Bicyclic derivative regulator, preparation method and application thereof

Abstract

A bicyclic compound represented by general formula (I) or its stereoisomer, a preparation method thereof and a pharmaceutical composition containing the compound, and use thereof in preparing drugs for treating cardiovascular diseases, digestive system diseases, central nervous system diseases and / or mental diseases.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a bicyclic derivative regulator and a preparation method and application thereof. Background Art

[0002] Depression is a common mental disorder that recurs and seriously impairs patients' ability to live in daily life. Despite extensive research, the exact neurobiological processes that lead to depression and the mechanisms by which antidepressants produce therapeutic effects are still not fully understood. Nearly 20% of people will suffer from depression at different stages of their lives. Currently, about 350 million people suffer from depression, and the number is gradually increasing. Existing drugs are often not effective in treating major depression. At least 30% of depressed patients do not achieve satisfactory results, and less than 50% of patients achieve remission. Therefore, there is a huge market demand for antidepressant drugs.

[0003] Clinically, it has been found that depression is often related to biological rhythms, and it may have an antidepressant effect by regulating circadian rhythms. Agomelatine, developed by Servier, is the only approved melatonin receptor agonist antidepressant. It has a strong agonist effect on melatonin MT1 and MT2 receptors, and an antagonist effect on 5-HT2C receptors. Melatonin receptors have the function of regulating circadian rhythms and sleep, and 5-HT2C receptors are involved in antidepressant functions. It has been clinically proven to have significant antidepressant effects, good tolerance and compliance, and can increase the continuity and quality of sleep in patients with major depressive disorder (MDD), and sexual dysfunction is significantly less than other antidepressants.

[0004] Agomelatine is a multi-target antidepressant with a new mechanism target, which has a good antidepressant effect, but its bioavailability is low (about 5%), and it has a significant first-pass effect in the liver. After absorption, 90% is metabolized by CYP1A2 enzyme, and 10% is metabolized by CYP2C9 enzyme, which can cause liver damage in individual differences. Clinically, Agomelatine has been found to have adverse effects on liver enzymes. More than 1% of patients will experience elevated ALT / AST (more than 3 times the upper limit of normal), and the increase is dose-dependent. The exposure of patients with mild and severe liver damage is significantly increased, causing further damage to liver function.

[0005] International application WO2019011279A1 reported the preclinical bioactivity data of compounds with MT1, MT2 agonists and 5-HT2C antagonists, showing improved absolute bioavailability, but no corresponding drugs have been marketed. Therefore, it is urgent to develop new antidepressant drugs with low first-pass liver effect, high absolute bioavailability, MT1 and MT2 receptor agonist activity and 5-HT2C antagonist activity to meet the huge market demand. Summary of the invention

[0006] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as follows:

[0007]

[0008] in:

[0009] M1 is N or CR1;

[0010] M2 is N or CR2;

[0011] M3 is N or CR3;

[0012] R1, R2 and R3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0013] R is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0014] R4, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0015] R7 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0016] R8, R8', R9 and R9' are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0017] Alternatively, any two of R8, R8', R9, R9' and the carbon atom to which they are connected form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl group may be further substituted.

[0018] In a further preferred embodiment of the present invention, the Selected from

[0019] In a further preferred embodiment of the present invention, R9 and R9' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0020] Alternatively, R9 and R9' together may form an oxo group or a thio group;

[0021] Alternatively, R9 and R9' together with the carbon atoms on which they are located form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may be substituted by one or more substituents.

[0022] In a preferred embodiment of the present invention, when M1 is CR1, M2 is CR2, and M3 is CR3, at least one of R2 and R3 is not hydrogen, and when M1 is CR1, M2 is CR2, M3 is CR3, and R is selected from C 1-6 Alkyl, deuterated methyl, and When R3 is not hydrogen.

[0023] In a further preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound is further represented by general formula (II):

[0024]

[0025] in:

[0026] R is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 is substituted by one or more substituents of aryl or 5-14 membered heteroaryl;

[0027] R1, R2 and R3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 is substituted by one or more substituents of aryl or 5-14 membered heteroaryl;

[0028] R4, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 is substituted by one or more substituents of aryl or 5-14 membered heteroaryl;

[0029] R7 is selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 is substituted by one or more substituents of aryl or 5-14 membered heteroaryl;

[0030] R8 and R8' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 is substituted by one or more substituents of aryl or 5-14 membered heteroaryl;

[0031] Alternatively, R8 and R8' are linked to form a C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group or the 5-14 membered heteroaryl group is substituted by one or more substituents.

[0032] In a preferred embodiment of the present invention, at least one of R2 and R3 is not hydrogen, and when R is selected from C 1-6 Alkyl, deuterated methyl, and When R3 is not hydrogen.

[0033] In a further preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, is characterized in that the compound is further represented by general formula (II-A):

[0034]

[0035] in:

[0036] M1 is N or CR1, preferably N or CH;

[0037] R is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0038] R1, R2 and R3 are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0039] R9 and R9' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12Cycloalkyl or 3-12 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 substituted by one or more substituents of aryl and 5-14 membered heteroaryl;

[0040] Alternatively, R9 and R9' together may form an oxo group or a thio group;

[0041] Alternatively, R9 and R9' together with the carbon atoms on which they are located form C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group may be substituted by one or more substituents.

[0042] In a preferred embodiment of the present invention, when M1 is CR1, at least one of R2 and R3 is not hydrogen, and when M1 is CR1, R is selected from C 1-6 Alkyl, deuterated methyl, and When R3 is not hydrogen.

[0043] In a preferred embodiment of the present invention, the R is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl and 3-12 membered heterocyclic groups, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 The aryl group and the 5- to 14-membered heteroaryl group are substituted by one or more substituents.

[0044] In a further preferred embodiment of the present invention, said R is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 The cycloalkyl group or the 3-8 membered heterocyclic group is substituted by one or more substituents.

[0045] In a further preferred embodiment of the present invention, the R is selected from deuterated methyl, ethyl, n-propyl, isopropyl, tert-butyl, tert-pentyl, 3-pentyl, cyclopropyl or oxetanyl, and the ethyl, n-propyl, isopropyl, tert-butyl, tert-pentyl, 3-pentyl, cyclopropyl or oxetanyl is further substituted with deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-8 The cycloalkyl group or the 3-8 membered heterocyclic group is substituted by one or more substituents.

[0046] In a preferred embodiment of the present invention, R1, R2 and R3 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group.

[0047] In a further preferred embodiment of the present invention, R1, R2 and R3 are each independently selected from hydrogen, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group.

[0048] In a further preferred embodiment of the present invention, R1, R2 and R3 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or tert-butyl.

[0049] In a preferred embodiment of the present invention, R4, R5 and R6 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group.

[0050] In a further preferred embodiment of the present invention, R4, R5 and R6 are each independently selected from hydrogen, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group.

[0051] In a further preferred embodiment of the present invention, R4, R5 and R6 are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or tert-butyl.

[0052] In a preferred embodiment of the present invention, R7 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group.

[0053] In a further preferred embodiment of the present invention, said R7 is selected from C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group.

[0054] In a further preferred embodiment of the present invention, said R7 is selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl or trifluoromethyl.

[0055] In a preferred embodiment of the present invention, R8 and R8' are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group.

[0056] In a further preferred embodiment of the present invention, said R8 and R8' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl.

[0057] In a further preferred embodiment of the present invention, said R8 and R8' are each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl.

[0058] Alternatively, in a preferred embodiment of the present invention, the R8, R8' and the carbon atom to which they are connected form C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, the C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, optionally further substituted with hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 The aryl group or the 5-10 membered heteroaryl group is substituted by one or more substituents.

[0059] In a further preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the compound is further represented by general formula (III):

[0060]

[0061] in:

[0062] M3 is N or CR3;

[0063] R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0064] Preferred are hydrogen, hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group;

[0065] More preferred are hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl or methoxy.

[0066] R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy or C 1-6 Hydroxyalkyl; preferably hydrogen;

[0067] R8 and R8' are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group;

[0068] Preferred are hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, cyano substituted C 1-3 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0069] More preferably, hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl;

[0070] Alternatively, R8 and R8' are linked to form a C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, the C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, optionally further substituted by deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 aryl or 5-14 membered heteroaryl, preferably C 3-12 CycloalkylCycloalkyl.

[0071] In a further preferred embodiment of the present invention, in the compound of the general formula (III), its stereoisomers or pharmaceutically acceptable salts thereof, when M3 is CH, R8 and R8' are hydrogen, R2 is not hydrogen.

[0072] In a further preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is further represented by the general formula (IV-A):

[0073]

[0074] R is selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, cyano substituted C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0075] Preferred C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 3-6 Cycloalkyl;

[0076] More preferably methyl, ethyl, deuterated methyl, deuterated ethyl or cyclopropyl;

[0077] Further preferred is methyl, deuterated methyl or cyclopropyl;

[0078] A methyl group is further preferred.

[0079] In a further preferred embodiment of the present invention, the compound, its stereoisomer or a pharmaceutically acceptable salt thereof is further represented by the general formula (IV-B):

[0080]

[0081] R2 or R3 are independently selected from deuterium, halogen, cyano or C 1-3 Alkyl; preferably deuterium, fluorine, chlorine, bromine or methyl;

[0082] n is 1, 2 or 3.

[0083] In a preferred embodiment of the present invention, the compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, the specific structure of the compound is as follows:

[0084]

[0085]

[0086]

[0087] The present invention further relates to a method for preparing a compound of formula (IV-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0088]

[0089] The compound of formula (VA) reacts with RX in the presence of a base to obtain a compound of general formula (IV-A), preferably, the base is selected from potassium carbonate or cesium carbonate;

[0090] in:

[0091] X is bromine or iodine;

[0092] The R is defined as in the general formula (IV-A).

[0093] The present invention further relates to a method for preparing a compound of formula (IV-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0094]

[0095] The compound of general formula (VB) is reacted with The reaction obtains a compound of formula (IV-B), wherein the base is preferably selected from potassium carbonate or cesium carbonate;

[0096] in:

[0097] X is bromine or iodine;

[0098] R2, R3 and n are as defined in the general formula (IV-B).

[0099] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

[0100] On the other hand, the present invention also aims to provide a pharmaceutical composition comprising a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and use thereof in the preparation of a melatonin receptor agonist drug.

[0101] On the other hand, the present invention also aims to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition is used in the preparation of MT1 and MT2 receptor agonists and 5-HT 2C Use of receptor antagonists in medicine.

[0102] Furthermore, the present invention also aims to provide a pharmaceutical composition comprising a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and use thereof in the preparation of drugs for treating or preventing cardiovascular diseases, digestive system diseases, central nervous system diseases and / or mental diseases.

[0103] The present invention also relates to a method for treating central nervous system diseases and / or mental diseases.

[0104] In a more preferred embodiment, the central nervous system disease and / or psychiatric disorder is selected from melatonin system diseases, tension, anxiety, seasonal affective disorder, schizophrenia, phobia, depression, major depressive disorder, sleep disorders, sleep disorders, insomnia or fatigue caused by jet lag, weight disorders, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, substance abuse disorders and / or withdrawal syndrome, tinnitus, autism, Alzheimer's disease, epileptic seizures, neuralgia or drug withdrawal symptoms, major depressive disorder or manic disease.

[0105] Detailed description of the invention

[0106] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0107] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, tert-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methyl Hexyl, 3-pentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

[0108] The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means -CH2-, "ethylene" means -(CH2)2-, "propylene" means -(CH2)3-, "butylene" means -(CH2)4-, etc.

[0109] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0110] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spiro rings, fused rings and bridged rings, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

[0111] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O). m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 8 ring atoms; most preferably, it contains 3 to 8 ring atoms; further preferably, it contains 1-3 nitrogen atoms, 3-8 membered heterocyclic groups, optionally substituted by 1-2 oxygen atoms, sulfur atoms, oxo groups, including nitrogen-containing monocyclic heterocyclic groups, nitrogen-containing spiro heterocyclic groups or nitrogen-containing fused heterocyclic groups.

[0112] Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl or tetrahydrothiopyran dioxide, and the like, preferably oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazepanyl, pyranyl or tetrahydrothiopyran dioxide. Phenyl, tetrahydrothiopyranyl, tetrahydrothiopyran dioxide, pyrrolidinyl, morpholinyl, piperidinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azepanyl, 1,4-diazepanyl and piperazinyl; polycyclic heterocyclic groups include spirocyclic, condensed ring and bridged heterocyclic groups; the spirocyclic, condensed ring and bridged heterocyclic groups involved are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0113] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0114] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, including benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms, and sulfur atoms; or further comprising a three-membered nitrogen-containing fused ring containing a benzene ring.

[0115] Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

[0116]

[0117] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0118] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 12 yuan, more preferably 5 yuan or 6 yuan, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl or thiazolyl; more preferably pyridyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0119]

[0120] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0121] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0122] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0123] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0124] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0125] "Alkenyl" refers to alkenyl, also known as olefin group, preferably alkenyl containing 2 to 8 carbon atoms, more preferably alkenyl containing 2 to 6 carbon atoms, further preferably alkenyl containing 2 to 4 carbon atoms, and most preferably alkenyl containing 2 to 3 carbon atoms. Non-limiting examples of alkenyl include: vinyl, propenyl. The alkenyl described herein can be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0126] "Alkynyl" refers to alkenyl, also known as alkynyl, which refers to an unsaturated hydrocarbon group containing (CH≡C-); preferably an alkynyl containing 2 to 8 carbon atoms, more preferably an alkynyl containing 2 to 6 carbon atoms, further preferably an alkynyl containing 2 to 4 carbon atoms, and most preferably an alkynyl containing 2 to 3 carbon atoms. The alkynyl group may be further substituted by other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0127] "Hydroxy" refers to an -OH group.

[0128] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0129] "Amino" refers to -NH2.

[0130] "Cyano" refers to -CN.

[0131] "Nitro" refers to -NO2.

[0132] "Carbonyl" refers to -C(O)-.

[0133] "Carboxy" refers to -C(O)OH.

[0134] "THF" refers to tetrahydrofuran.

[0135] "Ethyl acetate" means ethyl acetate.

[0136] "MeOH" refers to methanol.

[0137] "DMF" refers to N,N-dimethylformamide.

[0138] "DIPEA" refers to diisopropylethylamine.

[0139] "TFA" refers to trifluoroacetic acid.

[0140] "TEA" refers to triethylamine.

[0141] "MeCN" refers to acetylene.

[0142] "DMA" refers to N,N-dimethylacetamide.

[0143] "Et2O" refers to diethyl ether.

[0144] "DCM" refers to dichloromethane.

[0145] "DMAP" refers to 4-dimethylaminopyridine.

[0146] "DCC" refers to dicyclohexylcarbodiimide.

[0147] "DCE" refers to 1,2-dichloroethane.

[0148] "DDQ" refers to 2,3-dichloro-5,6-dicyanobenzoquinone.

[0149] "DIPEA" refers to N,N-diisopropylethylamine.

[0150] "NBS" refers to N-bromosuccinimide.

[0151] "NIS" refers to N-iodosuccinimide.

[0152] "NMP" refers to N-methylpyrrolidone.

[0153] "Cbz-Cl" refers to benzyl chloroformate.

[0154] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0155] "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0156] "HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0157] "KHMDS" refers to potassium hexamethyldisilazide.

[0158] "LiHMDS" refers to lithium bistrimethylsilylamide.

[0159] "MeLi" refers to methyllithium.

[0160] "n-BuLi" refers to n-butyllithium.

[0161] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0162] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0163] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0164] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0165] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0166] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0167] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0168] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0169] Example

[0170] The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR is measured using a Bruker AVANCE-400 nuclear magnetic spectrometer, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), and the internal standard is tetramethylsilane (TMS).

[0171] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 1200 Infinity Series mass spectrometer. HPLC was performed using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150×4.6mm chromatographic column).

[0172] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0173] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0174] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

[0175] Example 1

[0176] Preparation of N-(2-(7-cyclopropyloxy-2-fluoronaphthalen-1-yl)ethyl)acetamide

[0177]

[0178] Step 1: Preparation of 7-methoxynaphthalene-2-amine

[0179]

[0180] 7-methoxynaphthalene-2-ol (10 g, 57.5 mmol) was dissolved in aqueous ammonia (150 mL), sodium bisulfite (29.9 g, 287.5 mmol) was added, and the mixture was heated to 150° C. in a stew pot and stirred for 48 hours. The mixture was cooled to room temperature, and the solid was filtered out. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 7-methoxynaphthalene-2-amine (5.7 g, yield 57%).

[0181] MS m / z(ESI):174.0[M+H] + .

[0182] Step 2: Preparation of 1-bromo-7-methoxynaphthalene-2-amine

[0183]

[0184] 7-Methoxynaphthalene-2-amine (5.5 g, 31.6 mmol) was dissolved in DMF (100 mL), NBS (6.2 g, 34.8 mmol) was added, and the mixture was reacted at 110° C. for 4 hours. The mixture was cooled to room temperature, and water and ethyl acetate were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1-bromo-7-methoxynaphthalene-2-amine (6.8 g, yield 86%).

[0185] MS m / z(ESI):252.1[M+H] + ,254.1[M+H+2] + .

[0186] Step 3: Preparation of 1-bromo-2-fluoro-7-methoxynaphthalene

[0187]

[0188] 1-Bromo-7-methoxynaphthalene-2-amine (6.5 g, 25.9 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0°C, HBF4 (50 mL, 48%) solution was added, and then NaNO2 (5.4 g, 78.3 mmol) aqueous solution (10 mL) was added, and stirring was continued at 0°C for 1 hour, and NaBF4 (14.2 g, 129.1 mmol) was added. The mixture was gradually warmed to room temperature, and the precipitated solid was filtered, washed with water and ether. Vacuum drying was performed. The obtained solid was dissolved in xylene (100 mL) and heated to reflux for 2 hours. Washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1-bromo-2-fluoro-7-methoxynaphthalene (2.8 g, yield 43%).

[0189] Step 4: Preparation of 2-(2-fluoro-7-methoxynaphthalen-1-yl)acetonitrile

[0190]

[0191] 1-Bromo-2-fluoro-7-methoxynaphthalene (2.6 g, 10.2 mmol) was dissolved in anhydrous THF (50 mL), magnesium powder (1.2 g, 50.0 mmol) and elemental iodine (2 grains) were added, the atmosphere was replaced with nitrogen three times, the temperature was raised to 50°C, and the mixture was stirred for 0.5 hours. Under an ice-water bath, a solution of bromoacetonitrile (1.6 g, 13.3 mmol) in THF (20 mL) was added dropwise, the temperature was gradually raised to room temperature, the mixture was stirred for 1 hour, water was added to quench the mixture, the mixture was extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain 2-(2-fluoro-7-methoxynaphthalene-1-yl)acetonitrile (1.5 g, yield 68%).

[0192] MS m / z(ESI):216.1[M+H] + .

[0193] Step 5: Preparation of N-(2-(2-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide

[0194]

[0195] 2-(2-fluoro-7-methoxynaphthalen-1-yl)acetonitrile (1.4 g, 6.5 mmol) and acetic anhydride (1.4 g, 13.7 mmol) were dissolved in a dichloromethane / methanol (30 mL / 15 mL) solution, NiCl2·6H2O (920 mg, 3.9 mmol) was added at 0°C, stirred, sodium borohydride (1.1 g, 28.9 mmol) was added in batches, and stirred at room temperature for 3 hours. 6N HCl was added, water was added, filtered, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography was used to purify N-(2-(2-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide (1.3 g, yield 76%).

