Compound capable of treating atrial fibrillation

Abstract

A compound capable of treating atrial fibrillation, which is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compound can be applied to drugs for treating diseases such as atrial fibrillation or arrhythmia.

Description

Compounds for treating atrial fibrillation TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical compounds, and particularly relates to a pharmaceutical compound for treating atrial fibrillation. BACKGROUND

[0002] Atrial fibrillation (AF), also known as atrial flutter, is a supraventricular tachyarrhythmia with uncoordinated atrial electrical activation and ineffective atrial contraction. The diagnosis of atrial fibrillation is usually electrocardiographic, and single-lead electrocardiogram (≥ 30 s) or grade II lead electrocardiogram (≥ 10 s) shows that P wave disappears, and is replaced by irregularly sized, shaped and timed flutter waves (f waves), and RR interval is absolutely irregular, which can be diagnosed as atrial fibrillation. Atrial fibrillation is a common persistent arrhythmia, and the most common symptoms are palpitations, decreased exercise tolerance and chest discomfort, and some patients may also have dizziness, anxiety and increased urine output (Chinese Guidelines for Diagnosis and Treatment of Atrial Fibrillation. Chinese Journal of Cardiovascular Disease, 2023, 51(6): 572-618). Combined with severe organic heart disease, such as ventricular hypertrophy and dilatation, valvular damage, old myocardial infarction, hypertrophic cardiomyopathy, etc., the impact on heart function is more obvious, and it is often the main reason for inducing and aggravating heart failure. According to the duration of atrial fibrillation, the difficulty of converting and long-term maintaining sinus rhythm, and the treatment strategy selection, atrial fibrillation is divided into paroxysmal atrial fibrillation, persistent atrial fibrillation, persistent atrial fibrillation and permanent atrial fibrillation. Atrial fibrillation not only causes discomfort, but also can cause thrombosis, stroke, myocardial infarction, cardiac arrest and heart failure, etc. Complications, causing patients to be disabled, repeated hospitalization, increasing the risk of death, greatly reducing the quality of life of patients, affecting the lives of millions of people worldwide, and bringing certain economic burden to the society (Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS) [J]. European Heart Journal, 2021, Feb 1, 42(5): 373-498).

[0003] The incidence of atrial fibrillation increases with age, and the proportion of atrial fibrillation patients in people over 80 years old is almost 10%. With the extension of the life span of the general population and the increase of the diagnosis of atrial fibrillation, its prevalence is gradually increasing. According to the research data of global burden of disease (GBD), the number of patients per 100,000 people in North America is about 2364, in Western Europe is about 1880, in Eastern Europe is about 1758, and in East Asia is about 974 (Brundel BJJM, Ai X, Hills MT, et al. Atrial fibrillation [J]. Nature Reviews Disease Primers, 2022, Apr 7, 8(1): 21). A survey of 14339 respondents in China showed that the age-standardized prevalence of atrial fibrillation in Chinese adults was about 1.6%, and the prevalence in men, women, urban and rural areas was 1.7%, 1.4%, 1.6% and 1.7% respectively, which increased with age and had significant geographical differences, with a higher prevalence in central regions than in western and eastern regions (Shaobo Shi, Yanhong T, Qingyan Z, et al. Prevalence and risk of atrial fibrillation in China: A national cross-sectional epidemiological study [J]. The Lancet Regional Health-Western Pacific, 2022, Apr 11: 23). Hypertension, obesity, diabetes, hyperthyroidism, acute coronary syndrome, pulmonary embolism and genetic factors are important predisposing factors for atrial fibrillation, and infection, alcoholism, diarrhea, electrolyte imbalance, short sleep duration and other factors are common factors for inducing atrial fibrillation (Sagris M, Vardas EP, Theofilis P, et al. Atrial fibrillation: Pathogenesis, predisposing factors, and genetics [J]. International Journal of Molecular Sciences, 2021, 23(1): 6). These factors often act alone or in combination on the myocardium, stimulate the myocardium to produce reversible or irreversible changes, and thus participate in the occurrence and development of atrial fibrillation.

[0004] Atrial fibrillation is a disease with high morbidity and mortality. Rhythm control and rate control are two main therapeutic measures to improve the symptoms of patients with atrial fibrillation. Rhythm control refers to the restoration and maintenance of sinus rhythm. Antiarrhythmic drug therapy for restoring and maintaining sinus rhythm is the main therapeutic measure to improve the symptoms of patients with atrial fibrillation. Drugs for maintaining sinus rhythm include class Ic (sodium channel blockers such as propafenone) and class III antiarrhythmic drugs (potassium channel blockers such as amiodarone, dronedarone, sotalol, etc.). They can achieve the purpose of cardioversion by slowing the conduction velocity and / or prolonging the effective refractory period to terminate reentrant excitation.

[0005] Propafenone has been used in clinical practice for more than 40 years. It is mainly used for the conversion of newly developed atrial fibrillation. Its efficacy is poor for persistent atrial fibrillation and atrial flutter. Propafenone can significantly block sodium channels, significantly reduce the depolarization rate of myocardial cells, and has β receptor and potassium channel blocking effects. It also has a weak calcium channel blocking effect. To date, propafenone is still a first-line drug in clinical practice. However, due to its safety concerns, the actual dosage used is relatively low. Propafenone has a rapid effect, with an onset of action at 2-6 h after oral administration and 0.5-2.0 h after intravenous injection, with a conversion rate of 41%-91%. Common adverse reactions of propafenone include intraventricular block, atrial flutter with rapid ventricular rate, ventricular tachycardia, hypotension, and bradycardia after conversion. It should be used with caution in patients with organic heart disease, heart failure, or severe obstructive pulmonary disease (Chinese Society of Cardiac Electrophysiology and Pacing, Chinese Society of Cardiologists, Chinese Alliance of Atrial Fibrillation Center, Expert Working Committee on Prevention and Treatment of Atrial Fibrillation. Atrial fibrillation: current understanding and treatment recommendations (2021) [J]. Chinese Journal of Arrhythmia, 2022, 26(1): 15-88).

[0006] Amiodarone is the most effective antiarrhythmic drug, suitable for patients with atrial fibrillation with various cardiac comorbidities. Amiodarone is an iodine-containing compound, along with its active metabolite N-desmethylamiodarone, blocks various ion channels on cardiomyocytes by non-competitively antagonizing α and β receptors. However, due to a series of adverse reactions of amiodarone, it is not suitable for long-term use as a first-choice drug, and in the case of other antiarrhythmic drugs, amiodarone should be avoided as much as possible. The relative risk of adverse reactions of amiodarone is relatively high, the main reason is that it has high lipid solubility, large distribution volume, and is easy to deposit in the lung, liver, kidney, bone marrow, heart, fat and other parts. Therefore, whether oral or intravenous administration can cause varying degrees of liver damage, slow arrhythmia, pulmonary interstitial fibrosis, corneal pigmentation, thyroid function, and hematological abnormalities, and other adverse reactions (Moroi MK, Ruzie HM, Aboujamous NM, et al. Dataset for amiodarone adverse events compared to placebo using data from randomized controlled trials [J]. Data in Brief, 2020, 28: 104835). Pulmonary toxicity of amiodarone is one of the most serious adverse reactions, in the English instructions for amiodarone, it is clear that in some patients with ventricular arrhythmias, 400 mg of amiodarone per day can cause up to 10% to 17% of pulmonary toxicity, about 10% of patients with pulmonary toxicity will be fatal, and a black box warning is given for amiodarone (https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2010 / 018972s042lbl.pdf).

[0007] Dronedarone is a multi-channel blocker that can inhibit sodium, potassium and calcium ion channels, and also has a β receptor antagonism, which can be used for paroxysmal and persistent atrial fibrillation or atrial flutter patients to maintain sinus rhythm. Dronedarone belongs to benzofuran derivatives, which does not contain iodine in its chemical structure, has similar pharmacological properties as amiodarone, and is less effective than amiodarone in rhythm control, but can reduce thyroid toxicity, reduce lipophilicity, shorten half-life, and reduce organ toxicity caused by drug accumulation in organs such as lungs, eyes and thyroid. It is considered to be a drug with efficacy and safety for atrial fibrillation treatment, and was listed in the United States and Europe in 2009. Improving patient prognosis is one of the main reasons why dronedarone is approved for rhythm control in non-permanent atrial fibrillation patients. A multi-center randomized placebo-controlled study (dronedarone effect on cardiovascular events in atrial fibrillation patients) included 4628 patients with paroxysmal or persistent atrial fibrillation and atrial flutter, and the endpoint event was hospitalization or death of patients for any reason. After 21 months of follow-up, the results showed that dronedarone can significantly improve the end point of cardiovascular hospitalization or all-cause death in atrial fibrillation patients. On the basis of controlling ventricular rate and antithrombotic therapy, dronedarone can significantly reduce the mortality rate of cardiovascular diseases in atrial fibrillation patients (Hohnloser SH, Eickels MV, Christophe G, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation [J]. The New England Journal of Medicine, 2009, 360(7): 668-678). The adverse reactions of dronedarone are related to the dose, and the most common adverse reactions are gastrointestinal reactions, causing bradycardia and QT interval prolongation. In 2011, FDA reported a case report of dronedarone causing severe liver damage and even liver failure requiring liver transplantation (Xiaodong X, Donghui Y. Status and Prospect of Dronedarone in Treating Atrial Fibrillation [J]. Adv Cardiovasc Dis, July 2016, 37(4): 368-371). Due to the first-pass effect of the liver, the bioavailability of dronedarone is low, which is 4% without high-fat diet and 15% with high-fat diet.

[0008] Atrial fibrillation patients should first consider the safety of drugs when undergoing long-term maintenance of sinus rhythm therapy, and then consider effectiveness. Based on the current overall treatment situation, there are cases of single use of therapeutic drugs and insufficient treatment rate, and it is urgent to apply safer and more effective atrial fibrillation treatment drugs to clinical practice. SUMMARY

[0009] The purpose of the present application is to provide a new class of compounds having efficacy on atrial fibrillation on the basis of the prior art, which have better reliability and safety in the treatment of atrial fibrillation.

[0010] The purpose of the present application can be achieved by the following measures:

[0011] a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0012] wherein,

[0013] R 1 is selected from hydrogen or the following groups which are substituted or unsubstituted: C 1～7 alkyl, C 3～8 cycloalkyl or C 2～6 heterocycloalkyl;

[0014] R 2 is selected from hydrogen or the following groups which are substituted or unsubstituted: C 1～7 alkyl, C 3～8 cycloalkyl or C 2～6 heterocycloalkyl;

[0015] or R 1 and R 2 are connected to the end of Z to form a substituted or unsubstituted heterocycle;

[0016] Z is selected from substituted or unsubstituted C 2～5 alkylene;

[0017] X is selected from O or methylene;

[0018] R 3 or R 5 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, C 1～3 alkyl, C 1～3 substituted alkyl, C 1～3 substituted amino, C 1～3 alkoxy or C 1～3 substituted alkoxy;

[0019] R 4 or R 6 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, C 1～3 alkyl, C 1～3 substituted alkyl, C 1～3 substituted amino, C 1～3 alkoxy or C 1～3 substituted alkoxy;

[0020] R 7 is selected from hydroxyl, halogen, amino, carboxyl, substituted or unsubstituted C1～8 alkyl, substituted or non-substituted C 3～8 cycloalkyl, substituted or non-substituted C 1～4 alkoxy, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 one of the alkylene groups;

[0021] A 1 selected from N or C-R 8 , R 8 selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 one of the alkylene groups;

[0022] A 2 selected from N or C-R 9 , R 9 selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 one of the alkylene groups;

[0023] A 3 selected from N or C-R 10 , R 10 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 alkylene;

[0024] A 4 selected from N or C-R 11 , R 11 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 alkylene;

[0025] A 5 selected from N or C, A 6 is selected from C or N, and A 5 is selected from C or N, and A 6 are not simultaneously N or C;

[0026] and, when R 1 and R 2 are both C 3～6 alkyl, at least one of A 1 , A 2 , A 3 and A 4 is N, or R8 9 10 11 at least one of R 1～3 1～3 3 4 5 6 at least one of R 7

[0027] in R 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 one or more of the substituents in R 1-3 1-3 1-3 3-6 3-6 3-6 1-3 1-3 1-3

[0028] in formula (I), the six-membered ring in which A 1 2 3 4 5 6 5 6

[0029] in a preferred embodiment, A 5 6 5 6 i.e. the compounds of the application are preferably selected from compounds of formula (II) or (III), or a pharmaceutically acceptable salt thereof,​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0030] In a preferred embodiment, R 1 is selected from hydrogen or substituted or unsubstituted C 1～7 alkyl, C 3～6 cycloalkyl or C 2～6 heterocycloalkyl.

[0031] In a more preferred embodiment, R 1 is selected from hydrogen or substituted or unsubstituted C 1～7 alkyl, C 3～6 cycloalkyl, thiazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, piperidinyl, tetrahydrothiophenyl or hexahydropyrimidinyl.

[0032] In an even more preferred embodiment, R 1 or R 2 are each independently selected from hydrogen or substituted or unsubstituted C 1～2 alkyl, C7alkyl, C 3～6 cycloalkyl or C 2～6 heterocycloalkyl; or

[0033] R 1 or R 2 are each independently selected from hydrogen or substituted or unsubstituted C 1～7 alkyl, C 3～8 cycloalkyl or C 2～6 heterocycloalkyl, and R 1 and R 2 are not both C 3～6 alkyl; or

[0034] R 1 or R 2 are each independently selected from hydrogen or substituted or unsubstituted C 1～7 alkyl, C 3～8 cycloalkyl or C 2～6 heterocycloalkyl, and when R 1 and R 2 are each C 3～6 alkyl, at least one of A 1 , A 2 , A 3 and A 4 is N, or at least one of R 8 , R 9 , R 10 and R 11 is nitro, amino, cyano, C 1～3 substituted amino or C 1～3 alkylsulfonylamino, or R3 、R 4 、R 5 and R 6 At least one of them is cyano, or Z or R 7 Contains substituents.

[0035] In a preferred embodiment, R 2 is selected from hydrogen or substituted or unsubstituted groups: C 1～7 Alkyl, C 3～6 Cycloalkyl or C 2～6 Heterocycloalkyl.

[0036] In a more preferred embodiment, R 2 is selected from hydrogen or substituted or unsubstituted groups: C 1～7 Alkyl, C 3～6 Cycloalkyl, thiazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, piperidinyl, tetrahydrothiophenyl or hexahydropyrimidinyl.

[0037] In a preferred embodiment, R 1 With R 2 The ends of the substituted or unsubstituted C 2～6 Heterocycloalkyl.

[0038] In a more preferred embodiment, R 1 With R 2 The ends of the alkylene groups are connected to form a substituted or unsubstituted group consisting of thiazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, piperidinyl, tetrahydrothiophenyl or hexahydropyrimidinyl.

[0039] In a preferred embodiment, R 1 、R 2 or the substituent in Z is selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 alkoxy, phenyl or pyridyl.

[0040] R 1 With R 2 The substituents in the heterocyclic ring formed by connecting are derived from R 1 and R 2 The substituents in , therefore the substituents therein are preferably deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 1-3 Alkyl, halogenated C 1-3 Alkyl, deuterated C 1-3 Alkyl, C1-3 alkoxy or haloC 1-3 alkoxy.

[0041] In one preferred embodiment, R 3 or R 5 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, C 1～3 alkyl or C 1～3 substituted alkyl.

[0042] In one preferred embodiment, R 4 or R 6 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, nitro, amino or cyano.

[0043] In one preferred embodiment, R 4 , R 6 are each independently selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 1-3 cycloalkyl, deuterated C 1-3 ycloalkyl, C 1-3 alkyl, C 1-3 alkoxy or haloC 1-3 alkoxy.

[0044] In one preferred embodiment, R 7 is selected from carboxyl, substituted or non-substituted C 1～8 ycloalkyl, substituted or non-substituted C 1～4 alkoxy, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 alkylene.

[0045] In one preferred embodiment, R 3 , R 5 or R 7 are each independently selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 3-6 cycloalkyl, deuterated C 3-6 ycloalkyl, C 1-3 alkyl, C 1-3 alkoxy or haloC 7 alkoxy.

[0046] In one preferred embodiment, R 1～6 is selected from substituted or non-substituted C 1～6alkylsulfonylaminyl, substituted or non-substituted C 1～4 alkylene, aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 one of the substituents of the alkylene is selected from one or more of deuterium, halogen, cyano, hydroxyl, nitro.

[0047] In a preferred embodiment, R 3 or R 5 is selected from one or more of deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 3-6 cycloalkyl, deuterated C 3-6 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy.

[0048] In a preferred embodiment, R 7 is selected from one or more of deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 3-6 cycloalkyl, deuterated C 3-6 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy.

