TW202043200A - 2-oxo-1,2-dihydropyridin derivative, a preparation method thereof and a medical use thereof - Google Patents

Abstract

The present disclose relates to a 2-oxo-1,2-dihydropyridin derivative, a preparation method thereof and a medical use thereof. In particular, the present invention relates to a 2-oxo-1,2-dihydropyridin derivative as shown by general formula (IG), a preparation method thereof and a pharmaceutical composition containing the derivative, as well as a use thereof as a Nav inhibitor and a use thereof in the preparation of a medicament for preventing and/or treating pain or pain related diseases. The substituents in the general formula (IG) are the same as those defined in the description.

Description

2-Pendant oxy-1,2-dihydropyridine derivatives, preparation method thereof and application in medicine

The present disclosure belongs to the field of medicine, and relates to a 2-side oxy-1,2-dihydropyridine derivative, a preparation method thereof, and application in medicine. In particular, the present disclosure relates to the 2-side oxy-1,2-dihydropyridine derivative represented by the general formula (I), its preparation method, and a pharmaceutical composition containing the derivative, and its use as a Na _V inhibitor The use of the agent and its use in the preparation of medicines for treating and/or reducing pain and pain-related diseases.

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, which is a subjective feeling." Pain can be used as a warning signal to remind the body to pay 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 The nerve fibers are transmitted to the cell body part of the dorsal root ganglia (DRG), and finally 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 1.1 ~ Na _V 1.9. Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics (Rush AM, et al. J. Physiol. 2007, 579, 1-14). 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 (Goldin A.L., et al. Annu. Rev. Physiol . 2001, 63, 871-894). Both Na _V 1.4 and Na _V 1.6 are of TTX-S type, which are abundant in skeletal muscle and central nervous system respectively (Fozzard HA, et al. Physiol. Rev. 1996, 76, 887-926). Local anesthetic lidocaine for pain relief 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 TTX-R type, the coding gene is SCN10A, which mainly exists in trigeminal ganglion neurons and DRG neurons, and has the electrophysiological characteristics of slow inactivation and rapid recovery (Dib-Hajj SD, et al. Annu .Rev.Neurosci. 2010,33,325-347). 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 can increase the expression level of Na _V 1.8 in axons and neuron cell bodies (Sleeper AA, et al. J. Neurosci. 2000, 20, 7279-7289). The use of Na _V 1.8 antisense oligonucleotides can significantly relieve pain while reducing the expression of Na _V 1.8 (Yoshimura N., et al. J. Neurosci. 2001, 21, 8690-8696). After carrageenan was injected into the paws of rats, the expression of Na _V 1.8 in DRG neurons increased (Tanaka M., et al. G. NeuroReport 1998, 9, 967-972). Na _V 1.8 knock- out mice cannot show normal visceral inflammation pain (Kerr BJ, et al. NeuroReport 2001, 12, 3077-3080 ). The human gene Na _V 1.8 gain generation function mutations, leads to peripheral neuropathic pain (Faber CG, et al. Proc.Natl.Acad.Sci.USA 2012,109,19444-19449). 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 pain types.

Due to the lack of subtype selectivity, Na _V inhibitors used in clinical practice can inhibit sodium channels expressed in the heart and central nervous system, so the therapeutic window is narrow and the application range 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. Thus, there is a need to develop higher activity, better selectivity, better pharmacokinetic properties, fewer side effects of inhibitors of Na _V 1.8.

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

其中：

among them:

R ⁰ is a hydrogen atom or -CH ₂ OR ^x ;

M is CR ⁷ R ⁸ or S atom;

Ring A is aryl or heteroaryl;

R ^{1 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^{2 is} selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amine Substituted by one or more substituents in the group, nitro group, cyano group, hydroxy group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro , Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁷ and R ^{8 are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;

Alternatively, the R ⁷ and R ⁸ together with the connected carbon atoms form a carbonyl group, a cycloalkyl group and a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are optionally selected from alkyl groups, alkoxy groups, and pendant oxy groups. Substituted by one or more substituents in the group, halogen, amine, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^x is selected from a hydrogen _{atom, -S (O) 2 OH,} -S (O) 2 O - Q +, -PO (OR y) 2, -PO (OH) O - Q +, -PO (O -) ₂ 2Q ⁺ and _{^{-PO (O -) 2 W 2+}} ; Q + is a monovalent pharmaceutically acceptable cation; W ²⁺ cation is a pharmaceutically acceptable divalent;

R ^y is a hydrogen atom or an alkyl group;

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

t is 0, 1, or 2.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), 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 (I), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure or its mixture form, or its pharmaceutically acceptable salt,

其中：

among them:

M is CR ⁷ R ⁸ or S atom;

Ring A is aryl or heteroaryl;

R ^{1 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ^{2 is} selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amine Substituted by one or more substituents in the group, nitro group, cyano group, hydroxy group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group;

R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro , Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁷ and R ^{8 are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group;

Alternatively, the R ⁷ and R ⁸ together with the connected carbon atoms form a carbonyl group, a cycloalkyl group and a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are optionally selected from alkyl groups, alkoxy groups, and pendant oxy groups. Substituted by one or more substituents in the group, halogen, amine, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

t is 0, 1, or 2.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, nitro, hydroxyl, hydroxyalkyl Group, cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, Amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl group are substituted by one or more substituents.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or pyridyl.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, further 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,

其中：

among them:

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, an alkoxy group, a deuterated alkoxy group, and a haloalkyl group , Haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl The group and the heteroaryl group are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Substituted by one or more substituents in the aryl and heteroaryl groups; and

M, R ¹ , R ³ to R ⁶ and t are as defined in the compound of general formula (I).

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, further a compound represented by the general formula (IIG), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure or its mixture form, or its pharmaceutically acceptable salt,

其中：

among them:

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, an alkoxy group, a deuterated alkoxy group, and a haloalkyl group , Haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl The group and the heteroaryl group are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Substituted by one or more substituents in the aryl and heteroaryl groups; and

R ^x , M, R ¹ , R ³ to R ⁶ and t are as defined in the general formula (IG).

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group and a halogen The alkoxy group is preferably a hydrogen atom, a halogen and a haloalkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁶ are hydrogen atoms.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, deuterated alkyl, and alkane The oxy group, deuterated alkoxy group, cycloalkyl group, haloalkyl group and haloalkoxy group are preferably hydrogen atom, halogen and alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkane The group and the haloalkoxy group are preferably a hydrogen atom, a halogen and an alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is further a compound represented by general formula (III), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure or its mixture form, or its pharmaceutically acceptable salt,

其中：

among them:

M, R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (II).

