CN115433205A

CN115433205A - Polycyclic derivative receptor agonist, preparation method and application thereof

Info

Publication number: CN115433205A
Application number: CN202210627844.3A
Authority: CN
Inventors: 苏熠东; 李凯龙; 邓海宁; 黄志强; 俞文胜
Original assignee: Shanghai Hansoh Biomedical Co Ltd
Current assignee: Shanghai Hansoh Biomedical Co Ltd
Priority date: 2021-06-03
Filing date: 2022-06-06
Publication date: 2022-12-06

Abstract

The invention relates to a polycyclic derivative receptor agonist, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as a TAAR1 receptor agonist in treating, preventing or controlling neurological disorders, wherein each substituent in the general formula (I) is defined as the specification.

Description

Polycyclic derivative receptor agonist, preparation method and application thereof

Technical Field

The invention belongs to the technical field of biological medicines, and particularly relates to a polycyclic derivative receptor agonist and a preparation method and application thereof.

Background

Schizophrenia is the most prevalent psychosis, has a slow course, is prone to repeated attacks, exacerbations or exacerbations, and causes severe burden and adverse consequences to patients and their families. The mental patients can have positive symptoms such as delusions, hallucinations, thought language and behavior disorder and the like, negative symptoms such as no emotion and expression, poor speech, lack of pleasure and the like and symptoms such as cognitive disorder and the like. Although the development and clinical application of anti-schizophrenia drugs have been greatly developed in the past decades, the conventional antipsychotics (first generation) (haloperidol, methiopyridazine, etc.) and atypical antipsychotics (second generation) (clozapine, risperidone, olanzapine, aripiprazole, etc.) are directed against D2 and 5-HT2A target mechanisms, have a good therapeutic effect on positive symptoms, have an unsatisfactory improving effect on negative symptoms and cognitive impairment, and have side effects such as extrapyramidal tract and weight gain. Anti-schizophrenic drugs have also been studied at a number of non-D2/5-HT 2A receptors, including GlyT 1D 1, D4, D3, NMDA, mGluR2/3, AMPA 5-HT2C, nicotinic a7, muscarinic M1/M4, H3, NK-3, and the like. Although these targets have shown good efficacy in preclinical models, most of the new non-D2/5-HT 2A mechanistic drugs have shown limited or no success in clinical trials. Therefore, there is an urgent need to develop a new target drug for anti-schizophrenia, which can improve not only positive symptoms but also negative symptoms and cognitive impairment without extrapyramidal side effects.

Trace Amines (TAs) are structurally similar to classical monoamine neurotransmitters (DA, 5-HT and norepinephrine), and are present in very low concentrations in the brain of mammals, and are present in varying amounts in many psychiatric disorders (schizophrenia, depression, anxiety, parkinson's disease/attention deficit hyperactivity disorder). The TAAR1 receptor is a subtype of the TA1 receptor, a G protein-coupled receptor, and is expressed primarily in the presynaptic membrane of the axonal terminals of peripheral organs and cells (e.g., stomach, small intestine, duodenum, and leukocytes) and Central Nervous System (CNS) astrocytes and monoamine neurons, and functions to regulate DA, 5-HT, and glutamatergic activity.

The 5-HT1A receptor is a member of a G protein coupled receptor family, is a subtype of the 5-HT receptor, is distributed in the center and the periphery, is closely related to spirit, emotion, learning, memory and the like, the density of the 5-HT1A receptor of frontal and temporal cortex of a schizophrenic patient is increased, the activation of the 5-HT1A receptor can improve the negative symptoms of the schizophrenic patient, and the research finds that the activation of the 5-HT1A receptor is also related to the improvement of the positive symptoms.

WO-2011069063A2 published in international application is SEP-363856 which is a TAAR1 receptor agonist and a 5-HT1A receptor partial agonist, is used for treating schizophrenia, has good clinical second-stage test results, has curative effects on positive symptoms and negative symptoms and good safety, and enters clinical third-stage research at present. At present, the development of a drug with a novel target point which has both a curative effect on positive symptoms and negative symptoms and good safety for treating schizophrenia is urgently needed to meet huge market demands.

Disclosure of Invention

The invention provides a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein,

Z ¹ ，Z ² ，Z ³ each independently selected from N, CH or S;

R ³ ，R ⁴ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl,Deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl, optionally may be further substituted;

R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or alkylamino, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or alkylamino optionally being further substituted;

or, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Each together with adjacent atoms form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl or heteroaryl group, optionally may be further substituted;

R ⁹ ，R ¹⁰ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally being further substituted.

When R is ⁹ And R ¹⁰ One of them is H and the other is

When R is ⁵ ，R ⁶ Not H at the same time.

When R is ⁹ And R ¹⁰ One of them is H and the other is

When R is ⁵ ，R ⁶ Not H at the same time.

In one embodiment of the present invention, the compound of formula (I) is further represented by general formula (II-1) or (II-2):

R ³ ，R ⁴ selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, optionally may be further substituted;

R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, optionally further substituted;

or R ⁵ And R ⁶ Or R ⁷ And R ⁸ Each together with adjacent atoms form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups, optionally may be further substituted;

Further, R ³ ，R ⁴ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Deuterated alkyl, C substituted by one or more halogens _1-8 Alkyl radical, C _1-8 Alkoxy, C substituted by one or more halogens _1-8 Alkoxy radical, C _1-8 Alkylamino radical, C _1-8 Hydroxyalkyl, and optionally may be further substituted; more preferably, R ³ ，R ⁴ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, C substituted by one or more halogens _1-6 Alkyl radical, C _1-6 Alkoxy, C substituted by one or more halogens _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Hydroxyalkyl, and optionally may be further substituted; more preferably, R ³ ，R ⁴ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, C substituted by one or more halogens _1-4 Alkyl radical, C _1-4 Alkoxy, C substituted by one or more halogens _1-4 Alkoxy radical, C _1-4 Alkylamino radical, C _1-4 Hydroxyalkyl, and optionally further substituted with one or more of deuterium, halogen, C _1-4 Alkyl radical, C _3-8 Cycloalkyl substitution; more preferably, R ³ ，R ⁴ Selected from hydrogen, deuterium, fluorine, chlorine, methyl,

R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Deuterated alkyl, halogenated C _1-8 Alkyl radical, C _1-8 Alkoxy, halo C _1-8 Alkoxy radical, C _1-8 Alkylamino, and optionally may be further substituted; preferably, R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ Each independently selected from hydrogen, deuteriumHalogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, halogenated C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkylamino, and optionally may be further substituted; more preferably, R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, halogenated C _1-4 Alkyl radical, C _1-4 Alkoxy, halo C _1-4 Alkoxy radical, C _1-4 Alkylamino, optionally further substituted with one or more deuterium, halogen; more preferably, R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl;

or, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form C together with adjacent atoms _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-12 Aryl or 5-12 membered heteroaryl, and optionally may be further substituted; preferably, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form C together with adjacent atoms _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl, and optionally may be further substituted; more preferably, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form C together with adjacent atoms _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-8 Aryl or 5-8 membered heteroaryl, and optionally may be further substituted; more preferably, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form C together with adjacent atoms _3-5 Cycloalkyl, and optionally further substituted with one or more deuterium, halogen; more preferably, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form cyclopropyl with adjacent atoms;

R ⁹ ，R ¹⁰ each independently selected from hydrogen, deuterium, halogenAmino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, halogenated C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Deuterated alkylamino, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-12 Aryl or 5-12 membered heteroaryl, and optionally further substituted with one or more deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R ⁹ ，R ¹⁰ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, halogenated C _1-4 Alkyl radical, C _1-4 Alkoxy, halo C _1-4 Alkoxy radical, C _1-4 Alkylamino radical, C _1-4 Deuterated alkylamino, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, and optionally further substituted with one or more of deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; more preferably, R ⁹ ，R ¹⁰ Each independently selected from hydrogen, deuterium, halogen, C _1-4 Alkyl radical, C _1-4 Alkylamino radical, C _1-4 Deuterated alkylamino, 3-6-membered heterocyclyl, and optionally further substituted with one or more deuterium, halogen, C _1-4 Alkyl radical, C _1-4 Deuterated alkyl, halogenated C _1-4 Alkyl radical, C _3-6 Cycloalkyl substitution; more preferably, R ⁹ ，R ¹⁰ Each independently selected from hydrogen, deuterium, methyl,

Still further, in one embodiment of the present invention, R ³ ，R ⁴ Selected from hydrogen, deuterium, fluorine, chlorine, methyl,

R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form C together with adjacent atoms _3-5 Cycloalkyl, and optionally further substituted with one or more deuterium, halogen; r ⁹ ，R ¹⁰ Each independently selected from hydrogen, deuterium, halogen, C _1-4 Alkyl radical, C _1-4 Alkylamino radical, C _1-4 Deuterated alkylamino, 3-6-membered heterocyclyl, and optionally further substituted with one or more deuterium, halogen, C _1-4 Alkyl radical, C _1-4 Deuterated alkyl, halogenated C _1-4 Alkyl radical, C _3-6 Cycloalkyl substitution;

still further, in one embodiment of the present invention, R ³ ，R ⁴ Selected from hydrogen, deuterium, R ⁵ And R ⁶ Each independently forms a cyclopropyl group together with the adjacent atom, R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, R ⁹ ，

R ¹⁰ Each independently selected from hydrogen, deuterium, methyl,

Still further, in one embodiment of the present invention, the general formula (II-1) or (II-2) is further represented by the general formula (II-1A) or (II-2A):

R ³ ，R ⁴ ，R ⁷ ，R ⁸ ，R ⁹ ，R ¹⁰ is defined as in general formula (II-1)) Or (II-2).

Still further, in one embodiment of the present invention,

R ³ ，R ⁴ each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl or

R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, fluoro, chloro or methyl;

R ⁹ ，R ¹⁰ each independently selected from hydrogen, deuterium, methyl, 5-6 membered heterocyclic group containing 1-2 nitrogen atoms or

-CR ^b R ^c NHR ^d ；

R ^b ，R ^c Each independently selected from hydrogen, deuterium, fluoro, chloro or methyl, preferably hydrogen or deuterium;

R ^d is selected from C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Deuterated alkyl or C _3-6 A cycloalkyl group, preferably a methyl group, a trifluoromethyl group, a monofluoroethyl group, a difluoroethyl group, a trideuteromethyl group or a cyclopropyl group.

In one embodiment of the present invention, the compound of formula (I) is further represented by general formula (III):

m is selected from CR ¹⁹ R ²⁰ 、NR ¹⁹ O or S, R ¹⁹ 、R ²⁰ Each independently selected from hydrogen, deuterium, halogen or R ¹⁹ And R ²⁰ Together with adjacent atoms, form a cycloalkyl, heterocyclyl, aryl or heteroaryl group;

R ² selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, the alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl,Alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally further substituted;

R ¹¹ ，R ¹² ，R ¹³ ，R ¹⁴ ，R ¹⁵ ，R ¹⁶ ，R ¹⁷ ，R ¹⁸ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally being further substituted.

Preferably, R ² ，R ³ ，R ⁴ ，R ¹¹ ，R ¹² ，R ¹³ ，R ¹⁴ ，R ¹⁵ ，R ¹⁶ ，R ¹⁷ ，R ¹⁸ ，R ¹⁹ ，R ²⁰ Is not both H and when R is ³ When Cl is present, R ¹⁸ Is not H.

Further, in one embodiment of the present invention, M is selected from CR ¹⁹ R ²⁰ Or O, R ¹⁹ 、R ²⁰ Each independently selected from hydrogen, deuterium, halogen or R ¹⁹ And R ²⁰ Together with adjacent atoms forming C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-12 Aryl or 5-12 membered heteroaryl; preferably, R ¹⁹ 、R ²⁰ Each independently selected from hydrogen, deuterium, fluorine, chlorine or R ¹⁹ And R ²⁰ Together with adjacent atoms forming C _3-6 A cycloalkyl group; more preferably, R ¹⁹ 、R ²⁰ Each is independentSelected from hydrogen, fluorine or R ¹⁹ And R ²⁰ Form cyclopropyl together with adjacent atoms; further preferably, M is selected from CF ₂ O or

Even more preferably, M is O;

R ² selected from hydrogen, deuterium, halogen, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-12 Aryl or 5-12 membered heteroaryl, optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen; preferably, R ² Selected from hydrogen, deuterium, halogen, 3-8 membered heterocyclyl, optionally substituted with one or more deuterium, halogen; more preferably, R ² Selected from the group consisting of hydrogen, deuterium, fluorine,

R ³ ，R ⁴ selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Deuterated alkyl, C substituted by one or more halogens _1-8 Alkyl radical, C _1-8 Alkoxy, C substituted by one or more halogens _1-8 Alkoxy radical, C _1-8 Alkylamino radical, C _1-8 Hydroxyalkyl, and optionally may be further substituted; more preferably, R ³ ，R ⁴ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, C substituted by one or more halogens _1-6 Alkyl radical, C _1-6 Alkoxy, C substituted by one or more halogens _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Hydroxyalkyl, and optionally may be further substituted; more preferably, R ³ ，R ⁴ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, C substituted by one or more halogens _1-4 Alkyl radical, C _1-4 Alkoxy, C substituted by one or more halogens _1-4 Alkoxy radical, C _1-4 Alkylamino radical, C _1-4 Hydroxyalkyl, and optionally further substituted with one or more of deuterium, halogen, C _1-4 Alkyl radical, C _3-8 Cycloalkyl substitution; more preferably, R ³ ，R ⁴ Selected from hydrogen, deuterium, fluorine, chlorine, methyl,

R ¹¹ ，R ¹² ，R ¹³ ，R ¹⁴ ，R ¹⁵ ，R ¹⁶ ，R ¹⁷ ，R ¹⁸ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, halogenated C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Deuterated alkylamino, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-12 Aryl or 5-12 membered heteroaryl, said C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, halogenated C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Deuterated alkylamino, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-12 Aryl or 5-12 membered heteroaryl optionally may be further substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; preferably, R ¹¹ ，R ¹² ，R ¹³ ，R ¹⁴ ，R ¹⁵ ，R ¹⁶ ，R ¹⁷ ，R ¹⁸ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkylHalogen substituted C _1-4 Alkyl radical, C _1-4 Alkoxy, halo C _1-4 Alkoxy radical, C _1-4 Alkylamino radical, C _1-4 Deuterated alkylamino, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl, and optionally may be further substituted by one or more substituents; more preferably, R ¹¹ ，R ¹² ，R ¹³ ，R ¹⁴ ，R ¹⁵ ，R ¹⁶ ，R ¹⁷ ，R ¹⁸ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, methyl, ethyl, methyl substituted with one or more deuterium, ethyl substituted with one or more deuterium, methyl substituted with one or more halogen, ethyl substituted with one or more halogen; more preferably, R ¹¹ ，R ¹² ，R ¹³ ，R ¹⁴ ，R ¹⁵ ，R ¹⁶ ，R ¹⁷ ，R ¹⁸ Each independently selected from hydrogen, deuterium;

further, in one embodiment of the present application, M is O, R ² ，R ³ ，R ⁴ One and only one selected from D, F, cl and the others selected from H, R ¹¹ ，R ¹² ，R ¹³ ，R ¹⁴ ，R ¹⁵ ，R ¹⁶ ，R ¹⁷ ，R ¹⁸ Selected from H, D, and when R is ³ When Cl is present, R ¹⁸ Is not H.

