Myosin inhibitor and application thereof

Abstract

The invention discloses a myosin inhibitor and application thereof. The myosin inhibitor has a structure as shown in a formula I, has relatively good inhibitory activity, can be used for reducing and / or inhibiting excessive contraction of sarcoids, hypertrophy and disorder of cardiac muscle cells and increase of the degree of myocardial fibrosis, can be used for preventing and / or treating heart diseases, especially hypertrophic cardiomyopathy, can fill up the vacancy of anti-heart-disease drugs, and can be used for preparing drugs for treating heart diseases. Good application prospects and values are realized in the field of medicines. # imgabs0 #

Description

Technical Field

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

[0002] Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease, mainly characterized by unexplained symmetric or asymmetric hypertrophy of the ventricles. The histopathological changes have certain specificity, featuring myocardial cell hypertrophy, disarray, and fibrosis. HCM is usually defined as unexplained left ventricular hypertrophy (LVH), excluding the influence of other cardiac or systemic diseases. Mutations in genes encoding sarcomere proteins are the main cause of HCM, namely sarcomeric HCM. Currently, many mutant genes are known to cause HCM, among which mutations in β-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), troponin T (TNNT2), and actin (ACTC1) genes are the most prominent.

[0003] Currently, the drug treatment of HCM is mainly non-specific, using β-blockers and non-dihydropyridine calcium channel blockers (CCBs) to relieve the symptoms of patients. However, these treatments have not significantly improved the disease progression and prognosis of HCM. There is an urgent clinical need for a specific targeted drug against 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 participates in regulating the activity of myosin. Myosin is the main driving protein for muscle contraction. In muscle cells, myosin interacts with actin to form the basic structural unit of muscle fibers - the sarcomere. Mutations in myosin are considered to be the cause of HCM due to sarcomere hyperdynamic contraction and impaired relaxation. Therefore, inhibitors targeting myosin may become a new method for treating HCM. Myosin inhibitors can improve the disease by inhibiting excessive sarcomere contraction and can relieve and reverse the characteristics of HCM such as myocardial cell hypertrophy, disarray, and increased myocardial fibrosis. Therefore, there is a need to further develop novel drugs that are more effective against myosin. Summary of the Invention

[0005] In the first aspect of the present invention, there is provided a compound or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof, and the compound has the structure shown in Formula I:

[0006]

[0007] Wherein,

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

[0009] R B is selected from: H, D, halogen, C1-C 10 alkyl, C1-C 10 haloalkyl, -O(C 0-10 alkyl);

[0010] L1 is selected from: 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 is selected from: H, D, halogen, cyano, nitro, azide, 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, 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)(C0-10 (alkyl)(C 0-10 alkyl), wherein the C0-C6 alkylene, C0-C 10 alkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, and the H in the 3-10 membered heterocyclic group may optionally be 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 aryl, and the H in the 3-10 membered heterocyclic group may optionally be substituted by one or more of the following groups: halogen, C1-C 10 haloalkyl, C1-C 10 alkoxy, C1-C 10 haloalkoxy;

[0012] W1 is selected from: S, O,

[0013] 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;

[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, Part is selected from: A substituted or unsubstituted 5- or 6-membered nitrogen-containing heterocyclic group, A substituted or unsubstituted naphthyl group,

[0019]

[0020] Specifically, Partially is Wherein, R A Is one or more independent substituents on the benzene ring, and is selected from: H, D, halogen, cyano, nitro, azide, C1-C 10 Alkyl, -(C0-C6 alkylene)-(C3-C 10 Cycloalkyl), -(C0-C6 alkylene)-(C6-C 10 Aryl), -(C0-C6 alkylene)-(3- to 10-membered heterocyclic group), C1-C 10 Halogenated alkyl, C1-C 10 Halogenated alkoxy, -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 Aryl, 3- to 10-membered heterocyclic group in which H can 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-C10 (aryl), -(C0-C6 alkylene)-(3-10 membered heterocyclic group).

[0021] In some embodiments of the present invention, R A is H or D;

[0022] In some embodiments of the present invention, R A is a halogen, such as F, Cl, Br, I;

[0023] In some embodiments of the present invention, R A is a C1-C3 alkyl group, such as -CH3;

[0024] In some embodiments of the present invention, R A is a C1-C3 haloalkyl group, such as CF3;

[0025] In some embodiments of the present invention, R A is a C1-C3 alkoxy group, such as -OCH3;

[0026] In some embodiments of the present invention, R A is wherein, R A' has the above definition of R A such as

[0027] In some embodiments of the present invention, R A is wherein, R A' has the above definition of R A such as

[0028] In some embodiments of the present invention, is selected from: wherein, R A' has the above definition of R A such as

[0029] In some embodiments of the present invention, is selected from:

[0030] Specifically, part is a substituted or unsubstituted 5-6 membered nitrogen-containing heterocyclic group, for example,

[0031] wherein, R A1is one or more independent substituents on a 5- or 6-membered nitrogen-containing heteroaryl group, and is selected from: H, D, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0032] In some embodiments of the present invention, R A1 is H or D;

[0033] In some embodiments of the present invention, R A1 is a halogen, such as F, Cl, Br, I;

[0034] In some embodiments of the present invention, R A1 is a C1-C3 alkyl group, such as -CH3.

[0035] In some embodiments of the present invention, the substituted or unsubstituted 5- or 6-membered nitrogen-containing heterocyclic group is selected from:

[0036] Specifically, is part of wherein, R 72 , R 73 are 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 are independently selected from: C1-C6 haloalkyl.

[0037] Preferably, R 72 , R 73 are 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;

[0038] In some embodiments of the present invention, R 72 , R 73 are H.

