Myosin inhibitor and use thereof

Abstract

Disclosed in the present invention are a myosin inhibitor and a use thereof. The myosin inhibitor has a structure as shown in formula (I), has better inhibitory activity, and can be used for reducing and / or inhibiting sarcomere hypercontraction, cardiomyocyte hypertrophy, disorder and increased myocardial fibrosis, and preventing and / or treating heart diseases, especially hypertrophic cardiomyopathy. Thus, the myosin inhibitor can fill the gap in anti-heart disease drugs, and has excellent application prospects and value in the field of medicines.

Description

Myosin inhibitor and its application Technical Field

[0001] The present invention relates to the technical field of chemical medicine, and in particular to a myosin inhibitor and application thereof, which is used for treating heart disease, especially treating hypertrophic cardiomyopathy. Background Art

[0002] Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease characterized by unexplained symmetrical or asymmetrical ventricular hypertrophy. Histopathological changes are highly specific, characterized by cardiomyocyte hypertrophy, disorganized arrangement, and fibrosis. HCM is generally defined as left ventricular hypertrophy (LVH) of unknown etiology, excluding the influence of other cardiac or systemic diseases. Mutations in genes encoding sarcomere proteins are the primary cause of HCM, also known as sarcomeric HCM. Currently, a variety of gene mutations are known to cause HCM, with mutations in β-myosin heavy chain (MYH7), myosin binding protein C (MYBPC3), troponin T (TNNT2), and actin (ACTC1) being the most common.

[0003] Currently, drug treatments for HCM are mainly non-specific, using β-receptor antagonists and non-dihydropyridine calcium channel blockers (CCBs) to alleviate patient symptoms. However, these treatments do not significantly improve the disease progression and prognosis of HCM. There is an urgent need for a specific targeted drug for myosin mutations to change the current situation.

[0004] Myosin is a multifunctional linear polypeptide composed of heavy and light chains. The heavy chain is responsible for ATPase activity, while the light chain is involved in regulating myosin activity. Myosin is the primary motor protein for muscle contraction. In muscle cells, myosin interacts with actin to form the sarcomere, the basic structural unit of the muscle fiber. Mutations in myosin, resulting in hyperdynamic sarcomere contraction and impaired relaxation, are believed to be the cause of HCM. Therefore, inhibitors targeting myosin may offer a new therapeutic approach for HCM. Myosin inhibitors can ameliorate the disease by inhibiting sarcomere hypercontraction and can alleviate and reverse HCM hallmarks such as cardiomyocyte hypertrophy, disorganization, and increased myocardial fibrosis. Therefore, further development of new, more effective drugs targeting myosin is needed.

[0005] Summary of the Invention

[0006] In a first aspect of the present invention, a compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof is provided, wherein the compound has a structure shown in Formula I:

[0007] in,

[0008] A is a substituted or unsubstituted carbocyclic or heterocyclic ring;

[0009] R B Selected from: H, D, halogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -O(C 0-10 alkyl);

[0010] L1 is selected from the group consisting of: a single bond, C1-C6 alkylene, -O-, -S-, -N(C0-C6 alkyl)-, -C(O)-, -C(S)-, -C(O)-(C0-C6 alkylene)-, -C(S)-(C0-C6 alkylene)-, -C(O)-N(C0-C6 alkyl)-, -C(S)-N(C0-C6 alkyl)-, -SO-, -SO2-, -Si-, -C(O)O-;

[0011] R C Selected from: H, D, halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 alkyl), -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0- 10Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 alkyl), wherein the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 3-10 membered heterocyclic group may be arbitrarily substituted by one or more of the following groups: D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group); or, the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl and 3-10 membered heterocyclic groups may be arbitrarily substituted by one or more of the following groups: halogen, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 haloalkoxy;

[0012] W1 is selected from:

[0013] W2 is selected from: C, N, O, when W2 is N, R1' does not exist, when W2 is O, R1, R1' does not exist;

[0014] R1, R1', R2, R2' are independently selected from: H, D, (=O), C1-C 10 Alkyl, C1-C 10 Haloalkyl, -OH, -NH2, -COOH, -OC1-C 10 alkyl;

[0015] R2" is selected from: H, D, C1-C 10 Alkyl, -OH, -(C1-C6 alkylene)-COOR 21 、-(C1-C6 alkylene)-OR 21 、-(C1-C6 alkylene)-CONR 21 R 22 ;

[0016] R 21 is H or C1-C6 alkyl;

[0017] R 22 is H or C1-C6 alkyl.

[0018] Specifically, Some selected from: a substituted or unsubstituted 5-6 membered nitrogen-containing heterocyclic group, substituted or unsubstituted naphthyl,

[0019] Specifically, Part of Among them, R A is one or more independent substituents on the benzene ring selected from: H, D, halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 alkyl)SO2(C 0-10 alkyl), -O(C 0-10 alkyl), -CO(C 0-10 Alkyl), -COO(C 0-10 alkyl), -OCO(C 0-10 alkyl), -CON(C 0- 10 Alkyl)(C 0-10 Alkyl), -S(C 0-10 alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 alkyl), wherein the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 3-10 membered heterocyclic group may be arbitrarily substituted by one or more of the following groups: D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group).

[0020] In some embodiments of the present invention, R A H or D;

[0021] In some embodiments of the present invention, R A is a halogen, such as F, Cl, Br, I;

[0022] In some embodiments of the present invention, R A is a C1-C3 alkyl group, such as -CH3;

[0023] In some embodiments of the present invention, R A is a C1-C3 haloalkyl group, such as CF3;

[0024] In some embodiments of the present invention, R A is a C1-C3 alkoxy group, such as -OCH3;

[0025] In some embodiments of the present invention, R A for Among them, R A′ With the above R A The definition of

[0026] In some embodiments of the present invention, R A for Among them, R A' With the above R A The definition of

[0027] In some embodiments of the present invention, Selected from: Among them, R A' With the above R A Definition of .

[0028] In some embodiments of the present invention, Selected from:

[0029] Specifically, Some are substituted or unsubstituted 5-6 membered nitrogen-containing heterocyclic groups, for example, Among them, R A1is one or more independent substituents on a 5-6 membered nitrogen-containing heteroaryl group selected from the group consisting of H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

[0030] In some embodiments of the present invention, R A1 is H or D;

[0031] In some embodiments of the present invention, R A1 is a halogen, such as F, Cl, Br, I;

[0032] In some embodiments of the present invention, R A1 It is a C1-C3 alkyl group, such as -CH3.

[0033] In some embodiments of the present invention, the substituted or unsubstituted 5-6 membered nitrogen-containing heterocyclic group is selected from:

[0034] Specifically, Part of Among them, R 72 、R 73 independently selected from: H, -D, -CH3, -X, -CF3, -OH, -OCH3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -N3, -B(OH)2, -NO2, -COO(C1-C6 alkyl), -COOH, -CN, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl); or, R 72 、R 73 Independently selected from: C1-C6 haloalkyl.

[0035] Preferably, R 72 、R 73 Independently selected from: H, D, -F, -Br, -Cl, -I, -CH3, -CH2F, -CHF2, -CF3, -COOH, -CN, -COOCH3, -NH2, -NHCH3, -NO2, -OCH3, -OH, -TMS, -SO2CH3, -NHSO2CH3, -SO2NH2;

[0036] In some embodiments of the present invention, R 72 、R 73 For H.