[0196] MS m / z(ESI):262.1[M+H] + .

[0197] Step 6: Preparation of N-(2-(2-fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide

[0198]

[0199] N-(2-(2-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide (1.2 g, 4.6 mmol) was dissolved in dichloromethane (20 mL), cooled to 0°C under nitrogen protection, BBr3 (2.3 g, 9.2 mmol) was added dropwise, and stirred at room temperature for 3 hours. The mixture was washed with aqueous NaHCO3 solution and extracted with dichloromethane / methanol (10:1). The organic layer was washed with water and 10% aqueous sodium bicarbonate solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain N-(2-(2-fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide (930 mg, yield 82%).

[0200] MS m / z(ESI):248.1[M+H] + .

[0201] Step 7: Preparation of N-(2-(7-cyclopropyloxy-2-fluoronaphthalen-1-yl)ethyl)acetamide

[0202]

[0203] N-(2-(2-Fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide (100 mg, 0.41 mmol) was dissolved in DMF (5 mL), and cyclopropyl bromide (150 mg, 1.24 mmol) and Cs2CO3 (400 mg, 1.22 mmol) were added. The mixture was subjected to microwave reaction at 160°C for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by preparative HPLC to give N-(2-(7-cyclopropyloxy-2-fluoronaphthalen-1-yl)ethyl)acetamide (56 mg, 48% yield).

[0204] MS m / z(ESI):288.1[M+H] + .

[0205] Example 2A

[0206] Preparation of N-(2-(4-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide

[0207]

[0208] Step 1: Preparation of 5-amino-8-bromonaphthalene-2-ol

[0209]

[0210] Dissolve 5-aminonaphthalene-2-ol (10 g, 62.9 mmol) in DMF (100 mL), add NBS (12.3 g, 69.2 mmol), react at 110° C. for 3 hours, cool to room temperature, add water and ethyl acetate for extraction, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to give 5-amino-8-bromonaphthalene-2-ol (10.8 g, yield 72%).

[0211] MS m / z(ESI):238.1[M+H] + ,240.1[M+H+2] + .

[0212] Step 2: Preparation of 8-bromo-5-fluoronaphthalene-2-ol

[0213]

[0214] Dissolve 5-amino-8-bromonaphthalene-2-ol (5 g, 21.0 mmol) in tetrahydrofuran (100 mL), cool to 0°C, add HBF4 (40 mL, 48%) solution, then add NaNO2 (4.4 g, 63.8 mmol) in water (10 mL), continue stirring at 0°C for 1 hour, add NaBF4 (11.5 g, 104.5 mmol). Gradually warm to room temperature, filter the precipitated solid, wash with water, wash with ether. Vacuum dry. The obtained solid is dissolved in xylene (100 mL) and heated to reflux for 2 hours. Wash with water, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain 8-bromo-5-fluoronaphthalene-2-ol (3.5 g, yield 69%).

[0215] MS m / z(ESI):240.1[M+H] + ,243.1[M+H+2] + .

[0216] Step 3: Preparation of 4-bromo-1-fluoro-6-methoxynaphthalene

[0217]

[0218] 8-Bromo-5-fluoronaphthalene-2-ol (3H)-one (3.4 g, 14.2 mmol) was added to DMF (30 mL), K2CO3 (5.8 g, 42.0 mmol) was added, iodomethane (2.4 g, 16.9 mmol) was added dropwise at room temperature, and stirring was continued for 2 hours. Water and ethyl acetate were added for extraction, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 4-bromo-1-fluoro-6-methoxynaphthalene (3.4 g, yield 94%).

[0219] 1 H NMR (400MHz, Chloroform-d) δ8.06 (d, J = 9.0 Hz, 1H), 7.93-7.90 (m, 2H), 7.15 (d, J = 9.0 Hz, 1H), 6.92 (dd, J = 12, 7.8 Hz, 1H), 4.01 (s, 3H).

[0220] Step 4: Preparation of 2-(4-fluoro-7-methoxynaphthalen-1-yl)acetonitrile

[0221]

[0222] 4-Bromo-1-fluoro-6-methoxynaphthalene (3.3 g, 13.0 mmol) was dissolved in anhydrous THF (50 mL), magnesium powder (1.6 g, 66.7 mmol) and elemental iodine (2 grains) were added, the atmosphere was replaced with nitrogen three times, the temperature was raised to 50°C, and the mixture was stirred for 0.5 hours. In an ice-water bath, a solution of bromoacetonitrile (2.0 g, 16.8 mmol) in THF (20 mL) was added dropwise, the temperature was gradually raised to room temperature, the mixture was stirred for 1 hour, water was added to quench the mixture, the mixture was extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain 2-(4-fluoro-7-methoxynaphthalene-1-yl)acetonitrile (1.8 g, yield 64%).

[0223] 1 H NMR (400MHz, Chloroform-d) δ8.02(d,J=9.0Hz,1H),7.63(s,1H),7.08(d,J=9.0Hz,1H),6.92(m,2H),5.05(s,2H),3.99(s,3H).

[0224] Step 5: Preparation of N-(2-(4-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide

[0225]

[0226] 2-(4-fluoro-7-methoxynaphthalen-1-yl)acetonitrile (1.7 g, 7.9 mmol) and acetic anhydride (2.0 g, 19.8 mmol) were dissolved in a dichloromethane / methanol (30 mL / 15 mL) solution, NiCl2·6H2O (1.1 g, 4.7 mmol) was added at 0°C, stirred, sodium borohydride (1.3 g, 34.2 mmol) was added in batches, and stirred at room temperature for 5 hours. 6N HCl was added, water was added, filtered, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography was used for purification to obtain N-(2-(4-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide (1.5 g, yield 73%).

[0227] MS m / z(ESI):262.1[M+H] + .

[0228] 1 H NMR(400MHz,Chloroform-d)δ8.02(d,J=8.0Hz,1H),7.47(s,1H),7.21-7.15(m,2H),6.93-6.88 (m,1H),5.73(s,1H),3.99(s,3H),3.58-3.53(m,2H),3.20-3.16(t,J=8.0Hz,2H),1.95(s,3H).

[0229] Example 2

[0230] Preparation of N-(2-(7-cyclopropyloxy-4-fluoronaphthalen-1-yl)ethyl)acetamide

[0231]

[0232] Step 1: Preparation of N-(2-(4-fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide

[0233]

[0234] N-(2-(4-fluoro-7-methoxynaphthalen-1-yl)ethyl)acetamide (1.4 g, 5.4 mmol) was dissolved in dichloromethane (20 mL), cooled to 0°C under nitrogen protection, BBr3 (2.7 g, 10.8 mmol) was added dropwise, and stirred at room temperature for 3 hours. The mixture was washed with an aqueous solution of NaHCO3 and extracted with dichloromethane / methanol (10 / 1). The organic layer was washed with water and a 10% aqueous solution of sodium bicarbonate. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N-(2-(4-fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide (980 mg, 75% yield).

[0235] MS m / z(ESI):248.1[M+H] + .

[0236] Step 2: Preparation of N-(2-(7-cyclopropyloxy-4-fluoronaphthalen-1-yl)ethyl)acetamide

[0237]

[0238] N-(2-(4-Fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide (100 mg, 0.41 mmol) was dissolved in DMF (5 mL), and cyclopropyl bromide (150 mg, 1.24 mmol) and Cs2CO3 (400 mg, 1.22 mmol) were added. The mixture was subjected to microwave reaction at 160°C for 4 hours. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by preparative HPLC to give N-(2-(7-cyclopropyloxy-4-fluoronaphthalen-1-yl)ethyl)acetamide (44 mg, yield 38%).

[0239] MS m / z(ESI):288.1[M+H] + .

[0240] Example 2B

[0241] Preparation of N-(2-(4-fluoro-7-(methoxy-d3)naphthalen-1-yl)ethyl)acetamide

[0242]

[0243] Step 1: Preparation of N-(2-(4-fluoro-7-(methoxy-d3)naphthalen-1-yl)ethyl)acetamide

[0244]

[0245] To a solution of N-(2-(4-fluoro-7-hydroxynaphthalen-1-yl)ethyl)acetamide (80 mg, 323.54 μmol), KI (5.4 mg, 32.35 μmol) and Cs2CO3 (210 mg, 647.08 μmol) in DMF (2 mL) was added deuterated iodomethane (188 mg, 1.29 mmol) under N2, and the mixture was stirred at 50°C for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give N-(2-(4-fluoro-7-(methoxy-d3)naphthalen-1-yl)ethyl)acetamide (71.4 mg, yield 82%) as a white solid.

[0246] MS m / z(ESI):265.1[M+H] + .

[0247] 1 H NMR(400MHz,Chloroform-d)δ8.04(d,J=9.0Hz,1H),7.68(t,J=2.2Hz,1H),7.26–7.14(m,2H),6.9 2(dd,J=10.3,7.8Hz,1H),5.54(s,1H),3.60(q,J=6.8Hz,2H),3.20(t,J=7.2Hz,2H),1.95(s,3H).

[0248] Example 5

[0249] Preparation of N-(2-(7-(oxetan-3-oxy)naphth-1-yl)ethyl)acetamide

[0250]

[0251] Step 1: Preparation of N-(2-(7-hydroxynaphthalen-1-yl)ethyl)acetamide

[0252]

[0253] The substrate N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (511mg, 2.1mmol) was dissolved in anhydrous dichloromethane (10mL), replaced with nitrogen three times, cooled to 0°C under protection, and BBr3 (4.2mmol, 4.2mL) was added dropwise. After the addition was completed, the mixture was heated to room temperature and stirred for 30 minutes. The reaction solution was slowly poured into 150mL saturated NaHCO3 solution to quench the reaction. The dichloromethane extraction was performed, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by rapid column chromatography to obtain a white solid product N-(2-(7-hydroxynaphthalene-1-yl)ethyl)acetamide (300mg, yield 62%), which was a white solid.

[0254] MS m / z(ESI):230.1[M+H] + .

[0255] 1 H NMR (400MHz, DMSO) δ9.73(s,1H),8.00(s,1H),7.76(d,J=8.8Hz,1H),7.65(d,J=7.9Hz,1H),7.31(d,J=1.8Hz,1H ),7.26–7.16(m,2H),7.08(dd,J=8.8,2.2Hz,1H),3.38(s,1H),3.31(s,1H),3.04(t,J=7.5Hz,2H),1.81(s,3H).

[0256] Step 2: Preparation of N-(2-(7-(oxabutane-3-oxy)naphthalen-1-yl)ethyl)acetamide

[0257]

[0258] The substrate N-(2-(7-hydroxynaphthalene-1-yl)ethyl)acetamide (61.6 mg, 0.2 mmol), KI (49.8 mg, 300 μmol) and Cs2CO3 (97.8 mg, 300 μmol) were dissolved in DMF (1.5 mL), placed in a 5.0 mL microwave tube, and 3-bromooxabutane (137 mg, 1.0 mmol) was added. The reaction mixture was heated to 130°C for 1.5 hours. The reaction solution was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by rapid column chromatography to obtain a crude product, and then purified by preparative HPLC to obtain N-(2-(7-(oxabutane-3-oxy)naphthalene-1-yl)ethyl)acetamide (36 mg, yield 48%) as a white solid.

[0259] MS m / z(ESI):286.2[M+H] + .

[0260] 1 H NMR (400MHz, DMSO) δ8.16(t,J=5.6Hz,1H),7.87(d,J=8.9Hz,1H),7.73(d,J=7.6Hz,1H),7.34–7.26(m,3H),7.17(dd,J=8.9,2.4Hz,1H) ,5.52(t,J=5.5Hz,1H),5.11(t,J=6.7Hz,2H),4.62(dd,J=7.2,5.1Hz,2H),3.31–3.24(m,2H),3.09(dd,J=9.6,6.2Hz,2H),1.87(s,3H).

[0261] Example 6

[0262] Preparation of N-(2-(7-isopropoxynaphthalen-1-yl-3-d)ethyl)acetamide

[0263]

[0264] Step 1: Preparation of N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide

[0265]

[0266] The substrate N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide (5 g, 20.6 mmol) was dissolved in glacial acetic acid (50 mL), heated to 85°C (oil bath temperature), and a solution of bromine (4.0 g, 25.0 mmol) in AcOH (30 mL) was added dropwise. After the addition was complete, heating and stirring were continued for 3 hours. The reaction solution was cooled to room temperature, poured into water (150 mL), extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide (4.5 g, yield 68%).

[0267] MS m / z(ESI):322.1[M+H] + ,324.1[M+H+2] + .

[0268] Step 2: Preparation of N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide

[0269]

[0270] Dissolve N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide (200 mg, 0.62 mmol) in anhydrous THF (20 mL), cool to -78°C under nitrogen protection, add dropwise a THF solution (10 mL) of n-BuLi (1.6 mL, 1.6 mmol), and stir for 0.5 hours. Add dropwise D2O (1 mL), and continue stirring for 1 hour. Quench with water, adjust the pH to 6 with dilute hydrochloric acid, and extract with ethyl acetate. Dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide (87 mg, yield 57%).

[0271] MS m / z(ESI):245.1[M+H] + .

[0272] Step 3: Preparation of N-(2-(7-hydroxynaphthalen-1-yl-3-d)ethyl)acetamide

[0273]

[0274] N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide (80 mg, 0.33 mmol) was dissolved in dichloromethane (10 mL), cooled to 0°C under nitrogen protection, BBr3 (270 mg, 1.1 mmol) was added dropwise, and stirred at room temperature for 2 hours. The mixture was quenched with aqueous NaHCO3 solution and extracted with dichloromethane. The mixture was washed with water and 10% aqueous sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N-(2-(7-hydroxynaphthalen-1-yl-3-d)ethyl)acetamide (55 mg, yield 73%).

[0275] MS m / z(ESI):231.1[M+H] + .

[0276] Step 4: Preparation of N-(2-(7-isopropoxynaphthalen-1-yl-3-d)ethyl)acetamide

[0277]

[0278] Cs2CO3 (141.1 mg, 434.2 umol) and potassium iodide (18 mg, 108.56 umol) were added to N-(2-(7-hydroxynaphthalene-1-yl-3-d)ethyl)acetamide (50 mg, 217.13 umol) and 2-iodopropane (110.7 mg, 651.4 umol) in DMF (3 mL) under N2, and stirred at 50°C for 12 hours. Water was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to obtain N-(2-(7-isopropoxynaphthalene-1-yl-3-d)ethyl)acetamide (3 mg, yield 5%).

[0279] MS m / z(ESI):273.1[M+H] + .

[0280] 1 H NMR(400MHz,Chloroform-d)δ8.04(d,J=9.0Hz,1H),7.81(s,1H),7.75(s,1H),7.41(s,1H),7.35-7.26(m,1H),5.6 6(s,1H),4.75-4.70(m,1H),3.60(q,J=6.8Hz,2H),3.20(t,J=7.2Hz,2H),2.05(s,3H),1.30-1.28(d,J=8.0Hz,6H).

[0281] Example 7

[0282] Preparation of N-(2-(7-(pentane-3-oxy)naphthalen-1-yl-3-d)ethyl)acetamide

[0283]

[0284] Reference Example 6 for the preparation of N-(2-(7-(pentane-3-oxy)naphthalen-1-yl-3-d)ethyl)acetamide.

[0285] MS m / z(ESI):301.1[M+H] + .

[0286] 1H NMR(400MHz,Chloroform-d)δ8.06(d,J=9.0Hz,1H),7.81(s,1H),7.75(s,1H),7.41(s,1H),7.35-7.26(m,1H),5.66(s, 1H),4.75-4.70(m,1H),3.60(q,J=6.8Hz,2H),3.20(t,J=7.2Hz,2H),2.05(s,3H),1.76-1.72(m,4H),1.01-0.98(m,6H).

[0287] Example 8

[0288] Preparation of N-(2-(7-(tert-butoxy)naphthalen-1-yl-3-d)ethyl)acetamide

[0289]

[0290] Step 1: Preparation of N-(2-(3-bromo-7-methoxynaphthalen-1-yl)ethyl)acetamide

[0291]

[0292] The substrate N-(2-(7-methoxynaphthalen-1-yl)ethyl)acetamide (14.6 g, 60.0 mmol) was dissolved in AcOH (120 mL), heated to 85°C (oil bath temperature), and a solution of bromine (11.5 g, 72.0 mmol, 3.69 mL) in AcOH (30 mL) was added dropwise. After the addition was complete, stirring was continued for 0.5 hours. The reaction solution was cooled to room temperature, poured into water (500 mL), extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by reverse phase preparative column to obtain N-(2-(3-bromo-7-methoxynaphthalen-1-yl)ethyl)acetamide (15 g, yield 66%) as a white solid.

[0293] MS m / z(ESI):322.2[M+H] + .

[0294] 1H NMR (400MHz, DMSO) δ8.16–8.10(m,1H),7.99(d,J=1.4Hz,1H),7.83(d,J=9.0Hz,1H),7.62(d,J=1.8Hz,1H),7.47(dd,J=11.0,1.8Hz ,1H),7.22(dd,J=9.0,2.3Hz,1H),3.95(s,3H),3.38(dd,J=12.7,6.1Hz,1H),3.32(d,J=6.0Hz,1H),3.18–3.09(m,2H),1.83(s,3H).

[0295] Step 2: Preparation of N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide

[0296]

[0297] The substrate N-(2-(3-bromo-7-methoxynaphthalen-1-yl)ethyl)acetamide (3.9 g, 12 mmol) was dissolved in THF (60 mL), cooled to -75°C to -70°C under nitrogen protection, and n-BuLi (30.0 mmol, 12.5 mL) was added dropwise, followed by stirring at -75°C for 1.5 hours, and D2O (1.20 g, 60.00 mmol) was added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred overnight. The reaction solution was slowly poured into 200 mL of water to quench, extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide (1.2 g, yield 41%) as a yellow solid.

[0298] MS m / z(ESI):245.1[M+H] + .

[0299] Step 3: Preparation of N-(2-(7-hydroxynaphthalen-1-yl-3-d)ethyl)acetamide

[0300]

[0301] The substrate N-(2-(7-methoxynaphthalen-1-yl-3-d)ethyl)acetamide (1.2 g, 4.91 mmol) was dissolved in anhydrous dichloromethane (60 mL), cooled to 0°C under nitrogen protection, and BBr3 (10 mmol, 10 mL) was added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred for 30 min. The reaction solution was slowly poured into 150 mL of saturated NaHCO3 solution to quench the reaction. The mixture was extracted with dichloromethane, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography to obtain a white solid product N-(2-(7-hydroxynaphthalen-1-yl-3-d)ethyl)acetamide (1.05 g, yield 93%).

[0302] MS m / z(ESI):231.2[M+H] + .

[0303] 1 H NMR (400MHz, DMSO) δ9.73 (s, 1H), 8.01 (t, J = 5.2Hz, 1H), 7.76 (d, J = 8.8Hz, 1H), 7.65 (d, J = 4.3Hz, 1H), 7.31 (d, J = 2.0Hz, 1H),7.25(d,J=3.7Hz,1H),7.09(dd,J=8.8,2.3Hz,1H),3.35–3.29(m,2H),3.05(t,J=7.5Hz,2H),1.81(d,J=3.7Hz,3H).