[0039] In some embodiments of the present invention, is preferably

[0040] Specifically, part is For example,

[0041] In some embodiments of the present invention, is preferably

[0042] Specifically, the part is a substituted or unsubstituted naphthyl group, for example, wherein, R 41 、R 42 、R 43 、R 44 、R 45 、R 46 、R 47 represent substituents on the ring, which are independently selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclic group, heterocyclic alkyl, 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”;

[0043] R LSelected from: single bond, C1-C6 alkylene, C3-C6 heteroalkylene, C3-C6 cycloalkylene, C3-C6 heterocycloalkylene, -NR4C(O)-, -NR4SO-, -NR4SO2-, -C(O)-, -C(O)O-, -NR4-, -C(O)NR4-, -SO2NR4-, -SO2NR4-;

[0044] R4 is selected from: H, D, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic group, heterocyclic group alkyl, hydroxyl, alkoxy;

[0045] R' and R” are independently selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic group, heterocyclic group alkyl, halogen;

[0046] Preferably, R 41 、R 42 、R 43 、R 44 、R 45 、R 46 、R 47 are 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);

[0047] More preferably, R 42 、R 43 、R 45 、R 46 are 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.

[0048] In some embodiments of the present invention, the substituted or unsubstituted naphthyl group is selected from:

[0049] Specifically, Part is Wherein, W3 is selected from N or CH;

[0050] 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 ;

[0051] R 61 、R 62 are independently selected from: H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclic group, heterocyclic alkyl, 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”;

[0052] Preferably, W3 is N;

[0053] Preferably, R6 is H, D, CH3, -CH2COOH, -CH2COOCH3;

[0054] 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.

[0055] In some embodiments of the present invention, is

[0056] Specifically, part is wherein, R 31 is N or CR 36 ;

[0057] R 32 is NR 37 or -N=CR 38 -;

[0058] R 35 or R 37 is independently selected from: H, -D, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 , -(C1-C6 alkylene)-OR 61 , -(C1-C6 alkylene)-CONR 61 ;

[0059] R 33 、R 34 、R 36 、R 38 is independently selected from: H, -D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclic group, heterocyclic alkyl, 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”

[0060] Preferably, R 33 , R 34 , R 36 , R 38 is 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);

[0061] More preferably, R 33 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;

[0062] More preferably, R 34 , R 35 , R 37 is selected from: H, D, or methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

[0063] In some embodiments of the present invention, is

[0064] Specifically, part is wherein R 24 is absent or selected from: CR 23 , NR 27 ;

[0065] R 25 is selected from: CR 28 , NR 29 ;

[0066] R23 and R 26 and R 28 are independently selected from: H, -D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclic group, heterocyclic alkyl, 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"

[0067] R 27 and R 29 are 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 and R 29 are independently selected from: D

[0068] Preferably, R 23 and R 26 and 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.

[0069] Preferably, R 27 、R 29 Independently selected from: H, D or methyl, ethyl, propyl, isopropyl, butyl, tert-butyl;

[0070] 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.

[0071] In some embodiments of the present invention,

[0072] Specifically, Part is Wherein,

[0073] T1, T2, T3, T4, T5, T6, T7 are independently selected from: O, C-R7, or N;

[0074] X' is N, O, S;

[0075] Represents a single bond or a double bond;

[0076] In some embodiments of the present invention, when there is a single bond between T4 and T5, T4 and T5 together are -CONR8-;

[0077] T6, T7 are independently selected from: C-R7 or N;

[0078] In some embodiments of the present invention, when there is a single bond between T6 and T7, T6 and T7 together are -CONR8-;

[0079] When T1-T7 are selected from C-R7, each R7 can independently be 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 can independently be selected from: C1-C6 haloalkyl;

[0080] R8 is selected from: H, D, C1-C6 alkyl, -(C1-C6 alkylene)-COOR 61 、-(C1-C6 alkylene)-OR 61 、-(C1-C6 alkylene)-CONR 61 ;

[0081] 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;

[0082] Preferably, R8 is selected from: H or methyl, ethyl, propyl, isopropyl, butyl, tert-butyl.

[0083] In some embodiments of the present invention, selected from

[0084]

[0085] wherein, R7', R7'', R7''', R 7α 、R 7β have the above definition of R7, and R8' has the above definition of R8.

[0086] Specifically, Part is Among them, S3 is selected from: O, S, NR 91 , CR 92 R 93 ;

[0087] S1, S2, S4, S5, S6, S7 are independently selected from: N, CR 94 ;

[0088] R 92 , R 93 , R 94 are independently selected from: a linking bond, H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclic group, heterocyclic alkyl, 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”,

[0089] R 91 is selected from: a linking bond, H, -D, C1-C6 alkyl, -OH, -(C1-C6 alkylene)-COOR 61 , -(C1-C6 alkylene)-OR 61 , -(C1-C6 alkylene)-CONR 61 ,

[0090] Preferably, S1, S2, S4, S5, S6 are CR 94 ;

[0091] Preferably, R 92, R 93 , R 94 are independently selected from: a linking bond, 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 are independently selected from: -Br, -Cl, -I, C1-C6 haloalkyl;

[0092] More preferably, R 94 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.

[0093] In some embodiments of the present invention,

[0094] Specifically, part is wherein, Y1, Y2, Y3, Y4, Y5, Y6, Y7 are independently selected from: N or CR 11 ;

[0095] R 11 is selected from: a linking bond, H, D, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, aryl, aralkyl, heterocyclic group, heterocyclic group alkyl, 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”, -RL -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”;

[0096] Preferably, R 11 is independently selected from: a linking bond, 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 is independently selected from: -Br, -Cl, -I, C1-C6 haloalkyl.

[0097] Preferably, Y1, Y2, Y3, Y4, Y5, Y6 are CR 11 。

[0098] More preferably, R 11 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.

[0099] In some embodiments of the present invention, is

[0100]

[0101] In some embodiments of the present invention, part is preferably

[0102] In some embodiments of the present invention, part is selected from:

[0103]

[0104]

[0105] Specifically, R B is selected from: H, D, halogen, C1-C6 alkyl.

[0106] In some embodiments of the present invention, R B is H.

