Triazine diketone derivative, preparation method thereof and application of triazine diketone derivative in medicine

Abstract

The invention relates to a triazine diketone derivative, a preparation method thereof and application of the triazine diketone derivative in medicine. Specifically, the invention relates to a triazine diketone derivative as shown in a general formula (I), a preparation method of the triazine diketone derivative, a pharmaceutical composition containing the triazine diketone derivative and application of the triazine diketone derivative as a therapeutic agent. The invention relates to the field of medicines, in particular to the use in preparing a myosin inhibitor and the use in preparing a medicine for treating hypertrophic cardiomyopathy (HCM) or heart diseases with pathophysiologic characteristics related to the HCM. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202180065655.5, application date November 19, 2021, and invention name “Triazinedione derivatives, preparation methods thereof and their application in medicine”. Technical Field

[0002] The present disclosure belongs to the field of medicine, and relates to a triazinedione derivative, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a triazinedione derivative represented by general formula (I), a preparation method thereof, and a pharmaceutical composition containing the derivative, as well as its use in preparing myosin inhibitors and in preparing drugs for treating hypertrophic cardiomyopathy (HCM) or heart diseases with pathological and physiological characteristics associated with HCM. Background Art

[0003] Hypertrophic cardiomyopathy (HCM) is a dominant hereditary myocardial disease associated with gene mutations. The global incidence is about 0.2%, and it is the most important cause of sudden death in young people under 35 years old (C. Vaughan Tuohy, et al., European Journal of Heart Failure, 22, 2020, 228-240). The clinical manifestations are asymmetric hypertrophy of the left ventricular wall, often invading the ventricular septum, shrinking of the ventricular cavity, obstruction of left ventricular blood filling, and decreased ventricular diastolic compliance. According to the presence or absence of obstruction in the left ventricular outflow tract, it is divided into obstructive and non-obstructive hypertrophic cardiomyopathy. At present, the clinical treatment of hypertrophic cardiomyopathy mostly uses β-blockers and calcium ion channel blockers to reduce cardiac contraction and relieve symptoms. However, these treatments are only symptomatic and not curative. When HCM progresses to the late stage, heart transplantation is the only option (R adhakrishnan Ramaraj, Cardiology in Review, 16 (4), 2008, 172-180). Therefore, it is urgent to find a treatment method that targets the root cause of HCM.

[0004] Existing studies have found that 70% of HCM patients are caused by mutations in the sarcomeric protein gene. Multiple site mutations were found in 5-7% of patients. About 70 pathogenic mutations have been identified, but most of these mutations are family-specific, and only a few hot spots have been identified, such as MYH7 R403Q and R453C mutations (Norbert Frey, et al., Nature Reviews Cardiology, 9, 2011, 91-100; M. Sabater-Molina, et al., Clinical Genetics, 93, 2018, 3-14). Studies on the probability of gene mutations have found that about 30% of patients have MYH7 gene mutations. Compared with other sarcomeric protein genes, MYH7 can cause early onset of the disease and more severe myocardial hypertrophy. Myosin is a component unit of myofibril thick filaments and plays an important role in muscle movement. Its molecular shape is like a bean sprout, consisting of two heavy chains and multiple light chains. The myosin head binds to actin to form a cross-bridge, which greatly increases the ATPase activity of myosin, catalyzes the ATP hydrolysis reaction, generates energy to promote the sliding of the cross-bridge, and performs muscle contraction. Research results show that MYH7 gene mutations can lead to increased myosin ATPase activity, reduced proportion of myosin super-relaxed state (SRX), increased cross-bridges between myosin and actin, and abnormal cardiac contractile function (Eric M. Green, et al., Science, 351 (6273), 2016, 617-621; Ruth F. Sommese, et al., Proceedings of the National Academy Sciences, 110 (31), 2013, 12607-12612). Therefore, myosin is an important target for the treatment of hypertrophic cardiomyopathy.

[0005] Patent applications for myosin inhibitors that have been disclosed include WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1 and CN110698415A, etc. Summary of the invention

[0006] The purpose of the present disclosure is to provide a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0010] R1 is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, C(O)R 6 、C(O)OR 7 、S(O) t R 8 、S(O) t NR 9 R 10 、C(O)NR 9 R 10 NR 9 R 10 and

[0011] Each R 2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, C(O)R 6 、C(O)OR 7 、S(O) t R 8 、S(O) t NR 9 R 10 、C(O)NR 9 R 10 and NR 9 R 10 ;

[0012] or R 1 and an adjacent R 2 , or two adjacent R 2 , fused with ring A to form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxyl;

[0013] L2 is selected from a covalent bond, (CH2) r 、C(O)、NR a , oxygen atoms and sulfur atoms;

[0014] R a is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0015] Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0016] Each R 5are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0017] R 3a is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxyl;

[0018] R 3b is a hydrogen atom;

[0019] R 0 is alkyl or wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxyl;

[0020] L1 is a covalent bond or (CH2) r ;

[0021] Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0022] Each R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, hydroxyl, hydroxyalkyl, C(O)R 6 、C(O)OR 7 、S(O) t R 8 、S(O) t NR 9 R 10 、C(O)NR 9 R 10 , cycloalkyl, -(CH2) r -cycloalkyl, heterocyclic, -(CH2) r -Heterocyclic group, aryl group, -(CH2) r -Aryl, heteroaryl and -(CH2) r - heteroaryl;

[0023] R 6are the same or different at each occurrence and are each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl;

[0024] R 7 are the same or different at each occurrence and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0025] R 8 are the same or different at each occurrence and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group;

[0026] R 9 and R 10 are the same or different at each occurrence and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, -(CH2) r -cycloalkyl, heterocyclic, -(CH2) r -Heterocyclic group, aryl group, -(CH2) r -Aryl, heteroaryl and -(CH2) r -heteroaryl; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0027] p is 0, 1, 2, 3, 4, 5 or 6;

[0028] r is 0, 1, 2, 3, 4, 5 or 6;

[0029] m is 0, 1, 2, 3 or 4;

[0030] s is 0, 1, 2, 3, 4, 5, or 6; and

[0031] t is 0, 1, or 2.

[0032] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof:

[0033]

[0034] in:

[0035] Ring A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (I).

[0036] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from a 3- to 8-membered cycloalkyl, a 3- to 12-membered heterocyclyl, a 6- to 10-membered aryl and a 5- to 10-membered heteroaryl; preferably, ring A is a phenyl group.

[0037] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof:

[0038]

[0039] in:

[0040] R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (I).

[0041] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof:

[0042]

[0043] in:

[0044] R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (I).

[0045] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 C 1-6 Alkyl or Among them, the C 1-6 Alkyl is optionally selected from halogen, C 1-6 Alkoxy, C 1-6It is substituted by one or more substituents selected from the group consisting of haloalkoxy, cyano, amino and hydroxyl; L1 is a covalent bond or (CH2) r Ring B is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 4 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, oxo, cyano, hydroxyl and C 1-6 hydroxyalkyl; r is 0, 1, 2, 3, 4, 5 or 6; s is 0, 1 or 2.

[0046] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from C 1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 12-membered heterocyclic group; preferably, R 0 Selected from C 1-6 alkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic group; further preferably, R 0 is selected from isopropyl, tetrahydropyranyl and cyclohexyl; more preferably, R 0 isopropyl or tetrahydropyranyl; most preferably, R 0 It is tetrahydropyranyl.

[0047] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 C 1-6 Alkyl; preferably, R 0 It is isopropyl.

[0048] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and Preferably, R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and Among them, ring C, L2, R 5and p are as defined in the general formula (I).

[0049] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6.

[0050] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and Preferably, R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1 or 2.

[0051] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Haloalkoxy and Preferably, R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; p is 0, 1 or 2.

[0052] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Haloalkoxy or L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; p is 0, 1 or 2.

[0053] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Preferably, each R 2 The same or different, and each independently is a hydrogen atom or a halogen; more preferably, each R 2 are the same or different and are each independently halogen; most preferably, R 2 A fluorine atom.

[0054] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 and an adjacent R 2 , or two adjacent R 2 , fused with ring A to form a 3- to 8-membered cycloalkyl or a 3- to 12-membered heterocyclic group; preferably, R 1 and an adjacent R 2 , or two adjacent R 2 , fused with ring A to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group; more preferably, R 1and an adjacent R 2 It condenses with ring A to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.

[0055] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 and an adjacent R 2 , or two adjacent R 2 , fused with ring A to form a 3- to 8-membered cycloalkyl or a 3- to 12-membered heterocyclic group; preferably, R 1 and an adjacent R 2 It is fused with ring A to form a cyclopentyl group.

[0056] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 and an adjacent R 2 , or two adjacent R 2 , fused with phenyl to form a 3- to 8-membered cycloalkyl or a 3- to 12-membered heterocyclic group; preferably, R 1 and an adjacent R 2 , or two adjacent R 2 , fused with phenyl to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group; more preferably, R 1 and an adjacent R 2 Fused with phenyl to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.

[0057] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 and an adjacent R 2 , or two adjacent R 2 , fused with phenyl to form a 3- to 8-membered cycloalkyl or a 3- to 12-membered heterocyclic group; preferably, R 1 and an adjacent R 2 Fused with phenyl to form cyclopentyl.

[0058] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6; each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R 1 and an adjacent R 2 , or two adjacent R 2 , is fused with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group.

[0059] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R 1 and an adjacent R 2 It is fused with ring A to form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group.

[0060] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 It condenses with ring A to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.

[0061] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Haloalkoxy or L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 It condenses with ring A to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.

[0062] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Haloalkoxy or L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 It is fused with ring A to form a cyclopentyl group.

[0063] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6; each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R 1 and an adjacent R 2 , or two adjacent R 2 , fused with a phenyl group to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group.

[0064] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 It is fused with a phenyl group to form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group.

[0065] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Haloalkoxy or L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 Fused with phenyl to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.

[0066] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 1 C 1-6 Haloalkoxy or L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 Fused with phenyl to form cyclopentyl.

[0067] In some embodiments of the present disclosure, the compound represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 3a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 3a C 1-6 Alkyl; More preferably, R 3a It is methyl.

[0068] In some embodiments of the present disclosure, the compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) or their pharmaceutically acceptable salts, wherein m is 0, 1 or 2; preferably, m is 0 or 1.

[0069] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein for Wherein, ring M is a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group, R f Selected from hydrogen atoms, halogens and C 1-6 Alkyl, n is 0 or 1, R 1 and R 2As defined in general formula (I) or general formula (I-1); preferably, for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group, R 1 and R 2 As defined in general formula (I) or general formula (I-1); more preferably, Selected from

[0070] Most preferably, for

[0071] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein Selected from

[0072] In some embodiments of the present disclosure, the compound represented by the general formula (II), the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for Wherein, ring M is a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group, R f Selected from hydrogen atoms, halogens and C 1-6 Alkyl, n is 0 or 1, R 1 and R 2 As defined in general formula (II) or general formula (II-1); preferably, for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group, R 1 and R 2 As defined in general formula (II) or general formula (II-1); more preferably, Selected from Most preferably, for

[0073] In some embodiments of the present disclosure, the compound represented by the general formula (II), the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein Selected from

[0074] In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl; R 0 Selected from C 1-6alkyl, 3 to 8 membered cycloalkyl and 3 to 12 membered heterocyclic group; R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6; each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R 1 and an adjacent R 2 , or two adjacent R 2 , fused with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group; R 3a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; R 3b is a hydrogen atom; m is 0, 1 or 2.

[0075] In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl; R 0 C 1-6 Alkyl; R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6; each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R 1 and an adjacent R 2 , or two adjacent R 2 , fused with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group; R 3a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; R 3b is a hydrogen atom; m is 0, 1 or 2.

[0076] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 Selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic group; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 Fused with phenyl to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group; R 3a is methyl; R 3b is a hydrogen atom; m is 0 or 1.

[0077] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 C 1-6 Alkyl; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 Fused with phenyl to form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclic group; R 3a is methyl; R 3b is a hydrogen atom; m is 0 or 1.

[0078] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 C 1-6 Alkyl; R 1 C 1-6 Haloalkoxy or L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 Fused with phenyl to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl; R 3a is methyl; R 3b is a hydrogen atom; m is 0 or 1.

[0079] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 Selected from C 1-6alkyl, 3 to 8 membered cycloalkyl and 3 to 12 membered heterocyclic group; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6; each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; R 3a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; R 3b is a hydrogen atom; m is 0, 1 or 2.

[0080] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 C 1-6 Alkyl; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6; each R 2are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; R 3a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; R 3b is a hydrogen atom; m is 0, 1 or 2.

