Triazinedione derivatives, methods for preparing the same, and their pharmaceutical applications

Abstract

The present invention provides triazinedione derivatives, their preparation methods, and their pharmaceutical applications. Specifically, the present invention provides triazinedione derivatives represented by general formula (I), their preparation methods, pharmaceutical compositions containing said derivatives, and uses thereof as therapeutic agents, particularly their use in the preparation of myosin inhibitors and in the preparation of drugs for treating hypertrophic cardiomyopathy (HCM) or cardiac diseases with pathophysiological characteristics associated with HCM. JPEG2023550444000158.jpg50170

Description

[Technical Field]

[0001] This disclosure pertains to the pharmaceutical field and relates to triazinedione derivatives, methods for preparing the same, and their pharmaceutical applications. In particular, this disclosure relates to triazinedione derivatives represented by general formula (I), methods for preparing the same, pharmaceutical compositions containing the derivative, and their uses in the preparation of myosin inhibitors and in the preparation of agents for treating hypertrophic cardiomyopathy (HCM) or heart diseases with HCM-related pathophysiological characteristics. [Background technology]

[0002] Hypertrophic cardiomyopathy (HCM) is a dominant hereditary cardiomyopathy associated with gene mutations. Its global incidence is approximately 0.2%, and it is the leading cause of sudden cardiac death in young people under 35 years of age (C. Vaughan Tuohy, et al., European Journal of Heart Failure, 22, 2020, 228-240). Clinically, it is characterized by asymmetrical hypertrophy of the left ventricular wall, constant intrusion into the interventricular septum, reduced intraventricular lumen, impaired left ventricular blood filling, and decreased diastolic compliance. It is classified into obstructive and non-obstructive hypertrophic cardiomyopathy depending on the presence or absence of obstruction in the left ventricular outflow tract. Currently, clinical treatment for hypertrophic cardiomyopathy often involves reducing cardiac contractility with beta-blockers and calcium channel blockers to alleviate symptoms. However, these treatments only provide temporary relief. When HCM progresses to its terminal stage, the only option is a heart transplant (R adhakrishnan Ramaraj, Cardiology in Review, 16(4), 2008, 172-180). Therefore, the discovery of a treatment method that addresses the root cause of HCM is urgently needed.

[0003] Previous studies have shown that 70% of HCM patients have myotirin gene mutations. Of these, 5% to 7% of patients have mutations in multiple locations. Currently, over 70 pathogenic mutations have been identified, but many of these mutations are familial specific, and only a few hotspots have been identified, such as the 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 developing the disease due to gene mutations have found that MYH7 gene mutations account for approximately 30% of patients. Compared to other myotirin genes, MYH7 is associated with earlier disease onset and more severe myocardial hypertrophy. Myosin is the building block of the thick filaments of myofibrils and plays a crucial role in muscle movement. Its molecular shape is sprout-like, consisting of two heavy chains and multiple light chains. The head of myosin binds to actin to form a crossbridge, which greatly enhances myosin's ATP enzyme activity, catalyzes ATP hydrolysis, generates energy, promotes the gliding of the crossbridge, and causes muscle contraction. Research has shown that MYH7 gene mutations increase myosin ATP enzyme activity, reduce the proportion of myosin super-relaxed states (SRX), increase the crossbridge between myosin and actin, and cause cardiac contractile dysfunction (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 treating hypertrophic cardiomyopathy.

[0004] Patent applications for the myosin inhibitors currently disclosed include WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1, and CN110698415A, etc.

Summary of the Invention

[0005] The present disclosure aims to provide a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof:

Chemical Formula

Chemical Formula

[0006] In some embodiments of this disclosure, the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof is the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof: [ka] Eventually, Ring A, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (I).

[0007] In some embodiments of this disclosure, in the compounds represented by the above general formula (I), general formula (I-1), or pharmaceutically acceptable salts thereof, 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 ring A is a phenyl group.

[0008] In some embodiments of this disclosure, the compound represented by general formula (I) above or a pharmaceutically acceptable salt thereof is the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof: [ka] Eventually, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (I).

[0009] In some embodiments of this disclosure, the compound represented by general formula (I), general formula (I-1), general formula (II) above, or a pharmaceutically acceptable salt thereof, is the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof: [ka] Eventually, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (I).

[0010] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 0 C 1-6 Alkyl or [ka] And of those, C mentioned above 1-6 Alkyl alkyl groups can optionally be halogens, C 1-6 Alkoxy group, C 1-6 Substituted with one or more substituents selected from haloalkoxy groups, cyano groups, amino groups, and hydroxyl groups, L1 is covalently bonded or (CH2) r Ring B is selected from 3- to 8-membered cycloalkyl groups, 3- to 12-membered heterocyclyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups, and each R 4 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C2-6 An alkenyl group, C 2-6 An alkynyl group, C 1-6 An alkoxy group, C 1-6 A haloalkyl group, C 1-6 A haloalkoxy group, oxo, a cyano group, a hydroxy group and C 1-6 Selected from a hydroxyalkyl group, r is 0, 1, 2, 3, 4, 5 or 6, and s is 0, 1 or 2.

[0011] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, R 0 is, C 1-6 Selected from an alkyl group, a 3- to 8-membered cycloalkyl group and a 3- to 12-membered heterocyclyl group, preferably, R 0 is, C 1-6 Selected from an alkyl group, a 3- to 6-membered cycloalkyl group and a 3- to 6-membered heterocyclyl group, more preferably, R 0 is selected from an isopropyl group, a tetrahydropyranyl group and a cyclohexyl group, still more preferably, R 0 is an isopropyl group or a tetrahydropyranyl group, and most preferably, R 0 is a tetrahydropyranyl group.

[0012] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, R 0 is, C 1-6 An alkyl group, preferably, R 0 is an isopropyl group.

[0013] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof, R 1 is a halogen, C 1-6 An alkyl group, C 1-6 An alkoxy group, C 1-6 A haloalkyl group, C1-6 Haloalkoxy group and [ka] Selected from, preferably R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] Selected from among them, rings C, L2, and R 5 And p are as defined in general formula (I).

[0014] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 1 is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C 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, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5, or 6.

[0015] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 1 is halogen, C1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and [ka] Selected from, preferably R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group, and a 5- or 6-membered heteroaryl group, and each R 5 They are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 It is selected from hydroxyalkyl groups, and p is 0, 1, or 2.

[0016] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 1 is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and [ka] Selected from, preferably R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or oxygen atom, and ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 It is selected from alkyl groups, and p is 0, 1, or 2.

[0017] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Haloalkoxy group or [ka] L2 is a covalent bond or an oxygen atom, and the ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group, and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 It is selected from alkyl groups, and p is 0, 1, or 2.

[0018] In some embodiments of this disclosure, in compounds represented by the above general formulas (I), (I-1), (II), and (II-1), or pharmaceutically acceptable salts thereof, each R 2 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl and C 1-6 Selected from haloalkoxy groups, preferably each R 2 These are homologous or homologous and each is independently a hydrogen atom or a halogen, more preferably each R 2 These are homologous or different, and each is independently a halogen, most preferably R 2 This is a fluorine atom.

[0019] In some embodiments of this disclosure, in a compound represented by the above general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclyl group, preferably R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with ring A to form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, more preferably R 1 and one adjacent R 2 It condenses with ring A to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group.

[0020] In some embodiments of this disclosure, in a compound represented by the above general formula (I) or general formula (I-1) or a pharmaceutically acceptable salt thereof, R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclyl group, preferably R 1 and one adjacent R 2 It condenses with ring A to form a cyclopentyl group.

[0021] In some embodiments of this disclosure, in a compound represented by the above general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with a phenyl group to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocycline group, preferably R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with a phenyl group to form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycline group, more preferably R 1and one adjacent R 2 It condenses with a phenyl group to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group.

[0022] In some embodiments of this disclosure, in a compound represented by the above general formula (II) or general formula (II-1) or a pharmaceutically acceptable salt thereof, R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with a phenyl group to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocycline group, preferably R 1 and one adjacent R 2 It condenses with a phenyl group to form a cyclopentyl group.

[0023] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, R 1 is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and the ring C 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, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, and each R 2 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl and C 1-6 Selected from haloalkoxy groups, or R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclyl group.

[0024] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group and a 5 or 6-membered heteroaryl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, or 2, and each R 2 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl and C 1-6 Selected from haloalkoxy groups, or R 1 and one adjacent R 2 It condenses with ring A to form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycline group.

[0025] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, and each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, or R 1 and one adjacent R 2 It condenses with ring A to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group.

[0026] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, R 1 is C 1-6 Haloalkoxy group or [ka] L2 is a covalent bond or an oxygen atom, and ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, and each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, or R 1 and one adjacent R 2 It condenses with ring A to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group.

[0027] In some embodiments of the present disclosure, in the compounds represented by the above general formula (I) and general formula (I-1) or their pharmaceutically acceptable salts, R 1 is a C 1-6 haloalkoxy group or [Chemical formula] where L2 is a covalent bond or an oxygen atom, ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group, and a pyridyl group, each R 5 is the same or different and is independently selected from a hydrogen atom, a halogen, and a C 1-6 alkyl group, p is 0, 1, or 2, each R 2 is the same or different and is independently a hydrogen atom or a halogen, or R 1 and one adjacent R 2 condense with ring A to form a cyclopentyl group.

[0028] In some embodiments of the present disclosure, in the compounds represented by the above general formula (II) and general formula (II-1) or their pharmaceutically acceptable salts, R 1 is a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, and [Chemical formula] selected from, L2 is a covalent bond or an oxygen atom, ring C is selected from a 3- to 8-member cycloalkyl group, a 3- to 12-member heterocyclyl group, a 6- to 10-member aryl group, and a 5- to 10-member heteroaryl group, each R 5 is the same or different and is independently a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group, a C 1-6 haloalkoxy group, and a C 1-6Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, and each R 2 is the same or different and each is independently a hydrogen atom, a halogen, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group and C 1-6 haloalkoxy group, or R 1 and one adjacent R 2 , or two adjacent R 2 are condensed with a phenyl group to form a 3- to 8-member cycloalkyl group or a 3- to 12-member heterocyclyl group.

[0029] In some embodiments of the present disclosure, in the compounds represented by the above general formula (II) and general formula (II-1) or their pharmaceutically acceptable salts, R 1 is C 1-6 alkyl group, C 1-6 haloalkoxy group and

Chemical formula

[0030] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Haloalkoxy group or [ka] L2 is a covalent bond or an oxygen atom, and ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, and each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, or R 1 and one adjacent R 2 It condenses with a phenyl group to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group.

[0031] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 1 C 1-6 Haloalkoxy group or [ka] L2 is a covalent bond or an oxygen atom, and ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, and each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, or R 1 and one adjacent R 2 It condenses with a phenyl group to form a cyclopentyl group.

[0032] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 3a is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, preferably R 3a C 1-6 It is an alkyl group, more preferably R 3a This is a methyl group.

[0033] In some embodiments of this disclosure, in the compounds represented by the above-mentioned general formulas (I), (I-1), (II), (II-1), or pharmaceutically acceptable salts thereof, m is 0, 1, or 2, preferably m is 0 or 1.

[0034] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, [ka] teeth [ka] And of these, ring M is a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclyl group, R f is a hydrogen atom, halogen and C 1-6 Selected from alkyl groups, n is 0 or 1, R 1 and R 2 This is as defined in general formula (I) or general formula (I-1), and preferably, [ka] teeth [ka] wherein ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, and R 1 and R 2 are as defined in general formula (I) or general formula (I-1), and more preferably,

Chem.

Chem.

Chem.

Chem.

[0035] In some embodiments of the present disclosure, in the compound represented by the above general formula (I), general formula (I-1) or a pharmaceutically acceptable salt thereof,

Chem.

Chem.

[0036] In some embodiments of the present disclosure, in the compound represented by the above general formula (II), general formula (II-1) or a pharmaceutically acceptable salt thereof,

Chem.

Chem.

[0037] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] They are selected from among them.

[0038] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, ring A is a phenyl group, and R 0 C 1-6Selected from alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 12-membered heterocyclyl groups, R 1 is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C 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, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, and each R 2 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl and C 1-6 Selected from haloalkoxy groups, or R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclyl group, R 3a is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, R 3b m is a hydrogen atom, and m is 0, 1, or 2.

[0039] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, ring A is a phenyl group, and R 0 C 1-6 It is an alkyl group, R 1 is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C 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, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, and each R 2 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl and C 1-6 Selected from haloalkoxy groups, or R 1 and one adjacent R 2 , or two adjacent R 2 It condenses with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocyclyl group, R 3a is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, R3b m is a hydrogen atom, and m is 0, 1, or 2.

[0040] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 0 C 1-6 Selected from alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclyl groups, R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group and a 5- or 6-membered heteroaryl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, or 2, and each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, or R 1 and one adjacent R 2 It condenses with a phenyl group to form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycline group, R 3a It is a methyl group, and R 3b m is a hydrogen atom, and m is either 0 or 1.

[0041] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 0 C 1-6 It is an alkyl group, R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group and a 5- or 6-membered heteroaryl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, or 2, and each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, or R 1 and one adjacent R 2 It condenses with a phenyl group to form a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocycline group, R 3a It is a methyl group, and R 3b m is a hydrogen atom, and m is either 0 or 1.

[0042] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 0 C 1-6 It is an alkyl group, R 1 C 1-6 Haloalkoxy group or [ka] L2 is a covalent bond or an oxygen atom, and ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, and each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, or R 1 and one adjacent R2 It condenses with a phenyl group to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group, R 3a It is a methyl group, and R 3b m is a hydrogen atom, and m is either 0 or 1.

[0043] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, [ka] teeth [ka] And of these, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, R 0 C 1-6 Selected from alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 12-membered heterocyclyl groups, R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C 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, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, and each R 2 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C1-6 Alkoxy group, C 1-6 Haloalkyl and C 1-6 Selected from haloalkoxy groups, R 3a is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, R 3b m is a hydrogen atom, and m is 0, 1, or 2.

[0044] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] And of these, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, R 0 C 1-6 It is an alkyl group, R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C 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, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, and each R 2These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl and C 1-6 Selected from haloalkoxy groups, R 3a Ha, Rogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, R 3b m is a hydrogen atom, and m is 0, 1, or 2.