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein M is CR ⁷ R ⁸ ; R ⁷ and R ⁸ are as defined in the general formula (IG).

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, further 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,

其中：

among them:

R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (II).

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is further a compound represented by general formula (IVG), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure or its mixture form, or its pharmaceutically acceptable salt,

其中：

among them:

R ^x , R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (IG).

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is halogen, preferably chlorine; and R ⁵ is haloalkyl, preferably trifluoromethyl.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ^x is -PO(OH) ₂ .

Typical compounds of general formula (I) include but are not limited to:

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用的鹽。

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

Another aspect of the present disclosure provides a compound represented by general formula (IA), or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt,

其中：

among them:

R ^a is an alkyl group, preferably a methyl group;

M, ring A, R ¹ to R ⁶ , n and t are as defined in the compound of general formula (I). The compound of general formula (IA) is an intermediate for preparing the compound of general formula (I).

Typical compounds of general formula (IA) include but are not limited to:

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用的鹽。

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

Another aspect of the present disclosure provides a compound represented by the general formula (IIGA), or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , Or its pharmaceutically acceptable salt,

其中：

among them:

X is halogen; preferably Cl; and

M, R ¹ , R ³ to R ⁶ , R ⁹ to R ¹³ and t are as defined in the compound of general formula (IIG). The compound of general formula (IIGA) is an intermediate for preparing the compound of general formula (IIG).

Another aspect of the present disclosure provides a compound represented by the general formula (IVGA), or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof , Or its pharmaceutically acceptable salt,

其中：

among them:

X is halogen; preferably Cl;

R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (IVG). The compound of general formula (IVGA) is an intermediate for preparing the compound of general formula (IVG).

Typical compounds of general formula (IIGA) or general formula (IVGA), including but not limited to:

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體或其混合物形式，或其可藥用的鹽。

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

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

The compound of general formula (I) is obtained by reaction of compound of general formula (IA); wherein:

R ^a is an alkyl group, preferably a methyl group; and

M, ring A, R ¹ to R ⁶ , n and t are as defined in the compound of general formula (I).

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 its In the form of a mixture, or a pharmaceutically acceptable salt method thereof, the method includes:

The compound of general formula (II) is obtained by reaction of compound of general formula (IIA); wherein:

R ^a is an alkyl group, preferably a methyl group; and

M, R ¹ , R ³ to R ⁶ , R ⁹ to R ¹³ and t are as defined in the compound of general formula (II).

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

The compound of general formula (IIGA) is reacted with R ^x -OR ^p to obtain the compound of general formula (IIG); wherein:

X is halogen; preferably Cl;

R ^p is a hydrogen atom or Q ⁺ ; Q ⁺ is a pharmaceutically acceptable monovalent cation, preferably K ⁺ ; and

M, R ^x , R ¹ , R ³ to R ⁶ , R ⁹ to R ¹³ and t are as defined in the compound of general formula (IIG).

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

The compound of general formula (III) is obtained by reaction of compound of general formula (IIIA); wherein:

R ^a is an alkyl group, preferably a methyl group; and

M, R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (III).

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

The compound of general formula (IV) is obtained by reacting the compound of general formula (IVA); among them:

R ^a is an alkyl group, preferably a methyl group;

R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (IV).

Another aspect of the present disclosure relates to a preparation of a compound represented by general formula (IVG) or its tautomers, mesosomes, racemates, enantiomers, diastereomers or In the form of a mixture, or a pharmaceutically acceptable salt method thereof, the method includes:

The compound of general formula (IVGA) is reacted with R ^x -OR ^p to obtain compound of general formula (IVG); wherein:

X is halogen; preferably Cl;

R ^p is a hydrogen atom or Q ⁺ ; Q ⁺ is a pharmaceutically acceptable monovalent cation, preferably K ⁺ ; and

R ^x , R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (IVG).

Another aspect of the present disclosure relates to a pharmaceutical composition, which contains the compound represented by the general formula (IG) as described above, or its tautomer, mesosome, racemate, or enantiomer , Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.

The present disclosure also relates to a method for preparing the above-mentioned pharmaceutical composition, which comprises combining the compound represented by the general formula (IG) as described above, or its tautomer, meso, racemate, enantiomer The structure, diastereomer, or mixture form thereof, or pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier, diluent or excipient.

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

The present disclosure also relates to a compound represented by the general formula (IG) as described above, or a tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, it is used in the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Char-Martin-Tusan syndrome, Use in medicine for incontinence or arrhythmia. The pain is preferably selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, postoperative pain, visceral pain, intestinal pain and idiopathic pain.

The present disclosure also relates to a method for inhibiting a voltage-gated sodium ion channel in a subject, the method comprising administering to a patient in need thereof a compound represented by the general formula (IG) of the present disclosure, or a tautomer, 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 ion 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 drugs, the method comprising administering the present invention to a patient in need thereof The compound represented by the general formula (IG) as described above, or the tautomer, meso, racemate, enantiomer, diastereomer, or mixture form thereof is disclosed, Or its medicinal Salt, or a pharmaceutical composition as described above. The pain is preferably selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, postoperative pain, visceral pain, intestinal pain and idiopathic pain.

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

The present disclosure also relates to a compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or Its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition, is used as a drug for inhibiting voltage-gated sodium channels in a subject. The voltage-gated sodium ion channel is preferably Na _V 1.8.

The present disclosure also relates to a compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof, or The pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above, is used for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Chama-Martinus syndrome, incontinence or arrhythmia. The pain is preferably selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, postoperative pain, visceral pain, intestinal pain and idiopathic pain.

The neuropathic pain described in the present disclosure is preferably selected from trigeminal neuralgia, postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, burn syndrome, pain after amputation, and 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 injury, brachial plexus Avulsion, complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, idiopathic small fiber neuropathy, idiopathic 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 and 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 selected from fibromyalgia.

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 to 1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients. 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. The oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such composition may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives to provide pleasing to the eye 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 and disintegrating agents and lubricants. These tablets may be uncoated or they 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 or olive oil.

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. The aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, 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 aqueous 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.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be vegetable oil or mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids or partial esters. The emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants.

The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injection preparation may be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in an oil phase. The injection or microemulsion can be injected into the patient's blood stream by local large injection.

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 above-mentioned suitable dispersing or wetting agents and suspending agents can be used according to known techniques Prepare the suspension. 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.

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, 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 treatment mode, such as the mode of treatment, the daily dosage of compound (I), or the type of pharmaceutically acceptable salt It can be verified according to the traditional treatment plan.