[0107] In some embodiments of the present invention, R B is D.

[0108] In some embodiments of the present invention, R B is halogen, such as F, Cl, Br, I, especially F, Cl.

[0109] In some embodiments of the present invention, R B is C1-C3 alkyl, such as -CH3.

[0110] Specifically, L1 is selected from: single bond, -O-, -S-, -N(C0-C6 alkyl), -C(O)-, -C(S)-, -SO-, -SO2-, -Si-, -C(O)O-.

[0111] In some embodiments of the present invention, L1 is a single bond.

[0112] In some embodiments of the present invention, L1 is -C(O)-.

[0113] In some embodiments of the present invention, L1 is -SO2-.

[0114] In some embodiments of the present invention, L1 is -Si-.

[0115] Specifically, R C is 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-C10 The H in cycloalkyl, C6-C 10 aryl, or 3- to 10-membered heterocyclic group may optionally be 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- to 10-membered heterocyclic group); or, the C0-C6 alkylene, C0-C 10 alkyl, C3-C 10 cycloalkyl, C6-C 10 aryl, or 3- to 10-membered heterocyclic group may optionally be substituted by one or more of the following groups: halogen, C1-C 10 haloalkyl, C1-C 10 alkoxy, C1-C 10 haloalkoxy.

[0116] Preferably, R C is selected from: C1-C6 alkyl, C1-C6 haloalkyl, 3- to 6-membered cycloalkyl (such as ), substituted or unsubstituted 5- to 6-membered nitrogen-containing heterocyclic group, substituted or unsubstituted 5- to 6-membered oxygen-containing heterocyclic group, substituted or unsubstituted 5- to 6-membered sulfur-containing heterocyclic group (such as

[0117]

[0118] ); wherein, R C1 is one or more substituents on the ring, and is 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 is halogen, such as F, Cl, Br, I.

[0119] In some embodiments of the present invention, R C is selected from:

[0120] Or, R C is

[0121] In some embodiments of the present invention, R C is selected from:

[0122] In some embodiments of the present invention, is selected from:

[0123] Specifically, W1 is C, W2 is C; or, W1 is C, W2 is N; or, W1 is C, W2 is O;

[0124] R1 and R2 are independently selected from: H, (=O), C1-C3 alkyl, -COOH, -CF3, hydroxyl;

[0125] Preferably, both R1 and R2 are H;

[0126] Preferably, both R1 and R2 are D.

[0127] In some embodiments of the present invention, is Preferably is

[0128] In some embodiments of the present invention, the compound has the structure shown in Formula II:

[0129]

[0130] In some embodiments of the present invention, the compound has the structure shown in Formula III:

[0131]

[0132] In some embodiments of the present invention, the compound has the structure shown in Formula IV:

[0133]

[0134] In some embodiments of the present invention, the compound has the structure shown in Formula V:

[0135]

[0136] In some embodiments of the present invention, the compound has the structure shown in Formula VI:

[0137]

[0138] Wherein, R C' 、R C” has the above definition of R C .

[0139] In some embodiments of the present invention, the compound has the structure shown in Formula VII:

[0140]

[0141] Wherein,

[0142] X1 - X5 are independently selected from: C, N;

[0143] 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 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 Rs F together with the carbon atom to which they are attached form a carbocyclic or heterocyclic ring, and the H on the carbocyclic or 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.

[0144] In some embodiments of the present invention, X1 - X5 are all C.

[0145] In some embodiments of the present invention, X1 is N, and X2 - X5 are all C.

[0146] In some embodiments of the present invention, X2 is N, and X1, X3 - X5 are all C.

[0147] In some embodiments of the present invention, X3 is N, and X1, X2, X4, X5 are all C.

[0148] In some embodiments of the present invention, X4 is N, and X1 - X3, X5 are all C.

[0149] In some embodiments of the present invention, X5 is N, and X1 - X4 are all C.

[0150] In some embodiments of the present invention, X1 and X2 are both N, and X3 - X5 are all C.

[0151] In some embodiments of the present invention, X1 and X3 are both N, and X2, X4, X5 are all C.

[0152] In some embodiments of the present invention, X1 and X4 are both N, and X2, X3, X5 are all C.

[0153] In some embodiments of the present invention, X1 and X5 are both N, and X2 - X4 are all C.

[0154] In some embodiments of the present invention, both X2 and X3 are N, and X1, X4, and X5 are all C.

[0155] In some embodiments of the present invention, both X2 and X4 are N, and X1, X3, and X5 are all C.

[0156] In some embodiments of the present invention, both X2 and X5 are N, and X1, X3, and X4 are all C.

[0157] In some embodiments of the present invention, both X3 and X4 are N, and X1, X2, and X5 are all C.

[0158] In some embodiments of the present invention, both X3 and X5 are N, and X1, X2, and X4 are all C.

[0159] In some embodiments of the present invention, both X4 and X5 are N, and X1-X3 are all C.

[0160] Specifically, the carbocyclic or heterocyclic ring can be a 5- or 6-membered carbocyclic or heterocyclic ring. For example,

[0161]

[0162] Preferably, the carbocyclic or heterocyclic ring is selected from:

[0163]

[0164] In some embodiments of the present invention, the heterocyclic ring is

[0165] In some embodiments of the present invention, the carbocyclic ring is

[0166] In some embodiments of the present invention, the carbocyclic ring is

[0167] In some specific embodiments of the present invention, the compound is selected from the following structures:

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174] Or, the compound is selected from the following structures:

[0175]

[0176] In some embodiments of the present invention, the compound is selected from the following structures:

[0177]

[0178] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof, and one or more pharmaceutically acceptable excipients.

[0179] Specifically, in this pharmaceutical composition, the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate thereof can be used alone or in combination with other types of active ingredients.

[0180] Specifically, the pharmaceutically acceptable excipients can be selected from one or more of the following: fillers, binders, lubricants, disintegrants, antioxidants, buffers, bacteriostatic agents, suspending agents, solubilizers, thickeners, stabilizers, preservatives, etc.