[0049] In a preferred embodiment, A 1 is selected from N or C-R 8 , R 8 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonylaminyl, substituted or non-substituted C 1～6 alkoxycarbonyl, substituted or non-substituted C 1～6 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～6 alkylaminocarbonyl, substituted or non-substituted C 1～6 alkylaminocarbonyl-C 1～4 one of the substituents of the alkylene.

[0050] In a preferred embodiment, A 2 is selected from C-R 9 , R 9 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C1～3 alkylsulfonylamino, substituted or non-substituted C 1～6 alkoxycarbonyl, substituted or non-substituted C 1～6 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～6 alkylaminocarbonyl, substituted or non-substituted C 1～6 alkylaminocarbonyl-C 1～4 one of the alkylene groups.

[0051] In a preferred embodiment, A 3 is selected from C-R 10 , R 10 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonylamino, substituted or non-substituted C 1～6 alkoxycarbonyl, substituted or non-substituted C 1～6 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～6 alkylaminocarbonyl, substituted or non-substituted C 1～6 alkylaminocarbonyl-C 1～4 one of the alkylene groups.

[0052] In a preferred embodiment, A 4 is selected from N or C-R 11 , R 11 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonylamino, substituted or non-substituted C 1～6 alkoxycarbonyl, substituted or non-substituted C 1～6 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～6 alkylaminocarbonyl, substituted or non-substituted C 1～6 alkylaminocarbonyl-C 1～ one of the alkylene groups.

[0053] In a preferred embodiment, in R 8R 9 R 10 R 11 substituents in R 1-3 alkyl, haloC 1-3 alkyl, deuterated C 1-3 cycloalkyl, haloC 3-6 cycloalkyl, deuterated C 3-6 cycloalkyl, C 3-6 alkoxy, haloC 1-3 alkoxy, deuterated C 1-3 alkoxy, deuterated C 1-3 alkoxy, deuterated C

[0054] In a preferred embodiment, when R 1 and R 2 are both C 3～6 alkyl, at least one of A 1 , A 2 , A 3 and A 4 is N, or at least one of R 8 , R 9 , R 10 and R 11 is nitro, amino, cyano, C 1～3 substituted amino or C 1～3 alkylsulfonamido, or at least one of R 3 , R 4 , R 5 and R 6 is cyano, or contains a substituent in Z or R 7 .

[0055] The present application also provides a series of specific compounds or pharmaceutically acceptable salts thereof, wherein the compounds include:

[0056] The present application provides a pharmaceutical composition, which takes the compound, isomer or pharmaceutically acceptable salt thereof of the present application as an active ingredient, and is supplemented with a pharmaceutically acceptable adjuvant.

[0057] Unless otherwise specified, the following terms used in the claims and the specification have the following meanings:

[0058] "Hydrogen" refers to protium (1H), which is the primary stable isotope of the element hydrogen.

[0059] "Deuterium" refers to a stable form of isotope of hydrogen, also known as heavy hydrogen, and has the element symbol D.

[0060] "Halogen" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0061] "Cyano" means a -CN group.

[0062] "Alkyl" means a saturated aliphatic radical of 1 to 20 carbon atoms, including straight-chain and branched groups (the numerical ranges recited herein, e.g., "1 to 20", are used to describe groups, in this case alkyl groups, which can contain, e.g., 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, alkyl is a medium size alkyl group of 1 to 7 carbon atoms. Representative examples of alkyl in the present application include methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl, and the like. Preferably, alkyl is lower alkyl of 2 to 4 carbon atoms, e.g., ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, and the like. Alkyl groups can be substituted or unsubstituted. In the explanation of groups, R' is used to represent alkyl. Substituted alkyl means an alkyl group in which one or more H atoms is replaced by another group. Haloalkyl means an alkyl group in which one or more H atoms is replaced by a halogen.

[0063] "Alkoxy" means an -OR' group, i.e., an -O-(unsubstituted alkyl) and -O-(unsubstituted cycloalkyl) group, which further means -O-(unsubstituted alkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propyloxy, butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Substituted alkoxy means an alkoxy group in which one or more H atoms is replaced by another group.

[0064] "Cycloalkyl" means a monocyclic or bicyclic alkyl group having 3 or more C atoms, including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, bicycloheptyl.

[0065] "Alkoxycarbonyl" means a -C(=O)-O-alkyl group. C 1～8 in an alkoxycarbonyl group means the total number of C atoms in the alkyl group of the group, not including the C in the carbonyl. Alkoxycarbonyl preferably has C 1～8 in an alkoxycarbonyl group means the total number of C atoms in the alkyl group of the group, not including the C in the carbonyl. Alkoxycarbonyl preferably has C 1～6 in an alkoxycarbonyl group means the total number of C atoms in the alkyl group of the group, not including the C in the carbonyl. Alkoxycarbonyl preferably has C 1～5 in an alkoxycarbonyl group means the total number of C atoms in the alkyl group of the group, not including the C in the carbonyl. Alkoxycarbonyl preferably has C 1～4 in an alkoxycarbonyl group means the total number of C atoms in the alkyl group of the group, not including the C in the carbonyl. Alkoxycarbonyl preferably has C. Representative examples include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, and the like.

[0066] "Alkoxycarbonyl-alkylene" means a -alkylene-C(=O)-O-alkyl group. C 1～8 in an alkoxycarbonyl-alkylene group means the total number of C atoms in the alkyl group of the group, not including the C in the carbonyl. Alkoxycarbonyl-alkylene preferably has C 1～4 in an alkoxycarbonyl-alkylene group means the total number of C atoms in the alkyl group of the group, not including the C in the carbonyl. Alkoxycarbonyl-alkylene preferably has C 1～8 in an alkoxycarbonyl-alkylene group means the total number of C atoms in the alkyl group of the group, not including the C in the carbonyl. Alkoxycarbonyl-alkylene preferably has C1～4 C atoms in the alkylene group. Alkoxycarbonyl-alkylene preferably employs alkoxycarbonyl-C 1～8 alkoxycarbonyl-C 1～4 alkylene, C 1～7 alkoxycarbonyl-C 1～4 alkylene, C 1～6 alkoxycarbonyl-C 1～4 alkylene, C 1～5 alkoxycarbonyl-C 1～4 alkylene, C 1～4 alkoxycarbonyl-C 1～4 alkylene, C 1～8 alkoxycarbonyl-C 1～2 alkylene, C 1～7 alkoxycarbonyl-C 1～2 alkylene, C 1～6 alkoxycarbonyl-C 1～2 alkylene, C 1～5 alkoxycarbonyl-C 1～2 alkylene, C 1～4 alkoxycarbonyl-C 1～2 alkylene. Representative examples include, but are not limited to, methoxycarbonylmethylene, ethoxycarbonylmethylene, propoxycarbonylmethylene, isopropoxycarbonylmethylene, butoxycarbonylmethylene, isobutoxycarbonylmethylene, methoxycarbonyl ethylene, ethoxycarbonyl ethylene, propoxycarbonyl ethylene, isopropoxycarbonyl ethylene, butoxycarbonyl ethylene, isobutoxycarbonyl ethylene, and the like.

[0067] "Aminocarbonyl" means a -C(=O)-NH2group.

[0068] "Aminocarbonylalkylene" means an -alkylene-C(=O)-NH2group. Representative examples of aminocarbonylalkylene include, but are not limited to, aminocarbonylmethylene, aminocarbonyl ethylene, aminocarbonylpropylene, aminocarbonylbutylene, and the like. 1～4 C atoms in the alkylene group. Aminocarbonylalkylene preferably employs aminocarbonyl-C 1～4 alkylene, aminocarbonyl-C 1～4 alkylene, aminocarbonyl-C 1～3 alkylene, aminocarbonyl-C 1～2 alkylene. Representative examples include, but are not limited to, aminocarbonylmethylene, aminocarbonyl ethylene, aminocarbonylpropylene, aminocarbonylbutylene, and the like.

[0069] "Alkylaminocarbonyl" means a -C(=O)-NH-alkyl or -C(=O)-N(alkyl)2group. C 1～8 C atoms in the alkylamino group. Alkylaminocarbonyl preferably employs C 1～8 C atoms in the alkylamino group. Alkylaminocarbonyl preferably employs C 1～8 alkylaminocarbonyl, C 2～8 alkylaminocarbonyl, C 1～6Alkylaminocarbonyl, C 2～6 Alkylaminocarbonyl, C 1～4 Alkylaminocarbonyl, C 2～4 Alkylaminocarbonyl. Representative examples include, but are not limited to, methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, methylethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl, methylpropylaminocarbonyl, ethylpropylaminocarbonyl, butylaminocarbonyl, dibutylaminocarbonyl, methylbutylaminocarbonyl, ethylbutylaminocarbonyl, propylbutylaminocarbonyl, and the like.

[0070] "Alkylaminocarbonyl-alkylene" means an -alkylene-C(=O)-NH-alkyl or -alkylene-C(=O)-N(alkyl)2 group. 1～8 Alkylaminocarbonyl-C 1～4 C in the alkylene 1～8 Refers to the number of C atoms in the alkylamino group, where C 1～4 Refers to the number of C atoms in the alkylene group. Alkylaminocarbonyl-alkylene preferably adopts C 1～8 Alkylaminocarbonyl-C 1～4 Alkylene, C 1～8 Alkylaminocarbonyl-C 1～3 Alkylene, C 1～8 Alkylaminocarbonyl-C 1～2 Alkylene, C 1～6 Alkylaminocarbonyl-C 1～4 Alkylene, C 1～4 Alkylaminocarbonyl-C 1～4 Alkylene, C 1～6 Alkylaminocarbonyl-C 1～2 Alkylene, C 1～4 Alkylaminocarbonyl-C 1～2 Alkylene. Representative examples include, but are not limited to, methylaminocarbonylmethylene, dimethylaminocarbonylmethylene, ethylaminocarbonylmethylene, diethylaminocarbonylmethylene, methylethylaminocarbonylmethylene, propylaminocarbonylmethylene, dipropylaminocarbonylmethylene, methylpropylaminocarbonylmethylene, ethylpropylaminocarbonylmethylene, butylaminocarbonylmethylene, dibutylaminocarbonylmethylene, methylbutylaminocarbonylmethylene, ethylbutylaminocarbonylmethylene, propylbutylaminocarbonylmethylene, methylaminocarbonylethylene, dimethylaminocarbonylethylene, ethylaminocarbonylethylene, diethylaminocarbonylethylene, methylethylaminocarbonylethylene, propylaminocarbonylethylene, dipropylaminocarbonylethylene, methylpropylaminocarbonylethylene, ethylpropylaminocarbonylethylene, butylaminocarbonylethylene, dibutylaminocarbonylethylene, methylbutylaminocarbonylethylene, ethylbutylaminocarbonylethylene, propylbutylaminocarbonylethylene, and the like.

[0071] "carbonyl" means a C=0 or -C(=0)- group.

[0072] "hydroxyl" means an -OH group.

[0073] "carboxyl" or "carboxylic acid" means a -COOH group.

[0074] "nitro" means an -NO2 group.

[0075] "amino" means an -NH2 group.

[0076] "thiazolidinyl" means one of

[0077] "piperazinyl" means one of

[0078] "morpholinyl" means one of

[0079] "thiomorpholinyl" means one of

[0080] "pyrrolidinyl" means one of

[0081] "oxazolidinyl" means one of

[0082] "isoxazolidinyl" means one of

[0083] "piperidinyl" means one of

[0084] "tetrahydrofuranyl" means one of

[0085] "tetrahydrothiophenyl" means one of

[0086] "hexahydro pyrimidinyl" means one of

[0087] "heterocycloalkyl" means a cyclic saturated alkyl group having one or more O, N, S, P, etc. heteroatoms as ring atoms, representative examples of which include, but are not limited to, thiazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, piperidinyl, tetrahydrothiophenyl, hexahydro pyrimidinyl, etc.

[0088] ​​​​​​​​​​​"Heterocyclyl" means a cyclic group having, in addition to carbon atoms, one or more heteroatoms as ring members, which include heterocycloalkyl and heterocycloaryl groups. Depending on the number of ring members, it can include a three-membered heterocyclyl group, a four-membered heterocyclyl group, a five-membered heterocyclyl group, a six-membered heterocyclyl group, a benzo-fused heterocyclyl group, and the like. Common three-membered heterocyclyl groups include: oxiranyl, thiiranyl, and the like. Four-membered heterocyclyl groups include: tetrazolyl, β-propiolactonyl, β-propiolactam, and the like. Five-membered heterocyclyl groups include: furanyl, thiophenyl, pyrrolyl, thiazolyl, imidazolyl, tetrazolyl, triazolyl, and the like. Six-membered heterocyclyl groups include: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and the like. Fused heterocyclyl groups include: indolyl, quinolinyl, pteridinyl, acridinyl, and the like.

[0089] "Aryl" means a monocyclic or polycyclic aromatic group having, or not having, N, O, S, P, and the like as ring members, which include, but are not limited to, phenyl, naphthyl, pyridyl, pyrimidinyl, and the like.

[0090] "Pharmaceutically acceptable salt" means a salt of a compound of Formula (I) with an organic or inorganic acid, which retains the biological effectiveness and properties of the parent compound. Such salts include:

[0091] (1) Salts with acids, which are obtained by reaction of the free base of the parent compound with an inorganic or organic acid, such as, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, and perchloric acid, and the like, and organic acids such as, but not limited to, acetic acid, propionic acid, propenoic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene- 1 -sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid, or malonic acid, and the like.

[0092] (2) Salts in which an acidic proton in the parent compound is replaced by a metal ion, such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or coordinates with an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

[0093] "Pharmaceutical composition" means a mixture of one or more compounds described herein, or their pharmaceutically acceptable salts and prodrugs, with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0094] Hereinafter, unless specifically limited, the compounds of Formula (I) as active ingredients of therapeutic agents include all pharmaceutically acceptable salts thereof, which are to be construed as falling within the scope of the present application. In the present specification, they are simply referred to as "compounds of Formula (I)" for convenience.

[0095] The present application includes a pharmaceutical composition comprising any of the compounds, isomers, pharmaceutically acceptable salts or easily hydrolyzable prodrugs or esters thereof described in the present application as an active ingredient, supplemented with a pharmaceutically acceptable adjuvant.

[0096] The compounds, isomers or pharmaceutically acceptable salts thereof of the present application can be applied in the preparation of a drug for treating atrial fibrillation.

[0097] It is found that the compounds of the present application have excellent effects on treating atrial fibrillation, especially arrhythmia, and are potential drugs with better effects. BRIEF DESCRIPTION OF DRAWINGS

[0098] Figure 1 is a graph showing the effect of the test substance on the duration of atrial fibrillation in rats in Example 43 of the present application;

[0099] Figure 2 is a graph showing the effect of the test substance on the duration of atrial fibrillation in rats in Example 44 of the present application.

[0100] Figure 3 is a graph showing the effect of the test substance on the duration of atrial fibrillation in rats in Example 45 of the present application. DETAILED DESCRIPTION

[0101] The present application can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the content described in the examples is only for illustrating the present application, and should not and will not limit the present application described in detail in the claims.

[0102] Example 1: Synthesis of 5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)-2-[3- (diethylamino)propoxy]benzonitrile (6)

[0103] Step A: A solution of valeryl chloride (25.6 g, 213 mmol) in dichloromethane (200 mL) was added dropwise to a solution of 2-aminopyridine (20.0 g, 213 mmol) and triethylamine (21.5 g, 213 mmol) in dichloromethane (100 mL) at -78 °C. After the addition was completed, the resulting mixture was stirred at room temperature for 2 hours. Most of the solvent was removed under reduced pressure, water (300 mL) was added, the pH value was adjusted to 7-8 with a saturated sodium carbonate solution, and then extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 10: 1) to give N-(pyridin-2-yl)valeramide (1) (25.5 g) with a yield of 67.2%.

[0104] Step B: A mixture containing compound 1 (24.0 g, 135 mmol), 2-bromo-l-(3-iodo-4- methoxyphenyl)ethanone (48.0 g, 135 mmol) and toluene (240 mL) was stirred at reflux overnight. Most of the toluene was removed under reduced pressure, dichloromethane (500 mL) and water (200 mL) were added, and the pH value was adjusted to basic with 2 M sodium hydroxide solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (300 mL). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate: dichloromethane = 10: 1:0 to 10: 1: 1) to give (2-butylimidazo[l,2-a]pyridin-3-yl)(3-iodo-4-methoxyphenyl)methanone (2) (33.0 g). The yield was 56.3%.