This application provides a Na _V inhibitor or its prodrug with a novel structure as shown in the general formula (IG), which has a significant inhibitory effect on the activity of the Nav1.8 channel, in particular, R ⁴ in the general formula (IG) is When halogen, R ⁵ is haloalkyl, the biological activity of the entire molecule is significantly improved.

Definition of Terms

Unless stated to the contrary, the terms used in the specification and the scope of the patent application 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 1 to 6 An alkyl group of carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, second 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-dimethylpentyl, 3,3 -Dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Hexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl 2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2 -Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. 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, tertiary butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl Group, 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-methyl Benzylpentyl, 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 one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxy, or carboxylate.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined 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 alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, hetero Cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylate.

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, and more preferably 3 to 12 carbon atoms. 6 carbon atoms (for example, 3, 4, 5, or 6 carbon atoms), most containing 5 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 monocyclic rings with 5 to 20 members, which may contain one or more double bonds, but none of the rings have complete conjugate Π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 or 10 members). 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 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members single spiro cycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of carbon atoms with other rings in the system. 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 members, more preferably 7 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups. It is preferably a bicyclic or tricyclic ring, more preferably a 5-member/5-member or 5-member/6-member bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-member, 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 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the above-mentioned cycloalkyl (including monocyclic, spiro ring, fused ring and bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure The ring together is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl. Cycloalkyl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

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) _m (where m 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; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 5 to 6 ring atoms, of which 1 ~2 or 1~3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyranyl Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group that shares 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 ) _m (where m 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 members, more preferably 7 to 10 members. According to the number of spiro atoms shared 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 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members monospiro heterocyclic groups. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members. 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 ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the rest of the ring The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, 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) _m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 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 as described above (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) fused on an aryl, heteroaryl or cycloalkyl ring, which is combined with the parent structure The rings connected together are heterocyclic groups, non-limiting examples of which include:

和

等。

with

Wait.

The heterocyclic 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 alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane Thio group, heterocycloalkylthio group, pendant oxy group, carboxyl group or carboxylate group.

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) group with a conjugated π-electron system, preferably 6 to 10 members, for example Phenyl and naphthyl. The aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:

Aryl groups may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, and alkylthio , Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxy or carboxylate.

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. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, and thiazolyl , Pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyridine Azinyl and pyridazinyl, etc., preferably pyridazinyl and pyridyl; more preferably pyridinyl. The heteroaryl ring includes the above-mentioned heteroaryl ring fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected with the parent structure is a heteroaryl ring, a non-limiting example thereof include:

Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, pendant oxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkane Oxy group, cycloalkylthio group, heterocycloalkylthio group, carboxyl group or carboxylate group.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group 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 "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.

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

The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, where aryl and alkyl are as defined above.

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

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

The term "carbonyl" refers to C=O.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

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 term "halo" refers to a compound containing a -C(O)-halogen group.

The term "pharmaceutically acceptable monovalent cation" (Q ⁺ ) includes (such as N(R ^y ) ₄ , where R ^y is H or C ₁ -C ₄ alkyl), alkali metal ions (such as potassium, sodium, and lithium ions) ), dicyclohexylamine ion and N-methyl D-reduced glucosamine ion.

The term "pharmaceutically acceptable divalent cation" (W ²⁺ ) includes 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 pharmaceutically acceptable divalent cation (W ²⁺ ) can be replaced by two pharmaceutically acceptable monovalent cations (Q ⁺ ).

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs 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.

The compounds of the present disclosure also include 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.

"As needed" or "as needed" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group substituted by an alkyl group as required" means that an alkyl group may but does not have to be present. 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 at most 5, and more preferably 1 to 3 hydrogen atoms are independently 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 amine group or a hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.

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

The present disclosure provides a novel Na _V inhibitor having a structure of general formula (I), and a compound with such a structure has an excellent inhibitory effect on Na _V 1.8.

Synthetic method of the compound of the present disclosure

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

Option One

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

其中：

among them:

R ^a is an alkyl group, preferably a methyl group;

M, ring A, R ¹ to R ⁶ , n and t are as defined in the compound of general formula (I).

In the first step, the compound of general formula (I-1) and the compound of general formula (I-2) react under basic conditions in the presence of a chlorinating reagent to obtain a compound of general formula (IA);

In the second step, the compound of general formula (IA) is reacted under acidic conditions to obtain the compound of general formula (I).

The chlorinating reagent includes, but is not limited to, phosphorus oxychloride, phosphorus trichloride, sulfite dichloride and phosphorus pentachloride, preferably phosphorus oxychloride.

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine. Lithium propylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate, Sodium hydroxide and lithium hydroxide.

Reagents that provide acidic conditions include, but are not limited to, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid and sulfuric acid, preferably pyridine hydrobromide.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, acetonitrile, pyridine, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Benzene, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof.

Option II

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

其中：

among them:

R ^a is an alkyl group, preferably a methyl group;

M, R ¹ , R ³ to R ⁶ , R ⁹ to R ¹³ and t are as defined in the compound of general formula (II).

In the first step, a compound of general formula (II-1) and a compound of general formula (I-2) react under basic conditions in the presence of a chlorinating reagent to obtain a compound of general formula (IIA);

In the second step, the compound of general formula (IIA) is reacted under acidic conditions to obtain the compound of general formula (II).

The chlorinating reagent includes, but is not limited to, phosphorus oxychloride, phosphorus trichloride, sulfite dichloride and phosphorus pentachloride, preferably phosphorus oxychloride.

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine. Lithium propylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate, Sodium hydroxide and lithium hydroxide.

Reagents that provide acidic conditions include, but are not limited to, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid and sulfuric acid, preferably pyridine hydrobromide.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, acetonitrile, pyridine, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Benzene, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof.

third solution

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

其中：

among them:

R ^a is an alkyl group, preferably a methyl group;

M, R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (III).

In the first step, a compound of general formula (III-1) and a compound of general formula (I-2) react under basic conditions in the presence of a chlorinating reagent to obtain a compound of general formula (IIIA);

In the second step, the compound of general formula (IIIA) is reacted under acidic conditions to obtain the compound of general formula (III).

The chlorinating reagent includes, but is not limited to, phosphorus oxychloride, phosphorus trichloride, sulfite dichloride and phosphorus pentachloride, preferably phosphorus oxychloride.

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine. Lithium propylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate, Sodium hydroxide and lithium hydroxide.

Reagents that provide acidic conditions include, but are not limited to, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid and sulfuric acid, preferably pyridine hydrobromide.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, acetonitrile, pyridine, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Benzene, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof.