The present invention further provides a compound represented by the general formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein ring A is selected from monocyclic or bicyclic rings, preferably phenyl or a benzo 4-8 membered heterocyclic group, more preferably phenyl or a benzo 5-6 membered heterocyclic group containing 1-2 oxygen atoms, further preferably the following groups:

the following groups are even more preferred:

R ^a selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, halogenated C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 A deuterated alkylamino group; preferably, R ^a Selected from hydrogen or F;

R ²¹ selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally being further substituted; preferably, R ²¹ Is C substituted by one or more substituents _1-6 Alkylamino, the substituent being C _1-6 An alkyl group; more preferably, R ²¹ Is selected from

R ²² ，R ²³ Selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl optionally may be further substituted;

further, in one embodiment of the present application, R ²² ，R ²³ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-8 Alkyl radical、C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Deuterated alkyl, C substituted by one or more halogens _1-8 Alkyl radical, C _1-8 Alkoxy, C substituted by one or more halogens _1-8 Alkoxy radical, C _1-8 Alkylamino radical, C _1-8 Hydroxyalkyl, and optionally may be further substituted; more preferably, R ²² ，R ²³ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, C substituted by one or more halogens _1-6 Alkyl radical, C _1-6 Alkoxy, C substituted by one or more halogens _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Hydroxyalkyl and optionally may be further substituted; more preferably, R ²² ，R ²³ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, C substituted by one or more halogens _1-4 Alkyl radical, C _1-4 Alkoxy, C substituted by one or more halogens _1-4 Alkoxy radical, C _1-4 Alkylamino radical, C _1-4 Hydroxyalkyl, and optionally further substituted with one or more of deuterium, halogen, C _1-4 Alkyl radical, C _3-8 Cycloalkyl substitution; more preferably, R ²² ，R ²³ Selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl.

In one embodiment of the present invention, the compounds represented by formulas (I) to (IV) have the following structures:

the present invention also provides a process for the preparation of a compound of formula (II-1A or (II-2A) comprising the steps of:

reacting the general formula compound (M-1A) or (M-2A) with the general formula compound (M-2) to obtain a general formula compound (II-1A) or (II-2A); wherein R is ₃ 、R ₄ 、R ₇ 、R ₈ 、R ₉ And R ₁₀ The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of each formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients.

The invention also provides a preferable scheme, and relates to application of the compounds with the general formulas and stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition in preparation of TAAR1 receptor agonist drugs.

The invention also relates to application of the compounds with the general formulas and stereoisomers or pharmaceutically acceptable salts thereof or a pharmaceutical composition in preparing medicines for treating, preventing or controlling neurological disorders.

In some embodiments, the neurological disorder is selected from schizophrenia, social dysfunction disorder, or psychosis; the schizophrenia is selected from the group consisting of schizophrenic spectrum disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, paranoid schizophrenia, schizophreniform personality disorder or schizotypal personality disorder; <xnotran> , , , , , , , , , , (Tourette) , NOS , , , , , , , , , (Huntington), , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , lesche-Nyhane , (Wilson ), , . </xnotran>

Detailed description of the invention

Unless stated to the contrary, 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 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 8 carbon atoms, further preferably an alkyl group containing 1 to 6 carbon atoms, most preferably an alkyl group containing 1 to 3 carbon atoms. <xnotran> , , , , , , , , , 3584 zxft 3584- , 4284 zxft 4284- , 5325 zxft 5325- ,1- ,2- ,3- , ,1- -2- , 5623 zxft 5623- , 6262 zxft 6262- , 3256 zxft 3256- , 3456 zxft 3456- , 3838 zxft 3838- ,2- ,2- ,3- ,4- , 5749 zxft 5749- , ,4- ,1- ,2- ,3- ,4- ,5- , 6595 zxft 6595- , 6898 zxft 6898- , 3428 zxft 3428- , 3476 zxft 3476- ,2- ,3- , , 3734 zxft 3734- , 3757 zxft 3757- , 5852 zxft 5852- , 3575 zxft 3575- , 3625 zxft 3625- , 3826 zxft 3826- ,2- ,3- ,4- ,2- -2- ,2- -3- , ,2- -2- ,2- -3- , 3828 zxft 3828- , , 3925 zxft 3925- , </xnotran> 2,2-diethylhexyl, and the various branched isomers thereof, and the like. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.

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, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably an alkenyl group containing 2 to 12 carbon atoms, more preferably an alkenyl group containing 2 to 8 carbon atoms, further preferably an alkenyl group containing 2 to 6 carbon atoms, most preferably an alkenyl group containing 2 to 4 carbon atoms. Such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, or the like. The alkenyl group 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 "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, which is a straight or branched chain group containing 2 to 20 carbon atoms, preferably an alkynyl group containing 2 to 12 carbon atoms, more preferably an alkynyl group containing 2 to 8 carbon atoms, further preferably an alkynyl group containing 2 to 6 carbon atoms, most preferably an alkynyl group containing 2 to 4 carbon atoms. Such as ethynyl, propynyl, 1-butynyl, 2-butynyl or 3-butynyl and the like. Alkynyl 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 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, further preferably 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 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, C (O) or S (O) _m (wherein m is an integer of 0 to 2) but does not include a cyclic moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 6 ring atoms; further preferred is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing fused heterocyclic group.

Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1,4-diazepanyl, pyranyl, tetrahydrothiopyranyl dioxide, and the like; preferably oxetanyl, azetidinyl, thietanyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, tetrahydrothiopyranyl dioxide, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrazinyl, hexahydropyrimidinyl, azepinyl, 1,4-diazepanyl and piperazinyl,

Preferably piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, azetidinyl

Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or by any two or more of the ringsTwo or more atoms are further connected in parallel with other cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused on a heteroaryl, heterocyclic or cycloalkyl ring and comprises benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms and sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.

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

and the like.

The aryl group may be 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, carboxy or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, more preferably 8-12 membered fused bicyclic heteroaryl, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably pyridyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl or thiazolyl; more preferred are tetrazolyl, pyridyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl.

Non-limiting examples of the fused bicyclic heteroaryl include:

the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

and the like.

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, hydroxyl, 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, cyclopentyloxy, cyclohexyloxy, alkoxy 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, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples of the haloalkyl group include: trifluoromethyl, -CH ₂ CF ₃ 、

"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.

"deuterated alkyl" refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above. Non-limiting examples of such deuterated alkyls include: -CD ₃ ，-CD ₂ H，-CDH ₂ 。

"alkylamino" refers to an amino group wherein one or both of the two hydrogens of the amino group is replaced with an alkyl group, wherein alkyl is as defined above.

"deuterated alkylamino" refers to an amino group wherein one or both of the two hydrogens on the amino group is replaced with an alkyl group, wherein deuterated alkyl is as defined above.

"hydroxy" refers to an-OH group.

"halogen" means fluorine, chlorine, bromine or iodine.

"amino" means-NH ₂ 。

"cyano" means-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 "means diethyl ether.

"DCM" refers to dichloromethane.

"DIPEA" refers to N, N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodosuccinimide.

“Pd ₂ (dba) ₃ "refers to tris (dibenzylideneacetone) dipalladium.

"n-BuLi" refers to n-butyllithium.

“NaBH(OAc) ₃ "refers to sodium triacetoxyborohydride.

Different terms such as "X is A, B, or C", "X is A, B and C", "X is A, B or C", "X is A, B and C" all express the same meaning, i.e. X can be any one or more of A, B, C.

All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compounds of the examples related to the present invention can also be replaced by a deuterium atom.

"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" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in a mammalian body and which possess the requisite biological activity.

"stereoisomers" encompasses all enantiomerically/diastereomerically/stereoisomerically pure and enantiomerically/diastereomerically/stereoisomerically enriched compounds of the invention.

In describing optically active compounds, the prefixes R and S are used to denote the absolute configuration of the molecule relative to its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction of the plane of polarized light rotated by the optically active compound. The prefix (-) indicates that the compound is left-handed, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The prefix (+) indicates that the compound is right-handed, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) of the optical rotations are independent of the absolute configurations of the molecules, R and S.

Detailed Description

The present invention is further described with reference to the following examples, which should not be construed as limiting the scope of the invention.

Example 1

1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl-5,5-d 2) -N-methylmethanamine

The first step is as follows: preparation of 2- (thien-3-yl) ethane-1,1-d 2-1-ol

Under the protection of nitrogen, deuterated lithium aluminum hydride (500mg, 11.9 mmol) is suspended in anhydrous tetrahydrofuran (80 mL), and a solution of 3-thiopheneacetic acid (1.00g, 7.03mmol) in anhydrous tetrahydrofuran (20 mL) is added dropwise in a water bath. After the completion of the dropwise addition, the reaction solution was refluxed for 2 hours. Cooled to room temperature, added in portions with sodium sulfate decahydrate (10 g), stirred at room temperature for 2 hours, filtered, the solid washed with tetrahydrofuran (5 mL. Times.3), the filtrates combined, concentrated under reduced pressure to give 2- (thiophen-3-yl) ethyl-1,1-d 2-1-ol (0.72 g, yield: 79%) as a pale yellow oil.

MS m/z(ESI):131.0[M+H] ⁺ 。

The second step is that: preparation of 1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl-5,5-d 2) -N-methyl methylamine

2- (thien-3-yl) ethan-1,1-d 2-1-ol (0.72g, 5.53mmol), N-methylaminoacetaldehyde dimethyl acetal (0.66g, 5.54mmol) were dissolved in anhydrous 2-methyltetrahydrofuran (10 mL), and trifluoromethanesulfonic acid (1 mL) was added under stirring at room temperature, followed by reflux reaction for 2 hours. Most of the solvent was distilled off under normal pressure, and the residue was supplemented with anhydrous 2-methyltetrahydrofuran (10 mL), refluxed for 1 hour, concentrated under reduced pressure, dissolved in water (20 mL) and washed with dichloromethane (10 mL. Times.3). The aqueous phase was adjusted to pH >11 with 2M sodium hydroxide, extracted with dichloromethane (20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol =100, elution from 0 to 93) to give 1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl-5,5-d 2) -N-methyl methylamine (0.43 g, yield: 42%) as a brown oil.

MS m/z(ESI):186.2[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.18(d,J＝2.8Hz,1H),6.83(d,J＝2.8Hz,1H),4.92(br,1H),2.80-2.98(m,3H),2.61(m,1H),2.52(s,3H)。

Example 2

1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl-4,4-d 2) -N-methylmethanamine

The first step is as follows: 2-hydroxy-1- (thien-3-yl) ethan-1-one

2-bromo-1- (thien-3-yl) ethan-1-one (2.05g, 10mmol) was dissolved in methanol (20 mL) and water (5 mL) at room temperature, followed by addition of sodium formate (2.04g, 30mmol), heating under reflux overnight, and cooling to room temperature. TLC indicated the reaction was complete, methanol was removed by rotary evaporation, the residue was diluted with ethyl acetate (40 mL) and washed with saturated brine (10 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, rotary dried, and the crude product was used directly in the next reaction (0.85 g, colorless oil, yield: 60%).

The second step is that: 2- (Thien-3-yl) ethane-2,2-d 2-1-ol

2-hydroxy-1- (thiophene-3-yl) ethane-1-ketone is taken as a raw material, and 2- (thiophene-3-yl) ethane-2,2-d 2-1-alcohol is obtained by referring to the first step of the embodiment.

The third step: 1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl-4,4-d 2) -N-methylmethanamine

Starting from 2- (thien-3-yl) ethane-2,2-d 2-1-ol, reference example one second step yielded 1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl-4,4-d 2) -N-methylmethanamine.

MS m/z(ESI):186.1[M] ⁺ .

Example 3

1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethane-d 2-amine

The first step is as follows: preparation of 4,7-dihydro-5H-thieno [2,3-c ] pyran-7-carboxylic acid

2- (thien-3-yl) ethan-1-ol (6.40g, 50mmol) and glyoxylic acid monohydrate (5.06g, 55mmol) were dissolved in trifluoroacetic acid (25 mL) and reacted at 120 ℃ for 24 hours with tube sealing. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was taken up in water (80 mL), adjusted to a pH >11 with 2M sodium hydroxide and washed with methyl tert-butyl ether (30 mL. Times.3). The aqueous phase was adjusted to pH 2-3 with 6M hydrochloric acid, extracted with ethyl acetate (30 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4,7-dihydro-5H-thieno [2,3-c ] pyran-7-carboxylic acid (7.12 g, yield: 77%) as a yellow solid.

MS m/z(ESI):183.1[M-H] ^- 。

The second step is that: preparation of N-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-carboxamide

4,7-dihydro-5H-thieno [2,3-c ] pyran-7-carboxylic acid (1.00g, 5.43mmol), methylamine hydrochloride (0.44g, 6.52mmol), N-methylmorpholine (1.10g, 10.87mmol) and 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (1.35g, 7.06mmol) were added in this order to dichloromethane (50 mL) under nitrogen protection, and stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol =100:0 to 92, elution) to give N-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-carboxamide (0.89 g, yield: 83%) as a yellow solid.

MS m/z(ESI):198.0[M+H] ⁺ 。

The third step: preparation of 1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethane-d 2-amine

Under the protection of nitrogen, deuterated lithium aluminum tetrahydroxide (336mg, 8.00mmol) is suspended in anhydrous tetrahydrofuran (50 mL), and a solution of N-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-carboxamide (789mg, 4.00mmol) in anhydrous tetrahydrofuran (10 mL) is added dropwise in a water bath. After the completion of the dropwise addition, the reaction mixture was refluxed for 4 hours. Cooled to room temperature, sodium sulfate decahydrate (8 g) was added in portions, stirred at room temperature for 1 hour, filtered, the solid was washed with tetrahydrofuran (10 mL × 2), the filtrates were combined and concentrated under reduced pressure to give 1- (4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethane-d 2-amine (542 mg, yield: 73%) as a yellow oil.

MS m/z(ESI):186.3[M+H] ⁺ 。

¹ H NMR(400MHz,CDCl ₃ )δ7.18(d,J＝2.8Hz,1H),6.82(d,J＝2.8Hz,1H),4.93(br,1H),4.20(m,1H),3.78(t,J＝7.8Hz,1H),2.88(m,1H),2.60(m,1H),2.51(s,3H)。

Example 4

1- (4,4-difluoro-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethanamine

The first step is as follows: preparation of 2-bromo-3-iodothiophene

3-iodothiophene (22g, 104.7 mmol) was dissolved in N, N' -dimethylformamide (300 mL) to replace nitrogen, 1-bromopyrrolidine-2,5-dione (19.6 g, 110.0mmol) was added at 0 ℃ and the reaction was stirred at 30 ℃ for 18 hours. Then heated to 50 ℃ and stirred for 2 hours. To the reaction solution was added 500mL of water, followed by extraction with petroleum ether (200 mL. Times.2), and the organic phases were combined, washed with a saturated sodium chloride solution (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography to give the title product, 2-bromo-3-iodothiophene (30 g, yield 99.1%).

1H NMR(400MHz,CDCl3)δ7.23(d,J＝4.0Hz,1H),6.95(d,J＝8.0Hz,1H).

