CN116507621A

CN116507621A - Pyrimidine diketone derivative, preparation method and medical application thereof

Info

Publication number: CN116507621A
Application number: CN202180073230.9A
Authority: CN
Inventors: 张晓敏; 胡伟民; 马殿强; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-11-24
Filing date: 2021-11-24
Publication date: 2023-07-28
Also published as: TW202227402A; WO2022111498A1

Abstract

Pyrimidine dione derivatives of general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivatives, and use thereof as therapeutic agents, particularly use in preparing Myosin (Myosin) inhibitors and use in preparing medicines for treating Hypertrophic Cardiomyopathy (HCM) or heart diseases with pathophysiological characteristics related to HCM are provided.

Description

Pyrimidine diketone derivative, preparation method and medical application thereof

Technical Field

The present disclosure belongs to the field of medicine, and relates to a pyrimidinedione derivative, a preparation method thereof and an application thereof in medicine. In particular, the present disclosure relates to pyrimidinedione derivatives of general formula (I), a process for their preparation and pharmaceutical compositions containing them, as well as their use in the preparation of Myosin (Myosin) inhibitors and in the preparation of medicaments for the treatment of Hypertrophic Cardiomyopathy (HCM) or heart diseases with pathophysiological characteristics associated with HCM.

Background

Hypertrophic Cardiomyopathy (HCM) is a dominant inherited cardiomyopathy associated with gene mutations. Global morbidity is about 0.2% and is the most important cause of sudden death in young people under 35 years of age (c.vaughan Tuohy et al European Journal of Heart Failure,22,2020,228-240). Clinically, the characteristics are that the left ventricle wall is asymmetrically hypertrophic, is frequently invaded and is frequently separated, the inner cavity of the ventricle is reduced, the left ventricle blood filling is blocked, and the compliance of the ventricular diastole is reduced. The left ventricular outflow tract is classified into obstructive and non-obstructive hypertrophic cardiomyopathy according to the presence or absence of obstruction. Currently, beta-blockers and calcium channel blockers are mostly used clinically for treating hypertrophic cardiomyopathy to reduce heart contraction and relieve symptoms. However, these treatments are both palliative and not palliative. HCM progresses to advanced stages where only heart transplants can be performed (R adhakrishnan Ramaraj, cardiology in Review,16 (4), 2008, 172-180). Thus, it is urgent to find a therapeutic method for the root cause of HCM.

The existing study found that 70% of HCM patients are caused by the mutation of sarcomere protein gene. Wherein a plurality of site mutations are found in 5-7% of patients. More than about 70 pathogenic mutations have been identified, but most of these have family specificity, with only a few hot spots (hot spots) being identified, such as MYH7R403Q and R453C mutations (Norbert Frey, et al Nature Reviews Cardiology,9,2011,91-100; m.sabater-Molina, et al Clinical Genetics,93,2018,3-14). Studies on the probability of causing gene mutation have found that about 30% of patients with MYH7 gene mutation are involved. MYH7 causes early onset of disease and more severe myocardial hypertrophy compared to other sarcomere genes. Myosin is a constituent unit of myofibrillar crude muscle filaments and plays an important role in muscle movement. The molecular shape of the light chain is like bean sprout, and the light chain consists of two heavy chains and a plurality of light chains. The head of myosin is combined with actin to form transverse bridge, so that the ATPase activity of myosin is greatly raised, and the ATP hydrolysis reaction is catalyzed to produce energy to promote the transverse bridge to slide and to contract muscle. The results of the study indicate that mutations in the MYH7 gene lead to increased myosin ATPase activity, a reduced proportion of myoglobin super-relaxed State (SRX), and an increased cross-bridge between myoglobin and actin, leading to systolic dysfunction (Eric M.Green et al, science,351 (6273), 2016,617-621;Ruth F.Sommese,et al, proceedings of the National Academy Sciences,110 (31), 2013,12607-12612). Thus, myosin is an important target for the treatment of hypertrophic cardiomyopathy.

Patent applications for which myosin inhibitors have been disclosed include WO2014205223A1, WO2014205234A1, WO2019028360A1, WO2020092208A1, and CN110698415A, among others.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by general formula (I):

wherein:

ring A is

Ring B is cycloalkyl or a heterocyclic group containing a heteroatom selected from one of nitrogen atom, oxygen atom and sulfur atom;

each R is ¹ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxy;

X ¹ 、X ² and X ³ Identical or different and are each independently a nitrogen atom or CR ^a ；

Each R is ^a Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, 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 And NR ⁹ R ¹⁰ ；

R ² Selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxy;

R ³ is a hydrogen atom;

R ⁴ selected from the group consisting of a hydrogen atom, a halogen, and an alkyl group;

R ⁰ is alkyl orWherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxy;

L ₁ is a bond or (CH) ₂ ) _r ；

Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is ⁵ Identical or different and are each independently selected from the group consisting of hydrogen, 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, - (CH) ₂ ) _r -cycloalkyl, heterocyclyl, - (CH) ₂ ) _r -heterocyclyl, aryl, - (CH) ₂ ) _r -aryl, heteroaryl and- (CH) ₂ ) _r -heteroaryl;

R ⁶ selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, and, Heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is 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;

R ⁷ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ⁸ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁹ and R is ¹⁰ Identical or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, - (CH) ₂ ) _r -cycloalkyl, heterocyclyl, - (CH) ₂ ) _r -heterocyclyl, aryl, - (CH) ₂ ) _r -aryl, heteroaryl and- (CH) ₂ ) _r -heteroaryl;

or R is ⁹ And R is ¹⁰ Together with the nitrogen atom to which they are attached, form a heterocyclic group, which 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;

t is 0, 1, 2, 3 or 4;

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

s is 0, 1, 2, 3, 4, 5 or 6; and is also provided with

p is 0, 1 or 2.

In some embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-1):

wherein:

ring A, R ⁰ 、R ² 、R ³ And R is ⁴ As defined in formula (I).

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from Preferably, ring A isMore preferably, ring A isWherein the ring B, R ¹ 、R ^a And t is as defined in formula (I).

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a pharmaceutically acceptable salt thereof, wherein ring A isWherein the ring B, R ¹ 、R ^a And t is as defined in formula (I); preferably, ring A is selected from Wherein R is ¹ 、R ^a And t is as defined in formula (I); further preferably, ring A is selected from

More preferably, ring A is selected from Most preferably, ring A is

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a pharmaceutically acceptable salt thereof, wherein ring A isWherein the ring B, R ¹ 、R ^a And t is as defined in formula (I); preferably, ring A is selected from Wherein R is ¹ 、R ^a And t is as defined in formula (I); more preferably, ring A is selected from

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

wherein:

ring B, R ^a 、R ⁰ 、R ¹ 、R ² 、R ³ 、R ⁴ And t is as defined in formula (I).

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

wherein:

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

wherein:

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

wherein:

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ⁰ Is C _1-6 Alkyl orWherein, C is as follows _1-6 Alkyl is optionally selected fromHalogen, C _1-6 Alkoxy, C _1-6 One or more substituents of haloalkoxy, cyano, amino and hydroxy are substituted; l (L) ₁ Is a bond or (CH) ₂ ) _r The method comprises the steps of carrying out a first treatment on the surface of the Ring D is selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl, and 5 to 10 membered heteroaryl; each R is ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, oxo, cyano, hydroxy and C _1-6 A hydroxyalkyl group; 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.

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ⁰ Is C _1-6 An alkyl group; preferably, R ⁰ Is isopropyl.

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

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

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a pharmaceutically acceptable salt thereof, wherein X ¹ 、X ² And X ³ Identical or different and are each independently a nitrogen atom or CR ^a The method comprises the steps of carrying out a first treatment on the surface of the Each R is ^a Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 Hydroxyalkyl groups.

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl, amino, and hydroxyl; preferably, R ¹ Is a hydrogen atom.

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein each R ^a Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; preferably, each R ^a The same or different, and are each independently a hydrogen atom or a halogen; more preferably, each R ^a The same or different and are each independently a hydrogen atom or a fluorine atom.

In other embodiments of the present disclosure, the compounds of formula (II-1), formula (II-2), formula (III-1), formula (III-2) or pharmaceutically acceptable salts thereof, Wherein the method comprises the steps of Selected from the group consisting of Wherein each R ^a Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl, amino, and hydroxyl; t is 0 or 1; preferably, the method comprises the steps of,selected from the group consisting of More preferably, the process is carried out,selected from the group consisting of

In other embodiments of the present disclosure, the compound of formula (II-1), formula (III-1), or a pharmaceutically acceptable salt thereof, whereinSelected from the group consisting of Each R is ^a Identical or different and are each independently a hydrogen atom or a halogen, t being 0; preferably, the method comprises the steps of,selected from the group consisting ofMore preferably, the process is carried out,

in other embodiments of the present disclosure, the compound of formula (II-1), formula (III-1), or a pharmaceutically acceptable salt thereof, whereinIs thatEach R is ^a Identical or different and are each independently a hydrogen atom or a halogen, t being 0; preferably, the method comprises the steps of,is that

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ² Selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _1-6 A hydroxyalkyl group; preferably, R ² Is C _1-6 An alkyl group; more preferably, R ² Is methyl.

