Pyrimidinedione derivatives, processes for their preparation and their use in medicine

Abstract

Provided are pyrimidinedione derivatives of general formula (I), methods for preparing the same, pharmaceutical compositions containing the same, and uses of the same as therapeutic agents, particularly in the preparation of myosin inhibitors and in the preparation of medicaments for treating hypertrophic cardiomyopathy (HCM) or heart disease with pathophysiological features associated with HCM.

Description

Technical Field

[0001] The present disclosure relates to the field of medicine and relates to a pyrimidinedione derivative, a method for preparing the same, and its use in medicine. In particular, the present disclosure relates to a pyrimidinedione derivative represented by general formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and its use in the preparation of myosin inhibitors and in the preparation of a medicament for treating hypertrophic cardiomyopathy (HCM) or heart diseases with pathophysiological features associated with HCM. Background Art

[0002] Hypertrophic cardiomyopathy (HCM) is a dominant hereditary myocardial disease associated with gene mutations. The global incidence is approximately 0.2%, and it is the most important cause of sudden death in young people under 35 years old (C. Vaughan Tuohy, et al., European Journal of Heart Failure, 22, 2020, 228-240). Clinically, it is characterized by asymmetric hypertrophy of the left ventricular wall, often invading the ventricular septum, a smaller ventricular cavity, obstructed left ventricular blood filling, and decreased ventricular diastolic compliance. Depending on whether there is obstruction in the left ventricular outflow tract, it is divided into obstructive and non-obstructive hypertrophic cardiomyopathy. Currently, the treatment of hypertrophic cardiomyopathy in clinical practice mostly uses β-blockers and calcium channel blockers to reduce cardiac contractility and relieve symptoms. However, these treatments are only temporary solutions and not the root cause. When HCM progresses to the late stage, heart transplantation is the only option (R adhakrishnan Ramaraj, Cardiology in Review, 16 (4), 2008, 172-180). Therefore, it is urgent to find a treatment method targeting the root cause of HCM.

[0003] It has been found that 70% of HCM patients are caused by sarcomere protein gene mutations. Among them, 5-7% of patients are found to have multiple site mutations. About 70 pathogenic mutations have been identified, but most of these mutations are family-specific, and only a few hot spots have been identified, such as MYH7 R403Q and R453C mutations (Norbert Frey, et al., Nature Reviews Cardiology, 9, 2011, 91-100; M. Sabater-Molina, et al., Clinical Genetics, 93, 2018, 3-14). Studies on the pathogenicity of gene mutations have found that MYH7 gene mutation patients account for about 30%. Compared with other sarcomere protein genes, MYH7 causes early-onset and more severe cardiac hypertrophy. Myosin is the building block of thick myofilaments of myofibrils and plays an important role in muscle movement. Its molecular shape is like a sprout, which is composed of two heavy chains and multiple light chains. The myosin head binds to actin to form a cross-bridge, greatly increasing the ATPase activity of myosin, catalyzing ATP hydrolysis, generating energy to promote the sliding of the cross-bridge, and performing muscle contraction. Research results show that MYH7 gene mutations can cause myosin ATPase activity to increase, the proportion of myosin super-relaxed state (SRX) to decrease, and the cross-bridge between myosin and actin to increase, thereby causing abnormal cardiac contraction function (Eric M. Green, et al., Science, 351(6273), 2016, 617-621; Ruth F. Sommese, et al., Proceedings of the National Academy Sciences, 110(31), 2013, 12607-12612). Therefore, myosin is an important target for treating hypertrophic cardiomyopathy.

[0004] Patent applications for myosin inhibitors have been disclosed, including WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1 and CN110698415A, etc. SUMMARY

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

[0006]

[0007] wherein:

[0008] Ring A is

[0009] Ring B is a cycloalkyl group or a heterocyclyl group containing one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom;

[0010] each R 1 are the same or different and each is independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a hydroxyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; wherein each of said alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently optionally substituted with one or more substituents selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, an amino group, a nitro group and a hydroxyl group;

[0011] X 1 , X 2 and X 3 are the same or different and each is independently a nitrogen atom or CR a ;

[0012] each R a is the same or different and each is independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a C(O)R 6 , a C(O)OR 7 , a S(O) p R 8 , a S(O) p NR 9 R 10 , a C(O)NR 9 R 10 and a NR 9 R 10 ;

[0013] R 2 is selected from a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group; wherein each of said alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group is independently optionally substituted with one or more substituents selected from a halogen, an alkoxy group, a haloalkoxy group, a cyano group, an amino group, a nitro group and a hydroxyl group;

[0014] R 3 is a hydrogen atom;

[0015] R 4 is selected from a hydrogen atom, a halogen and an alkyl group;

[0016] R 0 is an alkyl group or wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, haloalkoxy, cyano, amino, nitro, and hydroxy;

[0017] L1is a bond or (CH2) r ;

[0018] Ring D is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0019] each R 5 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, oxo, cyano, nitro, hydroxy, hydroxyalkyl, C(O)R 6 , C(O)OR 7 , S(O) p R 8 , S(O) p NR 9 R 10 , C(O)NR 9 R 10 , cycloalkyl, -(CH2) r -cycloalkyl, heterocyclyl, -(CH2) r -heterocyclyl, aryl, -(CH2) r -aryl, heteroaryl, and -(CH2) r -heteroaryl;

[0020] R 6 is selected from the group consisting of a hydrogen atom, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

[0021] R 7 is selected from the group consisting of a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0022] R 8 is selected from the group consisting of a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

[0023] R 9 and R 10 are the same or different, and each is independently selected from the group consisting of a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, -(CH2) r -cycloalkyl, heterocyclyl, -(CH2) r -heterocyclyl, aryl, -(CH2) r-aryl, heteroaryl and -(CH2) r -heteroaryl;

[0024] or R 9 and R 10 Together with the nitrogen atom to which it is attached, it forms a heterocyclic group, wherein the heterocyclic group is optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0025] t is 0, 1, 2, 3, or 4;

[0026] r is 0, 1, 2, 3, 4, 5, or 6;

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

[0028] p is 0, 1 or 2.

[0029] In some embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof:

[0030]

[0031] in:

[0032] Ring A, R 0 、R 2 、R 3 and R 4 As defined in general formula (I).

[0033] In other embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from

[0034] Preferably, ring A is More preferably, ring A is Among them, ring B, R 1 、R a and t are as defined in general formula (I).

[0035] In other embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein ring A is Among them, ring B, R 1 、R a and t are as defined in general formula (I); preferably, ring A is selected from

[0036] wherein R 1 , R a and t are as defined in general formula (I); further preferably, ring A is selected from more preferably, ring A is selected from most preferably, ring A is

[0037] In other embodiments of the present disclosure, the compound according to general formula (I) or a pharmaceutically acceptable salt thereof, is a compound according to general formula (I-1) or a pharmaceutically acceptable salt thereof: wherein ring B, R 1 , R a and t are as defined in general formula (I); preferably, ring A is selected from wherein R 1 , R a and t are as defined in general formula (I); more preferably, ring A is selected from

[0038] In other embodiments of the present disclosure, the compound according to general formula (I) or a pharmaceutically acceptable salt thereof, is a compound according to general formula (II-1) or a pharmaceutically acceptable salt thereof:

[0039]

[0040] wherein:

[0041] ring B, R a , R 0 , R 1 , R 2 , R 3 , R 4 and t are as defined in general formula (I).

[0042] In other embodiments of the present disclosure, the compound according to general formula (I) or a pharmaceutically acceptable salt thereof, is a compound according to general formula (II-2) or a pharmaceutically acceptable salt thereof:

[0043]

[0044] wherein:

[0045] ring B, R a , R 0 , R 1 , R 2 , R 3 , R 4 and t are as defined in general formula (I).

[0046] In some embodiments of the present disclosure, the compound of general formula (I), general formula (I-1), general formula (II-1), or a pharmaceutically acceptable salt thereof, is a compound of general formula (III-1), or a pharmaceutically acceptable salt thereof:

[0047]

[0048] wherein:

[0049] ring B, R a , R 0 , R 1 , R 2 , R 3 , R 4 and t are as defined in general formula (I).

[0050] In some embodiments of the present disclosure, the compound of general formula (I), general formula (I-1), general formula (II-2), or a pharmaceutically acceptable salt thereof, is a compound of general formula (III-2), or a pharmaceutically acceptable salt thereof:

[0051]

[0052] wherein:

[0053] ring B, R a , R 0 , R 1 , R 2 , R 3 , R 4 and t are as defined in general formula (I).

[0054] In some embodiments of the present disclosure, the compound of general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R 0 is C 1-6 alkyl or wherein said C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, amino and hydroxyl; L1is a bond or (CH2) r ; ring D is selected from the group consisting of 3- to 8-membered cycloalkyl, 3- to 12-membered heterocyclyl, 6- to 10-membered aryl and 5- to 10-membered heteroaryl; each R 5 is the same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, oxo, cyano, hydroxy, and C 1-6 hydroxyalkyl; r is 0, 1, or 2; s is 0, 1, or 2; preferably, R 0 is C 1-6 alkyl or 3- to 6-membered heterocyclyl; more preferably, R 0 is isopropyl or tetrahydropyranyl; most preferably, R 0 is isopropyl.

[0055] In other embodiments of the present disclosure, the compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), or pharmaceutically acceptable salt thereof, is one wherein R 0 is C 1-6 alkyl; preferably, R 0 is isopropyl.

[0056] In other embodiments of the present disclosure, the compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), or pharmaceutically acceptable salt thereof, is one wherein ring B is 4- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl containing one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom; preferably, ring B is selected from the group consisting of cyclopentyl, cyclobutyl, cyclohexyl, and tetrahydrofuranyl; more preferably, ring B is tetrahydrofuranyl.

[0057] In other embodiments of the present disclosure, the compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), or pharmaceutically acceptable salt thereof, is one wherein ring B is 4- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl containing one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom; preferably, ring B is selected from the group consisting of cyclopentyl, cyclobutyl, and tetrahydrofuranyl.

[0058] In other embodiments of the present disclosure, the compound of Formula (I), Formula (I-1), or pharmaceutically acceptable salt thereof, is one wherein X 1 , X 2 , and X 3 are the same or different and each is independently a nitrogen atom or CR a ; each R a is the same or different and each is independently selected from the group consisting of a hydrogen atom, a halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6haloalkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, C

[0059] In other embodiments of the present disclosure, the compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), or pharmaceutically acceptable salt thereof, wherein each R 1 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkyl, C 1 is a hydrogen atom.

[0060] In other embodiments of the present disclosure, the compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), or pharmaceutically acceptable salt thereof, wherein each R a are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 haloalkyl; preferably, each R a are the same or different and each is independently a hydrogen atom or halogen; more preferably, each R a are the same or different and each is independently a hydrogen atom or a fluorine atom.

[0061] In other embodiments of the present disclosure, the compound of Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), or pharmaceutically acceptable salt thereof, wherein

[0062] selected from the group consisting of

[0063] wherein each R a are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 haloalkyl; each R 1 are the same or different and each is independently selected from the group consisting of a hydrogen atom, halogen, C 1-6alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, amino and hydroxy; t is 0 or 1 ; preferably, selected from

[0064] more preferably,

[0065] selected from

[0066] In some embodiments of the present disclosure, the compound represented by the general formula (II-1), the general formula (III-1) or a pharmaceutically acceptable salt thereof is represented by the following general formula (II-1-1) or (III-1-1): selected from each R a are the same or different and each independently a hydrogen atom or a halogen, t is 0; preferably, selected from more preferably, is

[0067] In some embodiments of the present disclosure, the compound represented by the general formula (II-1), the general formula (III-1) or a pharmaceutically acceptable salt thereof is represented by the following general formula (II-1-1) or (III-1-1): is each R a are the same or different and each independently a hydrogen atom or a halogen, t is 0; preferably, is

[0068] In some embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II-1), the general formula (II-2), the general formula (III-1), the general formula (III-2) or a pharmaceutically acceptable salt thereof is represented by the following general formula (I-1-1), (II-1-1), (II-2-1), (III-1-1) or (III-2-1): 2 selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 1-6 hydroxyalkyl; preferably, R 2 is C 1-6 alkyl; more preferably, R 2 is a methyl group.

[0069] In other embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II-1), the general formula (II-2), the general formula (III-1), the general formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from a hydrogen atom, a halogen, and C 1-6 alkyl group; preferably, R 4 is a hydrogen atom or C 1-6 alkyl group; more preferably, R 4 is a hydrogen atom.

[0070] In other embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II-1), the general formula (II-2), the general formula (III-1), the general formula (III-2), or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1; preferably, t is 0.

[0071] In other embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II-1), the general formula (II-2), the general formula (III-1), the general formula (III-2), or a pharmaceutically acceptable salt thereof, wherein ring A is ring B is a 4- to 6-membered cycloalkyl group or a 4- to 6-membered heterocyclic group containing one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom; each R a is the same or different, and each is independently selected from a hydrogen atom, a halogen, C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 haloalkyl group, and C 1-6 haloalkoxy group; each R 1 is the same or different, and each is independently selected from a hydrogen atom, a halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, C 1-6 alkoxy group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, amino group, and hydroxyl group; R 0 is a C 1-6 alkyl group or a 3- to 6-membered heterocyclic group; R 2 is selected from 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; R 3 is a hydrogen atom; R 4 is selected from a hydrogen atom, a halogen, and C 1-6 alkyl group; t is 0 or 1.

