WO2021032074A1

WO2021032074A1 - Benzamide fused aromatic ring derivative, preparation method therefor and application thereof in medicine

Info

Publication number: WO2021032074A1
Application number: PCT/CN2020/109692
Authority: WO
Inventors: 杨方龙; 郁楠; 王伟民; 刘志伟; 贺峰; 陶维康
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2019-08-19
Filing date: 2020-08-18
Publication date: 2021-02-25
Also published as: TW202115038A

Abstract

The present disclosure relates to a benzamide fused aromatic ring derivative, a preparation method therefor and an application thereof in medicine. Specifically, the present disclosure relates to a benzamide fused aromatic ring derivative represented by a general formula (I), a preparation method therefor, a pharmaceutical composition comprising the derivative and a use thereof as a therapeutic agent, as well as use thereof as an Na_V1.8 inhibitor and a use thereof in the preparation of a medicament for treating and/or preventing pain and pain-related diseases. Each substituent of the general formula (I) is the same as defined in the description.

Description

Benzamide fused aromatic ring derivatives, preparation method thereof and application in medicine

Technical field

The present disclosure belongs to the field of medicine, and relates to a benzamide fused aromatic ring derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially The use as a Na _V inhibitor and its use in preparing medicines for treating and/or reducing pain and pain-related diseases.

Background technique

Pain is a complex physical and psychological activity and one of the most common symptoms in clinical practice. The International Association for Pain Research defines pain as "an unpleasant feeling and emotional feeling accompanied by substantial or potential tissue damage. It is a subjective feeling." Pain can be used as a warning signal to remind The body pays attention to potential dangers and has an indispensable protective effect on the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that caused the pain disappears, strong or long-lasting pain can cause disorders of physiological functions and seriously affect the quality of life of the living body. Statistics show that about one-fifth of people in the world suffer from moderate to severe chronic pain.

Pain originates from nociceptors in the peripheral nervous system. This is a kind of free nerve endings, which are widely distributed in the skin, muscles, joints and visceral tissues of the whole body. It can convert the thermal, mechanical or chemical stimulation felt into nerve impulses (action potentials) and pass them through Incoming nerve fibers are transmitted to the body part of the dorsal root ganglia (DRG), and finally transmitted to the higher nerve center, causing pain. The generation and conduction of action potentials in neurons relies on voltage-gated sodium channels (Na _V ) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated and the channel opens, causing the influx of sodium ions, further depolarizing the cell membrane, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity is helpful for the treatment and relief of pain.

Na _V is a type of transmembrane ion channel protein. These proteins consist of an alpha subunit with a molecular weight of 260kD and a beta subunit with a molecular weight of 30-40kD. According to the different α subunits, it can be divided into 9 subtypes, Na _V ll ~ Na _V 1.9. Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics. According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium ion channels are classified into TTX sensitive (TTX-S) and TTX insensitive (TTX-R). Among them, Na _V 1.1, Na _V 1.2, Na _V 1.3, and Na _V 1.7 are TTX-S type, and the coding genes are located in human chromosome 2q23-24, and they are expressed in large amounts in neurons. Na _V 1.5, Na _V 1.8 and Na _V 1.9 are TTX-R type, and the coding gene is located on human chromosome 3p21-24. Among them, Na _V 1.5 is mainly present in cardiomyocytes, and Na _V 1.8 and Na _V 1. 9 are present in the peripheral nervous system. Both Na _V 1.4 and Na _V 1.6 are TTX-S type, which are abundant in skeletal muscle and central nervous system respectively. Local anesthetic lidocaine for pain by inhibiting Na _V. Non-selective Na _V inhibitors, such as lamotrigine, lacosamide, and mexiletine have been successfully used to treat chronic pain.

Na _V 1.8 is of TTX-R type, and the coding gene is SCN10A. It mainly exists in trigeminal ganglion neurons and DRG neurons, and has electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Na _V 1.8, the rise of action potential is mainly composed of Na _V 1.8 current. In some models of neuropathic pain, nerve damage will _{increase the expression level of Na V} 1.8 in axons and neuron cell bodies. The use of Na _V 1.8 antisense oligonucleotides can significantly relieve pain while _{reducing the expression of Na V 1.8.} After carrageenan was injected into the paws of rats, the expression _{of Na V 1.8 in DRG neurons increased.} Na _V 1.8 knockout mice cannot show normal visceral inflammation pain. After the human Na _V 1.8 gene has a functional gain mutation, it will cause peripheral neuralgia. Based on a series of animal experiments and human genetic evidence, selective inhibition of Na _V 1.8 has the potential to become a new type of analgesic therapy, which can be used for the treatment of inflammatory pain, nerve pain, postoperative pain, cancer pain and other types of pain.

Due to the lack of subtype selectivity in clinical use of Na _V inhibitors, it can inhibit sodium channels expressed in the heart and central nervous system, so the therapeutic window is narrow and the scope of application is limited. Na _V 1.8 is mainly distributed in the peripheral nervous system, so selective inhibition of Na _V 1.8 can effectively reduce side effects. Necessary to develop higher activity, better selectivity, better pharmacokinetic properties, fewer side effects of inhibitors of Na _V 1.8.

Summary of the invention

The purpose of the present disclosure is to provide a compound represented by general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt:

among them:

X is selected from CH, C atom and N atom;

Y is selected from CH, C atom and N atom;

M is selected from H ₂ , NH, O atom and S atom;

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

R ^{1 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

R ^{2 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -CH ₂ OR ^w , cycloalkyl and heterocyclic group; R ^{w is} selected from hydrogen atom, alkyl _{group, -S (O) 2 OH,} -S (O) 2 O - Q +, -PO (OH) 2, -PO (O -) 2 Q + 2 ,, - PO (OH) O ^- Q ⁺ and ^{_{^{-PO (O -) 2 W 2+}}} ; Q + is a monovalent pharmaceutically acceptable cation; W ²⁺ cation is a pharmaceutically acceptable divalent;

R ^{3 are the} same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

R ^{4 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

R ^{5 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

n is 0, 1, 2, 3, 4 or 5;

m is 0, 1, 2 or 3;

s is 0, 1, 2 or 3; and

t is 0, 1, 2, or 3.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the X is CH.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the Y is CH.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the M is an O atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from cycloalkyl, heterocyclic and aryl, preferably cycloalkyl, more preferably cyclopentyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Structure, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from cyclopentyl, cyclohexyl, phenyl and

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R ^{1 is the} same or different, and each independently is a hydrogen atom or an alkyl group, preferably a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R ^{2 is} selected from hydrogen atom, halogen, alkyl group and -CH ₂ OR ^w ; R ^w is -PO(OH) ₂ .

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R ^{3 is the} same or different, and each is independently selected from a hydrogen atom, a halogen and an alkyl group, preferably a halogen.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R ^{4 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group and a halogenated alkyl group, preferably a halogen or a halogenated alkyl group, and more Preferably, it is a Cl atom or a trifluoromethyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R ^{5 is the} same or different, and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group and a halogen, preferably a hydrogen atom or an alkyl group, and more Preferably it is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the n is 2.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer In the form of a construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, the s is 1 or 2, preferably 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by general formula (II), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:

Wherein X, Y, M, ring A, R ¹ , R ³ , R ⁴ , R ⁵ , m, n, s and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by general formula (III), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt, which is the compound represented by the general formula (IV), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:

The R ¹ , R ² , R ³ , R ⁴ , R ⁵ , m, n, s, and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by general formula (IVB) or (IVD), or its tautomer, meso, racemate, or Enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:

Wherein R ¹ , R ³ , R ⁴ , R ⁵ , m, n, s and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt, which is a compound represented by the general formula (V), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:

Wherein said R ^4a or R ^{4b are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro Group, cycloalkyl, heterocyclyl and heterocyclylalkyl;

The R ¹ , R ² , R ³ and m are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or its mixture form or its pharmaceutically acceptable salt, is a compound represented by the general formula (VB) or (IVD), or its tautomer, meso, racemate, or pair Enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:

The R ¹ , R ³ and m are as defined in the general formula (I).

In some embodiments of the present disclosure, the compounds represented by the general formulas (V), (VB) and (VD), or tautomers, mesosomes, racemates, enantiomers thereof Isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R ^4a is halogen, preferably Cl atom.

