 The 5- to 6-membered heteroaryl substituents are 5-membered heteroaryl groups containing one N atom and an additional heteroatom. In some embodiments, each R 9 Independently selected from halogens and C 1-3 Alkyl group. In some embodiments, R 2 C 1-5 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -CN, phenyl, and pyrazolyl, wherein the phenyl or pyrazolyl group is optionally substituted with halogen or C. 1-3 Alkyl substitution. In some embodiments, R 2 C 1-5 An alkyl group, optionally substituted with one to three substituents independently selected from: halogen, -NO2, =O, =S, =NH, -CN, and aryl, wherein the aryl group is optionally substituted with one to three halogens. In some embodiments, R 2 The aryl substituent is phenyl. In some embodiments, R 2 C 1-5 An alkyl group, optionally substituted with one to three substituents independently selected from: halogens, -CN, and phenyl, wherein the phenyl group is optionally substituted with one, two, or three halogens. In some embodiments, R 2 Selected from ethyl, In some implementation schemes, R 2 Selected from ethyl, In some implementation schemes, R 2 For saturated C 3-8 A carbon ring, optionally composed of one or more independently selected from halogens, C 1-3 Alkyl and C 4-6 The carbon ring is replaced by a substituent. In some embodiments, R 2 For saturated C 3-6 A carbon ring, optionally composed of one or more independently selected from halogens, C 1-3 Alkyl and C 4-6 The carbon ring is replaced by a substituent. In some embodiments, R 2 C on 4-6 The carbocyclic ring is aryl. In some embodiments, R 2 C on 4-6The carbon ring is phenyl. In some embodiments, R 2 Selected from C 3-6 Monocyclic cycloalkyl, C 5-6 Bridged cycloalkyl and C 5-6 Spirocycloalkyl, wherein each is optionally substituted with 1 to 3 substituents, which are independently selected from halogens, C 1-3 Alkyl and phenyl. In some embodiments, R 2 Selected from C 3-4 Monocyclic cycloalkyl, C5 bridged cycloalkyl, and C5 spirocycloalkyl, wherein each is optionally substituted by 1 to 3 substituents, which are independently selected from C5. 1-3 Alkyl and phenyl. In some embodiments, R 2 Selected from C 3-4 cycloalkyl, Each is optionally substituted with 1 to 3 substituents, which are independently selected from halogens, C 1-3 Alkyl and phenyl. In some embodiments, R 2 Selected from C 3-4 cycloalkyl, Each can be chosen by C 1-3 Alkyl or phenyl substitution. In some embodiments, R 2 Selected from In some implementation schemes, R 2 Selected from

[0261] In some implementations, for any compound or salt of formula (I'), R 25 For H or C 1-3 Alkyl group. In some embodiments, R 25 For H. In some implementations, R 25 C 1-3 alkyl.

[0262] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 2 and R 25 Together with the N atoms they are attached to, they form 4- to 6-membered rings, which are optionally bounded by one or more R atoms. 9 Replaced. In some implementations, R 2 and R 25 Together with the N atoms they are attached to, they form

[0263] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 2 Selected from optionally substituted C3-C6 cycloalkyl groups; and C1-6 The alkyl group is optionally substituted with one or more substituents independently selected from halogens, nitriles, optionally substituted phenyl groups, and optionally substituted 5-membered heteroaryl groups. In some embodiments, R 2 Selected from optionally substituted C3-C6 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl, and spiropentyl, wherein any one of them is optionally substituted. In some embodiments, R 2 Selected from alkyl groups, such as methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may optionally be substituted. In some embodiments, R 2 Selected from: -CH2CH3、 In some implementations, R 2 Selected from optionally substituted C4-C6 cycloalkyl groups; and C 1-5 An alkyl group, optionally substituted with one or more substituents independently selected from optionally substituted phenyl groups. In some embodiments, R 2 Selected from: -CH2CH3、

[0264] In some embodiments, n is 0 for any compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), or (Id). In some embodiments, p is 0 for any compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), or (Id). In some embodiments, p is 1 for any compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), or (Id). In some embodiments, p is 1 for any compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), or (Id); and R 8 It is a halogenated product.

[0265] In some embodiments, for a compound or salt of any one of formula (I'), (I), (Ia), (Ib), (Ic), or (Id), R 1 -A is further selected from hydrogen. For example, compounds disclosed herein can be represented as: Or its salt.

[0266] In some embodiments, the compounds disclosed herein are selected from the compounds in Table 1 or their salts.

[0267] In some respects, this disclosure provides compounds represented by formula (II'):

[0268]

[0269] Or its salt, 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 Selected from acetyl and C 1-5 Halogenated alkyl groups;

[0272] R 125 Selected from:

[0273] Hydrogen and C 1-6 Alkyl; or

[0274] R 125 With R 12 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0275] R 12 Selected from:

[0276] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 20 -SR 10 -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)R20 -S(O)R 20 -S(O)2R 20 , -NO2, =O, =S, =N(R 20 Substituents of -CN and -CN; and

[0277] C1 alkyl, which is C 3-10 The carbon ring or a 3- to 10-membered heterocyclic ring is substituted, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 19 Replaced; and

[0278] C 3-10 Carbon rings, which are optionally composed of one or more R 19 Replace; or

[0279] R 12 With R 125 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0280] R 14 Selected from:

[0281] Hydrogen; and

[0282] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0283] R 15 and R 16 Each selected from:

[0284] Hydrogen, halogen, -OR 20 -SR 20 -N(R) 20 2. -NO2 and -CN; and

[0285] C 1-6Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0286] R 17 and R 18 Each selected from:

[0287] Halogen, -OR 20 -SR 20 -N(R) 20 )2, -CN, -CHF2, -CF3 and -CH2F; and

[0288] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0289] Each R 19 Selected independently from:

[0290] 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

[0291] C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN; and

[0292] C 3-10 A carbon ring, optionally composed of one or more elements independently selected from halogens, -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 Substituents of ) and –CN are substituted;

[0293] Each R 20 Selected independently from:

[0294] Hydrogen; and

[0295] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups 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 1-6Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0296] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0297] w is 0, 1, or 2; and z is 0, 1, or 2.

[0298] In some respects, this disclosure provides compounds represented by formula (II):

[0299]

[0300] Or its salt, wherein:

[0301] T is selected from -O-, -NR 14 -、-CR 15 R 16 -、-C(O)-、-S-、-S(O)- and -S(O)2;

[0302] R 11 Selected from acetyl and C 1-5 Halogenated alkyl groups;

[0303] R 12 Selected from:

[0304] C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 20 -SR 10 -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(R20 )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 Substituents of -CN are used;

[0305] C1 alkyl, which is C 3-10 The carbon ring or a 3- to 10-membered heterocyclic ring is substituted, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 19 Replaced; and

[0306] C 3-10 Carbon rings, which are optionally composed of one or more R 19 replace;

[0307] R 14 Selected from:

[0308] Hydrogen and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0309] Each R 15 and R 16 Selected from:

[0310] Hydrogen, halogen, -OR 20 -SR 20 -N(R) 20 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0311] Each R 17 and R 18 Selected from:

[0312] Halogen, -OR 20 -SR 20 -N(R) 20 )2, -NO2, -CN, -CHF2, -CF3, -CH2F and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20-SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0313] Each R 19 Selected independently from:

[0314] 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

[0315] C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used;

[0316] C 3-10A carbon ring, optionally composed of one or more elements independently selected from halogens, -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 Substituents of ) and –CN are substituted;

[0317] Each R 20 Selected independently from:

[0318] Hydrogen; and

[0319] C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in carbocyclic rings and 3- to 10-membered heterocycles; and

[0320] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0321] w is 0, 1, or 2; and

[0322] z can be 0, 1, or 2.

[0323] In some embodiments, for compounds or salts of formula (II') or (II), T is -O- or -NR. 14 - In some implementations, T is –NH-. In some implementations, R 11 Selected from acetyl and C 1-2 Halogenated alkyl groups. In some embodiments, R 11 Selected from acetyl and C 1-2 Fluoroalkyl. In some embodiments, R 11 Selected from: acetyl, CHF2, -CF3, -CF2CH3, -CH2CHF2, and -CH2CF3. In some embodiments, for compounds or salts of formula (II') or (II), T is selected from -O-, -NR. 4 -、-CR 5 R 6 - and -C(O)-. In some implementations, T is selected from -O- and -NR-. 4 In some implementations, T is -C(O)-. In some implementations, T is –NR. 4 -, such as –NH-. In some embodiments, T is selected from -CR 5 R 6 -, such as -CHR 5 -, such as -CH2-. In some implementations, T is -O-.

[0324] In some embodiments, for compounds or salts of formula (II') or (II), R 11 Selected from C 1-5 Halogenated alkyl groups such as C 1-3 Halogenated alkyl groups. In some embodiments, R 11 Selected from C 1-3 Haloalkyl and T is -O-. In some embodiments, R 11 Selected from -CHF2, -CF3, -CF2CH3, -CH2CHF2, and -CH2CF3. In some embodiments, R 11 The choice is selected from -CHF2, -CF3, -CF2CH3, -CH2CHF2 and -CH2CF3, and T is -O-.

[0325] In some embodiments, for compounds or salts of formula (II') or (II), R 11 It is an acetyl group. In some embodiments, R 11 It is an acetyl group and T is -NR 14 -, such as T being -NH-.

[0326] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0327] C 1-4 Alkyl groups, optionally substituted with one or more substituents independently selected from halogens, -OH, -SH, -NH2, -NO2, =O, =S, =NH, -CN; and

[0328] (C 3-6 (Carbocyclic)-methyl and (5 to 6-membered heteroaryl)-methyl, wherein the C 3-6 The carbocyclic ring and the 5- to 6-membered heteroaryl substituents are each optionally occupied by one or more R 19 Replaced; and

[0329] C 3-6 Carbon rings, which are optionally composed of one or more R 19 Replace; or

[0330] R 12 With R 125 Together they form a 4- to 6-membered ring, which is optionally bounded by one or more R... 9 What it replaced.

[0331] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0332] C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0333] (C 3-6 cycloalkyl)-methyl, (aryl)-methyl and (6-membered heteroaryl)-methyl, wherein the C 3-6 The cycloalkyl, aryl, and 6-membered heteroaryl substituents are each optionally substituted by 1 to 3 substituents, which are independently selected from halogenated, C-substituted, and C-substituted substituents. 1-3 Alkyl, C 1-3 Halogenated alkyl, -OH, C 1-3 Hydroxyl alkyl and =O; and

[0334] C 4-6 cycloalkyl; or

[0335] R 12 With R 125 Together they form 4 to 6-membered rings that can be optionally substituted with aryl groups.

[0336] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0337] C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0338] (C 3-6 cycloalkyl)-methyl and (aryl)-methyl, wherein the C 3-6 The cycloalkyl and aryl substituents are each optionally substituted by 1 to 3 substituents, which are independently selected from halogenated and =O; and

[0339] C 4-6 cycloalkyl; or

[0340] R 12 With R 125 Together they form 4- to 6-membered rings that are optionally substituted with phenyl groups.

[0341] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from: ethyl, -CH2CHF2, -CH2CF3, Or R 12 and R 125 Together with the N atoms they are attached to, they form In some implementation schemes, R 12 Selected from: ethyl, -CH2CHF2, -CH2CF3, Or R 12 and R 125 Together with the N atoms they are attached to, they form

[0342] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0343] C 1-4 Alkyl groups, optionally substituted with one or more substituents independently selected from halogens, -OH, -SH, -NH2, -NO2, =O, =S, =NH, -CN; and

[0344] (C 3-6 (Carbocyclic)-methyl and (5 to 6-membered heteroaryl)-methyl, wherein the C 3-6 The carbocyclic ring and the 5- to 6-membered heteroaryl substituents are each optionally occupied by one or more R 19 Replaced; and

[0345] C 3-6 Carbon rings, which are optionally composed of one or more R 19 replace.

[0346] In some implementations, each R 19 Independently selected from halogenated, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, -NO2, =O, =S, =NH, and -CN. In some embodiments, each R 19 Independently selected from halogenated, C 1-3 Alkyl, C 1-3 Halogenated alkyl, -OH, C 1-3 Hydroxyalkyl and =O. In some embodiments, each R 19 Independently selected from halogenated, -OH, C 1-3 Hydroxyalkyl and =O. In some embodiments, each R 19 Independently selected from halogenated and =O.

[0347] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0348] C 1-4 Alkyl and C 1-4 Halogenated alkyl groups; and

[0349] (C 3-6 cycloalkyl)-methyl, (aryl)-methyl and (6-membered heteroaryl)-methyl, wherein the C 3-6 The cycloalkyl, aryl, and 6-membered heteroaryl substituents are each optionally replaced by one or more R 19 Replaced; and

[0350] C 3-6 cycloalkyl, which is optionally composed of one or more R 19 replace.

[0351] In some such implementations, when R 12 When R is (aryl)-methyl, the aryl group is phenyl. In some such embodiments, when R... 12 When it is (6-membered heteroaryl)-methyl, the 6-membered heteroaryl substituent on the methyl group is a pyridyl group. In some such embodiments, when R 12 For (C) 3-6 When cycloalkyl-methyl, the C on the methyl group... 3-6 The cycloalkyl group is cyclobutyl. In some such embodiments, R 12 It is cyclobutyl. In some embodiments, R 12 Each R 19 Independently selected from halogenated, C 1-3 Alkyl, C 1-3Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, -NO2, =O, =S, =NH, and -CN. In some embodiments, R 12 Each R 19 Independently selected from halogenated, C 1-3 Alkyl, C 1-3 Halogenated alkyl, -OH, C 1-3 Hydroxyalkyl and =O. In some embodiments, R 12 Each R 19 Independently selected from halogenated, -OH, C 1-3 Hydroxyalkyl and =O. In some embodiments, R 12 Each R 19 Independently selected from halogenated and =O.

[0352] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0353] C 1-4 Alkyl groups, optionally substituted with one or more substituents independently selected from halogens, -OH, -SH, -NH2, -NO2, =O, =S, =NH, -CN; and

[0354] (C 3-6 (Carbocyclic)-methyl, wherein the C 3-6 The carbocyclic substituent may optionally be further modified by one or more R 19 Replace; and

[0355] C 3-6 Carbon rings, which are optionally composed of one or more R 19 replace.

[0356] In some implementations, each R 19 Independently selected from halogenated, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, -NO2, =O, =S, =NH, and -CN. In some embodiments, each R 19 Independently selected from halogenated, C 1-3 Alkyl, C 1-3 Halogenated alkyl, -OH, C 1-3 Hydroxyalkyl and =O. In some embodiments, each R 19 Independently selected from halogenated, -OH, C 1-3Hydroxyalkyl and =O. In some embodiments, each R 19 Independently selected from halogenated and =O.

[0357] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0358] C 1-4 Alkyl and C 1-4 Halogenated alkyl groups;

[0359] (C 3-6 cycloalkyl)-methyl and (aryl)-methyl, wherein the C 3-6 The cycloalkyl and aryl substituents are each optionally further substituented by one or more R 19 Replace; and

[0360] C 3-6 cycloalkyl, which is optionally composed of one or more R 19 replace.

[0361] In some such embodiments, the aryl substituent on the methyl group is a phenyl group. In some such embodiments, the C on the methyl group... 3-6 The cycloalkyl substituent is cyclobutyl. In some such embodiments, the C on the methyl group... 3-6 The cycloalkyl group is cyclobutyl. In some embodiments, each R 19 Independently selected from halogenated, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, -NO2, =O, =S, =NH, and -CN. In some embodiments, each R 19 Independently selected from halogenated, C 1-3 Alkyl, C 1-3 Halogenated alkyl, -OH, C 1-3 Hydroxyalkyl and =O. In some embodiments, each R 19 Independently selected from halogenated, -OH, C 1-3 Hydroxyalkyl and =O. In some embodiments, each R 19 Independently selected from halogenated and =O.

[0362] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from: ethyl, -CH2CHF2, -CH2CF3, In some implementation schemes, R 12 Selected from ethyl, -CH2CHF2, -CH2CF3

[0363] In some embodiments, for compounds or salts of formula (II'), R 125 For H or C 1-3 Alkyl group. In some embodiments, R 125 For H. In some implementations, R 125 C 1-3 alkyl.

[0364] In some embodiments, for compounds or salts of formula (II'), R 12 and R 125 Together with the N atoms they are attached to, they form 4- to 6-membered rings, which are optionally bounded by one or more R atoms. 9 Replaced. In some implementations, R 12 and R 125 Together with the N atoms they are attached to, they form 4- to 6-membered rings optionally substituted with aryl groups. In some embodiments, R 12 and R 125 Together with the N atoms they are attached to, they form 4- to 6-membered rings optionally substituted with phenyl groups. In some embodiments, R 12 and R 125 Together with the N atoms they are attached to, they form

[0365] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0366] C 1-4 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 10 -N(R) 20 )2, -NO2, =O, =S, =N(R 20 Substituents of -CN are used;

[0367] C1 alkyl groups, which are phenyl, heteroaryl and C 3-6 Cycloalkyl substitution, wherein the phenyl, heteroaryl, and C 3-6 Each cycloalkyl group is optionally surrounded by one or more R 19 Replaced; and C 3-6 cycloalkyl, which is optionally composed of one or more R 19 replace.