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein R ⁴ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; preferably, R ⁴ Is a hydrogen atom or C _1-6 An alkyl group; more preferably, R ⁴ Is a hydrogen atom.

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

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a pharmaceutically acceptable salt thereof, wherein ring A isRing B is a 4-to 6-membered cycloalkyl group or a 4-to 6-membered heterocyclic group containing a heteroatom selected from one of nitrogen atom, oxygen atom and sulfur atom; each R is ^a Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl, amino, and hydroxyl; r is R ⁰ Is C _1-6 Alkyl or 3 to 6 membered heterocyclyl; r is R ² Selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _1-6 A hydroxyalkyl group; r is R ³ Is a hydrogen atom; r is R ⁴ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; t is 0 or 1.

In other embodiments of the present disclosure, the compound of formula (I), formula (I-1), or a pharmaceutically acceptable salt thereof, wherein ring A isRing B is a 4-to 6-membered cycloalkyl group or a 4-to 6-membered heterocyclic group containing a heteroatom selected from one of nitrogen atom, oxygen atom and sulfur atom; each R is ^a Identical or identicalDifferent from each other and each independently selected from hydrogen atom, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl, amino, and hydroxyl; r is R ⁰ Is C _1-6 An alkyl group; r is R ² Selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _1-6 A hydroxyalkyl group; r is R ³ Is a hydrogen atom; r is R ⁴ Is a hydrogen atom; t is 0 or 1.

In other embodiments of the present disclosure, the compound of formula (II-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein Selected from the group consisting of Each R is ^a The same or different, and are each independently a hydrogen atom or a halogen; r is R ¹ Is a hydrogen atom; r is R ⁰ Is C _1-6 Alkyl or 3 to 6 membered heterocyclyl; r is R ² Is C _1-6 An alkyl group; r is R ³ Is a hydrogen atom; r is R ⁴ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; t is 1.

In other embodiments of the present disclosure, the compound of formula (II-1), formula (II-2), formula (III-1), formula (III-2), or a pharmaceutically acceptable salt thereof, wherein Selected from the group consisting of Each R is ^a The same or different, and are each independently a hydrogen atom or a halogen; r is R ¹ Is a hydrogen atom; r is R ⁰ Is C _1-6 An alkyl group; r is R ² Is methyl; r is R ³ Is a hydrogen atom; r is R ⁴ Is a hydrogen atom; t is 1.

In other embodiments of the present disclosure, the compound of formula (II-1), formula (III-1), or a pharmaceutically acceptable salt thereof, whereinIs thatEach R is ^a The same or different, and are each independently a hydrogen atom or a halogen; t is 0; r is R ⁰ Is C _1-6 An alkyl group; r is R ² Is C _1-6 An alkyl group; r is R ³ Is a hydrogen atom; r is R ⁴ Is a hydrogen atom.

Table a typical compounds of the present disclosure include, but are not limited to:

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

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

wherein:

R ^w for leaving outA group, preferably halogen, more preferably chlorine;

ring A, R ⁰ 、R ² 、R ³ And R is ⁴ As defined in formula (I).

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

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

wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

ring A, R ⁰ 、R ² 、R ³ And R is ⁴ As defined in formula (I-1).

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

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

Wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

ring B, R ⁰ 、R ¹ 、R ^a 、R ² 、R ³ 、R ⁴ And t is as defined in formula (II-1).

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

nucleophilic substitution reaction of the compound represented by the general formula (IIA-2) or a salt thereof (preferably hydrochloride) with the compound represented by the general formula (V) to obtain a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof;

wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

ring B, R ⁰ 、R ¹ 、R ^a 、R ² 、R ³ 、R ⁴ And t is as defined in formula (II-2).

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

nucleophilic substitution reaction of the compound represented by the general formula (IIIA-1) or a salt thereof (preferably hydrochloride) with the compound represented by the general formula (V) to obtain a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

ring B, R ⁰ 、R ¹ 、R ^a 、R ² 、R ³ 、R ⁴ And t is as defined in formula (III-1).

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

Nucleophilic substitution reaction of the compound represented by the general formula (IIIA-2) or a salt thereof (preferably hydrochloride) with the compound represented by the general formula (V) to obtain a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof;

wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

ring B, R ⁰ 、R ¹ 、R ^a 、R ² 、R ³ 、R ⁴ And t is as defined in formula (III-2).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), and table a, or a pharmaceutically acceptable salt thereof, in accordance with the present disclosure, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2) and formula (III-2) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same in the preparation of a Myosin (Myosin) inhibitor.

The present disclosure further relates to the use of a compound of formula (I), formula (I-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, in the manufacture of a medicament for treating a disease or disorder selected from the group consisting of a 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), normal ejection fraction heart failure (HFpEF), intermediate heart values of ejection fraction (HFmREF), valve disease, valve stenosis, inflammatory cardiomyopathy, lux endocarditis, endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabricism, glycogen storage, heart failure, and congenital heart failure; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

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

The present disclosure further relates to a method of treating a disease or disorder (particularly a disease or disorder mediated by myosin) selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina, limited cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry-perot, left ventricular hypertrophy, refractory angina, and right-hand angina, or a pharmaceutical composition comprising the same, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (I-1), formula (II-2), or a pharmaceutically acceptable salt thereof; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure further relates to a compound represented by general formula (I), general formula (I-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 as a medicament.

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

The present disclosure further relates to a compound of formula (I), formula (I-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 in treating a disease or disorder selected from the group consisting of ejection fraction preserved diastolic heart failure, ischemic heart disease, angina, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, lux endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry four-way disease, left ventricular hypertrophy, refractory angina and pick's disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).

The compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, of the present disclosure may alter the natural history of HCM and other diseases, rather than merely ameliorate symptoms. The mechanism by which clinical benefit is imparted to HCM patients can be extended to patients with other forms of heart disease that together have similar pathophysiology, with or without the influence of significant genetic factors. For example, effective treatment of HCM by improving ventricular diastole during diastole may also be effective for a broader population characterized by diastolic dysfunction.

The compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may specifically target the root cause of a disorder or act on other downstream pathways. Accordingly, the compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), and Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may confer a benefit to patients suffering from diastolic heart failure, ischemic heart disease, angina or restrictive cardiomyopathy with a preserved ejection fraction.

The compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may also promote beneficial ventricular remodeling of left ventricular hypertrophy due to volume or pressure overload; such as chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension; the compounds or pharmaceutically acceptable salts thereof are combined with therapies aimed at correcting or alleviating the main cause of volume or pressure overload (valve repair/replacement, effective antihypertensive therapies). By lowering left ventricular filling pressure, the compounds may reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and/or reducing left atrial pressure may reduce the risk of sudden or permanent atrial fibrillation, and it reduces the 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 tract obstruction may reduce the likelihood of requiring intermittent ablative treatment (surgical or percutaneous) and the attendant risks of short-term and long-term complications thereof.

The compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), and table a or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may reduce the severity of chronic ischemic conditions associated with HCM, and thereby reduce the risk of Sudden Cardiac Death (SCD) or equivalent diseases thereof in patients with implantable cardioverter-defibrillators (frequent and/or repeated ICD discharges) and/or reduce the need for potentially toxic antiarrhythmic drugs.

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

The compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, of the present disclosure may reduce interstitial myocardial fibrosis and/or slow the progression of left ventricular hypertrophy, preventing or reversing left ventricular hypertrophy.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches or syrups.

As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

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

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

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

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable or mineral oil. The oil suspension may contain a thickener. Sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which injectable solution or microemulsion may be injected into the blood stream of a patient by topical bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

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

Dispersible powders and granules that produce an aqueous suspension by the addition of water can be used to administer the compounds of the present disclosure. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated straight or branched 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 Alkyl). The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C _1-12 Alkyl groups), more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C _1-6 Alkyl). Non-limiting examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 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-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. Most preferably a lower alkyl group having 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkylene" refers to a divalent alkyl group, where 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 An alkylene group). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C _1-12 Alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 An alkylene group). Non-limiting examples of alkylene groups include, but are not limited to: methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl group having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above 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 Alkenyl). The alkenyl group preferably has 2 to 6 carbon atoms (i.e. C _2-6 Alkenyl). Non-limiting examples include: ethenyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, where alkyl is as defined above 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 Alkynyl). The alkynyl group preferably has 2 to 6 carbon atoms (i.e., C _2-6 Alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, and the like. The alkoxy group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring having 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 having 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl), more preferably having 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl), most preferably having 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl), and particularly preferably having 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, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered, monocyclic, polycyclic group sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings, which may 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). The spirocycloalkyl groups are classified into single spirocycloalkyl groups or multiple spirocycloalkyl groups (e.g., double spirocycloalkyl groups) according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. 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/4-membered or 6-membered/5-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The connection point can be at any position.