[0045] In some embodiments of this disclosure, in a compound represented by the above general formula (I), general formula (I-1), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] And of these, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, R 0 C 1-6 It is an alkyl group, R 1 C 1-6 Haloalkoxy group or [ka] L2 is a covalent bond or an oxygen atom, and ring C 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, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C1-6 Selected from hydroxyalkyl groups, p is 0, 1, 2, 3, 4, 5 or 6, and each R 2 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl and C 1-6 Selected from haloalkoxy groups, R 3a is halogen, C 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, R 3b m is a hydrogen atom, and m is 0, 1, or 2.

[0046] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] And of these, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, R 0 C 1-6 Selected from alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclyl groups, R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is a covalent bond or an oxygen atom, and ring C is selected from 3- to 6-membered cycloalkyl groups, 3- to 6-membered heterocyclyl groups, and 5- or 6-membered heteroaryl groups, and each R 5These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, or 2, and each R 2 These are homologous or different, and each is independently a hydrogen atom or a halogen, R 3a It is a methyl group, and R 3b m is a hydrogen atom, and m is either 0 or 1.

[0047] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] And of these, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, R 0 C 1-6 It is an alkyl group, R 1 is C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] L2 is selected from a covalent bond or an oxygen atom, and ring C is selected from a 3- to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group and a 5- or 6-membered heteroaryl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Alkyl alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group and C 1-6 Selected from hydroxyalkyl groups, p is 0, 1, or 2, and each R 2These are homologous or different, and each is independently a hydrogen atom or a halogen, R 3a It is a methyl group, and R 3b m is a hydrogen atom, and m is either 0 or 1.

[0048] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] And of these, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, R 0 C 1-6 It is an alkyl group, R 1 C 1-6 Haloalkoxy group or [ka] L2 is a covalent bond or an oxygen atom, and ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 Selected from alkyl groups, p is 0, 1, or 2, and each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, R 3a It is a methyl group, and R 3b m is a hydrogen atom, and m is either 0 or 1.

[0049] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 0 The group is selected from isopropyl, tetrahydropyranyl, and cyclohexyl groups. [ka] teeth, [ka] And of these, ring M is a 3- to 6-membered cycloalkyl group or a 3- to 6-membered heterocyclyl group, R 1 C 1-6 Alkyl alkyl group, C 1-6 Haloalkoxy group and [ka] Selected from, each R 2 are homologous or different, and each is independently a hydrogen atom or a halogen, or R 1 and one adjacent R 2 It condenses with a phenyl group to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group, R 3a It is a methyl group, and R 3b L2 is a hydrogen atom, L2 is a covalent bond or an oxygen atom, and ring C is selected from a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R 5 These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. 1-6 It is selected from alkyl groups, and p is 0, 1, or 2.

[0050] In some embodiments of this disclosure, in a compound represented by the above general formula (II), general formula (II-1), or a pharmaceutically acceptable salt thereof, R 0 This is a tetrahydropyranyl group, [ka] teeth, [ka] And R 1 C 1-6 It is an alkyl group, R 2 is a hydrogen atom or a halogen, and R 3a It is a methyl group, and R 3b This is a hydrogen atom.

[0051] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves a nucleophilic substitution reaction between a compound represented by general formula (IA) or a salt thereof (preferably a hydrochloride salt) and a compound represented by general formula (V) to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Eventually, R w is a leaving group, preferably a pyrazolyl group, Ring A, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (I).

[0052] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] This method involves a nucleophilic substitution reaction between a compound represented by general formula (IA-1) or a salt thereof (preferably a hydrochloride salt) and a compound represented by general formula (V) to obtain a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof. Eventually, R w is a leaving group, preferably a pyrazolyl group, Ring A, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (I-1).

[0053] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method being: [ka] The method includes a nucleophilic substitution reaction between a compound represented by general formula (IIA) or a salt thereof (preferably a hydrochloride salt) and a compound represented by general formula (V) to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof. Eventually, R w is a leaving group, preferably a pyrazolyl group, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (II).

[0054] Another aspect of this disclosure relates to a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method being: [ka] The method includes a nucleophilic substitution reaction between a compound represented by general formula (IIA-1) or a salt thereof (preferably a hydrochloride salt) and a compound represented by general formula (V) to obtain a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof. Eventually, R w is a leaving group, preferably a pyrazolyl group, R0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (II-1).

[0055] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound 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 vectors, diluents, or excipients.

[0056] This disclosure further relates to the use of compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the preparation of myosin inhibitors.

[0057] This disclosure further relates to the use of compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for the treatment of diseases or conditions, wherein the diseases or conditions include preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM) (e.g., non-obstructive hypertrophic cardiomyopathy (nHCM) and obstructive hypertrophic cardiomyopathy (oHCM)), normal ejection fraction heart failure (HFpEF), and moderate ejection fraction heart failure. (HFmREF), selected from valvular heart disease, aortic stenosis, inflammatory cardiomyopathy, Refrel's endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, refractory angina pectoris 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), and most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0058] This disclosure further relates to the use of compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, in the preparation of agents for the treatment of myosin-mediated diseases or conditions, wherein the diseases or conditions include preserved ejection fraction diastolic failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), moderate ejection fraction heart failure (HFmREF), and valvular heart disease. The following conditions are selected from aortic stenosis, inflammatory cardiomyopathy, Loeffler's endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, refractory angina pectoris, 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), and most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0059] This disclosure further relates to a method for inhibiting myosin, which includes administering to a patient in need a therapeutically effective dose of the compounds represented by formula (I), formula (I-1), formula (II), formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing thereof.

[0060] This disclosure further relates to a method for treating a disease or medical condition, comprising administering to a target patient a therapeutically effective dose of a compound 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, or a pharmaceutical composition containing the same, wherein the disease or medical condition is preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), moderate ejection fraction heart failure (HFmREF), valvular heart disease The disease is selected from aortic stenosis, inflammatory cardiomyopathy, Loeffler's endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry 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), and most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0061] This disclosure further relates to a method for treating a disease or condition mediated by myosin, comprising administering to a target patient a therapeutically effective dose of the 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 containing the same, wherein the disease or condition is preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), moderate ejection fraction heart failure (HFm Selected from REF), valvular heart disease, aortic stenosis, inflammatory cardiomyopathy, Refrel's endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, refractory angina pectoris 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), and most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0062] This disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, used as pharmaceuticals.

[0063] This disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, which are used as myosin inhibitors.

[0064] This disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, for the treatment of diseases or conditions, wherein the diseases or conditions are preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), moderate ejection fraction heart failure (HFmREF), valvular heart disease, aortic stenosis, inflammatory heart disease A choice is made from myopathy, Lefrel's endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, refractory angina, and Chagas disease, preferably a choice is made 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), and most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0065] This disclosure further relates to compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, for the treatment of diseases or conditions mediated by myosin, wherein the diseases or conditions include preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), moderate ejection fraction heart failure (HFmREF), valvular heart disease, and aortic valve A choice is made from stenosis, inflammatory cardiomyopathy, Lefrel's endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, refractory angina, and Chagas disease, preferably a choice is made 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), and most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0066] The compounds represented by 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 containing them, can not only alleviate symptoms but also alter the natural history of HCM and other diseases. The mechanisms by which HCM patients receive clinical benefit are applicable to patients with other forms of heart disease, all of which have similar pathophysiology and may or may not be influenced by significant genetic factors. For example, effective treatment of HCM by improving ventricular dilation during diastole can also be effectively applied to a broader population characterized by diastolic dysfunction.

[0067] The compounds represented by 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 containing them, can specifically target the root cause of a disease or act on other downstream pathways. Accordingly, the compounds represented by 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 containing them, can benefit patients with preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, or restrictive cardiomyopathy.

[0068] The compounds shown in General Formula (I), General Formula (I-1), General Formula (II), General Formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, may also promote beneficial ventricular remodeling of left ventricular hypertrophy due to volume or pressure overload, and these compounds or pharmaceutically acceptable salts thereof may be used in combination with therapies to correct or reduce the causes of volume or pressure overload, such as chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension (valve repair / replacement, effective antihypertensive therapy). By reducing left ventricular filling pressure, the compounds may reduce the risk of pulmonary edema and respiratory failure. By reducing or eliminating functional mitral regurgitation and / or reducing left atrial pressure, the risk of paroxysmal or persistent atrial fibrillation may be reduced, as may the risk associated with 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 decrease the likelihood of needing septal ablation (surgery or percutaneous) and the associated risks of short-term and long-term complications.

[0069] The compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, can reduce the severity of HCM-related chronic focal anemia, thereby reducing the risk of sudden cardiac death (SCD) or equivalent in patients with implantable cardioverter-defibrillators (frequent and / or repeated ICD discharges), and / or reducing the demand for potentially toxic antiarrhythmic drugs.

[0070] The compounds represented by 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 containing them, are valuable in reducing or eliminating the need for concomitant drugs (which have associated potential toxicity, drug interactions, and / or side effects).

[0071] The compounds represented by general formula (I), general formula (I-1), general formula (II), general formula (II-1) and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, can reduce interstitial cardiomyopathy and / or mitigate the progression of left ventricular hypertrophy, and can block or reverse left ventricular hypertrophy.

[0072] Compound MYK-461( [ka] Example 1 of WO2014205223A1 is T 1 / 2 Because the effect is relatively long and clinical accumulation is relatively serious, constant adjustments are required in clinical administration, and the risk of drug administration becomes large. In contrast, the compound of Example 16 in this disclosure is T 1 / 2The time interval is significantly shortened. Furthermore, while the compound of Example 16 in this disclosure did not accumulate significantly in rats after repeated intragastric administration for 14 days, compound MYK-461 accumulated severely in rats. In an experiment to identify reactive metabolites in human liver microsomes, glutathione (GSH) conjugates associated with the compound of Example 16 in this disclosure were not detected, but GSH conjugates associated with compound MYK-461 were detected. This clearly shows that the compound of Example 16 in this disclosure has significant pharmacokinetic and toxicological advantages compared to compound MYK-461 and exhibits better safety.

[0073] The active compound can be prepared in a form suitable for administration by any suitable route, and the composition of this disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable vectors. Accordingly, the active compound of this disclosure can be prepared in dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or inhalation. The compound of this disclosure may also be prepared in sustained-release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, tablets, or syrups.

[0074] As a general guideline, the active compound is preferably in the form of a unit dose or in a form that the patient can administer to themselves as a monotherapy. The unit dose of the compound or composition relating to this disclosure may be expressed as a tablet, capsule, cachet, bottled solution, drug powder, granules, tablet, suppository, regenerated powder, or liquid formulation. A preferred unit dose may be 0.1 mg to 1000 mg.

[0075] The pharmaceutical composition relating to this disclosure may contain one or more additives in addition to the active compound, and the additives are selected from components such as fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the administration method, the composition may contain 0.1% to 99% by weight of the active compound.

[0076] The tablets comprise an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for mixing in the preparation of the tablets. These excipients may be inert excipients, granulators, disintegrants, binders, and lubricants. These tablets may be uncoated or coated by known techniques that mask the taste of the drug or slow its disintegration and absorption in the gastrointestinal tract, thereby providing a sustained-release effect over a long period.

[0077] An oral formulation may be provided in the form of a soft gelatin capsule containing the active ingredient and an inert solid diluent, or the active ingredient and a water-soluble vector or oily solvent.

[0078] The aqueous suspension comprises an active substance and excipients suitable for mixing in the preparation of the aqueous suspension. Such excipients are suspending agents, dispersing agents, or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.

[0079] An oily suspension can be prepared by suspending the active ingredient in vegetable oil or mineral oil. The oily suspension may contain a thickening agent. Sweeteners and flavoring agents may be added to provide a palatable formulation. These compositions can be preserved by adding antioxidants.

[0080] The pharmaceutical compositions relating to this disclosure may be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil, mineral oil, or a mixture thereof. A suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain mitigating agents, preservatives, colorants, and antioxidants.

[0081] The pharmaceutical compositions relating to this disclosure may be in the form of sterile aqueous solutions for injection. Acceptable solvents or solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection formulation may also be a sterile oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection solution or microemulsion can be injected into the patient's bloodstream by local injection in large quantities. Alternatively, it is preferable to administer the solution and microemulsion in a manner that can maintain a constant cycle concentration of the compound relating to this disclosure. A continuous intravenous infusion device can be used to maintain such a constant concentration. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous injection pump.

[0082] The pharmaceutical compositions relating to this disclosure may be in the form of sterile injection water or oily suspension for intramuscular and subcutaneous administration. Such suspensions can be prepared using the appropriate dispersants or wetting agents and suspending agents according to known techniques. The sterile injection formulation may also be a sterile injection solution or suspension prepared in a parenterally acceptable, non-toxic diluent or solvent. Furthermore, sterile fixative oils can be conveniently used as solvents or suspension media. For this purpose, any compounding fixative oil can be used. Fatty acids can also be used to prepare injection formulations.

[0083] The compounds relating to this disclosure 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 that is solid at room temperature but liquid in the rectum, and therefore dissolves in the rectum to release the drug.

[0084] The compounds relating to this disclosure can be administered by adding water to prepare aqueous suspensions of dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant, a wetting agent, a suspending agent, and one or more preservatives.

[0085] As is well known to those skilled in the art, the dosage of a drug depends on many factors, including, but not limited to, the activity of the specific compound used, the patient's age, weight, physical condition, behavior, diet, administration time, method of administration, rate of excretion, drug composition, and disease severity. Furthermore, the optimal treatment method, such as the mode of treatment, the daily dose of the compound, or the type of pharmaceutically acceptable salt, can be determined according to conventional treatment plans. Explanation of terms

[0086] Unless otherwise specified, terms used in the specification and claims have the following meanings: The term "alkyl group" refers to a saturated linear or branched aliphatic hydrocarbon group having 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., C 1-20 Alkyl alkyl group). The above alkyl group is an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 A alkyl group is preferred, and an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Alkyl groups are more preferred. Non-limiting examples of alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methyl Hexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, This includes 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched isomers thereof.Most preferably are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, and 2,3-dimethylbutyl group. The alkyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more selected from a D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0087] The term "alkylene group" refers to a divalent alkyl group, of which the alkyl group is as defined above and has 1 to 20 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., C 1-20 Alkylene group). The above alkylene group is an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 Preferably an alkylene group, and an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6Alkylene groups are more preferred. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylidene (-CH(CH3)-), 1,2-ethylidene (-CH2CH2)-, 1,1-propyridene (-CH(CH2CH3)-), 1,2-propyridene (-CH2CH(CH3)-), 1,3-propyridene (-CH2CH2CH2-), and 1,4-butylidene (-CH2CH2CH2CH2-). The alkylene group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo groups.