[0368] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from:

[0369] C 1-4 Alkyl groups, which are optionally substituted with one or more halogen substituents;

[0370] C1 alkyl, which is bonded by phenyl and C 3-6 Cycloalkyl substitution, wherein the phenyl and C 3-6 Each cycloalkyl group is optionally substituted with a halogen; and

[0371] C 3-6 Cycloalkyl groups, which may optionally be substituted with halogens.

[0372] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from: -CH2CH3, -CH2CF3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CHF2, -C(CH3)3, -CH2CH2CH2CH3,

[0373] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from C 1-6 Alkyl groups, such as methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any one of which may optionally be substituted, for example, substituted by one or more halogens. In some embodiments, R 12 Selected from: -CH2CH3, -CH2CF3, -CH(CH3)2, -CH2CH2CH3, -CH2CH(CH3)2, -CH2CHF2, -C(CH3)3, -CH2CH2CH2CH3.

[0374] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from C1 alkyl groups substituted with phenyl and C1 alkyl groups, wherein the C1 alkyl group is C 3-6 Cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl, and spiropentyl are substituted, any one of which may be optionally substituted. In some embodiments, R 12 for

[0375] In some embodiments, for compounds or salts of formula (II') or (II), R 12 Selected from C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl, and spiropentyl, are optionally substituted. In some embodiments, R 12 for

[0376] In some embodiments, for compounds or salts of formula (II') or (II), where w is 0.

[0377] In some embodiments, z is 1 for compounds or salts of formula (II') or (II). In some embodiments, z is 1 and R for compounds of formula (II). 18 It is CH3. In some embodiments, z is 0 for compounds of formula (II).

[0378] In some embodiments, for compounds or salts of any one of formula (II') or (II), R 11 -T is further selected from hydrogen. For example, compounds disclosed herein can be represented as: Or its salt.

[0379] In some embodiments, the compounds disclosed herein are selected from the compounds in Table 2 or their salts.

[0380] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z- or E-forms (or cis- or trans-forms). Furthermore, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z-, E-, and tautomeric forms.

[0381] A "tautomer" is a molecule in which it is possible for a proton to move from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist as tautomers. In situations where tautomerism is possible, a chemical equilibrium of tautomers will exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0382]

[0383] In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, for example, enriched with... 2 H, 3 H, 11 C 13 C and / or 14 The form of C content. In one particular embodiment, the compound is deuterated at at least one site. 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 drug action.

[0384] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence or absence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is enriched by... 13 C- or 14 Compounds with this structure other than C-enriched carbon substitutions are also within the scope of this disclosure.

[0385] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, isotopes such as deuterium ( 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Labeling compounds. Using... 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 All isotopic substitutions performed in I are within the expected scope. All isotopic variations of the compounds of this invention, whether radioactive or not, are included within the scope of this invention.

[0386] In some embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art and, by way of non-limiting example only, include the following synthetic methods.

[0387] Various methods are used to synthesize deuterium-substituted compounds, methods 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, 110pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0388] Deuteration starting materials are readily available and can be synthesized using the methods described herein to provide the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and structural units are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0389] 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 dehydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0390] This disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of this disclosure having sufficiently acidic, sufficiently basic, or both functional groups can react with any of a variety of inorganic bases, inorganic acids, and organic acids to form salts. Alternatively, inherently charged compounds, such as those with quaternary nitrogen, can form salts with suitable equilibrium ions, such as halides, bromides, chlorides, or fluorides, particularly bromides.

[0391] In some cases, the compounds described herein may exist in diastereomers, enantiomers, or other stereoisomers. The compounds presented herein include all diastereomers, enantiomers, and epimers, and suitable mixtures thereof. Separation of stereoisomers can be achieved by chromatography or by forming diastereomers and then 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.

[0392] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. Furthermore, the compounds described herein may be present in unsolvated forms as well as in forms solvated with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds described herein are also considered to be disclosed herein.

[0393] In some embodiments, the compound or salt of a compound may be a prodrug, for example, wherein the hydroxyl group in the parent compound is presented in the form of an ester or carbonate, or the carboxylic acid present in the parent compound is presented in the form of an ester. The term "prodrug" is intended to cover compounds that are converted into the agents disclosed herein under physiological conditions. A method of preparing a prodrug includes hydrolyzing one or more selected portions under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, for example, by conversion by specific target cells in the host animal. For example, esters or carbonates (e.g., esters of alcohols or carboxylic acids or esters of carbonates and phosphates) are preferred prodrugs of this disclosure.

[0394] The prodrug form of the compounds described herein (wherein the prodrug is metabolized in vivo to produce the compounds set forth herein) is 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.

[0395] Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they may become bioavailable through oral administration, while the parent drug may not. Prodrugs can help enhance the cellular permeability of a compound relative to the parent drug. Prodrugs may also have improved solubility in the drug composition compared to the parent drug. Prodrugs can be engineered as reversible drug derivatives and used as modifiers to enhance drug transport to site-specific tissues or increase drug retention within cells.

[0396] In some implementations, the prodrug design enhances the lipophilicity of the agent. In some implementations, the prodrug design increases effective water solubility. See, for example, Fedorak et al., Am. J. Physiol., 269: G210-218 (1995); McLoed et al., Gastroenterol, 106: 405-413 (1994); Hochhaus et al., Biomed. Chrom., 6: 283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACS Symposium Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and such disclosures are incorporated herein by reference. According to another embodiment, this disclosure provides a method for preparing compounds as defined above. These compounds can be synthesized using conventional techniques. Advantageously, these compounds can be readily synthesized from readily available starting materials.

[0397] Synthetic chemical transformations and methodologies that can be used to synthesize 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. Watts, Protective Groups in Organic Synthesis, 2nd edition (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).

[0398] Therapeutic applications

[0399] This disclosure provides pyridazinone compounds and their salts (such as compounds or salts of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II') or (II), or any compounds or salts of formula (III'), (III) or (IIIa) described below or anywhere else herein) for inhibiting myosin II.

[0400] This disclosure provides pyridazinone compounds and their salts (such as compounds or salts of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II') or (II), or any compounds or salts of formula (III'), (III) or (IIIa) described below or anywhere else herein) for the treatment of activity-induced injuries.

[0401] This disclosure provides pyridazolone compounds and their salts (such as compounds or salts of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II), or any compounds or salts of formula (III'), (III), or (IIIa) described below or anywhere else herein) for the treatment of neuromuscular conditions and movement disorders (such as spasticity). This disclosure provides pyridazolone compounds and their salts for the treatment of diseases. Administration methods of the pyridazolone compounds or salts discussed herein, such as compounds or salts of formula (I), (Ia), (Ib), (Ic), (Id), or (II), may be used for the treatment of neuromuscular conditions and movement disorders (such as spasticity). Examples of neuromuscular conditions include, but are not limited to, Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome. Examples of movement disorders include, but are not limited to, muscle spasticity disorders, spasticity associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, or cerebral palsy, or injury, or traumatic events such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis. Other conditions that may respond to inhibition of skeletal myosin II, skeletal troponin C, skeletal troponin I, skeletal troponin, skeletal regulatory light chain, skeletal myosin-binding protein C, or skeletal actin are also included.

[0402] In some respects, this disclosure provides a method for inhibiting myosin II or treating diseases such as neuromuscular diseases or movement disorders, comprising administering a compound of formula (III') to a subject in need:

[0403]

[0404] Or its salt, wherein:

[0405] Each Y is independently selected from C(R) 3 ), N and N + (-O - );

[0406] A does not exist or is selected from -O- or -NR. 4 -、-CR 5 R 6 -、-C(O)-、-S-、-S(O)- and -S(O)2-; R 1 Selected from:

[0407] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0408] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 The alkynyl group is replaced by a substituent, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 9 Replaced; or

[0409] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; and

[0410] When A does not exist, R 1 Additionally, it is selected from H and halogens;

[0411] R 25 Selected from:

[0412] Hydrogen and C 1-6 Alkyl; or

[0413] R 25 With R 2 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0414] R 2 Selected from:

[0415] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0416] C 3-10 A carbocyclic ring and 3 to 10-membered heterocycles, each 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 ), –CN, C 1-6 Alkyl and C 3-10 Carbon ring, wherein the C 1-6 Alkyl and C 3-10 The carbon ring is optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R)10 )2, replaced by substituents of -NO2 and -CN; or

[0417] R 2 With R 25 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles;

[0418] R 3 R 5 and R 6 Each is selected independently from:

[0419] Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and

[0420] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0421] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0422] R 4 Selected from:

[0423] Hydrogen; and

[0424] C1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0425] R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced;

[0426] R 7 and R 8 Each is selected independently from:

[0427] Halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN;

[0428] Each R 9 Selected independently from:

[0429] 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

[0430] C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used;

[0431] Each R 10 Selected independently from:

[0432] Hydrogen; and

[0433] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0434] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0435] n is 0, 1, or 2; and p is 0, 1, or 2.

[0436] This disclosure further provides a method for inhibiting myosin II or treating diseases such as neuromuscular diseases or movement disorders, comprising administering a compound of formula (III) to a subject in need:

[0437]

[0438] Or its salt, wherein:

[0439] Each Y is independently selected from C(R) 3 ), N and N + (-O - );

[0440] A is selected from -O- and -NR 4 -、-CR 5 R 6 -、-C(O)-、-S-、-S(O)- and -S(O)2-;

[0441] R 1 Selected from:

[0442] C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0443] C 3-10Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN; or

[0444] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced;

[0445] R 2 Selected from:

[0446] C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0447] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 Substituents of ) and –CN; and C 1-6 Alkyl and C 3-10 Carbon rings, any one of which may optionally be independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN;

[0448] R 3 R 5 and R 6 Selected independently from:

[0449] Hydrogen, halogen, -OR10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0450] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0451] R 4 Selected from:

[0452] Hydrogen; and

[0453] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced;

[0454] Each R 7 and R 8 Selected independently from:

[0455] Halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2, -CN, and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN;

[0456] Each R 9 Selected independently from:

[0457] 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

[0458] C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used;

[0459] Each R 10 Selected independently each time it appears.

[0460] Hydrogen; and

[0461] C 1-6 Alkyl, C 2-6 alkenyl, C2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in carbocyclic rings and 3- to 10-membered heterocycles; and

[0462] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0463] n is 0, 1, or 2; and

[0464] p is 0, 1, or 2.

[0465] In some embodiments, for compounds or salts 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 implementations, a Y is N. + (-O - And a Y is C(R) 3 In some implementations, each Y is N. In some implementations, one Y is N, and another Y is N. + (-O - ).

[0466] In some embodiments, for compounds or salts of formula (III') or (III), each Y is C(R) 3 In some embodiments, for compounds of formula (III') or (III), one Y is -CH-; and the other Y is -CR. 3 -

[0467] In some embodiments, compounds of formula (III') or (III) are represented by formula (IIIa):

[0468]

[0469] In some embodiments, for compounds or salts of any of formula (III'), (III), or (IIIa), -A- is absent; and R 1 Further selected from hydrogen, halogen, or methyl. In some embodiments, -AR 1 For H. In some implementations, -AR 1 It is a halogen. In some implementations, -AR 1 Methyl. For example, the compounds disclosed herein can be represented as... Or its salts. As another example, the compounds disclosed herein can be represented as Or its salts. As yet another example, the compounds of this disclosure can be represented as Or its salt.

[0470] In some embodiments, for compounds of formula (III), (III'), or (IIIa), A is -O- or -CHR. 5 -. In some implementations, R 5 For H; or R 5 and R 1 Together with the C atoms they are attached to, they form C 3-6 Cycloalkyl. In some embodiments, A is -O- or -CH2-; and R 1 C 1-3 An alkyl group, optionally substituted with one to three substituents, each independently selected from halogens and four-membered saturated heterocycles containing oxygen (optionally containing one or two additional heteroatoms). In some embodiments, A is -CH2-; and R 1 Selected from C 1-3 Alkyl groups (e.g., methyl, ethyl, and isopropyl) and (4-membered saturated heterocyclic)-methyl groups, optionally halogenated (e.g., In some implementations, one Y is -CH-; and the other Y is -CR. 3 -. In some implementations, A is -O-; and R 1 C 1-3 Alkyl or R 1 and R 3 Together with the atoms they are attached to, they form 6- to 7-membered saturated heterocycles containing oxygen atoms and one or two additional heteroatoms.

[0471] In some embodiments, for compounds of formula (III), (III'), or (IIIa), n is 0; and Partially selected from In some implementations, n is 0; and Partially selected from In some implementation schemes, Partially selected from: and their combinations.

[0472] In some embodiments, for compounds of formula (III), (III'), or (IIIa), -AR 1 -OC 1-3 Alkyl; n is 1; and R7 is halogenated or C 1-3 Alkyl group. In some such embodiments, -AR 1 It is methoxy. In some such embodiments, R7 is halo- or methyl. In some embodiments, Partially selected from:

[0473] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), A is selected from -O-, -NR. 4 -、-CR 5 R 6 - and -C(O)-. In some implementations, A is selected from -O- and -NR-. 4 In some implementations, A is -O-. In some implementations, A is -C(O)-. In some implementations, A is –NR. 4 -, such as –NH-. In some embodiments, A is selected from -CR 5 R 6 -e.g., -CH2-.

[0474] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R 1 Selected from C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 The substituted phenyl group, optionally replaced by one or more elements independently selected from halogens, -OR 10 -SR10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 2, -NO2, -CN and C 1-6 Alkyl groups are substituted; and 4- to 6-membered heterocyclic alkyl groups are optionally replaced by one or more groups independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN and C 1-6 Alkyl groups are substituted.

[0475] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R 1 Selected from C 1-3 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 The substituted phenyl group, optionally replaced by one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl groups are substituted; and 4- to 6-membered heterocyclic alkyl groups are optionally replaced by one or more groups independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl groups are substituted.

[0476] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R 1 Selected from C 1-3 Alkyl groups, optionally substituted with one or more substituents independently selected from halogens; and substituents of 4- to 6-membered heterocyclic alkyl groups and phenyl groups, any one of which may optionally be substituted with one or more substituents independently selected from halogens and C. 1-3Alkyl substituents. In some embodiments, R 1 Selected from -CHF2, -CF3, -CH3, -CH2CH2CF3, -CH2CF3, p-fluorophenyl, p-chlorophenyl,

[0477] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R 1 With R 4 Together they form an optional combination of one or more R 9 The 4- to 7-membered heterocycle is replaced. In some embodiments, the 4- to 7-membered heterocycle is selected from saturated heterocycles. In some embodiments, the 4- to 7-membered heterocycle is selected from α-monocyclic saturated heterocycles or spiro-saturated heterocycles, for example, Any one of them may be arbitrarily assigned to one or more R 9 Replaced. In some embodiments, the substituents on the 4- to 7-membered heterocycles are independently selected from halogens and C. 1-6 alkyl.

[0478] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R 1 With R 4 Together they form 4- to 7-membered heterocycles, selected from:

[0479] In some embodiments, for compounds or salts of any one of formula (III'), (III), or (IIIa), R 1 Selected from optionally substituted C3-C6 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl, and spiropentyl, wherein any one of them is optionally substituted. In some embodiments, R 1 Selected from alkyl groups, such as methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may optionally be substituted. In some embodiments, R 1 Selected from: In some implementations, R 1 Selected from optional replacements

[0480] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R 25 For H or C 1-3 Alkyl groups, such as CH3. In some embodiments, R 25 It is CH3.

[0481] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R25 For H; and R 2 Selected from:

[0482] C 1-6 Alkyl, (C 3-7 (Carbon ring)-C 1-3 Alkyl groups and (4 to 6-membered heterocyclic)-C 1-3 Alkyl, wherein C 1-3 C on alkyl 3-7 The carbocyclic ring and the 4- to 6-membered heterocyclic substituents are each optionally further substituented by one or more R 9 replace;

[0483] C 3-10 The carbon ring is optionally substituted by one to three independent substituents selected from the following: halogenated, C-shaped, ... 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OC 1-3 Alkyl and aryl, wherein C 3-10 The aryl substituents on the carbon ring are optionally further modified by one or more R... 9 Replace; and

[0484] 6- to 10-membered heterocycles containing 1 to 3 heteroatoms and one or more optionally substituted R atoms 9 .

[0485] In some such implementations, one Y is -CH-; and the other Y is -CR. 3 -

[0486] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R 25 For H; and R 2 Selected from:

[0487] C 1-4 Alkyl, (C 3-7 cycloalkyl)-C 1-2 Alkyl, (C 3-7 (cycloalkenyl)-C 1-2 Alkyl, (C 3-7 (aryl)-C 1-2 Alkyl and (5 to 6-membered heteroaryl)-C 1-2 Alkyl, wherein the C 1-2 C on alkyl 3-7 cycloalkyl, C 3-7 Cycloalkenyl, C 3-7 The aryl group and the 5- to 6-membered heteroaryl substituents are each optionally further substituents by one or more R groups. 9 replace;

[0488] C 3-9 Carbon ring, selected from C 3-7 cycloalkyl and C6-9 Aryl group, wherein each aryl group is optionally substituted by 1 to 3 substituents, which are independently selected from halogenated, C-terminated, and C-terminated groups. 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OC 1-3 alkyl and aryl, wherein the C 3-10 The aryl substituents on the carbon ring may optionally be further substituted with one or more halogens; and

[0489] 6- to 10-membered heterocycles containing 1 to 3 heteroatoms and one or more optionally substituted R atoms 9 .

