WO2020151728A1

WO2020151728A1 - 2-oxo-1,2-dihydropyridin derivative, preparation method therefor and medical uses thereof

Info

Publication number: WO2020151728A1
Application number: PCT/CN2020/073668
Authority: WO
Inventors: 郁楠; 杨方龙; 彭伟; 贺峰; 陶维康
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2019-01-25
Filing date: 2020-01-22
Publication date: 2020-07-30
Also published as: TW202043200A; CN112996774B; CN112996774A

Abstract

The present invention relates to a 2-oxo-1,2-dihydropyridin derivative, a preparation method therefor and the medical uses thereof. Specifically, the present invention relates to the 2-oxo-1,2-dihydropyridin derivative of general formula (IG) or the prodrug thereof, the preparation method therefor, a compound containing the derivative or the prodrug thereof, as well as the uses thereof for inhibiting NaV and the uses thereof in preparing a drug for treating and/or preventing pains and pain-related diseases. Each substituent of general formula (IG) is the same as that defined in the description.

Description

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

Technical field

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

Background technique

Pain is a complex physical and psychological activity and one of the most common symptoms in clinical practice. The International Association for Pain Research defines pain as "an unpleasant feeling and emotional feeling, accompanied by substantial or potential tissue damage, 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 transmit Incoming nerve fibers are transmitted to the 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, which further depolarizes 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 are composed of an alpha subunit with a molecular weight of 260kD and a beta subunit with a molecular weight of 30-40kD. According to the different α subunits, it can be divided into 9 subtypes, Na _V ll ~ Na _V 1.9. Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics (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 divided 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 abundantly present in skeletal muscle and central nervous system respectively (Fozzard HA, et al. Physiol. Rev. 1996, 76, 887-926). Local anesthetic lidocaine for pain by inhibiting Na _V. Non-selective Na _V inhibitors, such as lamotrigine, lacosamide, and mexiletine, have been successfully used to treat chronic pain.

Na _V 1.8 is 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 will 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 knockout 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 types of pain.

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

Summary of the invention

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

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, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkane Group, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro Substituted by one or more substituents in the group, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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 halogenated alkyl group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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

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, Substituted by one or more substituents among oxo, halogen, amino, 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 Form or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (I), or a tautomer, meso, racemate, enantiomer, Diastereoisomers 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;

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 Body or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{2 is} selected from hydrogen atom, halogen, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl Group, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said 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 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 a mixture thereof, 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 In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, further a compound represented by general formula (II), or a tautomer, meso, racemate, enantiomer, Diastereoisomers 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, a halogenated alkyl group, Halogenated alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, 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 One or more substituents in the heteroaryl group are substituted; 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 In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, and further a compound represented by the general formula (IIG), or a tautomer, meso, racemate, enantiomer, Diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

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 In the form of a mixture thereof, 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, and a halogenated alkyl group And halogenated alkoxy, hydrogen atom, halogen and halogenated alkyl are preferred.

In some embodiments of the present disclosure, the compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer Or a mixture thereof, 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 Body or a mixture thereof, 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 a hydrogen atom, a halogen, an alkyl group, and a deuterated alkane Group, alkoxy group, deuterated alkoxy group, cycloalkyl group, halogenated alkyl group and halogenated alkoxy group, 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 Body or a mixture thereof, 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 a hydrogen atom, a halogen, an alkyl group, and an alkoxy group , Halogenated alkyl and halogenated alkoxy, preferably hydrogen atom, halogen and alkyl.