[0088] The term "alkenyl group" refers to an alkyl group in which the molecule contains at least one carbon-carbon double bond, the definition of an alkyl group being as described above, and preferably an alkenyl group having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C 2-12 The above alkenyl group is an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkenyl groups are preferred. Non-limiting examples include vinyl groups, propenyl groups, isopropenyl groups, butenyl groups, etc. The alkenyl group may be substituted or unsubstituted, and if substituted, the substituent is preferably one or more selected from alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0089] The term "alkynyl group" refers to an alkyl group in which the molecule contains at least one carbon-carbon triple bond, the definition of which is as described above, and is an alkynyl group having 2 to 12 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) (i.e., C 2-12 The above alkynyl group is an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl groups are preferred. Non-limiting examples include ethynyl groups, propynyl groups, butynyl groups, pentynyl groups, hexynyl groups, etc. The alkynyl group may be substituted or unsubstituted, and if substituted, the substituent is preferably one or more selected from alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0090] The term "alkoxy group" refers to an -O-(alkyl group), and the definition of an alkyl group is as described above. Non-limiting examples include methoxy, ethoxy, propoxy, and butoxy groups. The alkoxy group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more selected from a D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0091] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring has 3 to 20 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) (i.e., a 3- to 20-membered cycloalkyl group), preferably having 3 to 12 carbon atoms (i.e., a 3- to 12-membered cycloalkyl group), preferably having 3 to 8 carbon atoms (i.e., a 3- to 8-membered cycloalkyl group), and more preferably having 3 to 6 carbon atoms (i.e., a 3- to 6-membered cycloalkyl group). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl groups, while polycyclic cycloalkyl groups include spirocycloalkyl groups, condensed cycloalkyl groups, and crosslinked cycloalkyl groups.

[0092] The term "spirocycloalkyl group" refers to a polycyclic group with 5 to 20 members, in which monocyclic rings share one carbon atom (referred to as a spiro atom), and which may contain one or more double bonds. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl groups or polyspirocycloalkyl groups (e.g., bisspirocycloalkyl groups), preferably monospirocycloalkyl groups and bisspirocycloalkyl groups. More preferably, it is a monospirocycloalkyl group with 3 / 5 members, 3 / 6 members, 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 5 members, 5 / 6 members, 6 / 6 members, 6 / 4 members, or 6 / 5 members. Non-limiting examples of spirocycloalkyl groups are: [ka] It includes, and its connection point may be at any position.

[0093] The term "condensed cycloalkyl group" refers to a 5- to 20-membered, all-carbon polycyclic group in which the rings share one adjacent pair of carbon atoms, and one or more of these rings may contain one or more double bonds. Preferably, it is 6- to 14 members, and more preferably 7- to 10 members (e.g., 7-, 8-, 9-, or 10-membered). Depending on the number of rings that make up the group, it can be classified into polycyclic condensed cycloalkyl groups such as bicyclic, tricyclic, and tetracyclic. Preferably, it is bicyclic or tricyclic, and more preferably 3- / 4-membered, 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 4-membered, 5- / 5-membered, 5- / 6-membered, 5- / 7-membered, 6- / 3-membered, 6- / 4-membered, 6- / 5-membered, 6- / 6-membered, 6- / 7-membered, 7- / 5-membered, or 7- / 6-membered bicyclic alkyl groups. Non-limiting examples of condensed cycloalkyl groups are: [ka] It includes, and its connection point may be at any position.

[0094] The term "crosslinked cycloalkyl group" refers to a 5- to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly linked, and which may contain one or more double bonds. Preferably, it is 6- to 14-membered, and more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Depending on the number of rings, it can be classified into polycyclic crosslinked cycloalkyl groups such as bicyclic, tricyclic, and tetracyclic, preferably bicyclic, tricyclic, or tetracyclic crosslinked cycloalkyl groups, and more preferably bicyclic or tricyclic crosslinked cycloalkyl groups. Non-limiting examples of crosslinked cycloalkyl groups are: [ka] It includes, and its connection point may be at any position.

[0095] The above cycloalkyl rings include those in which the above cycloalkyl group (including monocyclic, spirocyclic, fused, and crosslinked rings) is fused to an aryl group, a heteroaryl group, or a heterocycloalkyl ring, and among these, the ring linked to the parent structure is a cycloalkyl group, and non-limiting examples are: [ka] This includes, [ka] It is preferable.

[0096] The cycloalkyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0097] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 ring atoms, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur being optionally oxidized (i.e., to form a sulfoxide or sulfone), but not containing -OO-, -OS-, or -SS- ring portions, and the remaining ring atoms being carbon. Preferably, it has 3 to 12 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12), of which 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., a 3- to 12-membered heterocyclyl group), more preferably it has 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms (i.e., a 3- to 8-membered heterocyclyl group), even more preferably it has 3 to 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., a 3- to 6-membered heterocyclyl group), and most preferably it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms (i.e., a 5- or 6-membered heterocyclyl group). Non-exclusive examples of monocyclic heterocyclyl groups include pyrrolidinyl groups, tetrahydropyranyl groups, 1,2,3,6-tetrahydropyridyl groups, piperidinyl groups, piperazinyl groups, morpholinyl groups, thiomorpholinyl groups, and homopiperazinyl groups. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, condensed heterocyclyl groups, and cross-linked heterocyclyl groups.

[0098] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which monocyclic rings share one atom (referred to as a spiro atom), one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur being optionally oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of spiro atoms shared between the rings, the spiroheterocyclyl group is divided into a monospiroheterocyclyl group or a polyspiroheterocyclyl group (e.g., a bisspiroheterocyclyl group), preferably a monospiroheterocyclyl group or a bisspiroheterocyclyl group. More preferably, a 3-member / 5-member, 3-member / 6-member, 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, 5-member / 6-member or 6-member / 6-member monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups are: [ka] This includes, among others.

[0099] The term "condensed heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, in which the rings share one pair of adjacent atoms, and one or more rings may contain one or more double bonds, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur being optionally oxidized (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms being carbon. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings that make up the group, it can be classified into polycyclic condensed heterocyclyl groups such as bicyclic, tricyclic, and tetracyclic, preferably bicyclic or tricyclic condensed heterocyclyl groups, and more preferably bicyclic condensed heterocyclyl groups with 3 / 4 members, 3 / 5 members, 3 / 6 members, 4 / 4 members, 4 / 5 members, 4 / 6 members, 5 / 3 members, 5 / 4 members, 5 / 5 members, 5 / 6 members, 6 / 3 members, 6 / 4 members, 6 / 5 members, 6 / 6 members, 6 / 7 members, 7 / 5 members, or 7 / 6 members. Non-limiting examples of condensed heterocyclyl groups are: [ka] This includes, among others.

[0100] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 14 members, in which any two rings share two atoms that are not directly linked, and which may contain one or more double bonds, of which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, the sulfur being optionally oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms being carbon. Preferably, it has 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings, it can be classified into polycyclic bridged heterocyclyl groups such as bicyclic, tricyclic, and tetracyclic, preferably bicyclic, tricyclic, or tetracyclic bridged heterocyclyl groups, and more preferably bicyclic or tricyclic bridged heterocyclyl groups. Non-limiting examples of bridged heterocyclyl groups are: [ka] This includes, among others.

[0101] The above heterocyclyl rings include those in which the above heterocyclyl group (including monocycles, spiroheterocycles, fused heterocycles, and bridged heterocycles) is fused to an aryl group, a heteroaryl group, or a cycloalkyl ring, and among these, the ring linked to the parent structure is a heterocyclyl group, and non-limiting examples thereof are: [ka] This includes, among others.

[0102] The heterocyclyl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxo, heterocyclyloxo, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups.

[0103] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring that shares adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as a phenyl group and a naphthyl group. The above aryl ring includes those in which the above aryl ring is fused to a heteroaryl group, a heterocyclyl group, or a cycloalkyl ring, and among these, the ring linked to the parent structure is an aryl ring, and non-limiting examples are: [ka] Includes.

[0104] The aryl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxo groups, heterocyclyloxo groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0105] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4) and 5 to 14 ring atoms, of which the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably a 5- to 10-membered group (e.g., 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered), more preferably a 5- or 6-membered heteroaryl group, such as a furanyl group, thienyl group, pyridyl group, pyrrolyl group, N-alkylpyrrolyl group, pyridonyl group, N-alkylpyridone (e.g., [ka] Examples include pyrimidinyl groups, pyrazinyl groups, pyridadinyl groups, imidazolyl groups, pyrazolyl groups, triazolyl groups, and tetrazolyl groups. The above heteroaryl rings include those in which the above heteroaryl groups are fused to an aryl group, a heterocyclyl group, or a cycloalkyl ring, and among these, the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples thereof are, [ka] This includes, among others.

[0106] The heteroaryl group may be substituted or unsubstituted, and if substituted, it may be substituted at any available linking point. The substituent is preferably one or more selected from halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups.

[0107] The above-mentioned cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups include one residue derived by removing one hydrogen atom from a ring atom of the parent group, or residues derived by removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent group, i.e., "cycloalkylene groups," "heterocyclylene groups," "arylene groups," and "heteroarylene groups."

[0108] The term "amino protecting group" refers to an easily eliminate group introduced to an amino group to prevent it from being altered when other parts of the molecule react. Non-exclusive examples include (trimethylsilicon)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl groups. These groups may be optionally substituted with one to three substituents selected from halogens, alkoxy, or nitro groups.

[0109] The term "hydroxy protecting group" refers to an easily eliminated group introduced to a hydroxyl group, and generally involves a reaction at another functional group of the compound to block or protect the hydroxyl group. Non-exclusive examples include trimethylsilyl group (TMS), triethylsilyl group (TES), triisopropylsilyl group (TIPS), tert-butyldimethylsilane group (TBS), tert-butyldiphenylsilyl group, methyl group, tert-butyl, allyl group, benzyl group, methoxymethyl group (MOM), ethoxyethyl group, 2-tetrahydropyranyl group (THP), formyl group, acetyl group, benzoyl group, and p-nitrobenzoyl group.

[0110] The term "cycloalkyloxy group" refers to cycloalkyl-O-, where cycloalkyl is defined as described above.

[0111] The term "heterocyclyloxy group" refers to a heterocyclyl-O-, of which the heterocyclyl group is defined as described above.

[0112] The term "aryloxy group" refers to an aryl-O- group, of which the aryl group is defined as described above.

[0113] The term "heteroaryloxy group" refers to a heteroaryl-O- group, of which the heteroaryl group is defined as described above.

[0114] The term "alkylthio group" refers to alkyl-S-, and the alkyl group is as defined above.

[0115] The term "haloalkyl group" refers to a group in which an alkyl group is substituted with one or more halogens, where the alkyl group is as defined above.

[0116] The term "haloalkoxy group" refers to a group in which an alkoxy group is substituted with one or more halogens, where the alkoxy group is as defined above.

[0117] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.

[0118] The term "hydroxyalkyl group" refers to an alkyl group that is substituted with one or more hydroxyl groups, where the alkyl group is as defined above.

[0119] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0120] The term "hydroxyl group" refers to the -OH group.

[0121] The term "mercapto group" refers to the -SH group.

[0122] The term "amino group" refers to -NH2.

[0123] The term "cyano group" refers to -CN.

[0124] The term "nitro group" refers to -NO2.

[0125] The term "oxo" refers to "=O".

[0126] The term "carbonyl group" refers to C=O.

[0127] The term "carboxyl group" refers to -C(O)OH.

[0128] The term "carboxylic acid ester group" refers to -C(O)O(alkyl group), -C(O)O(cycloalkyl group), (alkyl group)C(O)O-, or (cycloalkyl group)C(O)O-, of which alkyl groups and cycloalkyl groups are as defined above.

[0129] The compounds relating to this disclosure may be in the form of specific geometric or stereoisomers. This disclosure is based on the premise that it includes all cis-trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures rich in enantiomers or diastereomers, and all such compounds are within the scope of this disclosure. Substituents such as alkyl groups may have other chiral carbon atoms. All such isomers and mixtures thereof are within the scope of this disclosure. Compounds containing chiral carbon atoms relating to this disclosure can be separated in the form of optically active pures or in the form of racemates. The optically active pures may be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0130] In the chemical structure of the compounds described in this disclosure, [ka] This type of bond indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, [ka] The combination is [ka] It may be so, or [ka] It is also acceptable to include both of these arrangements simultaneously.

[0131] In the chemical structure of the compounds described in this disclosure, [ka] This bond does not have a specified configuration; that is, it may be a Z configuration or an E configuration, or it may contain both configurations simultaneously. Any carbon-carbon double bond, even if only one configuration is named, may contain both the Z and E configurations.

[0132] The compounds and intermediates relating to this disclosure may exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms “tautomer” or “tautomer form” refer to structural isomers of different energies that can be interconverted over a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include interconversion by protrisis, such as keto-enol and imine-enamine, and lactam-lactim isomerization. An example of lactam-lactim equilibrium is between A and B as shown below.

[0133] [ka] All compounds in this disclosure can be described as either type A or type B. All tautomer forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomer.

[0134] This disclosure further includes several compounds of the disclosure that are isotopically labeled, the same as those described herein, but in which one or more atoms are substituted with atoms having atomic weights or mass numbers different from those commonly found in nature. Examples of isotopes that can be bound to the compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, respectively 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 and36 Examples include Cl. Such compounds may be used, for example, as analytical tools or probes in biometric measurements, or as imaging tracers for in vivo diagnosis of diseases, or as tracers in pharmacodynamic, pharmacokinetic, or receptor studies.

