Furan ring-containing compound as well as pharmaceutical composition and application thereof

Abstract

The invention relates to a furan ring-containing compound as well as a pharmaceutical composition and application thereof. Specifically disclosed is a compound represented by formula I or a pharmaceutically acceptable salt thereof. The compound provided by the invention has one or more of the following advantages: (1) the structure is novel; (2) the compound has a good retarding effect (inhibiting effect) on the activity of a Nav1.8 channel; and (3) the compound has good selectivity to other subtypes of Nav and is high in safety. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2023115572534 filed on November 21, 2023 and the priority of Chinese Patent Application No. 2024100374874 filed on January 10, 2024. This application cites the entire text of the above Chinese patent application. Technical Field

[0002] The invention relates to a compound containing a furan ring, a pharmaceutical composition thereof and application thereof. Background Art

[0003] Pain originates from nociceptors in the peripheral nervous system. This is a free nerve ending widely distributed in the skin, muscles, joints and visceral tissues throughout the body. It can convert the thermal, mechanical or chemical stimulation it senses into nerve impulses (action potentials) and transmit them to the cell body located in the dorsal root ganglion (DRG) via afferent nerve fibers, and finally to higher nerve centers, causing pain. The generation and conduction of action potentials in neurons depends on voltage-gated sodium channels (VGSC / Nav) on the cell membrane. Nav is the key medium for transmembrane information transmission along neurons.

[0004] According to statistics, about one-fifth of the world's population suffers from moderate to severe chronic pain. The global analgesic market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023. Among them, acute moderate to severe pain will grow steadily at a compound annual growth rate of 2.5% in the future, and the chronic pain market will grow at a compound annual growth rate of about 18%. Chronic pain is the main driving force for the continued growth of the global pain market in the next decade.

[0005] The secondary structure of voltage-gated sodium channels (VGSC / Nav) contains four domains (DI-DIV) that form a pore, each of which has six transmembrane α-helices (S1-S6), of which the S4 segment is a voltage sensor containing positively charged ions; the intracellular loop between DIII and DIV is considered to be a fast inactivation gate; Nav exists in three different states, and the closed state of inactivation has different kinetic performances of fast inactivation (within milliseconds) or slow inactivation (seconds). When the cell membrane is depolarized, the sodium ion channel is activated, the channel opens, causing sodium ions to flow in, further depolarizing the cell membrane, and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity helps to treat and relieve pain, and Nav is a potential peripheral target for the treatment of pain.

[0006] There are 9 main subtypes of human Nav, namely Nav1.1-Nav1.9. According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), Nav is divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R), and the tissue expression of different subtypes is extremely different. Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7 are TTX-S types, among which Nav1.1, Nav1.2 and Nav1.3 are expressed in large quantities in the central nervous system (CNS), Nav1.4 is present in large quantities in skeletal muscle, and Nav1.6 and Nav1.7 are mainly present in large quantities in the central nervous system. Nav1.5, Nav1.8 and Nav1.9 are of TTX-R type, among which Nav1.5 is mainly present in cardiomyocytes, and Nav1.8 and Nav1.9 are present in the dorsal root ganglia of the peripheral nervous system (PNS-DRG).

[0007] Studies have shown that changes in ion channels are the molecular basis for peripheral sensitization, central sensitization, and disinhibition after inflammation or neuropathological damage, and are also an important molecular mechanism for the occurrence of pain. Currently, Nav inhibitors have been proven to be effective. For example, the local anesthetic lidocaine relieves pain by inhibiting Nav. Non-selective Nav inhibitors such as lamotrigine, lacosamide, and mexiletine have been successfully used to treat chronic pain. However, the Nav inhibitors currently used in clinical practice lack subtype selectivity and can inhibit sodium ion channels expressed in the heart and central nervous system. The treatment window is narrow and the scope of application is limited. Nav1.8 is an important ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome. Highly selective Nav1.8 inhibitors are ideal targets for pain treatment, and when producing analgesic effects, the side effects are relatively small.

[0008] In the model of neuropathic pain, nerve damage increases the expression level of Nav1.8 in axons and neuronal cell bodies. The use of Nav1.8 antisense oligonucleotides can significantly relieve pain while reducing Nav1.8 expression. Nav1.8 knockout mice do not show normal visceral inflammatory pain. When the human Nav1.8 gene produces a gain-of-function mutation, it will cause peripheral neuropathy. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new type of analgesic therapy, which can be used to treat various types of pain such as inflammatory pain, neuralgia, postoperative pain and cancer pain.

[0009] Highly selective Nav inhibitors are one of the key research and development directions for voltage-gated sodium channels. Nav1.8 is mainly distributed in the peripheral nervous system and is confined to neurons that sense pain. It is a highly selective target for pain treatment, so selectively inhibiting Nav1.8 has good prospects for reducing potential toxic side effects. Nav inhibitors used in clinical practice lack subtype selectivity and can inhibit sodium ion channels expressed in the heart and central nervous system. Therefore, the therapeutic window is narrow and the scope of application is limited. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better selectivity, better pharmacokinetic properties, and fewer side effects to meet clinical needs. Summary of the invention

[0010] The technical problem to be solved by the present invention is to overcome the disadvantage of insufficient inhibition of Nav1.8 channels in the prior art. To this end, the present invention provides a furan ring-containing compound, a pharmaceutical composition thereof and its application. The compound of the present invention has one or more of the following advantages: (1) novel structure; (2) good blocking effect (inhibition effect) on Nav1.8 channel activity; (3) good selectivity for other Nav subtypes (such as Nav1.1, Nav1.2, Nav1.3 Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.9) and high safety.