[0105] Step C: A mixture containing compound 2 (33.0 g, 76.0 mmol), cuprous cyanide (10.2 g, 114 mmol) and DMF (200 mL) was stirred at 130 °C overnight. It was cooled to room temperature, ethyl acetate (800 mL), water (400 mL) and concentrated aqueous ammonia (200 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (400 mL). The combined organic layers were washed successively with 12% aqueous ammonia (200 mL x 2) and saturated brine (200 mL x 2), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting product was recrystallized from acetonitrile to give 5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)-2-methoxybenzonitrile (3) (20.2 g). The yield was 78.3%. 1 H NMR (DMSO-d6, 400 MHz) δ: 9.26-9.23 (m, 1H), 8.09 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 2.0, 8.8 Hz, 1H), 7.76-7.73 (m, 1H), 7.63-7.58 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.21-7.17 (m, 1H), 4.03 (s, 3H), 2.36 (t, J = 7.6 Hz, 2H), 1.57-1.53 (m, 2H), 1.14-1.05 (m, 2H), 0.71 (t, J = 7.6 Hz, 3H). MS (m / z): 334.1 [M+H] + .

[0106] Step D: A mixture containing sodium ethanethiolate (17.5 g, 208 mmol), compound 3 (20.0 g, 60.0 mmol) and DMF (140 mL) was stirred at 65 °C for 1 h. Cooled to room temperature, water (560 mL) was added, filtered through celite, the resulting filtrate was adjusted to pH 5-6 with 2 M aqueous citric acid solution. Filtered, the filter cake was recrystallized with acetonitrile to give 5-(2-butylimidazo[l,2- a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (4) (17.0 g). Yield 88.7%.

[0107] Step E: A mixture containing compound 4 (7.50 g, 23.5 mmol), potassium carbonate (8.10 g, 58.6 mmol), 1,3-dibromopropane (23.7 g, 117 mmol) and DMF (60 mL) was stirred at 65 °C for 5 h. Water (240 mL) was added, extracted with ethyl acetate (250 mL x 3). The combined organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the product was purified by column chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate: dichloromethane = 8: 1:0 ~ 8:4: 1 elution) to give 2-(3-bromopropoxy)-5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)benzonitrile (5) (9.15 g). Yield 88.4%.

[0108] Step F: A solution of compound 5 (8.95 g, 20.3 mmol) and diethylamine (30 mL) in THF (30 mL) was stirred at 45 °C overnight. Saturated potassium carbonate solution (50 mL) was added, extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the product was purified by column chromatography (200-300 mesh silica gel, dichloromethane: methanol = 40: 1 ~ 10: 1 elution) to give 5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)-2-[3-(diethylamino)propoxy]benzonitrile (6) (6.22 g). Yield 70.8%. 1H NMR (DMSO-d6, 400 MHz) δ: 9.27-9.24 (m, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 2.0, 8.8 Hz, 1H), 7.77-7.74 (m, 1H), 7.64-7.59 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.23-7.19 (m, 1H), 4.30 (t, J = 6.0 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H), 2.47-2.43 (m, 4H), 2.36 (t, J = 8.0 Hz, 2H), 1.90-1.87 (m, 2H), 1.57-1.53 (m, 2H), 1.12-1.07 (m, 2H), 0.96-0.93 (m, 6H), 0.72 (t, J = 7.6 Hz, 3H). MS (m / z): 433.2 [M+H] + .

[0109] Example 2: Synthesis of 3-bromo-5-(2-butylimidazo[l,2-a]pyridine-3- carbonyl)-2-[3-(diethylamino)propoxy]benzonitrile (9)

[0110] Step A: To a solution of compound 4 (8.0 g, 25.1 mmol) in DMF (80 mL) was added NBS (4.68 g, 26.3 mmol) portionwise. After the addition was complete, the resulting mixture was stirred at room temperature for 1.5 hours. Water (320 mL) was added and the mixture was filtered. The filter cake was washed with water and recrystallized from acetonitrile to give 3-bromo-5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)-2- hydroxybenzonitrile (7) (9.70 g). The yield was 96.8%.

[0111] The experimental procedures of Steps B and C were as described in Example 1, Steps E and F, to give 3-bromo-5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)-2-[3- (diethylamino)propoxy]benzonitrile (9). 1H NMR (DMSO-d6, 400 MHz) δ: 9.36-9.34 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.80-7.77 (m, 1H), 7.68-7.64 (m, 1H), 7.27-7.24 (m, 1H), 4.37 (t, J = 6.4 Hz, 2H), 2.63-2.60 (m, 2H), 2.51-2.48 (m, 4H), 2.31-2.27 (m, 2H), 2.01-1.92 (m, 2H), 1.57-1.53 (m, 2H), 1.15-1.09 (m, 2H), 0.96 (t, J = 6.8 Hz, 6H), 0.75 (t, J = 7.2 Hz, 3H). MS (m / z): 513.1 [M+H] + .

[0112] Example 3: Synthesis of 3-bromo-5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)-2-[2- hydroxy-3-(isopropylamino)propoxy]benzonitrile (11)

[0113] Step A: A mixture containing compound 7 (5.90 g, 14.8 mmol), epibromohydrin (10.1 g, 73.7 mmol), potassium carbonate (5.10 g, 36.9 mmol), potassium iodide (2.40 g, 14.5 mmol) and DMF (40 mL) was stirred at 65 °C overnight. Water (160 mL) was added and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with water (40 mL x 2) and saturated brine (40 mL) successively and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 4: 1) to give 3-bromo-5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)-2-[(oxirane-2-yl)methoxy]benzonitrile (10) (4.90 g). Yield 72.9%.

[0114] Step B: A mixture containing compound 10 (4.80 g, 10.6 mmol), cerium chloride heptahydrate (0.50 g, 1.34 mmol), polyethylene glycol 400 (40 mL) and isopropyl amine (12 mL) was stirred at 30 °C overnight. Water (200 mL) was added and extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with saturated brine (40 mL x 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 5: 1 ~ 3: 2) to give 3-bromo-5-(2-butylimidazo[l,2-a]pyridine-3-carbonyl)-2-[2-hydroxy-3- (isopropylamino)propoxy]benzonitrile (11). 1 H NMR (DMSO-d6, 400 MHz) δ: 9.36-9.34 (m, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.79-7.76 (m, 1H), 7.68-7.63 (m, 1H), 7.27-7.23 (m, 1H), 4.43-4.41 (m, 2H), 3.63-3.41 (m, 4H), 3.30-3.26 (m, 2H), 2.33-2.28 (m, 2H), 1.59-1.51 (m, 2H), 1.26-1.09 (m, 8H), 0.75 (t, J = 7.2 Hz, 3H). MS (m / z): 512.7 [M+H] + .

[0115] Example 4: Synthesis of (2-butylimidazo[l,2-a]pyridin-3-yl){4-[3-(diethylamino)propoxy]-3-fluoro-5-iodophenyl}methanone (17)

[0116] Step A: A solution of bromoacetyl bromide (26.2 g, 130 mmol) in dichloromethane (20 mL) was added dropwise to a mixture containing 2-fluoroanisole (13.7 g, 109 mmol), aluminum trichloride (15.9 g, 119 mmol) and dichloromethane (120 mL) under ice-water bath. After the addition, the resulting mixture was stirred at this temperature for another 1.5 hours. The reaction mixture was poured into ice-water (200 mL) and the aqueous layer was extracted with dichloromethane (200 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: dichloromethane = 1: 1) to give 2-bromo-l-(3-fluoro-4-methoxyphenyl)ethanone (12) (25.0 g) with a yield of 92.8%.

[0117] Step B: A mixture containing compound 1 (18.0 g, 101 mmol), compound 12 (25.0 g, 101 mmol) and toluene (180 mL) was stirred at reflux overnight. Most of the toluene was removed under reduced pressure, dichloromethane (200 mL) and water (200 mL) were added, and the pH was adjusted to basic with saturated potassium carbonate solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (200 mL x 2), and the combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate: dichloromethane = 10: 1:0 to 10: 1: 1) to give (2-butylimidazo[l,2-a]pyridin-3-yl)(3-fluoro-4-methoxyphenyl)methanone (13) (19.4 g) in 58.9% yield. MS (m / z): 327.1 [M+H] + .

[0118] Step C: 2M Boron tribromide solution (60 mL) was added dropwise to a solution of compound 13 (19.4 g, 59.4 mmol) in dichloromethane (200 mL) under ice-water bath, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-water (400 mL) portion-wise, and the pH was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (40 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was recrystallized from ethyl acetate / petroleum ether to give (2-butylimidazo[l,2-a]pyridin-3-yl)(3-fluoro-4-hydroxyphenyl)methanone (14) (11.5 g) in 62.0% yield.

[0119] Step D: A mixture containing compound 14 (11.5 g, 36.8 mmol), iodine (11.7 g, 46.1 mmol), sodium acetate (3.30 g, 40.2 mmol) and methanol (400 mL) was stirred at reflux for 1 hour, and then a solution containing sodium hydroxide (1.69 g, 42.3 mmol) in water (200 mL) was added. After the addition, the resulting mixture was stirred at the same temperature for 1 hour. It was cooled to room temperature, and saturated sodium sulfite solution was added until the color faded. The pH was then adjusted to 6-7 with acetic acid. Water (600 mL) was added, and the mixture was extracted with ethyl acetate (400 mL x 2). The combined organic phase was washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was recrystallized from acetonitrile to give (2-butylimidazo[l,2-a]pyridin-3-yl)(3-fluoro-4-hydroxy-5-iodophenyl)methanone (15) (16.0 g) in 99.2% yield.

[0120] Step E: A mixture containing compound 15 (12.0 g, 27.4 mmol), potassium carbonate (9.45 g, 68.5 mmol), 1,3-dibromopropane (27.6 g, 137 mmol) and DMF (90 mL) was stirred at 65 °C for 3 h. Water (300 mL) was added and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (150 mL x 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate: dichloromethane = 8: 1: 1) to give [4-(3-bromopropoxy)-3-fluoro-5-iodophenyl](2-butylimidazo[l,2-a]pyridin-3-yl)methanone (16) (14.0 g). The yield was 91.3%. 1 H NMR (DMSO-d6, 400 MHz) δ: 9.31-9.29 (m, 1H), 7.92-7.91 (m, 1H), 7.77-7.75 (m, 1H), 7.69-7.63 (m, 2H), 7.25-7.21 (m, 1H), 4.32-4.28 (m, 2H), 3.80 (t, J = 6.4 Hz, 2H), 2.34-2.28 (m, 4H), 1.60-1.52 (m, 2H), 1.16-1.10 (m, 2H), 0.75 (t, J = 7.6 Hz, 3H).

[0121] Step F: A solution of compound 16 (5.50 g, 9.84 mmol) and diethylamine (25 mL) in THF (25 mL) was stirred at 45 °C overnight. Saturated potassium carbonate solution (50 mL) was added and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with dichloromethane: methanol = 100: 1) to give (2-butylimidazo[l,2-a]pyridin-3-yl){4-[3-(diethylamino)propoxy]-3-fluoro-5-iodophenyl}methanone (17) (3.85 g). The yield was 71.0%. 1H NMR (DMSO-d6, 400 MHz) δ: 9.26-9.24 (m, 1H), 7.88-7.87 (m, 1H), 7.73-7.71 (m, 1H), 7.63-7.59 (m, 2H), 7.20-7.17 (m, 1H), 4.22-4.19 (m, 2H), 2.58 (t, J = 7.2 Hz, 2H), 2.47-2.41 (m, 4H), 2.31-2.27 (m, 2H), 1.88-1.81 (m, 2H), 1.57-1.50 (m, 2H), 1.12-1.07 (m, 2H), 0.92 (t, J = 7.2 Hz, 6H), 0.72 (t, J = 7.2 Hz, 3H). MS (m / z): 552.1 [M+H] + .

[0122] Example 5: Synthesis of (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl){3,5-dibromo-4-[3- (diethylamino)propoxy]phenyl}methanone (23)

[0123] Step A: To a solution of 4-methoxyacetophenone (25.0 g, 166 mmol) in DMF (100 mL) was added 60% sodium hydride (14.0 g, 350 mmol) portion wise at ice water bath. After addition, the resulting mixture was stirred at the same temperature for 40 min. Then methyl pentanoate (19.4 g, 167 mmol) was added drop wise to the above mixture. After addition, the resulting mixture was stirred at room temperature overnight. Water (300 mL) was added, the pH value was adjusted to 4-5 with 2M citric acid solution, then extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with water (150 mL x 3) and saturated brine (150 mL) successively, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: dichloromethane: ethyl acetate = 20: 1: 1). Yield: 28.8 g. Yield: 72.5%.

[0124] Step B: lodobenzylideneacetate (31.3 g, 97.2 mmol) and boron trifluoride etherate (2.30 g, 16.2 mmol) were added to a solution of 2-amino-5-fluoropyridine (9.07 g, 80.9 mmol) and compound 18 (19.0 g, 81.1 mmol) in THF (135 mL) under ice-water bath. After addition, the resulting mixture was stirred at room temperature overnight. Saturated brine (250 mL) was added, and the pH value was adjusted to 7-8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate: dichloromethane = 7:2:1) to give (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl)(4-methoxyphenyl)methanone (19) (18.0 g). The yield was 71.5%.

[0125] Step C: Boron tribromide (41.4 g, 165 mmol) was added dropwise to a solution of compound 19 (18.0 g, 55.2 mmol) in dichloromethane (180 mL) under ice-water bath. After addition, the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-water (400 mL) in batches, and the pH value was adjusted to 7-8 with saturated sodium bicarbonate solution, then extracted with dichloromethane (40 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was recrystallized with ethyl acetate / petroleum ether to give (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl)(4-hydroxyphenyl)methanone (20) (10.7 g). The yield was 62.1%.

[0126] Step D: NBS (12.7 g, 71.4 mmol) was added to a solution of compound 20 (10.7 g, 34.3 mmol) in DMF (110 mL) in batches. After addition, the resulting mixture was stirred at room temperature for 2 hours. Water (440 mL) was added, and the mixture was filtered. The filter cake was washed with water and recrystallized with acetonitrile to give (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl)(3,5-dibromo-4-hydroxyphenyl)methanone (21) (10.0 g). The yield was 62.0%.

[0127] The experimental operations of Steps E and F refer to those in Example 1, and (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl){3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (23) was obtained. 1H NMR (DMSO-d6, 400 MHz) δ: 9.35-9.33 (m, 1H), 7.97 (s, 2H), 7.88-7.84 (m, 1H), 7.79-7.74 (m, 1H), 4.10 (t, J = 6.4 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.49-2.45 (m, 4H), 2.33-2.28 (m, 2H), 1.99-1.92 (m, 2H), 1.59-1.51 (m, 2H), 1.18-1.09 (m, 2H), 0.96 (t, J = 7.2 Hz, 6H), 0.74 (t, J = 7.2 Hz, 3H). MS (m / z): 583.5 [M+H] + .

[0128] Example 6: Synthesis of (2-butyl-6-fluoroimidazo[l,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3- (diethylamino)propoxy]phenyl}methanone (28)

[0129] Compound 28 was synthesized from 2-amino-5-fluoropyrimidine and compound 18 following the experimental procedures described in steps B, C and D of Example 5 and steps E and F of Example 1. 1 H NMR (DMSO-d6, 400 MHz) δ: 9.35-9.33 (m, 1H), 7.97 (s, 2H), 7.88-7.84 (m, 1H), 7.79-7.74 (m, 1H), 4.10 (t, J = 6.4 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.49-2.45 (m, 4H), 2.33-2.28 (m, 2H), 1.99-1.92 (m, 2H), 1.59-1.51 (m, 2H), 1.18-1.09 (m, 2H), 0.96 (t, J = 7.2 Hz, 6H), 0.74 (t, J = 7.2 Hz, 3H). MS (m / z): 583.5 [M+H] + .

[0130] Example 7: Synthesis of {3-bromo-4-[3-(diethylamino)propoxy]phenyl}(2-butyl-6- fluoroimidazo[l,2-a]pyridin-3-yl)methanone (33)

[0131] Step A: To a solution of compound 29 (35.7 g, 114 mmol) in THF (300 mL) was added iodobenzene diacetate (44.0 g, 137 mmol) and boron trifluoride etherate (3.20 g, 22.5 mmol) successively at 0 °C. The resulting mixture was stirred at room temperature overnight. Saturated brine (150 mL) was added, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate: dichloromethane = 5: 1: 1) to give (3-bromo-4-methoxyphenyl)(2-butyl-6-fluoroimidazo[l,2- a]pyridin-3-yl)methanone (30) (21.0 g). Yield: 45.5%. MS (m / z): 407.0 [M+H]

[0132] Step B: To a solution of compound 29 (35.7 g, 114 mmol) in THF (300 mL) was added iodobenzene diacetate (44.0 g, 137 mmol) and boron trifluoride etherate (3.20 g, 22.5 mmol) successively at 0 °C. The resulting mixture was stirred at room temperature overnight. Saturated brine (150 mL) was added, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate: dichloromethane = 5: 1: 1) to give (3-bromo-4-methoxyphenyl)(2-butyl-6-fluoroimidazo[l,2- a]pyridin-3-yl)methanone (30) (21.0 g). Yield: 45.5%. MS (m / z): 407.0 [M+H] + .