In some embodiments of the present disclosure, the compounds represented by the general formulas (V), (VB) and (VD), or tautomers, mesosomes, racemates, enantiomers thereof Isomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R ^4b is haloalkyl, preferably trifluoromethyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, or diastereomer Conformer, or its mixture form or its pharmaceutically acceptable salt, which is the compound represented by the general formula (VI), or its tautomer, meso, racemate, enantiomer , Diastereomers, or mixtures or pharmaceutically acceptable salts thereof:

Wherein said R ^4c or R ^{4d are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro Group, cycloalkyl, heterocyclyl and heterocyclylalkyl;

The X, Y, ring A, M, R ¹ , R ² , R ³ , R ⁵ , m, s and t are as defined in the general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (VI), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said R ^4c is halogen, preferably a Cl atom.

In some embodiments of the present disclosure, the compound represented by the general formula (VI), or its tautomer, meso, racemate, enantiomer, or diastereomer The structure, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein said R ^4d is a haloalkyl group, preferably a trifluoromethyl group.

Typical compounds of the present disclosure include but are not limited to:

Or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof.

Another aspect of the present disclosure relates to the compound represented by the general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:

It can be used as an intermediate for preparing the compound represented by general formula (II);

Wherein said ^Ra is an alkyl group, preferably a methyl group;

The X, Y, M, ring A, R ¹ , R ³ , R ⁴ , R ⁵ , m, n, s and t are as defined in the general formula (I).

Another aspect of the present disclosure relates to a compound represented by general formula (IVA) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or its pharmaceutically acceptable salt:

Can be used as an intermediate for the preparation of compounds of general formula (IV),

Wherein said ^Ra is an alkyl group, preferably a methyl group;

The R ¹ , R ³ , R ⁴ , R ⁵ , m, n, s and t are as defined in the general formula (IV).

Another aspect of the present disclosure relates to a compound represented by the general formula (VA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof Form or its pharmaceutically acceptable salt:

Can be used as an intermediate for the preparation of compounds of general formula (V),

Wherein said ^Ra is an alkyl group, preferably a methyl group;

The R ¹ , R ³ , R ^4a , R ^4b and m are as defined in the general formula (V).

Another aspect of the present disclosure relates to the compound represented by the general formula (VIA) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:

Can be used as an intermediate for the preparation of compounds of general formula (VI),

Where Z is halogen;

Said R ^4c is halogen, R ^4d is halogenated alkyl or R ^4d is halogen, R ^4c is halogenated alkyl;

The X, Y, R ¹ and m are as defined in the general formula (VI).

Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form or pharmaceutically acceptable salt thereof Under acidic conditions, the compound of general formula (II) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its combination Medicinal salt,

Wherein, said ^Ra is an alkyl group, preferably a methyl group;

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IVB) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the general formula (IVA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form or pharmaceutically acceptable salt thereof Under acidic conditions, the compound of general formula (IVB) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its combination Medicinal salt,

Wherein, the ^Ra is an alkyl group, preferably a methyl group; the R ¹ , R ³ , R ⁴ , R ⁵ , m, n, s and t are as defined in the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VB) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (VA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt Under acidic conditions, the compound of general formula (VB) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form or its alternative Medicinal salt,

Wherein, the ^Ra is an alkyl group, preferably a methyl group; the R ^4a , R ^4b , R ¹ , R ³ , and m are as defined in the general formula (V).

The present disclosure relates to the preparation of compounds represented by general formula (II), (IVB) or (VB) or tautomers, mesosomes, racemates, enantiomers, diastereomers A method for constructing a structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the reagent providing acidic conditions includes but not limited to pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonate The acid is preferably pyridine hydrobromide.

Another aspect of the present disclosure relates to the compound represented by the general formula (IVC) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:

Can be used as an intermediate for preparing compounds of general formula (IVD),

The R ¹ , R ³ , R ⁴ , R ⁵ , m, n, s, and t are as defined in the general formula (IV).

Another aspect of the present disclosure relates to the compound represented by the general formula (VC) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt:

Can be used as an intermediate for preparing compounds of general formula (VD),

Another aspect of the present disclosure relates to a preparation of a compound represented by the general formula (IVD) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IVC) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt Heating reaction under acidic conditions to obtain the compound of general formula (IVD) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or Medicinal salt,

Wherein, the R ¹ , R ³ , R ⁴ , R ⁵ , m, n, s and t are as defined in the general formula (I).

Another aspect of the present disclosure relates to a preparation of a compound represented by the general formula (VD) or its tautomer, meso, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (VC) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt Heating reaction under acidic conditions to obtain the compound of general formula (VD) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or Medicinal salt,

Wherein, the R ^4a , R ^4b , R ¹ , R ³ and m are as defined in the general formula (V).

The present disclosure relates to the preparation of compounds represented by the general formula (IVD) or (VD) or tautomers, mesosomes, racemates, enantiomers, diastereomers, or In the form of a mixture or a pharmaceutically acceptable salt thereof, the reagent for providing acidic conditions includes, but is not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably Acetic acid; the heating reaction temperature is preferably 80°C.

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VI) or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, Or a method in the form of a mixture or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (VIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt and The compound of general formula (VIB) is reacted to obtain a compound of general formula (VI) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form or its pharmaceutically acceptable salt,

Wherein, said Z is halogen;

M is S atom or O atom;

The X, Y, ring A, R ¹ , R ³ , R ⁵ , m, s, and t are as defined in the general formula (VI).

The present disclosure relates to the preparation of intermediate compounds of the general formula (I) including but not limited to:

Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its tautomer, mesosome, racemic Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, Or the use of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation of a medicament for inhibiting voltage-gated sodium channels in a subject. The voltage-gated sodium channel is preferably Na _V 1.8.

The present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in preparation for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, and Char-Martin-Tusan syndrome , Incontinence or arrhythmia drugs. Preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

The present disclosure also relates to a method for inhibiting a voltage-gated sodium channel in a subject, the method comprising administering to a patient in need thereof the compound represented by the general formula (I) of the present disclosure or its tautomer, The meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. The voltage-gated sodium channel is preferably Na _V 1.8.

The present disclosure also relates to a method of treating and/or alleviating pain and pain-related diseases, multiple sclerosis, Char-Martin-Tuson syndrome, incontinence, or arrhythmia, the method comprising administering to a patient in need thereof The compound represented by the above-mentioned general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. Preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

The present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for use as a medicine.

The present disclosure also relates to a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used to inhibit voltage-gated sodium channels in a subject. The voltage-gated sodium channel is preferably Na _V 1.8.

The present disclosure also relates to a compound represented by the general formula (I) as described above or its tautomer, mesoisomer, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, and Charma-Martin syndrome , Incontinence or arrhythmia. Preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

The neuropathic pain described in the present disclosure is preferably selected from the group consisting of trigeminal neuralgia, postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, burn syndrome, post-amputation pain, pain after spinal cord injury, phantom Pain, painful neuroma, traumatic neuroma, Morton neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, nerve root pain, sciatica, nerve avulsion, brachial plexus avulsion Injuries, complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, primary small fiber neuropathy, primary sensory neuralgia, and trigeminal Autonomic headache.

The musculoskeletal pain described in the present disclosure is preferably selected from osteoarthritis pain, back pain, cold pain, burning pain and toothache.

The intestinal pain described in the present disclosure is preferably selected from inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis pain.

The inflammatory pain described in the present disclosure is preferably selected from rheumatoid arthritis pain and vulvar pain.

The idiopathic pain described in the present disclosure is preferably fibromyalgia.

The active compound can be prepared in a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or a form in which the patient can self-administer in a single dose. The expression mode of the unit dose of the compound or composition of the present disclosure can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation.

The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose can be 0.1-1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

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

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil. The oil suspension may contain thickening agents. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

By adding water, dispersible powders and granules suitable for preparing water suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweetening agents, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil, or mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. The acceptable solvents or solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. The sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local mass injection. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil can be used. In addition, fatty acids can also be used to prepare injections.

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

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of compound (I) or the amount of pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan.

Definition of Terms

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

The term "alkyl" refers to a saturated 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 containing 1 to 6 carbon atoms An alkyl group of carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred is a lower alkyl group containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably independently selected from H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl, and alkoxy , Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl substituted by one or more substituents.

The term "alkylene" refers to a saturated linear or branched aliphatic hydrocarbon group, which has 2 residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is A straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 12 carbon atoms, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylene (-CH _{2 -)} CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently optionally selected from alkyl, alkenyl, alkynyl , Alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy Substituted by one or more substituents in the group, cycloalkylthio, heterocycloalkylthio and oxo.

The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, halogenated alkyl groups, hydroxyl groups, It is substituted by one or more substituents among hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 The carbon atom more preferably contains 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure The ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.

Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) p (where p is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms, of which 1-3 are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 One is a heteroatom; most preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl and so on. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _p (where p is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, where one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _p (where p is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _p (where p is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring includes the heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the group is The structures linked together are heterocyclic groups, non-limiting examples of which include:

Wait.

The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. The fused polycyclic aryl group is a fused aryl group, including the above-mentioned aryl ring fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure Is an aryl ring, non-limiting examples include:

The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups. One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, Imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes the aforementioned heteroaryl group fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :

Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term monovalent cation includes ammonium, alkali metal ions (such as sodium, lithium, and potassium ions), dicyclohexylamine ions, and N-methyl-D-reduced glucosamine ions. Divalent cations include alkaline earth metal ions, such as calcium and magnesium ions, and divalent aluminum ions. It also includes amino acid cations, such as monovalent or divalent ions such as arginine, lysine, ornithine.

The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

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

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

The term "hydroxy" refers to the -OH group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

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

The term "hydroxy" refers to the -OH group.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "carbonyl" refers to C=O.

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

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

The present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

"Optional" or "optionally" means that the event or environment described later can but does not necessarily occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration of the biological body, facilitate the absorption of the active ingredient and then develop the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in the body of a mammal, and has due biological activity.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, in addition to using "deuterium" or "tritium" instead of hydrogen, or using ¹⁸ F-fluorine label ( ¹⁸ F isotope) instead of fluorine, or using ¹¹ C-, ¹³ C-, or ¹⁴ C-rich Compounds in which a set of carbons ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

Synthetic method of the compound of the present disclosure

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

Option One:

The preparation method of compound 1 of the present disclosure or its salt includes the following steps:

Compound 1f is reacted under acidic conditions to obtain compound 1;

The reagent for providing acidic conditions includes, but is not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably pyridine hydrobromide.

Option II:

The preparation method of compound 2 of the present disclosure or its salt includes the following steps:

In the first step, compound 1 undergoes an alkylation reaction in the presence of an alkylating reagent (preferably chloromethyl chloroformate) to obtain compound 2a.

In the second step, compound 2a is heated (preferably 80°C) under catalytic conditions (preferably tetrabutylammonium iodide) to perform phosphorylation reaction (preferably di-tert-butyl potassium phosphate) to obtain compound 2b,

In the third step, compound 2b is reacted under acidic conditions (acid reagent is preferably acetic acid) and heated (preferably 80°C) to obtain compound 2.

third solution

The compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmacologically The salt method used includes:

Wherein, said ^Ra is an alkyl group, preferably a methyl group;

Option Four

The compound represented by the general formula (IVB) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmacologically The salt method used includes:

Option Five

The compound represented by the general formula (VB) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmacologically The salt method used includes:

The reagents for providing acidic conditions include but are not limited to pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably pyridine hydrobromide.

Option Six

The compound represented by the general formula (IVD) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmaceutically acceptable The salt method used includes:

Option Seven

The compound represented by the general formula (VD) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or pharmacologically The salt method used includes:

The reagents that provide acidic conditions include, but are not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably acetic acid; the heating reaction temperature is preferably 80°C.

Option Eight

The compound represented by the general formula (VI) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmacologically The salt method used includes:

The compound of general formula (VIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its pharmaceutically acceptable salt and The compound of general formula (VIB) is reacted under basic conditions to obtain the compound of general formula (VI) or its tautomer, meso, racemate, enantiomer, diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt,

Wherein, said Z is halogen;

The reagents that provide basic conditions in the above synthesis scheme include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine. Lithium propylamide, lithium bistrimethylsilylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide, the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate , Potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.

detailed description

The following embodiments are used to further describe the present disclosure, but these embodiments do not limit the scope of the present disclosure.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of ^{10 -6 (ppm).} NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis and determination use Agilent 1260 DAD high performance liquid chromatograph.

The HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm～0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ~0.5mm.

Silica gel thin-layer chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.

There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.

The microwave reaction uses the CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system; B: n-hexane/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Example 1

5-chloro-2-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl )-4-(Trifluoromethyl)benzamide 1

first step

5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid 1b

Under an argon atmosphere, 2,2,6,6-tetramethylpiperidine (19.2 g, 135.93 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added to 200 mL of tetrahydrofuran. Cool down to 0°C, add n-butyl lithium (1.6M, 85.1mL) dropwise, control the temperature to be lower than 3°C, complete the addition in about 45 minutes, and react at 0°C for 1 hour. The temperature was lowered to -78°C, 1-chloro-4-fluoro-2-(trifluoromethyl)benzene 1a (18g, 90.66mmol, Shanghai Titan Technology Co., Ltd.) was added dropwise, and the reaction was carried out for 3 hours. Add excess dry ice, naturally heat to 0°C, and add 150 mL ice water. Separate the liquids, add 2N dilute hydrochloric acid dropwise to pH 5-6, extract with 50 mL ethyl acetate, and concentrate the organic phase under reduced pressure. The crude product was washed with n-hexane (50 mL), and then purified by silica gel column chromatography with developing solvent system A to obtain the title compound 1b (15 g), yield: 68%.

MS m/z(ESI): 241.1[M-1].

Second step

5-chloro-2-fluoro-4-(trifluoromethyl)benzoyl chloride 1c

Compound 1b (8.0 g, 33 mmol) was dissolved in 10 mL of thionyl chloride and reacted at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 1c (8.60 g), which was directly used in the next reaction without purification.

third step

5-chloro-2-fluoro-N-(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 1d

The crude compound 1c (8.60g, 32.98mmol) and 2-methoxypyridine-4-amine (4.90g, 39.5mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) were dissolved in 80mL of dichloromethane, and pyridine (11g, 139mmol), react at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system A to obtain the title compound 1d (10 g), yield: 87%.

MS m/z(ESI): 349.0[M+1].

the fourth step

7-Fluoro-2,3-dihydro-1H-indene-4-phenol 1e

The compound 4-fluoro-7-hydroxy-2,3-dihydro-1H-indanone 1g (2.60g, 15.65mmol, prepared by a well-known method Bioorganic&Medicinal Chemistry Letters, 2010, 20, 1004) was dissolved in 12mL trifluoro Acetic acid, triethylsilane (4.55g, 39.12mmol, 6.23mL) was added, and the reaction was stirred at 80°C in an oil bath for 4 hours to stop the reaction. Cool the reaction, concentrate the reaction solution, add 20mL saturated sodium bicarbonate solution, extract with ethyl acetate (30mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and develop by silica gel column chromatography Reagent system B was purified to obtain the title compound 1e (1.67g), yield: 70%.

MS m/z(ESI): 151.1[M-1].

the fifth step

5-chloro-2-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-methoxypyridin-4-yl)-4-(three Fluoromethyl)benzamide 1f

Compound 1d (550mg, 1.58mmol), compound 1e (240mg, 1.58mmol) and cesium carbonate (1028mg, 3.15mmol) were added to N,N-dimethylformamide (6.5mL) and reacted at 100°C for 1 hour. Cool to room temperature, add 50 mL of water, extract with ethyl acetate (50 mL×3), combine the organic phases, wash the organic phases with saturated sodium chloride solution (50 mL), dry with anhydrous sodium sulfate, and concentrate to obtain the crude title compound 1f (750 mg ), the crude product is used directly in the next step.

Sixth step

Pyridine hydrobromide (1248 mg, 7.80 mmol, Shanghai Adamas Co., Ltd.) was added to the N,N-dimethylformamide solution (7 mL) of crude compound 1f (750 mg), and reacted at 100° C. for 1 hour. The reaction solution was added with water 50mL, methanol 20mL, extracted with dichloromethane (100mL×3), combined the organic phases, washed with water (50mL), saturated sodium bicarbonate aqueous solution (50mL), dried with anhydrous sodium sulfate, filtered, concentrated and evaporated to dryness To obtain the title compound 1 (620 mg), yield: 85%.

MS m/z(ESI): 466.0[M-1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 10.66 (s, 1H), 8.04 (s, 1H), 7.33 (d, 1H), 7.24 (s, 1H), 7.02 ( t, 1H), 6.94-6.90 (m, 1H), 6.71 (s, 1H), 6.35 (dd, 1H), 2.90 (t, 2H), 2.76 (t, 2H), 2.10-1.96 (m, 2H) .