[0037] In some embodiments of the present invention, for Preferably

[0038] Specifically, Part of For example,

[0039] In some embodiments of the present invention, for Preferably

[0040] Specifically, Part is substituted or unsubstituted naphthyl, for example, Among them, R 41 、R 42 、R 43 、R 44 、R 45 、R 46 、R 47 represents a ring substituent independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl), -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R'、-R L -NR'R", -R L -NR'C(O)R”、-R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R";

[0041] R LSelected from: a single bond, C1-C6 alkylene, C3-C6 heteroalkylene, C3-C6 cycloalkylene, C3-C6 heterocyclylene, -NR4C(O)-, -NR4SO-, -NR4SO2-, -C(O)-, -C(O)O-, -NR4-, -C(O)NR4-, -SO2NR4-, -SO2NR4-;

[0042] R4 is selected from the group consisting of: H, D, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, and alkoxy;

[0043] R' and R" are independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen;

[0044] Preferably, R 41 、R 42 、R 43 、R 44 、R 45 、R 46 、R 47 Independently selected from: H, D, -CH3, -X, -CH2F, -CHF2, -CF3, -OH, -CN, -OCH3, -OCH2X, -OCHX2, -OCX3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NO2, -COO(C1-C6 alkyl), -COOH, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl);

[0045] More preferably, R 42 、R 43 、R 45 、R 46 Independently selected from: H, -F, -D, -Br, -Cl, -I, -CH3, -CH2F, -CHF2, -CF3, -COOH, -CN, -COOCH3, -NH2, -NHCH3, -N(CH3)2, -NO2, -OCH3, -OH, -TMS, -SO2CH3, -NHSO2CH3, -SO2NH2.

[0046] In some embodiments of the present invention, the substituted or unsubstituted naphthyl group is selected from:

[0047] Specifically, Part of wherein W3 is selected from N or CH;

[0048] R6 is selected from: H, D, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 ;

[0049] R 61 、R 62 Independently selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl), -N3, -B(OH)2, -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R'、-R L -NR'R", -R L -NR'C(O)R”、-R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R";

[0050] Preferably, W3 is N;

[0051] Preferably, R6 is H, D, CH3, -CH2COOH, -CH2COOCH3;

[0052] Preferably, R 61 、R 62Independently selected from H, -D, -F, -Br, -Cl, -I, -CH3, -CH2F, -CHF2, -CF3, -COOH, -CN, -COOCH3, -NH2, -NHCH3, -NO2, -OCH3, -OH, -TMS, -SO2CH3, -NHSO2CH3, -SO2NH2.

[0053] In some embodiments of the present invention, for

[0054] Specifically, Part of Among them, R 31 N or CR 36 ;

[0055] R 32 NR 37 or -N=CR 38 -;

[0056] R 35 or R 37 Independently selected from: H, -D, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 ;

[0057] R 33 、R 34 、R 36 、R 38 Independently selected from: H, -D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl)3, -N3, -B(OH)2, -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R'、-R L -NR'R", -RL -NR'C(O)R”、-R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R";

[0058] Preferably, R 33 、R 34 、R 36 、R 38 Independently selected from: H, -D, -CH3, -F, -CF3, -OH, -OCH3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NO2, -COO(C1-C6 alkyl), -COOH, -CN, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl);

[0059] More preferably, R 33 Selected from: H, -D, -F, -Br, -Cl, -I, -CH3, -CH2F, -CHF2, -CF3, -COOH, -CN, -COOCH3, -NH2, -NHCH3, -NO2, -OCH3, -OH, -TMS, -SO2CH3, -NHSO2CH3, -SO2NH2;

[0060] More preferably, R 34 、R 35 、R 37 Selected from: H, D or methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

[0061] In some embodiments of the present invention, for

[0062] Specifically, Part of Among them, R 24 Not present or selected from: CR 23 NR 27 ;

[0063] R 25 Selected from: CR 28 NR 29 ;

[0064] R 23 、R 26 、R 28 Independently selected from: H, -D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl)3, -N3, -B(OH)2, -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R'、-R L -NR'R", -R L -NR'C(O)R”、-R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R";

[0065] R 27 、R 29 Independently selected from: H, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 ; or, R 27 、R 29 Independently selected from: D.

[0066] Preferably, R 23 、R 26 、R 28independently selected from: H, -D, -CH3, -F, -CF3, -OH, -OCH3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NO2, -COO(C1-C6 alkyl), -COOH, -CN, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl); or, R 23 、R 26 、R 28 Independently selected from: -Br, -Cl, -I, C1-C6 haloalkyl.

[0067] Preferably, R 27 、R 29 Independently selected from: H, D or methyl, ethyl, propyl, isopropyl, butyl, tert-butyl;

[0068] More preferably, R 26 、R 28 Independently selected from: H, D, -F, -Br, -Cl, -I, -CH3, -CH2F, -CHF2, -CF3, -COOH, -CN, -COOCH3, -NH2, -NHCH3, -NO2, -OCH3, -OH, -TMS, -SO2CH3, -NHSO2CH3, -SO2NH2.

[0069] In some embodiments of the present invention, for

[0070] Specifically, Part of in,

[0071] T1, T2, T3, T4, T5, T6, T7 are independently selected from: O, C-R7, or N;

[0072] X' is N, O, or S;

[0073] represents a single bond or a double bond;

[0074] In some embodiments of the present invention, when there is a single bond between T4 and T5, T4 and T5 are together -CONR8-;

[0075] T6 and T7 are independently selected from: C-R7 or N;

[0076] In some embodiments of the present invention, when there is a single bond between T6 and T7, T6 and T7 together represent -CONR8-;

[0077] When T1-T7 is selected from C-R7, each R7 can be independently selected from: H, O, -D, -CH3, -X, -CF3, -OH, -OCH3, -OCH2X, -OCHX2, -OCX3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NO2, -COO(C1-C6 alkyl), -COOH, -CN, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl), -O(C1-C6 alkyl)NH(C1-C6 alkyl), Or, each R7 may be independently selected from: C1-C6 haloalkyl;

[0078] R8 is selected from: H, D, C1-C6 alkyl, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 ;

[0079] Preferably, R7 is selected from: H, -D, -F, -Br, -Cl, -I, -CH3, -CH2F, -CHF2, -CF3, -COOH, -CN, -COOCH3, -NH2, -NHCH3, -NO2, -OCH3, -OH, -TMS, -SO2CH3, -NHSO2CH3, -SO2NH2, a substituted or unsubstituted morpholine ring, particularly preferably an unsubstituted morpholine ring;

[0080] Preferably, R8 is selected from: H or methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

[0081] In some embodiments of the present invention, Selected from Among them, R7', R7", R7'', R 7α 、R 7β R7 has the same meaning as above, and R8' has the same meaning as above.

[0082] Specifically, Part of Wherein, S3 is selected from: O, S, NR91 , CR 92 R 93 ;

[0083] S1, S2, S4, S5, S6, S7 are independently selected from: N, CR 94 ;

[0084] R 92 、R 93 、R 94 Independently selected from: a linker, H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl), -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R'、-R L -NR'R", -R L -NR'C(O)R”、-R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R”、

[0085] R 91 Selected from: linker, H, -D, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 、

[0086] Preferably, S1, S2, S4, S5, and S6 are CR 94 ;

[0087] Preferably, R 92 、R 93 、R 94Independently selected from: a linker, H, D, -CH3, -F, -CF3, -OH, -OCH3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NO2, -COO(C1-C6 alkyl), -COOH, -CN, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl), or, R 92 、R 93 、R 94 Independently selected from: -Br, -Cl, -I, C1-C6 haloalkyl;

[0088] More preferably, R 94 Selected from H, -D, -F, -Br, -Cl, -I, -CH3, -CH2F, -CHF2, -CF3, -COOH, -CN, -COOCH3, -NH2, -NHCH3, -NO2, -OCH3, -OH, -TMS, -SO2CH3, -NHSO2CH3, -SO2NH2.