[0490] In some such implementations, one Y is -CH-; and the other Y is -CR. 3 -

[0491] In some embodiments, for compounds or salts of formula (III'), (III), or (IIIa), R 2 Selected from optionally substituted C3-C6 cycloalkyl groups; and C 1-6 The alkyl group is optionally substituted with one or more substituents independently selected from halogens, nitriles, optionally substituted phenyl groups, and optionally substituted 5-membered heteroaryl groups. In some embodiments, R 2 Selected from optionally substituted C3-C6 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl, and spiropentyl, wherein any one of them is optionally substituted. In some embodiments, R 2 Selected from alkyl groups, such as methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may optionally be substituted. In some embodiments, R 2 Selected from: -CH2CH3、 In some implementations, R 2 Selected from optionally substituted C4-C6 cycloalkyl groups; and C 1-5 An alkyl group, optionally substituted with one or more substituents independently selected from optionally substituted phenyl groups. In some embodiments, R 2 Selected from: -CH2CH3、

[0492] In some embodiments, p is 0 for compounds or salts of formula (III'), (III) or (IIIa).

[0493] In some embodiments, for compounds or salts of any one of formula (III'), (III), or (IIIa), R 1-A is further selected from hydrogen. For example, the compounds disclosed herein can be represented as: Or its salt.

[0494] This document presents a method for treating neuromuscular and motor disorders by reducing skeletal muscle contraction. Treatment of subjects with neuromuscular and motor disorders with a selective skeletal muscle fast-twitch (type II) myosin inhibitor of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can reduce muscle damage by preventing excessive, uncoordinated muscle contraction and thus reducing muscle breakdown. Furthermore, the method disclosed herein can reduce muscle damage while minimizing the impact on the subject's physical function. Preservation of function can be achieved either by limiting the level of destructive forces generated in type II fibers or by increasing dependence on healthier type I fibers. Inhibition of skeletal muscle myosin II reduces skeletal muscle contraction or uncoordinated muscle spasms. In some embodiments, the skeletal muscle myosin II inhibitor is a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) disclosed herein.

[0495] In some embodiments, this document discloses a method for inhibiting myosin II, comprising administering to a subject in need a compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II). In some embodiments, the compound or salt does not significantly inhibit myocardial contraction. In some embodiments, the compound or salt does not significantly inhibit myocardial contraction. In some embodiments, the compound or salt reduces myocardial force by less than 10%.

[0496] In some aspects, methods for treating neuromuscular conditions or movement disorders may include administering a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) to inhibit skeletal muscle contraction. In some embodiments, the compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) 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 implementations, myocardial contraction is inhibited by 2% or less. In some implementations, myocardial contraction is inhibited by 1% or less.

[0497] Before and after treatment with compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II), subjects' activities of daily living (ADL) or habitual physical activity can be monitored. ADL or habitual physical activity depends on the subject and, depending on their ability and daily routine, may range from simple walking to extensive exercise. The treatment options and dosages of the skeletal muscle contraction inhibitors discussed in this article can be personalized to subjects so that ADL and habitual physical activity remain unchanged.

[0498] In some aspects, methods of treating neuromuscular diseases or movement disorders may include administering a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) to inhibit skeletal muscle contraction. The dosage of the compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) may be relative to the amount required to reduce skeletal muscle contraction by 50%. The dosage of the compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) may be less than the amount required to reduce skeletal muscle contraction by 50% relative to the subject's pre-treatment skeletal muscle contractile capacity. The compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) may be administered in an amount that reduces skeletal muscle contraction by 5% to 45% relative to the subject's pre-treatment skeletal muscle contractile capacity. In some cases, the amount of compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) applied relative to the subject's pre-treatment skeletal muscle contractility may reduce skeletal muscle contractility 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 some embodiments, the compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) may be applied in an amount that reduces skeletal muscle contractility by 1% to 50% relative to the subject's pre-treatment skeletal muscle contractility.

[0499] In some aspects, methods of treating neuromuscular diseases or movement disorders may include administering a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) to inhibit type I skeletal muscle contraction. The dosage of the type I skeletal muscle contraction inhibitor may 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 may be less than the amount required to reduce type I skeletal muscle contraction by 20% relative to the subject's pre-treatment type I skeletal muscle contraction capacity. The type I skeletal muscle contraction inhibitor may be administered at a dosage that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the subject's pre-treatment type I skeletal muscle contraction capacity. In some cases, the dosage of the inhibitor may reduce type I skeletal muscle contraction by less than 0.01%, less than 0.1%, less than 0.5%, less than 1%, less than 5%, less than 10%, less than 15%, or less than 20% relative to the subject's pre-treatment type I skeletal muscle contraction capacity. In some implementations, the inhibitor may be administered in an amount that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the subject's pre-treatment type I skeletal muscle contraction capacity.

[0500] In some respects, methods of treating neuromuscular diseases or movement disorders may include administering compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) to inhibit type II skeletal muscle contraction. The dosage of a type II skeletal muscle contraction inhibitor may be relative to the amount required to reduce type II skeletal muscle contraction by 90%. The dosage of a type II skeletal muscle contraction inhibitor may be less than the amount required to reduce type II skeletal muscle contraction by 90% relative to the subject's pre-treatment type II skeletal muscle contraction capacity. A type II skeletal muscle contraction inhibitor may be administered at a dosage that reduces type II skeletal muscle contraction by 5% to 75% relative to the subject's pre-treatment type II skeletal muscle contraction capacity. In some cases, the dosage of the inhibitor may reduce type II skeletal muscle contractility by less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, or even less than 90% relative to the subject's pre-treatment type II skeletal muscle contractility. In some embodiments, the inhibitor may be administered in an amount that reduces type II skeletal muscle contractility by 1% to 50% relative to the subject's pre-treatment type II skeletal muscle contractility.

[0501] In some aspects, methods for treating injury caused by contraction in skeletal muscle fibers may include administering compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) to inhibit skeletal muscle contraction and / or skeletal muscle myosin II. In some embodiments, the inhibitor does not significantly inhibit myocardial contraction.

[0502] In some implementations, damage caused by contraction in skeletal muscle fibers originates from involuntary skeletal muscle contractions. Involuntary skeletal muscle contractions may be associated with neuromuscular disorders or spasticity-related conditions. In some implementations, damage caused by contraction in skeletal muscle fibers may originate from voluntary skeletal muscle contractions, such as during physical activity.

[0503] In some embodiments, administration of a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) to a subject modulates one or more biomarkers associated with muscle contraction. Examples of biomarkers include, but are not limited to, creatinine kinase (CK), troponin T (TnT), troponin C (TnC), troponin I (TnI), pyruvate kinase (PK), lactate dehydrogenase (LDH), myoglobin, subtypes of TnI (e.g., TnI of cardiac muscle, slow-twitch skeletal muscle, fast-twitch skeletal muscle), and inflammatory markers (IL-1, IL-6, IL-4, TNF-α). Biomarkers may also include measures of muscle inflammation, such as edema. The levels of the biomarkers described herein may increase relative to pre-treatment levels, or the levels of the biomarkers may decrease relative to pre-treatment levels. Modulation of one or more biomarkers with the inhibitors described herein may indicate treatment for neuromuscular diseases such as those described herein.

[0504] CK levels increase during activity compared to when the subject is inactive (e.g., sleeping), therefore CK is a potential measure for assessing skeletal muscle breakdown caused by skeletal muscle contraction. In some embodiments, a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) may be administered to the subject prior to mild, moderate, or vigorous activity to reduce or prevent skeletal muscle breakdown due to activity. Moderate to vigorous activity may depend on the subject's ability and may include physical activity that increases the heart rate by at least 20% or more relative to the subject's resting heart rate, such as approximately 50% or more. Examples of moderate to vigorous activity include walking, running, weightlifting, cycling, swimming, hiking, etc.

[0505] In some embodiments, compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) are administered before, during, or after moderate or vigorous activity to reduce or prevent skeletal muscle breakdown due to activity. Compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can reduce CK levels in untreated subjects performing the same activity. CK levels can be measured in the peripheral blood of the subject during or after the activity. Administration of the inhibitors described herein can reduce CK levels in active subjects by 5% to 90% relative to untreated subjects performing the same activity, thereby reducing or preventing skeletal muscle breakdown due to activity. Administration of the inhibitors described herein can regulate CK levels by about 5% to about 90% relative to untreated subjects performing the same activity, thereby reducing or preventing skeletal muscle breakdown due to activity. Administration of the inhibitors described herein can reduce CK levels by at least about 5% relative to untreated subjects performing the same activity, thereby reducing or preventing skeletal muscle breakdown due to activity. Compared to untreated subjects performing the same activity, administration of the inhibitors described herein can modulate CK levels by up to approximately 90%. Compared to untreated subjects performing the same activity, administration of the inhibitors described herein can reduce CK levels by approximately 5% to approximately 15%, approximately 5% to approximately 25%, approximately 5% to approximately 35%, approximately 5% to approximately 45%, approximately 5% to approximately 55%, approximately 5% to approximately 65%, approximately 5% to approximately 75%, approximately 5% to approximately 85%, approximately 5% to approximately 90%, approximately 15% to approximately 25%, approximately 15% to approximately 35%, approximately 15% to approximately 45%, approximately 15% to approximately 55%, approximately 15% to approximately 65%, approximately 15% to approximately 75%, approximately 15% to approximately 85%, approximately 15% to approximately 90%, approximately 25% to approximately 35%, approximately 25% to approximately 45%, approximately 25% to approximately 55%, approximately 25% to approximately 65%, approximately 25% to approximately 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 the breakdown of skeletal muscle due to activity.Compared to untreated subjects performing the same activity, administration of the inhibitors described herein can modulate CK levels by approximately 5%, 15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, or 90%, thereby reducing or preventing skeletal muscle breakdown due to activity.

[0506] Administration of a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) to a subject can modulate the levels of inflammatory markers, for example, reducing the levels of one or more inflammatory markers relative to an untreated subject or a pre-treatment subject. The levels of inflammatory markers can be measured in the peripheral blood of the subject. Examples of inflammatory markers may include, but are not limited to, IL-1, IL-6, and TNF-α. Inflammatory markers can also be in the form of conditions such as edema, which can be measured using magnetic resonance imaging. The level of the inflammatory marker in the peripheral blood may increase relative to the subject's pre-treatment level of the inflammatory marker. Alternatively, the level of the inflammatory marker in the peripheral blood may decrease relative to the subject's pre-treatment level of the inflammatory marker. Administration of the inhibitor described herein can modulate the level of the inflammatory marker by 5% to 90% relative to the subject's pre-treatment level of the inflammatory marker. In some cases, the level of the inflammatory marker can be modulated by about 5% to about 90% relative to the subject's pre-treatment level of the inflammatory marker. In some cases, the level of inflammatory markers may be adjusted by at least about 5% relative to the subject's pre-treatment level. In other cases, the level of inflammatory markers may be adjusted by up to about 90% relative to the subject's pre-treatment level. In some cases, the levels of inflammatory markers may be adjusted relative to the subject's pre-treatment levels by approximately 5% to 15%, approximately 5% to 25%, approximately 5% to 35%, approximately 5% to 45%, approximately 5% to 55%, approximately 5% to 65%, approximately 5% to 75%, approximately 5% to 85%, approximately 5% to 90%, approximately 15% to 25%, approximately 15% to 35%, approximately 15% to 45%, approximately 15% to 55%, approximately 15% to 65%, approximately 15% to 75%, approximately 15% to 85%, approximately 15% to 90%, approximately 25% to 35%, approximately 25% to 45%, approximately 25% to 55%, and approximately 25% to 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 levels of inflammatory markers may be adjusted by approximately 5%, 15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, or 90% relative to the pre-treatment levels of the subject's inflammatory markers.

[0507] Administration of a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) to a subject modulates the level of circulating skeletal muscle fast-twitch troponin I (fS-TnI). The level of fS-TnI can be measured in peripheral blood. The level of fS-TnI in peripheral blood may increase after administration of the inhibitor relative to the subject's pre-treatment level. Alternatively, the level of fS-TnI in peripheral blood may decrease after administration of the inhibitor relative to the subject's pre-treatment level. Administration of the inhibitor described herein may modulate the level of fS-TnI by 5% to 90% relative to the subject's pre-treatment level. In some cases, the level of fS-TnI may be modulated by at least about 5% relative to the subject's pre-treatment level. In some cases, the level of fS-TnI may be modulated by up to about 90% relative to the subject's pre-treatment level. In some cases, the fS-TnI level can be adjusted relative to the subject's pre-treatment level by approximately 5% to 15%, approximately 5% to 25%, approximately 5% to 35%, approximately 5% to 45%, approximately 5% to 55%, approximately 5% to 65%, approximately 5% to 75%, approximately 5% to 85%, approximately 5% to 90%, approximately 15% to 25%, approximately 15% to 35%, approximately 15% to 45%, approximately 15% to 55%, approximately 15% to 65%, approximately 15% to 75%, approximately 15% to 85%, approximately 15% to 90%, approximately 25% to 35%, approximately 25% to 45%, approximately 25% to 55%, and approximately 25% to 65%. Approximately 25% to approximately 75%, approximately 25% to approximately 85%, approximately 25% to approximately 90%, approximately 35% to approximately 45%, approximately 35% to approximately 55%, approximately 35% to approximately 65%, approximately 35% to approximately 75%, approximately 35% to approximately 85%, approximately 35% to approximately 90%, approximately 45% to approximately 55%, approximately 45% to approximately 65%, approximately 45% to approximately 75%, approximately 45% to approximately 85%, approximately 45% to approximately 90%, approximately 55% to approximately 65%, approximately 55% to approximately 75%, approximately 55% to approximately 85%, approximately 55% to approximately 90%, approximately 65% ​​to approximately 75%, approximately 65% ​​to approximately 85%, approximately 65% ​​to approximately 90%, approximately 75% to approximately 85%, approximately 75% to approximately 90%, or approximately 85% to approximately 90%. In some cases, the level of fS-TnI can be adjusted by approximately 5%, 15%, 25%, 35%, 45%, 55%, 65%, 75%, 85%, or 90% relative to the subject's pre-treatment level of fS-TnI.

[0508] Troponin subtypes can be measured in subjects before and after administration of compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II). Inhibition of skeletal muscle contraction may not inhibit some troponin subtypes, such as cardiac troponin I (cTnI) or skeletal muscle slow-twitch troponin I (ssTnI). In some cases, inhibition of skeletal muscle contraction may not significantly inhibit cTnI or ssTnI. As used herein, the term "not significant" with respect to cTnI or ssTnI means a reduction of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to cTnI or ssTnI before administration of the inhibitor.

[0509] Application of compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can reduce involuntary muscle contractions. Involuntary muscle contractions can be reduced by 20% to 90% compared to pre-treatment involuntary muscle contractions. In some cases, involuntary muscle contractions can be reduced by at least about 20% compared to pre-treatment involuntary muscle contractions. In some cases, involuntary muscle contractions can be reduced by up to about 90% compared to pre-treatment involuntary muscle contractions. In some cases, compared to pre-treatment involuntary muscle contractions, involuntary muscle contractions may be reduced by approximately 20% to 25%, approximately 20% to 30%, approximately 20% to 40%, approximately 20% to 50%, approximately 20% to 70%, approximately 20% to 75%, approximately 20% to 80%, approximately 20% to 85%, approximately 20% to 90%, approximately 25% to 30%, approximately 25% to 40%, approximately 25% to 50%, approximately 25% to 70%, approximately 25% to 75%, approximately 25% to 80%, approximately 25% to 85%, approximately 25% to 90%, approximately 30% to 40%, approximately 30% to 50%, approximately 30% to 70%, approximately 30% to 75%, etc. 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, involuntary muscle contractions can be reduced by approximately 20%, 25%, 30%, 40%, 50%, 70%, 75%, 80%, 85%, or 90% compared to pre-treatment levels.