[0133] Step C, D and E: Steps C, E and F in Example 4, to give {3-bromo-4-[3-(diethylamino)propoxy]phenyl}(2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl)methanone (33). 1H NMR (CDC13, 400 MHz) δ: 9.28-9.26 (m, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.68-7.61 (m, 2H), 7.37-7.33 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 4.18 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 6.4 Hz, 2H), 2.58-2.51 (m, 6H), 2.03-1.99 (m, 2H), 1.68-1.60 (m, 2H), 1.20-1.15 (m, 2H), 1.03 (t, J = 7.2 Hz, 6H), 0.78 (t, J = 7.2 Hz, 3H). MS (m / z): 506.1 [M+H] + .

[0134] Example 8: Synthesis of 3-bromo-5-(2-butyl-6-fluoroimidazo[l,2-a]pyridine-3- carbonyl)-2-[3-(diethylamino)propoxy]benzonitrile (40)

[0135] Step A: To a solution of (3-iodo-4-methoxyphenyl)ethanone (50.0 g, 181 mmol) in DMF (200 mL) was added 60% sodium hydride (15.2 g, 380 mmol) portion wise under ice water bath. After addition, the resulting mixture was stirred at the same temperature for another 40 min. Then methyl pentanoate (21.0 g, 181 mmol) was added drop wise to the above mixture. After addition, the resulting mixture was stirred at room temperature overnight. Water (800 mL) was added, the pH value was adjusted to 4-5 with 2M hydrochloric acid solution, then extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with water (300 mL x 3) and saturated brine (300 mL) successively, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: dichloromethane: ethyl acetate = 20: 1: 1). Yield 36.4 g. Yield 55.8%.

[0136] Step B: lodobenzylideneacetate (27.9 g, 86.6 mmol) and boron trifluoride etherate (2.05 g, 14.4 mmol) were added to a solution of 2-amino-5-fluoropyridine (8.09 g, 72.2 mmol) and compound 34 (26.0 g, 72.2 mmol) in THF (100 mL) under ice-water bath. After addition, the resulting mixture was stirred at room temperature overnight. Saturated brine (150 mL) was added, and the pH value was adjusted to 7-8 with saturated sodium bicarbonate solution, then extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate: dichloromethane = 10: 1: 1-10: 3: 3) to give (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl)(3-iodo-4-methoxyphenyl)methanone (35) (19.0 g). Yield 58.2%.

[0137] Step C: A mixture containing compound 35 (19.0 g, 42.0 mmol), cuprous cyanide (5.60 g, 62.5 mmol) and DMF (140 mL) was stirred at 130 °C overnight. Cooled to room temperature, ethyl acetate (300 mL), water (400 mL) and concentrated ammonia (50 mL) were added. Layered, the aqueous layer was extracted with ethyl acetate (400 mL x 2). The combined organic layers were successively washed with water (200 mL x 2) and saturated brine (200 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resulting product was recrystallized with petroleum ether / ethyl acetate to give 5-(2-butyl-6-fluoroimidazo[l,2-a]pyridine-3-carbonyl)-2-methoxylbenzonitrile (36) (11.3 g). Yield 76.6%.

[0138] Step D: Boron tribromide (32.2 g, 129 mmol) was added dropwise to a solution of compound 36 (11.3 g, 32.2 mmol) in dichloromethane (170 mL) under ice-water bath. After addition, the resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into ice water (400 mL) in batches, and the pH value was adjusted to 9-10 with saturated potassium carbonate solution. Layered, the aqueous layer was extracted with dichloromethane (100 mL x 2), and the product was in the aqueous phase. The aqueous phase was adjusted to pH 5-6 with 2M citric acid solution, then extracted with dichloromethane (200 mL x 4). The combined organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was recrystallized with ethyl acetate / petroleum ether to give 5-(2-butyl-6-fluoroimidazo[l,2-a]pyridine-3-carbonyl)-2-hydroxylbenzonitrile (37) (6.20 g). Yield 57.1%. MS (m / z): 335.8 [M-H] - .

[0139] Step E: NBS (3.60 g, 20.2 mmol) was added portionwise to a solution of compound 37 (6.20 g, 18.4 mmol) in DMF (48 mL). After the addition was complete, the resulting mixture was stirred at room temperature for 1.5 h. Water (200 mL) and saturated sodium sulfite solution (30 mL) were added, and the pH was adjusted to 5-6 with 2 M citric acid solution. The mixture was filtered. The filter cake was washed with water and recrystallized from acetonitrile to give 3-bromo-5-(2-butyl-6-fluoroimidazo[l,2- a]pyridine-3-carbonyl)-2-hydroxybenzonitrile (38) (7.10 g). Yield 92.7%. MS (m / z): 418.0 [M+H] + .

[0140] The experimental procedure of Step F and G was the same as that of Step E and F in Example 1 to give 3-bromo-5-(2-butyl-6-fluoroimidazo[l,2-a]pyridine-3-carbonyl)-2-[3- (diethylamino)propoxy]benzonitrile (40). 1 H NMR (DMSO-d6, 400 MHz) δ: 9.35-9.34 (m, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.89-7.85 (m, 1H), 7.80-7.75 (m, 1H), 4.38 (t, J = 6.4 Hz, 2H), 2.60 (t, J = 7.2 Hz, 2H), 2.48-2.44 (m, 4H), 2.32-2.28 (m, 2H), 1.97-1.91 (m, 2H), 1.59-1.51 (m, 2H), 1.15-1.09 (m, 2H), 0.95 (t, J = 7.2 Hz, 6H), 0.75 (t, J = 7.2 Hz, 3H). MS (m / z): 530.7 [M+H] + .

[0141] Example 9: Synthesis of 3-bromo-5-(2-butyl-6-fluoroimidazo[l,2-a]pyridine-3- carbonyl)-2-[3-(diethylamino)-2-hydroxypropoxy]benzonitrile (41)

[0142] A mixture of compound 10 (8.0 g, 17.6 mmol), calcium trifluoromethanesulfonate (2.98 g, 8.81 mmol), diethylamine (12.9 g, 176 mmol) and acetonitrile (60 mL) was stirred at room temperature overnight. Water (180 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: dichloromethane: ethyl acetate = 3: 1: 1) to give 3-bromo-5-(2-butyl-6-fluoroimidazo[l,2-a]pyridine-3-carbonyl)-2-[3-(diethylamino)-2- hydroxypropoxy]benzonitrile (41). 1 H NMR (CDC13, 400 MHz) δ: 9.41-9.38 (m, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.73-7.70 (m, 1H), 7.55-7.51 (m, 1H), 7.10-7.06 (m, 1H), 4.45-4.37 (m, 2H), 4.15-4.11 (m, 1H), 2.77-2.59 (m, 4H), 2.48-2.44 (m, 2H), 1.71-1.63 (m, 2H), 1.23-1.18 (m, 2H), 1.13-1.08 (m, 8H), 0.82 (t, J = 7.2 Hz, 3H). MS (m / z): 528.6 [M+H] + .

[0143] Example 10: Synthesis of {3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}[6-fluoro-2-(l- hydroxybutyl)imidazo[l,2-a]pyridin-3-yl)methanone (46)

[0144] Step A: To a solution of compound 21 (9.40 g, 20.0 mmol) and triethylamine (4.0 g, 39.5 mmol) in dichloromethane (100 mL) was added acetyl chloride (2.40 g, 30.6 mmol) at ice-water bath. After addition, the resulting mixture was stirred at room temperature for 1 hour. Water (50 mL) was added and the mixture was partitioned. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2,6-dibromo-4-(2-butyl-6-fluoroimidazo[l,2-a]pyridine-3-carbonyl)phenyl acetate (42) (8.50 g). Yield 83.0%.

[0145] Step B: To a solution of compound 42 (6.30 g, 12.3 mmol) in carbon tetrachloride (60 mL) was added NBS (2.40 g, 13.5 mmol) and AIBN (200 mg, 1.22 mmol). After addition, the resulting mixture was stirred at reflux under nitrogen for 5 h. Cooled to room temperature, water (50 mL) was added, the layers were separated, and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic layers were washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give {2-(l-bromobutyl)-6-fluoroimidazo[l,2- a]pyridin-3-yl}(3,5-dibromo-4-hydroxyphenyl)methanone (43) as a crude product (8.20 g). This compound was used in the next step without further purification. MS (m / z): 550.8 [M+H] + .

[0146] Step C: A mixture containing compound 43 crude product (8.20 g), potassium acetate (13.6 g, 139 mmol) and DMF (80 mL) was stirred at 40 °C overnight. Water (240 mL) was added, and the mixture was extracted with ethyl acetate (120 mL x 3). The combined organic layers were washed successively with water (60 mL x 3) and saturated brine (60 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 1: 10 ~ 1: 1) to give (3,5-dibromo-4-hydroxyphenyl){6-fluoro-2-(l-hydroxybutyl)imidazo[l,2- a]pyridin-3-yl}methanone (44) (3.0 g). The overall yield for two steps of B and C was 50.2%. 1 H NMR (CDC13, 400 MHz) δ: 9.20-9.18 (m, 1H), 7.98 (s, 2H), 7.79-7.75 (m, 1H), 7.47-7.42 (m, 1H), 4.64 (t, J = 7.2 Hz, 1H), 2.34-2.27 (m, 2H), 1.34-1.08 (m, 2H), 0.81 (t, J = 7.2 Hz, 3H). MS (m / z): 468.9 [M-H20+H] + .

[0147] Step D and E: Refer to the experimental procedures of Step E and F in Example 1 to give {3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}[6-fluoro-2-(l-hydroxybutyl)imidazo[l,2- a]pyridin-3-yl)methanone (46). 1H NMR (CDC13, 400 MHz) δ: 9.27-9.26 (m, 1H), 7.95 (s, 2H), 7.79-7.75 (m, 1H), 7.49-7.44 (m, 1H), 4.57 (t, J = 7.2 Hz, 1H), 4.20-4.16 (m, 2H), 2.78-2.74 (m, 2H), 2.62-2.57 (m, 4H), 2.33-2.24 (m, 2H), 2.13-2.04 (m, 2H), 1.37-1.12 (m, 2H), 1.07 (t, J = 7.2 Hz, 6H), 0.80 (t, J = 7.2 Hz, 3H). MS (m / z): 598.1 [M+H] + .

[0148] Example 11: Synthesis of (2-butylimidazo[l,2-a]pyrimidin-3-yl){3,5-dibromo-4-[2- (diethylamino)ethoxy]phenyl}methanone (50)

[0149] The experimental procedure for Steps A and B is described in Example 5, Steps B and C, wherein 2-amino-5-fluoropyridine in Example 5, Step B is replaced with 2- amino pyrimidine to give (2-butylimidazo[l,2-a]pyrimidin-3-yl)(4- hydroxyphenyl)methanone (48).

[0150] Step C: Bromine (34.0 g, 213 mmol) was added dropwise to a solution of compound 48 (30.0 g, 102 mmol) and sodium acetate (33.0 g, 402 mmol) in acetic acid (300 mL) under water bath. After the addition, the resulting mixture was stirred at room temperature for 1 hour. Water (900 mL) was added, filtered, the filter cake was rinsed with water (90 mL), then recrystallized with petroleum ether / ethyl acetate to give (2-butylimidazo[l,2-a]pyrimidin-3-yl)(3,5-dibromo-4- hydroxyphenyl)methanone (49) (40.0 g). The yield was 86.5%.

[0151] Step D: A mixture of compound 49 (5.0 g, 11.0 mmol), 2-diethylamino-l- bromoethane hydrobromide (3.45 g, 13.2 mmol), potassium carbonate (4.57 g, 33.1 mmol) and DMF (40 mL) was stirred at 85 °C for 0.5 h. Water (160 mL) was added and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with water (50 mL x 3) and saturated brine (50 mL) successively and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 1: 1 ~ 0: 1) to give (2-butylimidazo[l,2-a]pyrimidin-3-yl){3,5-dibromo-4-[2- (diethylamino)ethoxy]phenyl}methanone (50) (1.0 g). Yield 16.5%. 1 H NMR (CDC13, 400 MHz) δ: 9.64-9.62 (m, 1H), 8.77-8.76 (m, 1H), 7.87 (s, 2H), 7.14-7.11 (m, 1H), 4.18 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.8 Hz, 2H), 2.73-2.67 (m, 4H), 2.57-2.53 (m, 2H), 1.76-1.70 (m, 2H), 1.28-1.20 (m, 2H), 1.10 (t, J = 7.2 Hz, 6H), 0.83 (t, J = 7.2 Hz, 3H). MS (m / z): 553.0 [M+H] + .

[0152] Example 12: Synthesis of (2-butyl-7-fluoroimidazo[l,2-a]pyridin-3-yl){3,5-dibromo-4-[3- (diethylamino)propoxy]phenyl}methanone (54)

[0153] Compound 54 was synthesized from 2-amino-4-fluoropyridine and compound 18 following the experimental procedures of Step B and C in Example 5 and Step C and D in Example 11, wherein 2-diethylamino-l-bromoethane hydrobromide in Example 11 Step C was replaced with 3-chloro-l-diethylaminopropane. 1H NMR (CDC13, 400 MHz) δ: 9.43-9.39 (m, 1H), 7.84 (s, 2H), 7.33-7.30 (m, 1H), 6.93-6.88 (m, 1H), 4.14 (t, J = 6.4 Hz, 2H), 2.76-2.73 (m, 2H), 2.61-2.56 (m, 4H), 2.47-2.43 (m, 2H), 2.11-2.04 (m, 2H), 1.70-1.63 (m, 2H), 1.25-1.18 (m, 2H), 1.07 (t, J = 7.2 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H). MS (m / z): 584.0 [M+H] + .

[0154] Example 13: Synthesis of (2-butylimidazo[l,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3- (diethylamino)propoxy]phenyl}methanone (55)

[0155] Compound 55 was synthesized from 3-chloro-l-diethylamino propan and compound 49 following the experimental procedure described in step D of Example 11. 1 H NMR (CDC13, 400 MHz) δ: 9.64-9.62 (m, 1H), 8.77-8.76 (m, 1H), 7.87 (s, 2H), 7.14-7.11 (m, 1H), 4.15 (t, J = 6.4 Hz, 2H), 2.77-2.73 (m, 2H), 2.62-2.53 (m, 6H), 2.12-2.05 (m, 2H), 1.76-1.72 (m, 2H), 1.26-1.20 (m, 2H), 1.07 (t, J = 7.2 Hz, 6H), 0.83 (t, J = 7.2 Hz, 3H). MS (m / z): 567.0 [M+H] + .

[0156] Example 14: Synthesis of {3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}(6-fluoro-2- propylimidazo[l,2-a]pyridin-3-yl)methanone (60)

[0157] Compound 60 was synthesized following the experimental procedure described in steps A, B and C of Example 5 and steps C and D of Example 11, wherein methyl pentanoate in step A of Example 5 was replaced with methyl butanoate and 2-diethylamino-l-bromoethane hydrobromide in step C of Example 11 was replaced with 3-chloro-l-diethylamino propan. 1H NMR (DMSO-d6, 400 MHz) δ: 9.34-9.31 (m, 1H), 7.96 (s, 2H), 7.87-8.83 (m, 1H), 7.78-7.73 (m, 1H), 4.11 (t, J = 6.8 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.52-2.45 (m, 4H), 2.31-2.27 (m, 2H), 1.99-1.94 (m, 2H), 1.64-1.58 (m, 2H), 0.96 (t, J = 7.2 Hz, 6H), 0.74 (t, J = 7.2 Hz, 3H). MS (m / z): 570.0 [M+H] + .

[0158] Example 15: Synthesis of (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl){3,5-dibromo-4-[2- (diethylamino)ethoxy]phenyl}methanone (61)

[0159] To a solution of compound 21 (5.0 g, 10.6 mmol) and diethylaminoethanol (1.50 g, 12.8 mmol) in THF (50 mL) was added triphenylphosphine (5.60 g, 21.4 mmol) and diisopropyl azodicarboxylate (3.20 g, 15.8 mmol). After the addition, the resulting mixture was stirred at room temperature overnight. Water (100 mL) was added, and the pH value was adjusted to 1-2 with 2 M hydrobromic acid solution. The product was extracted with ethyl acetate (20 mL x 3). The aqueous phase was adjusted to pH 8-9 with saturated sodium carbonate solution, and then extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 1: 1-0: 1) to give (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl){3,5-dibromo-4-[2-(diethylamino)ethoxy]phenyl}methanone (61). 1 H NMR (CDC13, 400 MHz) δ: 9.40-9.38 (m, 1H), 7.84 (s, 2H), 7.78-7.64 (m, 1H), 7.44-7.39 (m, 1H), 4.16 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.72-2.66 (m, 4H), 2.49-2.45 (m, 2H), 1.67-1.62 (m, 2H), 1.27-1.25 (m, 2H), 1.09 (t, J = 7.2 Hz, 6H), 0.81 (t, J = 7.2 Hz, 3H). MS (m / z): 570.0 [M+H] + .