Example 2

(4-(5-Chloro-2-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)benzamide)-2 -Oxopyridine-1(2H)-yl)methyl dihydrogen phosphate 2

first step

5-chloro-N-(1-(chloromethyl)-2oxo-1,2-dihydropyridin-4-yl)-2-((7-fluoro-2,3-dihydro-1H-indene -4-yl)oxy)-4-(trifluoromethyl)benzamide 2a

At room temperature, compound 1 (200mg, 0.43mmol) was dissolved in a mixed solution of 8.8mL of dichloromethane and N,N-dimethylformamide (V:V=10:1), and chloroformic acid chloride was slowly added with stirring. Methyl ester (275mg, 2.13mmol), after the addition, react at room temperature for 16 hours. Cool the reaction, concentrate the reaction solution, add saturated sodium bicarbonate solution (20mL), extract with ethyl acetate (30mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and use silica gel column chromatography Purified with the developing solvent system B to obtain the title compound 2a (195 mg), yield: 89%.

MS m/z(ESI): 513.0[M-1].

Second step

((4-(5-chloro-2-((7-fluoro-2,3-dihydro-1H-inden-4-yl)oxy)-4-(trifluoromethyl)benzamide)- 2-oxopyridyl-1(2H)-yl)methyl)di-tert-butyl phosphate 2b

Compound 2a (110 mg, 0.21 mmol) was dissolved in ethyl acetate (6.0 mL), and potassium di-tert-butyl phosphate (63.6 mg, 0.256 mmol) and tetrabutylammonium iodide (7.1 mg, 0.021 mmol) were added. The reaction was heated to 80°C and stirred for 1 hour. Cool the reaction to room temperature, concentrate, add saturated sodium bicarbonate solution (20mL), extract with ethyl acetate (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude title compound 2b (147mg), the product was used directly in the next step without purification.

third step

The crude compound 2b (147 mg, 0.213 mmol) was dissolved in 3 mL of a mixed solution of acetonitrile, acetic acid and water (V:V:V=1:1:1). The reaction was heated to 80°C and stirred for 1.5 hours to stop the reaction. The reaction was cooled to room temperature, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 2 (80 mg), yield: 65% .

MS m/z(ESI): 575.0[M-1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.79 (s, 1H), 8.05 (s, 1H), 7.63 (d, 1H), 7.22 (s, 1H), 7.02 (t, 1H), 6.95 6.87 (m, 1H), 6.84 (d, 1H), 6.40 (dd, 1H), 5.52 (d, 2H), 3.60-3.10 (s, 2H), 2.90 (t, 2H), 2.75 (t, 2H) ,2.10-1.98(m,2H).

Example 3

5-chloro-2-((5,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2-dihydropyridine- 4-yl-4-(trifluoromethyl)benzamide 3

first step

2,4-Difluorophenyl 3-chloropropionate 3b

The compound 2,4-difluorophenol 3a (5g, 38.4mmol (Shaoyuan Technology (Shanghai) Co., Ltd.)) was dissolved in dichloromethane (60mL), and pyridine (3.4g, 43mmol) was added. Slowly add 3-chloropropionyl chloride (5.9 g, 46.5 mmol Shaoyuan Technology (Shanghai) Co., Ltd.) dropwise under ice-water bath cooling, and react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium bicarbonate solution (40 mL) was added, extracted with ethyl acetate (40 mL×2), and the organic phases were combined. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by silica gel column chromatography with developing solvent system B to obtain the title compound 3b (7.5 g), yield: 89%.

Second step

4,6-Difluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one 3c

Compound 3b (6g, 27.2mmol) was mixed with aluminum trichloride (11g, 82.5mmol) uniformly, and reacted at 100°C for 15 minutes, and then heated to 170°C and reacted for 3 hours. Cool to room temperature, slowly add ice water and ethyl acetate, and crush the lumps with the help of an ultrasonic cleaner. It was filtered with Celite, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 3c (2.7 g), yield: 54%.

third step

5,7-Difluoro-2,3-dihydro-1H-indene-4-phenol 3d

Compound 3c (2.0 g, 10.9 mmol) was dissolved in trifluoroacetic acid (12 mL), triethylsilane (3.8 g, 32.7 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added, and reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Add saturated sodium bicarbonate solution (50 mL), extract with ethyl acetate (50 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by silica gel column chromatography with developing solvent system B to obtain the title compound 3d (1.0 g), yield: 52%.

the fourth step

5-chloro-2-((5,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-methoxypyridin-4-yl)-4 -(Trifluoromethyl)benzamide 3e

Compound 1d (200mg, 0.6mmol), compound 3d (98mg, 0.6mmol) and cesium carbonate (281mg, 0.9mmol) were added to N,N-dimethylformamide (10mL) and reacted at 80°C for 2 hours. The reaction was cooled to room temperature, filtered under reduced pressure, and the filtrate was used directly in the next step.

MS m/z(ESI): 499.2[M+1].

the fifth step

Pyridine hydrobromide (190 mg, 1.2 mmol) was added to the filtrate of the previous step and reacted at 100°C for 1 hour. The reaction solution was cooled to room temperature, and ethyl acetate (50 mL) and saturated sodium bicarbonate solution (50 mL) were added. The organic phase was separated, washed with water and saturated brine, dried with anhydrous sodium sulfate, filtered, concentrated, and purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain The title compound 3 (50 mg), yield: 18%.

MS m/z(ESI): 485.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 10.69 (s, 1H), 8.05 (s, 1H), 7.33-7.31 (m, 1H), 7.26-7.22 (m, 1H) ), 7.15 (s, 1H), 6.72 (s, 1H), 6.37-6.35 (m, 1H), 3.30-2.86 (m, 2H), 2.77-2.74 (m, 2H), 2.08-2.04 (m, 2H) ).

Example 4

5-chloro-2-((6,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2-dihydropyridine- 4-yl)-4-(trifluoromethyl)benzamide 4

first step

3,4-Difluorophenyl 3-chloropropionate 4b

Using the synthetic route of Example 3, the starting material 2,4-difluorophenol in the first step was replaced with compound 3,4-difluorophenol to obtain the title compound 4b (3.5g).

Second step

4,5-Difluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one 4c

Using the synthetic route of Example 3, the second step raw material 2,4-difluorophenyl 3-chloropropionate was replaced with the compound 3,4-difluorophenyl 3-chloropropionate to obtain the title compound 4c( 3.5g).

third step

6,7-Difluoro-2,3-dihydro-1H-indene-4-phenol 4d

Using the synthetic route of Example 3, the raw material 4,6-difluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one in the third step was replaced with 4,5-difluoro-7-hydroxy -2,3-dihydro-1H-inden-1-one to obtain the title compound 4d (1.2 g).

MS m/z(ESI): 171.2[M+1].

the fourth step

5-chloro-2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 4e

Compound 1d (1 g, 2.87 mmol) was dissolved in N,N-dimethylformamide (15 mL), pyridine hydrobromide (918 mg, 5.7 mmol) was added, and the reaction was carried out at 100°C for 1 hour. The reaction solution was cooled to room temperature, and ethyl acetate (15 mL) and saturated sodium bicarbonate solution (20 mL) were added. A white solid precipitated, filtered, and the filter cake was dried to obtain the title compound 4e (720 mg), yield: 75%.

MS m/z(ESI): 335.5[M+1].

the fifth step

Compound 4d (78mg, 0.45mmol), compound 4e (150mg, 0.45mmol) and cesium carbonate (293mg, 0.9mmol) were added to N,N-dimethylformamide (10mL) in sequence and reacted at 80°C for 2 hours. The reaction solution was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added. The organic phase was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system A to obtain the crude product, and then ethyl acetate/n-hexane=1/ 10 (v/v) beating to obtain the title compound 4 (140 mg), yield: 64%.

MS m/z(ESI): 485.5[M+1].

¹ H NMR(400MHz,DMSO-d ₆ )δ11.28(s,1H),10.64(s,1H),8.04(s,1H),7.40(s,1H),7.32-7.31(d,1H), 7.02-6.98(m,1H),6.66(s,1H),6.31-6.29(m,1H),2.94-2.89(m,2H),2.75-2.71(m,2H),2.07-1.99(m,2H) ).

Example 5

5-chloro-2-((4-fluoronaphthalene-1-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 5

Using the synthesis method of Example 4, the fifth step raw material 6,7-difluoro-2,3-dihydro-1H-indene-4-phenol was replaced with the compound 4-fluoro-1-naphthol (Shaoyuan Technology (Shanghai) Co., Ltd.) to obtain the title compound 5 (80 mg), yield: 33%.

MS m/z(ESI): 476.8[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.26 (br, 1H), 10.80 (s, 1H), 8.08-8.15 (m, 3H), 7.69-7.70 (m, 2H), 7.27-7.35 (m , 3H), 7.19-7.20 (m, 1H), 6.68 (s, 1H), 6.33-6.35 (m, 1H).