[0510] Compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be used to improve a subject's activities of daily living (ADL) or habitual physical activity because they can restore mature, functional, and undamaged muscles. Examples of ADL or habitual activities include, but are not limited to, climbing stairs, wake-up time, timed rise from a seat, habitual walking speed, North Star dynamic assessment, incremental / endurance round-trip walking, and 6-minute walking distance test. The level or capacity of ADL or habitual physical activity can be measured before and after administration of the skeletal muscle inhibitor. Inhibition of skeletal muscle contraction may not affect ADL or habitual physical activity. In some cases, inhibition of skeletal muscle contraction may not significantly affect ADL or habitual physical activity. As used herein, the term "ADL" or "habitual physical activity" is not explicitly defined as a reduction in ADL or habitual physical activity level of less than 20%, less than 15%, less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to ADL or habitual physical activity prior to administration of the inhibitor. Skeletal muscle contraction or force in subjects can be measured before and after administration of a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II). Such measurements can be performed to generate dose-response curves for compounds or salts of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II). The dose of compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be adjusted by about 5% to 50% relative to a dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dose of a skeletal muscle contraction inhibitor can be adjusted by at least about 5% relative to a dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dose of a skeletal muscle contraction inhibitor can be adjusted by up to about 50% relative to a dose that reduces type II skeletal muscle contraction by 90%.In some cases, relative to a dose that reduces type II skeletal muscle contraction by 90%, the dose of skeletal muscle contraction inhibitor can be adjusted by approximately 5% to approximately 10%, approximately 5% to approximately 15%, approximately 5% to approximately 20%, approximately 5% to approximately 25%, approximately 5% to approximately 30%, approximately 5% to approximately 35%, approximately 5% to approximately 40%, approximately 5% to approximately 50%, approximately 10% to approximately 15%, approximately 10% to approximately 20%, approximately 10% to approximately 25%, approximately 10% to approximately 30%, approximately 10% to approximately 35%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 15% to approximately 20%, approximately 15% to ... % to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 50%, about 35% to about 40%, about 35% to about 50%, or about 40% to about 50%. In some cases, the dose of a skeletal muscle contraction inhibitor may be adjusted by approximately 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to a dose that reduces type II skeletal muscle contraction by 90%. Skeletal muscle contraction can be measured before and after administration of the skeletal muscle contraction inhibitor by muscle strength testing using surface electrodes after nerve stimulation (e.g., plantar flexion after peroneal nerve stimulation of the leg), isolated limb assay, heart rate monitor or activity monitor, or equivalent methods.

[0511] Myocardial strength or myocardial contractility of a subject can be measured before and after administration of a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II). Inhibition of skeletal muscle contraction may not inhibit myocardial contractility or myocardial strength. In some embodiments, inhibition of skeletal muscle contraction may not significantly inhibit myocardial contraction. In some embodiments relating to myocardial contraction, the term "not significantly" means that myocardial strength 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 myocardial strength before administration of the inhibitor. Myocardial strength or myocardial contractility of a subject after administration of a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) may be within 0.1% to 10% of myocardial contractility or myocardial strength before administration of the inhibitor. In some embodiments, administration of a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can inhibit skeletal muscle contraction and myocardial contraction or myocardial force. In some embodiments, the reduction in myocardial force is greater than 0.1%, greater than 0.5%, greater than 1%, greater than 2%, greater than 4%, greater than 6%, greater than 8%, or greater than 10%. In some embodiments, the reduction in skeletal muscle contraction and myocardial contraction is described by a ratio to each other. For example, in some embodiments, the ratio of the reduction in skeletal muscle contraction to the reduction in myocardial contraction is about 1:1 to about 100:1, about 2:1 to about 50:1, about 3:1 to about 40:1, about 4:1 to about 30:1, about 5:1 to about 20:1, about 7:1 to about 15:1, or about 8:1 to about 12:1. Myocardial force or myocardial contraction can be measured using echocardiography (partial shortening) or other equivalent tests.

[0512] Tidal volume in the lungs of a subject can be measured before and after administration of a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II). In some embodiments, administration of the compound or salt may not inhibit tidal volume in the lungs. In some cases, administration may not significantly inhibit tidal volume in the lungs. In some embodiments relating to 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 administration of the inhibitor. Tidal volume in the lungs of a subject can be measured using a forced expiratory volume in one second (FEV1) test or a forced vital capacity (FVC) test, or equivalent tests thereof.

[0513] Smooth muscle contraction in subjects can be measured before and after administration of a skeletal muscle contraction inhibitor. Inhibition of skeletal muscle contraction may not inhibit smooth muscle contraction. In some cases, inhibition of skeletal muscle contraction may not significantly inhibit smooth muscle contraction. As used herein, the term "not significant" regarding smooth muscle contraction means a reduction in smooth muscle contraction of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to smooth muscle contraction before administration of the inhibitor. Smooth muscle contraction in subjects can be assessed by measuring their blood pressure.

[0514] Neuromuscular coupling in subjects can be measured before and after administration of compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II). Inhibition of skeletal muscle contraction with the inhibitors described herein may not impair neurotransmission, neurotransmitter release, or electrical depolarization in the subject's skeletal muscle. In some cases, inhibition of skeletal muscle contraction may not significantly impair neuromuscular coupling in the subject. As used herein, the term "not apparent" refers to a reduction in neuromuscular coupling levels in the subject of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or less than 0.1% relative to the level of neuromuscular coupling in the subject before administration of the inhibitor. Neuromuscular coupling in subjects can be assessed by measuring neurally induced electrical depolarization of skeletal muscle, which is performed by recording the electrical activity generated by skeletal muscle after electrical stimulation or voluntary stimulation using electromyography (EMG) with surface or needle electrodes.

[0515] In some respects, methods for treating neuromuscular diseases or movement disorders may include administering compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II), wherein the compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) inhibit myosin ATPase activity, native skeletal muscle myofibril ATPase (calcium-regulated), or a reconstructed S1 containing actin, tropomyosin, and troponin. In vitro assays can be used to test the effect of the test compound or inhibitor on myosin ATPase activity. Test compounds can be screened to assess their inhibitory activity against muscle contraction. Inhibitory activity can be determined using absorbance assays to identify actin-activated ATPase activity. Rabbit muscle myosin subfraction 1 (S1) can be mixed with polymerized actin and dispersed into nucleotide-free assay plate wells. The test compound can then be added to the wells using a needle array. The reaction can be initiated with MgATP. The amount of ATP consumed in the test container over a defined time period can be compared with the amount of ATP consumed in the control container. The defined time period can be from 5 minutes to 20 minutes. ATP consumption can be determined by direct or indirect assay. Test compounds that reproducibly and strongly inhibit myosin S1 ATPase activity can be further evaluated in dose-response assays to determine the in vitro IC50 of the compound on dissected muscle. This assay can be performed by indirectly measuring ATPase activity by coupling myosin with pyruvate kinase and lactate dehydrogenase to provide an absorbance detection method at 340 nm based on the conversion of NADH to NAD+ driven by ADP accumulation. In some cases, the test compound can be selected as a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) if the ATP consumption in the test container is reduced by at least 20% compared to the control container. In kinetic assays, the test compound can be selected when the inhibition of NAD+ production is enhanced by at least 20%.

[0516] In in vitro assays, the selected inhibitor or test compound may not inhibit cardiac myosin S1 ATPase. In some cases, when the test compound or compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) are tested in an in vitro assay, cardiac myosin S1 ATPase or myocardial fibrils or remodeling systems may be inhibited by less than 10%, less than 8%, less than 5%, less than 3%, less than 2%, less than 1%, or less than 0.5%.

[0517] Test compounds for skeletal muscle contraction can be tested on detached fibers. Individual skeletal muscle fibers treated to remove the membrane and allow direct activation of contraction upon calcium administration can be used. Inhibitor compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) inhibit contraction of individual skeletal muscle fibers by about 5% to about 90% relative to pre-treatment values ​​or untreated control individual skeletal muscle fibers. Inhibitors inhibit contraction of individual skeletal muscle fibers by at least about 5% relative to pre-treatment values ​​or untreated control individual skeletal muscle fibers. Inhibitors inhibit contraction of individual skeletal muscle fibers by up to about 90% relative to pre-treatment values ​​or untreated control individual skeletal muscle fibers. Compared to pre-treatment capacity or untreated control single skeletal muscle fibers, the inhibitors inhibited the contraction of single skeletal muscle fibers by approximately 5% to 10%, approximately 5% to 20%, approximately 5% to 30%, approximately 5% to 40%, approximately 5% to 50%, approximately 5% to 60%, approximately 5% to 70%, approximately 5% to 80%, approximately 5% to 90%, approximately 10% to 20%, approximately 10% to 30%, approximately 10% to 40%, approximately 10% to 50%, approximately 10% to 60%, approximately 10% to 70%, approximately 10% to 80%, approximately 10% to 90%, approximately 20% to 30%, approximately 20% to 40%, approximately 20% to 50%, and approximately 20% to 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%. Compared to pre-treatment capacity or untreated control individual skeletal muscle fibers, the inhibitors inhibited the contraction of individual skeletal muscle fibers by approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0518] Compared to pre-treatment values ​​or untreated control single skeletal muscle, inhibitory compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can inhibit the contraction of a single skeletal muscle by about 5% to about 90%. Compared to pre-treatment values ​​or untreated control single skeletal muscle, the inhibitor can inhibit the contraction of a single skeletal muscle by at least about 5%. Compared to pre-treatment values ​​or untreated control single skeletal muscle, the inhibitor can inhibit the contraction of a single skeletal muscle by up to about 90%. Compared to pre-treatment capacity or untreated control single skeletal muscle, the inhibitor can inhibit the contraction of a single skeletal muscle by approximately 5% to 10%, approximately 5% to 20%, approximately 5% to 30%, approximately 5% to 40%, approximately 5% to 50%, approximately 5% to 60%, approximately 5% to 70%, approximately 5% to 80%, approximately 5% to 90%, approximately 10% to 20%, approximately 10% to 30%, approximately 10% to 40%, approximately 10% to 50%, approximately 10% to 60%, approximately 10% to 70%, approximately 10% to 80%, approximately 10% to 90%, approximately 20% to 30%, approximately 20% to 40%, approximately 20% to 50%, and approximately 20% to 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%. Compared to pre-treatment capacity or untreated control single skeletal muscle, inhibitors can suppress contraction of single skeletal muscle by approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

[0519] The effects of the test compound on slow type I skeletal muscle fibers, myocardial bundles, or pulmonary muscle fibers can be evaluated. The test compound or an inhibitory compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be selected to not significantly modulate the function of slow type I skeletal muscle fibers, myocardial bundles, or pulmonary muscle fibers, and to be specific for type II skeletal muscle. As used herein, the term "significant modulation" can refer to a reduction in muscle contractility of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% after inhibitor administration relative to pre-inhibitory muscle strength / contraction.

[0520] In some aspects, a method for treating neuromuscular diseases or movement disorders may include administering to a subject in need a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II), wherein the compound of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) reduces skeletal muscle contraction by 5% to 90% in an in vitro assay. The in vitro assay used may be a mouse model. The mouse model used may be a malnourished mouse model, such as the MDX mouse. The MDX mouse has a point mutation in its myoglobin gene that changes the amino acid encoding glutamine to threonine, resulting in nonfunctional myoglobin, leading to DMD characterized by increased muscle damage and weakness. The extensor digitorum longus muscle can be dissected from an MDX mouse and mounted on a lever arm. The muscle can be immersed in an oxygenated Kreb solution to maintain muscle function. The test compound or a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be applied to the muscle. An isometric (fixed-length) contraction step can then be performed, in which the muscle is stimulated with a series of electrical pulses. An eccentric (lengthening) contraction step can be performed, in which the muscle is stretched to 10%, 15%, 20%, 25%, or 30% greater than its resting length during relaxation or stimulation with electrical pulses. This can be repeated 4, 5, 6, 7, or 8 times to induce muscle fiber damage. The electrical pulses can have frequencies from approximately 110 Hz to 150 Hz. The electrical pulses can have frequencies of 110, 115, 120, 125, 130, 135, 140, 145, or 150 Hz. A series of electrical pulses can comprise single pulses of different frequencies. For each pulse, the duration of each pulse in a series of electrical pulses can be between 0.1 seconds and 0.5 seconds. The duration of each pulse can be 0.1, 0.2, 0.3, 0.35, 0.4, or 0.5 seconds. Muscle fascia damage can also be measured by incubating the muscle in Active Orange after isometric or eccentric contractions. Active Orange is a fluorescent dye absorbed by muscle fibers with fascial damage. The number or proportion of dye-positive fibers can then be quantified histologically. When the test power decreases and / or the proportion of dye-positive fibers is at least 20% less than the control power decreases and / or dye absorption, the test compound can be selected as a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II).

[0521] The force produced by the muscle can be measured using a series of isometric or eccentric contractions. The change in force produced by the muscle before and after a series of isometric or eccentric contractions can be calculated as the test force decrease and compared with the change in force produced by muscle contraction from the first pulse to the last pulse in a control sample not exposed to the test compound (control force decrease). The force decrease can be used as a representative of muscle damage, and when the test force decrease is at least 20% less than the control force decrease, the test compound or an inhibitory compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be selected.

[0522] pharmaceutical preparations

[0523] The compositions and methods described herein may be considered suitable for use as pharmaceutical compositions administered to subjects in need. The pharmaceutical composition may comprise at least a compound or salt of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) as described herein, and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersants, suspending agents, and / or thickeners.

[0524] Pharmaceutical compositions of compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be formulated using one or more physiologically acceptable carriers, including excipients and adjuvants. The formulation can be modified according to the chosen route of administration. Pharmaceutical compositions comprising compounds, salts, or conjugates can be manufactured, for example, by lyophilizing the compound, salt, or conjugate, mixing, dissolving, emulsifying, encapsulating, or embedding the conjugate. Pharmaceutical compositions may also comprise compounds, salts, or conjugates in free base form or in pharmaceutically acceptable salt form.

[0525] Methods for formulating compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) 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 some respects, solid compositions may also contain non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, and other pharmaceutically acceptable additives. Alternatively, the compound, salt, or conjugate may be in lyophilized or powder form for reconstitution with a suitable medium, such as sterile, pyrogen-free water, prior to use.

[0526] Pharmaceutical compositions of compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) may contain at least one active ingredient (e.g., a compound, salt, or conjugate, and other pharmaceutical agents). The active ingredient may be encapsulated in microcapsules (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared by cohesive technology or by interfacial polymerization, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or crude emulsions.

[0527] Compositions and formulations can be sterilized. Sterilization can be accomplished through aseptic filtration.

[0528] Compositions comprising compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be formulated for administration as an injection. Non-limiting examples of injectable formulations may include sterile suspensions, solutions, or emulsions in oily or aqueous media. Suitable oily media may include, but are not limited to, lipophilic solvents or media such as fatty oils or synthetic fatty acid esters, or liposomes. Aqueous injectable 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 in lyophilized or powder form for reconstitution with a suitable media such as sterile pyrogen-free water prior to use.

[0529] For parenteral administration, compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be formulated into unit-dose injectable forms (e.g., solutions, suspensions, emulsions) with pharmaceutically acceptable parenteral mediators. Such mediators can be inherently non-toxic and non-therapeutic. Mediators can be water, saline, Ringer's solution, dextran solution, and 5% human serum albumin. Non-aqueous mediators, such as non-volatile oils and ethyl oleate, can also be used. Liposomes can be used as carriers. Mediators may contain small amounts of additives, such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0530] In one embodiment, the present invention relates to methods and compositions of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) for oral delivery to a subject in need. In one embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject via a mucosal layer in the mouth or esophagus. In another embodiment, the composition is formulated to deliver one or more pharmaceutically active agents to a subject via a mucosal layer in the stomach and / or intestine.

[0531] In one embodiment, the composition of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) is provided in an improved release formulation. Suitable improved release dose mediators include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble barrier coatings, enteric coatings, permeation devices, multiply-particulate devices, and combinations thereof. The composition may also contain a non-release control excipient.

[0532] In another embodiment, the compositions of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) are provided in an enteric-coated dosage form. These enteric-coated dosage forms may also contain non-release control excipients. In one embodiment, the composition is in the form of enteric-coated granules as a controlled-release capsule for oral administration. The composition may further contain cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, mannitol, or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric-coated pellets as a controlled-release capsule for oral administration. The composition may further contain glyceryl monostearate 40-50, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium stearate, C-type methacrylic acid copolymer, polysorbate 80, sugar spheres, talc, and triethyl citrate.

[0533] In another embodiment, the composition of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) is an enteric-coated controlled-release tablet for oral administration. The composition may further comprise palm wax, cropovidone, diacetylated glycerol monoester, ethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearoyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0534] Sustained-release articles comprising compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can also be prepared. Examples of sustained-release articles may include a semi-permeable matrix of a solid hydrophobic polymer, which may contain compounds, salts, or conjugates, and these matrices may be in the form of molded 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 L-glutamic acid ethyl ester, non-degradable ethylene-vinyl acetate, and degradable lactic acid-glycolic acid copolymers such as LUPRON DEPO. TM (i.e., injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

[0535] Pharmaceutical formulations containing compounds or salts of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be prepared for storage by mixing the compound, salt, or conjugate with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. The formulation may be a lyophilized preparation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers may be non-toxic to the recipient at the employed dose and concentration. Acceptable carriers, excipients, and / or stabilizers may include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives, peptides; proteins such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming ions such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycol.

[0536] In another embodiment, the composition of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) may further comprise calcium stearate, povidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium dodecyl sulfate, titanium dioxide, and triethyl citrate.

[0537] In another embodiment, the compositions of formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') are provided in an effervescent formulation. These effervescent formulations may also contain non-release-controlled excipients.

[0538] In another embodiment, compositions of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can be provided in a dosage form having at least one component that promotes immediate release of the active agent and at least one component that promotes controlled release of the active agent. In a further embodiment, the dosage form may be capable of providing discontinuous release of the compound in the form of at least two consecutive pulses spaced 0.1 to 24 hours apart. The composition may contain one or more release-controlled and non-release-controlled excipients, such as those suitable for ruptureable semipermeable membranes and as expandable substances.