[0089] In some embodiments of the present invention, for

[0090] Specifically, Part of Wherein, Y1, Y2, Y3, Y4, Y5, Y6, and Y7 are independently selected from: N or CR 11 ;

[0091] R 11 Selected from: linker, H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl), -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L-SO-R', -R L -SO2-R'、-R L -NR'R", -R L -NR'C(O)R”、-R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R";

[0092] Preferably, R 11 independently selected from: a linker, H, -D, -CH3, -F, -CF3, -OH, -OCH3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NO2, -COO(C1-C6 alkyl), -COOH, -CN, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl); or, R 11 Independently selected from: -Br, -Cl, -I, C1-C6 haloalkyl.

[0093] Preferably, Y1, Y2, Y3, Y4, Y5, and Y6 are CR 11 .

[0094] More preferably, R 11 Selected from: H, D, -F, -Br, -Cl, -I, -CH3, -CH2F, -CHF2, -CF3, -COOH, -CN, -COOCH3, -NH2, -NHCH3, -NO2, -OCH3, -OH, -TMS, -SO2CH3, -NHSO2CH3, -SO2NH2.

[0095] In some embodiments of the present invention, for

[0096] In some embodiments of the present invention, Part of Preferably

[0097] In some embodiments of the present invention, Some selected from:

[0098] Specifically, R B Selected from: H, D, halogen, C1-C6 alkyl.

[0099] In some embodiments of the present invention, R B For H.

[0100] In some embodiments of the present invention, R B It is D.

[0101] In some embodiments of the present invention, R B is halogen, such as F, Cl, Br, I, especially F, Cl.

[0102] In some embodiments of the present invention, R B It is a C1-C3 alkyl group, such as -CH3.

[0103] Specifically, L1 is selected from: a single bond, -O-, -S-, -N(C0-C6 alkyl), -C(O)-, -C(S)-, -SO-, -SO2-, -Si-, -C(O)O-.

[0104] In some embodiments of the present invention, L1 is a single bond.

[0105] In some embodiments of the present invention, L1 is -C(O)-.

[0106] In some embodiments of the present invention, L1 is -SO2-.

[0107] In some embodiments of the present invention, L1 is -Si-.

[0108] Specifically, R C Selected from: C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), C1-C 10 Haloalkyl, -CO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 alkyl), wherein the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 3-10 membered heterocyclic group may be arbitrarily substituted by one or more of the following groups: D, C1-C10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group); or, the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl and 3-10 membered heterocyclic groups may be arbitrarily substituted by one or more of the following groups: halogen, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkoxy.

[0109] Preferably, R C Selected from: C1-C6 alkyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl (such as ), a substituted or unsubstituted 5-6 membered nitrogen-containing heterocyclic group, a substituted or unsubstituted 5-6 membered oxygen-containing heterocyclic group, a substituted or unsubstituted 5-6 membered sulfur-containing heterocyclic group (such as ); where R C1 is one or more substituents on the ring selected from: H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; In some embodiments of the present invention, R C1 is H or D; in some embodiments of the present invention, R C1 is C1-C3 alkyl, such as -CH3; in some embodiments of the present invention, R C1 It is a halogen, such as F, Cl, Br, and I.

[0110] In some embodiments of the present invention, R C Selected from: or, R C for

[0111] In some embodiments of the present invention, R C Selected from:

[0112] In some embodiments of the present invention, Selected from:

[0113] Specifically, W1 is C, W2 is C; or, W1 is C, W2 is N; or, W1 is C, W2 is O;

[0114] R1 and R2 are independently selected from: H, (=O), C1-C3 alkyl, -COOH, -CF3, hydroxyl;

[0115] Preferably, R1 and R2 are both H;

[0116] Preferably, R1 and R2 are both D.

[0117] In some embodiments of the present invention, for Preferably

[0118] In some embodiments of the present invention, the compound has the structure shown in Formula II:

[0119] In some embodiments of the present invention, the compound has the structure shown in Formula III:

[0120] In some embodiments of the present invention, the compound has the structure shown in Formula IV:

[0121] In some embodiments of the present invention, the compound has the structure shown in Formula V:

[0122] In some embodiments of the present invention, the compound has the structure shown in Formula VI:

[0123] Among them, R C' 、R C” With the above R C Definition of .

[0124] In some embodiments of the present invention, the compound has the structure shown in Formula VII:

[0125] in,

[0126] X1-X5 are independently selected from: C, N;

[0127] R Fis one or more independent substituents on the ring selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, heterocyclic group, wherein the phenyl and heterocyclic group are optionally substituted by one or more groups selected from the following: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl; or, two R F The carbon atoms to which it is attached form a carbocyclic ring or a heterocyclic ring, and the H on the carbocyclic ring or the heterocyclic ring is optionally substituted by one or more groups selected from the following: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0128] In some embodiments of the present invention, X1-X5 are all C.

[0129] In some embodiments of the present invention, X1 is N, and X2-X5 are all C.

[0130] In some embodiments of the present invention, X2 is N, and X1, X3-X5 are all C.

[0131] In some embodiments of the present invention, X3 is N, and X1, X2, X4, and X5 are all C.

[0132] In some embodiments of the present invention, X4 is N, and X1-X3 and X5 are all C.

[0133] In some embodiments of the present invention, X5 is N, and X1-X4 are all C.

[0134] In some embodiments of the present invention, X1 and X2 are both N, and X3-X5 are all C.

[0135] In some embodiments of the present invention, X1 and X3 are both N, and X2, X4, and X5 are all C.

[0136] In some embodiments of the present invention, X1 and X4 are both N, and X2, X3, and X5 are all C.

[0137] In some embodiments of the present invention, X1 and X5 are both N, and X2-X4 are all C.

[0138] In some embodiments of the present invention, X2 and X3 are both N, and X1, X4, and X5 are all C.

[0139] In some embodiments of the present invention, X2 and X4 are both N, and X1, X3, and X5 are all C.

[0140] In some embodiments of the present invention, X2 and X5 are both N, and X1, X3, and X4 are all C.

[0141] In some embodiments of the present invention, X3 and X4 are both N, and X1, X2, and X5 are all C.

[0142] In some embodiments of the present invention, X3 and X5 are both N, and X1, X2, and X4 are all C.

[0143] In some embodiments of the present invention, X4 and X5 are both N, and X1-X3 are all C.

[0144] Specifically, the carbocyclic or heterocyclic ring may be a 5-6 membered carbocyclic or heterocyclic ring, for example,

[0145] Preferably, the carbocyclic or heterocyclic ring is selected from:

[0146] In some embodiments of the present invention, the heterocycle is

[0147] In some embodiments of the present invention, the carbocyclic ring is

[0148] In some embodiments of the present invention, the carbocyclic ring is

[0149] In some specific embodiments of the present invention, the compound is selected from the following structures:

[0150] Or, the compound is selected from the following structures:

[0151] In some embodiments of the present invention, the compound is selected from the following structures:

[0152] The second aspect of the present invention provides a pharmaceutical composition comprising the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof, and one or more pharmaceutically acceptable excipients.

