CN116249691A - Bicyclic derivative regulator, preparation method and application thereof - Google Patents

Bicyclic derivative regulator, preparation method and application thereof Download PDF

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CN116249691A
CN116249691A CN202180061354.5A CN202180061354A CN116249691A CN 116249691 A CN116249691 A CN 116249691A CN 202180061354 A CN202180061354 A CN 202180061354A CN 116249691 A CN116249691 A CN 116249691A
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alkyl
cycloalkyl
haloalkyl
hydroxyalkyl
alkenyl
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刘世强
王永升
袁逸达
鲍孟
黄胜爱
包如迪
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Abstract

A bicyclo compound shown in a general formula (I) or a stereoisomer thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in preparing medicaments for treating cardiovascular diseases, digestive system diseases, central nervous system diseases and/or mental diseases.

Description

Bicyclic derivative regulator, preparation method and application thereof Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a dicyclic derivative regulator, a preparation method and application thereof.
Background
Depression is a common mental disorder that repeatedly attacks and severely impairs the patient's ability to live in daily life. Despite extensive research, the exact neurobiological processes leading to depression and the mechanisms by which antidepressants produce therapeutic effects are not completely understood. Approximately 20% of people will develop depression at various stages of life, and currently about 3.5 hundred million people suffer from depression, and the number is expanding. The existing medicine is often not ideal in treatment effect on major depressive disorder, at least 30% of depressed patients do not achieve satisfactory treatment effect, and only less than 50% of patients achieve remission. Thus, antidepressants have great market demands.
Clinical findings that depression is often associated with biological rhythms may have antidepressant effects by modulating circadian rhythms. Agomelatine developed by Servier is the only approved melatonin receptor agonist antidepressant, has strong agonism to melatonin MT1 and MT2 receptors and antagonism to 5-HT2C receptors. Melatonin receptors have the ability to regulate circadian rhythms, regulate sleep, and 5-HT2C receptors are involved in antidepressant function. Clinically, the traditional Chinese medicine composition has obvious antidepressant effect, better tolerance and compliance, can increase the sleep continuity and quality of patients with Major Depressive Disorder (MDD), and has obviously smaller sexual dysfunction than other antidepressants.
Agomelatine is a multi-target antidepressant with a brand new mechanism target, has good antidepressant effect, but has low bioavailability (about 5 percent), obvious first pass effect on liver, and 90 percent of the Agomelatine is metabolized by CYP1A2 enzyme after absorption, and 10 percent of Agomelatine is metabolized by CYP2C9 enzyme, so that individual differential liver injury can be caused. Clinically, agomelatine has adverse effect on liver enzymes, ALT/AST elevation (3 times higher than the normal upper limit) occurs in more than 1% of patients, and the elevation has dose dependency, and exposure of patients with slight and severe liver function injury is obviously increased, so that liver function is further damaged.
International application WO2019011279A1 reports preclinical bioactivity data for compounds with MT1, MT2 agonists and 5-HT2C antagonists, showing improved absolute bioavailability, but no corresponding drugs have been marketed yet. Therefore, development of new antidepressant drugs with low liver first pass effect, high absolute bioavailability, MT1 and MT2 receptor agonistic activity and 5-HT2C antagonism is needed to meet the huge market demand.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structure of the compound is as follows:
Figure PCTCN2021108795-APPB-000001
wherein:
M 1 is N or CR 1 ；
M 2 Is N or CR 2 ；
M 3 Is N or CR 3 ；
R 1 、R 2 And R is 3 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
r is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxy, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;
R 4 、R 5 And R is 6 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
R 7 selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxy, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, arylA group or heteroaryl, said amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
R 8 、R 8 ’、R 9 and R is 9 ' each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
Alternatively, R 8 、R 8 ’、R 9 、R 9 Any two of the groups and the carbon atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted.
In a further preferred embodiment of the invention, the
Figure PCTCN2021108795-APPB-000002
Selected from the group consisting of
Figure PCTCN2021108795-APPB-000003
Figure PCTCN2021108795-APPB-000004
In a further preferred embodiment of the invention, R 9 And R is 9 ' each independently 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 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said 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 heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
alternatively, R 9 And R is 9 ' taken together may form an oxo or thioxo group;
alternatively, R 9 And R is 9 ' together with the carbon atom in which they are located form C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 Cycloalkyl and 3-12 membered heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl.
In a preferred embodiment of the invention, when M 1 Is CR (CR) 1 、M 2 Is CR (CR) 2 、M 3 Is CR (CR) 3 When R is 2 And R is 3 At least one of which is other than hydrogen, andwhen M 1 Is CR (CR) 1 、M 2 Is CR (CR) 2 、M 3 Is CR (CR) 3 R is selected from C 1-6 Alkyl, deuterated methyl,
Figure PCTCN2021108795-APPB-000005
When R is 3 Is not hydrogen.
In a further preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is further represented by formula (II):
Figure PCTCN2021108795-APPB-000006
wherein:
r 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 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 In aryl or 5-to 14-membered heteroaryl groupsIs substituted by one or more substituents;
R 1 、R 2 and R is 3 Each independently 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
R 4 、R 5 and R is 6 Each independently 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
R 7 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 group、C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
R 8 and R is 8 ' each independently 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
alternatively, R 8 And R is 8 ' linking forms a C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl.
In a preferred embodiment of the invention, R 2 And R is 3 At least one is other than hydrogen, and when R is selected from C 1-6 Alkyl, deuterated methyl,
Figure PCTCN2021108795-APPB-000007
When R is 3 Is not hydrogen.
In a further preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof, is characterized in that the compound is further represented by the general formula (II-a):
Figure PCTCN2021108795-APPB-000008
wherein:
M 1 is N or CR 1 Preferably N or CH;
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 heterocyclyl, said 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 heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
R 1 、R 2 and R is 3 Each independently 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 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said 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 heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
R 9 And R is 9 ' each independently 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 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said 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 heterocyclyl, eitherOptionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
alternatively, R 9 And R is 9 ' taken together may form an oxo or thioxo group;
alternatively, R 9 And R is 9 ' together with the carbon atom in which they are located form C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 Cycloalkyl and 3-12 membered heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl.
In a preferred embodiment of the invention, when M 1 Is CR (CR) 1 When R is 2 And R is 3 At least one of which is other than hydrogen, and when M 1 Is CR (CR) 1 R is selected from C 1-6 Alkyl, deuterated methyl,
Figure PCTCN2021108795-APPB-000009
When R is 3 Is not hydrogen.
In a preferred embodiment of the invention, 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 heterocyclyl, said 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 heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl.
In a further preferred embodiment of the invention, said R is selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted with 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 3-8 Cycloalkyl or 3-8 membered heterocyclyl.
In a further preferred embodiment of the invention, R is selected from deuterated methyl, ethyl, n-propyl, isopropyl, tert-butyl, tert-pentyl, 3-pentyl, cyclopropyl or oxetanyl, said ethyl, n-propyl, isopropyl, tert-butyl, tert-pentyl, 3-pentyl, cyclopropyl or oxetanyl being further substituted with deuterium, halogen, amino, hydroxy, cyanoRadicals, nitro radicals, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl.
In a preferred embodiment of the invention, R is 1 、R 2 And R is 3 Each independently 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 or 3-12 membered heterocyclyl.
In a further preferred embodiment of the invention, said R 1 、R 2 And R is 3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, 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, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl.
In a further preferred embodiment of the invention, said R 1 、R 2 And R is 3 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or tert-butyl.
In a preferred embodiment of the invention, R is 4 、R 5 And R is 6 Each independently 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 or 3-12 membered heterocyclyl.
In a further preferred embodiment of the invention, said R 4 、R 5 And R is 6 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, 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, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl.
In a further preferred embodiment of the invention, said R 4 、R 5 And R is 6 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or tert-butyl.
In a preferred embodiment of the invention, R is 7 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 or 3-12 membered heterocyclyl.
In a further preferred embodiment of the invention, said R 7 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 Haloalkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl.
In a further preferred embodiment of the invention, said R 7 Selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl or trifluoromethyl.
In a preferred embodiment of the invention, R is 8 And R is 8 ' each independently 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 or 3-12 membered heterocyclyl.
In a further preferred embodiment of the invention, said R 8 And R is 8 ' each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, 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 heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl.
In a further preferred embodiment of the invention, said R 8 And R is 8 ' each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl.
Alternatively, in a preferred embodiment of the present invention, said R 8 、R 8 ' and the carbon atom to which they are attached form C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 3-8 Cycloalkyl and 3-8 membered heterocyclyl, optionally further substituted with 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 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substituents in the aryl or 5-10 membered heteroaryl group.
In a further preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is further represented by formula (III):
Figure PCTCN2021108795-APPB-000010
Wherein:
M 3 is N or CR 3 ；
R 2 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 or 3-12 membered heterocyclyl;
preferably hydrogen, deuterium, halogen, amino, hydroxy, 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, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
more preferred is hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl or methoxy.
R 3 Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, and C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 HaloalkanesOxy or C 1-6 A hydroxyalkyl group; preferably hydrogen;
R 8 and R is 8 ' each independently 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 or 3-12 membered heterocyclyl;
preferably hydrogen, deuterium, halogen, amino, hydroxy, 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 heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl;
more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl;
alternatively, R 8 And R is 8 ' linking forms a C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl; preferably form C 3-12 Cycloalkyl groups.
In a further preferred embodiment of the present invention, the compound of formula (III), a stereoisomer thereof orPharmaceutically acceptable salts thereof, when M 3 Is CH, R 8 And R is 8 When' is hydrogen, R 2 Is not hydrogen.
In Sup>A further preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof is further represented by the general formulSup>A (IV-Sup>A):
Figure PCTCN2021108795-APPB-000011
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;
preferably C 1-3 Alkyl, C 1-3 Deuterated alkyl or C 3-6 Cycloalkyl;
more preferably methyl, ethyl, deuterated methyl, deuterated ethyl or cyclopropyl;
further preferred are methyl, deuterated methyl or cyclopropyl;
methyl is more preferable.
In a further preferred embodiment of the present invention, the compound, stereoisomer or pharmaceutically acceptable salt thereof is further represented by the general formula (IV-B):
Figure PCTCN2021108795-APPB-000012
R 2 or R is 3 Independently selected from deuterium, halogen, cyano or C 1-3 An alkyl group; deuterium, fluorine, chlorine, bromine or methyl is preferred;
n is 1, 2 or 3.
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has the following specific structure:
Figure PCTCN2021108795-APPB-000013
Figure PCTCN2021108795-APPB-000014
Figure PCTCN2021108795-APPB-000015
the invention further relates to Sup>A process for the preparation of Sup>A compound of general formulSup>A (IV-Sup>A), sup>A stereoisomer thereof or Sup>A pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021108795-APPB-000016
reacting Sup>A compound of formulSup>A (V-Sup>A) with R-X in the presence of Sup>A base to give Sup>A compound of formulSup>A (IV-Sup>A), preferably the base is selected from potassium carbonate or cesium carbonate;
wherein:
x is bromine or iodine;
the R is defined as Sup>A general formulSup>A (IV-A).
The invention further relates to a process for the preparation of a compound of general formula (IV-B), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
Figure PCTCN2021108795-APPB-000017
The compound of the formula (V-B) is reacted with
Figure PCTCN2021108795-APPB-000018
The reaction gives compounds of the formula (IV-B), preferably by base selectionFrom potassium carbonate or cesium carbonate;
wherein:
x is bromine or iodine;
R 2 、R 3 and n is as defined for formula (IV-B).
The invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and the use of the pharmaceutical composition as described above for the preparation of a melatonin receptor agonist drug.
In another aspect, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in the preparation of MT1 and MT2 receptor agonists and 5-HT 2C Use in receptor antagonist medicaments.
Further, the invention also aims to provide application of the compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof in preparing medicines for treating or preventing cardiovascular diseases, digestive system diseases, central nervous system diseases and/or mental diseases.
The invention also relates to a method of treating a central nervous system disorder and/or a psychotic disorder.
In a more preferred embodiment, the central nervous system disorder and/or psychotic disorder is selected from the group consisting of melatonin system disorders, stress, anxiety disorders, seasonal affective disorders, schizophrenia, phobia, depression, major depressive disorder, sleep disorders, insomnia or fatigue caused by jet lag, body weight disorders, mood disorders, schizophreniform 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 syndromes, tinnitus, autism, alzheimer's disease, seizure, neuralgia or drug-withdrawal symptoms major depressive disorder or manic disorder.
Detailed description of the invention
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 8 carbon atoms, even more preferably an alkyl group containing from 1 to 6 carbon atoms, and most preferably an alkyl group containing from 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 4-heptyl, 1-propylbutyl 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 3-pentyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, N-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof, and the like. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH 2 - "ethylene" means- (CH) 2 ) 2 - "propylene" means- (CH) 2 ) 3 "butylene" means- (CH) 2 ) 4 -and the like.
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, and the like. Alkenyl groups may be 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms; further preferred is a 3-8 membered heterocyclic group containing 1 to 3 nitrogen atoms, optionally substituted with 1 to 2 oxygen atoms, sulfur atoms, oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing condensed heterocyclic group.
Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1, 4-diazepinyl, pyranyl, or tetrahydrothiopyran dioxide, and the like, with oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydrothiopyran dioxide, pyrrolidinyl, morpholinyl, piperidinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azepinyl, 1, 4-diazepinyl, and piperazinyl being preferred; polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl 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 heterocyclyl is a heterocyclyl containing 1-3 nitrogen, oxygen, sulfur atoms; or further comprises a ternary nitrogen-containing fused ring containing a benzene ring.
Wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2021108795-APPB-000019
Figure PCTCN2021108795-APPB-000020
Etc.
Aryl groups may be 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, and the like, preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl, or thiazolyl; more preferably pyridyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2021108795-APPB-000021
Figure PCTCN2021108795-APPB-000022
Etc.
Heteroaryl groups 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, the alkoxy groups can 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl groups, also known as alkenyl groups, preferably alkenyl groups containing 2 to 8 carbon atoms, more preferably alkenyl groups containing 2 to 6 carbon atoms, even more preferably alkenyl groups containing 2 to 4 carbon atoms, and most preferably alkenyl groups containing 2 to 3 carbon atoms. Non-limiting examples of alkenyl groups include: ethenyl and propenyl. Wherein said alkenyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"alkynyl" refers to alkenyl, also known as alkynyl, refers to unsaturated hydrocarbyl containing (CH≡C-); alkynyl groups having 2 to 8 carbon atoms are preferred, alkynyl groups having 2 to 6 carbon atoms are more preferred, alkynyl groups having 2 to 4 carbon atoms are still more preferred, and alkynyl groups having 2 to 3 carbon atoms are most preferred. Wherein said alkynyl group may be further substituted with other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"carbonyl" means-C (O) -.
"carboxy" means-C (O) OH.
"THF" refers to tetrahydrofuran.
"ethyl acetate" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"TEA" refers to triethylamine.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2 O "refers to diethyl ether.
"DCM" refers to dichloromethane.
"DMAP" refers to 4-dimethylaminopyridine.
"DCC" refers to dicyclohexylcarbodiimide.
"DCE" refers to 1,2 dichloroethane.
"DDQ" refers to 2, 3-dichloro-5, 6-dicyanobenzoquinone.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"NMP" refers to N-methylpyrrolidone.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2 (dba) 3 "means tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.
"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bis (trimethylsilylamide).
"MeLi" refers to lithium-based.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "means sodium triacetoxyborohydride.
The terms "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", etc. all express the same meaning, that is, X may be any one or several of A, B, C.
The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Examples
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C) 18 150X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.
Example 1
Preparation of N- (2- (7-cyclopropyloxy-2-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000023
The first step: preparation of 7-methoxynaphthalene-2-amine
Figure PCTCN2021108795-APPB-000024
7-Methoxynaphthalene-2-ol (10 g,57.5 mmol) was dissolved in aqueous ammonia (150 mL), sodium bisulphite (29.9 g,287.5 mmol) was added, and the mixture was stirred in a pot at 150℃for 48 hours, cooled to room temperature, the solid was filtered off, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulphate, filtered, concentrated, and purified by column chromatography to give 7-Methoxynaphthalene-2-amine (5.7 g, 57% yield).