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

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 In the form of a mixture, or a pharmaceutically acceptable salt thereof,

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:

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

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 general formula (IVGA), or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof,

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:

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

The compound of general formula (I) is obtained by reacting compound of general formula (IA);

among them:

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 the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer Or its mixture form, or its pharmaceutically acceptable salt method, the method includes:

The compound of general formula (II) is obtained by reacting the compound of general formula (IIA);

among them:

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 its mixture form, or its pharmaceutically acceptable salt method, 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; 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 its mixture form, or its pharmaceutically acceptable salt method, the method includes:

The compound of general formula (III) is obtained by reacting the compound of general formula (IIIA);

among them:

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 preparation of the compound represented by general formula (IV) or its tautomer, meso, racemate, enantiomer, diastereomer Or its mixture form, or its pharmaceutically acceptable salt method, 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, and diastereomers Or its mixture form, or its pharmaceutically acceptable salt method, the method includes:

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

among them:

X is halogen; preferably Cl;

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, meso, racemate, enantiomer Conformers, 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, and The enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are 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 its tautomer, meso, racemate, enantiomer, or diastereomer , Or the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for inhibiting a 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 its tautomer, meso, racemate, enantiomer, or diastereomer , Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above in the preparation for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Xia-Martin-Tusan syndrome Use in medicines for symptom, 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 a compound represented by the above-mentioned general formula (IG) of the present disclosure, or a tautomer thereof, to a patient in need thereof Isomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions 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 to a patient in need thereof The compound represented by the above-mentioned general formula (IG) of the present disclosure, or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof Form, or a pharmaceutically acceptable salt thereof, 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 a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used as a medicine.

The present disclosure also relates to a compound represented by the general formula (IG), or a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which 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 a tautomer, meso, racemate, enantiomer, diastereomer or a mixture thereof , Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, which is used for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Chama-Martinus syndrome, incontinence or heart rhythm Abnormal. The pain mentioned therein 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 the group consisting of trigeminal neuralgia, postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, burn syndrome, pain after amputation, pain after spinal cord injury, phantom Pain, painful neuroma, traumatic neuroma, Morton neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, nerve root pain, sciatica, nerve avulsion, brachial plexus avulsion Injuries, complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, 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 may be 0.1-1000 mg.

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

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. The oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients, granulating and disintegrating agents and lubricants. These tablets may be uncoated or may be coated by a known technique that masks the taste of the drug or delays 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 sweeteners. Flavoring agent.

Oil suspensions can be formulated by suspending the active ingredients in vegetable oil or mineral oil. The oil suspension may contain thickeners. 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 sweeteners, 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 include water, Ringer's solution and isotonic sodium chloride solution. The sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. The injection or microemulsion can be injected into the patient's bloodstream by local large-scale 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 suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation can 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, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of the compound (I) or the amount of pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan.

This application provides a Na _V inhibitor or its prodrug with a novel structure represented by the general formula (IG), which has a significant inhibitory effect on the activity of the Nav1.8 channel, especially R ⁴ in the general formula (IG) When R ⁵ is halogen and 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 claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms Atom of the alkyl group. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl 2-methylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl. Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, 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, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, 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 group is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, 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, more preferably 3 to 6 Carbon atoms (e.g. 3, 4, 5 or 6 carbon atoms), most preferably 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl groups, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, 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 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

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

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

The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused, and bridged rings) fused on an aryl, heteroaryl or heterocycloalkyl ring, where 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, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.

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 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrazole Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and 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 5- to 20-membered monocyclic rings, 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 yuan, more preferably 7 to 10 yuan. 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 a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, one or more of the 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 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, 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 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

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

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, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. The 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 include :

The aryl group may be 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, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl 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. Heteroaryl groups are 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, thiazolyl, pyridine Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and pyridazinyl, etc., preferably pyridazinyl and pyridinyl; more preferably pyridinyl. The heteroaryl ring includes the aforementioned heteroaryl ring fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, which is not limiting Examples include:

The heteroaryl 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, alkane Thio, alkylamino, halogen, mercapto, hydroxy, oxo, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, Cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

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), where alkyl and cycloalkyl are as defined above.