[0153] Specifically, in the pharmaceutical composition, the compound of the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate can be used alone or in combination with other types of active ingredients.

[0154] Specifically, the pharmaceutically acceptable excipients may be selected from one or more of fillers, binders, lubricants, disintegrants, antioxidants, buffers, antibacterial agents, suspending agents, solubilizers, thickeners, stabilizers, preservatives, and the like.

[0155] Specifically, the pharmaceutical composition can be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory tract administration, etc.).

[0156] In some embodiments of the present invention, the pharmaceutical composition is an oral preparation, including, but not limited to, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., instant-release preparations, sustained-release preparations, sustained-release microcapsules).

[0157] In some embodiments of the present invention, the pharmaceutical composition is an injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection).

[0158] In other embodiments of the present invention, the pharmaceutical composition is an intravenous drip, a transdermal absorption preparation, a lotion, a suppository (eg, a rectal suppository, a vaginal suppository), a nasal preparation, a pulmonary preparation (inhalation), an eye drop, and the like.

[0159] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be a capsule, tablet, or any other dosage form; in addition, the unit dosage form can also be a packaged preparation, such as tablets, capsules, and powders packaged in vials or ampoules.

[0160] Specifically, the amount of active ingredient in the unit dose formulation can be varied or adjusted from 0.1 mg to 1000 mg (e.g., 0.1, 1, 5, 10, 20, 40, 50, 100, 200, 400, 500, 1000 mg), depending on the specific application and efficacy of the active ingredient. If desired, the composition may further comprise other suitable therapeutic agents.

[0161] The third aspect of the present invention provides the use of the compound of the first aspect or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates as myosin inhibitors, such as in the preparation of anti-heart disease drugs.

[0162] Specifically, the heart disease is selected from: congenital heart disease, coronary atherosclerotic heart disease, rheumatic heart disease, hypertensive heart disease, pulmonary heart disease, infectious heart disease, endocrine heart disease, hematological heart disease, nutritional metabolic heart disease, cardiomyopathy, cardiac tumor, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary hypertension, mitral stenosis, aortic stenosis, aortic aneurysm, thoracic aortic dissection, diastolic heart failure, left ventricular outflow obstruction, ischemic heart disease, and angina pectoris.

[0163] In some embodiments of the invention, the heart disease is hypertrophic cardiomyopathy.

[0164] The fourth aspect of the present invention provides use of the compound of the first aspect or its pharmaceutically acceptable salts, stereoisomers, esters, prodrugs, solvates in the preparation of drugs for preventing and / or treating heart disease.

[0165] Specifically, the heart disease is selected from: congenital heart disease, coronary atherosclerotic heart disease, rheumatic heart disease, hypertensive heart disease, pulmonary heart disease, infectious heart disease, endocrine heart disease, hematological heart disease, nutritional metabolic heart disease, cardiomyopathy, cardiac tumor, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary hypertension, mitral stenosis, aortic stenosis, aortic aneurysm, thoracic aortic dissection, diastolic heart failure, left ventricular outflow obstruction, ischemic heart disease, and angina pectoris.

[0166] In some embodiments of the invention, the heart disease is hypertrophic cardiomyopathy.

[0167] The fifth aspect of the present invention provides a method for preventing and / or treating heart disease, which comprises the step of administering an effective amount of the compound described in the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or the pharmaceutical composition described in the second aspect.

[0168] In some embodiments of the invention, the method is performed in vivo.

[0169] The sixth aspect of the present invention provides a method for preventing and / or treating heart disease, which comprises the step of administering to a subject in need thereof an effective amount of the compound of the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or the pharmaceutical composition of the second aspect.

[0170] Specifically, the subject is an animal; in some embodiments of the present invention, the subject is a mammal, such as a human, a monkey, a cat, a dog, a mouse, a bat, etc.; in some embodiments of the present invention, the subject is a bird.

[0171] The present invention provides a novel myosin inhibitor with excellent inhibitory activity, which can be used to reduce and / or inhibit excessive sarcomere contraction, cardiomyocyte hypertrophy, disorder and increased myocardial fibrosis, prevent and / or treat heart disease, especially hypertrophic cardiomyopathy, and fill the gap in anti-heart disease drugs. It has very good application prospects and value in the medical field. BRIEF DESCRIPTION OF THE DRAWINGS

[0172] Figure 1 shows the IC of T003 and X1 inhibiting myosin ATPase activity 50 curve chart. DETAILED DESCRIPTION

[0173] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention relates.

[0174] In the present invention, the term "aliphatic group" refers to a straight or branched hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a cyclic hydrocarbon group that is completely saturated or contains one or more unsaturated units (also referred to herein as "aliphatic ring", "cycloalkyl"), which is connected to the rest of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl and the like. Typical aliphatic groups contain 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms.

[0175] The term "carbocycle" refers to a compound in which the ring is composed entirely of carbon atoms and can be divided into alicyclic compounds and aromatic compounds.

[0176] The term "alkyl" refers to a straight or branched hydrocarbon chain radical that does not contain unsaturated bonds and is connected to the rest of the molecule by a single bond. Typical alkyl groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, etc. If the alkyl group is substituted by a cycloalkyl group, it is a corresponding "cycloalkylalkyl" radical, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted by an aryl group, it is a corresponding "aralkyl" radical, such as benzyl, diphenylmethyl, or phenethyl. If the alkyl group is substituted by a heterocyclyl group, it is a corresponding "heterocyclylalkyl" radical. "Alkylene" generally refers to an alkanediyl group with two free valence bonds. Typical alkylene groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methylene, ethylene, propylene, butylene, etc. In the present invention, C0 alkyl refers to H, i.e., C 0-10 Alkyl (or C0-C 10 Alkyl) includes H and C 1-10 Alkyl (or C1-C 10 alkyl).

[0177] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by losing two hydrogen atoms from an alkane molecule, which can be a straight chain or branched chain and is connected to the rest of the molecule by a single bond. In this context, a typical alkylene group has 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, preferably 1 to 6 carbon atoms, such as methylene (-CH2-), ethylene, propylene, butylene, etc. In the present invention, a C0 alkylene group refers to a single bond, i.e., C 0-10 Alkylene (or C0-C 10 Alkylene) includes single bonds and C 1-10 Alkylene (or C1-C 10 alkylene).

[0178] The term "alkoxy" refers to a substituent formed when the hydrogen in a hydroxy group is replaced by an alkyl group. Typical alkoxy groups contain 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0179] The term "cycloalkyl" refers to a saturated or partially saturated (especially saturated) monocyclic or polycyclic group, which may contain 1 to 4 monocyclic and / or condensed rings, 3-18 carbon atoms, preferably 3-10 (e.g., 3, 4, 5, 6, 7, 8, 9, 10) carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl, etc.

[0180] The term "aryl" refers to a monocyclic or polycyclic radical, including a polycyclic radical containing a monocyclic aromatic group and / or a fused aromatic group, such as a radical containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. Typical aryl groups are those containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc. "Arylene" refers to a divalent radical derived from an aromatic hydrocarbon by removing two hydrogen atoms.