MS m/z(ESI):174.0[M+H] + .
And a second step of: preparation of 1-bromo-7-methoxynaphthalene-2-amine
Figure PCTCN2021108795-APPB-000025
7-Methoxynaphthalen-2-amine (5.5 g,31.6 mmol) was dissolved in DMF (100 mL), NBS (6.2 g,34.8 mmol) was added, reacted for 4 hours at 110℃and cooled to room temperature, 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-methoxynaphthalen-2-amine (6.8 g, 86% yield).
MS m/z(ESI):252.1[M+H] + ,254.1[M+H+2] + .
And a third step of: preparation of 1-bromo-2-fluoro-7-methoxynaphthalene
Figure PCTCN2021108795-APPB-000026
1-bromo-7-methoxynaphthalen-2-amine (6.5 g,25.9 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0deg.C, and HBF was added 4 (50 mL, 48%) solution, howeverPost-addition of NaNO 2 (5.4 g,78.3 mmol) in water (10 mL) and stirring at 0deg.C was continued for 1 hour, naBF was added 4 (14.2 g,129.1 mmol). Gradually heating to room temperature, filtering to obtain solid, washing with water and diethyl ether. And (5) vacuum drying. The resulting solid was dissolved in xylene (100 mL) and heated at reflux for 2 hours. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 1-bromo-2-fluoro-7-methoxynaphthalene (2.8 g, 43% yield).
Fourth step: preparation of 2- (2-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile
Figure PCTCN2021108795-APPB-000027
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 particles) were added, nitrogen was replaced three times, and the temperature was raised to 50℃and stirred for 0.5 hours. A solution of bromoacetonitrile (1.6 g,13.3 mmol) in THF (20 mL) was added dropwise under ice-water bath and gradually warmed to room temperature, stirred for 1 hour, quenched with water, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 2- (2-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile (1.5 g, 68% yield).
MS m/z(ESI):216.1[M+H] + .
Fifth step: preparation of N- (2- (2-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000028
2- (2-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile (1.4 g,6.5 mmol) and acetic anhydride (1.4 g,13.7 mmol) were dissolved in dichloromethane/methanol (30 mL/15 mL) solution and NiCl was added at 0deg.C 2 ·6H 2 O (920 mg,3.9 mmol), stirring, adding sodium borohydride (1.1 g,28.9 mmol) in portions, stirring at room temperature for 3 hours. Adding 6N HCl, adding water, filtering, extracting aqueous phase with dichloromethane,the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography purification gave N- (2- (2-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide (1.3 g, 76% yield).
MS m/z(ESI):262.1[M+H] + .
Sixth step: preparation of N- (2- (2-fluoro-7-hydroxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000029
N- (2- (2-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide (1.2 g,4.6 mmol) was dissolved in dichloromethane (20 mL), cooled to 0deg.C under nitrogen protection, and BBr was added dropwise 3 (2.3 g,9.2 mmol) was stirred at room temperature for 3 hours. Adding NaHCO 3 The aqueous solution was washed and extracted with dichloromethane/methanol (10:1). The organic layer was washed with water and 10% aqueous sodium bicarbonate. Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N- (2- (2-fluoro-7-hydroxynaphthalen-1-yl) ethyl) acetamide (930 mg, yield 82%).
MS m/z(ESI):248.1[M+H] + .
Seventh step: preparation of N- (2- (7-cyclopropyloxy-2-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000030
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), cs was added 2 CO 3 (400 mg,1.22 mmol) was reacted for 4 hours with microwaves at 160℃and extracted with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC to give N- (2- (7-cyclopropoxy-2-fluoronaphthalen-1-yl) ethyl) acetamide (56 mg, 48% yield).
MS m/z(ESI):288.1[M+H] + .
Example 2A
Preparation of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000031
The first step: preparation of 5-amino-8-bromonaphthalene-2-ol
Figure PCTCN2021108795-APPB-000032
5-Aminonaphthalene-2-ol (10 g,62.9 mmol) was dissolved in DMF (100 mL), NBS (12.3 g,69.2 mmol) was added, the mixture was reacted at 110℃for 3 hours, cooled to room temperature, 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 5-amino-8-bromonaphthalene-2-ol (10.8 g, yield 72%).
MS m/z(ESI):238.1[M+H] + ,240.1[M+H+2] + .
And a second step of: preparation of 8-bromo-5-fluoronaphthalene-2-ol
Figure PCTCN2021108795-APPB-000033
5-amino-8-bromonaphthalene-2-ol (5 g,21.0 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0deg.C, and HBF was added 4 (40 mL, 48%) solution, then NaNO was added 2 (4.4 g,63.8 mmol) in water (10 mL) and stirring at 0deg.C was continued for 1 hour, naBF was added 4 (11.5 g,104.5 mmol). Gradually heating to room temperature, filtering to obtain solid, washing with water and diethyl ether. And (5) vacuum drying. The resulting solid was dissolved in xylene (100 mL) and heated at reflux for 2 hours. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give 8-bromo-5-fluoronaphthalene-2-ol (3.5 g, 69% yield).
MS m/z(ESI):240.1[M+H] + ,243.1[M+H+2] + .
And a third step of: preparation of 4-bromo-1-fluoro-6-methoxynaphthalene
Figure PCTCN2021108795-APPB-000034
8-bromo-5-fluoronaphthalen-2-ol (3H) -one (3.4 g,14.2 mmol) was added to DMF (30 mL) and K was added 2 CO 3 Methyl iodide (2.4 g,16.9 mmol) was added dropwise at room temperature (5.8 g,42.0 mmol), and stirring was continued for 2 hours. Extraction with water and ethyl acetate, washing the combined organic phases with saturated brine, drying over anhydrous sodium sulfate, filtration, concentration, and column chromatography purification gave 4-bromo-1-fluoro-6-methoxynaphthalene (3.4 g, 94% yield).
1 H NMR(400MHz,Chloroform-d)δ8.06(d,J＝9.0Hz,1H),7.93-7.90(m,2H),7.15(d,J＝9.0Hz,1H),6.92(dd,J＝12,7.8Hz,1H),4.01(s,3H).
Fourth step: preparation of 2- (4-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile
Figure PCTCN2021108795-APPB-000035
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 particles) were added, nitrogen was replaced three times, and the temperature was raised to 50℃and stirred for 0.5 hours. Bromoacetonitrile (2.0 g,16.8 mmol) in THF (20 mL) was added dropwise to the mixture in an ice-water bath, gradually warmed to room temperature, stirred for 1 hour, quenched with water, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 2- (4-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile (1.8 g, 64% yield).
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).
Fifth step: preparation of N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000036
2- (4-fluoro-7-methoxynaphthalen-1-yl) acetylnitrile (1.7 g,7.9 mmol) and acetic anhydride (2.0 g,19.8 mmol) were dissolved in dichloromethane/methanol (30 mL/15 mL) solution and NiCl was added at 0deg.C 2 ·6H 2 O (1.1 g,4.7 mmol), sodium borohydride (1.3 g,34.2 mmol) was added in portions and stirred at room temperature for 5 hours. 6N HCl was added, water was added, the mixture was filtered, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography purification gave N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide (1.5 g, 73% yield).
MS m/z(ESI):262.1[M+H] + .
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).
Example 2
Preparation of N- (2- (7-cyclopropyloxy-4-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000037
The first step: preparation of N- (2- (4-fluoro-7-hydroxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000038
N- (2- (4-fluoro-7-methoxynaphthalen-1-yl) ethyl) acetamide (1.4 g,5.4 mmol) was dissolved in dichloromethane (20 mL), cooled to 0deg.C under nitrogen protection, and BBr was added dropwise 3 (2.7 g,10.8 mmol) was stirred at room temperature for 3 hours. Adding NaHCO 3 Washing the mixture by using an aqueous solution,extraction with dichloromethane/methanol (10/1). The organic layer was washed with water and 10% aqueous sodium bicarbonate. 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).
MS m/z(ESI):248.1[M+H] + .
And a second step of: preparation of N- (2- (7-cyclopropyloxy-4-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000039
N- (2- (4-fluoro-7-hydroxynaphthalen-1-yl) ethyl) acetamide (100 mg,0.41 mmol) was dissolved in DMF (5 mL), cyclopropyl bromide (150 mg,1.24 mmol) was added, cs 2 CO 3 (400 mg,1.22 mmol) was reacted for 4 hours with microwaves at 160℃and extracted with water and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC to give N- (2- (7-cyclopropoxy-4-fluoronaphthalen-1-yl) ethyl) acetamide (44 mg, 38% yield).
MS m/z(ESI):288.1[M+H] + .
Example 2B
Preparation of N- (2- (4-fluoro-7- (methoxy-d 3) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000040
The first step: preparation of N- (2- (4-fluoro-7- (methoxy-d 3) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000041
N 2 Next to N- (2- (4-fluoro-7-hydroxynaphthalen-1-yl) ethyl) acetamide (80 mg, 323.54. Mu. Mol), KI (5.4 mg, 32.35. Mu. Mol) and Cs 2 CO 3 To a solution of (210 mg, 647.08. Mu. Mol) in DMF (2 mL) was added deuterated iodomethane (188 mg,1.29 mmol) and the mixture was stirred at 50℃for 4 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give N- (2- (4-fluoro-7- (methoxy-d 3) naphthalen-1-yl) ethyl) acetamide (71.4 mg, yield 82%) as a white solid by preparative HPLC purification.
MS m/z(ESI):265.1[M+H] + .
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(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).
Example 5
Preparation of N- (2- (7- (oxetan-3-oxy) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000042
The first step: preparation of N- (2- (7-hydroxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000043
The substrate N- [2- (7-methoxy-1-naphthyl) ethyl]Acetamide (511 mg,2.1 mmol) was dissolved in anhydrous dichloromethane (10 mL), replaced three times with nitrogen, cooled to 0deg.C under protection, and BBr was added dropwise 3 (4.2 mmol,4.2 mL) was added dropwise, the mixture was stirred at room temperature for 30 minutes, and the reaction solution was slowly poured into 150mL of saturated NaHCO 3 The reaction was quenched in solution. Dichloromethane extraction, combining organic layers, anhydrous Na 2 SO 4 Drying and concentration gave a crude product which was purified by flash column chromatography to give the product N- (2- (7-hydroxynaphthalen-1-yl) ethyl) acetamide (300 mg, 62% yield) as a white solid.
MS m/z(ESI):230.1[M+H] + .
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).
And a second step of: preparation of N- (2- (7- (oxetan-3-oxy) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000044
The substrates N- (2- (7-hydroxynaphthalen-1-yl) ethyl) acetamide (61.6 mg,0.2 mmol), KI (49.8 mg, 300. Mu. Mol) and Cs were combined 2 CO 3 (97.8 mg, 300. Mu. Mol) was dissolved in DMF (1.5 mL) and placed in a 5.0mL microwave tube, 3-bromooxetane ring (137 mg,1.0 mmol) was added. The reaction was carried out at 130℃for 1.5 hours with microwaves. The reaction solution was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, concentrating to give a crude product, purifying by flash column chromatography to give a crude product, and purifying by preparative HPLC to give N- (2- (7- (oxetan-3-oxy) naphthalen-1-yl) ethyl) acetamide (36 mg, yield 48%) as a white solid.
MS m/z(ESI):286.2[M+H] + .
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).
Example 6
Preparation of N- (2- (7-isopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000045
The first step: preparation of N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000046
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 85deg.C (oil bath temperature), and a solution of bromine (4.0 g,25.0 mmol) in AcOH (30 mL) was added dropwise. After the completion of the dropwise addition, the mixture was heated and stirred for 3 hours. The reaction solution was cooled to room temperature, which was then poured into water (150 mL), extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography to give N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide (4.5 g, yield 68%).
MS m/z(ESI):322.1[M+H] + ,324.1[M+H+2] + .
And a second step of: preparation of N- (2- (7-methoxynaphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000047
N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide (200 mg,0.62 mmol) was dissolved in anhydrous THF (20 mL), cooled to-78deg.C under nitrogen, and a solution of N-BuLi (1.6 mL,1.6 mmol) in THF (10 mL) was added dropwise and stirred for 0.5 h. Dropwise adding D 2 O (1 mL) and stirring was continued for 1 hour. Quenching with water, regulating pH to 6 with dilute hydrochloric acid, and extracting with ethyl acetate. Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N- (2- (7-methoxynaphthalen-1-yl-3-d) ethyl) acetamide (87 mg, yield 57%).
MS m/z(ESI):245.1[M+H] + .
And a third step of: preparation of N- (2- (7-hydroxynaphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000048
N- (2- (7-Methoxynaphthalen-1-yl-3-d) ethyl) acetamide (80 mg,0.33 mmol) was dissolved in dichloromethane (10 mL), cooled to 0deg.C under nitrogen protection, and BBr was added dropwise 3 (270 mg,1.1 mmol) was stirred at room temperature for 2 hours. Adding NaHCO 3 The aqueous solution was quenched and extracted with dichloromethane. Washed with water and 10% aqueous sodium bicarbonate. 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%).
MS m/z(ESI):231.1[M+H] + .
Fourth step: preparation of N- (2- (7-isopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000049
N 2 Cs was added to DMF (3 mL) of N- (2- (7-hydroxynaphthalen-1-yl-3-d) ethyl) acetamide (50 mg,217.13 mol), 2-iodopropane (110.7 mg,651.4 mol) 2 CO 3 (141.1 mg, 434.2. Mu. Mol), potassium iodide (18 mg, 108.56. Mu. Mol) and stirred at 50℃for 12 hours. The reaction mixture was extracted with water and dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give N- (2- (7-isopropoxyhnaphthalen-1-yl-3-d) ethyl) acetamide (3 mg, yield 5%) by preparative HPLC purification.
MS m/z(ESI):273.1[M+H] + .
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),5.66(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),1.30-1.28(d,J＝8.0Hz,6H).
Example 7
Preparation of N- (2- (7- (pentane-3-oxy) naphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000050
Preparation of N- (2- (7- (pentane-3-oxy) naphthalen-1-yl-3-d) ethyl) acetamide reference example 6.
MS m/z(ESI):301.1[M+H] + .
1 H 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).
Example 8
Preparation of N- (2- (7- (tert-butoxy) naphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000051
The first step: preparation of N- (2- (3-bromo-7-methoxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000052
The substrate N- (2- (7-methoxynaphthalen-1-yl) ethyl) acetamide (14.6 g,60.0 mmol) was dissolved in AcOH (120 mL), heated to 85deg.C (oil bath temperature), and a solution of bromine (11.5 g,72.0mmol,3.69 mL) in AcOH (30 mL) was added dropwise. After the completion of the dropwise addition, stirring was continued for 0.5 hour. The reaction solution was cooled to room temperature, which was then poured into water (500 mL), extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified with a reverse phase preparative column to give N- (2- (3-bromo-7-methoxynaphthalen-1-yl) ethyl) acetamide (15 g, yield 66%) as a white solid.
MS m/z(ESI):322.2[M+H] + .
1 H 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).
And a second step of: preparation of N- (2- (7-methoxynaphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000053
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-75deg.C to-70deg.C under nitrogen protection, N-BuLi (30.0 mmol,12.5 mL) was added dropwise, and then stirred at-75deg.C for 1.5 hours, D was added dropwise 2 O (1.20 g,60.00 mmol) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was slowly poured into 200mL of water to quench, extracted with ethyl acetate, and the organic layers were combined, anhydrous Na 2 SO 4 Drying, concentrating to obtain crude product, and purifying by column chromatography to obtain target compound N- (2- (7-methoxynaphthalene-1-yl-3-d) ethyl) acetamide (1.2 g, yield 41%) as yellow solid.
MS m/z(ESI):245.1[M+H] + .
And a third step of: preparation of N- (2- (7-hydroxynaphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000054
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 0deg.C under nitrogen protection, and BBr was added dropwise 3 (10 mmol,10 mL) was added, and the mixture was stirred at room temperature for 30min. The reaction solution was slowly poured into 150mL of saturated NaHCO 3 The reaction was quenched in solution. Dichloromethane extraction, combining organic layers, anhydrous Na 2 SO 4 Drying, concentrating to obtain crude product, and purifying by column chromatography to obtain white solid product N- (2- (7-hydroxynaphthalene-1-yl-3-d) ethyl) acetamide (1.05 g, yield 93%).