[0081] In some embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 C 1-6 Alkyl; R 1 C 1-6 Haloalkoxy or L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6; each R 2 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; R 3a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; R 3b is a hydrogen atom; m is 0, 1 or 2.

[0082] In some embodiments of the present disclosure, the compound represented by the general formula (II), the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 Selected from C 1-6 alkyl, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocyclic group; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; R 3a is methyl; R 3b is a hydrogen atom; m is 0 or 1.

[0083] In some embodiments of the present disclosure, the compound represented by the general formula (II), the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 C 1-6 Alkyl; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 6-membered cycloalkyl, 3 to 6-membered heterocyclyl and 5 or 6-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; R 3a is methyl; R 3b is a hydrogen atom; m is 0 or 1.

[0084] In some embodiments of the present disclosure, the compound represented by the general formula (II), the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 0 C 1-6 Alkyl; R 1 C 1-6 Haloalkoxy or L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; R 3a is methyl; R 3b is a hydrogen atom; m is 0 or 1.

[0085] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 is selected from isopropyl, tetrahydropyranyl and cyclohexyl; for Wherein, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclic group; R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and Each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 Fused with phenyl to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl; R 3a is methyl; R 3b is a hydrogen atom; L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 Alkyl; p is 0, 1 or 2.

[0086] In some embodiments of the present disclosure, the compound represented by the general formula (II) or the general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein R 0 is tetrahydropyranyl; for R 1 C 1-6 Alkyl; R 2 is a hydrogen atom or a halogen; R 3a is methyl; R3b A hydrogen atom.

[0087] Table A Typical compounds of the present disclosure include, but are not limited to:

[0088]

[0089]

[0090]

[0091]

[0092] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0093]

[0094] The compound represented by the general formula (IA) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0095] in:

[0096] R w is a leaving group, preferably a pyrazolyl group;

[0097] Ring A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (I).

[0098] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0099]

[0100] The compound represented by the general formula (IA-1) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (I-1) or its pharmaceutically acceptable salt;

[0101] in:

[0102] R w is a leaving group, preferably a pyrazolyl group;

[0103] Ring A, R 0 , R 1 , R 2 , R 3a , R 3band m are as defined in the general formula (I-1).

[0104] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0105]

[0106] The compound represented by the general formula (IIA) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;

[0107] in:

[0108] R w is a leaving group, preferably a pyrazolyl group;

[0109] R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (II).

[0110] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0111]

[0112] The compound represented by the general formula (IIA-1) or a salt thereof (preferably a hydrochloride) undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof;

[0113] in:

[0114] R w is a leaving group, preferably a pyrazolyl group;

[0115] R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (II-1).

[0116] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0117] The present disclosure further relates to the use of compounds represented by formula (I), formula (I-1), formula (II), formula (II-1) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, in the preparation of myosin inhibitors.

[0118] The present disclosure further relates to the use of the compounds of formula (I), formula (I-1), formula (II), formula (II-1) and Table A or their pharmaceutically acceptable salts or pharmaceutical compositions comprising the same in the preparation of a medicament for treating a disease or condition, wherein the disease or condition is selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM) (such as non-obstructive hypertrophic cardiomyopathy (nHCM) and obstructive hypertrophic cardiomyopathy (oHCM)), heart failure with normal ejection fraction (HFpEF), heart failure with intermediate ejection fraction (HFpEF), and heart failure with normal ejection fraction (HFpEF). The present invention relates to a cardiomyopathy selected from the group consisting of ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, myocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from the group consisting of ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0119] The present disclosure further relates to the use of the compounds shown in general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A or their pharmaceutically acceptable salts or pharmaceutical compositions comprising the same in the preparation of a medicament for treating a disease or condition mediated by Myosin, wherein the disease or condition is selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with intermediate ejection fraction (HFmREF), valvular disease, Aortic stenosis, inflammatory cardiomyopathy, Loeffler's endocarditis, myocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0120] The present disclosure further relates to a method for inhibiting myosin, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0121] The present disclosure further relates to a method for treating a disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II), formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with intermediate ejection fraction (HFmREF), valvular disease, Aortic stenosis, inflammatory cardiomyopathy, Loeffler's endocarditis, myocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0122] The present disclosure further relates to a method for treating a disease or condition mediated by Myosin, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II), formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with intermediate ejection fraction (HFmREF), Valvular disease, aortic stenosis, inflammatory cardiomyopathy, Loeffler's endocarditis, myocardial endocarditis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0123] The present disclosure further relates to a compound represented by formula (I), formula (I-1), formula (II), formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0124] The present disclosure further relates to a compound shown in general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a myosin inhibitor.

[0125] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II), formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating a disease or condition selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with mid-range ejection fraction (HFmREF), valvular disease, aortic stenosis, Inflammatory cardiomyopathy, Loeffler's endocarditis, myocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0126] The present disclosure further relates to a compound of formula (I), formula (I-1), formula (II), formula (II-1) and Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating a disease or condition mediated by Myosin, wherein the disease or condition is selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with intermediate ejection fraction (HFmREF), valvular disease, aortic Valvular stenosis, inflammatory cardiomyopathy, Loeffler's endocarditis, myocardial endocarditis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0127] The compounds shown in the general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A disclosed herein or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, can change the natural history of HCM and other diseases, rather than just relieving symptoms. The mechanism of clinical benefit to HCM patients can be extended to patients with other forms of heart disease, which share similar pathophysiology and have or do not have significant genetic factors. For example, effective treatment of HCM by improving ventricular relaxation during diastole can also be effectively used in a wider range of populations characterized by diastolic dysfunction.

[0128] The compounds shown in the general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A of the present invention or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, can specifically target the root cause of the disease or act on other downstream pathways. Therefore, the compounds shown in the general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A of the present invention or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, can provide benefits to patients with diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris or restrictive cardiomyopathy.

[0129] The compounds of the general formula (I), general formula (I-1), general formula (II), general formula (II-1) and shown in Table A disclosed herein or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, can also promote beneficial ventricular remodeling due to left ventricular hypertrophy caused by volume or pressure overload; for example, chronic mitral regurgitation, chronic aortic stenosis or chronic systemic hypertension; the compounds or their pharmaceutically acceptable salts are combined with therapies aimed at correcting or alleviating the main causes of volume or pressure overload (valve repair / replacement, effective antihypertensive therapy). By reducing left ventricular filling pressure, the compounds can reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and / or reducing left atrial pressure can reduce the risk of sudden or persistent atrial fibrillation, and it reduces the concomitant risk of arterial thromboembolic complications including but not limited to cerebral artery embolic stroke. Reducing or eliminating dynamic and / or static left ventricular outflow tract obstruction can reduce the possibility of requiring septal ablation therapy (surgical or percutaneous) and its concomitant risks of short-term and long-term complications.

[0130] The compounds of the present invention represented by formula (I), formula (I-1), formula (II), formula (II-1) and Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, can reduce the severity of the chronic ischemic state associated with HCM, and thereby reduce the risk of sudden cardiac death (SCD) or its equivalent in patients with implantable cardioverter-defibrillators (frequent and / or repeated ICD discharges) and / or reduce the need for potentially toxic antiarrhythmic drugs.

[0131] The compounds of the present invention, represented by the general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same, are valuable in reducing or eliminating the need for concurrent drugs (with their associated potential toxicity, drug-drug interactions and / or side effects).

[0132] The compounds of the general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A disclosed herein or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same can reduce interstitial myocardial fibrosis and / or slow down the progression of left ventricular hypertrophy, and prevent or reverse left ventricular hypertrophy.

[0133] Compound MYK-461( Example 1 of WO2014205223A1) Due to T 1 / 2 The accumulation is relatively long in clinical practice, and clinical administration needs to be constantly adjusted, which increases the risk of medication. The T of the compound in Example 16 of the present disclosure is 1 / 2There is a significant shortening. In addition, the compound of Example 16 of the present disclosure did not accumulate significantly in rats after repeated oral administration to rats for 14 days, while the compound MYK-461 accumulated severely in rats. In the reactive metabolite identification experiment in human liver microsomes, no glutathione (GSH) conjugates related to the compound of Example 16 of the present disclosure were detected, but GSH conjugates related to the compound MYK-461 were detected. It can be seen that the compound of Example 16 of the present disclosure has obvious pharmacokinetic and toxicokinetic advantages over the compound MYK-461, and exhibits better safety.

[0134] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compound of the present disclosure can also be formulated into a sustained release dosage form, such as a tablet, a hard or soft capsule, an aqueous or oily suspension, an emulsion, an injection, a dispersible powder or granules, a suppository, a lozenge or a syrup.

[0135] As a general guide, the active compound is preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the disclosed compound or composition can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0136] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0137] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0138] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0139] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0140] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0141] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0142] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0143] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0144] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0145] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0146] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the best treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0147] Terminology

[0148] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0149] The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. Most preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0150] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 Alkylene). Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0151] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, preferably an alkenyl group (i.e., C 2 to 12) carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12). 2-12 The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 The term "alkenyl" refers to an alkylene group (alkylene group). Non-limiting examples include ethenyl, propenyl, isopropenyl, butenyl, etc. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0152] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above, and an alkynyl group (i.e., C 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) of carbon atoms. 2-12 The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0153] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0154] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 3 to 20-membered cycloalkyl), preferably 3 to 12 carbon atoms (i.e., 3 to 12-membered cycloalkyl), preferably 3 to 8 carbon atoms (i.e., 3 to 8-membered cycloalkyl), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyls include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, etc.; polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0155] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, spirocycloalkyl is divided into single spiral cycloalkyl or multi-spirocycloalkyl (such as double spiral cycloalkyl), preferably single spiral cycloalkyl and double spiral cycloalkyl. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 6 yuan, 6 yuan / 4 yuan or 6 yuan / 5 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0156] Its connection point can be at any position.

[0157] The term "condensed cycloalkyl" refers to 5 to 20 yuan, a full carbon polycyclic group sharing a pair of adjacent carbon atoms between the rings, wherein one or more rings may contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g. 7, 8, 9 or 10 yuan). According to the number of the composition ring, it can be divided into polycyclic condensed cycloalkyls such as bicyclic, tricyclic, tetracyclic, preferably bicyclic or tricyclic, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 5 yuan / 7 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan of bicyclic alkyl. Non-limiting examples of condensed cycloalkyl include:

[0158]

[0159] , whose connection points can be at any position.

[0160] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, polycyclic bridged cycloalkyls such as bicyclic, tricyclic, and tetracyclic can be divided, preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyls, more preferably bicyclic or tricyclic bridged cycloalkyls. Non-limiting examples of bridged cycloalkyls include:

[0161] Its connection point can be at any position.

[0162] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred

[0163] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0164] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having from 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably, there are 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) ring atoms, of which 1-4 (e.g., 1, 2, 3 and 4) are heteroatoms (i.e., 3 to 12-membered heterocyclyl); more preferably, there are 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (e.g., 1, 2 and 3) (i.e., 3 to 8-membered heterocyclyl); more preferably, there are 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e., 3 to 6-membered heterocyclyl); most preferably, there are 5 or 6 ring atoms, of which 1-3 are heteroatoms (i.e., 5 or 6-membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl, etc. The polycyclic heterocyclic group includes a spirocyclic heterocyclic group, a fused-ring heterocyclic group and a bridged-ring heterocyclic group.

[0165] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group or a multi-spiro heterocyclic group (such as a double spiral heterocyclic group), preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0166] wait.

[0167] The term "fused heterocyclic radical" refers to 5 to 20 yuan, a polycyclic heterocyclic group that shares a pair of atoms adjacent to each other between the rings, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of the composition rings, it can be divided into polycyclic fused heterocyclic radicals such as bicyclic, tricyclic, tetracyclic, preferably bicyclic or tricyclic fused heterocyclic radicals, more preferably 3 yuan / 4 yuan, 3 yuan / 5 yuan, 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 3 yuan, 5 yuan / 4 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan, 6 yuan / 3 yuan, 6 yuan / 4 yuan, 6 yuan / 5 yuan, 6 yuan / 6 yuan, 6 yuan / 7 yuan, 7 yuan / 5 yuan or 7 yuan / 6 yuan bicyclic fused heterocyclic radicals. Non-limiting examples of fused heterocyclic groups include:

[0168]

[0169] wait.

[0170] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic and other polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclic groups include:

[0171] wait.

[0172] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0173] wait.

[0174] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

[0175] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0176]

[0177] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0178] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably a 5- to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably a 5- or 6-membered heteroaryl group, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyridonyl, N-alkylpyridone (e.g., The heteroaryl ring includes the above-mentioned heteroaryl fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0179]

[0180] wait.