[0181] The term "heterocyclyl" includes heteroaromatic and heteroalicyclic groups containing 1 to 3 monocyclic and / or fused rings and 3 to about 18 ring atoms. Preferred heteroaromatic and heteroalicyclic groups contain 5 to about 10 ring atoms. Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms. Examples of heteroaryl groups include, but are not limited to, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazolyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazolyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridinyl, etc. Suitable heteroalicyclic groups in the compounds of the present invention contain 1, 2 or 3 heteroatoms selected from N, O or S atoms. Examples of heteroalicyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxirane, thiirane, azepinyl, oxazepanyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydro- ... 1-Hydroxy-1-pyridyl, 2-Hydroxy-1-pyridyl, 3-Hydroxy-1-pyridyl, 4-Hydroxy-1-pyridyl, 2-Hydroxy-1-pyridyl, 3 ...

[0182] The above groups may be substituted at one or more available positions by one or more suitable groups, such as OR', =O, SR', SOR', SO2R', OSO2R', OSO3R', NO2, NHR', N(R')2, =NR', N(R')COR', N(COR')2, N(R')SO2R', N(R')C(=NR')N(R')R', N3, CN, halogen, COR', COOR', OCOR', OCOOR', OCONHR', OCON(R')2, CONHR', CON(R')2, CON(R')OR', CON(R')SO2R', PO(OR')2, PO(OR')R', PO(OR')(N(R')R'), C1-C 12 Alkyl, C3-C 10 Cycloalkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, aryl and heterocyclic groups, wherein each R' group is independently selected from hydrogen, OH, NO2, NH2, SH, CN, halogen, COH, CO alkyl, COOH, C1-C 12 Alkyl, C3-C 10 Cycloalkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, aryl and heterocyclyl. Where these groups themselves are substituted, the substituents may be selected from the aforementioned list.

[0183] The term "halogen" refers to bromine, chlorine, iodine or fluorine. In the present invention, "-X" and "halogen" are used interchangeably.

[0184] The term "haloalkyl" refers to a group formed by replacing one or more hydrogen atoms on an alkyl group with a halogen atom (F, Cl, Br, I), such as -CH2Rh, -CHRh2, -CRh3, where Rh is F, Cl, Br or I, such as -CHF2, -CH2F, -CF3. Another example is -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0185] The term "pharmaceutically acceptable salt" refers to an acidic or basic salt that is theoretically non-toxic, non-irritating, and non-allergenic, and that can achieve or provide clinically acceptable pharmacokinetic properties, absorption, distribution, and metabolic properties of the drug molecule, thereby achieving the intended purpose. The salts described herein include pharmaceutically acceptable acidic or basic salts of the acidic, basic, or amphiphilic groups of the compound. A list of suitable salts can be found in SM Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0186] The pharmaceutically acceptable salts of the present invention include acid addition salts and base addition salts.

[0187] Such acid addition salts include, but are not limited to, salts from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic and phosphonic acids, and salts from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids and aliphatic and aromatic sulfonic acids. The present invention relates to the preparation of the present invention and the like.Therefore, these salts include but are not limited to sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate and mesylate, also comprise amino acid whose salt such as arginate, gluconate, galacturonate etc.Acid addition salts can be prepared by making free alkali form contact with sufficient amount of required acid in a conventional manner.Free alkali form can be regenerated by making salt form contact with alkali, and separate this free alkali in a conventional manner.

[0188] Base addition salts of the present invention refer to salts formed with metals or amines, such as hydroxides of alkali metals and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with a sufficient amount of the desired base in a conventional manner to form the salt. The free acid form can be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner.

[0189] The term "solvate" is understood to mean any form of a compound of the invention in which the compound is linked to another molecule (usually a polar solvent) by a non-covalent bond, and particularly includes hydrates and alcoholates, such as methanolates. Preferred solvates are hydrates.

[0190] The term "prodrug" is used in its broad sense and encompasses derivatives that can be converted into compounds of the invention in vivo. Examples of prodrugs include, but are not limited to, derivatives and metabolites of compounds, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Preferably, the prodrug with a carboxyl functional group is a lower alkyl ester of a carboxylic acid. The carboxylic acid ester is readily obtained by esterification of any carboxylic acid moiety present in the molecule. Prodrugs can generally be prepared by known methods, such as those described in Burger "Medicinal Chemistry and Drug Discovery, 6th Edition" (Donald J. Abraham ed., 2001, Wiley) and "Design and Applications of Prodrugs" (H. Bundgaard ed., 1985, Harwood Academic Publishers).

[0191] The term "absent" indicates that the linking group is a bond.

[0192] Any compound involved herein is intended to represent such a specific compound and some deformation or some form thereof. In particular, the compound involved herein may have an asymmetric center, and therefore there are different enantiomers or diastereomeric forms. Thus, any given compound involved herein represents any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Similarly, there may also be stereoisomers or geometric isomers of double bonds, whereby in some cases, molecules may exist as (E)-isomers or (Z)-isomers (trans and cis isomers). If a molecule comprises multiple double bonds, each double bond will have its own stereoisomerism, which may be the same or different from the stereoisomerism of other double bonds of the molecule. In addition, the compound involved herein may have atropisomers. All stereoisomers of the compound involved herein, including enantiomers, diastereoisomers, geometric isomers and atropisomers, and mixtures thereof, are within the scope of the present invention.

[0193] The disclosures of various publications, patents, and published patent specifications cited herein are incorporated by reference in their entirety.

[0194] The following will clearly and completely describe the technical solutions of the present invention in conjunction with the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts shall fall within the scope of protection of the present invention.

[0195] Example 1: Synthesis of Compound T001

[0196] 1. Synthesis of compound 1a

[0197] Isopropyl urea (1.0 eq) was dissolved in methanol, and dimethyl malonate (1.1 eq) and sodium methoxide (2.0 eq) were added. The reaction was stirred at 60°C overnight under nitrogen. After completion of the reaction, which was monitored by LC-MS, the reaction solution was cooled to room temperature and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was concentrated under reduced pressure and dissolved in anhydrous ethanol and stirred at room temperature for 2 hours. The solution was filtered and the filtrate was concentrated. After purification by silica gel column chromatography, the filtrate was concentrated and dried to obtain compound 1a.

[0198] 2. Synthesis of compound 1b

[0199] Compound 1a (1.0 eq) and triethylbenzyl ammonium chloride (1.5 eq) were dissolved in POCl3 and stirred at 40°C under nitrogen for 6 hours. After the reaction was completed, as monitored by LC-MS, the reaction system was cooled to room temperature and the POCl3 was removed by distillation under reduced pressure. The residue was dissolved in DCM and washed three times with saturated ammonium chloride solution. The retained organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain a yellow solid, namely, compound 1b.

[0200] 3. Synthesis of compound T001

[0201] Compound 1b (1.0 eq.) and 1-phenylcyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T001.

[0202] Example 2: Synthesis of Compound T002

[0203] Compound 1b (1.0 eq.) and 1-(3-fluorophenyl)cyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T002.

[0204] Example 3: Synthesis of Compound T003

[0205] Compound 1b (1.0 eq.) and 1-(3-bromophenyl)cyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T003.

[0206] Example 4: Synthesis of Compound T004

[0207] 1. Synthesis of compound 4a

[0208] Propylurea (1.0 eq) was dissolved in methanol, and dimethyl malonate (1.1 eq) and sodium methoxide (3.1 eq) were added. The reaction was stirred at 60°C overnight under nitrogen. After completion of the reaction, which was monitored by LC-MS, the reaction solution was cooled to room temperature and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was concentrated under reduced pressure and dissolved in anhydrous ethanol and stirred at room temperature for 2 hours. The solution was filtered and the filtrate was concentrated. After purification by silica gel column chromatography, the solution was concentrated and dried to obtain compound 4a.