[0160] Example 16: Synthesis of (2-butyl-6-fluoroimidazo[l,2-a]pyrimidin-3-yl){3,5- dibromo-4-[2-(diethylamino)ethoxy]phenyl}methanone (62)

[0161] The experimental procedure for the synthesis of compound 62 from compound 26 and diethylaminoethanol is described in Example 15. 1 H NMR (CDC13, 400 MHz) δ: 9.64-9.62 (m, 1H), 8.76-8.75 (m, 1H), 7.86 (s, 2H), 4.18 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.72-2.66 (m, 4H), 2.57-2.51 (m, 2H), 1.75-1.70 (m, 2H), 1.26-1.23 (m, 2H), 1.09 (t, J = 7.2 Hz, 6H), 0.82 (t, J = 7.2 Hz, 3H). MS (m / z): 571.0 [M+H] + .

[0162] Example 17: Synthesis of {3,5-dibromo-4-[2-(diethylamino)ethoxy]phenyl}(6-fluoro-2- propylimidazo[l,2-a]pyridin-3-yl)methanone (64)

[0163] The experimental procedure for the synthesis of compound 64 from compound 59 and dibromoethane is described in steps E and F in Example 1. 1 H NMR (CDC13, 400 MHz) δ: 9.40-9.38 (m, 1H), 7.84 (s, 2H), 7.68-7.64 (m, 1H), 7.44-7.39 (m, 1H), 4.18 (t, J = 6.8 Hz, 2H), 3.03 (t, J = 6.8 Hz, 2H), 2.72-2.68 (m, 4H), 2.47-2.43 (m, 2H), 1.72-1.68 (m, 2H), 1.09 (t, J = 7.2 Hz, 6H), 0.81 (t, J = 7.2 Hz, 3H). MS (m / z): 556.0 [M+H] + .

[0164] Example 18: Synthesis of 3-bromo-5-(2-butyl-6-fluoroimidazo[l,2-a]pyrimidine-3- carbonyl)-2-[3-(diethylamino)propoxy]benzonitrile (69)

[0165] The experimental operations of Steps A and B refer to Steps B and C in Example 8, wherein the 2-amino-5-fluoropyridine in Example 8 Step B is replaced with 2-amino-5-fluoropyrimidine to obtain 5-(2-butyl-6-fluoroimidazo[l,2-a]pyrimidine-3-carbonyl)-2-methoxylbenzonitrile (66).

[0166] Step C: Lithium bromide (2.70 g, 31.1 mmol) and sodium acetate (3.40 g, 41.4 mmol) were added to a solution of compound (3.70 g, 10.5 mmol) in NMP (40 mL) at 78 °C. After the addition was completed, the resulting mixture was stirred at 140 °C overnight. After cooling to room temperature, water (160 mL) was added, the pH value was adjusted to 8-9 with saturated potassium carbonate solution, and then extracted with ethyl acetate (100 mL). The product was in the aqueous phase. The aqueous phase was adjusted to pH 5-6 with 2M citric acid solution, and then extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with water (50 mL x 3) and saturated brine (50 mL) successively, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with dichloromethane:methanol = 100:1-50:1) to obtain 5-(2-butyl-6-fluoroimidazo[l,2-a]pyrimidine-3-carbonyl)-2-hydroxylbenzonitrile (67) (2.20 g). The yield was 61.9%.

[0167] Step D: Bromine (1.10 g, 6.88 mmol) was added dropwise to a solution of compound 67 (2.20 g, 6.50 mmol) and sodium acetate (1.0 g, 12.2 mmol) in acetic acid (20 mL) under water bath. After the addition was completed, the resulting mixture was stirred at room temperature for 1 hour. Water (200 mL) was added, filtered, and dried to obtain 3-bromo-5-(2-butyl-6-fluoroimidazo[l,2-a]pyrimidine-3-carbonyl)-2-hydroxylbenzonitrile (68) (2.70 g). The yield was 99.6%.

[0168] Step E: To a solution of compound 68 (2.70 g, 6.47 mmol) and 3-diethylamino-1- propanol (1.0 g, 7.62 mmol) in THF (30 mL) was added triphenylphosphine (2.70 g, 10.3 mmol) and diisopropyl azodicarboxylate (2.10 g, 10.4 mmol). After the addition was complete, the resulting mixture was stirred at 50 °C overnight. Water (100 mL) was added, and the pH was adjusted to 1-2 with 2 M hydrobromic acid solution. The product was extracted with ethyl acetate (50 mL x 3), and the aqueous phase was obtained. The aqueous phase was adjusted to pH 8-9 with saturated potassium carbonate solution, and then extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 2:1-1:1) to give 3-bromo-5-(2-butyl-6-fluoroimidazo[l,2-a]pyrimidine-3-carbonyl)-2-[3- (diethylamino)propoxy]benzonitrile (69). 1 H NMR (CDC13, 400 MHz) δ: 9.64-9.62 (m, 1H), 8.79-8.78 (m, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 4.48 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 7.2 Hz, 2H), 2.64-2.53 (m, 6H), 2.14-2.07 (m, 2H), 1.78-1.70 (m, 2H), 1.26-1.20 (m, 2H), 1.07 (t, J = 7.2 Hz, 6H), 0.83 (t, J = 7.2 Hz, 3H). MS (m / z): 532.2 [M+H] + .

[0169] Example 19: Synthesis of (2-butyl-6-fluoroimidazo[l,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3- (4,4-dimethylpiperidin-l-yl)propoxy]phenyl}methanone (70)

[0170] A solution of compound 27 (136 mg, 0.230 mmol) and 4,4-dimethylpiperidine (20 mg, 0.177 mmol) in THF (30 mL) was stirred at 40 °C overnight. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate: triethylamine = 70:30:1) to give (2-butyl-6-fluoroimidazo[l,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3-(4,4- dimethylpiperidin-l-yl)propoxy]phenyl}methanone (70). 1H NMR (CDC13, 400 MHz) δ: 9.64-9.62 (m, 1H), 8.77 (d, J = 2.8 Hz, 1H), 7.86 (s, 2H), 4.16 (t, J = 6.4 Hz, 2H), 2.66 (t, J = 3.6 Hz, 2H), 2.56 (t, J = 3.6 Hz, 2H), 2.48-2.45 (m, 4H), 2.13-2.11 (m, 2H), 1.77-1.71 (m, 2H), 1.45-1.42 (m, 4H), 1.26-1.22 (m, 2H), 0.94 (s, 6H), 0.83 (t, J = 7.2 Hz, 3H). MS (m / z): 625.0 [M+H] + .

[0171] Example 20: Synthesis of (2-butyl-6-fluoroimidazo[l,2-a]pyrimidin-3-yl)[3,5- dibromo-4-(3-morpholinopropoxy)phenyl]methanone (71)

[0172] Compound 71 was synthesized from compound 26 and 3-(4-morpholin)-l- propanol following the experimental procedure described in Example 15. 1 H NMR (CDC13, 400 MHz) δ: 9.64-9.63 (m, 1H), 8.77 (d, J = 3.2 Hz, 1H), 7.87 (s, 2H), 4.17 (t, J = 6.4 Hz, 2H), 3.75 (t, J = 4.8 Hz, 4H), 2.67 (t, J = 7.2 Hz, 2H), 2.58-2.54 (m, 6H), 2.16-2.09 (m, 2H), 1.77-1.73 (m, 2H), 1.29-1.22 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H). MS (m / z): 599.0 [M+H] + .

[0173] Example 21: Synthesis of (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl){3,5-dibromo-4-[3- (ethylamino)propoxy]phenyl}methanone (72)

[0174] A mixture containing compound 22 (170 mg, 0.288 mmol), ethylamine hydrochloride (234 mg, 2.87 mmol), potassium carbonate (477 mg, 3.54 mmol) and DMF (4 mL) was stirred at room temperature overnight. Water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with water (15 mL x 2) and saturated brine (15 mL) successively and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 6: 1 ~ 1: 2) to give (2-butyl-6-fluoroimidazo[l,2-a]pyridin-3-yl){3,5-dibromo-4-[3- (ethylamino)propoxy]phenyl}methanone (72). 1 H NMR (CDC13, 400 MHz) δ: 9.41-9.39 (m, 1H), 7.85 (s, 2H), 7.69-7.65 (m, 1H), 7.45-7.40 (m, 1H), 4.17 (t, J = 6.0 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H), 2.73 (q, J = 7.2 Hz, 2H), 2.47 (t, J = 8.0 Hz, 2H), 2.13-2.08 (m, 2H), 1.68-1.64 (m, 2H), 1.23-1.14 (m, 5H), 0.82 (t, J = 7.2 Hz, 3H). MS (m / z): 556.0 [M+H] + .

[0175] Example 22: Synthesis of 3-bromo-5-(2-butylimidazo[l,2-a]pyrimidine-3- carbonyl)-2-[3-(diethylamino)propoxy]benzonitrile (77)

[0176] Compound 77 was synthesized from 2-aminopyrimidine and compound 34 following the procedures of step B and C in Example 8, step D in Example 1 and step D and E in Example 18. 1H NMR (CDC13, 400 MHz) δ: 9.57-9.55 (m, 1H), 8.72-8.71 (m, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.09-7.07 (m, 1H), 4.40 (t, J = 6.4 Hz, 2H), 2.68 (t, J = 7.2 Hz, 2H), 2.55-2.46 (m, 6H), 2.06-1.99 (m, 2H), 1.72-1.66 (m, 2H), 1.19-1.13 (m, 2H), 0.99 (t, J = 7.2 Hz, 6H), 0.76 (t, J = 7.2 Hz, 3H). MS (m / z): 514.0 [M+H] + .

[0177] Example 23: Synthesis of (2-butylimidazo[l,2-a]pyridin-3-yl){3,5-dibromo-4-[3- (ethylamino)propoxy]phenyl}methanone (79) formate salt

[0178] The experimental procedure for synthesizing compound 79 from compound 49 is described in step E of Example 1 and Example 21, followed by purification by preparative HPLC to give compound 79 formate salt. 1 H NMR (DMSO-d6, 400 MHz) δ: 9.56-9.54 (m, 1H), 8.82-8.81 (m, 1H), 8.34 (s, 1H), 8.01 (s, 2H), 7.38-7.36 (m, 1H), 4.13 (t, J = 6.0 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.82 (q, J = 7.2 Hz, 2H), 2.38-2.34 (m, 2H), 2.12-2.10 (m, 2H), 1.64-1.56 (m, 2H), 1.18-1.12 (m, 5H), 0.77 (t, J = 7.2 Hz, 3H). MS (m / z): 539.0 [M+H] + .

[0179] Example 24: Synthesis of {4-{3-[di(pentadeuterioethyl)amino]propoxy}-3,5-dibromo- phenyl}(2-butylimidazo[l,2-a]pyrimidin-3-yl)methanone (80)

[0180] The experimental procedure for synthesizing compound 80 from compound 78 and diethyl-D10-amine hydrochloride is described in Example 21. 1H NMR (CDC13, 400 MHz) δ: 9.64-9.62 (m, 1H), 8.77-8.76 (m, 1H), 7.87 (s, 2H), 7.13-7.11 (m, 1H), 4.15 (t, J = 6.4 Hz, 2H), 2.77 (t, J = 7.6 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 2.12-2.08 (m, 2H), 1.75-1.73 (m, 2H), 1.26-1.20 (m, 2H), 0.83 (t, J = 7.6 Hz, 3H). MS (m / z): 577.1 [M+H] + .

[0181] Example 25: Synthesis of (2-butyl-6-methoxyimidazo[l,2-a]pyrimidin-3-yl){3,5- dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (86)

[0182] Step A: A mixture containing p-hydroxyacetophenone (2.0 g, 14.7 mmol), methyl pentanoate (1.70 g, 14.6 mmol), potassium tert-butoxide (4.94 g, 44.0 mmol) and THF (20 mL) was stirred at reflux overnight. Saturated brine (60 mL) was added, the pH value was adjusted to 5-6 with 2M citric acid solution, and then extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 9: 1-6: 1) to give l-(4-hydroxyphenyl)heptane-l,3-dione (81) (2.20 g). The yield was 68.5%.

[0183] Step B: Acetyl chloride (705 mg, 8.98 mmol) was added to a solution of compound 81 (2.20 g, 10.0 mmol) in dichloromethane (22 mL) under an ice-water bath, and the resulting mixture was stirred at room temperature overnight. Water (30 mL) was added, and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 10: 1) to give 4-(3-oxoheptanoyl)phenyl acetate (82) (800 mg). The yield was 34.0%.

[0184] Step C: lodobenzylideneacetate (1.10 g, 3.42 mmol) and boron trifluoride etherate (86 mg, 0.606 mmol) were added to a solution of 2-amino-5-methoxypyrimidine (381 mg, 3.04 mmol) and compound 82 (800 mg, 3.05 mmol) in THF (6 mL) under ice-water bath. After addition, the mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 4: 1 ~ 1:3) to give 4-(2-butyl-6-methoxylimidazo[l,2-a]pyrimidine-3-carbonyl)phenyl acetate (83) (470 mg). Yield: 42.1%.

[0185] Step D: A mixture containing compound 83 (470 mg, 1.28 mmol), potassium carbonate (470 mg, 3.40 mmol) and methanol (5 mL) was stirred at room temperature overnight. Water (20 mL) was added and the pH value was adjusted to 5-6 with 2M citric acid solution, then extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give (2-butyl-6-methoxylimidazo[l,2-a]pyrimidine-3-yl)(4-hydroxyphenyl)methanone (84) (390 mg). Yield: 93.6%.

[0186] The experimental operations of steps E and F refer to steps D and E in Example 18 to give (2-butyl-6-methoxylimidazo[l,2-a]pyrimidine-3-yl){3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (86). 1 H NMR (CDCI3, 400 MHz) δ: 9.26 (d, J = 2.8 Hz, 1H), 8.62 (d, J = 2.8 Hz, 1H), 7.86 (s, 2H), 4.20 (t, J = 5.6 Hz, 2H), 3.95 (s, 3H), 3.35-3.31 (m, 2H), 3.15-3.10 (m, 4H), 2.52-2.46 (m, 4H), 1.75-1.68 (m, 2H), 1.41 (t, J = 7.2 Hz, 6H), 1.24-1.18 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H). MS (m / z): 597.1 [M+H] + .

[0187] Example 26: Synthesis of (2-butyl-6-deuterated imidazo[1,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (91)

[0188] The experimental operation of step A refers to step B in Example 5, wherein the 2-amino-5-fluoropyridine in step B of Example 5 is replaced by 2-amino-5-bromopyrimidine to obtain (6-bromo-2-butylimidazo[1,2-a]pyrimidin-3-yl)(4-methoxyphenyl)methanone (87).

[0189] Step B: A mixture containing compound 87 (2.50 g, 6.44 mmol), potassium phosphate (2.0 g, 9.43 mmol), palladium acetate (218 mg, 0.962 mmol), n-butyldi(1-adamantyl)phosphine (692 mg, 1.93 mmol), toluene (20 mL), and deuterated methanol (2.5 mL) was stirred at 80°C overnight under nitrogen, then at 95°C for 24 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, elution with petroleum ether:ethyl acetate = 4:1 to 0:1) to give (2-butyl-6-deuteroimidazo[1,2-a]pyrimidin-3-yl)(4-methoxyphenyl)methanone (88) (900 mg). The yield was 45.1%.

[0190] The experimental procedures of steps C, D and E refer to step C in Example 5 and steps D and E in Example 18 to obtain (2-butyl-6-deuterated imidazo[1,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (91). 1 H NMR (CDCl3, 400MHz) δ: 9.65-9.63 (m, 1H), 8.77 (d, J=2.4Hz, 1H), 7.87 (s, 2H), 4.20 (t, J=5.6Hz, 2H), 3.47-3. 43 (m, 2H), 3.25-3.23 (m, 4H), 2.56-2.52 (m, 4H), 1.78-1.70 (m, 2H), 1.50-1.46 (m, 8H), 0.82 (t, J=7.2Hz, 3H). MS(m / z):567.0[M+H] + .

[0191] Example 27: Synthesis of (2-butyl-6-nitroimidazo[1,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (95)

[0192] The experimental procedure for synthesis of compound 95 using compound 18 and 2-amino-5-nitropyrimidine as materials was referred to steps B and C in example 5 and steps D and E in example 18. 1 H NMR (CDC13, 400 MHz) δ: 9.15 (s, 1H), 8.53 (s, 2H), 7.90 (s, 1H), 4.17-4.13 (m, 2H), 3.37 (t, J = 7.6 Hz, 2H), 2.94-2.89 (m, 2H), 2.76-2.71 (m, 4H), 2.20-2.15 (m, 2H), 1.70-1.68 (m, 2H), 1.53-1.48 (m, 2H), 1.17-1.12 (m, 6H), 1.00 (t, J = 7.6 Hz, 3H). MS (m / z): 611.0 [M+H] + .

