Pyridazinone derivative and use thereof

Abstract

The present invention relates to a pyridazinone derivative and a use thereof. Specifically, the present invention relates to a compound represented by general formula (I), a preparation method therefor, a pharmaceutical composition thereof, and a use of the compound represented by general formula (I) or the pharmaceutical composition thereof in the preparation, prevention and / or treatment of Myosin-mediated diseases, wherein each substituent in general formula (I) is as defined in the description.

Description

Pyridazinone derivatives and uses thereof

[0001] Cross-reference to related applications

[0002] This application claims priority to Chinese Patent Application No. 202410643115.6, filed May 23, 2024, entitled “Pyridazinone derivatives and uses thereof,” Chinese Patent Application No. 202411199426.4, filed August 29, 2024, entitled “Pyridazinone derivatives and uses thereof,” and Chinese Patent Application No. 202411616630.1, filed November 13, 2024, entitled “Pyridazinone derivatives and uses thereof,” the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present application relates to a Myosin inhibitor, stereoisomers, pharmaceutically acceptable salts thereof, and uses thereof in the manufacture of a medicament for treating Myosin-mediated related diseases. BACKGROUND

[0004] Skeletal muscle has two main roles that are critical to the human body: 1) muscle contraction, which produces the state of movement and maintains posture; and 2) skeletal muscle is also the site of glucose, fatty acid, and amino acid metabolism. In a normal human body during daily activities, the contraction of skeletal muscle is closely related to muscle stress, breakdown, and remodeling, which are very critical for muscle adaptation. However, in patients with progressive muscular dystrophy, such as Duchenne muscular dystrophy (DMD), muscle contraction leads to muscle breakdown that is difficult to repair, with continuous rounds of amplification. As the patient ages, these changes gradually accumulate and develop into a pathological process, which leads to excessive inflammation, fibrosis, and accumulation of fat deposits in the muscle, which in turn progresses to a sharp decline in physical function, ultimately leading to death.

[0005] DMD is a genetic disease that affects skeletal muscle. Becker muscular dystrophy (BMD) is a variant of DMD, which was first reported by German physician Peter Emil Becker in the 1950s. Both are characterized by progressive muscle degeneration and weakness. Currently, there is still a need for drugs that can treat patients with DMD or BMD. SUMMARY

[0006] The present application provides a compound of general formula (I), (II), stereoisomers or pharmaceutically acceptable salts thereof, which is a Myosin inhibitor, has good physicochemical properties, such as higher solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, small side effects, has the advantages of oral administration, fast absorption, high clearance rate, etc.

[0007] The present application relates to a compound represented by general formula (I), (II), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0008] wherein,

[0009] X is CR 10 or N; in some embodiments, X is CH or N;

[0010] L is a bond, O, NH, S, C(O), S(O), S(O)2, -(CR L1 R L2 ) n -; in some embodiments, L is a bond, -O-, -S-, -Se-, -C(O)-, -CH2-, -CF2-, -C(CH3)2-, -CH(CH3)-,

[0011] L1is a bond, O, NH, S, Se, C(O), S(O), S(O)2, -(CR L1 R L2 ) n -; in some embodiments, L1is a bond, -O-, -S-, -Se-, -C(O)-, -CH2-, -CF2-, -C(CH3)2-, -CH(CH3)-, in some embodiments, L1is a bond, O, S, Se; in some embodiments, L1is a bond, O;

[0012] Ring A is C 4-7 cycloalkyl; in some embodiments, Ring A is cyclobutyl, cyclopentyl, cyclohexyl; in some embodiments, Ring A is cyclobutyl; in some embodiments, Ring A is cyclopentyl; in some embodiments, Ring A is cyclohexyl;

[0013] R A is H, deuterium, halogen, hydroxyl, cyano, amino, or C 1-6 alkyl; in some embodiments, R A is H, deuterium, halogen, hydroxyl, cyano, amino, or C 1-3 alkyl; in some embodiments, R A is H, deuterium, halogen, cyano, methyl, ethyl;

[0014] R L1 and R L2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C 1-6 alkyl; in some embodiments, R L1 and R L2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C 1-3 alkyl; in some embodiments, R L1 and R L2each independently hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, or methyl;

[0015] or R L1 and R L2 form, together with the carbon atom to which they are attached, a C 3-7 cycloalkyl, optionally further substituted with 1-3 groups selected from R c or R L1 and R L2 form, together with the carbon atom to which they are attached, a C 4-7 cycloalkyl, optionally further substituted with 1-3 groups selected from R c in some embodiments, R L1 and R L2 form, together with the carbon atom to which they are attached, a cyclopropyl group;

[0016] in some embodiments, L is a bond, O, NH, S, C(O), S(O), S(O)2, -CH2-; in some embodiments, L is -CH2-;

[0017] R 1a and R 1b each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl; in some embodiments, R 1a and R 1b each independently hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 deuteroalkyl, or C 1-3 haloalkyl; in some embodiments, R 1a and R 1b each independently hydrogen, deuterium, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl;

[0018] or R 1a and R 1b form, together with the carbon atom to which they are attached, a C 4-7 cycloalkyl, 4-7 membered heterocycloalkyl, optionally further substituted with 1-3 groups selected from R c in some embodiments, R 1a and R 1b form, together with the carbon atom to which they are attached, a C 4-5 cycloalkyl, 4-5 membered heterocycloalkyl, optionally further substituted with 1-3 groups selected from R c in some embodiments, R 1a and R 1b form, together with the carbon atom to which they are attached, a cyclobutyl, oxetanyl, optionally further substituted with 1-3 groups selected from R cSubstitution of groups;

[0019] R 2 R 3 R 4 and R 5 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 alkylthio or C 1-6 Alkylamine group; in some embodiments, R 2 R 3 R 4 and R 5 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Halogenated alkoxy groups; in some embodiments, R 2 R 3 R 4 and R 5 Each is independently hydrogen;

[0020] R 6 R 7 R 8 R 9 and R 10 Each of these elements independently represents hydrogen, deuterium, halogen, hydroxyl, cyano, amino, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Alkylamino, -S(O)R, -S(O)2R, -C(O)R, -OC(O)R, -C(O)OR, -C(O)N(R)2;

[0021] R represents hydrogen, deuterium, amino, or C.1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl; in some embodiments, R is hydrogen, deuterium, amino, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, or C 3-6 cycloalkyl;

[0022] in some embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, or C 1-3 haloalkoxy; in some embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, methyl, or trifluoromethyl; in some embodiments, R 6 , R 9 , and R 10 are each independently hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, methyl, or trifluoromethyl;

[0023] in some embodiments, R 2 and R 4 link with the carbon atom to which they are attached to form a C 4-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted with 1-3 groups selected from R c ; in some embodiments, R 2 and R 4 link with the carbon atom to which they are attached to form a C 4-7 cycloalkyl, phenyl, optionally further substituted with 1-3 groups selected from Rc R 2 and R 4 and the carbon atom to which they are attached join to form a cyclopentyl, cyclohexyl, cycloheptyl, phenyl, optionally further substituted with 1-3 groups selected from R c ;

[0024] In some embodiments, R 4 and R 5 and the carbon atom to which they are attached join to form a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted with 1-3 groups selected from R c ; In some embodiments, R 4 and R 5 and the carbon atom to which they are attached join to form a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, optionally further substituted with 1-3 groups selected from R c ; In some embodiments, R 4 and R 5 and the carbon atom to which they are attached join to form a cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, isoxazolyl, optionally further substituted with 1-3 groups selected from R c ;

[0025] In some embodiments, R L1 or R L2 and R 9 and the carbon atom to which they are attached join to form a C 3-6 cycloalkyl, optionally further substituted with 1-3 groups selected from R c ; In some embodiments, R L1 or R L2 and R 9 and the carbon atom to which they are attached join to form a C 4-6 cycloalkyl, optionally further substituted with 1-3 groups selected from R c ; In some embodiments, R L1 or R L2 and R 9 and the carbon atom to which they are attached join to form a cyclopentyl, cyclohexyl, optionally further substituted with 1-3 groups selected from R c ;

[0026] In some embodiments, R 6 and R 10 , R 10 and R 7 , R 7 and R 8 , R8 and the carbon atom to which it is attached to form a C 9 ring alkyl, 4-7 membered heterocycloalkyl, optionally further substituted by 1-3 groups selected from R 3-6 and R c , R 6 and R 10 , R 10 and R 7 , R 7 and R 8 , R 8 and R 9 any one of which forms a C 4-6 ring alkyl, 5-7 membered heterocycloalkyl, optionally further substituted by 1-3 groups selected from R c and R 6 , R 10 and R 10 , R 7 and R 7 , R 8 and R 8 , R 9 any one of which forms a cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, azetidinyl, oxetanyl, optionally further substituted by 1-3 groups selected from R c and R 7 , R 8 and the carbon atom to which it is attached to form a cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, optionally further substituted by 1-3 groups selected from R c ;

[0027] R c is deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 halogenated alkoxy, C 1-3 alkylidene, or C 1-3 halogenated alkylidene; in some embodiments, R c is deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; in some embodiments, R c is deuterium, fluorine, chlorine, hydroxyl, cyano, oxo, methyl, ethenyl, ethynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylene, ethylene, 1-methylethylene, fluoromethylene, or difluoromethylene;

[0028] In some embodiments, is selected from

[0029] In some embodiments, is selected from

[0030] In some embodiments, is selected from

[0031] In some embodiments, is selected from

[0032] In some embodiments, is selected from

[0033] In some embodiments, is selected from

[0034] In some embodiments, is selected from

[0035] n is 0, 1, 2, 3, 4, 5; in some embodiments, n is 0, 1, 2, 3; in some embodiments, n is 1 or 2; in some embodiments, n is 1.