[0304] Step 4: Preparation of N-(2-(7-(tert-butoxy)naphthalen-1-yl-3-d)ethyl)acetamide

[0305]

[0306] The substrate N-(2-(7-hydroxynaphthalene-1-yl-3-d)ethyl)acetamide (134 mg, 582 umol) was dissolved in anhydrous dichloromethane (5.0 mL), (Boc)2O (317.5 mg, 1.45 mmol) and Mg(ClO4)2 (26 mg, 116 umol) were added, and the mixture was heated to 50°C and refluxed for 2 hours under nitrogen replacement protection. The reaction solution was cooled to room temperature, slowly added to 100 mL of water, and then 50 mL of saturated NaHCO3 aqueous solution was added. The organic layers were extracted with ethyl acetate, combined, washed with saturated brine, and dried over anhydrous Na2SO4. Concentration was performed to obtain a crude product, which was purified by preparative HPLC to obtain the target compound N-(2-(7-(tert-butyloxy)naphthalene-1-yl-3-d)ethyl)acetamide (54.6 mg, yield 33%) as a white solid.

[0307] MS m / z(ESI):287.2[M+H] +.

[0308] 1 H NMR (400MHz, DMSO) δ8.04(s,1H),7.84(d,J=8.8Hz,1H),7.74(s,1H),7.67(d,J=1.7Hz,1H),7.32(s,1H),7. 19(dd,J=8.8,2.1Hz,1H),3.34(d,J=6.7Hz,1H),3.29(s,1H),3.13–3.07(m,2H),1.82(s,3H),1.39(s,9H).

[0309] Example 10

[0310] Preparation of N-(2-(6-chloro-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide

[0311]

[0312] Step 1: Preparation of 4-(3-chloro-4-methoxyphenyl)-4-carbonylbutyric acid

[0313]

[0314] At 0℃, under nitrogen protection, add AlCl3 (71.4g, 0.54mol) and 1-chloro-2-methoxybenzene (30mL, 0.24mol) to dichloromethane (300mL), add dihydrofuran-2,5-dione (26.8g, 0.27mol) in batches, heat to 50℃ and stir for 2 hours. Cool to room temperature, pour the reaction solution into vigorously stirred ice water, add concentrated hydrochloric acid (65mL), and stir for 0.5 hours. Filter, wash the filter cake with water, and then slurry and filter with ethanol-water to obtain pink solid 4-(3-chloro-4-methoxyphenyl)-4-carbonylbutyric acid (55g, yield 98%).

[0315] MS m / z(ESI):241.1[MH] - .

[0316] Step 2: Preparation of 4-(3-chloro-4-methoxyphenyl)butyric acid

[0317]

[0318] Under nitrogen protection, Et3SiH (12 mL) was added dropwise to TFA (20 mL) of 4-(3-chloro-4-methoxyphenyl)-4-carbonylbutyric acid (8 g, 33 mmol), heated to 120°C, and stirred for 5 hours. After the reaction solution was concentrated, DMF (10 mL) was added, slowly poured into vigorously stirred water, filtered, the filter cake was washed with water, and dried to obtain 4-(3-chloro-4-methoxyphenyl)butyric acid (7 g, yield 93%) as a white solid.

[0319] MS m / z(ESI):227.1[MH] - .

[0320] Step 3: Preparation of 6-chloro-7-methoxy-3,4-dihydronaphthalen-1(2H)-one

[0321]

[0322] Under nitrogen protection, MeSO3H (7 mL) was added dropwise to 4-(3-chloro-4-methoxyphenyl)butyric acid (7 g, 30.7 mmol) in TFA (30 mL), heated to 120°C, and stirred for 7 hours. After cooling to room temperature, the reaction solution was poured into ice water, filtered, the filter cake was washed with water, and then slurried with ethanol-water and filtered, and dried to obtain a yellow solid 6-chloro-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (3.6 g, yield 56%).

[0323] 1 H NMR(400MHz,Chloroform-d)δ7.54(s,1H),7.27(s,1H),3.92(s,3H),2.89-2.85(m,2H),2.65-2.61(m,2H),2.13-2.10(m,2H)

[0324] Step 4: Preparation of 2-(6-chloro-7-methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile

[0325]

[0326] Under nitrogen protection, 2-cyanoacetic acid (3.6 g, 42.5 mmol), heptanoic acid (1.12 g, 8.6 mmol), benzylamine (920 mg, 8.6 mmol) were added to a toluene (140 mL) solution of 6-chloro-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (3.6 g, 17 mmol), and heated to 140°C and stirred for 12 hours. After cooling to room temperature, the reaction solution was quenched by adding brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and then slurried with ethanol-water at 90°C, filtered, and dried to obtain a yellow solid 2-(6-chloro-7-methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile (3 g, yield 76%).

[0327] 1 H NMR (400MHz, d-DMSO) δ7.27(s,1H),6.99(s,1H),6.24(s,1H),3.87(s,5H),2.68-2.64(m,2H),2.28-2.19(m,2H)

[0328] Step 5: Preparation of 2-(6-chloro-7-methoxynaphthalen-1-yl)acetonitrile

[0329]

[0330] DDQ (3.2 g, 14.1 mmol) was added to 2-(6-chloro-7-methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile (3 g, 12.9 mmol) in dichloromethane (30 mL) at -10°C under nitrogen protection, and stirred for 0.5 hours at 20°C. The reaction solution was filtered, and the organic phase was washed with saturated Na2CO3 aqueous solution, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow solid 2-(6-chloro-7-methoxynaphthalen-1-yl)acetonitrile (2.8 g, yield 94%).

[0331] 1 H NMR (400MHz, Chloroform-d) δ7.88(s,1H),7.69-7.67(d,J=8.0Hz,1H),7.53-7.51(d,J=8.0Hz,1H),7.36-7.32(m,1H),7.07(s,1H),4.03(s,5H).

[0332] Step 6: Preparation of N-(2-(6-chloro-7-methoxynaphthalen-1-yl)ethyl)acetamide

[0333]

[0334] -10 ℃, under nitrogen protection, NiCl2.6H2O (1.8 g, 0.8 mmol), acetic anhydride (2.72 mL, 0.8 mmol) were added to 2-(6-chloro-7-methoxynaphthalen-1-yl)acetonitrile (2.8 g, 12 mmol) in CH2Cl2-MeOH (100 mL-50 mL), and NaBH4 (2.1 g, 54 mmol) was added in batches, and stirred at 20 ℃ for 12 hours. Cooled to 0 ℃, hydrochloric acid (3M / L, 40 mL) was added to the reaction solution, stirred for 1 hour, concentrated, extracted with ethyl acetate, washed with saturated NaHCO3 aqueous solution, washed with brine, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain yellow solid N-(2-(6-chloro-7-methoxynaphthalen-1-yl)ethyl)acetamide (1 g, yield 30%).

[0335] MS m / z(ESI):278.1[M+H] + .

[0336] 1 H NMR(400MHz,d-DMSO)δ8.15(s,1H),8.08(s,1H),7.79(s,1H),7.72-7.70(d,J=8.0H z,1H),7.37-7.30(m,2H),4.06(s,3H),3.34(s,2H),3.16-3.12(m,2H),1.84(s,3H).

[0337] Step 7: Preparation of N-(2-(6-chloro-7-hydroxynaphthalen-1-yl)ethyl)acetamide

[0338]

[0339] At 0°C, under nitrogen protection, BBr3 (3.6 mL, 3.6 mmol) was added to a solution of N-(2-(6-chloro-7-methoxynaphthalen-1-yl)ethyl)acetamide (500 mg, 1.8 mmol) in dichloromethane (30 mL), and stirred at 20°C for 12 hours. The reaction solution was extracted with dichloromethane, washed with saturated NaHCO3 aqueous solution, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain N-(2-(6-chloro-7-hydroxynaphthalen-1-yl)ethyl)acetamide (400 mg, yield 85%).

[0340] MS m / z(ESI):264.1[M+H] + .

[0341] 1 H NMR(400MHz,d-DMSO)δ10.56(s,1H),8.01-7.98(m,2H),7.67-7.65(m,1H),7.5 0(s,1H),7.28-7.23(m,2H),3.39-3.34(m,2H),3.07-3.03(m,2H),1.81(s,3H).

[0342] Step 8: Preparation of N-(2-(6-chloro-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide

[0343]

[0344] Under nitrogen protection, Cs2CO3 (160 mg, 0.5 mmol) and potassium iodide (30 mg, 0.2 mmol) were added to N-(2-(6-chloro-7-hydroxynaphthalene-1-yl)ethyl)acetamide (100 mg, 0.4 mmol) and bromocyclopropane (100 mg, 0.8 mmol) in NMP (3 mL), and the mixture was stirred in microwave at 170°C for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative HPLC to give N-(2-(6-chloro-7-cyclopropyloxynaphthalene-1-yl)ethyl)acetamide (10 mg, 8% yield).

[0345] MS m / z(ESI):304.1[M+H] + .

[0346] 1 H NMR(400MHz,Chloroform-d)δ7.89-7.82(m,1H),7.67(s,1H),7.51-7.46(m,2H),7.15-7.11(m,1H),5.54 (s,1H),3.75-3.71(m,1H),3.60(t,J=6.8Hz,2H),3.20(t,J=7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).

[0347] Embodiment 11

[0348] Preparation of N-(2-(6-bromo-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide

[0349]

[0350] Preparation of N-(2-(6-bromo-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide Reference Example 10.

[0351] MS m / z(ESI):348.1[M+H] + ,350.1[M+H+2] + .

[0352] 1 H NMR(400MHz,Chloroform-d)δ7.92-7.85(m,1H),7.71(s,1H),7.53-7.47(m,2H),7.16-7.14(m,1H),5.56 (s,1H),3.75-3.71(m,1H),3.60(t,J=6.8Hz,2H),3.20(t,J=7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).

[0353] Example 12

[0354] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl-3-d)ethyl)acetamide

[0355]

[0356] Reference Example 6 for the preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl-3-d)ethyl)acetamide.

[0357] MS m / z(ESI):271.1[M+H] + .

[0358] 1 H NMR (400MHz, DMSO) δ8.01(s,1H),7.93(dd,J=9.9,2.3Hz,1H),7.80(m,J=13.3,5.4Hz,1H),7.72(d,J=3.1Hz,1H),7.44(s,1H),7.01-6 .94(m,1H),4.05–3.99(m,1H),3.37(d,J=8.0Hz,2H),3.14(t,J=7.4Hz,2H),1.81(s,3H),0.91(q,J=5.7Hz,2H),0.72(d,J=7.1Hz,2H).

[0359] Example 13

[0360] Preparation of N-(2-(7-cyclopropyloxy-3-fluoronaphthalen-1-yl)ethyl)acetamide

[0361]

[0362] Step 1: Preparation of N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide

[0363]

[0364] The substrate N-(2-(7-methoxy-1-naphthyl)ethyl)acetamide (14.6 g, 60.0 mmol) was dissolved in glacial acetic acid (120 mL), heated to 85°C (oil bath temperature), and a solution of bromine (11.51 g, 72.0 mmol, 3.69 mL) in AcOH (30 mL) was added dropwise. After the addition was complete, heating and stirring were continued for 3 hours. The reaction solution was cooled to room temperature, poured into water (500 mL), extracted with ethyl acetate (200 mL×3), the organic layers were combined, washed with saturated NaCl (150 mL×3), the organic layer was dried over Na2SO4, and concentrated to obtain a crude product, which was purified by reverse phase to obtain a white solid N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide (12.0 g, yield 62%).

[0365] MS m / z(ESI):322.1[M+H] + ,324.1[M+H+2] + .

[0366] Step 2: Preparation of N-(2-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborin-2-yl)naphthalen-1-yl)ethyl)acetamide

[0367]

[0368] The substrate N-[2-(3-bromo-7-methoxy-1-naphthyl)ethyl]acetamide (1.61 g, 5.0 mmol), naphthalene alcohol borate (2.54 g, 7.9 mmol) and potassium acetate (1.47 g, 15.0 mmol) were dissolved in anhydrous dioxane (45 mL), replaced with nitrogen three times, and Pd(dppf)Cl2 (731 mg, 1.0 mmol) was added, and heated to 90°C for 2 hours. The reaction solution was concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound N-(2-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboric acid-2-yl)naphthalene-1-yl)ethyl)acetamide (1.6 g, yield 87%) as a yellow solid.

[0369] MS m / z(ESI):370.1[M+H] + .

[0370] Step 3: Preparation of N-(2-(7-methoxy-3-(boric acid)naphthalen-1-yl)ethyl)acetamide

[0371]

[0372] The substrate N-(2-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxoboric acid-2-yl)naphthalen-1-yl)ethyl)acetamide (1.4 g, 3.8 mmol) was dissolved in acetone (40 mL) and water (40 mL), and ammonium acetate (1.46 g, 19.0 mmol) and NaIO4 (4.05 g, 19.0 mmol) were added. The mixture was heated to 25°C and reacted for 4 hours. The reaction solution was concentrated to obtain a crude product, which was extracted with a mixed solvent (THF:EA=1:1), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The target compound N-(2-(7-methoxy-3-(boric acid)naphthalen-1-yl)ethyl)acetamide (766 mg, yield 70%) was purified by column chromatography as a yellow solid.

[0373] MS m / z(ESI):286.1[MH] - .

[0374] Step 4: Preparation of N-[2-(3-fluoro-7-methoxy-1-naphthyl)ethyl]acetamide

[0375]

[0376] At room temperature, the reagent NaOH (121 mg, 3.0 mmol) was dissolved in MeOH (10 mL), and then the substrate N-(2-(7-methoxy-3-(boronic acid)naphthalen-1-yl)ethyl)acetamide (722 mg, 2.5 mmol) was added, and then stirred at 25°C for 15 minutes. Then, the reaction solution was cooled to 0°C, and the reagent AgOTf (1.94 g, 7.5 mmol) was added, and stirred at 0°C for 30 minutes. Then, the reaction solution solvent was concentrated at low temperature 0°C using an oil pump, and the residual methanol was removed by solvent azeotropy with acetone (5 mL×3) to obtain a crude product. The crude product was dissolved in acetone (10 mL), and activated 3A molecular sieves (350 mg) were added, and then F-TEDA-BF4 (935 mg, 2.6 mmol) was added. Then, it was stirred at 0°C for 1 hour. The reaction solution was slowly added to 100 mL of water, extracted with ethyl acetate (150 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to give N-[2-(3-fluoro-7-methoxy-1-naphthyl)ethyl]acetamide (214 mg, yield 33%).

[0377] MS m / z(ESI):262.1[M+H] + .

[0378] Step 5: Preparation of N-[2-(3-fluoro-7-hydroxy-1-naphthyl)ethyl]acetamide

[0379]

[0380] The substrate N-[2-(3-fluoro-7-methoxy-1-naphthyl)ethyl]acetamide (241 mg, 922.3 μmol) was dissolved in anhydrous dichloromethane (10 mL), cooled to 0°C under nitrogen replacement protection, and BBr3 (1.84 mmol, 3.0 mL) was added dropwise. After the addition was complete, stirring was continued for 30 minutes. The reaction solution was added dropwise to 100 mL of water to quench, and then 100 mL of saturated NaHCO3 aqueous solution was added, extracted with dichloromethane (100 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Column chromatography purification gave the target compound N-[2-(3-fluoro-7-hydroxy-1-naphthyl)ethyl]acetamide (204 mg, yield 89%).

[0381] MS m / z(ESI):248.1[M+H] + .

[0382] Step 6: Preparation of N-(2-(7-cyclopropyl-3-fluoronaphthalen-1-yl)ethyl)acetamide

[0383]

[0384] The substrate N-[2-(3-fluoro-7-hydroxy-1-naphthyl)ethyl]acetamide (49 mg, 0.2 mmol) and cyclopropyl bromide (121 mg, 1.0 mmol) were dissolved in NMP (1 mL), placed in a 5.0 mL microwave tube, and Cs2CO3 (98 mg, 300 μmol) and KI (50 mg, 300 μmol) were added. The reaction was carried out at 180° C. for 2 hours. The reaction solution was concentrated and the solvent was removed to obtain a crude product N-(2-(7-cyclopropyl-3-fluoronaphthyl-1-yl)ethyl)acetamide (10 mg, yield 17%), a yellow liquid.

[0385] MS m / z(ESI):288.1[M+H] + .

[0386] 1H NMR (400MHz, DMSO) δ8.07(s,1H),7.82(dd,J=13.3,5.4Hz,2H),7.52(dd,J=9.9,2.3Hz,1H),7.28–7.21(m,2H),4.05– 3.99(m,1H),3.37(d,J=8.0Hz,2H),3.14(t,J=7.4Hz,2H),1.81(s,3H),0.91(q,J=5.7Hz,2H),0.72(d,J=7.1Hz,2H).

[0387] Embodiment 14

[0388] Preparation of N-(2-(7-cyclopropyloxy-3-chloronaphthalen-1-yl)ethyl)acetamide

[0389]

[0390] Step 1: Preparation of N-(2-(7-cyclopropyl-3-chloronaphthalen-1-yl)ethyl)acetamide

[0391]

[0392] Under nitrogen protection, CuCl (113 mg, 1.14 mmol) was added to a DMF (2 mL) solution of N-(2-(7-cyclopropyl-3-bromonaphthalen-1-yl)ethyl)acetamide (20 mg, 57 μmol), and the mixture was stirred at 140°C for 3 hours in a microwave oven until the reaction was complete. Saturated brine was added to the reaction solution, and the mixture was extracted with dichloromethane (3*10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and then N-(2-(7-cyclopropyl-3-chloronaphthalen-1-yl)ethyl)acetamide (7 mg, yield 38%) was prepared by an acid method.

[0393] MS m / z(ESI):304.1[M+H] + ,306.1[M+H+2] + .

[0394] 1 H NMR (400MHz, DMSO) δ8.07(s,1H),7.84(dd,J=5.4,3.4Hz,2H),7.80(s,1H),7.35(d,J=2.0Hz,1H),7.26(dd,J=9.0,2.3 Hz,1H),4.07–4.00(m,1H),3.37(s,2H),3.16–3.09(m,2H),1.81(s,3H),0.92(d,J=7.3Hz,2H),0.73(d,J=7.1Hz,2H).

[0395] Embodiment 15

[0396] Preparation of N-(2-(7-cyclopropyloxy-3-bromonaphthalen-1-yl)ethyl)acetamide

[0397]

[0398] Step 1: Preparation of N-(2-(7-hydroxy-3-bromonaphthalen-1-yl)ethyl)acetamide

[0399]

[0400] At 0°C, under nitrogen protection, BBr3 (1M, 20.48 mL) was added dropwise to a solution of N-(2-(7-methoxy-3-bromonaphthalen-1-yl)ethyl)acetamide (3.3 g, 10.24 mmol) in dichloromethane (30 mL). The mixture was stirred at 30°C for 1 hour until the reaction was complete. The mixture was poured into a saturated aqueous NaHCO3 solution at 0°C and extracted with dichloromethane-methanol (10 / 1). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give N-(2-(7-hydroxy-3-bromonaphthalen-1-yl)ethyl)acetamide (3 g, yield 95%).