[0181] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0182] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing a hydrogen atom, or residues derived from the same ring atom or two different ring atoms of the parent by removing two hydrogen atoms, namely "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

[0183] The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.

[0184] The term "hydroxy protecting group" refers to a group introduced on a hydroxy group that is easily removed and is usually used to block or protect the hydroxy group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

[0185] The term "cycloalkyloxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0186] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0187] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0188] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0189] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0190] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0191] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0192] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0193] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0194] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0195] The term "hydroxy" refers to -OH.

[0196] The term "thiol" refers to -SH.

[0197] The term "amino" refers to -NH2.

[0198] The term "cyano" refers to -CN.

[0199] The term "nitro" refers to -NO2.

[0200] The term "oxo" refers to "=0".

[0201] The term "carbonyl" refers to C=O.

[0202] The term "carboxy" refers to -C(O)OH.

[0203] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0204] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms may be isolated in optically pure form or in racemic form. Optically pure forms may be resolved from racemic mixtures or synthesized by using chiral raw materials or chiral reagents.

[0205] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations.

[0206] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, i.e., it can be Z, E, or both. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

[0207] Compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. Lactam-lactim equilibrium examples are between A and B as shown below.

[0208]

[0209] All compounds in the present disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

[0210] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl, etc. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for disease, or as tracers for pharmacodynamic, pharmacokinetics or receptor studies.

[0211] The present disclosure also includes various deuterated compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated compounds, or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Unless otherwise specified, when a position is specifically designated as deuterium (D), the position should be understood to have a deuterium (i.e., at least 10% deuterium incorporation) with an abundance of at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). Examples of compounds having a natural abundance greater than deuterium may be at least 1000 times more abundant in deuterium, at least 2000 times more abundant in deuterium, at least 3000 times more abundant in deuterium, at least 4000 times more abundant in deuterium, at least 5000 times more abundant in deuterium, at least 6000 times more abundant in deuterium, or more.

[0212] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally C substituted with halogen or cyano 1-6 "Alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted with halogen or cyano and the case where the alkyl is not substituted with halogen and cyano.

[0213] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently replaced by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0214] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0215] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0216] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0217] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0218] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0219] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0220] Synthesis method of the disclosed compound

[0221] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0222] Solution 1

[0223] The present invention discloses a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0224]

[0225] The compound represented by the general formula (IA) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction directly or in the presence of a base with the compound represented by the general formula (V) to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt;

[0226] in:

[0227] R w is a leaving group, preferably a pyrazolyl group;

[0228] Ring A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (I).

[0229] Solution 2

[0230] The present invention discloses a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0231]

[0232] The compound represented by the general formula (IA-1) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction directly or in the presence of a base with the compound represented by the general formula (V) to obtain the compound represented by the general formula (I-1) or its pharmaceutically acceptable salt;

[0233] in:

[0234] R w is a leaving group, preferably a pyrazolyl group;

[0235] Ring A, R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (I-1).

[0236] Option 3

[0237] The present invention discloses a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0238]

[0239] The compound represented by the general formula (IIA) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction directly or in the presence of a base with the compound represented by the general formula (V) to obtain the compound represented by the general formula (II) or its pharmaceutically acceptable salt;

[0240] in:

[0241] R w is a leaving group, preferably a pyrazolyl group;

[0242] R 0 , R 1 , R 2, R 3a , R 3b and m are as defined in the general formula (II).

[0243] Option 4

[0244] The present invention discloses a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0245]

[0246] The compound represented by the general formula (IIA-1) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction directly or in the presence of a base with the compound represented by the general formula (V) to obtain the compound represented by the general formula (II-1) or its pharmaceutically acceptable salt;

[0247] in:

[0248] R w is a leaving group, preferably a pyrazolyl group;

[0249] R 0 , R 1 , R 2 , R 3a , R 3b and m are as defined in the general formula (II-1).

[0250] In the above scheme, the base includes organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, preferably triethylamine and N,N-diisopropylethylamine; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide.

[0251] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.

[0252] The above nucleophilic substitution reaction is a conventional reaction, and the reaction temperature is 100-160°C, preferably 120°C.

[0253] The above nucleophilic substitution reaction is a conventional reaction, and the reaction time is 10-20 hours, preferably 16 hours.

[0254] The above nucleophilic substitution reaction can also be carried out in a microwave, and the reaction temperature of the microwave reaction is 100-160°C, preferably 140°C.

[0255] The above nucleophilic substitution reaction can also be carried out in a microwave, and the reaction time of the microwave reaction is 0.5-4 hours, preferably 2 hours. DETAILED DESCRIPTION

[0256] The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

[0257] Example

[0258] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0259] MS was measured using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0260] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0261] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0262] High performance liquid chromatography was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

[0263] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0264] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0265] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0266] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0267] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0268] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0269] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0270] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0271] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0272] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0273] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0274] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0275] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0276] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0277] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0278] Example 1

[0279] 6-(((S)-1-(2-fluoro-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 1

[0280]

[0281] first step

[0282] 3-Isopropyl-6-(1H-pyrazol-1-yl)-1,3,5-triazine-2,4(1H,3H)-dione 1c

[0283] 2-isocyanatopropane 1a (4.06 g, 47.71 mmol, Shanghai Titan Technology Co., Ltd.) and 1H-pyrazole-1-carboxamidine hydrochloride 1b (6.66 g, 45.44 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were dissolved in N,N-dimethylacetamide (35 mL), cooled to -10 ° C, 1,8-diazabicycloundec-7-ene (12.00 g, 47.65 mmol) was added dropwise, and the dropwise addition was completed after 5 minutes. The reaction was stirred for 30 minutes in an ice bath. N,N'-carbonyldiimidazole (9.80 g, 68.08 mmol) was added in an ice bath, cooled to -5 ° C, 1,8-diazabicycloundec-7-ene (17.14 g, 68.06 mmol) was added dropwise, and the dropwise addition was completed after 10 minutes. The reaction was stirred for 1 hour in an ice bath. At room temperature, 2N hydrochloric acid (132 mL) was added, and the mixture was added dropwise after 30 minutes. The filter cake was collected by filtration and dried in vacuo to obtain the title product 1c (3.30 g, yield: 32.9%).

[0284] MS m / z(ESI):222.0[M+1].

[0285] Step 2

[0286] (S)-2-Fluoro-5-((tetrahydrofuran-3-yl)oxy)benzaldehyde 1e

[0287] 4-Fluoro-3-formylphenylboronic acid 1d (10.00 g, 59.55 mmol, Hanhai Chemical Co., Ltd.) and (S)-tetrahydrofuran-3-ol (15.80 g, 179.33 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were dissolved in dichloromethane (100 mL), and copper acetate (22.00 g, 121.13 mmol), pyridine (10.00 g, 126.42 mmol) and triethylamine (13.00 g, 128.71 mmol) were added, and stirred at room temperature for 24 hours. Filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1e (1.00 g, yield: 8.0%).

[0288] MS m / z(ESI):211.0[M+1].

[0289] Step 3

[0290] (R)-N-(2-Fluoro-5-(((S)-tetrahydrofuran-3-yl)oxy)benzylidene)-2-methylpropane-2-sulfenamide 1f

[0291] Compound 1e (1.00 g, 4.76 mmol) and (R)-2-methylpropane-2-sulfenamide (580 mg, 4.78 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (20 mL), cesium carbonate (1.90 g, 5.83 mmol) was added, and stirred at room temperature for 16 hours. Filtered and concentrated under reduced pressure to obtain the crude product of the title product 1f (1.40 g, yield: 93.9%). The crude product was used directly in the next step without purification.

[0292] MS m / z(ESI):313.9[M+1].

[0293] Step 4

[0294] (R)-N-((S)-1-(2-fluoro-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide 1 g

[0295] The crude compound 1f (100 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL) and replaced with nitrogen three times. The reaction was cooled to -60 ° C, and a 3M methylmagnesium bromide solution in 2-methyltetrahydrofuran (0.22 mL, 0.66 mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 5 hours under nitrogen protection. A saturated ammonium chloride solution (10 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 1g (105 mg, yield: 99.9%).

[0296] MS m / z(ESI):330.0[M+1].

[0297] Step 5

[0298] (S)-1-(2-Fluoro-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)ethan-1-amine hydrochloride 1h

[0299] Dissolve compound 1g (105mg, 0.32mmol) in ethanol (5mL), cool to 0℃, and add thionyl chloride (101mg, 0.85mmol, Shanghai Hushi Chemical Co., Ltd.) dropwise. Stir the reaction at room temperature for 1 hour. Concentrate under reduced pressure to obtain the crude product of the title product 1h (83mg, yield: 99.5%). The crude product is used directly in the next step without purification.

[0300] MS m / z(ESI):208.9[M-16].

[0301] Step 6

[0302] 6-(((S)-1-(2-fluoro-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 1

[0303] Compound 1c (70 mg, 0.32 mmol) and compound 1h (83 mg, 0.32 mmol) were dissolved in N-methylpyrrolidone (8 mL), triethylamine (64 mg, 0.63 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 1 (6 mg, yield: 5.0%).

[0304] MS m / z(ESI):379.0[M+1].

[0305] 1 H NMR(500MHz,DMSO-d6)δ10.50(brs,1H),7.66(brs,1H),7.11(m,1H),6.92(m,1H),6.84(m,1H),5.22(m,1H ),4.96(m,1H),4.80(m,1H),3.89-3.71(m,4H),2.19(m,1H),2.02-1.88(m,1H),1.39(d,3H),1.29(d,6H).

[0306] Example 2

[0307] 6-(((S)-1-(2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 2

[0308]

[0309] first step

[0310] (R)-2-Fluoro-5-((tetrahydrofuran-3-yl)oxy)benzaldehyde 2a

[0311] Compound 1d (10 g, 59.5 mmol) and (R)-tetrahydrofuran-3-ol (10 g, 113 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (100 mL), and pyridine (10 g, 126 mmol, adamas), triethylamine (13 g, 129 mmol, adamas), anhydrous copper acetate (23 g, 127 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were added, and the reaction was stirred for 24 hours. Filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 2a (1.9 g, yield: 15.2%).

[0312] MS m / z(ESI):211.0[M+1].

[0313] Step 2

[0314] (R)-N-(2-Fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)benzylidene)-2-methylpropane-2-sulfenamide 2b

[0315] Compound 2a (1.9 g, 9.04 mmol) and (R)-2-methylpropane-2-sulfenamide (1.1 g, 9.08 mmol, adamas) were dissolved in dichloromethane (30 mL), cesium carbonate (3.6 g, 11.4 mmol) was added, and the mixture was stirred for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain a crude product of the title product 2b (2.8 g, yield: 98.8%).

[0316] MS m / z(ESI):313.9[M+1].

[0317] Step 3

[0318] (R)-N-((S)-1-(2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide 2c

[0319] The crude compound 2b (300 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL) and replaced with nitrogen three times. The reaction was cooled to -60 ° C, and a 3M methylmagnesium bromide solution in 2-methyltetrahydrofuran (0.67 mL, 2.01 mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 5 hours under nitrogen protection. A saturated ammonium chloride solution (10 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 2c (315 mg, yield: 99.9%). MS m / z (ESI): 330.0 [M+1].

[0320] Step 4

[0321] (S)-1-(2-Fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)ethylamine hydrochloride 2d

[0322] Compound 2c (315 mg, 0.96 mmol) was dissolved in ethanol (6 mL), cooled to 0°C, and thionyl chloride (303 mg, 2.55 mmol, Shanghai Hushi Chemical Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 2d (250 mg, yield: 99.9%). The crude product was used directly in the next step without purification.

[0323] MS m / z(ESI):208.9[M-16].

[0324] Step 5

[0325] 6-(((S)-1-(2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 2

[0326] Compound 1c (164 mg, 0.74 mmol) and compound 2d (250 mg, 0.96 mmol) were dissolved in N-methylpyrrolidone (8 mL), triethylamine (75 mg, 0.74 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 2 (30 mg, yield: 10.7%).

[0327] MS m / z(ESI):379.0[M+1].

[0328] 1 H NMR (500MHz, DMSO-d6): δ10.52(brs,1H),7.27(brs,1H),7.13(m,1H),6.92-6.83(m,2H),5.20(m,1H ),4.97(m,1H),4.79(m,1H),3.88-3.73(m,4H),2.20(m,1H),1.95(m,1H),1.39(d,3H),1.29(d,6H).