[0011] The present invention solves the technical problem of the present invention through the following technical solutions:

[0012] The present invention provides a compound as shown in Formula I or a pharmaceutically acceptable salt thereof,

[0013] ;

[0014] Among them, R 1 , R 2 and R 3 are independently halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, -OR 1-1 , by one or more R 1-2 Substituted C 1 -C 6 Alkyl or one or more R 1-3 Substituted C 1 -C 6 Alkoxy;

[0015] R 1-1 C 3 -C 6Cycloalkyl or 3-8 membered heterocycloalkyl; in the 3-8 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0016] Each R 1-2 are each independently a halogen;

[0017] Each R 1-3 Each independently is C 1 -C 6 Alkoxy;

[0018] X 1 N, N + -O - or CR X1 ;

[0019] R X1 is hydrogen, halogen, or C substituted by one or more halogens 1 -C 6 alkyl;

[0020] X 2 is O or NH;

[0021] R 4 is hydrogen or C 1 -C 6 alkyl;

[0022] R 5 C 1 -C 6 Alkoxy, -OH, -NR 5-1 R 5-2 or -CN;

[0023] R 5-1 and R 5-2 are independently hydrogen or C 1 -C 6 alkyl;

[0024] n is 0, 1, 2 or 3;

[0025] R 6 For hydrogen, halogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy or C 1 -C 6 Alkoxy;

[0026] R 7 is hydrogen or C 1 -C 6 alkyl;

[0027] R 8 Hydrogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy or C 1 -C 6 Alkoxy.

[0028] In some embodiments, in the compound shown in Formula I, R 1 , R 2 and R 3 are independently halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, -OR 1-1 , by one or more R 1-2 Substituted C 1 -C 6 Alkyl or one or more R 1 -3 Substituted C 1 -C 6 Alkoxy;

[0029] R 1-1 C 3 -C 6 Cycloalkyl or 3-8 membered heterocycloalkyl; in the 3-8 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0030] Each R 1-2 are each independently a halogen;

[0031] Each R 1-3 Each independently is C 1 -C 6 Alkoxy;

[0032] X 1 N, N + -O - or CR X1 ;

[0033] R X1 is hydrogen, halogen, or C substituted by one or more halogens 1 -C 6 alkyl;

[0034] X 2 is O or NH;

[0035] R 4 is hydrogen or C 1 -C 6 alkyl;

[0036] R 5 C 1 -C 6 Alkoxy, -OH or -NR 5-1 R 5-2 ;

[0037] R 5-1 and R 5-2 are independently hydrogen or C 1 -C 6 alkyl;

[0038] n is 0, 1, 2 or 3;

[0039] R 6 For hydrogen, halogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy or C 1 -C 6 Alkoxy;

[0040] R 7 is hydrogen or C 1 -C 6 alkyl;

[0041] R 8 Hydrogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy or C 1 -C 6 Alkoxy.

[0042] In some embodiments, R 1 , R 2 and R 3 wherein the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0043] In some embodiments, R 1 , R 2 and R 3 In the C 1 -C 6 Alkyl and one or more R 1-2 Substituted C 1 -C 6C in the alkyl group 1 -C 6 The alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0044] In some embodiments, R 1 , R 2 and R 3 In the C 3 -C 6 The cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0045] In some embodiments, R 1 , R 2 and R 3 In the C 1 -C 6 Alkoxy and one or more R 1-3 Substituted C 1 -C 6 C in alkoxy 1 -C 6 The alkoxy groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy or ethoxy.

[0046] In some embodiments, R 1-1 In the C 3 -C 6 The cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0047] In some embodiments, R 1-1 The heteroatoms in the 3-8 membered heterocycloalkyl are N and / or O; the number of heteroatoms is preferably 1 or 2. The 3-8 membered heterocycloalkyl is preferably a 4-6 membered heterocycloalkyl; more preferably ;For example .

[0048] In some embodiments, R 1-2 In the above, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0049] In some embodiments, R 1-3 In the C 1 -C 6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

[0050] In some embodiments, R X1 wherein the halogen and C substituted by one or more halogens 1-C 6 The halogen in the alkyl group is each independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0051] In some embodiments, R X1 wherein the C substituted by one or more halogens 1 -C 6 C in the alkyl group 1 -C 6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0052] In some embodiments, R 5 In the C 1 -C 6 The alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy or ethoxy.

[0053] In some embodiments, R 5-1 and R 5-2 In the C 1 -C 6 The alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0054] In some embodiments, R 6 In the above, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0055] In some embodiments, R 7 In the C 1 -C 6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0056] In some embodiments, R 8 In the C 1 -C 6 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0057] In some embodiments, R 1 C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, -OR 1-1 , by one or more R 1-2 Substituted C 1 -C 6 Alkyl or one or more R1-3 Substituted C 1 -C 6 Alkoxy.

[0058] In some embodiments, R 2 It is a halogen.

[0059] In some embodiments, R 3 It is a halogen.

[0060] In some embodiments, R 4 For hydrogen.

[0061] In some embodiments, R 5-1 For hydrogen.

[0062] In some embodiments, R 5-2 is hydrogen or C 1 -C 6 alkyl.

[0063] In some embodiments, R 6 It is a halogen.

[0064] In some embodiments, R 7 C 1 -C 6 alkyl.

[0065] In some embodiments, R 8 C 1 -C 6 alkyl.