[0072] In other embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (I-1), the general formula (II-1), the general formula (II-2), the general formula (III-1), the general formula (III-2), or a pharmaceutically acceptable salt thereof, wherein ring A is Ring B is a 4- to 6-membered cycloalkyl group or a 4- to 6-membered heterocyclyl group containing one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom; each R a are the same or different and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkyl group and a C 1-6 haloalkoxy group; each R 1 are the same or different and each is independently selected from a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 haloalkyl group, a C 1-6 alkoxy group, a C 1-6 haloalkoxy group, a C 1-6 hydroxyalkyl group, an amino group and a hydroxy group; R 0 is a C 1-6 alkyl group; R 2 is selected from 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 1-6 hydroxyalkyl group; R 3 is a hydrogen atom; R 4 is a hydrogen atom; t is 0 or 1.

[0073] In other embodiments of the present disclosure, the compound represented by the general formula (II-1), the general formula (II-2), the general formula (III-1), the general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein is selected from each R a are the same or different and each is independently a hydrogen atom or a halogen; R 1 is a hydrogen atom; R 0 is a C 1-6 alkyl group or a 3- to 6-membered heterocyclyl group; R 2 is a C 1-6 alkyl group; R 3 is a hydrogen atom; R 4 is selected from a hydrogen atom, a halogen and a C 1-6 alkyl group; t is 1.

[0074] In other embodiments of the present disclosure, the compound represented by the general formula (II-1), the general formula (II-2), the general formula (III-1), the general formula (III-2) or a pharmaceutically acceptable salt thereof, wherein is selected from each Ra the same or different, and each independently is a hydrogen atom or a halogen; R 1 is a hydrogen atom; R 0 is C 1-6 alkyl; R 2 is a methyl group; R 3 is a hydrogen atom; R 4 is a hydrogen atom; t is 1.

[0075] In some embodiments of the present disclosure, the compound represented by the general formula (II-1), the general formula (III-1) or a pharmaceutically acceptable salt thereof, wherein is each R a the same or different, and each independently is a hydrogen atom or a halogen; t is 0; R 0 is C 1-6 alkyl; R 2 is C 1-6 alkyl; R 3 is a hydrogen atom; R 4 is a hydrogen atom.

[0076] Table A Representative compounds of the present disclosure include, but are not limited to:

[0077]

[0078]

[0079]

[0080]

[0081] Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0082]

[0083] a nucleophilic substitution reaction of a compound represented by the general formula (IA) or a salt thereof (preferably a hydrochloride) with a compound represented by the general formula (V) to obtain a compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof;

[0084] wherein:

[0085] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0086] ring A, R 0 , R 2 , R 3 , and R 4 are as defined in the general formula (I).

[0087] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0088]

[0089] a nucleophilic substitution reaction of a compound represented by general formula (IA-1) or a salt thereof (preferably a hydrochloride salt) with a compound represented by general formula (V) to obtain a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof;

[0090] wherein:

[0091] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0092] ring A, R 0 , R 2 , R 3 , and R 4 are as defined in general formula (I-1).

[0093] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0094]

[0095] a nucleophilic substitution reaction of a compound represented by general formula (IIA-1) or a salt thereof (preferably a hydrochloride salt) with a compound represented by general formula (V) to obtain a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof;

[0096] wherein:

[0097] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0098] ring B, R 0 , R 1 , R a , R 2 , R 3 , R 4 , and t are as defined in general formula (II-1).

[0099] Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0100]

[0101] a compound represented by General Formula (II-2) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction of a compound represented by General Formula (IIIA-2) or a salt thereof (preferably a hydrochloride) and a compound represented by General Formula (V);

[0102] wherein:

[0103] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0104] ring B, R 0 , R 1 , R a , R 2 , R 3 , R 4 and t are as defined in General Formula (II-2).

[0105] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formula (III-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0106]

[0107] a compound represented by General Formula (III-1) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction of a compound represented by General Formula (IIIA-1) or a salt thereof (preferably a hydrochloride) and a compound represented by General Formula (V);

[0108] wherein:

[0109] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0110] ring B, R 0 , R 1 , R a , R 2 , R 3 , R 4 and t are as defined in General Formula (III-1).

[0111] Another aspect of the present disclosure relates to a method for producing a compound represented by General Formula (III-2) or a pharmaceutically acceptable salt thereof, the method comprising:

[0112]

[0113] a compound represented by General Formula (III-2) or a pharmaceutically acceptable salt thereof is obtained by a nucleophilic substitution reaction of a compound represented by General Formula (IIIA-2) or a salt thereof (preferably a hydrochloride) and a compound represented by General Formula (V);

[0114] wherein:

[0115] Rw is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0116] ring B, R 0 , R 1 , R a , R 2 , R 3 , R 4 and t are defined as in general formula (III-2).

[0117] Another aspect of the present disclosure relates to a pharmaceutical composition containing a compound of general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2) and Table A, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0118] The present disclosure further relates to the use of a compound of general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a Myosin inhibitor.

[0119] The present disclosure further relates to the use of a compound of general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment of a disease or disorder, in particular for the treatment of a disease or disorder mediated by Myosin, selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM) such as non-obstructive hypertrophic cardiomyopathy (nHCM) and obstructive hypertrophic cardiomyopathy (oHCM), heart failure with preserved ejection fraction (HFpEF), heart failure with mid-range ejection fraction (HFmREF), valvular disease, aortic stenosis, inflammatory cardiomyopathy, Loeffler endocarditis, myocardial endomyolial 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 the group consisting of ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0120] The present disclosure further relates to a method of inhibiting Myosin comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0121] The present disclosure further relates to a method of treating a disease or disorder, in particular treating a disease or disorder mediated by Myosin, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, the disease or disorder being selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with mid-range ejection fraction (HFmREF), valvular disease, aortic valve stenosis, inflammatory cardiomyopathy, Loeffler endocarditis, myocardial endomyolosarcoma, infiltrative cardiomyopathy, hemochromatosis, Fabry’s disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina, and Chagas disease; preferably selected from the group consisting of ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0122] The present disclosure further relates to a compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

[0123] The present disclosure further relates to a compound of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a Myosin inhibitor.

[0124] The present disclosure further relates to a compound of general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment of a disease or condition, in particular in the treatment of a disease or condition mediated by myosin, selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic cardiomyopathy (HCM), heart failure with mid-range ejection fraction (HFmREF), valvular disease, aortic valve stenosis, inflammatory cardiomyopathy, Loefler endocarditis, myocardial endomyolial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, refractory angina, and Chagas disease; preferably selected from ischemic heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy (HCM), inflammatory cardiomyopathy, infiltrative cardiomyopathy, congenital heart disease, and left ventricular hypertrophy; more preferably hypertrophic cardiomyopathy (HCM); most preferably non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

[0125] The compounds of general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, of the present disclosure can alter the natural history of HCM and other diseases, rather than merely palliating symptoms. The mechanism of clinical benefit to patients with HCM can be extended to patients with other forms of heart disease that share similar pathophysiology, with or without the influence of significant genetic factors. For example, effective treatment of HCM by improving ventricular relaxation during diastole can also be effective in a broader population characterized by diastolic dysfunction.

[0126] The compounds of general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, of the present disclosure can specifically target the root cause of the condition or act on other downstream pathways. Thus, the compounds of general formula (I), general formula (I-1), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, of the present disclosure can give benefit to patients with diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, or restrictive cardiomyopathy.

[0127] The compounds of the present disclosure of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can also promote beneficial ventricular remodeling in left ventricular hypertrophy due to volume or pressure overloading; for example, chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension; in combination with therapies aimed at correcting or mitigating the primary cause of volume or pressure overloading (valve repair / replacement, effective antihypertensive therapy). By reducing left ventricular filling pressures, the compounds can reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and / or reducing left atrial pressures can reduce the risk of paroxysmal or persistent atrial fibrillation, and its concomitant risk of arterial thromboembolic complications including, but not limited to, cerebral arterial embolic stroke. Reducing or eliminating dynamic and / or static left ventricular outflow obstruction can reduce the likelihood of requiring septal ablation therapy (surgical or percutaneous) and its concomitant risk of short- and long-term complications.

[0128] The compounds of the present disclosure of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can reduce the severity of the chronic ischemic state associated with HCM, and thereby reduce the risk of sudden cardiac death (SCD) or its equivalent in patients with implantable cardioverter-defibrillators (frequent and / or repetitive ICD discharges) and / or reduce the need for potentially toxic antiarrhythmic drugs.

[0129] The compounds of the present disclosure of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, are valuable in reducing or eliminating the need for concurrent medications (with their concomitant potential toxicities, drug-drug interactions, and / or side effects).

[0130] The compounds of the present disclosure of Formula (I), Formula (I-1), Formula (II-1), Formula (II-2), Formula (III-1), Formula (III-2), and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, can reduce interstitial myocardial fibrosis and / or slow the progression of left ventricular hypertrophy, arrest or reverse left ventricular hypertrophy.

[0131] The active compounds can be prepared into various pharmaceutically acceptable dosage forms for administration by any of the routes conventionally used for such purposes, depending on the purpose and needs of treatment. Thus, the active compounds of the present disclosure can be formulated into various dosage forms for oral, parenteral (e.g., intravenous, intramuscular or subcutaneous), inhalation or insufflation. The compounds of the present disclosure can also be formulated into sustained release dosage forms such as tablets, hard or soft gelatin capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.

[0132] As a general guide, the active compounds are preferably in unit dosage form, or in a form suitable for self-administration by a patient in a single dose. The expression unit dose of the compounds or compositions of the present disclosure can be tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders or liquid preparations. Suitable unit doses can be 0.1-1000 mg.

[0133] The pharmaceutical compositions of the present disclosure can contain, in addition to the active compounds, one or more adjuvants selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the method of administration, the compositions can contain 0.1 to 99% by weight of the active compounds.

[0134] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. The tablets can be uncoated or they can be coated by known techniques to mask the unpleasant taste or odor of the drug, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

[0135] Oral preparations can also be provided in the form of soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

[0136] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspensions can also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0137] Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil or mineral oil with or without the addition of a fractionated medicinal carrier. The oil suspensions can contain a thickening agent. Sweetening and flavoring agents can be added to provide a palatable vehicle for the active ingredient. These compositions can be preserved by the addition of an anti-oxidant.

[0138] The pharmaceutical compositions of the present disclosure can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifying agents can be naturally-occurring phosphatides, such as soybean phoshatide, and the like. The emulsions can also contain sweetening agents, flavoring agents, preservatives and antioxidants.

[0139] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can also be a sterile injectable oil-in-water microemulsion where the active ingredient is dissolved in the oily phase. The injectable form can be a solution or microemulsion in a local massive amount that is injected into the blood stream of a patient. Alternatively, the solution or microemulsion can be administered in such a way as to maintain a constant circulating concentration of the compound of the present disclosure. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. Model 5400 intravenous pump.

[0140] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous or oleaginous suspension for intramuscular or subcutaneous administration. This suspension can be formulated according to known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0141] The compounds of the present disclosure can be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are

[0142] The compounds of the present disclosure can be administered in the form of dispersible powders or granules suitable for preparation of an aqueous suspension by the addition of water. These compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent and one or more preservatives.

[0143] The dosage of the drug to be administered depends on various factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the body weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like, as is well known to those skilled in the art. In addition, the optimal therapeutic regimen, such as the mode of treatment, the daily amount of the compound, or the kind of the pharmaceutically acceptable salt, can be verified according to the conventional therapeutic regimen.

[0144] Terminology

[0145] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0146] The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof, and the like. Most preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available attachment point with one or more substituents preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0147] The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined above, having from 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., C 1-20 The alkylene group preferably has from 1 to 12 carbon atoms (i.e., C 1-12alkylene having 1 to 6 carbon atoms (i.e., C 1-6 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- propylidene (-CH(CH2CH3)-), 1,2-propylidene (-CH2CH(CH3)-), 1,3-propylidene (- CH2CH2CH2-), 1,4-butylidene (-CH2CH2CH2CH2-), and the like. Alkylene groups can be substituted or unsubstituted, and when substituted, can be substituted at any available attachment point with one or more substituents preferably selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0148] The term "alkenyl" refers to an alkyl group, as defined above, that contains at least one carbon-carbon double bond, 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 alkenyl group preferably has 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0149] The term "alkynyl" refers to an alkyl group, as defined above, that contains at least one carbon-carbon triple bond, having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 The alkynyl group preferably has 2 to 6 carbon atoms (i.e., C 2-6 Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0150] The term "alkoxy" refers to -0-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propyloxy, and butyloxy, and the like. The alkoxy group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0151] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring having from 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms (i.e., 3 to 20 membered cycloalkyl), preferably from 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl), more preferably from 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), most preferably from 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl), and particularly preferably from 4 to 6 carbon atoms (i.e., 4 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0152] The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group sharing one carbon atom (termed a spiro atom) between rings, which can contain one or more double bonds. Preferably 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spirocycloalkyl groups are classified as mono- or polyspirocycloalkyl (e.g., dispirocycloalkyl) depending on the number of spiro atoms shared between rings, preferably mono- and dispirocycloalkyl. More preferably 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, 6-membered / 4-membered, or 6-membered / 5-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0153] which can be attached at any position.

[0154] The term "fused ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, sharing adjacent pairs of carbon atoms between the rings, wherein one or more of the rings can contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bi-, tri-, tetra-, and so on, polycyclic fused ring alkyl according to the number of constituent rings, preferably bi- or tri-cyclic fused ring alkyl, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered bicyclic alkyl. Non-limiting examples of fused ring alkyl include:

[0155]

[0156] The point of attachment can be at any position.