[0193] Example 28: Synthesis of {3-bromo-4-[3-(diethylamino)propoxy]-5-ethylphenyl}(2- butylimidazo[l,2-a]pyrimidin-3-yl)methanone (100)

[0194] The experimental procedure for synthesis of compound 100 using 3-ethyl-4-methoxyacetophenone, methyl pentanoate and 2-aminopyrimidine as materials was referred to steps A, B and C in example 5 and steps D and E in example 18. 1 H NMR (CDC13, 400 MHz) δ: 9.65-9.63 (m, 1H), 8.76-8.75 (m, 1H), 7.76 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.13-7.11 (m, 1H), 4.08 (t, J = 5.6 Hz, 2H), 3.41-3.37 (m, 2H), 3.23-3.17 (m, 4H), 3.20 (q, J = 7.2 Hz, 2H), 2.56-2.46 (m, 4H), 1.74-1.66 (m, 2H), 1.46 (t, J = 7.2 Hz, 6H), 1.27 (t, J = 7.6 Hz, 3H), 1.21-1.14 (m, 2H), 0.79 (t, J = 7.6 Hz, 3H). MS (m / z): 516.9 [M+H] + .

[0195] Example 29: Synthesis of {3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}[2- (ethoxymethyl)imidazo[l,2-a]pyrimidin-3-yl)methanone (106)

[0196] The experimental procedure for synthesizing compound 106 using 4-methoxyacetophenone, ethyl 2-ethoxyacetate, and 2-aminopyridine as starting materials is described in steps A and B in Example 5, step D in Example 1, step D in Example 5, and steps E and F in Example 1. 1 H NMR (CDC13, 400 MHz) δ: 9.40 (d, J = 6.8 Hz, 1H), 7.97 (s, 2H), 7.79-7.76 (m, 1H), 7.56-7.51 (m, 1H), 7.12-7.09 (m, 1H), 4.31 (s, 2H), 4.16 (t, J = 6.0 Hz, 2H), 3.38 (q, J = 6.8 Hz, 2H), 2.94-2.90 (m, 2H), 2.77-2.72 (m, 4H), 2.21-2.15 (m, 2H), 1.22-1.15 (m, 9H). MS (m / z): 567.7 [M+H] + .

[0197] Example 30: Synthesis of 2-butyl-3-{3,5-dibromo-4-[3-(diethylamino)propoxy]benzoyl}imidazo[l,2- a]pyridine-6-carbonitrile (107)

[0198] The experimental procedure for synthesizing compound 107 using compound 18 and 2-amino-5- cyanopyridine as starting materials is described in steps B, C, and D in Example 5, and steps E and F in Example 1. 1 H NMR (CDC13, 400 MHz) δ: 9.40 (d, J = 6.8 Hz, 1H), 7.97 (s, 2H), 7.79-7.76 (m, 1H), 7.56-7.51 (m, 1H), 7.12-7.09 (m, 1H), 4.31 (s, 2H), 4.16 (t, J = 6.0 Hz, 2H), 3.38 (q, J = 6.8 Hz, 2H), 2.94-2.90 (m, 2H), 2.77-2.72 (m, 4H), 2.21-2.15 (m, 2H), 1.22-1.15 (m, 9H). MS (m / z): 567.7 [M+H] + .

[0199] Example 31: Synthesis of (2-butyl-6-methylimidazo[l,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3- (diethylamino)propoxy]phenyl}methanone (108)

[0200] The experimental procedure for synthesizing compound 108 starting from compound 18 and 2-amino-5-methylpyrimidine is described in steps B and C in Example 5 and steps D and E in Example 18. 1 H NMR (CDC13, 400 MHz) δ: 9.46 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 2.8 Hz, 1H), 7.85 (s, 2H), 4.18 (t, J = 5.6 Hz, 2H), 3.16 (s, 2H), 2.97 (s, 4H), 2.52-2.46 (m, 5H), 2.34 (s, 2H), 1.73-1.68 (m, 2H), 1.38-1.18 (m, 8H), 0.82 (t, J = 7.2 Hz, 3H). MS (m / z): 580.8 [M+H] + .

[0201] Example 32: Synthesis of (2-butyl-6-trifluoromethylimidazo[l,2-a]pyrimidin-3-yl){3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (113)

[0202] The experimental procedure for synthesizing compound 113 starting from compound 18 and 2-amino-5-trifluoromethylpyrimidine is described in steps B, C and D in Example 5 and steps E and F in Example 1. 1 H NMR (CDC13, 400 MHz) δ: 10.22 (s, 1H), 8.93 (s, 1H), 7.47 (s, 2H), 4.14 (t, J = 6.0 Hz, 2H), 3.57-3.40 (m, 6H), 3.15-3.08 (m, 2H), 2.94-2.88 (m, 2H), 2.31-2.27 (m, 2H), 1.49-1.43 (m, 2H), 1.39-1.26 (m, 6H), 0.90 (t, J = 7.2 Hz, 3H). MS (m / z): 665.8 [M+CH3OH+H] + .

[0203] Example 33: Synthesis of (2-butylpyrazolo[l,5-a]pyridin-3-yl){3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (120)

[0204] Step A: A mixture containing 1-aminoiodopyridine (3.50 g, 15.8 mmol), ethyl 2-heptynoate (2.40 g, 15.6 mmol), potassium carbonate (6.50 g, 47.0 mmol) and DMF (60 mL) was stirred at room temperature overnight. Water (240 mL) was added and extracted with ethyl acetate (70 mL x 3). The combined organic phase was washed with water (40 mL x 2) and saturated brine (40 mL) successively and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 20: 1 ~ 4: 1) to give ethyl 2-butylpyrazolo[l,5-a]pyridine-3-carboxylate (114) (3.0 g). The yield was 76.9%. 1 H NMR (DMSO-d6, 400 MHz) δ: 8.78-8.76 (m, 1H), 8.04-8.01 (m, 1H), 7.55-7.53 (m, 1H), 7.11-7.07 (m, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 1.72-1.65 (m, 2H), 1.38-1.34 (m, 5H), 0.92 (t, J = 7.2 Hz, 3H).

[0205] Step B: A mixture containing compound 114 (3.0 g, 12.0 mmol), lithium hydroxide hydrate (1.50 g, 35.8 mmol), methanol (25 mL) and water (25 mL) was stirred at 60 °C overnight. Most of the solvent was removed under reduced pressure, water (60 mL) was added and the pH value was adjusted to 5-6 with 2M hydrochloric acid. Filtration was followed by suspending the filter cake in water (25 mL) and adding concentrated sulfuric acid (10 mL). After addition, the resulting mixture was stirred at 80 °C overnight. Cooling to room temperature, the pH value was adjusted to 8-9 with 2M sodium hydroxide solution and then extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 2-butylpyrazolo[l,5-a]pyridine (115) (1.40 g). The yield was 67.0%.

[0206] Step C: A mixture containing compound 115 (900 mg, 5.17 mmol), 4- methoxybenzoyl chloride (815 mg, 4.78 mmol) and aluminum trichloride (956 mg, 7.17 mmol) was stirred at 100 °C for 4 h. After cooling, ethyl acetate (30 mL) and water (30 mL) were added, then the pH value was adjusted to 9-10 with 2 M aqueous sodium hydroxide solution. The layers were separated, the aqueous layer was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with ethyl acetate: petroleum ether = 10:1-5:1) to give (2-butylpyrazolo[l,5-a]pyridin-3-yl)(4-methoxyphenyl)methanone (116) (600 mg). The yield was 40.6%.

[0207] The experimental procedures of Steps D, E, F and G refer to Steps C and D in Example 5 and Steps E and F in Example 1. (2-Butylpyrazolo[l,5-a]pyridin-3-yl){3,5-dibromo-4-[3- (diethylamino)propoxy]phenyl}methanone (120) was obtained. 1 H NMR (CDC13, 400 MHz) δ: 8.50-8.48 (m, 1H), 7.86 (s, 2H), 7.54-7.52 (m, 1H), 7.36-7.34 (m, 1H), 6.96-6.92 (m, 1H), 4.15 (t, J = 6.0 Hz, 2H), 2.87-2.80 (m, 4H), 2.66-2.64 (m, 4H), 2.13-2.10 (m, 2H), 1.72-1.64 (m, 2H), 1.37-1.33 (m, 2H), 1.10 (t, J = 7.2 Hz, 6H), 0.87 (t, J = 7.2 Hz, 3H). MS (m / z): 565.8 [M+H] + .

[0208] Example 34: Synthesis of (2-Butylpyrazolo[l,5-a]pyridin-3-yl){3,5-dibromo-4-[3- (cyclopentylamino)propoxy]phenyl}methanone (121)

[0209] The experimental procedures for synthesizing compound 121 using compound 119 and cyclopentylamine as starting materials refer to Step F in Example 1. 1H NMR (CDC13, 400 MHz) δ: 8.50-8.48 (m, 1H), 7.86 (s, 2H), 7.54-7.52 (m, 1H), 7.37-7.33 (m, 1H), 6.96-6.93 (m, 1H), 4.21 (t, J = 5.6 Hz, 2H), 3.45-3.41 (m, 1H), 3.31-3.27 (m, 2H), 2.87-2.83 (m, 2H), 2.48-2.45 (m, 2H), 2.11-2.08 (m, 2H), 1.70-1.62 (m, 6H), 1.37 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 4H). MS (m / z): 577.8 [M+H] + .

[0210] Example 35: Synthesis of (2-butylpyrazolo[l,5-a]pyridin-3-yl){3,5-dibromo-4-[3- (benzylamino)propoxy]phenyl}methanone (122)

[0211] The experimental procedure for the synthesis of compound 122 using compound 119 and benzylamine as starting materials is described in Step F in Example 1. MS (m / z): 600.0 [M+H] + .

[0212] Example 36: Synthesis of {3-bromo-4-[3-(diethylamino)propoxy]-5-nitrophenyl}(2- butylimidazo[l,2-a]pyridin-3-yl)methanone (128)

[0213] Step A: To a solution of 3-nitro-4-methoxyacetophenone (3.0 g, 15.4 mmol) in methanol (30 mL) was added bromine (2.70 g, 16.9 mmol) dropwise under ice water bath. After the addition was completed, the resulting mixture was stirred at 30 °C for 2 hours. The solvent was evaporated under reduced pressure and the resulting product was recrystallized from petroleum ether / ethyl acetate to give l-(4-methoxy-3-nitrophenyl)-2-bromoethan-l-one (123) (4.0 g). Yield: 94.8%.

[0214] Step B: A mixture containing compound 1 (2.80 g, 15.7 mmol), compound 123 (4.0 g, 14.6 mmol) and toluene (30 mL) was stirred at reflux overnight. Most of the toluene was removed under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added, then the pH value was adjusted to basic with 2 M sodium hydroxide solution. The layers were separated, the aqueous layer was extracted with ethyl acetate (50 mL). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 5: 1 ~ 1: 1) to give (4-methoxy-3-nitrophenyl) (2-butylimidazo[l,2-a]pyridin-3-yl)methanone (124) (1.40 g). The yield was 27.1%. 1 H NMR (DMSO-d6, 400 MHz) δ: 9.26-9.24 (m, 1H), 8.23 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 1H), 7.56-7.53 (m, 1H), 7.23-7.19 (m, 1H), 4.04 (s, 3H), 2.41 (t, J = 7.6 Hz, 2H), 1.58-1.54 (m, 2H), 1.12-1.07 (m, 2H), 0.71 (t, J = 7.6 Hz, 3H).

[0215] Step C: Boron tribromide (3.0 g, 12.0 mmol) was added dropwise to a solution of compound 124 (1.40 g, 3.96 mmol) in dichloromethane (14 mL) under an ice-water bath, after the addition was completed, the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water (50 mL) in batches, the pH value was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, then extracted with dichloromethane (40 mL x 3). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 5: 1 ~ 1: 1) to give (4-hydroxy-3-nitrophenyl) (2-butylimidazo[l,2-a]pyridin-3-yl)methanone (125) (650 mg). The yield was 48.4%.

[0216] Step D: NBS (375 mg, 2.11 mmol) was added to a solution of compound 125 (650 mg, 1.92 mmol) in acetonitrile (6 mL) in batches, after the addition was completed, the resulting mixture was stirred at room temperature for 1 hour. Filtration, the filter cake was eluted with 2 M sodium bisulfite solution, then recrystallized with acetonitrile to give (5-bromo-4-hydroxy-3-nitrophenyl) (2-butylimidazo[l,2-a]pyridin-3-yl)methanone (126) (700 mg). The yield was 87.2%.

[0217] The experimental operations of Steps E and F refer to Steps E and F in Example 1, to obtain {3-bromo-4-[3-(diethylamino)propoxy]-5-nitrophenyl}(2-butylimidazo[l,2- a]pyridin-3-yl)methanone (128). 1 H NMR (CDC13, 400 MHz) δ: 9.43-9.40 (m, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.74-7.71 (m, 1H), 7.56-7.52 (m, 1H), 7.11-7.08 (m, 1H), 4.28 (t, J = 6.0 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 2.63-2.58 (m, 4H), 2.51-2.47 (m, 2H), 2.10-2.05 (m, 2H), 1.71-1.66 (m, 2H), 1.26-1.17 (m, 2H), 1.07 (t, J = 7.2 Hz, 6H), 0.81 (t, J = 7.2 Hz, 3H). MS (m / z): 530.9 [M+H] + .

[0218] Example 37: Synthesis of {2-butyl-6-fluoroimidazo[l,2-a]pyrimidin-3-yl}{3,5-dibromo-4-{{l-[(diethylamino)methyl]cyclopropyl}methoxy}phenyl}methanone (130)

[0219] The experimental operations of synthesizing compound 130 refer to Steps E and F in Example 1, using compound 26 and l,l-bis-bromomethylcyclopropane as raw materials. 1 H NMR (CDC13, 400 MHz) δ: 9.63-9.61 (m, 1H), 8.76-8.75 (m, 1H), 7.53 (s, 2H), 4.10 (s, 2H), 2.62-2.54 (m, 7H), 1.78-1.70 (m, 2H), 1.26-1.20 (m, 2H), 1.01 (s, 6H), 0.83 (t, J = 7.2 Hz, 6H), 0.54 (s, 2H). MS (m / z): 610.7 [M+H] + .

[0220] Example 38: Synthesis of {2-(cyclopropylmethyl)imidazo[l,2-a]pyridin-3-yl}{3,5-dibromo-4-[3-(diethylamino)propoxy]phenyl}methanone (135)

[0221] The experimental operations for synthesizing compound 135 from p-methoxyacetophenone, ethyl cyclopropylacetate and 2-aminopyridine were carried out by referring to step A and B in example 5, step D in example 1 and step D and E in example 18 successively. Compound 133: 1 H NMR (DMSO-d6, 400 MHz) δ: 10.36 (s, 1H), 9.09-9.06 (m, 1H), 7.75-7.73 (m, 1H), 7.62-7.53 (m, 3H), 7.16-7.12 (m, 1H), 6.91-6.87 (m, 2H), 2.42 (d, J = 6.8 Hz, 2H), 0.99-0.92 (m, 1H), 0.34-0.30 (m, 2H), 0.03-(-)0.07 (m, 2H). Compound 135: 1 H NMR (CDC13, 400 MHz) δ: 9.37 (d, J = 7.2 Hz, 1H), 7.86 (s, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.54-7.49 (m, 1H), 7.09-7.05 (m, 1H), 4.17 (t, J = 6.0 Hz, 2H), 2.85 (s, 4H), 2.46 (d, J = 6.8 Hz, 2H), 2.26 (s, 2H), 1.38-1.34 (m, 8H), 1.08-1.03 (m, 1H), 0.49-0.47 (m, 2H), 0.09-0.07 (m, 2H). MS (m / z): 564.0 [M+H] + .

[0222] Example 39: Synthesis of {3-bromo-5-chloro-4-[3-(diethylamino)propoxy]phenyl}(2-butylimidazo[l,2-a]pyrimidin-3-yl)methanone (140)

[0223] The experimental operations for synthesizing compound 140 from 3-chloro-4-methoxyacetophenone, methyl pentanoate and 2-aminopyrimidine were carried out by referring to step A, B and C in example 5 and step D and E in example 18. 1H NMR (CDC13, 400 MHz) δ: 9.77-9.75 (m, 1H), 8.75-8.74 (m, 1H), 7.83-7.81 (m, 2H), 7.71-7.70 (m, 1H), 4.20-4.17 (m, 2H), 2.96 (s, 2H), 2.80 (s, 4H), 2.57-2.52 (m, 2H), 2.24-2.19 (m, 2H), 1.74-1.69 (m, 2H), 1.26-1.19 (m, 8H), 0.82 (t, J = 7.2 Hz, 3H). MS (m / z): 562.3 [M+Na+CH3CN] + .