The term "fused ring alkyl" refers to an all-carbon polycyclic group having 5 to 20 members with an adjacent pair of carbon atoms shared between the rings, wherein one or more of the rings may 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). The polycyclic condensed ring alkyl group may be classified into a bicyclic, tricyclic, tetracyclic or the like according to the number of constituent rings, and is preferably a bicyclic or tricyclic condensed ring alkyl group, more preferably a 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 group. Non-limiting examples of fused ring alkyl groups include:

the connection point can be at any position.

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly attached, which may 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). Polycyclic bridged cycloalkyl groups such as bicyclic, tricyclic, tetracyclic and the like can be classified according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl groups, more preferably bicyclic or tricyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

The connection point can be at any position.

The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples includeEtc.; preferably

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent having 3 to 20 ring atoms in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 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 preferred have 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), wherein 1-3 is a heteroatom (e.g., 1,2, and 3) (i.e., 3 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms, 1-3 of which are heteroatoms (i.e., 3 to 6 membered heterocyclyl); most preferably a 4-to 6-membered heterocyclic group having one heteroatom selected from nitrogen atom, oxygen atom and sulfur atom; particularly preferably having 5 or 6 ring atoms, of which 1 to 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 heterocyclic groups include spiro heterocyclic groups, fused ring heterocyclic groups, and bridged ring heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may 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). The spiroheterocyclyl groups are classified into single spiroheterocyclyl groups or multiple spiroheterocyclyl groups (e.g., double spiroheterocyclyl groups) according to the number of common spiro atoms between rings, with single and double spiroheterocyclyl groups being preferred. 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 or 6-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:

etc.

The term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group having a ring sharing an adjacent pair of atoms, one or more of which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a polycyclic fused heterocyclic group such as a bicyclic, tricyclic, tetracyclic and the like, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 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/3-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-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 fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

Etc.

The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Polycyclic bridged heterocyclic groups such as a bicyclic, tricyclic, tetracyclic and the like can be classified according to the number of constituent rings, and are preferably bicyclic, tricyclic or tetracyclic bridged heterocyclic groups, more preferably bicyclic or tricyclic bridged heterocyclic groups. Non-limiting examples of bridged heterocyclyl groups include:

etc.

The heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

etc.

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

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

aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to heteroaromatic systems containing 1 to 4 heteroatoms (e.g., 1, 2, 3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably a 5 to 10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered) heteroaryl, more preferably a 5 or 6 membered heteroaryl, e.g., furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyridonyl, N-alkylpyridinone (e.g.) Etc.), pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

etc.

Heteroaryl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

The term "amino protecting group" refers to an easily removable group introduced on an amino group in order to keep the amino group unchanged when the reaction is performed at other positions of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxy protecting group" refers to an easily removable group introduced on a hydroxy group, typically used to block or protect the hydroxy group to allow the reaction to proceed 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.

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

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

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

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

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

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

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

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

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

The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

In the chemical structure of the compounds of the present disclosure, the bondIndicating unspecified configuration, i.e. bonds if chiral isomers are present in the chemical structureMay beOr at the same time contain Two configurations. In the chemical structure of the compounds of the present disclosure, the bondThe configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are included. For all carbon-carbon double bonds, Z and E are included even if only one configuration is named.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of lactam-lactam balances are as follows:

all tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.

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

The present disclosure also includes various deuterated forms of the compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2), and compounds shown in Table A. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to synthesize deuterated forms of the compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2) and the compounds shown in Table A with reference to the relevant literature. In preparing the deuterated forms of the compounds of formula (I), formula (I-1), formula (II-2), formula (III-1), formula (III-2) and the compounds shown in Table A, commercially available deuterated starting materials may be used, or may be synthesized using conventional techniques with deuterated reagents. Deuterated reagents include, but are not limited to, deuterated borane, trideutero borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium.

"optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may be, but need not be, present, and this description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen and cyano.

"substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

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

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the intended effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

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

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

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises the steps of:

a compound shown in a general formula (IA) or a salt thereof (preferably hydrochloride) and a compound shown in a general formula (V) generate nucleophilic substitution reaction under the condition of microwaves in the presence of alkali to obtain a compound shown in a general formula (I) or a pharmaceutically acceptable salt thereof;

wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

ring A, R ⁰ 、R ² 、R ³ And R is ⁴ As defined in formula (I).

Scheme II

A process for the preparation of a compound of formula (I-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises the steps of:

A compound shown in a general formula (IA-1) or a salt (preferably hydrochloride) thereof and a compound shown in a general formula (V) undergo nucleophilic substitution reaction under the microwave condition in the presence of alkali to obtain a compound shown in the general formula (I-1) or a pharmaceutically acceptable salt thereof;

wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

ring A, R ⁰ 、R ² 、R ³ And R is ⁴ As defined in formula (I-1).

Scheme III

A process for the preparation of a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises the steps of:

a compound shown in a general formula (IIA-1) or a salt (preferably hydrochloride) thereof and a compound shown in a general formula (V) undergo nucleophilic substitution reaction under the microwave condition in the presence of alkali to obtain a compound shown in a general formula (II-1) or a pharmaceutically acceptable salt thereof;

wherein:

R ^w as leaving groups, preferably halogen, more preferablyIs a chlorine atom;

Scheme IV

A process for the preparation of a compound of formula (II-2) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises the steps of:

a compound shown in a general formula (IIA-2) or a salt (preferably hydrochloride) thereof and a compound shown in a general formula (V) undergo nucleophilic substitution reaction under the microwave condition in the presence of alkali to obtain a compound shown in a general formula (II-2) or a pharmaceutically acceptable salt thereof;

Wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

Scheme five

A process for the preparation of a compound of formula (III-1) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises the steps of:

a compound shown in a general formula (IIIA-1) or a salt (preferably hydrochloride) thereof and a compound shown in a general formula (V) undergo nucleophilic substitution reaction under the microwave condition in the presence of alkali to obtain a compound shown in a general formula (III-1) or a pharmaceutically acceptable salt thereof;

wherein:

R ^w as leaving groupA group, preferably halogen, more preferably chlorine;

Scheme six

A process for the preparation of a compound of formula (III-2) or a pharmaceutically acceptable salt thereof, according to the present disclosure, which comprises the steps of:

a compound shown in a general formula (IIIA-2) or a salt (preferably hydrochloride) thereof and a compound shown in a general formula (V) undergo nucleophilic substitution reaction under the microwave condition in the presence of alkali to obtain a compound shown in a general formula (III-2) or a pharmaceutically acceptable salt thereof;

wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

The base includes organic bases and inorganic bases, the organic bases include but are not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, 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.

The above reaction is preferably carried out in a solvent, including but 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-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane, and mixtures thereof.

The reaction temperature of the above-mentioned microwave reaction is 120 to 140℃and preferably 130 ℃.

The reaction time of the above-mentioned microwave reaction is 0.5 to 4 hours, preferably 2 hours.

Detailed Description

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

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q actual (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatography.

Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

High performance liquid chromatography was performed using Waters 2767, waters 2767-SQ detector 2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaoshi chemical technologies (Shanghai) limited (Accela ChemBio Inc), dary chemicals, and the like.

The reaction can be carried out under argon atmosphere or nitrogen atmosphere without any particular explanation in examples.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

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

First step

(R) -N- (1- (2, 3-dihydro-1H-inden-5-yl) ethylidene) -2-methylpropane-2-sulfinamide 1c

To 1- (2, 3-dihydro-1H-inden-5-yl) ethan-1-one 1a (1.0 g,6.3mmol, technical (Shanghai) chemical industry development Co., ltd.) and (R) -2-methylpropane-2-sulfinamide 1b (1.1 g,8.8mmol, shanghai taitan technologies Co., ltd.) in dry tetrahydrofuran (20 mL) was added 1M triisopropoxytitanium chloride hexane solution (7.5 mL,7.5mmol, shanghai taitan technologies Co., ltd.). The reaction was stirred at 65℃for 16 hours. Saturated aqueous sodium hydrogencarbonate (30 mL) was added, and extraction was performed with ethyl acetate (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (570.0 mg, yield: 34.7%).

MS m/z(ESI)：264.0[M+1]。

Second step

(R) -N- ((S) -1- (2, 3-dihydro-1H-inden-5-yl) ethyl) -2-methylpropane-2-sulfinamide 1d

To anhydrous tetrahydrofuran (10 mL) of compound 1c (570 mg,2.2 mmol) was added dropwise a 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (3.5 mL,3.5mmol, shanghai-Tech Co., ltd.) at-78deg.C. The reaction was carried out at 0℃for 1 hour. Saturated aqueous ammonium chloride (20 mL) was added and extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 1d (570 mg), which was used in the next step without purification.

MS m/z(ESI)：266.1[M+1]。

Third step

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

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

MS m/z(ESI)：145.1[M-16]。

Fourth step

Crude compound 1e (430.0 mg,2.2 mmol), 6-chloro-3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 1f (413.6 mg,2.2mmol, prepared using the procedure for the synthesis of compound 1.3 at page 27 of the specification in patent application WO2014205223A 1) and N, N-diisopropylethylamine (1.4 g,10.9 mmol) were dissolved in anhydrous 1, 4-dioxane (6 mL). The reaction was carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 40% (v/v) to 95% (v/v) over 12.1 min, detection wavelength 214&254 nm) to give the title product 1 (140.0 mg, yield: 20.6%).