MS m/z(ESI):231.2[M+H] + .
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).
Fourth step: preparation of N- (2- (7- (tert-butoxy) naphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000055
The substrate N- (2- (7-hydroxynaphthalen-1-yl-3-d) ethyl) acetamide (134 mg, 222. Mu. Mol) was dissolved in anhydrous dichloromethane (5.0 mL) and added (Boc) 2 O (317.5 Mg,1.45 mmol) and Mg (ClO) 4 ) 2 (26 mg,116 umol) was heated to 50℃under reflux under nitrogen substitution protection for 2 hours. The reaction solution was cooled to room temperature, slowly added to 100mL of water, and then 50mL of saturated NaHCO was added 3 An aqueous solution. Ethyl acetate extraction, combining organic layers, washing with saturated brine, anhydrous Na 2 SO 4 And (5) drying. Concentration gave the crude product which was purified by preparative HPLC to give the title compound N- (2- (7- (tert-butoxy) naphthalen-1-yl-3-d) ethyl) acetamide (54.6 mg, 33% yield) as a white solid.
MS m/z(ESI):287.2[M+H] + .
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).
Example 10
Preparation of N- (2- (6-chloro-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000056
The first step: preparation of 4- (3-chloro-4-methoxyphenyl) -4-carbonylbutyric acid
Figure PCTCN2021108795-APPB-000057
AlCl was added to dichloromethane (300 mL) at 0deg.C under nitrogen blanket 3 (71.4 g,0.54 mol), 1-chloro-2-methoxybenzene (30 mL,0.24 mol) was added in portions to dihydrofuran-2, 5-dione (26.8 g,0.27 mol), and the mixture was heated to 50℃and stirred for 2 hours. Cooled to room temperature, the reaction mixture was poured into vigorously stirred ice water, concentrated hydrochloric acid (65 mL) was added, and stirred for 0.5 hours. Filtration, filter cake washing with water, and filtration with ethanol-water slurry gave 4- (3-chloro-4-methoxyphenyl) -4-carbonylbutyric acid as a pink solid (55 g, 98% yield).
MS m/z(ESI):241.1[M-H] - .
And a second step of: preparation of 4- (3-chloro-4-methoxyphenyl) butanoic acid
Figure PCTCN2021108795-APPB-000058
Et was added dropwise to TFA (20 mL) of 4- (3-chloro-4-methoxyphenyl) -4-carbonylbutyric acid (8 g,33 mmol) under nitrogen 3 SiH (12 mL), heated to 120deg.C and stirred for 5 hours. After the reaction solution was concentrated, DMF (10 mL) was added, and the mixture was slowly poured into vigorously stirred water, filtered, and the cake was washed with water, and dried to give 4- (3-chloro-4-methoxyphenyl) butanoic acid (7 g, yield 93%) as a white solid.
MS m/z(ESI):227.1[M-H] - .
And a third step of: preparation of 6-chloro-7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one
Figure PCTCN2021108795-APPB-000059
MeSO was added dropwise to TFA (30 mL) of 4- (3-chloro-4-methoxyphenyl) butanoic acid (7 g,30.7 mmol) under nitrogen 3 H (7 mL), heated to 120deg.C and stirred for 7 hours. Cooling to room temperature, pouring the reaction solution into ice water, filtering, washing a filter cake with water, pulping and filtering with ethanol-water, and drying to obtain yellow solid 6-chloro-7-methoxy-3, 4-dihydronaphthalene-1 (2H) -one (3.6 g, yield 56%).
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)
Fourth step: preparation of 2- (6-chloro-7-methoxy-3, 4-dihydronaphthalen-1-yl) acetylnitrile
Figure PCTCN2021108795-APPB-000060
To a solution of 6-chloro-7-methoxy-3, 4-dihydronaphthalen-1 (2H) -one (3.6 g,17 mmol) in toluene (140 mL) under nitrogen was added 2-cyanoacetic acid (3.6 g,42.5 mmol), heptanoic acid (1.12 g,8.6 mmol), benzylamine (920 mg,8.6 mmol), which was heated to 140℃and stirred for 12 hours. Cooling to room temperature, adding salt water into the reaction solution for quenching, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, concentrating, pulping with ethanol-water at 90 ℃, filtering, and drying to obtain yellow solid 2- (6-chloro-7-methoxy-3, 4-dihydronaphthalen-1-yl) acetylnitrile (3 g, yield 76%).
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)
Fifth step: preparation of 2- (6-chloro-7-methoxynaphthalen-1-yl) acetylnitrile
Figure PCTCN2021108795-APPB-000061
DDQ (3.2 g,14.1 mmol) was added to 2- (6-chloro-7-methoxy-3, 4-dihydronaphthalen-1-yl) acetylnitrile (3 g,12.9 mmol) in dichloromethane (30 mL) at-10deg.C under nitrogen and stirred at 20deg.C for 0.5 h. The reaction solution was filtered, and the organic phase was taken up in saturated Na 2 CO 3 Washing with aqueous solution, washing with brine, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain 2- (6-chloro-7-methoxynaphthalen-1-yl) acetylnitrile (2.8 g, yield 94%) as a yellow solid.
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).
Sixth step: preparation of N- (2- (6-chloro-7-methoxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000062
To 2- (6-chloro-7-methoxynaphthalen-1-yl) acetylnitrile (2.8 g,12 mmol) under nitrogen at-10deg.C 2 Cl 2 To MeOH (100 mL-50 mL) was added NiCl 2 .6H 2 O (1.8 g,0.8 mmol), acetic anhydride (2.72 mL,0.8 mmol), naBH was added in portions 4 (2.1 g,54 mmol) at 20℃for 12 hours. Cooling to 0deg.C, adding hydrochloric acid (3M/L, 40 mL), stirring for 1 hr, concentrating, extracting with ethyl acetate, and saturated NaHCO 3 Washing with aqueous solution, washing with brine, drying over anhydrous sodium sulfate, filtering, and purifying by column chromatography to obtain N- (2- (6-chloro-7-methoxynaphthalen-1-yl) ethyl) acetamide (1 g, yield 30%) as a yellow solid.
MS m/z(ESI):278.1[M+H] + .
1 H NMR(400MHz,d-DMSO)δ8.15(s,1H),8.08(s,1H),7.79(s,1H),7.72-7.70(d,J＝8.0Hz,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).
Seventh step: preparation of N- (2- (6-chloro-7-hydroxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000063
To N- (2- (6-chloro-7-methoxynaphthalen-1-yl) ethyl) acetamide (500 mg,1.8 mmol) in dichloromethane (30 mL) at 0deg.C under nitrogen 3 (3.6 mL,3.6 mmol) was stirred at 20deg.C for 12 hours. The reaction solution is added with dichloromethane for extraction, saturated NaHCO is added 3 Washing with aqueous solution, washing with brine, drying over anhydrous sodium sulfate, filtering and concentrating to obtain N- (2- (6-chloro-7-hydroxynaphthalen-1-yl) ethyl) acetamide (400 mg, yield 85%).
MS m/z(ESI):264.1[M+H] + .
1 H NMR(400MHz,d-DMSO)δ10.56(s,1H),8.01-7.98(m,2H),7.67-7.65(m,1H),7.50(s,1H),7.28-7.23(m,2H),3.39-3.34(m,2H),3.07-3.03(m,2H),1.81(s,3H).
Eighth step: preparation of N- (2- (6-chloro-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000064
To N- (2- (6-chloro-7-hydroxynaphthalen-1-yl) ethyl) acetamide (100 mg,0.4 mmol), bromocyclopropane (100 mg,0.8 mmol) in NMP (3 mL) under nitrogen was added Cs 2 CO 3 (160 mg,0.5 mmol), potassium iodide (30 mg,0.2 mmol), and stirring with microwaves at 170℃for 2 hours. The reaction solution was extracted with water and dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated to give N- (2- (6-chloro-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide (10 mg, yield 8%) by preparative HPLC purification.
MS m/z(ESI):304.1[M+H] + .
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).
Example 11
Preparation of N- (2- (6-bromo-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000065
Preparation of N- (2- (6-bromo-7-cyclopropylnaphthalen-1-yl) ethyl) acetamide reference example 10.
MS m/z(ESI):348.1[M+H] + ,350.1[M+H+2] + .
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).
Example 12
Preparation of N- (2- (7-cyclopropoxy-naphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000066
Preparation of N- (2- (7-Cyclopropyloxynaphthalen-1-yl-3-d) ethyl) acetamide reference example 6.
MS m/z(ESI):271.1[M+H] + .
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).
Example 13
Preparation of N- (2- (7-cyclopropyloxy-3-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000067
The first step: preparation of N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000068
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 85deg.C (oil bath temperature), and a solution of bromine (11.51 g,72.0mmol,3.69 mL) in AcOH (30 mL) was added dropwise. After the completion of the dropwise addition, the mixture was heated and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (500 mL), extracted with ethyl acetate (200 mL. Times.3), the organic layers were combined, washed with saturated NaCl (150 mL. Times.3), and the organic layer Na 2 SO 4 Drying, concentration gave a crude product which was purified by reverse phase to give N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide as a white solid (12.0 g, 62% yield).
MS m/z(ESI):322.1[M+H] + ,324.1[M+H+2] + .
And a second step of: preparation of N- (2- (7-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000069
The substrate N- [2- (3-bromo-7-methoxy-1-naphthyl) ethyl]Acetamide (1.61 g,5.0 mmol), pinacol borate (2.54 g,7.9 mmol) and potassium acetate (1.47 g,15.0 mmol) were dissolved in anhydrous dioxane (45 mL), replaced three times with nitrogen, and Pd (dppf) Cl was added 2 (731 mg,1.0 mmol) was heated to 90℃and reacted for 2 hours. The reaction solution was concentrated to obtain a crude product, and the target compound N- (2- (7-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethyl) acetamide (1.6 g, yield 87%) was obtained as a yellow solid by column chromatography purification.
MS m/z(ESI):370.1[M+H] + .
And a third step of: preparation of N- (2- (7-methoxy-3- (boronic acid) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000070
The substrate N- (2- (7-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-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 NaIO were added 4 (4.05 g,19.0 mmol). Heated to 25℃and reacted for 4 hours. The reaction solution was concentrated to obtain a crude product, the mixed solvent (THF: ea=1:1) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by column chromatography to obtain the objective compound N- (2- (7-methoxy-3- (boronic acid) naphthalen-1-yl) ethyl) acetamide (766 mg, yield 70%) as a yellow solid.
MS m/z(ESI):286.1[M-H] - .
Fourth step: preparation of N- [2- (3-fluoro-7-methoxy-1-naphthyl) ethyl ] acetamide
Figure PCTCN2021108795-APPB-000071
Reagent NaOH (121 mg,3.0 mmol) was dissolved in MeOH (10 mL) at room temperature, after which substrate N- (2- (7-methoxy-3- (boronic acid) naphthalen-1-yl) ethyl) acetamide (720 mg,2.5 mmol) was added and then stirred at 25℃for 15 min. Then, the reaction mixture was cooled to 0℃and AgOTf (1.94 g,7.5 mmol) was added thereto, followed by stirring at 0℃for 30 minutes. Then, the reaction solution was concentrated in a solvent at a low temperature of 0℃by an oil pump, and residual methanol was removed by azeotropic distillation with acetone (5 mL. Times.3) through the solvent to obtain a crude product. The crude product was dissolved in acetone (10 mL) and activated 3A molecular sieve (350 mg) was added followed by F-TEDA-BF 4 (935 mg,2.6 mmol). Then stirred at 0℃for 1 hour. The reaction mixture was slowly added to 100mL of water, extracted with ethyl acetate (150 mL. Times.3), the organic phases combined, and anhydrous sulfurDrying sodium acid, concentrating to obtain crude product, and purifying by column chromatography to obtain N- [2- (3-fluoro-7-methoxy-1-naphthyl) ethyl group]Acetamide (214 mg, 33% yield).
MS m/z(ESI):262.1[M+H] + .
Fifth step: preparation of N- [2- (3-fluoro-7-hydroxy-1-naphthyl) ethyl ] acetamide
Figure PCTCN2021108795-APPB-000072
The substrate N- [2- (3-fluoro-7-methoxy-1-naphthyl) ethyl]Acetamide (241 mg, 922.3. Mu. Mol) was dissolved in anhydrous dichloromethane (10 mL), cooled to 0deg.C under nitrogen substitution protection, and BBr was added dropwise 3 (1.84 mmol,3.0 mL) and stirring was continued for 30 min after the addition. The reaction was quenched by dropwise addition to 100mL of water followed by addition of 100mL of saturated NaHCO 3 The aqueous solution was extracted with dichloromethane (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product. Purifying by column chromatography to obtain target compound N- [2- (3-fluoro-7-hydroxy-1-naphthyl) ethyl]Acetamide (204 mg, 89% yield).
MS m/z(ESI):248.1[M+H] + .
Sixth step: preparation of N- (2- (7-cyclopropyl-3-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000073
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 5.0mL microwave tube, and Cs was added 2 CO 3 (98 mg, 300. Mu. Mol) and KI (50 mg, 300. Mu. Mol). The reaction was carried out at 180℃for 2 hours with microwaves. The reaction solution was concentrated, and the solvent was removed to give crude N- (2- (7-cyclopropyl-3-fluoronaphthalen-1-yl) ethyl) acetamide (10 mg, yield 17%) as a yellow liquid.
MS m/z(ESI):288.1[M+H] + .
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).
Example 14
Preparation of N- (2- (7-cyclopropyloxy-3-chloronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000074
The first step: preparation of N- (2- (7-cyclopropyl-3-chloronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000075
To a solution of N- (2- (7-cyclopropyl-3-bromonaphthalen-1-yl) ethyl) acetamide (20 mg, 57. Mu. Mol) in DMF (2 mL) under nitrogen was added CuCl (113 mg,1.14 mmol), and the mixture was stirred at 140℃for 3 hours under nitrogen to complete the reaction. The reaction mixture was extracted with saturated brine and dichloromethane (3×10 ml). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated, and then subjected to acid treatment to give N- (2- (7-cyclopropyl-3-chloronaphthalen-1-yl) ethyl) acetamide (7 mg, yield 38%).
MS m/z(ESI):304.1[M+H] + ,306.1[M+H+2] + .
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＝9.0,2.3Hz,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).
Example 15
Preparation of N- (2- (7-cyclopropyloxy-3-bromonaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000076
The first step: preparation of N- (2- (7-hydroxy-3-bromonaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000077
To a solution of N- (2- (7-methoxy-3-bromonaphthalen-1-yl) ethyl) acetamide (3.3 g,10.24 mmol) in dichloromethane (30 mL) at 0deg.C under nitrogen was added dropwise BBr 3 (1M, 20.48 mL), stirred at 30deg.C for 1 hour, and reacted completely. Pouring the mixture into saturated NaHCO at 0deg.C 3 In aqueous solution, dichloromethane-methanol (10/1) was extracted. 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, 95% yield).
MS m/z(ESI):308.1[M+H] + ,310.1[M+H+2] + .
And a second step of: preparation of N- (2- (7-cyclopropyl-3-bromonaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000078
N- (2- (7-hydroxy-3-bromonaphthalen-1-yl) ethyl) acetamide (2.5 g,8.11 mmol), potassium iodide (134 mg,0.81 mmol) and Cs under nitrogen 2 CO 3 Bromocyclopropane (1.96 g,16.22 mmol) was added to DMF (10 mL) (5.27 g,16.2 mmol) and the mixture was stirred with microwaves at 170℃for 4 hours to complete the reaction. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography [ dichloromethane/methanol=1/0 to 50/1 ]]N- (2- (7-cyclopropyl-3-bromonaphthalen-1-yl) ethyl) acetamide (1.3 g, 46% yield) was obtained as a yellow oil.
MS m/z(ESI):348.1[M+H] + ,350.1[M+H+2] + .
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).
Example 18
Preparation of N- (2- (4-chloro-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000079
Preparation of N- (2- (4-chloro-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide reference example 2.
MS m/z(ESI):304.1[M+H] + .
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).