Example 6

5-chloro-2-((4-fluoro-2,3-dihydrobenzofuran-7-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl) -4-(Trifluoromethyl)benzamide 6

first step

7-Bromo-4-fluoro-2,3-dihydrobenzofuran 6b

The compound 7-bromo-4-fluorobenzofuran 6a (1.0g, 4.65mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in ethanol, rhodium carbon (150mg, 1.46mmol) was added, and hydrogen was replaced three times. Reverse the atmosphere at room temperature overnight. The crude product (1g) of title compound 6b was obtained by filtration and concentration, which was directly used in the next reaction.

Second step

4-fluoro-2,3-dihydrobenzofuran-7-phenol 6c

Compound 6b (700mg, 3.22mmol) was dissolved in N,N-dimethylformamide (10mL), and pinacol diborate (1.24g, 4.88mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added, [ 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (391mg, 0.46mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) and potassium acetate (95mg, 0.97mmol). Under argon protection, the temperature was raised to 80°C and reacted overnight. The reaction was cooled, the reaction solution was concentrated, saturated sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran, cooled to 0°C, and sodium hydroxide solution (1M, 2mL) and hydrogen peroxide (0.5mL) were added dropwise. It was naturally raised to room temperature and reacted for 2 hours. Saturated sodium thiosulfate solution was added dropwise to the reaction solution under ice bath. It was extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 6c (120 mg), which was directly used in the next reaction.

third step

5-chloro-2-((4-fluoro-2,3-dihydrobenzofuran-7-yl)oxy)-N-(2-methoxypyridin-4-yl)-4-(trifluoro (Methyl)benzamide 6d

Using the synthesis method of Example 3, the third step raw material 3c was replaced with compound 6c to obtain the title compound 6d (80 mg).

the fourth step

Using the synthesis method of Example 3, the fifth step raw material 3e was replaced with compound 6d to obtain the title compound 6 (50 mg), yield: 17%.

MS m/z(ESI): 468.9[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.30 (br, 1H), 10.65 (s, 1H), 8.01 (s, 1H), 7.32-7.34 (m, 1H), 7.12 (s, 1H), 7.04-7.06 (m, 1H), 6.72-6.77 (m, 2H), 6.37-6.38 (m, 1H), 4.60-4.65 (m, 2H), 3.26-3.30 (m, 2H).

Example 7

5-chloro-2-((4-fluoro-5,6,7,8-tetrahydronaphthalene-1-yl)oxy)-N-(2-oxo-1,2-dihydropyridine-4- Yl)-4-(trifluoromethyl)benzamide 7

first step

4-fluorophenyl 4-chlorobutyrate 7b

Using the synthetic route of Example 3, the first step raw materials 2,4-difluorophenol and 3-chloropropionyl chloride were replaced with the compounds 4-fluorophenol (Shaoyuan Technology (Shanghai) Co., Ltd.) and 4-chlorobutyryl chloride ( Shanghai Adamas Co., Ltd.) to obtain the title compound 7b (1.5g).

Second step

5-Fluoro-8-hydroxy-3,4-dihydronaphthalene-1(2H)-one 7c

Using the synthetic route of Example 3, the second step raw material 2,4-difluorophenyl 3-chloropropionate was replaced with the compound 4-fluorophenyl 4-chlorobutyrate to obtain the title compound 7c (1g).

third step

4-fluoro-5,6,7,8-tetralin-1-ol 7d

Using the synthetic route of Example 3, the raw material 4,6-difluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one in the third step was replaced with the compound 5-fluoro-8-hydroxy-3 ,4-Dihydronaphthalene-1(2H)-one to obtain the title compound 7d (680 mg).

MS m/z(ESI): 167.2[M+1].

the fourth step

Using the synthetic route of Example 4, the fifth step raw material 6,7-difluoro-2,3-dihydro-1H-inden-4-ol was replaced with the compound 4-fluoro-5,6,7,8-tetra Hydronaphthalene-1-ol to obtain the title compound 7 (70 mg), yield: 33%.

MS m/z(ESI): 481.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 10.66 (s, 1H), 8.03 (s, 1H), 7.33-7.29 (t, 2H), 7.02-6.98 (t, 1H) ), 6.89-6.87 (t, 1H), 6.68 (s, 1H), 6.34-6.32 (t, 1H), 3.39 (s, 1H), 2.85-2.79 (m, 1H), 2.72-2.68 (m, 1H) ), 2.26-2.21 (m, 1H), 1.65-1.61 (m, 1H), 1.22-1.21 (m, 3H).

Example 8

5-chloro-2-((7-fluoro-3,3-dimethyl-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2 -Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 8

first step

4-Fluoro-7-methoxy-2,3-dihydro-1H-inden-1-one 8a

Compound 1g (500mg, 3mmol) was dissolved in N,N-dimethylformamide (5mL), potassium carbonate (831mg, 6mmol) and methyl iodide (1.28g, 9mmol) were added and reacted at room temperature for 16 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 8a (348 mg), yield: 64% .

MS m/z(ESI): 181.0[M+1].

Second step

4-fluoro-7-methoxy-1,1-dimethyl-2,3-dihydro-1H-indene 8b

Cool the dichloromethane (10mL) to -40°C, add titanium tetrachloride dichloromethane solution (1M, 8.2mmol, 8.2mL), add dimethyl zinc toluene solution (1M, 11.7mmol, 11.7mL) dropwise, React at -40°C for 30 minutes. Add compound 8a (700mg, 3.89mmol) in dichloromethane (10mL) solution, and react at room temperature for 16 hours. The reaction solution was cooled to -40°C, and methanol (10 mL) was added dropwise to quench the reaction. Stir for 20 minutes, add water (50mL), extract with dichloromethane (50mL×2), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography with developing solvent system B to obtain the title compound 8b (590mg ), yield: 78%.

third step

7-Fluoro-3,3-dimethyl-2,3-dihydro-1H-inden-4-phenol 8c

Compound 8b (590 mg, 3 mmol) was dissolved in dichloromethane (10 mL), cooled in an ice bath, and boron tribromide dichloromethane solution (1M, 15.2 mmol, 15.2 mL) was added dropwise, and reacted at room temperature for 16 hours. The reaction solution was cooled in an ice bath, water (50 mL) was added dropwise, and extracted with dichloromethane (50 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 8c (400 mg), yield: 73%.

MS m/z(ESI): 179.1[M-1].

the fourth step

5-chloro-2-((7-fluoro-3,3-dimethyl-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2- Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 8

Compound 4e (200mg, 0.6mmol), compound 8c (155mg, 0.7mmol) and cesium carbonate (389mg, 1.2mmol) were added to N,N-dimethylformamide (3mL) and reacted at 100°C for 1 hour. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 8 (125 mg), yield: 42%.

MS m/z(ESI): 495.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.35 (s, 1H), 10.74 (s, 1H), 8.08 (s, 1H), 7.36 (d, 1H), 7.15 (s, 1H), 7.06 ( t, 1H), 6.88-6.79 (m, 2H), 6.40 (dd, 1H), 2.91 (t, 2H), 1.93 (t, 2H), 1.22 (s, 6H).

Example 9

5-chloro-2-((7-fluoro-2,3-dihydrobenzofuran-4-yl)oxy)-N-(2-oxo-1,2-dihydropyridin-4-yl) -4-(Trifluoromethyl)benzamide 9

first step

4-bromo-2-(2,2-diethoxyethoxy)-1-fluorobenzene 9b

Add bromoacetaldehyde diethyl acetal (11.7mL, 100mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) and sodium iodide (750mg, 5mmol) into N containing 2-fluoro-5-bromophenol 9a (5.48mL, 50mmol) , N-dimethylformamide (100mL) solution. Potassium carbonate (13.8g, 100mmol) was added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 9b (12 g).