[0036] In some embodiments, the application relates to a compound of Formula (I), (II), a stereoisomer, or a pharmaceutically acceptable salt thereof:

[0037] wherein:

[0038] X is CR 10 or N;

[0039] L is a bond, O, NH, S, C(O), S(O), S(O)2, -(CR L1 R L2 ) n -;

[0040] L1is a bond, O, NH, S, Se, C(O), S(O), S(O)2, -(CR L1 R L2 ) n -;

[0041] Ring A is C 4-7 cycloalkyl;

[0042] R A is H, deuterium, halogen, hydroxyl, cyano, amino, or C 1-6 alkyl;

[0043] R L1 and R L2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C 1-6 alkyl; or R L1 and R L2 link with the carbon atom to which they are attached to form a C 4-7 cycloalkyl, optionally further substituted with 1-3 groups selected from R c ;

[0044] R 1a and R 1b are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl, or C 1-6 haloalkyl;

[0045] or R 1a and R 1b link with the carbon atom to which they are attached to form a C 4-7 cycloalkyl, 4-7 membered heterocycloalkyl, optionally further substituted with 1-3 groups selected from R c ;

[0046] R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C1-6 haloalkoxy, C 1-6 alkylthio or C 1-6 alkylamino;

[0047] or, R 2 and R 4 form, together with the carbon atom to which they are attached, a C 4-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted by 1-3 groups selected from R c ;

[0048] or, R 4 and R 5 form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted by 1-3 groups selected from R c ;

[0049] R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -S(O)R, -S(O)2R, -C(O)R, -OC(O)R, -C(O)OR, -C(O)N(R)2;

[0050] R is hydrogen, deuterium, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy or C 3-6 cycloalkyl;

[0051] or, R L1 or R L2 and R 9 form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl, optionally further substituted by 1-3 groups selected from Rc substituted with 1-3 groups selected from R

[0052] or R 6 and R 10 , R 10 and R 7 , R 7 and R 8 , R 8 and R 9 any one group together with the carbon atom to which it is attached form a C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, optionally further substituted with 1-3 groups selected from R c

[0053] R c is deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, C 1-3 halogenated alkoxy, C 1-3 alkylalkylidene, or C 1-3 halogenated alkylalkylidene;

[0054] n is 0, 1, 2, 3, 4, 5.

[0055] In particular, a second embodiment relates to a compound according to Formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0056] wherein:

[0057] X is CR 10 or N;

[0058] L is a bond, O, NH, S, C(O), S(O), S(O)2, -(CR L1 R L2 ) n -;

[0059] R L1 and R L2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C 1-6 alkyl;

[0060] R 1a and R 1b are each independently hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl, or C 1-6 halogenated alkyl;​

[0061] or R 1a and R 1b and the carbon atoms to which they are attached join to form a C 4-7 cycloalkyl, 4-7 membered heterocycloalkyl, optionally further substituted by 1-3 groups selected from R c ;

[0062] R 2 , R 3 , R 4 and R 5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, or C 1-6 alkylamino;

[0063] or, R 2 and R 4 and the carbon atoms to which they are attached join to form a C 4-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted by 1-3 groups selected from R c ;

[0064] or, R 4 and R 5 and the carbon atoms to which they are attached join to form a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted by 1-3 groups selected from R c ;

[0065] R 6 , R 7 , R 8 , R 9 and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C1-6 alkylthio, C 1-6 alkylamino, -S(O)R, -S(O)2R, -C(O)R, -OC(O)R, -C(O)OR, -C(O)N(R)2;

[0066] R is hydrogen, deuterium, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl;

[0067] or, R L1 or R L2 and R 9 and the carbon atoms to which they are attached link to form a C 3-6 cycloalkyl, optionally further substituted with 1-3 groups selected from R c ;

[0068] or, R 6 and R 10 , R 10 and R 7 , R 7 and R 8 , R 8 and R 9 any one of the groups R 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, optionally further substituted with 1-3 groups selected from R c ;

[0069] R c is deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene, or C 1-3 haloalkylidene;

[0070] n is 0, 1, 2, 3, 4, 5.

[0071] In particular third embodiments, compounds of Formula (I), stereoisomers, or pharmaceutically acceptable salts thereof, are provided that satisfy one or more of the following embodiments:

[0072] (1) X is CH or N;

[0073] (2) L is a bond, O, NH, S, C(O), S(O), S(O)2, -CH2-, in some embodiments, L is -CH2-;

[0074] (3) R L1 and R L2 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, or C 1-3 alkyl, in some embodiments, R L1 and R L2 are each independently hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, or methyl;

[0075] (4) R 1a and R 1b are each independently hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 deuteroalkyl, or C 1-3 haloalkyl, in some embodiments, R 1a and R 1b are each independently hydrogen, deuterium, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl, or trifluoromethyl;

[0076] (5) R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, or C 1-3 haloalkoxy, in some embodiments, R 2 , R 3 , R 4 , and R 5 are each independently hydrogen;

[0077] (6) R 6 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, or C 1-3 haloalkoxy, in some embodiments, R 6 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, methyl, or trifluoromethyl;

[0078] (7) R is hydrogen, deuterium, amino, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, or C 3-6 cycloalkyl;

[0079] (8) R 2 and R 4 link with the carbon atom to which they are attached to form C 4-7 cycloalkyl, phenyl, optionally further substituted with 1-3 groups selected from R c , in some embodiments, R 2 and R 4 link with the carbon atom to which they are attached to form cyclopentyl, cyclohexyl, cycloheptyl, phenyl, optionally further substituted with 1-3 groups selected from R c ;

[0080] (9) R 4 and R 5 link with the carbon atom to which they are attached to form C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, optionally further substituted with 1-3 groups selected from R c , in some embodiments, R 4 and R 5 link with the carbon atom to which they are attached to form cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, isoxazolyl, optionally further substituted with 1-3 groups selected from R c ;

[0081] (10) R L1 or R L2 and R 9 link with the carbon atom to which they are attached to form C 4-6 cycloalkyl, optionally further substituted with 1-3 groups selected from R c , in some embodiments, R L1 or R L2 and R9 with the carbon atom to which it is attached forming a cyclopentyl, cyclohexyl, optionally further substituted with 1-3 groups selected from R c

[0082] (11) R 6 and R 10 , R 10 and R 7 , R 7 and R 8 , R 8 and R 9 any one of which groups is linked via a carbon atom to which it is attached to form a C 4-6 cycloalkyl, 5-7 membered heterocycloalkyl, optionally further substituted with 1-3 groups selected from R c 6 and R 10 , R 10 and R 7 , R 7 and R 8 , R 8 and R 9 any one of which groups is linked via a carbon atom to which it is attached to form a cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, azetidinyl, oxetanyl, optionally further substituted with 1-3 groups selected from R c 6 and R 10 , R 10 and R 7 , R 7 and R 8 , R 8 and R 9 any one of which groups is linked via a carbon atom to which it is attached to form a cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, optionally further substituted with 1-3 groups selected from R c

[0083] (12) R c is deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuterated alkyl, C 1-3 halogenated alkyl, C 1-3 alkoxy, C 1-3 halogenated alkoxy, C 1-3 alkylidene, or C 1-3 halogenated alkylidene, in some embodiments, R c ​​​​deuterium, fluorine, chlorine, hydroxyl, cyano, oxo, methyl, ethenyl, ethynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylene, ethylene, 1-methylethylene, fluoromethylene, or difluoromethylene;

[0084] (13) n is 0, 1, 2, 3, in some embodiments, n is 1 or 2.

[0085] In a particular fourth embodiment, the compound of Formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:

[0086] L is -CH2-;

[0087] selected from

[0088] L1is a bond, -O-, -S-, -Se-, -C(O)-, -CH2-, -CF2-, -C(CH3)2-, -CH(CH3)-,

[0089] selected from

[0090] In a particular fifth embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is -CH2-;

[0091] selected from

[0092] R 1a and R 1b are each independently hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 deuteroalkyl, or C 1-3 haloalkyl;

[0093] R 2 , R 3 , R 4 , and R 5 are each independently hydrogen.

[0094] In a particular sixth embodiment, the compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following Table I:

[0095] Table I:

[0096] Secondly, the present application also provides a pharmaceutical composition containing the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of the preceding technical solutions, and a pharmaceutically acceptable carrier and / or excipient.

[0097] Further, the pharmaceutical composition or pharmaceutical preparation contains 1-1500 mg of the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of the preceding technical solutions, and a pharmaceutically acceptable carrier and / or excipient.

[0098] Further, the present application also provides the use of the compound, stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to any one of the preceding embodiments in the preparation of a medicament for treating / preventing a Myosin-mediated disease. Further, the Myosin-mediated disease includes but is not limited to muscular dystrophy.

[0099] The present application also provides a method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of the preceding technical solutions, and a pharmaceutically acceptable carrier and / or excipient, preferably 1-1500 mg, and preferably the disease is muscular dystrophy.

[0100] The present application also provides a method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of the preceding technical solutions, and a pharmaceutically acceptable carrier and / or excipient, preferably 1-1500 mg, and preferably the disease is muscular dystrophy.

[0101] An "effective amount" or "therapeutically effective amount" as described herein refers to an amount of a compound disclosed herein that, when administered, will relieve to some extent one or more of the symptoms of the disease or condition being treated. In some embodiments, the result is a decrease and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, that will elicit the biological or medical response (e.g., reduce or alleviate disease symptoms) in a tissue, system, animal, individual, or human. An example of a therapeutically effective amount includes, but is not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1500 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg;50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, 100-200 mg;

[0102] In some embodiments, the pharmaceutical composition or formulation of the present application contains a therapeutically effective amount of the compound, stereoisomer or pharmaceutically acceptable salt thereof of any one of the above.

[0103] The present application further relates to a pharmaceutical composition or a pharmaceutical formulation comprising a therapeutically effective amount of the compound, stereoisomer or pharmaceutically acceptable salt thereof of any one of the above and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition can be in the form of a unit formulation (the amount of the principal drug in the unit formulation is also referred to as "formulation strength"). In some embodiments, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the compound, stereoisomer or pharmaceutically acceptable salt thereof of any one of the above.

[0104] The present application further relates to a method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount, preferably 1-1500 mg, of any one of the compounds, stereoisomer or pharmaceutically acceptable salt thereof described above, and one or more pharmaceutically acceptable carriers or excipients, the disease preferably being a muscular dystrophy.

[0105] The present application further relates to a method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount, preferably 1-1500 mg, of any one of the compounds, stereoisomer or pharmaceutically acceptable salt thereof described above, and one or more pharmaceutically acceptable carriers or excipients, the disease preferably being a muscular dystrophy.

[0106] The present application relates to a kit, which can include a composition in single or multiple dose forms, the kit comprising the compound, stereoisomer or pharmaceutically acceptable salt thereof described in any one of the above aspects of the present application, in the same amount as in the above pharmaceutical composition.

[0107] The amount of the compound, stereoisomer or pharmaceutically acceptable salt thereof of the present application in the present application is in each case calculated as the free base.

[0108] "Formulation strength" means the amount of drug substance contained in each unit of formulation, tablet or other unit.

[0109] Synthesis route

[0110] The compounds of the present application can be prepared by those skilled in the art with reference to known organic synthesis techniques, starting from commercially available chemicals and / or chemicals described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, including suppliers such as Titan Scientific, Acros Organics, Shanghai Derui, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Yushi, Drugmaker and Bailingwei Technology, etc.