Example 19
Preparation of N- (2- (7-cyclopropyloxy-2-fluoronaphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000080
Preparation of N- (2- (7-cyclopropoxy-2-fluoronaphthalen-1-yl-3-d) ethyl) acetamide reference example 6.
MS m/z(ESI):289.1[M+H] + .
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).
Example 20
Preparation of N- (2- (7-cyclopropyloxy-4-fluoronaphthalen-1-yl-3-d) ethyl) acetamide
Figure PCTCN2021108795-APPB-000081
Preparation of N- (2- (7-cyclopropoxy-4-fluoronaphthalen-1-yl-3-d) ethyl) acetamide reference example 6.
MS m/z(ESI):289.1[M+H] + .
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).
Example 21
Preparation of N- (2- (7-cyclopropyloxy-3, 6-difluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000082
Preparation of N- (2- (7-cyclopropoxy-3, 6-difluoronaphthalen-1-yl) ethyl) acetamide reference example 10.
MS m/z(ESI):306.1[M+H] + .
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).
Example 22
Preparation of N- (2- (7-cyclopropyloxy-3, 8-difluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000083
Preparation of N- (2- (7-cyclopropoxy-3, 8-difluoronaphthalen-1-yl) ethyl) acetamide reference example 10.
MS m/z(ESI):306.1[M+H] + .
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).
Example 23
Preparation of N- (2- (3-chloro-7-cyclopropyloxy-6-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000084
Preparation of N- (2- (3-chloro-7-cyclopropyloxy-6-fluoronaphthalen-1-yl) ethyl) acetamide reference example 10.
MS m/z(ESI):322.1[M+H] + ,324.1[M+H+2] + .
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).
Example 24
Preparation of N- (2- (6-chloro-7-cyclopropyloxy-3-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000085
Preparation of N- (2- (6-chloro-7-cyclopropyloxy-3-fluoronaphthalen-1-yl) ethyl) acetamide reference example 10.
MS m/z(ESI):322.1[M+H] + ,324.1[M+H+2] + .
1 H NMR(400MHz,CDCl 3 )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).
Example 25
Preparation of N- (2- (3, 6-dichloro-7-cyclopropoxy-naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000086
The first step: preparation of N- (2- (3-bromo-6-chloro-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000087
60℃，N 2 A solution of bromine (126 mg, 790. Mu. Mol, 40.47. Mu.L) in AcOH (1 mL) was added dropwise to N- (2- (6-chloro-7-cyclopropylnaphthalen-1-yl) ethyl) acetamide (0.2 g, 658.37. Mu. Mol) in AcOH (5 mL) and stirred at 60℃for 2 hours. Cooled to 0 ℃, saturated saline and ethyl acetate are added for extraction. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, followed by column chromatography purification to give N- (2- (3-bromo-6-chloro-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide (25 mg, yield 10%).
MS m/z(ESI):382.1[M+H] + .
And a second step of: preparation of N- (2- (3, 6-dichloro-7-cyclopropoxy-naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000088
N 2 CuCl (26 mg, 261.32. Mu. Mol) was added to N- (2- (3-bromo-6-chloro-7-cyclopropylnaphthalen-1-yl) ethyl) acetamide (10 mg, 26.13. Mu. Mol) in DMF (3 mL) and stirred at 140℃for 2 hours. The reaction mixture was added to saturated brine, and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, concentrated, and purified by preparative HPLC to give N- (2)- (3, 6-dichloro-7-cyclopropoxynaphthalen-1-yl) ethyl) acetamide as a white solid (4.5 mg, 47% yield).
MS m/z(ESI):338.1[M+H] + .
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).
Example 26
Preparation of N- (1- (7-cyclopropoxy-3-fluoronaphthalen-1-yl) propan-2-yl) acetamide
Figure PCTCN2021108795-APPB-000089
The first step: preparation of 1- (7-methoxynaphthalen-1-yl) propan-2-amine
Figure PCTCN2021108795-APPB-000090
The substrate N- (2- (7-methoxynaphthalen-1-yl) ethyl) acetamide (3.94 g,0.02 mol) was dissolved in anhydrous THF (15 mL), meMgI (30.0mmol,10.0mL,3M in THF) was added dropwise under nitrogen substitution, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0deg.C, meOH (40 mL) was slowly added dropwise, and NaBH was added 4 (2.26 g,60.00 mmol). Stirring at room temperature for 24 hours. The reaction solution was slowly poured into 200mL of water to quench, extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying and concentration gave crude 1- (7-methoxynaphthalen-1-yl) propan-2-amine (368 mg, 8% yield) as a yellow liquid.
MS m/z(ESI):216.2[M+H] + .
And a second step of: preparation of N- (1- (7-methoxynaphthalen-1-yl) propan-2-yl) acetamide
Figure PCTCN2021108795-APPB-000091
The substrate 1- (7-methoxynaphthalen-1-yl) propan-2-amine (268 mg,1.7 mmol) was dissolved in dichloromethane (30 mL), TEA (719 mg,5.12mmol,0.72 mL) was added, stirred at room temperature for 10 minutes, cooled to 0℃and acetic anhydride (262 mg,2.56 mmol) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was quenched in 100mL of water, extracted with dichloromethane, the organic layers were combined, and anhydrous Na 2 SO 4 Drying and concentrating to obtain crude product. Purification by column chromatography gave the title compound N- (1- (7-methoxynaphthalen-1-yl) propan-2-yl) acetamide (300 mg, 82% yield) as a white solid.
MS m/z(ESI):258.0[M+H] + .
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).
And a third step of: preparation of N- (1- (3-bromo-7-methoxynaphthalen-1-yl) propan-2-yl) acetamide
Figure PCTCN2021108795-APPB-000092
The substrate N- (1- (7-methoxynaphthalen-1-yl) propan-2-yl) acetamide (230 mg,0.89 mmol) was dissolved in AcOH (5 mL), heated to 85 ℃ (oil bath temperature) and a solution of bromine (144 mg,0.9 mmol) in AcOH (1 mL) was added dropwise. After the completion of the dropwise addition, the mixture was heated and stirred for 0.5 hour. The reaction solution was cooled to room temperature, poured into water (50 mL), extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, concentration gave a crude product, which was purified by column chromatography to give N- (1- (3-bromo-7-methoxynaphthalen-1-yl) propan-2-yl) acetamide (270 mg, yield 87%) as a white solid.
MS m/z(ESI):336.2[M+H] + .
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).
Fourth step: preparation of N- (1- (7-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) propan-2-yl) acetamide
Figure PCTCN2021108795-APPB-000093
The substrate N- (1- (3-bromo-7-methoxynaphthalen-1-yl) propan-2-yl) acetamide (270 mg,0.8 mmol), 4, 5-tetramethyl-2- (4, 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), replaced three times with nitrogen and Pd (dppf) Cl was added under protection 2 (117 mg,0.16 mmol) was heated to 90℃and reacted for 2 hours. The reaction solution was concentrated to dryness to give a crude product, which was purified by column chromatography to give the objective compound N- (1- (7-methoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) propan-2-yl) acetamide (276 mg, yield 90%) as a yellow solid.
MS m/z(ESI):384.2[M+H] + .
Fifth step: preparation of (4- (2-acetamidopropyl) -6-methoxynaphthalen-2-yl) boronic acid
Figure PCTCN2021108795-APPB-000094
The substrate N- (1- (7-methoxy-3- (4, 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), NH was added 4 OAc (280 mg,3.6 mmol) and NaIO 4 (770 mg,3.6 mmol). Heated to 25 deg.c and reacted for 1.5 hr. Will be reversedConcentrating the solution to obtain crude product, adding water, extracting with ethyl acetate, mixing organic layers, and anhydrous Na 2 SO 4 Drying, concentrating to obtain crude product, and purifying by column chromatography to obtain target compound (4- (2-acetamidopropyl) -6-methoxynaphthalen-2-yl) boric acid (130 mg, yield 60%) as yellow solid.
MS m/z(ESI):302.2[M+H] + .
Sixth step: preparation of N- (1- (3-fluoro-7-methoxynaphthalen-1-yl) propan-2-yl) acetamide
Figure PCTCN2021108795-APPB-000095
Reagent NaOH (21 mg, 525. Mu. Mol) was dissolved in MeOH (1 mL) at room temperature, followed by addition of substrate (4- (2-acetamidopropyl) -6-methoxynaphthalen-2-yl) boronic acid (130 mg, 432. Mu. Mol) followed by stirring at 25℃for 15 min (external temperature, oil bath temperature). The reaction mixture was cooled to 0℃and AgOTf (334 mg,1.3 mmol) was added and stirred at 0℃for 30 minutes. Then, the reaction solution was concentrated to dryness in a solvent by an oil pump at 0℃and residual methanol was removed by azeotropic distillation with acetone using the solvent to obtain a crude product. The crude product was dissolved in acetone (3 mL) and activated 3A molecular sieve (350 mg) was added followed by F-TEDA-BF 4 (161 mg, 454. Mu. Mol). Then stirred at room temperature for 1 hour. The reaction solution was slowly added to 10mL of water, extracted with ethyl acetate, and the organic layers were combined, anhydrous Na 2 SO 4 Drying, concentrating to obtain crude product, and purifying by column chromatography to obtain target compound N- (1- (3-fluoro-7-methoxynaphthalene-1-yl) propan-2-yl) acetamide (86 mg, yield 60%) as white solid.
MS m/z(ESI):276.1[M+H] + .
Seventh step: preparation of N- (1- (3-fluoro-7-hydroxynaphthalen-1-yl) propan-2-yl) acetamide
Figure PCTCN2021108795-APPB-000096
The substrate N- (1- (3-fluoro-7-hydroxynaphthalen-1-yl) propan-2-yl) acetamide (86 mg, 310.8. Mu. Mol) was dissolved in dichloromethane (15 mL), cooled to 0℃under nitrogen protection, and BBr was added dropwise 3 (3mL，1M in CH 2 Cl 2 ) After the completion of the dropwise addition, the mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was slowly poured into 100mL of saturated NaHCO 3 The reaction was quenched in solution. Dichloromethane extraction, combining organic layers, anhydrous Na 2 SO 4 Drying, concentrating to obtain crude product, and purifying by column chromatography to obtain white solid N- (1- (3-fluoro-7-hydroxynaphthalen-1-yl) propan-2-yl) acetamide (77 mg, yield 95%) as white solid.
MS m/z(ESI):262.1[M+H] + .
Eighth step: preparation of N- (1- (7-cyclopropoxy-3-fluoronaphthalen-1-yl) propan-2-yl) acetamide
Figure PCTCN2021108795-APPB-000097
The substrates N- (1- (3-fluoro-7-hydroxynaphthalen-1-yl) propan-2-yl) acetamide (39 mg,0.15 mmol) and bromocyclopropane (91 mg,0.75 mmol) were dissolved in NMP (2 mL), placed in a 5.0mL microwave tube and Cs was added 2 CO 3 (73 mg, 225. Mu. Mol) and KI (37 mg, 225. Mu. Mol). The reaction is carried out for 4 hours at 180 ℃ by microwaves. The reaction solution was concentrated, and the solvent was removed to give a crude product, which was purified by preparative HPLC (alkaline method) to give the target compound N- (1- (7-cyclopropoxy-3-fluoronaphthalen-1-yl) propan-2-yl) acetamide (9.5 mg, yield 21%) as a white solid.
MS m/z(ESI):302.1[M+H] + .
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＝16.1,3.0Hz,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).
Example 27
Preparation of N- (1- (7-cyclopropoxy-3-fluoronaphthalen-1-yl) -2-methylpropan-2-yl) acetamide
Figure PCTCN2021108795-APPB-000098
Preparation of N- (1- (7-cyclopropoxy-3-fluoronaphthalen-1-yl) -2-methylpropan-2-yl) acetamide reference example 26.
MS m/z(ESI):316.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
Example 28
Preparation of N- (1- ((7-cyclopropyloxy-3-fluoronaphthalen-1-yl) methyl) cyclopropyl) acetamide
Figure PCTCN2021108795-APPB-000099
The first step: preparation of 1- ((7-cyclopropoxy-3-fluoronaphthalen-1-yl) methyl) cyclopropan-1-amine
Figure PCTCN2021108795-APPB-000100
30℃,N 2 To 2- (7-cyclopropoxy-3-fluoronaphthalen-1-yl) acetylnitrile (610 mg,2.54 mmol) and titanium tetraisopropoxide (79mg, 2.79mmol,583.30 uL) in THF (10 mL) was added dropwise ethyl magnesium bromide (676 mg,5.07 mmol) and stirred at 30℃for 1 hour. Adding BF 3 .Et 2 O (1M, 5.07 mL), the mixture was stirred for 1 hour. The mixture was poured into NaOH (10%) at 0 ℃, and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentratedColumn chromatography purification gave 1- ((7-cyclopropoxy-3-fluoronaphthalen-1-yl) methyl) cyclopropan-1-amine (150 mg, 26% yield).
MS m/z(ESI):272.1[M+H] + .
And a second step of: preparation of N- (1- ((7-cyclopropyloxy-3-fluoronaphthalen-1-yl) methyl) cyclopropyl) acetamide
Figure PCTCN2021108795-APPB-000101
0℃，N 2 Acetic anhydride (135 mg,1.32 mmol) was added dropwise to 1- ((7-cyclopropoxy-3-fluoronaphthalen-1-yl) methyl) cyclopropan-1-amine (0.15 g, 550. Mu. Mol) and DIEA (256 mg,1.98mmol, 344.84. Mu.L) in DCM (10 mL) and stirred at 30℃for 1 hour. The concentrated reaction solution was filtered and purified by preparative HPLC to give N- (1- ((7-cyclopropoxy-3-fluoronaphthalen-1-yl) methyl) cyclopropyl) acetamide (77 mg, 43% yield) as a white solid.
MS m/z(ESI):314.1[M+H] + .
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),4.02(s,1H),3.59(s,2H),1.98(s,3H),0.95-0.80(m,4H),0.79-0.76(m,4H).
Example 31
Preparation of N- (2- (7-cyclopropyloxy isoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000102
Preparation of N- (2- (7-cyclopropoxyisoquinolin-1-yl) ethyl) acetamide reference example 2.
MS m/z(ESI):271.1[M+H] + .
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).
Example 32
Preparation of N- (2- (7-cyclopropoxy-naphthalen-1-yl) ethyl) -2, 2-trifluoroacetamide
Figure PCTCN2021108795-APPB-000103
Preparation of N- (2- (7-Cyclopropyloxynaphthalen-1-yl) ethyl) -2, 2-trifluoroacetamide reference example 1.
MS m/z(ESI):324.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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).
Example 33
Preparation of N- (2- (7-cyclopropoxy-naphthalen-1-yl) ethyl) cyclopropanecarboxamide
Figure PCTCN2021108795-APPB-000104
Preparation of N- (2- (7-Cyclopropyloxynaphthalen-1-yl) ethyl) cyclopropanecarboxamide reference example 1.
MS m/z(ESI):296.1[M+H] + .
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).
Example 34
Preparation of N- (2- (7-cyclopropoxy-naphthalen-1-yl) ethyl) propanamide
Figure PCTCN2021108795-APPB-000105
Preparation of N- (2- (7-Cyclopropyloxynaphthalen-1-yl) ethyl) propanamide reference example 1.
MS m/z(ESI):284.1[M+H] + .
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).
Example 35
Preparation of N- (2- (7-cyclopropoxy-naphthalen-1-yl) ethyl) isobutyramide
Figure PCTCN2021108795-APPB-000106
Preparation of N- (2- (7-Cyclopropyloxynaphthalen-1-yl) ethyl) isobutyramide reference example 1.
MS m/z(ESI):298.1[M+H] + .
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,10H).
Example 36
Preparation of N- (2- (7-cyclopropyloxy-3-methylnaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000107
The first step: preparation of N- (2- (7-cyclopropyl-3-methylnaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000108
Substrate N- (2- (7-cyclopropyl-3-bromonaphthalen-1-yl)) Ethyl) acetamide (104 mg,0.3 mmol), cs 2 CO 3 (293 mg, 900. Mu. Mol) and trimethyl borate (75 mg, 720. Mu. Mol, 83.87. Mu.L) were dissolved in anhydrous dioxane (5 mL) and water (1 mL), nitrogen was replaced three times, and Pd (dppf) Cl was added 2 (44 mg, 60. Mu. Mol) was heated to 110℃for 4 hours. The reaction solution was concentrated to obtain a crude product, which was extracted with water, ethyl acetate (80 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated to obtain the crude product, which was purified by column chromatography to obtain N- (2- (7-cyclopropyl-3-methylnaphthalen-1-yl) ethyl) acetamide (24 mg, yield 27%) as a white solid product, which was purified by preparative HPLC.