The term "acyl halide" 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 that differs in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, in addition to using "deuterium" or "tritium" instead of hydrogen, or using ¹⁸ F-fluorine label ( ¹⁸ F isotope) instead of fluorine, or using ¹¹ C-, ¹³ C-, or ¹⁴ C-rich Compounds in which collective 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 the 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, tri-deuterated Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

"Optional" or "optionally" means that the event or environment described later can but does not have to occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but 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 up to 5, more preferably 1 to 3 hydrogen atoms independently of each other substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

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

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

The present disclosure provides novel inhibitors of NaV having formula (I) structure, a compound having such a structure has an excellent inhibitory effect of 1.8 to Na _V.

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 The preparation method of medicinal salt includes the following steps:

among them:

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

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, thionyl chloride 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, Lithium diisopropylamide, 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 Sulfoxide, 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 thereof, or The preparation method of medicinal salt includes the following steps:

among them:

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

In the first step, the compound of general formula (II-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 (IIA);

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

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 The preparation method of medicinal salt includes the following steps:

among them:

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

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).

Option Four

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

among them:

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

In the first step, the compound of general formula (IV-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 (IVA);

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

Option Five

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

The compound of general formula (IIGA) and R ^x -OR ^p react 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 tert-butyl phosphate) Ester), it can be further hydrolyzed under weak acid (preferably acetic acid) conditions to obtain the final compound,

among them:

X is halogen; preferably Cl;

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

Option Six

The compound represented by the general formula (IVG) of the present disclosure, or its tautomer, mesosome, racemate, enantiomer, diastereomer or its mixture form, or its The preparation method of medicinal salt 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 tertiary phosphoric acid) Butyl ester), the final compound can be further hydrolyzed under weak acid (preferably acetic acid) conditions,

among them:

X is halogen; preferably Cl;

detailed description

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). The NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

The measurement of MS uses Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS).

waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector) THERMO Ultimate3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

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

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

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

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

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

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., Darui Chemicals and other companies.

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

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

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

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

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

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

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

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

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

Example 1

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

first step

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

The polished magnesium bar (760mg, 31.7mmol, medicine) was cut into small pieces and added to tetrahydrofuran (80mL), 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, add compound 1a (4.5g, 23.7mmol, Shaoyuan Technology (Shanghai) Co., Ltd.). The reaction was heated at 45°C for 1 hour, all the magnesium bars disappeared and a gray homogeneous 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. Add N,N-dimethylformamide (14.1g, 192.9mmol, Bailingwei Technology Co., Ltd.) dropwise, and gradually raise to room temperature to react 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 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 the 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 the 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

Dissolve 1g (2.2g, 6.1mmol) of compound in methanol (40mL) and water (20mL), add sodium hydroxide solution (5M, 6mL, 30mmol, Sinopharm Chemical Reagent Co., Ltd.), heat up to 40℃ and react for 3 hours . Cool, adjust the pH to 2 with 4M hydrochloric acid, and extract with dichloromethane (10 mL×3). The organic phase was dried 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 (788mg, 6.34mmol, 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

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°C. React for 1.5 hours. Cooled, filtered, and the filtrate was purified by high performance liquid chromatography (Waters 2767-SQ Detecor 2, 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)benzene Formamide 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-methylbromobenzene in the first step was replaced with the compound 4-fluoro-2-methoxybromobenzene 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 the 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 the 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

Dissolve compound 2c (130mg, 0.26mmol) in toluene (5mL), add tetrakistriphenylphosphine palladium (32mg, 0.03mmol, Bailingwei Technology Co., Ltd.), potassium fluoride (60mg, 1.03mmol, Sinopharm Chemical Reagent Co., Ltd. ), potassium bromide (44mg, 0.37mmol, Sinopharm Chemical Reagent Co., Ltd.) and cyclopropylboronic acid (44mg, 0.51mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), filled with argon gas, and placed in a microwave reactor , React at 100°C for 1 hour. Concentrate 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

Compound 2f (143mg, 0.3mmol) was dissolved in N,N-dimethylformamide, pyridine hydrobromide (300mg, 1.89mmol, Shaoyuan Technology (Shanghai) Co., Ltd.) was added, the temperature was raised to 100°C, and the reaction was 1.5 hour. After cooling, filtering, the filtrate was purified by high performance liquid chromatography (Waters 2767-SQ Detecor 2, 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)benzene Formamide

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)benzyl Amide

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): δ7.77 (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(3H)-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 the 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 hydrogen (78mg, 3.4mmol, Sinopharm Chemical Reagent Co., Ltd.) in 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 with anhydrous sodium sulfate, filtered, 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 thionyl 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). After reacting at room temperature overnight, the reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography with developing solvent system A to obtain the title compound 5g (130mg) with a yield of 97%.