[0539] In another embodiment, the composition of formula (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) is provided in a dosage form for oral administration to a subject in need, comprising one or more pharmaceutically acceptable excipients or carriers encapsulated in an intermediate reactive layer containing an anti-gastric juice polymeric layered material, which is partially neutralized with alkali and has cation exchange capacity and an anti-gastric juice outer layer.

[0540] In some embodiments, the compositions of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) provided herein may be in single-dose or multiple-dose form. As used herein, a single-dose form refers to a physically discrete unit suitable for administration to human or non-human animal subjects and individually packaged. Each unit dose may contain a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, along with the desired pharmaceutical carrier or excipient. Examples of single-dose forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, the single-dose form may be administered in several portions or multiple times. A multiple-dose form is multiple identical single-dose forms packaged in a single container so that they can be administered in separate single-dose forms. Examples of multiple-dose forms include, but are not limited to, vials, bottles, pint bottles, or gallon bottles containing tablets or capsules. In another embodiment, the multiple-dose form contains different pharmaceutical active agents.

[0541] In some embodiments, compositions of formulas (I'), (I), (Ia), (Ib), (Ic), (Id), (II'), or (II) can also be formulated into improved release dosage forms, including immediate release, delayed release, extended release, sustained release, pulsatile release, controlled release, extended, 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 Practice of Pharmacy, ibid.; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2002; Vol. 126, the entire contents of which are incorporated herein by reference).

[0542] combination therapy

[0543] This article also relates to combination therapies, such as the co-administration of the disclosed compounds and additional active agents as part of a specific treatment regimen designed to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effect of such combination therapy includes, but is not limited to, the synergistic pharmacokinetic or pharmacodynamic effects resulting from the combination of therapeutic agents. The co-administration of these therapeutic agents is typically carried out over a defined time period (usually hours, days, weeks, months, or years, depending on the chosen combination). Combination therapies are intended to cover the sequential administration of multiple therapeutic agents, i.e., where the various therapeutic agents are administered at different times, and are also intended to cover the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0544] For example, substantially simultaneous administration is achieved by administering to a subject a single formulation or composition (e.g., tablets or capsules of various therapeutic agents in a fixed proportion) or multiple single formulations (e.g., capsules), each of which is administered simultaneously. The sequential or substantially simultaneous administration of the various therapeutic agents is achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissues. The therapeutic agents are administered via the same route or via different routes. For example, the first therapeutic agent in a selected combination is administered via intravenous injection, while the other therapeutic agents in the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally, or all therapeutic agents are administered via intravenous injection.

[0545] The components of the combination are administered to the patient simultaneously or sequentially. It should be understood that these components are contained in the same pharmaceutically acceptable carrier and therefore administered simultaneously. Alternatively, the active ingredient is contained in a separate pharmaceutical carrier, such as a conventional oral dosage form, for simultaneous or sequential administration.

[0546] In some embodiments, the compounds or salts of this disclosure may be administered in combination with oral corticosteroids. In some embodiments, the compounds or salts of this disclosure are administered in combination with deflazacort. In some embodiments, the compounds or salts of this disclosure are administered in combination with prednisone. In some embodiments, the compounds or salts of this disclosure are administered in combination with morpholino antisense oligomers. In some embodiments, the compounds or salts of this disclosure are administered in combination with exon skipping therapy. In some embodiments, the additional therapeutic agent is eteplirsen or atalulone.

[0547] In some embodiments, the compounds or salts of this disclosure are used in combination with gene therapy. In some embodiments, the compounds or salts of this disclosure are used in combination with adeno-associated virus (AAV) containing a gene encoding an alternative protein (e.g., dystrophin) or a truncated form thereof (e.g., microdystrophin). In some embodiments, the compounds or salts of this disclosure are administered in combination with vamorolone.

[0548] Example

[0549] The invention will now be described in general terms and will be more readily understood by referring to the following embodiments, which are included only for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to limit the invention in any way.

[0550] The following synthetic schemes are provided for illustrative purposes and not for limitation. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to them. It should also be understood that those skilled in the art will be able to prepare the compounds disclosed herein in a similar manner as described below by using suitable starting materials and modifying the synthetic route as needed. Typically, starting materials and reagents are available from commercial suppliers or synthesized from sources known to those skilled in the art or prepared as described herein.

[0551] Example 1. Synthesis of N-ethyl-2-(3-(4-methoxyphenyl)-6-oxopyridazine-1(6H)-yl)acetamide using a general scheme

[0552]

[0553] Example 2. Synthesis of Exemplary Scheme - N-Ethyl-2-(3-(4-methoxyphenyl)-6-oxopyridazine-1(6H)-yl)acetamide

[0554]

[0555] 6-Bromopyridazine-3(2H)-one is combined with a haloacetate (e.g., 2-bromomethyl ester), cesium carbonate, and an aprotic solvent (e.g., DMF). If necessary, the mixture is gently heated to increase the halogen substitution rate. Separation of the major product yields the corresponding N-substituted pyridazinone. Heating the ester (e.g., methyl ester) in solution of an alcoholic alkylamine (e.g., ethylamine) produces the relative acetamide. The Suzuki reaction at the C-4 bromine position in dioxane / water using a palladium catalyst (e.g., [1,1-bis(diphenylphosphine)ferrocene]dichloropalladium(II)) and a weak base (e.g., potassium acetate) produces a diaryl core in good yield.

[0556] Examples 1 and 2 can be modified appropriately to prepare the compounds described in Tables 1, 2 and 3 of this document.

[0557] Example 3: Synthesis of N-ethyl-2-(6-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)pyridazine-1(6H)-yl)acetamide (compound II-6)

[0558]

[0559] Step 1: Methyl 2-(3-bromo-6-oxopyridazine-1(6H)-yl)acetate

[0560] Cs₂CO₃ (7.5 g, 23.0 mmol) and methyl 2-bromoacetate (1.92 g, 12.6 mmol) were added to a solution of (20 mL). The resulting mixture was stirred at 0 °C for 1 hour. The reaction was then quenched by adding 20 mL of saturated NH₄Cl aqueous solution. The mixture was extracted with 2 x 20 mL EA. The combined organic phases were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain the residue, which was purified by silica gel chromatography to give the title compound (2.2 g, 77.9%) as a white solid. LC / MS (ESI): 247 [M+H] + .

[0561] Step 2: 2-(3-bromo-6-oxopyridazine-1(6H)-yl)-N-ethylacetamide

[0562] A mixture of methyl 2-(3-bromo-6-oxo-1,6-dihydropyridazin-1-yl)acetate (2 g, 8.10 mmol), 35% ethylamine in EtOH solution (8 mL), and methanol (8 mL) was stirred at 70 °C for 3 hours. The mixture was concentrated under vacuum to obtain a residue, which was purified by silica gel chromatography (Flash 80 g, 50% EA:PE) to give the title compound (1.98 g, 77.9%) as a white solid. LC / MS (ESI): 260 [M+H] + .

[0563] Step 3: N-ethyl-2-(6-oxo-3-(4-(2,2,2-trifluoroethoxy)phenyl)pyridazine-1(6H)-yl)acetyl amine

[0564] Under a nitrogen atmosphere, a mixture of 2-(3-bromo-6-oxo-1,6-dihydropyridazin-1-yl)-N-ethylacetamide (2.0 g, 7.69 mmol), [4-(2,2,2-trifluoroethoxy)phenyl]boronic acid (1.87 g, 8.50 mmol), K₂CO₃ (3.22 g, 23.3 mmol), and Pd(dppf)Cl₂ (560 mg, 0.765 mmol) in dioxane was stirred at 90 °C for 3 h. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by silica gel chromatography (100% EA) to give a simply purified product. Further purification was achieved by reversed-phase rapid chromatography (C18 silica gel; mobile phase, aqueous acetonitrile, gradient 10% to 50% over 20 min; detector, UV 254 nm) to give the title compound (2.3 g, 84.2%) as a white solid. 1 H NMR (DMSO-d6, 300MHz): δ8.14(t,J=5.4Hz,1H),8.06(d,J=9.6Hz,1H),7.88-7.84(m,2H),7.21-7.16(m,2H),7.05(d ,J=9.9Hz,1H),4.85(q,J=9.0Hz,2H),4.72(s,2H),3.17-3.08(m,2H),1.05(t,J=7.2Hz,3H); LC / MS(ESI):356[M+H] + .

[0565] Example 4: Synthesis of 2-[3-[6-(difluoromethoxy)pyridin-3-yl]-6-oxo-1,6-dihydropyridazin-1-yl]-N-ethylacetamide (compound I-7)

[0566]

[0567] Step 1: 5-Bromo-2-(difluoromethoxy)pyridine

[0568] A mixture of 5-bromopyridin-2-ol (1 g, 5.75 mmol), ClCF2COONa (0.876 g, 5.75 mmol), and Cs2CO3 (2.81 g, 8.62 mmol) in DMF (20 mL) was heated at 100 °C for 3 hours. LC-MS showed the formation of the desired compound. 40 mL of water and 40 mL of EA were added to the reaction mixture. The organic phase was separated, washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue, which was purified by silica gel chromatography (PE / EA = 100 / 1) to give the title compound (0.3 g, 23.30%) as a colorless oil.

[0569] Steps 2 and 3: 2-[3-[6-(difluoromethoxy)pyridin-3-yl]-6-oxo-1,6-dihydropyridazin-1-yl]-N-ethyl Acetamide

[0570] Under a nitrogen atmosphere, a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentanone e (3.0 g, 11.6 mmol), 5-bromo-2-(difluoromethoxy)pyridine (1.3 g, 5.80 mmol), Pd(dppf)Cl2 (425 mg, 0.58 mmol) and KOAc (1.71 g, 17.4 mmol) in dioxane (20 mL) was stirred at 90 °C for 2 hours. Then, 2-(3-bromo-6-oxo-1,6-dihydropyridazin-1-yl)-N-ethylacetamide (1.51 g, 5.80 mmol), Pd(dppf)Cl2 (425 mg, 0.58 mmol), and K2CO3 (2.41 g, 17.5 mmol), and H2O (2 mL) were added. The mixture was stirred at 90 °C for 2 hours under a N2 atmosphere. The reaction mixture was concentrated under vacuum to obtain a residue, which was purified by silica gel chromatography (100% EA) to give a simply purified product. Further purification was performed by reversed-phase rapid chromatography (C18 silica gel; mobile phase, ACN aqueous solution, 10% to 50% gradient over 20 minutes; detector, UV 254) to give the title compound (0.9 g, 47.9%) as a white solid. 1 H NMR(DMSO-d6,300MHz): δ8.77(d,J=2.1Hz,1H),8.37(dd,J1=8.4Hz,J2=2.4Hz,1H),8.15-8.12(m,2H),7.77(t,J=72.6Hz,1H),7.23 (dd, J1=8.7Hz, J2=0.3Hz, 2H), 7.12 (d, J=9.9Hz, 1H), 4.74 (s, 2H), 3.14-3.10 (m, 2H), 1.05 (t, J=7.2Hz, 3H); LC / MS (ESI): 325[M+H] + .

[0571] Example 5: Synthesis of N-ethyl-2-[6-oxo-3-[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]-1,6-dihydropyridazin-1-yl]acetamide (compound I-10)

[0572]

[0573] Step 1: N-Ethyl-2-(3-(6-fluoropyridin-3-yl)-6-oxopyridazin-1(6H)-yl)acetamide

[0574] Under a nitrogen atmosphere, a mixture of 2-(3-bromo-6-oxo-1,6-dihydropyridazin-1-yl)-N-ethylacetamide (1.0 g, 3.85 mmol), (6-fluoropyridin-3-yl)boronic acid (650 mg, 4.61 mmol), Pd(dppf)Cl2 (281 mg, 0.384 mmol, 0.10 equiv), and K2CO3 (1.59 g, 11.505 mmol) in dioxane (10 mL) / H2O (1.0 mL) was stirred at 100 °C for 2 hours. The reaction was concentrated under vacuum to obtain a residue, which was purified by silica gel chromatography (Flash 40 g, 50-80% EA:PE) to give the title compound (0.65 g, 61.2%) as a white solid. LC / MS (ESI): 277 [M+H] + .

[0575] Step 2: N-Ethyl-2-[6-oxo-3-[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]-1,6-dihydropyridyl [Zinc-1-yl]acetamide

[0576] A mixture of N-ethyl-2-[3-(6-fluoropyridin-3-yl)-6-oxo-1,6-dihydropyridazin-1-yl]acetamide (100 mg, 0.36 mmol) and Cs₂CO₃ (120 mg, 0.37 mmol) in 3,3,3-trifluoroprop-1-ol (1 mL) was stirred at 90 °C for 2 hours. The reaction mixture was purified by preparative HPLC to give the title compound (68 mg, 50.7%) as a white solid. 1 H NMR (DMSO-d6, 400MHz): δ8.70 (d, J = 2.4Hz, 1H), 8.20 (dd, J1 = 8.8Hz, J1 = 2.8Hz, 1H), 8.15 (t, J = 4.8Hz, 1H), 8.10 (d, J = 10.0Hz, 1H), 7.09 (d, J = 10.0Hz ,1H),6.97(d,J=8.4Hz,1H),4.72(s,2H),4.56(t,J=6.0Hz,2H),3.15-3.0 9(m,2H),2.87-2.79(m,2H),1.05(t,J=7.2Hz,3H); LC / MS(ESI):371[M+H] + .

[0577] The following compounds were synthesized according to Example 5:

[0578]

[0579]

[0580]

[0581] Example 6: Synthesis of 2-[3-[6-([bicyclo[1.1.1]pentan-1-yl]amino)pyridin-3-yl]-6-oxo-1,6-dihydropyridazin-1-yl]-N-ethylacetamide (compound I-36)

[0582]

[0583] Step 1: N-(bicyclo[1.1.1]pentan-1-yl)-5-bromopyridin-2-amine

[0584] A mixture of 5-bromo-2-fluoropyridine (200 mg, 1.136 mmol), bicyclo[1.1.1]pentane-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 hours. The residue was added to a silica gel column and eluted with ethyl acetate / petroleum ether (1:2) to produce 110 mg (40.48%) of the title compound as a solid; LCMS (ESI): 239 [M+H]. + .

[0585] Step 2: N-(bicyclo[1.1.1]pentan-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentanyl) Alkyl-2-yl)pyridine-2-amine

[0586] 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), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1,3,2-dioxaborhexacyclopentane (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) were added. The flask was purged and an inert nitrogen atmosphere was maintained. The reaction mixture was stirred at 80 °C for 4 hours and confirmed by LC-MS. This reaction can be used directly for the next step without further treatment.

[0587] Step 3: 2-[3-[6-([bicyclo[1.1.1]pentan-1-yl]amino)pyridin-3-yl]-6-oxo-1,6-dihydro] [1-pyridazine]-N-ethylacetamide

[0588] Add 2-(3-bromo-6-oxopyridazin-1(6H)-yl)-N-ethylacetamide (119 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) to a mixture of N-(bicyclo[1.1.1]pentan-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)pyridine-2-amine (131 mg, 0.46 mmol, 1.0 equiv), K2CO3 (95 mg, 0.69 mmol, 1.5 equiv), and H2O (0.1 mL). Purge the flask and maintain an inert nitrogen atmosphere. Stir the resulting solution at 90 °C for 2 hours. Dilute the solution with water and extract with EtOAc(x3). The combined organic compounds were washed with brine, dried over Na₂SO₄, and the solvent was removed under vacuum. The crude product was purified by silica gel chromatography (Flash 300 g, 50-100% EtOAc:cyclohexane). The crude product was further purified by RP-HPLC to give a white solid (51.3 mg, 43.3%). 1 H NMR (DMSO-d6, 300MHz): δ8.54(d,J=2.1Hz,1H),8.10(t,J=5.1Hz,1H),8.00(d,J=9.9Hz,1H),7.88(dd,J1=8.7Hz,J1=2.4Hz 1H),7.59(s,1H),7.04(d,J=9.9Hz,1H),6.59(d,J=8.7Hz,1H),4.67(s,2H) ,3.16-3.07(m,2H),2.47(s,1H),2.10(s,6H),1.04(t,J=7.2Hz,3H); LC / MS R t =0.848 min; MS m / z: 340 [M+H] + .

[0589] The following compounds were synthesized according to Example 6:

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599] Example 7: Synthesis of N-ethyl-2-(6-oxo-3-(2-(2-(trifluoromethoxy)ethoxy)pyrimidin-5-yl)pyridazin-1(6H)-yl)acetamide (compound I-49)

[0600]

[0601] N-Ethyl-2-(6-oxo-3-(2-(2-(trifluoromethoxy)ethoxy)pyrimidin-5-yl)pyridazine-1(6H)-yl)

[0602] Acetamide

[0603] To a stirred mixture of N-ethyl-2-(6-oxo-3-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-1(6H)-yl)acetamide (100.00 mg, 0.272 mmol, 1.00 equiv) in 2-methoxy-ethanol (1 mL), K₂CO₃ (112.89 mg, 0.817 mmol, 3 equiv) was added in portions, and the solution was stirred at 70 °C for 2 hours. 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 HNMR(CDCl3-d,300MHz,)δ8.97(s,2H),7.80-7.63(m,1H),7.20-7.14(m,1H),6.21(br,1H),4.86(d,J =15Hz,2H),4.72(t,J=4.8Hz,2H),4.38(t,J=4.8Hz,2H),3.40-3.31(m,2H),1.28-1.17(m,3H).LC / MS Rt=1.496min; MS m / z:388[M+H] + .