[0135] This disclosure further includes compounds in various deuterated forms. Each available hydrogen atom bonded to a carbon atom may be independently substituted with a deuterium atom. Those skilled in the art can synthesize compounds in deuterated forms by referring to relevant literature. Compounds in deuterated forms may, when prepared, use commercially available deuterated starting materials or may be synthesized by conventional art using deuterating reagents, which include, but are not limited to, borane deuterated, borane trihydrofuran solution, lithium aluminum hydride deuterated, iodoethane deuterated, and iodomethane deuterated. Unless otherwise specified, where one position is specifically designated as deuterium(D), that position should be understood to be deuterium having an abundance at least 1000 times higher than the natural abundance of deuterium (0.015%) (i.e., incorporating at least 10% deuterium). Compounds in the example that have a higher abundance of deuterium than the natural abundance of deuterium may be deuterium with an abundance of at least 1000 times, at least 2000 times, at least 3000 times, at least 4000 times, at least 5000 times, at least 6000 times, or more.

[0136] "Optionally" or "optionally" means that the event or situation described thereafter may or may not occur, and this description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "C where C is optionally substituted with a halogen or cyano group." 1-6The term "alkyl group" means that a halogen or cyano group may or may not be present, and this description includes cases where the alkyl group is substituted with a halogen or cyano group, and cases where the alkyl group is not substituted with a halogen or cyano group.

[0137] "Substitutable" means that one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3, are substituted with a number of substituents that correspond to each other independently. Those skilled in the art can determine possible or impossible substitutions (experimentally or theoretically) with little effort. For example, an amino or hydroxyl group with free hydrogen can become unstable if it is bonded to a carbon atom with an unsaturated (e.g., olefin) bond.

[0138] "Pharmaceutical composition" indicates a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, and other components such as physiologically / pharmaceutically acceptable vectors and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism and contribute to the absorption of the active ingredient, thereby exerting further biological activity.

[0139] "Pharmacologically acceptable salt" refers to a salt of the compound relating to this disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in the body of a mammal and possess the desired biological activity. Salts may be prepared individually during the final separation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Generally, bases for producing pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. Generally, acids for forming pharmaceutically acceptable salts include inorganic acids and organic acids.

[0140] With respect to drugs or pharmacological agents, the term "therapeutic effective dose" refers to a sufficient amount of the drug or agent that is non-toxic while producing the desired effect. The effective dose is determined on a person-by-person basis, depending on the subject's age and general condition, as well as the specific active substance. A suitable effective dose for an individual can be determined by general testing by those skilled in the art.

[0141] As used herein, the term “pharmaceutically acceptable” means that these compounds, materials, compositions and / or dosage forms are, within reasonable medical judgment, free from excessive toxicity, irritation, allergic reactions or other problems or complications, applicable to patient tissues, have a reasonable profit-benefit ratio, and are effective for the desired use.

[0142] As used herein, the singular forms "one," "one kind," and "the said" include multiple quotations, and vice versa, unless otherwise specified in the context.

[0143] The term "approximately," when used with parameters such as pH, concentration, and temperature, indicates that these parameters may vary within ±10%, and more preferably within ±5%. As those skilled in the art will understand, when parameters are not critical, the numbers are generally given simply for illustrative purposes, not as limitations. Synthesis method of the compound related to this disclosure

[0144] To achieve the objectives of this disclosure, this disclosure adopts the following technical proposals.

[0145] Technical proposal A method for preparing a compound represented by general formula (I) relating to this disclosure or a pharmaceutically acceptable salt thereof, wherein the method is: [ka] The process includes the step of directly subjecting a compound represented by general formula (IA) or a salt thereof (preferably a hydrochloride salt) to a compound represented by general formula (V), or subjecting it to a nucleophilic substitution reaction in the presence of a base, to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Eventually, R w is a leaving group, preferably a pyrazolyl group, Ring A, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (I).

[0146] Technical plan 2 A method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof relating to this disclosure, wherein the method is: [ka] The process includes the step of directly nucleophilically substituting a compound represented by general formula (IA-1) or a salt thereof (preferably a hydrochloride salt) with a compound represented by general formula (V), or nucleophilically substituting it in the presence of a base, to obtain a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof. Eventually, R w is a leaving group, preferably a pyrazolyl group, Ring A, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (I-1).

[0147] Technical plan 3 A method for preparing a compound represented by general formula (II) relating to this disclosure or a pharmaceutically acceptable salt thereof, wherein the method is: [ka] The process includes the step of directly subjecting a compound represented by general formula (IIA) or a salt thereof (preferably a hydrochloride salt) to a compound represented by general formula (V) through a nucleophilic substitution reaction, or to a nucleophilic substitution reaction in the presence of a base, to obtain a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof. Eventually, R w is a leaving group, preferably a pyrazolyl group, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (II).

[0148] Technical plan 4 A method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, wherein the method is: [ka] The process includes the step of directly nucleophilically substituting a compound represented by general formula (IIA-1) or a salt thereof (preferably a hydrochloride salt) with a compound represented by general formula (V), or nucleophilically substituting it in the presence of a base to obtain a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof. Eventually, R w is a leaving group, preferably a pyrazolyl group, R 0 , R 1 , R 2 , R 3a , R 3b And m are as defined in general formula (II-1).

[0149] In the above proposed technology, the above bases include organic bases and inorganic bases, and the above organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethylate, sodium tert-butoxide and potassium tert-butoxide, and are preferably triethylamine and N,N-diisopropylethylamine, and the above 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.

[0150] The above reaction is preferably carried out in a solvent, and the solvents used include, but are 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.

[0151] The above nucleophilic substitution reaction is a normal reaction, with a reaction temperature of 100°C to 160°C, preferably 120°C.

[0152] The above nucleophilic substitution reaction is a typical reaction, with a reaction time of 10 to 20 hours, preferably 16 hours.

[0153] The above nucleophilic substitution reaction may be carried out using microwaves, with a reaction temperature of 100°C to 160°C, preferably 140°C.

[0154] The above nucleophilic substitution reaction may be carried out using microwaves, with a reaction time of 0.5 to 4 hours, preferably 2 hours. [Modes for carrying out the invention]

[0155] The present disclosure will be further described below in accordance with the examples, but these examples are not intended to limit the scope of the present disclosure.

[0156] Examples The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) was 10 -6 The results were expressed in units of ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for the NMR measurements, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard.

[0157] For MS measurements, the following liquid chromatograph mass spectrometers were used: Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole 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).

[0158] High-performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489.

[0159] For chiral HPLC analysis, an Agilent 1260 DAD high-performance liquid chromatograph was used.

[0160] For preparative high-performance liquid chromatography, the Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs were used.

[0161] For chiral preparative chromatography, a Shimadzu LC-20AP preparative chromatograph was used.

[0162] For the CombiFlash high-speed preparative chromatograph, the CombiFlash Rf200 (TELEDYNE ISCO) was used.

[0163] For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) were 0.15 mm to 0.2 mm, and the specifications for separation and purification of products by thin-layer chromatography were 0.4 mm to 0.5 mm.

[0164] In silica gel column chromatography, silica gel of 200-300 mesh size, manufactured by Yantai Huanghai Silica Gel, was commonly used as a vector.

[0165] Kinase mean inhibition rate and IC 50 A NovoStar microplate reader (BMG GmbH, Germany) was used to measure the values.

[0166] The known starting materials relating to this disclosure may be synthesized by or in accordance with methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. (Shanghai), and Dalui Chemicals.

[0167] Unless otherwise specified in the examples, the reactions can all be carried out in an argon or nitrogen atmosphere.

[0168] An argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of approximately 1 L.

[0169] A hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of approximately 1 L.

[0170] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and either a QL-500 type hydrogen generator or an HC2-SS type hydrogenator were used.

[0171] The hydrogenation reaction typically involved repeating the process of evacuating the system and filling it with hydrogen three times.

[0172] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0173] In the examples, unless otherwise specified, "solution" refers to an aqueous solution.

[0174] Unless otherwise specified in the examples, the reaction temperature is 20°C to 30°C at room temperature.

[0175] Thin-layer chromatography (TLC) was used to monitor the progress of the reaction in the examples. The developing solvent used in the reaction, the eluent system for column chromatography used for purifying the compound, and the developing solvent system for thin-layer chromatography included A: n-hexane / ethyl acetate system and B: dichloromethane / methanol system. The volume ratio of the solvents may be adjusted according to the polarity of the compound, or by adding small amounts of basic or acidic reagents such as triethylamine and acetic acid.

[0176] Example 1 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 [ka] [ka]

[0177] Step 1 3-Isopropyl-6-(1H-pyrazole-1-yl)-1,3,5-triazine-2,4(1H,3H)-dione 1c 2-Isocyanatopropane 1a (4.06 g, 47.71 mmol, Shanghai Taitan Technology Co., Ltd.) and 1H-pyrazole-1-formamidine hydrochloride 1b (6.66 g, 45.44 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) were dissolved in N,N-dimethylacetamide (35 mL), cooled to -10°C, and 1,8-diazabicycloundeca-7-ene (12.00 g, 47.65 mmol) was added dropwise until the addition was complete after 5 minutes, and the reaction was continued with stirring in an ice bath for 30 minutes. In an ice bath, N,N'-carbonyldiimidazole (9.80 g, 68.08 mmol) was added, the mixture was cooled to -5°C, and 1,8-diazabicycloundeca-7-ene (17.14 g, 68.06 mmol) was added dropwise until completion after 10 minutes. The reaction was then stirred in an ice bath for 1 hour. At room temperature, 2 N hydrochloric acid (132 mL) was added dropwise until completion after 30 minutes. The mixture was filtered, the filter cake was collected, and it was vacuum-dried to obtain the title product 1c (3.30 g, yield: 32.9%). MS m / z (ESI): 222.0 [M+1].

[0178] Step 2 (S)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)benzaldehyde 1e 4-Fluoro-3-formylphenylphenylboronic 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), 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 the mixture was stirred at room temperature for 24 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 1e (1.00 g, yield: 8.0%). MS m / z (ESI): 211.0 [M+1].

[0179] Step 3 (R)-N-(2-fluoro-5-(((S)-tetrahydrofuran-3-yl)oxy)phenylmethylidene)-2-methylpropane-2-sulfenamide 1f Compound 1e (1.00 g, 4.76 mmol) and (R)-2-methylpropane-2-sulfenamide (580 mg, 4.78 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (20 mL), cesium carbonate (1.90 g, 5.83 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was 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. MS m / z (ESI): 313.9 [M+1].

[0180] Step 4 (R)-N-((S)-1-(2-fluoro-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide 1g Crude product of compound 1f (100 mg, 0.32 mmol) was dissolved in dichloromethane (5 mL) and purged three times with nitrogen gas. The reaction was cooled to -60°C, and 2-methyltetrahydrofuran solution of 3 M magnesium methylbromide (0.22 mL, 0.66 mmol, Shanghai Taitan Technology Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 5 hours 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 (20 mL × 2), the organic phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system B by silica gel column chromatography to obtain 1 g of the title product (105 mg, yield: 99.9%). MS m / z (ESI): 330.0 [M+1].

[0181] Step 5 (S)-1-(2-fluoro-5-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)ethane-1-amine hydrochloride 1h 1 g (105 mg, 0.32 mmol) of the compound was dissolved in ethanol (5 mL), cooled to 0°C, and thionyl chloride (101 mg, 0.85 mmol, Shanghai Husi 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 1h (83 mg, yield: 99.5%). The crude product was used directly in the next step without purification. MS m / z (ESI): 208.9 [M-16].

[0182] Step 6 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 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 1 (6 mg, yield: 5.0%). MS m / z (ESI): 379.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.50 (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).

[0183] Example 2 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 [ka] [ka]

[0184] Step 1 (R)-2-fluoro-5-((tetrahydrofuran-3-yl)oxy)benzaldehyde 2a Compound 1d (10 g, 59.5 mmol) and (R)-tetrahydrofuran-3-ol (10 g, 113 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (100 mL), pyridine (10 g, 126 mmol, Adamas), triethylamine (13 g, 129 mmol, Adamas), and copper acetate anhydride (23 g, 127 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) were added, and the reaction was stirred for 24 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 2a (1.9 g, yield: 15.2%). MS m / z (ESI): 211.0 [M+1].

[0185] Step 2 (R)-N-(2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)phenylmethylidene)-2-methylpropane-2-sulfenamide 2b 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 reacted with stirring for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the crude product of title product 2b (2.8 g, yield: 98.8%). MS m / z (ESI): 313.9 [M+1].

[0186] Step 3 (R)-N-((S)-1-(2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide 2c Crude product of compound 2b (300 mg, 0.96 mmol) was dissolved in dichloromethane (10 mL) and purged three times with nitrogen gas. The reaction was cooled to -60°C, and 2-methyltetrahydrofuran solution of 3 M magnesium methylbromide (0.67 mL, 2.01 mmol, Shanghai Taitan Technology Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 5 hours 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 (20 mL × 2), the organic phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system B by silica gel column chromatography to obtain the title product 2c (315 mg, yield: 99.9%). MS m / z (ESI): 330.0 [M+1].

[0187] Step 4 (S)-1-(2-fluoro-5-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)ethylamine hydrochloride 2d 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 Husi 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. MS m / z (ESI): 208.9 [M-16].

[0188] Step 5 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 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 2 (30 mg, yield: 10.7%). MS m / z (ESI): 379.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6): δ 10.52 (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).

[0189] Example 3 3-Isopropyl-6-(((1S)-1-(3-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 3 [ka] [ka]

[0190] Step 1 Tetrahydrofuran-3-ylmethanesulfonate 3b 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 methanesulfonyl chloride (2.84 g, 24.9 mmol, Shanghai Guoyao Group Chemical Reagents Co., Ltd.) was added at 0°C. The mixture was reacted at room temperature for 24 hours. Water (100 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 3b (3.1 g, yield: 82.2%). 1 H NMR (500 MHz, CDCl3) δ 5.34 (m, 1H), 4.06-3.89 (m, 4H), 3.06 (s, 3H), 2.29-2.24 (m, 2H).