[0111] Specific and analogous reactants can be identified selectively by the use of the Index of Known Chemical Substances prepared by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and online. Chemicals that are known but not commercially available in catalogs can alternatively be prepared by custom chemical synthesis houses, many of which standard chemical supply houses (such as those listed above) offer custom synthesis services.

[0112] Terminology

[0113] 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 application belongs. If there is a conflict between the definitions provided in this application and those in dictionaries or other references, the definitions provided in this application control. Where a name, trademark or tradename is used herein, it is intended to refer to the corresponding product or active ingredient thereof. All patents, published patent applications, and publications recited herein are incorporated herein by reference.

[0114] The term "alkyl" refers to saturated straight-chain or branched-chain aliphatic hydrocarbon groups having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., "C 1-20 alkyl". The alkyl group preferably has from 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably from 1 to 8 carbon atoms (i.e., C 1-8 alkyl), even more preferably from 1 to 6 carbon atoms (i.e., C 1-6 alkyl), and most preferably from 1 to 3 carbon atoms (i.e., C 1-3Non-limiting examples include: methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the alkyl group is substituted with a substituent, the substituent is not further substituted.

[0115] The term "alkylene" refers to a divalent straight chain and branched chain saturated alkyl group. Examples of alkylene include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and the like.

[0116] The term "alkenyl" refers to a straight-chain hydrocarbon or branched-chain hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and still further such as 2 to 4 carbon atoms, examples of which include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, and the like; the alkenyl group can be substituted or non-substituted, and when substituted, the substituents can be substituted at any available attachment point. When the alkenyl group is substituted with a substituent, the substituent is not further substituted.

[0117] The term "alkynyl" refers to a straight-chain hydrocarbon or branched-chain hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and still further containing 2 to 4 carbon atoms, examples of which include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonylnyl, and 4-decynyl, and the like; the alkynyl group can be substituted or non-substituted, and when substituted, the substituents can be substituted at any available attachment point. When the alkynyl group is substituted with a substituent, the substituent is not further substituted.

[0118] The term "heterocycle" or "heterocyclyl" means a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, containing, if not specified, from 1 to 3 heteroatoms selected from N, O or S, including monocyclic heterocycles, bicyclic bridged heterocycles, bicyclic fused heterocycles and bicyclic spiro heterocycles, and the like, and, if not specified, 3 to 12 membered heterocycles, more preferably 4 to 12 membered heterocycles, more preferably 4 to 10 membered heterocycles, and further preferably 4 to 7 membered heterocycles. The definition includes heterocycloalkyl and heteroaryl groups. The N, S in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclyl group can be attached at a heteroatom or carbon atom, non-limiting examples include epoxyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azacycloheptanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyridazinyl, imidazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dihydrothiopyranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, oxazolyl, dihydrooxazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl and oxaspiro[3.3]heptanyl, and the like.

[0119] The term "cycloalkyl" means a saturated or partially unsaturated monocyclic cyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or a polycyclic cyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms, i.e., C 3-20 cycloalkyl. The cycloalkyl group preferably has from 3 to 12 carbon atoms in the ring (i.e., C 3-12 cycloalkyl), more preferably from 3 to 8 carbon atoms in the ring (i.e., C 3-8 cycloalkyl), further preferably from 3 to 6 carbon atoms in the ring (i.e., C 3-6 cycloalkyl), and most preferably from 3 to 5 carbon atoms in the ring (i.e., C 3-5 cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like. Non-limiting examples of polycyclic cycloalkyl groups include: spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0120] The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (termed a spiro atom) between single rings, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 spirocycloalkyl).

[0121] The term "fused cycloalkyl" refers to a all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 fused cycloalkyl). It can contain one or more double bonds, but no ring has a fully conjugated pi-electron system.

[0122] The term "bridged cycloalkyl" refers to a all-carbon polycyclic group in which any two rings share two non-adjacent carbon atoms, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., C 5-20 bridged cycloalkyl). It contains one or more double bonds, but no ring has a fully conjugated pi-electron system.

[0123] The cycloalkyl groups include polycyclic cycloalkyl groups that can be fused to aryl, heteroaryl, or heterocycloalkyl rings, where the rings that are connected together with the parent structure are cycloalkyl groups, such as, for example, C 5-6 cycloalkyl and phenyl, C 5-6 cycloalkyl and 5-6 membered heteroaryl, C 5-6 cycloalkyl and 5-6 membered heterocycloalkyl, and the like, preferably cyclopentyl and 5 membered heterocycloalkyl, cyclopentyl and 6 membered heterocycloalkyl, cyclopentyl and 5 membered heteroaryl, cyclopentyl and 6 membered heteroaryl, cyclohexyl and 5 membered heterocycloalkyl, cyclohexyl and 6 membered heterocycloalkyl, cyclohexyl and 5 membered heteroaryl, cyclohexyl and 6 membered heteroaryl, and the like. The cycloalkyl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the cycloalkyl groups are substituted with a substituent, the substituent is not further substituted.

[0124] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocycloalkyl) or a polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 3-20 membered heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O)m and S(O) n a ring member, the remaining ring atoms being carbon. The heterocycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3-12 membered heterocycloalkyl), wherein 1 to 4 ring atoms are selected from N, O, and S atoms, more preferably 3 to 8 ring atoms (i.e., 3-8 membered heterocycloalkyl), wherein 1 to 4, 1 to 3, or 1 to 2 ring atoms are selected from N, O, and S atoms, further preferably 3 to 6 ring atoms (i.e., 3-6 membered heterocycloalkyl), wherein 1 to 4, 1 to 3, or 1 to 2 ring atoms are selected from N, O, and S atoms, most preferably 5 to 6 ring atoms (i.e., 5-6 membered heterocycloalkyl), wherein 1 to 4, 1 to 3, or 1 to 2 ring atoms are selected from N, O, and S atoms. Non-limiting examples of monocyclic heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolanyl, 2,2-difluoro-1,3-dioxolanyl, cyclopentanonyl, 2,2-difluorocyclopentanonyl, azepinyl, oxolanyl, or azolidinyl, and the like. Non-limiting examples of polycyclic heterocycloalkyl groups include spiroheterocycloalkyl, fused heterocycloalkyl, and bridged heterocycloalkyl.

[0125] The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group that shares one atom (referred to as a spiro atom) between single rings, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered spiroheterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n a ring member, the remaining ring atoms being carbon. It can contain one or more double bonds, but no ring has a fully conjugated pi-electron system.

[0126] The term "fused heterocycloalkyl" or "annelated heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered fused heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) nring members are carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system.

[0127] The term "bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two non-adjacent atoms, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5-20 membered bridged heterocycloalkyl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, P(O) m and S(O) n ring members are carbon. It can contain one or more double bonds, but no ring has a completely conjugated pi-electron system.

[0128] The heterocycloalkyl groups include polycyclic heterocycloalkyl groups that can be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocycloalkyl group, for example, including 5-6 membered heterocycloalkyl and phenyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl and C 5-6 6 membered heteroaryl, 6 membered heterocycloalkyl and 6 membered heterocycloalkyl, 6 membered heterocycloalkyl and 5 membered heteroaryl, 6 membered heterocycloalkyl and 6 membered heteroaryl, and the like. The heterocycloalkyl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment). When the heterocycloalkyl group is substituted with a substituent, the substituent is not further substituted.

[0129] The term "aryl" refers to an all-carbon monocyclic or fused ring hydrocarbon group (i.e., a monocyclic aryl group or a polycyclic aryl group) having a completely conjugated pi-electron system (i.e., C 6-14 aryl groups). The aryl groups preferably have 6 to 12 carbon atoms (i.e., C 6-12 aryl groups). The aryl groups more preferably have 6 to 10 carbon atoms (i.e., C 6-10 aryl groups). The aryl groups further preferably are phenyl or naphthyl, most preferably phenyl. The monocyclic aryl groups, for example, phenyl. Non-limiting examples of polycyclic aryl groups include naphthyl, anthryl, phenanthryl, and the like.

[0130] The aryl group includes polycyclic systems that can be fused to a heteroaryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to benzo[a]C[b]. 3-8 Cycloalkyl, benzo3-8 heterocycloalkyl, benzo5-6 heteroaryl, preferably benzoC 4-6 The aryl group comprises cycloalkyl, benzo4-6-membered heterocycloalkyl, and benzo5-6-membered heteroaryl groups, with further preferred groups being benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzoazacyclobutyl, benzooxacyclobutyl, benzooxacyclopentyl, benzoazacyclopentyl, benzooxacyclohexyl, benzozacyclohexyl, benzothiophene, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzopyridyl, benzopyrimidinyl, benzopyridonel, benzopyrazinyl, and benzopyridazinyl. The aryl group may be optionally substituted or unsubstituted; when substituted, the substituent may be substituted at any usable connection point. When the aryl group is substituted by a substituent, the substituent is not further substituted.

[0131] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., monocyclic heteroaryl) or a fused polycyclic heteroaryl group (i.e., polycyclic heteroaryl) having a conjugated π-electron system, having 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3, or 4) ring atoms are selected from nitrogen, oxygen, and P(O). m and S(O) n The heteroatom (where m and n are integers from 0 to 2) is preferably selected from nitrogen, oxygen, or sulfur, but does not include the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. The heteroaryl group is preferably a heteroaryl group having 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group is preferably a heteroaryl group having 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furanyl, pyranyl, thiophene, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazole, pyrazolyl, triazolyl, tetrazolyl, pyrroleyl, pyridinyl, pyrimidinyl, pyridoneyl, pyrazinyl, pyrazinyl, etc. The polycyclic heteroaryl group is preferably a 5-6 membered heteroaryl group with a 5-6 membered heteroaryl group or a 5-10 membered heteroaryl group with a C group. 6-10 Aryl or C 6-10aryl and 5-6 membered heteroaryl, further preferred 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl or phenyl and 5-6 membered heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothienyl, pyridopyrrolyl, benzo-γ-pyrone, pyridine-γ-pyrone and the like.

[0132] The heteroaryl groups include polycyclic ring systems fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, including but not limited to 5-6 membered heteroaryl and C 3-8 cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, preferably 5-6 membered heteroaryl and C 4-6 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl. The heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the heteroaryl groups are substituted with substituents, the substituents are not further substituted. Non-limiting examples include: and the like.

[0133] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkoxy). The alkoxy group preferably has 1 to 8 carbon atoms (i.e., C 1-8 alkoxy), more preferably 1 to 6 carbon atoms (i.e., C 1-6 alkoxy), most preferably 1 to 3 carbon atoms (i.e., C 1-3 alkoxy). Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like. The alkoxy group can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the alkoxy group is substituted with substituents, the substituents are not further substituted.