The second step: preparation of ethyl 2- (2-bromothien-3-yl) -2,2-difluoroacetate

Copper powder (2.20g, 34.61mmol) was added to dimethyl sulfoxide (50 mL) to replace nitrogen, and 2-bromo-3-iodothiophene (5g, 17.3mmol) was further added, followed by stirring at room temperature for one hour. Additional ethyl 2-bromo-2,2-difluoroacetate (10.5g, 51.9mmol) was added and the reaction stirred at room temperature for 18 hours. Water (300 mL) was added, followed by petroleum ether (300 mL) and stirring for half an hour, filtration, separation of the organic phase, washing of the organic phase with saturated brine (300 mL), drying over anhydrous sodium sulfate, filtration, concentration of the filtrate under reduced pressure, and column chromatography of the crude product on silica gel afforded the title product, ethyl 2- (2-bromothien-3-yl) -2,2-difluoroacetate (2.6 g, 52.7% yield).

1H NMR(400MHz,CDCl3)δ7.31(d,J＝4.0Hz,1H),7.11(d,J＝8.0Hz,1H),4.36(q,J＝8.0Hz,2H),1.34(t,J＝8.0Hz,3H).

The third step: preparation of 2- (2-bromo-3-thiophene) -2,2-difluoroethanol

Ethyl 2- (2-bromothien-3-yl) -2,2-difluoroacetate (2.6g, 9.1mmol) was dissolved in methanol (40 mL), cooled to 0 deg.C, sodium borohydride (759.0mg, 20.0mmol) was added, and the reaction was stirred at 0 deg.C for 1 hour. Water (30 mL) was added, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was chromatographed on a silica gel column to give the title product 2- (2-bromo-3-thiophene) -2,2-difluoroethanol (2.2 g, 99.3% yield).

The fourth step: preparation of [2- (3-bromo-2-thiophene) -2,2-difluoroethoxy ] -tert-butyldimethylsilane

2- (2-bromo-3-thiophene) -2,2-difluoroethanol (2.2g, 9.1mmol) was dissolved in dichloromethane (30 mL), imidazole (1.23g, 18.1mmol) and tert-butylchlorodimethylsilane (2.0g, 13.6 mmol) were added, and the reaction was stirred at room temperature for 18 hours. Water (20 mL) was added, the aqueous phase was extracted with dichloromethane (20 mL. Times.2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, spun-dried, the filtrate was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel to give the title product [2- (3-bromo-2-thiophene) -2,2-difluoroethoxy ] -tert-butyldimethylsilane (3 g, 92.8% yield).

1H NMR(400MHz,CDCl3)δ7.23(d,J＝4.0Hz,1H),7.01(d,J＝4.0Hz,1H),4.44-4.02(m,2H),0.82(s,9H),0.00(s,6H).

The fifth step: preparation of tert-butyl N- [2- [2- [2- [ tert-butyl (dimethyl) silyl ] oxy-1,1-difluoroethyl ] -3-thienyl ] -2-hydroxyethyl ] -N-methylcarbamate

[2- (3-bromo-2-thiophene) -2,2-difluoroethoxy ] -tert-butyldimethylsilane (1.0g, 2.8mmol) was dissolved in tetrahydrofuran (20 mL), nitrogen was replaced, cooling was performed to-70 ℃ and n-butyllithium (2.5M, 1.2mL, 4.3mmol) was slowly added dropwise, and the reaction was stirred at this temperature for one hour. A solution of tert-butyl N-methyl-N- (2-oxyethyl) carbamate (727mg, 4.2mmol) in tetrahydrofuran (5 mL) was added, the reaction was stirred at this temperature for one hour, and then slowly warmed to room temperature and stirred for 1 hour. Water (50 mL) was added, the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was chromatographed on a silica gel column to give the title product tert-butyl N- [2- [2- [2- [ tert-butyl (dimethyl) silyl ] oxy-1,1-difluoroethyl ] -3-thienyl ] -2-hydroxyethyl ] -N-methylcarbamate (800 mg, yield: 63%).

And a sixth step: preparation of tert-butyl N- [2- [2- (1,1-difluoro-2-hydroxyethyl) -3-thienyl ] -2-hydroxyethyl ] -N-methylcarbamate

Tert-butyl N- [2- [2- [2- [ tert-butyl (dimethyl) silyl ] oxy-1,1-difluoroethyl ] -3-thienyl ] -2-hydroxyethyl ] -N-methylcarbamate (0.7g, 1.6 mmol) was dissolved in tetrahydrofuran (10 mL), tetrabutylammonium fluoride (1M, 3.2mL,3.2 mmol) was added and the reaction stirred at 10 ℃ for 2 hours. Water (50 mL) was added, the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was chromatographed on a silica gel column to give the title product tert-butyl N- [2- [2- (1,1-difluoro-2-hydroxyethyl) -3-thienyl ] -2-hydroxyethyl ] -N-methylcarbamate (0.5 g, yield: 95.6%).

The seventh step: preparation of tert-butyl N- [ (4,4-difluoro-5,7-dihydrothiophene [2,3-c ] pyran-7-yl) methyl ] -N-methylcarbamate

Tert-butyl N- [2- [2- (1,1-difluoro-2-hydroxyethyl) -3-thienyl ] -2-hydroxyethyl ] -N-methylcarbamate (0.5 g,1.5 mmol) was dissolved in ethyl acetate (30 mL), N, N-diethylethylamine (599.9 mg,5.9 mmol) was added, cooled to 0 deg.C, a solution of methanesulfonyl chloride (203.7 mg, 1.8mmol) in ethyl acetate (10 mL) was slowly added, and the reaction stirred at this temperature for 2 hours. Water (30 mL) was added, the aqueous phase was extracted with ethyl acetate (20 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spun dry to give the crude product. THF (20 mL) was added to the crude product, cooled to 0 deg.C, and potassium tert-butoxide (323.5 mg,2.9 mmol) was added and the reaction stirred at 0 deg.C for 3 hours. Water (50 mL) was added, the aqueous phase was extracted with ethyl acetate (30 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was chromatographed on a silica gel column to give the title product tert-butyl N- [ (4,4-difluoro-5,7-dihydrothiophene [2,3-c ] pyran-7-yl) methyl ] -N-methylcarbamate (120 mg, yield: 26.0%).

Eighth step: preparation of 1- (4,4-difluoro-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methyl-methylamine

Tert-butyl N- [ (4,4-difluoro-5,7-dihydrothiophene [2,3-c ] pyran-7-yl) methyl ] -N-methylcarbamate (120mg, 0.38mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (3 mL) was slowly added dropwise, and the reaction was stirred at room temperature for 2 hours. The solvent was dried by spinning, a saturated sodium carbonate solution (30 mL) was added, the aqueous phase was extracted with ethyl acetate (20 mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by silica gel column chromatography to give the title product 1- (4,4-difluoro-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methyl-methylamine (60 mg, yield: 75.0%).

MS m/z(ESI):220.1[M+H]+.

The compound was resolved again on a chiral column (column: CHIRALCEL OJ-H4.6 x 150mm,5 μm; detection wavelength (nm): 214; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH: DEA = 70; run length (min): 8; linear mode: isocratic) to give compound 4-1 (16.5mg, rt (retention time) =2.667 min), compound 4-2 (15.5mg, rt (retention time) =3.193 min).

Compound 4-1 (hydrochloride salt): 1H NMR (400MHz, DMSO). Delta.9.51 (brs, 1H), 9.07 (brs, 1H), 7.76 (d, J =4.0Hz, 1H), 7.35 (d, J =4.0Hz, 1H), 5.42-5.40 (m, 1H), 4.43-4.37 (m, 1H), 4.17-4.08 (m, 1H), 3.53-3.49 (m, 1H), 3.35-3.32 (m, 1H), 2.61 (s, 3H).

MS:220.1[M+H]+.

Compound 4-2 (hydrochloride salt): 1H NMR (400MHz, DMSO). Delta.9.50 (brs, 1H), 9.06 (brs, 1H), 7.76 (d, J =4.0Hz, 1H), 7.35 (d, J =4.0Hz, 1H), 5.42-5.40 (m, 1H), 4.43-4.37 (m, 1H), 4.17-4.08 (m, 1H), 3.53-3.49 (m, 1H), 3.35-3.32 (m, 1H), 2.61 (s, 3H).

MS:220.1[M+H]+

Example 5

N-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methylamine

The first step is as follows: methyl 2- (thien-3-yl) propionate

Methyl 2- (thien-3-yl) acetate (1.0 g,6.4 mmol) was dissolved in N, N-dimethylformamide (15 mL) under ice-bath, then sodium hydrogen (1.02g, 60%,25.6 mmol) was added in portions, stirred for 30 minutes under ice-bath, then methyl iodide (9.1g, 64mmol) was added, and stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (60 mL), followed by quenching with a saturated ammonium chloride solution, liquid separation, and the organic phase was then washed with a saturated brine (10 mL × 5), dried over anhydrous sodium sulfate, filtered, and spin-dried, and the crude product was separated by flash column chromatography (petroleum ether: ethyl acetate = 9:1) to give methyl 2- (thiophen-3-yl) propionate (0.32 g, yellow oil, yield: 29%).

The second step is that: 2- (thien-3-yl) propan-1-ol

Methyl 2- (thiophen-3-yl) propionate (0.32g, 1.88mmol) was dissolved in dichloromethane (5 mL) under ice bath to replace nitrogen, and diisobutylaluminum hydride (1.0M/n-hexane solution, 4.7mL,4.7 mmol) was added and reacted at room temperature for five hours, TLC indicated the end of the reaction. The reaction was quenched with saturated ammonium chloride solution and then extracted with dichloromethane (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by preparative thin layer chromatography (petroleum ether: ethyl acetate = 5:1) to give 2- (thien-3-yl) propan-1-ol (0.20 g, colorless oil, yield 75%).

The third step: n-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methylamine

2- (Thien-3-yl) propan-1-ol (50mg, 0.35mmol) was dissolved in 1,4-dioxane (3 mL) at room temperature, then 2,2-dimethoxy-N-methyl-ethylamine (62.84mg, 0.53mmol) was added, stirred at room temperature for 10min, then trifluoromethanesulfonic acid (158.29mg, 1.05mmol) was added dropwise and stirred at room temperature overnight. LCMS indicated the reaction was complete, the reaction was neutralized with aqueous sodium hydroxide (2N), adjusted to PH 9-10, then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun dry, and the crude product was separated by preparative chromatography. Lyophilization afforded the product, (20 mg, white solid).

MS m/z(ESI):198.1[M+H] ⁺ .

Example 6

(S) -N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) cyclopropylamine and (R) -N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) cyclopropylamine

The first step is as follows: n- (2,2-dimethoxyethyl) cyclopropylamine

Cyclopropylamine (0.57g, 10mmol) was dissolved in N, N-dimethylformamide (10 mL) at room temperature, and then potassium carbonate (4.14g, 30mmol) and 2-bromo-1,1-dimethoxyethane (1.77g, 10.5mmol) were added, heated to 80 ℃ for three hours, LCMS indicated that the reaction was completed, cooled to room temperature, the reaction solution was diluted with ethyl acetate (30 mL) and then washed with saturated brine (10 mL. Times.3), the organic phase was dried with anhydrous sodium sulfate, filtered, and dried by spin-drying, and the crude product was directly used in the next reaction (1.31 g, colorless oil, yield: 90%).

MS m/z(ESI):146.1[M+H] ⁺ .

The second step is that: n- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) cyclopropylamine

2- (thien-3-yl) ethan-1-ol (100mg, 0.78mmol) was dissolved in 1'4-dioxane (5 mL) at room temperature, then N- (2,2-dimethoxyethyl) cyclopropylamine (170mg, 1.17mmol) was added, stirred for 10min at room temperature, then trifluoromethanesulfonic acid (351mg, 2.34mmol) was added dropwise and stirred overnight at room temperature. LCMS indicated the reaction was complete, the reaction was neutralized with aqueous sodium hydroxide (2N), pH adjusted to 9-10, then extracted with ethyl acetate, the organic phases combined, dried over anhydrous sodium sulfate, filtered, spun dried and the crude product separated by preparative chromatography. The solution was decanted from acetonitrile and lyophilized to give the product (52 mg, white solid).

MS m/z(ESI):210.1[M+H] ⁺ .

The third step: (S) -N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) cyclopropylamine and (R) -N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) cyclopropylamine

Chiral resolution of N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) cyclopropylamine gives (S) -N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) cyclopropylamine and (R) -N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) cyclopropylamine

MS m/z(ESI):210.1[M+H] ⁺ .

Example 7

N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) -2-fluoroethane-1-amine

The first step is as follows: n- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) -2-fluoroethane-1-amine

N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) -2-fluoroethane-1-amine was obtained by reference example 6 using 2-fluoroethane-1-amine as a raw material.

MS m/z(ESI):216.1[M+H] ⁺ .

Example 8

N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) -2,2-difluoroethan-1-amine

The first step is as follows: n- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) -2,2-difluoroethan-1-amine

Starting from 2,2-difluoroethan-1-amine, N- ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl) -2,2-difluoroethan-1-amine was obtained in reference example 6.

MS m/z(ESI):234.1[M+H] ⁺ .

Example 9

1- (4-fluoro-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethanamine

The first step is as follows: 1- (4-fluoro-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethanamine

1- (4-fluoro-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethanamine was obtained in reference example 4 using 2-bromo-2-fluoroethane-1-ol as a starting material.

MS m/z(ESI):202.1[M+H] ⁺ .

Example 10

1- (3-cyclopropyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethanamine

The first step is as follows: 2- (4-Cyclopropylthiophen-3-yl) ethan-1-ol

2- (4-Bromophthen-3-yl) ethan-1-ol (2.07g, 10mmol), cyclopropylboronic acid (1.29g, 15mmol), sodium carbonate (2.12g, 20mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.73g, 1mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL) at room temperature, nitrogen was replaced, heating was carried out to 100 ℃ for 14 hours, cooling was carried out to room temperature, diatomaceous earth was filtered, diatomaceous earth was washed with ethyl acetate, the reaction solution was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by Flash column chromatography to give 2- (4-cyclopropylthiophen-3-yl) ethan-1-ol (0.84 g, yield: 50%).

The second step is that: 1- (3-cyclopropyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethanamine

1- (3-cyclopropyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) -N-methylmethanamine was obtained in reference example 4 using 2- (4-cyclopropylthiophen-3-yl) ethan-1-ol as a starting material.

MS m/z(ESI):224.1[M+H] ⁺ .

Example 11

N-methyl-1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methylamine

The first step is as follows: preparation of 1- (thien-3-yl) cyclopropane-1-carbonitrile

2- (Thien-3-yl) acetonitrile (5g, 40.6 mmol) and 1-bromo-2-chloroethane (6.4g, 44.7 mmol) were dissolved in dimethyl sulfoxide (30 mL), added slowly dropwise to a strongly stirred solution of sodium hydrogen (6.49g, 162.4 mmol) in DMSO (50 mL), and the reaction was stirred at room temperature overnight. Water (100 mL) was added, extracted with ethyl acetate (50mL × 2), washed with brine (50mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate =100/1 to 5/1) to give 1- (thien-3-yl) cyclopropane-1-carbonitrile (2.5 g, yield: 41%) as a white solid.

1H NMR(400MHz,CDCl3-d)δ7.32–7.30(m,1H)，7.19–7.17(m,1H)，6.91–6.89(m,1H)，1.70–1.67(m,2H),1.37–1.34(m,2H).