Sixth step

Dissolve compound 5g (130mg, 0.31mmol) in N,N-dimethylformamide (3mL), add pyridine hydrobromide (150mg, 0.94mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), and react at 100°C for 1 hour . 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 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 to 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-(tri Fluoromethyl)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-d3)benzene to obtain the 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)benzoyl)-2-oxopyridine-1(2H)-yl)form 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 In 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)benzamido)-2-oxopyridine-1(2H)-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.) was added, tetrabutyl iodide Ammonium (3.76mg, 0.011mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), react 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 crude title compound 7b (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)benzamido)-2-oxopyridine-1(2H)-yl) 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-SQDetecor2, 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 effect of the compound on the Na _V 1.8 ion channel can be obtained.

1 Experimental materials and instruments

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

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

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

4) Inverted microscope: TL4 (Olympus)

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

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

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

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

2 experimental steps

2.1 Compound preparation

Except for the NaOH and KOH used for acid-base titration, the compounds for preparing intracellular and extracellular fluids were purchased from Sigma (St. Louis, MO). The extracellular fluid (mM) is: NaCl, 137; KCl, 4; CaCl ₂ , 1.8; MgCl _2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). Intracellular fluid (mM) is aspartic acid, 140; 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, the drug solution is added to each pipeline in order from low to high concentration, and each pipeline is marked.

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 aspirator 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 of each concentration does not exceed five minutes.

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

2.3 Test voltage equation (resting) and results

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

3 data analysis

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

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

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

实施例编号Example number	IC ₅₀(nM) IC ₅₀ (nM)
11	1.61.6
22	0.360.36
33	0.410.41
44	1.311.31
55	43.943.9

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 concentration of the drug in plasma at different times after the rats were intragastrically administered the compound of Example 3 and the compound of Example 7. To study the pharmacokinetic behavior of the compound of the present disclosure in rats and evaluate its pharmacokinetic characteristics.

2. Test plan

2.1 Experimental drugs

Example 3 compound and Example 7 compound.

2.2 Experimental animals

8 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 the drug, add 5% DMSO, 5% tween80 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 intragastric administration. 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 food was taken 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:

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 pharmacokinetic absorption of the compound of the present disclosure is good, and has obvious pharmacokinetic advantages.

Claims

A compound represented by the general formula (IG), or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or it can be Medicinal 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, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkane Group, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro Substituted by one or more substituents in the group, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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 halogenated alkyl group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 7 and R 8 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle Group, aryl and heteroaryl;

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, Substituted by one or more substituents among oxo, halogen, amino, 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) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof Form, 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,

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, halogenated alkyl, halogenated alkoxy, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkane Group, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally selected from alkyl, haloalkyl, halogen, amino, nitro Substituted by one or more substituents in the group, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

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 halogenated alkyl group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 7 and R 8 are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocycle Group, aryl and heteroaryl;

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, Substituted by one or more substituents among oxo, halogen, amino, 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) according to claim 1 or 2, 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.
The compound represented by the general formula (IG) according to any one of claims 1 to 3, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (II), or tautomers, mesosomes, racemates, enantiomers thereof Isomers, 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, a halogenated alkyl group, Halogenated alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, 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 One or more substituents in the heteroaryl group are substituted; and

M, R 1 , R 3 to R 6 and t are as defined in claim 1.
The compound represented by the general formula (IG) according to claim 1, or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIG), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure or its mixture form, or its pharmaceutically acceptable salt,