[0401] MS m / z(ESI):308.1[M+H] + ,310.1[M+H+2] + .

[0402] Step 2: Preparation of N-(2-(7-cyclopropyl-3-bromonaphthalen-1-yl)ethyl)acetamide

[0403]

[0404] Under nitrogen protection, cyclopropane bromide (1.96 g, 16.22 mmol) was added to N-(2-(7-hydroxy-3-bromonaphthalen-1-yl)ethyl)acetamide (2.5 g, 8.11 mmol), potassium iodide (134 mg, 0.81 mmol) and Cs2CO3 (5.27 g, 16.2 mmol) in DMF (10 mL). The mixture was stirred in microwave at 170°C for 4 hours until the reaction was complete. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [dichloromethane / methanol=1 / 0 to 50 / 1] to obtain N-(2-(7-cyclopropyl-3-bromonaphthalen-1-yl)ethyl)acetamide (1.3 g, yield 46%) as a yellow oil.

[0405] MS m / z(ESI):348.1[M+H] + ,350.1[M+H+2] + .

[0406] 1 H NMR(400MHz,DMSO)δ8.08(s,1H),8.00(s,1H),7.86–7.78(m,2H),7.46(s,1H),7.25(dd,J=8.9,2.0Hz,1H),4 .08–3.99(m,1H),3.35(d,J=7.6Hz,2H),3.16–3.07(m,2H),1.81(s,3H),0.92(q,J=6.1Hz,2H),0.72(s,2H).

[0407] Embodiment 18

[0408] Preparation of N-(2-(4-chloro-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide

[0409]

[0410] Reference Example 2 for the preparation of N-(2-(4-chloro-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide.

[0411] MS m / z(ESI):304.1[M+H] + .

[0412] 1 H NMR(400MHz,Chloroform-d)δ8.14(d,J=9.0Hz,1H),7.72(t,J=2.2Hz,1H),7.32–7.19(m,2H),6.99(dd,J=10.4,7.8Hz,1H ),5.59(s,1H),3.98(tt,J=6.2,3.0Hz,1H),3.65(q,J=6.8Hz,2H),3.24(t,J=7.2Hz,2H),1.98(s,3H),0.98–0.76(m,4H).

[0413] Embodiment 19

[0414] Preparation of N-(2-(7-cyclopropyloxy-2-fluoronaphthalen-1-yl-3-d)ethyl)acetamide

[0415]

[0416] Reference Example 6 for the preparation of N-(2-(7-cyclopropyloxy-2-fluoronaphthalen-1-yl-3-d)ethyl)acetamide.

[0417] MS m / z(ESI):289.1[M+H] + .

[0418] 1 H NMR(400MHz,Chloroform-d)δ8.01(d,J=9.0Hz,1H),7.79(s,1H),7.32-7.28(d,J=6.0Hz,1H),6.98(dd,J=10.6,7.8Hz,1H ),5.54(s,1H),3.94(tt,J=6.2,3.0Hz,1H),3.60(q,J=6.8Hz,2H),3.20(t,J=7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).

[0419] Embodiment 20

[0420] Preparation of N-(2-(7-cyclopropyloxy-4-fluoronaphthalen-1-yl-3-d)ethyl)acetamide

[0421]

[0422] Reference Example 6 for the preparation of N-(2-(7-cyclopropyloxy-4-fluoronaphthalen-1-yl-3-d)ethyl)acetamide.

[0423] MS m / z(ESI):289.1[M+H] + .

[0424] 1 H NMR(400MHz,Chloroform-d)δ8.01(d,J=9.0Hz,1H),7.79(s,1H),7.38-7.34(d,J=6.0Hz,1H),6.92(dd,J=10.6,7.8Hz,1H ),5.54(s,1H),3.94(tt,J=6.2,3.0Hz,1H),3.60(q,J=6.8Hz,2H),3.20(t,J=7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).

[0425] Embodiment 21

[0426] Preparation of N-(2-(7-cyclopropyloxy-3,6-difluoronaphthalen-1-yl)ethyl)acetamide

[0427]

[0428] The preparation of N-(2-(7-cyclopropyloxy-3,6-difluoronaphthalen-1-yl)ethyl)acetamide was prepared according to Example 10.

[0429] MS m / z(ESI):306.1[M+H] + .

[0430] 1 H NMR(400MHz,Chloroform-d)δ7.82(d,J=8.0Hz,1H),7.32-7.25(m,2H),6.92(d,J=12.0,1H),5.54(s,1H), 3.94(tt,J=6.2,3.0Hz,1H),3.60(q,J=6.8Hz,2H),3.20(t,J=7.2Hz,2H),1.95(s,3H),0.98–0.76(m,4H).

[0431] Embodiment 22

[0432] Preparation of N-(2-(7-cyclopropyloxy-3,8-difluoronaphthalen-1-yl)ethyl)acetamide

[0433]

[0434] The preparation of N-(2-(7-cyclopropyloxy-3,8-difluoronaphthalen-1-yl)ethyl)acetamide was prepared according to Example 10.

[0435] MS m / z(ESI):306.1[M+H] + .

[0436] 1 H NMR(400MHz,Chloroform)δ7.70(dd,J=14.9,3.0Hz,1H),7.14(dt,J=16.1,3.1Hz,1H),7.06(dd,J=16.0,3.0Hz,1H),6.91(dd,J=15.0,10 .1Hz,1H),5.54(s,1H),3.53(p,J=16.3Hz,1H),3.43–3.34(m,2H),3.31–3.23(m,2H),1.80(s,3H),0.87–0.67(m,2H),0.41–0.19(m,2H).

[0437] Embodiment 23

[0438] Preparation of N-(2-(3-chloro-7-cyclopropyloxy-6-fluoronaphthalen-1-yl)ethyl)acetamide

[0439]

[0440] Preparation of N-(2-(3-chloro-7-cyclopropyloxy-6-fluoronaphthalen-1-yl)ethyl)acetamide Reference Example 10.

[0441] MS m / z(ESI):322.1[M+H] + ,324.1[M+H+2] + .

[0442] 1 H NMR(400MHz,Chloroform)δ7.57(s,1H),7.39(s,1H),7.17(s,1H),6.85(s,1H),5.70( s,1H),3.53(s,1H),3.38(s,2H),3.26(s,2H),1.79(s,3H),0.74(s,2H),0.28(s,2H).

[0443] Embodiment 24

[0444] Preparation of N-(2-(6-chloro-7-cyclopropyloxy-3-fluoronaphthalen-1-yl)ethyl)acetamide

[0445]

[0446] Preparation of N-(2-(6-chloro-7-cyclopropyloxy-3-fluoronaphthalen-1-yl)ethyl)acetamide Reference Example 10.

[0447] MS m / z(ESI):322.1[M+H] + ,324.1[M+H+2] + .

[0448] 1 H NMR (400MHz, CDCl3) δ7.89 (s, 1H), 7.77-7.73 (m, 2H), 7.37 (d, J = 4Hz, 1H), 5.63 (s, 1H), 4.06–3.97 (m,1H),3.62–3.55(m,2H),3.25–3.21(m,2H),1.81(s,3H),0.96–0.87(m,2H),0.75–0.68(m,2H).

[0449] Embodiment 25

[0450] Preparation of N-(2-(3,6-dichloro-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide

[0451]

[0452] Step 1: Preparation of N-(2-(3-bromo-6-chloro-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide

[0453]

[0454] At 60°C, under N2, a solution of bromine (126 mg, 790 μmol, 40.47 μL) in AcOH (1 mL) was added dropwise to N-(2-(6-chloro-7-cyclopropyloxynaphthalene-1-yl)ethyl)acetamide (0.2 g, 658.37 μmol) in AcOH (5 mL), and stirred at 60°C for 2 hours. The mixture was cooled to 0°C, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N-(2-(3-bromo-6-chloro-7-cyclopropyloxynaphthalene-1-yl)ethyl)acetamide (25 mg, yield 10%).

[0455] MS m / z(ESI):382.1[M+H]+ .

[0456] Step 2: Preparation of N-(2-(3,6-dichloro-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide

[0457]

[0458] CuCl (26 mg, 261.32 μmol) was added to DMF (3 mL) of N-(2-(3-bromo-6-chloro-7-cyclopropyloxynaphthalene-1-yl)ethyl)acetamide (10 mg, 26.13 μmol) under N2, and stirred for 2 hours at 140°C in a microwave. Saturated brine was added to the reaction solution, and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give N-(2-(3,6-dichloro-7-cyclopropyloxynaphthalene-1-yl)ethyl)acetamide as a white solid (4.5 mg, yield 47%).

[0459] MS m / z(ESI):338.1[M+H] + .

[0460] 1 H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.75(s,1H),7.68(s,1H),7.24(s,1H),5.54(s,1H ),4.02(s,1H),3.61(q,J=6.8Hz,2H),3.25(t,J=7.2Hz,2H),1.98(s,3H),1.02–0.96(m,4H).

[0461] Embodiment 26

[0462] Preparation of N-(1-(7-cyclopropyloxy-3-fluoronaphthalen-1-yl)propan-2-yl)acetamide

[0463]

[0464] Step 1: Preparation of 1-(7-methoxynaphthalen-1-yl)propane-2-amine

[0465]

[0466] The substrate N-(2-(7-methoxynaphthalen-1-yl)ethyl)acetamide (3.94 g, 0.02 mol) was dissolved in anhydrous THF (15 mL). Under nitrogen replacement protection, MeMgI (30.0 mmol, 10.0 mL, 3 M in THF) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled to 0 ° C, and MeOH (40 mL) was slowly added dropwise. After the addition was completed, NaBH4 (2.26 g, 60.00 mmol) was added. The mixture was stirred at room temperature for 24 hours. The reaction solution was slowly poured into 200 mL of water to quench, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, 1-(7-methoxynaphthalen-1-yl)propane-2-amine (368 mg, yield 8%), as a yellow liquid.

[0467] MS m / z(ESI):216.2[M+H] + .

[0468] Step 2: Preparation of N-(1-(7-methoxynaphthalen-1-yl)propan-2-yl)acetamide

[0469]

[0470] The substrate 1-(7-methoxynaphthalen-1-yl)propane-2-amine (368 mg, 1.7 mmol) was dissolved in dichloromethane (30 mL), TEA (519 mg, 5.12 mmol, 0.72 mL) was added, stirred at room temperature for 10 minutes, cooled to 0°C, and acetic anhydride (262 mg, 2.56 mmol) was added dropwise. After the addition was completed, it was stirred at room temperature for 2 hours. The reaction solution was poured into 100 mL of water to quench, extracted with dichloromethane, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product. The target compound N-(1-(7-methoxynaphthalen-1-yl)propane-2-yl)acetamide (300 mg, yield 82%) was purified by column chromatography as a white solid.

[0471] MS m / z(ESI):258.0[M+H] + .

[0472] 1 H NMR (400MHz, CDCl3) δ7.78–7.72(m,2H),7.69–7.65(m,1H),7.24(d,J=4.9Hz,2H),7.15(dd,J=8.9,2.1Hz,1H),4.42 (s,1H),4.05(s,3H),3.64(dd,J=13.2,3.4Hz,1H),2.76(dd,J=13.0,9.5Hz,1H),2.00(s,3H),1.10(d,J=6.5Hz,3H).

[0473] Step 3: Preparation of N-(1-(3-bromo-7-methoxynaphthalen-1-yl)propan-2-yl)acetamide

[0474]

[0475] The substrate N-(1-(7-methoxynaphthalen-1-yl)propane-2-yl)acetamide (230 mg, 0.89 mmol) was dissolved in AcOH (5 mL), heated to 85°C (oil bath temperature), and a solution of bromine (144 mg, 0.9 mmol) in AcOH (1 mL) was added dropwise. After the addition was complete, heating and stirring were continued for 0.5 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography to obtain N-(1-(3-bromo-7-methoxynaphthalen-1-yl)propane-2-yl)acetamide (270 mg, yield 87%) as a white solid.

[0476] MS m / z(ESI):336.2[M+H] + .

[0477] 1 H NMR (400MHz, Chloroform) δ7.97–7.91(m,2H),7.54(dd,J=20.6,2.9Hz,2H),6.99(dd,J=14.8,3.0Hz,1H),5.53(s,1H),4.28– 4.14(m,1H),3.81(s,3H),3.37(dd,J=24.8,13.5Hz,1H),3.12(dd,J=24.8,13.6Hz,1H),1.99(s,3H),1.14(d,J=12.0Hz,3H).

[0478] Step 4: Preparation of N-(1-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)propan-2-yl)acetamide

[0479]

[0480] The substrate N-(1-(3-bromo-7-methoxynaphthalen-1-yl)propan-2-yl)acetamide (270 mg, 0.8 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (406 mg, 10.0 mmol) and KOAc (157 mg, 1.6 mmol) were dissolved in anhydrous dioxane (5 mL), and the atmosphere was replaced with nitrogen three times. Pd(dppf)Cl2 (117 mg, 0.16 mmol) was added under protection, and the reaction was heated to 90°C (external temperature) for 2 hours. The reaction liquid was concentrated to dryness to obtain a crude product, which was purified by column chromatography to give the target compound N-(1-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)propan-2-yl)acetamide (276 mg, yield 90%) as a yellow solid.

[0481] MS m / z(ESI):384.2[M+H] + .

[0482] Step 5: Preparation of (4-(2-acetylaminopropyl)-6-methoxynaphthalen-2-yl)boric acid

[0483]

[0484] The substrate N-(1-(7-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)propan-2-yl)acetamide (276 mg, 0.72 mmol) was dissolved in acetone (10 mL) and water (10 mL), and NH4OAc (280 mg, 3.6 mmol) and NaIO4 (770 mg, 3.6 mmol) were added. The mixture was heated to 25°C (external temperature) and reacted for 1.5 hours. The reaction liquid was concentrated to dryness to obtain a crude product, which was then extracted with ethyl acetate and the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product. The target compound (4-(2-acetylaminopropyl)-6-methoxynaphthalen-2-yl)boronic acid (130 mg, yield 60%) was purified by column chromatography as a yellow solid.

[0485] MS m / z(ESI):302.2[M+H] + .

[0486] Step 6: Preparation of N-(1-(3-fluoro-7-methoxynaphthalen-1-yl)propan-2-yl)acetamide

[0487]

[0488] At room temperature, the reagent NaOH (21 mg, 525 μmol) was dissolved in MeOH (1 mL), and then the substrate (4-(2-acetylaminopropyl)-6-methoxynaphthalen-2-yl) boronic acid (130 mg, 432 μmol) was added, and then stirred at 25°C (external temperature, oil bath temperature) for 15 minutes. The reaction solution was cooled to 0°C, and the reagent AgOTf (334 mg, 1.3 mmol) was added, and stirred at 0°C for 30 minutes. Then, the reaction solution solvent was concentrated to dryness at 0°C using an oil pump, and the residual methanol was removed by solvent azeotropy with acetone to obtain a crude product. The crude product was dissolved in acetone (3 mL), and activated 3A molecular sieves (350 mg) were added, and then F-TEDA-BF4 (161 mg, 454 μmol) was added. Then, it was stirred at room temperature for 1 hour. The reaction solution was slowly added to 10 mL of water, extracted with ethyl acetate, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography to obtain the target compound N-(1-(3-fluoro-7-methoxynaphthalen-1-yl)propan-2-yl)acetamide (86 mg, yield 60%) as a white solid.

[0489] MS m / z(ESI):276.1[M+H] + .

[0490] Step 7: Preparation of N-(1-(3-fluoro-7-hydroxynaphthalen-1-yl)propan-2-yl)acetamide

[0491]

[0492] The substrate N-(1-(3-fluoro-7-hydroxynaphthalene-1-yl)propane-2-yl)acetamide (86 mg, 310.8 μmol) was dissolved in dichloromethane (15 mL), cooled to 0° C. under nitrogen protection, BBr3 (3 mL, 1M in CH2Cl2) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was slowly poured into 100 mL saturated NaHCO3 solution to quench the reaction. The mixture was extracted with dichloromethane, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to give a crude product, which was purified by column chromatography to give a white solid product N-(1-(3-fluoro-7-hydroxynaphthalene-1-yl)propane-2-yl)acetamide (77 mg, 95% yield), which was a white solid.

[0493] MS m / z(ESI):262.1[M+H] + .

[0494] Step 8: Preparation of N-(1-(7-cyclopropyloxy-3-fluoronaphthalen-1-yl)propan-2-yl)acetamide

[0495]

[0496] The substrate N-(1-(3-fluoro-7-hydroxynaphthalene-1-yl)propane-2-yl)acetamide (39 mg, 0.15 mmol) and bromocyclopropane (91 mg, 0.75 mmol) were dissolved in NMP (2 mL), placed in a 5.0 mL microwave tube, and Cs2CO3 (73 mg, 225 μmol) and KI (37 mg, 225 μmol) were added. Microwave at 180°C for 4 hours. The reaction solution was concentrated and the solvent was removed to obtain a crude product, which was purified by preparative HPLC (alkaline method) to obtain the target compound N-(1-(7-cyclopropyloxy-3-fluoronaphthalene-1-yl)propane-2-yl)acetamide (9.5 mg, yield 21%) as a white solid.

[0497] MS m / z(ESI):302.1[M+H] + .

[0498] 1 H NMR(500MHz,Chloroform)δ7.93(dd,J=15.0,2.9Hz,1H),7.72(d,J=2.9Hz,1H),7.14(dt,J=1 6.1,3.0Hz,1H),7.01(dd,J=15.0,3.1Hz,1H),6.72(dd,J=15.9,2.9Hz,1H),5.87(s,1H),4.21 (dd,J=24.1,12.1Hz,1H),3.53(p,J=16.5Hz,1H),3.37(dd,J=24.8,12.2Hz,1H),3.12(dd,J= 24.7,12.3Hz,1H),1.99(s,3H),1.14(d,J=12.0Hz,3H),0.83–0.67(m,2H),0.35–0.14(m,2H).

[0499] Embodiment 27

[0500] Preparation of N-(1-(7-cyclopropyloxy-3-fluoronaphthalen-1-yl)-2-methylpropane-2-yl)acetamide

[0501]

[0502] Reference Example 26 for the preparation of N-(1-(7-cyclopropyloxy-3-fluoronaphthalen-1-yl)-2-methylpropan-2-yl)acetamide.

[0503] MS m / z(ESI):316.1[M+H] + .

[0504] 1H NMR (400MHz, CDCl3) δ7.88 (s, 1H), 7.78-7.70 (m, 3H), 7.36 (d, J = 4Hz, 1H), 5.63 (s, 1H), 4.07 –3.97(m,1H),3.25(s,2H),1.81(s,3H),1.47(s,6H),0.94–0.87(m,2H),0.75–0.66(m,2H).

[0505] Embodiment 28

[0506] Preparation of N-(1-((7-cyclopropyloxy-3-fluoronaphthalen-1-yl)methyl)cyclopropyl)acetamide

[0507]

[0508] Step 1: Preparation of 1-((7-cyclopropyloxy-3-fluoronaphthalen-1-yl)methyl)cyclopropane-1-amine

[0509]

[0510] At 30°C, ethylmagnesium bromide (676 mg, 5.07 mmol) was added dropwise to 2-(7-cyclopropyloxy-3-fluoronaphthalen-1-yl)acetonitrile (610 mg, 2.54 mmol) and tetraisopropoxytitanium (790 mg, 2.79 mmol, 583.30 uL) in THF (10 mL) under N2, and stirred at 30°C for 1 hour. BF3.Et2O (1 M, 5.07 mL) was added and the mixture was stirred for 1 hour. At 0°C, the mixture was poured into NaOH (10%) and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain 1-((7-cyclopropyloxy-3-fluoronaphthalen-1-yl)methyl)cyclopropane-1-amine (150 mg, yield 26%).