Option Four

The compound represented by the general formula (IV) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture form thereof, or its medicine The salt preparation method used includes the following steps:

其中：

among them:

R ^a is an alkyl group, preferably a methyl group;

R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (IV).

In the first step, a compound of general formula (IV-1) and a compound of general formula (I-2) react under basic conditions in the presence of a chlorinating reagent to obtain a compound of general formula (IVA);

In the second step, the compound of general formula (IVA) is reacted under acidic conditions to obtain the compound of general formula (IV).

The chlorinating reagent includes, but is not limited to, phosphorus oxychloride, phosphorus trichloride, sulfite dichloride and phosphorus pentachloride, preferably phosphorus oxychloride.

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, pyridine, hexahydropyridine, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropylamine. Lithium propylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide. The inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium carbonate, potassium acetate, cesium carbonate, Sodium hydroxide and lithium hydroxide.

Reagents that provide acidic conditions include, but are not limited to, pyridine hydrobromide, hydrobromic acid, acetic acid, hydrochloric acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, trifluoroacetic acid and sulfuric acid, preferably pyridine hydrobromide.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, acetonitrile, pyridine, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Benzene, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof.

Option Five

The compound represented by the general formula (IIG) of the present disclosure, or its tautomer, mesosome, racemate, enantiomer, diastereomer or its mixture form, or its medicine The salt preparation method used includes the following steps:

The compound of general formula (IIGA) and R ^x -OR ^{p are} reacted in the presence of a phase transfer catalyst (preferably tetrabutylammonium iodide) to obtain a compound of general formula (IIG); when R ^x is a phosphate (preferably phosphoric acid) In the case of tertiary butyl ester), the final compound can be further hydrolyzed under weak acid (preferably acetic acid) conditions, wherein:

X is halogen; preferably Cl;

R ^p is a hydrogen atom or Q ⁺ ; Q ⁺ is a pharmaceutically acceptable monovalent cation, preferably K ⁺ ;

M, R ^x , R ¹ , R ³ to R ⁶ , R ⁹ to R ¹³ and t are as defined in the compound of general formula (IIG).

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, acetonitrile, pyridine, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Benzene, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof.

Option Six

The compound represented by the general formula (IVG) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmacologically The salt preparation method used includes the following steps:

The compound of general formula (IVGA) and R ^x -OR ^{p are} reacted in the presence of a phase transfer catalyst (preferably tetrabutylammonium iodide) to obtain a compound of general formula (IVG); when R ^x is a phosphate (preferably In the case of tert-butyl phosphate), the final compound can be further hydrolyzed under weak acid (preferably acetic acid) conditions, wherein:

X is halogen; preferably Cl;

R ^p is a hydrogen atom or Q ⁺ ; Q ⁺ is a pharmaceutically acceptable monovalent cation, preferably K ⁺ ;

R ^x , R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in the compound of general formula (IVG).

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, acetonitrile, pyridine, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl Benzene, 1,4-dioxane, water, N , N -dimethylformamide and mixtures thereof.

The present disclosure is further described below in conjunction with embodiments, 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 Methyl Silane (TMS).

The measurement of MS uses an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS instrument (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.

The chiral HPLC analysis and determination used Agilent 1260 DAD high performance liquid chromatograph.

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

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.

The silica gel column 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, Companies such as Darui Chemicals.

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 and filled with hydrogen, and the operation is repeated 3 times.

The microwave reaction uses a 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, 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, C: petroleum ether/acetic acid In the ethyl ester system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

5-chloro-2-(4-fluoro-2-methylbenzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzene Formamide 1

first step

(4-Fluoro-2-methylphenyl)magnesium bromide 1b

The polished magnesium bar (760 mg, 31.7 mmol, medicine) was cut into small pieces, and added to tetrahydrofuran (80 mL), protected by argon. At room temperature, drop in trimethylchlorosilane (345mg, 3.17mmol, Shaoyuan Technology (Shanghai) Co., Ltd.). Add 1-bromo-4-fluoro-2-methylbenzene 1a (1.5g, 7.9mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), after heating to initiate the reaction, compound 1a (4.5g, 23.7mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added. The reaction was heated at 45°C for 1 hour, all the magnesium bars disappeared and a gray uniform liquid was formed to obtain the title compound 1b solution (0.4M, 80 mL). The product was directly used in the next reaction without purification.

Second step

2-bromo-4-chloro-5-(trifluoromethyl)benzaldehyde 1d

Tetrahydrofuran (100 mL) and lithium hexamethyldisilazide (1M, 120 mL, 120 mmol, Titan Chemical) were cooled to -78°C under argon protection. 4-bromo-2-chloro-1-(trifluoromethyl)benzene 1c (25g, 96.36mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added dropwise, and the reaction was kept at low temperature for 2 hours. N , N -dimethylformamide (14.1 g, 192.9 mmol, Bailingwei Technology Co., Ltd.) was added dropwise, and the reaction was gradually raised to room temperature for 16 hours. Water was added and extracted with ethyl acetate (50 mL×3). The organic phase was dried with anhydrous sodium sulfate. After filtration, 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 1d (3.14 g), yield: 28%.

¹ H NMR (400MHz, CDCl ₃ ) δ 10.32 (s, 1H), 8.23 (s, 1H), 7.87 (s, 1H).

third step

2-Bromo-4-chloro-5-(trifluoromethyl)phenyl)(4-fluoro-2-methylphenyl)methanol 1e

Compound 1d (900 mg, 3.13 mmol) was dissolved in tetrahydrofuran (10 mL), and the prepared compound 1b solution (7.97 mmol, 19.92 mL) was added dropwise, and reacted at room temperature for 1 hour. Saturated ammonium chloride solution was added and extracted with ethyl acetate (10 mL×3). The organic phase was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 1e (900 mg) with a yield of 72%.

¹ HNMR (400MHz, CD ₃ OD) δ 8.04 (s, 1H), 7.93 (s, 1H), 7.0-7.03 (m, 1H), 6.87-6.90 (m, 2H), 6.17 (s, 1H), 2.5 (s,3H).

the fourth step

1-Bromo-5-chloro-2-(4-fluoro-2-methylbenzyl)-4-(trifluoromethyl)benzene 1f

Dissolve compound 1e (4g, 10.1mmol) in dichloromethane (50mL), cool to 0°C, add trifluoroacetic acid (10mL, Titan Chemical), dropwise add triethylsilane (6mL, Shaoyuan Technology (Shanghai) Co., Ltd. ), react at 0°C for 1 hour. The reaction was quenched by adding water, and extracted with ethyl acetate (10 mL×3). The organic phase was dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 1f (3.2 g) with a yield of 83%.

the fifth step

Methyl 5-chloro-2-(4-fluoro-2-methylbenzyl)-4-(trifluoromethyl)benzoate 1g

Compound 1f (3.3 g, 8.64 mmol) was dissolved in methanol (60 mL). Add palladium acetate (388.31mg, 1.73mmol, Bailingwei Technology Co., Ltd.), 1,1'-bis(diphenylphosphine) ferrocene (960mg, 1.73mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), triethylamine (2.63g, 25.94mmol, Sinopharm Chemical Reagent Co., Ltd.). The reaction system was connected to a carbon monoxide balloon and reacted at 60°C for 16 hours. After filtering through Celite, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain 1 g (2.2 g) of the title compound as a white solid with a yield of 71%.