[0224] Example 40: Synthesis of {3-chloro-4-[3-(diethylamino)propoxy]phenyl}(2-butylimidazo[l,2- a]pyrimidin-3-yl)methanone (141)

[0225] The experimental procedure for the synthesis of compound 141 from compound 138 is described in Step E in Example 18. 1 H NMR (CDC13, 400 MHz) δ: 9.77-9.75 (m, 1H), 8.75-8.74 (m, 1H), 7.83-7.81 (m, 2H), 7.71-7.70 (m, 1H), 4.20-4.17 (m, 2H), 2.96 (s, 2H), 2.80 (s, 4H), 2.57-2.52 (m, 2H), 2.24-2.19 (m, 2H), 1.74-1.69 (m, 2H), 1.26-1.19 (m, 8H), 0.82 (t, J = 7.2 Hz, 3H). MS (m / z): 562.3 [M+Na+CH3CN] + .

[0226] Example 41: Synthesis of (2-butylimidazo[l,2-a]pyrazin-3-yl){3,5-dibromo-4-[3- (diethylamino)propoxy]phenyl}methanone (146)

[0227] The experimental procedure for the synthesis of compound 146 from compound 18 and amino pyrazine is described in Steps B, C and D in Example 5 and Steps E and F in Example 1. 1H NMR (CDC13, 400 MHz) δ: 9.20 (d, J = 1.6 Hz, 1H), 9.09 (dd, J = 1.6, 4.4 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H), 7.89 (s, 2H), 4.16 (t, J = 6.4 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H), 2.69-2.64 (m, 4H), 2.59-2.55 (m, 2H), 2.17-2.10 (m, 2H), 1.75-1.67 (m, 2H), 1.28-1.21 (m, 2H), 1.11 (t, J = 7.2 Hz, 6H), 0.83 (t, J = 7.2 Hz, 3H). MS (m / z): 567.0 [M+H] + .

[0228] Example 42: Synthesis of (2-butylimidazo[l,2-a]pyridin-3-yl){4,6-dibromo-5-[3- (diethylamino)propoxy]pyridin-2-yl}methanone (152)

[0229] Step A: A mixture containing l-(5-methoxypyridin-2-yl)ethanone (12.7 g, 84.0 mmol), methyl pentanoate (11.7 g, 100 mmol), potassium tert-butoxide (19.8 g, 176 mmol) and THF (150 mL) was stirred at 50 °C overnight. Saturated brine (150 mL) was added, the pH value was adjusted to 4-5 with 2M citric acid solution, then extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 20: 1-4: 1) to give l-(5-methoxypyridin-2-yl)heptane-l,3-dione (147) (16.0 g). The yield was 81.0%.

[0230] Step B: lodobenzylidene acetate (25.3 g, 78.5 mmol) and boron trifluoride etherate (1.90 g, 13.4 mmol) were added to a solution of 2-aminopyridine (6.20 g, 65.9 mmol) and compound 147 (16.0 g, 68.1 mmol) in THF (120 mL) under ice-water bath. After addition, the resulting mixture was stirred at room temperature overnight. Saturated brine (120 mL) was added, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate (200 mL x 2). The combined organic layers were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, petroleum ether: ethyl acetate = 1:0 to 1:1). (2-Butylimidazo[l,2-a]pyridin-3-yl)(5-methoxypyridin-2-yl)methanone (148) (12.1 g) was obtained. The yield was 59.4%.

[0231] Step C: A mixture containing sodium ethanethiolate (15.8 g, 183 mmol), compound 148 (11.4 g, 36.9 mmol) and DMF (100 mL) was stirred at 60 °C overnight. After cooling to room temperature, water (400 mL) was added, and the pH value was adjusted to 5-6 with 2 M aqueous citric acid solution, followed by extraction with ethyl acetate (200 mL x 3). The combined organic phases were washed with water (150 mL x 2) and saturated brine (150 mL) successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, dichloromethane:methanol = 20:1). (2-Butylimidazo[l,2-a]pyridin-3-yl)(5-hydroxypyridin-2-yl)methanone (149) (5.80 g) was obtained. The yield was 53.2%.

[0232] Step D: Bromine (5.80 g, 36.3 mmol) was added dropwise to a solution of compound 149 (5.10 g, 17.2 mmol) and sodium acetate (5.60 g, 68.3 mmol) in acetic acid (50 mL) under water bath. After addition, the resulting mixture was stirred at room temperature for 1 h. Water (200 mL) was added, and the mixture was filtered. The filter cake was washed with saturated sodium bicarbonate solution and recrystallized from acetonitrile to give (2-butylimidazo[l,2-a]pyridin-3-yl)(4,6-dibromo-5-hydroxypyridin-2-yl)methanone (150) (6.0 g). The yield was 77.0%.

[0233] Step E: A mixture containing compound 150 (1.0 g, 2.21 mmol), potassium carbonate (610 mg, 4.41 mmol), 1,3-dibromopropane (2.20 g, 10.9 mmol) and DMF (10 mL) was stirred at 75 °C for 2 h. Water (40 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (15 mL x 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, eluted with petroleum ether: ethyl acetate = 20: 1 ~ 2: 1) to give (2-butylimidazo[l,2-a]pyridin-3-yl)[4,6-dibromo-5-(3-bromopropoxy)pyridin-2-yl]methanone (151) (210 mg). Yield 16.6%. 1 H NMR (CDC13, 400 MHz) δ: 9.49-9.47 (m, 1H), 8.02 (s, 1H), 7.72-7.69 (m, 1H), 7.54-7.49 (m, 1H), 7.09-7.05 (m, 1H), 4.30 (t, J = 5.6 Hz, 2H), 3.85 (t, J = 6.4 Hz, 2H), 2.50-2.46 (m, 4H), 1.76-1.68 (m, 2H), 1.29-1.21 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

[0234] Step F: A solution of compound 151 (210 mg, 0.366 mmol) and diethylamine (4 mL) in THF (2 mL) was stirred at 40 °C overnight. Water (10 mL) was added and extracted with ethyl acetate (10 mL x 3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (200-300 mesh silica gel, dichloromethane:methanol = 50: 1 ~ 20: 1) to give (2-butylimidazo[l,2-a]pyridin-3-yl){4,6-dibromo-5-[3-(diethylamino)propoxy]pyridin-2-yl}methanone (152). 1H NMR (CDC13, 400 MHz) δ: 9.64-9.63 (m, 1H), 8.21 (s, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.53-7.49 (m, 1H), 7.11-7.07 (m, 1H), 4.25 (t, J = 5.6 Hz, 2H), 3.46-3.41 (m, 2H), 3.22-3.20 (m, 4H), 2.84 (t, J = 7.6 Hz, 2H), 2.59-2.52 (m, 2H), 1.73-1.63 (m, 2H), 1.49 (t, J = 7.2 Hz, 6H), 1.34-1.24 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H). MS (m / z): 567.0 [M+H] + .

[0235] Example 43: Pharmacodynamic test of compounds on SD rat atrial fibrillation model

[0236] 1. Materials and methods

[0237] 1.1 Materials

[0238] 1.1.1 Reagents and instruments

[0239] Compound 6, compound 9 and compound 17 were prepared into 5 mg / mL suspensions. Preparation method: an appropriate amount of compound was added into a DMSO solution according to the required concentration to dissolve completely (so that the final concentration of DMSO was 5%), and then the remaining volume of 0.5% CMC-Na solution was added. The mixture was stirred uniformly by a magnetic stirrer to prepare the required concentration of suspension. The suspension was continuously stirred by a magnetic stirrer before administration.

[0240] Dronedarone hydrochloride tablets (400 mg / tablet, purchased from Sanofi Winthrop Industrie) were prepared into 5 mg / mL suspensions with 0.5% CMC-Na solution.

[0241] 66 μg / mL Ach and 10 mg / mL CaCl2 mixed solution preparation method: an appropriate amount of acetylcholine chloride powder was weighed into a brown narrow-mouth bottle, and then an appropriate amount of 10 mg / mL CaCl2 solution was added to prepare a 66 μg / mL Ach and 10 mg / mL CaCl2 mixed solution.

[0242] The main instrument was a multi-channel physiological recorder purchased from BIOPAC Company, USA, model MP160.

[0243] 1.1.2 Experimental animals

[0244] SD rats, 45 male, body weight 240-300 g (Sichuan Weitong Lihua Experimental Animal Technology Co., Ltd.); Each group of rats was normally fed in the animal room for 1 week before the experiment, and then modeling was performed.

[0245] 1.2 Method and modeling

[0246] SD rats were divided into blank control group and modeling group according to body weight, and the modeling group was injected with a mixture of acetylcholine and calcium chloride in the tail vein (66 μg / kg Ach and 10 mg / kg CaCl2 mixed solution) for modeling, and the modeling was performed for 7 days in succession; The electrocardiogram of the rats was recorded by a multi-channel physiological recorder, and the typical atrial fibrillation change (unequal R-R interval, P wave disappearance, and appearance of small f wave) was used as the modeling success, and the modeling successful rats were grouped according to the duration of atrial fibrillation, 8 rats in each group, and the corresponding test substance was given once a day by gavage; The blank control group and the model group were both given 0.5% CMC-Na solution, and the test substance group and the dronedarone group were given 50 mg / kg of test substance or dronedarone, respectively.

[0247] The modeling was continued during the administration, and the administration was performed for three weeks. In the second and third weeks after the administration, the electrocardiogram of the rats was recorded by a multi-channel physiological recorder 1 h after oral administration of the rats, and the effect of the test substance on the duration of atrial fibrillation was evaluated.

[0248] 1.3 Electrocardiogram (lead II) examination

[0249] The rats were anesthetized with 1-3% isoflurane and maintained until their breathing was stable, and needle electrodes were inserted subcutaneously into the limbs of the rats; The mixed solution of acetylcholine chloride and calcium chloride was injected into the tail vein, and lead II electrocardiogram was detected by a multi-channel physiological recorder at the same time, and the duration of atrial fibrillation of each group of rats was analyzed and recorded; The atrial fibrillation time was defined: the typical atrial fibrillation wave f wave and P wave disappearance in electrocardiogram were used as the atrial fibrillation occurrence mark, and the recovery of sinus rhythm, i.e. f wave disappearance and P wave appearance, was used as the termination of atrial fibrillation, and the time from the beginning to the end was the duration of atrial fibrillation occurrence.

[0250] 1.4 Statistical analysis

[0251] The quantitative indicators such as the duration of atrial fibrillation were described by mean ± standard deviation (X ± SD). For normal and variance equal groups, single factor variance analysis (ANOVA) was used first, and further multiple comparisons between groups used Tukey's HSD test; For groups not meeting normal distribution or variance, Kruskal-Wallis H test (K-W method) was used for analysis, and multiple comparisons between groups used Dunn's method. P<0.05 was considered to have statistical significance.

[0252] 2. Results

[0253] 2.1 Effect of test substance on duration of atrial fibrillation in rats

[0254] Figure 1 shows that the average duration of atrial fibrillation of each modeling group of rats is about 12-13 s after tail vein injection of acetylcholine and calcium chloride mixture for 7 days, and the average duration of atrial fibrillation of the blank control group is 0 s, indicating that the rat atrial fibrillation model is successfully established.

[0255] In the second week after administration, the efficacy of compounds 9 and 17 in significantly inhibiting the duration of atrial fibrillation was observed compared with the model group. In the third week after administration, the efficacy of compounds 6, 9 and 17 in significantly inhibiting the duration of atrial fibrillation was observed compared with the model group, and the efficacy was more obvious compared with that of dildalol; and the duration of atrial fibrillation of the compound 9 group was less than the baseline duration of atrial fibrillation at the time of grouping, indicating that the compound had a significant therapeutic effect on rat atrial fibrillation.

[0256] Example 44: Efficacy test of compounds on SD rat atrial fibrillation model

[0257] 1. Materials and methods

[0258] 1.1 Materials

[0259] 1.1.1 Reagents and instruments

[0260] Compound 28, compound 40, prepared as a suspension of 5 mg / mL. Preparation method: take an appropriate amount of compound, first add DMSO solution until it is completely dissolved (so that the final concentration of DMSO is 5%), then add the remaining volume of 0.5% CMC-Na solution, continuously stir with a magnetic stirrer to mix evenly, and prepare a suspension of the required concentration. Before administration, it needs to be continuously stirred and mixed evenly with a magnetic stirrer.

[0261] Dronedarone hydrochloride tablets (400 mg / tablet, purchased from Sanofi Winthrop Industrie), amiodarone hydrochloride (batch number A129574, purchased from Aladdin Reagent (Shanghai) Co., Ltd.), prepared as a suspension of 5 mg / mL with 0.5% CMC-Na solution.

[0262] 66 μg / mL Ach and 10 mg / mL CaCl2 mixed solution preparation method: weigh an appropriate amount of acetylcholine chloride powder into a brown narrow-mouth bottle, and then prepare a 66 μg / mL Ach and 10 mg / mL CaCl2 mixed solution by adding an appropriate amount of 10 mg / mL CaCl2 solution.

[0263] The main instrument is a multi-channel physiological recorder, purchased from BIOPAC Company, USA, model MP160.

[0264] 1.1.2 Experimental animals

[0265] SD rats, 48 male, body weight 240-300g (Sichuan Weitong Lihua Experimental Animal Technology Co., Ltd.); Each group of rats was normally fed in the animal room for 1 week before the experiment, and then modeling was performed.

[0266] 1.2 Method and modeling

[0267] SD rats were divided into blank control group and modeling group according to body weight, and the modeling group was injected with a mixture of acetylcholine and calcium chloride in the tail vein (66 μg / kg Ach and 10 mg / kg CaCl2 mixed solution) for modeling, and the modeling was performed for 7 days in succession; The electrocardiogram of the rats was recorded by a multi-channel physiological recorder, and the typical atrial fibrillation change (unequal R-R interval, P wave disappearance, and appearance of small f wave) was used as the modeling success, and the modeling successful rats were grouped according to the duration of atrial fibrillation, 8 rats in each group, and the corresponding test substance was given once a day by gavage; Among them, the blank control group and the model group were given 0.5% CMC-Na solution, and the test substance group, the dronedarone group and the amiodarone group were given 50 mg / kg of the test substance, hydrochloric acid dronedarone and hydrochloric acid amiodarone respectively.

[0268] During the administration period, the modeling was continued, and the administration was performed for three weeks. In the second and third weeks after administration, the electrocardiogram of the rats was recorded by a multi-channel physiological recorder 1 hour after oral administration of the rats, and the effect of the test substance on the duration of atrial fibrillation was evaluated.

[0269] 1.3 Electrocardiogram (lead II) examination

[0270] The rats were anesthetized with 1-3% isoflurane and waited for stable breathing, and then needle electrodes were inserted subcutaneously into the limbs of the rats; The mixed solution of acetylcholine chloride and calcium chloride was injected into the tail vein, and the lead II electrocardiogram was detected by a multi-channel physiological recorder at the same time, and the duration of atrial fibrillation of each group of rats was analyzed and recorded; The atrial fibrillation time is defined: the typical atrial fibrillation wave f wave and P wave disappearance in electrocardiogram are used as the atrial fibrillation occurrence mark, and the recovery of sinus rhythm, i.e. f wave disappearance and P wave appearance, is used as the atrial fibrillation termination, and the time from the beginning to the end is the duration of the occurrence of atrial fibrillation.

[0271] 1.4 Statistical analysis

[0272] The quantitative indicators such as the duration of atrial fibrillation were expressed as mean ± standard deviation Description. The comparison among multiple groups with normal distribution and equal variance first uses one-way ANOVA (ANOVA), and further multiple comparisons between groups use Tukey's HSD test; If it does not satisfy the normal distribution or the variance is not equal, Kruskal-Wallis H test (K-W method) is used for analysis, and multiple comparisons between groups use Dunn's method. P<0.05 is statistically significant.

[0273] 2. Results

[0274] 2.1 Effect of the test substance on the duration of atrial fibrillation in rats

[0275] Figure 2 shows that the average duration of atrial fibrillation of each modeling group of rats was 13.74±3.43s after tail vein injection of acetylcholine and calcium chloride mixture for 7 days, while the average duration of atrial fibrillation of the blank control group was 0s, indicating that the rat atrial fibrillation model was successfully established.

[0276] In the second and third weeks after administration, compared with the model group, the efficacy of compounds 28 and 40 in significantly inhibiting the duration of atrial fibrillation was more obvious than that of decanidaron and amiodarone; the duration of atrial fibrillation of the compound 28 and compound 40 groups was less than the baseline atrial fibrillation duration at the time of grouping, indicating that the compounds had obvious therapeutic effect on rat atrial fibrillation.

[0277] Example 45: Efficacy test of compounds on SD rat atrial fibrillation model

[0278] 1. Materials and methods

[0279] 1.1 Materials

[0280] 1.1.1 Reagents and instruments

[0281] Compound 23, compound 55, prepared as a suspension of 5mg / mL. Preparation method: take an appropriate amount of compound, first add DMSO solution until it is completely dissolved (make the final concentration of DMSO 5%), then add the remaining volume of 0.5% CMC-Na solution, continuously stir with a magnetic stirrer to mix evenly, prepare the suspension of the required concentration, and continuously stir with a magnetic stirrer before administration.