MS m/z(ESI):284.1[M+H] + .
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),3.64(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).
Example 37
Preparation of N- [2- [ 3-bromo-7- (cyclopropyloxy) -1-naphthyl ] -1, 1-dideutero-ethyl ] acetamide
Figure PCTCN2021108795-APPB-000109
The first step: preparation of 1, 1-dideuterium-2- (7-methoxy-1-naphthalene) ethylamine
Figure PCTCN2021108795-APPB-000110
LiAlD was added to 2- (7-methoxy-1-naphthyl) acetonitrile (3 g,15.2 mmol) in THF (30 mL) at 0deg.C under nitrogen 4 (1.83 g,44.6 mmol) was stirred at 30℃for 1 hour. Cooled to 0 ℃, na was added to the reaction solution 2 SO 4 ·10H 2 O, adding ethyl acetate for extraction, drying the organic phase by using anhydrous sodium sulfate, and concentrating to obtain crude 1, 1-dideuterium-2- (7-methoxy-)1-naphthalene) ethylamine (2 g, 65% yield). Directly used in the next step.
MS m/z(ESI):204.1[M+H] + .
And a second step of: preparation of N- [1, 1-dideuterium-2- (7-methoxy-1-naphthalene) ethyl ] acetamide
Figure PCTCN2021108795-APPB-000111
Acetic anhydride (2.01 g,19.7 mmol) was added to 1, 1-dideutero-2- (7-methoxy-1-naphthalene) ethylamine (2 g,9.8 mmol) and triethylamine (2.99 g,29.5mmol,4.1 mL) in dichloromethane (6.7 mL) under nitrogen at 0deg.C, and stirred at 30deg.C for 2 hours. Cooled to 0 ℃, brine is added and dichloromethane extraction is carried out. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to give N- [1, 1-dideutero-2- (7-methoxy-1-naphthalene) ethyl ] acetamide (2 g, 83% yield) as a yellow oil.
MS m/z(ESI):246.1[M+H] + .
And a third step of: preparation of N- [1, 1-dideutero-2- (7-hydroxy-1-naphthyl) ethyl ] acetamide
Figure PCTCN2021108795-APPB-000112
N- [1, 1-dideuterium-2- (7-methoxy-1-naphthalene) ethyl under the protection of nitrogen at 0 DEG C]To a solution of acetamide (2 g,8.2 mmol) in dichloromethane (20 mL) was added BBr 3 (1M, 16.31 mL) was gradually warmed to 30℃and stirred for 1 hour. Cooling to 0deg.C, adding saturated NaHCO into the reaction solution 3 Quenching the aqueous solution, adding dichloromethane for extraction, washing the organic phase with brine, drying over anhydrous sodium sulfate, filtering, concentrating to obtain N- [1, 1-dideuterium-2- (7-hydroxy-1-naphthyl) ethyl]Acetamide (1.5 g, 80% yield) as a yellow solid.
MS m/z(ESI):232.1[M+H] + .
Fourth step: preparation of N- (2- (7-cyclopropoxy-naphthalen-1-yl) ethyl-1, 1-dideuterium) acetamide
Figure PCTCN2021108795-APPB-000113
Under the protection of nitrogen, N- [1, 1-dideuterium-2- (7-hydroxy-1-naphthyl) ethyl group]Acetamide (1.5 g,6.5 mmol), KI (108 mg, 648. Mu. Mol) and Cs 2 CO 3 A solution of (4.2 g,13 mmol) in DMF (8 mL) was added bromocyclopropane (2.35 g,19.5 mmol) and the mixture was stirred for 2 hours at 170 ℃. Cooled to room temperature, brine was added and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to give N- (2- (7-cyclopropoxy naphthalen-1-yl) ethyl-1, 1-dideukom) acetamide (0.9 g, 51% yield) as a brown oil.
MS m/z(ESI):272.1[M+H] + .
Fifth step: preparation of N- [2- [ 3-bromo-7- (cyclopropyloxy) -1-naphthyl ] -1, 1-dideutero-ethyl ] acetamide
Figure PCTCN2021108795-APPB-000114
To a solution of N- (2- (7-cyclopropylnaphthalen-1-yl) ethyl-1, 1-dideuterium) acetamide (0.2 g, 737. Mu. Mol) in AcOH (5 mL) at 70℃under nitrogen was added dropwise a solution of bromine (141 mg, 884. Mu. Mol) in AcOH (2 mL) and stirred at 70℃for 7 hours. Cooled to 0 ℃, brine is added, and extraction is performed with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography, followed by purification by preparative HPLC to give N- [2- [ 3-bromo-7- (cyclopropyloxy) -1-naphthyl ] -1, 1-dideutero-ethyl ] acetamide (20 mg, yield 7%).
MS m/z(ESI):350.1[M+H] + ,352.1[M+H+2] + .
1 H NMR(400MHz,CDCl 3 )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).
Example 38
Preparation of N- [2- [ 3-chloro-7- (cyclopropyloxy) -1-naphthyl ] -1, 1-dideutero-ethyl ] acetamide
Figure PCTCN2021108795-APPB-000115
The first step: preparation of N- [2- [ 3-chloro-7- (cyclopropyloxy) -1-naphthyl ] -1, 1-dideutero-ethyl ] acetamide
Figure PCTCN2021108795-APPB-000116
To N- [2- [ 3-bromo-7- (cyclopropyloxy) -1-naphthyl ] -1, 1-dideutero-ethyl ] acetamide (20 mg, 57. Mu. Mol) in DMF (2 mL) was added CuCl (113 mg,1.14 mmol) under nitrogen and stirred at 140℃for 3 hours. The reaction mixture was added with saturated brine and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated before purification by preparative HPLC to give N- [2- [ 3-chloro-7- (cyclopropyloxy) -1-naphthyl ] -1, 1-dideutero-ethyl ] acetamide (7 mg, 38% yield).
MS m/z(ESI):306.1[M+H] + ,308.1[M+H+2] + .
1 H NMR(400MHz,DMSO-d 6 )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).
Example 39
Preparation of N- (2- (3-bromo-7-cyclopropyloxynaphthalen-1-yl) ethyl) -2, 2-difluoroacetamide
Figure PCTCN2021108795-APPB-000117
Preparation of N- (2- (3-bromo-7-cyclopropylnaphthalen-1-yl) ethyl) -2, 2-difluoroacetamide reference example 15.
MS m/z(ESI):384.1[M+H] + .
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).
Example 40
Preparation of N- (2- (7-cyclopropyloxy-3-methoxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000118
The first step: preparation of N- (2- (3-bromo-7-hydroxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000119
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 0deg.C under nitrogen protection, and BBr was added dropwise 3 (40 mL,1M dichloromethane) was added, and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction solution was slowly poured into 200mL of saturated NaHCO 3 The reaction was quenched in solution. Dichloromethane extraction, combining organic layers, anhydrous Na 2 SO 4 Drying, concentrating to obtain crude product, and purifying by column chromatography to obtain white solid N- (2- (3-bromo-7-hydroxynaphthalen-1-yl) ethyl) acetamide (1.05 g, yield 85%) as white solid.
MS m/z(ESI):309.2[M+H] + .
And a second step of: preparation of N- (2- (3-bromo-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000120
The substrate N- (2- (3-bromo-7-hydroxynaphthalen-1-yl) ethyl) acetamide (616 mg,2.0 mmol), cs 2 CO 3 (977 mg,3.0 mmol) and potassium iodide (498 mg,3.0 mmol) were dissolved in DMA (5.0 mL), placed in a 25mL microwave tube, and bromocyclopropane (1.21 g,10 mmol) was added. The reaction is carried out for 4 hours at 180 ℃ by microwaves. Extracting with water and ethyl acetate, mixing the organic layers, washing with saturated saline, and drying the organic layer with anhydrous Na 2 SO 4 Drying, concentrating to obtain crude product, and purifying by column chromatography to obtain yellow solid N- (2- (3-bromo-7-cyclopropoxy naphthalene-1-yl) ethyl) acetamide (1.05 g, yield 85%).
MS m/z(ESI):348.1[M+H] + .
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).
And a third step of: preparation of N- (2- (7-cyclopropoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000121
The substrate N- (2- (3-bromo-7-cyclopropyloxynaphthalen-1-yl) ethyl) acetamide (700 mg,2.01 mmol), 4, 5-tetramethyl-2- (4, 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) and Pd (dppf) Cl was added under nitrogen protection 2 (295 mg, 402. Mu. Mol) was heated to 100℃for 10 hours. The reaction solution was concentrated to dryness to give a crude product, which was purified by column chromatography to give the objective compound N- (2- (7-cyclopropoxy-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethyl) acetamide (760 mg, yield 79%) as a yellow solid.
MS m/z(ESI):396.2[M+H] + .
Fourth step: preparation of (4- (2-acetamidoethyl) -6-cyclopropyloxynaphthalen-2-yl) boronic acid
Figure PCTCN2021108795-APPB-000122
The substrate N- (2- (7-cyclopropoxy-3- (4, 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 H 2 O (15 mL) to which NH was added 4 OAc (741mg, 9.61 mmol) and NaIO 4 (2.06 g,9.61 mmol). Heated to 25 deg.c and reacted for 1.5 hr. Concentrating the reaction solution to obtain crude product, adding water, extracting with ethyl acetate, mixing organic layers, and anhydrous Na 2 SO 4 Drying, concentrating to obtain crude product, and purifying by column chromatography to obtain target compound (4- (2-acetamido ethyl) -6-cyclopropoxy naphthalene-2-yl) boric acid (245 mg, yield 33%) as yellow solid.
MS m/z(ESI):314.1[M+H] + .
Fifth step: preparation of N- (2- (7-cyclopropoxy-3-hydroxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000123
(4- (2-Acetaminoethyl) -6-cyclopropyloxynaphthalen-2-yl) boronic acid (245 mg, 780. Mu. Mol) was dissolved in tetrahydrofuran (2 mL) and water (4 mL), cooled to 0deg.C, and NH was added 4 HCO 3 (75 mg, 950. Mu. Mol) and then H were added dropwise 2 O 2 (64.6 mg,1.9mmol,2.2 mL). Stirring at room temperature for 1 hour. Saturated Na was slowly added to the reaction solution 2 SO 3 The reaction was quenched with water, extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, concentrating to give a crude product, and purifying by column chromatography to give N- (2- (7-cyclopropoxy-3-hydroxynaphthalen-1-yl) ethyl) acetamide (209 mg, yield 71%) as pale yellow solid.
MS m/z(ESI):286.1[M+H] + .
Sixth step: preparation of N- (2- (7-cyclopropyloxy-3-methoxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000124
The substrates N- (2- (7-cyclopropoxy-3-hydroxynaphthalen-1-yl) ethyl) acetamide (57 mg,0.2 mmol), meI (142 mg,1.0 mmol) and K 2 CO 3 (55 mg, 400. Mu. Mol) was dissolved in acetonitrile (10 mL) and stirred at room temperature under nitrogen overnight. The reaction solution was extracted with ethyl acetate, and the organic layers were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, concentration gave a crude product, which was then purified by preparative HPLC (acid method, then base method) to give N- (2- (7-cyclopropoxy-3-methoxynaphthalen-1-yl) ethyl) acetamide (25 mg, 41.70% yield) as a white solid.
MS m/z(ESI):300.1[M+H] + .
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).
Example 41
Preparation of N- (2- (3-bromo-7- (2-methoxyethoxy) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000125
Preparation of N- (2- (3-bromo-7- (2-methoxyethoxy) naphthalen-1-yl) ethyl) acetamide reference example 15.
MS m/z(ESI):366.1[M+H] + ,368.1[M+H+2] + 。
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),5.77(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).
Example 42
Preparation of N- (2- (3-chloro-7- (3-methoxypropoxy) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000126
Preparation of N- (2- (3-chloro-7- (3-methoxypropoxy) naphthalen-1-yl) ethyl) acetamide reference example 14.
MS m/z(ESI):336.1[M+H] + ,338.1[M+H+2] + 。
1 H NMR(400MHz,CDCl 3 )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).
Example 43
Preparation of N- (2- (3-chloro-7- (2-ethoxyethoxy) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000127
Preparation of N- (2- (3-chloro-7- (3-methoxypropoxy) naphthalen-1-yl) ethyl) acetamide reference example 14.
MS m/z(ESI):336.1[M+H] + ,338.1[M+H+2] + .
1 H NMR(400MHz,CDCl 3 )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＝15.0,2.9Hz,1H),5.60(s,1H),4.40(t,J＝14.6Hz,2H),3.76(t,J＝14.6Hz,2H),3.49–3.34(m,4H),3.30–3.21(m,2H),1.80(s,3H),1.13(t,J＝11.8Hz,3H).
Example 44
Preparation of N- (2- (6-cyclopropyloxy quinolin-4-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000128
The first step: preparation of 2- (6-methoxy-4-quinolinyl) -N, N-dimethyl-vinylamine
Figure PCTCN2021108795-APPB-000129
A solution of 6-methoxy-4-methyl-quinoline (970 mg,5.6 mmol) in t-butoxydi (dimethylamino) methane (9 mL) was stirred at 110℃for 60 hours. The reaction solution was concentrated to give 2- (6-methoxy-4-quinolinyl) -N, N-dimethyl-vinylamine (1.28 g, yield 100%) as a black oil, which was used directly in the next reaction.
MS m/z(ESI):229.1[M+H] + 。
And a second step of: preparation of 2- (6-methoxy-4-quinolinyl) acetylnitrile
Figure PCTCN2021108795-APPB-000130
Hydroxylamine sulfonic acid (1.9 g,16.8 mmol) was added to a solution of 2- (6-methoxy-4-quinolinyl) -N, N-dimethyl-vinylamine (1.28 g,5.6 mmol) in acetonitrile (60 mL) and water (40 mL) to precipitate a large amount of solid. Heated to 50 ℃ and stirred for 5 hours. To the reaction solution was added water (60 mL), the mixture was adjusted to pH 9 with sodium carbonate solid, extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, concentrated and purified by column chromatography to give 2- (6-methoxy-4-quinolinyl) acetylnitrile (1 g, yield 90%) as a yellow solid.
MS m/z(ESI):199.1[M+H] + 。
And a third step of: preparation of N- [2- (6-methoxy-4-quinolinyl) ethyl ] acetamide
Figure PCTCN2021108795-APPB-000131
Nickel chloride hexahydrate (576 mg,2.4 mmol), acetic anhydride (989 mg,9.7 mmol) and sodium borohydride (611 mg,16.1 mmol) were added to a solution of 2- (6-methoxy-4-quinolinyl) acetylnitrile (800 mg,4 mmol) in methylene chloride (20 mL) and methanol (10 mL) at-10℃and the solution turned black after addition and stirring at room temperature for 3 hours. Concentrated hydrochloric acid (3 mL) was added dropwise to the mixture in an ice-water bath, and the mixture was stirred at room temperature for 1 hour. Water (100 mL) was added, the aqueous phase was adjusted to pH 9 with sodium carbonate, extracted with ethyl acetate, and the organic phase was concentrated and purified by column chromatography to give N- [2- (6-methoxy-4-quinolinyl) ethyl ] acetamide (700 mg, 67% yield) as a pink solid.
MS m/z(ESI):245.1[M+H] + .
Fourth step: preparation of N- (2- (6-hydroxyquinolin-4-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000132
To a solution of N- [2- (6-methoxy-4-quinolinyl) ethyl ] acetamide (200 mg, 819. Mu. Mol) in methylene chloride (15 mL) at 0deg.C was added a solution of boron tribromide in methylene chloride (1.0M, 8 mL) and the mixture was stirred for 1 hour. The reaction was quenched with water (30 mL), adjusted to pH 9 with sodium carbonate solid, extracted with dichloromethane, the organic phases were 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, 53% yield) as a yellow solid.