The second step is that: preparation of 1- (thien-3-yl) cyclopropane-1-carboxylic acid

1- (Thien-3-yl) cyclopropane-1-carbonitrile (2g, 13.4 mmol) was added to 4M aqueous lithium hydroxide (30 mL) and the reaction was stirred at 100 ℃ overnight. Water (30 mL) was added, the pH of the solution was adjusted to 4 with 2M hydrochloric acid, a white solid precipitated, filtered, and the solid was dried by suction to give the compound 1- (thien-3-yl) cyclopropane-1-carboxylic acid (1.8 g, yield: 80%) as a white solid.

1H NMR(400MHz,CDCl3-d)δ7.25–7.24(m,1H)，7.16–7.15(m,1H)，7.09–7.08(m,1H)，1.67–1.65(m,2H),1.28–1.25(m,2H).

The third step: preparation of (1- (thien-3-yl) cyclopropyl) methanol

1- (thien-3-yl) cyclopropane-1-carboxylic acid (0.8g, 4.8mmol) was dissolved in tetrahydrofuran (20 mL), lithium aluminum hydride (234mg, 6.2mmol) was added at 0 ℃ and the mixture was stirred at room temperature for half an hour. The reaction was quenched by addition of saturated brine (30 mL), the aqueous phase was extracted with EA (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1- (thien-3-yl) cyclopropyl) methanol (200 mg, yield: 27%) as a colorless liquid.

1H NMR(400MHz,CDCl3-d)δ7.20–7.18(m,1H)，7.05–7.04(m,1H)，6.92–6.91(m,1H)，3.63(s,2H)，2.31(brs,1H)，0.84-0.77(m,4H).

The fourth step: preparation of N-methyl-1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methylamine

Starting from (1- (thien-3-yl) cyclopropyl) methanol, the second step of reference example 1 gave N-methyl-1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methylamine.

MS m/z(ESI):210.1[M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ7.41–7.40(m,1H)，6.67–6.65(m,1H)，5.14–5.11(m,1H)，3.85–3.82(m,1H)，3.62–3.59(m,1H)，3.24–3.13(m,2H)，2.55(s,3H),1.05–0.80(m,4H).

The fifth step: preparation of S-N-methyl-1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methylamine and R-N-methyl-1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methylamine

The compound was resolved again using a chiral column (column: CHIRALPAK OJ-H4.6 x 150mm,5 μm; detection wavelength (nm): 214; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH: DEA =85: 0.1%; run length (min): 12; linear mode: isocratic) to give compound 11-1 (30mg, rt (retention time) =2.840 min), compound 11-2 (30mg, rt (retention time) =3.613 min).

Example 12

N- ((5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methyl) methane-d 3-amine

The first step is as follows: preparation of 2,2-dimethoxy-N- (methyl-d 3) ethan-1-amine

An aqueous solution of 2,2-dimethoxyacetaldehyde (5g, 48mmol) and a solution of methane-d 3-amine (1.6g, 48mmol) in tetrahydrofuran were mixed, added to methanol (50 mL), and the reaction was stirred at room temperature overnight. Sodium borohydride (1.8g, 48mmol) was added and the reaction stirred at room temperature for 2 hours. Water (100 mL) was added, extracted with ethyl acetate (50mL x 2), washed with brine (50mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2,2-dimethoxy-N- (methyl-d 3) ethan-1-amine (5.9 g, yield: 100 percent crude, purity 50%) as a colorless liquid.

The second step is that: preparation of N- ((5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methyl) methane-d 3-amine

Starting from [1- (3-thienyl) cyclopropyl ] methanol, reference example 1, the second step yielded N- ((5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methyl) methane-d 3-amine.

Compound (hydrochloride salt): 1H NMR (400MHz, DMSO). Delta.8.65 (brs, 1H), 7.42 (d, J =8.0Hz, 1H), 6.68 (d, J =4.0Hz, 1H), 5.22-5.20 (m, 1H), 3.84-3.80 (m, 1H), 3.66-3.63 (m, 1H), 3.30-3.19 (m, 2H), 1.30-1.23 (m, 2H), 0.94-0.84 (m, 2H).

MS m/z(ESI):213.1[M+H]+.

Example 13

1- (2 ' -chloro-5 ' H,7' H-spiro [ cyclopropane-1,4 ' -thieno [2,3-c ] pyran ] -7' -yl) -N-methyl methylamine

The first step is as follows: preparation of 1- (2 ' -chloro-5 ' H,7' H-spiro [ cyclopropane-1,4 ' -thieno [2,3-c ] pyran ] -7' -yl) -N-methylmethanamine

N-methyl-1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methylamine (200mg, 1mmol) was dissolved in acetonitrile (10 mL), N-chloro-succinimide (160mg, 1.2mmol) was added, and the reaction was stirred at 70 ℃ for 2 hours. Water (30 mL) was added, extracted with ethyl acetate (20mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by high performance liquid chromatography to give 1- (2 ' -chloro-5 ' H,7' H-spiro [ cyclopropane-1,4 ' -thieno [2,3-c ] pyran ] -7' -yl) -N-methylmethanamine (50 mg) as a white solid.

MS m/z(ESI):244.1[M+H] ⁺ .

Example 14

N-methyl-1- (4 'H,6' H-spiro [ cyclopropane-1,7 '-thieno [3,2-c ] pyran ] -4' -yl) methylamine

The first step is as follows: 1- (2-thienyl) cyclopropanecarbonitrile

A solution of 2-thiopheneacetonitrile (5 g, 40.59mmol) and 1-bromo-2-chloroethane (6.4 g, 44.63mmol) in dimethyl sulfoxide (80 mL) was added dropwise to a suspension of dimethyl sulfoxide (80 mL) containing sodium hydrogen (6.49g, 162.37mmol,60% weight percent purity) while cooling on ice. After the addition was completed, the reaction was carried out at room temperature for 16 hours. The reaction was quenched by addition of ammonium chloride solution, 500mL of water was added, and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was then purified by column chromatography (petroleum ether: ethyl acetate =10: 1-5:1) to give the product 1- (2-thienyl) cyclopropanecarbonitrile (3g, 20.11mmol, yield: 49.53%).

¹ H NMR(400MHz,Chloroform-d)δ7.19(d,J＝5.1Hz,1H),7.07(d,J＝3.3Hz,1H),6.94(t,J＝4.4Hz,1H),1.79–1.71(m,2H),1.47–1.40(m,2H).

The second step is that: 1- (2-thienyl) cyclopropanecarboxylic acid

1- (2-thienyl) Cyclopropanecarbonitrile (1g, 6.70mmol) was reacted with an aqueous solution of lithium hydroxide (10mL, 960mg,40.08mmol, 4M) at 100 ℃ for 16 hours. The pH was adjusted to 3-4 with dilute hydrochloric acid, ethyl acetate was added thereto for extraction, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1- (2-thienyl) cyclopropanecarboxylic acid (720 mg,4.28mmol, yield: 63.87%).

ESI:169.1[M+H] ⁺

The third step: [1- (2-thienyl) cyclopropyl ] methanol

1- (2-thienyl) cyclopropanecarboxylic acid (720mg, 4.28mmol) was dissolved in tetrahydrofuran (20 mL), and a borane-tetrahydrofuran solution (1M, 6.42mL) was added dropwise thereto while cooling on ice. After 3 hours at room temperature, the reaction was quenched with methanol in an ice bath. Concentration under reduced pressure gave a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to give [1- (2-thienyl) cyclopropyl ] methanol (650 mg,4.21mmol, yield: 98.46%).

The fourth step: n-methyl-1-spiro [4,6-dihydrothieno [3,2-c ] pyran-7,1' -cyclopropane ] -4-yl-methylamine

Reacting [1- (2-thioalkenyl) cyclopropyl]Methanol (30g, 194.5 mmol) and 2,2-dimethoxy-N-methylethylamine (11.59g, 97.26mmol) were dissolved in 1,4-dioxane (160 mL), 1,4-dioxane (40 mL) dissolved with trifluoromethanesulfonic acid (40 mL) was added dropwise while cooling on ice, and the reaction was carried out at room temperature for 16 hours. The reaction mixture was made alkaline by adding 4M sodium hydroxide solution, and extracted with dichloromethane (50 mL. Times.3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (DCM: meOH (+ 10% ₃ .H ₂ O) = 8:1) to obtain a brown product N-methyl-1-spiro [4,6-dihydrothieno [3,2-c)]Pyran-7,1' -cyclopropane]-4-yl-methylamine (20g, 95.55mmol, yield: 49.12%).

MS:210.0[M+1] ⁺ .

The compound was resolved on a chiral column (column: CHIRALPAK OJ-H4.6 x 250mm,5 μm; detection wavelength (nm): 254; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: IPA: DEA = 70; run length (min): 12; linear mode: isocratic) to give compound P14-1 (7.65g, rt (retention time) =2.520 min), compound P14-2 (7.40g, rt (retention time) =2.837 min).

¹ H NMR(400MHz,DMSO-d ₆ )δ9.14(s,1H),8.76(s,1H),7.34–7.30(m,1H),6.96–6.92(m,1H),5.18–5.06(m,1H),3.86–3.79(m,1H),3.73–3.67(m,1H),3.59–3.50(m,1H),3.24–3.13(m,1H),2.60(s,3H),1.11–1.00(m,2H),0.92–0.81(m,2H).

MS:210.0[M+1] ⁺ .

Example 15

N-methyl-1- (2 ' -methyl-4 ' H,6' H-spiro [ cyclopropane-1,7 ' -thieno [3,2-c ] pyran ] -4' -yl) methylamine

The first step is as follows: preparation of tert-butyl ((4 'H,6' H-spiro [ cyclopropane-1,7 '-thieno [3,2-c ] pyran ] -4' -yl) methyl) (methyl) carbamate

N-methyl-1- (4 'H,6' H-spiro [ cyclopropane-1,7 '-thieno [3,2-c ] pyran ] -4' -yl) methylamine (100mg, 0.5 mmol) was dissolved in dichloromethane (10 mL), triethylamine (150mg, 1.5 mmol) and di-tert-butyl dicarbonate (130mg, 0.6 mmol) were added, and the reaction was stirred at room temperature overnight. Water (30 mL) was added, extraction was performed with ethyl acetate (20mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography to give tert-butyl ((4 'H,6' H-spiro [ cyclopropane-1,7 '-thieno [3,2-c ] pyran ] -4' -yl) methyl) (methyl) carbamate (130 mg, yield: 88%) as a colorless gum.

MS m/z(ESI):310.1[M+H] ⁺ .

The second step is that: preparation of tert-butylmethyl ((2 ' -methyl-4 ' H,6 ') H-spiro [ cyclopropane-1,7 ' -thieno [3,2-c ] pyran ] -4' -yl) methyl) carbamate

Tert-butyl ((4 'H,6' H-spiro [ cyclopropane-1,7 '-thieno [3,2-c ] pyran ] -4' -yl) methyl) (methyl) carbamate (120mg, 0.4 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to-70 deg.C, n-butyllithium (0.25mL, 0.5 mmol) was added, the reaction was stirred at this temperature for 1 hour, iodomethane (70mg, 0.5 mmol) was added, and the reaction was stirred at this temperature for 3 hours. Water (30 mL) was added, extracted with ethyl acetate (20mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated by column chromatography to give tert-butylmethyl ((2 ' -methyl-4 ' H,6' H-spiro [ cyclopropane-1,7 ' -thieno [3,2-c ] pyran ] -4' -yl) methyl) carbamate (40 mg, yield: 33%) as a colorless gum.

MS m/z(ESI):324.1[M+H] ⁺ .

The third step: preparation of N-methyl-1- (2 ' -methyl-4 ' H,6' H-spiro [ cyclopropane-1,7 ' -thieno [3,2-c ] pyran ] -4' -yl) methylamine

Tert-butylmethyl ((2 '-methyl-4' H,6 ') H-spiro [ cyclopropane-1,7' -thieno [3,2-c ] pyran ] -4 '-yl) methyl) carbamate (40mg, 0.12mmol) was dissolved in dioxane (5 mL), hydrochloric acid/dioxane (2 mL) was added, the reaction was stirred at room temperature for 1 hour, the solvent was dried by spinning, and the crude product was separated by high performance liquid chromatography to give N-methyl-1- (2' -methyl-4 'H,6' H-spiro [ cyclopropane-1,7 '-thieno [3,2-c ] pyran ] -4' -yl) methylamine (15 mg) as a white solid.

MS m/z(ESI):224.1[M+H] ⁺ .

Example 16

1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) ethane-1-amine

The first step is as follows: preparation of 1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) ethane-1-amine

Starting from [1- (3-thienyl) cyclopropyl ] methanol, reference example 1, the second step, yielded 1- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) ethane-1-amine.

MS m/z(ESI):210.1[M+H]+.

The compounds were resolved again on a chiral column (column: CHIRALCEL OD-H4.6 x 150mm,5 μm; detection wavelength (nm): 214; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH: DEA = 90; run length (min): 8; linear mode: isocratic) to give a mixture of compounds 16-1 and 16-2 (30.0mg, rt (retention time) =3.147 min), compound 16-3 (11.7 mg, rt (retention time) =3.500 min), 16-4 (10.4mg, rt (retention time) =4.097 min).

The mixture of compounds 16-1 and 16-2 was resolved again using a chiral column (column: CHIRALPAK IC.6 x 250mm,5 μm; wavelength of detection (nm): 214; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH: DEA =90

Example 17

2- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) pyrrolidine

The first step is as follows: preparation of 2- (dimethoxymethyl) pyrrolidine hydrochloride

Tert-butyl 2-formylpyrrolidine-1-carboxylic acid ester (5 g, 25mmol) was dissolved in methanol (50 mL), cooled to 0 ℃, and a solution of acetyl chloride (3.9g, 50mmol) in methanol (15 mL) was added to stir the reaction at room temperature for 1 hour, followed by addition of trimethyl orthoformate (26g, 250mmol) and stirring at room temperature for 48 hours. The solvent was spin dried, ethyl acetate (150 mL) was added to the crude product, and the mixture was stirred under reflux for 2 hours, cooled to 0 ℃ to precipitate a solid, filtered, and the solid was drained to give 2- (dimethoxymethyl) pyrrolidine hydrochloride (2.7 g, yield: 60%) as a white solid.

The second step: preparation of 2- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) pyrrolidine

Starting from 2- (dimethoxymethyl) pyrrolidine hydrochloride, the second step of reference example 1 gave 2- (5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) pyrrolidine.

MS m/z(ESI):236.1[M+H] ⁺ .

Example 18

4,4-difluoro-3- (thien-2-yl) piperidine

The first step is as follows: tert-butyl 4-carbonyl-3- (thien-2-yl) piperidine-1-carboxylic acid ester

2-bromothiophene (0.98g, 6 mmol), tert-butyl 4-carbonylpiperidine-1-carboxylate (0.80g, 4 mmol), sodium tert-butoxide (0.58g, 6 mmol), BINAP (0.09g, 0.14mmol), pd at room temperature ₂ (dba) ₃ (0.08g, 0.09mmol) was dissolved in toluene (10 mL), heated to 60 deg.C, reacted for 14 hours, cooled to room temperature, filtered through celite,the celite was washed with ethyl acetate, the reaction solution was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spinning, and the crude product was separated by Flash column chromatography to give tert-butyl 4-carbonyl-3- (thiophen-2-yl) piperidine-1-carboxylate (0.11 g, yield: 10%).