[0157] The term "bridged ring alkyl" refers to a fully carbon polycyclic group of 5 to 20 members, sharing two non-adjacent carbon atoms between any two rings, which can contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Can be divided into bi-, tri-, tetra-, and so on, polycyclic bridged ring alkyl according to the number of constituent rings, preferably bi-, tri-, or tetra-cyclic bridged ring alkyl, more preferably bi- or tri-cyclic bridged ring alkyl. Non-limiting examples of bridged ring alkyl include:

[0158] The point of attachment can be at any position.

[0159] The cycloalkyl ring includes cycloalkyl (including monocyclic, spirocyclic, fused, and bridged) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include and the like; preferably

[0160] The cycloalkyl group can be substituted or unsubstituted, when substituted it can be substituted at any available point of attachment, the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0161] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring-like substituent having from 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), but does not include ring moieties of -0-0-, -0-S-, or -S-S-, with the remaining ring atoms being carbon. Preferably, there are from 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) ring atoms, of which 1-4 (e.g., 1, 2, 3, and 4) are heteroatoms (i.e., 3- to 12-membered heterocyclyl); further preferably, there are from 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1-3 are heteroatoms (i.e., 3- to 8-membered heterocyclyl); more preferably, there are from 3 to 6 ring atoms, of which 1-3 are heteroatoms (i.e., 3- to 6-membered heterocyclyl); most preferably, there are from 4 to 6-membered heterocyclyl having one heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom; particularly preferably, there are 5 or 6 ring atoms, of which 1-3 are heteroatoms (i.e., 5- or 6-membered heterocyclyl). Non-limiting examples of monocyclic heterocyclyl groups include: pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spirocyclic, fused, and bridged heterocyclyl groups.

[0162] The term "spiroheterocyclyl" refers to a 5- to 20-membered, polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between rings, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It can contain one or more double bonds. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spiroheterocyclyl groups are classified as either single- or multi- spiroheterocyclyl groups (e.g., bispiroheterocyclyl groups), preferably single- and bispiroheterocyclyl groups. More preferably, 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, 5 / 6-, or 6 / 6 single spiroheterocyclyl groups. Non-limiting examples of spiroheterocyclyl groups include:

[0163] and the like.

[0164] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, sharing adjacent pairs of atoms between the rings, one or more of which rings can contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings comprising the ring system, it can be referred to as a bicyclic, tricyclic, tetracyclic, etc. fused heterocyclyl, preferably a bicyclic or tricyclic fused heterocyclyl, more preferably a 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl groups include:

[0165]

[0166] etc.

[0167] The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, sharing two non-adjacent atoms between any two of the rings, which can contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of rings comprising the ring system, it can be referred to as a bicyclic, tricyclic, tetracyclic, etc. bridged heterocyclyl, preferably a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, more preferably a bicyclic or tricyclic bridged heterocyclyl. Non-limiting examples of bridged heterocyclyl groups include:

[0168] etc.

[0169] The heterocyclyl ring includes fused heterocyclyl (including monocyclic, spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl) as described above fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0170] etc.

[0171] The heterocyclyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0172] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing pairs of adjacent carbon atoms) groups having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to a heteroaryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring that is attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0173]

[0174] The aryl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0175] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably a 5- to 10-membered (e.g., 5-, 6-, 7-, 8-, 9-, or 10-membered) heteroaryl group, more preferably a 5- or 6-membered heteroaryl group, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyridinone, N-alkylpyridinone (such as The heteroaryl ring includes heteroaryl rings fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0176]

[0177] The heteroaryl ring includes heteroaryl rings fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring that is attached to the parent structure is the heteroaryl ring, non-limiting examples of which include:

[0178] The heteroaryl group can be substituted or unsubstituted, and when substituted, the substituents can be substituted at any available point of attachment with one or more substituents preferably selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0179] The above cycloalkyl, heterocyclyl, aryl, and heteroaryl groups include residues derived from removal of one hydrogen atom from a parent ring atom, or two hydrogen atoms from the same ring atom or two different ring atoms of the parent, i.e., "cycloalkylene," "heterocyclylene," "arylene," "heteroarylene."

[0180] The term "amino protecting group" refers to a labile group introduced on an amino group to keep it unchanged while reactions are performed on other parts of the molecule. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxy carbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups can optionally be substituted with 1-3 substituents selected from halo, alkoxy, or nitro.

[0181] The term "hydroxy protecting group" refers to a labile group introduced on a hydroxy group, typically to block or protect the hydroxy group while reactions are performed on other functional groups of the compound. Non-limiting examples include trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl, methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like.

[0182] The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

[0183] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0184] The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

[0185] The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halogens.

[0186] The term "haloalkoxy" refers to an alkoxy group as defined above substituted with one or more halogens.

[0187] The term "deuteroalkyl" refers to an alkyl group as defined above substituted with one or more deuterium atoms.

[0188] The term "hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxyl groups.

[0189] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0190] The term "hydroxyl" refers to -OH.

[0191] The term "mercapto" refers to -SH.

[0192] The term "amino" refers to -NH2.

[0193] The term "cyano" refers to -CN.

[0194] The term "nitro" refers to -NO2.

[0195] The term "oxo" means "=O".

[0196] The term "carbonyl" means C=0.

[0197] The term "carboxyl" means -C(0)OH.

[0198] The term "carboxylate" means -C(0)0(alkyl), -C(0)0(cycloalkyl), (alkyl)C(0)0- or (cycloalkyl)C(0)0-, wherein alkyl, cycloalkyl are defined as above.

[0199] The compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-forms, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures and other mixtures thereof, e.g., mixtures of enantiomers or diastereomers, all of which are intended to be within the scope of the present disclosure. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present disclosure. The compounds of the present disclosure containing an asymmetric carbon atom can be isolated in optically active form or as racemic mixtures. Optically active forms can be obtained, by resolution of racemic mixtures or by synthesis from optically active raw materials or from optically active intermediates.

[0200] In the chemical structures of the compounds of the present disclosure, the bond is not designated as to configuration, i.e., if chiral isomers are present in the chemical structure, the bond may be or or both configurations are included. In the chemical structures of the compounds of the present disclosure, the bond is not designated as to configuration, i.e., it can be in the Z configuration or the E configuration, or both configurations are included. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included. The compounds and intermediates of the present disclosure can also exist in different tautomeric forms and all such forms are embraced within the scope of the present disclosure. The term "tautomers" or "tautomeric forms" refers to different energy structures that can interconvert via low energy barriers. For example, prototropic tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. An example of a lactam-lactim equilibrium is as follows:

[0201]

[0202]

[0203] ​​All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomer.

[0204] The present disclosure also includes some isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, and the like. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for disease, or as tracers for pharmacokinetic, pharmacodynamic, or receptor studies.

[0205] The present disclosure also includes various deuterated forms of the compounds of Formula (I), Formula (I-l), Formula (II-l), Formula (II-2), Formula (III-l), Formula (III-2), and the compounds shown in Table A. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. One skilled in the art would be able to synthesize deuterated forms of the compounds of Formula (I), Formula (I-l), Formula (II-l), Formula (II-2), Formula (III-l), Formula (III-2), and the compounds shown in Table A with reference to the pertinent literature. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of the compounds of Formula (I), Formula (I-l), Formula (II-l), Formula (II-2), Formula (III-l), Formula (III-2), and the compounds shown in Table A, or they can be synthesized using conventional techniques employing deuterated reagents. Deuterated reagents include, but are not limited to, deuterated borane, trideuteroborane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane, among others. Unless otherwise specified, when a position is designated specifically as deuterium (D), the position is understood to have deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). The deuterium in the example compounds can be in an abundance of at least 1000 times greater than the natural abundance of deuterium, at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater.

[0206] "Optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted with halo or cyano" means that the alkyl group can or can not be substituted with halo or cyano, and that the description includes instances where the alkyl group is substituted with halo or cyano and instances where the alkyl group is not substituted with halo or cyano. 1-6 "Alkyl" means that halo or cyano can or can not be present, and that the description includes instances where the alkyl group is substituted with halo or cyano and instances where the alkyl group is not substituted with halo or cyano.

[0207] "Substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, of a group are independently replaced with a corresponding number of substituents. One skilled in the art can determine, without undue experimentation, through either experiment or theory, what substitutions are possible or impossible. For example, an amino or hydroxyl group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0208] "Pharmaceutical composition" means a mixture that comprises one or more of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof, together with one or more other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject, and to facilitate absorption, resulting in the active ingredient exerting a biological effect.

[0209] "Pharmaceutically acceptable salt" means a salt of a compound of the present disclosure that is safe and effective for use in a mammal, and possesses the desired biological activity. Salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable base or acid with the appropriate compound. Bases commonly employed to form pharmaceutically acceptable salts include inorganic bases, for example, sodium and potassium bases, as well as organic bases, for example, ammonia. Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

[0210] The term "therapeutically effective amount" with respect to a pharmaceutical or pharmacological agent means a sufficient amount of the agent to provide the desired effect, without undue toxicity. The effective amount will vary depending on the subject's age and general condition, as well as the particular active agent, and appropriate effective amounts can be determined by one of skill in the art in connection with the treatment of an individual case using routine testing.

[0211] The term "pharmaceutically acceptable" as used herein means that the compounds, materials, compositions, and / or dosage forms are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, and effective for their intended use.

[0212] As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0213] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, numbers are often given only to the nearest whole number for simplicity, not limitation, when the parameter is not critical.

[0214] Synthesis method of the disclosed compound

[0215] To achieve the purposes of the present disclosure, the present disclosure adopts the following technical solutions:

[0216] Scheme 1

[0217] The present disclosure provides a preparation method of the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

[0218]

[0219] The compound represented by general formula (IA) or a salt thereof (preferably hydrochloride) and the compound represented by general formula (V) undergo a nucleophilic substitution reaction in the presence of a base under microwave conditions to obtain the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof;

[0220] in:

[0221] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0222] Ring A, R 0 、R 2 、R 3 and R 4 As defined in general formula (I).

[0223] Option 2

[0224] The present invention discloses a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0225]

[0226] The compound represented by the general formula (IA-1) or a salt thereof (preferably a hydrochloride) and the compound represented by the general formula (V) undergo a nucleophilic substitution reaction in the presence of a base under microwave conditions to obtain the compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof;

[0227] in:

[0228] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0229] Ring A, R 0 、R 2 、R 3 and R 4 As defined in general formula (I-1).

[0230] Option 3

[0231] The present invention discloses a method for preparing a compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0232]

[0233] The compound represented by general formula (IIA-1) or a salt thereof (preferably a hydrochloride) and the compound represented by general formula (V) undergo a nucleophilic substitution reaction in the presence of a base under microwave conditions to obtain the compound represented by general formula (II-1) or a pharmaceutically acceptable salt thereof;

[0234] in:

[0235] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0236] Ring B, R 0 、R 1 、Ra , R 2 , R 3 , R 4 and t are as defined in general formula (II-1).

[0237] Scheme IV

[0238] A process for the preparation of a compound of general formula (II-2) or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0239]

[0240] nucleophilic substitution reaction of a compound of general formula (IIA-2) or a salt thereof (preferably hydrochloride) with a compound of general formula (V) in the presence of a base under microwave conditions to give a compound of general formula (II-2) or a pharmaceutically acceptable salt thereof;

[0241] wherein:

[0242] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0243] ring B, R 0 , R 1 , R a , R 2 , R 3 , R 4 and t are as defined in general formula (II-2).

[0244] Scheme V

[0245] A process for the preparation of a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof, comprising the steps of:

[0246]

[0247] nucleophilic substitution reaction of a compound of general formula (IIIA-1) or a salt thereof (preferably hydrochloride) with a compound of general formula (V) in the presence of a base under microwave conditions to give a compound of general formula (III-1) or a pharmaceutically acceptable salt thereof;

[0248] wherein:

[0249] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0250] ring B, R 0 , R 1 , R a , R 2 , R 3 , R 4and t are as defined in general formula (III-2).

[0251] Scheme six

[0252] The present disclosure provides a method for preparing a compound of general formula (III-2) or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0253]

[0254] The compound of general formula (IIIA-2) or a salt thereof (preferably hydrochloride) and the compound of general formula (V) undergo a nucleophilic substitution reaction in the presence of a base under microwave conditions to obtain the compound of general formula (III-2) or a pharmaceutically acceptable salt thereof;

[0255] wherein:

[0256] R w is a leaving group, preferably a halogen, more preferably a chlorine atom;

[0257] ring B, R 0 , R 1 , R a , R 2 , R 3 , R 4 and t are as defined in general formula (III-2).

[0258] The base includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, preferably N,N-diisopropylethylamine; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide.

[0259] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to N-methylpyrrolidone, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and a mixture thereof.

[0260] The reaction temperature of the above microwave reaction is 120-140°C, preferably 130°C.

[0261] The reaction time of the above microwave reaction is 0.5-4 hours, preferably 2 hours. DETAILED DESCRIPTION

[0262] The present disclosure is further described in connection with the following examples, which are not intended to limit the scope of the present disclosure.

[0263] Examples

[0264] The structure of the compounds was determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured by a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.

[0265] MS was measured by Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), THERMO Ultimate3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0266] High performance liquid chromatography (HPLC) analysis used Agilent HPLC 1200 DAD, Agilent HPLC 1200 VWD, and Waters HPLC e2695-2489 high performance liquid chromatograph.