[0134] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl, cycloalkyl are defined as above, having 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) carbon atoms (i.e., C 1-10 alkylthio). The alkylthio group preferably has 1 to 8 carbon atoms (i.e., C 1-8alkylthio), more preferably alkylthio having 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), more preferably alkylthio having 1 to 3 carbon atoms (i.e., C 1-3 alkylthio), more preferably alkylthio having 1 to 3 carbon atoms (i.e., C Non-limiting examples include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. The alkylthio group can be optionally substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment. When the alkylthio group is substituted with a substituent, the substituent is not further substituted.

[0135] The term "halo" or "halogen" or "halogenated" shall be understood to mean a fluorine (F), chlorine (CI), bromine (Br), or iodine (I) atom, preferably a fluorine, chlorine, bromine atom.

[0136] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl, and the like, preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0137] The term "haloalkoxy" refers to an alkoxy group, wherein alkoxy is defined above, substituted with one or more halogen. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, and the like; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0138] The term "alkylidene" refers to a divalent free radical alkyl structure formed by the loss of two hydrogen atoms, wherein alkyl is defined above. Non-limiting examples include: methylidene ethylidene 1-methylethylidene

[0139] The term "haloalkylidene" refers to an alkylidene group, wherein alkylidene is defined above, substituted with one or more halogen. Non-limiting examples include: fluoromethylidene difluoromethylidene

[0140] The term "mercapto" refers to -SH.

[0141] The term "hydroxy" refers to -OH.

[0142] The term "nitro" refers to -NO2.

[0143] The term "amino" refers to -NH2.

[0144] The term "cyano" refers to -CN.

[0145] The term "carboxy" refers to -C(O)OH.

[0146] The term "aldehyde" refers to -CHO.

[0147] The term "oxo" or "oxo group" means =0.

[0148] The term "carbonyl" means C=0.

[0149] The term "aminoacyl" means -C(0)NH2.

[0150] The term "sulfonyl" means -S(0)2.

[0151] The term "deuteroalkyl" means an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.

[0152] The term "deuteroalkoxy" means an alkoxy group substituted with one or more deuterium, wherein alkoxy is as defined above.

[0153] The term "haloalkoxy" means an alkoxy group substituted with one or more halogen, wherein alkoxy is as defined above.

[0154] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl, wherein alkyl is as defined above.

[0155] The term "alkylamino" means alkyl-NH-, wherein alkyl is as defined above.

[0156] The term "alkenylene" means a divalent straight and branched chain alkenyl group.

[0157] The term "alkynylene" means a divalent straight and branched chain alkynyl group.

[0158] The terms "comprise", "comprising", "have", "having", "include", "including", or "contain", "containing", or "comprise", or "comprising", or "involve", and other grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. It will be understood by those within the art that, in some instances, the terms "comprise", "comprising", "have", "having", "include", "including", or "contain", "containing", or "comprise", or "comprising", or "involve", can cover instances in which one or more additional elements or steps are added.

[0159] The term "one or more" or similar expressions "at least one" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0160] When a range of values is disclosed, any value, and any included range, within the range is also specifically disclosed. In particular, each value ranging from the lower to the upper limit of a disclosed range is specifically included in the disclosure. The disclosure of a value range explicitly discloses all possible sub-ranges falling within the range.

[0161] In the present text, "Z" and "-Z-" are both meant to represent the same specific group, which can be used interchangeably.

[0162] As used herein, the expression m-n means the range from m to n and subranges from each point within the range to n and to m. For example, the expressions "C2-C8" or "C2-C8" mean a range of 2 to 8 and subranges from each point within the range to 8 and to 2. For example, the expression "C2-C8" or "C2-C8" means a range of 2 to 8 and subranges from each point within the range to 8 and to 2. 2-8" encompasses a range of 2-8 carbon atoms and is to be understood as also encompassing any sub-range within this range, as well as each individual number within this range, e.g., C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C6" or "C3-C6" is to be understood as encompassing a range of 3-6 carbon atoms and is to be understood as also encompassing any sub-range within this range, as well as each individual number within this range, e.g., C3-C5, C4-C6, C3-C4, C3-C5, C3-C6, C4-C5, C4-C6, C5-C6, etc., as well as C3, C4, C5, C6, etc. By way of further example, the expression "C1-C6" or "C1-C6" encompasses a range of 1-6 carbon atoms and is to be understood as also encompassing any sub-range within this range, as well as each individual number within this range, e.g., C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. By way of still further example, the expression "three to ten" is to be understood as encompassing any sub-range within this range, as well as each individual number within this range, e.g., three to five, three to six, three to seven, three to eight, four to five, four to six, four to seven, four to eight, five to seven, five to eight, six to seven, six to eight, nine to ten, etc., as well as three, four, five, six, seven, eight, nine, ten, etc. Other similar expressions are to be understood in a similar manner. 10 3-10 10 10 1-6

[0163] The expressions "X is selected from A, B, or C," "X is selected from A, B, and C," "X is A, B, or C," "X is A, B, and C," and the like are used interchangeably herein and are meant to convey the same meaning, i.e., that X can be any one of A, B, C, or any number of A, B, C.

[0164] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl can or can not be present, and this description includes instances in which the cycloalkyl is substituted with alkyl and instances in which the cycloalkyl is not substituted with alkyl.

[0165] ​​​​​The terms "substituted" and "substitution" mean one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When describing the lack of substitution, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure of the compound is such that it is stable. When describing that each carbon atom in a group can be optionally replaced with a heteroatom, provided that the normal valency of the group is not exceeded, and that a stable compound results. Exemplary substituents include, but are not limited to: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 5-12 aryl, 5-12 membered heteroaryl, -CO-(C 3-8 cycloalkyl), -CO-(3-8 membered heterocycloalkyl), -CO-(C 5-12 aryl), -CO-(5-12 membered heteroaryl), hydroxy, C 1-6 alkoxy, C 5-12 aryloxy, thiol, C 1-6 alkylthio, cyano, halogen, oxo, aldehyde, SF5, SCF3, -N3, C 1-6 alkylthiocarbonyl, C 1-6 alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, carboxyl, haloC 1-6 alkyl, haloC 1-6 alkoxy, amino, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -HC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -CH=N(C 1-6 alkyl), -CH=N-O(C 1-6alkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C 1-6 alkyl), -NHSO2(C

[0166] If a substituent group is described as "optionally substituted" the substituent group can be unsubstituted or can be substituted. If an atom or group is described as being optionally substituted with one or more of a list of substituents, then one or more hydrogens on the atom or group are each independently replaced with an optionally substituent. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this can also mean that the corresponding group is "non-substituted" or "unsubstituted". Unless indicated, as used herein, the point of attachment of a substituent group can be from any suitable position on the substituent group.

[0167] When the bond to a substituent group is shown to be through a bond to a ring atom, then such substituent group can be bonded to any ring-forming atom in the substitutable ring.

[0168] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each occurrence is independent of its definition at every other occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, then the group can be optionally substituted with up to four R substituents, and the selection of each R substituent is independent of the selection of each other R substituent.

[0169] When a linking group is recited without specifying the direction of attachment, then the direction of attachment includes both left-to-right and right-to-left reading orders, e.g., A-L-B, L selected from -M-W-, includes A-M-W-B and A-W-M-B, with A-M-W-B being preferred.

[0170] The compounds of the present application can exist in particular geometric or stereoisomeric forms. Stereoisomers are molecules that have the same atomic order but differ in the spatial arrangement of their atoms. All such compounds of the present application, including cis and trans isomers, optical isomers, and racemic mixtures and other mixtures thereof, are intended to be within the scope of the present application. The substituents of the compounds of the present application can have additional asymmetric carbon atoms. All such isomers, as well as mixtures thereof, are intended to be within the scope of the present application. In certain embodiments, preferred compounds are those isomeric compounds that exhibit more optimal biological activity. Purified or partially purified isomers and stereoisomers, or racemic or diastereomeric mixtures of the compounds of the present application are also intended to be within the scope of the present application. Purification and separation of such materials can be accomplished by standard techniques known in the art.

[0171] The compounds of the present application also include tautomeric forms thereof. Tautomers are functional groups that can be interconverted by a reversible chemical reaction, often involving the migration of a hydrogen atom and a pi bond (double or triple bond) and resulting in a change in the structure of a molecule. Examples of such pairs are aldehyde / keto-enol, imine-enamine.

[0172] Any hydrogen atom in the compounds of the present application can be replaced by its isotope deuterium.

[0173] The compounds of the present application include all suitable isotopic variations of the compounds. The term "isotopic variations" means the replacement of at least one atom with an atom having the same atomic number but an atomic mass different from the atomic mass of the atom that it replaces. Examples of isotopes that can be present in the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F,36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, preferably deuterium.

[0174] Deuterated drugs have advantages of reducing side effects, increasing drug stability, enhancing efficacy, prolonging drug biological half-life, etc. compared with non-deuterated drugs. All isotopic composition changes of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and the partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

[0175] In the compounds of the present application, when a position is specifically designated as deuterium, D, the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% incorporation of deuterium). In some embodiments, the abundance of deuterium of each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (i.e., at least 99.5% incorporation of deuterium).

[0176] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for its intended use.

[0177] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application which is safe and effective for use in mammals, and possesses the desirable biological activity.

[0178] The term "pharmaceutical composition" refers to a composition comprising one or more compounds of the present application or physiologically / pharmaceutically acceptable salts or prodrugs thereof, and other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption of the active ingredient to exert a biological activity.

[0179] The term "pharmaceutically acceptable carrier" refers to those agents that do not cause significant irritation to an organism, and do not abrogate the biological activity and properties of the active compound. The "pharmaceutically acceptable carrier" includes, but is not limited to, a glidant, a sweetener, a diluent, a preservative, a dye / colorant, a flavoring agent, a surfactant, a wetting agent, a dispersant, a disintegrant, a stabilizer, a solvent, or an emulsifier.

[0180] The term "administration" or "administering" and the like, refer to methods allowing a compound or composition to be delivered to the desired site of biological action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0181] As used herein, the term "treatment" includes alleviating, abating or ameliorating a disease or condition, preventing the symptoms of other conditions, improving or preventing the underlying metabolic factors causing the symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, and extending to prophylaxis. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that the patient can experience an improvement in his / her quality of life, even though the patient can still be afflicted with the disorder. By prophylactic benefit is meant that the composition is used in a patient who is not yet displaying symptoms of the disease to prevent or delay onset of these symptoms.