[0511] MS m / z(ESI):272.1[M+H] + .

[0512] Step 2: Preparation of N-(1-((7-cyclopropyloxy-3-fluoronaphthalen-1-yl)methyl)cyclopropyl)acetamide

[0513]

[0514] Acetic anhydride (135 mg, 1.32 mmol) was added dropwise to a solution of 1-((7-cyclopropyloxy-3-fluoronaphthalen-1-yl)methyl)cyclopropane-1-amine (0.15 g, 550 μmol) and DIEA (256 mg, 1.98 mmol, 344.84 μL) in DCM (10 mL) at 0°C under N2, and stirred at 30°C for 1 hour. After concentration, the reaction solution was filtered and purified by preparative HPLC to give N-(1-((7-cyclopropyloxy-3-fluoronaphthalen-1-yl)methyl)cyclopropyl)acetamide (77 mg, yield 43%) as a white solid.

[0515] MS m / z(ESI):314.1[M+H] + .

[0516] 1 H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.68-7.65(m,2H),7.38(s,1H),7.22-7.20(d,J=8.0H z,1H),6.44(s,1H),4.02(s,1H),3.59(s,2H),1.98(s,3H),0.95-0.80(m,4H),0.79-0.76(m,4H).

[0517] Embodiment 31

[0518] Preparation of N-(2-(7-cyclopropyloxyisoquinolin-1-yl)ethyl)acetamide

[0519]

[0520] Reference Example 2 for the preparation of N-(2-(7-cyclopropyloxyisoquinolin-1-yl)ethyl)acetamide.

[0521] MS m / z(ESI):271.1[M+H] + .

[0522] 1 H NMR (400MHz, DMSO) δ8.28(d,J=4Hz,1H),8.14–8.02(m,1H),7.88(d,J=8Hz,1H),7.69–7.58(m,2H),7.45–7.38(m, 1H),4.05–3.92(m,1H),3.58–3.45(m,2H),3.40–3.31(m,2H),1.81(s,3H),0.95–0.87(m,2H),0.75–0.66(m,2H).

[0523] Embodiment 32

[0524] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl)-2,2,2-trifluoroacetamide

[0525]

[0526] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl)-2,2,2-trifluoroacetamide Reference Example 1.

[0527] MS m / z(ESI):324.1[M+H] + .

[0528] 1 H NMR (400MHz, CDCl3) δ7.72(d,J=8Hz,1H),7.67(d,J=8Hz,1H),7.59(s,1H),7.30-7.24(m,2H),7.15–7.12(m,1H ),5.66(s,1H),4.06–3.94(m,1H),3.57–3.44(m,2H),3.40–3.30(m,2H),0.95–0.88(m,2H),0.76–0.65(m,2H).

[0529] Embodiment 33

[0530] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl)cyclopropanecarboxamide

[0531]

[0532] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl)cyclopropanecarboxamide Reference Example 1.

[0533] MS m / z(ESI):296.1[M+H] + .

[0534] 1 H NMR (400MHz, DMSO-d6) δ7.73-7.66(m,2H),7.59(s,1H),7.30-7.24(m,2H),7.14(dd,J=12Hz,4Hz,1H),5. 63(s,1H),4.04-4.01(m,1H),3.62-3.57(m,2H),3.25-3.21(m,2H),1.43-1.38(m,1H),1.01-0.79(m,8H).

[0535] Embodiment 34

[0536] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl)propionamide

[0537]

[0538] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl)propanamide Reference Example 1.

[0539] MS m / z(ESI):284.1[M+H] + .

[0540] 1 H NMR (400MHz, DMSO-d6) δ7.74-7.65(m,2H),7.58(s,1H),7.31-7.23(m,2H),7.14(dd,J=12Hz,4Hz,1H),5. 60(s,1H),4.03-4.00(m,1H),3.64-3.59(m,2H),3.26-3.22(m,2H),1.42-1.39(m,2H),1.01-0.81(m,7H).

[0541] Embodiment 35

[0542] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl)isobutyramide

[0543]

[0544] Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl)isobutyramide Reference Example 1.

[0545] MS m / z(ESI):298.1[M+H] + .

[0546] 1 H NMR (400MHz, DMSO-d6) δ7.73-7.66(m,2H),7.59(s,1H),7.30-7.24(m,2H),7.14(dd,J=12Hz,4Hz,1H),5.6 3(s,1H),4.04-4.01(m,1H),3.62-3.57(m,2H),3.25-3.21(m,2H),1.43-1.38(m,1H),1.01-0.79(m,10H).

[0547] Embodiment 36

[0548] Preparation of N-(2-(7-cyclopropyloxy-3-methylnaphthalen-1-yl)ethyl)acetamide

[0549]

[0550] Step 1: Preparation of N-(2-(7-cyclopropyl-3-methylnaphthalen-1-yl)ethyl)acetamide

[0551]

[0552] Substrate N-(2-(7-cyclopropyl-3-bromonaphthalen-1-yl)ethyl)acetamide (104 mg, 0.3 mmol), Cs2CO3 (293 mg, 900 μmol) and trimethyl borate (75 mg, 720 μmol, 83.87 μL) were dissolved in anhydrous dioxane (5 mL) and water (1 mL), replaced with nitrogen three times, added Pd(dppf)Cl2 (44 mg, 60 μmol), heated to 110°C for 4 hours. The reaction solution was concentrated to obtain a crude product, water was added, and ethyl acetate (80 mL×3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain a crude product, and then purified by preparative HPLC to obtain a white solid product N-(2-(7-cyclopropyl-3-methylnaphthalen-1-yl)ethyl)acetamide (24 mg, yield 27%).

[0553] MS m / z(ESI):284.1[M+H] + .

[0554] 1 H NMR(400MHz, CDCl3)δ7.65(dd,J=17.5,5.3Hz,2H),7.46(s,1H),7.16(dd,J=10.7,3.9Hz,2H),3.93–3.87(m,1H),3.6 4(dd,J=13.2,6.7Hz,2H),3.22(t,J=7.0Hz,2H),2.46(s,3H),1.94(s,3H),0.92–0.87(m,2H),0.82(t,J=6.3Hz,2H).

[0555] Embodiment 37

[0556] Preparation of N-[2-[3-bromo-7-(cyclopropyloxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide

[0557]

[0558] Step 1: Preparation of 1,1-dideutero-2-(7-methoxy-1-naphthyl)ethylamine

[0559]

[0560] At 0℃, under nitrogen protection, add LiAlD4 (1.83g, 44.6mmol) to THF (30mL) of 2-(7-methoxy-1-naphthyl)acetonitrile (3g, 15.2mmol), and stir at 30℃ for 1 hour. Cool to 0℃, add Na2SO4·10H2O to the reaction solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate and concentrate to obtain crude 1,1-dideuterio-2-(7-methoxy-1-naphthyl)ethylamine (2g, yield 65%). Use it directly in the next step.

[0561] MS m / z(ESI):204.1[M+H] + .

[0562] Step 2: Preparation of N-[1,1-dideutero-2-(7-methoxy-1-naphthyl)ethyl]acetamide

[0563]

[0564] At 0°C, acetic anhydride (2.01 g, 19.7 mmol) was added to 1,1-dideutero-2-(7-methoxy-1-naphthyl)ethylamine (2 g, 9.8 mmol) and triethylamine (2.99 g, 29.5 mmol, 4.1 mL) in dichloromethane (6.7 mL) under nitrogen protection, and stirred at 30°C for 2 hours. Cooled to 0°C, brine was added, and dichloromethane was extracted. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain N-[1,1-dideutero-2-(7-methoxy-1-naphthyl)ethyl]acetamide (2 g, yield 83%) as a yellow oil.

[0565] MS m / z(ESI):246.1[M+H] + .

[0566] Step 3: Preparation of N-[1,1-dideuterio-2-(7-hydroxy-1-naphthyl)ethyl]acetamide

[0567]

[0568] At 0°C, under nitrogen protection, add BBr3 (1M, 16.31mL) to a solution of N-[1,1-dideutero-2-(7-methoxy-1-naphthyl)ethyl]acetamide (2g, 8.2mmol) in dichloromethane (20mL), gradually warm to 30°C and stir for 1 hour. Cool to 0°C, quench the reaction solution with saturated NaHCO3 aqueous solution, extract with dichloromethane, wash the organic phase with brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain N-[1,1-dideutero-2-(7-hydroxy-1-naphthyl)ethyl]acetamide (1.5g, yield 80%) as a yellow solid.

[0569] MS m / z(ESI):232.1[M+H] + .

[0570] Step 4: Preparation of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl-1,1-dideutero)acetamide

[0571]

[0572] Under nitrogen protection, add cyclopropane bromide (2.35 g, 19.5 mmol) to a DMF (8 mL) solution of N-[1,1-dideutero-2-(7-hydroxy-1-naphthyl)ethyl]acetamide (1.5 g, 6.5 mmol), KI (108 mg, 648 μmol) and Cs2CO3 (4.2 g, 13 mmol), and stir in microwave at 170°C for 2 hours. Cool to room temperature, add brine, and extract with dichloromethane. Combine the organic layers, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl-1,1-dideutero)acetamide (0.9 g, yield 51%) as a brown oil.

[0573] MS m / z(ESI):272.1[M+H] + .

[0574] Step 5: Preparation of N-[2-[3-bromo-7-(cyclopropyloxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide

[0575]

[0576] At 70°C, under nitrogen protection, add a solution of bromine (141 mg, 884 μmol) in AcOH (2 mL) to a solution of N-(2-(7-cyclopropyloxynaphthalen-1-yl)ethyl-1,1-dideutero)acetamide (0.2 g, 737 μmol) in AcOH (5 mL), and stir at 70°C for 7 hours. Cool to 0°C, add brine, and extract with ethyl acetate. Combine the organic layers, wash with water, dry over anhydrous sodium sulfate, filter, concentrate, purify by column chromatography, and then purify by preparative HPLC to obtain N-[2-[3-bromo-7-(cyclopropyloxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide (20 mg, yield 7%).

[0577] MS m / z(ESI):350.1[M+H] + ,352.1[M+H+2] + .

[0578] 1H NMR(400MHz, CDCl3)δ7.82(s,1H),7.68–7.64(m,2H),7.37(s,1H),7.21-7.18(dd,J=8.0,4.0Hz,1H ),5.62(s,1H),3.94-3.91(m,1H),3.20(s,2H),1.96(s,3H),0.97–0.90(m,2H),0.83-0.79(m,2H).

[0579] Embodiment 38

[0580] Preparation of N-[2-[3-chloro-7-(cyclopropyloxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide

[0581]

[0582] Step 1: Preparation of N-[2-[3-chloro-7-(cyclopropyloxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide

[0583]

[0584] Under nitrogen protection, CuCl (113 mg, 1.14 mmol) was added to DMF (2 mL) of N-[2-[3-bromo-7-(cyclopropyloxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide (20 mg, 57 μmol), and stirred at 140°C in a microwave for 3 hours. Saturated brine was added to the reaction solution, and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give N-[2-[3-chloro-7-(cyclopropyloxy)-1-naphthyl]-1,1-dideutero-ethyl]acetamide (7 mg, yield 38%).

[0585] MS m / z(ESI):306.1[M+H] + ,308.1[M+H+2] + .

[0586] 1 H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.86–7.81(m,3H),7.35(s,1H),7.27-7.24(dd,J=8.0,2 .0Hz,1H),4.06-4.03(m,1H),3.12(s,2H),1.81(s,3H),0.95-0.90(m,2H),0.74-0.70(m,2H).

[0587] Embodiment 39

[0588] Preparation of N-(2-(3-bromo-7-cyclopropyloxynaphthalen-1-yl)ethyl)-2,2-difluoroacetamide

[0589]

[0590] Reference Example 15 for the preparation of N-(2-(3-bromo-7-cyclopropyloxynaphthalen-1-yl)ethyl)-2,2-difluoroacetamide.

[0591] MS m / z(ESI):384.1[M+H] + .

[0592] 1 H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.68-7.65(m,2H),7.38(s,1H),7.22-7.20(d,J=8.0Hz,1H),6.44(s ,1H),6.03-5.75(t,J=56Hz,1H),4.02(s,1H),3.61(q,J=6.8Hz,2H),3.25(t,J=7.2Hz,2H),0.95-0.80(m,4H).

[0593] Embodiment 40

[0594] Preparation of N-(2-(7-cyclopropyloxy-3-methoxynaphthalen-1-yl)ethyl)acetamide

[0595]

[0596] Step 1: Preparation of N-(2-(3-bromo-7-hydroxynaphthalen-1-yl)ethyl)acetamide

[0597]

[0598] The substrate N-(2-(3-bromo-7-methoxynaphthalen-1-yl)ethyl)acetamide (1.29 g, 4.0 mmol) was dissolved in dichloromethane (40 mL), cooled to 0°C under nitrogen protection, and BBr3 (40 mL, 1 M dichloromethane solution) was added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred for 30 minutes. The reaction solution was slowly poured into 200 mL of saturated NaHCO3 solution to quench the reaction. The mixture was extracted with dichloromethane, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography to obtain a white solid product N-(2-(3-bromo-7-hydroxynaphthalen-1-yl)ethyl)acetamide (1.05 g, yield 85%), which was a white solid.

[0599] MS m / z(ESI):309.2[M+H] + .

[0600] Step 2: Preparation of N-(2-(3-bromo-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide

[0601]

[0602] The substrate N-(2-(3-bromo-7-hydroxynaphthalene-1-yl)ethyl)acetamide (616 mg, 2.0 mmol), Cs2CO3 (977 mg, 3.0 mmol) and potassium iodide (498 mg, 3.0 mmol) were dissolved in DMA (5.0 mL), placed in a 25 mL microwave tube, and bromocyclopropane (1.21 g, 10 mmol) was added. Microwave at 180°C and reacted for 4 hours. Water was added, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography to obtain a yellow solid product N-(2-(3-bromo-7-cyclopropyloxynaphthalene-1-yl)ethyl)acetamide (1.05 g, yield 85%).

[0603] MS m / z(ESI):348.1[M+H] + .

[0604] 1 H NMR(400MHz,DMSO)δ8.08(s,1H),8.00(s,1H),7.87–7.77(m,2H),7.46(s,1H),7.25(dd,J=8.9,2.0Hz,1H) ,4.10–3.97(m,1H),3.37–3.32(m,2H),3.17–3.08(m,2H),1.81(s,3H),0.92(q,J=6.1Hz,2H),0.72(s,2H).

[0605] Step 3: Preparation of N-(2-(7-cyclopropyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethyl)acetamide

[0606]

[0607] The substrate N-(2-(3-bromo-7-cyclopropyloxynaphthalen-1-yl)ethyl)acetamide (700 mg, 2.01 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.02 g, 4.02 mmol) and KOAc (591 mg, 6.03 mmol) were dissolved in anhydrous dioxane (10 mL). Under nitrogen protection, Pd(dppf)Cl2 (294 mg, 402 μmol) was added and heated to 100°C (external temperature) for 10 hours. The reaction liquid was concentrated to dryness to obtain a crude product, which was purified by column chromatography to give the target compound N-(2-(7-cyclopropyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethyl)acetamide (760 mg, yield 79%) as a yellow solid.

[0608] MS m / z(ESI):396.2[M+H] + .

[0609] Step 4: Preparation of (4-(2-acetylaminoethyl)-6-cyclopropyloxynaphthalene-2-yl)boric acid

[0610]

[0611] The substrate N-(2-(7-cyclopropyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethyl)acetamide (760 mg, 1.92 mmol) was dissolved in acetone (15 mL) and H2O (15 mL), and NH4OAc (741 mg, 9.61 mmol) and NaIO4 (2.06 g, 9.61 mmol) were added. The mixture was heated to 25°C (external temperature) and reacted for 1.5 hours. The reaction liquid was concentrated to dryness to obtain a crude product, which was then extracted with ethyl acetate and the organic layers were combined, dried over anhydrous Na2SO4, and concentrated to obtain a crude product. The target compound (4-(2-acetylaminoethyl)-6-cyclopropyloxynaphthalen-2-yl)boronic acid (245 mg, yield 33%) was purified by column chromatography as a yellow solid.

[0612] MS m / z(ESI):314.1[M+H] + .

[0613] Step 5: Preparation of N-(2-(7-cyclopropyloxy-3-hydroxynaphthalen-1-yl)ethyl)acetamide

[0614]

[0615] (4-(2-acetylaminoethyl)-6-cyclopropyloxynaphthalene-2-yl)boric acid (245 mg, 780 μmol) was dissolved in tetrahydrofuran (2 mL) and water (4 mL), cooled to 0°C, NH4HCO3 (75 mg, 950 μmol) was added, and then H2O2 (64.6 mg, 1.9 mmol, 2.2 mL) was added dropwise. Stir at room temperature for 1 hour. Saturated aqueous Na2SO3 solution was slowly added to the reaction solution to quench the reaction, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated to obtain a crude product, which was purified by column chromatography to obtain N-(2-(7-cyclopropyloxy-3-hydroxynaphthalene-1-yl)ethyl)acetamide (209 mg, yield 71%) as a light yellow solid.

[0616] MS m / z(ESI):286.1[M+H] + .

[0617] Step 6: Preparation of N-(2-(7-cyclopropyloxy-3-methoxynaphthalen-1-yl)ethyl)acetamide

[0618]

[0619] The substrate N-(2-(7-cyclopropyloxy-3-hydroxynaphthalene-1-yl)ethyl)acetamide (57 mg, 0.2 mmol), MeI (142 mg, 1.0 mmol) and K2CO3 (55 mg, 400 μmol) were dissolved in acetonitrile (10 mL) and stirred at room temperature overnight under nitrogen protection. The reaction solution was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and the organic layers were dried over anhydrous Na2SO4 and concentrated to obtain a crude product, which was then purified by preparative HPLC (acid method, then alkaline method) to obtain N-(2-(7-cyclopropyloxy-3-methoxynaphthalene-1-yl)ethyl)acetamide (25 mg, yield 41.70%) as a white solid.

[0620] MS m / z(ESI):300.1[M+H] + .

[0621] 1 H NMR (400MHz, DMSO) δ8.07(t,J=5.3Hz,1H),7.72(dd,J=13.6,5.3Hz,2H),7.17(dd,J=8.5,1.9Hz,2H),7.00(d,J=2.2Hz,1H),4. 01–3.95(m,1H),3.83(s,3H),3.36–3.33(m,2H),3.08(t,J=7.5Hz,2H),1.82(s,3H),0.89(q,J=5.9Hz,2H),0.73–0.66(m,2H).

[0622] Embodiment 41

[0623] Preparation of N-(2-(3-bromo-7-(2-methoxyethoxy)naphthalen-1-yl)ethyl)acetamide

[0624]

[0625] Reference Example 15 for the preparation of N-(2-(3-bromo-7-(2-methoxyethoxy)naphthalen-1-yl)ethyl)acetamide.