[0267] Chiral HPLC analysis measurement used Agilent 1260 DAD high performance liquid chromatograph.

[0268] High performance liquid preparation used Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatograph.

[0269] Chiral preparation used Shimadzu LC-20AP preparative chromatograph.

[0270] CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0271] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography is 0.15mm-0.2mm. The specification of the product purified by thin layer chromatography is 0.4mm-0.5mm.

[0272] The silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0273] The determination of the average inhibition rate of the kinase and IC 50 The value is measured by NovoStar enzyme marker (Germany BMG company).

[0274] The known starting materials of the present disclosure can be synthesized according to the methods known in the art or purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, etc.

[0275] Unless otherwise specified in the examples, the reactions can be carried out under argon atmosphere or nitrogen atmosphere.

[0276] The argon atmosphere or nitrogen atmosphere refers to that the reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1L.

[0277] The hydrogen atmosphere refers to that the reaction bottle is connected with a hydrogen balloon with a volume of about 1L.

[0278] The pressurized hydrogenation reaction uses Parr 3916EKX type hydrogenation instrument and Qinglan QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument.

[0279] The hydrogenation reaction is generally vacuumed, filled with hydrogen, and the operation is repeated for 3 times.

[0280] The microwave reaction uses CEM Discover-S 908860 type microwave reactor.

[0281] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0282] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃-30℃.

[0283] The reaction progress in the examples is monitored by thin layer chromatography (TLC). The developing agent used in the reaction, the eluent used in the column chromatography for purifying the compound, and the developing agent system of the thin layer chromatography include: A: n-hexane / ethyl acetate system, B: dichloromethane / methanol system. The volume ratio of the solvents is adjusted according to the polarity of the compound. A small amount of triethylamine and acetic acid or other basic or acidic reagents can also be added for adjustment.

[0284] Example 1

[0285] (S)-6-((1-(2,3-dihydro-1H-inden-5-yl)ethyl)amino)-3-isopropylpyrimidine- 2,4(1H,3H)-dione 1

[0286]

[0287] First Step

[0288] (R)-N-(1-(2,3-dihydro-1H-inden-5-yl)ethenyl)-2-methylpropane-2-sulfonamide 1c

[0289] To 1-(2,3-dihydro-1H-inden-5-yl)ethan-1-one 1a (1.0 g, 6.3 mmol, TCI (Shanghai) Chemical Industry Development Co., Ltd.) and (R)-2-methylpropane-2-sulfonamide 1b (1.1 g, 8.8 mmol, Titan Scientific Co., Ltd.) in anhydrous tetrahydrofuran (20 mL), 1M titanium triisopropoxide chloride in hexane (7.5 mL, 7.5 mmol, Titan Scientific Co., Ltd.) was added. The reaction was stirred at 65 °C for 16 hours. Saturated aqueous sodium bicarbonate solution (30 mL) was added, and ethyl acetate (50 mL x 2) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (570.0 mg, yield: 34.7%).

[0290] MS m / z (ESI): 264.0 [M+1].

[0291] Second Step

[0292] (R)-N-((S)-1-(2,3-dihydro-1H-inden-5-yl)ethyl)-2-methylpropane-2-sulfonamide 1d

[0293] To compound 1c (570 mg, 2.2 mmol) in anhydrous tetrahydrofuran (10 mL), 1M lithium tri-sec-butylborohydride in tetrahydrofuran (3.5 mL, 3.5 mmol, Titan Scientific Co., Ltd.) was added dropwise at -78 °C. The reaction was stirred at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution (20 mL) was added, and ethyl acetate (30 mL x 2) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product 1d crude (570 mg), which was used directly in the next step without purification.

[0294] MS m / z (ESI): 266.1 [M+1].

[0295] Third Step

[0296] (S)-1-(2,3-dihydro-1H-inden-5-yl)ethylamine hydrochloride 1e

[0297] The crude compound 1d (570 mg, 2.2 mmol) was dissolved in methanol (3 mL), and 4M hydrogen chloride solution in 1,4-dioxane (2 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. Concentration under reduced pressure gave the crude title product 1e (430.0 mg), which was used in the next step without purification.

[0298] MS m / z (ESI): 145.1 [M-16].

[0299] Fourth step

[0300] (S)-6-((1-(2,3-dihydro-1H-inden-5-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione 1

[0301] The crude compound 1e (430.0 mg, 2.2 mmol), 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione 1f (413.6 mg, 2.2 mmol, prepared using the method described in patent application "WO2014205223A1, page 27, compound 1.3") and N,N-diisopropylethylamine (1.4 g, 10.9 mmol) were dissolved in dry 1,4-dioxane (6 mL). The reaction was stirred at 130 °C for 2 hours in a microwave. Concentration under reduced pressure and purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 μm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 40% (v / v) to 95% (v / v) in 12.1 minutes, detection wavelengths 214 & 254 nm) gave the title product 1 (140.0 mg, yield: 20.6%).

[0302] MS m / z (ESI): 314.1 [M+1].

[0303] 1 H NMR (500 MHz, DMSO-d6) δ 7.19 (s, 1H), 7.18 (d, 1H), 7.07 (d, 1H), 6.82 (br s, 2H), 4.92 (m, 1H), 4.41 (m, 1H), 4.31 (s, 1H), 2.85-2.79 (m, 4H), 2.02-1.96 (m, 2H), 1.37 (d, 3H), 1.27 (dd, 6H).

[0304] Example 2

[0305] (S)-6-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-3-isopropylpyrimidine- 2,4(1H,3H)-dione 2

[0306]

[0307]

[0308] First step

[0309] (R)-N-(1-(2,3-dihydro-1H-inden-4-yl)ethylidene)-2-methylpropane-2- sulfonamide 2b

[0310] To a solution of 1-(2,3-dihydro-1H-inden-4-yl)ethan-1-one 2a (500.0 mg, 3.1 mmol, TCI (Shanghai) Chemical Industry Development Co., Ltd.) and compound 1b (530.0 mg, 4.4 mmol) in anhydrous tetrahydrofuran (10 mL) was added 1M titanium triisopropoxide chloride in hexane (3.8 mL, 3.8 mmol). The reaction was stirred at 65 °C for 16 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 2b (220.0 mg, yield: 26.8%).

[0311] MS m / z (ESI): 264.0 [M+1].

[0312] Second step

[0313] (R)-N-((S)-1-(2,3-dihydro-1H-inden-4-yl)ethyl)-2-methylpropane-2-sulfonamide 2c

[0314] To a solution of compound 2b (220.0 mg, 0.8 mmol) in anhydrous tetrahydrofuran (5 mL) was added 1M lithium tri-sec-butylborohydride in tetrahydrofuran (1.4 mL, 1.4 mmol) dropwise at -78 °C. The reaction was stirred at 0 °C for 1 hour. Saturated aqueous ammonium chloride solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product 2c (220 mg) as a crude product, which was used directly in the next step without purification.

[0315] MS m / z (ESI): 266.1 [M+1].

[0316] Third step

[0317] (S)-1-(2,3-dihydro-1H-inden-4-yl)ethylamine hydrochloride 2d

[0318] The crude compound 2c (220.0 mg, 0.8 mmol) was dissolved in methanol (1 mL), and 4M hydrogen chloride solution in 1,4-dioxane (1 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. Concentration under reduced pressure gave the crude title product 2d (166.0 mg), which was used directly in the next step without purification.

[0319] MS m / z (ESI): 145.1 [M-16].

[0320] Fourth step

[0321] (S)-6-((1-(2,3-dihydro-1H-inden-4-yl)ethyl)amino)-3-isopropylpyrimidine- 2,4(1H,3H)-dione 2

[0322] The crude compound 2d (166.0 mg, 0.8 mmol), compound 1f (188.6 mg, 0.8 mmol) and N,N-diisopropylethylamine (543.0 g, 4.2 mmol) were dissolved in anhydrous 1,4-dioxane (6 mL). The reaction was stirred at 130 °C for 2 hours. Concentration under reduced pressure, purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 pm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 35% (v / v) to 95% (v / v) in 15.1 minutes, detection wavelength 214 & 254 nm) gave the title product 2 (40.0 mg, yield: 15.2%).

[0323] MS m / z (ESI): 314.1 [M+1].

[0324] 1 H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.14-7.11 (m, 2H), 7.06 (t, 1H), 6.46 (s, 1H), 4.90 (m, 1H), 4.58 (m, 1H), 4.22 (s, 1H), 2.94 (m, 1H), 2.88-2.81 (m, 3H), 2.06-2.00 (m, 2H), 1.37 (d, 3H), 1.27 (dd, 6H).

[0325] Example 3

[0326] (S)-6-((1-(dicyclo[4.2.0]octa-1(6),2,4-trien-3-yl)ethyl)amino)-3- isopropylpyrimidine-2,4(1H,3H)-dione 3

[0327]

[0328] First step

[0329] (R)-N-(dicyclo[4.2.0]octa-l(6),2,4-trien-3-ylmethyIidene)-2-methylpropane-2- sulfonamide 3b Compound 3a (2.9 g, 22.0 mmol, prepared by the synthetic method of compound 257 on page 512-513 of the specification of patent application "WO2019023147A1") and compound lb (2.8 g, 23.0 mmol) were dissolved in dichloromethane (40 mL). Cesium carbonate (8.6 g, 26.4 mmol) was added and the reaction was stirred for 16 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title product 3b (5.7 g) as a crude product which was used in the next step without purification.

[0330] MS m / z (ESI): 236.1 [M+1].

[0331] Second step

[0332] (R)-N-((S)-l-(dicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)ethyl)-2-methylpropane-2- sulfonamide 3c

[0333] To a solution of compound 3b (2.8 g, 12.1 mmol) in anhydrous dichloromethane (80 mL) was added dropwise 3M methyl magnesium bromide in methyl tetrahydrofuran (8.1 mL, 24.2 mmol, Shanghai Titan Science and Technology Co., Ltd.) at -50 °C. The reaction was stirred at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (50 mL) was added and dichloromethane (50 mL x 2) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate. Filtration was followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography using eluent system A to give the title product 3c (2.0 g, yield: 66.2%).

[0334] MS m / z (ESI): 252.1 [M+1].

[0335] Third step

[0336] (S)-l-(dicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)ethylamine hydrochloride 3d

[0337] Compound 3c (500.0 mg, 2.0 mmol) was dissolved in methanol (3 mL) and 4M hydrogen chloride in 1,4-dioxane (2 mL) was added dropwise. The reaction was stirred at room temperature for 1 hour. Concentration under reduced pressure gave the title product 3d (366.0 mg) as a crude product which was used in the next step without purification.

[0338] MS m / z (ESI): 131.1 [M-16].

[0339] Fourth step (S)-6-((l-(bicyclo[4.2.0]octa-l(6),2,4-trien-3-yl)ethyl)amino)-3- isopropylpyrimidine-2,4(lH,3H)-dione 3

[0340] Compound 3d crude (366.0 mg, 2.0 mmol), compound If (377.3 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.3 g, 10.1 mmol) were dissolved in anhydrous 1,4-dioxane (6 mL). The microwave reaction was carried out at 130 °C for 2 hours. Concentration under reduced pressure and purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 pm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile from 30% (v / v) to 95% (v / v) in 13.1 minutes, detection wavelength 214 & 254 nm) gave the title product 3 (208.0 mg, yield: 34.7%).

[0341] MS m / z (ESI): 300.1 [M+1].

[0342] 1 H NMR (500 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.14 (dd, 1H), 7.05 (s, 1H), 7.04 (d, 1H), 6.48 (s, 1H), 4.90 (m, 1H), 4.42 (m, 1H), 4.31 (s, 1H), 3.12-3.08 (m, 4H), 1.37 (d, 3H), 1.26 (dd, 6H).

[0343] Example 4

[0344] (S)-6-((l-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(lH,3H)- dione 4

[0345]

[0346] First step

[0347] (R)-N-(2,3-dihydrobenzofuran-6-yl)methylidene)-2-methylpropane-2-sulfmamide 4b

[0348] Dissolve 2,3-dihydrobenzofuran-6-carboxaldehyde 4a (1.0 g, 6.8 mmol, Jiangsu Aikang Biomedical Research and Development Co., Ltd.) and compound 1b (860.0 mg, 7.1 mmol, Shanghai Titan Science and Technology Co., Ltd.) in dichloromethane (40 mL). Add cesium carbonate (2.6 g, 8.1 mmol) and stir the reaction for 16 hours. Filter the reaction and concentrate the filtrate under reduced pressure to obtain the title product 4b crude (1.8 g), which is used directly in the next step without purification.

[0349] MS m / z (ESI): 252.0 [M+1].

[0350] Second step

[0351] (R)-N-((S)-1-(2,3-dihydrobenzofuran-6-yl)ethyl)-2-methylpropane-2-sulfmamide 4c

[0352] At -50 °C, add 3M methyl magnesium bromide in methyl tetrahydrofuran (4.9 mL, 14.6 mmol) dropwise to compound 4b crude (1.7 g, 6.8 mmol) in anhydrous dichloromethane (45 mL). Stir the reaction at room temperature for 16 hours under nitrogen atmosphere. Add saturated aqueous ammonium chloride solution (30 mL) and extract with dichloromethane (30 mL x 2). Dry the combined organic phase with anhydrous sodium sulfate. Filter and concentrate the residue under reduced pressure. Purify the residue with silica gel column chromatography using eluent system A to obtain the title product 4c (1.6 g, yield: 90.6%).

[0353] MS m / z (ESI): 268.1 [M+1].