[0181] Specifically, the pharmaceutical composition can be administered by any suitable route, such as enteral administration (e.g., oral, sublingual, rectal administration) or parenteral administration (e.g., intravenous, intramuscular, intranasal, intraocular, intracerebral, intravaginal, intraperitoneal, transdermal, subcutaneous, intradermal, respiratory administration, etc.) routes.

[0182] 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, oral tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), lozenges, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules).

[0183] In some embodiments of the present invention, the pharmaceutical composition is an injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection).

[0184] In other embodiments of the present invention, the pharmaceutical composition is an intravenous drip preparation, a transdermal absorption preparation, a lotion, a suppository (e.g., rectal suppository, vaginal suppository), a nasal preparation, a pulmonary preparation (inhalant), an eye drop, etc.

[0185] Specifically, the pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is further divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a capsule, tablet or any 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, etc.

[0186] Specifically, the amount of the active ingredient in the unit dose preparation can be changed or adjusted between 0.1 mg and 1000 mg (for example, 0.1, 1, 5, 10, 20, 40, 50, 100, 200, 400, 500, 1000 mg), depending on the specific application and potency of the active ingredient. If necessary, the composition may also contain other suitable therapeutic agents.

[0187] In a third aspect of the present invention, there is provided the use of the compound described in the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate as a myosin inhibitor, such as in the preparation of a drug for treating heart diseases.

[0188] Specifically, the heart diseases are selected from: congenital heart disease, coronary atherosclerotic heart disease, rheumatic heart disease, hypertensive heart disease, pulmonary heart disease, infectious heart disease, endocrine heart disease, hematologic heart disease, nutritional and metabolic heart disease, cardiomyopathy, heart 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, angina pectoris.

[0189] In some embodiments of the present invention, the heart disease is hypertrophic cardiomyopathy.

[0190] In a fourth aspect of the present invention, there is provided the use of the compound described in the first aspect or its pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate in the preparation of a drug for preventing and / or treating heart diseases.

[0191] Specifically, the heart diseases are selected from: congenital heart disease, coronary atherosclerotic heart disease, rheumatic heart disease, hypertensive heart disease, pulmonary heart disease, infectious heart disease, endocrine heart disease, hematologic heart disease, nutritional and metabolic heart disease, cardiomyopathy, heart 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, angina pectoris.

[0192] In some embodiments of the present invention, the heart disease is hypertrophic cardiomyopathy.

[0193] The fifth aspect of the present invention provides a method for preventing and / or treating heart diseases, 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.

[0194] In some embodiments of the present invention, the method is carried out in vivo.

[0195] The sixth aspect of the present invention provides a method for preventing and / or treating heart diseases, 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 to a subject in need thereof.

[0196] 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.

[0197] The present invention provides a novel myosin inhibitor, which has excellent inhibitory activity and can be used to reduce and / or inhibit excessive contraction of sarcomeres, cardiomyocyte hypertrophy, disorder, and increased degree of myocardial fibrosis, prevent and / or treat heart diseases, especially hypertrophic cardiomyopathy, can fill the gap of anti-heart disease drugs, and has very good application prospects and value in the pharmaceutical field. Brief Description of the Drawings

[0198] Figure 1 Shown is the IC of T003 and X1 in inhibiting myosin ATPase activity 50 Curve graph. Detailed Description of the Invention

[0199] Unless otherwise defined, all scientific and technical terms used in the present invention have the same meaning as commonly understood by those skilled in the technical field to which the present invention pertains.

[0200] In the present invention, the term "aliphatic group" refers to a straight-chain or branched hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a cycloalkyl group (also referred to herein as "alicyclic ring", "cycloalkyl") that is completely saturated or contains one or more unsaturated units, which is connected to other parts of the molecule by a single bond. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and their mixtures, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (cycloalkyl)alkenyl, etc. 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.

[0201] The term "carbocyclic ring" refers to a ring in a compound molecule that consists entirely of carbon atoms and can be divided into alicyclic compounds and aromatic compounds.

[0202] The term "alkyl group" refers to a straight-chain or branched-chain hydrocarbon radical that does not contain an unsaturated bond, and the hydrocarbon radical is connected to other parts of the molecule by a single bond. Typical alkyl groups contain 1 to 12 (such as 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 "cycloalkylalkyl" radical accordingly, such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, etc. If the alkyl group is substituted by an aryl group, then it is an "arylalkyl" radical accordingly, such as benzyl, diphenylmethyl or phenethyl. If the alkyl group is substituted by a heterocyclic group, then it is a "heterocyclic alkyl" radical accordingly. "Alkylene" generally refers to an alkanediyl with two free valence bonds. Typical alkylene contains 1 to 12 (such as 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, that is, C 0-10 alkyl (or C0-C 10 alkyl) includes H and C 1-10 alkyl (or C1-C 10 alkyl).

[0203] The term "alkylene" refers to a hydrocarbon group (divalent alkyl) formed by removing two hydrogen atoms from an alkane molecule. It can be straight-chain or branched-chain and is connected to other parts of the molecule by a single bond. In this article, typical alkylene has 1 to 10 (such as 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, C0 alkylene refers to a single bond, that is, C 0-10 alkylene (or C0-C 10 alkylene) includes a single bond and C 1-10 alkylene (or C1-C 10 alkylene).

[0204] The term "alkoxy" refers to a substituent formed by replacing the hydrogen in a hydroxyl group with an alkyl group. Typical alkoxy contains 1 to 12 (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, etc.

[0205] 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 fused rings, contain 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.

[0206] The term "aryl" refers to a monocyclic or polycyclic radical, including polycyclic radicals containing monoaryl groups and / or fused aryl groups, such as containing 1-3 monocyclic or fused rings and 6-18 (e.g., 6, 8, 10, 12, 14, 16, 18) carbon ring atoms. Typical aryls are aryls containing 6-12 carbon ring atoms, such as phenyl, naphthyl, biphenyl, indenyl, etc. "Arylene" refers to a divalent group derived from an aromatic hydrocarbon by removing two hydrogen atoms.