[0066] In some embodiments, in the compound shown in Formula I, R 1 , R 2 and R 3 are independently halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, -OR 1-1 , by one or more R 1-2 Substituted C 1 -C 6 Alkyl or one or more R 1 -3 Substituted C 1 -C 6 Alkoxy;

[0067] R 1-1 C 3 -C 6Cycloalkyl or 3-8 membered heterocycloalkyl; in the 3-8 membered heterocycloalkyl, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0068] Each R 1-2 are each independently a halogen;

[0069] Each R 1-3 Each independently is C 1 -C 6 Alkoxy;

[0070] X 1 CR X1 ;

[0071] R X1 is hydrogen, halogen, or C substituted by one or more halogens 1 -C 6 alkyl;

[0072] X 2 for NH;

[0073] R 4 is hydrogen or C 1 -C 6 alkyl;

[0074] R 5 -OH, -NR 5-1 R 5-2 or -CN;

[0075] R 5-1 and R 5-2 are independently hydrogen or C 1 -C 6 alkyl;

[0076] n is 0, 1, 2 or 3;

[0077] R 6 For hydrogen, halogen, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 Alkyl-C 1 -C 6 Alkoxy or C 1 -C 6 Alkoxy;

[0078] R 7 is hydrogen or C 1 -C 6 alkyl;

[0079] R 8 Hydrogen, hydroxyl, C 1 -C 6 Alkyl, C1 -C 6 Alkyl-C 1 -C 6 Alkoxy or C 1 -C 6 Alkoxy.

[0080] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is a compound of Formula I-1 or a pharmaceutically acceptable salt thereof:

[0081] ;

[0082] R 1 C 1 -C 6 Alkoxy or one or more R 1-3 Substituted C 1 -C 6 Alkoxy;

[0083] Each R 1-3 Each independently is C 1 -C 6 Alkoxy;

[0084] R 2 is a halogen;

[0085] R 3 is a halogen;

[0086] X 1 N or CR X1 ;

[0087] R X1 is a halogen;

[0088] X 2 is O or NH;

[0089] R 4 is hydrogen;

[0090] R 5 is -OH or -CN;

[0091] R 7 C 1 -C 6 alkyl;

[0092] R 8 C 1 -C 6 alkyl.

[0093] In some embodiments, R 1 Methyl, cyclopropyl, methoxy, -CF 3 , , or .

[0094] In some embodiments, R 2 For fluorine.

[0095] In some embodiments, R 3 For fluorine.

[0096] In some embodiments, X 1 N, N + -O - , CH, CF or C-CF 3 .

[0097] In some embodiments, R 5 Methoxy, ethoxy, -OH, -NH 2 、-NH(CH 3 ) or -CN.

[0098] In some embodiments, for , , , , , or .

[0099] In some embodiments, the compound as shown in Formula I is any of the following compounds:

[0100]

[0101] .

[0102] The present invention provides a pharmaceutical composition, comprising:

[0103] (1) the compound of formula I or a pharmaceutically acceptable salt thereof, and

[0104] (2) Pharmaceutically acceptable excipients.

[0105] The present invention provides an application of a substance A in preparing a drug for treating a disease; the disease may be pain, a pain-related disease, multiple sclerosis, incontinence or arrhythmia;

[0106] The substance A is the compound shown in formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0107] In some embodiments, the pain is one or more of acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain.

[0108] The present invention provides an application of the substance A in the preparation of a drug for inhibiting voltage-gated sodium channels; the voltage-gated sodium channels are preferably Na V 1.8.

[0109] The present invention provides an application of the substance A in preparing a voltage-gated sodium channel inhibitor; the voltage-gated sodium channel is preferably Na V 1.8.

[0110] In some embodiments, the voltage-gated sodium channel inhibitor can be used in mammals in vivo; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample for comparison, or prepared into a kit according to conventional methods in the art to provide rapid detection of the effect of inhibiting voltage-gated sodium channels.

[0111] The present invention provides an application of the substance A in the preparation of a drug for a disease caused by abnormal activation of a voltage-gated sodium channel; the voltage-gated sodium channel is preferably Na V 1.8; The disease may be pain, a pain-related disease, multiple sclerosis, incontinence or cardiac arrhythmia.

[0112] The present invention also provides a method for preparing the compound shown in Formula I: the compound is prepared by the following route 1 or route 2:

[0113] Route 1:

[0114] Formula (Z1) and (Z2) are condensed to obtain formula (Z3), formula (Z3) is reduced to obtain formula (Z4), formula (Z4) is reduced by DIBAL-H to obtain formula (Z5), formula (Z5) is reacted with acetyl chloride to obtain formula (Z6), formula (Z6) is reacted in TMSCN / BF 3 OE 2 The general formula (Z7) is obtained under the following conditions, the general formula (Z7) is hydrolyzed to obtain the general formula (Z8), the general formula (Z8) is condensed with an amine to obtain the general formula (Z9), and the general formula (Z9) is reacted with ammonia methanol or hydroxylamine to obtain a compound as shown in Formula I:

[0115] ;

[0116] Route 2:

[0117] The general formula (Z7) is subjected to boron tribromide conditions to obtain the general formula (Z10), the general formula (D10) is subjected to a nucleophilic substitution reaction with a halogenated alkane or an alkyl sulfonate to obtain the general formula (Z11), the general formula (Z11) is hydrolyzed to obtain the general formula (Z12), the general formula (Z12) is condensed with an amine to obtain the general formula (Z13), and the general formula (Z13) is subjected to conditions such as ammonia methanol or hydroxylamine to obtain a compound as shown in Formula I:

[0118] ;

[0119] Among them, R 9 -C(=O)OC 1 -C 6 Alkyl or CN;

[0120] R 2 , R 3 , X 1 , X 2 , R 4 , R 5 , R 6 , R 7 , R 8 and n is as defined in any of the above items;

[0121] When R 1 For halogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, C 1 -C 6 Alkoxy, with one or more R 1-2 Substituted C 1 -C 6 When the alkyl group is present, the compound as shown in Formula I is prepared by route 1;

[0122] When R 1 OR 1-1 or one or more R 1-3 Substituted C 1 -C 6 When the alkoxy group is present, the compound as shown in Formula I is prepared by Route 2.