[0354] Third step

[0355] (S)-1-(2,3-dihydrobenzofuran-6-yl)ethylamine hydrochloride 4d

[0356] Dissolve compound 4c (534.0 mg, 2.0 mmol) in methanol (3 mL) and add 4M hydrogen chloride in 1,4-dioxane (2 mL) dropwise. Stir the reaction at room temperature for 1 hour. Concentrate under reduced pressure to obtain the title product 4d crude (400.0 mg), which is used directly in the next step without purification.

[0357] MS m / z (ESI): 147.1 [M-16].

[0358] Fourth step

[0359] (S)-6-((1-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione 4

[0360] Compound 4d crude (399.4 mg, 2.0 mmol), compound If (377.3 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.3 g, 10.1 mmol) were dissolved in anhydrous 1,4-dioxane (6 mL). The reaction was carried out at 130 °C for 2 h in a microwave. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex Prep C18, 5 pm 30*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile from 28% (v / v) to 48% (v / v) in 15 min, detection wavelength 214 & 254 nm) to give the title product 4 (170.0 mg, yield: 26.9%).

[0361] MS m / z (ESI): 316.1 [M+1].

[0362] 1 H NMR (500 MHz, DMSO-d6) d 9.76 (s, 1H), 7.18 (d, 1H), 6.77 (dd, 1H), 6.73 (s, 1H), 6.47 (s, 1H), 4.90 (m, 1H), 4.50 (t, 2H), 4.41 (m, 1H), 4.31 (s, 1H), 3.12 (t, 2H), 1.37 (d, 3H), 1.26 (dd, 6H).

[0363] Example 5

[0364] (S)-3-isopropyl-6-((1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)- pyrimidine-2,4(1H,3H)-dione 5

[0365]

[0366] First step

[0367] (R)-2-methyl-N-(1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethenyl)propane-2- sulfonamide 5b

[0368] To compound 5a (2.0 g, 11.5 mmol, Alfa Aesar (Tianjin) Chemicals Ltd.) and compound 1b (2.1 g, 17.3 mmol) in anhydrous tetrahydrofuran (20 mL), tetraethoxytitanium (4.0 g, 17.3 mmol, AnguChem) was added. The reaction was stirred at 65 °C for 16 h. Saturated sodium bicarbonate solution (60 mL) was added, and ethyl acetate (100 mL x 2) was extracted. The organic phase was combined and dried over anhydrous sodium sulfate. Filtration, and concentration under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to give the title product 5b (2.6 g, yield: 81.6%).

[0369] MS m / z (ESI): 278.0 [M+1].

[0370] Second step

[0371] (R)-2-methyl-N-((S)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)propane-2- sulfonamide 5c

[0372] To compound 5b (600 mg, 2.2 mmol) in anhydrous tetrahydrofuran (10 mL), 1M lithium tri-sec-butylborohydride in tetrahydrofuran (3.5 mL, 3.5 mmol, Shanghai Titan Science & Technology Co., Ltd.) was added dropwise at -78 °C. The reaction was stirred at 0 °C for 1 h. Saturated aqueous ammonium chloride solution (20 mL) was added, and ethyl acetate (30 mL x 2) was extracted. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title product 5c crude (600 mg), which was used directly in the next step without purification.

[0373] MS m / z (ESI): 280.1 [M+1].

[0374] Third step

[0375] (S)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanamine hydrochloride 5d

[0376] Compound 5c crude (600 mg, 2.2 mmol) was dissolved in methanol (3 mL), and 4M hydrogen chloride in 1,4-dioxane (2.2 mL) was added dropwise. The reaction was stirred for 1 h. Concentration under reduced pressure gave the title product 5d crude (455.0 mg), which was used directly in the next step without purification.

[0377] MS m / z (ESI): 159.1 [M-16].

[0378] Fourth step

[0379] (S)-3-Isopropyl-6-((1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethyl)amino)pyrimidine- 2,4(1H,3H)-dione 5

[0380] The crude compound 5d (380.4 mg, 2.2 mmol), 6-chloro-3-isopropylpyrimidine- 2,4(1H,3H)-dione 1f (409.3 mg, 2.2 mmol) and N,N-diisopropylethylamine (1.4 g, 10.9 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction was carried out at 130 °C for 2 h in the microwave. Concentration under reduced pressure and purification by high-performance liquid chromatography (Welch Ultimate XB-C18, 5 pm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile from 35% (v / v) to 95% (v / v) in 16.1 min, detection wavelength 214 & 254 nm) afforded the title product 5 (170.0 mg, yield: 23.9%).

[0381] MS m / z (ESI): 328.2 [M+1].

[0382] 1 H NMR (500 MHz, DMSO-d6) d 9.74 (s, 1H), 7.03-7.00 (m, 3H), 6.44 (d, 1H), 4.90 (m, 1H), 4.48 (m, 1H), 4.33 (s, 1H), 2.71-2.66 (m, 4H), 1.73-1.71 (m, 4H), 1.35 (d, 3H), 1.27 (dd, 6H).

[0383] Example 6

[0384] (S)-6-((1-(2,3-Dihydrobenzofuran-4-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)- dione 6

[0385]

[0386] First step

[0387] (R)-N-((2,3-Dihydrobenzofuran-4-yl)methylidene)-2-methylpropane-2-sulfmamide 6b

[0388] Dissolve 2,3-dihydrobenzofuran-4-carboxaldehyde 6a (1.0 g, 6.8 mmol, Shanghai Biotech Co., Ltd.) and compound 1b (860.0 mg, 7.1 mmol) in dichloromethane (13 mL). Add cesium carbonate (2.6 g, 8.1 mmol) and stir the reaction for 16 hours. Filter the reaction and concentrate the filtrate under reduced pressure to give the title product 6b crude (1.7 g) which is used directly in the next step without further purification.

[0389] MS m / z (ESI): 252.0 [M+1].

[0390] Second Step

[0391] (R)-N-((S)-1-(2,3-dihydrobenzofuran-4-yl)ethyl)-2-methylpropane-2-sulfmamide 6c

[0392] At -50 °C, to compound 6b crude (1.7 g, 6.8 mmol) in anhydrous dichloromethane (45 mL), add 3M methyl magnesium bromide in methyl tetrahydrofuran (5.0 mL, 14.9 mmol) dropwise. Stir the reaction at room temperature for 16 hours under nitrogen atmosphere. Add saturated aqueous ammonium chloride solution (30 mL) and extract with dichloromethane (30 mL x 2). Dry the combined organic phase over anhydrous sodium sulfate, filter and concentrate the residue under reduced pressure. Purify the residue on a silica gel column with eluent system A to give the title product 6c (1.6 g, yield: 88.5%).

[0393] MS m / z (ESI): 268.1 [M+1].

[0394] Third Step

[0395] (S)-1-(2,3-dihydrobenzofuran-4-yl)ethylamine hydrochloride 6d

[0396] Dissolve compound 6c (534.0 mg, 2.0 mmol) in methanol (3 mL) and add 4M hydrogen chloride in 1,4-dioxane (2 mL) dropwise. Stir the reaction for 1 hour. Concentrate under reduced pressure to give the title product 6d crude (400.0 mg) which is used directly in the next step without further purification.

[0397] MS m / z (ESI): 147.1 [M-16].

[0398] Fourth Step

[0399] (S)-6-((1-(2,3-dihydrobenzofuran-4-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione 6

[0400] Compound 6d crude (399.4 mg, 2.0 mmol), compound 1f (377.3 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.3 g, 10.1 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction was carried out at 130 °C for 2 hours under microwave. Concentration under reduced pressure, purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 pm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 45% (v / v) to 95% (v / v) in 15.1 minutes, detection wavelength 214 & 254 nm) gave the title product 6 (138.0 mg, yield: 21.9%).

[0401] MS m / z (ESI): 316.1 [M+1].

[0402] 1 H NMR (500 MHz, DMSO-d6) δ 9.78 (s, 1H), 7.09 (t, 1H), 6.77 (d, 1H), 6.67 (d, 1H), 6.48 (s, 1H), 4.91 (m, 1H), 4.58-4.50 (m, 2H), 4.44 (m, 1H), 4.27 (s, 1H), 3.25 (m, 1H), 3.14 (m, 1H), 1.38 (d, 3H), 1.27 (d, 6H).

[0403] Example 7

[0404] (S)-6-((1-(2,3-dihydrobenzofuran-7-yl)ethyl)amino)-3-isopropylpyrimidine- 2,4(1H,3H)-dione 7

[0405]

[0406] First step

[0407] (R)-N-(2,3-dihydrobenzofuran-7-yl)methylidene)-2-methylpropane-2- sulfinamide 7b

[0408] Compound 1b (860.0 mg, 7.1 mmol) and 2,3-dihydrobenzofuran-7-carbaldehyde 7a (1.0 g, 6.8 mmol, Shanghai Biotech Co., Ltd.) were dissolved in dichloromethane (13 mL). Cesium carbonate (2.6 g, 8.1 mmol) was added and the reaction was stirred for 16 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title product 7b crude (1.7 g), which was used directly in the next step without purification.

[0409] MS m / z (ESI): 252.0 [M+1].

[0410] Second Step

[0411] (R)-N-((S)-1-(2,3-dihydrobenzofuran-7-yl)ethyl)-2-methylpropane-2-sulfonamide 7c

[0412] To the crude compound 7b (1.7 g, 6.8 mmol) in anhydrous dichloromethane (45 mL) was added dropwise 3M methyl magnesium bromide in methyl tetrahydrofuran (5.0 mL, 14.9 mmol) at -50 °C. The reaction was stirred at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added, and dichloromethane (30 mL x 2) was used to extract. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 7c (1.6 g, yield: 86.8%).

[0413] MS m / z (ESI): 268.1 [M+1].

[0414] Third Step

[0415] (S)-1-(2,3-dihydrobenzofuran-7-yl)ethylamine hydrochloride 7d

[0416] Compound 7c (534.0 mg, 2.0 mmol) was dissolved in methanol (3 mL), and 4M hydrogen chloride in 1,4-dioxane (2 mL) was added dropwise. The reaction was stirred for 1 hour. Concentration under reduced pressure gave the crude title product 7d (400.0 mg), which was used directly in the next step without purification.

[0417] MS m / z (ESI): 147.1 [M-16].

[0418] Fourth Step

[0419] (S)-6-((1-(2,3-dihydrobenzofuran-7-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione 7

[0420] Compound 7d crude (399.4 mg, 2.0 mmol), compound 1f (377.3 mg, 2.0 mmol) and N,N-diisopropylethylamine (1.3 g, 10.1 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction was carried out at 130 °C for 2 hours under microwave. Concentrated under reduced pressure, purified by high performance liquid chromatography (Boston Phlex Prep C18, 5 μm 30*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 30% (v / v) to 50% (v / v) in 15 minutes, detection wavelength 214 & 254 nm) to give the title product 7 (200.0 mg, yield: 31.7%).

[0421] MS m / z (ESI): 316.2 [M+1].

[0422] 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.14 (d, 1H), 7.04 (d, 1H), 6.81 (t, 1H), 6.42 (d, 1H), 4.90 (m, 1H), 4.58 (t, 2H), 4.47 (m, 1H), 4.33 (s, 1H), 3.18 (t, 2H), 1.38 (d, 3H), 1.26 (dd, 6H).

[0423] Example 8

[0424] (S)-3-isopropyl-6-((1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)amino)pyrimidine- 2,4(1H,3H)-dione 8

[0425]

[0426] First step

[0427] (R)-2-methyl-N-((5,6,7,8-tetrahydronaphthalen-1-yl)methylidene)propane-2- sulfmamide 8b

[0428] 5,6,7,8-Tetrahydronaphthalene-1-carbaldehyde 8a (1.0 g, 6.3 mmol, Shanghai Biotech Co., Ltd.) and compound 1b (794.0 mg, 6.6 mmol) were dissolved in dichloromethane (12 mL). Cesium carbonate (2.5 g, 7.5 mmol) was added and the reaction was stirred for 16 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title product 8b crude (1.6 g), which was used directly in the next step without purification.

[0429] MS m / z (ESI): 264.1 [M+1].

[0430] Second step

[0431] (R)-2-methyl-N-((S)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)propane-2- sulfmamide 8c

[0432] To the crude compound 8b (1.6 g, 6.3 mmol) in anhydrous dichloromethane (45 mL) was added 3M methyl magnesium bromide in methyltetrahydrofuran (4.6 mL, 13.8 mmol) dropwise at -50 °C. The reaction was stirred at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added, and dichloromethane (30 mL x 2) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 8c (1.5 g, yield: 85.7%).

[0433] MS m / z (ESI): 280.1 [M+1].

[0434] Third step

[0435] (S)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethanamine hydrochloride 8d

[0436] Compound 8c (558.9 mg, 2.0 mmol) was dissolved in methanol (3 mL), and 4M hydrogen chloride in 1,4-dioxane (2 mL) was added dropwise. The reaction was stirred for 1 hour. Concentration under reduced pressure gave the crude title product 8d (424.0 mg), which was used directly in the next step without purification.

[0437] MS m / z (ESI): 159.1 [M-16].

[0438] Fourth step

[0439] (S)-3-isopropyl-6-((1-(5,6,7,8-tetrahydronaphthalen-1-yl)ethyl)amino)pyrimidine- 2,4(1H,3H)-dione 8

[0440] Compound 8d crude (423.5 mg, 2.0 mmol), compound 1f (377.3 mg, 2.0 mmol), and N,N-diisopropylethylamine (1.3 g, 10.1 mmol) were dissolved in anhydrous 1,4-dioxane (5 mL). The reaction was microwaved at 130 °C for 2 hours. Concentration under reduced pressure, and purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 μm, 30 mm x 150 mm, eluent system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 60% (v / v) to 95% (v / v) in 15.1 minutes, detection wavelength 214 & 254 nm) gave the title product 8 (200.0 mg, yield: 30.5%).