[0191] Step 2 3-((tetrahydrofuran-3-yl)oxy)benzaldehyde 3c 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 x 2), the organic phases were combined, and the mixture was concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 3c (710 mg, yield: 90.2%). MS m / z (ESI): 193.0 [M+1].

[0192] Step 3 (R)-2-methyl-N-(3-((tetrahydrofuran-3-yl)oxy)phenylmethylidene)propan-2-sulfenamide 3d 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 reacted with stirring for 16 hours. The mixture was filtered, concentrated, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 3d (1.08 g, yield: 99.0%). MS m / z (ESI): 296.0 [M+1].

[0193] Step 4 (R)-2-methyl-N-((1S)-1-(3-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)propan-2-sulfenamide 3e 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 solution of 2-methyltetrahydrofuran in 3 M magnesium methylbromide (1.2 mL, 3.6 mmol) was added dropwise. The reaction was heated to room temperature and stirred for 16 hours. At 0°C, saturated ammonium chloride aqueous solution (20 mL) was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 3e (490 mg, yield: 92.9%). MS m / z (ESI): 312.1[M+1].

[0194] Step 5 (1S)-1-(3-((tetrahydrofuran-3-yl)oxy)phenyl)ethylamine hydrochloride 3f 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 mixture was concentrated under reduced pressure to obtain the crude product of the title product 3f (390 mg, 102%), which was used directly in the next step without purification. MS m / z (ESI): 208.1 [M+1].

[0195] Step 6 3-Isopropyl-6-(((1S)-1-(3-((tetrahydrofuran-3-yl)oxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 3 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 3 (40 mg, yield: 16.4%). MS m / z (ESI): 361.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.45 (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).

[0196] Example 4 (S)-3-isopropyl-6-((1-(3-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 4 [ka] [ka]

[0197] Step 1 3-((6-methylpyridine-3-yl)oxy)benzaldehyde 4b (3-formylphenyl)boronic acid 4a (800 mg, 5.34 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) and 6-methylpyridine-3-phenol (300 mg, 275 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (6.0 mL), triethylamine (560 mg, 5.54 mmol), pyridine (440 mg, 5.56 mmol), and copper acetate anhydrous (1.0 g, 5.51 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) were added, and the reaction was stirred for 24 hours. The mixture was filtered over diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 4b (410 mg, yield: 69.9%). MS m / z (ESI): 214.0 [M+1].

[0198] Step 2 (R)-2-methyl-N-(3-((6-methylpyridine-3-yl)oxy)phenylmethylidene)propan-2-sulfenamide 4c 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 mixture was reacted with stirring for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 4c (560 mg, yield: 92.0%). MS m / z (ESI): 317.1 [M+1].

[0199] Step 3 (R)-2-methyl-N-((S)-1-(3-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)propane-2-sulfenamide 4d Compound 4c (500 mg, 1.58 mmol) was dissolved in dichloromethane (10 mL). Under nitrogen protection, the reaction was cooled to -60°C, and a solution of 2-methyltetrahydrofuran in 3 M magnesium methylbromide (1.1 mL, 3.3 mmol, Shanghai Taitan Technology Co., Ltd.) was added dropwise. The reaction was heated to room temperature and stirred for 16 hours. At 0°C, saturated ammonium chloride aqueous solution (20 mL) was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 4d (480 mg, yield: 91.3%). MS m / z (ESI): 333.1[M+1].

[0200] Step 4 (S)-1-(3-((6-methylpyridine-3-yl)oxy)phenyl)ethylamine hydrochloride 4e 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 Husi 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. MS m / z (ESI): 229.0 [M+1].

[0201] Step 5 (S)-3-isopropyl-6-((1-(3-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 4 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 4 (4 mg, yield: 1.8%). MS m / z (ESI): 382.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.46 (brs, 1H), 8.24 (s, 1H), 7.40-7.34 (m, 3H), 7.27 (m, 1H), 7.13 (m, 1H), 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).

[0202] Example 5 (S)-3-isopropyl-6-((1-(3-(trifluoromethoxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 5 [ka] [ka]

[0203] Step 1 (R)-2-methyl-N-(3-(trifluoromethoxy)phenylmethylidene)propane-2-sulfenamide 5b 3-(trifluoromethoxy)benzaldehyde 5a (1.0 g, 5.26 mmol, Shanghai Bi De 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 reacted with stirring for 16 hours. The mixture was filtered, concentrated, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 5b (1.45 g, yield: 94.0%). MS m / z (ESI): 294.0 [M+1].

[0204] Step 2 (R)-2-methyl-N-((S)-1-(3-(trifluoromethoxy)phenyl)ethyl)propane-2-sulfenamide 5c 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 solution of 2-methyltetrahydrofuran in 3 M magnesium methylbromide (1.2 mL, 3.6 mmol) was added dropwise. The reaction was heated to room temperature and stirred for 16 hours. At 0°C, saturated ammonium chloride aqueous solution (20 mL) was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (20 mL x 2), the organic phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 5c (490 mg, yield: 92.9%). MS m / z (ESI): 310.0 [M+1].

[0205] Step 3 (S)-1-(3-(trifluoromethoxy)phenyl)ethylamine hydrochloride 5d 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 Husi 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. MS m / z (ESI): 188.8 [M-16].

[0206] Step 4 (S)-3-isopropyl-6-((1-(3-(trifluoromethoxy)phenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 5 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 5 (30 mg, yield: 15.6%). MS m / z (ESI): 359.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.49 (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).

[0207] Example 6 (S)-6-((1-(5-cyclopropyl-2-fluorophenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 6 [ka] [ka]

[0208] Step 1 5-Cyclopropyl-2-Fluorobenzaldehyde 6b 5-bromo-2-fluorobenzaldehyde 6a (10.00 g, 49.26 mmol, Shanghai Bide 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, the mixture was purged three times with nitrogen gas, and stirred at 100°C for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 6b (7.00 g, yield: 86.6%). 1 H NMR (500 MHz, CDCl3) δ 10.32 (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).

[0209] Step 2 (R)-N-(5-cyclopropyl-2-fluorophenylmethylidene)-2-methylpropane-2-sulfenamide 6c Compound 6b (1.00 g, 6.09 mmol) and (R)-2-methylpropane-2-sulfenamide (738 mg, 6.09 mmol, Shanghai Bi De Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (20 mL), cesium carbonate (2.38 g, 7.30 mmol) was added, and the mixture was reacted with stirring for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain the 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. MS m / z (ESI): 268.0 [M+1].

[0210] Step 3 (R)-N-((S)-1-(5-cyclopropyl-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfenamide 6d Crude product of compound 6c (1.62 g, 6.06 mmol) was dissolved in dichloromethane (10 mL) and purged three times with nitrogen gas. The reaction was cooled to -60°C, and 2-methyltetrahydrofuran solution of 3 M magnesium methylbromide (4.25 mL, 12.75 mmol, Shanghai Taitan Technology Co., Ltd.) was added dropwise. The reaction was stirred at room temperature for 5 hours 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 phase was combined, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system B by silica gel column chromatography to obtain the title product 6d (1.70 g, yield: 99.0%). MS m / z (ESI): 284.0 [M+1].

[0211] Step 4 (S)-1-(5-cyclopropyl-2-fluorophenyl)ethylamine hydrochloride 6e 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 Husi 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. MS m / z (ESI): 179.9 [M+1].

[0212] Step 5 (S)-6-((1-(5-cyclopropyl-2-fluorophenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 6 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 6 (50 mg, yield: 21.3%). MS m / z (ESI): 333.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.48 (brs, 1H), 7.20 (brs, 1H), 7.12 (m, 1H), 7.06 (m, 1H), 6.98 (m, 1H), 5.22 (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).

[0213] Example 7 (S)-6-((1-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione7 [ka] [ka]

[0214] Step 1 (R)-N-(Bicyclo[4.2.0]octa-1(6),2,4-triene-3-ylmethylidene)-2-methylpropane-2-sulfenamide 7b Bicyclo[4.2.0]octa-1(6),2,4-triene-3-aldehyde 7a (2.9 g, 22.0 mmol, obtained by the method disclosed in step 1 on pages 512-513 of the specification in patent application WO2019023147A1) 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 mixture was reacted with stirring for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of title product 7b (5.7 g), which was used directly in the next step without purification. MS m / z (ESI): 236.1 [M+1].

[0215] Step 2 (R)-N-((S)-1-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethyl)-2-methylpropane-2-sulfenamide 7c To a solution of the crude product of compound 7b (2.8 g, 12.1 mmol) in anhydrous dichloromethane (80 mL) at -50°C, a solution of 3 M magnesium methylbromide in methyltetrahydrofuran (8.1 mL, 24.2 mmol, Shanghai Taitan Technology Co., Ltd.) was added dropwise. The mixture was reacted at room temperature for 16 hours under nitrogen protection. A saturated aqueous solution of ammonium chloride (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 7c (2.0 g, yield: 66.2%). MS m / z (ESI): 252.1 [M+1].

[0216] Step 3 (R)-1-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethylamine hydrochloride 7d Compound 7c (500.0 mg, 2.0 mmol) was dissolved in methanol (3 mL), and a 1,4-dioxane solution in 4 M hydrogen chloride (2 mL) was added dropwise. The reaction was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 7d (366.0 mg), which was used directly in the next step without purification. MS m / z (ESI): 131.1 [M-16].

[0217] Step 4 (S)-6-((1-(Bicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione7 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 (Boston Phlex C18 150 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 7 (30 mg, yield: 12.1%). MS m / z (ESI): 301.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.46 (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).

[0218] Example 8 (S)-6-((1-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 8 [ka] [ka]

[0219] Step 1 (R)-N-((2,3-dihydrobenzofuran-6-yl)methylidene)-2-methylpropane-2-sulfenamide 8b 2,3-Dihydrobenzofuran-6-aldehyde 8a (1.0 g, 6.8 mmol, Jiangsu Aikang Biomedical Research and Development Co., Ltd.) and (R)-2-methylpropane-2-sulfenamide (860.0 mg, 7.1 mmol, Shanghai Taitan Technology Co., Ltd.) were dissolved in dichloromethane (40 mL). Cesium carbonate (2.6 g, 8.1 mmol) was added, and the mixture was reacted with stirring for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 8b (1.8 g). The crude product was used directly in the next step without purification. MS m / z (ESI): 252.0 [M+1].

[0220] Step 2 (R)-N-((S)-1-(2,3-dihydrobenzofuran-6-yl)ethyl)-2-methylpropane-2-sulfenamide 8c At -50°C, a solution of crude compound 8b (1.7 g, 6.8 mmol) in anhydrous dichloromethane (45 mL) was added dropwise to a solution of methyltetrahydrofuran in 3 M magnesium methylbromide (4.9 mL, 14.6 mmol). 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 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 resulting residue was purified by silica gel column chromatography using eluent system A to obtain the title product 8c (1.6 g, yield: 90.6%). MS m / z (ESI): 268.1 [M+1].

[0221] Step 3 (S)-1-(2,3-dihydrobenzofuran-6-yl)ethylamine hydrochloride 8d Compound 8c (534.0 mg, 2.0 mmol) was dissolved in methanol (3 mL), and a 1,4-dioxane solution in 4 M hydrogen chloride (2 mL) was added dropwise. The reaction was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 8d (400.0 mg), which was used directly in the next step without purification. MS m / z (ESI): 147.1 [M-16].

[0222] Step 4 (S)-6-((1-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 8 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 8 (15 mg, yield: 6.2%). MS m / z (ESI): 317.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.45 (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).

[0223] Example 9 (S)-6-((1-(2,3-dihydro-1H-inden-5-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 9 [ka] [ka]

[0224] Step 1 (R)-N-(1-(2,3-dihydro-1H-inden-5-yl)ethylidene)-2-methylpropane-2-sulfenamide 9b 1-(2,3-dihydro-1H-inden-5-yl)ethane-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 Taitan Technology Co., Ltd.) were added to anhydrous tetrahydrofuran (20 mL) with a 1 M chlorotriisopropoxytitaniumhexane solution (7.5 mL, 7.5 mmol, Shanghai Taitan Technology Co., Ltd.). The mixture was reacted at 65°C for 16 hours with stirring. Saturated sodium bicarbonate aqueous solution (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 9b (570.0 mg, yield: 34.7%). MS m / z (ESI): 264.0 [M+1].

[0225] Step 2 (R)-N-((S)-1-(2,3-dihydro-1H-inden-5-yl)ethylidene)-2-methylpropane-2-sulfenamide 9c At -78°C, compound 9b (570 mg, 2.2 mmol) was added dropwise to anhydrous tetrahydrofuran (10 mL) with 1 M lithium tri-sec-butylbohydride tetrahydrofuran solution (3.5 mL, 3.5 mmol, Shanghai Taitan Technology Co., Ltd.). The mixture was reacted at 0°C for 1 hour. Saturated ammonium chloride aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain the crude product of the title product 9c (570 mg), which was used directly in the next step without purification. MS m / z (ESI): 266.1 [M+1].

[0226] Step 3 (S)-1-(2,3-dihydro-1H-inden-5-yl)ethylamine hydrochloride 9d The crude product of compound 9c (570 mg, 2.2 mmol) was dissolved in methanol (3 mL), and a 1,4-dioxane solution in 4 M hydrogen chloride (2 mL) was added dropwise. The reaction was stirred for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product of the title product 9d (430.0 mg), which was used directly in the next step without purification. MS m / z (ESI): 145.1 [M-16].

[0227] Step 4 (S)-6-((1-(2,3-dihydro-1H-inden-5-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 9 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 9 (30 mg, yield: 12.4%). MS m / z (ESI): 315.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.45 (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).

[0228] Example 10 (S)-3-isopropyl-6-((1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 10 [ka] [ka]

[0229] Step 1 (R)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethylidene)propane-2-sulfenamide 10b 1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethane-1-one 10a (2.0 g, 11.5 mmol, Alfa Aesar (Tianjin) Chemical Co., Ltd.) and (R)-2-methylpropane-2-sulfenamide (2.1 g, 17.3 mmol, Shanghai Taitan Technology Co., Ltd.) were mixed in anhydrous tetrahydrofuran (20 mL), to which tetraethoxytitanium (4.0 g, 17.3 mmol, Energy Chemical) was added. The mixture was reacted at 65°C for 16 hours with stirring. Saturated sodium bicarbonate aqueous solution (60 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the resulting 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].