[0329] Example 3

[0330] 3-Isopropyl-6-(((1S)-1-(3-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 3

[0331]

[0332] first step

[0333] Tetrahydrofuran-3-yl methanesulfonate 3b

[0334] Tetrahydrofuran-3-ol 3a (2.0 g, 22.7 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and triethylamine (3.4 g, 33.7 mmol) were dissolved in dichloromethane (20 mL), and methylsulfonyl chloride (2.84 g, 24.9 mmol, Shanghai Sinopharm Chemical Reagent Co., Ltd.) was added at 0°C, and the mixture was reacted at room temperature for 24 hours. Water (100 mL) was added, and the mixture was extracted with dichloromethane (20 mL×2), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3b (3.1 g, yield: 82.2%).

[0335] 1 H NMR (500MHz, CDCl3) δ5.34(m,1H),4.06-3.89(m,4H),3.06(s,3H),2.29-2.24(m,2H).

[0336] Step 2

[0337] 3-((Tetrahydrofuran-3-yl)oxy)benzaldehyde 3c

[0338] Compound 3b (700 mg, 4.21 mmol) and 3-hydroxybenzaldehyde (500 mg, 4.09 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were dissolved in N,N-dimethylformamide (10 mL), potassium carbonate (850 mg, 6.16 mmol) was added, and the mixture was reacted at 90°C for 16 hours. The mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL×2), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3c (710 mg, yield: 90.2%).

[0339] MS m / z(ESI):193.0[M+1].

[0340] Step 3

[0341] (R)-2-Methyl-N-(3-((tetrahydrofuran-3-yl)oxy)benzylidene)propane-2-sulfenamide 3d

[0342] Compound 3c (710 mg, 3.69 mmol) and (R)-2-methylpropane-2-sulfenamide (450 mg, 3.71 mmol) were dissolved in dichloromethane (10 mL), cesium carbonate (1.5 g, 4.60 mmol) was added, and the mixture was stirred for 16 hours. The mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3d (1.08 g, yield: 99.0%).

[0343] MS m / z(ESI):296.0[M+1].

[0344] Step 4

[0345] (R)-2-Methyl-N-((1S)-1-(3-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)propane-2-sulfenamide 3e

[0346] Compound 3d (500 mg, 1.69 mmol) was dissolved in dichloromethane (10 mL). Under nitrogen protection, the mixture was cooled to -60 °C and a 3M methylmagnesium bromide solution in 2-methyltetrahydrofuran (1.2 mL, 3.6 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 16 hours. At 0 °C, a saturated aqueous ammonium chloride solution (20 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 3e (490 mg, yield: 92.9%).

[0347] MS m / z(ESI):312.1[M+1].

[0348] Step 5

[0349] (1S)-1-(3-((Tetrahydrofuran-3-yl)oxy)phenyl)ethylamine hydrochloride 3f

[0350] Compound 3e (490 mg, 1.57 mmol) was dissolved in ethanol (5.0 mL), and thionyl chloride (220 mg, 1.85 mmol) was added at 0°C. The mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product of the title product 3f (390 mg, 102%), which was used directly in the next step without purification.

[0351] MS m / z(ESI):208.1[M+1].

[0352] Step 6

[0353] 3-Isopropyl-6-(((1S)-1-(3-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 3

[0354] Compound 1c (150 mg, 0.68 mmol) and compound 3f (211 mg, 0.87 mmol) were dissolved in N-methylpyrrolidone (6 mL), triethylamine (69 mg, 0.68 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 3 (40 mg, yield: 16.4%).

[0355] MS m / z(ESI):361.0[M+1].

[0356] 1 H NMR(500MHz,DMSO-d6)δ10.45(brs,1H),7.28-7.25(m,2H),6.92-6.88(m,2H),6.81(m,1H),5.02- 4.98(m,2H),4.81(m,1H),3.90-3.74(m,4H),2.19(m,1H),1.92(m,1H),1.40(d,3H),1.29(d,6H).

[0357] Example 4

[0358] (S)-3-Isopropyl-6-((1-(3-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 4

[0359]

[0360] first step

[0361] 3-((6-Methylpyridin-3-yl)oxy)benzaldehyde 4b

[0362] (3-Formylphenyl)boronic acid 4a (800 mg, 5.34 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and 6-methylpyridine-3-ol (300 mg, 275 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (6.0 mL), triethylamine (560 mg, 5.54 mmol), pyridine (440 mg, 5.56 mmol) and anhydrous copper acetate (1.0 g, 5.51 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were added, and the reaction was stirred for 24 hours. Celite was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4b (410 mg, yield: 69.9%).

[0363] MS m / z(ESI):214.0[M+1].

[0364] Step 2

[0365] (R)-2-Methyl-N-(3-((6-methylpyridin-3-yl)oxy)benzylidene)propane-2-sulfenamide 4c

[0366] Compound 4b (410 mg, 1.92 mmol) and (R)-2-methylpropane-2-sulfenamide (235 mg, 1.94 mmol, adamas) were dissolved in dichloromethane (6 mL), cesium carbonate (760 mg, 2.33 mmol) was added, and the reaction was stirred for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 4c (560 mg, yield: 92.0%).

[0367] MS m / z(ESI):317.1[M+1].

[0368] Step 3

[0369] (R)-2-Methyl-N-((S)-1-(3-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)propane-2-sulfenamide 4d

[0370] Compound 4c (500 mg, 1.58 mmol) was dissolved in dichloromethane (10 mL). Under nitrogen protection, the reaction was cooled to -60 ° C, and 3M methylmagnesium bromide in 2-methyltetrahydrofuran solution (1.1 mL, 3.3 mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise. The reaction was heated to room temperature and stirred for 16 hours. At 0 ° C, saturated aqueous ammonium chloride solution (20 mL) was added to separate the organic phase. The aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 4d (480 mg, yield: 91.3%).

[0371] MS m / z(ESI):333.1[M+1].

[0372] Step 4

[0373] (S)-1-(3-((6-methylpyridin-3-yl)oxy)phenyl)ethylamine hydrochloride 4e

[0374] Compound 4d (250 mg, 0.75 mmol) was dissolved in ethanol (6 mL), cooled to 0°C, and thionyl chloride (238 mg, 2.00 mmol, Shanghai Hushi Chemical Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 4e (199 mg, yield: 99.9%). The crude product was used directly in the next step without purification.

[0375] MS m / z(ESI):229.0[M+1].

[0376] Step 5

[0377] (S)-3-Isopropyl-6-((1-(3-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 4

[0378] Compound 1c (129 mg, 0.58 mmol) and compound 4e (200 mg, 0.76 mmol) were dissolved in N-methylpyrrolidone (6 mL), triethylamine (59 mg, 0.58 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 4 (4 mg, yield: 1.8%).

[0379] MS m / z(ESI):382.0[M+1].

[0380] 1 H NMR(500MHz,DMSO-d6)δ10.46(brs,1H),8.24(s,1H),7.40-7.34(m,3H),7.27(m,1H),7.13(m,1 H),7.05(s,1H),6.86(m,1H),5.03(m,1H),4.80(m,1H),2.45(s,3H),1.39(d,3H),1.29(d,6H).

[0381] Example 5

[0382] (S)-3-Isopropyl-6-((1-(3-(trifluoromethoxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 5

[0383]

[0384]

[0385] first step

[0386] (R)-2-Methyl-N-(3-(trifluoromethoxy)benzylidene)propane-2-sulfenamide 5b

[0387] 3-(Trifluoromethoxy)benzaldehyde 5a (1.0 g, 5.26 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) and (R)-2-methylpropane-2-sulfenamide (640 mg, 5.28 mmol) were dissolved in dichloromethane (20 mL), cesium carbonate (2.1 g, 6.44 mmol) was added, and the mixture was stirred for 16 hours. The mixture was filtered, concentrated, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5b (1.45 g, yield: 94.0%).

[0388] MS m / z(ESI):294.0[M+1].

[0389] Step 2

[0390] (R)-2-Methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfenamide 5c

[0391] Compound 5b (500 mg, 1.70 mmol) was dissolved in dichloromethane (10 mL). Under nitrogen protection, the mixture was cooled to -60 °C and a 3M methylmagnesium bromide solution in 2-methyltetrahydrofuran (1.2 mL, 3.6 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 16 hours. At 0 °C, a saturated aqueous ammonium chloride solution (20 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 5c (490 mg, yield: 92.9%).

[0392] MS m / z(ESI):310.0[M+1].

[0393] Step 3

[0394] (S)-1-(3-(Trifluoromethoxy)phenyl)ethylamine hydrochloride 5d

[0395] Compound 5c (250 mg, 0.81 mmol) was dissolved in ethanol (10 mL), cooled to 0°C, and thionyl chloride (256 mg, 2.15 mmol, Shanghai Hushi Chemical Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 5d (195 mg, yield: 99.9%). The crude product was used directly in the next step without purification.

[0396] MS m / z(ESI):188.8[M-16].

[0397] Step 4

[0398] (S)-3-Isopropyl-6-((1-(3-(trifluoromethoxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 5

[0399] Compound 1c (119 mg, 0.54 mmol) and compound 5d (195 mg, 0.81 mmol) were dissolved in N-methylpyrrolidone (6 mL), triethylamine (54 mg, 0.53 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 5 (30 mg, yield: 15.6%).

[0400] MS m / z(ESI):359.0[M+1].

[0401] 1 H NMR(500MHz,DMSO-d6)δ10.49(brs,1H),7.68(brs,1H),7.48(m,1H),7.40-7 .35(m,2H),7.25(m,1H),5.10(m,1H),4.81(m,1H),1.42(d,3H),1.29(d,6H).

[0402] Example 6

[0403] (S)-6-((1-(5-cyclopropyl-2-fluorophenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 6

[0404]

[0405] first step

[0406] 5-Cyclopropyl-2-fluorobenzaldehyde 6b

[0407] 5-Bromo-2-fluorobenzaldehyde 6a (10.00 g, 49.26 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) and cyclopropylboronic acid (6.35 g, 73.93 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were dissolved in 1,4-dioxane (100 mL) and water (5 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.42 g, 2.96 mmol) and tripotassium phosphate (27.15 g, 128.07 mmol) were added, nitrogen was replaced three times, and stirred at 100°C for 16 hours. Filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 6b (7.00 g, yield: 86.6%).

[0408] 1 H NMR (500MHz, CDCl3) δ10.32(s,1H),7.52(m,1H),7.31(m,1H),7.05(m,1H),1.91(m,1H),1.01-0.97(m,2H),0.70-0.66(m,2H).

[0409] Step 2

[0410] (R)-N-(5-cyclopropyl-2-fluorobenzylidene)-2-methylpropane-2-sulfenamide 6c

[0411] Compound 6b (1.00 g, 6.09 mmol) and (R)-2-methylpropane-2-sulfenamide (738 mg, 6.09 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (20 mL), cesium carbonate (2.38 g, 7.30 mmol) was added, and the mixture was stirred for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain a crude product of the title product 6c (1.62 g, yield: 99.5%). The crude product was used directly in the next step without purification.

[0412] MS m / z(ESI):268.0[M+1].

[0413] Step 3

[0414] (R)-N-((S)-1-(5-cyclopropyl-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide 6d

[0415] The crude compound 6c (1.62 g, 6.06 mmol) was dissolved in dichloromethane (10 mL) and replaced with nitrogen three times. The reaction was cooled to -60 ° C, and a 3M methylmagnesium bromide solution in 2-methyltetrahydrofuran (4.25 mL, 12.75 mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 5 hours under nitrogen protection. A saturated ammonium chloride solution (10 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 mL × 2), and the organic phases were combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 6d (1.70 g, yield: 99.0%).

[0416] MS m / z(ESI):284.0[M+1].

[0417] Step 4

[0418] (S)-1-(5-Cyclopropyl-2-fluorophenyl)ethylamine hydrochloride 6e

[0419] Compound 6d (300 mg, 1.06 mmol) was dissolved in ethanol (10 mL), cooled to 0°C, and thionyl chloride (335 mg, 2.82 mmol, Shanghai Hushi Chemical Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 6e (228 mg, yield: 99.9%). The crude product was used directly in the next step without purification.

[0420] MS m / z(ESI):179.9[M+1].

[0421] Step 5

[0422] (S)-6-((1-(5-cyclopropyl-2-fluorophenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 6

[0423] Compound 1c (156 mg, 0.71 mmol) and compound 6e (190 mg, 0.88 mmol) were dissolved in N-methylpyrrolidone (8 mL), triethylamine (71 mg, 0.71 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 6 (50 mg, yield: 21.3%).

[0424] MS m / z(ESI):333.0[M+1].

[0425] 1 H NMR(500MHz,DMSO-d6)δ10.48(brs,1H),7.20(brs,1H),7.12(m,1H),7.06(m,1H),6.98(m,1H),5.2 2(m,1H),4.80(m,1H),1.92(m,1H),1.40(d,3H),1.29(d,6H),0.95-0.91(m,2H),0.65-0.62(m,2H).