[0209] 2. Synthesis of compound 4b

[0210] Compound 4a (1.0 eq) and triethylbenzylammonium chloride (1.5 eq) were dissolved in POCl3, and the mixture was stirred at 40°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature and POCl3 was removed by distillation under reduced pressure. The residue was dissolved in DCM and washed three times with saturated ammonium chloride solution. The organic phase was retained, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain a yellow solid, namely compound 4b.

[0211] 3. Synthesis of compound 4

[0212] Compound 4b (1.0 eq.) and 1-phenylcyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T004.

[0213] Example 5: Synthesis of Compound T005

[0214] 1. Synthesis of compound 5a

[0215] To a stirred solution of 1,1,1-trifluoropropane-2-amine (1.0 eq) in DCM (15 mg) was added trimethylsilyl isocyanate (2.2 eq) dropwise at 0°C. The reaction mixture was stirred at the same temperature for 30 minutes and then slowly heated to room temperature overnight. The resulting solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude residue was recrystallized from MeOH:Et2O (1:20) to give compound 5a.

[0216] 2. Synthesis of compound 5b

[0217] Compound 5a (1.0 eq) was dissolved in methanol, and dimethyl malonate (1.1 eq) and sodium methoxide (3.1 eq) were added. The reaction was stirred at 60°C overnight under nitrogen. After completion of the reaction, which was monitored by LC-MS, the reaction solution was cooled to room temperature and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was concentrated under reduced pressure, and the resulting mixture was dissolved in anhydrous ethanol and stirred at room temperature for 2 hours. The solution was filtered, the filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain compound 5b.

[0218] 3. Synthesis of compound 5c

[0219] Compound 5b (1.0 eq) and triethylbenzylammonium chloride (1.5 eq) were dissolved in POCl3 and stirred at 40°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature and POCl3 was removed by distillation under reduced pressure. The residue was dissolved in DCM and washed three times with saturated ammonium chloride solution. The organic phase was retained, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain a yellow solid, namely compound 5c.

[0220] 4. Synthesis of compound T005

[0221] Compound 5c (1.0 eq) and 1-phenylcyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T005.

[0222] Example 6: Synthesis of Compound T006

[0223] 1. Synthesis of compound 6a

[0224] Dissolve 1-cyclopropylurea in methanol, add dimethyl malonate (1.1 eq) and sodium methoxide (3.1 eq), and stir at 60°C under nitrogen overnight. After completion of the reaction, monitored by LC-MS, cool the reaction solution to room temperature and adjust the pH to 2-3 with dilute hydrochloric acid. Concentrate under reduced pressure, and the resulting mixture is dissolved in anhydrous ethanol and stirred at room temperature for 2 hours. Filter the solution, concentrate the filtrate, purify it by silica gel column chromatography, concentrate, and dry it to obtain compound 6a.

[0225] 2. Synthesis of compound 6b

[0226] Compound 6a (1.0 eq) and triethylbenzyl ammonium chloride (1.5 eq) were dissolved in POCl3 and stirred at 40°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature and POCl3 was removed by distillation under reduced pressure. The residue was dissolved in DCM and washed three times with saturated ammonium chloride solution. The organic phase was retained, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain a yellow solid, namely compound 6b.

[0227] 3. Synthesis of compound T006

[0228] Compound 6b (1.0 eq.) and 1-phenylcyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T006.

[0229] Example 7: Synthesis of Compound T007

[0230] 1. Synthesis of compound 7a

[0231] To a stirred solution of 4,4-difluorocyclohexylamine (1.0 eq) in DCM (15 mg) was added trimethylsilyl isocyanate (2.2 eq) dropwise at 0°C. The reaction mixture was stirred at the same temperature for 30 minutes and then slowly heated to room temperature overnight. The resulting solution was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The crude residue was recrystallized from MeOH:Et2O (1:20) to give compound 7a.

[0232] 2. Synthesis of compound 7b

[0233] Compound 7a (1.0 eq) was dissolved in methanol, and dimethyl malonate (1.1 eq) and sodium methoxide (3.1 eq) were added. The reaction was stirred at 60°C overnight under nitrogen. After completion of the reaction, which was monitored by LC-MS, the reaction solution was cooled to room temperature and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was concentrated under reduced pressure, and the resulting mixture was dissolved in anhydrous ethanol and stirred at room temperature for 2 hours. The solution was filtered, the filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain compound 7b.

[0234] 3. Synthesis of compound 7c

[0235] Compound 7b (1.0 eq) and triethylbenzylammonium chloride (1.5 eq) were dissolved in POCl3, and the mixture was stirred at 40°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature and POCl3 was removed by distillation under reduced pressure. The residue was dissolved in DCM and washed three times with saturated ammonium chloride solution. The organic phase was retained, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain a yellow solid, namely compound 7c.

[0236] 4. Synthesis of compound T007

[0237] Compound 7c (1.0 eq) and 1-phenylcyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T007.

[0238] Example 8: Synthesis of Compound T008

[0239] 1. Synthesis of compound 8a

[0240] Phenylurea (1.0 eq) was dissolved in methanol, and dimethyl malonate (1.1 eq) and sodium methoxide (3.1 eq) were added. The reaction was stirred at 60°C overnight under nitrogen. After completion of the reaction, which was monitored by LC-MS, the reaction solution was cooled to room temperature and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was concentrated under reduced pressure, and the resulting mixture was dissolved in anhydrous ethanol and stirred at room temperature for 2 hours. The solution was filtered, the filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain compound 8a.

[0241] 2. Synthesis of compound 8b

[0242] Compound 8a (1.0 eq) and triethylbenzylammonium chloride (1.5 eq) were dissolved in POCl3 and stirred at 40°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature and POCl3 was removed by distillation under reduced pressure. The residue was dissolved in DCM and washed three times with saturated ammonium chloride solution. The organic phase was retained, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain compound 8b.

[0243] 3. Synthesis of compound T008

[0244] Compound 8b (1.0 eq.) and 1-phenylcyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, as monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T008.

[0245] Example 9: Synthesis of Compound T009

[0246] 1. Synthesis of compound 9a

[0247] 2-Aminopyridine (1.0 eq) and KNCO (1.2 eq) were stirred and refluxed in H2O overnight. After the reaction was completed, the mixture was cooled to room temperature, and a NaCl-saturated aqueous phase was added. The precipitate was separated by filtration to obtain compound 9a.

[0248] 2. Synthesis of compound 9b

[0249] Compound 9a was dissolved in methanol, and dimethyl malonate (1.1 eq) and sodium methoxide (3.1 eq) were added. The reaction was stirred at 60°C overnight under nitrogen. After completion of the reaction, which was monitored by LC-MS, the reaction solution was cooled to room temperature and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was concentrated under reduced pressure, and the resulting mixture was dissolved in anhydrous ethanol and stirred at room temperature for 2 hours. The solution was filtered, the filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain compound 9b.

[0250] 3. Synthesis of compound 9c

[0251] Compound 9b (1.0 eq) and triethylbenzylammonium chloride (1.5 eq) were dissolved in POCl3, and the mixture was stirred at 40°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature and POCl3 was removed by distillation under reduced pressure. The residue was dissolved in DCM and washed three times with saturated ammonium chloride solution. The organic phase was retained, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain a yellow solid, namely compound 9c.