[0626] MS m / z(ESI):366.1[M+H] + ,368.1[M+H+2] + .

[0627] 1 H NMR (400MHz, CDCl3) δ7.80(s,1H),7.64(d,J=9.0Hz,1H),7.46(s,1H),7.35(d,J=1.4Hz,1H),7.22(dd,J=8.9,2.0Hz,1H),5.7 7(s,1H),4.33–4.28(m,2H),3.86–3.81(m,2H),3.55(dd,J=13.0,6.4Hz,2H),3.47(s,3H),3.18(t,J=7.2Hz,2H),1.96(s,3H).

[0628] Embodiment 42

[0629] Preparation of N-(2-(3-chloro-7-(3-methoxypropoxy)naphthalen-1-yl)ethyl)acetamide

[0630]

[0631] Reference Example 14 for the preparation of N-(2-(3-chloro-7-(3-methoxypropoxy)naphthalen-1-yl)ethyl)acetamide.

[0632] MS m / z(ESI):336.1[M+H] + ,338.1[M+H+2] + .

[0633] 1 H NMR (400MHz, CDCl3) δ7.82 (s, 1H), 7.66 (d, J =9.0Hz,1H),7.38(d, J =12.6Hz,2H),7.17(d, J=8.9Hz,1H),4.23(t, J =6.1Hz,2H),3.61(t, J =6.1Hz,4H),3.38(s,3H),3.20(t, J =7.0Hz,2H),2.16–2.10(m,2H),1.97(s,3H).

[0634] Embodiment 43

[0635] Preparation of N-(2-(3-chloro-7-(2-ethoxyethoxy)naphthalen-1-yl)ethyl)acetamide

[0636]

[0637] Reference Example 14 for the preparation of N-(2-(3-chloro-7-(3-methoxypropoxy)naphthalen-1-yl)ethyl)acetamide.

[0638] MS m / z(ESI):336.1[M+H] + ,338.1[M+H+2] + .

[0639] 1 H NMR (400MHz, CDCl3) δ7.91(dd,J=15.0,2.9Hz,1H),7.61(d,J=3.1Hz,1H),7.49(t,J=3.0Hz,1H),7.21(d,J=3.1Hz,1H),6.97(dd,J=15.0,2.9H z,1H),5.60(s,1H),4.40(t,J=14.6Hz,2H),3.76(t,J=14.6Hz,2H),3.4 9–3.34(m,4H),3.30–3.21(m,2H),1.80(s,3H),1.13(t,J=11.8Hz,3H).

[0640] Embodiment 44

[0641] Preparation of N-(2-(6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide

[0642]

[0643] Step 1: Preparation of 2-(6-methoxy-4-quinolyl)-N,N-dimethyl-ethyleneamine

[0644]

[0645] A solution of 6-methoxy-4-methyl-quinoline (970 mg, 5.6 mmol) in tert-butoxybis(dimethylamino)methane (9 mL) was stirred at 110° C. for 60 hours. The reaction solution was concentrated to give 2-(6-methoxy-4-quinolyl)-N,N-dimethyl-ethyleneamine (1.28 g, yield 100%) as a black oil, which was used directly in the next step.

[0646] MS m / z(ESI):229.1[M+H] + .

[0647] Step 2: Preparation of 2-(6-methoxy-4-quinolyl)acetonitrile

[0648]

[0649] Add hydroxylamine sulfonic acid (1.9 g, 16.8 mmol) to a solution of 2-(6-methoxy-4-quinolyl)-N,N-dimethyl-ethyleneamine (1.28 g, 5.6 mmol) in acetonitrile (60 mL) and water (40 mL), and a large amount of solid precipitates. Heat to 50°C and stir for 5 hours. Add water (60 mL) to the reaction solution, adjust the pH to 9 with solid sodium carbonate, extract with ethyl acetate, combine the organic phases, wash with saturated brine, concentrate, and purify by column chromatography to obtain 2-(6-methoxy-4-quinolyl)acetonitrile (1 g, yield 90%) as a yellow solid.

[0650] MS m / z(ESI):199.1[M+H] + .

[0651] Step 3: Preparation of N-[2-(6-methoxy-4-quinolyl)ethyl]acetamide

[0652]

[0653] To a solution of 2-(6-methoxy-4-quinolyl)acetonitrile (800 mg, 4 mmol) in dichloromethane (20 mL) and methanol (10 mL) was added nickel chloride hexahydrate (576 mg, 2.4 mmol), acetic anhydride (989 mg, 9.7 mmol), and sodium borohydride (611 mg, 16.1 mmol) at -10°C. The solution turned black and was stirred at room temperature for 3 hours. Concentrated hydrochloric acid (3 mL) was added dropwise under an ice-water bath and stirred at room temperature for 1 hour. Water (100 mL) was added and the mixture was washed with ethyl acetate. The aqueous phase was adjusted to pH 9 with sodium carbonate and extracted with ethyl acetate. The organic phase was concentrated and purified by column chromatography to obtain N-[2-(6-methoxy-4-quinolyl)ethyl]acetamide (700 mg, yield 67%) as a pink solid.

[0654] MS m / z(ESI):245.1[M+H]+ .

[0655] Step 4: Preparation of N-(2-(6-hydroxyquinolin-4-yl)ethyl)acetamide

[0656]

[0657] Add a dichloromethane solution of boron tribromide (1.0 M, 8 mL) to a dichloromethane solution (15 mL) of N-[2-(6-methoxy-4-quinolyl)ethyl]acetamide (200 mg, 819 μmol) at 0°C, and stir for 1 hour. The reaction is quenched with water (30 mL), adjusted to pH ~ 9 with solid sodium carbonate, extracted with dichloromethane, the organic phases are combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N-(2-(6-hydroxyquinolin-4-yl)ethyl)acetamide (100 mg, yield 53%) as a yellow solid.

[0658] MS m / z(ESI):231.1[M+H] + .

[0659] Step 5: Preparation of N-(2-(6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide

[0660]

[0661] Cesium carbonate (160 mg, 0.5 mmol) and potassium iodide (30 mg, 0.2 mmol) were added to N-(2-(6-hydroxyquinolin-4-yl)ethyl)acetamide (100 mg, 0.43 mmol) and bromocyclopropane (100 mg, 0.8 mmol) in N-methylpyrrolidone (3 mL), and the mixture was stirred at 170°C for 2 hours in a microwave oven. The reaction solution was added to water (40 mL), extracted with dichloromethane, concentrated, separated by high performance liquid chromatography, and freeze-dried to give N-(2-(6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide (10 mg, yield 8%).

[0662] MS m / z(ESI):271.1[M+H] + .

[0663] 1H NMR (400MHz, DMSO) δ8.63(d,J=4Hz,1H),8.17–8.04(m,1H),7.92(d,J=8Hz,1H),7.60(d,J=4Hz,1H),7.44–7.36(m,1H),7.32 (d,J=4Hz,1H),4.06–3.93(m,1H),3.43–3.37(m,2H),3.17(t,J=8Hz,2H),1.81(s,3H),0.95–0.87(m,2H),0.77–0.65(m,2H).

[0664] Embodiment 45

[0665] Preparation of N-(2-(2-chloro-6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide

[0666]

[0667] Step 1: Preparation by 1-oxidation of 4-(2-acetylaminoethyl)-6-cyclopropyloxyquinoline

[0668]

[0669] N-(2-(6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide (100 mg, 0.37 mol) and m-chloroperbenzoic acid (149 mg, 0.74 mol, 85%) were stirred at room temperature for 13 hours in dichloromethane (15 mL). The solution was concentrated and purified by column chromatography to give 4-(2-acetylaminoethyl)-6-cyclopropyloxyquinoline 1-oxidation (95 mg, 90% yield) as a yellow solid.

[0670] MS m / z(ESI):287.1[M+H] + .

[0671] Step 2: Preparation of N-(2-(2-chloro-6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide

[0672]

[0673] 4-(2-Acetylaminoethyl)-6-cyclopropyloxyquinoline 1-oxide (95 mg, 0.33 mol) was stirred in phosphorus oxychloride (5 mL) at 100°C for 1 hour. The mixture was slowly poured into an aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, separated by high performance liquid chromatography, and freeze-dried to obtain N-(2-(2-chloro-6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide (12 mg, yield 11%) as a white solid.

[0674] MS m / z(ESI):305.1[M+H] + ,307.1[M+H+2] + .

[0675] 1 H NMR (400MHz, DMSO) δ8.19–8.05(m,1H),7.86(d,J=8Hz,1H),7.63(d,J=4Hz,1H),7.48–7.43(m,1H),7.41(s,1H ),4.06–3.93(m,1H),3.47–3.40(m,2H),3.38–3.32(m,2H),1.80(s,3H),0.95–0.85(m,2H),0.77–0.65(m,2H).

[0676] Embodiment 46

[0677] Preparation of N-(2-(2-bromo-6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide

[0678]

[0679] Reference Example 45 for the preparation of N-(2-(2-bromo-6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide.

[0680] MS m / z(ESI):349.1[M+H] + ,351.1[M+H+2] + .

[0681] 1 H NMR (400MHz, DMSO) δ8.19–8.05(m,1H),7.87(d,J=8Hz,1H),7.63(d,J=4Hz,1H),7.48–7.43(m,1H),7.45(s,1H ),4.06–3.95(m,1H),3.46–3.44(m,2H),3.37–3.32(m,2H),1.81(s,3H),0.95–0.86(m,2H),0.75–0.65(m,2H).

[0682] Embodiment 47

[0683] Preparation of N-(2-(6-cyclopropyloxy-2-fluoroquinolin-4-yl)ethyl)acetamide

[0684]

[0685] Reference Example 45 for the preparation of N-(2-(6-cyclopropyloxy-2-fluoroquinolin-4-yl)ethyl)acetamide.

[0686] MS m / z(ESI):289.1[M+H] + .

[0687] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.86(d,J=8Hz,1H),7.64(d,J=4Hz,1H),7.47-7.41(m,2 H),4.04-4.01(m,1H),3.62-3.57(m,2H),3.25-3.21(m,2H),1.43(s,3H),1.01-0.89(m,4H).

[0688] Embodiment 48

[0689] Preparation of N-(2-(6-cyclopropyloxy-2-methylquinolin-4-yl)ethyl)acetamide

[0690]

[0691] Reference Example 36 for the preparation of N-(2-(6-cyclopropyloxy-2-methylquinolin-4-yl)ethyl)acetamide.

[0692] MS m / z(ESI):285.1[M+H] + .

[0693] 1 H NMR (400MHz, DMSO) δ8.19–8.04(m,1H),7.84(d,J=8Hz,1H),7.63(d,J=4Hz,1H),7.48–7.43(m,1H),7.31(s,1H),4.06 –3.93(m,1H),3.47–3.40(m,2H),3.38–3.32(m,2H),2.50(s,3H),1.80(s,3H),0.95–0.88(m,2H),0.76–0.65(m,2H).

[0694] Embodiment 49

[0695] Preparation of N-(2-(7-methoxyisoquinolin-1-yl)ethyl)acetamide

[0696] Step 1: Preparation of 7-methoxy-1-methylisoquinoline

[0697]

[0698] 1-(3-Methoxyphenyl)ethane-1-amine (5g, 33.1mmol), 2,2-diethoxyacetaldehyde (6.6g, 50mmol) were dissolved in toluene (100mL), heated to reflux and stirred for 5 hours. The reaction solution was concentrated, phosphorus oxychloride (50mL) was added, and heated to reflux for 15 hours. The reaction solution was concentrated, ice water was added, and ethyl acetate was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated. 7-methoxy-1-methylisoquinoline (1.9g, yield 33%) was obtained by column chromatography purification.

[0699] MS m / z(ESI):174.1[M+H] + .

[0700] Step 2: Preparation of (Z)-2-(7-methoxyisoquinolin-1-yl)-N,N-dimethylethylene-1-amine

[0701]

[0702] 7-Methoxy-1-methylisoquinoline (1.8 g, 10.3 mmol) was added to 1-tert-butoxy-N,N,N',N'-tetramethylmethanediamine (2.7 g, 15.5 mmol), heated to 110°C and stirred for 60 hours. The reaction solution was concentrated to obtain (Z)-2-(7-methoxyisoquinolin-1-yl)-N,N-dimethylvinyl-1-amine as a black oily product, which was directly used in the next step (2.8 g, crude product).

[0703] MS m / z(ESI):229.1[M+H] + .

[0704] Step 3: Preparation of 2-(7-methoxyisoquinolin-1-yl)acetonitrile

[0705]

[0706] (Z)-2-(7-methoxyisoquinolin-1-yl)-N,N-dimethylvinyl-1-amine (2.8 g) was dissolved in acetonitrile / water (50 mL / 30 mL), (aminooxy)sulfonic acid (3.4 g, 30.1 mmol) was added, and the mixture was heated to 50°C and stirred for 13 hours. The reaction solution was adjusted to pH 9 with solid sodium carbonate, and water (60 mL) was added. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated and purified by column chromatography to give 2-(7-methoxyisoquinolin-1-yl)acetonitrile (1.7 g, two-step yield 83%).

[0707] MS m / z(ESI):199.1[M+H] + .

[0708] Step 4: Preparation of N-(2-(7-methoxyisoquinolin-1-yl)ethyl)acetamide

[0709]

[0710] 2-(7-methoxyisoquinolin-1-yl)acetonitrile (1.5 g, 7.5 mmol) was dissolved in MeOH / CH2Cl2 (20 mL / 50 mL), NiCl2.6H2O (1.1 g, 4.6 mmol) was added, and the mixture was stirred to dissolve. Acetic anhydride (1.9 g, 18.6 mmol) was added, and NaBH4 (1.1 g, 28.9 mmol) was added in batches, and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with concentrated hydrochloric acid (1 mL) and stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction solution, and the pH was adjusted to 9 with sodium carbonate, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated and purified by column chromatography to obtain N-(2-(7-methoxyisoquinolin-1-yl)ethyl)acetamide (380 mg, yield 21%).

[0711] MS m / z(ESI):245.1[M+H] + .

[0712] 1 H NMR (400MHz, DMSO) δ8.28(d,J=4Hz,1H),8.15–8.04(m,1H),7.88(d,J=12Hz,1H),7.67–7.64(m,1H),7 .62(d,J=4Hz,1H),7.46–7.37(m,1H),3.96(s,3H),3.54–3.47(m,2H),3.38–3.32(m,2H),1.81(s,3H).

[0713] Embodiment 50

[0714] Preparation of N-(2-(3-chloro-7-methoxyisoquinolin-1-yl)ethyl)acetamide

[0715]

[0716] Step 1: Preparation by 2-oxidation of 1-(2-acetylaminoethyl)-7-methoxyisoquinoline

[0717]

[0718] N-(2-(6-cyclopropyloxyquinolin-4-yl)ethyl)acetamide (60 mg, 0.25 mol) and m-chloroperbenzoic acid (100 mg, 0.5 mol, 85%) were stirred in dichloromethane (15 mL) at room temperature for 3 hours. The mixture was directly concentrated and purified by column chromatography to give 1-(2-acetylaminoethyl)-7-methoxyisoquinoline 2-oxide (60 mg, yield 94%) as a yellow solid.

[0719] MS m / z(ESI):261.1[M+H] + .

[0720] Step 2: Preparation of N-(2-(3-chloro-7-methoxyisoquinolin-1-yl)ethyl)acetamide

[0721]

[0722] 4-(2-Acetylaminoethyl)-6-cyclopropyloxyquinoline 1-oxide (60 mg, 0.23 mol) was stirred in phosphorus oxychloride (5 mL) at 100°C for 1 hour. The mixture was slowly poured into an aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, concentrated, separated by high performance liquid chromatography, and freeze-dried to obtain N-(2-(3-chloro-7-methoxyisoquinolin-1-yl)ethyl)acetamide (15 mg, yield 22%) as a yellow solid.

[0723] MS m / z(ESI):279.1[M+H] + ,281.1[M+H+2] + .

[0724] 1 H NMR(400MHz,DMSO)δ8.39(s,1H),8.13–8.02(m,2H),7.75–7.67(m,1H),7.62– 7.55(m,1H),4.00(s,3H),3.53–3.47(m,2H),3.35–3.30(m,2H),1.80(s,3H).

[0725] Embodiment 51

[0726] Preparation of N-(2-(7-methoxy-3-methylisoquinolin-1-yl)ethyl)acetamide

[0727]

[0728] Reference Example 36 for the preparation of N-(2-(7-methoxy-3-methylisoquinolin-1-yl)ethyl)acetamide.

[0729] MS m / z(ESI):259.1[M+H]+ .

[0730] 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.10–8.02(m,2H),7.71–7.64(m,1H),7.60–7.52 (m,1H),4.00(s,3H),3.53–3.47(m,2H),3.35–3.30(m,2H),2.51(s,3H),1.80(s,3H).

[0731] Embodiment 52

[0732] Preparation of N-(2-(7-cyclopropyloxyisoquinolin-1-yl)ethyl)acetamide

[0733]

[0734] Preparation of N-(2-(7-cyclopropyloxyisoquinolin-1-yl)ethyl)acetamide Reference Example 1.

[0735] MS m / z(ESI):271.1[M+H] + .

[0736] 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=4Hz,1H),8.09(s,1H),7.88(d,J=12Hz,1H),7.66-7.62(m,2H),7.42(dd ,J=8Hz,4Hz,1H),4.04-4.01(m,1H),3.53-3.48(m,2H),3.36-3.33(m,2H),1.81(s,3H),1.01-0.89(m,4H).

[0737] Embodiment 53

[0738] Preparation of N-(2-(3-chloro-7-cyclopropyloxyisoquinolin-1-yl)ethyl)acetamide

[0739]

[0740] Reference Example 45: Preparation of N-(2-(3-chloro-7-cyclopropyloxyisoquinolin-1-yl)ethyl)acetamide.

[0741] MS m / z(ESI):305.1[M+H] + .

[0742] 1H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.08(d,J=8Hz,1H),7.71(d,J=4Hz,1H),7.58(dd,J=8Hz,4Hz,1H) ,5.63(s,1H),4.04-4.01(m,1H),3.52-3.47(m,2H),3.36-3.33(m,2H),1.80(s,3H),1.01-0.89(m,4H).

[0743] Embodiment 54

[0744] Preparation of N-(2-(7-cyclopropyloxy-3-methylisoquinolin-1-yl)ethyl)acetamide

[0745]

[0746] Reference Example 36 for the preparation of N-(2-(7-cyclopropyloxy-3-methylisoquinolin-1-yl)ethyl)acetamide.

[0747] MS m / z(ESI):285.1[M+H] + .

[0748] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),8.10(d,J=8Hz,1H),7.72(d,J=4Hz,1H),7.60(dd,J=8Hz,4Hz,1H),5.63( s,1H),4.03-4.01(m,1H),3.53-3.47(m,2H),3.37-3.33(m,2H),2.53(s,3H),1.80(s,3H),1.01-0.89(m,4H).