MS m/z(ESI):231.1[M+H] + 。
Fifth step: preparation of N- (2- (6-cyclopropyloxy quinolin-4-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000133
To N- (2- (6-hydroxyquinolin-4-yl) ethyl) acetamide (100 mg,0.43 mmol), bromocyclopropane (100 mg,0.8 mmol) and N-methylpyrrolidone (3 mL) was added cesium carbonate (160 mg,0.5 mmol), potassium iodide (30 mg,0.2 mmol) and stirred for 2 hours at 170℃under microwave. The reaction mixture was added to water (40 mL), extracted with dichloromethane, concentrated, and separated by HPLC, and lyophilized to give N- (2- (6-cyclopropyloxy-quinolin-4-yl) ethyl) acetamide (10 mg, yield 8%).
MS m/z(ESI):271.1[M+H] + 。
1 H 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).
Example 45
Preparation of N- (2- (2-chloro-6-cyclopropyloxy quinolin-4-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000134
The first step: preparation of 4- (2-acetamido ethyl) -6-cyclopropoxy quinoline 1-oxidation
Figure PCTCN2021108795-APPB-000135
N- (2- (6-Cyclopropyloxyquinolin-4-yl) ethyl) acetamide (100 mg,0.37 mol) and m-chloroperoxybenzoic acid (149 mg,0.74mol, 85%) were stirred in dichloromethane (15 mL) at room temperature for 13 hours. Concentration and column chromatography purification gave 4- (2-acetamidoethyl) -6-cyclopropyloxy quinoline 1-oxidation (95 mg, yield 90%) as a yellow solid.
MS m/z(ESI):287.1[M+H] + 。
And a second step of: preparation of N- (2- (2-chloro-6-cyclopropyloxy quinolin-4-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000136
4- (2-Acetaminoethyl) -6-cyclopropoxy quinoline 1-oxide (95 mg,0.33 mol) was stirred in phosphorus oxychloride (5 mL) at 100℃for 1 hour. Slowly poured into aqueous sodium carbonate (100 mL), extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and separated by high performance liquid chromatography, and lyophilized to give N- (2- (2-chloro-6-cyclopropyloxy quinolin-4-yl) ethyl) acetamide (12 mg, 11% yield) as a white solid.
MS m/z(ESI):305.1[M+H] + ，307.1[M+H+2] + 。
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).
Example 46
Preparation of N- (2- (2-bromo-6-cyclopropyloxy quinolin-4-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000137
Preparation of N- (2- (2-bromo-6-cyclopropyloxy-quinolin-4-yl) ethyl) acetamide reference example 45.
MS m/z(ESI):349.1[M+H] + ，351.1[M+H+2] + 。
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).
Example 47
Preparation of N- (2- (6-cyclopropyloxy-2-fluoroquinolin-4-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000138
Preparation of N- (2- (6-cyclopropoxy-2-fluoroquinolin-4-yl) ethyl) acetamide reference example 45.
MS m/z(ESI):289.1[M+H] + .
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,2H),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).
Example 48
Preparation of N- (2- (6-cyclopropyloxy-2-methylquinolin-4-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000139
Preparation of N- (2- (6-cyclopropoxy-2-methylquinolin-4-yl) ethyl) acetamide reference example 36.
MS m/z(ESI):285.1[M+H] + .
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).
Example 49
Preparation of N- (2- (7-methoxyisoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000140
The first step: preparation of 7-methoxy-1-methylisoquinoline
Figure PCTCN2021108795-APPB-000141
1- (3-methoxyphenyl) ethane-1-amine (5 g,33.1 mmol), 2-diethoxyacetaldehyde (6.6 g,50 mmol) was dissolved in toluene (100 mL), heated to reflux and stirred for 5 hours. The reaction mixture was concentrated, phosphorus oxychloride (50 mL) was added thereto, and the mixture was heated under reflux for 15 hours. The reaction solution was concentrated, ice water was added thereto, extraction was performed with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and purified by column chromatography to give 7-methoxy-1-methylisoquinoline (1.9 g, yield 33%).
MS m/z(ESI):174.1[M+H] + .
And a second step of: preparation of (Z) -2- (7-methoxyisoquinolin-1-yl) -N, N-dimethylethylene-1-amine
Figure PCTCN2021108795-APPB-000142
7-methoxy-1-methylisoquinoline (1.8 g,10.3 mmol) was added to 1-tert-butoxy-N, N, N ', N' -tetramethylenediamine (2.7 g,15.5 mmol), heated to 110℃and stirred for 60 hours. The reaction solution was concentrated to give (Z) -2- (7-methoxyisoquinolin-1-yl) -N, N-dimethylethylene-1-amine as a black oily product, which was used directly in the next reaction (2.8 g, crude product).
MS m/z(ESI):229.1[M+H] + .
And a third step of: preparation of 2- (7-methoxyisoquinolin-1-yl) acetylnitrile
Figure PCTCN2021108795-APPB-000143
(Z) -2- (7-methoxyisoquinolin-1-yl) -N, N-dimethylethylene-1-amine (2.8 g) was dissolved in acetonitrile/water (50 mL/30 mL), and (aminooxy) sulfonic acid (3.4 g,30.1 mmol) was added thereto, and heated to 50℃and stirred for 13 hours. The reaction solution was adjusted to pH-9 with sodium carbonate solid, water (60 mL), ethyl acetate extraction, 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) acetylnitrile (1.7 g, two-step yield 83%).
MS m/z(ESI):199.1[M+H] + .
Fourth step: preparation of N- (2- (7-methoxyisoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000144
2- (7-methoxyisoquinolin-1-yl) acetylnitrile (1.5 g,7.5 mmol) was dissolved in MeOH/CH 2 Cl 2 (20 mL/50 mL) and NiCl was added 2 .6H 2 O (1.1 g,4.6 mmol), dissolved by stirring, acetic anhydride (1.9 g,18.6 mmol) was added and NaBH was added in portions 4 (1.1 g,28.9 mmol) was stirred at room temperature for 3 hours. Quenched with concentrated hydrochloric acid (1 mL) and stirred at room temperature for 1 hour. To the reaction solution was added water (50 mL), the mixture was adjusted to pH 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 give N- (2- (7-methoxyisoquinolin-1-yl) ethyl) acetamide (380 mg, yield 21%).
MS m/z(ESI):245.1[M+H] + .
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).
Example 50
Preparation of N- (2- (3-chloro-7-methoxyisoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000145
The first step: preparation of 1- (2-acetamido ethyl) -7-methoxy isoquinoline by 2-oxidation
Figure PCTCN2021108795-APPB-000146
N- (2- (6-Cyclopropyloxyquinolin-4-yl) ethyl) acetamide (60 mg,0.25 mol) and m-chloroperoxybenzoic acid (100 mg,0.5mol, 85%) were stirred in dichloromethane (15 mL) at room temperature for 3 hours. Direct concentration and column chromatography purification gave 1- (2-acetamidoethyl) -7-methoxyisoquinoline 2-oxidation (60 mg, 94% yield) as a yellow solid.
MS m/z(ESI):261.1[M+H] + 。
And a second step of: preparation of N- (2- (3-chloro-7-methoxyisoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000147
4- (2-Acetaminoethyl) -6-cyclopropoxy-quinoline 1-oxide (60 mg,0.23 mol) was stirred in phosphorus oxychloride (5 mL) at 100℃for 1 hour. Slowly poured into aqueous sodium carbonate (100 mL), extracted with ethyl acetate, the organic phase washed with saturated brine, concentrated and subjected to HPLC, and lyophilized to give N- (2- (3-chloro-7-methoxyisoquinolin-1-yl) ethyl) acetamide (15 mg, 22% yield) as a yellow solid.
MS m/z(ESI):279.1[M+H] + ，281.1[M+H+2] + 。
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).
Example 51
Preparation of N- (2- (7-methoxy-3-methylisoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000148
Preparation of N- (2- (7-methoxy-3-methylisoquinolin-1-yl) ethyl) acetamide reference example 36.
MS m/z(ESI):259.1[M+H] + .
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).
Example 52
Preparation of N- (2- (7-cyclopropyloxy isoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000149
Preparation of N- (2- (7-cyclopropoxyisoquinolin-1-yl) ethyl) acetamide reference example 1.
MS m/z(ESI):271.1[M+H] + .
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).
Example 53
Preparation of N- (2- (3-chloro-7-cyclopropyloxyisoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000150
Preparation of N- (2- (3-chloro-7-cyclopropyloxyisoquinolin-1-yl) ethyl) acetamide reference example 45.
MS m/z(ESI):305.1[M+H] + .
1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.08(d,J＝8Hz,1H),7.71(d,J＝4 Hz,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).
Example 54
Preparation of N- (2- (7-cyclopropyloxy-3-methylisoquinolin-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000151
Preparation of N- (2- (7-cyclopropoxy-3-methylisoquinolin-1-yl) ethyl) acetamide reference example 36.
MS m/z(ESI):285.1[M+H] + .
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).
Example 55
Preparation of N- [2- [ 3-bromo-7- (cyanomethoxy) -1-naphthyl ] ethyl ] acetamide
Figure PCTCN2021108795-APPB-000152
The first step: preparation of N- [2- [ 3-bromo-7- (cyanomethoxy) -1-naphthyl ] ethyl ] acetamide
Figure PCTCN2021108795-APPB-000153
N- [2- (3-bromo-7-hydroxy-1-naphthyl) ethyl ] acetamide (50 mg, 162.25. Mu. Mol), bromoacetonitrile (58 mg, 486. Mu. Mol) and potassium carbonate (67 mg, 486. Mu. Mol) were stirred in acetonitrile (5 mL) at 80℃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=15/1) to give N- [2- [ 3-bromo-7- (cyanomethoxy) -1-naphthyl ] ethyl ] acetamide as a white solid (40 mg, yield 68%).
MS m/z(ESI):347.0[M+H] + ，349.0[M+H+2] + .
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).
Example 56
Preparation of N- (2- (3-chloro-7- (cyanomethoxy) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000154
The first step: preparation of N- (2- (3-chloro-7-hydroxynaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000155
N- [2- (3-bromo-7-hydroxy-1-naphthyl) ethyl ] acetamide (130 mg, 422. Mu. Mol) and cuprous chloride (418 mg,4.22 mmol) were stirred in N, N-dimethylformamide (3 mL) at 140℃for 1 hour with microwaves. To the reaction solution were added 30mL of water and ethyl acetate (20 mL), filtered, extracted with ethyl acetate (20 mL. Times.2), and the organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate and concentrated to give N- (2- (3-chloro-7-hydroxynaphthalen-1-yl) ethyl) acetamide as a yellow oil (70 mg, yield 63%).
MS m/z(ESI):264.1[M+H] + ，266.1[M+H+2] + .
And a second step of: preparation of N- (2- (3-chloro-7- (cyanomethoxy) naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000156
N- [2- (3-chloro-7-hydroxy-1-naphthyl) ethyl ] acetamide (70 mg, 265. Mu. Mol), bromoacetonitrile (95 mg, 796. Mu. Mol) and potassium carbonate (110 mg, 796. Mu. Mol) were stirred in acetonitrile (3 mL) at 80℃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=15/1) to give N- (2- (3-chloro-7- (cyanomethoxy) naphthalen-1-yl) ethyl) acetamide as a white solid (30 mg, yield 35%).
MS m/z(ESI):303.1[M+H] + ,305.1[M+H+2] + .
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).
Example 57
Preparation of N- (2- (7- (cyanomethoxy) -3-methyl-1-naphthyl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000157
The first step: preparation of N- (2- (7-hydroxy-3-methyl-naphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000158
N- [2- (3-bromo-7-hydroxy-1-naphthyl) ethyl group]Acetamide (100 mg, 324. Mu. Mol), trimethylboroxine (122 mg, 973. Mu. Mol), cs 2 CO 3 (211mg，649μmol)，Pd(dppf)Cl 2 DCM (27 mg, 32. Mu. Mol) in dioxane (3 mL) and water (0.3 mL) under nitrogen was stirred for 1 h at 100deg.C. LC-MS showed the reaction was complete. The reaction solution was directly used for the next reaction.
MS m/z(ESI):244.1[M+H] + .
And a second step of: preparation of N- (2- (7- (cyanomethoxy) -3-methyl-1-naphthyl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000159
To the reaction solution of the above step, bromoacetonitrile (117 mg, 974. Mu. Mol) and potassium carbonate (135 mg, 974. Mu. Mol) were added, and the mixture was stirred at 80℃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 give the crude product as a white solid of N- (2- (7- (cyanomethoxy) -3-methyl-1-naphthyl) ethyl) acetamide (23 mg, 24% yield).
MS m/z(ESI):283.1[M+H] + .
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).
Example 59
Preparation of N- (2- (7- (cyanomethoxy) -4-fluoronaphthalen-1-yl) ethyl) acetamide
Figure PCTCN2021108795-APPB-000160
Preparation of N- (2- (7- (cyanomethoxy) -4-fluoronaphthalen-1-yl) ethyl) acetamide reference example 57.
MS m/z(ESI):287.1[M+H] + .
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(dd,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).
Example 60
Preparation of N- (2- (3-bromo-7-cyclopropoxy-naphthalen-1-yl) -3-hydroxypropyl) acetamide
Figure PCTCN2021108795-APPB-000161
First step preparation of ethyl 2-cyano-2- (7-methoxy-1-naphthyl) acetate
Figure PCTCN2021108795-APPB-000162
2- (7-methoxy-1-naphthyl) acetylnitrile (2.5 g,12.7 mmol), naH (1.1 g,25.4mmol,60% purity) was added to tetrahydrofuran (40 mL), after mixing well, diethyl carbonate (3 g,25.4 mmol) was added to the reaction solution for 2 hours, the reaction was continued for 1 hour, quenching, ethyl acetate extraction, concentration under reduced pressure, and separation and purification of the crude product by flash chromatography column to give ethyl 2-cyano-2- (7-methoxy-1-naphthyl) acetate (2 g, yield 58%) as a target compound as yellow oil.
MS m/z(ESI):270.1[M+H] + .
Second step preparation of 3-amino-2- (7-methoxy-1-naphthyl) propan-1-ol
Figure PCTCN2021108795-APPB-000163
LiAlH is prepared 4 THF (10 mL) was added (113 mg,2.97 mmol), and after mixing well, ethyl 2-cyano-2- (7-methoxy-1-naphthyl) acetate (200 mg, 742.68. Mu. Mol) was added to the reaction solution and the reaction was continued for 1 hour, quenched, extracted with dichloromethane, concentrated under reduced pressure, and crude 3-amino-2- (7-methoxy-1-naphthyl) propan-1-ol (100 mg, 432.36. Mu. Mol, 58% yield) was directly used for the next reaction.
MS m/z(ESI):232.1[M+H] + .
Third step 3-acetamido-2- (7-methoxynaphthalen-1-yl) propyl acetate
Figure PCTCN2021108795-APPB-000164
3-amino-2- (7-methoxy-1-naphthyl) propan-1-ol (100 mg, 432.36. Mu. Mol, crude), K 2 CO 3 (178 mg,1.30 mmol) EtOAc/H is added 2 O (20 mL), after mixing uniformly, acetyl chloride (51 mg, 648.54. Mu. Mol) was added dropwise at 0℃and reacted for 1 hour, extracted with ethyl acetate, concentrated under reduced pressure, and the crude product was separated and purified by Pre-HPLC to give the objective compound 3-acetamido-2- (7-methoxynaphthalen-1-yl) propyl acetate (40 mg, yield 33%).
MS m/z(ESI):316.1[M+H] + .
Fourth step of preparation of [ 3-acetamido-2- (3-bromo-7-methoxy-1-naphthyl) propyl ] acetate
Figure PCTCN2021108795-APPB-000165
3-acetamido-2- (7-methoxynaphthalen-1-yl) propyl acetate (40 mg,0.15 mmol), br 2 (35 mg,0.22 mmol) was added to acetic acid (5 mL), reacted at 70℃for 3 hours, concentrated under reduced pressure, and the crude product was separated and purified by flash chromatography to give the objective compound [ 3-acetamido-2- (3-bromo-7-methoxy-1-naphthyl) propyl ]]Acetate (40 mg, 80% yield).
MS m/z(ESI):394.1[M+H] + .