MS m/z (ESI): 359.1 [M-1].

Sixth step

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

Compound 1g (2.2g, 6.1mmol) was dissolved in methanol (40mL) and water (20mL), sodium hydroxide solution (5M, 6mL, 30mmol, Sinopharm Chemical Reagent Co., Ltd.) was added, and the temperature was raised to 40°C for 3 hours. . Cool, adjust the pH to 2 with 4M hydrochloric acid, and extract with dichloromethane (10 mL×3). For organic phase Dry with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title crude compound 1h (2.1g). The product was directly used in the next reaction without purification.

MS m/z (ESI): 345.1 [M-1].

Seventh step

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

Compound 1h (1.1g, 3.17mmol) was dissolved in pyridine (20mL), cooled to -20°C, and phosphorus oxychloride (4.86g, 31.7mmol, Sinopharm Chemical Reagent Co., Ltd.) was added dropwise. After the addition is complete, add 4-amino-2-methoxypyridine (788 mg, 6.34 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), and react at -20°C for half an hour. The reaction solution was poured into ice water, extracted with dichloromethane (10 mL×3), and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1i (1.4 g). The product was directly used in the next reaction without purification.

MS m/z (ESI): 451.2 [M-1].

Eighth step

5-chloro-2-(4-fluoro-2-methylbenzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzene Formamide 1

Dissolve compound 1i (1.4g, 3.1mmol) in N , N -dimethylformamide, add pyridine hydrobromide (2.5g, 15.7mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), and raise the temperature to 100℃ , React for 1.5 hours. After cooling and filtering, the filtrate was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 1 (1 g) with a yield of 74%.

MS m/z (ESI): 439.1 [M+1].

¹ H NMR (400MHz, DMSO- d ₆ ) δ 11.25 (s, 1H), 10.53 (s, 1H), 7.90 (s, 1H), 7.56 (s, 1H), 7.27 (d, 1H), 6.88- 6.98 (m, 3H), 6.88 (s, 1H), 6.28 (d, 1H), 4.08 (s, 2H), 2.10 (s, 3H).

Example 2

5-chloro-2-(2-cyclopropyl-4-fluorobenzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 2

first step

Methyl 5-chloro-2-(4-fluoro-2-hydroxybenzyl)-4-(trifluoromethyl)benzoate 2b

Using the synthetic route of Example 1, the raw material 4-fluoro-2-methyl bromobenzene in the first step was replaced with the compound 4-fluoro-2-methoxy bromobenzene to obtain 5-chloro-2-(4-fluoro Methyl-2-methoxybenzyl)-4-(trifluoromethyl)benzoate 2a (250 mg). Compound 2a (250 mg, 0.66 mmol) was dissolved in tetrahydrofuran, cooled in an ice-water bath, boron tribromide (3.33 g, 13.3 mmol, Sinopharm Chemical Reagent Co., Ltd.) was added dropwise, and reacted overnight at room temperature. Methanol was added for reaction, concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain title compound 2b (120 mg), yield: 50%.

Second step

Methyl 5-chloro-2-(4-fluoro-2-(((trifluoromethyl)sulfonyl)oxy)benzyl)-4-(trifluoromethyl)benzoate 2c

Under ice bath, dissolve compound 2b (120mg, 0.33mmol) and N -phenylbis(trifluoromethanesulfonimide) (178mg, 0.49mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) in dichloromethane (3mL) ) And acetonitrile (3mL) mixed solvent (v/v=1/1). Cesium carbonate (216 mg, 0.66 mmol) was added, and the mixture was raised to room temperature to react for 3 hours. It was concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 2c (130 mg), yield: 79%.

third step

Methyl 5-chloro-2-(2-cyclopropyl-4-fluorobenzyl)-4-(trifluoromethyl)benzoate 2d

Compound 2c (130mg, 0.26mmol) was dissolved in toluene (5mL), tetrakistriphenylphosphine palladium (32mg, 0.03mmol, Bailingwei Technology Co., Ltd.), potassium fluoride (60mg, 1.03mmol, Sinopharm Chemical Reagent Co., Ltd.) was added ), potassium bromide (44mg, 0.37mmol, Sinopharm Chemical Reagent Co., Ltd.) and cyclopropylboronic acid (44mg, 0.51mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), filled with argon and placed in a microwave reactor , React at 100°C for 1 hour. Concentrated under reduced pressure to obtain the crude title compound 2d (120 mg). The product was directly used in the next reaction without purification.

the fourth step

5-chloro-2-(2-cyclopropyl-4-fluorobenzyl)-4-(trifluoromethyl)benzoic acid 2e

Compound 2d (120 mg, 0.31 mmol) was dissolved in methanol (4 mL) and water (2 mL), sodium hydroxide (25 mg, 0.625 mmol) was added, and the temperature was raised to 40° C. to react for 3 hours. Cool, adjust to pH=2 with dilute hydrochloric acid, and extract with dichloromethane (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2e (115 mg). The product was directly used in the next reaction without purification.

the fifth step

5-chloro-2-(2-cyclopropyl-4-fluorobenzyl) -N -(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 2f

Compound 2e (115mg, 0.31mmol) was dissolved in pyridine (3mL), cooled to -20°C, and phosphorus oxychloride (142mg, 0.93mmol, Sinopharm Chemical Reagent Co., Ltd.) was added dropwise. After the addition is complete, add 4-amino-2-methoxypyridine (77 mg, 0.62 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), and react at -20°C for half an hour. The reaction solution was poured into ice water and extracted with dichloromethane (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 2f (143 mg). The product was directly used in the next reaction without purification.

Sixth step

5-chloro-2-(2-cyclopropyl-4-fluorobenzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 2

Dissolve compound 2f (143mg, 0.3mmol) in N , N -dimethylformamide, add pyridine hydrobromide (300mg, 1.89mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), raise the temperature to 100°C, and react 1.5 hours. After cooling and filtering, the filtrate was purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 2 (30 mg).