Second step

4-bromo-7-fluorobenzofuran 9c

Compound 9b (7g, 22.8mmol) was dissolved in chlorobenzene (80mL), polyphosphoric acid (14g, 45.6mmol) was added, the temperature was raised to 130°C, and the reaction was carried out for 3 hours. Cool to room temperature, pour into saturated sodium bicarbonate solution, extract with ethyl acetate (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and prepare by high performance liquid chromatography (Waters 2767 -SQ Detecor2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 9c (1g), yield: 20%.

third step

2-(7-Fluorobenzofuran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxapentaborane 9d

Compound 9c (500mg, 2.32mmol) was dissolved in N,N-dimethylformamide (10mL), and pinacol diborate (900mg, 3.54mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added, [1, 1'-bis(diphenylphosphine)ferrocene]palladium dichloride (600mg, 0.71mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) and potassium acetate (460mg, 4.68mmol). Under argon protection, the temperature was raised to 80°C and reacted overnight. Cool the reaction, concentrate the reaction solution, add 20mL saturated sodium bicarbonate solution, extract with ethyl acetate (30mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and develop by silica gel column chromatography Purification by reagent system B gave the title compound 9d (600 mg).

the fourth step

7-Fluorobenzofuran-4-phenol 9e

Compound 9d (600mg, 2.3mmol) was dissolved in tetrahydrofuran, cooled to 0°C, and sodium hydroxide solution (1M, 2mL) and hydrogen peroxide (0.5mL) were added dropwise. It was naturally raised to room temperature and reacted for 2 hours. Saturated sodium thiosulfate solution was added dropwise to the reaction solution under ice bath. It was extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 9e (300 mg), which was directly used in the next reaction.

the fifth step

7-Fluoro-2,3-dihydrobenzofuran-4-phenol 9f

Compound 9e (300 mg, 1.97 mmol) was dissolved in acetic acid (5 mL), palladium on carbon (30 mg) was added, hydrogen replacement was performed three times, and the reaction was reversed at room temperature under a hydrogen atmosphere overnight. Filtration and concentration gave the title compound 9f crude product (100 mg), which was directly used in the next reaction.

MS m/z(ESI): 153.1[M-1].

Sixth step

5-chloro-2-((7-fluoro-2,3-dihydrobenzofuran-4-yl)oxy)-N-(2-methoxypyridin-4-yl)-4-(trifluoro (Methyl)benzamide 9g

Using the synthesis method of Example 3, the third step raw material 3d was replaced with compound 9f to obtain the title compound 9g (80mg).

Seventh step

Using the synthesis method of Example 3, the fifth step raw material 3e was replaced with compound 9g to obtain the title compound 9 (60 mg), yield: 14%.

MS m/z(ESI): 468.9[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.30 (br, 1H), 8.05 (s, 1H), 7.6 (s, 1H), 7.30-7.32 (m, 1H), 7.08-7.11 (m, 1H) ), 6.70 (s, 1H), 6.50-6.53 (m, 1H), 6.32-6.35 (m, 1H), 4.62-4.66 (m, 2H), 3.08-3.16 (m, 2H).

Example 10

5-chloro-2-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2 -Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 10

first step

4-fluoro-2-(3-methyl-2-en-1-yl)phenol 10a

Compound 7a (1.5g, 13.4mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in toluene (50mL), sodium hydrogen (1.17g, 29.4mmol, 60% purity) was added and reacted at 60°C for 2 hours. Cool to 35°C, slowly add 1-bromo-3-methyl-2-ene (3g, 20mmol) dropwise, and react at room temperature for 16 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (50 mL×3), and the organic phases were combined. Wash with water (50mL), saturated sodium chloride solution (50mL), dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by silica gel column chromatography with developing solvent system B to obtain the title compound 10a (1.29g). Rate: 52%.

MS m/z(ESI): 179.0[M-1].

Second step

4-fluoro-1-methoxy-2-(3-methyl-2-en-1-yl)benzene 10b

Compound 10a (1.29 g, 7.16 mmol) was dissolved in acetonitrile (10 mL), methyl iodide (2.65 g, 18.7 mmol) and potassium carbonate (2.47 g, 17.90 mmol) were added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 10b (820 mg), yield: 59%.

third step

7-Fluoro-4-methoxy-1,1-dimethyl-2,3-dihydro-1H-indene 10c

Compound 10b (770 mg, 3.96 mmol) was added to polyphosphoric acid (14 g, 41.4 mmol) and reacted at 120°C for 2 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), extracted with ethyl acetate (50 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title Compound 10c (540 mg), yield: 70%.

the fourth step

7-Fluoro-1,1-dimethyl-2,3-dihydro-1H-indene-4-phenol 10d

Dissolve 10c (540 mg, 2.8 mmol) in dichloromethane (10 mL), cool in an ice bath, add boron tribromide dichloromethane solution (1M, 13.9 mmol, 13.9 mL) dropwise, and react at room temperature for 16 hours. The reaction solution was cooled in an ice bath, water (20 mL) was added dropwise to quench the reaction, extracted with dichloromethane (20 mL×2), and the organic phases were combined. It was washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 10d (320 mg), yield: 64%.

the fifth step

Compound 4e (200mg, 0.6mmol), compound 10d (130mg, 0.6mmol) and cesium carbonate (292mg, 0.9mmol) were added to N,N-dimethylformamide (3mL) and reacted at 100°C for 1 hour. The filtrate was purified by high performance liquid chromatography (Waters 2767-SQ Detecor 2, elution system: trifluoroacetic acid, water, acetonitrile) to obtain the title compound 10 (100 mg), yield: 34%.

MS m/z(ESI): 495.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.29 (s, 1H), 10.61 (s, 1H), 8.02 (s, 1H), 7.34 (s, 1H), 7.31 (d, 1H), 6.97 ( t, 1H), 6.85-6.82 (m, 1H), 6.54 (s, 1H), 6.31 (dd, 1H), 2.76 (t, 2H), 1.85 (t, 2H), 1.29 (s, 6H).

Example 11

5-chloro-2-((4-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)oxy)-N-(2-oxo-1,2- Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 11

first step

7-Bromo-4-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran 11b

Under vigorous stirring, compound 3-chloro-2-methyl-1-propene (1.81g, 20.00mmol, Shanghai Adamas Co., Ltd.) was slowly added dropwise to compound 11a (7.60g, 39.79mmol, Shaoyuan Technology (Shanghai) ) Ltd.) and sulfuric acid (976mg, 10mmol) at 30°C for 30 minutes. The reaction solution was diluted with methyl tert-butyl ether (50 mL), the organic phase was washed with water (50 mL×2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was placed in an aqueous sodium hydroxide solution (20 wt%, 100 mL) and reacted at room temperature for 16 hours. The reaction solution was extracted with methyl tert-butyl ether (50 mL), the organic phase was washed with water (50 mL×2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title Compound 11b (700 mg), yield: 14%.

Second step

4-fluoro-3,3-dimethyl-2,3-dihydrobenzofuran-7-phenol 11c

Compound 11b (700 mg, 2.9 mmol) and triisopropyl borate (699 mg, 3.72 mmol) were added to tetrahydrofuran (5 mL) and replaced with argon three times. The reaction solution was cooled to -78°C, and n-butyllithium (2.5M, 4.3mmol, 1.7mL) was slowly added dropwise. It was naturally raised to room temperature and reacted for 16 hours. Cool in an ice bath, and slowly add methanol (5ml) to quench the reaction. Add hydrogen peroxide (2g) and sodium hydroxide solution (10wt%, 30mL) dropwise, and react at room temperature for 0.5 hours. Add saturated sodium chloride solution (40 mL), extract with ethyl acetate (20 mL×3), and combine the organic phases. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by silica gel column chromatography with developing solvent system A to obtain the title compound 11c (270 mg), yield: 51%.

MS m/z(ESI): 183.1[M+1].

third step

With reference to the synthesis method of Example 4, the raw material 4d in the fifth step was replaced with compound 11c to obtain the title compound 11 (140 mg), yield: 51%.

MS m/z(ESI): 497.0[M+1].

¹ H NMR(400MHz, DMSO-d ₆ )δ11.35(br,1H), 10.68(s,1H), 8.01(s,1H), 7.34(d,1H), 7.15(s,1H), 7.05( dd, 1H), 6.76-6.72 (m, 2H), 6.38 (dd, 1H), 4.28 (s, 2H), 1.39 (3, 6H).

Example 12

5-chloro-2-((4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)oxy)-N-(2-oxo-1,2- Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 12

first step

1-Bromo-4-fluoro-2-((2-methylallyl)oxy)benzene 12b

The compound 2-bromo-5-fluorophenol 12a (5g, 26.2mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in N,N-dimethylformamide (50mL), and potassium carbonate (5.5g, 39.9mmol) ), 3-chloro-2-methylprop-1-ene (2.4g, 26.5mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added dropwise, and reacted at 60°C for 16 hours. The reaction solution was cooled to room temperature, saturated sodium bicarbonate solution (40 mL) was added, extracted with ethyl acetate (40 mL×2), and the organic phases were combined. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by silica gel column chromatography with developing solvent system B to obtain the title compound 12b (7.5 g), yield: 89%.