[0207] The term "heterocyclic group" includes heteroaromatic groups and heterocycloaliphatic groups containing 1 to 3 monocyclic and / or fused rings and 3 to about 18 ring atoms. Preferred heteroaromatic groups and heterocycloaliphatic groups contain 5 to about 10 ring atoms. Suitable heteroaryl groups in the compounds of the present invention contain 1, 2 or 3 kinds of heteroatoms selected from N, O or S atoms. Examples of heteroaryl groups, for example, but not limited to, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indazinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl and furanopyridyl, etc. Suitable heterocycloaliphatic groups in the compounds of the present invention contain 1, 2 or 3 kinds of heteroatoms selected from N, O or S atoms. Examples of heterocycloaliphatic groups, for example, but not limited to, pyrrolidinyl, tetrahydrofuryl, dihydrofuran, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, thiiranyl, azepinyl, oxazepinyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinuclidinyl, etc.

[0208] The above-mentioned 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, =N-R', 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 group, 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 heterocyclic group. Among them, these groups are themselves substituted, and the substituents can be selected from the aforementioned list.

[0209] The term "halogen" refers to bromine, chlorine, iodine or fluorine. In the present invention, "-X" and "halogen" can be used interchangeably.

[0210] The term "haloalkyl" refers to a group formed by substituting one or more hydrogen atoms on the alkyl group with halogen atoms (F, Cl, Br, I), such as -CH2Rh, -CHRh2, -CRh3, wherein Rh is F, Cl, Br or I, such as -CHF2, -CH2F, -CF3. Also for example, -CH2-CF3, -CH2CH2-CF3, -CH2CH2CH2-CF3.

[0211] The term "pharmaceutically acceptable salt" refers to an acidic salt or basic salt that is theoretically non-toxic, non-irritating and non-allergenic, and can achieve or provide clinically acceptable pharmacokinetic properties, absorption, distribution and metabolism properties of the drug molecule, and can achieve the expected purpose. The salts described in the present invention include pharmaceutically acceptable acidic salts or basic salts of acidic groups, basic groups or amphoteric groups of the compound. A list of suitable salts can be found in S.M. Birge, et al., J. Pharm. Sci., 66, 1-19 (1977).

[0212] The pharmaceutically acceptable salts of the present invention include acid addition salts and base addition salts.

[0213] The acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acid, and salts derived from organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodide, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, and mesylate, and also include salts of amino acids such as arginine salt, gluconate, galacturonate, etc. The acid addition salts can be prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to form the salt. The free base form can be regenerated by contacting the salt form with a base and separated in a conventional manner.

[0214] The 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 formed 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. The 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 separated in a conventional manner.

[0215] The term "solvate" should be understood to mean any form of the compounds of the present invention, in which the compound is linked to another molecule (usually a polar solvent) by non-covalent bonds, especially including hydrates and alcoholates, such as methanolates. The preferred solvate is the hydrate.

[0216] The term "prodrug" is used in its broadest sense and encompasses derivatives that are convertible in vivo to the compounds of the present invention. Examples of prodrugs include, but are not limited to, derivatives and metabolites of the compounds, including biolyzable moieties such as biolyzable amides, biolyzable esters, biolyzable carbamates, biolyzable carbonates, biolyzable ureas, and biolyzable phosphate analogs. Preferably, prodrugs having a carboxyl functional group are lower alkyl esters of carboxylic acids. The carboxylic acid esters are 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).

[0217] The term "absent" means that the linking group is a bond.

[0218] Any compound referred to herein is intended to represent such a specific compound and certain of its variations or certain forms. In particular, the compounds referred to herein may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. Accordingly, any given compound referred to herein represents any one of the racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Similarly, there may be stereoisomers or geometric isomers of double bonds, and thus in some cases, the molecule may exist as the (E)-isomer or the (Z)-isomer (trans and cis isomers). If the molecule contains multiple double bonds, then each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds of the molecule. In addition, atropisomers may exist for the compounds referred to herein. All stereoisomers of the compounds referred to herein, including enantiomers, diastereoisomers, geometric isomers, and atropisomers, and mixtures thereof, are within the scope of the present invention.

[0219] The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entirety.

[0220] Next, in combination with the embodiments of the present invention, the technical solutions of the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without making creative efforts belong to the scope of protection of the present invention.

[0221] Example 1: Synthesis of Compound T001

[0222]

[0223] 1. Synthesis of Compound 1a

[0224]

[0225] Dissolve isopropylurea (1.0 e.q.) in methanol, add dimethyl malonate (1.1 e.q.) and sodium methoxide (2.0 e.q.), and stir the reaction overnight at 60 °C under nitrogen protection. After monitoring the end of the reaction 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, dissolve the obtained mixture in absolute ethanol, and stir at room temperature for 2 hours. Filter the solution by suction and then concentrate the filtrate. After purification by silica gel column chromatography, concentrate and dry to obtain Compound 1a.

[0226] 2. Synthesis of Compound 1b

[0227]

[0228] Dissolve Compound 1a (1.0 e.q.) and triethylbenzylammonium chloride (1.5 e.q.) in POCl3, and stir the reaction at 40 °C for 6 hours under nitrogen protection. After monitoring the completion of the reaction by LC-MS, distill off POCl3 under reduced pressure after the reaction system cools to room temperature. Dissolve the residue in DCM, wash it three times with saturated ammonium chloride solution, retain the organic phase, dry it with anhydrous sodium sulfate, filter by suction, concentrate the filtrate, and after purification by silica gel column chromatography, concentrate and dry to obtain a yellow solid, namely Compound 1b.