MS m/z(ESI)：314.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ7.19(s,1H),7.18(d,1H),7.07(d,1H),6.82(brs,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)。

Example 2

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

First step

(R) -N- (1- (2, 3-dihydro-1H-inden-4-yl) ethylene) -2-methylpropane-2-sulfinamide 2b

To a solution of 1- (2, 3-dihydro-1H-inden-4-yl) ethan-1-one 2a (500.0 mg,3.1mmol, technical (Shanghai) chemical industry development Co., ltd.) and compound 1b (530.0 mg,4.4 mmol) in anhydrous tetrahydrofuran (10 mL) was added 1M solution of triisopropoxytitanium chloride in hexane (3.8 mL,3.8 mmol). The reaction was stirred at 65℃for 16 hours. Saturated aqueous sodium bicarbonate (15 mL) was added and extracted with ethyl acetate (50 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 2b (220.0 mg, yield: 26.8%).

MS m/z(ESI)：264.0[M+1]。

Second step

(R) -N- ((S) -1- (2, 3-dihydro-1H-inden-4-yl) ethyl) -2-methylpropane-2-sulfinamide 2c

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

MS m/z(ESI)：266.1[M+1]。

Third step

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

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

MS m/z(ESI)：145.1[M-16]。

Fourth step

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 carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 35% (v/v) to 95% (v/v) over 15.1 min, detection wavelength 214&254 nm) to give the title product 2 (40.0 mg, yield: 15.2%).

MS m/z(ESI)：314.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.75(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)。

Example 3

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

First step

(R) -N- (bicyclo [4.2.0] oct-1 (6), 2, 4-trien-3-ylmethylene) -2-methylpropan-2-sulfinamide 3b bicyclo [4.2.0] oct-1 (6), 2, 4-trien-3-carbaldehyde 3a (2.9 g,22.0mmol, prepared using the method of synthesis of Compound 257 at pages 512-513 of the specification of patent application "WO2019023147A 1") and Compound 1b (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 stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 3b (5.7 g), which was used in the next step without purification.

MS m/z(ESI)：236.1[M+1]。

Second step

(R) -N- ((S) -1- (bicyclo [4.2.0] oct-1 (6), 2, 4-trien-3-yl) ethyl) -2-methylpropan-2-sulfinamide 3c

To a solution of crude compound 3b (2.8 g,12.1 mmol) in anhydrous dichloromethane (80 mL) at-50deg.C was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (8.1 mL,24.2mmol, shanghai Taitan technologies Co., ltd.). The reaction was carried out at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (50 mL) was added and extracted with methylene chloride (50 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 3c (2.0 g, yield: 66.2%).

MS m/z(ESI)：252.1[M+1]。

Third step

(S) -1- (bicyclo [4.2.0] oct-1 (6), 2, 4-trien-3-yl) ethanamine hydrochloride 3d

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

MS m/z(ESI)：131.1[M-16]。

Fourth step

Crude compound 3d (366.0 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 (6 mL). The reaction was carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 30% (v/v) to 95% (v/v) over 13.1 min, detection wavelength 214&254 nm) to give the title product 3 (208.0 mg, yield: 34.7%).

MS m/z(ESI)：300.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.75(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)。

Example 4

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

First step

(R) -N- (2, 3-Dihydrobenzofuran-6-yl) methylene) -2-methylpropane-2-sulfinamide 4b

2, 3-Dihydrobenzofuran-6-carbaldehyde 4a (1.0 g,6.8mmol, jiangsu Aikang Biometrics Co., ltd.) and Compound 1b (860.0 mg,7.1mmol, shanghai Taitan technologies Co., ltd.) were dissolved in dichloromethane (40 mL). Cesium carbonate (2.6 g,8.1 mmol) was added and the reaction stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 4b (1.8 g), which was used in the next step without purification.

MS m/z(ESI)：252.0[M+1]。

Second step

(R) -N- ((S) -1- (2, 3-Dihydrobenzofuran-6-yl) ethyl) -2-methylpropane-2-sulfinamide 4c

To crude compound 4b (1.7 g,6.8 mmol) in dry dichloromethane (45 mL) was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (4.9 mL,14.6 mmol) at-50 ℃. The reaction was carried out at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (30 mL) was added and extracted with methylene chloride (30 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 4c (1.6 g, yield: 90.6%).

MS m/z(ESI)：268.1[M+1]。

Third step

(S) -1- (2, 3-Dihydrobenzofuran-6-yl) ethylamine hydrochloride 4d

Compound 4c (534.0 mg,2.0 mmol) was dissolved in methanol (3 mL), and a solution of 4M hydrogen chloride in 1, 4-dioxane (2 mL) was added dropwise. The reaction was carried out at room temperature for 1 hour. Concentration under reduced pressure afforded the title product as crude 4d (400.0 mg), which was used in the next step without purification.

MS m/z(ESI)：147.1[M-16]。

Fourth step

Crude compound 4d (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 (6 mL). The reaction was carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex Prep C, 5 μm 30. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 28% (v/v) to 48% (v/v) over 15 minutes, detection wavelength 214&254 nm) to give the title product 4 (170.0 mg, yield: 26.9%).

MS m/z(ESI)：316.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.76(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)。

Example 5

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

First step

(R) -2-methyl-N- (1- (5, 6,7, 8-tetrahydronaphthalen-2-yl) ethylidene) propane-2-sulfinamide 5b

To 1- (5, 6,7, 8-tetrahydronaphthalen-2-yl) ethan-1-one 5a (2.0 g,11.5mmol, alfa Angstrom chemical Co., ltd.) and compound 1b (2.1 g,17.3 mmol) in anhydrous tetrahydrofuran (20 mL) was added tetraethoxytitanium (4.0 g,17.3mmol, an Naiji chemical). The reaction was stirred at 65℃for 16 hours. Saturated sodium bicarbonate solution (60 mL) was added and extracted with ethyl acetate (100 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 5b (2.6 g, yield: 81.6%).

MS m/z(ESI)：278.0[M+1]。

Second step

(R) -2-methyl-N- ((S) -1- (5, 6,7, 8-tetrahydronaphthalen-2-yl) ethyl) propane-2-sulfinamide 5c

To anhydrous tetrahydrofuran (10 mL) of compound 5b (600 mg,2.2 mmol) was added dropwise a 1M solution of lithium tri-sec-butylborohydride in tetrahydrofuran (3.5 mL,3.5mmol, shanghai Taitan technologies Co., ltd.) at-78 ℃. The reaction was carried out at 0℃for 1 hour. Saturated aqueous ammonium chloride (20 mL) was added and extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude title product 5c (600 mg), which was used in the next step without purification.

MS m/z(ESI)：280.1[M+1]。

Third step

(S) -1- (5, 6,7, 8-tetrahydronaphthalen-2-yl) ethylamine hydrochloride 5d

The crude compound 5c (600 mg,2.2 mmol) was dissolved in methanol (3 mL) and a solution of 4M hydrogen chloride in 1, 4-dioxane (2.2 mL) was added dropwise. The reaction was stirred for 1 hour. Concentration under reduced pressure afforded the title product 5d as crude (455.0 mg) which was used in the next step without purification.

MS m/z(ESI)：159.1[M-16]。

Fourth step

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

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 for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 35% (v/v) to 95% (v/v) over 16.1 min, detection wavelength 214&254 nm) to give the title product 5 (170.0 mg, yield: 23.9%).

MS m/z(ESI)：328.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.74(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)。

Example 6

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

First step

(R) -N- ((2, 3-Dihydrobenzofuran-4-yl) methylidene) -2-methylpropane-2-sulfinamide 6b

2, 3-Dihydrobenzofuran-4-carbaldehyde 6a (1.0 g,6.8mmol, shanghai Bi-pharmaceutical technologies Co., ltd.) and Compound 1b (860.0 mg,7.1 mmol) were dissolved in dichloromethane (13 mL). Cesium carbonate (2.6 g,8.1 mmol) was added and the reaction stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 6b (1.7 g), which was used in the next step without purification.

MS m/z(ESI)：252.0[M+1]。

Second step

(R) -N- ((S) -1- (2, 3-Dihydrobenzofuran-4-yl) ethyl) -2-methylpropane-2-sulfinamide 6c

To crude compound 6b (1.7 g,6.8 mmol) in dry dichloromethane (45 mL) was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (5.0 mL,14.9 mmol) at-50deg.C. The reaction was carried out at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (30 mL) was added and extracted with methylene chloride (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 6c (1.6 g, yield: 88.5%).

MS m/z(ESI)：268.1[M+1]。

Third step

(S) -1- (2, 3-Dihydrobenzofuran-4-yl) ethylamine hydrochloride 6d

Compound 6c (534.0 mg,2.0 mmol) was dissolved in methanol (3 mL), and a 4M solution of 1, 4-dioxane (2 mL) in hydrogen chloride was added dropwise. The reaction was stirred for 1 hour. Concentration under reduced pressure afforded the title product as crude 6d (400.0 mg), which was used in the next step without purification.