[0182] The term "active ingredient," "therapeutic agent," "active substance," or "active agent" refers to a chemical entity that is effective in treating or preventing a disorder, disease, or condition of interest. The term "neuropsychiatric disorder" refers to the general class of neurological and psychiatric disorders, including neurological and / or psychiatric disorders.

[0183] For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0184] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0185] The term "room temperature" refers to a temperature ranging from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature ranging from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature ranging from 18°C ​​to 25°C.

[0186] "Equivalent" or its abbreviation "eq" is the equivalent amount of other raw materials required based on the equivalence relationship of a chemical reaction, using the basic raw materials used in each step as a reference (1 equivalent).

[0187] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application. Beneficial effects

[0188] The compounds of this invention are Myosin inhibitors. These compounds have excellent Myosin inhibitory activity, good pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, and low toxicity. They also have the advantages of oral administration, rapid absorption, and high clearance rate, and can be used to prevent and / or treat Myosin-mediated diseases. Detailed Implementation

[0189] The present invention will be described in detail below through embodiments. Unless otherwise specified, experimental methods under conventional conditions were used in the embodiments. The embodiments are provided to better illustrate the present invention, but should not be construed as limiting the invention to the examples given. Non-essential improvements and adjustments made to the implementation schemes by those skilled in the art based on the above description are still within the scope of protection of the present invention.

[0190] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured with a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS);

[0191] MS was measured with (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0192] HPLC was measured using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C 18 100x4.6mm, 3.5μM);

[0193] Thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography is 0.15mm-0.20mm, and the specification of the product used in thin layer chromatography separation and purification is 0.4mm-0.5mm;

[0194] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0195] Explanation of terms:

[0196] PEPPSI-SIPR catalyst: (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)(3- chloropyridyl)palladium(II) dichloride

[0197] Pd-PEPPSI-Ipent catalyst: dichloro(1,3-bis(2,6-di-3-pentylphenyl)imidazole-2-ylidene)(3- chloropyridyl)palladium(II)

[0198] XPhos Pd G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2-(2'-amino-1,1'- biphenyl))palladium(II)

[0199] Examples

[0200] The embodiments of the present application will be described in detail below with examples, but those skilled in the art will understand that the following examples are only used to illustrate the present application, and should not be regarded as limiting the scope of the present application. The specific conditions are not specified in the examples, and the conventional conditions or the conditions recommended by the manufacturer are used. The reagents or instruments used are not specified by the manufacturer, and are conventional products that can be obtained commercially. The proportions or percentages used in this text are by weight, unless otherwise specified.

[0201] Example 1

[0202] First step: potassium tert-butoxide (12.74 g, 113.5 mmol) was added to N,N- dimethylformamide (100 mL) solvent, and cooled to below -50°C under nitrogen protection. Compound 1A (10 g, 56.75 mmol) and difluoromethyl (2-pyridyl) sulfone (10.96 g, 56.75 mmol) were dissolved in N,N-dimethylformamide (20 mL) and slowly added to the above reaction solution at -50°C, and stirred at -50°C for 2 hours. Slowly add 3 mol / L hydrochloric acid aqueous solution (50 mL), slowly rise to room temperature and stir for 1 hour. Add ethyl acetate (300 mL) and saturated ammonium chloride aqueous solution (300 mL), extract and separate, dry the organic phase with anhydrous sodium sulfate, and concentrate. The residue was purified by silica gel column to obtain compound 1B (4.8 g, yield: 40.23%).

[0203] Second step: Compound 1B (4.8 g, 22.83 mmol) was added to dichloromethane (50 mL) solvent, and cooled to -78°C under nitrogen protection. 1 mol / L boron tribromide dichloromethane solution (50 mL) was slowly added dropwise, and after the addition was completed, the temperature was maintained and stirred for 2 hours. Slowly add saturated sodium bicarbonate aqueous solution (100 mL), extract and separate, dry the organic phase with anhydrous sodium sulfate, and concentrate to obtain compound 1C (3.1 g, crude product), which was directly used in the next step reaction.

[0204] LC-MS (ESI): m / z = 121.2 [M+H] + .

[0205] Third step: Compound 1C (2.70 g, 22.48 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium hydride (0.72 g, 17.98 mmol) was added portionwise at 0°C. After stirring at room temperature for 40 min, 5-bromo-2-chloropyrimidine (3.00 g, 15.51 mmol) was dissolved in tetrahydrofuran (10 mL) and added to the above system, and stirring was continued for 3 hours. Dilute with water, extract with ethyl acetate three times, collect the organic phase, dry with anhydrous sodium sulfate, and concentrate. The residue was purified by silica gel column chromatography to obtain compound 1D (1.70 g, yield: 27.29%).

[0206] LC-MS (ESI): m / z = 277.0; 279.0 [M+H] + .

[0207] Fourth Step: Compound 1D (1.70 g, 6.14 mmol), potassium acetate (1.51 g, 15.35 mmol), bis(pinacolato)diboron (1.64 g, 6.45 mmol) and XPhos Pd G2 (0.48 g, 6.45 mmol) were dissolved in 1,4-dioxane (60 mL), replaced with nitrogen for 3 times, stirred for 3 hours under the nitrogen atmosphere at 110 °C. Filtered with celite, the filter cake was washed with 1,4-dioxane, the filtrate was collected and concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 1E (1.13 g, yield: 56.82%).

[0208] LC-MS (ESI): m / z = 325.1 [M+H] + .

[0209] Fifth Step: Compound 1E (1.13 g, 3.49 mmol), 6-bromo-3-pyridazinone (0.61 g, 3.49 mmol), potassium phosphate tribasic (0.74 g, 3.49 mmol) and PEPPSI-SIPR catalyst (0.24 g, 0.35 mmol) were dissolved in 1,4-dioxane (60 mL), replaced with nitrogen for 3 times, stirred for 3 hours under the nitrogen atmosphere at 110 °C. After cooling, filtered, the filter cake was washed with ethyl acetate, the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 1F (0.1 g, yield: 9.82%).

[0210] LC-MS (ESI): m / z = 293.1 [M+H] + .

[0211] Sixth Step: Compound 1F (0.10 g, 0.34 mmol), 3-chloromethyl-5-fluoropyridine hydrochloride (62 mg, 0.34 mmol) and cesium carbonate (0.12 g, 0.85 mmol) were dissolved in acetonitrile (20 mL), and then stirred at 80 °C for 2 hours. After cooling, filtered, ethyl acetate and saturated brine were added, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was purified by reverse phase column chromatography to obtain compound 1 (47 mg, yield: 34.22%).

[0212] 1H NMR (400 MHz, CDC13) δ 8.90-8.86 (m, 2H), 8.65-8.38 (m, 2H), 7.66-7.52 (m, 2H), 7.14-7.09 (m, 1H), 5.44-5.37 (m, 2H), 5.36-5.28 (m, 1H), 3.28-3.17 (m, 2H), 3.00-2.87 (m, 2H);

[0213] LC-MS (ESI): m / z = 402.0 [M+H] + .

[0214] Example 2

[0215] First step: Compound 1A (20.00 g, 114 mmol) was dissolved in methanol (200 mL), sodium borohydride (8.59 g, 227 mmol) was added portionwise under ice bath, then the reaction was carried out at room temperature for 5 hours. After the reaction was completed, most of the methanol was removed by concentration, saturated aqueous ammonium chloride solution (200 mL) and ethyl acetate (200 mL) were added to the residue, and the extraction was separated. The organic phase was dried over anhydrous sodium sulfate, and then concentrated to obtain compound 2A (20.00 g of crude product), which was directly used in the next step reaction.

[0216] LC-MS (ESI): m / z = 201.1 [M+Na] + .

[0217] Second step: Compound 2A (27.64 g, 155.10 mmol) was added to tetrahydrofuran (300 mL) solvent, and sodium hydride (6.20 g, 155.10 mmol) was added portionwise under ice bath in nitrogen atmosphere. The reaction was stirred for 1 hour. 5-Bromo-2-chloropyrimidine (25.00 g, 129.25 mmol) was added to the reaction. The reaction was carried out at room temperature for 4 hours. After the reaction was completed, saturated ammonium chloride (500 mL) and ethyl acetate (500 mL) were added, and the extraction was separated. The organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 2B (33.30 g, yield: 76.88%).

[0218] LC-MS (ESI): m / z = 335.0, 337.0 [M+H] + .

[0219] Third step: 1 mol / L of boron tribromide dichloromethane solution (200 mL) was added to a three-necked flask, and cooled to below -70°C under nitrogen atmosphere. Compound 2B (33.00 g, 98.45 mmol) was dissolved in dichloromethane (30 mL) solvent, and slowly added dropwise to the three-necked flask at below -70°C, and stirred for 1 hour. After the reaction was completed, the reaction solution was directly poured into saturated aqueous sodium bicarbonate solution, and extracted and separated. The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound 2C (21.60 g, yield: 85.38%).

[0220] LC-MS (ESI): m / z = 245.0; 247.0 [M+H] + .

[0221] Fourth step: Compound 2C (20.60 g, 84.06 mmol) and dimethyl sulfoxide (7.88 g, 100.87 mmol) were added to dichloromethane (250 mL) solvent, and cooled to -78°C under nitrogen protection. Oxalyl chloride (12.80 g, 100.87 mmol) was slowly added dropwise at -60°C, and stirred for 30 minutes after the addition was completed. Triethylamine (17.01 g, 168.12 mmol) was slowly added, and the temperature was increased to room temperature. After the reaction was completed, water was added to quench the reaction, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 2D (5.60 g, yield: 27.41%).

[0222] LC-MS (ESI): m / z = 243.1; 245.1 [M+H] + .

[0223] Fifth step: Compound 2D (2.50 g, 10.29 mmol) was added to tetrahydrofuran solvent, and TEBBE reagent (1 mol / L, 12.35 mL) was added after nitrogen replacement, and reacted at room temperature overnight. After the reaction was completed, ethyl acetate and saturated brine were added, and extracted and separated. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 2E (0.50 g, yield: 20.16%).

[0224] LC-MS (ESI): m / z = 241.1, 243.1 [M+H] + .

[0225] Sixth Step: Compound 2E (0.50 g, 2.07 mmol), bis(pinacolato)diboron (0.55 g, 2.17 mmol) and potassium acetate (0.51 g, 5.17 mmol) were added to 1,4-dioxane (20 mL) solvent, after nitrogen replacement, XPhos Pd G2 (0.16 g, 0.21 mmol) was added, after nitrogen replacement again, the temperature was raised to 110 °C for 5 hours. After the reaction was completed, the temperature was lowered and filtered, and the filtrate was concentrated to obtain compound 2F (crude product), which was directly used in the next step reaction.