[0229] 3. Synthesis of Compound T001

[0230]

[0231] Mix Compound 1b (1.0 e.q.) and 1-phenylcyclopropylamine (5 e.q.), and heat and stir overnight at 120 °C under nitrogen protection. After monitoring the completion of the reaction by LC-MS, concentrate the crude reaction mixture to dryness, and purify it by silica gel column chromatography eluting with ethyl acetate to obtain Compound T001.

[0232] Example 2: Synthesis of Compound T002

[0233]

[0234] Compound 1b (1.0 e.q.) and 1-(3-fluorophenyl)cyclopropanamine (5 e.q.) were heated and stirred overnight at 120 °C under nitrogen protection. After the reaction was monitored by LC-MS and completed, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T002.

[0235] Example 3: Synthesis of Compound T003

[0236]

[0237] Compound 1b (1.0 e.q.) and 1-(3-bromophenyl)cyclopropanamine (5 e.q.) were heated and stirred overnight at 120 °C under nitrogen protection. After the reaction was monitored by LC-MS and completed, the crude reaction mixture was concentrated to dryness and purified by silica gel column chromatography eluting with ethyl acetate to obtain compound T003.

[0238] Example 4: Synthesis of Compound T004

[0239]

[0240] 1. Synthesis of Compound 4a

[0241]

[0242] Propionylurea (1.0 e.q.) was dissolved in methanol, dimethyl malonate (1.1 e.q.) and sodium methoxide (3.1 e.q.) were added, and the mixture was stirred at 60 °C overnight under nitrogen protection. After the reaction was monitored by LC-MS and ended, 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, the resulting mixture was dissolved in absolute ethanol and stirred at room temperature for 2 hours. The solution was filtered by suction and the filtrate was concentrated, and after purification by silica gel column chromatography, it was concentrated and dried to obtain compound 4a.

[0243] 2. Synthesis of Compound 4b

[0244]

[0245] Dissolve compound 4a (1.0 e.q.) and triethylbenzylammonium chloride (1.5 e.q.) in POCl3. Under nitrogen protection, stir and react at 40 °C for 6 hours. After monitoring the reaction by LC-MS and waiting for the reaction system to cool to room temperature, remove POCl3 by distillation under reduced pressure. Dissolve the residue in DCM, wash it three times with saturated ammonium chloride solution, retain the organic phase, dry it with anhydrous sodium sulfate, filter it by suction, concentrate the filtrate, purify it by silica gel column chromatography, and then concentrate and dry to obtain a yellow solid, namely compound 4b.

[0246] 3. Synthesis of compound 4

[0247]

[0248] Mix compound 4b (1.0 e.q.) and 1-phenylcyclopropylamine (5 e.q.), and heat and stir overnight at 120 °C under nitrogen protection. After monitoring the reaction by LC-MS and completion of the reaction, concentrate the crude reaction mixture to dryness, and purify it by silica gel column chromatography eluting with ethyl acetate to obtain compound T004.

[0249] Example 5: Synthesis of compound T005

[0250]

[0251] 1. Synthesis of compound 5a

[0252]

[0253] Drop trimethylsilyl isocyanate (2.2 e.q.) into a stirred solution of 1,1,1-trifluoropropan-2-amine (1.0 e.q) in DCM (15 mg) at 0 °C. Stir the reaction mixture at the same temperature for 30 minutes, then slowly heat to room temperature overnight. Stir the resulting solution at room temperature for 2 hours, and then concentrate it under reduced pressure. Recrystallize the crude residue from MeOH:Et2O (1:20) to obtain compound 5a.

[0254] 2. Synthesis of compound 5b

[0255]

[0256] Dissolve compound 5a (1.0 e.q.) in methanol, add dimethyl malonate (1.1 e.q.) and sodium methoxide (3.1 e.q.), and stir and react overnight at 60 °C under nitrogen protection. After monitoring the reaction by LC-MS and completion of the reaction, cool the reaction solution to room temperature, and adjust the pH to 2 - 3 with dilute hydrochloric acid. Concentrate under reduced pressure, dissolve the obtained mixture in absolute ethanol, and stir at room temperature for 2 hours. Filter the solution by suction, concentrate the filtrate, purify it by silica gel column chromatography, and then concentrate and dry to obtain compound 5b.

[0257] 3. Synthesis of Compound 5c

[0258]

[0259] Dissolve Compound 5b (1.0 e.q.) and triethylbenzylammonium chloride (1.5 e.q.) in POCl3. Under nitrogen protection, stir the reaction at 40 °C for 6 hours. After monitoring the reaction completion by LC-MS, when the reaction system cools to room temperature, remove POCl3 by distillation under reduced pressure. Dissolve the residue in DCM, wash it three times with saturated ammonium chloride solution, retain the organic phase, dry it with anhydrous sodium sulfate, filter it by suction, concentrate the filtrate, purify it by silica gel column chromatography, and then concentrate and dry to obtain a yellow solid, namely Compound 5c.

[0260] 4. Synthesis of Compound T005

[0261]

[0262] Mix Compound 5c (1.0 e.q.) and 1-phenylcyclopropylamine (5 e.q.), and stir and heat at 120 °C overnight under nitrogen protection. After monitoring the reaction completion by LC-MS, concentrate the crude reaction mixture to dryness, and purify it by silica gel column chromatography eluting with ethyl acetate to obtain Compound T005.

[0263] Example 6: Synthesis of Compound T006

[0264]

[0265] 1. Synthesis of Compound 6a

[0266]

[0267] Dissolve 1-cyclopropylurea in methanol, add dimethyl malonate (1.1 e.q.) and sodium methoxide (3.1 e.q.), and stir the reaction at 60 °C overnight under nitrogen protection. After monitoring the reaction completion 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, dissolve the obtained mixture in absolute ethanol, and stir at room temperature for 2 hours. Filter the solution by suction and then concentrate the filtrate. Purify it by silica gel column chromatography and then concentrate and dry to obtain Compound 6a.