[0123] Terminology

[0124] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0125] In the present invention, the “ " means that the structural fragment is connected to the rest of the molecule through this bond. For example, It refers to cyclopropyl.

[0126] In the present invention, the "-" at the end of a group means that the group is connected to the rest of the molecule through this site. For example, -OH refers to a hydroxyl group.

[0127] In the present invention, the term "one or more" refers to 1, 2, 3, 4 or 5, such as 1, 2 or 3.

[0128] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0129] In the present invention, the term "alkyl" refers to a group having a specified number of carbon atoms (e.g., C 1 -C 6 ) is a straight or branched, saturated, monovalent hydrocarbon group. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0130] In the present invention, the term "alkoxy" refers to a group R Y -O-, R Y The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0131] In the present invention, the term "cycloalkyl" refers to a cycloalkyl group having a specified number of carbon atoms (e.g., 3 -C 6 ), cyclic, saturated, monovalent hydrocarbon group. Cycloalkyl groups include, but are not limited to: , , wait.

[0132] In the present invention, the term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group with a specified number of ring atoms (e.g., 3-12, 4-8, 5, 6 or 7), a specified number of heteroatoms (e.g., 1, 2 or 3), and a specified type of heteroatom (one or more of N, O and S). Heterocycloalkyl is connected to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes, but is not limited to: , , , , , wait.

[0133] In the present invention, the term "pharmaceutically acceptable excipients" refers to all substances contained in pharmaceutical preparations other than active pharmaceutical ingredients, which are generally divided into two categories: excipients and additives. For details, please refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) and Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno CHancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0134] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0135] The reagents and raw materials used in the present invention are commercially available.

[0136] The positive and progressive effects of the present invention are that the compounds of the present invention have one or more of the following advantages: (1) novel structure; (2) good blocking effect (inhibitory effect) on Nav1.8 channel activity; (3) good selectivity for other Nav subtypes (such as Nav1.1, Nav1.2, Nav1.3 Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.9) and high safety. DETAILED DESCRIPTION

[0137] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0138] Example 1 Synthesis of BX20-9-021

[0139] Step 1: Synthesis of Intermediate A2

[0140] The synthetic route is shown below:

[0141]

[0142] Method: Compound A1 (18.00 g, 95.76 mmol) was dissolved in toluene (300 mL), and SM1 (13.32 g, 87.07 mmol), Pd (PPh 3 ) 4 (3.19 g, 2.76 mmol), Cu 2 O (0.37 g, 2.62 mmol) and K 2 CO 3 (41.19 g, 298.06 mmol), replaced by N 2 The reaction mixture was stirred at 100°C for 16 hours. After the reaction, the mixture was filtered through diatomaceous earth and washed with EA. The filtrate was collected and extracted with saturated brine. The organic phase was dried. After concentration under reduced pressure, it was purified by column chromatography to obtain a white solid compound A2 (7.60 g, 40.4 %).

[0143] Step 2: Synthesis of Intermediate A3

[0144] The synthetic route is shown below:

[0145]

[0146] Method: Compound A2 (7.60 g, 35.16 mmol) was dissolved in THF (80 mL), and lithium hydroxide aqueous solution (3.39 g LiOH·H 2 O was dissolved in 40 mL HO 2 O, 80.87 mmol), the reaction mixture was stirred at 50 °C for 3 h. After the reaction, DCM was added to dilute the layers, and H 2 The mixture was extracted three times with 4% HCl and 1N HCl was added to adjust the pH value to 5. The mixture was extracted three times with DCM and the organic phases were combined, dried and concentrated under reduced pressure to obtain compound A3 (5.90 g, 83.0%) as a white solid.

[0147] Step 3: Synthesis of intermediate S2

[0148] The synthetic route is shown below:

[0149]

[0150] Method: Compound S1 (15.50 g, 98.05 mmol) was dissolved in Et 2 O (155 mL) to replace N 2, cool to about 0℃, keep the temperature at 0~10℃, and add MeLi.LiBr (209 mL, 313.76 mmol, 1.5 M in Et 2 O), and the temperature was naturally raised to room temperature for 12 hours after the reaction was completed. 2 O (100 mL), saturated sodium chloride solution (20 mL) was added to quench, citric acid (25.04 g) was added, and stirred for 0.5 h. Et 2 O was extracted three times, the organic phases were combined, dried, and concentrated under reduced pressure to 30 g to obtain crude S2 (about 35% in Et 2 O, 30 g).

[0151] Step 4: Synthesis of intermediate S3

[0152] The synthetic route is shown below:

[0153]

[0154] Method: Compound A3 (5.90 g, 29.20 mmol) was dissolved in MeCN (210 mL) and stirred until clear. The mixture was cooled in an ice-water bath and CDI (7.00 g, 30.70 mmol) was added to replace N 2 , keep the temperature below 10 ℃ and stir for 1.5 hours, add S2 (about 35% in Et 2 O, 15 g, 30 mmol), K 2 CO 3 (5.00 g, 36.50 mmol), the reaction mixture was stirred at 35 °C for 12 hours. After the reaction, water and dilute hydrochloric acid were added to the reaction solution and stirred until clear, extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to obtain a white solid S3 (7.40 g, 78.7 %). MS (ESI, m / z) 323 [M+H] + .