[0252] 4. Synthesis of compound T009

[0253] Compound 9c (1.0 eq) and 1-phenylcyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T009.

[0254] Example 10: Synthesis of Compound T010

[0255] 1. Synthesis of compound 10a

[0256] 3,5-Difluoroaniline (1.0 eq) and KNCO (1.2 eq) were stirred and refluxed in H2O overnight. After the reaction was completed, the mixture was cooled to room temperature, and a NaCl-saturated aqueous phase was added. The precipitate was separated by filtration to obtain compound 10a.

[0257] 2. Synthesis of compound 10b

[0258] Compound 10a was dissolved in methanol, and dimethyl malonate (1.1 eq) and sodium methoxide (3.1 eq) were added. The reaction was stirred at 60°C overnight under nitrogen. After completion of the reaction, which was monitored by LC-MS, the reaction solution was cooled to room temperature and the pH was adjusted to 2-3 with dilute hydrochloric acid. The mixture was concentrated under reduced pressure, and the resulting mixture was dissolved in anhydrous ethanol and stirred at room temperature for 2 hours. The solution was filtered, the filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain compound 10b.

[0259] 3. Synthesis of compound 10c

[0260] Compound 10b (1.0 eq) and triethylbenzylammonium chloride (1.5 eq) were dissolved in POCl3, and the reaction was stirred at 40°C for 6 hours under nitrogen protection. After the reaction was completed, the reaction system was cooled to room temperature and POCl3 was distilled off under reduced pressure. The residue was dissolved in DCM and washed three times with saturated ammonium chloride solution. The organic phase was retained, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, purified by silica gel column chromatography, concentrated, and dried to obtain a white solid, namely compound 10c.

[0261] 4. Synthesis of compound T010

[0262] Compound 10c (1.0 eq) and 1-phenylcyclopropylamine (5 e.q.) were heated and stirred at 120°C overnight under nitrogen. After completion of the reaction, monitored by LC-MS, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T010.

[0263] Table 1 Compound number, structural formula, molecular weight and 1 H NHR Information

[0264] Example 11: Inhibitory activity of compounds on myosin ATPase activity

[0265] A biochemical assay combining the release of ADP (adenosine diphosphate) from myosin with an enzyme-coupled system consisting of pyruvate kinase and lactate dehydrogenase (PK / LDH) was used to evaluate the ability of small molecules to inhibit the ATPase activity of rabbit skeletal muscle myosin by dynamically monitoring changes in NADH absorbance as a function of time. The specific enzyme-coupled reaction involves PK converting ADP to ATP (adenosine triphosphate) by converting PEP (phosphoenolpyruvate) to pyruvate, followed by LDH converting pyruvate to lactate by converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide). Myosin was obtained from rabbit skeletal muscle (S35330, Yuanye Biotechnology). All enzyme activities were measured in a buffer solution of 10 mM MOPOS (3-(N-morpholino)propanesulfonic acid), pH 7.0, 2 mM MgCl2, 0.15 mM EGTA, 0.1 mg / mL BSA (bovine serum albumin), and 1 mM DTT. The final assay conditions were 30 nM myosin, 200 U / mL PK, 40 U / mL LDH, 1 mM ATP, 0.25 mM NADH, and 1 mM PEP.

[0266] Compounds were serially diluted in DMSO to achieve the desired final concentration of compound in a volume of 50 mL at a fixed concentration of 2% (v / v) DMSO. 37 mL of myosin and 1 mL of the serial compound dilutions were added to a clear 384-well plate and incubated for 15 min. The enzymatic reaction was initiated by adding 12 mL of a solution containing ATP, PEP, NADH, and PK / LDH. The progress of the reaction was monitored at ambient temperature using a Molecular Devices ID5 plate reader. The plate reader was set to read absorbance at 340 nm in kinetic mode for 30 minutes with 3 min intervals. The data were recorded as the slope of the absorbance response versus time. The slope was normalized to the slope of the DMSO control group, and the normalized ratio was plotted as a function of the small molecule drug concentration and the data were fitted to a four-parameter fit using GraphPad Prism. The midpoint of the curve was the IC 50 and is the concentration that inhibits 50% of the total response. Any drug that fails to achieve 50% inhibition at a single concentration test is reported as the IC 50 Greater than the highest concentration tested (i.e., IC 50 >100 μM), and the highest concentration of the remaining compounds was set at 200 mM.

[0267] Among them, compound X1 in Table 2 is a reference compound, and its structural formula is It was synthesized with reference to Example 1 of patent document WO2014205223A1.

[0268] Table 2 Biochemical and cellular activities of compounds

[0269] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

[0270] The aforementioned embodiments and methods described in the present invention may be varied based on the ability, experience, and preference of those skilled in the art.

[0271] In the present invention, merely listing the steps of the method in a certain order does not constitute any limitation on the order of the method steps.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, or solvate thereof, wherein the compound has a structure shown in Formula I: in, A is a substituted or unsubstituted carbocyclic or heterocyclic ring; R B Selected from: H, D, halogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, -O(C 0-10 alkyl); L1 is selected from: a single bond, C1-C6 alkylene, -O-, -S-, -N(C0-C6 alkyl), -C(O)-, -C(S)-, -C(O)-(C0-C6 alkylene)-, -C(S)-(C0-C6 alkylene)-, -C(O)-N(C0-C6 alkyl)-, -C(S)-N(C0-C6 alkyl)-, -SO-, -SO2-, -Si-, -C(O)O-; R C Selected from: H, D, halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0- 10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 alkyl), wherein the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 3-10 membered heterocyclic group may be arbitrarily substituted by one or more of the following groups: D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group); or, the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 3-10 membered heterocyclic group may be arbitrarily substituted by one or more of the following groups: halogen, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy; W1 is selected from: ONLY, W2 is selected from: C, N, O. When W2 is N, R1' does not exist. When W2 is O, R1 and R1' do not exist. R1, R1', R2, R2' are independently selected from: H, D, (=O), C1-C 10 Alkyl, C1-C 10 Haloalkyl, -OH, -NH2, -COOH, -OC1-C 10 alkyl; R2" is selected from: H, D, C1-C 10 Alkyl, -OH, -(C1-C6 alkylene)-COOR 21 、-(C1-C6 alkylene)-OR 21 、-(C1-C6 alkylene)-CONR 21 R 22 ; R 21 is H or C1-C6 alkyl; R 22 It is H or C1-C6 alkyl.