[0441] MS m / z (ESI): 328.2 [M+1].

[0442] 1 H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.12-7.08 (m, 2H), 6.97 (m, 1H), 6.45 (d, 1H), 4.90 (m, 1H), 4.59 (m, 1H), 4.17 (s, 1H), 2.80-2.73 (m, 3H), 2.65 (m, 1H), 1.81-1.76 (m, 2H), 1.73-1.68 (m, 2H), 1.34 (d, 3H), 1.27 (dd, 6H).

[0443] Example 9

[0444] (S)-6-((1-(1,3-dihydroisochromen-4-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)- dione 9

[0445]

[0446] First step

[0447] 1,3-Dihydroisochromene-4-carbaldehyde 9b

[0448] To a solution of 4-bromo-1,3-dihydroisochromene 9a (1.0 g, 5.0 mmol, Shanghai Biotech Co., Ltd.) in anhydrous tetrahydrofuran (12 mL) was added dropwise 2.5 M n-butyllithium in n-hexane (2.4 mL, 6.0 mmol, Shanghai Titan Science & Technology Co., Ltd.) at -78 °C. The reaction was stirred at -78 °C for 30 min under nitrogen atmosphere. Anhydrous N,N-dimethylformamide (550.2 mg, 7.5 mmol) was added and the reaction was stirred at -78 °C for 30 min. The reaction was slowly warmed to room temperature and stirred for 1 h. Saturated aqueous ammonium chloride solution (20 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phase was combined and concentrated under reduced pressure to give the title product 9b as a crude product (731.0 mg), which was used directly in the next step without further purification.

[0449] MS m / z (ESI): 149.1 [M+1].

[0450] Second step

[0451] (R)-N-((1,3-dihydroisochromen-4-yl)methylidene)-2-methylpropane-2-sulfmamide 9c

[0452] Compound 9b (731.0 g, 4.9 mmol) and compound 1b (627.9 mg, 5.2 mmol) were dissolved in dichloromethane (10 mL). Cesium carbonate (1.9 g, 5.9 mmol) was added and the reaction was stirred for 16 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to obtain the title product 9c crude (1.3 g), which was used directly in the next step without purification.

[0453] MS m / z (ESI): 252.1 [M+1].

[0454] Third step

[0455] (R)-N-((S)-1-(1,3-dihydroisochromen-4-yl)ethyl)-2-methylpropane-2-sulfmamide 9d

[0456] To the compound 9c crude (1.3 g, 5.1 mmol) in anhydrous dichloromethane (30 mL) was added 3M methyl magnesium bromide in methyl tetrahydrofuran (3.7 mL, 11.0 mmol) dropwise at -50°C. The reaction was stirred at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added and dichloromethane (30 mL x 2) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title product 9d (838.0 g, yield: 62.5%).

[0457] MS m / z (ESI): 268.2 [M+1].

[0458] Fourth step

[0459] (S)-1-(1,3-dihydroisochromen-4-yl)ethylamine hydrochloride 9e

[0460] Compound 9d (838.0 mg, 3.0 mmol) was dissolved in methanol (3 mL) and 4M hydrogen chloride in 1,4-dioxane (3 mL) was added dropwise. The reaction was stirred for 1 hour. It was concentrated under reduced pressure to obtain the title product 9e crude (626.0 mg), which was used directly in the next step without purification.

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

[0462] Fifth step (S)-6-((1-(1,3-dihydroisochromen-4-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione 9

[0463] Compound 9e crude (313.0 mg, 1.6 mmol), compound 1f (294.2 mg, 1.6 mmol) and N,N-diisopropylethylamine (1.0 g, 8.0 mmol) were dissolved in anhydrous 1,4-dioxane (3 mL). The reaction was carried out at 130 °C for 2 hours by microwave. Concentration under reduced pressure, purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 μm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 20% (v / v) to 95% (v / v) in 15.1 minutes, detection wavelength 214 & 254 nm) gave the title product 9 (89.0 mg, yield: 18.0%).

[0464] MS m / z (ESI): 316.1 [M+1].

[0465] 1 H NMR (500 MHz, DMSO-d6) δ 7.30-7.27 (m, 1H), 7.23-7.19 (m, 2H), 6.00 (s, 1H), 5.15 (d, 1H), 5.01-4.89 (m, 4H), 4.44-4.39 (m, 1H), 4.19 (s, 1H) 1.38 (d, 3H), 1.27 (d, 6H).

[0466] Example 10

[0467] (S)-6-((1-(2,3-dihydrobenzofuran-5-yl)ethyl)amino)-3-isopropylpyrimidine- 2,4(1H,3H)-dione 10

[0468]

[0469]

[0470] First step

[0471] (R)-N-((2,3-dihydrobenzofuran-5-yl)methylidene)-2-methylpropane-2- sulfinamide 10b

[0472] Compound 1b (4.3 g, 35.5 mmol) and 2,3-dihydrobenzofuran-5-carbaldehyde 10a (5.0 g, 33.7 mmol, Shanghai Biotech Co., Ltd.) were dissolved in dichloromethane (65 mL). Cesium carbonate (13.2 g, 40.6 mmol) was added and the reaction was stirred for 16 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the title product 10b crude (8.5 g), which was used directly in the next step without purification.

[0473] MS m / z (ESI): 252.1 [M+1].

[0474] Second Step

[0475] (R)-N-((S)-1-(2,3-dihydrobenzofuran-5-yl)ethyl)-2-methylpropane-2-sulfonamide 10c

[0476] To the crude compound 10b (8.5 g, 33.8 mmol) in anhydrous dichloromethane (225 mL) was added dropwise 3M methyl magnesium bromide in methyl tetrahydrofuran (25.0 mL, 74.4 mmol) at -50°C. The reaction was stirred at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (100 mL) was added, and dichloromethane (100 mL x 2) was used to extract. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 10c (7.5 g, yield: 82.9%).

[0477] MS m / z (ESI): 268.1 [M+1].

[0478] Third Step

[0479] (S)-1-(2,3-dihydrobenzofuran-5-yl)ethylamine hydrochloride 10d

[0480] Compound 10c (100.0 mg, 0.4 mmol) was dissolved in methanol (1 mL), and 4M hydrogen chloride in 1,4-dioxane (0.4 mL) was added dropwise. The reaction was stirred for 1 hour. Concentration under reduced pressure gave the title product 10d crude (75.0 mg), which was used directly in the next step without purification.

[0481] MS m / z (ESI): 147.1 [M-16].

[0482] Fourth Step

[0483] (S)-6-((1-(2,3-dihydrobenzofuran-5-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione 10

[0484] Compound 10d crude (65.9 mg, 0.3 mmol), compound If (62.3 mg, 0.3 mmol) and N,N-diisopropylethylamine (213.3 g, 1.7 mmol) were dissolved in anhydrous 1,4-dioxane (1 mL). The microwave reaction was carried out at 130 °C for 2 hours. Concentration under reduced pressure and purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 pm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile from 23% (v / v) to 95% (v / v) in 18.1 min, detection wavelength 214 & 254 nm) gave the title product 10 (21.3 mg, yield: 20.5%).

[0485] MS m / z (ESI): 316.1 [M+1].

[0486] 1 H NMR (500 MHz, DMSO-d6) d 7.20 (s, 1H), 7.04 (d, 1H), 6.71 (d, 1H), 6.54 (s, 1H), 4.94-4.89 (m, 1H), 4.49 (t, 2H), 4.39 (t, 1H), 4.34 (s, 1H), 3.15 (t, 2H), 1.36 (d, 3H), 1.27 (d, 6H).

[0487] Example 11

[0488] (S)-6-((1-(2,3-dihydrobenzofuran-4-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4- yl)pyrimidine

[0489] -2,4(1H,3H)-dione 11

[0490]

[0491] First step

[0492] (S)-6-((1-(2,3-dihydrobenzofuran-4-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4- yl)pyrimidine

[0493] -2,4(1H,3H)-dione 11

[0494] Compound 6d crude (200.0 mg, 1.0 mmol), compound 11a (231.1 mg, 1.0 mmol, prepared by the method described in the patent application “Synthesis of intermediate 4d in Example 5 of the specification of CN110698415A”) and N,N-diisopropylethylamine (647.3 g, 5.0 mmol) were dissolved in anhydrous 1,4-dioxane (3 mL). Microwave reaction at 130 °C for 2 hours. Concentration under reduced pressure, purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 μm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 20% (v / v) to 95% (v / v) in 15.1 minutes, detection wavelength 214 & 254 nm) to obtain the title product 11 (100.0 mg, yield: 28.0%).

[0495] MS m / z (ESI): 358.1 [M+1].

[0496] 1 H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.09 (t, 1H), 6.77 (d, 1H), 6.66 (d, 1H), 6.50 (s, 1H), 4.79-4.72 (m, 1H), 4.58-4.50 (m, 2H), 4.46-4.42 (m, 1H), 4.31 (s, 1H), 3.86 (dd, 2H), 3.31-3.22 (m, 3H), 3.18-3.11 (m, 1H), 2.56-2.52 (m, 2H), 1.39 (d, 3H), 1.32 (dd, 2H).

[0497] Example 12

[0498] (S)-6-((1-(2,3-dihydrobenzofuran-7-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine

[0499] -2,4(1H,3H)-dione 12

[0500]

[0501] First step

[0502] (S)-6-((1-(2,3-dihydrobenzofuran-7-yl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine

[0503] -2,4(1H,3H)-dione 12

[0504] Crude compound 7d (200.0 mg, 1.0 mmol), compound 11a (231.1 mg, 1.0 mmol), and N,N-diisopropylethylamine (647.3 g, 5.0 mmol) were dissolved in anhydrous 1,4-dioxane (3 mL). The reaction was microwaved at 130°C for 2 hours. The mixture was concentrated under reduced pressure and purified by high-performance liquid chromatography (Welch Ultimate XB-C18, 5 μm, 30 mm x 150 mm, eluent: water (10 mM ammonium bicarbonate) followed by acetonitrile, acetonitrile increasing from 20% (v / v) to 95% (v / v) over 15.1 minutes, detection at 214 & 254 nm) to afford the title product 12 (100.0 mg, 28.0% yield).

[0505] MS m / z (ESI): 358.2 [M+1].

[0506] 1 H NMR(500MHz,DMSO-d6)δ9.94(s,1H),7.14(d,1H),7.04(d,1H),6.81(t,1H),6.45(s,1H),4.78-4.73(m,1H),4.58(t,2H),4 .52-4.46(m,1H),4.37(s,1H),3.87(dd,2H),3.31-3.25(m,2H),3.19(t,2H),2.55-2.52(m,2H),1.39(d,3H),1.31(d,2H).

[0507] Example 13

[0508] (S)-6-((1-(5-fluoro-2,3-dihydrobenzofuran-4-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione 13

[0509]

[0510]

[0511] first step

[0512] Methyl 5-fluorobenzofuran-6-carboxylate 13b

[0513] Dissolve 4-bromo-5-fluorobenzofuran 13a (3.20 g, 14.88 mmol, prepared using the synthetic method of intermediate A1.2b on page 17 of the specification of patent application "US20160176882A1") in methanol (50 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.26 g, 1.49 mmol) and N,N-diisopropylethylamine (3.01 g, 29.75 mmol), replace carbon monoxide gas three times, stir the reaction at 70 °C for 40 hours. Filter, concentrate under reduced pressure, purify the residue obtained by silica gel column chromatography with eluent system A to obtain the title product 13b (1.50 g, yield: 51.9%).

[0514] MS m / z (ESI): 194.8 [M+1].

[0515] Second step

[0516] 5-Fluoro-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester 13c

[0517] Dissolve compound 13b (1.0 g, 5.2 mmol) in methanol (30 mL), add 10% palladium carbon hydrogenation catalyst (400 mg, wet), replace hydrogen gas three times, stir at room temperature for 16 hours. Filter, concentrate under reduced pressure, purify the residue obtained by silica gel column chromatography with eluent system A to obtain the title product 13c (913.0 mg g, yield: 90.5%).

[0518] MS m / z (ESI): 197.1 [M+1].

[0519] Third step

[0520] (5-Fluoro-2,3-dihydrobenzofuran-6-yl)methanol 13d

[0521] Dissolve compound 13c (900.0 mg, 4.6 mmol) in anhydrous tetrahydrofuran (9 mL) solution, dropwise add 2M lithium borohydride tetrahydrofuran solution (4.6 mL, 9.2 mmol), react at room temperature for 16 hours. Quench the reaction with methanol (5 mL) under ice bath, adjust the solution pH to 6 with 1M hydrochloric acid, extract with ethyl acetate (30 mL x 2). Combine the organic phase, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the residue obtained by silica gel column chromatography with eluent system A to obtain the title product 13d (695.8 mg, yield: 90.2%).

[0522] MS m / z (ESI): 151.0 [M-17].

[0523] Fourth step

[0524] 5-fluoro-2,3-dihydrobenzofuran-6-carbaldehyde 13e

[0525] Compound 13d (695.8 mg, 4.1 mmol) was dissolved in dichloromethane (10 mL), and Dess-Martin oxidant (3.5 g, 8.3 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated sodium thiosulfate (20 mL) and saturated sodium bicarbonate (20 mL) under ice bath, and extracted with dichloromethane (30 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 13e (600 mg, yield: 88.2%).