MS m/z(ESI):282.1[M+H] ⁺ .

The second step is that: tert-butyl 4,4-difluoro-3- (thiophen-2-yl) piperidine-1-carboxylic acid ester

Tert-butyl 4-carbonyl-3- (thiophen-2-yl) piperidine-1-carboxylate (0.11g, 0.39mmol) was dissolved in dichloromethane (5 mL) at room temperature, then diethylaminosulfur trifluoride (0.25g, 1.2mmol) was added, and the mixture was heated under reflux for three hours, LCMS indicated the completion of the reaction, and cooled to room temperature. The reaction solution was diluted with dichloromethane (20 mL), then washed with saturated sodium bicarbonate solution, washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was chromatographed on a Flash column to give tert-butyl 4,4-difluoro-3- (thiophen-2-yl) piperidine-1-carboxylic acid ester (83 mg, yield: 70%).

MS m/z(ESI):304.1[M+H] ⁺ .

The third step: 4,4-difluoro-3- (thien-2-yl) piperidine

Tert-butyl 4,4-difluoro-3- (thiophen-2-yl) piperidine-1-carboxylate (0.08g, 0.28mmol) was dissolved in dichloromethane (5 mL) at room temperature, then trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours, LCMS indicated the end of the reaction. Spin dry, dissolve the residue with ethyl acetate (20 mL), then wash sequentially with saturated sodium bicarbonate solution, saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, spin dry, and isolate the crude product by preparative chromatography. This product was lyophilized (50 mg).

MS m/z(ESI):204.1[M+H] ⁺ .

Example 19

2- (thien-2-yl-5-d) morpholine

The first step is as follows: 2- (benzyl (2-hydroxyethyl) amino) -1- (thien-2-yl) ethan-1-one

2-bromo-1- (thiophen-2-yl) ethan-1-one (7 g, 34.11mmol), 2- (benzylamino) ethan-1-ol (7.73g, 51.21mmol), potassium carbonate (14.11g, 102.41mmol) were dissolved in 75mL of N, N dimethylformamide, stirred at room temperature for 2 hours, the reaction was diluted with water (100 mL), and extracted with ethyl acetate (100 mLx 4). The organic phases were combined, dried over anhydrous sodium sulfate and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to give the title product 2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one 19b (5.8 g, yield 61.7%) as a yellow oil.

MS m/z(ESI):276.1[M+H] ⁺

The second step is that: 2- (benzyl (2-hydroxyethyl) amino) -1- (thien-2-yl) ethan-1-ol

Dissolving 2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one (5.81g, 21.11mmol) in methanol (50 mL), adding sodium borohydride (2.39g, 63.31mmol) at 0 ℃, stirring at room temperature for 1.5 h, quenching with ice water at 0 ℃, spin-drying directly, diluting with water (100 mL), extracting with ethyl acetate (200 mLx 3), combining the organic phases, drying with anhydrous sodium sulfate, purifying the residue by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1)

The title product, 2- (2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-ol 19c (5.4 g, yield 93.11%) was obtained as a light yellow oil.

MS m/z(ESI):278.1[M+H] ⁺

The third step: 4-benzyl-2- (thien-2-yl) morpholine

2- (2- (benzyl (2-hydroxyethyl) amino) -1- (thien-2-yl) ethan-1-ol (5.41g, 19.51mmol) was dissolved in aqueous hydrogen bromide (40% strength, 20 mL), stirred at room temperature for 4 hours.0 deg.C aqueous sodium carbonate was added dropwise to adjust pH =8, ethyl acetate (100 mLx 3), the organic phases were combined, dried over anhydrous sodium sulfate and spun dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to give the title product 4-benzyl-2- (thien-2-yl) morpholine 19d (3.51 g, 66% yield) as a pale yellow solid.

MS m/z(ESI):260.1[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ7.60–7.43(m,6H),7.14–7.03(m,2H),5.09(d,1H),4.43(s,2H),4.14(d,1H),3.92(t,1H),3.58(d,1H),3.23(t,3H).

The fourth step: 2- (thien-2-yl) morpholine

4-benzyl-2- (thien-2-yl) morpholine (3.4g, 13mmol) was dissolved in dichloromethane (30 mL), 2-chloroethyl chloroformate (2.39g, 63.31mmol) was added at 0 deg.C, stirred at room temperature for 3 hours, directly spin-dried, dissolved in methanol, stirred at 67 deg.C for 5 hours, and the reaction was directly spin-dried to give the title product, 2- (thien-2-yl) morpholine 19e (crude), as a pale yellow oil.

MS m/z(ESI):170.1[M+H] ⁺

The fifth step: 2- (Thien-2-yl) morpholine-4-carboxylic acid tert-butyl ester

2- (thien-2-yl) morpholine (crude), di-tert-butyl dicarbonate (4.25g, 19.5 mmol), triethylamine (3.95g, 39mmol) were dissolved in 40mL of dichloromethane, stirred at room temperature for 2 hours, the reaction was diluted with water (50 mL) and extracted with dichloromethane (50 mLx 4) and the organic phases combined, dried over anhydrous sodium sulfate and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to give the title product, tert-butyl 2- (thien-2-yl) morpholine-4-carboxylate 1f (2.5 g, 71% yield over two steps).

MS m/z(ESI):214.0[M+1-56]

¹ H NMR(400MHz,CDCl ₃ )δ7.35–7.22(m,1H),7.08–6.86(m,2H),4.69(dd,1H),4.15(d,1H),4.02–3.81(m,2H),3.68(td,2.8Hz,1H),3.15–2.93(m,2H),1.50(s,9H).

And a sixth step: 2- (5-Bromothiophen-2-yl) morpholine-4-carboxylic acid tert-butyl ester

Tert-butyl 2- (thien-2-yl) morpholine-4-carboxylate 19f (622mg, 2.31mmol) was dissolved in 6mL DMF and NBS (493mg, 2.78mmol) was added and stirred at room temperature for 16 h. Ethyl acetate (30 mL) was added, washed successively with water (10 mLx 3), saturated sodium chloride (10 mL), then dried over anhydrous sodium sulfate, concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 9:1) to give 19g (535 mg, 66% yield) of a white solid.

MS m/z(ESI):291.9[M+1-56]

¹ H NMR(400MHz,CDCl ₃₎ δ6.93(d,1H),6.76(dd,1H),5.30(s,1H),4.60(dd,1H),4.12(dd,1H),4.00–3.76(m,2H),3.04(m,2H),1.48(s,9H).

The seventh step: preparation of tert-butyl 2- (thien-2-yl-5-d) morpholine-4-carboxylate

Tert-butyl 2- (5-bromothiophene-2-yl) morpholine-4-carboxylate is added into deuterium water, and deuterated sodium hydroxide is added to react for 16 hours at room temperature. Adding ethyl acetate for extraction, drying an organic phase, and concentrating under reduced pressure to obtain a product of tert-butyl 2- (thiophene-2-yl-5-d) morpholine-4-carboxylic ester for 19 hours.

MS:271.2[M+H] ⁺ .

Eighth step: preparation of 2- (thien-2-yl-5-d) morpholine

To tert-butyl 2- (thien-2-yl-5-d) morpholine-4-carboxylate was added 4M dioxane hydrochloride solution and reacted at room temperature for 1 hour. Concentrating under reduced pressure to obtain the product 2- (thiophene-2-yl-5-d) morpholine.

MS:171.2[M+H] ⁺ .

Example 20

2- (5-fluorothien-2-yl) morpholine

The first step is as follows: preparation of 5-fluoro-N-methoxy-N-methylthiophene-2-carboxamide

5-Fluorothiophene-2-carboxylic acid (2.0g, 13.69mmol) was dissolved in tetrahydrofuran (30 mL), and dimethylhydroxylamine hydrochloride (2.67g, 27.37mmol), 1-hydroxybenzotriazole (1.85g, 13.69mmol), N, N-diisopropylethylamine (8.84g, 68.43mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.25g, 27.37mmol) were added under ice bath, and reacted at room temperature for 16 hours. The mixture was washed with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (30ml × 3), washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was then purified by column chromatography (petroleum ether: ethyl acetate =20, 1-1:1) to give the product 5-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (2.5 g, yield: 96.5%).

¹ H NMR(400MHz,CDCl ₃ )δ7.68(t,J＝4.0Hz,1H),6.55(dd,J＝1.6,4.0Hz,1H),3.79(s,3H),3.36(s,3H).

The second step is that: preparation of 1- (5-fluorothien-2-yl) ethan-1-one

5-fluoro-N-methoxy-N-methylthiophene-2-carboxamide is dissolved in tetrahydrofuran (30 mL), and 3M methyl magnesium chloride tetrahydrofuran solution (6.6 mL, 19.8mmol) is added dropwise in ice bath, and after the dropwise addition, the reaction is carried out at room temperature for 2 hours. The reaction was quenched by addition of saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (20ml × 2), washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate =20, 1-5:1) to give the product 1- (5-fluorothien-2-yl) ethan-1-one (1.6 g, yield: 84.2%).

MS:144.8[M+H] ⁺ .

The third step: preparation of 2-bromo-1- (5-fluorothien-2-yl) ethan-1-one

1- (5-Fluorothien-2-yl) ethan-1-one (629mg, 4.37mmol) was dissolved in chloroform (10 mL), pyridine tribromide (1.63g, 5.1 mmol) was added, and the reaction was carried out at room temperature for 2 hours. Water (20 mL) was added, the organic phase was separated, washed with water and brine, respectively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product, which was then purified by column chromatography (petroleum ether: ethyl acetate =20: 1-5:1) to give the product 2-bromo-1- (5-fluorothiophen-2-yl) ethan-1-one (684 mg, yield: 70%).

The fourth step: 2- (5-fluorothien-2-yl) morpholine

Reference example 19 gave the product 2- (5-fluorothien-2-yl) morpholine.

MS:187.8[M+H] ⁺ .

Example 21

2- (4-fluorothien-2-yl) morpholine

The product 2- (4-fluorothien-2-yl) morpholine was obtained by using 4-fluorothiophene-2-carboxylic acid as a starting material in reference example 20.

MS:187.8[M+H] ⁺ .

Example 22

2- (3-fluorothien-2-yl) morpholine

The product 2- (3-fluorothien-2-yl) morpholine was obtained by using 3-fluorothiophene-2-carboxylic acid as a starting material in reference example 20. MS:187.8[ deg. ] M +H] ⁺ .

Example 23

2- (thien-2-yl-5-d) morpholine-2-d

Reference example 19 the first step gave the product 2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one.

MS m/z(ESI):276.1[M+H] ⁺

2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one (5.81g, 21.11mmol) was dissolved in deuterated methanol (50 mL), sodium deuterated borohydride (2.39g, 63.31mmol) was added at 0 deg.C, stirred at room temperature for 1.5 hours, quenched by addition of ice water at 0 deg.C, spun directly, diluted with water (100 mL), extracted with ethyl acetate (200 mLx 3), the organic phases combined, dried over anhydrous sodium sulfate, and the residue purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to give the title product 2- (2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-ol 1c (5.4 g, yield 93.11%), as a pale yellow oil.

MS m/z(ESI):280.1[M+H] ⁺

The product 2- (thien-2-yl-5-d) morpholine-2-d was obtained in the third to eighth steps with reference to example 19.

MS m/z(ESI):172.1[M+H] ⁺

Example 24

2- (5-chlorothien-2-yl) morpholine-2-d

2-bromo-1- (thiophen-2-yl) ethan-1-one (7 g, 34.11mmol), 2- (benzylamino) ethan-1-ol (7.73g, 51.21mmol), potassium carbonate (14.11g, 102.41mmol) were dissolved in 75mL of N, N dimethylformamide, stirred at room temperature for 2 hours, the reaction was diluted with water (100 mL), and extracted with ethyl acetate (100 mLx 4). The organic phases were combined, dried over anhydrous sodium sulfate and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1) to give the title product 2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one (5.8 g, yield 61.7%) as a yellow oil.

MS m/z(ESI):276.1[M+H] ⁺

The second step is that: 2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-d-1-ol-d

2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one (5.81g, 21.10mmol) was dissolved in methanol (50 mL), sodium borodeuteride (2.65g, 63.30mmol) was added at 0 ℃, stirred at room temperature for 1.5 hours, quenched by addition of ice water at 0 ℃, spin-dried directly, diluted with water (100 mL), extracted with ethyl acetate (200 mLx 3), the organic phases combined, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to give the title product (5.5 g, yield 93.3%) as a pale yellow oil.

MS m/z(ESI):280.1[M+H] ⁺

The third step: 4-benzyl-2- (thien-2-yl) morpholine-2-d

2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-d-1-ol-d (5.5g, 19.69mmol) was dissolved in an aqueous solution of hydrogen bromide (concentration 40%,20 mL) and stirred at room temperature for 4 hours. Aqueous sodium carbonate solution was added dropwise at 0 ℃ to adjust pH =8, ethyl acetate (100 mLx 3), the organic phases were combined, dried over anhydrous sodium sulfate and dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to give the title product (3.50 g, yield 68%) as a pale yellow solid.

MS m/z(ESI):261.1[M+H] ⁺

The fourth step: 2- (thien-2-yl) morpholine-2-d

4-benzyl-2- (thiophen-2-yl) morpholine-2-d (3.4g, 13mmol) was dissolved in dichloromethane (30 mL), 2-chloroethyl chloroformate (2.39g, 63.31mmol) was added at 0 deg.C, stirred at room temperature for 3 hours, directly spin-dried, dissolved with methanol, stirred at 67 deg.C for 5 hours, and the reaction was directly spin-dried to give the crude title product as a pale yellow oil which was used directly in the next step.

MS m/z(ESI):171.1[M+H] ⁺

The fifth step: 2- (Thiophen-2-yl) morpholine-4-carboxylic acid tert-butyl ester-2-d

2- (thien-2-yl) morpholine-2-d (crude), di-tert-butyl dicarbonate (4.25g, 19.5 mmol), triethylamine (3.95g, 39mmol) were dissolved in 40mL of dichloromethane, stirred at room temperature for 2 hours, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mLx 4) and the organic phases combined, dried over anhydrous sodium sulfate and dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to give the title product, tert-butyl 2- (thien-2-yl) morpholine-4-carboxylate-2-d (2.1 g, 59.5% yield in two steps).

MS m/z(ESI):215.1[M+1-56]

And a sixth step: preparation of tert-butyl 2- (5-chlorothien-2-yl) morpholine-4-carboxylate-2-d

Tert-butyl 2- (thien-2-yl) morpholine-4-carboxylate-2-d (300mg, 1.11mmol) was dissolved in N, N-dimethylformamide (10 mL), and N-chlorosuccinimide (193mg, 1.44mmol) was added and reacted at room temperature for 2 hours. Water was added and extracted with ethyl acetate (20 mL). The organic phase was dried and concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give the product tert-butyl 2- (5-chlorothien-2-yl) morpholine-4-carboxylate-2-d (110 mg, yield: 33%).

1H NMR(400MHz,CDCl3)δ6.84–6.73(m,2H),4.22–4.01(m,1H),3.99–3.92(m,1H),3.91–3.79(m,1H),3.69–3.59(m,1H),3.13–2.92(m,2H),1.48(s,9H).

MS:305.1[M+1].