Second step

6-Bromo-3-fluoro-2-(2-methylallyl)phenol 12c

Compound 12b (600 mg, 2.45 mmol) was added to N-methylpyrrolidone (1 mL) and reacted at 200° C. for 1 hour in a microwave reactor. Cooled to room temperature, purified by silica gel column chromatography with developing solvent system B to obtain the title compound 12c (250 mg), yield: 42%.

third step

7-Bromo-4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran 12d

Compound 12c (2.5 g, 10.2 mmol) and p-toluenesulfonic acid monohydrate (7.8 g, 41 mmol) were added to toluene (50 mL) and reacted under reflux for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 12d (2.5 g), yield: 100%.

the fourth step

4-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-phenol 12e

Compound 12d (1 g, 4.1 mmol) and triisopropyl borate (1 g, 5.3 mmol) were added to tetrahydrofuran (20 mL) and replaced with argon three times. The reaction solution was cooled to -78°C, and n-butyllithium (2.5M, 6.1mmol, 2.45mL) was slowly added dropwise. It was naturally raised to room temperature and reacted for 16 hours. Cool in an ice bath, and slowly add methanol (5ml) to quench the reaction. Add hydrogen peroxide (2g) and sodium hydroxide solution (10wt%, 10mL) dropwise, and react at room temperature for 0.5 hours. Add saturated sodium chloride solution (40 mL), extract with ethyl acetate (20 mL×3), and combine the organic phases. Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by silica gel column chromatography with developing solvent system A to obtain the title compound 12e (350 mg), yield: 47%.

the fifth step

Using the synthetic route of Example 4, the fifth step raw material 4d was replaced with compound 12e to obtain the title compound 12 (197 mg), yield: 44%.

MS m/z(ESI):497.0[M+1]

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.32 (s, 1H), 10.72 (s, 1H), 8.01 (s, 1H), 7.35-7.33 (d, 1H), 7.12-7.08 (m, 1H) ), 7.03 (s, 1H), 6.79-6.74 (m, 1H), 6.42-6.41 (d, 1H), 3.14 (s, 2H), 1.40 (s, 6H).

Examples 13 and 14

5-chloro-2-((7-fluoro-2-hydroxy-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2-dihydropyridine -4-yl)-4-(trifluoromethyl)benzamide 13

5-chloro-2-((2,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2-dihydropyridine- 4-yl)-4-(trifluoromethyl)benzamide 14

first step

2,4-Difluoro-7-hydroxy-2,3-dihydro-1H-inden-1-one 13

Compound 1g (1.44g, 8.7mmol), 1-(chloromethyl)-4-fluoro-1,4-diazobicyclo[2.2.2]octane difluoroborate (3.69g, 10.4mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), concentrated sulfuric acid (90mg, 0.87mmol) was placed in methanol (30mL) and reacted at 50°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with the developing solvent system B to obtain the title compound 13a (1.11 g), yield: 69%. MS m/z(ESI): 183.1[M-1].

Second step

4-Fluoro-7-hydroxy-1-oxo-2,3-dihydro-1H-inden-2-yl 2,2,2-trifluoroacetate 13b

2,7-Difluoro-2,3-dihydro-1H-indene-4-phenol 13c

Compound 13a (1 g, 5.4 mmol) was dissolved in trifluoroacetic acid (10 mL), cooled to° C., triethylsilane (2.09 g, 18 mmol) was added dropwise, and the mixture was naturally warmed to room temperature to react for 16 hours. It was concentrated under reduced pressure and purified by silica gel column chromatography with the developing solvent system B to obtain a mixture (600 mg) of the title compound 13b and compound 13c.

MS m/z(ESI): 263.0[M-1](13b).

MS m/z(ESI): 169.2[M-1](13c).

third step

Referring to the synthesis method of Example 4, the raw material 4d in the fifth step was replaced with compounds 13b and 13c to obtain the title compound 13 (220 mg) and the title compound 14 (90 mg).

Compound 13:

MS m/z(ESI): 483.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.28 (br, 1H), 10.66 (s, 1H), 8.04 (s, 1H), 7.32 (d, 1H), 7.15 (s, 1H), 7.06 ( t, 1H), 6.99-6.95 (m, 1H), 6.72 (s, 1H), 6.36 (dd, 1H), 5.01 (d, 1H), 4.54-4.49 (m, 1H), 3.09 (dd, 1H) , 2.92 (dd, 1H), 2.78 (dd, 1H), 2.63 (dd, 1H).

Compound 14:

MS m/z(ESI): 484.9[M+1].

¹ H NMR(400MHz, DMSO-d ₆ )δ11.28(br,1H), 10.66(s,1H), 8.06(s,1H), 7.31(d,1H), 7.23(s,1H), 7.12( t,1H),7.03-7.00(m,1H),6.70(s,1H),6.35(dd,1H),5.62-5.57(m,0.5H),5.49-5.44(m,0.5H),3.22- 2.95 (m, 4H).

Examples 15 and 16

(R)-5-chloro-2-((2,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2- Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 15

(S)-5-chloro-2-((2,7-difluoro-2,3-dihydro-1H-inden-4-yl)oxy)-N-(2-oxo-1,2- Dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 16

Compound 14 (90mg, 0.18mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALCEL OJ, 50*250mm, 10μm; mobile phase: n-hexane/ethanol/diethylamine=80/20/0.1(v/ v/v), flow rate: 60 mL/min), collect the corresponding components, and concentrate under reduced pressure to obtain the title compound (20 mg, 40 mg).

Single configuration compound (longer retention time):

MS m/z(ESI):485.0[M+1]

Chiral HPLC analysis: retention time 4.264 minutes, chiral purity: >99% (column: OJ-H Phenomenex Lux Cellulose-3 150*4.6mm, 5μm with guard column; mobile phase: n-hexane/ethanol/diethylamine =80/20/0.1(v/v/v)).

¹ H NMR(400MHz,DMSO-d ₆ )δ11.28(br,1H), 10.68(s,1H), 8.06(s,1H), 7.31(d,1H), 7.23(s,1H), 7.11( t,1H),7.03-7.00(m,1H),6.70(s,1H),6.35(dd,1H),5.62-5.57(m,0.5H),5.49-5.46(m,0.5H),3.22- 2.95 (m, 4H).

Single configuration compound (shorter retention time):

MS m/z(ESI):485.0[M+1]

Chiral HPLC analysis: retention time 3.425 minutes, chiral purity: >99% (column: OJ-H Phenomenex Lux Cellulose-3 150*4.6mm, 5μm with guard column; mobile phase: n-hexane/ethanol/diethylamine =80/20/0.1(v/v/v)).

¹ H NMR (400MHz, DMSO-d ₆ )δ 11.25 (br, 1H), 10.66 (s, 1H), 8.06 (s, 1H), 7.31 (d, 1H), 7.23 (s, 1H), 7.12 ( t,1H),7.03-7.00(m,1H),6.72(s,1H),6.38(dd,1H),5.62-5.59(m,0.5H),5.49-5.44(m,0.5H),3.22- 2.95 (m, 4H).

Test case:

Biological evaluation

The following further describes and explains the present disclosure in conjunction with test examples, but these examples are not meant to limit the scope of the present disclosure.

Test Example 1. Determination of the inhibitory activity of the compound of the present disclosure on Nav1.8

The purpose of the experiment is to investigate the effect of the compound on the Na _V 1.8 ion channel in an _{in vitro experiment, and the Na V} 1.8 ion channel is stably expressed on HEK293 cells. After the Na _V 1.8 current is stable, comparing the Na _V 1.8 current before and after the compound application, the influence of the compound on the Na _{V 1.8 ion channel can be obtained.}

1 Experimental materials and instruments

1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments)/MultiClamp 700A (Axon instrument)

2) Digital-to-analog converter: Digidata 1440A (Axon CNS)/Digidata 1550A (Axon instruments)

3) Micro-manipulator: MP-225 (SUTTER instrument)

4) Inverted microscope: TL4 (Olympus)

5) Glass microelectrode drawing instrument: PC-10 (NARISHIGE)

6) Microelectrode glass capillary: B12024F (Wuhan Micro-Exploration Scientific Instrument Co., Ltd.)

7) Dimethyl sulfoxide (DMSO): D2650 (Sigma-Aldrich)

8) Tetrodotoxin (TTX): AF3014 (Affix Scientific)

2 experimental steps

2.1 Compound preparation

Except for the NaOH and KOH used for acid-base titration, the compounds for preparing intracellular and extracellular fluids were purchased from Sigma (St. Louis, MO). The extracellular fluid (mM) is: NaCl, 137; KCl, 4; CaCl ₂ , 1.8; MgCl ₂ , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). Intracellular fluid (mM) is aspartic acid, 140; MgCl ₂ , 2; EGTA11; HEPES, 10; pH 7.2 (CsOH titration). All test compound and control compound solutions contained 1 μM TTX.