[0426] Example 7

[0427] (S)-6-((1-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 7

[0428]

[0429]

[0430] first step

[0431] (R)-N-(Bicyclo[4.2.0]oct-1(6),2,4-trien-3-ylmethylidene)-2-methylpropane-2-sulfenamide 7b

[0432] Bicyclo[4.2.0]octane-1(6),2,4-triene-3-carboxaldehyde 7a (2.9 g, 22.0 mmol, prepared by the method disclosed in step 1 of the patent application "WO2019023147A1, pages 512-513") and (R)-2-methylpropane-2-sulfenamide (2.8 g, 23.0 mmol) were dissolved in dichloromethane (40 mL). Cesium carbonate (8.6 g, 26.4 mmol) was added and the reaction was stirred for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 7b (5.7 g), which was used directly in the next step without purification.

[0433] MS m / z(ESI):236.1[M+1].

[0434] Step 2

[0435] (R)-N-((S)-1-(Bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)ethyl)-2-methylpropane-2-sulfenamide 7c

[0436] To a solution of the crude compound 7b (2.8 g, 12.1 mmol) in anhydrous dichloromethane (80 mL) was added dropwise 3 M methyl magnesium bromide in methyltetrahydrofuran (8.1 mL, 24.2 mmol, Shanghai Titan Technology Co., Ltd.) at -50°C. The mixture was reacted at room temperature for 16 hours under nitrogen protection. Saturated aqueous ammonium chloride solution (50 mL) was added and extracted with dichloromethane (50 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 7c (2.0 g, yield: 66.2%).

[0437] MS m / z(ESI):252.1[M+1].

[0438] Step 3

[0439] (S)-1-(Bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)ethylamine hydrochloride 7d

[0440] Compound 7c (500.0 mg, 2.0 mmol) was dissolved in methanol (3 mL), and a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added dropwise. The reaction was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product of the title product 7d (366.0 mg), which was used directly in the next step without purification.

[0441] MS m / z(ESI):131.1[M-16].

[0442] Step 4

[0443] (S)-6-((1-(bicyclo[4.2.0]oct-1(6),2,4-trien-3-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 7

[0444] Compound 1c (182 mg, 0.82 mmol) and compound 7d (182 mg, 0.99 mmol) were dissolved in N-methylpyrrolidone (6 mL), triethylamine (83 mg, 0.82 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (BostonPhlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 7 (30 mg, yield: 12.1%).

[0445] MS m / z(ESI):301.0[M+1].

[0446] 1H NMR(500MHz,DMSO-d6)δ10.46(brs,1H),7.22(brs,1H),7.15(m,1H),7.10-7.01 (m,2H),4.96(m,1H),4.80(m,1H),3.14-3.08(m,4H),1.39(d,3H),1.29(d,6H).

[0447] Example 8

[0448] (S)-6-((1-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 8

[0449]

[0450] first step

[0451] (R)-N-((2,3-dihydrobenzofuran-6-yl)methylidene)-2-methylpropane-2-sulfenamide 8b

[0452] 2,3-Dihydrobenzofuran-6-carboxaldehyde 8a (1.0 g, 6.8 mmol, Jiangsu Aikang Biopharmaceutical R&D Co., Ltd.) and (R)-2-methylpropane-2-sulfenamide (860.0 mg, 7.1 mmol, Shanghai Titan Technology Co., Ltd.) were dissolved in dichloromethane (40 mL). Cesium carbonate (2.6 g, 8.1 mmol) was added and stirred for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 8b (1.8 g), which was used directly in the next step without purification.

[0453] MS m / z(ESI):252.0[M+1].

[0454] Step 2

[0455] (R)-N-((S)-1-(2,3-dihydrobenzofuran-6-yl)ethyl)-2-methylpropane-2-sulfenamide 8c

[0456] To a solution of the crude compound 8b (1.7 g, 6.8 mmol) in anhydrous dichloromethane (45 mL) at -50°C, a 3M solution of methylmagnesium bromide in methyltetrahydrofuran (4.9 mL, 14.6 mmol) was added dropwise. The mixture was reacted at room temperature for 16 hours under nitrogen protection. A saturated aqueous solution of ammonium chloride (30 mL) was added and extracted with dichloromethane (30 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 8c (1.6 g, yield: 90.6%).

[0457] MS m / z(ESI):268.1[M+1].

[0458] Step 3

[0459] (S)-1-(2,3-Dihydrobenzofuran-6-yl)ethylamine hydrochloride 8d

[0460] Compound 8c (534.0 mg, 2.0 mmol) was dissolved in methanol (3 mL), and a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added dropwise. The reaction was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product of the title product 8d (400.0 mg), which was used directly in the next step without purification.

[0461] MS m / z(ESI):147.1[M-16].

[0462] Step 4

[0463] (S)-6-((1-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 8

[0464] Compound 1c (168 mg, 0.76 mmol) and compound 8d (186 mg, 0.93 mmol) were dissolved in N-methylpyrrolidone (8 mL), triethylamine (77 mg, 0.76 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 8 (15 mg, yield: 6.2%).

[0465] MS m / z(ESI):317.0[M+1].

[0466] 1 H NMR(500MHz,DMSO-d6)δ10.45(brs,1H),7.21-7.16(m,2H),6.80-6.74(m,2H),4.95( m,1H),4.80(m,1H),4.52-4.49(m,2H),3.14-3.11(m,2H),1.39(d,3H),1.29(d,6H).

[0467] Example 9

[0468] (S)-6-((1-(2,3-dihydro-1H-inden-5-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 9

[0469]

[0470] first step

[0471] (R)-N-(1-(2,3-dihydro-1H-inden-5-yl)ethylidene)-2-methylpropane-2-sulfenamide 9b

[0472] To anhydrous tetrahydrofuran (20 mL) of 1-(2,3-dihydro-1H-inden-5-yl)ethan-1-one 9a (1.0 g, 6.3 mmol, TCI (Shanghai) Chemical Industry Development Co., Ltd.) and (R)-2-methylpropane-2-sulfenamide (1.1 g, 8.8 mmol, Shanghai Titan Technology Co., Ltd.), 1 M triisopropoxytitanium chloride hexane solution (7.5 mL, 7.5 mmol, Shanghai Titan Technology Co., Ltd.) was added. The reaction was stirred at 65°C for 16 hours. Saturated sodium bicarbonate aqueous solution (30 mL) was added and extracted with ethyl acetate (50 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 9b (570.0 mg, yield: 34.7%).

[0473] MS m / z(ESI):264.0[M+1].

[0474] Step 2

[0475] (R)-N-((S)-1-(2,3-dihydro-1H-inden-5-yl)ethyl)-2-methylpropane-2-sulfenamide 9c

[0476] At -78°C, 1M tri-sec-butylborohydride lithium tetrahydrofuran solution (3.5 mL, 3.5 mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise to anhydrous tetrahydrofuran (10 mL) of compound 9b (570 mg, 2.2 mmol). The mixture was reacted at 0°C for 1 hour. Saturated aqueous ammonium chloride solution (20 mL) was added and extracted with ethyl acetate (30 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain a crude product of the title product 9c (570 mg), which was used directly in the next step without purification.

[0477] MS m / z(ESI):266.1[M+1].

[0478] Step 3

[0479] (S)-1-(2,3-Dihydro-1H-inden-5-yl)ethylamine hydrochloride 9d

[0480] The crude compound 9c (570 mg, 2.2 mmol) was dissolved in methanol (3 mL), and a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added dropwise. The reaction was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude title product 9d (430.0 mg), which was used directly in the next step without purification.

[0481] MS m / z(ESI):145.1[M-16].

[0482] Step 4

[0483] (S)-6-((1-(2,3-dihydro-1H-inden-5-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 9

[0484] Compound 1c (170 mg, 0.77 mmol) and compound 9d (186 mg, 0.94 mmol) were dissolved in N-methylpyrrolidone (8 mL), triethylamine (78 mg, 0.77 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 9 (30 mg, yield: 12.4%).

[0485] MS m / z(ESI):315.0[M+1].

[0486] 1 H NMR(500MHz,DMSO-d6)δ10.45(brs,1H),7.20-7.17(m,3H),7.08(m,1H),4.98(m, 1H),4.80(m,1H),2.85-2.80(m,4H),2.03-1.97(m,2H),1.39(d,3H),1.29(d,6H).

[0487] Example 10

[0488] (S)-3-Isopropyl-6-((1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 10

[0489]

[0490] first step

[0491] (R)-2-Methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethylidene)propane-2-sulfenamide 10b

[0492] Tetraethoxytitanium (4.0 g, 17.3 mmol, Anaiji Chemical) was added to anhydrous tetrahydrofuran (20 mL) of 1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethan-1-one 10a (2.0 g, 11.5 mmol, Alfa Aesar (Tianjin) Chemical Co., Ltd.) and (R)-2-methylpropane-2-sulfinamide (2.1 g, 17.3 mmol, Shanghai Titan Technology Co., Ltd.). The reaction was stirred at 65 ° C for 16 hours. Saturated sodium bicarbonate aqueous solution (60 mL) was added and extracted with ethyl acetate (100 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 10b (2.6 g, yield: 81.6%). MS m / z (ESI): 278.0 [M+1].

[0493] Step 2

[0494] (R)-2-Methyl-N-((S)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)propane-2-sulfenamide 10c

[0495] Compound 10b (350 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL) and replaced with nitrogen three times. The reaction was cooled to -78 °C and a 1 M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (2.02 mL, 2.02 mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise. The reaction was stirred at 0 °C for 1 hour under nitrogen protection. Saturated ammonium chloride solution (10 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title product 10c (340 mg, yield: 96.4%).

[0496] MS m / z(ESI):280.0[M+1].

[0497] Step 3

[0498] (S)-1-(5,6,7,8-Tetrahydronaphthalen-2-yl)ethylamine hydrochloride 10d

[0499] Compound 10c (340 mg, 1.22 mmol) was dissolved in ethanol (10 mL), cooled to 0°C, and thionyl chloride (290 mg, 2.43 mmol, Shanghai Hushi Chemical Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 10d (257 mg, yield: 99.8%). The crude product was used directly in the next step without purification.

[0500] MS m / z(ESI):158.9[M-16].

[0501] Step 4 (S)-3-isopropyl-6-((1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 10

[0502] Compound 1c (271 mg, 1.23 mmol) and compound 10d (257 mg, 1.47 mmol) were dissolved in N-methylpyrrolidone (8 mL), triethylamine (124 mg, 1.23 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 10 (40 mg, yield: 9.9%).

[0503] MS m / z(ESI):329.0[M+1].

[0504] 1 H NMR(500MHz,DMSO-d6)δ10.48(brs,1H),7.23(brs,1H),7.04-6.99(m,3H),4.94(m ,1H),4.80(m,1H),2.71-2.63(m,4H),1.75-1.69(m,4H),1.37(d,3H),1.29(d,6H).

[0505] Embodiment 11

[0506] (S)-6-((1-(5-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 11

[0507]

[0508] first step

[0509] 5-Fluorobenzofuran-6-carboxylic acid methyl ester 11b

[0510] 6-Bromo-5-fluorobenzofuran 11a (3.20 g, 14.88 mmol, prepared by the patent application "Synthesis method of intermediate A1.2b on page 36 of WO2017219948A1 specification") was dissolved in methanol (50 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.26 g, 1.49 mmol) and N,N-diisopropylethylamine (3.01 g, 29.75 mmol) were added, replaced with carbon monoxide gas three times, and stirred at 70°C for 40 hours. Filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography with eluent system A to obtain the title product 11b (1.50 g, yield: 51.9%).

[0511] MS m / z(ESI):194.8[M+1].

[0512] Step 2

[0513] 5-Fluoro-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester 11c

[0514] Compound 11b (1.50 g, 7.73 mmol) was dissolved in methanol (50 mL), 10% palladium carbon hydrogenation catalyst (wet) was added, hydrogen was replaced three times, and the reaction was stirred for 16 hours. Filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 11c (1.37 g, yield: 90.4%).

[0515] MS m / z(ESI):196.8[M+1].

[0516] Step 3

[0517] (5-Fluoro-2,3-dihydrobenzofuran-6-yl)methanol11d

[0518] Compound 11c (1.37 g, 7.0 mmol) was dissolved in tetrahydrofuran (30 mL) solution, and 2 M lithium borohydride tetrahydrofuran solution (34.9 mL, 69.8 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours. Methanol (5 mL) was added to quench the reaction under ice bath, and the pH of the reaction solution was adjusted to 6 with 1 M hydrochloric acid, and extracted with ethyl acetate (30 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. Filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 11d (1.05 g, yield: 89.4%).

[0519] MS m / z(ESI):190.0[M+22].