[0749] Embodiment 55

[0750] Preparation of N-[2-[3-bromo-7-(cyanomethoxy)-1-naphthyl]ethyl]acetamide

[0751]

[0752] Step 1: Preparation of N-[2-[3-bromo-7-(cyanomethoxy)-1-naphthyl]ethyl]acetamide

[0753]

[0754] N-[2-(3-bromo-7-hydroxy-1-naphthyl)ethyl]acetamide (50 mg, 162.25 μmol), bromoacetonitrile (58 mg, 486 μmol) and potassium carbonate (67 mg, 486 μmol) were stirred in acetonitrile (5 mL) at 80° C. for 1 hour. The reaction solution was filtered, washed with ethyl acetate, the organic phase was concentrated, and purified by flash column chromatography (dichloromethane / methanol=15 / 1) to give N-[2-[3-bromo-7-(cyanomethoxy)-1-naphthyl]ethyl]acetamide as a white solid (40 mg, yield 68%).

[0755] MS m / z(ESI):347.0[M+H] + ,349.0[M+H+2] + .

[0756] 1 H NMR (400MHz, DMSO) δ8.18–8.10(m,1H),8.06(s,1H),7.93(d,J=9.0Hz,1H),7.83-7.82(m,1H),7.52 -7.51(m,1H),7.38–7.29(m,1H),5.39(s,2H),3.36–3.25(m,2H),3.14(t,J=8Hz,2H),1.83(s,3H).

[0757] Embodiment 56

[0758] Preparation of N-(2-(3-chloro-7-(cyanomethoxy)naphthalen-1-yl)ethyl)acetamide

[0759]

[0760] Step 1: Preparation of N-(2-(3-chloro-7-hydroxynaphthalen-1-yl)ethyl)acetamide

[0761]

[0762] N-[2-(3-bromo-7-hydroxy-1-naphthyl)ethyl]acetamide (130 mg, 422 μmol) and cuprous chloride (418 mg, 4.22 mmol) were stirred in N,N-dimethylformamide (3 mL) at 140°C for 1 hour under microwave. Water (30 mL) and ethyl acetate (20 mL) were added to the reaction solution, filtered, and extracted with ethyl acetate (20 mL×2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated to give N-(2-(3-chloro-7-hydroxynaphth-1-yl)ethyl)acetamide as a yellow oil (70 mg, yield 63%).

[0763] MS m / z(ESI):264.1[M+H] +,266.1[M+H+2] + .

[0764] Step 2: Preparation of N-(2-(3-chloro-7-(cyanomethoxy)naphthalen-1-yl)ethyl)acetamide

[0765]

[0766] N-[2-(3-chloro-7-hydroxy-1-naphthyl)ethyl]acetamide (70 mg, 265 μmol), bromoacetonitrile (95 mg, 796 μmol) and potassium carbonate (110 mg, 796 μmol) were stirred in acetonitrile (3 mL) at 80° C. for 1 hour. The reaction solution was filtered, washed with ethyl acetate, the organic phase was concentrated, and purified by flash column chromatography (dichloromethane / methanol=15 / 1) to give N-(2-(3-chloro-7-(cyanomethoxy)naphthalen-1-yl)ethyl)acetamide as a white solid (30 mg, yield 35%).

[0767] MS m / z(ESI):303.1[M+H] + ,305.1[M+H+2] + .

[0768] 1 H NMR (400MHz, DMSO) δ8.20–8.09(m,1H),7.96–7.88(m,2H),7.86–7.80(m,1H),7.43–7.38(m ,1H),7.37–7.30(m,1H),5.39(s,2H),3.43–3.33(m,2H),3.15(t,J=8Hz,2H),1.83(s,3H).

[0769] Embodiment 57

[0770] Preparation of N-(2-(7-(cyanomethoxy)-3-methyl-1-naphthyl)ethyl)acetamide

[0771]

[0772] Step 1: Preparation of N-(2-(7-hydroxy-3-methyl-naphthalen-1-yl)ethyl)acetamide

[0773]

[0774] N-[2-(3-bromo-7-hydroxy-1-naphthyl)ethyl]acetamide (100 mg, 324 μmol), trimethylcyclotriboroxane (122 mg, 973 μmol), Cs2CO3 (211 mg, 649 μmol), Pd(dppf)Cl2-DCM (27 mg, 32 μmol) in dioxane (3 mL) and water (0.3 mL) were stirred in a microwave at 100 ° C for 1 hour under nitrogen protection. LC-MS showed that the reaction was complete. The reaction solution was directly used for the next step.

[0775] MS m / z(ESI):244.1[M+H] + .

[0776] Step 2: Preparation of N-(2-(7-(cyanomethoxy)-3-methyl-1-naphthyl)ethyl)acetamide

[0777]

[0778] Bromoacetonitrile (117 mg, 974 μmol) and potassium carbonate (135 mg, 974 μmol) were added to the reaction solution of the previous step, and stirred at 80°C for 1 hour. The reaction solution was filtered, washed with ethyl acetate, and the organic phase was concentrated and purified by flash column chromatography (dichloromethane / methanol = 0%-3%) to obtain a crude product, which was purified by preparative HPLC to obtain N-(2-(7-(cyanomethoxy)-3-methyl-1-naphthyl)ethyl)acetamide as a white solid (23 mg, yield 24%).

[0779] MS m / z(ESI):283.1[M+H] + .

[0780] 1 H NMR (400MHz, DMSO) δ8.18–8.07(m,1H),7.82(d,J=8Hz,1H),7.79–7.74(m,1H),7.54(s,1H),7. 29–7.18(m,2H),5.35(s,2H),3.47–3.27(m,2H),3.18–3.01(m,2H),2.42(s,3H),1.85(s,3H).

[0781] Embodiment 59

[0782] Preparation of N-(2-(7-(cyanomethoxy)-4-fluoronaphthalen-1-yl)ethyl)acetamide

[0783]

[0784] Reference Example 57 was used to prepare N-(2-(7-(cyanomethoxy)-4-fluoronaphthalen-1-yl)ethyl)acetamide.

[0785] MS m / z(ESI):287.1[M+H] + .

[0786] 1 H NMR(400MHz,Chloroform-d)δ8.04(d,J=9.0Hz,1H),7.68(t,J=2.2Hz,1H),7.26–7.14(m,2H),6.92(d d,J=10.3,7.8Hz,1H),5.54(s,1H),,5.35(s,2H),3.35-3.31(m,2H),3.12-3.08(m,2H),2.42(s,3H).

[0787] Embodiment 60

[0788] Preparation of N-(2-(3-bromo-7-cyclopropyloxynaphthalen-1-yl)-3-hydroxypropyl)acetamide

[0789]

[0790] Step 1: Preparation of ethyl 2-cyano-2-(7-methoxy-1-naphthyl) acetate

[0791]

[0792] 2-(7-methoxy-1-naphthyl)acetonitrile (2.5 g, 12.7 mmol) and NaH (1.1 g, 25.4 mmol, 60% purity) were added to tetrahydrofuran (40 mL), mixed evenly, and reacted at 70° C. for 2 hours. Diethyl carbonate (3 g, 25.4 mmol) was added to the reaction solution, and the reaction was continued for 1 hour. The reaction was quenched, extracted with ethyl acetate, and concentrated under reduced pressure. The crude product was separated and purified by flash chromatography to obtain the target compound ethyl 2-cyano-2-(7-methoxy-1-naphthyl) acetate (2 g, yield 58%) as a yellow oil.

[0793] MS m / z(ESI):270.1[M+H] + .

[0794] Step 2: Preparation of 3-amino-2-(7-methoxy-1-naphthyl)propan-1-ol

[0795]

[0796] LiAlH4 (113 mg, 2.97 mmol) was added to THF (10 mL), mixed evenly, and stirred at 0°C. Ethyl 2-cyano-2-(7-methoxy-1-naphthyl) acetate (200 mg, 742.68 μmol) was added to the reaction solution, and the reaction was continued for 1 hour. The mixture was quenched, extracted with dichloromethane, and concentrated under reduced pressure. The crude product 3-amino-2-(7-methoxy-1-naphthyl)propan-1-ol (100 mg, 432.36 μmol, yield 58%) was directly used in the next reaction.

[0797] MS m / z(ESI):232.1[M+H] + .

[0798] Step 3: 3-Acetylamino-2-(7-methoxynaphthalen-1-yl)propyl acetate

[0799]

[0800] 3-Amino-2-(7-methoxy-1-naphthyl)propan-1-ol (100 mg, 432.36 μmol, crude product) and K2CO3 (179 mg, 1.30 mmol) were added to EtOAc / H2O (20 mL). After mixing evenly, acetyl chloride (51 mg, 648.54 μmol) was added dropwise at 0°C. The mixture was reacted for 1 hour, extracted with ethyl acetate, and concentrated under reduced pressure. The crude product was separated and purified by Pre-HPLC to obtain the target compound 3-acetylamino-2-(7-methoxynaphthalen-1-yl)propyl acetate (40 mg, yield 33%).

[0801] MS m / z(ESI):316.1[M+H] + .

[0802] Step 4: Preparation of [3-acetylamino-2-(3-bromo-7-methoxy-1-naphthyl)propyl]acetate

[0803]

[0804] 3-Acetylamino-2-(7-methoxynaphthalen-1-yl)propyl acetate (40 mg, 0.15 mmol) and Br2 (35 mg, 0.22 mmol) were added to acetic acid (5 mL), reacted at 70° C. for 3 hours, concentrated under reduced pressure, and the crude product was separated and purified by flash chromatography to obtain the target compound [3-acetylamino-2-(3-bromo-7-methoxy-1-naphthyl)propyl] acetate (40 mg, yield 80%).

[0805] MS m / z(ESI):394.1[M+H] + .

[0806] Step 5: Preparation of N-(2-(3-bromo-7-hydroxynaphthalen-1-yl)-3-hydroxypropyl)acetamide

[0807]

[0808] [3-Acetylamino-2-(3-bromo-7-methoxy-1-naphthyl)propyl]acetate (40 mg, 0.1 mmol) and BBr3 (1 M, 2 mL) were added to dichloromethane (5 mL), reacted at room temperature for 1 hour, quenched with water, extracted with dichloromethane, concentrated under reduced pressure, and the crude product was separated and purified by flash chromatography to obtain the target compound N-(2-(3-bromo-7-hydroxynaphthalen-1-yl)-3-hydroxypropyl)acetamide (20 mg, yield 60%).

[0809] MS m / z(ESI):338.1[M+H] + .

[0810] Step 6: N-[2-[3-bromo-7-(cyclopropyloxy)-1-naphthyl]-3-hydroxy-propyl]acetamide

[0811]

[0812] N-(2-(3-bromo-7-hydroxynaphthalen-1-yl)-3-hydroxypropyl)acetamide (20 mg, 59 μmol), bromocyclopropane (31.8 mg, 263.0 μmol), KI (1.1 mg, 6.57 μmol), and Cs2CO3 (42.7 mg, 131.5 μmol) were added to DMF (2 mL), mixed evenly, reacted at 170°C for 4 hours, concentrated under reduced pressure, and the crude product was separated and purified by Pre-HPLC to obtain the target compound N-[2-[3-bromo-7-(cyclopropyloxy)-1-naphthyl]-3-hydroxy-propyl]acetamide (4 mg, yield 16%).

[0813] MS m / z(ESI):378.1[M+H] + .

[0814] 1 H NMR (400MHz, DMSO-d6) δ8.06 (s, 1H), 7.93-7.87 (m, 3H), 7.50 (d, J = 2Hz, 1H) 7.35 (dd, J = 8.8, 2Hz, 1H), 4.82 (brs, 1H),4.03-4.01(m,1H),3.85-3.70(m,3H),3.52-3.49(m,1H),3.29-3.27(m,1H),1.81(s,3H),1.01-0.90(m,4H).

[0815] Embodiment 61

[0816] Preparation of N-(2-(3-chloro-7-cyclopropyloxynaphthalen-1-yl)-3-hydroxypropyl)acetamide

[0817]

[0818] Reference Example 14 for the preparation of N-(2-(3-chloro-7-cyclopropyloxynaphthalen-1-yl)-3-hydroxypropyl)acetamide.

[0819] MS m / z(ESI):334.1[M+H] + .

[0820] 1 H NMR (400MHz, DMSO-d6) δ8.08 (s, 1H), 7.94-7.86 (m, 3H), 7.49 (d, J = 2Hz, 1H) 7.34 (dd, J = 8.8, 2Hz, 1H), 4.81 (brs, 1H),4.04-4.01(m,1H),3.84-3.71(m,3H),3.52-3.49(m,1H),3.29-3.27(m,1H),1.80(s,3H),1.01-0.89(m,4H).

[0821] Embodiment 62

[0822] Preparation of N-(2-(7-cyclopropyloxy-3-methylnaphthalen-1-yl)-3-hydroxypropyl)acetamide

[0823]

[0824] Reference Example 36 for the preparation of N-(2-(7-cyclopropyloxy-3-methylnaphthalen-1-yl)-3-hydroxypropyl)acetamide.

[0825] MS m / z(ESI):314.1[M+H] + .

[0826] 1 H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.83-7.78(m,2H),7.54(s,1H),7.25-7.22(m,2H),4.81(brs,1H),4.04-4. 01(m,1H),3.84-3.71(m,3H),3.52-3.49(m,1H),3.29-3.27(m,1H),2.40(s,3H),1.80(s,3H),1.01-0.89(m,4H).

[0827] Other compound information is as follows in Table 1:

[0828] Table 1 Compound information

[0829]

[0830]

[0831]

[0832] Biological test evaluation

[0833] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0834] 1. Cell function experiment

[0835] Test Example 1: Determination of the Effect of the Compounds of the Invention on Calcium Flux in Cells Stably Expressing MT1 / MT2 Receptors

[0836] 1. Experimental purpose:

[0837] The compounds were tested for their agonistic effects on the activity of HEK293-MT1 / HEK293-MT2 cells.

[0838] 2. Experimental instruments and reagents:

[0839] 2.1 Instruments:

[0840] 384-well assay plate (Corning: 3764);

[0841] 384-well-Echo compound plate (Labcyte: LP-0200);

[0842] 384-well compound plate (PE: 6008590);

[0843] Bravo Tip (Agilent: 10734-202);

[0844] FLIPR Tip (Molecular Device: 9000-0764);

[0845] Plate reader FLIPR Tetra (Molecular Device);

[0846] Liquid handling stations Bravo (Agilent) and ECHO 550 (LABCYTE);

[0847] Liquid pipette Multidrop Combi (ThermoFisher).

[0848] 2.2 Reagents:

[0849] DMEM, high glucose (Gibco: 12100);

[0850] Fetal bovine serum (Biosera: FB-1058 / 500);

[0851] P / S (Biosera: XC-A4122);

[0852] 5X Matrigel(Corning: 354230);

[0853] HBSS (Sigma: H1387);

[0854] HEPES (Invitrogen: 15630080);

[0855] Fluo-8 AM (AAT Bioquest: 21080);

[0856] Probenecid (Sigma: P8761);

[0857] Pluronic F-127 (Sigma: P2443-250G);

[0858] 1000X Fluo-8 AM (2 mM): Fluo-8 AM was dissolved in DMSO, shaken for 1-2 min, and stored at -20°C after aliquoting;

[0859] Complete culture medium: DMEM+10% FBS+1X P / S;

[0860] Cell seeding medium: DMEM+10% FBS+1X PS;

[0861] Assay buffer 1: 1X HBSS + 20 mM HEPES + 1 mM Probenecid + 0.025% Pluronic F-127;

[0862] Experimental buffer 2: 1X HBSS + 20mM HEPES + 0.075% Pluronic F-127; 1XMatrigel: 5X Matrigel diluted with DMEM;

[0863] Cell lines:

[0864] HDB HEK293-MT1;

[0865] HDB HEK293-MT2.

[0866] 3. Experimental methods:

[0867] 1) HEK293-MT1 / HEK293-MT2 cells were cultured in complete medium at 37°C and 5% CO2 until the confluency was 70% to 90%.

[0868] 2) Coat 384-well cell plates with 1X Matrigel, 5uL per well, at room temperature for 10-30 minutes.

[0869] 3) The digested cells were resuspended in a cell seeding medium, 8,000 cells / well / 20 μL were seeded into a 384-well cell culture plate, and cultured at 37° C. and 5% CO 2 for 24 hours.

[0870] 4) Take the cell culture plate out of the CO2 incubator and equilibrate it at room temperature for 10 minutes.

[0871] 5) Take out 1000X Fluo-8 AM and dilute it to 1X Fluo-8 AM with assay buffer 1 equilibrated to room temperature, with a concentration of 2 μM.

[0872] 6) Remove the culture medium from the cell culture plate, add 20 μL 1X Fluo-8 AM to each well, centrifuge at 300 rpm for 60 seconds at room temperature, and incubate at room temperature in the dark for 1 hour.

[0873] 7) Prepare the positive control compound and the test compound working solution (3X):

[0874] ① Use the Bravo instrument to dilute the compound to 11 concentration points on a 384-well Echo compound plate (LABCYTE: LP-0200);

[0875] ② Then use the instrument ECHO to transfer 90nL of compound per well (compound storage concentration, such as the highest concentration point 10mM) to a 384-well compound plate (PE: 6008590);

[0876] ③ Use Multidrop Combi to add 30 μL of experimental buffer 2 to 384-well compound plate (PE: 6008590), dilute the positive control compound and the test compound to 30 μM (3X), and place at room temperature for use.

[0877] 8) Add 10 μL of the diluted 3X compound to the experimental wells of the corresponding 384-well cell plate using the FLIPR Tetra and read and collect data simultaneously.

[0878] 4. Experimental data processing method:

[0879] FLIPR Tetra reads and collects the fluorescence signal value (RFU), takes the maximum RFU value, and calculates the percentage activation data {% activation rate = (RFUsample-RFUlow control) / (RFUhigh control-RFUlow control)×100} according to the reading values ​​of the Low control (DMSO control) and High control (100nM positive compound) experimental groups. The concentration of the test compound is 11 concentrations ranging from 10μM to 0.17nM after the reaction system is diluted 3 times. XLFit is used to fit the percentage activation rate and 11 point concentration data to the parameter nonlinear logic formula to calculate the EC of the compound. 50 value.

[0880] 5. Experimental results:

[0881] Table 2 EC of compounds on HEK293-MT1 / HEK293-MT2 cells 50 value

[0882]

[0883] Note: “NA” means not detected.

[0884] 6. Experimental conclusion:

[0885] The example compounds shown in the present invention show good agonist activity in the experiment of affecting calcium flow in cells stably expressing MT1 and MT2 receptors.

[0886] Test Example 2: The compounds of the present invention have an effect on the stable expression of 5-HT 2C Determination of the effects of receptor cells on calcium flux

[0887] 1. Experimental purpose:

[0888] Effects of test compounds on HEK293-5HT 2C Antagonism of cell activity.

[0889] 2. Experimental instruments and reagents:

[0890] 2.1 Instruments:

[0891] 384-well assay plate (Corning: 3764);

[0892] 384-well-Echo compound plate (Labcyte: LP-0200);

[0893] 384-well compound plate (PE: 6008590);

[0894] Bravo Tip (Agilent: 10734-202);

[0895] FLIPR Tip (Molecular Device: 9000-0764);

[0896] Plate reader FLIPR Tetra (Molecular Device);

[0897] Liquid handling stations Bravo (Agilent) and ECHO 550 (LABCYTE);

[0898] Liquid pipette Multidrop Combi (ThermoFisher).