MS m/z (ESI): 463.1 [M-1].

¹ H NMR (400MHz, CD ₃ OD) δ 7.77 (s, 1H), 7.55 (s, 1H), 7.39-7.40 (m, 1H), 6.98-6.99 (m, 2H), 6.80-6.81 (m, 1H) ), 6.73 (m, 1H), 6.63-6.65 (m, 1H), 4.36 (s, 2H), 1.79 (m, 1H), 0.84-0.87 (m, 2H), 0.57-0.59 (m, 2H).

Example 3

5-chloro-2-(4-fluoro-2-methoxybenzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl) Benzamide 3

Using the synthetic route of Example 1, the first step raw material 1-bromo-4-fluoro-2-methylbenzene was replaced with 1-bromo-4-fluoro-2-methoxybenzene to obtain the title compound 3 (150mg ).

MS m/z (ESI): 455.1 [M+1].

¹ H NMR(400MHz,CD ₃ OD) δ 7.69(s,2H),7.44(d,1H),7.11-7.06(m,2H),6.70-6.66(m,2H),6.55-6.51(m,1H) ), 4.12(s, 2H), 3.69(s, 3H).

Example 4

5-chloro-2-(2-ethyl-4-fluorobenzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzene Formamide 4

Using the synthetic route of Example 1, the first step raw material 1-bromo-4-fluoro-2-methylbenzene was replaced with the compound 1-bromo-4-fluoro-2-ethylbenzene to obtain the title compound 4 (50mg ).

MS m/z (ESI): 451.2 [M-1].

¹ H NMR (400MHz, CD ₃ OD): δ 7.77 (m, 1H), 7.54 (m, 1H), 7.38-7.40 (m, 1H), 6.96-7.00 (m, 2H), 6.90-6.92 (m, 1H), 6.82-6.86 (m, 1H), 6.61-6.63 (m, 1H), 4.21 (s, 2H), 2.55-2.61 (m, 2H), 1.11-1.14 (m, 3H).

Example 5

2-(4-Fluoro-2-methylbenzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 5

first step

2-((4-Fluoro-2-methylphenyl)(hydroxy)methyl)-4-(trifluoromethyl)benzoic acid 5c

The compound 2-bromo-4-(trifluoromethyl)benzoic acid 5a (1g, 3.72mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in tetrahydrofuran (50mL), cooled to -78℃, and n-butyl was added dropwise Lithium (2.5M, 6mL, 14.9mmol, Bailingwei Technology Co., Ltd.). The reaction was maintained at -78°C for 1 hour, and 4-fluoro-2-methylbenzaldehyde 5b (771 mg, 5.58 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was dissolved in tetrahydrofuran (10 mL) and dropped into the above reaction solution. The temperature was raised to -20°C and reacted for 1 hour. A small amount of methanol was reacted, and the reaction solution was concentrated under reduced pressure to obtain the crude title compound 5c (1 g). The product was directly used in the next reaction without purification.

Second step

3-(4-Fluoro-2-methylphenyl)-5-(trifluoromethyl)isobenzofuran-1(3 H )-one 5d

Compound 5c (1g) was dissolved in acetic acid (50 mL), hydrobromic acid (2 mL, Sinopharm Chemical Reagent Co., Ltd.) was added, and reacted at 90°C overnight. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system B to obtain the title compound 5d (600 mg) with a yield of 52%.

third step

2-(4-Fluoro-2-methylbenzyl)-4-(trifluoromethyl)benzoic acid 5e

Put palladium acetate (44mg, 0.2mmol, Bailingwei Technology Co., Ltd.) and sodium hydride (78mg, 3.4mmol, Sinopharm Chemical Reagent Co., Ltd.) into N , N -dimethylacetamide (1mL) under argon protection , React for 10 minutes. Compound 5d (310mg, 1mmol) was dissolved in N , N -dimethylacetamide (1mL), dropped into the above reaction solution, and reacted at room temperature for 2.5 hours. Dilute hydrochloric acid was added to the reaction solution, the residue was filtered off, and the filtrate was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, 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 5e (200 mg) with a yield of 67%.

the fourth step

2-(4-fluoro-2-methylbenzyl)-4-(trifluoromethyl)benzoyl chloride 5f

Compound 5e (100mg, 0.32mmol) was dissolved in sulphurous chloride (2mL) and reacted at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound 5f (105 mg), which was directly used in the next reaction.

the fifth step

2-(4-Fluoro-2-methylbenzyl) -N -(2-methoxypyridin-4-yl)-4-(trifluoromethyl)benzamide 5g

Compound 5f (105 mg, 0.32 mmol), 4-amino-4-methoxypyridine (79 mg, 0.64 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), pyridine (1 mL) were added to dichloromethane (5 mL). Room temperature reaction Should be overnight, 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 5g (130mg) with a yield of 97%.

Sixth step

2-(4-Fluoro-2-methylbenzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide 5

Compound 5g (130mg, 0.31mmol) was dissolved in N , N -dimethylformamide (3mL), and pyridine hydrobromide (150mg, 0.94mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added and reacted at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with the developer system A to obtain the title compound 5 (30 mg) with a yield of 24%.

MS m/z (ESI): 405.0 [M+1].

¹ H NMR(400MHz,CD ₃ OD) δ 7.66(s,2H),7.54-7.56(m,1H),7.46(s,1H),7.22(s,1H),6.95-6.97(m,1H), 6.84-6.87 (m, 1H), 6.76-6.79 (m, 2H), 4.21 (s, 2H), 2.19 (s, 3H).

Example 6

5-Chloro-2-(4-fluoro-2-(methoxy- d ₃ )benzyl) -N -(2-oxo-1,2-dihydropyridin-4-yl)-4-( Trifluoromethyl) benzamide 6

Using the synthetic route of Example 1, the first step raw material 1-bromo-4-fluoro-2-methylbenzene was replaced with 1-bromo-4-fluoro-2-(methoxy- d ₃ )benzene to obtain Title compound 6 (20 mg).

MS m/z (ESI): 458.1 [M+1].

Example 7

(4-(5-Chloro-2-(4-fluoro-2-methylbenzyl)-4-(trifluoromethyl)benzyl)-2-oxopyridine-1(2 H )- Base) methyl dihydrogen phosphate 7

first step

5-chloro- N -(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylbenzyl)-4 -(Trifluoromethyl)benzamide 7a

Put compound 1 (50mg, 0.11mmol) and 1,4-diazabicyclo[2.2.2]octane (6.40mg, 0.06mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) in N , N -dimethyl Formamide (1 mL) and dichloromethane (15 mL). Under the protection of argon, chloromethyl chloroformate (22mg, 0.17mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added dropwise, reacted at 60°C for 3 hours, and stirred at room temperature overnight. Water was added and extracted with ethyl acetate (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude title compound 7a (55 mg). The product was directly used in the next reaction without purification.