MS m/z(ESI)：147.1[M-16]。

Fourth step

Crude compound 6d (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 for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 45% (v/v) to 95% (v/v) over 15.1 min, detection wavelength 214&254 nm) to give the title product 6 (138.0 mg, yield: 21.9%).

MS m/z(ESI)：316.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.78(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)。

Example 7

(S) -6- ((1- (2, 3-Dihydrobenzofuran-7-yl) ethyl) amino) -3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 7

First step

(R) -N- (2, 3-Dihydrobenzofuran-7-yl) methylene) -2-methylpropane-2-sulfinamide 7b

2, 3-Dihydrobenzofuran-7-carbaldehyde 7a (1.0 g,6.8mmol, shanghai Bi-pharmaceutical technologies Co., ltd.) and Compound 1b (860.0 mg,7.1 mmol) were dissolved in dichloromethane (13 mL). Cesium carbonate (2.6 g,8.1 mmol) was added and the reaction stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 7b (1.7 g), which was used in the next step without purification.

MS m/z(ESI)：252.0[M+1]。

Second step

(R) -N- ((S) -1- (2, 3-Dihydrobenzofuran-7-yl) ethyl) -2-methylpropane-2-sulfinamide 7c

To crude compound 7b (1.7 g,6.8 mmol) in dry dichloromethane (45 mL) was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (5.0 mL,14.9 mmol) at-50deg.C. The reaction was carried out at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (30 mL) was added and extracted with methylene chloride (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 7c (1.6 g, yield: 86.8%).

MS m/z(ESI)：268.1[M+1]。

Third step

(S) -1- (2, 3-Dihydrobenzofuran-7-yl) ethylamine hydrochloride 7d

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

MS m/z(ESI)：147.1[M-16]。

Fourth step

Crude compound 7d (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 for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex Prep C, 5 μm 30. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 30% (v/v) to 50% (v/v) over 15 minutes, detection wavelength 214&254 nm) to give the title product 7 (200.0 mg, yield: 31.7%).

MS m/z(ESI)：316.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.87(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)。

Example 8

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

First step

(R) -2-methyl-N- ((5, 6,7, 8-tetrahydronaphthalen-1-yl) methylen) propane-2-sulfinamide 8b

5,6,7, 8-tetrahydronaphthalene-1-carbaldehyde 8a (1.0 g,6.3mmol, shanghai Bi-pharmaceutical technologies 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 stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 8b (1.6 g), which was used in the next step without purification.

MS m/z(ESI)：264.1[M+1]。

Second step

(R) -2-methyl-N- ((S) -1- (5, 6,7, 8-tetrahydronaphthalen-1-yl) ethyl) propane-2-sulfinamide 8c

To crude compound 8b (1.6 g,6.3 mmol) in dry dichloromethane (45 mL) was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (4.6 mL,13.8 mmol) at-50 ℃. The reaction was carried out at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (30 mL) was added and extracted with methylene chloride (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 8c (1.5 g, yield: 85.7%).

MS m/z(ESI)：280.1[M+1]。

Third step

(S) -1- (5, 6,7, 8-tetrahydronaphthalen-1-yl) ethylamine hydrochloride 8d

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

MS m/z(ESI)：159.1[M-16]。

Fourth step

Crude compound 8d (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 carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 60% (v/v) to 95% (v/v) over 15.1 min, detection wavelength 214&254 nm) to give the title product 8 (200.0 mg, yield: 30.5%).

MS m/z(ESI)：328.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.74(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)。

Example 9

(S) -6- ((1- (1, 3-dihydroisobenzofuran-4-yl) ethyl) amino) -3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 9

First step

1, 3-Dihydroisobenzofuran-4-carbaldehyde 9b

To an anhydrous tetrahydrofuran solution (12 mL) of 4-bromo-1, 3-dihydroisobenzofuran 9a (1.0 g,5.0mmol, shanghai Bi-pharmaceutical technologies Co., ltd.) was added dropwise a 2.5M n-hexane solution (2.4 mL,6.0mmol, shanghai Taitan technologies Co., ltd.) at-78 ℃. The reaction was stirred at-78℃for 30 minutes under nitrogen atmosphere. Anhydrous N, N-dimethylformamide (550.2 mg,7.5 mmol) was added thereto, and the mixture was reacted at 78℃for 30 minutes. The reaction was slowly warmed to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride (20 mL) was added, the ethyl acetate (30 mL. Times.2) was extracted, the organic phases were combined and concentrated under reduced pressure to give crude title product 9b (731.0 mg), which was used in the next step without purification.

MS m/z(ESI)：149.1[M+1]。

Second step

(R) -N- ((1, 3-Dihydroisobenzofuran-4-yl) methylen-2-methylpropane-2-sulfinamide 9c

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 stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 9c (1.3 g), which was used in the next step without purification.

MS m/z(ESI)：252.1[M+1]。

Third step

(R) -N- ((S) -1- (1, 3-dihydroisobenzofuran-4-yl) ethyl) -2-methylpropane-2-sulfinamide 9d

To crude compound 9c (1.3 g,5.1 mmol) in dry dichloromethane (30 mL) was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (3.7 mL,11.0 mmol) at-50deg.C. The reaction was carried out at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (30 mL) was added and extracted with methylene chloride (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 9d (838.0 g, yield: 62.5%).

MS m/z(ESI)：268.2[M+1]。

Fourth step

(S) -1- (1, 3-Dihydroisobenzofuran-4-yl) ethylamine hydrochloride 9e

Compound 9d (838.0 mg,3.0 mmol) was dissolved in methanol (3 mL) and a solution of 4M hydrogen chloride in 1, 4-dioxane (3 mL) was added dropwise. The reaction was stirred for 1 hour. Concentration under reduced pressure afforded crude title product 9e (626.0 mg), which was used in the next step without purification.

MS m/z(ESI)：147.1[M-16]。

Fifth step

Crude compound 9e (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 for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 20% (v/v) to 95% (v/v) over 15.1 min, detection wavelength 214&254 nm) to give the title product 9 (89.0 mg, yield: 18.0%).

MS m/z(ESI)：316.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ7.30-7.27(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)。

Example 10

(S) -6- ((1- (2, 3-Dihydrobenzofuran-5-yl) ethyl) amino) -3-isopropylpyrimidine-2, 4 (1H, 3H) -dione 10

First step

(R) -N- ((2, 3-Dihydrobenzofuran-5-yl) methylidene) -2-methylpropane-2-sulfinamide 10b

2, 3-Dihydrobenzofuran-5-carbaldehyde 10a (5.0 g,33.7mmol, shanghai Bi-pharmaceutical technologies Co., ltd.) and Compound 1b (4.3 g,35.5 mmol) were dissolved in dichloromethane (65 mL). Cesium carbonate (13.2 g,40.6 mmol) was added and the reaction stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude product of the title product 10b (8.5 g), which was used in the next step without purification.

MS m/z(ESI)：252.1[M+1]。

Second step

(R) -N- ((S) -1- (2, 3-Dihydrobenzofuran-5-yl) ethyl) -2-methylpropane-2-sulfinamide 10c

To crude compound 10b (8.5 g,33.8 mmol) in dry dichloromethane (225 mL) was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (25.0 mL,74.4 mmol) at-50 ℃. The reaction was carried out at room temperature for 16 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (100 mL) was added and extracted with methylene chloride (100 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 10c (7.5 g, yield: 82.9%).

MS m/z(ESI)：268.1[M+1]。

Third step

(S) -1- (2, 3-Dihydrobenzofuran-5-yl) ethylamine hydrochloride 10d

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

MS m/z(ESI)：147.1[M-16]。

Fourth step

Crude compound 10d (65.9 mg,0.3 mmol), compound 1f (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 reaction was carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 23% (v/v) to 95% (v/v) over 18.1 min, detection wavelength 214&254 nm) to give the title product 10 (21.3 mg, yield: 20.5%).

MS m/z(ESI)：316.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ7.20(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)。

Example 11

(S) -6- ((1- (2, 3-Dihydrobenzofuran-4-yl) ethyl) amino) -3- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4 (1H, 3H) -dione 11

First step

Crude compound 6d (200.0 mg,1.0 mmol), compound 11a (231.1 mg,1.0mmol, prepared using the method for synthesizing intermediate 4d, example 5, pages 18-19 of the specification in patent application CN110698415 a) and N, N-diisopropylethylamine (647.3 g,5.0 mmol) were dissolved in anhydrous 1, 4-dioxane (3 mL). The reaction was carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 20% (v/v) to 95% (v/v) over 15.1 min, detection wavelength 214&254 nm) to give the title product 11 (100.0 mg, yield: 28.0%).

MS m/z(ESI)：358.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.84(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)。

Example 12

(S) -6- ((1- (2, 3-Dihydrobenzofuran-7-yl) ethyl) amino) -3- (tetrahydro-2H-pyran-4-yl) pyrimidine-2, 4 (1H, 3H) -dione 12

First step

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 carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 20% (v/v) to 95% (v/v) over 15.1 min, detection wavelength 214&254 nm) to afford the title product 12 (100.0 mg, yield: 28.0%).