[0230] Step 2 (R)-2-methyl-N-((S)-1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl)propane-2-sulfenamide 10c Compound 10b (350 mg, 1.26 mmol) was dissolved in tetrahydrofuran (10 mL) and purged three times with nitrogen gas. The reaction was cooled to -78°C, and a solution of 1 M lithium tri-sec-butylbohydride in tetrahydrofuran (2.02 mL, 2.02 mmol, Shanghai Taitan Technology Co., Ltd.) was added dropwise. The reaction was stirred at 0°C for 1 hour 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), the organic phase was combined, washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 10c (340 mg, yield: 96.4%). MS m / z (ESI): 280.0 [M+1].

[0231] Step 3 (S)-1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethylamine hydrochloride 10d 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 Husi 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. MS m / z (ESI): 158.9 [M-16].

[0232] Step 4 (S)-3-isopropyl-6-((1-(5,6,7,8-tetrahydronaphthalene-2-yl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 10 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 10 (40 mg, yield: 9.9%). MS m / z (ESI): 329.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.48 (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).

[0233] Example 11 (S)-6-((1-(5-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 11 [ka] [ka]

[0234] Step 1 5-Fluorobenzofuran-6-carboxylate methyl-11b 6-bromo-5-fluorobenzofuran 11a (3.20 g, 14.88 mmol, prepared by the method for synthesizing intermediate A1.2b on page 36 of the specification of patent application WO2017219948A1) 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. The mixture was substituted three times with carbon monoxide gas and reacted with stirring at 70°C for 40 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 11b (1.50 g, yield: 51.9%). MS m / z (ESI): 194.8 [M+1].

[0235] Step 2 5-Fluoro-2,3-dihydrobenzofuran-6-carboxylate methyl-11c Compound 11b (1.50 g, 7.73 mmol) was dissolved in methanol (50 mL), 10% palladium-carbon hydrogenation catalyst (wet) was added, and the mixture was purged three times with hydrogen gas and reacted with stirring for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified with eluent system A by silica gel column chromatography to obtain the title product 11c (1.37 g, yield: 90.4%). MS m / z (ESI): 196.8 [M+1].

[0236] Step 3 (5-Fluoro-2,3-dihydrobenzofuran-6-yl)methanol 11d Compound 11c (1.37 g, 7.0 mmol) was dissolved in tetrahydrofuran solution (30 mL), and 2 M lithium borohydride solution (34.9 mL, 69.8 mmol) was added dropwise. The reaction was stirred at room temperature for 16 hours. The reaction was quenched in an ice bath with methanol (5 mL), the reaction mixture was adjusted to pH=6 with 1 M hydrochloric acid, and extracted with ethyl acetate (30 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain the title product 11d (1.05 g, yield: 89.4%). MS m / z (ESI): 190.0 [M+22].

[0237] Step 4 5-Fluoro-2,3-dihydrobenzofuran-6-aldehyde 11e Compound 11d (1.05 g, 6.24 mmol) was dissolved in dichloromethane (20 mL) solution, and Dess-Martin oxidizing agent (3.97 g, 9.36 mmol) was added. The mixture was reacted at room temperature for 2 hours. The reaction was quenched in an ice bath with saturated sodium thiosulfate (20 mL) and saturated sodium bicarbonate (20 mL), and the mixture was extracted with dichloromethane (30 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 11e (1.03 g, yield: 99.3%). MS m / z (ESI): 167.0 [M+1].

[0238] Step 5 (R)-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methylidene)-2-methylpropane-2-sulfenamide 11f Compound 11e (1.30 g, 7.82 mmol) and (R)-2-methylpropane-2-sulfenamide (1.42 g, 11.72 mmol, Shanghai Bi De Pharmaceutical Technology Co., Ltd.) were dissolved in dichloromethane (20 mL). Cesium carbonate (1.58 g, 14.09 mmol) was added, and the reaction was carried out with stirring for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 11f (2.80 g). The crude product was used directly in the next step without purification. MS m / z (ESI): 270.0 [M+1].

[0239] Step 6 (R)-N-((S)-1-(5-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl)-2-methylpropane-2-sulfenamide 11g At -50°C, a solution of 2.80 g, 10.40 mmol of the crude product of compound 11f was added dropwise to 45 mL of anhydrous dichloromethane, to which a solution of 3 M magnesium methylbromide in methyltetrahydrofuran (6.93 mL, 20.79 mmol) was added. The mixture was reacted at room temperature for 2 hours under nitrogen protection. 30 mL of saturated ammonium chloride aqueous solution was added, and the mixture was extracted with dichloromethane (30 mL x 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain 11 g of the title product (1.50 g, yield: 50.56%). MS m / z (ESI): 286.0 [M+1].

[0240] Step 7 (S)-1-(5-fluoro-2,3-dihydrobenzofuran-6-yl)ethylamine hydrochloride 11h 11 g (300 mg, 1.05 mmol) of the compound 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 the crude product of the title product 11h (228 mg), which was used directly in the next step without purification. MS m / z (ESI): 164.9 [M-16].

[0241] Step 8 (S)-6-((1-(5-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 11 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 11 (90 mg, yield: 25.7%). MS m / z (ESI): 334.9 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.52 (brs, 1H), 7.28 (brs, 1H), 7.08 (d, 1H), 6.75 (m, 1H), 5.14 (m, 1H), 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).

[0242] Example 12 (S)-6-((1-(2-fluoro-5-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 12 [ka] [ka]

[0243] Step 1 2-Fluoro-5-((6-methylpyridine-3-yl)oxy)benzaldehyde 12a Compound 1d (61.55 g, 363.25 mmol) and 6-methylpyridine-3-phenol (20.00 g, 183.28 mmol, Shanghai Bide 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 copper acetate anhydride (66.58 g, 366.57 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) were added, and the reaction was stirred for 24 hours. The mixture was filtered over diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 12a (8.00 g, yield: 18.9%). MS m / z (ESI): 231.9 [M+1].

[0244] Step 2 (R)-N-(2-fluoro-5-((6-methylpyridine-3-yl)oxy)phenylmethylidene)-2-methylpropane-2-sulfenamide 12b 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 reacted with stirring for 16 hours. The mixture was filtered, concentrated under reduced pressure, and the resulting residue was purified using eluent system A by silica gel column chromatography to obtain the title product 12b (8.20 g, yield: 70.9%). MS m / z (ESI): 334.9 [M+1].

[0245] Step 3 (R)-N-((S)-1-(2-fluoro-5-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)-2-methylpropane-2-sulfenamide 12c Compound 12b (8.20 g, 24.52 mmol) was dissolved in dichloromethane (100 mL). Under nitrogen protection, the reaction was cooled to -60°C, and a solution of 2-methyltetrahydrofuran in 3 M magnesium methylbromide (17.2 mL, 51.49 mmol, Shanghai Taitan Technology Co., Ltd.) was added dropwise. The reaction was raised to room temperature and stirred for 5 hours. At 0°C, saturated aqueous ammonium chloride (100 mL) was added, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (80 mL x 2), the organic phase was 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 12c (2.10 g, yield: 24.4%). MS m / z (ESI): 349.0[M-1].

[0246] Step 4 (S)-1-(2-fluoro-5-((6-methylpyridine-3-yl)oxy)phenyl)ethylamine hydrochloride 12d 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. MS m / z (ESI): 247.0 [M+1].

[0247] Step 5 (S)-6-((1-(2-fluoro-5-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 12 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 12 (480 mg, yield: 38.3%). MS m / z (ESI): 399.9 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.53 (brs, 1H), 8.22 (d, 1H), 7.34-7.21 (m, 4H), 7.12 (m, 1H), 6.95 (m, 1H), 5.22 (m, 1H), 4.79 (m, 1H), 2.45 (s, 3H), 1.41 (d, 3H), 1.29 (d, 6H).

[0248] Example 13 (S)-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 13 [ka] [ka]

[0249] Step 1 (R)-N-((S)-1-(2-fluoro-5-methylphenyl)ethyl)-2-methylpropane-2-sulfenamide 13b (R)-N-(2-fluoro-5-methylphenylmethylidene)-2-methylpropane-2-sulfenamide 13a (6.90 g, 28.59 mmol, prepared according to the method for the synthesis of intermediate 3B on page 56 of the specification of patent application WO2020092208A1) was dissolved in dichloromethane (100 mL) and purged three times with nitrogen gas. The reaction was cooled to -60°C and a solution of 2-methyltetrahydrofuran in 3 M magnesium methylbromide (19.1 mL, 57.18 mmol) was added dropwise. The reaction was stirred at room temperature for 2 hours under nitrogen protection. A saturated ammonium chloride solution (100 mL) was added and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (80 mL x 2), the organic phase was 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 13b (5.60 g, yield: 76.1%). MS m / z (ESI): 258.0 [M+1].

[0250] Step 2 (S)-1-(2-fluoro-5-methylphenyl)ethylamine hydrochloride 13c 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. MS m / z (ESI): 153.9 [M+1].

[0251] Step 3 (S)-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dione 13 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 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 13 (400 mg, yield: 40.6%). MS m / z (ESI): 306.9 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.42 (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).

[0252] Example 14 (S)-6-((1-(2-fluoro-5-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 14 [ka] [ka]

[0253] Step 1 4-Isocyanatotetrahydro-2H-pyran-14b At 15°C, a solution of 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 Taitan Technology Co., Ltd.) in anhydrous dichloromethane (120 mL) was gradually added dropwise to bis(trichloromethyl) carbonate (11.9 g, 40.0 mmol, Shanghai Taitan Technology Co., Ltd.) in anhydrous dichloromethane (120 mL). The reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product of the title product 14b. The crude product was used directly in the next step without purification.

[0254] Step 2 6-(1H-pyrazole-1-yl)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 14c At -10°C, 1,8-diazabicyclo[5.4.0]undeca-7-ene (15.2 g, 100.0 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was gradually added dropwise to a solution of the crude products of compound 1b (10.5 g, 95.2 mmol) and compound 14b in anhydrous N,N-dimethylacetamide (120 mL). The reaction was stirred at 0°C for 1 hour. Then, at 0°C, carbonyldiimidazole (23.2 g, 142.8 mmol, Shanghai Bide Pharmaceutical Technology Co., Ltd.) and 1,8-diazabicyclo[5.4.0]undeca-7-ene (21.7 g, 142.8 mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) were added. The reaction was stirred at 60°C for 16 hours. The reaction mixture was concentrated under reduced pressure, dichloromethane was added to the resulting residue, the mixture was stirred, filtered, and the filtered cake was collected and dried under reduced pressure to obtain the title product 14c (16.6 g, 2-step yield: 63.4%). MS m / z (ESI): 264.1 [M+1].

[0255] Step 3 (S)-6-((1-(2-fluoro-5-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 14 Compound 14c (148.3 mg, 0.7 mmol) and compound 12d (198.0 mg, 0.7 mmol) were dissolved in N-methylpyrrolidone (2 mL), and N,N-diisopropylethylamine (452.6 mg, 3.5 mmol) was added. The mixture was microwaved at 140°C for 2 hours. The mixture was purified by high-performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30 mm*150 mm, eluent: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile concentration increased from 16% (v / v) to 36% (v / v) over 20 minutes, 30 mL / min, detection wavelengths 214 nm & 254 nm) to obtain the title product 14 (95.0 mg, yield: 30.7%). MS m / z (ESI): 442.1 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 8.20 (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).

[0256] Example 15 (S)-6-((1-(3-((6-methylpyridine-3-yl)oxy)phenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazine-2,4(1H,3H)-dione 15 [ka] [ka] Compound 14c (337.0 mg, 1.3 mmol) and compound 4e (338.9 mg, 0.7 mmol) were dissolved in N-methylpyrrolidone (4 mL), and N,N-diisopropylethylamine (827.3 mg, 6.4 mmol) was added. The reaction was carried out in a microwave at 140°C for 2 hours. The mixture was purified by high-performance liquid chromatography (Sharpsil-T Prep C18 5 μm 30 mm*150 mm, eluent: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile concentration increased from 16% (v / v) to 36% (v / v) over 20 minutes, 30 mL / min, detection wavelengths 214 nm & 254 nm) to obtain the title product 15 (166.0 mg, yield: 30.6%). MS m / z (ESI): 424.1 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 8.24 (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).

[0257] Example 16 (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 [ka] [ka] Compound 14c (425 mg, 1.61 mmol) and compound 13c (297 mg, 1.94 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction was stirred at 120°C for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Boston Phlex C18 150 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 16 (310 mg, yield: 55.1%). MS m / z (ESI): 349.0 [M+1]. 1H NMR (500 MHz, DMSO-d6) δ 10.50 (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).

[0258] Example 17 (S)-3-Cyclohexyl-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 17 [ka] [ka]

[0259] Step 1 3-Cyclohexyl-6-(1H-pyrazole-1-yl)-1,3,5-triazine-2,4(1H,3H)-dione 17b Cyclohexyl isocyanate 17a (8.97 g, 71.66 mmol, Shanghai Taitan 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, and 1,8-diazabicycloundeca-7-ene (17.18 g, 68.22 mmol) was added dropwise until completion after 5 minutes, and the reaction was continued stirring in an ice bath for 30 minutes. Then, in an ice bath, N,N'-carbonyldiimidazole (14.73 g, 102.33 mmol) was added, the reaction was cooled to -5°C, and 1,8-diazabicycloundeca-7-ene (25.77 g, 102.33 mmol) was added dropwise until completion after 10 minutes, and the reaction was continued stirring in an ice bath for 1 hour. At room temperature, 197 mL of 2 N hydrochloric acid was added, and the addition was completed dropwise after 30 minutes. The mixture was filtered, the filtered cake was collected, and it was vacuum-dried to obtain the title product 17b (16.00 g, yield: 89.8%). MS m / z (ESI): 262.0 [M+1].