[0155] Step 5: Synthesis of S4

[0156] The synthetic route is shown below:

[0157]

[0158] Method: Compound S3 (9.00 g, 28.0 mmol) was dissolved in anhydrous methanol (800 mL) and anhydrous tetrahydrofuran (160 mL) and stirred until clear. The mixture was cooled to -40 °C and the first batch of NiCl 2 6H 2O (6.80 g, 28.6 mmol) and NaBH 4 (5.60 g, 148.4 mmol), the second batch of NiCl 2 6H 2 O (6.80 g, 28.6 mmol) and NaBH 4 (5.60 g, 148.4 mmol), the reaction is complete after addition. After the reaction is completed, saturated ammonium chloride is slowly added to the reaction solution at -40 °C to quench and stir for 30 min, then naturally warm to room temperature, filter with diatomaceous earth, extract with DCM, wash with concentrated brine, dry with anhydrous sodium sulfate, concentrate and purify with column chromatography to obtain colorless oily compound S4 (3.57 g, 39.3%). MS (ESI, m / z) 325 [M+H] + .

[0159] The NMR spectrum is:

[0160] 1 H NMR (400 MHz, CDCl 3 ) δ = 6.96-6.83 (m, 2H), 4.47 (d, J = 9.6 Hz,1H), 4.02 (d, J = 2.8 Hz, 1H), 2.92-2.84 (m, 1H), 1.70 (s, 3H), 0.81-0.78 (m,3H).

[0161] Step 6: Synthesis of S5

[0162] The synthetic route is shown below:

[0163]

[0164] Method: Compound S4 (3.57 g, 11.0 mmol) was dissolved in toluene (30 mL) and N 2 , cooled to -30℃, DiBAL-H (1.5 M, 7.7 mL, 11.6 mmol) was slowly added dropwise, and the reaction mixture was stirred at -25 ~ -30℃ for 2 hours. After the reaction, the reaction solution was added to saturated ammonium chloride to quench, filtered through diatomaceous earth, extracted with EA, washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a colorless oily compound S5 (3.53 g, crude). MS (ESI, m / z) 327[M+H] + .

[0165] Step 7: Synthesis of S6

[0166] The synthetic route is shown below:

[0167]

[0168] Method: Compound S5 (3.53 g, 10.8 mmol) was dissolved in anhydrous DCM (30 mL) and stirred until clear. Et 3 N (2.18 g, 21.6 mmol), cooled to 0~10 ℃ in an ice-water bath, slowly added AcCl (1.70 g, 21.6 mmol), and after the addition, warmed to room temperature and stirred for 1 hour. After the reaction, saturated ammonium chloride was added to the reaction solution to quench, extracted with DCM, washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oily compound S6 (4.36 g, crude). MS (ESI, m / z) 369[M+H] + .

[0169] Step 8: Synthesis of S7

[0170] The synthetic route is shown below:

[0171]

[0172] Method: Compound S6 (4.36 g, 11.8 mmol) was dissolved in anhydrous DCM (40 mL) and stirred to dissolve. 2 , cooled to -78°C, and TMSCN (3.52 g, 35.5 mmol) and BF 3 OE 2 (5.04 g, 35.5 mmol), after the addition, stir at -60 °C for 1 hour, and then naturally warm to room temperature and stir for 12 hours. After the reaction, add saturated sodium carbonate solution to the reaction solution for quenching, filter on diatomaceous earth, extract with DCM, wash with concentrated brine, dry with anhydrous sodium sulfate, concentrate and purify with column chromatography to obtain colorless oily compound S7 (2.25 g, 56.9 %). MS (ESI, m / z) 336 [M+H] + .

[0173] Step 9: Synthesis of S8

[0174] The synthetic route is shown below:

[0175]

[0176] Method: Compound S7 (2.25 g, 6.7 mmol) was dissolved in MeOH (50 mL), and KOH aqueous solution (2.63 g KOH dissolved in 10 mL H 2O, 46.9 mmol), the reaction mixture was stirred at 60 ° C for 12 h. After the reaction, MTBE was added for extraction, the aqueous phase was adjusted to pH <5 by adding hydrochloric acid, and MTBE was added for extraction. The organic phase was washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oily compound S8 (2.20 g, crude product). MS (ESI, m / z) 355 [M+H] +

[0177] Step 10: Synthesis of intermediate S10

[0178] The synthetic route is shown below:

[0179]

[0180] Method: S8 (150 mg, 0.42 mmol) was dissolved in DCM (5 mL) and DMF (20 μL), and oxalyl chloride (0.3 mL, 3.20 mmol) was slowly added dropwise. The reaction was allowed to react at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure at 40 °C, dissolved in DCM (5 mL), and slowly added dropwise to a solution of 4-aminopyridine-2-carboxylic acid methyl ester (140 mg, 0.91 mmol) and TEA (142 mg, 1.4 mmol) in DCM (5 mL). The reaction was allowed to react at room temperature for 1 h. After the reaction was completed, saturated NH 4 Cl solution (30 mL) was quenched, and DCM (30 mL×3) was added for extraction. The organic phases were combined and washed with saturated NaCl solution and anhydrous Na 2 SO 4 After drying and concentration, yellow oily compound S9 (390 mg, crude) was obtained. MS (ESI, m / z) 489 [M+H] + .

[0181] Step 11: Synthesis of Intermediate S11

[0182] The synthetic route is shown below:

[0183]

[0184] Method: S10 (390 mg, 0.80 mmol) was dissolved in methanol (15 mL), and NaOH (1 N, 15 mL) was added and stirred at room temperature overnight. After the reaction, the pH was adjusted to 3-4, extracted with EA, dried over sodium sulfate, and concentrated to obtain S11 (300 mg, crude product). MS (ESI, m / z) 475 [M+H] + .

[0185] Step 12: Synthesis of BX20-9-021

[0186] The synthetic route is shown below:

[0187]

[0188] Method: S11 (150 mg, 0.31 mmol) was dissolved in DMF (3 mL), and EDCI (96 mg, 0.5 mmol), DMAP (122 mg, 1 mmol) and A1 (42 mg, 0.5 mmol) were added. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, water was added to quench, EA was extracted, and the mixture was dried over sodium sulfate. After concentration, the mixture was purified by preparative chromatography and freeze-dried to obtain a light yellow solid BX20-9-021 (13 mg, yield 8.4%). MS (ESI, m / z) 504 [M+H] + .