MS m/z(ESI)：358.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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)。

Example 13

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

First step

5-fluorobenzofuran-6-carboxylic acid methyl ester 13b

4-bromo-5-fluorobenzofuran 13a (3.20 g,14.88mmol, prepared by the method of synthesis of intermediate A1.2b on page 17 of the specification of patent application "U.S. Pat. No. 3, 20160176882,1") was dissolved in methanol (50 mL), and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (1.26 g,1.49 mmol) and N, N-diisopropylethylamine (3.01 g,29.75 mmol) were added, carbon monoxide gas was replaced three times, and the reaction was stirred at 70℃for 40 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 13b (1.50 g, yield: 51.9%).

MS m/z(ESI)：194.8[M+1]。

Second step

5-fluoro-2, 3-dihydrobenzofuran-6-carboxylic acid methyl ester 13c

Compound 13b (1.0 g,5.2 mmol) was dissolved in methanol (30 mL), 10% palladium on carbon hydrogenation catalyst (400 mg, wet) was added, hydrogen was replaced three times, and stirred at room temperature for 16 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 13c (913.0 mg, yield: 90.5%).

MS m/z(ESI)：197.1[M+1]。

Third step

(5-fluoro-2, 3-dihydrobenzofuran-6-yl) methanol 13d

Compound 13c (900.0 mg,4.6 mmol) was dissolved in anhydrous tetrahydrofuran (9 mL), and a 2M solution of lithium borohydride in tetrahydrofuran (4.6 mL,9.2 mmol) was added dropwise and reacted at room temperature for 16 hours. The reaction was quenched by addition of methanol (5 mL) in an ice bath, the pH of the solution was adjusted to 6 with 1M hydrochloric acid, and extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 13d (695.8 mg, yield: 90.2%).

MS m/z(ESI)：151.0[M-17]。

Fourth step

5-fluoro-2, 3-dihydrobenzofuran-6-carbaldehyde 13e

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 and reacted at room temperature for 2 hours. The reaction was quenched by addition of saturated sodium thiosulfate (20 mL) and saturated sodium bicarbonate (20 mL) in an ice bath, and extracted with methylene chloride (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 13e (600 mg, yield: 88.2%).

MS m/z(ESI)：167.1[M+1]。

Fifth step

(R) -N- ((5-fluoro-2, 3-dihydrobenzofuran-6-yl) methylen-2-methylpropane-2-sulfinamide 13f

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

MS m/z(ESI)：270.0[M+1]。

Sixth step

(R) -N- ((S) -1- (5-fluoro-2, 3-dihydrobenzofuran-6-yl) ethyl) -2-methylpropane-2-sulfinamide 13g

To a solution of crude compound 13f (973.0 mg,3.6 mmol) in dry dichloromethane (25 mL) was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (2.7 mL,8.0 mmol) at-50 ℃. The reaction was carried out at room temperature for 2 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (30 mL) was added and extracted with methylene chloride (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 13g (610.0 mg, yield: 59.1%).

MS m/z(ESI)：286.0[M+1]。

Seventh step

(S) -1- (5-fluoro-2, 3-dihydrobenzofuran-6-yl) ethylamine hydrochloride 13h

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

MS m/z(ESI)：164.9[M-16]。

Eighth step

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 carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 25% (v/v) to 95% (v/v) over 17.1 min, detection wavelength 214&254 nm) to afford the title product 13 (85.0 mg, yield: 25.5%).

MS m/z(ESI)：334.1[M+1]。

¹ H NMR(500MHz,DMSO-d6)δ9.76(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)。

Example 14

(S) -6- ((1- (2, 3-Dihydrobenzofuran-6-yl) ethyl) amino) -3-isopropyl-5-methylpyrimidine-2, 4 (1H, 3H) -dione 14

First step

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

Metallic sodium (431.3 mg,18.0 mmol) was dissolved in anhydrous methanol (25 mL). 1-isopropyl urea 14a (1.1 g,10.0mmol, prepared by the method of synthesizing intermediate 2a at page 14 of the specification of patent application "CN 1100698415A") and dimethyl 2-methylmalonate 14b (2.2 g,15.1mmol, shanghai Bi de technology Co., ltd.) were added. The reaction was heated at reflux for 40 hours. After the reaction solution was cooled, concentrated hydrochloric acid was added dropwise to adjust the pH of the solution to 5. The residue was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B to give the title product 14c (1.5 g, yield: 81.5%).

MS m/z(ESI)：185.1[M+1]。

Second step

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

To compound 14c (1.3 g,6.8 mmol) and benzyltrimethylammonium chloride (2.0 g,9.6mmol, shanghai taitant technologies Co., ltd.) was added phosphorus oxychloride (3 mL). The reaction was carried out at 50℃for 16 hours under nitrogen atmosphere. Concentrated under reduced pressure, dichloromethane (20 mL) was added and washed twice with water. The organic phase was collected, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 14d (790 mg, yield: 57.5%).

MS m/z(ESI)：203.1[M+1]。

Third step

Crude compound 4d (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 reaction was carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 45% (v/v) to 95% (v/v) over 20.1 min, detection wavelength 214&254 nm) to give the title product 14 (10.6 mg, yield: 6.0%).

MS m/z(ESI)：330.2[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.24(brs,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)。

Example 15

(S) -6- ((1- (5-fluoro-2, 3-dihydrobenzofuran-6-yl) ethyl) amino) -3-isopropyl-5-methylpyrimidine-2, 4 (1H, 3H) -dione 15

First step

5-fluorobenzofuran-6-carboxylic acid methyl ester 15b

6-bromo-5-fluorobenzofuran 15a (3.20 g,14.88mmol, prepared by the method of synthesis of intermediate A1.2b on page 36 of the specification of patent application "WO2017219948A 1") was dissolved in methanol (50 mL), and [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (1.26 g,1.49 mmol) and N, N-diisopropylethylamine (3.01 g,29.75 mmol) were added, carbon monoxide gas was replaced three times, and stirred at 70℃for 40 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 15b (1.50 g, yield: 51.9%).

MS m/z(ESI)：194.8[M+1]。

Second step

5-fluoro-2, 3-dihydrobenzofuran-6-carboxylic acid methyl ester 15c

Compound 15b (1.50 g,7.73 mmol) was dissolved in methanol (50 mL), 10% palladium on carbon hydrogenation catalyst (wet) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 16 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 15c (1.37 g, yield: 90.4%).

MS m/z(ESI)：196.8[M+1]。

Third step

(5-fluoro-2, 3-dihydrobenzofuran-6-yl) methanol 15d

Compound 15c (1.37 g,7.0 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL), and a 2M solution of lithium borohydride in tetrahydrofuran (34.9 mL,69.8 mmol) was added dropwise and reacted at room temperature for 16 hours. The reaction was quenched by addition of methanol (5 mL) in an ice bath, the pH of the solution was adjusted to 6 with 1M hydrochloric acid, and extracted with ethyl acetate (30 mL. Times.2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 15d (1.05 g, yield: 89.4%).

MS m/z(ESI)：190.0[M+22]。

Fourth step

5-fluoro-2, 3-dihydrobenzofuran-6-carbaldehyde 15e

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 and reacted at room temperature for 2 hours. The reaction was quenched by addition of saturated sodium thiosulfate (20 mL) and saturated sodium bicarbonate (20 mL) in an ice bath, and extracted with methylene chloride (30 mL. Times.2). The organic phases were combined and dried over anhydrous sodium sulfate. The residue obtained was purified by silica gel column chromatography with eluent system A, followed by filtration, concentration under reduced pressure, to give the title product 15e (1.03 g, yield: 99.3%).

MS m/z(ESI)：167.0[M+1]。

Fifth step

(R) -N- ((5-fluoro-2, 3-dihydrobenzofuran-6-yl) methylen-2-methylpropane-2-sulfinamide 15f

Compound 15e (1.30 g,7.82 mmol) and (R) -2-methylpropane-2-sulfinamide (1.42 g,11.72mmol, shanghai Pichia technology) were dissolved in dichloromethane (20 mL). Cesium carbonate (1.58 g,14.09 mmol) was added and the reaction stirred for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 15f (2.80 g), which was used in the next step without purification.

MS m/z(ESI)：270.0[M+1]。

Sixth step

(R) -N- ((S) -1- (5-fluoro-2, 3-dihydrobenzofuran-6-yl) ethyl) -2-methylpropane-2-sulfinamide 15g

To a solution of crude compound 15f (2.80 g,10.40 mmol) in anhydrous dichloromethane (45 mL) at-50deg.C was added dropwise a solution of 3M methyl magnesium bromide in methyltetrahydrofuran (6.93 mL,20.79 mmol). The reaction was carried out at room temperature for 2 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride (30 mL) was added and extracted with methylene chloride (30 mL. Times.2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by high performance liquid chromatography (Boston Phlex C18X 30mm,5 μm, elution system: water (10 mmol ammonium bicarbonate), acetonitrile, 20-95% acetonitrile, 20 min gradient elution, flow rate: 30 mL/min) to give the title product 15g (1.50 g, yield: 50.56%).