Fifth step, preparation of N- (2- (3-bromo-7-hydroxynaphthalen-1-yl) -3-hydroxypropyl) acetamide
Figure PCTCN2021108795-APPB-000166
To [ 3-acetamido-2- (3-bromo-7-methoxy-1-naphthyl) propyl group]Acetate (40 mg,0.1 mmol), BBr 3 (1M, 2 mL) was added to methylene chloride (5 mL), and the mixture was reacted at room temperature for 1 hour, and thenWater quenching, dichloromethane extraction, decompression concentration, and flash chromatography column separation and purification of the crude product to obtain the target compound N- (2- (3-bromo-7-hydroxynaphthalen-1-yl) -3-hydroxypropyl) acetamide (20 mg, yield 60%).
MS m/z(ESI):338.1[M+H] + .
Sixth step N- [2- [ 3-bromo-7- (cyclopropyloxy) -1-naphthyl ] -3-hydroxy-propyl ] acetamide
Figure PCTCN2021108795-APPB-000167
N- (2- (3-bromo-7-hydroxynaphthalen-1-yl) -3-hydroxypropyl) acetamide (20 mg, 59. Mu. Mol), bromocyclopropane (31.8 mg, 263.0. Mu. Mol), KI (1.1 mg, 6.57. Mu. Mol), cs 2 CO 3 (42.7 mg, 131.5. Mu. Mol) was added to DMF (2 mL), after mixing well, reacted at 170℃for 4 hours, concentrated under reduced pressure, and the crude product was isolated and purified by Pre-HPLC to give the target compound N- [2- [ 3-bromo-7- (cyclopropyloxy) -1-naphthyl ]]-3-hydroxy-propyl]Acetamide (4 mg, 16% yield).
MS m/z(ESI):378.1[M+H] + .
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).
Example 61
Preparation of N- (2- (3-chloro-7-cyclopropyloxynaphthalen-1-yl) -3-hydroxypropyl) acetamide
Figure PCTCN2021108795-APPB-000168
Preparation of N- (2- (3-chloro-7-cyclopropyloxynaphthalen-1-yl) -3-hydroxypropyl) acetamide reference example 14.
MS m/z(ESI):334.1[M+H] + .
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).
Example 62
Preparation of N- (2- (7-cyclopropyloxy-3-methylnaphthalen-1-yl) -3-hydroxypropyl) acetamide
Figure PCTCN2021108795-APPB-000169
Preparation of N- (2- (7-cyclopropoxy-3-methylnaphthalen-1-yl) -3-hydroxypropyl) acetamide reference example 36.
MS m/z(ESI):314.1[M+H] + .
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).
Other compound information is given in table 1 below:
table 1 compound information
Figure PCTCN2021108795-APPB-000170
Figure PCTCN2021108795-APPB-000171
Figure PCTCN2021108795-APPB-000172
Biological test evaluation
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
1. Cell function experiment
Test example 1 determination of the Effect of the Compounds of the invention on calcium flux in cells stably expressing the MT1/MT2 receptor
1. The purpose of the experiment is as follows:
the compounds were tested for agonism of HEK293-MT1/HEK293-MT2 cell activity.
2. Laboratory instruments and reagents:
2.1 instrument:
384 well-assay plate (Corning: 3764);
384 well-Echo compound plate (Labcyte: LP-0200);
384 well-compound plates (PE: 6008590);
Bravo Tip(Agilent：10734-202)；
FLIPR Tip(Molecular Device：9000-0764)；
plate reader FLIPR Tetra (Molecular Device);
pipetting stations Bravo (Agilent) and ECHO 550 (labcytoe);
liquid applicator Multidrop Combi (ThermoFisher).
2.2 reagents:
DMEM,high glucose(Gibco：12100)；
fetal bovine serum (Biosera: FB-1058/500);
P/S(Biosera：XC-A4122)；
5X Matrigel(Corning：354230)；
HBSS(Sigma：H1387)；
HEPES(Invitrogen：15630080)；
Fluo-8 AM(AAT Bioquest：21080)；
Probenecid(Sigma：P8761)；
Pluronic F-127(Sigma：P2443-250G)；
1000X Fluo-8 AM (2 mM): dissolving Fluo-8 AM in DMSO, oscillating for 1-2min, packaging, and storing at-20deg.C;
complete medium: dmem+10% fbs+1x P/S;
cell inoculation medium: dmem+10% fbs+1x PS;
experiment buffer 1:1X HBSS+20mM HEPES+1mM Probenecid+0.025%Pluronic F-127;
experiment buffer 2:1X HBSS+20mM HEPES+0.075%Pluronic F-127;1X Matrigel: diluting 5X Matrigel with DMEM;
cell lines:
HDB HEK293-MT1；
HDB HEK293-MT2。
3. the experimental method comprises the following steps:
1) HEK293-MT1/HEK293-MT2 cell line was cultured in complete medium at 37℃with 5% CO 2 To 70 to 90 percent of fusion degree.
2) 384 well-cell plates were coated with 1X Matrigel, 5uL per well, and room temperature for 10-30 min.
3) Resuspending the cell digest in cell seeding medium, seeding 8,000 cells/well/20. Mu.L to 384 well-cell plates, 5% CO at 37℃ 2 Culturing for 24 hours.
4) The cell culture plates were removed from the CO2 incubator and equilibrated for 10 minutes at room temperature.
5) 1000 XFluo-8 AM was removed and diluted to 1 XFluo-8 AM, 2. Mu.M, with assay buffer 1 equilibrated to room temperature.
6) The medium of the cell culture plate was removed, 20. Mu.L of 1 XFluo-8 AM was added to each well, and after centrifugation at 300rpm at room temperature for 60 seconds, the cells were incubated at room temperature for 1 hour in the absence of light.
7) Positive control compound and test compound working solution (3X) are prepared:
(1) the compounds were diluted 11 concentration spots on 384 well-Echo compound plates (LABCYTE: LP-0200) with the apparatus Bravo;
(2) then 90nL of compound per well (compound storage concentration, e.g.10 mM at peak concentration) was transferred to 384 well-compound plates (PE: 6008590) using the apparatus ECHO;
(3) 30. Mu.L of assay buffer 2 to 384 well-plates (PE: 6008590) were added with Multidrop Combi, and the positive control compound and test compound were diluted to 30. Mu.M (3X) and left at room temperature for use.
8) mu.L of diluted 3X compound was added to the experimental wells of the corresponding 384-well cell plate using FLIPR Tetra, while the collected data were read.
4. The experimental data processing method comprises the following steps:
FLIPR Tetra reads and collects fluorescence signal value (RFU), takes the maximum RFU value, calculates the data of percent activation {% activation = (RFUsample-RFUlow control)/(RFUhigh control-RFUlow control) ×100} according to the read values of the Low control (DMSO control) and the High control (100 nM positive compound) experimental group, calculates the EC of the compound by using the XLfit percentage activation and 11 point concentration data to parameter nonlinear logic formula, wherein the concentration of the compound to be tested is 10 mu M to 0.17nM after 3 times dilution of the reaction system 50 Values.
5. Experimental results:
EC of Table 2 Compounds on HEK293-MT1/HEK293-MT2 cells 50 Value of
Figure PCTCN2021108795-APPB-000173
Note that: "NA" means undetected.
6. Conclusion of experiment:
the compounds of the examples shown in the present invention show good agonistic activity in experiments of the effect of cells stably expressing MT1 and MT2 receptors on calcium flux.
Test example 2 Compounds of the invention are stably expressing 5-HT 2C Determination of the influence of recipient cells on calcium flux
1. The purpose of the experiment is as follows:
detection of compound pair HEK293-5HT 2C Antagonism of cellular activity.
2. Laboratory instruments and reagents:
2.1 instrument:
384 well-assay plate (Corning: 3764);
384 well-Echo compound plate (Labcyte: LP-0200);
384 well-compound plates (PE: 6008590);
Bravo Tip(Agilent：10734-202)；
FLIPR Tip(Molecular Device：9000-0764)；
plate reader FLIPR Tetra (Molecular Device);
pipetting stations Bravo (Agilent) and ECHO 550 (labcytoe);
liquid applicator Multidrop Combi (ThermoFisher).
2.2 reagents:
DMEM,high glucose(Gibco：12100)；
fetal bovine serum (Biosera: FB-1058/500);
P/S(Biosera：XC-A4122)；
5X Matrigel(Corning：354230)；
HBSS(Sigma：H1387)；
HEPES(Invitrogen：15630080)；
Fluo-8 AM(AAT Bioquest：21080)；
Probenecid(Sigma：P8761)；
Pluronic F-127(Sigma：P2443-250G)
1000X Fluo-8 AM (2 mM): dissolving Fluo-8 AM in DMSO, oscillating for 1-2min, packaging, and storing at-20deg.C;
complete medium: dmem+10% fbs+1x P/S;
cell inoculation medium: dmem+10% fbs+1x PS;
liquid-changing culture medium: dmem+1X P/S;
experiment buffer 1:1X HBSS+20mM HEPES+1mM Probenecid+0.025%Pluronic F-127;
experiment buffer 2:1X HBSS+20mM HEPES+0.075%Pluronic F-127;1X Matrigel: diluting 5X Matrigel with DMEM;
cell lines: HDB HEK293-5HT 2C 。
3. The experimental method comprises the following steps:
1)HEK293-5HT 2C the cell strain is cultured in complete culture medium at 37 ℃ and 5% CO 2 To 70 to 90 percent of fusion degree.
2) 384 well-cell plates were coated with 1X Matrigel, 5. Mu.L per well, and room temperature for 10-30 min.
3) Resuspending the cell digest in cell seeding medium, seeding 8,000 cells/well/20. Mu.L to 384 well-cell plates, 5% CO at 37℃ 2 Culturing for 24 hours.
4) The cells were observed under a microscope to have attached. The inoculation medium was removed and 20. Mu.L of serum-free medium pre-warmed to 37℃was added to each well, 5% CO at 37 ℃was added 2 Incubation was carried out overnight (18 hours).
5) Cell culture plate was removed from CO 2 The incubator was removed and equilibrated at room temperature for 10 minutes.
6) 1000 XFluo-8 AM was removed and diluted to 1 XFluo-8 AM, 2. Mu.M, with assay buffer 1 equilibrated to room temperature.
7) The medium of the cell culture plate was removed, 20. Mu.L of 1 XFluo-8 AM was added to each well, and after centrifugation at 300rpm at room temperature for 60 seconds, the cells were incubated at room temperature for 1 hour in the absence of light.
8) Positive control compound and test compound working solution (3X) are prepared:
(1) the compounds were diluted 11 concentration spots on 384 well-Echo compound plates (LABCYTE: LP-0200) with the apparatus Bravo;
(2) then 90nL of compound per well (compound storage concentration, e.g.10 mM at peak concentration) was transferred to 384 well-compound plates (PE: 6008590) using the apparatus ECHO;
(3) 30. Mu.L of assay buffer 2 to 384 well-plates (PE: 6008590) were added with Multidrop Combi, and the positive control compound and test compound were diluted to 30. Mu.M (3X) and left at room temperature for use.
9) mu.L of diluted 3X compound was added to the experimental wells of the corresponding 384-well cell plate using FLIPR Tetra, while the collected data were read.
4. The experimental data processing method comprises the following steps:
FLIPR Tetra read and collect fluorescence signal value (RFU), take maximum RFU value, calculate percent activated data {% activation = (RFUsample-RFUlow control)/(RFUhigh control-RFUlow control). Times.100 }, according to read values of Low control (DMSO control) and High control (100 nM positive compound) experimental group, the concentration of the compound to be tested was 10 after 3 times dilution of the reaction system Mu M to 0.17nM, IC of the compound was calculated using XLfit fit percent activation and 11 point concentration data to parametric nonlinear logic formula 50 Values.
5. Experimental results:
table 3 Compound pair HEK293-5HT 2C IC of cell 50 Value of
Figure PCTCN2021108795-APPB-000174
6. Conclusion of experiment:
the compounds of the examples of the present invention are shown to be stable in the expression of 5HT 2C The receptor cells show a certain antagonism in the experiments of the influence of the receptor cells on the calcium flux.
Test example 3, rat pharmacokinetic assay
3.1. Study purposes:
the pharmacokinetic behavior of the compounds of the invention in vivo (plasma) in rats by intravenous and oral administration was studied using SD rats as test animals.
3.2. Test protocol
3.2.1 test drug:
the compound of the embodiment of the invention is self-made.
3.2.2 test animals:
SD rats were 3 in each group, male. Shanghai JieJie laboratory animal Co., ltd., animal production license number (SCXK (Shanghai) 2013-0006N0.311620400001794).
3.2.3 preparation of drug:
intravenous drug formulation: (5%DMSO+10%Solutol HS15+85%PBS preparation method)
Weighing the compound of the embodiment, firstly adding 5% DMSO, carrying out vortex and ultrasonic treatment for 2min to completely dissolve the compound, then adding 10% Solutol HS15, carrying out vortex and ultrasonic treatment for 2min to completely dissolve the compound, finally adding 85% PBS, and carrying out vortex and ultrasonic treatment for 5min to obtain colorless transparent clear solution with the concentration of 0.2mg/mL.
The preparation of orally administered medicine comprises the following steps: (0.5% CMC-Na (1% Tween 80))
5g of sodium carboxymethylcellulose (CMC-Na, viscosity: 800-1200 Cps) was weighed, dissolved in 1000mL of purified water, and 10g of Tween80 was added. Mixing and stirring uniformly to obtain a clear solution.
The compound of the example was weighed and dissolved in the solution, shaken well and sonicated for 15 minutes to give a colorless clear solution at a concentration of 0.5mg/mL.
3.2.4 dosing:
intravenous administration:
SD rats were dosed at 1mg/kg in 3 groups, IV each after one night of fasting, and 5mL/kg of dosing volume.
Oral administration:
SD rats were 3 animals per group, and had a PO dose of 5mg/kg and a dosing volume of 10mL/kg after one night of fasting.
3.2.5 sample collection:
intravenous administration:
blood is collected for 0.2mL at 0h,0.083h,0.25h,0.5h,1.0h,2.0h and 4.0h jugular vein before and after administration, and is placed in an EDTA-2K test tube, centrifuged at 6000rpm at 4 ℃ for 6min to separate blood plasma, and the blood plasma is stored at-80 ℃; the feed was fed 4h after administration.
Oral administration:
blood is collected for 0.2mL at the jugular vein for 0.25h,0.5h,1.0h,2.0h and 4.0h before and after administration, and the obtained mixture is placed in an EDTA-2K test tube, centrifuged at 6000rpm for 6min at 4 ℃ to separate blood plasma, and the blood plasma is preserved at-80 ℃; the feed was fed 4h after administration.
3.3 experimental results:
the final measurement results were obtained by LCMS/MS method, see tables 4 and 5
Table 4: rat intravenous administration pharmacokinetic parameters of the Compounds of the invention
Figure PCTCN2021108795-APPB-000175
Table 5: oral administration pharmacokinetic parameters of the Compounds of the invention in rats
Figure PCTCN2021108795-APPB-000176
3.4 experimental conclusion:
the data show that the compounds of the examples of the present invention have good exposure and bioavailability in rat plasma at an oral dose of 5 mg/kg.
Test example 4 CYP enzyme phenotype identification test
4.1 purpose of experiment
And (3) adopting a CYPs recombinase incubation system, and primarily judging the main metabolic enzymes of the compound in the metabolic process of the human body according to the metabolic conditions of different subtype CYPs recombinases on the compound.
4.2 Experimental procedure
4.2.1 preparation of solution:
10.0mM NADPH, 16.7mg NADPH (reduced nicotinamide adenine dinucleotide phosphate) was weighed to 2mL in 100mM phosphate buffer. Each CYPs recombinase was diluted to 12.5pmol/L with 100mM phosphate buffer, and mixed well.
Preparing a reaction solution of a compound to be tested:
the compound of the test example was weighed, diluted to 10mM with DMSO and then diluted to 10. Mu.M with 100mM phosphate buffer.
4.2.2 experimental procedure:
1. in a 96-well plate, 400. Mu.L of recombinase and 50. Mu.L of test compound are added and pre-incubated for 10min.