2. The compound according to claim 1, characterized in that A is selected from: Among them, R A is one or more independent substituents on the benzene ring selected from: H, D, halogen, cyano, nitro, azido, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Haloalkoxy, -N(C 0-10 Alkyl)(C 0-10 Alkyl), -N(C 0-10 alkyl)CO(C 0-10 Alkyl), -N(C 0-10 alkyl)CON(C 0-10 Alkyl), -N(C 0-10 Alkyl)SO2(C 0-10 Alkyl), -O(C 0-10 Alkyl), -CO(C 0-10 Alkyl), -COO(C 0-10 Alkyl), -OCO(C 0-10 Alkyl), -CON(C 0-10 Alkyl)(C 0-10 Alkyl), -S(C 0-10 Alkyl), -SO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -SO2N(C 0-10 Alkyl)(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 alkyl), wherein the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 3-10 membered heterocyclic group may be arbitrarily substituted by one or more of the following groups: D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclyl); R A1 is one or more independent substituents on a 5-6 membered nitrogen-containing heteroaryl group selected from the group consisting of H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R 72 , R 73 independently selected from: H, -D, -CH3, -X, -CF3, -OH, -OCH3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -N3, -B(OH)2, -NO2, -COO(C1-C6 alkyl), -COOH, -CN, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl); or, R 72 , R 73 Independently selected from: C1-C6 haloalkyl; R 41 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 represents a ring substituent independently selected from the group consisting of: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl), -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R', -R L -NR'R", -R L -NR'C(O)R", -R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R"; R L Selected from: a single bond, C1-C6 alkylene, C3-C6 heteroalkylene, C3-C6 cycloalkylene, C3-C6 heterocyclylene, -NR4C(O)-, -NR4SO-, -NR4SO2-, -C(O)-, -C(O)O-, -NR4-, -C(O)NR4-, -SO2NR4-, -SO2NR4-; R4 is selected from the group consisting of: H, D, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, hydroxyl, alkoxy; R' and R" are independently selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen; W3 is selected from N or CH; R6 is selected from: H, D, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 ; R 61 , R 62 Independently selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl), -N3, -B(OH)2, -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R', -R L -NR'R", -R L -NR'C(O)R", -R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R"; R 31 N or CR 36 ; R 32 NR 37 or -N=CR 38 -; R 35 or R 37 Independently selected from: H, -D, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 ; R 33 , R 34 , R 36 , R 38 Independently selected from: H, -D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl)3, -N3, -B(OH)2, -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R', -R L -NR'R", -R L -NR'C(O)R", -R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R"; R 24 Not present or selected from: CR 23 NR 27 ; R 25 Selected from: CR 28 NR 29 ; R 23 , R 26 , R 28 Independently selected from: H, -D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl)3, -N3, -B(OH)2, -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R', -R L -NR'R", -R L -NR'C(O)R", -R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R"; R 27 , R 29 Independently selected from: H, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 or, R 27 , R 29 Independently selected from: D; T1, T2, T3, T4, T5, T6, T7 are independently selected from: O, C-R7, or N; X' is N, O, S; When T1-T7 is selected from C-R7, each R7 can be independently selected from: H, O, -D, -CH3, -X, -CF3, -OH, -OCH3, -OCH2X, -OCHX2, -OCX3, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkyl), -NO2, -COO(C1-C6 alkyl), -COOH, -CN, -Si(CH3)3, -NHSO2(C1-C6 alkyl), -SO2NH2, -SO2(C1-C6 alkyl), -N(C1-C6 alkyl)SO2(C1-C6 alkyl), -SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)(C1-C6 alkyl), -O(C1-C6 alkyl)NH(C1-C6 alkyl), Or, each R7 may be independently selected from: C1-C6 haloalkyl; R8 is selected from: H, D, C1-C6 alkyl, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 ; S3 is selected from: O, S, NR 91 , CR 92 R 93 ; S1, S2, S4, S5, S6, S7 are independently selected from: N, CR 94 ; R 92 , R 93 , R 94 independently selected from: a linker, H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl), -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R', -R L -NR'R", -R L -NR'C(O)R", -R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R" R 91 Selected from: linker, H, -D, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 , Y1, Y2, Y3, Y4, Y5, Y6, Y7 are independently selected from: N or CR 11 ; R 11 Selected from: linker, H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, halogen, -Si(C1-C6 alkyl), -NO2-R L -COR', -R L -C(O)OR'、-R L -C(O)NR'R", -R L -CH=NR'、-R L -CN, -R L -OR', -R L -OC(O)R'、-R L -SO-NR'R", -R L -SO2-NR'R", -R L -SO-R', -R L -SO2-R', -R L -NR'R", -R L -NR'C(O)R", -R L -NR'SOR", -R L -NR'SO2R", -NR'-R L -NR'R", -R L -NO2, -R L -N=CR'R"; Preferably, Part of Among them, R A' With the above R A Definition of; Preferably, Part of Preferably, Part of Preferably, Part of Preferably, Part of More preferably, Some selected from:

3. The compound according to claim 1, characterized in that R B Selected from: H, D, halogen, C1-C6 alkyl.

4. The compound according to claim 1, characterized in that L1 is selected from: a single bond, -O-, -S-, -N(C0-C6 alkyl), -C(O)-, -C(S)-, -SO-, -SO2-, -Si-, -C(O)O-.

5. The compound according to claim 1, characterized in that R C Selected from: C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group), C1-C 10 Haloalkyl, -CO(C 0-10 Alkyl), -SO2(C 0-10 Alkyl), -Si(C 0-10 Alkyl)(C 0-10 Alkyl)(C 0-10 alkyl), wherein the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 3-10 membered heterocyclic group may be arbitrarily substituted by one or more of the following groups: D, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group); or, the C0-C6 alkylene, C0-C 10 Alkyl, C3-C 10 Cycloalkyl, C6-C 10 The H in the aryl group and the 3-10 membered heterocyclic group may be arbitrarily substituted by one or more of the following groups: halogen, C1-C 10 Halogenated alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy; Preferably, R C Selected from: C1-C6 alkyl, C1-C6 haloalkyl, Among them, R C1 is one or more substituents on the ring selected from: H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; More preferably, R C Selected from: or, R C for More preferably, R C Selected from: Preferably, Selected from:

6. The compound according to claim 1, characterized in that W1 is C, W2 is C; or, W1 is C, W2 is N; or, W1 is C, W2 is O.

7. The compound according to claim 1, characterized in that R1 and R2 are independently selected from: H, (=O), C1-C3 alkyl, -COOH, -CF3, hydroxyl; preferably, R1 and R2 are both H, or, R1 and R2 are both D.

8. The compound according to claim 1, characterized in that for Preferably 9. The compound according to any one of claims 1 to 8, characterized in that The compound has a structure shown in Formula II:

10. The compound according to claim 9, characterized in that The compound has the following structure: Among them, R C' , R C” With the above R C Definition of; Preferably, the compound has a structure shown in Formula VII: in, X1-X5 are independently selected from: C, N; R F is one or more independent substituents on the ring selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, phenyl, heterocyclic group, wherein the phenyl, heterocyclic group is optionally substituted by one or more groups selected from the following: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl; or, two R F Together with the carbon atom to which it is attached, it forms a carbocyclic ring or a heterocyclic ring, wherein H on the carbocyclic ring or the heterocyclic ring is optionally substituted by one or more groups selected from the following: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; Preferably, the carbocyclic or heterocyclic ring is selected from:

11. The compound according to claim 1, characterized in that The compound is selected from the following structures: Or, the compound is selected from the following structures: Preferably, the compound is selected from the following structures:

12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof, and one or more pharmaceutically acceptable excipients.

13. Use of the compound according to any one of claims 1 to 11 or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for preventing and / or treating heart disease.

14. The use according to claim 13, characterized in that The heart disease is selected from the group consisting of congenital heart disease, coronary atherosclerotic heart disease, rheumatic heart disease, hypertensive heart disease, cor pulmonale, infectious heart disease, endocrine heart disease, hematologic heart disease, nutritional metabolic heart disease, cardiomyopathy, cardiac tumor, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, pulmonary hypertension, mitral stenosis, aortic stenosis, aortic aneurysm, thoracic aortic dissection, diastolic heart failure, left ventricular outflow obstruction, ischemic heart disease, and angina pectoris; Preferably, the heart disease is hypertrophic cardiomyopathy.

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