The storage concentration of the test compound is 9 mM, dissolved in dimethyl sulfoxide (DMSO). Re-dissolve in the extracellular fluid on the day of the test and prepare the required concentration.

2.2 Manual patch clamp test process

1) After the compound is formulated into a solution with a specified concentration, add the drug solution to each pipeline in order from low to high concentration, and mark each pipeline.

2) Transfer the cells to the perfusion tank, apply positive pressure in the electrode, touch the electrode tip to the cell, adjust the three-way valve of the suction device to a three-way state, and then apply negative pressure to the electrode to form a high resistance seal between the electrode and the cell Pick up. Continue to apply negative pressure to rupture the cell membrane and form a current path.

3) After the cell rupture current is stabilized, perfusion of different concentrations is performed sequentially. If the current is stable for at least one minute, the next concentration can be changed for perfusion. The perfusion time for each concentration does not exceed five minutes.

4) Clean the perfusion tank. Flush according to the concentration of the drug solution from high to low, and rinse for 20 seconds with each concentration of drug solution. Finally, rinse with extracellular fluid for 1 min.

2.3 Test voltage equation (resting) and results

Clamp the cell at -80mV, and then depolarize it to 10mV with a square wave lasting 10 milliseconds to obtain a Na _V 1.8 current. This procedure is repeated every 5 seconds. Detect the maximum current caused by the square wave, after it stabilizes, perfusion the test compound, when the reaction stabilizes, calculate the blocking strength.

3 data analysis

The data will be stored in the computer system for analysis. Data collection and analysis will use pCLAMP 10 (Molecular Devices, Union City, CA), and management personnel will review the analysis results. Current stability means that the current changes within a limited range over time. The magnitude of the current stabilized is used to calculate the effect of the compound's solubility.

The inhibitory activity of the compounds of the present disclosure on Nav1.8 was determined by the above test, and the measured IC ₅₀ value is shown in Table 1.

_{Table 1 The IC 50 of the} compounds of the present disclosure for inhibition of Nav1.8 channel activity

Conclusion: The compounds in the present disclosure have a significant inhibitory effect on the activity of the Nav1.8 channel.

Claims

A compound represented by the general formula (I), or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or Medicinal salt:

among them:

X is selected from CH, C atom and N atom;

Y is selected from CH, C atom and N atom;

M is selected from CH 2 , NH, O atom and S atom;

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

R 1 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

R 2 is selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, -CH 2 OR w , cycloalkyl and heterocyclic group; R w is selected from hydrogen atom, alkyl group, -S (O) 2 OH, -S (O) 2 O - Q +, -PO (OH) 2, -PO (O -) 2 Q + 2, -PO (OH) O - Q + and -PO (O -) 2 W 2+ ; Q + is a monovalent pharmaceutically acceptable cation; W 2+ cation is a pharmaceutically acceptable divalent;

R 3 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

R 4 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

R 5 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, hetero Cyclic and heterocyclylalkyl;

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

m is 0, 1, 2 or 3;

s is 0, 1, 2 or 3; and

t is 0, 1, 2, or 3.
The compound represented by general formula (I) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, wherein the X is CH.
The compound represented by the general formula (I) according to claim 1 or 2, or its tautomer, meso, racemate, enantiomer, diastereomer, Or its mixture form or its pharmaceutically acceptable salt, wherein said Y is CH.
The compound represented by the general formula (I) according to any one of claims 1-3, or its tautomer, meso, racemate, enantiomer, diastereomer An isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the M is an O atom.
The compound represented by the general formula (I) according to any one of claims 1 to 4, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein said ring A is selected from cycloalkyl, heterocyclic and aryl, preferably cycloalkyl.
The compound represented by the general formula (I) according to any one of claims 1 to 5, or its tautomer, meso, racemate, enantiomer, diastereomer An isomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein said R 1 is a hydrogen atom or an alkyl group, preferably a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1 to 6, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R 2 is selected from hydrogen atom, halogen, alkyl group and -CH 2 OR w ; R w is -PO(OH) 2 .
The compound represented by the general formula (I) according to any one of claims 1-7, or its tautomer, meso, racemate, enantiomer, diastereomer The isomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, wherein said R 3 is selected from hydrogen atom, halogen and alkyl, preferably halogen.
The compound represented by the general formula (I) according to any one of claims 1-8, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof or pharmaceutically acceptable salts thereof, wherein said R 4 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group and a halogenated alkyl group, preferably a halogen or a halogenated alkyl group.
The compound represented by the general formula (I) according to any one of claims 1-9, or its tautomer, meso, racemate, enantiomer, diastereomer An isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the R 5 is selected from a hydrogen atom, an alkyl group, a hydroxyl group and a halogen, preferably a hydrogen atom or an alkyl group, and more preferably a hydrogen atom.
The compound represented by the general formula (I) according to any one of claims 1-10, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the n is 2.
The compound represented by the general formula (I) according to any one of claims 1-11, or its tautomer, meso, racemate, enantiomer, diastereomer An isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the s is 1 or 2, preferably 1.
The compound represented by general formula (I) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt:

Wherein, X, Y, M, ring A, R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in claim 1.
The compound represented by general formula (I) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt:

Wherein, X, Y, M, ring A, R 1 , R 3 , R 4 , R 5 , m, n, s and t are as defined in claim 1.
The compound represented by general formula (I) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IV), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt:

Wherein said R 1 , R 2 , R 3 , R 4 , R 5 , m, n, s and t are as defined in claim 1.
The compound represented by general formula (I) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt:

Wherein said R 4a or R 4b are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro Group, cycloalkyl, heterocyclyl and heterocyclylalkyl;

The R 1 , R 2 , R 3 and m are as defined in claim 1.
The compound represented by general formula (I) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VI), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure, or its mixture form or its pharmaceutically acceptable salt:

Wherein said R 4c or R 4d are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro Group, cycloalkyl, heterocyclyl and heterocyclylalkyl;

The X, Y, ring A, M, R 1 , R 2 , R 3 , R 5 , m, s, and t are as defined in claim 1.
The compound represented by the general formula (I) according to any one of claims 1-17, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are selected from:
A compound represented by the general formula (IIA), or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its forms or Medicinal salt:

Wherein said Ra is an alkyl group, preferably a methyl group;

The X, Y, M, ring A, R 1 , R 3 , R 4 , R 5 , m, n, s, and t are as defined in claim 1.
A compound represented by the general formula (VIA), or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form or its Medicinal salt:

Where Z is halogen;

Said R 4c is halogen, R 4d is halogenated alkyl, or R 4d is halogen, R 4c is halogenated alkyl;

The X, Y, R 1 and m are as defined in claim 1.
A method for preparing the compound represented by the general formula (II) according to claim 13, or its tautomer, meso, racemate, enantiomer, or diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method includes:

The compound of general formula (IIA), or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture of its form or its pharmaceutically acceptable salt Under acidic conditions, the compound of the general formula (II) is obtained, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof or Its medicinal salt,

Wherein, said Ra is an alkyl group, preferably a methyl group;

The X, Y, M, ring A, R 1 , R 3 , R 4 , R 5 , m, n, s, and t are as defined in claim 1.
A method for preparing the compound represented by the general formula (VI) according to claim 17, or its tautomer, meso, racemate, enantiomer, diastereomer , Or its mixture form or its pharmaceutically acceptable salt method, the method includes:

Compounds of general formula (VIA), or tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts Reacting with a compound of general formula (VIB) to obtain a compound of general formula (VI), or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form or its pharmaceutically acceptable salt,

Wherein, said Z is halogen;

M is S atom or O atom;

The X, Y, ring A, R 1 , R 3 , R 5 , m, s, and t are as defined in claim 17.
The compounds shown below, or tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts:
A pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) according to any one of claims 1-18, or a tautomer or meso Isomers, racemates, enantiomers, diastereomers, or mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients Agent.
The compound represented by the general formula (I) according to any one of claims 1-18, or its tautomer, meso, racemate, enantiomer, diastereomer Isomer, or its mixture form or its pharmaceutically acceptable salt, or the use of the pharmaceutical composition according to claim 24 in the preparation of a medicament for inhibiting voltage-gated sodium channels in a subject, preferably, the voltage The gated sodium channel is Na V 1.8.
The compound represented by the general formula (I) according to any one of claims 1-18, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 24 in the preparation of the treatment and/or reduction of pain and pain-related diseases, multiple sclerosis, Xia-Ma-Figure 3 For the use in medicines for syndrome, incontinence or arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, Intestinal pain and idiopathic pain.