2. NADPH 50. Mu.L was added.
3. At 0,5,10,15,20 and 30min, 50. Mu.L of each of these was removed and 200. Mu.L of acetonitrile stop solution containing an internal standard was added.
4. And (5) centrifuging and sampling.
4.3 experimental results:
table 6: example Compound CYP enzyme phenotype identification results
Figure PCTCN2021108795-APPB-000177
Figure PCTCN2021108795-APPB-000178
4.4 experimental conclusion:
the above data shows that compounds of the present examples have reduced metabolic dependence on CYP1A2 and that the increased metabolic proportion of other CYP enzyme subtypes to the compounds of the present examples can reduce compound variability.
Test example 5 CYP enzyme single-point inhibition test
5.1 purpose of experiment
And the inhibition condition of the compound on the CYP450 enzyme subtype is rapidly predicted by a single-point method by adopting a human liver microsome incubation system.
5.2 Experimental procedure
5.2.1 preparation of solution:
2.5mM NADPH, 4.165mg NADPH (reduced nicotinamide adenine dinucleotide phosphate) was weighed to 2mL in 100mM phosphate buffer. 0.25mg/mL microsomes, 50. Mu.L of 20mg/mL microsomes, and 4mL of 100mM phosphate buffer were added and mixed well.
Preparing a reaction solution of a compound to be tested:
the compound of the test example was weighed, diluted to 10mM with DMSO and then diluted to 100. Mu.M with 100mM phosphate buffer.
5.2.2 experimental procedure:
1. in a 96-well plate, 40. Mu.L of liver microsomes, 10. Mu.L of substrate, 10. Mu.L of test compound were added and pre-incubated for 3min.
2. NADPH 40. Mu.L was added.
3. 300. Mu.L of acetonitrile stop solution containing an internal standard was added at 20 min.
4. And (5) centrifuging and sampling.
5.3 experimental results:
table 7: example Compound CYP enzyme Single Point inhibition results
Figure PCTCN2021108795-APPB-000179
Note that:
strong inhibition: IC (integrated circuit) 50 <1. Mu.M; moderate inhibition: 1 mu M<IC 50 <10. Mu.M; weak inhibition: IC (integrated circuit) 50 >10μM
5.4 experimental conclusion:
the data show that the compounds of the examples of the present invention have strong inhibition to CYP1A2, no strong inhibition to other CYP enzyme subtypes, and little risk of DDI (drug interactions).
Test example 6, plasma protein binding Rate experiment
6.1 experimental purposes:
the purpose of this experimental procedure was to detect plasma protein binding of the compounds of the examples in plasma.
6.2 laboratory instruments and materials:
liquid phase mass spectrometer, centrifuge, vortex, pipette, continuous liquid feeder, 96-well plate, tissue homogenizer (used in tissue sample analysis), 50% methanol water solution, and acetonitrile solution of internal standard and blank matrix (plasma, urine or tissue homogenate, etc.) are added.
6.3 experimental procedure:
6.3.1 preparation of stock solution of analyte A
The compound of the example was formulated with DMSO as a 1mM solution A.
6.3.2 preparation of plasma solution B
Solution A was added to the plasma solution to prepare 5uM solution B.
6.3.3 Process flow
1) 200uL of solution B was added to the membrane.
2) 350uLPBS was added to the membrane.
3) Incubate in a 37℃water bath for 6h.
4) The samples were diluted and mass detected.
6.4 chromatographic conditions:
instrument: shimadzu LC-20AD;
chromatographic column: phenomenex
Figure PCTCN2021108795-APPB-000180
C18 (50 x 4.6mm,5 μm particle size);
mobile phase: a: acetonitrile, 0.1% formic acid solution, 0-0.5 min: 5%A-90% A, 2.0-2.1 min:90% A.fwdarw. 5%A; flow rate: 0.8mL/min; run time: 5.0min; sample injection volume: 5. Mu.L.
6.5 Mass Spectrometry conditions:
an instrument, namely an API4000 type liquid chromatography-mass spectrometer, AB company in the United states;
the ion source is an electrospray ionization source (ESI);
drying gas (N) 2 ) The temperature is 500 ℃;
the electrospray voltage is 5500V;
the detection mode is positive ion detection;
the scanning mode is a selective reaction monitoring (MRM) mode; the scan time was 0.1s.
6.6 experimental results:
table 8: example Compounds plasma protein binding Rate (%)
Numbering device Human body Rat (rat) A mouse Dogs
Example 2A 93.6 89.6 93.5 98.6
Example 14 99.9 99.4 / /
Example 15 100.0 99.7 / /
Example 56 97.6 97.1 94.8 99.2
6.7 experimental conclusion:
the compounds of the examples of the present invention show high plasma protein binding rates with small species differences.
Test example 7 evaluation of efficacy in rat acquisition helplessness and sugar water preference model
7.1 Experimental purposes:
the objective of this experiment was to evaluate the antidepressant effect of the test compounds in the SD rat acquisition helplessness (LH model) and the syrup preference model.
7.2 experimental animals:
SD rats, male, 7-8 weeks old, 136.
7.3 laboratory apparatus:
TABLE 9 Main experiment instrument
Figure PCTCN2021108795-APPB-000181
7.4 experimental procedure:
7.4.1. adaptation to
After 136 SD male rats reached the experimental facility, the experiment was started after one week of adaptation in the facility, and was adapted in the experimental room for 2 days before starting training.
7.4.2. Training
The animals were placed in the shuttle box and the animals were confined to one side of the shuttle box and the sole received 60 current levels of 0.8mA for 15 seconds with 2 seconds of acoustic stimulation before each shock was initiated, with a 20 second interval between the two.
7.4.3. Screening
After the animals were placed in the shuttle box, the shuttle door was opened and the animals were allowed to freely shuttle within the box, the sole received 30 shots of current of 0.6mA for a duration of 10 seconds (if the animals escaped to the other side during the current duration, the shock stopped), 2 seconds of sound and light stimulation were provided before each shock started, the interval between the two shots was 20 seconds, and recordings were made:
number of active evasions: actively evade to the non-electric shock side under the stimulation of sound and light
Passive escape times: after the sound and illumination stimulation is finished, the electric shock escapes to the non-electric shock side in the continuous process
Number of escape failures: still not evade after electric shock is finished
Animals with failure times of 20 times or more are considered as unoccupied and can be used for drug screening
7.4.4. Grouping
Immediately grouping the animals after finishing the learning unassisted screening, and randomly grouping the screened learning unassisted animals according to the escape failure times for compound screening test.
7.4.5. Administration of drugs
The first administration was performed after the control group and the compound group were completely divided, and the administration was continued for seven days, with a volume of 10mL/kg. The positive compounds (imipramine group) were administered four consecutive days before the start of the first learning unassisted test, with a dosing volume of 2mL/kg.
7.4.6. Testing
7.4.6.1 learning helplessness test (LH model)
The study performance unassisted tests were performed on days 2 and 5 of compound dosing (days 1 and 4 of positive compound dosing), 0.5 hours after positive compound dosing, and the number of shock evasion tests, rat evasion failures and shuttles to rats was recorded for analysis after 0.25 or 0.5 hours of test compound dosing.
Experimental results:
table 10: example Compound LH experimental rats were tested for number of evasion failures and shuttling times
Numbering device Number of escape failures Shuttle times
Vehicle 24.2 5.8
Prominozine (64 mg/kg) 10.7 19.9
Examples2A(20mg/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
Conclusion of experiment:
in the LH model, the compounds of the examples have a tendency to reduce the rate of escape failure in rats.
7.4.6.2 sugar water preference test
After day 4 of compound dosing, animals were given two bottles of plain water acclimation;
on the 5 th day of compound administration, after the completion of the acquisition helplessness test, one bottle of ordinary water is replaced by 1% sugar water, and the position is replaced for 6 times within 24 hours;
after the end of the administration of the compound on day 6, the compound is fasted and water is forbidden;
1 hour after the end of the day 7 dosing of the compounds, one bottle of sugar water and one bottle of plain water were added and tested for water consumption for 1, 12 and 24 hours.
Sugar water preference rate = sugar water intake/(normal water intake + sugar water intake) ×100%
Data collection and analysis:
data were collected using Excel software. Data analysis was performed using Prism (GraphPad software, inc.) software, and Fisher's LSD multiplex comparison test data was attached using One-way ANOVA. p <0.05 was considered to be a significant difference.
Experimental results:
table 11: example compound sucrose preference experiments 12h and 24h rat sugar water preference
Numbering device Preference for 12h sugar water (%) 24h sugar preference (%)
Vehicle 64.0 63.0
Agomelatine (20 mg/kg) 65.3 66.4
Example 2A (20 mg/kg) 84.0 84.9**
Example 56 (20 mg/kg) 78.3 83.1*
Note that: * p <0.05; * P <0.01
Conclusion of experiment:
in the syrup preference experiment, compared with the veccle group, the compound to be tested can obviously increase the syrup preference rate of rats for 12h and 24h, and no obvious side effect is found in the experiment.

Claims (17)

  1. A compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021108795-APPB-100001
    wherein:
    M 1 is N or CR 1 ；
    M 2 Is N or CR 2 ；
    M 3 Is N or CR 3 ；
    Figure PCTCN2021108795-APPB-100002
    Selected from the group consisting of
    Figure PCTCN2021108795-APPB-100003
    Figure PCTCN2021108795-APPB-100004
    R 1 、R 2 And R is 3 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
    r is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxy, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;
    R 4 、R 5 And R is 6 Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
    R 7 selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxy, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
    R 8 、R 8 ’、R 9 and R is 9 ' each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, optionally further substituted;
    Alternatively, R 8 、R 8 ’、R 9 、R 9 Any two of the groups and the carbon atoms to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, where the cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally may beFurther substituted.
  2. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is further represented by the general formula (II):
    Figure PCTCN2021108795-APPB-100005
    wherein:
    r 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 Hydroxyalkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
    R 1 、R 2 And R is 3 Each independently 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
    R 4 、R 5 and R is 6 Each independently 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
    R 7 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 One of aryl or 5-14 membered heteroarylSubstituted with one or more substituents;
    R 8 and R is 8 ' each independently 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said 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 heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl;
    alternatively, R 8 And R is 8 ' together with the carbon atom to which they are attached form a C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl.
  3. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is further represented by the general formula (II-a):
    Figure PCTCN2021108795-APPB-100006
    wherein:
    M 1 is N or CR 1 Preferably N or CH;
    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 heterocyclyl, said 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 heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
    R 1 、R 2 And R is 3 Each independently selected from hydrogenDeuterium, 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 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said 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 heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
    R 9 and R is 9 ' each independently 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 Hydroxyalkyl, C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said 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 heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
    alternatively, R 9 And R is 9 ' taken together may form an oxo or thioxo group;
    alternatively, R 9 And R is 9 ' together with the carbon atom to which they are attached form C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 Cycloalkyl and 3-12 membered heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl.
  4. A compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein 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 heterocyclyl, said 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 heterocyclyl, optionally further substituted with 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 heterocyclyl, C 6-14 One or more substituents in aryl and 5-14 membered heteroaryl;
    preferably C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, said C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted with 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 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
    more preferably methyl, deuteromethyl, isopropyl, tert-butyl, tert-amyl, 3-amyl, cyclopropyl or oxetanyl, said methyl, isopropyl, tert-butyl, tert-amyl, 3-amyl, cyclopropyl or oxetanyl being further substituted by deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl.
  5. A compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 And R is 3 Each independently selected from hydrogen, deuterium, halogen, amino, hydroxyCyano, 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 or 3-12 membered heterocyclyl;
    preferably hydrogen, deuterium, halogen, amino, hydroxy, 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, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
    more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or tert-butyl.
  6. A compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 4 、R 5 And R is 6 Each independently 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 or 3-12 membered heterocyclyl;
    preferably hydrogen, deuterium, halogen, amino, hydroxy, 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, C 3-8 Cycloalkyl radicalsOr a 3-8 membered heterocyclyl;
    more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl or tert-butyl.
  7. A compound according to any one of claims 1 to 3, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 7 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 or 3-12 membered heterocyclyl;
    preferably 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, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
    more preferably methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl or trifluoromethyl.
  8. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is further represented by the general formula (III):
    Figure PCTCN2021108795-APPB-100007
    wherein:
    M 3 is N or CR 3 ；
    R 2 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 or 3-12 membered heterocyclyl; preferably hydrogen, deuterium, halogen, amino, hydroxy, 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, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, tert-butyl or methoxy;
    R 3 selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, and 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 A hydroxyalkyl group; preferably hydrogen;
    R 8 and R is 8 ' each independently 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 or 3-12 membered heterocyclyl; preferably hydrogen, deuterium, halogen, amino, hydroxy, 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 group,C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl; more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl;
    alternatively, R 8 And R is 8 ' linking forms a C 3-12 Cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 Cycloalkyl or 3-to 12-membered heterocyclyl, optionally further substituted by 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 heterocyclyl, C 6-14 One or more substituents in aryl or 5-14 membered heteroaryl; preferably form C 3-12 Cycloalkyl;
    when M 3 Is CH, R 8 And R is 8 When' is hydrogen, R 2 Is not hydrogen.
  9. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, 2 or 8, wherein R 8 And R is 8 ' each independently 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 or 3-12 membered heterocyclyl;
    preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated compoundsAlkyl, 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 heterocyclyl, C 6-10 Aryl or 5-10 membered heteroaryl;
    more preferably hydrogen, deuterium, fluorine, chlorine, bromine, methyl or ethyl;
    alternatively, R 8 、R 8 ' and the carbon atom to which they are attached form C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted with 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 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 One or more substituents in the aryl or 5-10 membered heteroaryl group.
  10. Sup>A compound according to claim 3, wherein the compound is further represented by the general formulSup>A (IV-Sup>A):
    Figure PCTCN2021108795-APPB-100008
    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;
    methyl, deuterated methyl or cyclopropyl are preferred.
  11. A compound according to claim 3, wherein the compound is further represented by the general formula (IV-B):
    Figure PCTCN2021108795-APPB-100009
    R 2 Or R is 3 Independently selected from deuterium, halogen, cyano or C 1-3 Alkyl, preferably deuterium, fluorine, chlorine, bromine or methyl;
    n is 1, 2 or 3.
  12. A compound according to any one of claims 1 to 11, a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the specific structure of the compound is as follows:
    Figure PCTCN2021108795-APPB-100010
    Figure PCTCN2021108795-APPB-100011
    Figure PCTCN2021108795-APPB-100012
  13. a process for preparing a compound of claim 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
    Figure PCTCN2021108795-APPB-100013
    reacting Sup>A compound of formulSup>A (V-A) with R-X in the presence of Sup>A base to give Sup>A compound of formulSup>A (IV-A),
    wherein:
    x is bromine or iodine;
    r is as defined in claim 10;
    alternatively, a process for preparing a compound of claim 11, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of:
    Figure PCTCN2021108795-APPB-100014
    the compound of the formula (V-B) is reacted with
    Figure PCTCN2021108795-APPB-100015
    The reaction gives compounds of the general formula (IV-B), in which:
    x is bromine or iodine;
    R 2 、R 3 and n is as defined in claim 11.
  14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-12, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  15. Use of a compound according to any one of claims 1 to 12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the preparation of a melatonin receptor agonist medicament.
  16. A compound according to any one of claims 1 to 12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for use in the preparation of an MT1 and MT2 receptor agonist and 5-HT 2C Use in receptor antagonist medicaments.
  17. Use of a compound according to any one of claims 1 to 12, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the treatment or prophylaxis of cardiovascular diseases, digestive system diseases, central nervous system diseases and/or psychotic diseases; preferably, the central nervous system and/or psychiatric disorder is selected from melatonin system disorders, stress, anxiety disorders, seasonal affective disorders, schizophrenia, phobia, depression, major depressive disorder, sleep disorders, insomnia or fatigue caused by jet lag, weight disorders, mood disorders, schizophrenic lineage disorders, spasticity disorders, memory disorders and/or cognitive disorders, movement disorders, personality disorders, autism lineage disorders, pain, traumatic brain injury, substance abuse disorders and/or withdrawal syndromes, tinnitus, autism, alzheimer's disease, epileptic seizures, neuralgia or drug addiction withdrawal symptoms major depressive disorder or manic disorder.
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