MS m/z(ESI)：286.0[M+1]。

Seventh step

(S) -1- (5-fluoro-2, 3-dihydrobenzofuran-6-yl) ethylamine hydrochloride for 15h

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

MS m/z(ESI)：164.9[M-16]。

Eighth step

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 carried out for 2 hours at 130℃with microwaves. Concentrated under reduced pressure and purified by high performance liquid chromatography (Welch Ultimate XB-C18,5 μm,30 mM. Times.150 mM, elution system: water (10 mM ammonium bicarbonate), acetonitrile rising from 25% (v/v) to 95% (v/v) over 18.1 min, detection wavelength 214&254 nm) to give the title product 15 (10.0 mg, yield: 5.8%).

MS m/z(ESI)：348.1[M+1]。

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)。

Biological evaluation

The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1 inhibition effect of the compounds of the present disclosure on myosin ATPase Activity

The following methods were used to determine the inhibitory effect of the compounds of the present disclosure on myosin atpase activity, and the experimental methods are briefly described below:

1. Experimental material and instrument

1. Myocardial Actin (cardiotec action) (Cytoskeleton, AD 99)

2. Myosin motor protein S1 Fragment (Myosin Motor Protein S Fragment) (Cytoskeleton, CS-MYS 03)

3、ATP(Sigma，A7699-1G)

4、UltraPure ^TM 1M Tris-HCI buffer, pH 7.5 (Thermo, 15567027)

5、CytoPhos ^TM Phosphate detection biological reagent box (Phosphate Assay Biochem Kit) (Cytoskeleton, BK 054)

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

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

8、EGTA(Sigma，E3889-100G)

9. 96 well plate (Corning, 3697)

10. U-shaped bottom 96 well plate (Corning 3795)

11. Enzyme label instrument (BMG, PHERAstar)

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

2. Experimental procedure

Myocardial actin 1.61. Mu.M, myosin motor protein S1 fragment 0.07. Mu.M was mixed with different concentrations of small molecule compound (initial 100. Mu.M, 3-fold gradient 9 concentrations) and incubated at 37℃for 1 hour. ATP 120. Mu.M was added and incubated at 37℃for 2 hours. Finally, adding CytoPhos into each hole ^TM The detection solution (70. Mu.L/well) in the phosphate detection biological kit was incubated at room temperature for 10min. Reading OD value of 650nM wavelength with enzyme label instrument, calculating Pi amount according to standard curve, processing data with GraphPad software, plotting inhibition curve according to compound concentration and corresponding inhibition rate, and calculating compound concentration (IC) when inhibition rate reaches 50% ₅₀ Values. The experimental results are detailed in table 1.

TABLE 1 inhibitory Activity of the compounds of the present disclosure against myosin ATPase

Examples numbering	IC ₅₀ (μM)
1	0.13
2	0.94
3	0.13
4	0.24
5	0.04
6	1.41
7	1.94
8	8.28
9	3.67
10	0.10
11	0.57
12	0.78

13	0.66
14	4.55
15	2.31

Conclusion: the compounds of the present disclosure have inhibitory effects on myosin atpase.

Test example 2: pharmacokinetic evaluation of the compounds of the present disclosure in SD rats

1. Summary

SD rats are taken as test animals, and the LC/MS/MS method is used for measuring the drug concentration in plasma at different times after the SD rats are subjected to gastric lavage and intravenous injection of the compound to be tested. Pharmacokinetic behavior of the compounds of the present disclosure in SD rats was studied and their pharmacokinetic profile was assessed.

2. Experimental protocol

2.1 Experimental drugs

EXAMPLE 9 Compounds MYK-461Example 1 of WO2014205223A 1), compound ACompound 107 of WO2014205223 A1).

2.2 laboratory animals

SD rat drug substitution of the compound of example 9: SD rats were divided into 2 groups of 4 on average, each group being provided by the Vitrenia areolata laboratory animal Limited company, producing license numbers: SCXK (Zhe) 2019-0001.

SD rat drug substitution of Compound MYK-461: SD rats were divided into 2 groups of 8, each of which was provided by Shanghai Meidixi biological medicine Co., ltd.

SD rat drug substitution of compound a: SD rats were divided into 2 groups of 4 on average, each group being provided by the Vitrenia areolata laboratory animal Limited company, producing license numbers: SCXK (Zhe) 2019-0001.

2.3 pharmaceutical formulation

A certain amount of the compound of example 9 was weighed, and 5% dmso, 5% tween 80 and 90% physiological saline were added to prepare a colorless clear solution.

Weighing a certain amount of compound MYK-461, and adding 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare colorless clear solution.

Weighing a certain amount of compound A, and adding 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare colorless clear solution.

2.4 administration of drugs

SD rats were administered by gastric lavage and intravenous injection after one night, the doses were 2mg/kg and 1mg/kg, respectively, and the volumes were 10mL/kg and 5mL/kg, respectively.

3. Operation of

The intragastric administration group is subjected to blood sampling of 0.2mL from the eye socket before and after administration for 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h, 11.0h and 24.0h, placed in an EDTA-K2 anticoagulation test tube, centrifuged at 10000rpm for 1min (4 ℃), plasma is separated in 1h, and the blood is stored at-20 ℃ for testing. The blood collection to centrifugation process was operated under ice bath conditions. The feed was fed 2h after administration.

The intravenous administration group was subjected to blood sampling 5min, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 11.0h and 24.0h before and after administration, and the same-gastric administration group was treated.

Determining the content of a compound to be detected in the plasma of SD rats after the administration of drugs by intragastric administration and intravenous injection at different concentrations: SD rat plasma at each time after administration was taken 20. Mu.L, 50. Mu.L of an internal standard solution (internal standard of the compound of example 9: verapamil 100ng/mL; internal standard of the compound MYK-461: warfarin 100ng/mL; internal standard of the compound A: tolbutamide 100 ng/mL), acetonitrile 200. Mu.L, vortex-mixed for 5min, centrifuged for 10min (3700 rpm), and plasma samples were taken 0.5. Mu.L of supernatant for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 2 pharmacokinetic parameters of the presently disclosed compounds in SD rats

Conclusion: the compound of example 9 of the present disclosure is well absorbed in the drug substitution in SD rats. In addition, the compound of example 9 of the present disclosure is a compound that is less than T of compound MYK-461 and compound A _1/2 Has obvious shortening. Compound MYK-461 is due to T _1/2 Longer, more serious accumulation in clinic, and the clinical administration needs to be continuously regulated, thus increasing the administration risk. Shortening T _1/2 Can reduce or avoid clinical medicine accumulation in vivo, is beneficial to the determination of the dosage of the medicine for patients and avoids the risk caused by accumulation. It is apparent that example 9 of the present disclosure has a significant pharmacokinetic advantage over compounds MYK-461 and compound a.

Test example 3: pharmacokinetic evaluation of compounds of the present disclosure in cynomolgus monkeys

1. Summary

The method is characterized in that the cynomolgus monkey is taken as a tested animal, and the LC/MS/MS method is used for measuring the concentration of the drug in the blood plasma at different moments after the compound to be tested is administrated by the stomach infusion and intravenous injection of the cynomolgus monkey. Pharmacokinetic behavior of the compounds of the present disclosure in cynomolgus monkeys was studied and their pharmacokinetic profile was assessed.

2. Experimental protocol

2.1 Experimental drugs

Example 9 compound, compound MYK-461.

2.2 laboratory animals

Cynomolgus monkey drug substitution of the compound of example 9: 8 cynomolgus monkeys, each half of which is equally divided into 2 groups of 4, each group being provided by Shanghai Meidixi biological medicine Co.

Cynomolgus monkey drug generation of compound MYK-461: the cynomolgus monkeys were divided into 2 groups of 6 males on average, each group of 3, supplied by Shanghai Meidixi biological medicine Co.

2.3 pharmaceutical formulation

An amount of the compound of example 9 was weighed, and 5% dmso, 20% pg, 20% peg400, and 55% physiological saline were added to prepare Cheng Chengming solution.

A certain amount of compound MYK-461 is weighed, and 5% DMSO, 20% PG, 20% PEG400 and 55% physiological saline are added to prepare Cheng Chengming solution.

2.4 administration of drugs

The cynomolgus monkey is respectively infused into the stomach and injected intravenously after being fasted for one night, the administration doses are respectively 2mg/kg and 0.5mg/kg, and the administration volumes are respectively 5mL/kg and 2mL/kg.

3. Operation of

The gastric lavage administration group is used for taking 1.0mL of blood from the vein of forelimbs before and after 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h, placing the blood into an EDTA-K2 anticoagulation test tube, centrifuging at 10000rpm for 5min (4 ℃), separating plasma in 1h, and preserving at-80 ℃ to be tested. The blood collection to centrifugation process was operated under ice bath conditions. The medicine is taken after 3 hours of administration and can be drunk freely.