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, a halogenated alkyl group, Halogenated alkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, 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 One or more substituents in the heteroaryl group are substituted; and

R x , M, R 1 , R 3 to R 6 and t are as defined in claim 1.
The compound represented by the general formula (IG) according to any one of claims 1 to 5, or its tautomer, meso, racemate, enantiomer, or diastereomer Isomers 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 alkoxy group, Haloalkyl and haloalkoxy.
The compound represented by the general formula (IG) according to any one of claims 4 to 6, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers 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, alkyl, deuterium Alkyl, alkoxy, deuterated alkoxy, cycloalkyl, haloalkyl and haloalkoxy.
The compound represented by the general formula (IG) according to claim 4, or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof Form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III), or a tautomer, meso, racemate, enantiomer, or diastereomer Structure or its mixture form, or its pharmaceutically acceptable salt,

among them:

M, R 1 , R 4 , R 5 , R 9 , R 11 and t are as defined in claim 4.
The compound represented by the general formula (IG) according to any one of claims 1 to 8, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein M is CR 7 R 8 ; R 7 and R 8 are as defined in claim 1.
The compound represented by the general formula (IG) according to any one of claims 1 to 4 and 6 to 9, or a tautomer, meso, racemate, or enantiomer thereof , Diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IV), or tautomers, mesoisomers, racemates, 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 claim 1.
The compound represented by the general formula (IG) according to claim 1 or 5, or its tautomer, meso, racemate, enantiomer, diastereomer or In the form of a mixture, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IVG), or a tautomer, meso, racemate, enantiomer, or non-pair 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 claim 1.
The compound represented by the general formula (IG) according to any one of claims 1 to 11, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 1 is a hydrogen atom.
The compound represented by the general formula (IG) according to any one of claims 1 to 12, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R 4 is halogen; and R 5 is haloalkyl.
The compound represented by the general formula (IG) according to any one of claims 1, 5, and 11, or its tautomer, meso, racemate, enantiomer, non- Enantiomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R x is -PO(OH) 2 .
The compound represented by the general formula (IG) according to any one of claims 1 to 14, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, the compound is selected from:
A compound represented by the general formula (IA), or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or Medicinal salt,

among them:

R a is an alkyl group;

M, ring A, R 1 to R 6 , n, and t are as defined in claim 2.
The compound represented by the general formula (IA) according to claim 16, or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof Form, 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 mixture thereof, or Medicinal 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 claim 5.
The compound represented by the general formula (IIGA) according to claim 18, or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof Form, or a pharmaceutically acceptable salt thereof, the compound is selected from:
A method for preparing the compound represented by the general formula (I) according to claim 2, or its tautomer, meso, racemate, enantiomer, diastereomer Or its mixture form, or its pharmaceutically acceptable salt method, the method comprises:

The compound of general formula (I) is obtained by reacting 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 claim 2.
A method for preparing the compound represented by the general formula (IIG) according to claim 5, or its tautomer, meso, racemate, enantiomer, diastereomer Or its mixture form, or its pharmaceutically acceptable salt method, the method comprises:

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; 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 claim 5.
A pharmaceutical composition comprising the compound represented by the general formula (IG) according to any one of claims 1 to 15, or its tautomer, meso, racemate, or Enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
The compound represented by the general formula (IG) according to any one of claims 1 to 15, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers or mixtures thereof, or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition according to claim 22 in the preparation of a medicament for inhibiting voltage-gated sodium ion channels in a subject, preferably, said The voltage-gated sodium ion channel is Na V 1.8.
The compound represented by the general formula (IG) according to any one of claims 1 to 15, or its tautomer, meso, racemate, enantiomer, diastereomer Isomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 22 in the preparation of the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, Xia-horse-figure For use in medicines for tris syndrome, incontinence or arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, postoperative pain, internal organs Pain, bowel pain, and idiopathic pain.