[0520] Step 4

[0521] 5-Fluoro-2,3-dihydrobenzofuran-6-carbaldehyde 11e

[0522] Compound 11d (1.05 g, 6.24 mmol) was dissolved in dichloromethane (20 mL) solution, Dess-Martin oxidant (3.97 g, 9.36 mmol) was added, and the reaction was allowed to react at room temperature for 2 hours. Under an ice bath, saturated sodium thiosulfate (20 mL) and saturated sodium bicarbonate (20 mL) were added to quench the reaction, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 11e (1.03 g, yield: 99.3%).

[0523] MS m / z(ESI):167.0[M+1].

[0524] Step 5

[0525] (R)-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methylidene)-2-methylpropane-2-sulfenamide 11f

[0526] Compound 11e (1.30 g, 7.82 mmol) and (R)-2-methylpropane-2-sulfenamide (1.42 g, 11.72 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (20 mL). Cesium carbonate (1.58 g, 14.09 mmol) was added and stirred for 16 hours. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 11f (2.80 g), which was used directly in the next step without purification.

[0527] MS m / z(ESI):270.0[M+1].

[0528] Step 6

[0529] (R)-N-((S)-1-(5-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl)-2-methylpropane-2-sulfenamide 11 g

[0530] At -50°C, to a solution of the crude compound 11f (2.80 g, 10.40 mmol) in anhydrous dichloromethane (45 mL), a 3M solution of methyl magnesium bromide in methyltetrahydrofuran (6.93 mL, 20.79 mmol) was added dropwise. The mixture was reacted at room temperature for 2 hours under nitrogen protection. A saturated aqueous solution of ammonium chloride (30 mL) was added and extracted with dichloromethane (30 mL×2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 11 g (1.50 g, yield: 50.56%).

[0531] MS m / z(ESI):286.0[M+1].

[0532] Step 7

[0533] (S)-1-(5-Fluoro-2,3-dihydrobenzofuran-6-yl)ethylamine hydrochloride 11h

[0534] Compound 11g (300 mg, 1.05 mmol) was dissolved in ethanol (10 mL), and thionyl chloride (250 mg, 2.10 mmol) was added dropwise. The reaction was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product of the title product 11h (228 mg), which was used directly in the next step without purification.

[0535] MS m / z(ESI):164.9[M-16].

[0536] Step 8

[0537] (S)-6-((1-(5-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 11

[0538] Compound 1c (232 mg, 1.05 mmol) and compound 11h (228 mg, 1.05 mmol) were dissolved in N-methylpyrrolidone (6 mL), triethylamine (106 mg, 1.05 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 11 (90 mg, yield: 25.7%).

[0539] MS m / z(ESI):334.9[M+1].

[0540] 1 H NMR(500MHz,DMSO-d6)δ10.52(brs,1H),7.28(brs,1H),7.08(d,1H),6.75(m,1H),5.14(m,1 H),4.79(m,1H),4.53-4.50(m,2H),3.16-3.13(m,2H),1.38-1.37(d,3H),1.30-1.28(d,6H).

[0541] Example 12

[0542] (S)-6-((1-(2-fluoro-5-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 12

[0543]

[0544]

[0545] first step

[0546] 2-Fluoro-5-((6-methylpyridin-3-yl)oxy)benzaldehyde 12a

[0547] Compound 1d (61.55 g, 363.25 mmol) and 6-methylpyridine-3-ol (20.00 g, 183.28 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (800 mL), triethylamine (37.02 g, 366.53 mmol), pyridine (28.99 g, 366.50 mmol) and anhydrous copper acetate (66.58 g, 366.57 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) were added, and the reaction was stirred for 24 hours. Celite was used for filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 12a (8.00 g, yield: 18.9%).

[0548] MS m / z(ESI):231.9[M+1].

[0549] Step 2

[0550] (R)-N-(2-Fluoro-5-((6-methylpyridin-3-yl)oxy)benzylidene)-2-methylpropane-2-sulfenamide 12b

[0551] Compound 12a (8.00 g, 34.60 mmol) and (R)-2-methylpropane-2-sulfenamide (6.29 g, 51.90 mmol) were dissolved in dichloromethane (200 mL), cesium carbonate (20.30 g, 62.27 mmol) was added, and the mixture was stirred for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to obtain the title product 12b (8.20 g, yield: 70.9%).

[0552] MS m / z(ESI):334.9[M+1].

[0553] Step 3

[0554] (R)-N-((S)-1-(2-fluoro-5-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide 12c

[0555] Compound 12b (8.20 g, 24.52 mmol) was dissolved in dichloromethane (100 mL). Under nitrogen protection, the reaction mixture was cooled to -60°C, and a 3M solution of methylmagnesium bromide in 2-methyltetrahydrofuran (17.2 mL, 51.49 mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise. The reaction mixture was heated to room temperature and stirred for 5 hours. At 0°C, a saturated aqueous solution of ammonium chloride (100 mL) was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (80 mL×2), and the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 min gradient elution, flow rate: 30 mL / min) to give the title product 12c (2.10 g, yield: 24.4%).

[0556] MS m / z(ESI):349.0[M-1].

[0557] Step 4

[0558] (S)-1-(2-Fluoro-5-((6-methylpyridin-3-yl)oxy)phenyl)ethylamine hydrochloride 12d

[0559] Compound 12c (1.10 g, 3.14 mmol) was dissolved in ethanol (12 mL), cooled to 0°C, and thionyl chloride (747 mg, 6.28 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 12d (887 mg, yield: 99.9%). The crude product was used directly in the next step without purification.

[0560] MS m / z(ESI):247.0[M+1].

[0561] Step 5

[0562] (S)-6-((1-(2-fluoro-5-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 12

[0563] Compound 1c (694 mg, 3.14 mmol) and compound 12d (887 mg, 3.14 mmol) were dissolved in N-methylpyrrolidone (12 mL), triethylamine (317 mg, 3.13 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 12 (480 mg, yield: 38.3%).

[0564] MS m / z(ESI):399.9[M+1].

[0565] 1 H NMR(500MHz,DMSO-d6)δ10.53(brs,1H),8.22(d,1H),7.34-7.21(m,4H),7.12(m,1 H),6.95(m,1H),5.22(m,1H),4.79(m,1H),2.45(s,3H),1.41(d,3H),1.29(d,6H).

[0566] Embodiment 13

[0567] (S)-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 13

[0568]

[0569] first step

[0570] (R)-N-((S)-1-(2-Fluoro-5-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide 13b

[0571] (R)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfenamide 13a (6.90 g, 28.59 mmol, prepared by the patent application "Synthesis method of intermediate 3B on page 56 of WO2020092208A1 specification") was dissolved in dichloromethane (100 mL) and replaced with nitrogen three times. The reaction was cooled to -60 ° C, and a 3M methylmagnesium bromide solution in 2-methyltetrahydrofuran (19.1 mL, 57.18 mmol) was added dropwise. The reaction was stirred at room temperature for 2 hours under nitrogen protection. Saturated ammonium chloride solution (100 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (80 mL×2), and the organic phases were combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (BostonPhlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 min gradient elution, flow rate: 30 mL / min) to give the title product 13b (5.60 g, yield: 76.1%).

[0572] MS m / z(ESI):258.0[M+1].

[0573] Step 2

[0574] (S)-1-(2-Fluoro-5-methylphenyl)ethylamine hydrochloride 13c

[0575] Compound 13b (670 mg, 2.60 mmol) was dissolved in ethanol (10 mL), cooled to 0°C, and thionyl chloride (620 mg, 5.21 mmol) was added dropwise. The reaction was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 13c (493 mg, yield: 99.9%). The crude product was used directly in the next step without purification.

[0576] MS m / z(ESI):153.9[M+1].

[0577] Step 3

[0578] (S)-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 13

[0579] Compound 1c (712 mg, 3.22 mmol) and compound 13c (493 mg, 2.60 mmol) were dissolved in N-methylpyrrolidone (10 mL), triethylamine (326 mg, 3.22 mmol) was added, and the mixture was stirred at 120° C. for 16 hours. The mixture was purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 13 (400 mg, yield: 40.6%).

[0580] MS m / z(ESI):306.9[M+1].

[0581] 1 H NMR (500MHz, DMSO-d6) δ10.42(brs,1H),7.22-7.05(m,4H),5.21(m,1H),4.79(m,1H),2.28(s,3H),1.40(d,3H),1.29(d,6H).

[0582] Embodiment 14

[0583] (S)-6-((1-(2-fluoro-5-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 14

[0584]

[0585]

[0586] first step

[0587] 4-Isocyanatotetrahydro-2H-pyran 14b

[0588] At 15°C, tetrahydro-2H-pyran-4-amine 14a (10.0 g, 100.0 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and N,N-diisopropylethylamine (28.4 g, 220.0 mmol, Shanghai Titan Technology Co., Ltd.) in anhydrous dichloromethane (120 mL) were slowly added dropwise to bis(trichloromethyl) carbonate (11.9 g, 40.0 mmol, Shanghai Titan Technology Co., Ltd.) in anhydrous dichloromethane (30 mL). The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of the title product 14b. The crude product was used directly in the next step without purification.

[0589] Step 2

[0590] 6-(1H-pyrazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 14c

[0591] To a solution of compound 1b (10.5 g, 95.2 mmol) and crude compound 14b in anhydrous N,N-dimethylacetamide (120 mL) was slowly added 1,8-diazobispiro[5.4.0]undec-7-ene (15.2 g, 100.0 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) at -10°C. The reaction was stirred at 0°C for 1 hour. Subsequently, carbonyldiimidazole (23.2 g, 142.8 mmol, Shanghai Bid Pharmaceutical Technology Co., Ltd.) and 1,8-diazobispiro[5.4.0]undec-7-ene (21.7 g, 142.8 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were added to the reaction at 0°C. The reaction was stirred at 60°C for 16 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane was added to the residue, stirred, filtered, and the filter cake was collected and dried under reduced pressure to obtain the title product 14c (16.6 g, two-step yield: 63.4%).

[0592] MS m / z(ESI):264.1[M+1].

[0593] Step 3

[0594] (S)-6-((1-(2-fluoro-5-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 14

[0595] Compound 14c (148.3 mg, 0.7 mmol) and compound 12d (198.0 mg, 0.7 mmol) were dissolved in N-methylpyrrolidone (2 mL), N,N-diisopropylethylamine (452.6 mg, 3.5 mmol) was added, and microwave reaction was performed at 140°C for 2 hours. Purification by high performance liquid chromatography (Sharpsil-T Prep C18 5um 30*150mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 16% (v / v) to 36% (v / v) in 20 minutes, 30 mL / min, detection wavelength 214 & 254 nm) gave the title product 14 (95.0 mg, yield: 30.7%).

[0596] MS m / z(ESI):442.1[M+1].

[0597] 1H NMR(500MHz,DMSO-d6)δ8.20(s,1H),7.79(brs,1H),7.30(m,1H),7.23-7.19(m,2H),7.14(m,1H),6.92(m,1H),5. 26(m,1H),4.66(m,1H),3.87-3.83(m,2H),3.32-3.25(m,3H),2.51-2.44(m,3H),2.41(s,3H),1.42-1.33(m,4H).

[0598] Embodiment 15

[0599] (S)-6-((1-(3-((6-methylpyridin-3-yl)oxy)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 15

[0600]

[0601] Compound 14c (337.0 mg, 1.3 mmol) and compound 4e (338.9 mg, 0.7 mmol) were dissolved in N-methylpyrrolidone (4 mL), N,N-diisopropylethylamine (827.3 mg, 6.4 mmol) was added, and microwave reaction was performed at 140°C for 2 hours. Purification by high performance liquid chromatography (Sharpsil-T Prep C18 5um 30*150mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 16% (v / v) to 36% (v / v) in 20 minutes, 30 mL / min, detection wavelength 214 & 254 nm) gave the title product 15 (166.0 mg, yield: 30.6%).

[0602] MS m / z(ESI):424.1[M+1].

[0603] 1 H NMR(500MHz,DMSO-d6)δ8.24(d,1H),7.66(brs,1H),7.36-7.33(m,2H),7.26(d,1H),7.14(d 1H),7.05(s,1H),6.85(d 1H),5.04(m,1H),4.66(m,1H),3.89-3.85(m,2H),3.31-3.27(m,3H),2.51-2.47(m,3H),2.45(s,3H),1.41-1.38(m,4H).

[0604] Example 16

[0605] (S)-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 16

[0606]

[0607]

[0608] Compound 14c (425 mg, 1.61 mmol) and compound 13c (297 mg, 1.94 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 120°C for 16 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 16 (310 mg, yield: 55.1%).