[0899] 2.2 Reagents:

[0900] DMEM, high glucose (Gibco: 12100);

[0901] Fetal bovine serum (Biosera: FB-1058 / 500);

[0902] P / S (Biosera: XC-A4122);

[0903] 5X Matrigel(Corning: 354230);

[0904] HBSS (Sigma: H1387);

[0905] HEPES (Invitrogen: 15630080);

[0906] Fluo-8 AM (AAT Bioquest: 21080);

[0907] Probenecid (Sigma: P8761);

[0908] Pluronic F-127 (Sigma: P2443-250G)

[0909] 1000X Fluo-8 AM (2 mM): Fluo-8 AM was dissolved in DMSO, shaken for 1-2 min, and stored at -20°C after aliquoting;

[0910] Complete culture medium: DMEM+10% FBS+1X P / S;

[0911] Cell seeding medium: DMEM+10% FBS+1X PS;

[0912] Replacement medium: DMEM + 1X P / S;

[0913] Assay buffer 1: 1X HBSS + 20 mM HEPES + 1 mM Probenecid + 0.025% Pluronic F-127;

[0914] Assay buffer 2: 1X HBSS + 20 mM HEPES + 0.075% Pluronic F-127; 1X Matrigel: 5X Matrigel diluted with DMEM;

[0915] Cell line: HDB HEK293-5HT 2C .

[0916] 3. Experimental methods:

[0917] 1) HEK293-5HT 2C Cell lines were cultured in complete medium at 37°C, 5% CO2 to 70% to 90% confluency.

[0918] 2) Coat a 384-well cell plate with 1X Matrigel, 5 μL per well, at room temperature for 10-30 minutes.

[0919] 3) The digested cells were resuspended in a cell seeding medium, 8,000 cells / well / 20 μL were seeded into a 384-well cell culture plate, and cultured at 37° C. and 5% CO 2 for 24 hours.

[0920] 4) Observe under a microscope to confirm that the cells have adhered to the wall. Remove the inoculation medium, add 20 μL of serum-free replacement medium preheated to 37°C to each well, and culture at 37°C with 5% CO2 overnight (18 hours).

[0921] 5) Take the cell culture plate out of the CO2 incubator and equilibrate it at room temperature for 10 minutes.

[0922] 6) Take out 1000X Fluo-8 AM and dilute it to 1X Fluo-8 AM with assay buffer 1 equilibrated to room temperature, with a concentration of 2 μM.

[0923] 7) Remove the culture medium from the cell culture plate, add 20 μL 1X Fluo-8 AM to each well, centrifuge at 300 rpm for 60 seconds at room temperature, and incubate at room temperature in the dark for 1 hour.

[0924] 8) Prepare the positive control compound and the test compound working solution (3X):

[0925] ① Use the Bravo instrument to dilute the compound to 11 concentration points on a 384-well Echo compound plate (LABCYTE: LP-0200);

[0926] ② Then use the ECHO instrument to transfer 90nL of compound per well (compound storage concentration, such as the highest concentration point 10mM) to a 384-well compound plate (PE: 6008590);

[0927] ③ Use Multidrop Combi to add 30 μL of experimental buffer 2 to 384-well compound plate (PE: 6008590), dilute the positive control compound and the test compound to 30 μM (3X), and place at room temperature for use.

[0928] 9) Add 10 μL of the diluted 3X compound to the experimental wells of the corresponding 384-well cell plate using the FLIPR Tetra and read and collect data simultaneously.

[0929] 4. Experimental data processing method:

[0930] FLIPR Tetra reads and collects the fluorescence signal value (RFU), takes the maximum RFU value, and calculates the percentage activation data {% activation rate = (RFUsample-RFUlow control) / (RFUhigh control-RFUlow control)×100} according to the reading values ​​of the Low control (DMSO control) and High control (100nM positive compound) experimental groups. The concentration of the test compound is 11 concentrations ranging from 10μM to 0.17nM after the reaction system is diluted 3 times. XLFit is used to fit the percentage activation rate and 11 point concentration data to the parameter nonlinear logic formula to calculate the IC of the compound. 50 value.

[0931] 5. Experimental results:

[0932] Table 3 Effects of compounds on HEK293-5HT 2C IC of cells 50 value

[0933]

[0934] 6. Experimental conclusion:

[0935] The example compounds shown in the present invention have the ability to stabilize the expression of 5HT 2C The receptor cells showed a certain antagonistic effect in the experiment of calcium flow.

[0936] Test Example 3: Pharmacokinetics in rats

[0937] 3.1. Research objectives:

[0938] SD rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in rats (plasma) after intravenous and oral administration.

[0939] Experimental plan

[0940] 3.2.1 Trial Drugs:

[0941] The compounds of the present invention are self-made.

[0942] 3.2.2 Experimental Animals:

[0943] There were 3 male SD rats in each group. Shanghai JXJ Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).

[0944] 3.2.3 Drug preparation:

[0945] Intravenous drug preparation: (5% DMSO + 10% Solutol HS15 + 85% PBS preparation method)

[0946] The example compound was weighed, 5% DMSO was added first, vortexed and sonicated for 2 min to completely dissolve it, then 10% Solutol HS15 was added, vortexed and sonicated for 2 min to completely dissolve it, and finally 85% PBS was added, vortexed and sonicated for 5 min to obtain a colorless, transparent, clear solution with a concentration of 0.2 mg / mL.

[0947] Oral drug preparation: (0.5% CMC-Na (1% Tween 80))

[0948] Weigh 5g sodium carboxymethyl cellulose (CMC-Na, viscosity: 800-1200Cps), dissolve in 1000mL purified water, add 10g Tween 80, mix and stir to form a clear solution.

[0949] The example compound was weighed, dissolved in the solution, shaken, and sonicated for 15 minutes to obtain a colorless clear solution with a concentration of 0.5 mg / mL.

[0950] 3.2.4 Administration:

[0951] Intravenous administration:

[0952] Three male SD rats were administered IV after overnight fasting at a dose of 1 mg / kg in a volume of 5 mL / kg.

[0953] Oral administration:

[0954] Three male SD rats were administered PO after overnight fasting at a dose of 5 mg / kg in a dosing volume of 10 mL / kg.

[0955] 3.2.5 Sample collection:

[0956] Intravenous administration:

[0957] Before administration and at 0h, 0.083h, 0.25h, 0.5h, 1.0h, 2.0h, and 4.0h after administration, 0.2mL of blood was collected from the jugular vein and placed in an EDTA-2K tube. The blood was centrifuged at 6000rpm for 6min at 4℃ to separate the plasma, which was then stored at -80℃. Food was consumed 4h after administration.

[0958] Oral administration:

[0959] Before administration and 0.25h, 0.5h, 1.0h, 2.0h, and 4.0h after administration, 0.2mL of blood was collected from the jugular vein, placed in an EDTA-2K tube, centrifuged at 6000rpm for 6min at 4℃ to separate plasma, and stored at -80℃; food was taken 4h after administration.

[0960] 3.3 Experimental results:

[0961] The final determination results were obtained by LCMS / MS method, see Table 4 and Table 5

[0962] Table 4: Pharmacokinetic parameters of the compounds of the present invention administered intravenously to rats

[0963]

[0964] Table 5: Pharmacokinetic parameters of the compounds of the present invention in rats after oral administration

[0965]

[0966] 3.4 Experimental conclusion:

[0967] The data in the table show that when the oral administration dose is 5 mg / kg, the exposure amount and bioavailability of the example compounds of the present invention in rat plasma are good.

[0968] Test Example 4: CYP enzyme phenotype identification experiment

[0969] 4.1 Experimental Purpose

[0970] The CYPs recombinant enzyme incubation system is used to preliminarily determine the main metabolic enzyme of the compound in the human body based on the metabolism of the compound by different subtypes of CYPs recombinant enzymes.

[0971] 4.2 Experimental procedures

[0972] 4.2.1 Solution preparation:

[0973] 10.0mM NADPH, weigh 16.7mg NADPH (reduced nicotinamide adenine dinucleotide phosphate) and add 100mM phosphate buffer to 2mL. Dilute each CYPs recombinant enzyme to 12.5pmol / L with 100mM phosphate buffer and mix well.

[0974] Preparation of the reaction solution of the test compound:

[0975] The compound of the example to be tested was weighed, diluted to 10 mM with DMSO, and then diluted to 10 μM with 100 mM phosphate buffer.

[0976] 4.2.2 Experimental process:

[0977] 1. In a 96-well plate, add 400 μL of recombinant enzyme and 50 μL of the test compound and pre-incubate for 10 min.

[0978] 2. Add 50 μL of NADPH.

[0979] 3. Take out 50 μL at 0, 5, 10, 15, 20 and 30 min respectively and add 200 μL of acetonitrile stop solution containing internal standard.

[0980] 4. Centrifuge and inject.

[0981] 4.3 Experimental results:

[0982] Table 6: CYP enzyme phenotype identification results of example compounds

[0983]

[0984]

[0985] 4.4 Experimental conclusion:

[0986] The above data show that the metabolic dependence of the example compounds of the present invention on CYP1A2 is reduced, and the metabolic ratio of other CYP enzyme subtypes to the example compounds is increased, which can reduce the variability of the compounds.

[0987] Test Example 5: CYP enzyme single-point inhibition test

[0988] 5.1 Experimental Purpose

[0989] The human liver microsome incubation system was used to quickly predict the inhibition of compounds on CYP450 enzyme subtypes using the single-point method.

[0990] 5.2 Experimental procedures

[0991] 5.2.1 Solution preparation:

[0992] 2.5mM NADPH, weigh 4.165mg NADPH (reduced nicotinamide adenine dinucleotide phosphate) and add 100mM phosphate buffer to 2mL. 0.25mg / mL microsomes, 50μL 20mg / mL microsomes, add 4mL 100mM phosphate buffer and mix well.

[0993] Preparation of the reaction solution of the test compound:

[0994] The compound of the example to be tested was weighed, diluted to 10 mM with DMSO, and then diluted to 100 μM with 100 mM phosphate buffer.

[0995] 5.2.2 Experimental process:

[0996] 1. In a 96-well plate, add 40 μL liver microsomes, 10 μL substrate, and 10 μL test compound and pre-incubate for 3 min.

[0997] 2. Add 40 μL of NADPH.

[0998] 3. At 20 min, add 300 μL of acetonitrile stop solution containing internal standard.

[0999] 4. Centrifuge and inject.

[1000] 5.3 Experimental results:

[1001] Table 7: Single-site inhibition results of CYP enzymes by example compounds

[1002]

[1003] Note:

[1004] Strong inhibition: IC 50 <1μM; Moderate inhibition: 1μM <IC 50 <10μM; weak inhibition: IC 50 >10μM

[1005] 5.4 Experimental conclusion:

[1006] The above data show that the compounds of the embodiments of the present invention have strong inhibition on CYP1A2, but no strong inhibition on other CYP enzyme subtypes, and the risk of DDI (drug-drug interaction) is small.

[1007] Test Example 6: Plasma protein binding rate experiment

[1008] 6.1 Experimental Purpose:

[1009] The purpose of this experimental method is to detect the plasma protein binding of the example compounds in plasma.

[1010] 6.2 Experimental instruments and materials:

[1011] Liquid phase mass spectrometer, centrifuge, vortexer, pipette, continuous liquid adder, 96-well plate, tissue homogenizer (used for tissue sample analysis), 50% methanol aqueous solution, acetonitrile solution with internal standard, blank matrix (plasma, urine or tissue homogenate, etc.).

[1012] 6.3 Experimental steps:

[1013] 6.3.1 Preparation of stock solution of test substance A

[1014] The example compounds were prepared into 1 mM solution A using DMSO.

[1015] 6.3.2 Preparation of plasma solution B

[1016] Take solution A and add it to the plasma solution to prepare 5uM solution B.

[1017] 6.3.3 Processing Flow

[1018] 1) Add 200uL of solution B into the membrane.

[1019] 2) Add 350uL PBS outside the membrane.

[1020] 3) Incubate in a 37°C water bath for 6 h.

[1021] 4) The samples are processed, diluted and tested by mass spectrometry.

[1022] 6.4 Chromatographic conditions:

[1023] Instrument: Shimadzu LC-20AD;

[1024] Chromatographic column: Phenomenex Gemiu C18 (50*4.6mm, 5μm particle size);

[1025] Mobile phase: A: acetonitrile, B: 0.1% formic acid solution, 0-0.5 min: 5% A→90% A, 2.0-2.1 min: 90% A→5% A; flow rate: 0.8 mL / min; running time: 5.0 min; injection volume: 5 μL.

[1026] 6.5 Mass spectrometry conditions:

[1027] Instrument: API4000 liquid chromatography-mass spectrometer, AB Company, USA;

[1028] The ion source was electrospray ionization (ESI);

[1029] Drying gas (N2) temperature 500°C;

[1030] The electrospray voltage was 5500 V;

[1031] The detection method is positive ion detection;

[1032] The scanning mode was selected reaction monitoring (MRM) and the scanning time was 0.1 s.

[1033] 6.6 Experimental results:

[1034] Table 8: Plasma protein binding rate of example compounds (%)

[1035]

[1036]

[1037] 6.7 Experimental conclusion:

[1038] The compounds of the examples of the present invention show high plasma protein binding rates with little species difference.

[1039] Test Example 7. Evaluation of drug efficacy in rat learned helplessness and sugar water preference models

[1040] 7.1 Experimental Purpose:

[1041] The purpose of this experiment was to evaluate the antidepressant effects of the test compounds in the learned helplessness (LH model) and sugar water preference models of SD rats.

[1042] 7.2 Experimental Animals:

[1043] 136 SD rats, male, 7-8 weeks old.

[1044] 7.3 Experimental instruments:

[1045] Table 9. Main instruments of the experiment

[1046]

[1047] 7.4 Experimental method and process:

[1048] 7.4.1. Adaptation

[1049] After 136 SD male rats arrived at the experimental facility, they were acclimated to the facility for one week before the experiment began. They were acclimated to the experimental room for 2 days before the training began.

[1050] 7.4.2. Training

[1051] The animals were placed in a shuttle box and restrained on one side of the box. The soles of their feet received 60 electric shocks with a current intensity of 0.8 mA and a duration of 15 seconds. There was a 2-second sound stimulus before each electric shock, and the interval between the two was 20 seconds.

[1052] 7.4.3. Screening

[1053] After the animal is placed in the shuttle box, the shuttle door is opened and the animal can shuttle freely in the box. The sole of the foot receives 30 electric currents with an intensity of 0.6 mA and a duration of 10 seconds (if the animal escapes to the other side during the current, the electric shock stops). There will be 2 seconds of sound and light stimulation before each electric shock, and the interval between the two times is 20 seconds. Record:

[1054] Active escape times: Active escape to the non-shock side under sound and light stimulation

[1055] Passive escape times: After the sound and light stimulation ends, the patient escapes to the non-shocked side while the electric shock continues. Escape failure times: The patient still does not escape after the electric shock ends.

[1056] Animals that fail to escape more than 20 times are considered to have learned helplessness and can be used for drug screening.

[1057] 7.4.4. Grouping

[1058] The animals were grouped immediately after the learned helplessness screening was completed. The screened learned helpless animals were randomly grouped according to the number of escape failures and used for compound screening tests.

[1059] 7.4.5. Drug administration

[1060] The first administration was carried out after the control group and the compound group were divided into groups, and the administration volume was 10 mL / kg for seven consecutive days. The positive compound (imipramine group) was administered before the first learned helplessness test, and the administration volume was 2 mL / kg for four consecutive days.

[1061] Testing

[1062] 7.4.6.1 Learned helplessness test (LH model)

[1063] The learned helplessness test was performed on the 2nd and 5th day of compound administration (the 1st and 4th day of positive compound administration). The positive compound was administered 0.5 hours later and the test compound was administered 0.25 or 0.5 hours later. The rats were then tested for electric shock escape. The number of escape failures and shuttles of the rats was recorded for analysis.

[1064] Experimental results:

[1065] Table 10: Number of escape failures and shuttling times of rats in the LH experiment of Example Compounds

[1066] serial number Escape failure count Shuttle times Vehicle 24.2 5.8 Imipramine (64 mg / kg) 10.7 19.9 Example 2A (20 mg / kg) 19.9 10.5 Example 2A (50 mg / kg) 20.0 10.2 Example 56 (20 mg / kg) 24.8 5.2 Example 56 (50 mg / kg) 26.5 3.6

[1067] Experimental conclusion:

[1068] In the LH model, the example compounds had a tendency to reduce the escape failure rate of rats.

[1069] 7.4.6.2 Sugar water preference test

[1070] After the fourth day of compound administration, the animals were given two bottles of normal water for acclimatization;

[1071] On the fifth day of compound administration, after the learned helplessness test, one of the bottles of ordinary water was replaced with 1% sugar water, and the position was changed six times within 24 hours;

[1072] After the compound administration on day 6, no food or water was allowed;

[1073] One hour after the end of compound administration on day 7, one bottle of sugar water and one bottle of normal water were added, and water consumption was tested for 1, 12, and 24 hours.

[1074] Sugar water preference rate = sugar water intake / (normal water intake + sugar water intake)*100%

[1075] Data collection and analysis:

[1076] Data were collected using Excel software. Data were analyzed using Prism (GraphPad software, Inc.) software, and one-way ANOVA with Fisher's LSD multiple comparison test was used. p<0.05 was considered to be a significant difference.

[1077] Experimental results:

[1078] Table 11: Example compounds sucrose preference test 12h and 24h rat sugar water preference

[1079] serial number 12h sugar water preference (%) 24h sugar water preference (%) Vehicle 64.0 63.0 Agomelatine (20mg / kg) 65.3 66.4 Example 2A (20 mg / kg) 84.0 84.9** Example 56 (20 mg / kg) 78.3 83.1*

[1080] Note: *p<0.05; **p<0.01

[1081] Experimental conclusion:

[1082] In the sugar water preference experiment, compared with the vehicle group, the test compound was able to significantly increase the sugar water preference rate of rats at 12h and 24h, and no obvious side effects were found in the experiment.

Claims

1. A compound represented by the general formula (IV-A) or a pharmaceutically acceptable salt thereof: R is selected from C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 C substituted with haloalkyl or cyano 1-3 alkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: R is selected from methyl or deuterated methyl.

3. The compound or a pharmaceutically acceptable salt thereof, characterized in that: The specific structure of the compound is:

4. A method for preparing the compound of claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of: The compound of formula (VA) reacts with RX in the presence of a base to obtain a compound of general formula (IV-A), in: X is bromine or iodine; R is as defined in claim 1.

5. A pharmaceutical composition comprising a therapeutically effective dose of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

6. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5 in the preparation of a melatonin receptor agonist drug.

7. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5, in the preparation of MT1 and MT2 receptor agonists and 5-HT 2C Use of receptor antagonists in medicine.

8. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5, in the preparation of a drug for treating or preventing central nervous system diseases and / or mental illnesses.

9. The use according to claim 8, characterized in that The central nervous system disease and / or mental disease is selected from melatonin system disease, schizophrenia, phobia, depression, autism, Alzheimer's disease, epileptic seizure or mania.

10. The use according to claim 8, characterized in that The central nervous system disease and / or psychiatric disorder is selected from stress, anxiety, sleep disorders, sleep disturbances, fatigue caused by jet lag, major depressive disorder, mood disorders, schizophrenia spectrum disorders, spastic disorders, memory disorders and / or cognitive disorders, movement disorders or personality disorders.

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