[0268] 2. Synthesis of Compound 6b

[0269]

[0270] Dissolve compound 6a (1.0 e.q.) and triethylbenzylammonium chloride (1.5 e.q.) in POCl3. Under nitrogen protection, stir the reaction at 40 °C for 6 hours. After monitoring the reaction by LC-MS until completion, remove POCl3 by distillation under reduced pressure after the reaction system cools to room temperature. Dissolve the residue in DCM, wash it three times with saturated ammonium chloride solution, retain the organic phase, dry it over anhydrous sodium sulfate, filter by suction, concentrate the filtrate, purify it by silica gel column chromatography, and then concentrate and dry to obtain a yellow solid, namely compound 6b.

[0271] 3. Synthesis of compound T006

[0272]

[0273] Mix compound 6b (1.0 e.q.) and 1-phenylcyclopropylamine (5 e.q.), and heat and stir overnight at 120 °C under nitrogen protection. After monitoring the reaction by LC-MS until completion, concentrate the crude reaction mixture to dryness, and purify it by silica gel column chromatography eluting with ethyl acetate to obtain compound T006.

[0274] Example 7: Synthesis of compound T007

[0275]

[0276] 1. Synthesis of compound 7a

[0277]

[0278] Drop trimethylsilyl isocyanate (2.2 e.q.) into a stirred solution of 4,4-difluorocyclohexylamine (1.0 e.q.) in DCM (15 mg) at 0 °C. Stir the reaction mixture at the same temperature for 30 minutes, then slowly heat to room temperature overnight. Stir the resulting solution at room temperature for 2 hours, and then concentrate it under reduced pressure. Recrystallize the crude residue from MeOH:Et2O (1:20) to obtain compound 7a.

[0279] 2. Synthesis of compound 7b

[0280]

[0281] Dissolve compound 7a (1.0 e.q.) in methanol, add dimethyl malonate (1.1 e.q.) and sodium methoxide (3.1 e.q.), and stir the reaction overnight at 60 °C under nitrogen protection. After monitoring the reaction by LC-MS until completion, cool the reaction solution to room temperature, and adjust the pH to 2 - 3 with dilute hydrochloric acid. Concentrate under reduced pressure, dissolve the resulting mixture in absolute ethanol, and stir at room temperature for 2 hours. Filter the solution by suction and concentrate the filtrate. Purify it by silica gel column chromatography, and then concentrate and dry to obtain compound 7b.

[0282] 3. Synthesis of Compound 7c

[0283]

[0284] Dissolve Compound 7b (1.0 e.q.) and triethylbenzylammonium chloride (1.5 e.q.) in POCl3. Under nitrogen protection, stir the reaction at 40 °C for 6 hours. After monitoring the reaction by LC-MS until completion, remove POCl3 by distillation under reduced pressure after the reaction system cools to room temperature. Dissolve the residue in DCM, wash it three times with saturated ammonium chloride solution, retain the organic phase, dry it with anhydrous sodium sulfate, filter it by suction, concentrate the filtrate, purify it by silica gel column chromatography, and then concentrate and dry to obtain a yellow solid, namely Compound 7c.

[0285] 4. Synthesis of Compound T007

[0286]

[0287] Mix Compound 7c (1.0 e.q.) and 1-phenylcyclopropylamine (5 e.q.), and heat and stir overnight at 120 °C under nitrogen protection. After monitoring the reaction by LC-MS until completion, concentrate the crude reaction mixture to dryness, and purify it by silica gel column chromatography eluting with ethyl acetate to obtain Compound T007.

[0288] Example 8: Synthesis of Compound T008

[0289]

[0290] 1. Synthesis of Compound 8a

[0291]

[0292] Dissolve phenylurea (1.0 e.q.) in methanol, add dimethyl malonate (1.1 e.q.) and sodium methoxide (3.1 e.q.), and stir the reaction overnight at 60 °C under nitrogen protection. After monitoring the reaction by LC-MS until completion, cool the reaction solution to room temperature and adjust the pH to 2 - 3 with dilute hydrochloric acid. Concentrate under reduced pressure, dissolve the obtained mixture in absolute ethanol, and stir at room temperature for 2 hours. Filter the solution by suction and then concentrate the filtrate. Purify it by silica gel column chromatography, and then concentrate and dry to obtain Compound 8a.

[0293] 2. Synthesis of Compound 8b

[0294]

[0295] Dissolve compound 8a (1.0 e.q.) and triethylbenzylammonium chloride (1.5 e.q.) in POCl3. Under nitrogen protection, stir and react at 40 °C for 6 hours. After monitoring the reaction by LC-MS and waiting for the reaction system to cool to room temperature, remove POCl3 by distillation under reduced pressure. Dissolve the residue in DCM, wash it three times with saturated ammonium chloride solution, retain the organic phase, dry it with anhydrous sodium sulfate, filter it by suction, concentrate the filtrate, purify it by silica gel column chromatography, and then concentrate and dry it to obtain compound 8b.

[0296] 3. Synthesis of compound T008

[0297]

[0298] Mix compound 8b (1.0 e.q.) and 1-phenylcyclopropylamine (5 e.q.), and heat and stir overnight at 120 °C under nitrogen protection. After monitoring the reaction by LC-MS and completing the reaction, concentrate the crude reaction mixture to dryness, and purify it by silica gel column chromatography eluted with ethyl acetate to obtain compound T008.

[0299] Example 9: Synthesis of compound T009

[0300]

[0301] 1. Synthesis of compound 9a

[0302]

[0303] Stir and reflux 2-aminopyridine (1.0 e.q) and KNCO (1.2 e.q) in H2O overnight. After the reaction is completed, cool to room temperature, add saturated NaCl aqueous phase, and filter and separate the precipitate to obtain compound 9a.