[0260] Step 2 (S)-3-Cyclohexyl-6-((1-(2-fluoro-5-methylphenyl)ethyl)amino)-1,3,5-triazine-2,4(1H,3H)-dione 17 Compound 17b (680 mg, 2.60 mmol) and compound 13c (392 mg, 2.56 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction was stirred at 120°C for 16 hours. The reaction mixture was concentrated to dry and purified by high-performance liquid chromatography (Boston Phlex C18 150 mm*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20%~95% acetonitrile, gradient elution for 20 minutes, flow rate: 30 mL / min) to obtain the title product 17 (420 mg, yield: 46.6%). MS m / z (ESI): 347.0 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 10.45 (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).

[0261] Biological evaluation The present disclosure will be further explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present disclosure.

[0262] Test Example 1: Inhibitory effect of the compound relating to this disclosure on myosin ATP enzyme activity. The following method is for measuring the inhibitory effect of the compounds relating to this disclosure on myosin ATP enzyme activity, and the experimental method is briefly described below.

[0263] 1. Experimental materials and equipment 1. Cardiac actin (Cytoskeleton, AD99) 2. Myosin Motor Protein S1 Fragment (Cytoskeleton, CS-MYS03) 3. ATP (Sigma, A7699-1G) 4. UltraPure TM 1 M Tris-HCl buffer, pH 7.5 (Thermo, 15567027) 5. CytoPhos TM Phosphate detection bioreagent kit (Cytoskeleton, BK054) 6. Magnesium chloride solution (Sigma, 68475-100ML-F) 7. Potassium chloride solution (Sigma, 60142-100ML-F) 8. EGTA (Sigma, E3889-100G) 9, 96-well plate (Corning, 3697) 10. U-shaped bottom 96-well plate (Corning, 3795) 11. Microplate readers (BMG, PHERAstar) 12. Constant temperature incubator (Shanghai BoXun, SPX-100B-Z)

[0264] 2. Experimental Procedure 1.61 μM cardiac actin and 0.07 μM myosin motor protein S1 fragment were mixed with different concentrations of low molecular weight compounds (starting at 100 μM, followed by a 3-fold gradient dilution to obtain 9 different concentrations) and incubated at 37°C for 1 hour. Then, 120 μM ATP was added and incubated at 37°C for 2 hours. Finally, CytoPhos was added to each well. TMThe detection solution (70 μL / well) from the phosphate detection bioreagent kit was added and incubated at room temperature for 10 minutes. The OD values ​​at 650 nM wavelength were read using a microplate reader, the amount of Pi was calculated using a standard curve, the data was processed with GraphPad software, and inhibition curves were drawn based on each concentration of the compound and the corresponding inhibition rate, and the IC value was the concentration of the compound at which the inhibition rate reached 50%. 50 The values ​​were calculated. The experimental results are shown in detail in Table 1.

[0265] [Table 2] Conclusion: The compounds described herein have excellent inhibitory activity against myosin ATP enzymes.

[0266] Test Example 2: Pharmacokinetic evaluation of the compounds relating to this disclosure in Beagle dogs. 1. Summary Using Beagle dogs as the target animals, the plasma drug concentrations of the compounds awaiting measurement were measured at different time points in Beagle dogs administered intragastricly and intravenously using the LC / MS / MS method. The pharmacokinetic behavior of the compounds related to this disclosure in Beagle dogs was studied, and their pharmacokinetic characteristics were evaluated.

[0267] 2. Experimental Design 2.1 Experimental Drugs Compound of Example 16, Compound MYK-461( [ka] (Example 1 of WO2014205223A1).

[0268] 2.2 Laboratory Animals Pharmacokinetics of the compound in Example 16 in Beagle dogs: Eight Beagle dogs, half male and half female, were provided by Shanghai Medicilon Biopharmaceutical Co., Ltd., and were divided equally into two groups of four dogs each.

[0269] Pharmacokinetics of compound MYK-461 in Beagle dogs: Six male Beagle dogs were provided by Shanghai Medicilon Biopharmaceutical Co., Ltd., divided equally into two groups of three dogs each.

[0270] 2.3 Preparation of drugs A certain amount of the compound from Example 16 was weighed, and a clear solution was prepared by adding 5% DMSO, 30% PG, 30% PEG400, and 35% physiological saline.

[0271] A certain amount of compound MYK-461 was weighed, and a clear solution was prepared by adding 5% DMSO, 20% PG, 20% PEG400, and 55% physiological saline.

[0272] 2.4 Administration After fasting Beagle dogs overnight, the drugs were administered intragastricly and intravenously, with doses of 2 mg / kg and 0.5 mg / kg, respectively, and volumes of administration of 5 mL / kg and 2 mL / kg, respectively.

[0273] 3, operation In the intragastric administration group, 1.0 mL of blood was collected from the jugular vein or forelimb vein before administration and at 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 anticoagulation test tube, centrifuged at 10000 rpm for 5 min (4°C), and the plasma was separated within 1 hour. The sample was then stored at -80°C for measurement. The process from blood collection to centrifugation was performed under ice bath conditions. Food was administered 3 hours after administration.

[0274] In the intravenous injection group, blood samples were collected before administration and at 5 min, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 12.0 h, and 24.0 h after administration, and the processing was the same as for the gastric administration group.

[0275] The content of the compounds awaiting measurement in the plasma of Beagle dogs administered different concentrations of the drug intragastricly and intravenously was measured. Specifically, 30 μL of plasma from Beagle dogs was taken at each time point after administration, and internal standard solutions (internal standard for the compound in Example 16: warfarin 100 ng / mL, internal standard for compound MYK-461: tolbutamide 100 ng / mL) and 300 μL of methanol were added. The mixture was vortexed for 1 minute, centrifuged for 7 minutes (centrifugation force 18000 g), and 200 μL of the supernatant was transferred to a 96-well plate. 1 μL of the supernatant was taken from the plasma sample and performed LC / MS / MS analysis.

[0276] 4. Results of pharmacokinetic parameters

[0277] [Table 3-1] [Table 3-2] Conclusion: The compound of Example 16 in this disclosure exhibits good pharmacokinetic absorption in Beagle dogs. Furthermore, the compound of Example 16 in this disclosure exhibits T 1 / 2 The length becomes significantly shorter. Compound MYK-461 is T 1 / 2 Because the effect is relatively long-lasting and clinical accumulation is relatively serious, constant adjustments are needed in clinical administration, and the risk of administration increases. 1 / 2 By shortening the time to administration, the accumulation of clinical drugs in the body can be reduced or avoided, contributing to the determination of the dosage for patients and avoiding the risks associated with accumulation. It is clear that the compound of Example 16 in this disclosure has a significant pharmacokinetic advantage compared to compound MYK-461.

[0278] Test Example 3: Pharmacokinetic evaluation of the compounds related to this disclosure in cynomolgus monkeys 1. Summary Using cynomolgus monkeys as the control animals, the drug concentrations in plasma were measured at different time points in cynomolgus monkeys that received the compounds awaiting measurement via intragastric administration and intravenous injection, using the LC / MS / MS method. The pharmacokinetic behavior of the compounds related to this disclosure in cynomolgus monkeys was studied, and their pharmacokinetic characteristics were evaluated.

[0279] 2. Experimental Design 2.1 Experimental Drugs Compound MYK-461 of Example 16.

[0280] 2.2 Laboratory Animals Pharmacokinetics of the compound in Example 16 in cynomolgus monkeys: Eight cynomolgus monkeys, half male and half female, were provided by Shanghai Medicilon Biopharmaceutical Co., Ltd., and were divided equally into two groups of four monkeys each.

[0281] Pharmacokinetics of compound MYK-461 in cynomolgus monkeys: Six male cynomolgus monkeys were provided by Shanghai Medicilon Biopharmaceutical Co., Ltd., and were divided equally into two groups of three monkeys each.

[0282] 2.3 Preparation of drugs A certain amount of the compound from Example 16 was weighed, and a clear solution was prepared by adding 5% DMSO, 30% PG, 30% PEG400, and 35% physiological saline.

[0283] A certain amount of compound MYK-461 was weighed, and a clear solution was prepared by adding 5% DMSO, 20% PG, 20% PEG400, and 55% physiological saline.

[0284] 2.4 Administration After fasting the cynomolgus monkeys overnight, the drugs were administered intragastricly and intravenously, with doses of 2 mg / kg and 0.5 mg / kg, respectively, and volumes of administration of 5 mL / kg and 2 mL / kg, respectively.

[0285] 3, operation In the intragastric administration group, 1.0 mL of blood was collected from the forelimb vein before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration. This blood was placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000 rpm for 5 min (4°C), and the plasma was separated within 1 hour. The sample was then stored at -80°C for measurement. The process from blood collection to centrifugation was performed under ice bath conditions. Food was given 3 hours after administration, and the subjects were allowed to drink water freely.

[0286] In the intravenous injection group, blood samples were collected before administration and at 5 min, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 12.0 h, and 24.0 h after administration, and the processing was the same as for the gastric administration group.

[0287] The content of compounds awaiting measurement in the plasma of cynomolgus monkeys administered different concentrations of the drug intragastricly and intravenously was measured. Specifically, 20 μL of plasma from cynomolgus monkeys was taken at each time point after administration, and internal standard solutions (internal standard for compound 16: verapamil 10 ng / mL, internal standard for compound MYK-461: camptothecin 100 ng / mL) and 400 μL of methanol were added. The mixture was vortexed for 1 minute, and the mixture was centrifuged for 7 minutes (centrifugation force 18000 g). 200 μL of the supernatant was transferred to a 96-well plate, and 2 μL of the supernatant was taken from the plasma sample and analyzed by LC / MS / MS.

[0288] 4. Results of pharmacokinetic parameters

[0289] [Table 4] Conclusion: The compound of Example 16 in this disclosure exhibits good pharmacokinetic absorption in cynomolgus monkeys. Furthermore, the compound of Example 16 in this disclosure exhibits T 1 / 2 The length becomes significantly shorter. Compound MYK-461 is T 1 / 2 Because the effect is relatively long-lasting and clinical accumulation is relatively serious, constant adjustments are needed in clinical administration, and the risk of administration increases. 1 / 2By shortening the time to administration, the accumulation of clinical drugs in the body can be reduced or avoided, contributing to the determination of the dosage for patients and avoiding the risks associated with accumulation. It is clear that the compound of Example 16 in this disclosure has a significant pharmacokinetic advantage compared to compound MYK-461.

[0290] Test Example 4: Evaluation of the toxicological kinetics of the compound disclosed herein after repeated intragastric administration to SD rats for 14 days. 1. Summary Using SD rats as test animals, the concentrations of the drug protozoa in plasma and administration solutions were measured at different time points in SD rats that had been intragastricly administered the compounds awaiting measurement, using the LC / MS / MS method. The toxicological behavior of the compounds related to this disclosure in SD rats was studied, and their toxicological characteristics were evaluated.

[0291] 2. Experimental Design 2.1 Test reagent Compound MYK-461 of Example 16.

[0292] 2.2 Laboratory Animals We received 24 SD rats, half male and half female, from Vienna Lihua Laboratory Animals Co., Ltd., which were divided equally into 6 groups of 4 rats each.

[0293] 2.3 Preparation of drugs A certain amount of the compound from Example 16 was weighed, and 15% PEG400 and 85% (10% TPGS + 1% HPMC K100LV) were added to prepare a pale yellow homogeneous suspension solution. A certain amount of compound MYK-461 was weighed, and a colorless, transparent solution was prepared by adding 0.5% MC.

[0294] 2.4 Administration The compounds in Example 16 were administered intragastricly. The dosages were 5 mg / kg, 15 mg / kg, and 30 mg / kg, respectively, with a dosage volume of 10 mL / kg.

[0295] The dosages of compound MYK-461 were 0.5 mg / kg, 1.5 mg / kg, and 3 mg / kg, respectively, with a dosage volume of 10 mL / kg for each.

[0296] 3, operation On day 1, 0.2 mL of blood was collected from the orbit at 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, and 24.0 h after administration. On days 7 and 14, 0.2 mL of blood was collected from the orbit before administration and at 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, and 24.0 h after administration. The samples were placed in EDTA-K2 anticoagulation test tubes, centrifuged at 10000 rpm for 1 min (4°C), and the plasma was separated within 1 hour. The samples were then stored at -20°C for measurement. The process from blood collection to centrifugation was performed under ice bath conditions. The subjects were fed 2 hours after administration.

[0297] The content of the compounds awaiting measurement in the plasma of SD rats administered intragastricly at different concentrations was measured. Specifically, 20 μL of plasma from SD rats at each time point after administration was taken, 50 μL of internal standard solution (internal standard for compound 16: verapamil 100 ng / mL, internal standard for compound MYK-461: camptothecin 100 ng / mL) and 200 μL of acetonitrile were added, mixed by vortex for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 1 μL of supernatant was taken from the plasma sample and analyzed by LC / MS / MS.

[0298] 4. Results of toxicological parameters

[0299] [Table 5] Conclusion: The compound of Example 16 in this disclosure did not show significant accumulation in SD rats after repeated intragastric administration for 14 days, whereas compound MYK-461 showed serious accumulation in SD rats, increasing the risk of administration. It is clear that the compound of Example 16 in this disclosure has a significant toxicological advantage compared to compound MYK-461.

[0300] Test Example 5: Identification of reactive metabolites of the compounds relating to this disclosure in human liver microsomes The following experimental methods were used to identify the reactive metabolites of the compounds relating to this disclosure in human liver microsomes.

[0301] 1. Experimental materials and equipment 1. Phosphate buffer (purchased from Shanghai Biotechnology), 2. NADPH (ACROS, A2646-71-1) 3. Human liver microsomes (Corning Gentest, Cat No. 452161, Lot No. 905002) 4. Thermo UHPLC-Q-Exactive Orbitrap mass spectrometer (Thermo Fisher Scientific) 5. Acquity BEH C 18 Column, 2.1 mm × 100 mm, 1.7 μm (Waters, USA) 6. Positive control compound (Diclofenac).

[0302] 2. Experimental drugs Compound MYK-461 of Example 16.

[0303] 3. Experimental Procedure 1. Preparation of test compound solution: The test compound was appropriately measured, precisely weighed, dissolved in an appropriate amount of DMSO, and then uniformly mixed to obtain a stock solution with a concentration of 30 mM. The stock solution with a concentration of 10 mM was diluted 10-fold with 50% acetonitrile / water (v / v) to obtain working solution 1 with a concentration of 3.0 mM. Working solution 1 with a concentration of 3.0 mM was diluted 10-fold with PBS to obtain working solution 2 with a concentration of 300 μM, which was stored at 4°C before use.