[0226] LC-MS (ESI): m / z = 289.1 [M+H] + .

[0227] Seventh Step: Compound 2F (597.00 mg, 2.07 mmol), 6-bromo-3-pyridazinone (0.38 g, 2.17 mmol) and potassium phosphate (0.44 g, 2.07 mmol) were added to 1,4-dioxane (20 mL) solvent, after nitrogen replacement, Pd-PEPPSI-Ipent catalyst (0.14 g, 0.21 mmol) was added, after nitrogen replacement again, the temperature was raised to 110 °C for 4 hours. After the reaction was completed, the temperature was lowered and filtered, and ethyl acetate and saturated brine were added, the organic phase was collected and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain compound 2G (0.25 g, yield: 47.09%).

[0228] LC-MS (ESI): m / z = 257.0 [M+H] + .

[0229] Eighth Step: Compound 2G (0.20 g, 0.78 mmol), potassium carbonate (269.51 mg, 1.95 mmol) and 3-chloromethyl-5-fluoropyridine hydrochloride (141.97 mg, 0.78 mmol) were sequentially added to the solvent, and the temperature was raised to 80 °C for 2 hours. After the reaction was completed, ethyl acetate and saturated brine were added, the organic phase was collected and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the obtained residue was purified by reverse phase column chromatography to obtain compound 2 (42 mg, yield: 14.73%).

[0230] 1H NMR (400 MHz, CDC13) δ 8.89 (s, 2H), 8.59-8.54 (m, 1H), 8.46-8.40 (m, 1H), 7.64-7.59 (m, 1H), 7.58-7.54 (m, 1H), 7.13-7.06 (m, 1H), 5.41 (s, 2H), 5.35-5.24 (m, 1H), 5.00-4.90 (m, 2H), 3.26-3.12 (m, 2H), 3.05-2.92 (m, 2H);

[0231] LC-MS (ESI): m / z = 366.1 [M+H] + .

[0232] Example 3

[0233] First Step: Compound 3A (0.2 g, 1.23 mmol) was dissolved in dichloromethane (10 mL), dichlorosulfoxide (0.16 g, 1.35 mmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain compound 3B (0.24 g crude), which was directly used for the next step reaction.

[0234] Second Step: 6-Bromo-3-pyridazine alcohol (1 g, 5.71 mmol), compound 3B (1.13 g, 6.28 mmol) and potassium carbonate (2.37 g, 17.13 mmol) were dissolved in N,N dimethylformamide (10 mL) and stirred at 70°C for 2 hours. After cooling to room temperature, the resulting residue was concentrated and purified by silica gel column chromatography to obtain compound 3C (1.40 g, yield: 76.82%).

[0235] LC-MS (ESI): m / z = 319.1 [M+H] + .

[0236] Third Step: Compound 3C (1.00 g, 3.13 mmol), 2-chloropyrimidine-5-boronic acid (0.50 g, 3.16 mmol), potassium carbonate (1.30 g, 9.39 mmol) and PEPPSI-IPR catalyst (0.21 g, 0.31 mmol) were dissolved in a mixed solvent of 1,4-dioxane (10 mL) and water (2 mL), protected by nitrogen, and stirred at 90°C for 2.5 hours. After cooling to room temperature, the resulting residue was concentrated and purified by silica gel column chromatography to obtain compound 3D (0.87 g, yield: 78.79%).

[0237] LC-MS (ESI): m / z = 353.1 [M+H] + .

[0238] Fourth Step: Compound 1C (61 mg, 0.51 mmol) was dissolved in dry tetrahydrofuran (20 mL), sodium hydride (16.00 mg, 0.41 mmol) was added, stirred for half an hour, then compound 3D (0.12 g, 0.34 mmol) was added, stirred at room temperature overnight. After cooling, direct concentration, the obtained residue was purified by reverse phase column chromatography to obtain compound 3 (55.00 mg, yield: 37.05%).

[0239] 1 H NMR (400 MHz, CDC13) δ 8.92 (s, 2H), 7.82-7.72 (m, 2H), 7.67-7.60 (m, 1H), 7.53-7.46 (m, 1H), 7.19-7.08 (m, 1H), 5.48 (s, 2H), 5.41-5.30 (m, 1H), 3.31-3.21 (m, 2H), 3.18-3.11 (m, 2H), 3.01-2.90 (m, 2H), 2.77-2.67 (m, 2H);

[0240] LC-MS (ESI): m / z = 437.2 [M+H] + .

[0241] Example 4

[0242] First Step: Compound 3A (1.80 g, 11.10 mmol) was added to dichloromethane (50 mL) solvent, triphenylphosphine (3.49 g, 13.32 mmol) was added, and the temperature was lowered to 0°C under nitrogen protection, and carbon tetrabromide (4.42 g, 13.32 mmol) was slowly added. Reaction at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure, toluene was added and stirred for 1 hour, filtered, and the filtrate was washed with saturated brine, and the organic phase was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound 4A (2.10 g, yield: 84.07%).

[0243] LC-MS (ESI): m / z = 224.9, 226.9 [M+H] + .

[0244] Second Step: Compound 2G (100 mg, 0.39 mmol), compound 4A (87.8 mg, 0.39 mmol), and potassium carbonate (134.8 mg, 0.98 mmol) were sequentially added to N,N-dimethylformamide (8 mL), and the temperature was raised to 80°C for reaction for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by reverse phase column chromatography to obtain compound 4 (77.00 mg, yield: 49.28%).

[0245] 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 2H), 8.06 (d, 1H), 7.27 - 7.06 (m, 4H), 5.31 - 5.17 (m, 3H), 4.98 - 4.89 (m, 2H), 3.21 - 3.08 (m, 2H), 2.93 - 2.75 (m, 6H), 2.04 - 1.92 (m, 2H);

[0246] LC-MS (ESI): m / z = 401.2 [M+H] + .

[0247] Example 5

[0248] Compound 2G (100 mg, 0.39 mmol), compound 5A (90.6 mg, 0.43 mmol) and potassium carbonate (134.8 mg, 0.98 mmol) were added into N,N-dimethylformamide (8 mL) sequentially, and the reaction was carried out at 80 °C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by preparative HPLC to obtain compound 5 (61.00 mg, yield: 40.45%).

[0249] 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 2H), 8.06 (d, 1H), 7.27 - 7.06 (m, 4H), 5.31 - 5.17 (m, 3H), 4.98 - 4.89 (m, 2H), 3.21 - 3.08 (m, 2H), 2.93 - 2.75 (m, 6H), 2.04 - 1.92 (m, 2H);

[0250] LC-MS (ESI): m / z = 401.2 [M+H] + .

[0251] Example 6

[0252] Compound 2G (100 mg, 0.39 mmol), compound 6A (81.1 mg, 0.43 mmol), potassium carbonate (134.8 mg, 0.98 mmol) were added into N,N-dimethylformamide (8 mL) sequentially, and the reaction was carried out at 80 °C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by preparative HPLC to obtain compound 6 (67.00 mg, yield: 47.12%).

[0253] 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 2H), 8.08 (d, 1H), 7.52-7.42 (m, 2H), 7.22-7.09 (m, 3H), 5.36-5.19 (m, 3H), 4.99-4.91 (m, 2H), 3.21-3.09 (m, 2H), 2.92-2.79 (m, 2H);

[0254] LC-MS (ESI): m / z = 365.2 [M+H] + .

[0255] Biological test evaluation

[0256] The following examples further illustrate the present application, but are not meant to limit the scope of the application.

[0257] The chemical structure of the following Comparative Example 1 of the present application is shown below, which was prepared according to the method of compound 6 of International Patent Application WO2020097266A1,

[0258] I. Rabbit skeletal muscle myosin activity assay method

[0259] The purpose of this test is to evaluate the ability of the compound to inhibit the hydrolysis of ATP by rabbit skeletal muscle myosin. The determination method is as follows:

[0260] 1. Solution preparation:

[0261] • Preformed F-actin filaments (#AKF99-B, Cytoskeleton) were diluted to 1 mg / mL with Reaction buffer (25 mM Tris-HCL, PH 7.5 + 35 mM KCl + 0.1 mM EGTA + 1 mM MgCl2);

[0262] • Rabbit myosin (#MY02-A, Cytoskeleton) was diluted to 0.1 mg / mL with Resuspension buffer (15 mM Tris-HCL, PH 7.5 + 0.2 M KCl + 1 mM MgCl2);

[0263] • ATP (#BSA04-001, Cytoskeleton) was diluted to 3 mM working solution with 15 mM Tris-HCL (PH = 7.5);

[0264] 2. Experimental procedure:

[0265] • Actin control wells add 13 μL reaction buffer + 12 μL F-actin;

[0266] • Positive control wells add 10 μL reaction buffer + 12 μL F-actin + 3 μL Myosin;

[0267] • Compound wells add 10 μL compound working solution + 12 μL F-actin + 3 μL Myosin;

[0268] • Start reaction by adding 5 μL ATP working solution to all test wells, and add Pi standard simultaneously according to the instruction (#BK054, Cytoskeleton);

[0269] • Incubate at 37 °C for exactly 60 min after gentle mixing;

[0270] • Add 70 μL CytoPhos Reagent (#BK054, Cytoskeleton) to each well to stop the reaction after 10 min incubation.

[0271] 3. Detection:

[0272] Detect OD value of each well at 650 nm using endpoint method. Fit standard curve according to Pi concentration and OD value, and calculate Pi concentration of each test well. Inhibition (%) = (Pi positive control well - Pi test well) / Pi positive control well * 100%. Fit Inhibition %-Enzyme concentration curve using Graphpad Prism 8 software, and calculate IC 50 .

[0273] 4. Test results: IC 50 of compound on rabbit skeletal muscle myosin hydrolysis ATP inhibition activity is less than 1000 μM, IC 50 of some preferred compounds is less than 200 μM, IC 50 of some more preferred compounds is less than 100 μM, IC 50 of some more preferred compounds is less than 50 μM, IC 50 of some more preferred compounds is less than 20 μM, IC 50 of some more preferred compounds is less than 2.5 μM; see Table 1 for specific results of some examples.

[0274] Table 1. IC

[0275] of compound on rabbit skeletal muscle myosin hydrolysis ATP inhibition activity is less than 1000 μM, IC 50≤2.5μM, where A represents 2.5μM <IC 50 ≤20μM, B indicates 20μM <IC 50 ≤50μM, where C represents 50μM <IC 50 ≤100μM, where D represents 100μM <IC 50 ≤200μM.