MS m/z (ESI): 487.0 [M+1].

Second step

((4-(5-Chloro-2-(4-fluoro-2-methylbenzyl)-4-(trifluoromethyl)benzamide)-2-oxopyridine-1(2 H )-(Yl)methyl)di-tert-butyl phosphate 7b

Compound 7a (55mg, 0.11mmol) was dissolved in N , N -dimethylformamide (3mL), and di-tert-butyl phosphate potassium salt (56mg, 0.22mmol, Sinopharm Chemical Reagent Co., Ltd.), tetrabutyl Ammonium iodide (3.76mg, 0.011mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), reacted at 70°C for 3 hours. Water was added and extracted with ethyl acetate (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound 7b crude product (70 mg). The product was directly used in the next reaction without purification. MS m/z (ESI): 659.2 [M-1].

third step

(4-(5-Chloro-2-(4-fluoro-2-methylbenzyl)-4-(trifluoromethyl)benzamide)-2-oxopyridine-1(2 H ) -Base) methyl dihydrogen phosphate 7

Compound 7b (70 mg, 0.1 mmol) was dissolved in a mixed solvent of acetonitrile (1 mL), acetic acid (1 mL) and water (1 mL), and reacted at 70°C for 3 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters 2767-SQ Detecor2, elution system: ammonium bicarbonate, water, acetonitrile) to obtain the title compound 7 (15 mg).

MS m/z(ESI): 548.8[M+1]

¹ H NMR (400MHz, DMSO- d ₆ ) δ 10.64 (s, 1H), 7.88 (s, 1H), 7.67 (d, 1H), 7.49 (s, 1H), 7.18 (br, 2H), 6.76-6.96 (m, 3H), 6.28 (d, 1H), 5.31 (d, 2H), 4.05 (s, 2H), 2.09 (s, 3H).

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 sulfide (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; MgCl2, 2; EGTA 11; 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 each concentration of the drug solution for 20 seconds. Finally, rinse with extracellular fluid for 1 min.

2.3 Test voltage equation (resting) and results

The cells were clamped at -80mV, and then depolarized 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 induced by the square wave, after it stabilizes, perfuse the test compound, and calculate the blocking strength when the reaction stabilizes.

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 refers to The current changes over time within a limited range. 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 values are shown in Table 1.

結論：本公開中的化合物對Nav1.8通道活性具有明顯的抑制效果。

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

Pharmacokinetic evaluation

Test Example 2. Pharmacokinetic test of the compound of the present disclosure

1. Summary

Using rats as the test animals, the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the rats were given the compound of Example 3 and the compound of Example 7 by intragastric administration. To study the pharmacokinetic behavior of the compound of the present disclosure in rats and evaluate its pharmacokinetic characteristics.

2. Test plan

2.1 Test drug

Example 3 compound and Example 7 compound.

2.2 Experimental animals

Eight healthy adult SD rats, half male and half male, were divided into 2 groups, 4 rats in each group, purchased from Shanghai Jiesjie Experimental Animal Co., Ltd.

2.3 Drug preparation

Weigh a certain amount of medicine, add 5% DMSO, 5% tween 80, and 90% normal saline to prepare a colorless and clear solution of 0.2 mg/mL.

2.4 Administration

SD rats were fasted overnight and then administered by gavage. The dose was 2.0 mg/kg and the volume was 10.0 mL/kg.

3. Operation

Rats were given the compound of Example 3 and Example 7 by gavage, and 0.2 mL of blood was collected from the orbit before and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours after the administration, and placed in heparinized In the test tube, the plasma was separated by centrifugation at 3500 rpm for 10 minutes at 4°C, stored at -20°C, and eating 2 hours after administration.

Determine the content of the test compound in rat plasma after gavage of different concentrations of drugs: Take 25μL of rat plasma at each time after administration, add 30μL of internal standard solution, 200μL of acetonitrile, vortex for 5 minutes, and centrifuge for 10 minutes (3600 rpm), take 2μL of supernatant from plasma sample for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds of the present disclosure are as follows:

結論：上述研究結果證實，在大鼠中，實施例7化合物在體內轉化為實施例1化合物。並且，本公開化合物的藥物代謝吸收良好，具有明顯的藥物代謝動力學優勢。

Conclusion: The above research results confirmed that in rats, the compound of Example 7 was transformed into the compound of Example 1 in vivo. In addition, the compound of the present disclosure has good drug metabolism and absorption, and has obvious pharmacokinetic advantages.

Claims (28)

A compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer or its mixture form, or its pharmaceutically acceptable Of salt,