[0304] 2. Synthesis of compound 9b

[0305]

[0306] Dissolve compound 9a in methanol, add dimethyl malonate (1.1 e.q.) and sodium methoxide (3.1 e.q.), and stir and react overnight at 60 °C under nitrogen protection. After monitoring the reaction by LC-MS and completing the reaction, cool the reaction solution to room temperature, and adjust the pH to 2-3 with dilute hydrochloric acid. Concentrate under reduced pressure, dissolve the obtained mixture in absolute ethanol, and stir at room temperature for 2 hours. Filter the solution by suction and then concentrate the filtrate. Purify it by silica gel column chromatography, and then concentrate and dry it to obtain compound 9b.

[0307] 3. Synthesis of compound 9c

[0308]

[0309] Dissolve compound 9b (1.0 e.q.) and triethylbenzylammonium chloride (1.5 e.q.) in POCl3. Under nitrogen protection, stir and react at 40 °C for 6 hours. After monitoring the reaction by LC-MS until completion, after the reaction system cools to room temperature, remove POCl3 by distillation under reduced pressure. Dissolve the residue in DCM, wash it three times with saturated ammonium chloride solution, retain the organic phase, dry it with anhydrous sodium sulfate, filter by suction, concentrate the filtrate, purify it by silica gel column chromatography, and then concentrate and dry to obtain a yellow solid, namely compound 9c.

[0310] 4. Synthesis of compound T009

[0311]

[0312] Mix compound 9c (1.0 e.q.) and 1-phenylcyclopropylamine (5 e.q.), and heat and stir overnight at 120 °C under nitrogen protection. After monitoring the reaction by LC-MS until completion, concentrate the crude reaction mixture to dryness, and purify it by silica gel column chromatography eluting with ethyl acetate to obtain compound T009.

[0313] Example 10: Synthesis of compound T010

[0314]

[0315] 1. Synthesis of compound 10a

[0316]

[0317] Stir and reflux 3,5-difluoroaniline (1.0 e.q) and KNCO (1.2 e.q) in H2O overnight. After the reaction is completed, cool to room temperature, add saturated aqueous NaCl to the aqueous phase, and filter and separate the precipitate to obtain compound 10a.

[0318] 2. Synthesis of compound 10b

[0319]

[0320] Dissolve compound 10a in methanol, add dimethyl malonate (1.1 e.q.) and sodium methoxide (3.1 e.q.), and stir and react overnight at 60 °C under nitrogen protection. After monitoring the reaction by LC-MS until completion, cool the reaction solution to room temperature, and adjust the pH to 2 - 3 with dilute hydrochloric acid. Concentrate under reduced pressure, dissolve the obtained mixture in absolute ethanol, and stir at room temperature for 2 hours. Filter the solution by suction and then concentrate the filtrate. Purify it by silica gel column chromatography, and then concentrate and dry to obtain compound 10b.

[0321] 3. Synthesis of compound 10c

[0322]

[0323] Dissolve compound 10b (1.0 e.q.) and triethylbenzylammonium chloride (1.5 e.q.) in POCl3. Under nitrogen protection, stir and react at 40 °C for 6 hours. After monitoring the end of the reaction by LC-MS, after the reaction system is cooled to room temperature, remove POCl3 by distillation under reduced pressure. Dissolve the residue in DCM, wash it three times with saturated ammonium chloride solution, retain the organic phase, dry it with anhydrous sodium sulfate, filter by suction, concentrate the filtrate, purify it by silica gel column chromatography, and then concentrate and dry to obtain a white solid, namely compound 10c.

[0324] 4. Synthesis of compound T010

[0325]

[0326] Mix compound 10c (1.0 e.q.) and 1-phenylcyclopropylamine (5 e.q.), and heat and stir overnight at 120 °C under nitrogen protection. After monitoring the completion of the reaction by LC-MS, concentrate the crude reaction mixture to dryness, and purify it by silica gel column chromatography eluting with ethyl acetate to obtain compound T010.

[0327] Table 1 Compound number, structural formula, molecular weight and 1 H NHR information

[0328]

[0329]

[0330] Example 11: Inhibitory activity of the compound on myosin ATPase activity

[0331] A biochemical assay method that combines the release of ADP (adenosine diphosphate) from myosin with an enzyme coupling system composed of pyruvate kinase and lactate dehydrogenase (PK / LDH) is used to evaluate the ability of small molecules to inhibit the ATPase activity of rabbit skeletal muscle myosin by dynamically monitoring the change in absorbance of NADH as a function of time. The specific enzyme coupling reaction: PK converts ADP to ATP (adenosine triphosphate) by converting PEP (phosphoenolpyruvate) to pyruvate, and then LDH converts pyruvate to lactate by converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide). The source of myosin is rabbit skeletal muscle (S35330, Yuanye Bio). 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.

[0332] The compounds were serially diluted in DMSO to achieve the final expected concentration of the compounds at a fixed concentration of 2% (v / v) of DMSO in a volume of 50 mL. 37 μL of myosin and 1 μL of the compound serial dilution were successively added to a transparent 384-well plate and incubated for 15 min, and the enzymatic reaction was started by adding 12 μL of a solution containing ATP, PEP, NADH, and PK / LDH. The reaction progress was monitored at ambient temperature using a Molecular Devices ID5 plate reader. The plate reader was set to read the absorbance at 340 nm in kinetic mode for 30 minutes at 3-minute 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 then 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 this curve is the IC 50 and is the concentration when 50% of the total response is inhibited. Any drug for which the single-point concentration test concentration could not achieve 50% inhibition was reported as IC 50 greater than the highest concentration tested (i.e., IC 50 > 100 μM), and the highest concentration of the remaining compounds was set to 200 mM.

[0333] Among them, compound X1 in Table 2 is a reference compound, and its structural formula is It was synthesized according to Example 1 of the reference patent document WO2014205223A1.

[0334] Biochemical and Cellular Activities of the Compounds in Table 2

[0335]

[0336]

[0337] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

[0338] The foregoing embodiments and methods described in the present invention may vary based on the capabilities, experience, and preferences of those skilled in the art.

[0339] The listing of the steps of the method in a certain order in the present invention 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: 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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