[0604] Example 8: Synthesis of N-ethyl-2-(3-(6-(methylthio)pyridin-3-yl)-6-oxopyridazin-1(6H)-yl)acetamide (compound I-63)

[0605]

[0606] Step 1: 2-(3-(6-chloropyridin-3-yl)-6-oxopyridazin-1(6H)-yl)-N-ethylacetamide

[0607] K2CO3 (478.24 mg, 3.460 mmol, 3.0 equiv) and Pd(dbpf)Cl2 (93.88 mg, 0.115 mmol, 0.1 equiv) were added in portions to a stirred mixture of 2-(3-bromo-6-oxo-1,6-dihydropyridazin-1-yl)-N-acetamide (300 mg, 1.153 mmol, 1 equiv) and (6-chloropyridin-3-yl)boronic acid (217.81 mg, 1.384 mmol, 1.20 equiv) in 1,4-dioxane (3 mL) and H2O (0.3 mL) under a nitrogen atmosphere. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1) to give 2-[3-(6-chloropyridin-3-yl)-6-oxo-1,6-dihydropyridazin-1-yl]-N-ethylacetamide (310 mg, 91.81%) as a yellow-green solid. MS m / z: 293 [M+H] +

[0608] Step 2: N-Ethyl-2-(3-(6-(methylthio)pyridin-3-yl)-6-oxopyridazin-1(6H)-yl)acetamide

[0609] A mixture of 2-[3-(6-chloropyridin-3-yl)-6-oxopyridazin-1-yl]-N-ethylacetamide (100.00 mg, 0.342 mmol, 1.00 equiv) and (methylthio)sodium (71.82 mg, 1.025) in DMSO (3.00 mL) was stirred at 25 °C for 2 h. The reaction was quenched at 25 °C with saturated NH4Cl (aq.). The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH aqueous solution, 10% to 50% gradient, 10 min; detector, UV 254 nm. The desired product was detected by LCMS, yielding N-ethyl-2-[3-[6-(methylthio)pyridin-3-yl]-6-oxopyridazin-1-yl]acetamide (44.9 mg, 41.28%) as a white solid. 1 H NMR(400MHz, DMSO-d6)δ8.94(d,J=1.2Hz,1H),8.16-8.09(m,3H),7.44-7.42(m,1H),7.10( d,J=9.2Hz,1H),4.73(s,2H),3.15-3.09(m,2H),2.57(s,3H),1.05(t,J=7.2Hz,3H).LC / MS Rt=1.544min; MS m / z:305[M+H] + .

[0610] Example 9: Synthesis of 2-[3-(2-[bicyclo[1.1.1]pentan-1-ylamino]pyrimidin-5-yl)-6-oxopyridazine-1-yl]-N-ethylacetamide (compound I-59)

[0611]

[0612] Step 1: N-[bicyclo[1.1.1]pentan-1-yl]-5-bromopyrimidin-2-amine

[0613] To a stirred solution of 5-bromo-2-fluoropyrimidine (2.00 g, 11.30 mmol) in DMF (20.00 mL), bicyclo[1.1.1]pentane-1-amine (1.41 g, 16.95 mmol), K₂CO₃ (3.12 g, 22.60 mmol), and hydrogen chloride (618.05 mg, 16.95 mmol) were added. The resulting solution was stirred at room temperature for 1 hour. The reaction was quenched with H₂O (100 mL) and extracted with 3 x 20 mL EtOAc. The combined organic phases were concentrated to obtain a residue, which was purified by silica gel chromatography (EtOAc / PE = 1 / 5–1 / 1). The collected fractions were combined and concentrated under vacuum to give the title compound (2.45 g, 90.29%) as a white solid. MS m / z: 240, 242 [M+H] + .

[0614] Step 2: 2-[bicyclo[1.1.1]pentane-1-ylamino]pyrimidine-5-ylboronic acid

[0615] To a stirred solution of N-[bicyclo[1.1.1]pentan-1-yl]-5-bromopyrimidine-2-amine (2.45 g, 10.20 mmol) in dioxane (25.00 mL), bis(pinacol)diboron (3.89 g, 15.306 mmol), KOAc (2.00 mg, 20.40 mmol), and Pd(dppf)Cl2 (373.31 mg, 0.51 mmol) were added. The flask was purged and kept under a nitrogen inert atmosphere. The reaction mixture was stirred at 80 °C for 4 hours and confirmed by LC-MS. This reaction can be used directly for the next step without further treatment.

[0616] Step 3: 2-[3-(2-[bicyclo[1.1.1]pentan-1-ylamino]pyrimidin-5-yl)-6-oxopyridazin-1-yl]ethyl Methyl ester

[0617] To a stirred solution of 2-[bicyclo[1.1.1]pentan-1-ylamino]pyrimidin-5-ylboronic acid (1.89 g, 9.22 mmol) in dioxane (30.00 mL), methyl 2-(3-bromo-6-oxopyridazin-1-yl)acetate (3.40 g, 13.76 mmol), K₂CO₃ (2.54 g, 18.39 mmol), Pd(dppf)Cl₂ (337.00 mg, 0.46 mmol), and H₂O (3.00 mL) were added. The flask was purged and kept under a nitrogen inert atmosphere. The resulting solution was stirred at 90 °C for 2 hours. The solution was diluted with water and extracted with EtOAc (x³). The combined organic matter was washed with brine, dried over Na₂SO₄, and the solvent was removed under vacuum. Purified by silica gel chromatography (Flash 300g, 50-100% EtOAc:cyclohexane) to give the title compound (2.7g, 89.47%) as a brown solid. MS m / z: 328 [M+H] + .

[0618] Step 4: 2-[3-(2-[bicyclo[1.1.1]pentan-1-ylamino]pyrimidin-5-yl)-6-oxopyridazin-1-yl]- N-Ethylacetamide

[0619] A mixture of methyl 2-[3-(2-[bicyclo[1.1.1]pentan-1-ylamino]pyrimidin-5-yl)-6-oxopyridazin-1-yl]acetate (2.70 g, 8.25 mmol) in ethylamine solution (35% EtOH, 15 mL) was stirred at 80 °C for 4 hours. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (EtOAc / PE = 1 / 5-1 / 1). The collected fractions were combined and concentrated under vacuum to give the title compound (2 g, 71.24%) as a white solid.

[0620] 1 H NMR (400MHz, DMSO-d6): δ8.79(s,2H),8.28(s,1H),8.12(t,J=5.6Hz,1H),8.01(d,J=10.0Hz,1H),7.05( d,J=9.6Hz,1H),4.69(s,2H),3.17-3.06(m,2H),2.46(s,1H),2.09(s,6H),1.04(t,J=7.2Hz,3H); LC / MS Rt=2.202min; MS m / z:341.1[M+H] + .

[0621] The following compounds were synthesized according to Example 9:

[0622]

[0623]

[0624] Example 10: Synthesis of N-ethyl-2-[6-oxo-3-[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]-1,6-dihydropyridazin-1-yl]acetamide (compound I-10)

[0625]

[0626] Step 1: N-Ethyl-2-(3-(6-fluoropyridin-3-yl)-6-oxopyridazin-1(6H)-yl)acetamide

[0627] Under a nitrogen atmosphere, a mixture of 2-(3-bromo-6-oxo-1,6-dihydropyridazin-1-yl)-N-ethylacetamide (1.0 g, 3.85 mmol), (6-fluoropyridin-3-yl)boronic acid (650 mg, 4.61 mmol), Pd(dppf)Cl2 (281 mg, 0.384 mmol, 0.10 equiv), and K2CO3 (1.59 g, 11.505 mmol) in dioxane (10 mL) / H2O (1.0 mL) was stirred at 100 °C for 2 hours. The reaction 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 (0.65 g, 61.2%) as a white solid. MS m / z: 277 [M+H] +

[0628] Step 2: N-Ethyl-2-[6-oxo-3-[6-(3,3,3-trifluoropropoxy)pyridin-3-yl]-1,6-dihydropyridyl [Zinc-1-yl]acetamide

[0629] A mixture of N-ethyl-2-[3-(6-fluoropyridin-3-yl)-6-oxo-1,6-dihydropyridazin-1-yl]acetamide (100 mg, 0.36 mmol) and Cs₂CO₃ (120 mg, 0.37 mmol) in 3,3,3-trifluoroprop-1-ol (1 mL) was stirred at 90 °C for 2 hours. The reaction mixture was purified by preparative HPLC to give the title compound (68 mg, 50.7%) as a white solid. 1 H NMR (DMSO-d6, 400MHz): δ8.70(d,J=2.4Hz,1H),8.20(dd,J=8.8Hz,2.8Hz,1H),8.15(t,J=4.8Hz,1H),8.10(d,J=10.0Hz,1H),7.09(d,J=1 0.0Hz,1H),6.97(d,J=8.4Hz,1H),4.72(s,2H),4.56(t,J=6.0Hz,2H),3.15-3.09(m,2H),2.87-2.79(m,2H),1.05(t,J=7.2Hz,3H); LC / MS R t=1.379 min; MS m / z: 371 [M+H] +

[0630] The following compounds were synthesized according to Example 11.

[0631]

[0632]

[0633]

[0634] Example 11: Synthesis of N-cyclobutyl-2-[3-[2-(2-methylpropoxy)pyrimidin-5-yl]-6-oxopyridazin-1-yl]acetamide (compound I-79)

[0635]

[0636] Step 1: N-cyclobutyl-2-[3-[2-(2-methylpropoxy)pyrimidin-5-yl]-6-oxopyridazin-1-yl]acetyl amine

[0637] To a mixture of N-cyclobutyl-2-(6-oxo-3-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-1(6H)-yl)acetamide (2.00 g, 5.217 mmol, 1.00 equiv) and 2-methylprop-1-ol (20 mL), K₂CO₃ (1.422 g, 10.435 mmol, 2.00 equiv) was added in portions, and the solution was stirred at 80 °C for 4 hours. The resulting mixture was concentrated under reduced pressure. The crude product (1.6 g) was purified by preparative HPLC to give the title compound (800 mg, 42.90%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.04(s,2H),8.46(d,J=7.6Hz,1H),8.10(d,J=9.6Hz,1H),7.12(d,J=9.6Hz,1H),4.71( s,2H),4.25-4.14(m,2H),2.20-2.02(m,2H),1.97-1.87(m,2H),1.67-1.58(m,2H),0.99(d,J=6.8Hz,6H).LC / MS Rt=1.327min; MS m / z:358[M+H] + .

[0638] The following compounds were synthesized according to Example 11:

[0639]

[0640] Example 12. Assay of ATPase in skeletal myofibrils

[0641] Overview: Myosin ATPase activity was assessed using a coupled reaction system in which ADP produced by myosin ATPase function is coupled to the loss of NADH via a pyruvate kinase / lactate dehydrogenase (PK-LDH) system. ATPase activity produces ADP, which serves as a substrate for PK to produce pyruvate and regenerate ATP. Pyruvate is then used as a substrate by LDH to oxidize NADH to NAD+. The reaction rate was monitored by the time-dependent loss of NADH using absorbance at 340 nm. The inhibition of ATPase activity by the determined compounds was indicated by a decrease in the rate of NADH loss relative to the mediator-treated control within the experimental time window. To assess the selectivity of the determined compounds for skeletal myofibrils, reverse screening of the compounds was performed in cardiac myofibrils.

[0642] Materials: The following stock solutions and reagents are used in the skeletal myofibril ATPase assay:

[0643]

[0644] Stock solution of pCa buffer. Combine PIPES, CaCl2, and EGTA solutions with 70 mL of water. Adjust the pH to 7.0 and bring the final volume to 100 mL.

[0645]

[0646]

[0647] Buffer A and Buffer B. Store buffers on ice until used.

[0648] Buffer preparation

[0649]

[0650] Skeletal 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 to a sufficiently large tube at approximately twice the required volume and cap it. Thaw the myofibrils by rolling them in a water bath at room temperature for approximately 15 minutes and then cool them on ice. Buffers A and B are prepared by adjusting the volume according to the number of wells and stored on ice. Add 0.5 μL of the analyte compound to the well. Dispense 25 μL of buffer A to the well, followed by 25 μL of buffer B. Measure the absorbance of the wells at 340 nm using a kinetic protocol, reading the wells every 1.5–2 minutes for 45 minutes. Approximate the slope of the data by subtracting the minimum absorbance value from the maximum value for each well. This is done in SoftMax Pro software or a spreadsheet program such as Excel. Normalize the data using GraphPadPrism 8.0 by assigning 100% of the values ​​to the 1% DMSO medium wells. Typically, the normalized 0% value is simply assigned to the (Max-Min) value of 0. The normalized data are fitted to a four-parameter logistic sigmoidal equation, with the bottom bound to 0 or greater. The compounds in Tables 1, 2, and 3 were tested, and the results are presented in Tables 4a-4c of this paper. A = IC 50 Less than or equal to 10 μM; B =

[0651] IC 50 Greater than 10 μM and less than 100 μM; C = IC 50 Greater than 100 μM.

[0652] Example 13. Assay of cardiac myofibril ATPase

[0653] According to Example 10, reverse screening was performed using frozen myofibril microspheres obtained from heart tissue. This assay was performed in the same manner as described above, but with the following significant differences: the final pore concentration of the myofibrils was 1.0 mg / mL, and KCl was omitted from the formulation.

[0654] The compounds listed in Tables 1 through 4 were tested, and the results are presented in Tables 5a-5c of this paper. A = IC 50 Less than or equal to 10 μM; B = IC 50 Greater than 10 μM and less than 100 μM; C = IC 50 Greater than 100 μM; D = IC 50 Greater than 60μM.

[0655] Example 14. Tibialis anterior muscle measurement

[0656] Skeletal muscle in patients with Duchenne muscular dystrophy (DMD) and MDX mice is deficient in myoglobin and is more susceptible to contraction-induced injury than control muscles. Susceptibility to limb muscle injury in MDX mice following administration of the compounds disclosed herein was evaluated using two maximally activated in situ segments of the tibialis anterior (TA) muscle. Stress segments at 20% of muscle fiber length were initiated from a plateau of isometric contraction. The degree of injury was assessed by isometric insufficiency after one minute.

[0657] animal

[0658] Mice aged 2–19 months were tested. Specific pathogen-free (SPF) C57BL control and mdx mice were either purchased or bred in-house from crosses purchased from Jackson Laboratories. All control mice were of the C57BL / 10J strain, except for the 19-month-old mice, which were C57BL / 6. The use of C57BL / 6 mice for the oldest group was necessary because, unlike C57BL / 10J mice, C57BL / 6 mice can be purchased from an aged rodent population maintained by the National Institute on Aging.

[0659] In-situ preparation

[0660] Mice were anesthetized by an initial intraperitoneal injection of Avertin (tribromoethanol; 13-17 μL / g). Anesthesia was supplemented until no response to tactile stimulation was detected. This level of anesthesia was maintained throughout the experiment using additional doses of Avertin. The TA tendon was exposed through an incision at the ankle. The tendon was severed a few millimeters from the muscle end. The tendon was sutured as close as possible to the muscle attachment point with 4.0 nylon sutures, folded back, and sutured again. The tendon and exposed muscle were kept moist by periodic application of isotonic saline. Mice were placed on a heated platform maintained at 37°C. The mouse's feet were secured to the platform with cloth strips, and the knees were fixed in clamps between sharp screws. The tendon of the muscle was securely fastened to a lever arm of a servo motor. The servo motor controlled the position of the muscle and monitored the forces generated by the muscle. All data were displayed on a digital oscilloscope and stored on a computer.

[0661] The TA muscle is stimulated with 0.2-ms pulses using two needle electrodes, which penetrate the skin on either side of the peroneal nerve near the knee. The stimulation voltage and subsequent muscle length (Lo) are adjusted for the maximum isometric twitching force (Pt). While holding at Lo, the muscle is stimulated at increasing frequencies, gradually increasing from 150 Hz to 50 Hz until the maximum force (Po) is reached, typically at 250 Hz. A rest period of 1 to 2 minutes is allowed between each tetanic contraction. Muscle length is measured using calipers based on well-defined anatomical landmarks near the knee and ankle. Optimal fiber length is determined by multiplying Lo by the TA Lf / Lo ratio of 0.6.

[0662] Extended contraction protocol

[0663] Each muscle is stretched twice in situ, stimulating the muscle at 250Hz, the frequency most likely to induce po (post-exposure). A program consisting of only two contractions is used to avoid fatigue. The stretch begins with a plateau of isometric contraction at Lo. The time progression of this program is as follows: Figure 1 As shown. At time 0, stimulation begins, and the muscle remains immobile for 100 ms to allow for maximum activation. From the plateau of maximum isometric contraction, a length change of 20% Lf (LC1) is applied at a rate of 1 Lf / s. Stimulation ceases at the end of the stretch climb. The muscle is held at the stretch length for 100 ms and then returned to Lo at the same rate. A second extended contraction (LC2) is performed after 10 minutes, identical to the first. Maximum isometric force is measured after 1 minute, and then again every 5 minutes for 15 minutes. Insufficiency is calculated as the difference between the isometric force during LC1 and the maximum isometric force measured at any given time, and expressed as a percentage of the isometric force during LC1. Recovery within 15 minutes after the two extended contraction protocols is quantified as the difference between the isometric force measured at 15 minutes and the isometric force after the second extended contraction, and expressed as a percentage of the initial Po.