[0526] MS m / z (ESI): 167.1 [M+1].

[0527] Fifth step

[0528] (R)-N-((5-fluoro-2,3-dihydrobenzofuran-6-yl)methylidene)-2-methylpropane-2- sulfonamide 13f

[0529] Compound 13e (600 mg, 3.6 mmol) and (R)-2-methylpropane-2-sulfonamide (460.0 mg, 3.8 mmol, Shanghai Biotech) were dissolved in dichloromethane (7 mL). Cesium carbonate (1.4 g, 4.4 mmol) was added, and the reaction was stirred for 16 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 13f (973.0 mg), which was used directly in the next step without purification.

[0530] MS m / z (ESI): 270.0 [M+1].

[0531] Sixth step

[0532] (R)-N-((S)-1-(5-fluoro-2,3-dihydrobenzofuran-6-yl)ethyl)-2-methylpropane-2- sulfonamide 13g

[0533] To a solution of the crude compound 13f (973.0 mg, 3.6 mmol) in anhydrous dichloromethane (25 mL) at -50 °C, 3M methylmagnesium bromide in methyltetrahydrofuran (2.7 mL, 8.0 mmol) was added dropwise. The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (30 mL) was added, and dichloromethane (30 mL x 2) was used for extraction. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to give the title product 13g (610.0 mg, yield: 59.1%).

[0534] MS m / z (ESI): 286.0 [M+1].

[0535] Seventh Step

[0536] (S)-1-(5-Fluoro-2,3-dihydrobenofuran-6-yl)ethylamine hydrochloride 13h

[0537] Compound 13g (600.0 mg, 2.1 mmol) was dissolved in methanol (3 mL), and 4M hydrogen chloride in 1,4-dioxane (2.1 mL) was added dropwise. The reaction was stirred for 1 hour. Concentration under reduced pressure gave the crude title product 13h (460.0 mg), which was used directly in the next step without purification.

[0538] MS m / z (ESI): 164.9 [M-16].

[0539] Eighth Step (S)-6-((1-(5-Fluoro-2,3-dihydrobenofuran-4-yl)ethyl)amino)-3- isopropylpyrimidine-2,4(1H,3H)-dione 13

[0540] Compound 13h (217.7 mg, 1.0 mmol), compound 1f (188.7 mg, 1.0 mmol) and N,N-diisopropylethylamine (646.4 g, 5.0 mmol) were dissolved in anhydrous 1,4-dioxane (2 mL). The reaction was microwaved at 130 °C for 2 hours. Concentration under reduced pressure, and purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 pm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 25% (v / v) to 95% (v / v) in 17.1 minutes, detection wavelength 214 & 254 nm) gave the title product 13 (85.0 mg, yield: 25.5%).

[0541] MS m / z (ESI): 334.1 [M+1].

[0542] 1 H NMR (500 MHz, DMSO-d6) δ 9.76 (s, 1H), 6.93 (t, 1H), 6.66 (d, 1H), 6.43 (s, 1H), 4.93-4.87 (m, 1H), 4.63-4.50 (m, 3H), 4.24 (s, 1H), 3.30-3.25 (m, 1H), 3.22-3.15 (m, 1H), 1.46 (d, 3H), 1.27 (d, 6H).

[0543] Example 14

[0544] (S)-6-((1-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-5-methylpyrimidine- 2,4(1H,3H)-dione 14

[0545]

[0546] First step

[0547] 1 -isopropyl-5-methylpyrimidine-2,4,6(1H,3H,5H)-trione 14c

[0548] Sodium metal (431.3 mg, 18.0 mmol) was dissolved in anhydrous methanol (25 mL). 1 -isopropylurea 14a (1.1 g, 10.0 mmol, prepared by the method of patent application “CN1100698415A specification, page 14, synthesis of intermediate 2a”) and dimethyl 2-methylmalonate 14b (2.2 g, 15.1 mmol, Shanghai Bide Technology Co., Ltd.) were added. The reaction was heated to reflux for 40 hours. After the reaction solution was cooled, concentrated hydrochloric acid was added dropwise to adjust the solution pH to 5. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to obtain the title product 14c (1.5 g, yield: 81.5%).

[0549] MS m / z (ESI): 185.1 [M+1].

[0550] Second step

[0551] 6-chloro-3-isopropyl-5-methylpyrimidine-2,4(1H,3H)-dione 14d

[0552] To compound 14c (1.3 g, 6.8 mmol) and benzyltrimethylammonium chloride (2.0 g, 9.6 mmol, Shanghai Titan Science and Technology Co., Ltd.), phosphorus oxychloride (3 mL) was added. The reaction was carried out at 50°C for 16 hours under a nitrogen atmosphere. Concentrated under reduced pressure, dichloromethane (20 mL) was added, washed with water twice. The organic phase was collected and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title product 14d (790 mg, yield: 57.5%). MS m / z (ESI): 203.1 [M+1].

[0553] Third step (S)-6-((1-(2,3-dihydrobenzofuran-6-yl)ethyl)amino)-3-isopropyl-5-methylpyrimidine- 2,4(1H,3H)-dione 14

[0554] Compound 4d crude (106.0 mg, 0.5 mmol), compound 14d (108.0 mg, 0.5 mmol) and N,N-diisopropylethylamine (342.8 mg, 2.7 mmol) were dissolved in anhydrous 1,4-dioxane (1.5 mL). The mixture was subjected to microwave reaction at 130 °C for 2 hours. Concentration under reduced pressure, purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 μm, 30 mm*150 mm, elution system: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile increased from 45% (v / v) to 95% (v / v) in 20.1 min, detection wavelength 214 & 254 nm) gave the title product 14 (10.6 mg, yield: 6.0%).

[0555] MS m / z (ESI): 330.2 [M+1].

[0556] 1 H NMR (500 MHz, DMSO-d6) δ 9.24 (br s, 1H), 7.15 (d, 1H), 6.80 (d, 1H), 6.75 (s, 1H), 6.18 (d, 1H), 5.04-4.94 (m, 2H), 4.49 (t, 2H), 3.11 (t, 2H), 1.75 (s, 3H), 1.40 (d, 3H), 1.27 (t, 6H).

[0557] Example 15

[0558] (S)-6-((1-(5-Fluoro-2,3-dihydrobenofuran-6-yl)ethyl)amino)-3-isopropyl-5- methylpyrimidine

[0559] -2,4(1H,3H)-dione 15

[0560]

[0561] First step

[0562] 5-Fluorobenzofuran-6-carboxylic acid methyl ester 15b

[0563] Dissolve 6-bromo-5-fluorobenzofuran 15a (3.20 g, 14.88 mmol, prepared by the method described in the patent application "WO2017219948A1 specification page 36 synthesis of intermediate A1.2b") in methanol (50 mL), add [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (1.26 g, 1.49 mmol) and N,N-diisopropylethylamine (3.01 g, 29.75 mmol), replace carbon monoxide gas three times, stir at 70°C for 40 hours. Filter, concentrate under reduced pressure, purify the obtained residue by silica gel column chromatography with eluent system A to obtain the title product 15b (1.50 g, yield: 51.9%).

[0564] MS m / z (ESI): 194.8 [M+1].

[0565] Second step

[0566] 5-Fluoro-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester 15c

[0567] Dissolve compound 15b (1.50 g, 7.73 mmol) in methanol (50 mL), add 10% palladium carbon hydrogenation catalyst (wet), replace hydrogen gas three times, stir at room temperature for 16 hours. Filter, concentrate under reduced pressure, purify the obtained residue by silica gel column chromatography with eluent system A to obtain the title product 15c (1.37 g, yield: 90.4%).

[0568] MS m / z (ESI): 196.8 [M+1].

[0569] Third step

[0570] (5-Fluoro-2,3-dihydrobenzofuran-6-yl)methanol 15d

[0571] Dissolve compound 15c (1.37 g, 7.0 mmol) in anhydrous tetrahydrofuran (30 mL), dropwise add 2M lithium borohydride tetrahydrofuran solution (34.9 mL, 69.8 mmol), react at room temperature for 16 hours. Quench the reaction with methanol (5 mL) under ice bath, adjust the solution pH to 6 with 1M hydrochloric acid, extract with ethyl acetate (30 mL x 2). Combine the organic phase, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, purify the obtained residue by silica gel column chromatography with eluent system A to obtain the title product 15d (1.05 g, yield: 89.4%).

[0572] MS m / z (ESI): 190.0 [M+22].

[0573] Fourth step

[0574] 5-Fluoro-2,3-dihydrobenzofuran-6-carbaldehyde 15e

[0575] Compound 15d (1.05 g, 6.24 mmol) was dissolved in dichloromethane (20 mL), and Dess-Martin oxidant (3.97 g, 9.36 mmol) was added. The reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding saturated sodium thiosulfate (20 mL) and saturated sodium bicarbonate (20 mL) under ice bath, and extracted with dichloromethane (30 mL x 2). The organic phase was combined and dried over anhydrous sodium sulfate. After filtration, the residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system A to obtain the title product 15e (1.03 g, yield: 99.3%).

[0576] MS m / z (ESI): 167.0 [M+1].

[0577] Fifth step

[0578] (R)-N-((5-Fluoro-2,3-dihydrobenofuran-6-yl)methylidene)-2-methylpropane-2- sulfinamide 15f

[0579] Compound 15e (1.30 g, 7.82 mmol) and (R)-2-methylpropane-2-sulfinamide (1.42 g, 11.72 mmol, Shanghai Biotech) were dissolved in dichloromethane (20 mL). Cesium carbonate (1.58 g, 14.09 mmol) was added, and the reaction was stirred for 16 hours. The reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 15f (2.80 g) as a crude product. The crude product was used directly in the next step without purification.

[0580] MS m / z (ESI): 270.0 [M+1].

[0581] Sixth step

[0582] (R)-N-((S)-1-(5-Fluoro-2,3-dihydrobenofuran-6-yl)ethyl)-2-methylpropane-2- sulfinamide 15g

[0583] To a solution of compound 15f crude (2.80 g, 10.40 mmol) in anhydrous dichloromethane (45 mL) was added 3M methyl magnesium bromide in methyltetrahydrofuran (6.93 mL, 20.79 mmol) dropwise at -50 °C. The reaction was stirred at room temperature for 2 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (30 mL) was added, and dichloromethane (30 mL x 2) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (Boston Phlex C18 150*30 mm, 5 μm, eluent: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile in 20 min gradient elution, flow rate: 30 mL / min) to give the title product 15g (1.50 g, yield: 50.56%).

[0584] MS m / z (ESI): 286.0 [M+1].

[0585] Seventh step

[0586] (S)-1-(5-Fluoro-2,3-dihydrobenofuran-6-yl)ethylamine hydrochloride 15h

[0587] Compound 15g (300 mg, 1.05 mmol) was dissolved in ethanol (10 mL), and thionyl chloride (250 mg, 2.10 mmol) was added dropwise. The reaction was stirred for 1 hour. Concentration under reduced pressure gave the title product 15h crude (228 mg), which was used in the next step without purification.

[0588] MS m / z (ESI): 164.9 [M-16].

[0589] Eighth step

[0590] (S)-6-((1-(5-Fluoro-2,3-dihydrobenofuran-6-yl)ethyl)amino)-3-isopropyl-5- methylpyrimidine-2,4(lH,3H)-dione 15

[0591] Compound 15h (108.9 mg, 0.5 mmol), compound 14c (101.4 mg, 0.5 mmol), and N,N-diisopropylethylamine (323.4 mg, 2.5 mmol) were dissolved in anhydrous 1,4-dioxane (1.5 mL). The reaction was stirred at 130 °C for 2 hours under microwave. Concentration under reduced pressure, and purification by high performance liquid chromatography (Welch Ultimate XB-C18, 5 μm, 30 mm*150 mm, eluent: water (10 mM ammonium bicarbonate), acetonitrile, acetonitrile was increased from 25% (v / v) to 95% (v / v) in 18.1 min, detection wavelength: 214 & 254 nm) gave the title product 15 (10.0 mg, yield: 5.8%).

[0592] MS m / z (ESI): 348.1 [M+1].

[0593] 1 H NMR(500MHz,DMSO-d6)δ8.83(brs,1H),7.05(d,1H),6.70(d,1H),6.00(d,1H),5.28-5.25( m,1H),4.99-4.96(m,1H),4.50(t,2H),3.13(t,2H),1.74(s,3H),1.41(d,3H),1.28(d,6H).