[0189] 1 H NMR (400 MHz, CD 3 OD) δ = 8.45 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 2.4Hz, 1H), 7.87 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 7.13-7.09 (m, 1H), 7.00-6.94 (m,1H), 5.07 (d, J = 10.4 Hz, 1H), 4.32 (dd, J = 10.4 Hz, 8.0 Hz, 1H), 3.99 (d,J = 2.4 Hz, 3H), 3.80 (s, 3H), 2.83-2.75 (m, 1H), 1.65 (s, 3H), 0.82-0.79 (m,3H).

[0190] Example 2: Synthesis of BX20-9-022

[0191] Step 1: Synthesis of intermediate S11

[0192] Reference Example 1 Step 1 to Step 11

[0193] Step 2: Synthesis of BX20-9-022

[0194] The synthetic route is shown below:

[0195]

[0196] Method: S11 (150 mg, 0.31 mmol) was dissolved in DMF (3 mL), EDCI (96 mg, 0.5 mmol), DMAP (122 mg, 1 mmol) and A1 (49 mg, 0.5 mmol) were added, and the reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, water was added to quench, EA was extracted, and sodium sulfate was dried. After concentration, it was purified by preparative chromatography and freeze-dried to obtain a light yellow solid BX20-9-021 (13 mg, yield 8.1%). MS (ESI, m / z) 518 [M+H] + .

[0197] 1 H NMR (400 MHz, CD 3 OD) δ = 8.45 (d, J = 5.6 Hz, 1H), 8.22 (d, J = 2.4Hz, 1H), 7.87 (dd, J = 5.6 Hz, 2.4 Hz, 1H), 7.13-7.09 (m, 1H), 7.00-6.94 (m,1H), 5.07 (d, J = 10.4 Hz, 1H), 4.32 (dd, J = 10.4 Hz, 8.0 Hz, 1H), 4.04-3.98(m, 5H), 3.80 (s, 3H), 2.83-2.74 (m, 1H), 1.65 (s, 3H), 1.29 (t, J = 6.8 Hz, 3H), 0.82-0.79 (m, 3H).

[0198] Example 3: Synthesis of BX20-9-029

[0199] Step 1: Synthesis of intermediate S8

[0200] Reference Example 1 Steps 1-9

[0201] Step 2: Synthesis of intermediate S9'

[0202] The synthetic route is shown below:

[0203]

[0204] Method: S8 (150 mg, 0.424 mmol) was dissolved in DCM (6 mL), 1 drop of DMF was added, the temperature was lowered to 0 °C, oxalyl chloride (0.1 mL, 1.272 mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, dissolved in DCM (5 mL), and slowly added dropwise to a DCM / NMP (10:1, 5.5 mL) solution of A1 (69 mg, 0.509 mmol) and TEA (154 mg, 1.527 mmol), and stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, dissolved in EA, quenched by adding water (15 mL), extracted with EA, the organic phases were combined, washed once with water and saturated aqueous NaCl solution, and anhydrous Na 2 SO 4 After drying and concentration under reduced pressure, yellow oily compound S9' (250 mg, crude product) was obtained. MS (ESI, m / z) 473 [M+H] + .

[0205] Step 3: Synthesis of BX20-9-029

[0206] The synthetic route is shown below:

[0207]

[0208] Method: Compound S9' (250 mg, crude product, 0.424 mmol) was dissolved in EtOH (6 mL) and NH 2 OH (112 mg, 1.696 mmol, 50%), the reaction solution was stirred at 80 °C for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and purified by preparative chromatography (formic acid system), and freeze-dried to obtain a white solid BX20-9-029 (128 mg, 60 %). MS (ESI, m / z) 497[M+H] + .

[0209] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.62 (s, 1H), 7.75 (dd, J= 6.8 Hz, 2.8 Hz, 1H), 7.67-7.62 (m, 1H), 7.21-7.12 (m, 3H), 5.77 (s, 2H),5.04 (d, J = 10.4 Hz, 3H), 4.27-4.20 (m, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.79-2.71 (m, 1H), 1.59 (s, 3H), 0.75-0.69 (m, 3H).

[0210] Example 4: Synthesis of BX20-9-033

[0211] Step 1: Synthesis of intermediate S10

[0212] Reference Example 1 Step 1 to Step 10 Synthesis

[0213] Step 2: Synthesis of compound BX20-9-033

[0214] The synthetic route is shown below:

[0215]

[0216] Method: Compound S10 (180 mg, 0.37 mmol) was dissolved in MeOH (8 mL), and NH 2 OH (50% in water, 220 mg, 3.4 mmol), stirred at room temperature for 24 hours. After the reaction, the reaction solution was concentrated under reduced pressure at 40 °C, purified by preparative chromatography (formic acid system), and freeze-dried to obtain a white solid powder BX20-9-033 (58 mg, yield 32.2%). MS (ESI, m / z) 489 [M+H] + .

[0217] 1 H NMR (400MHz, DMSO-d 6)δ = 11.39 (s,1H), 10.74 (s, 1H), 9.09 (s, 1H),8.45 (d, J = 5.2 Hz, 1H), 8.23 ​​(d, J = 2.0 Hz, 1H), 7.81 (dd, J = 5.2 Hz, J =2.0 Hz, 1H), 7.21-7.13 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H), 4.22 (dd, J = 10.4Hz, J = 8.0 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.81-2.73 (m, 1H), 1.61 (s,3H), 0.74-0.72 (m, 3H).