[0276] Conclusion: The compounds of this invention exhibit strong inhibitory activity against ATP hydrolysis by myosin in rabbit skeletal muscle, and the IC50 of some compounds is [not specified]. 50 Less than 1 μM, IC50 of compound 1 50 The IC50 of compound 2 is 0.6 μM. 50 The IC50 of compound 4 was 0.5 μM. 50 The IC50 of compound 5 was 0.3 μM. 50 The IC50 of compound 6 was 0.5 μM. 50 The IC value is 0.2 μM, compared to Comparative Example 1. 50 The concentration was 2.8 μM, indicating that the compound of the present invention has better inhibitory activity against the hydrolysis of ATP by rabbit skeletal muscle myosin compared to Comparative Example 1.

[0277] II. Methods for Analyzing Cardiac Myosin SII Activity

[0278] The purpose of this experiment was to evaluate the ability of the compound to inhibit the hydrolysis of ATP by cardiac myosin SII. The assay method is as follows:

[0279] 1. Solution preparation:

[0280] • Prepared F-actin filaments (#AKF99-B, Cytoskeleton) were diluted to 1 mg / mL with reaction buffer (15 mM Tris-HCl, pH 7.5 + 10 mM KCl + 0.1 mM EGTA + 2 mM MgCl2);

[0281] Cardiac Muscle Myosin (#MY03-A, Cytoskeleton) was diluted to 1 mg / mL with Resuspension buffer (15 mM Tris-HCl, pH 7.5 + 0.2 M KCl + 1 mM MgCl2).

[0282] • ATP (#BSA04-001, Cytoskeleton) was diluted with 15 mM Tris-HCl (pH = 7.5) to prepare a 3 mM working solution;

[0283] 2. Preparation of working solution for the compound: The final concentration of the compound is 100 μM.

[0284] 3. Experimental procedure:

[0285] • Compound wells add 10 μL compound working solution + 12 μL Preformed F-actin filaments + 3 μL Cardiac Muscle myosin;

[0286] • Positive control wells add 10 μL DMSO-containing reaction buffer + 12 μL Preformed F-actin filaments + 3 μL Cardiac Muscle myosin;

[0287] • Negative control wells add 10 μL DMSO-containing reaction buffer + 12 μL Preformed F-actin filaments + 3 μL Resuspension buffer;

[0288] • All test wells add 5 μL 3 mM ATP working solution to start the reaction, mix gently and incubate at 37°C for 2 h;

[0289] • After the reaction is completed, take 6 μL of the reaction solution, dilute 5-fold with 24 μL reaction buffer, and then use the Phosphate Reagent Kit (#BK054, Cytoskeleton) to detect the content of product Pi;

[0290] • The Pi standard wells are added according to the instructions;

[0291] • Add 70 μL of CytoPhos Reagent (#BK054, Cytoskeleton) to each well, incubate at room temperature for 10 min, and then detect.

[0292] 4. Detection:

[0293] 650 nm, detect the OD value of each well. According to the Pi standard concentration and OD value, a standard curve is fitted, and the Pi concentration of each test well is obtained. Inhibition (%) = (positive control well-test well) / positive control well*100%.

[0294] Table 2 Inhibition rate of compounds on cardiac muscle myosin SII

[0295] Conclusion: The compounds of the present application, such as the compounds of the examples, have no inhibitory activity on cardiac muscle myosin SII.

[0296] III. Smooth muscle myosin S1 fragment activity analysis method

[0297] The purpose of this assay is to evaluate the ability of compounds to inhibit the hydrolysis of ATP by smooth muscle myosin S1 fragment. The assay method is as follows:

[0298] 1. Solution preparation

[0299] • F-actin polymer: Cardiac Actin powder (#CS-AD99, Cytoskeleton) was dissolved in buffer (5 mM Pipes-KOH solution, pH = 7.0, containing 100 μΜ ATP and 500 μΜ DTT) to a 2 mg / mL solution, and incubated at room temperature for 30 min. Then 2 mM MgCl2and 2 mM EGTA were added, and incubated at room temperature for 40 min.

[0300] • Smooth muscle S1 fragment (#CS-MYS05, Cytoskeleton) was diluted to a 0.7 mg / mL solution with pre-cooled PM12 buffer (12 mM Pipes-KOH solution, pH = 7.0, containing 2 mM MgCl2) containing 1 mM DTT;

[0301] • ATP (#BSA04-001, Cytoskeleton) was diluted to a 5 mM working solution with 15 mM Tris-HCL (pH = 7.5);

[0302] 2. Compound working solution: final concentration of compounds was 100 μΜ

[0303] 3. Experimental procedure:

[0304] • Compound wells were added with 10 μL compound working solution + 6 μL F-actin polymer + 4 μL Smooth muscle S1 fragment solution;

[0305] • Positive control wells were added with 10 μL DMSO-containing PM12 buffer + 6 μL F-actin polymer + 4 μL Smooth muscle S1 fragment solution;

[0306] • Negative control wells were added with 10 μL DMSO-containing PM12 buffer + 6 μL F-actin polymer + 4 μL PM12 buffer;

[0307] • All test wells were added with 10 μL 5 mM ATP working solution to start the reaction, and gently mixed and incubated at 37 °C for 20 min;

[0308] • After the reaction, 6 μL of the reaction solution was taken, diluted 5 times with 24 μL of PM12 buffer, and then the content of product Pi was detected by a phosphate reagent kit (#BK054, Cytoskeleton);

[0309] • The standard sample was added according to the instructions, 70 μL of CytoPhos Reagent (#BK054, Cytoskeleton) was added to all wells, and then the detection was performed after incubation at room temperature for 10 min.

[0310] 4. Detection: The OD value of each well was detected at 650 nm. The standard curve was fitted according to the Pi standard sample concentration and the OD value, and the Pi concentration of each test well was calculated. Inhibition (%) = (positive control well-test well) / positive control well*100%.

[0311] Table 3 Inhibition rate of compounds on smooth muscle myosin S1

[0312] Conclusion: The compound of the present application, such as the compound of the examples, has no inhibitory activity on smooth muscle myosin S1.

[0313] Four, mouse pharmacokinetic test

[0314] 1. Test animals: male C57 mice, 22-25 g, 9 per compound. Purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0315] 2. Test design: On the test day, the C57 mice were randomly divided according to the body weight. Fasting for 12-14 h without water restriction 1 day before administration, and feeding 4 h after administration. According to Table 4.1, the administration was performed.

[0316] Table 4.1 Administration information Note: Intravenous administration vehicle: 10% DMA+10% Solutol+80% Saline; gavage administration vehicle: 5% DMA+5% Solutol+90% Saline (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline)

[0317] Before and after administration, 0.06 mL of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm at 4°C for 10 min, and the plasma was collected. At the same time, the tibialis anterior muscle tissue of the mouse was taken, the surface residual blood was washed with physiological saline, and then homogenized after drying. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0318] Table 4.2 Pharmacokinetic parameters of compounds in the tibialis anterior muscle of mice

[0319] Conclusion: The compound of the present application, such as the example compound, has good pharmacokinetic characteristics in mice, good tissue distribution selectivity and exposure in the tibialis anterior muscle of mice, indicating that the compound of the present application has good target organ targeting.

[0320] Five, rat pharmacokinetic test

[0321] 1. Test animals: male SD rats, about 220 g, 6-8 weeks old, 6 rats per compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0322] 2. Test design: On the test day, the SD rats were randomly divided by weight. Fasting for 12-14 h without water 1 day before administration, and feeding 4 h after administration. According to Table 5.1, the drug was administered.

[0323] Table 5.1 Drug information Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Intragastric administration vehicle: 0.5% MC (MC: methylcellulose)

[0324] 0.15 mL of blood was taken from the orbit under isoflurane anesthesia before and after administration, and placed in an EDTA K2 centrifuge tube. Centrifugation at 5000 rpm, 4°C for 10 min, and collection of plasma. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0325] Conclusion: The compound of the present application, such as the example compound, has good pharmacokinetic characteristics in rats.

[0326] Six, beagle pharmacokinetic test

[0327] 1. Test animals: male beagle dogs, about 8-11 kg, 6 dogs per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0328] 2. Test method: On the test day, the beagle dogs were randomly divided by weight. Fasting for 12-14 h without water 1 day before administration, and feeding 4 h after administration. According to Table 6.1, the drug was administered.

[0329] Table 6.1 Drug information Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Intragastric administration vehicle: 0.5% MC

[0330] 1 mL of blood was taken from the jugular vein or limb vein before and after administration, and placed in an EDTA K2 centrifuge tube. Centrifugation at 5000 rpm, 4°C for 10 min, and collection of plasma. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0331] Conclusion: The compounds of the present application, such as the example compounds, have good pharmacokinetic characteristics in beagle dogs.

[0332] Seven, monkey pharmacokinetic test

[0333] 1. Test animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0334] 2. Test method: On the test day, the monkeys were randomly divided into groups according to body weight. Fasting without water for 14-18 h before administration, and feeding 4 h after administration. According to Table 7.1, the drug was administered.

[0335] Table 7.1 Drug information Note: Intravenous administration vehicle: 5% DMA + 5% Solutol + 90% Saline; Intragastric administration vehicle: 0.5% MC

[0336] 1.0 mL of blood was taken from the limbs before and after administration, and placed in EDTAK2 centrifuge tubes. Centrifugation at 5000 rpm, 4°C for 10 min, and collection of plasma. Before analysis, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0337] Conclusion: The compounds of the present application, such as the example compounds, have good pharmacokinetic characteristics in monkeys.

[0338] Eight, hERG potassium ion channel effect test

[0339] 1. Experimental platform: electrophysiological hand-held patch clamp system

[0340] 2. Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium ion channel

[0341] 3. Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel, hERG potassium channel current was recorded by whole-cell patch clamp technique at room temperature. Glass microelectrode was drawn by glass electrode embryo (BF150-86-10, Sutter) through a drawing instrument, and the tip resistance of the electrode after perfusion with electrode internal solution was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe and connected to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by computer through pClamp 10 software, the sampling frequency was 10 kHz, and the filter frequency was 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV, and the hERG potassium current (I hERG) from -80 mV to +20 mV for 2 s depolarization, followed by a repolarization to -50 mV for 1 s, and then back to -80 mV. This voltage protocol was applied every 10 s, and the hERG potassium current was allowed to stabilize (at least 1 min) before the drug administration process was started. Each test concentration of compound was applied for at least 1 min, and at least 2 cells were tested for each concentration (n≥2).