[0664] After a final assessment of isometric force, the TA muscle was removed from the mice. Tendon and elongation contractions caused muscle damage and a decrease in Po. The experimental protocol consisted of two muscle stretches during maximal activation, followed by maximal activation to measure the decrease in maximal isometric force (Po). Muscle length change relative to 20% stress relative to fiber length (Lf) is shown, where 100% corresponds to the optimal muscle length (Lo) for force development. The muscle was stretched at a rate of 2 Lf / s. The decrease in Po after two stretching protocols in representative mdx mice is shown. Each elongation contraction began at the plateau of maximal isometric contraction. A second elongation contraction (LC2) occurred 10 minutes after the first elongation contraction (LC1). The maximum force during the isometric contraction was measured 10 minutes after LC2 (t1 min) and again 15 minutes after recovery (t15 min). Insufficiency was calculated by dividing the difference between Po during LC1 and Po measured at any time after LC1 by the Po during LC1 and multiplying by 100%. Sutures were removed from the muscle and the muscle was weighed. After removal of the TA muscle, deeply anesthetized mice were euthanized by inducing pneumothorax. The total muscle fiber cross-sectional area (CSA) of the TA muscle was calculated by dividing the muscle mass by the product of Lf and 1.06 mg / mm³ (density of mammalian skeletal muscle). The ratio Po was calculated by dividing Po by the CSA. Experimental results are shown in […]. Figure 3-6 .

[0665] Figure 3 This study demonstrates the reduction in force of the disclosed compound prior to injury at 100 Hz. 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 changes in force were recorded before initiating the eccentric injury protocol. This metric provides an indication of the relative ability of the compound to reduce force in the target tissue.

[0666] Figure 4 The results show a reduction in post-damage force of the compounds disclosed herein at 175 Hz.

[0667] Maximum force was measured in situ at 175 Hz in TA muscle 10 minutes before and after two rounds of eccentric (prolonged) contractions. In MDX mice, prolonged contractions produced an exaggerated decrease in force. This measurement provides an indication of the compound's ability to reduce the relative decrease in force after eccentric contractions. Figure 5 This demonstrates a decrease in intermediate elongation force of the compounds disclosed herein. TA muscle in situ injury is caused by two maximal eccentric contractions, each with 20% elongation, spaced 10 minutes apart. This metric measures the relative decrease in pre-elongation force between the first and second contractions.

[0668] Figure 6 The compounds of this disclosure show an increase in TA mass after damage.

[0669] In MDX mice, elongated TA muscle injury resulted in a delayed increase in muscle weight after injury. This is likely due to fluid accumulation in the form of edema. Muscles (injured and contralateral) were removed from the mice one hour after injury and weighed. The relative increase in weight of the injured muscle relative to the contralateral muscle was recorded. A decrease in this relative change indicates a reduction in post-injury edema.

[0670] In some embodiments, this disclosure provides compounds of formula (I) in Table 1.

[0671] Table 1

[0672]

[0673]

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703] In some embodiments, this disclosure provides compounds of formula (II) or (II') in Table 2.

[0704] Table 2

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716] In some embodiments, this disclosure provides compounds of formula (III') or (III) in Tables 3a-3c.

[0717] Table 3A

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727] Table 3B

[0728]

[0729]

[0730]

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740] Table 3C

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755] The skeletal IC of the disclosed compound 50 The values ​​are shown in Table 4A.

[0756] Table 4A

[0757]

[0758]

[0759] 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.

[0760] The skeletal IC of the disclosed compound 50 The values ​​are shown in Table 4B.

[0761] Table 4B

[0762]

[0763]

[0764] A = IC 50 Less than or equal to 10 μM; B = IC 50 Greater than 10 μM and less than 100 μM; C = IC 50Greater than 100 μM.

[0765] The skeletal IC of the compounds disclosed herein 50 The values ​​are shown in Table 4C.

[0766] Table 4C

[0767]

[0768]

[0769]

[0770] 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.

[0771] Some compounds disclosed herein have cardiac IC as shown in Table 5A. 50 value.

[0772] Table 5A

[0773]

[0774]

[0775] 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.

[0776] Some compounds disclosed herein have cardiac IC as shown in Table 5B. 50 value.

[0777] Table 5B

[0778]

[0779] 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.

[0780] Some compounds disclosed herein possess cardiac IC as shown in Table 5C. 50 value.

[0781] Table 5C

[0782]

[0783]

[0784]

[0785]

[0786] 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 greater than 100 μM.

[0787] While preferred embodiments of the invention have been shown and described herein, these embodiments will be apparent to those skilled in the art if provided by way of example only. Many variations, modifications, 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 the practice of the invention. The following claims are intended to define the scope of the invention and thereby cover the methods and structures and their equivalents within the scope of these claims.

Claims

1. Compounds represented by formula (I'): Or its salt, wherein: Each X is independently selected from C(R) 3 ), N and N + (-O - ), wherein at least one X is N or N + (-O - ); A is selected from -O- and -NR 4 -、-CR 5 R 6 -and-S-; R 1 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 , -N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 The alkynyl group is replaced by a substituent, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 9 Replaced; or R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; R 25 Selected from: Hydrogen and C 1-6 Alkyl; or R 25 With R 2 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles; R 2 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 , -N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、 -N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、-S(O)2R 10 、-NO2、=O、=S、=N(R 10 )、-CN、 C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 A carbocyclic ring and 3 to 10-membered heterocycles, each optionally substituted by one or more substituents independently selected from: halogens, -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 and C 3-10 Carbon ring, wherein the C 1-6 Alkyl and C 3-10 The carbon ring is optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 2 With R 25 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles; R 3 R 5 and R 6 Each is selected independently from: Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 4 Selected from: Hydrogen; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced; R 7 and R 8 Each is selected independently from: Halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; Each R 9 Selected independently from: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 、-C(O)OR 10 、-OC(O)R 10 、-S(O)R 10 、 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used; Each R 10 Selected independently from: Hydrogen; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups; n is 0, 1, or 2; and p is 0, 1, or 2.

2. The compound or salt according to claim 1, wherein the compound of formula (I') is represented by formula (I): in: R 1 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 , -N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、 -N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN; or R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 and R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 What it replaced.

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

4. The compound or salt according to claim 1 or 2, wherein the compound of formula (I') or (I) is represented by formula (Ic) or formula (Id):

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

6. The compound or salt according to claim 1 or 2, wherein A is selected from -S-, -O-, -NR. 4 -and-CHR 5 -,in: R 4 It is hydrogen or C 1-3 Alkyl; or R 4 and R 1 Together with the N atoms to which they are attached, they form a group optionally bounded by one or more R atoms. 9 Replaced 4- to 9-membered heterocycles; R 5 It is hydrogen; or R 5 and R 1 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. 9 Replacement C 3-6 Carbon ring.

7. The compound or salt according to claim 6, wherein A is -O-.

8. The compound or salt according to claim 6, wherein A is -NR 4 - 9. The compound or salt according to claim 8, wherein A is -NH-.

10. The compound or salt according to claim 6, wherein A is -CHR 5 - 11. The compound or salt according to claim 1 or 2, wherein R 1 Selected from: C 1-6 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =NH, =N(C 1-3 Alkyl), -CN, C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein the C 3-6 The carbon ring or 3- to 6-membered heterocycle is optionally separated by one or more R 9 Replaced; and C 3-8 Carbon rings and 3- to 8-membered heterocycles containing 1 to 3 heteroatoms, wherein the C 3-8 The carbon ring and the 3- to 8-membered heterocycle are each optionally separated by one or more R 9 Replaced; or R 1 With R 4 Together they form 4 to 9-membered heterocycles, which are optionally separated by one or more R 9 The 4- to 9-membered heterocycles are selected from monocyclic, bridged, and spirocyclic rings, optionally containing one or two additional heteroatoms; or R 1 With R 5 Together they form C 3-6 cycloalkyl, which is optionally composed of one or more R 9 What it replaced.

12. The compound or salt according to claim 11, wherein R 1 Selected from: C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OC 1-3 Haloalkyl, -N(C) 1-3 Alkyl)2, C 4-6 Cycloalkyl groups and 4-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 The cycloalkyl or 4-membered saturated heterocycle is optionally substituted by 1 to 3 substituents, which are independently selected from halogens and C. 1-3 Alkyl groups; and C 4-8 Saturated carbon rings and 4- to 6-membered saturated heterocycles containing one or two heteroatoms, wherein the C 4-8 The saturated carbocyclic ring and the 4- to 6-membered saturated heterocyclic ring are each optionally substituted by 1 to 3 substituents, which are independently selected from halogens, -OH, and -OC. 1-3 Alkyl, -OC 1-3 Haloalkyl, -SH, -NH2, -NO2, =O, =S, =NH, -CN, C 1-3 Alkyl and C 1-3 Hydroxyalkyl; or R 1 With R 4 Together they form 4 to 9-membered heterocycles selected from 4 to 6-membered monocyclic rings, 7 to 9-membered bridged rings, and 7-membered spirocyclic rings, each optionally containing one or two additional heteroatoms, and each optionally substituted with 1 to 3 substituents selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -NO2, =O, =S, =NH and -CN, wherein the C 1-3 The alkyl group may optionally be further substituted with a group selected from -OH, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl; or R 1 With R 5 Together they form C 3-6 Cycloalkyl.

13. The compound or salt according to claim 12, wherein R 1 Selected from: C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OC 1-3 Haloalkyl, C 4-6 Cycloalkyl groups and 4-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 The cycloalkyl or 4-membered saturated heterocycle is optionally substituted by 1 to 3 substituents, which are independently selected from halogens and C. 1-3 Alkyl groups; and C 4-6 cycloalkyl, C 5-8 Bridged cycloalkyl groups, phenyl groups, and 4- to 6-membered saturated heterocycles containing one heteroatom, wherein the C 4-6 cycloalkyl, C 5-8 The bridged cycloalkyl group, phenyl group, and 4- to 6-membered saturated heterocycle are each optionally substituted with 1 to 3 substituents, which are independently selected from halogens, -OH, and -OC. 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Alkyl and C 1-3 Hydroxyalkyl; or R 1 With R 4 Together they form 4 to 7-membered heterocycles selected from aziridine, pyrrolidine, piperidine, morpholine, spiro-aziridine, bridged piperidine, and bridged morpholine, each optionally bounded by 1 to 3 R groups. 9 The substitutions, wherein the spiro-azacyclobutane, bridged piperidine, and bridged morpholine each optionally contain additional heteroatoms; and wherein each R 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and -OC 1-3 Halogenated alkyl groups, wherein the C 1-3 Alkyl groups may optionally be further divided by a -OC 1-3 Halogenated alkyl substitution; or R 1 With R 5 Together they form C 3-6 Cycloalkyl.

14. The compound or salt according to claim 11, wherein R 1 Selected from C 1-6 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =NH, =N(C 1-3 Alkyl), -CN, C 3-6 Carbon rings and 3- to 6-membered heterocycles, wherein the C 3-6 The carbon ring or 3- to 6-membered heterocycle is optionally separated by one or more R 9 What it replaced.

15. The compound or salt according to claim 14, wherein R 1 Selected from C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OH, -OC. 1-3 Alkyl, -OC 1-3 Halogenated alkyl groups, -NH2, -NH(C) 1-3 alkyl), -N(C) 1-3 Alkyl)2, C 4-6 cycloalkyl groups and 4- to 6-membered saturated heterocycles, wherein the C 4-6 The cycloalkyl group and the 4- to 6-membered saturated heterocycle are each optionally substituted with 1 to 3 substituents, which are independently selected from halogens and C. 1-3 alkyl.

16. The compound or salt according to claim 15, wherein R 1 Selected from C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OC 1-3 Haloalkyl, -N(C) 1-3 Alkyl)2, C 4-6 cycloalkyl and 4-membered saturated heterocycles, wherein the C 4-6 The cycloalkyl or 4-membered saturated heterocycle is optionally substituted by 1 to 3 substituents, which are independently selected from halogens and C. 1-3 alkyl.

17. The compound or salt according to claim 16, wherein R 1 Selected from C 1-4 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -OC 1-3 Haloalkyl, C 4-6 cycloalkyl and 4-membered saturated heterocycles, wherein the C 4-6 The cycloalkyl or 4-membered saturated heterocycle is optionally substituted by 1 to 3 substituents, which are independently selected from halogens and C. 1-3 alkyl.

18. The compound or salt according to claim 17, wherein the C 4-6 Cycloalkyl is cyclobutyl.

19. The compound or salt according to claim 17 or 18, wherein the 4-membered saturated heterocycle is an oxobutyryl.

20. The compound or salt according to claim 15, wherein R 1 Selected from -CH3, -CH(CH3)2, -CH2CH2CH3, -C(CH3)3, -CHF2, -CF3, -CH2CF3, CH2CH2CF3, -CH2CH2-O-CF3, 21. The compound or salt according to claim 15, wherein R 1 Selected from -CH3, -CH2CH2CH3, -C(CH3)3, -CHF2, -CF3, CH2CF3, CH2CH2CF3, -CH2CH2-O-CF3, 22. The compound or salt according to claim 11, wherein R 1 Selected from C 3-8 Carbon rings and 3- to 8-membered heterocycles, wherein the C 3-8 The carbon ring and the 3- to 8-membered heterocycle are each optionally separated by one or more R 9 What it replaced.

23. The compound or salt according to claim 22, wherein R 1 Selected from C 4-8 Saturated carbon rings and 4- to 6-membered saturated heterocycles, wherein the C 4-8 Saturated carbon rings and 4- to 6-membered saturated heterocycles are each optionally separated by 1 to 3 R 9 replace.

24. The compound or salt according to claim 23, wherein R 1 Selected from C 4-6 cycloalkyl, C 5-8 Bridged cycloalkyl, phenyl, and 4- to 6-membered saturated heterocycles, wherein the C 4-6 cycloalkyl, C 5-8 Bridged cycloalkyl, phenyl, and 4- to 6-membered saturated heterocycles are each optionally bounded by 1 to 3 R... 9 replace.

25. The compound or salt according to claim 24, R 1 Selected from Each can be randomly assigned to 1 to 3 Rs 9 replace.

26. The compound or salt according to claim 25, wherein R 1 Selected from Each can be randomly assigned to 1 to 3 Rs 9 replace.

27. The compound or salt according to any one of claims 22 to 26, wherein R 1 Each R 9 Independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected independently by one or more halogens, -OH, -OC. 1-3 Alkyl and -OC 1-3 The alkyl halogroup is substituted by a substituent.

28. The compound or salt according to claim 27, wherein R 1 Each R 9 Independently selected from halogens, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -SH, -NH2, -NO2, =O, =S, =NH, -CN, C 1-3 Alkyl and C 1-3 Hydroxyalkyl.

29. The compound or salt according to claim 28, wherein R 1 Each R 9 Independently selected from halogens, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, C 1-3 Alkyl and C 1-3 Hydroxyalkyl.

30. The compound or salt according to claim 29, wherein R 1 Each R 9 Independently selected from halogens, -OH, C 1-3 Alkyl and C 1-3 Hydroxyalkyl.

31. The compound or salt according to any one of claims 22 to 25, wherein R 1 Selected from 32. The compound or salt according to claim 31, wherein R 1 Selected from 33. The compound or salt according to claim 8, wherein R 1 and R 4 Together with the N atoms to which they are attached, they form 4 to 9-membered heterocycles, which are optionally bounded by one or more R atoms. 9 The 4 to 9-membered heterocyclic rings are selected from monocyclic rings, bridged rings, and spiral rings.

34. The compound or salt according to claim 33, wherein R 1 and R 4 Together with the N atoms they are attached to, they form 4 to 9-membered heterocycles, selected from 4 to 6-membered monocyclic rings, 7 to 9-membered bridged rings, and 7-membered spirocyclic rings, each optionally bounded by 1 to 3 R atoms. 9 replace.

35. The compound or salt according to claim 33, wherein R 1 and R 4 Together with the N atoms they are attached to, they form optional groups of 1 to 3 R atoms. 9 Replaced 4- to 7-membered heterocycles.

36. The compound or salt according to claim 33, wherein R 1 and R 4 The 4- to 7-membered heterocycles formed are selected from aziridine, pyrrolidine, piperidine, morpholine, spiro-aziridine, bridged piperidine, and bridged morpholine, each optionally bounded by 1 to 3 R groups. 9 replace.

37. The compound or salt according to claim 33, wherein R 1 and R 4 Together with the N atoms they are attached to, they form 4 to 9-membered heterocycles, selected from... Each of these is arbitrarily divided by 1 to 3 Rs. 9 What it replaced.

38. The compound or salt according to claim 33, wherein R 1 and R 4 Together with the N atoms they are attached to, they form 4- to 7-membered heterocycles, selected from... Each of these is arbitrarily divided by 1 to 3 Rs. 9 What it replaced.