[0218] Example 5: Synthesis of BX20-9-034

[0219] Step 1: Synthesis of intermediate S10

[0220] Reference Example 1 Step 1 to Step 10 Synthesis

[0221] Step 2: Synthesis of compound BX20-9-034

[0222] The synthetic route is shown below:

[0223]

[0224] Method: Compound S10 (180 mg, 0.37 mmol) was dissolved in EtOH (2 mL), and N 2 H 4 ·H 2 O (50 mg, 1.0 mmol), stirred at 85°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography, and freeze-dried to obtain a white solid powder BX20-9-034 (62 mg, yield 34.4%). MS (ESI, m / z) 488 [M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d 6)δ = 10.78 (s,1H), 9.84 (s, 1H), 8.47 (d, J =5.6 Hz, 1H), 8.25 (s, 1H), 7.82 (dd, J = 5.6 Hz, J = 2.0 Hz, 1H), 7.20-7.16(m, 2H), 5.11 (d, J = 10.0 Hz, 1H), 4.28-4.23 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.79-2.76 (m, 1H), 1.61 (s, 3H), 0.74-0.72 (m, 3H).

[0226] Example 6: Synthesis of BX20-9-035

[0227] Step 1: Synthesis of intermediate S11

[0228] Reference Example 1 Step 1 to Step 11 Synthesis

[0229] Step 2: Synthesis of intermediate 35-3

[0230] The synthetic route is shown below:

[0231]

[0232] Method: Compound S11 (175 mg, 0.36 mmol) was dissolved in DMF (5 mL), DIEA (160 mg, 1.24 mmol), EDCI (138 mg, 0.72 mmol) and HOBt (60 mg, 0.44 mmol) were added in sequence, stirred at room temperature for 10 min, and then SM1 (53 mg, 0.3 mmol) was added and stirred at room temperature for 16 hours. After the reaction, the reaction solution was extracted with EA (30 mL×3), the organic phases were combined, washed with saturated brine, and anhydrous Na 2 SO 4 After drying, the product was concentrated under reduced pressure to give a yellow oily liquid 35-3 (210 mg, crude). MS (ESI, m / z) 602 [M+H] + .

[0233] Step 3: Synthesis of compound BX20-9-035

[0234] The synthetic route is shown below:

[0235]

[0236] Method: Compound 35-3 (210 mg, 0.35 mmol) was dissolved in DCM (2 mL), HCl / 1,4-dioxane (1.75 mL, 6.98 mmol) was added dropwise, and stirred at room temperature for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography, and freeze-dried to obtain a white solid powder BX20-9-035 (23 mg, yield 13.1 %). MS (ESI, m / z) 502.2[M+H] +

[0237] 1 H NMR (400MHz, DMSO-d 6 )δ = 10.76 (s,1H), 10.13 (s, 1H), 8.47 (d, J =5.6 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 5.6 Hz, J = 2.0 Hz, 1H),7.21-7.13 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H), 4.25 (dd, J = 10.4 Hz, J = 8.0Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.81-2.73 (m, 1H), 2.52 (s, 3H), 1.61 (s,3H), 0.74-0.72 (m, 3H).

[0238] Example 7: Synthesis of BX20-9-036

[0239] Step 1: Synthesis of S8

[0240] Reference Example 1 Step 1 to Step 9 Synthesis

[0241] Step 2: Synthesis of S9

[0242] The synthetic route is shown below:

[0243]

[0244] Method: Compound S8 (0.15 g, 0.42 mmol) was dissolved in DCM (4 mL) and stirred until dissolved. DMF (0.1 mL) was added and the mixture was cooled to 0 °C in an ice-water bath. Oxalyl chloride (0.11 g, 0.84 mmol) was added dropwise. After the addition, the mixture was heated to room temperature and stirred for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain crude product S9 which was directly used in the next step.

[0245] Step 3: Synthesis of 36-1

[0246] The synthetic route is shown below:

[0247]

[0248] Method: Compound SM1 (76 mg, 0.64 mmol) was dissolved in NMP (2 mL), TEA (86 mg, 0.85 mmol) was added, and S9 (crude, diluted with 5 mL DCM, 0.42 mmol) was slowly added, and stirred at room temperature for 0.5 hours. After the reaction was completed, saturated ammonium chloride was added to quench, and DCM was extracted. The organic phases were combined, washed with concentrated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain a brown oil 36-1 (0.33 g, crude). MS (ESI, m / z) 456 [M+H] + .

[0249] Step 4: Synthesis of BX20-9-036

[0250] The synthetic route is shown below:

[0251]

[0252] Method: Compound 36-1 (0.33 g, crude, about 0.4 mmol) was dissolved in EtOH (6 mL) and NH 2 OH (0.11 g, 1.72 mmol, 50 wt % aqueous solution), the reaction solution was heated to 80 ° C and stirred for 1 hour. After the reaction, it was concentrated under reduced pressure and purified by preparative chromatography (neutral system), and freeze-dried to obtain a white solid BX20-9-036 (102 mg, 49.7 %). MS (ESI, m / z) 489 [M+H] + .

[0253] 1 H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 2H), 8.42 (d, J = 5.6 Hz, 1H), 8.16-8.14 (m, 1H), 7.65-7.62 (m, 1H), 7.21-7.11 (m, 2H), 5.80 (s, 2H), 5.08(d, J = 10.0 Hz, 1H), 4.27-4.22 (m, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.81–2.72(m, 1H), 1.60 (s, 3H), 0.74-0.70 (m, 3H).

[0254] Example 8: Synthesis of BX20-9-037

[0255] Step 1: Synthesis of 36-1

[0256] Reference Example 7 Steps 1 to 3

[0257] Step 2: Synthesis of 37-1

[0258] The synthetic route is shown below:

[0259]

[0260] Method: Compound 36-1 (220 mg, crude, about 0.4 mmol) was dissolved in DCE (5 mL) and stirred until clear. The mixture was cooled to 0 °C and m-CPBA (0.35 g, 1.72 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and added to NaHCO 3 The mixture was quenched in water, extracted with DCM / MeOH, the organic phases were combined, washed with brine, dried, and concentrated under reduced pressure to obtain a brown oil 37-1 (0.26 g, crude). MS (ESI, m / z) 472[M+H] + .