The intravenous administration group was subjected to blood sampling 5min, 0.25h, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 12.0h and 24.0h before and after administration, and the same-gastric administration group was treated.

Determining the content of a compound to be detected in the blood plasma of the cynomolgus monkey after the medicine with different concentrations is infused into the stomach and is administrated by intravenous injection: at each time after administration, 20. Mu.L of cynomolgus monkey plasma was taken, an internal standard solution (internal standard of the compound of example 9: warfarin 100ng/mL; internal standard of the compound MYK-461: camptothecin 100 ng/mL) was added, 400. Mu.L of methanol was vortexed and mixed for 1min, centrifuged for 7min (centrifugal force 18000 g), and 4. Mu.L of the supernatant was taken from the plasma sample for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 3 pharmacokinetic parameters of the compounds of the present disclosure in cynomolgus monkeys

Conclusion: the compound of example 9 of the present disclosure is well absorbed in the cynomolgus monkey in vivo. In addition, T of the compound of example 9 of the present disclosure _1/2 Has obvious shortening. Compound MYK-461 is due to T _1/2 Longer, more serious accumulation in clinic, and the clinical administration needs to be continuously regulated, thus increasing the administration risk. Shortening T _1/2 Can reduce or avoid clinical medicine accumulation in vivo, is beneficial to the determination of the dosage of the medicine for patients and avoids the risk caused by accumulation. It is apparent that the compound of example 9 of the present disclosure has a significant pharmacokinetic advantage over the compound MYK-461.

Test example 4: evaluation of toxicology of compound of the present disclosure for 14 days of gastric lavage repeat administration to Beagle dogs

1. Summary

The concentration of the drug in the plasma at various times after the administration of the test compound by gavage to Beagle dogs was determined using LC/MS method using Beagle dogs as the test animals. The compounds of the present disclosure were studied for their pharmacokinetic behavior in Beagle dogs and their pharmacokinetic profile was evaluated.

2. Experimental protocol

2.1 test drug

Example 9 compound, compound MYK-461.

2.2 laboratory animals

Beagle dogs were 16, each male and female half, and were grouped into 4 groups of 4, each, supplied by Suzhou West mountain laboratory animals Inc.

2.3 pharmaceutical formulation

An amount of the compound of example 9 was weighed and added to 15% peg400 and 85% (10%TPGS+1%HPMC K100LV) to make a translucent solution.

Weighing a certain amount of compound MYK-461, and adding 0.5% MC to prepare a semitransparent solution.

2.4 administration of drugs

The compound of example 9 was administered by gavage at 1mg/kg and 3mg/kg, respectively, and at 5mL/kg.

The administration dose of the compound MYK-461 is 0.3mg/kg and 1mg/kg respectively, and the administration volumes are 5mL/kg.

3. Operation of

0.2mL of blood is collected from the eye sockets before and after the administration of 0.5h, 1.0h, 2.0h, 4.0h, 6.0h, 8.0h, 12.0h and 24.0h on the 1 st day, 0.5h, 1.0h, 2.0h, 4.0h, 8.0h, 11.0h and 24.0h on the 7 th day and 14 th day, 0.2mL of blood is collected from the forelimb veins before and after the administration of blood, and blood plasma is separated and stored at-20 ℃ to be tested. The blood collection process was operated under ice bath conditions.

Determination of the content of the test compounds in Beagle canine plasma after gavage administration of different concentrations of the drug: 20. Mu.L of Beagle canine plasma at each time after administration was taken, 20. Mu.L of an internal standard solution (vortioxetine, supplied by the company of Biotechnology Co., st.C.), 400. Mu.L of methanol, vortex mixing for 10min, centrifugation for 10min (centrifugal force 2600 g), and 0.5. Mu.L of the supernatant was taken from the plasma sample for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

TABLE 4 toxicological kinetic parameters of the compounds of the present disclosure in Beagle dogs

Conclusion: the accumulation of the compound of example 9 of the present disclosure in Beagle dogs after 14 days of gastric lavage repeated administration was not evident, whereas the accumulation of the compound MYK-461 in Beagle dogs was severe, increasing the risk of administration. It is apparent that the compound of example 9 of the present disclosure has a significant pharmacokinetic advantage over the compound MYK-461.

Claims

A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

ring A is

Ring B is cycloalkyl or a heterocyclic group containing a heteroatom selected from one of nitrogen atom, oxygen atom and sulfur atom;

each R is ¹ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxy;

X ¹ 、X ² And X ³ Identical or different and are each independently a nitrogen atom or CR ^a ；

Each R is ^a Identical or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, 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 And NR ⁹ R ¹⁰ ；

R ² Selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxy;

R ³ is a hydrogen atom;

R ⁴ selected from the group consisting of a hydrogen atom, a halogen, and an alkyl group;

R ⁰ is alkyl orWherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, alkoxy, haloalkoxy, cyano, amino, nitro and hydroxy;

L ₁ is a bond or (CH) ₂ ) _r ；

Ring D is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is ⁵ Identical or different and are each independently selected from the group consisting of hydrogen, 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, - (CH) ₂ ) _r -cycloalkyl, heterocyclyl, - (CH) ₂ ) _r -heterocyclyl, aryl, - (CH) ₂ ) _r -aryl, heteroaryl and- (CH) ₂ ) _r -heteroaryl;

R ⁶ selected from hydrogen atomsSon, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein each of said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is 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;

R ⁷ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ⁸ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁹ and R is ¹⁰ Identical or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, - (CH) ₂ ) _r -cycloalkyl, heterocyclyl, - (CH) ₂ ) _r -heterocyclyl, aryl, - (CH) ₂ ) _r -aryl, heteroaryl and- (CH) ₂ ) _r -heteroaryl;

or R is ⁹ And R is ¹⁰ Together with the nitrogen atom to which they are attached, form a heterocyclic group, which 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;

t is 0, 1, 2, 3 or 4;

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

s is 0, 1, 2, 3, 4, 5 or 6; and is also provided with

p is 0, 1 or 2.
The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (I-1):

wherein:

ring A, R ⁰ 、R ² 、R ³ And R is ⁴ As defined in claim 1.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring a is selected from

Wherein the ring B, R ¹ 、R ^a And t is as defined in claim 1.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 3, which is a compound represented by the general formula (II-1) or the general formula (II-2):

wherein:

ring B, R ^a 、R ⁰ 、R ¹ 、R ² 、R ³ 、R ⁴ And t is as defined in claim 1.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by the general formula (III-1) or the general formula (III-2):

wherein:

ring B, R ^a 、R ⁰ 、R ¹ 、R ² 、R ³ 、R ⁴ And t is as defined in claim 1.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R ⁰ Is C _1-6 Alkyl or 3 to 6 membered heterocyclyl; preferably, R ⁰ Is isopropyl or tetrahydropyranyl.
A compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring B is a 4 to 6 membered cycloalkyl group or a 4 to 6 membered heterocyclyl group containing a heteroatom selected from one of a nitrogen atom, an oxygen atom and a sulfur atom; preferably, ring B is selected from cyclopentyl, cyclobutyl, cyclohexyl and tetrahydrofuranyl.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein each R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl, C _1-6 Alkoxy, C _1-6 Haloalkoxy, C _1-6 Hydroxyalkyl, amino, and hydroxyl; preferably, R ¹ Is a hydrogen atom.
A compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8Wherein each R is ^a Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl and C _1-6 Haloalkoxy groups; preferably, each R ^a The same or different, and are each independently a hydrogen atom or a halogen.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ² Selected from halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and C _1-6 A hydroxyalkyl group; preferably, R ² Is C _1-6 An alkyl group; more preferably, R ² Is methyl.
A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ⁴ Selected from hydrogen atoms, halogens and C _1-6 An alkyl group; preferably, R ⁴ Is a hydrogen atom or C _1-6 An alkyl group; more preferably, R ⁴ Is a hydrogen atom.
A compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the following compounds:
a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises:

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

wherein:

R ^w a leaving group, preferably halogen, more preferably a chlorine atom;

ring A, R ⁰ 、R ² 、R ³ And R is ⁴ As defined in claim 1.
A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 for the preparation of a Myosin (Myosin) inhibitor.
Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for the treatment of a disease or condition selected from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, restrictive cardiomyopathy, diastolic dysfunction, hypertrophic Cardiomyopathy (HCM), normal ejection fraction heart failure (HFpEF), ejection fraction intermediate heart failure (HFmREF), valve disease, aortic valve stenosis, inflammatory cardiomyopathy, taylor endocarditis, myocardial endocardial fibrosis, invasive cardiomyopathy, hemochromatosis, fabry's disease, glycogen storage disease, congenital heart disease, fabry tetray disease, left ventricular hypertrophy, refractory angina and chagas disease; preferably selected from ischemic heart disease, limited cardiomyopathy, hypertrophic Cardiomyopathy (HCM), inflammatory cardiomyopathy, invasive cardiomyopathy, congenital heart disease and left ventricular hypertrophy; more preferably Hypertrophic Cardiomyopathy (HCM); most preferred are non-obstructive hypertrophic cardiomyopathy (nHCM) or obstructive hypertrophic cardiomyopathy (oHCM).