The compound was resolved again using a chiral column (column: CHIRALPAK AD-H4.6 x 250mm,5 μm; detection wavelength (nm): 254; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH: DEA = 95; run length (min): 12; linear mode: isocratic) to give compound 24-1 (70mg, rt (retention time) =5.387 min), compound 24-2 (70mg, rt (retention time) =6.777 min).

MS m/z(ESI):305.1[M+H] ⁺

The seventh step: preparation of 2- (5-chlorothien-2-yl) morpholine-2-d

Reference example 19 gave the product S-2- (5-chlorothien-2-yl) morpholine-2-d (24-P1), and the product R-2- (5-chlorothien-2-yl) morpholine-2-d (24-P2). MS m/z (ESI) 205.1[ 2 ] M + H ]

Example 25

2- (5-chlorothien-2-yl) morpholine-5,5-d 2

The first step is as follows: preparation of 2-chloro-N- (2-carbonyl-2- (thien-2-yl) ethyl) acetamide

2-amino-1- (thien-2-yl) ethanone (3 g, 21.3mmol) and triethylamine (3.23g, 31.9mmol) were dissolved in dichloromethane (30 mL), and chloroacetyl chloride (2.83g, 22.3mmol) was added dropwise while cooling on ice, and reacted at room temperature for 1 hour. Water was added to quench the reaction, the organic phase was separated, dried and concentrated under reduced pressure to give the product 2-chloro-N- (2-carbonyl-2- (thiophen-2-yl) ethyl) acetamide (4.3 g, yield: 93%).

MS m/z(ESI):218.0[M+H] ⁺

The second step is that: preparation of 2-chloro-N- (2-hydroxy-2- (thien-2-yl) ethyl) acetamide

Reference example 19 gave the product 2-chloro-N- (2-hydroxy-2- (thiophen-2-yl) ethyl) acetamide.

MS m/z(ESI):220.0[M+H] ⁺

The third step: preparation of 6- (thien-2-yl) morpholin-3-one

2-chloro-N- (2-carbonyl-2- (thiophen-2-yl) ethyl) acetamide (1g, 4.55mmol) was dissolved in tetrahydrofuran (20 mL), and potassium tert-butoxide (613mg, 5.46mmol) was added under ice bath, and reacted at room temperature for 16 hours. The reaction was quenched with water and extracted with ethyl acetate (20 mL). The organic phase was dried and concentrated under reduced pressure to give a crude product, which was then purified by column chromatography to give the product 6- (thien-2-yl) morpholin-3-one (530 mg, yield: 64%).

MS m/z(ESI):184.0[M+H] ⁺

The fourth step: preparation of 2- (thien-2-yl) morpholine-5,5-d 2

6- (thien-2-yl) morpholin-3-one (530mg, 2.89mmol) was dissolved in tetrahydrofuran (10 mL), deuterated lithium aluminum hydride (73mg, 1.74mmol) was added under ice bath, and then heated to reflux for 1 hour. The reaction solution was cooled in an ice bath, and sodium sulfate decahydrate was added to quench the reaction. Filtration and drying yielded 2- (thien-2-yl) morpholine-5,5-d 2 (350 mg, yield: 71%).

MS m/z(ESI):172.1[M+H] ⁺

The product 2- (5-chlorothien-2-yl) morpholine-5,5-d 2 is obtained in the fifth to seventh steps with reference to example 24.

MS m/z(ESI):206.0[M+H] ⁺

Example 26

2- (5-chlorothien-2-yl) morpholine-3,3-d 2

The first step is as follows: preparation of 2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one-2,2-d 2

2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one (3 00mg, 1.1mmol) was dissolved in monodeuterated methanol (5 mL), and triethylamine (220mg, 2.2mmol) and deuterium oxide (65mg, 3.3mmol) were added under ice bath. After reacting at 50 ℃ for 2 hours, concentration under reduced pressure gave the product 2- (benzyl (2-hydroxyethyl) amino) -1- (thiophen-2-yl) ethan-1-one-2,2-d 2 (300 mg, yield: 99%).

MS:278.2[M+H] ⁺ .

The product 2- (5-chlorothien-2-yl) morpholine-3,3-d 2 was obtained from the second to seventh steps in reference example 24.

MS:206.2[M+H] ⁺ .

Example 27

2- (4-chlorothien-2-yl) morpholine

The product 2- (4-chlorothiophene-2-yl) morpholine was obtained from 4-chlorothiophene-2-carboxylic acid as the starting material in reference example 20. MS:204.2[ m ] +H] ⁺ .

Example 28

2- (5-chlorothien-3-yl) morpholine-5,5-d 2

The product 2- (5-chlorothien-3-yl) morpholine-5,5-d 2 was obtained in reference example 25 using 2-amino-1- (5-chlorothien-2-yl) ethane-1-one as the starting material.

MS:206.2[M+H] ⁺ .

Example 29

4- (thien-2-yl-5-d) -6-azaspiro [2.5] octane

The first step is as follows: tert-butyl 4-methylene-3- (thien-2-yl) piperidine-1-carboxylic acid ester

Methyltriphenylphosphonium bromide (3.57g, 10mmol) was dissolved in dimethyl sulfoxide (40 mL) under ice-bath to replace nitrogen, and then sodium hydrogen (0.6g, 60%,15 mmol) was added, followed by stirring for 30 minutes under ice-bath, and then tert-butyl 4-carbonyl-3- (thiophen-2-yl) piperidine-1-carboxylate (3.38g, 12mmol) was added, and the mixture was stirred at room temperature overnight. The reaction solution was quenched with a saturated ammonium chloride solution, then diluted with ethyl acetate (100 mL), then washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by Flash column chromatography to give tert-butyl 4-methylene-3- (thiophen-2-yl) piperidine-1-carboxylate (1.96 g, yield: 70%).

MS m/z(ESI):280.1[M+H] ⁺ .

The second step is that: tert-butyl 4- (thien-2-yl) -6-azaspiro [2.5] octane-6-carboxylate

Diethyl zinc (5 mL,1.0M,5 mmol) was dissolved in methylene chloride (30 mL) at-40 ℃ to replace nitrogen, and then diiodomethane (2.68g, 10 mmol) was added, and the mixture was stirred at-40 ℃ for one hour, and then a solution of tert-butyl 4-methylene-3- (thien-2-yl) piperidine-1-carboxylate (0.70g, 2.5 mmol) in methylene chloride (10 mL), and the mixture was stirred at-40 ℃ and warmed to room temperature and stirred overnight. The reaction solution was quenched with a saturated ammonium chloride solution, followed by extraction with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spin-dried, and the crude product was separated by Flash column chromatography to give tert-butyl 4- (thiophen-2-yl) -6-azaspiro [2.5] octane-6-carboxylate (0.48 g, yield: 65%).

MS m/z(ESI):294.1[M+H] ⁺ .

The third step: 4- (thien-2-yl-5-d) -6-azaspiro [2.5] octane

Starting from tert-butyl 4- (thien-2-yl) -6-azaspiro [2.5] octane-6-carboxylic acid ester, 4- (thien-2-yl-5-d) -6-azaspiro [2.5] octane was obtained in the sixth, seventh and eighth steps of reference example 19.

MS m/z(ESI):195.1[M+H] ⁺ .

Example 30

1- (5 ' -Fluorospiro [ cyclopropane-1,4 ' -isochroman ] -1' -yl) -N-methylmethanamine

The first step is as follows: 1- (5 ' -Fluorospiro [ cyclopropane-1,4 ' -isochroman ] -1' -yl) -N-methylmethanamine

1- (5 ' -Fluorospiro [ cyclopropane-1,4 ' -isochroman ] -1' -yl) -N-methylmethanamine was obtained in reference example 1 using (2-fluorophenyl) cyclopropylcarboxylic acid as a starting material.

MS m/z(ESI):222.1[M+H] ⁺ .

Examples 31 and 32

1- (8 '-Fluorospiro [ cyclopropane-1,4' -isochroman ] -1 '-yl) -N-methylmethanamine and 1- (6' -Fluorospiro [ cyclopropane-1,4 '-isochroman ] -1' -yl) -N-methylmethanamine

1- (8 '-Fluorospiro [ cyclopropane-1,4' -isochroman ] -1 '-yl) -N-methylmethanamine and 1- (6' -Fluorospiro [ cyclopropane-1,4 '-isochroman ] -1' -yl) -N-methylmethanamine were obtained in reference example 1 using (3-fluorophenyl) cyclopropylcarboxylic acid as a starting material.

MS m/z(ESI):222.1[M+H] ⁺ .

Examples 33 and 34

N-methyl-1- (5 'H,7' H-spiro [ cyclopropane-1,8 '- [1,3] dioxazolo [4,5-g ] isochromen ] -5' -yl) methylamine and N-methyl-1- (7 'H,9' H-spiro [ cyclopropane-1,6 '- [1,3] dioxazolo [4,5-h ] isochromen ] -9' -yl) methylamine

Starting from 1- (benzo [ D ] [1,3] dioxol-5-yl) cyclopropanecarboxylic acid, N-methyl-1- (5H, 7' H-spiro [ cyclopropane-1,8 ' - [1,3] dioxazolo [4,5-g ] isochromene ] -5' -yl) methylamine and N-methyl-1- (7 ' H,9' H-spiro [ cyclopropane-1,6 ' - [1,3] dioxazolo [4,5-h ] isochromene ] -9' -yl) methylamine were obtained in reference example 1.

MS m/z(ESI):248.1[M+H] ⁺ .

Examples 35 to 110

Example 111

(5 'H,7' H-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methylamine

[1- (3-thienyl) cyclopropyl ] methanol (1.2g, 7.78mmol) and 2,2-dimethoxyethylamine (1.06g, 10.11mmol) were dissolved in dioxane (30 mL), trifluoromethanesulfonic acid (3.55g, 23.34mmol) was added at 0 ℃, and the reaction was stirred at 25 ℃ for 72 hours. Saturated aqueous sodium carbonate (100 mL) was added to adjust pH to 10, the aqueous phase was extracted with DCM (100 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the crude product was separated by column chromatography (dichloromethane/methanol =100/1 to 10/1) to give the racemic product (5 'h,7' h-spiro [ cyclopropane-1,4 '-thieno [2,3-c ] pyran ] -7' -yl) methylamine (500 mg, 32.9% yield).

MS m/z(ESI):196.1[M+H]+.

The compound was resolved again using a chiral column (column: CHIRALCEL AS-H4.6 x 150mm,5 μm; detection wavelength (nm): 214; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH: DEA = 90; run length (min): 8; linear mode: isocratic) to give compound 111-1 (124mg, rt (retention time) =3.893 min), compound 111-2 (115mg, rt (retention time) =4.500 min).

Compound 111-1 (hydrochloride salt): 1H NMR (400mhz, dmso) δ 8.16 (brs, 3H), 7.45 (d, J =8hz, 1h), 6.69 (d, J =8hz, 1h), 5.15-5.11 (m, 1H), 3.84-3.81 (m, 1H), 3.66-3.63 (m, 1H), 3.30-3.27 (m, 1H), 3.12-3.06 (m, 1H), 1.35-1.23 (m, 1H), 1.03-0.84 (m, 4H).

MS:196.1[M+1].

Compound 111-2 (hydrochloride salt): 1H NMR (400MHz, DMSO). Delta.8.23 (brs, 3H), 7.45 (d, J =8Hz, 1H), 6.69 (d, J =8Hz, 1H), 5.16-5.13 (m, 1H), 3.83-3.80 (m, 1H), 3.67-3.64 (m, 1H), 3.28-3.26 (m, 1H), 3.12-3.08 (m, 1H), 1.35-1.23 (m, 1H), 1.05-0.82 (m, 4H).

MS:196.1[M+1].

Example 112

(4 'H,6' H-spiro [ cyclopropane-1,7 '-thieno [3,2-c ] pyran ] -4' -yl) methylamine

Referring to example 111, example 19 to the fifth step yielded tert-butyl ((4 'H,6' H-spiro [1,7 '-thienyl [3,2-c ] pyran ] -4' -yl) methylcarbamate

MS:296.1[M+1] ⁺ .

The compounds were resolved on a chiral column (column: CHIRALPAK AD-H4.6 x 250mm,5 μm; detection wavelength (nm): 254; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH = 80; run length (min): 12; linear mode: isocratic) to give compound 2 (7.65g, rt (retention time) =5.047 min), compound 2' (7.40g, rt (retention time) =5.427 min).

Eighth Steps 112-1 and 112-2 according to example 19

Compound 112-1:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.03(s,3H),7.33–7.28(m,1H),7.00–6.95(m,1H),5.00–4.93(m,1H),3.86–3.80(m,1H),3.72–3.66(m,1H),3.48–3.44(m,1H),3.06–3.00(m,1H),1.09–1.00(m,2H),0.91–0.82(m,2H).

MS:196.1[M+1] ⁺ .

compound 112-2:

¹ H NMR(400MHz,DMSO-d ₆ )δ8.04(s,3H),7.34–7.28(m,1H),7.00–6.97(m,1H),5.00–4.93(m,1H),3.86–3.80(m,1H),3.72–3.65(m,1H),3.48–3.40(m,1H),3.07–2.97(m,1H),1.12–0.99(m,2H),0.94–0.80(m,2H).

MS:196.1[M+1] ⁺ .

example 113

N-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl-d 3-amine

The first step is as follows: preparation of methyl 2- (thien-3-yl) propyl ester

Thiophene-3-acetic acid methyl ester (1.20g, 7.68mmol) was dissolved in N, N-dimethylformamide (20 mL) under ice bath, nitrogen gas was replaced, then sodium hydrogen (768.24mg, 19.21mmol,60% w/w) was added, stirring was performed for 30 minutes under ice bath, then iodomethane (8.72g, 61.46mmol) was added dropwise, stirring was performed overnight at room temperature, and TLC indicated that the reaction was complete. The reaction was quenched with saturated ammonium chloride solution, a solid precipitated, filtered to remove the solid, the solid was washed with ethyl acetate, the reaction was diluted with ethyl acetate (200 mL), the layers were separated, the organic phase was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried, and the residue was purified by flash silica gel chromatography (petroleum ether as mobile phase) to give the desired methyl 2- (thiophen-3-yl) propyl ester as a colorless oil (1 g crude, containing disubstituted impurities).

MS:171.0[M+1].

The second step is that: 2- (thien-3-yl) propan-1-ol

Methyl 2- (thien-3-yl) propyl ester (1 g crude, containing the second generation impurity) was dissolved in dichloromethane (20 mL) under ice-bath, nitrogen was replaced, and diisobutylaluminum hydride (12mmol, 12mL, 1M) was added and stirred at room temperature overnight. TLC indicated the reaction was complete, the reaction was quenched with saturated ammonium chloride solution and a solid precipitated, filtered, the solid was washed with dichloromethane, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, spun-dried and the residue was chromatographed using preparative thin layer chromatography (PE: EA = 1:1) to give the product 2- (thien-3-yl) propan-1-ol (0.25 g).

MS:143.0[M+1].