[0342] 4. Data processing: Data analysis was processed using pClamp 10, GraphPad Prism 5 and Excel software. The inhibition of hERG potassium current (peak of hERG tail current induced at -50 mV) by different concentrations of compounds was calculated using the following formula: Inhibition% = [1 - (I / Io)] x 100%

[0343] where Inhibition% represents the percentage of inhibition of hERG potassium current by the compound, and I and Io represent the amplitude of hERG potassium current after and before drug administration, respectively.

[0344] Compound IC 50 The IC50value was calculated using GraphPad Prism 5 software by fitting the data to the following equation: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))

[0345] where X is the Log value of the test concentration, Y is the percentage of inhibition at the corresponding concentration, and Bottom and Top are the minimum and maximum percentage of inhibition, respectively.

[0346] Conclusion: The compounds of the present application, such as the example compounds, do not inhibit the hERG potassium channel current.

[0347] IX. CYP450 enzyme inhibition test

[0348] The purpose of this study was to evaluate the effects of test substances on the activities of five isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and different concentrations of test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction was completed, the samples were processed and the specific metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the changes in CYP enzyme activity, and the IC 50 values were calculated to evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.

[0349] Table 8 IC of compounds on CYP enzyme inhibition 50 Values

[0350] Conclusion: The compounds of the present application, such as the example compounds, do not inhibit the five isoforms of human liver microsomal cytochrome P450 (CYP).

[0351] Ten, PK / PD detection of Dmd (Mdx) gene mutant mouse model

[0352] Purpose of the experiment: B10-Dmd-KO (Mdx) mice are Dmd gene frame-shift mutation resulting in DMD function loss mice, phenotype analysis shows that B10-Dmd-KO mice have a series of characteristics of DMD patients. This study investigates the effect of compound administration on CK and TNNI2 in the plasma of Mdx mice.

[0353] Experimental animals: B10-Dmd-KO (C57BL / 10ScSnJGpt-Dmdem3Cd4 / Gpt), male, 5-7 weeks old, body weight 28-30g, supplier: Jiangsu Jucu Yakang Biotechnology Co., Ltd.

[0354] Experimental process:

[0355] 1) Running training (D-5): Mdx mice were trained in batches, with training parameters for three time periods, initial speed of 4m / min, maintained for 2min, then 8m / min, maintained for 8min, finally 12m / min, maintained for 30min, a total of 40min;

[0356] 2) Grip strength test (D-2): three times per round, three rounds;

[0357] 3) Grouping (D0): after anesthesia with isoflurane (concentration: 5%, gas flow rate: 1L / min), blood (about 150μL) was collected from the orbital venous sinus of the animals using a capillary tube into a 0.6mL centrifuge tube containing EDTA anticoagulant, and the CK value was detected to serve as the baseline value for grouping;

[0358] 4) Dosing, grip, and blood collection (D1): after the compound was dissolved in the vehicle 5% DMA+5% HS-15+90% Saline, the mice were orally administered, then the grip strength test was started (three times per round, three rounds), and after 1h of the test, the animals were anesthetized with isoflurane (concentration: 5%, gas flow rate: 1L / min), blood (about 300μL) was collected from the orbital venous sinus of the animals using a capillary tube into a 0.6mL centrifuge tube containing EDTA anticoagulant (to ensure that the blood collected is 6h after administration);

[0359] 5) Running, blood sampling, sample collection (D2): After 22h20min of drug administration, a 40min run was performed (same running parameters as above), and 1h after the run completion, the mice were anesthetized by isoflurane (concentration: 5%, gas flow rate: 1 L / min) inhalation, and blood samples (≥300 μL) were collected from the orbital sinus using a capillary tube into 0.6 mL centrifuge tubes containing EDTA anticoagulant, followed by euthanasia of the animals. The tibialis anterior muscle (left leg), the soleus muscle (both legs), and the heart muscle were collected, weighed, and recorded, and then were placed in homogenization tubes, frozen in liquid nitrogen, and stored at -80°C.

[0360] Sample processing: After centrifugation of the EDTA-anticoagulated whole blood at 3000 rpm and 4°C for 10 min, the serum was collected and aliquoted. The separated serum was subjected to biochemical instrument (full-automatic biochemical instrument Roche C311) detection of CK value and TNNI2 value (Mouse TNNI2 Elisa Kit, ABBEXA, E2207370Y); the serum concentration of the compound and the drug concentration of the tibialis anterior muscle, the soleus muscle, and the heart muscle were detected by LC / MS instrument.

[0361] Conclusion: The compound of the present application, such as the compound of the examples, has a good inhibitory effect on the CK value in the plasma in the Dmd (Mdx) gene mutant mouse model.

Claims

1. A compound of Formula (I), (II), a stereoisomer, or a pharmaceutically acceptable salt thereof: ###0001### ###0002### (I) (II) wherein: X is CR 10 or N; L is a bond, O, NH, S, C(O), S(O), S(O)2, -(CR L1 R L2 ) n -; L1is a bond, O, NH, S, Se, C(O), S(O), S(O)2, -(CR L1 R L2 ) n -; Ring A is C 4-7 cycloalkyl; R A H, deuterium, halogen, hydroxyl, cyano, amino or C 1-6 alkyl; R L1 and R L2 each independently is hydrogen, deuterium, halogen, hydroxyl, cyano, amino or C 1-6 alkyl; or R L1 and R L2 with the carbon atom to which it is attached forming C 3-7 cycloalkyl, optionally further substituted with 1-3 groups selected from R c of the following: R 1a and R 1b each independently is hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuteroalkyl or C 1-6 haloalkyl; or R 1a and R 1b with the carbon atom to which it is attached forming C 4-7 cycloalkyl, 4-7 membered heterocycloalkyl, optionally further substituted by 1-3 groups selected from R c R R 2 , R 3 , R 4 , and R 5 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, or C 1-6 alkylamino; or R 2 and R 4 with the carbon atom to which they are attached forming C 4-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted by 1-3 groups selected from R c ; or R 4 and R 5 with the carbon atom to which they are attached forming C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, optionally further substituted by 1-3 groups selected from R c ; R 6 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 alkylamino, -S(O)R, -S(O)2R, -C(O)R, -OC(O)R, -C(O)OR, -C(O)N(R)2; R is hydrogen, deuterium, amino, C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 deuteroalkoxy, C 1-6 haloalkoxy, or C 3-6 cycloalkyl; or R L1 or R L2 and R 9 with the carbon atom to which they are attached forming C 3-6 cycloalkyl, optionally further substituted with 1-3 groups selected from R c of the following: or, R 6 and R 10 , R 10 and R 7 , R 7 and R 8 , R 8 and R 9 any one group together with the carbon atom to which it is attached form a C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, optionally further substituted by 1-3 groups selected from R c ; R c is deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene; n is 0, 1, 2, 3, 4, 5.

2. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein which satisfies one or more of the following conditions: (1) X is CH or N; (2) L is a bond, O, NH, S, C(O), S(O), S(O)2, -CH2-, preferably -CH2-; (3) R L1 and R L2 each independently is hydrogen, deuterium, halogen, hydroxyl, cyano, amino or C 1-3 alkyl, preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino or methyl; (4) R 1a and R 1b each independently is hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 deuteroalkyl or C 1-3 haloalkyl, preferably hydrogen, deuterium, fluorine, chlorine, methyl, monofluoromethyl, difluoromethyl or trifluoromethyl; (5) R 2 (6) R 3 (7) R 4 (8) R 5 each independently is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, or C 1-3 haloalkoxy, preferably hydrogen; (6) R 6 (7) R 7 (8) R 8 (9) R 9 (10) R 10 each independently is hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, or C 1-3 haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, methyl, or trifluoromethyl; (7) R is hydrogen, deuterium, amino, C 1-3 alkyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 deuteroalkoxy, C 1-3 haloalkoxy, or C 3-6 cycloalkyl; (8) R 2 and R 4 with the carbon atom to which it is attached forming a C 4-7 cycloalkyl, phenyl, optionally further substituted by 1-3 groups selected from R c , preferably forming a cyclopentyl, cyclohexyl, cycloheptyl, phenyl group, optionally further substituted by 1-3 groups selected from R c ; (9) R 4 and R 5 with the carbon atom to which it is attached forming a C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, optionally further substituted by 1-3 groups selected from R c , preferably forming a cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, pyrazolyl, isoxazolyl group, optionally further substituted by 1-3 groups selected from R c ; (10) R L1 or R L2 and R 9 with the carbon atom to which they are attached forming a C 4-6 cycloalkyl, optionally further substituted by 1-3 groups selected from R c preferably forming a cyclopentyl, cyclohexyl group, optionally further substituted by 1-3 groups selected from R c ; (11)R 6 and R 10 R 10 and R 7 R 7 and R 8 R 8 and R 9 Any group of carbon atoms in the matrix linked with it forms a C 4-6 Cycloalkyl, 5-7 membered heterocycloalkyl, optionally further selected by 1-3 members chosen from R c The groups are substituted, preferably linked to form cyclobutenyl, cyclopentenyl, cyclopentadienyl, or cyclohexenyl, optionally further substituted with 1-3 groups selected from R c Substitution of groups; (12) R c is deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 deuteroalkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, C 1-3 alkylidene or C 1-3 haloalkylidene, preferably deuterium, fluorine, chlorine, hydroxyl, cyano, oxo, methyl, ethenyl, ethynyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, methylene, ethylene, 1 -methyl ethylene, fluoromethylene or difluoromethylene; (13) n is 0, 1, 2, 3, preferably 1 or 2.

3. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, L is -CH2-; selected from the group consisting of L1is a bond, -0-, -S-, -Se-, -C(O)-, -CH2-, -CF2-, -C(CH3)2-, -CH(CH3)-, selected from the group consisting of 4. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein, L is -CH2-; selected from the group consisting of R 1a and R 1b each independently is hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 deuteroalkyl or C 1-3 haloalkyl; R 2 , R 3 , R 4 and R 5 are each independently hydrogen.

5. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of any one of claims 1-4, wherein, one of the structures selected from Table I.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-5, and one or more pharmaceutically acceptable carriers or excipients.

7. The pharmaceutical composition according to claim 6, comprising 1-1500 mg of a compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-5, and one or more pharmaceutically acceptable carriers or excipients.

8. Use of a compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-5, or a pharmaceutical composition according to claim 6 or 7, for the manufacture of a medicament, preferably a medicament for the prevention and / or treatment of a Myosin-mediated disease.

9. The use according to claim 8, wherein the Myosin-mediated disease is selected from muscular dystrophy.

10. A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of a compound, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1-5, or a pharmaceutical composition according to claim 6 or 7, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably muscular dystrophy.

Images