[0282] Dronedarone hydrochloride tablets (400mg / tablet, purchased from Sanofi Winthrop Industrie), amiodarone hydrochloride (batch number A129574, purchased from Aladdin Reagent (Shanghai) Co., Ltd.), prepared as a suspension of 5mg / mL with 0.5% CMC-Na solution.

[0283] 66μg / mL Ach and 10mg / mL CaCl2 mixed solution preparation method: weigh an appropriate amount of acetylcholine chloride powder into a brown narrow-mouth bottle, add an appropriate amount of 10mg / mL CaCl2 solution to prepare a 66μg / mL Ach and 10mg / mL CaCl2 mixed solution;

[0284] The main instrument is a multi-channel physiological recorder, purchased from BIOPAC Company, USA, model MP160.

[0285] 1.1.2 Experimental animals

[0286] SD rats, 48 male, weighing 240-300 g (Sichuan Weitong Lihua Experimental Animal Technology Co., Ltd.); Each group of rats was normally fed in the animal room for 1 week before the experiment, and then modeling was performed.

[0287] 1.2 Method and modeling

[0288] SD rats were divided into blank control group and modeling group according to body weight, and the modeling group was injected with a mixture of acetylcholine and calcium chloride in the tail vein (66 μg / kg Ach and 10 mg / kg CaCl2 mixed solution) for modeling, and the modeling was performed for 7 days in succession; The electrocardiogram of the rats was recorded by a multi-channel physiological recorder, and the typical atrial fibrillation change (unequal R-R interval, P wave disappearance, and appearance of small f wave) was used as the modeling success, and the modeling successful rats were grouped according to the duration of atrial fibrillation, 8 rats in each group, and the corresponding test substance was given once a day by gavage; Among them, the blank control group and the model group were given 0.5% CMC-Na solution, and the test substance group, the dronedarone group and the amiodarone group were given 50 mg / kg of the test substance, hydrochloric acid dronedarone and hydrochloric acid amiodarone respectively.

[0289] During the administration period, the modeling was continued, and the administration was performed for three weeks. In the second and third weeks after administration, the electrocardiogram of the rats was recorded by a multi-channel physiological recorder 1 hour after oral administration of the rats, and the effect of the test substance on the duration of atrial fibrillation was evaluated.

[0290] 1.3 Electrocardiogram (lead II) examination

[0291] The rats were anesthetized with 1-3% isoflurane and waited for stable breathing, and then needle electrodes were inserted subcutaneously into the limbs of the rats; The mixed solution of acetylcholine chloride and calcium chloride was injected into the tail vein, and the lead II electrocardiogram was detected by a multi-channel physiological recorder at the same time, and the duration of atrial fibrillation of each group of rats was analyzed and recorded; The atrial fibrillation time is defined: the typical atrial fibrillation wave f wave and P wave disappearance in electrocardiogram are used as the atrial fibrillation occurrence mark, and the recovery of sinus rhythm, i.e. f wave disappearance and P wave appearance, is used as the atrial fibrillation termination, and the time from the beginning to the end is the duration of the occurrence of atrial fibrillation.

[0292] 1.4 Statistical analysis

[0293] The quantitative indicators such as the duration of atrial fibrillation were expressed as mean ± standard deviation Description. For normal and variance equal multiple comparisons, single factor variance analysis (ANOVA) was used first, and further multiple comparisons between groups used Tukey's HSD test; If not normal distribution or variance is not equal, Kruskal-Wallis H test (K-W method) is used for analysis, and multiple comparisons between groups use Dunn's method. P<0.05 is statistically significant.

[0294] 2. Results

[0295] 2.1 Effect of the test substance on the duration of atrial fibrillation in rats

[0296] Figure 3 shows that the average duration of atrial fibrillation of each modeling group of rats was 13.1 ± 4.2 s after intravenous injection of acetylcholine and calcium chloride mixture for 7 days, while the average duration of atrial fibrillation of the blank control group was 0 s, indicating that the rat atrial fibrillation model was successfully established.

[0297] In the second and third weeks after administration, compared with the model group, the efficacy of significantly inhibiting the duration of atrial fibrillation of the compound 23 and compound 55 groups was more obvious than that of decanidaron and amiodarone; the duration of atrial fibrillation of the compound 23 and compound 55 groups was less than the basic duration of atrial fibrillation at the time of grouping, indicating that the compounds had obvious therapeutic effect on rat atrial fibrillation.

[0298] The same test was also performed on the compounds obtained in Examples 3, 9, 11-19, 21-24, 26-27, 30-34, 37-39, and 41, and the duration of atrial fibrillation of each compound group on the 14th day of the administration period was better than or similar to that of decanidaron.

[0299] Example 46: Compound toxicity test on in vitro cynomolgus monkey lung organoids

[0300] 1. Reagents and consumables

[0301] 2. Experimental method

[0302] Cynomolgus monkey lung organoids (CmLOs) were derived from cynomolgus monkey lung tissue, organoids were embedded in Matrigel and cultured using complete medium. Cynomolgus monkey organoids were dissociated into a uniform size of organoid cluster suspension by continuous mechanical blowing and centrifugation (250g, 5min, 4℃; 2 times), and resuspended in organoid complete medium containing Matrigel and cultured at 37℃, 5% CO2. On Day-2, 70 cynomolgus monkey lung organoid clusters / well were plated in a 96-well culture plate using 120uL / well of complete medium, and on Day 0, amiodarone, compound 23, compound 28 and compound 55 were diluted with DMSO to obtain a final concentration of 4.8, 19.5, 78.1, 19.5, 312.5, 312.5, 1250, 5000 and 20000 nM of the compounds for incubation with the organoids, with 0.5% DMSO as the negative control. On Day 2, Day 4 and Day 6, the organoid complete medium and test compounds were replaced. On Day 7, the cell viability (3D) of the cynomolgus monkey organoids was detected using the CTG (3D) cell viability kit, and the IC 50 .

[0303] 3. Experimental results

[0304] Amiodarone-induced organoid cell viability (3D) IC of cynomolgus monkey lung organoids after treatment with different compounds 50 The cell activity (3D) IC50 of compound 23, compound 28 and compound 55 were significantly higher than that of amiodarone, indicating that compared with amiodarone, the compounds of the present invention can significantly improve the safety of the lungs. The experimental results are shown in Table 1.

[0305] Table 1: Cell viability of compounds in cynomolgus monkey lung organoids (3D)

[0306] Example 47: Pharmacokinetics of the compound in SD rats

[0307] 1. Materials and Methods

[0308] Appropriate amounts of amiodarone, compound 23, compound 28, and compound 55 solid powders were weighed separately, and a certain volume of solvent (5% DMSO + 15% Solutol HS15 + 85% saline) was added. Vortex and sonicate to obtain 0.5 mg / mL and 1 mg / mL solutions for intravenous injection and oral administration to experimental animals.

[0309] SD rats, male, SPF grade, 6-8 weeks old, were purchased from JH Laboratory Animal Co. LTD. License number: SCXK(SH)2022-0009, certificate number: 20220009024966.

[0310] Animals were fasted overnight before oral administration and were fed again 4 hours after administration, with free access to water. Two groups were assigned for each test compound: an intravenous administration group and an oral administration group. The intravenous administration group received a 0.5 mg / mL concentration of 1 mg / kg in a 2 mL / kg dosing volume. The oral administration group received a 1 mg / mL concentration of 1 mg / mL in a 10 mL / kg dosing volume.

[0311] Blood samples (150 μL / sample) were collected from the jugular vein of SD rats before and 5 minutes (intravenous administration group only), 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration. The samples were placed in a centrifuge tube containing the anticoagulant sodium heparin and centrifuged at 4°C, 2000g for 5 minutes to separate the plasma. The plasma samples were analyzed by LC / MS / MS to detect the concentration of each test compound in the plasma samples. The non-compartmental model-related parameters were determined by Calculated using Professional software.

[0312] The formula for calculating bioavailability is F% = (Dose (IV) ×AUC(0-t)(PO) ) / (Dose (PO) x AUC (0-t)(IV) ) x 100%.

[0313] 2. Experimental results

[0314] The SD rat pharmacokinetic parameters of each compound obtained according to the above method are shown in Table 2. The pharmacokinetic parameters of each compound of the present application are good. Compared with amiodarone, the bioavailability of each compound is higher, and the reduction of half-life does not easily cause accumulation in vivo.

[0315] Table 2. SD rat pharmacokinetic parameters of each compound administered orally or intravenously *: calculated from AUC INF

[0316] The above examples are only used to illustrate the technical solutions of the present application, and are not intended to limit the present application; although the present application has been described in detail with reference to the foregoing examples, it should be understood by those skilled in the art that the technical solutions described in the foregoing examples can still be modified, or some of the technical features can be replaced by equivalents; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.​

Claims

1. A compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 selected from hydrogen or substituted or non-substituted: C 1～7 alkyl, C 3～8 cycloalkyl or C 2～6 heterocycloalkyl; R 2 selected from hydrogen or substituted or non-substituted: C 1～7 alkyl, C 3～8 cycloalkyl or C 2～6 heterocycloalkyl; or R 1 with R 2 at the end of the chain form a substituted or unsubstituted heterocycle; Z is selected from substituted or non-substituted C 2～5 alkylene; X is selected from O or methylene; R 3 or R 5 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, C 1～3 alkyl, C 1～3 substituted alkyl, C 1～3 substituted amino, C 1～3 alkoxy or C 1～3 substituted alkoxy; R 4 or R 6 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, C 1～3 alkyl, C 1～3 substituted alkyl, C 1～3 substituted amino, C 1～3 alkoxy or C 1～3 substituted alkoxy; R 7 selected from hydroxyl, halogen, amino, carboxyl, substituted or non-substituted C 1～8 alkyl, substituted or non-substituted C 3～8 cycloalkyl, substituted or non-substituted C 1～4 alkoxy, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylamino, substituted or non-substituted C 1～8 alkylamino-C 1～4 alkylene; A 1 selected from N or C-R 8 , R 8 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 alkylene; A 2 selected from N or C-R 9 , R 9 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 alkylene; A 3 selected from N or C-R 10 , R 10 is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 alkylene; A 4 selected from N or C-R 11 , R 11 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, substituted or non-substituted aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylaminocarbonyl, substituted or non-substituted C 1～8 alkylaminocarbonyl-C 1～4 alkylene; A 5 selected from N or C, A 6 selected from C or N, and A 5 and A 6 are not simultaneously N or C; And, when R 1 and R 2 All C 3～6 When alkyl, A 1 、A 2 、A 3 and A 4 At least one of them is N or R 8 、R 9 、R 10 and R 11 At least one of them is nitro, amino, cyano, C 1～3 Substituted amino or C 1～3 Alkylsulfonylamino, or R 3 、R 4 、R 5 and R 6 At least one of them is cyano, or Z or R 7 Contains substituents; In R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , Z, A 1 , A 2 , A 3 , A 4 the substituents are selected from one or more of deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 1-3 alkyl, haloC 1-3 alkyl, deuterated C 1-3 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, deuterated C 3-6 cycloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, deuterated C 1-3 alkoxy, aryl.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein is selected from a compound represented by Formula (II) or Formula (III), or a pharmaceutically acceptable salt thereof, 3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is selected from hydrogen or substituted or unsubstituted: C 1～7 alkyl, C 3～6 cycloalkyl, or C 2～6 heterocycloalkyl; preferably, R 1 is hydrogen or substituted or unsubstituted: C 1～7 alkyl, C 3～6 cycloalkyl, thiazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, piperidinyl, tetrahydrothiophenyl, or hexahydropyrimidinyl; R 2 is selected from hydrogen or substituted or unsubstituted: C 1～7 alkyl, C 3～6 cycloalkyl, or C 2～6 heterocycloalkyl; preferably, R 2 is hydrogen or substituted or unsubstituted: C 1～7 alkyl, C 3～6 cycloalkyl, thiazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, piperidinyl, tetrahydrothiophenyl, or hexahydropyrimidinyl; or R 1 With R 2 The ends of the substituted or unsubstituted C 2～6 Heterocycloalkyl; preferably, or R 1 With R 2 The ends of the groups are connected to form a substituted or unsubstituted group: thiazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, piperidinyl, tetrahydrothiophenyl or hexahydropyrimidinyl; R 1 , R 2 or the substituents in Z are selected from deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 1-3 alkyl, haloC 1-3 alkyl, deuterated C 1-3 alkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, phenyl or pyridyl.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 or R 2 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C 1～2 alkyl, C7alkyl, C 3～6 cycloalkyl, or C 2～6 heterocycloalkyl; or R 1 or R 2 are each independently selected from the group consisting of hydrogen or a substituted or unsubstituted C 1～7 alkyl, C 3～8 cycloalkyl or C 2～6 heterocycloalkyl group, and R 1 and R 2 are not simultaneously a C 3～6 alkyl group; or R 1 or R 2 are each independently selected from the group consisting of hydrogen or substituted or unsubstituted C 1～7 alkyl, C 3～8 cycloalkyl or C 2～6 heterocycloalkyl, and when R 1 and R 2 are both C 3～6 alkyl, at least one of A 1 , A 2 , A 3 and A 4 is N, or at least one of R 8 , R 9 , R 10 and R 11 is nitro, amino, cyano, C 1～3 substituted amino or C 1～3 alkylsulfonylamino, or at least one of R 3 , R 4 , R 5 and R 6 is cyano, or contains a substituent in Z or R 7 .

5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 3 or R 5 are each independently selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, nitro, amino, cyano, C 1～3 alkyl or C 1～3 substituted alkyl; R 4 or R 6 are each independently selected from hydrogen, deuterium, hydroxyl, halogen, nitro, amino, or cyano; R 7 selected from carboxyl, substituted or non-substituted C 1～8 alkyl, substituted or non-substituted C 1～4 alkoxy, substituted or non-substituted C 1～8 alkoxycarbonyl, substituted or non-substituted C 1～8 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～8 alkylamino, substituted or non-substituted C 1～8 alkylamino-C 1～4 one of alkylene, R 3 , R 5 , or R 7 is selected from one or more of deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 3-6 cycloalkyl, deuterated C 3-6 cycloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R 7 selected from substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 1～6 alkoxy, substituted or unsubstituted C 1～4 alkylene, aminocarbonyl-C 1～4 alkylene, substituted or unsubstituted C 1～8 alkylamino, substituted or unsubstituted C 1～4 alkylene, substituted or unsubstituted C A 1 selected from N or C-R 8 , R 8 is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～6 alkoxycarbonyl, substituted or non-substituted C 1～6 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～ 4alkylene, substituted or non-substituted C 1～6 alkylaminocarbonyl, substituted or non-substituted C 1～6 alkylaminocarbonyl-C 1～4 alkylene; A 2 selected from C-R 9 , R 9 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～6 alkoxycarbonyl, substituted or non-substituted C 1～6 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～6 alkylaminocarbonyl, substituted or non-substituted C 1～6 alkylaminocarbonyl-C 1～4 alkylene; A 3 selected from C-R 10 , R 10 is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～6 alkoxycarbonyl, substituted or non-substituted C 1～6 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～6 alkylaminocarbonyl, substituted or non-substituted C 1～6 alkylaminocarbonyl-C 1～4 alkylene; A 4 selected from N or C-R 11 , R 11 is selected from hydrogen, deuterium, hydroxyl, halogen, nitro, cyano, carboxyl, substituted or non-substituted amino, substituted or non-substituted C 1～3 alkyl, substituted or non-substituted C 1～3 alkoxy, substituted or non-substituted C 1～3 alkylsulfonamido, substituted or non-substituted C 1～6 alkoxycarbonyl, substituted or non-substituted C 1～6 alkoxycarbonyl-C 1～4 alkylene, aminocarbonyl, substituted or non-substituted aminocarbonyl-C 1～4 alkylene, substituted or non-substituted C 1～6 alkylaminocarbonyl, substituted or non-substituted C 1～6 alkylaminocarbonyl-C 1～4 alkylene; wherein R 8 , R 9 , R 10 , R 11 is selected from one or more of deuterium, halogen, cyano, hydroxyl, nitro, amino, carboxyl, C 1-3 alkyl, haloC 1-3 alkyl, deuterated C 1-3 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, deuterated C 3-6 cycloalkyl, C 1-3 alkoxy, haloC 1-3 alkoxy, deuterated C 1-3 alkoxy.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound comprises:

8. A pharmaceutical composition comprising the compound, isomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 as an active ingredient, in combination with a pharmaceutically acceptable adjuvant.

9. Use of the compound, isomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 for the manufacture of a medicament for treating atrial fibrillation.

10. Use of the compound, isomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 for the manufacture of a medicament for treating arrhythmia.

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