[0304] 2. Preparation of phosphate buffer: K2HPO4 and KH2PO4 were weighed appropriately and dissolved in 4 L of pure water to prepare a buffer solution with a concentration of 100 mM. The pH was then adjusted to 7.4 with phosphoric acid or sodium hydroxide.

[0305] 3. Preparation of liver microsome solution: A suitable amount of liver microsome stock solution (concentration of 20 mg / mL) from each species was taken and diluted to a 1.43 mg / mL microsome solution with 100 mM phosphate buffer (pH 7.4).

[0306] 4. Preparation of NADPH cofactor solution: NADPH and magnesium chloride were appropriately weighed and dissolved in appropriate amounts of 100 mM phosphate buffer (pH 7.4) to achieve concentrations of 10 mM and 30 mM, respectively, and prepared for use.

[0307] 5. Preparation of glutathione (GSH) solution: GSH was appropriately weighed and dissolved in an appropriate amount of 100 mM phosphate buffer (pH 7.4) to a concentration of 50 mM, and prepared for use.

[0308] 6. The incubation systems are as follows:

[0309] [Table 6] 20 μL of 300 μM working solution 2 was precisely pipetteed into a 1.5 mL centrifuge tube, and 140 μL of 1.43 mg / mL liver microsome solution was added to achieve a liver microsome protein concentration of 1 mg / mL in the incubation system. Furthermore, 20 μL of 10 mM NADPH solution and 20 μL of 50 mM GSH solution were added, and the system was placed in a 37°C constant temperature incubator, shaken, and incubated, with the timer started. 60 mins after the start of incubation, the incubation sample was removed from the incubator, 1000 μL of ice-cold acetonitrile solution was added to stop the reaction, and the mixture was left at room temperature for 10 minutes before being centrifuged at 12000 rpm for 10 minutes. All supernatant was pipetteed into a centrifuge tube and concentrated under vacuum at 37°C until dry. The residue was redissolved in 200 μL of 25% acetonitrile / aqueous solution, centrifuged at 12000 rpm for 10 min, and the supernatant was pipetteed into a 96-well plate. 5 μL was aspirated and performed LC / MS analysis. For blank samples, 20 μL of PBS was added instead of working solution 2. For NCF samples, 20 μL of PBS was added instead of GSH solution. Testing for the positive control, diclofenac (10 μM), was the same as for the test compound. Data were collected, processed and analyzed using Xcalibur software, and the compounds relating to this disclosure were analyzed by precise mass spectrometry and secondary mass spectrometry fragments to determine whether they were metabolically activated and generated reactive metabolites.

[0310] [Table 7] Conclusion: In the experiment, no GSH conjugates associated with the compound of Example 16 of this disclosure were detected, but GSH conjugates associated with compound MYK-461 were detected. Therefore, it is clear that the compound of Example 16 of this disclosure exhibits better safety than compound MYK-461.

Claims

1. A compound represented by the general formula (I) below, or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Eventually, Ring A is a phenyl group, R １ is a halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, C(O)R ６ , C(O)OR ７ , S(O) ｔ R[[ID=⑨]] ８ , S(O) ｔ NR ９ R １０ , C(O)NR ９ R １０ , NR ９ R １０ and a group of the following formula It should be noted that there may be some inaccuracies in the original text. For example, the "⑨" in the original seems to be an incorrect numbering. It is recommended to double-check the original text for more accurate translation. 【Chemistry 2】 Selected from the group consisting of, Each R ２ These are homologous or different, and each is independently a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, 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 Selected from the group consisting of, Or, R １ and one adjacent R ２ , or two adjacent R ２ It condenses with ring A to form a 3- to 8-membered cycloalkyl group or a 3- to 12-membered heterocycline group, of which the 3- to 8-membered cycloalkyl group or 3- to 12-membered heterocycline group is optionally substituted with one or more substituents selected from the group consisting of hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, and hydroxyl groups. L ２ is a covalent bond, (CH ２ ) ｒ , C(O), NR ａ Selected from the group consisting of oxygen atoms and sulfur atoms, R ａ This is selected from the group consisting of a hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, 3- to 8-membered cycloalkyl group, 3- to 12-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group. Ring C is selected from the group consisting of 3- to 8-membered cycloalkyl groups, 3- to 12-membered heterocyclyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups. Each R ５ These are homologous or different and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, hydroxyalkyl group, 3- to 8-membered cycloalkyl group, 3- to 12-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group. R ３ａ This is selected from the group consisting of halogens, alkyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, and hydroxyalkyl groups, and of which the alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogens, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, and hydroxyl groups. R ３ｂ It is a hydrogen atom, R ０ is an alkyl group or the following group 【Transformation 3】 The alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogens, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, and hydroxyl groups. L １ It is a covalent bond, Ring B is selected from the group consisting of 3- to 8-membered cycloalkyl groups, 3- to 12-membered heterocyclyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups. Each R ４ These are homologous or different, and each is independently a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, oxo, cyano group, nitro group, hydroxy group, hydroxyalkyl group, C(O)R ６ , C(O)OR ７ , S(O) ｔ R ８ , S(O) ｔ NR ９ R １０ , and C(O)NR ９ R １０ Selected from the group consisting of, R ６ Each of these groups is homologous or different in appearance, and each is independently selected from the group consisting of a hydrogen atom, alkyl group, haloalkyl group, 3- to 8-membered cycloalkyl group, 3- to 12-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group, of which the alkyl group, 3- to 8-membered cycloalkyl group, 3- to 12-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group are independently and optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, nitro group, hydroxy group, and hydroxyalkyl group. R ７ Each occurrence is homologous or different, and each is independently selected from the group consisting of a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, 3- to 8-membered cycloalkyl group, 3- to 12-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group. R ８ Each occurrence is homologous or different, and each is independently selected from the group consisting of a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, hydroxy group, 3- to 8-membered cycloalkyl group, 3- to 12-membered heterocyclyl group, 6- to 10-membered aryl group, and 5- to 10-membered heteroaryl group. R ９ and R １０ Each instance is homologous or different, and each is independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, 3- to 8-membered cycloalkyl group, -(CH ２ ) ｒ -3-membered to 8-membered cycloalkyl groups, 3-membered to 12-membered heterocyclyl groups, -(CH ２ ) ｒ -3-membered to 12-membered heterocyclyl group, 6-membered to 10-membered aryl group, -(CH ２ ) ｒ -6-membered to 10-membered aryl groups, 5-membered to 10-membered heteroaryl groups and -(CH ２ ) ｒ - Selected from the group consisting of 5-membered to 10-membered heteroaryl groups, or R ９ and R １０ This forms a 3- to 12-membered heterocyclyl group together with the linked nitrogen atom, and the 3- to 12-membered heterocyclyl group is optionally substituted with one or more substituents selected from the group consisting of halogens, alkyl groups, oxo, alkenyl groups, alkynyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, 3- to 8-membered cycloalkyl groups, 3- to 12-membered heterocyclyl groups, 6- to 10-membered aryl groups, and 5- to 10-membered heteroaryl groups. 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. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

2. A compound represented by the general formula (I-1) below, or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 Eventually, Ring A, R ０ , R １ , R ２ , R ３ａ , R ３ｂ and m are as defined in claim 1, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

3. A compound represented by the general formula (II) below, or a pharmaceutically acceptable salt thereof, 【Transformation 5】 Eventually, R ０ , R １ , R ２ , R ３ａ , R ３ｂ and m are as defined in claim 1, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

4. A compound represented by the general formula (II-1) below, or a pharmaceutically acceptable salt thereof, 【Transformation 6】 Eventually, R ０ , R １ , R ２ , R ３ａ , R ３ｂ and m are as defined in claim 1, A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

5. R ０ C １－６ A compound represented by the general formula (I) described in claim 1, selected from the group consisting of alkyl groups, 3- to 8-membered cycloalkyl groups, and 3- to 12-membered heterocyclyl groups, or a pharmaceutically acceptable salt thereof.

6. R ０ C １－６ A compound represented by the general formula (I) described in claim 1, selected from the group consisting of alkyl groups, 3- to 6-membered cycloalkyl groups, and 3- to 6-membered heterocyclyl groups, or a pharmaceutically acceptable salt thereof.

7. R ０ is a compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of an isopropyl group, a tetrahydropyranyl group, and a cyclohexyl group.

8. R ０ The compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, wherein is a tetrahydropyranyl group.

9. R １ is halogen, C １－６ Alkyl alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy groups and the following groups 【Transformation 7】 selected from the group consisting of L ２ is a covalent bond or an oxygen atom, ring C is selected from the group consisting of a 3- to 8-member cycloalkyl group, a 3- to 12-member heterocyclyl group, a 6- to 10-member aryl group and a 5- to 10-member heteroaryl group, each R ５ is the same or different and each is independently a hydrogen atom, a halogen, C １－６ alkyl group, C １－６ alkoxy group, C １－６ haloalkyl group, C １－６ haloalkoxy group and C １－６ hydroxyalkyl group, p is 0, 1, 2, 3, 4, 5 or 6, R ２ is a hydrogen atom, a halogen, C １－６ alkyl group, C ２－６ alkenyl group, C ２－６ alkynyl group, C １－６ alkoxy group, C １－６ haloalkyl group and C １－６ haloalkoxy group, or R １ and one adjacent R ２ , or two adjacent R ２ is condensed with ring A to form a 3- to 8-member cycloalkyl group or a 3- to 12-member heterocyclyl group, a compound represented by the general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

10. R １ C １－６ Alkyl alkyl group, C １－６ Haloalkoxy groups and the following groups 【Transformation 8】 Selected from the group consisting of L ２ is a covalent bond or oxygen atom, and ring C is selected from the group consisting of a cyclopropyl group, a tetrahydrofuranyl group and a pyridyl group, and each R ５ These are homologous or different, and each is independently a hydrogen atom, a halogen, and C. １－６ Selected from the group consisting of alkyl groups, p is 0, 1, or 2, and each R ２ are homologous or different, and each is independently a hydrogen atom or a halogen, or R １ and one adjacent R ２ The compound represented by general formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound condenses with ring A to form a cyclobutyl group, a tetrahydrofuranyl group, a cyclopentyl group, and a cyclohexyl group.

11. R ３ａ is halogen, C １－６ Alkyl alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group and C １－６ A compound represented by the general formula (I) described in claim 1, selected from the group consisting of hydroxyalkyl groups, or a pharmaceutically acceptable salt thereof.

12. R ３ａ C １－６ A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, which is an alkyl group.

13. R ３ａ The compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof, wherein is a methyl group.

14. R ０ This is a tetrahydropyranyl group, which is a substructure in the general formula (II-1) shown below. 【Chemistry 9】 The basis of the following equation 【Chemistry 10】 And R １ C １－６ It is an alkyl group, R ２ is a hydrogen atom or a halogen, R ３ａ R is a methyl group, ３ｂ is a hydrogen atom, in the general formula (I) described in claim 4. The indicated compound or a pharmaceutically acceptable salt thereof.

15. Compound of the following formula 【Chemistry 11】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

16. Compound of the following formula 【Chemistry 12】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

17. Compounds of the following formula 【Chemistry 13】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

18. Compound of the following formula 【Chemistry 14】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

19. Compound of the following formula 【Chemistry 15】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

20. The compound of the following formula 【Chemistry 16】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

21. The compound of the following formula 【Chemistry 17】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

22. The compound of the following formula [Chemistry 18] A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

23. The compound of the following formula 【Chemistry 19】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

24. The compound of the following formula 【Chemistry 20】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

25. The compound of the following formula 【Chemistry 21】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

26. The compound of the following formula 【Chemistry 22】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

27. ​​The compound of the following formula 【Chemistry 23】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

28. The compound of the following formula 【Chemistry 24】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

29. The compound of the following formula 【Chemistry 25】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

30. The compound of the following formula 【Chemistry 26】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

31. The compound of the following formula 【Chemistry 27】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

32. The compound of the following formula 【Chemistry 28】 A compound represented by general formula (I) as described in claim 1, or a pharmaceutically acceptable salt thereof.

33. A method for preparing a compound represented by the general formula (I) below or a pharmaceutically acceptable salt thereof, 【Chemistry 29】 This method involves a nucleophilic substitution reaction between a compound represented by general formula (IA) or a salt thereof and a compound represented by general formula (V) to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof. Eventually, R ｗ is a leaving group, Ring A, R ０ , R １ , R ２ , R ３ａ , R ３ｂ and m are as defined in claim 1, A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof.

34. The salt of the compound represented by general formula (IA) is a hydrochloride salt, and / or R ｗ The method according to claim 33, wherein is a pyrazolyl group.

35. A pharmaceutical composition comprising a compound represented by general formula (I) as described in any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable vectors, diluents, or excipients.

36. A compound represented by general formula (I) according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use as a myosin inhibitor.

37. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or medical condition, wherein the disease or medical condition is selected from the group consisting of preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), moderate ejection fraction heart failure (HFmREF), valvular heart disease, aortic stenosis, inflammatory cardiomyopathy, Loeffler's endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, refractory angina pectoris, and Chagas disease.

38. The compound according to claim 37, wherein the disease or condition is 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.

39. The compound according to claim 37, wherein the disease or condition is hypertrophic cardiomyopathy (HCM).

40. The compound according to claim 37, wherein the disease or condition is non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

41. The pharmaceutical composition according to claim 35 for use as a myosin inhibitor.

42. A pharmaceutical composition according to claim 35 for use in the treatment of a disease or medical condition, wherein the disease or medical condition is selected from the group consisting of preserved ejection fraction diastolic heart failure, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), moderate ejection fraction heart failure (HFmREF), valvular heart disease, aortic stenosis, inflammatory cardiomyopathy, Refrel endocarditis, cardiomyopathy and endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, refractory angina pectoris, and Chagas disease.

43. The pharmaceutical composition according to claim 42, wherein the disease or condition is 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.

44. The pharmaceutical composition according to claim 42, wherein the disease or condition is hypertrophic cardiomyopathy (HCM).

45. The pharmaceutical composition according to claim 42, wherein the disease or condition is non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

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