39. The compound or salt according to any one of claims 33 to 38, wherein R 1 and R 4 Each R on the formed ring 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 ) and -CN, wherein the C 1-3 The alkyl group may optionally be further substituted with a group selected from -OH, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups.

40. The compound or salt according to claim 39, wherein R is... 1 and R 4 Each R on the formed ring 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -NO2, =O, =S, =NH and -CN, wherein the C 1-3 The alkyl group may optionally be further substituted with a group selected from -OH, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups.

41. The compound or salt according to claim 40, wherein R... 1 and R 4 Each R on the formed ring 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Haloalkyl, -OH, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl and =O, wherein the C 1-3 The alkyl group may optionally be further substituted with a group selected from -OH, -OC 1-3 Alkyl and -OC 1-3 Halogenated alkyl groups.

42. The compound or salt according to claim 41, wherein R... 1 and R 4 Each R on the formed ring 9 Independently selected from halogens, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and -OC 1-3 Halogenated alkyl groups, wherein the C 1-3 Alkyl groups may optionally be further divided by a -OC 1-3 Halogenated alkyl substitution.

43. The compound or salt according to claim 33, wherein R 1 and R 4 Together with the N atoms they are attached to, they form 4 to 9-membered heterocycles, selected from...

44. The compound or salt according to claim 33 or 35, wherein R 1 and R 4 Together with the N atoms they are attached to, they form 4- to 7-membered heterocycles, selected from...

45. The compound or salt according to claim 10, wherein R 1 and R 5 Together with the atoms they are attached to, they form C 3-6 Carbon rings, which are optionally composed of one or more R 9 What it replaced.

46. ​​The compound or salt according to claim 45, wherein R 1 and R 5 Together with the atoms they are attached to, they form C 3-6 cycloalkyl, which is optionally composed of one or more R 9 What it replaced.

47. The compound or salt according to claim 46, wherein R 1 and R 5 Together with the atoms they are attached to, they form It is optionally controlled by one or more R 9 What it replaced.

48. The compound or salt according to claim 11, wherein R 1 Selected from -CH3, -CH(CH3)2, -CH2CH2CH3, -C(CH3)3, -CHF2, -CF3, -CH2CF3, CH2CH2CF3, -CH2CH2-O-CF3, Or R 1 and R 4 Together with the N atoms they are attached to, they form Or R 1 and R 5 Together with the atoms they are attached to, they form 49. The compound or salt according to claim 48, wherein R 1 Selected from -CH3, -CH2CH2CH3, -C(CH3)3, -CHF2, -CF3, -CH2CF3, CH2CH2CF3, -CH2CH2-O-CF3, Or R 1 and R 4 Together with the N atoms they are attached to, they form Or R 1 and R 5 Together with the atoms they are attached to, they form 50. The compound or salt according to claim 1 or 2, wherein R 1 Selected from C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; Phenyl, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 2, -NO2, -CN and C 1-6 Substituents of alkyl groups; and 4 to 6-membered heterocyclic alkyl groups, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN and C 1-6 Alkyl groups are substituted.

51. The compound or salt according to claim 11, wherein R 1 Selected from: C 1-3 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; Phenyl, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Substituents of alkyl groups; and 4 to 6-membered heterocyclic alkyl groups, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl groups are substituted.

52. The compound or salt according to claim 51, wherein R 1 Selected from C10 ... 1-3 Alkyl groups; and 4 to 6-membered heterocyclic alkyl groups and phenyl groups, any one of which may optionally be independently selected from halogens and C. 1-3 Alkyl groups are substituted.

53. The compound or salt according to claim 52, wherein R 1 Selected from -CHF2, -CF3, -CH3, -CH2CH2CF3, -CH2CF3, p-fluorophenyl, p-chlorophenyl, 54. The compound or salt according to claim 8, wherein R 1 With R 4 Together they form an optional combination of one or more R 9 Replaced 4- to 7-membered heterocycles.

55. The compound or salt according to claim 54, wherein R 1 With R 4 Together they form 4- to 7-membered heterocycles, selected from: Any one of them may be arbitrarily assigned to one or more R 9 What it replaced.

56. The compound or salt according to claim 55, wherein R 1 With R 4 Together they form 4- to 7-membered heterocycles, selected from:

57. The compound or salt according to claim 1 or 2, wherein R 2 Selected from: C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 The phenyl group is substituted with substituents of -CN, phenyl, and 5- to 6-membered heteroaryl groups, wherein each of the phenyl and 5- to 6-membered heteroaryl groups is optionally replaced by one or more R groups. 9 Replaced; and Saturated C 3-8 A carbon ring, optionally composed of one or more independently selected from halogens, C 1-3 Substituents of alkyl and phenyl groups; or R 2 and R 25 Together with the N atoms they are attached to, they form 4- to 6-membered rings, which are optionally bounded by one or more R atoms. 9 What it replaced.

58. The compound or salt according to claim 57, wherein R 2 Selected from: C 1-5 Alkyl groups, optionally substituted with 1 to 3 substituents independently selected from: halogens, -NO2, =O, =S, =NH, -CN, phenyl, and 5 to 6-membered heteroaryl groups containing 1 to 3 heteroatoms, wherein the phenyl and 5 to 6-membered heteroaryl groups are each optionally substituted with 1 to 3 substituents independently selected from halogens and C. 1-3 Alkyl groups; and C 3-6 Monocyclic cycloalkyl, C 5-6 Bridged cycloalkyl and C 5-6 Spirocycloalkyl, wherein each is optionally substituted with 1 to 3 substituents, which are independently selected from halogens, C 1-3 Alkyl and phenyl; or R 2 and R 25 Together with the N atoms they are attached to, they form 4 to 6-membered rings.

59. The compound or salt according to claim 58, wherein R 2 Selected from: C10, which is optionally substituted with 1 to 3 substituents 1-5 Alkyl group, wherein the substituent is independently selected from halogens, -CN, and phenyl groups, wherein the phenyl group is optionally substituted with one, two, or three halogens; and C 3-4 cycloalkyl, Each can be chosen by C 1-3 Alkyl or phenyl substitution; or R 2 and R 25 Together with the N atoms they are attached to, they form nitrogen-containing heterocyclic butyl groups.

60. The compound or salt according to claim 57, wherein R 2 C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, =O, =S, =N(R 10 The phenyl group is substituted with a substituent of -CN, phenyl, and a 5- to 6-membered heteroaryl group containing 1 to 3 heteroatoms, wherein the phenyl and the 5- to 6-membered heteroaryl group are each optionally replaced by one or more R groups. 9 What it replaced.

61. The compound or salt according to claim 60, wherein R 2 C 1-5 Alkyl groups, optionally substituted with 1 to 3 substituents independently selected from: halogen, -NO2, =O, =S, =NH, -CN, phenyl, and 5 to 6-membered heteroaryl groups containing 1 to 3 heteroatoms, wherein the phenyl and 5 to 6-membered heteroaryl groups are each optionally substituted with 1 to 3 R groups. 9 replace.

62. The compound or salt according to claim 61, wherein R 2 It is replaced by a phenyl group.

63. The compound or salt according to claim 61, wherein the 5- to 6-membered heteroaryl substituent is a 5-membered heteroaryl containing an N atom and an additional heteroatom.

64. The compound or salt according to claim 1 or 2, wherein R 2 Each R 9 Independently selected from halogens and C 1-3 alkyl.

65. The compound or salt according to claim 1 or 2, wherein R 2 C 1-5 Alkyl group, optionally substituted with one to three independent substituents selected from: halogen, -CN, phenyl, and pyrazolyl, wherein the phenyl or pyrazolyl group is optionally substituted with halogen or C. 1-3 Alkyl substitution.

66. The compound or salt according to claim 1 or 2, wherein R 2 C 1-5 Alkyl group, optionally substituted with 1 to 3 substituents independently selected from the following: halogen, -NO2, =O, =S, =NH, -CN and phenyl, wherein the phenyl group is optionally substituted with 1 to 3 halogens.

67. The compound or salt according to claim 66, wherein R 2 It is replaced by a phenyl group.

68. The compound or salt according to claim 1 or 2, wherein R 2 C 1-5 Alkyl group, optionally substituted with one to three substituents independently selected from the following: halogen, -CN and phenyl, wherein the phenyl group is optionally substituted with one, two or three halogens.

69. The compound or salt according to claim 60, wherein R 2 Selected from ethyl, 70. The compound or salt according to claim 69, wherein R 2 Selected from ethyl, 71. The compound or salt according to claim 57, wherein R 2 For saturated C 3-8 A carbon ring, optionally composed of one or more independently selected from halogens, C 1-3 Alkyl and C 4-6 The carbon ring is replaced by substituents.

72. The compound or salt according to claim 71, wherein R 2 For saturated C 3-6 A carbon ring, optionally composed of one or more independently selected from halogens, C 1-3 Alkyl and C 4-6 The carbon ring is replaced by substituents.

73. The compound or salt according to claim 71 or 72, wherein R 2 C on 4-6 The carbon ring is phenyl.

74. The compound or salt according to claim 1 or 2, wherein R 2 Selected from C 3-6 Monocyclic cycloalkyl, C 5-6 Bridged cycloalkyl and C 5-6 Spirocycloalkyl, wherein each is optionally substituted with 1 to 3 substituents, which are independently selected from halogens, C 1-3 Alkyl and phenyl.

75. The compound or salt according to claim 74, wherein R 2 Selected from C 3-4 Monocyclic cycloalkyl, C5 bridged cycloalkyl, and C5 spirocycloalkyl, wherein each is optionally substituted by 1 to 3 substituents, which are independently selected from C5. 1-3 Alkyl and phenyl.

76. The compound or salt according to claim 75, wherein R 2 Selected from C 3-4 cycloalkyl, Each is optionally selected from 1 to 3 independently chosen from halogens, C 1-3 Alkyl and phenyl substituents.

77. The compound or salt according to claim 76, wherein R 2 Selected from C 3-4 cycloalkyl, Each can be chosen by C 1-3 Alkyl or phenyl substitution.

78. The compound or salt according to claim 77, wherein R 2 Selected from 79. The compound or salt according to claim 78, wherein R 2 Selected from 80. The compound or salt according to claim 57, wherein R 2 and R 25 Together with the N atoms they are attached to, they form 4- to 6-membered rings, which are optionally bounded by one or more R atoms. 9 What it replaced.

81. The compound or salt according to claim 80, wherein R 2 and R 25 Together with the N atoms they are attached to, they form 82. The compound or salt according to claim 57, wherein R 2 Selected from ethyl, Or R 2 and R 25 Together with the N atoms they are attached to, they form 83. The compound or salt according to claim 82, wherein R 2 Selected from ethyl, Or R 2 and R 25 Together with the N atoms they are attached to, they form 84. The compound or salt according to claim 1 or 2, wherein R 2 Selected from optionally substituted C3-C6 cycloalkyl groups; and C 1-6 Alkyl groups, optionally substituted with one or more substituents independently selected from halogens, nitriles, optionally substituted phenyl groups, and optionally substituted 5-membered heteroaryl groups.

85. The compound or salt according to claim 84, wherein R 2 Selected from: -CH2CH3、 86. The compound or salt according to claim 85, wherein R 2 Selected from optionally substituted C4-C6 cycloalkyl groups; and C 1-5 Alkyl groups, which are optionally substituted with one or more substituents independently selected from optionally substituted phenyl groups.

87. The compound or salt according to claim 86, wherein R 2 Selected from: -CH2CH3、 88. The compound or salt according to claim 1 or 2, wherein n is 0.

89. The compound or salt according to claim 1 or 2, wherein p is 0.

90. The compound or salt according to claim 1 or 2, wherein p is 1; and wherein R 8 It is a halogenated product.

91. The compound or salt according to claim 1 or 2, wherein the compound or salt is selected from: And the salt of any one of them.

92. The compound or salt according to claim 1 or 2, wherein the compound or salt is selected from: And the salt of any one of them.

93. The compound or salt according to claim 1 or 2, wherein the compound or salt is selected from: And the salt of any one of them.

94. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 93 and a pharmaceutically acceptable excipient.

95. Use of compounds of formula (III') or salts thereof in the preparation of medicaments for the treatment of neuromuscular disorders: in: Each Y is independently selected from C(R) 3 ), N and N + (-O - ); At least one of Y is N or N + (-O - ); A is selected from -O- and -NR 4 -、-CR 5 R 6 -and-S-; R 1 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 , -N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、 -N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 The alkynyl group is replaced by a substituent, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 9 Replaced; or R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; R 25 Selected from: Hydrogen and C 1-6 Alkyl; or R 25 With R 2 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles; R 2 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 , -N(R 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 A carbocyclic ring and 3 to 10-membered heterocycles, each 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 ), –CN, C 1-6 Alkyl and C 3-10 Carbon ring, wherein the C 1-6 Alkyl and C 3-10 The carbon ring is optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 2 With R 25 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles; R 3 R 5 and R 6 Each is selected independently from: Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 4 Selected from: Hydrogen; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced; R 7 and R 8 Each is selected independently from: Halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; Each R 9 Selected independently from: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used; Each R 10 Selected independently from: Hydrogen; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups; n is 0, 1, or 2; and p is 0, 1, or 2. The neuromuscular disorders mentioned therein are selected from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, facial-scapular-humeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome.

96. The use according to claim 95, wherein the compound or salt of formula (III') is represented by formula (III): in: A is selected from -O- and -NR 4 -、-CR 5 R 6 -and-S-; R 1 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN; or R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; R 2 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 and C 3-10 The carbon ring is replaced by a substituent, wherein the C 1-6 Alkyl and C 3-10 Each carbon ring is optionally selected by one or more independently chosen from halogens, -OR 10 -SR 10 -N(R) 10 )2. Substitution of -NO2 and -CN.

97. Use of any compound or salt of claims 1 to 93 in the preparation of a medicament for treating activity-induced muscle injury.

98. The use according to claim 95, wherein the neuromuscular disease is Duchenne muscular dystrophy.

99. The use according to claim 95, wherein the neuromuscular disease is Becker muscle dystrophy.

100. The use according to claim 95, wherein the neuromuscular disorder is limb girdle dystrophy.

101. Use of compounds or salts of formula (III') in the preparation of medicaments for treating diseases: in: Each Y is independently selected from C(R) 3 ), N and N + (-O - ); At least one of Y is N or N + (-O - ); A is selected from -O- and -NR 4 -、-CR 5 R 6 -and-S-; R 1 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 , -N(R 10 )2、-C(O)R 10 、-C(O)N(R 10 )2、-N(R 10 )C(O)R 10 、-C(O)OR 10 、-OC(O)R 10 、 -N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 The alkynyl group is replaced by a substituent, wherein the C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each of the alkynyl groups is optionally surrounded by one or more R groups. 9 Replaced; or R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; R 25 Selected from: Hydrogen and C 1-6 Alkyl; or R 25 With R 2 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles; R 2 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 , -N(R 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 A carbocyclic ring and 3 to 10-membered heterocycles, each 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 ), –CN, C 1-6 Alkyl and C 3-10 Carbon ring, wherein the C 1-6 Alkyl and C 3-10 The carbon ring is optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 2 With R 25 Together they form a 3- to 6-membered heterocycle, wherein the 3- to 6-membered heterocycle is optionally selected independently by one or more elements selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles; R 3 R 5 and R 6 Each is selected independently from: Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 4 Selected from: Hydrogen; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced; R 7 and R 8 Each is selected independently from: Halogen, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; Each R 9 Selected independently from: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN are used; Each R 10 Selected independently from: Hydrogen; and C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups; n is 0, 1, or 2; and p is 0, 1, or 2. The diseases mentioned are selected from multiple sclerosis, Parkinson's disease, Alzheimer's disease, cerebral palsy, stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, and amyotrophic lateral sclerosis.

102. The use according to claim 101, wherein the compound or salt of formula (III') is represented by formula (III): in: A is selected from -O- and -NR 4 -、-CR 5 R 6 -and-S-; R 1 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 Substituents of -CN and -CN; or R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; R 2 Selected from: C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -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 and C 3-10 The carbon ring is replaced by a substituent, wherein the C 1-6 Alkyl and C 3-10 Each carbon ring is optionally selected by one or more independently chosen from halogens, -OR 10 -SR 10 -N(R) 10 )2. Substitution of -NO2 and -CN.

103. The use according to any one of claims 95, 97 and 101, wherein the medicament further comprises an additional therapeutic agent.

104. The use according to claim 103, wherein the additional therapeutic agent is a corticosteroid.

105. The use according to claim 104, wherein the corticosteroid is defcodone or prednisone.

106. The use according to claim 103, wherein the additional therapeutic agent is vamorolone.

107. The use according to claim 103, wherein the additional therapeutic agent is a gene therapy.

108. The use according to claim 107, wherein the gene therapy is a gene therapy employing the myoglobin gene or a variant or truncated form thereof.

109. The use according to claim 107, wherein the gene therapy is a gene therapy employing microprotein.

110. The use according to claim 103, wherein the additional therapeutic agent is eteplirsen.

111. The use according to claim 103, wherein the additional therapeutic agent is atalulus.

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