[0594] Biological evaluation

[0595] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0596] Test Example 1: Inhibitory effect of the disclosed compounds on myosin ATPase activity

[0597] The following method was used to determine the inhibitory effect of the disclosed compounds on myosin ATPase activity. The experimental method is briefly described as follows:

[0598] 1. Experimental Materials and Instruments

[0599] 1. Cardiac Actin (Cytoskeleton, AD99)

[0600] 2. Myosin Motor Protein S1 Fragment (Cytoskeleton, CS-MYS03)

[0601] 3. ATP (Sigma, A7699-1G)

[0602] 4. UltraPure TM 1M Tris-HCl buffer, pH 7.5 (Thermo, 15567027)

[0603] 5. CytoPhos TM Phosphate Assay Biochem Kit (Cytoskeleton, BK054)

[0604] 6. Magnesium chloride solution (Sigma, 68475-100ML-F)

[0605] 7. Potassium chloride solution (Sigma, 60142-100ML-F)

[0606] 8. EGTA (Sigma, E3889-100G)

[0607] 9. 96-well plate (Corning, 3697)

[0608] 10. U-bottom 96-well plate (Corning, 3795)

[0609] 11. Microplate reader (BMG, PHERAstar)

[0610] 12. Constant temperature incubator (Shanghai Boxun, SPX-100B-Z)

[0611] II. Experimental steps

[0612] Cardiac actin 1.61 μM, myosin motor protein S1 fragment 0.07 μM were mixed with different concentrations of small molecule compounds (the first concentration was 100 μM, 3-fold gradient dilution of 9 concentrations), and incubated at 37°C for 1 hour. Then ATP 120 μM was added, and incubated at 37°C for 2 hours. Finally, CytoPhos TM The detection solution (70 μL / well) in the phosphate detection kit was incubated at room temperature for 10 min. The OD value at 650 nM wavelength was read by the microplate reader, the amount of Pi was calculated according to the standard curve, the data was processed by GraphPad software, the inhibition curve was drawn according to the concentration of each compound and the corresponding inhibition rate, and the concentration of the compound when the inhibition rate reached 50% was calculated as IC 50 The experimental results are shown in Table 1.

[0613] Table 1 Inhibition activity of the compounds of the present disclosure on myosin ATPase

[0614]

[0615]

[0616] Conclusion: The compounds of the present disclosure have an inhibitory effect on myosin ATPase.

[0617] Test Example 2: Pharmacokinetic evaluation of the compounds of the present disclosure in SD rats

[0618] 1. Abstract

[0619] SD rats were used as test animals, and the drug concentration in the plasma of SD rats at different time points after oral gavage and intravenous injection of the test compound was determined by LC / MS / MS method. The pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied, and the pharmacokinetic characteristics were evaluated.

[0620] 2. Experimental scheme

[0621] 2.1 Experimental reagents

[0622] Example 9 compound, compound MYK-461 Example 1 of WO2014205223A1), compound A Example 107 of WO2014205223A1).

[0623] 2.2 Experimental animals

[0624] SD rat pharmacokinetics of Example 9 compound: 8 SD rats, half male and half female, were evenly divided into 2 groups, 4 rats in each group, provided by Zhejiang Vantoll Life Experimental Animal Technology Co., Ltd., production license number: SCXK(Zhe)2019-0001.

[0625] SD rat pharmacokinetics of compound MYK-461: 8 SD rats, half male and half female, were evenly divided into 2 groups, 4 rats in each group, provided by Shanghai Medisi Biopharm Co., Ltd.

[0626] SD rat pharmacokinetics of compound A: 8 SD rats, half male and half female, were evenly divided into 2 groups, 4 rats in each group, provided by Zhejiang Vantoll Life Experimental Animal Technology Co., Ltd., production license number: SCXK(Zhe)2019-0001.

[0627] 2.3 Drug preparation

[0628] A certain amount of Example 9 compound was weighed and added to 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare a colorless and transparent solution.

[0629] A certain amount of compound MYK-461 was weighed and added to 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare a colorless and transparent solution.

[0630] A certain amount of compound A was weighed and added to 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare a colorless and transparent solution.

[0631] 2.4 Drug administration

[0632] The SD rats were fasted overnight and administered by gavage and intravenous injection, respectively, at a dose of 2 mg / kg and 1 mg / kg, and a volume of 10 mL / kg and 5 mL / kg, respectively.

[0633] 3. Operation

[0634] The gavage administration group was sampled 0.2 mL of blood from the eye socket 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, 11.0 h, and 24.0 h after administration, and the blood was placed in an EDTA-K2 anticoagulation test tube. Centrifugation was performed at 10,000 rpm for 1 min (4°C), and the plasma was separated within 1 h and stored at -20°C for testing. The blood sampling and centrifugation process was performed under ice bath conditions. Food was provided 2 h after administration.

[0635] The intravenous injection administration group was sampled before administration and at 5 min, 0.25 h, 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 11.0 h, and 24.0 h after administration, and the blood was treated in the same manner as the gavage administration group.

[0636] The content of the test compound in the plasma of SD rats after gavage and intravenous injection administration of different concentrations of the drug was determined: 20 μL of the plasma of SD rats at each time point after administration was taken, 50 μL of an internal standard solution (the internal standard for the compound of Example 9: verapamil 100 ng / mL; the internal standard for compound MYK-461: warfarin 100 ng / mL; the internal standard for compound A: tolbutamide 100 ng / mL) was added, 200 μL of acetonitrile was added, vortex mixing was performed for 5 min, centrifugation was performed for 10 min (3700 rpm), and 0.5 μL of the supernatant of the plasma sample was subjected to LC / MS / MS analysis.

[0637] 4. Pharmacokinetic parameter results

[0638] Table 2. Pharmacokinetic parameters of the compound of the present disclosure in SD rats

[0639]

[0640] Conclusion: The compound of Example 9 of the present disclosure is well absorbed in SD rats. In addition, the T 1 / 2 of the compound of Example 9 of the present disclosure is significantly shorter than that of compound MYK-461 and compound A. 1 / 2 The T 1 / 2 of the compound of Example 9 of the present disclosure is significantly shorter than that of compound MYK-461 and compound A.

[0641] Test Example 3: Pharmacokinetic evaluation of the compound of the present disclosure in cynomolgus monkeys

[0642] 1. Abstract

[0643] The cynomolgus monkeys were used as the test animals, and LC / MS / MS method was used to determine the drug concentration in the plasma of the cynomolgus monkeys at different time points after the test compound was administered by gavage and intravenous injection. The pharmacokinetic behavior of the compound of the present disclosure in the cynomolgus monkeys was studied, and the pharmacokinetic characteristics were evaluated.

[0644] 2. Experimental scheme

[0645] 2.1 Experimental drugs

[0646] The compound of Example 9, compound MYK-461.

[0647] 2.2 Experimental animals

[0648] Pharmacokinetics of the compound of Example 9 in cynomolgus monkeys: 8 cynomolgus monkeys, half male and half female, were evenly divided into 2 groups, 4 in each group, and were provided by Shanghai Medisi Biopharmaceutical Co., Ltd.

[0649] Pharmacokinetics of compound MYK-461 in cynomolgus monkeys: 6 cynomolgus monkeys, male, were evenly divided into 2 groups, 3 in each group, and were provided by Shanghai Medisi Biopharmaceutical Co., Ltd.

[0650] 2.3 Drug preparation

[0651] A certain amount of the compound of Example 9 was weighed and added into 5% DMSO, 20% PG, 20% PEG400 and 55% physiological saline to prepare a clear solution.

[0652] A certain amount of compound MYK-461 was weighed and added into 5% DMSO, 20% PG, 20% PEG400 and 55% physiological saline to prepare a clear solution.

[0653] 2.4 Drug administration

[0654] The cynomolgus monkeys were fasted overnight and then administered by gavage and intravenous injection, respectively, at a dose of 2 mg / kg and 0.5 mg / kg, and a volume of 5 mL / kg and 2 mL / kg, respectively.

[0655] 3. Operation

[0656] The gavage administration group was subjected to blood sampling of 1.0 mL 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, and the blood was placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10,000 rpm for 5 min (4°C), and the plasma was separated within 1 h and stored at -80°C for testing. The blood sampling and centrifugation processes were operated under ice bath conditions. Food was given 3 h after administration, and water was given freely.

[0657] The intravenous injection administration group was subjected to blood sampling 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 blood was treated in the same manner as the gavage administration group.

[0658] Determination of the test compound in the plasma of cynomolgus monkeys after intravenous injection and oral administration of different concentrations of the drug: 20 μL of cynomolgus monkey plasma at each time point after administration was taken, 400 μL of methanol was added, vortex mixed for 1 min, centrifuged for 7 min (centrifugal force 18000 g), and 4 μL of the supernatant of the plasma sample was subjected to LC / MS / MS analysis.

[0659] 4. Pharmacokinetic parameter results

[0660] Table 3 Pharmacokinetic parameters of the compound of the present disclosure in cynomolgus monkeys

[0661]

[0662]

[0663] Conclusion: The compound of Example 9 of the present disclosure is well absorbed in vivo in cynomolgus monkeys. In addition, the T 1 / 2 is significantly shortened. Compound MYK-461 has a relatively long T 1 / 2 and accumulates in the body more seriously in clinic, and thus the clinical administration needs to be constantly adjusted, increasing the risk of drug use. Shortening the T 1 / 2 can reduce or avoid the accumulation of the drug in the body in clinic, which is beneficial for determining the dosage of the drug for patients and avoiding the risk caused by accumulation. Obviously, the compound of Example 9 of the present disclosure has obvious pharmacokinetic advantages over compound MYK-461.

[0664] Test Example 4: Toxicokinetic evaluation of the compound of the present disclosure on Beagle dogs after repeated oral administration for 14 days

[0665] 1. Abstract

[0666] Beagle dogs were used as test animals, and the drug concentration in the plasma of the Beagle dogs at different time points after oral administration of the test compound was determined by LC / MS / MS method. The toxicokinetic behavior of the compound of the present disclosure in Beagle dogs was studied, and its toxicokinetic characteristics were evaluated.

[0667] 2. Experimental scheme

[0668] 2.1 Test drug

[0669] Example 9 compound, compound MYK-461.

[0670] 2.2 Experimental animals

[0671] Beagle dogs, 16, half male and half female, were divided into 4 groups, 4 in each group, provided by Suzhou Xishan Middle School Experimental Animal Co., Ltd.

[0672] 2.3 Drug preparation

[0673] A certain amount of the compound of Example 9 was weighed and added to 15% PEG400 and 85% (10% TPGS + 1% HPMC K100LV) to prepare a translucent solution.

[0674] A certain amount of compound MYK-461 was weighed and added to 0.5% MC to prepare a translucent solution.

[0675] 2.4 Administration

[0676] Gavage administration, the administration dose of the compound of Example 9 was 1 mg / kg and 3 mg / kg, and the administration volume was 5 mL / kg.

[0677] The administration dose of compound MYK-461 was 0.3 mg / kg and 1 mg / kg, and the administration volume was 5 mL / kg.

[0678] 3. Operation

[0679] On the first day, 0.2 mL of blood was taken from the eye socket before administration and 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, and on the 7th day and the 14th day, 0.2 mL of blood was taken from the front limb vein before administration and 0.5 h, 1.0 h, 2.0 h, 4.0 h, 8.0 h, 11.0 h, and 24.0 h after administration, and the plasma was separated and stored at -20℃ for testing. The blood collection process was operated under ice bath conditions.

[0680] Determination of the content of the test compound in the plasma of Beagle dogs after gavage administration of different concentrations of drugs: 20 μL of Beagle dog plasma at each time point after administration was taken, 20 μL of internal standard solution (vortioxetine, provided by Suzhou Guochen Biological Technology Co., Ltd.) was added, 400 μL of methanol was added, vortex mixed for 10 min, centrifuged for 10 min (centrifugal force 2600 g), and 0.5 μL of supernatant of the plasma sample was taken for LC / MS / MS analysis.

[0681] 4. Results of toxicokinetic parameters

[0682] Table 4 Toxicokinetic parameters of the compound of the present disclosure in Beagle dogs

[0683]

[0684] Conclusion: The accumulation of the compound of Example 9 of the present disclosure in the body of Beagle dogs is not obvious after repeated gavage administration for 14 days, while the compound MYK-461 is seriously accumulated in the body of Beagle dogs, increasing the risk of drug use. Obviously, the compound of Example 9 of the present disclosure has obvious advantages in toxicokinetics compared with the compound MYK-461.

Claims

1. A compound represented by general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof: in: Selected from R 1 is a hydrogen atom; Each R a are the same or different and are each independently a hydrogen atom or a halogen; R 2 is methyl; R 3 is a hydrogen atom; R 4 A hydrogen atom or C 1-6 alkyl; R 0 is isopropyl or tetrahydropyranyl; t is 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III-1) or general formula (III-2) or a pharmaceutically acceptable salt thereof: in: Ring B, R a 、R 0 、R 1 、R 2 、R 3 、R 4 and t as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein for 4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R a A hydrogen atom.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 A hydrogen atom.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:

7. A method for preparing a compound represented by general formula (II-1) or general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising: The compound represented by the general formula (IIA-1) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof; The compound represented by the general formula (IIA-2) or a salt thereof undergoes a nucleophilic substitution reaction with the compound represented by the general formula (V) to obtain the compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof; in: R w is a leaving group; R a 、R 1 ,t,R 0 、R 2 、R 3 and R 4 As defined in claim 1.

8. The method according to claim 7, wherein the compound represented by general formula (IIA-1) or a salt thereof is a hydrochloride, and the compound represented by general formula (IIA-2) or a salt thereof is a hydrochloride.

9. The method according to claim 7, wherein R w It is a halogen.

10. The method according to claim 7, wherein R w A chlorine atom.

11. A pharmaceutical composition comprising a compound represented by general formula (II-1) or general formula (II-2) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

12. The pharmaceutical composition according to claim 11, further comprising one or more pharmaceutically acceptable carriers or diluents.

13. Use of the compound represented by general formula (II-1) or general formula (II-2) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 or 12 in the preparation of a myosin inhibitor.

14. Use of a compound represented by general formula (II-1) or general formula (II-2) according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 or 12 in the preparation of a medicament for treating a disease or condition, wherein the disease or condition is hypertrophic cardiomyopathy.

15. The use according to claim 14, wherein the disease or disorder is non-obstructive hypertrophic cardiomyopathy or obstructive hypertrophic cardiomyopathy.

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