[0609] MS m / z(ESI):349.0[M+1].

[0610] 1 H NMR(500MHz,DMSO-d6)δ10.50(brs,1H),7.28-7.05(m,4H),5.22(m,1H),4.64(m,1H),3 .90-3.86(m,2H),3.33-3.27(m,2H),2.54-2.42(m,2H),2.28(s,3H),1.45-1.39(m,5H).

[0611] Embodiment 17

[0612] (S)-3-Cyclohexyl-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 17

[0613]

[0614] first step

[0615] 3-Cyclohexyl-6-(1H-pyrazol-1-yl)-1,3,5-triazine-2,4(1H,3H)-dione 17b

[0616] Cyclohexyl isocyanate 17a (8.97 g, 71.66 mmol, Shanghai Titan Technology Co., Ltd.) and compound 1b (10.00 g, 68.22 mmol) were dissolved in N, N-dimethylacetamide (50 mL), the reaction was cooled to -10 ° C, 1,8-diazabicycloundec-7-ene (17.18 g, 68.22 mmol) was added dropwise, and the dropwise addition was completed after 5 minutes. The reaction was stirred for 30 minutes in an ice bath. Subsequently, N, N'-carbonyldiimidazole (14.73 g, 102.33 mmol) was added in an ice bath, the reaction was cooled to -5 ° C, 1,8-diazabicycloundec-7-ene (25.77 g, 102.33 mmol) was added dropwise, and the dropwise addition was completed after 10 minutes. The reaction was stirred for 1 hour in an ice bath. 2N hydrochloric acid (197 mL) was added at room temperature, and the dropwise addition was completed after 30 minutes. The filter cake was collected by filtration and dried in vacuo to give the title product 17b (16.00 g, yield: 89.8%).

[0617] MS m / z(ESI):262.0[M+1].

[0618] Step 2

[0619] (S)-3-Cyclohexyl-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 17

[0620] Compound 17b (680 mg, 2.60 mmol) and compound 13c (392 mg, 2.56 mmol) were dissolved in 1,4-dioxane (10 mL) and stirred at 120°C for 16 hours. The reaction solution was concentrated to dryness and purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 minutes gradient elution, flow rate: 30 mL / min) to obtain the title product 17 (420 mg, yield: 46.6%).

[0621] MS m / z(ESI):347.0[M+1].

[0622] 1 H NMR(500MHz,DMSO-d6)δ10.45(brs,1H),7.27-7.05(m,4H),5.21(m,1H),4.38(m,1H),2.28(s,3H),2.23-2.14 (m,2H),1.75-1.72(m,2H),1.58(m,1H),1.50-1.47(m,2H),1.41-1.40(d,3H),1.28-1.18(m,2H),1.07(m,1H).

[0623] Biological evaluation

[0624] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0625] Test Example 1: Inhibitory effect of the disclosed compounds on myosin ATPase activity.

[0626] The following method is used to determine the inhibitory effect of the disclosed compounds on myosin ATPase activity. The experimental method is briefly described as follows:

[0627] 1. Experimental Materials and Instruments

[0628] 1. Cardiac actin (Cytoskeleton, AD99)

[0629] 2. Myosin Motor Protein S1 Fragment (Cytoskeleton, CS-MYS03)

[0630] 3. ATP (Sigma, A7699-1G)

[0631] 4. UltraPure TM 1M Tris-HCl buffer, pH 7.5 (Thermo, 15567027)

[0632] 5. CytoPhos TM Phosphate detection biological kit (Cytoskeleton, BK054)

[0633] 6. Magnesium chloride solution (Sigma, 68475-100ML-F)

[0634] 7. Potassium chloride solution (Sigma, 60142-100ML-F)

[0635] 8. EGTA (Sigma, E3889-100G)

[0636] 9. 96-well plate (Corning, 3697)

[0637] 10. U-bottom 96-well plate (Corning, 3795)

[0638] 11. Microplate reader (BMG, PHERAstar)

[0639] 12. Constant temperature incubator (Shanghai Boxun, SPX-100B-Z)

[0640] 2. Experimental steps

[0641] Cardiac actin 1.61 μM, myosin motor protein S1 fragment 0.07 μM and small molecule compounds of different concentrations (first concentration 100 μM, 3-fold gradient dilution to 9 concentrations) were mixed and incubated at 37°C for 1 hour. Then ATP 120 μM was added and incubated at 37°C for 2 hours. Finally, CytoPhos TM The detection solution (70 μL / well) in the phosphate detection biological kit was incubated at room temperature for 10 min. The OD value at a wavelength of 650 nM was read using an ELISA reader, and the amount of Pi was calculated based on the standard curve. The data was processed using GraphPad software, and the inhibition curve was drawn based on the concentration of the compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated, i.e., IC 50 The experimental results are shown in Table 1.

[0642] Table 1 Inhibitory activity of the disclosed compounds on myosin ATPase

[0643] Example No. <![CDATA[IC 50 (μM)]]> 1 2.41 2 2.55 3 5.11 4 1.66 5 1.98 6 0.45 7 1.33 8 3.75 9 0.68 10 0.62 11 1.39 12 0.81 13 1.00 14 0.35 15 1.13 16 1.06

[0644] Conclusion: The disclosed compounds have a good inhibitory effect on myosin ATPase.

[0645] Test Example 2: Pharmacokinetic evaluation of the disclosed compound in Beagle dogs

[0646] 1. Summary

[0647] Beagle dogs were used as test animals, and the drug concentration in plasma at different times after oral gavage and intravenous injection of the test compound was determined by LC / MS / MS. The pharmacokinetic behavior of the disclosed compound in Beagle dogs was studied, and its pharmacokinetic characteristics were evaluated.

[0648] 2. Experimental plan

[0649] 2.1 Experimental drugs

[0650] Example 16 Compound, Compound MYK-461 ( Example 1 of WO2014205223A1).

[0651] 2.2 Experimental animals

[0652] Pharmacokinetics of the compound in Example 16 in Beagle dogs: 8 Beagle dogs, half male and half female, were equally divided into 2 groups, with 4 dogs in each group, provided by Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0653] Pharmacokinetics of compound MYK-461 in Beagle dogs: 6 male Beagle dogs were equally divided into 2 groups, 3 dogs in each group, provided by Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0654] 2.3 Drug preparation

[0655] A certain amount of the compound of Example 16 was weighed, and 5% DMSO, 30% PG, 30% PEG400 and 35% saline were added to prepare a clear solution.

[0656] A certain amount of compound MYK-461 was weighed, and 5% DMSO, 20% PG, 20% PEG400 and 55% saline were added to prepare a clear solution.

[0657] 2.4 Administration

[0658] Beagle dogs were fasted overnight and the drugs were administered by gavage and intravenous injection, with the dosages of 2 mg / kg and 0.5 mg / kg, respectively, and the administration volumes of 5 mL / kg and 2 mL / kg, respectively.

[0659] 3. Operation

[0660] For the oral administration group, 1.0 mL of blood was collected from the jugular vein or forelimb vein before administration and 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 6.0 h, 8.0 h, 12.0 h, and 24.0 h after administration. The blood was placed in an EDTA-K2 anticoagulant tube and centrifuged at 10,000 rpm for 5 min (4 ° C). The plasma was separated within 1 h and stored at -80 ° C for testing. The blood collection and centrifugation process was operated under ice bath conditions. Food was taken 3 h after administration.

[0661] Blood was collected from the intravenous injection group before administration and at 5 minutes, 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, 12.0 hours, and 24.0 hours after administration, and the treatment was the same as that of the oral gavage group.

[0662] Determine the content of the test compound in the plasma of Beagle dogs after oral gavage and intravenous injection of different concentrations of the drug: take 30 μL of Beagle dog plasma at each time after administration, add internal standard solution (internal standard of the compound of Example 16: warfarin 100 ng / mL; internal standard of compound MYK-461: tolbutamide 100 ng / mL), 300 μL of methanol, vortex mix for 1 minute, centrifuge for 7 minutes (centrifugal force 18000g), transfer 200 μL of supernatant to a 96-well plate, and take 1 μL of the supernatant of the plasma sample for LC / MS / MS analysis.

[0663] 4. Pharmacokinetic parameter results

[0664] Table 2 Pharmacokinetic parameters of the disclosed compounds in Beagle dogs

[0665]

[0666]

[0667] Conclusion: The pharmacokinetic absorption of the compound in Example 16 of the present disclosure in Beagle dogs is good. 1 / 2 The compound MYK-461 has a significant shortening due to T 1 / 2 It is relatively long, and the accumulation is serious in clinical practice. Clinical medication needs to be adjusted continuously, which increases the risk of medication. 1 / 2 , can reduce or avoid clinical drug accumulation in the body, which is beneficial to determine the dosage of patients and avoid the risk caused by accumulation. Obviously, the compound of Example 16 disclosed in the present invention has obvious pharmacokinetic advantages over the compound MYK-461.

[0668] Test Example 3: Pharmacokinetic evaluation of the disclosed compound in cynomolgus monkeys

[0669] 1. Summary

[0670] Using cynomolgus monkeys as test animals, the drug concentration in plasma at different times after oral gavage and intravenous injection of the test compound was determined by LC / MS / MS method to study the pharmacokinetic behavior of the disclosed compound in cynomolgus monkeys and evaluate its pharmacokinetic characteristics.

[0671] 2. Experimental plan

[0672] 2.1 Experimental drugs

[0673] Example 16 compound, compound MYK-461.

[0674] 2.2 Experimental animals

[0675] Pharmacokinetics of the compound in Example 16 in cynomolgus monkeys: 8 cynomolgus monkeys, half male and half female, were equally divided into 2 groups, with 4 monkeys in each group, provided by Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0676] Pharmacokinetics of compound MYK-461 in cynomolgus monkeys: 6 male cynomolgus monkeys were equally divided into 2 groups, 3 in each group, provided by Shanghai Medicilon Biopharmaceutical Co., Ltd.

[0677] 2.3 Drug preparation

[0678] A certain amount of the compound of Example 16 was weighed, and 5% DMSO, 30% PG, 30% PEG400 and 35% saline were added to prepare a clear solution.

[0679] A certain amount of compound MYK-461 was weighed, and 5% DMSO, 20% PG, 20% PEG400 and 55% saline were added to prepare a clear solution.

[0680] 2.4 Administration

[0681] After fasting overnight, cynomolgus monkeys were given drugs by gavage and intravenous injection, with the dosages being 2 mg / kg and 0.5 mg / kg, respectively, and the dosage volumes being 5 mL / kg and 2 mL / kg, respectively.

[0682] 3. Operation

[0683] For the oral administration group, 1.0 mL of blood was collected from the forelimb vein before administration and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration, placed in an EDTA-K2 anticoagulant tube, centrifuged at 10,000 rpm for 5 min (4 ° C), and plasma was separated within 1 h and stored at -80 ° C for testing. The blood collection and centrifugation process were operated under ice bath conditions. Food was taken 3 h after administration, and water was available freely.

[0684] Blood was collected from the intravenous injection group before administration and at 5 minutes, 0.25 hours, 0.5 hours, 1.0 hours, 2.0 hours, 4.0 hours, 8.0 hours, 12.0 hours, and 24.0 hours after administration, and the treatment was the same as that of the oral gavage group.

[0685] Determine the content of the test compound in the plasma of cynomolgus monkeys after oral gavage and intravenous injection of different concentrations of the drug: take 20 μL of cynomolgus monkey plasma at each time after administration, add internal standard solution (internal standard of the compound of Example 16: verapamil 10 ng / mL; internal standard of compound MYK-461: camptothecin 100 ng / mL), 400 μL of methanol, vortex mix for 1 minute, centrifuge for 7 minutes (centrifugal force 18000g), transfer 200 μL of supernatant to a 96-well plate, and take 2 μL of the supernatant of the plasma sample for LC / MS / MS analysis.

[0686] 4. Pharmacokinetic parameter results

[0687] Table 3 Pharmacokinetic parameters of the disclosed compounds in cynomolgus monkeys

[0688]

[0689] Conclusion: The pharmacokinetic absorption of the compound of Example 16 of the present disclosure in cynomolgus monkeys is good. In addition, the T 1 / 2 The compound MYK-461 has a significant shortening due to T 1 / 2 It is relatively long, and the accumulation is serious in clinical practice. Clinical medication needs to be adjusted continuously, which increases the risk of medication. 1 / 2, can reduce or avoid clinical drug accumulation in the body, which is beneficial to determine the dosage of patients and avoid the risk caused by accumulation. Obviously, the compound of Example 16 disclosed in the present invention has obvious pharmacokinetic advantages over the compound MYK-461.