The third step: n-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl-d 3-amine

2- (thien-3-yl) propan-1-ol (150mg, 1.05mmol) was dissolved in 1'4-dioxane (3 mL) at room temperature, then 2,2-dimethoxy-N- (trideuteromethyl) ethylamine (193.30mg, 1.58mmol) was added, stirred for 10 minutes at room temperature, then trifluoromethanesulfonic acid (474.88mg, 3.16mmol) was added dropwise and stirred at room temperature overnight. LCMS indicated the reaction was complete, the reaction was neutralized with aqueous sodium hydroxide (2N), adjusted to PH 9-10, then extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, spun dry, and the crude product was separated by preparative chromatography. Removing acetonitrile from the prepared solution by spinning, extracting with ethyl acetate, combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, spinning to dry, separating the crude product by preparative HPLC to obtain the product N-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl-d 3-amine (106 mg, yield: 49%)

MS:201.1[M+1].

The fourth step: (S, S) -N-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl-d 3-amine, (S, R) -N-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl-d 3-amine, (R, S) -N-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl-d 3-amine and (R, R) -N-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl-d 3-amine are prepared

The product obtained by the manual resolution of N-methyl-1- (4-methyl-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl) methyl-d 3-amine is as follows, the absolute configuration is not determined:

a chromatographic column: CHIRALPAK OJ-H4.6 x 150mm,5 μm; detection wavelength (nm): 214; temperature (. Degree. C.): 35; flow rate (mL/min): 1; mobile phase: hexane EtOH DEA = 85; the running time (min) is 12; linear mode: isocratic), compound 113-1 (3.9mg, rt (retention time) =2.790 min), compound 113-2 (3.6mg, rt (retention time) =3.592 min), 113-3 (3.5mg, rt (retention time) =5.832 min), compound 113-4 (15.9mg, rt (retention time) =7.753 min) were obtained.

Example 114

(4-methyl-4,7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methylamine

The product (4-methyl-4,7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl) methylamine is synthesized in the third step of example 113 by using aminoacetaldehyde dimethyl acetal as a raw material, and then is obtained by manual resolution as follows, and the absolute configuration is not determined.

A chromatographic column: CHIRALPAK OJ-H4.6 x 150mm,5 μm; detection wavelength (nm): 214; temperature (. Degree. C.): 35; flow rate (mL/min): 1; mobile phase: hexane EtOH DEA = 85; the running time (min) is 12; linear mode: isocratic), compound 114-1 (RT (retention time) =2.181 min), compound 114-2 (, RT (retention time) =3.013 min), 114-3 (RT (retention time) =4.117 min), compound 114-4 (RT (retention time) =5.6510 min) were obtained.

MS:184.1[M+1].

Example 115

N-methyl-1- (spiro [ cyclopropane-1,4 '-isochroman ] -1' -yl) methylamine

The first step is as follows: preparation of N-methyl-1- (spiro [ cyclopropane-1,4 '-isochroman ] -1' -yl) methylamine

The product, N-methyl-1- (spiro [ cyclopropane-1,4 '-isochroman ] -1' -yl) methylamine, was synthesized by the third step in reference example 112 using (1-phenylcyclopropyl) methanol and methylaminoacetaldehyde dimethyl acetal as starting materials.

MS:204.1[M+1].

Example 116

2- (thien-2-yl) morpholine-2-d

Referring to example 19, the second step replaces sodium borohydride with deuterated sodium borohydride to give the product 2- (thien-2-yl) morpholine-4-carboxylic acid tert-butyl ester-2-d. Remaining Synthesis referring to example 19, the product 2- (thien-2-yl) morpholine-2-d was obtained

¹ H NMR(400MHz,CDCl ₃ )δ7.31–7.27(m,1H),7.05–7.01(m,1H),7.01–6.98(m,1H),4.27–4.05(m,1H),4.03–3.96(m,1H),3.94–3.83(m,1H),3.73–3.63(m,1H),3.15–2.96(m,2H),1.48(s,9H).

MS:271.1[M+1] ⁺ .

The compound was resolved again using a chiral column (column: CHIRALPAK OJ-H4.6 x 250mm,5 μm; detection wavelength (nm): 230; temperature (° c): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH: DEA = 90; run length (min): 12; linear mode: isocratic) to give compound 2-1 (60mg, rt (retention time) =4.247 min), compound 2-2 (60mg, rt (retention time) =5.397 min).

Reference example 19 step eight gives two single chiral compounds as follows

Chiral compound 116-1,2- (thiophen-2-yl) morpholine-2-d (P1),

¹ H NMR(400MHz,DMSO-d ₆ )δ9.80(s,2H),7.61–7.53(m,1H),7.18–7.12(m,1H),7.08–7.00(m,1H),4.11–4.03(m,1H),4.02–3.92(m,1H),3.54–3.46(m,1H),3.27–3.18(m,1H),3.15–3.00(m,2H).

MS:171.1[M+1].

chiral compound 116-2,2- (thiophen-2-yl) morpholine-2-d (P2),

¹ H NMR(400MHz,DMSO-d ₆ )δ9.60(s,2H),7.61–7.53(m,1H),7.17–7.11(m,1H),7.08–7.02(m,1H),4.11–4.04(m,1H),3.99–3.90(m,1H),3.55–3.48(m,1H),3.27–3.20(m,1H),3.14–3.02(m,2H).

MS:171.1[M+1] ⁺ .

example 117

(2-chloro-4,7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl-4,4-d 2) methylamine

The first step is as follows: preparation of methyl 2- (thien-3-yl) acetate-d 2:

methyl 2- (thien-3-yl) acetate (2g, 11.75mmol) was dissolved in deuterated methanol (20 mL), and sodium methoxide (2.43g, 35.25mmol) was added and reacted at 70 ℃ for 48 hours. Water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (30 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the product (1.8 g,10.45mmol,88.95% yield).

1H NMR(400MHz,CDCl3)δ7.31–7.28(m,1H),7.15(s,1H),7.05–7.01(m,1H),3.72–3.69(m,3H).

The second step is that: preparation of 2- (thien-3-yl) ethane-2,2-d 2-1-ol

Methyl 2- (thien-3-yl) acetate-d 2 (2g, 11.61mmol) was dissolved in tetrahydrofuran (40 mL), and lithium aluminum hydride (881.32mg, 23.22mmol) was added and reacted at room temperature for 3 hours. TLC (PE: EA = 5:1) detection showed completion of the reaction, the reaction solution was quenched with sodium sulfate decahydrate and filtered, and the filtrate was concentrated under reduced pressure to give the product (1.2g, 9.22mmol,79.37% yield).

The third step: preparation of tert-butyl ((2-chloro-4,7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl-4,4-d 2) methyl) carbamate

Referring to the third step of example 113, the fifth step of example 19 and the sixth step of example 24, tert-butyl ((2-chloro-4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl-4,4-d 2) methyl) carbamate was obtained.

MS:250.2[M-56+1] ⁺ .

The compound was resolved again on a chiral column (column: CHIRALPAK IC 4.6.4.6 × 250mm,5 μm; detection wavelength (nm): 254; temperature (oC): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH = 90; run length (min): 12; linear mode: isocratic) to give compound P1 (80mg, rt (retention time) =9.300 min), compound P2 (80mg, rt (retention time) =11.783 min).

Eighth step 117-1 according to example 19

1H NMR(400MHz,DMSO-d6)δ8.15(s,3H),6.99(s,1H),5.00–4.93(m,1H),4.15–4.07(m,1H),3.80–3.72(m,1H),3.24–3.16(m,1H),3.08–2.98(m,1H).

MS:206.0[M+1]+.

Eighth step 117-2 according to example 19

1H NMR(400MHz,DMSO-d6)δ8.09(s,3H),6.99(s,1H),4.99–4.92(m,1H),4.13–4.07(m,1H),3.80–3.72(m,1H),3.25–3.17(m,1H),3.09–2.99(m,1H).

MS:206.0[M+1]+.

Example 118

N- (4,7-dihydro-5H-thiophene [2,3-c ] pyran-7-yl-4,4-d 2) methyl) methane-d 3-amine

Referring to the third step of example 113, example 19 obtained the fifth step of tert-butyl ((4,7-dihydro-5H-thieno [2,3-c ] pyran-7-yl-4,4-d 2) methyl) (methyl-d 3) carbamate:

1H NMR(400MHz,CDCl3)δ7.20–7.15(m,1H),6.86–6.80(m,1H),5.05–4.91(m,1H),4.19–4.11(m,1H),3.86–3.72(m,2H),3.29–3.19(m,1H),1.48(s,9H).

MS:289.0[M+1]+.

the compound was resolved on a chiral column (column: CHIRALPAK IC 4.6.4.6 x 250mm,5 μm; detection wavelength (nm): 254; temperature (. Degree. C.): 35; flow rate (mL/min): 1; mobile phase: hexane: etOH = 70; run length (min): 12; linear mode: isocratic) to give compound P1 (80mg, RT (retention time) =5.380 min), compound P2 (80mg, RT (retention time) =5.913 min).

Reference example 19 eighth step 118-1

¹ H NMR(400MHz,DMSO-d ₆ )δ9.11(s,2H),7.55–7.45(m,1H),7.01–6.88(m,1H),5.25–5.13(m,1H),4.18–4.08(m,1H),3.82–3.70(m,1H),3.40–3.35(m,1H),3.23–3.13(m,1H).

MS:189.1[M+1] ⁺ .

Eighth step 118-2 according to example 19

¹ H NMR(400MHz,DMSO-d ₆ )δ9.04(s,2H),7.55–7.45(m,1H),6.98–6.90(m,1H),5.24–5.12(m,1H),4.19–4.08(m,1H),3.83–3.71(m,1H),3.37–3.33(m,1H),3.23–3.14(m,1H).

MS:189.1[M+1] ⁺ .

Biological test evaluation

The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.

1. Cell function test

Test example 1 measurement of Effect of the Compound of the present invention on cAMP content in cells stably expressing TAAR1 receptor

1. Purpose of the experiment:

the activation of the TAAR1 receptor by the compound is measured.

2. Laboratory instruments and reagents:

2.1 Instrument:

384 well-assay plates (Perkin Elmer; 6007680)

96-well conical btm PP Plt nature RNASE/Dnase-free plate(ThermoFisher；249944)

EnVision(Perkin Elmer)

2.2 reagent:

Fetal Bovine Serum(Gibco，10999141)

Ham's F-12K(Kaighn's)Medium(Hyclone；SH30526.01)

Penicillin-Streptomycin，Liquid(Gibco；15140122)

Hygromycin B

BSA stabilizer(Perkin Elmer；CR84-100)

cAMP kit(Cisbio；62AM4PEC)

IBMX(Sigma；I5879)

HEPES(Gibco；15630080)

HBSS(Gibco；14025076)

TrypLE(ThermoFisher；12604021)

DMEM

3. the experimental method comprises the following steps:

1) Preparation of an experimental buffer: 1 × HBSS + 2mM HEPES +0.1% BSA +500 μ M IBMX.

2) Complete medium:

Ham's F12K+10％Fetal Bovine Serum+1*Penicillin-Streptomycin+200μg/mL Hygromycin B for CHO

DMEM+10％Fetal Bovine Serum+1*Penicillin-Streptomycin+200μg/mL Hygromycin B for HEK293

3) Culturing TAAR1 cell line at 37 ℃ and 5% CO ₂ In complete medium under ambient conditions; after TrypLE digestion, cells were resuspended in experimental buffer, seeded into 384 cell culture plates at 8000 cells/15 ul/well.

4) Compounds were diluted with assay buffer and 5. Mu.L of compound was added to each well and incubated at 37 ℃ for 30 minutes.

5) The cAMP-d2 and Anti-cAMP-Eu3+ are frozen and thawed, and diluted by 20 times by using lysine buffer; add 10. Mu.L cAMP-d2 to the experimental well, then add 10. Mu.L Anti-cAMP-Eu3+ to the experimental well; the reaction plate was centrifuged at 200g for 30s at room temperature, allowed to stand at 25 ℃ for 1h, and data was collected by Envision

4. The experimental data processing method comprises the following steps:

1)Z’factor＝1-3*(SDMax+SDMin)/(MeanMax-MeanMin)；

2)CVMax＝(SDMax/MeanMax)*100％；

3)CVMin＝(SDMin/MeanMin)*100％；

4)S/B＝Singal/Background；

5) Compound EC was calculated using GraphPad non-linear fitting equation ₅₀ :

Y＝Bottom+(Top-Bottom)/(1+10^((LogEC ₅₀ -X)*HillSlope))

X: log value of compound concentration; y: activation%

5. The experimental results are as follows:

EXAMPLES EC of Compounds on cAMP in cells stably expressing TAAR1 receptor ₅₀ Value of

6. And (4) experimental conclusion:

the compounds of the examples shown in the invention show good agonistic activity in experiments on the effect of cells stably expressing TAAR1 receptor on cAMP.

Test example 2 determination of the Effect of Compounds of the invention on cAMP levels in cells stably expressing 5-HT1A receptors

1. Purpose of the experiment:

the activation of 5-HT1A receptors by compounds is measured.

2. Laboratory instruments and reagents:

2.1 Instrument:

384 well-assay plates (Perkin Elmer; 6007680)

96-well conical btm PP Plt nature RNASE/Dnase-free plate(ThermoFisher；249944)

EnVision(Perkin Elmer)

2.2 reagent:

Fetal Bovine Serum(Gibco，10999141C)

FBS Dialyzed(Invitrogen；30067334)

Ham's F-12K(Kaighn's)Medium(Hyclone；SH30526.01)

Penicillin-Streptomycin，Liquid(Gibco；15140122)

Hygromycin B(Invivogen；ant-hg-5)

Lipofectamine LTX and Plus TM Reagent(Invivogen；15338-100)

Serotonin HCl(Selleck；S4244)

Forskolin(Selleckchem；S2449)

BSA stabilizer(Perkin Elmer；CR84-100)

cAMP kit(Cisbio；62AM4PEC)

IBMX(Sigma；I5879)

HEPES(Gibco；15630080)

HBSS(Gibco；14025076)

3. the experimental method comprises the following steps:

2) Complete medium: ham's F K +10% FBS +1 Penicilin-Streptomyces +600 μ g/mL Hygromycin B; experiment culture medium: ham's F K +10% DFBS +1 Penicilin-Streptomycin +

3) Culturing 5-HT1A cell line at 37 deg.C under 5% CO2 environment, inoculating with complete culture medium to 6cm cell culture dish, and culturing overnight at inoculation density of 0.9 × 10 ⁶ 。

4) 6ug of GNAI3 plasmid was transfected with Lipo LTX transfection reagent and cultured overnight at 37 ℃ in 5% CO2 environment.

5) Cells were digested, resuspended in assay buffer, plated into 384 cell culture plates at 8000 density per well and 15 μ l per well.

6) Compounds were diluted with assay buffer, 2.5. Mu.L of compound was added to each well and incubated at 37 ℃ for 5 minutes.

7) 2.5. Mu.l of 4uM 8 forskolin diluted in the previous step was added and incubated at 37 ℃ for 10 minutes

8) The cAMP-d2 and Anti-cAMP-Eu3+ are frozen and thawed, and diluted by lysine buffer; add 10. Mu.L cAMP-d2 to the experimental wells, then add 10. Mu.L Ulight-Anti-cAMP to the experimental wells; the reaction plate was centrifuged at 200g for 30s at room temperature, allowed to stand at 25 ℃ for 1h, and data was collected by Envision

4. The experimental data processing method comprises the following steps:

1)

％Activity＝(Signalcmpd-SignalAve_VC)/(SignalAve_PC-SignalAve_VC)×100

2) Compound EC was calculated using GraphPad non-linear fitting equation ₅₀ :

Y＝Bottom+(Top-Bottom)/(1+10^((LogEC ₅₀ -X)*HillSlope))

X: log value of compound concentration; y: activation%

5. And (4) experimental conclusion:

the compounds of the examples shown in the present invention showed good partial agonistic activity in experiments on the effect of cAMP by stably expressing 5-HT1A receptor cells.