among them: R ⁰ is a hydrogen atom or -CH ₂ OR ^x ; M is CR ⁷ R ⁸ or S atom; Ring A is aryl or heteroaryl; R ^{1 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R ^{2 is} selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amine Substituted by one or more substituents in the group, nitro group, cyano group, hydroxy group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro , Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁷ and R ^{8 are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group; Alternatively, the R ⁷ and R ⁸ together with the connected carbon atoms form a carbonyl group, a cycloalkyl group and a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are optionally selected from alkyl groups, alkoxy groups, and pendant oxy groups. Substituted by one or more substituents in the group, halogen, amine, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ^x is selected from a hydrogen _{atom, -S (O) 2 OH,} -S (O) 2 O - Q +, -PO (OR y) 2, -PO (OH) O - Q +, -PO (O -) ₂ 2Q ⁺ and _{^{-PO (O -) 2 W 2+}} ; Q + is a monovalent pharmaceutically acceptable cation; W ²⁺ cation is a pharmaceutically acceptable divalent; R ^y is a hydrogen atom or an alkyl group; n is 0, 1, 2, 3, 4 or 5; and t is 0, 1, or 2. The compound represented by the general formula (IG) as described in the first item of the scope of patent application, or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is a compound represented by the general formula (I), or a tautomer, meso, racemate, enantiomer, or diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them: M is CR ⁷ R ⁸ or S atom; Ring A is aryl or heteroaryl; R ^{1 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R ^{2 is} selected from hydrogen atom, halogen, alkyl, deuterated alkyl, alkoxy, deuterated alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl , Cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amine Substituted by one or more substituents in the group, nitro group, cyano group, hydroxy group, alkoxy group, haloalkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro , Hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁷ and R ^{8 are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, Heterocyclic group, aryl group and heteroaryl group; Alternatively, the R ⁷ and R ⁸ together with the connected carbon atoms form a carbonyl group, a cycloalkyl group and a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group are optionally selected from alkyl, alkoxy, side Substituted by one or more substituents among oxy, halogen, amine, cyano, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n is 0, 1, 2, 3, 4 or 5; and t is 0, 1, or 2. The compound represented by the general formula (IG) described in item 1 or 2 of the scope of patent application, or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the ring A is phenyl or pyridyl. The compound represented by the general formula (IG), or its tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (II), or tautomers, mesoisomers, racemates, enantiomers thereof Conformers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them: R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, an alkoxy group, a deuterated alkoxy group, and a haloalkyl group , Haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl The group and the heteroaryl group are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Substituted by one or more substituents in the aryl and heteroaryl groups; and M, R ¹ , R ³ ~R ⁶ and t are as defined in item 1 of the scope of patent application. The compound represented by the general formula (IG) as described in the first item of the scope of patent application, or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is a compound represented by general formula (IIG), or a tautomer, meso, racemate, enantiomer, or diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them: R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a deuterated alkyl group, an alkoxy group, a deuterated alkoxy group, and a haloalkyl group , Haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl The group and the heteroaryl group are optionally selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclic group , Substituted by one or more substituents in the aryl and heteroaryl groups; and R ^x , M, R ¹ , R ³ to R ⁶ and t are as defined in item 1 of the scope of patent application. The compound represented by the general formula (IG), or its tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ³ , R ⁴ , R ⁵ and R ^{6 are the} same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkane Oxy, haloalkyl and haloalkoxy. The compound represented by the general formula (IG), or its tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ^{13 are the} same or different, and are each independently selected from hydrogen atom, halogen, and alkane Group, deuterated alkyl, alkoxy, deuterated alkoxy, cycloalkyl, haloalkyl and haloalkoxy. The compound represented by the general formula (IG) as described in item 4 of the scope of patent application, or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, it is a compound represented by the general formula (III), or a tautomer, meso, racemate, enantiomer, or diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them: M, R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in item 4 of the scope of patent application. The compound represented by the general formula (IG) as described in any one of the scope of patent application 1 to 8, or its tautomer, meso, racemate, enantiomer, and non-pair Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein M is CR ⁷ R ⁸ ; R ⁷ and R ⁸ are as defined in item 1 of the scope of the patent application. The compound represented by the general formula (IG) as described in any one of items 1 to 4 and 6 to 9 in the scope of the patent application, or its tautomer, meso, racemate, enantiomer Conformer, diastereomer or its mixture form, or its pharmaceutically acceptable salt, which is the compound represented by general formula (IV), or its tautomer, meso, racemate , Enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them: R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in item 1 of the scope of patent application. The compound represented by the general formula (IG) as described in item 1 or 5 of the scope of patent application, or its tautomer, meso, racemate, enantiomer, diastereomer Forms or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IVG), or tautomers, mesoisomers, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them: R ^x , R ¹ , R ⁴ , R ⁵ , R ⁹ , R ¹¹ and t are as defined in item 1 of the scope of patent application. The compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the R ¹ is a hydrogen atom. The compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, non- Enantiomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is halogen; and R ⁵ is haloalkyl. The compound represented by the general formula (IG) as described in any one of items 1, 5 and 11 in the scope of the patent application, or its tautomer, meso, racemate, enantiomer , Diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the R ^x is -PO(OH) ₂ . The compound represented by the general formula (IG), or its tautomers, mesosomes, racemates, enantiomers, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

A compound represented by the general formula (IA), or its tautomer, meso, racemate, enantiomer, diastereomer or its mixture form, or its pharmaceutically acceptable Of salt,

among them: R ^a is an alkyl group; M, ring A, R ¹ to R ⁶ , n and t are as defined in item 2 of the scope of the patent application. The compound represented by the general formula (IA) described in item 16 of the scope of the patent application, or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, the compound is selected from:

A compound represented by the general formula (IIGA), or its tautomer, meso, racemate, enantiomer, diastereomer or its mixture form, or its pharmaceutically acceptable Of salt,

among them: X is halogen; preferably Cl; and M, R ¹ , R ³ to R ⁶ , R ⁹ to R ¹³ and t are as defined in item 5 of the scope of patent application. The compound represented by the general formula (IIGA) described in item 18 of the scope of patent application, or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, the compound is selected from:

A method for preparing the compound represented by the general formula (I) described in item 2 of the scope of patent application, or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a body or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method includes:

The compound of general formula (I) is obtained by reacting the compound of general formula (IA); among them: R ^a is an alkyl group; and M, ring A, R ¹ to R ⁶ , n and t are as defined in item 2 of the scope of the patent application. A preparation of the compound represented by the general formula (IIG) described in item 5 of the scope of patent application, or its tautomer, meso, racemate, enantiomer, diastereomer In the form of a body or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method includes:

The compound of general formula (IIGA) is reacted with R ^x -OR ^p to obtain the compound of general formula (IIG); among them: X is halogen; R ^p is a hydrogen atom or Q ⁺ ; Q ⁺ is a pharmaceutically acceptable monovalent cation; and M, R ^x , R ¹ , R ³ to R ⁶ , R ⁹ to R ¹³ and t are as defined in item 5 of the scope of patent application. The method described in item 21 of the scope of patent application, wherein the X is Cl. The method described in item 21 of the scope of patent application, wherein the R ^p is K ⁺ . A pharmaceutical composition, which contains the compound represented by the general formula (IG) as described in any one of the scope of the patent application, or its tautomer, meso, racemate, and Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. A compound represented by the general formula (IG) described in any one of items 1 to 15 in the scope of patent application, or its tautomer, meso, racemate, enantiomer, non- Enantiomers or their mixture forms, or their pharmaceutically acceptable salts, or the use of the pharmaceutical composition as described in item 24 of the scope of the patent application, which is used in the preparation of inhibitors of voltage-gated sodium ion channels in subjects drug. The use described in item 25 of the scope of patent application, wherein the voltage-gated sodium ion channel is Na _V 1.8. A compound represented by the general formula (IG) described in any one of items 1 to 15 in the scope of the patent application, or its tautomer, meso, racemate, enantiomer, non- Enantiomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or the use of the pharmaceutical composition as described in item 24 of the scope of the patent application, which is used in the preparation of treatment and/or relief of pain and pain-related diseases, Medications for multiple sclerosis, Charmaine-Martin syndrome, incontinence or arrhythmia. As described in item 27 of the scope of patent application, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, postoperative pain, visceral pain, intestinal pain and special Pain.