[0690] Test Example 4: Toxicokinetic evaluation of the disclosed compounds in SD rats by repeated oral administration for 14 days

[0691] 1. Summary

[0692] SD rats were used as test animals, and the concentration of the original drug in plasma and the administration solution at different times after the test compound was administered to SD rats by gavage was determined by LC / MS / MS method. The toxicokinetic behavior of the disclosed compound in SD rats was studied, and its toxicokinetic characteristics were evaluated.

[0693] 2. Experimental plan

[0694] 2.1 Trial Drugs

[0695] Example 16 compound, compound MYK-461.

[0696] 2.2 Experimental animals

[0697] Twenty-four SD rats, half male and half female, were equally divided into 6 groups, with 4 rats in each group, half male and half female, provided by Weitonglihua Experimental Animal Co., Ltd.

[0698] 2.3 Drug preparation

[0699] A certain amount of the compound of Example 16 was weighed, and 15% PEG400 and 85% (10% TPGS+1% HPMCK100LV) were added to prepare a light yellow uniform suspension solution.

[0700] A certain amount of compound MYK-461 was weighed and 0.5% MC was added to prepare a colorless clear solution.

[0701] 2.4 Administration

[0702] The dosage of the compound of Example 16 by intragastric administration was 5 mg / kg, 15 mg / kg, and 30 mg / kg, respectively, and the administration volume was 10 mL / kg, respectively.

[0703] The dosages of compound MYK-461 were 0.5 mg / kg, 1.5 mg / kg, and 3 mg / kg, respectively, and the administration volumes were all 10 mL / kg.

[0704] 3. Operation

[0705] On the first day, 0.2 mL of blood was collected from the eye socket at 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, and 24.0 h after administration. On the 7th and 14th days, 0.2 mL of blood was collected from the eye socket before administration and 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, and 24.0 h after administration. The blood was placed in an EDTA-K2 anticoagulant tube and centrifuged at 10,000 rpm for 1 min (4°C). The plasma was separated within 1 hour and stored at -20°C for testing. The blood collection and centrifugation process was operated under ice bath conditions. Food was taken 2 hours after administration.

[0706] Determine the content of the test compound in the plasma of SD rats after oral administration of different concentrations of the drug: take 20 μL of SD rat plasma at each time after administration, add 50 μL of internal standard solution (internal standard of the compound of Example 16: verapamil 100 ng / mL; internal standard of compound MYK-461: camptothecin 100 ng / mL), 200 μL of acetonitrile, vortex mix for 5 minutes, centrifuge for 10 minutes (3700 rpm), and take 1 μL of the supernatant of the plasma sample for LC / MS / MS analysis.

[0707] 4. Toxicokinetic parameter results

[0708] Table 4 Toxicokinetic parameters of the disclosed compounds in SD rats

[0709]

[0710]

[0711] Conclusion: The compound of Example 16 of the present disclosure did not accumulate significantly in the body of SD rats after repeated oral administration for 14 days, while the compound MYK-461 accumulated severely in the body of SD rats, increasing the risk of medication. Obviously, the compound of Example 16 of the present disclosure has a significant toxicokinetic advantage over the compound MYK-461.

[0712] Test Example 5: Identification of Reactive Metabolites of the Disclosed Compounds in Human Liver Microsomes

[0713] The reactive metabolites of the disclosed compounds in human liver microsomes were identified using the following experimental methods:

[0714] 1. Experimental Materials and Instruments

[0715] 1. Phosphate buffer (purchased from Shanghai Biotech)

[0716] 2. NADPH (ACROS, A2646-71-1)

[0717] 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 905002)

[0718] 4. Thermo UHPLC-Q-Exactive Orbitrap mass spectrometer (Thermo Fisher Scientific)

[0719] 5. Acquity BEH C 18 Column, 2.1×100 mm, 1.7 μm (Waters, USA)

[0720] 6. Positive control compound (Diclofenac).

[0721] 2. Experimental Drugs

[0722] Example 16 compound, compound MYK-461.

[0723] 3. Experimental steps

[0724] 1. Preparation of test compound solution: Take an appropriate amount of the test compound, weigh it accurately, add an appropriate amount of DMSO to dissolve it and mix it evenly to obtain a stock solution with a concentration of 30mM. Dilute the stock solution with a concentration of 10mM 10 times with 50% acetonitrile / water (v / v) to obtain a working solution 1 with a concentration of 3.0mM. Dilute the working solution 1 with a concentration of 3.0mM 1 10 times with PBS to obtain a working solution 2 with a concentration of 300μM, and store it at 4℃ before use.

[0725] 2. Preparation of phosphate buffer: Weigh appropriate amounts of K2HPO4 and KH2PO4 respectively, dissolve them in 4L of pure water to make a buffer solution with a concentration of 100mM, and then adjust the pH value to 7.4 with phosphoric acid or sodium hydroxide.

[0726] 3. Preparation of liver microsome solution: Take an appropriate amount of liver microsome storage solution (concentration of 20 mg / mL) of each species and dilute it to 1.43 mg / mL microsome solution with 100 mM phosphate buffer (pH 7.4).

[0727] 4. Preparation of NADPH cofactor solution: Weigh appropriate amounts of NADPH and magnesium chloride, dissolve them in an appropriate amount of 100 mM phosphate buffer (pH 7.4) to make the concentrations of NADPH and magnesium chloride 10 mM and 30 mM respectively, and set aside.

[0728] 5. Preparation of glutathione (GSH) solution: Weigh an appropriate amount of GSH and dissolve it in an appropriate amount of 100 mM phosphate buffer (pH 7.4) to make the concentration of GSH 50 mM and set aside.

[0729] 6. The incubation system is as follows:

[0730] Liver microsomal protein concentration 1mg / mL Species people Test compound concentration 30μM NADPH concentration 1.0mM <![CDATA[MgCl2 concentration]]> 3.0mM GSH concentration 5mM Incubation medium 100mM PBS System pH 7.4 Incubation temperature 37℃ Incubation time 60min Incubation volume 200μL Positive Control Diclofenac (10 μM)

[0731] Accurately pipette 20 μL of working solution 2 with a concentration of 300 μM, add it to a 1.5 mL centrifuge tube, and then add 140 μL of liver microsome solution with a concentration of 1.43 mg / mL, so that the liver microsome protein concentration in the incubation system is 1 mg / mL. Then add 20 μL of NADPH solution with a concentration of 10 mM and 20 μL of GSH solution with a concentration of 50 mM, put it in a 37 ° C constant temperature incubator for shaking incubation, and start timing. 60 minutes after the start of incubation, remove the incubation sample from the incubator, add 1000 μL of ice-cold acetonitrile solution, stop the reaction, leave it at room temperature for 10 minutes, and centrifuge it at 12000 rpm for 10 minutes. Pipette all the supernatant into a centrifuge tube and concentrate it to dryness in a vacuum at 37 ° C. The residue is reconstituted with 200 μL of 25% acetonitrile / water solution, centrifuged at 12000 rpm for 10 minutes, and the supernatant is transferred to a 96-well plate, and 5 μL is aspirated for LC / MS analysis. For blank samples, 20 μL PBS was added to replace working solution 2. For NCF samples, 20 μL PBS was added to replace GSH solution. The positive control diclofenac (10 μM) was the same as the test compound. The collected data was processed and analyzed by Xcalibur software, and the secondary mass spectrometry fragmentation analysis was performed based on the accurate molecular weight to determine whether the disclosed compounds would undergo metabolic activation to produce reactive metabolites.

[0732] Table 5 Identification of reactive metabolites of the disclosed compounds in human liver microsomes

[0733] Compound result Example 16 Negative MYK-461 Positive

[0734] Conclusion: No GSH conjugates related to the compound of Example 16 of the present disclosure were detected in the experiment, but GSH conjugates related to the compound MYK-461 were detected. Therefore, it can be seen that the compound of Example 16 of the present disclosure exhibits better safety than the compound MYK-461.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R 1 is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, C(O)R 6 、C(O)OR 7 、S(O) t R 8 、S(O) t NR 9 R 10 、C(O)NR 9 R 10 NR 9 R 10 and Each R 2 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, C(O)R 6 、C(O)OR 7 、S(O) t R 8 、S(O) t NR 9 R 10 、C(O)NR 9 R 10 and NR 9 R 10 ; or R 1 and an adjacent R 2 , or two adjacent R 2 , fused with ring A to form a cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more substituents selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxyl; L2 is selected from a covalent bond, (CH2) r 、C(O)、NR a , oxygen atoms and sulfur atoms; R a is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Ring C is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 5 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 3a is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently substituted by one or more substituents selected from halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxyl; R 3b is a hydrogen atom; R 0 is alkyl or wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxyl; L1 is a covalent bond or (CH2) r ; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Each R 4 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, hydroxyl, hydroxyalkyl, C(O)R 6 、C(O)OR 7 、S(O) t R 8 、S(O) t NR 9 R 10 、C(O)NR 9 R 10 , cycloalkyl, -(CH2) r -cycloalkyl, heterocyclic, -(CH2) r -Heterocyclic group, aryl group, -(CH2) r -Aryl, heteroaryl and -(CH2) r - heteroaryl; R 6 are the same or different at each occurrence and are each independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl and hydroxyalkyl; R 7 are the same or different at each occurrence and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 8 are the same or different at each occurrence and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group; R 9 and R 10 are the same or different at each occurrence and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, -(CH2) r -cycloalkyl, heterocyclic, -(CH2) r -Heterocyclic group, aryl group, -(CH2) r -Aryl, heteroaryl and -(CH2) r -heteroaryl; or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; p is 0, 1, 2, 3, 4, 5 or 6; r is 0, 1, 2, 3, 4, 5 or 6; m is 0, 1, 2, 3 or 4; s is 0, 1, 2, 3, 4, 5, or 6; and t is 0, 1, or 2.

2. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof: in: Ring A, R 0 , R 1 , R 2 , R 3a , R 3b and m as defined in claim 1.

3. The compound of claim 1 or 2, wherein the ring A is selected from a 3- to 8-membered cycloalkyl group, a 3- to 12-membered heterocyclyl group, a 6- to 10-membered aryl group, and a 5- to 10-membered heteroaryl group; preferably, the ring A is a phenyl group.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 3, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof: in: R 0 , R 1 , R 2 , R 3a , R 3b and m as defined in claim 1.

5. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof: in: R 0 , R 1 , R 2 , R 3a , R 3b and m as defined in claim 1.

6. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 0 Selected from C 1-6 alkyl, 3 to 8-membered cycloalkyl and 3 to 12-membered heterocyclic group; preferably, R 0 Selected from C 1-6 alkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocyclic group; further preferably, R 0 is selected from isopropyl, tetrahydropyranyl and cyclohexyl; more preferably, R 0 isopropyl or tetrahydropyranyl; most preferably, R 0 It is tetrahydropyranyl.

7. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 and 6, wherein R 1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from 3 to 8-membered cycloalkyl, 3 to 12-membered heterocyclyl, 6 to 10-membered aryl and 5 to 10-membered heteroaryl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; p is 0, 1, 2, 3, 4, 5 or 6; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Haloalkyl and C 1-6 Haloalkoxy; or R 1 and an adjacent R 2 , or two adjacent R 2 , is fused with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclic group.

8. A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, 6 to 7, wherein R 1 Selected from C 1-6 Alkyl, C 1-6 Haloalkoxy and L2 is a covalent bond or an oxygen atom; Ring C is selected from cyclopropyl, tetrahydrofuranyl and pyridyl; each R 5 are the same or different and are each independently selected from hydrogen atoms, halogens and C 1-6 alkyl; p is 0, 1 or 2; each R 2 are the same or different and are each independently a hydrogen atom or a halogen; or R 1 and an adjacent R 2 It condenses with ring A to form cyclobutyl, tetrahydrofuranyl, cyclopentyl and cyclohexyl.

9. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 3a Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkyl; preferably, R 3a C 1-6 Alkyl; More preferably, R 3a It is methyl.

10. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, which is selected from any one of the following compounds:

11. A compound or a salt thereof, which is selected from any of the following compounds:

12. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (IA) or its salt (preferably hydrochloride) undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (I) or its pharmaceutically acceptable salt; in: R w is a leaving group, preferably a pyrazolyl group; Ring A, R 0 , R 1 , R 2 , R 3a , R 3b and m as defined in claim 1.

13. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

14. Use of the compound represented by general formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 13 in the preparation of a myosin inhibitor.

15. Use of a compound of formula (I) according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 13 in the preparation of a medicament for treating a disease or condition selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with normal ejection fraction (HFpEF), heart failure with mid-range ejection fraction (HFmREF), valvular disease, aortic stenosis, inflammatory heart disease, Cardiomyopathy, Loeffler's endocarditis, myocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

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