Test example 3 determination of the Effect of the Compounds of the invention on 5-HT1D receptor cellular cAMP content

1. Purpose of the experiment:

the activation of 5-HT1D receptors by compounds is measured.

2. Laboratory instruments and reagents:

2.1 Instrument:

384 well-assay plates (Perkin Elmer; 6007680)

96-well conical btm PP Plt nature RNASE/Dnase-free plate(ThermoFisher；249944)

EnVision(Perkin Elmer)

2.2 reagent:

Fetal Bovine Serum(Gibco，10999141C)

FBS Dialyzed(Invitrogen；30067334)

Ham's F-12K(Kaighn's)Medium(Hyclone；SH30526.01)

Penicillin-Streptomycin，Liquid(Gibco；15140122)

Lipofectamine LTX and Plus TM Reagent(Invitrogen；15338-100)

Serotonin HCl(Selleck；S4244)

Forskolin(Selleckchem；S2449)

BSA stabilizer(Perkin Elmer；CR84-100)

cAMP kit(Cisbio；62AM4PEC)

IBMX(Sigma；I5879)

HEPES(Gibco；15630080)

HBSS(Gibco；14025076)

3. the experimental method comprises the following steps:

Complete medium:

Ham's F12K+10％FBS Dialyzed

2) Culturing the CHO-GNAI3 cell line at 37 ℃ 5% CO ₂ Inoculating with complete culture medium to 6cm cell culture dish overnight under the condition of environment, and inoculating with density of 0.9 × 10 ⁶ 。

3) Transfection of the 5HT1D plasmid into CHO-GNAI3 cells was incubated overnight.

4) Cells were digested, resuspended in assay buffer, plated into 384 cell culture plates at 8000 density per well and 15 μ l per well.

5) Compounds were diluted with assay buffer, 2.5. Mu.L of compound was added to each well and incubated at 37 ℃ for 5 minutes.

6) 2.5. Mu.l of 4uM 8 forskolin diluted in the previous step was added and incubated at 37 ℃ for 10 minutes

7) The cAMP-d2 and Anti-cAMP-Eu3+ are frozen and thawed, and diluted by lysine buffer; add 10. Mu.L cAMP-d2 to the experimental wells, then add 10. Mu.L Ulight-Anti-cAMP to the experimental wells; the reaction plate was centrifuged at 200g for 30s at room temperature, allowed to stand at 25 ℃ for 1h, and data was collected by Envision

4. The experimental data processing method comprises the following steps:

1)％Activity＝(Signalcmpd-SignalAve_VC)/(SignalAve_PC-SignalAve_VC)×100

Y＝Bottom+(Top-Bottom)/(1+10^((LogEC ₅₀ -X)*HillSlope))

X: log value of compound concentration; y: activation%

5. The experimental results are as follows:

EC50 values of the Effect of the Compounds of the examples on the cAMP content of 5-HT1D receptor cells

Examples	EC50(nM)
		14-1	129
112-1	54
		118-2	124

6. The experimental conclusion is that:

the compounds of the examples shown in the present invention showed good partial agonistic activity in experiments of the effect of transient expression of 5-HT1D receptor cells on cAMP.

Test example 4 determination of the binding Capacity of Compounds of the invention to 5-HT1A receptor

1. Purpose of the experiment:

the purpose of this test example was to measure the affinity of compounds for the 5-HT1A receptor.

2. Laboratory instruments and reagents:

2.1 Instrument:

vortex mixer (IKA; MS3 basic)

Electric constant temperature incubator (Shanghai Yiheng; DHP-9032)

Micro-plate vibrating screen (VWR; 12620-928)

TopCount(PerkinElmer；NTX)

Universal Harvester(PerkinElmer；UNIFILTER-96)

2.2 Experimental reagents:

[ ³ H]-8-Hydroxy-DPAT(PerkinElmer NET 929250UC)

Metergoline(Sigma；M3668-500MG)

ULTIMA GOLD(Perkin Elmer；77-16061)

96round deep well plate 1.1mL(Perkin Elmer；P-DW-11-C)

UNIFILTER-96GF/B filter plate(PerkinElmer；6005174)

PEI，branched(Sigma；408727)

centrifuge tube (BD, 352096

Loading slot(JET BIOFIL；LTT001050)

Pipette tip (Axygen; T-300-R-S, T-200-Y-R-S, T-1000-B-R-S)

Magnesium sulfate (Sigma; M2643)

Tris-base(Sigma；77-86-1)

Bovine Serum AIbumin(Sigma；9048-46-8)

EDTA(Invitrogen；15575-038)

HCl(Beijing XingJing Precision Chemical Technology CO.,LTD)

L-Ascorbic acid(Sigma；255564-100G)

3. The experimental method comprises the following steps:

experiment buffer solution: 50mM Tris-HCl pH 7.4,10mM MgSO4,0.5mM EDTA,0.1% ascorbic acid; washing liquid: 50mM Tris-HCl pH 7.4,4 ℃ storage;0.5% PEI solution:0.5ml PEI dissolution in 100mL ddH2O, storage at 4 deg.C

mu.L of test compound (0.005 nM-100nM, 10 concentrations in total) and 95. Mu.L buffer were added to the 96-well assay plate. Prepare 1.5. Mu.L of cell membrane and 298.5ul reaction buffer, shake for 5min at 600 rpm. Each well was filled with 100. Mu.L of a buffer solution and [2 ] ³ H]Adding a mixed solution of-8-Hydroxy-DPAT (final concentration of 0.5 nM) into the reaction system, shaking at 600rpm for 5min, and incubating at 27 ℃ for 30min. UNIFILTER-96GF/B filter plate preincubated for 1h with 0.5% PEI was washed 2 times with 1ml/well buffer and the cell membrane suspension was added to the UNIFILTER-96GF/B filter plate and washed 4 times with buffer, incubated for 10min at 55 ℃ and 40. Mu.L ULTIMA GOLD per well and counted by liquid scintillation.

4. The experimental data processing method comprises the following steps:

percentage inhibition calculated from readings of High control (DMSO control) and Low control (100 nM positive compound) test groups by TopCount reading CPM (Counts per minute) values ³ H]-Ketanserin binding data {% inhibition = (CPM) _sample -CPM _{low control} )/(CPM _{high control} -CPM _{low control} ) X 100, concentration of compound 10 after 3-fold dilution of the reaction system from 100nM to 0.005nM, IC of compound calculated using GraphPad prism fitting percent inhibition and ten-point concentration data to parametric nonlinear logical equations ₅₀ The value is obtained.

5. The experimental results are as follows:

example Compounds stably express the IC of 5-HT1A receptor cell Effect on cAMP ₅₀ The value is obtained.

Examples	IC ₅₀ (nM)
		11-1	34
11-2	70
		14-1	51
24-1	70
		111-1	83
112-1	83

5. And (4) experimental conclusion:

the compounds of the invention have good affinity for 5-HT 1A.

Claims

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:

Z ¹ ，Z ² ，Z ³ each independently selected from N, CH or S, optionally further substituted;

R ³ ，R ⁴ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitroAlkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy or hydroxyalkyl, optionally may be further substituted;

When R is ⁹ And R ¹⁰ One of them is H and the other is

When R is ⁵ ，R ⁶ Not H at the same time.

When R is ⁹ And R ¹⁰ One of them is H and the other is

When R is ⁵ ，R ⁶ Is not simultaneousIs H.

2. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 1, which is further represented by general formula (II-1) or (II-2):

R ³ ，R ⁴ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl, optionally may be further substituted;

R ⁹ ，R ¹⁰ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl, optionally can be substitutedIs further substituted.

3. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 2,

R ³ ，R ⁴ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Deuterated alkyl, C substituted with one or more halogens _1-8 Alkyl radical, C _1-8 Alkoxy, one or more halogen substituted C _1-8 Alkoxy radical, C _1-8 Alkylamino or C _1-8 Hydroxyalkyl, and optionally may be further substituted;

preferably, R ³ ，R ⁴ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, C substituted with one or more halogens _1-6 Alkyl radical, C _1-6 Alkoxy, one or more halogen substituted C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 Hydroxyalkyl, and optionally may be further substituted; more preferably, R ³ ，R ⁴ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, C substituted with one or more halogens _1-4 Alkyl radical, C _1-4 Alkoxy, one or more halogen substituted C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 Hydroxyalkyl, and optionally further substituted with one or more of deuterium, halogen, C _1-4 Alkyl or C _3-8 Cycloalkyl substitution;

more preferably, R ³ ，R ⁴ Each independently selected from hydrogen, deuterium, fluorine, chlorine, methyl or

R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Deuterated alkyl, halogenated C _1-8 Alkyl radical, C _1-8 Alkoxy, halo C _1-8 Alkoxy radical, C _1-8 Alkylamino, and optionally may be further substituted;

preferably, R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, halogenated C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy or C _1-6 Alkylamino, and optionally may be further substituted; more preferably, R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, halogenated C _1-4 Alkyl radical, C _1-4 Alkoxy, halo C _1-4 Alkoxy or C _1-4 Alkylamino, optionally further substituted with one or more deuterium, halogen;

more preferably, R ⁵ ，R ⁶ ，R ⁷ ，R ⁸ Each independently selected from hydrogen, deuterium, fluoro, chloro or methyl;

or, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form C together with adjacent atoms _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-12 Aryl or 5-12 membered heteroaryl, and optionally may be further substituted;

preferably, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form C together with adjacent atoms _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl, and optionally may be further substituted; more preferably, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively adjacent to atom oneForm C _3-8 Cycloalkyl, 3-8 membered heterocyclyl, C _6-8 Aryl or 5-8 membered heteroaryl, and optionally may be further substituted;

more preferably, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form C together with adjacent atoms _3-5 Cycloalkyl, and optionally further substituted with one or more deuterium or halogen;

further preferably, R ⁵ And R ⁶ Or R ⁷ And R ⁸ Respectively form cyclopropyl with adjacent atoms;

R ⁹ ，R ¹⁰ each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, halogenated C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radical, C _1-6 Alkylamino radical, C _1-6 Deuterated alkylamino, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-12 Aryl or 5-12 membered heteroaryl, and optionally further substituted with one or more deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

preferably, R ⁹ ，R ¹⁰ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, halogenated C _1-4 Alkyl radical, C _1-4 Alkoxy, halo C _1-4 Alkoxy radical, C _1-4 Alkylamino radical, C _1-4 Deuterated alkylamino, C _3-10 Cycloalkyl, 3-10 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, and optionally further substituted with one or more deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroarylGeneration;

more preferably, R ⁹ ，R ¹⁰ Each independently selected from hydrogen, deuterium, halogen, C _1-4 Alkyl radical, C _1-4 Alkylamino radical, C _1-4 Deuterated alkylamino or 3-6-membered heterocyclyl, and optionally further substituted with one or more deuterium, halogen, C _1-4 Alkyl radical, C _1-4 Deuterated alkyl, halogenated C _1-4 Alkyl or C _3-6 Cycloalkyl substitution;

further preferably, R ⁹ ，R ¹⁰ Each independently selected from hydrogen, deuterium, methyl,

4. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 2, which is further represented by general formula (II-1A) or (II-2A):

R ³ ，R ⁴ ，R ⁷ ，R ⁸ ，R ⁹ and R ¹⁰ Is as defined in claim 2.

5. The compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 4,

R ⁹ ，R ¹⁰ each independently selected from hydrogen, deuterium, methyl, 5-6 membered heterocyclic group containing 1-2 nitrogen atoms or-CR ^b R ^c NHR ^d ；

R ^d is selected from C _1-3 Alkyl radical, C _1-3 Haloalkyl, C _1-3 Deuterated alkyl or C _3-6 A cycloalkyl group, preferably a methyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trideuteromethyl or cyclopropyl group.

6. A compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

the following groups are even more preferred:

R ^a selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, halogenated C _1-6 Alkyl radical, C _1-6 Alkoxy, halo C _1-6 Alkoxy radicalBase, C _1-6 Alkylamino radical, C _1-6 A deuterated alkylamino group; preferably, R ^a Selected from hydrogen or F;

R ²¹ selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, deuterated alkylamino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally being further substituted; preferably, R ²¹ Is C substituted by one or more substituents _1-6 Alkylamino, the substituent being C _1-6 An alkyl group; more preferably, R ²¹ Is selected from

R ²² ，R ²³ Each independently selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl, wherein said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, or hydroxyalkyl, optionally may be further substituted;

preferably, R ²² ，R ²³ Each independently selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-8 Alkyl radical, C _2-8 Alkenyl radical, C _2-8 Alkynyl, C _1-8 Deuterated alkyl, C substituted with one or more halogens _1-8 Alkyl radical, C _1-8 Alkoxy, one or more halogen substituted C _1-8 Alkoxy radical, C _1-8 Alkylamino or C _1-8 Hydroxyalkyl, and optionally may be further substituted;

more preferably, R ²² ，R ²³ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _2-6 Alkenyl radical, C _2-6 Alkynyl, C _1-6 Deuterated alkyl, C substituted with one or more halogens _1-6 Alkyl radical, C _1-6 Alkoxy, one or more halogen substituted C _1-6 Alkoxy radical, C _1-6 Alkylamino or C _1-6 Hydroxyalkyl and optionally may be further substituted;

further preferably, R ²² ，R ²³ Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C _1-4 Alkyl radical, C _2-4 Alkenyl radical, C _2-4 Alkynyl, C _1-4 Deuterated alkyl, C substituted with one or more halogens _1-4 Alkyl radical, C _1-4 Alkoxy, one or more halogen substituted C _1-4 Alkoxy radical, C _1-4 Alkylamino or C _1-4 Hydroxyalkyl, and optionally further substituted with one or more of deuterium, halogen, C _1-4 Alkyl radical, C _3-8 Cycloalkyl substitution;

even more preferably, R ²² ，R ²³ Each independently selected from hydrogen, deuterium, fluoro, chloro, methyl or ethyl.

7. The compound, the stereoisomer or the pharmaceutically acceptable salt thereof is characterized by having the following structure:

8. the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, according to claim 6, wherein the compound has the structure:

9. a process for the preparation of a compound of formula (II-1A or (II-2A) as defined in claim 4, comprising the steps of:

reacting the general formula compound (M-1A) or (M-2A) with the general formula compound (M-2) to obtain a general formula compound (II-1A) or (II-2A); wherein R is ₃ 、R ₄ 、R ₇ 、R ₈ 、R ₉ And R ₁₀ As defined above.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

11. Use of a compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a TAAR1 receptor agonist medicament.

12. Use of a compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the treatment, prevention or management of neurological disorders.

13. The use according to claim 11, wherein the neurological disorder is selected from schizophrenia, social dysfunction disorders or psychosis; preferably, schizophrenia is selected from the group consisting of schizophrenic disorders, acute schizophrenia, chronic schizophrenia, NOS schizophrenia, paranoid schizophrenia, schizophreniform personality disorder or schizotypal personality disorder; <xnotran> , , , , , , , , , , , , NOS , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , lesche-Nyhane , , , . </xnotran>