[0261] Step 3: Synthesis of BX20-9-037

[0262] The synthetic route is shown below:

[0263]

[0264] Method: Compound 37-1 (0.26 g, crude) was dissolved in EtOH (6 mL) and NH 2 OH (0.11 g, 1.72 mmol, 50 wt% aqueous solution), the reaction solution was heated to 80 °C and stirred for 0.5 hours. After the reaction was completed, it was directly concentrated under reduced pressure and purified by preparative chromatography (alkaline system), and freeze-dried to obtain a light yellow solid BX20-9-037 (22 mg, 10.4%). MS (ESI, m / z) 505 [M+H] + .

[0265] 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.15 (s, 1H), 8.21-8.15(m, 2H), 7.71-7.67 (m, 1H), 7.21-7.11 (m, 2H), 6.78 (s, 2H), 5.07 (d, J =10.0 Hz, 1H), 4.26-4.20 (m, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.80-2.71 (m, 1H), 1.60 (s, 3H), 0.74-0.70 (m, 3H).

[0266] Example 9: Synthesis of BX20-9-038

[0267] Step 1: Synthesis of intermediate S8

[0268] Reference Example 1 Step 1 to Step 9

[0269] Step 2: Synthesis of intermediate 38-1

[0270]

[0271] Method: S8 (150 mg, 0.42 mmol) was dissolved in DCM (3 mL), and one drop of DMF was added. Oxalyl chloride (160 mg, 1.26 mmol) was added dropwise at 0°C, and the reaction solution was stirred at room temperature for 0.5 h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain crude S9 (170 mg, crude), which was used directly in the next step. Int 38 (79 mg, 0.466 mmol) was dissolved in DCM (2 mL), TEA (91 mg, 0.9 mmol) was added, and then a DCM (2 mL) solution of S9 (170 mg, crude) was added dropwise, and stirred at room temperature for 0.5 h. After the reaction, water and DCM were added for extraction, washed with brine, and concentrated under reduced pressure to obtain a yellow oily liquid 38-1 (197 mg, crude). MS (ESI, m / z) 506 [M+H] + .

[0272] Step 3: Synthesis of intermediate BX20-9-038

[0273]

[0274] Method: Dissolve compound 38-1 (180 mg, 0.37 mmol) in MeOH (2 mL), add NH 2OH (100 mg, 1.5 mmol, 50 wt% aqueous solution) was added and stirred at room temperature for 72 hours. After the reaction, the reaction solution was concentrated under reduced pressure, purified by preparative chromatography (prepared with formic acid), and freeze-dried to obtain a light yellow solid powder BX20-9-038 (62 mg, yield 34.4%). MS (ESI, m / z) 507 [M+H] + .

[0275] 1 H NMR (400MHz, DMSO-d 6 )δ = 10.95 (brs,1H), 10.41 (s, 1H), 9.26 (brs,1H), 7.84-7.81 (m, 1H), 7.74-7.69 (m, 1H), 7.26-7.12 (m, 3H), 5.05 (d, J =10.4 Hz, 1H), 4.23 (dd, J = 10.4 Hz, J = 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.79-2.72 (m, 1H), 1.60 (s, 3H), 0.74-0.70 (m, 3H).

[0276] Example 10: Synthesis of BX20-9-039

[0277] Step 1: Synthesis of intermediate S7

[0278] Reference Example 1 Step 1 to Step 8 to synthesize intermediate S7.

[0279] Step 2: Synthesis of intermediate 39-1

[0280] The synthetic route is shown below:

[0281]

[0282] Method: S7 (1.1 g, 3.28 mmol) was dissolved in DCM (15 mL) and N 2 Replace, cool to -78 °C, slowly add BBr 3 (2.1 mL, 21.32 mmol), after the addition, the temperature was raised to 0 °C and stirred for 3 hours. After the reaction, the reaction solution was slowly added dropwise to ice water, extracted with DCM, washed with saturated NaCl aqueous solution, and anhydrous Na 2 SO 4 After drying and concentration under reduced pressure, yellow oily compound 39-1 (1.0 g, crude product) was obtained. MS (ESI, m / z) 322 [M+H] +.

[0283] Step 3: Synthesis of intermediate 39-2

[0284] The synthetic route is shown below:

[0285]

[0286] Method: 39-1 (500 mg, crude product, about 1.5 mmol) was dissolved in DMF (5 mL) and Cs 2 CO 3 (2.1mL, 21.32 mmol) and 1-iodo-2-methoxyethane (1.15g, 6.2 mmol), heated to 70 °C and stirred for 16 hours. After the reaction, water was added to quench, EA was extracted, washed with saturated NaCl aqueous solution, anhydrous Na 2 SO 4 After drying and concentration under reduced pressure, yellow oily compound 39-2 (450 mg, crude product) was obtained. MS (ESI, m / z) 380 [M+H] + .

[0287] Step 4: Synthesis of intermediate 39-3

[0288] The synthetic route is shown below:

[0289]

[0290] Method: 39-2 (450 mg, crude, 1.18 mmol) was dissolved in MeOH (7.5 mL), and KOH aqueous solution (462 mg, 8.26 mmol, dissolved in 1.5 mL water) was added, and the temperature was raised to 60 °C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, diluted with water, extracted with MTBE, and the aqueous phase was added with 1N HCl to adjust the pH to <3, extracted with EA, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain yellow oily compound 39-3 (430 mg, crude). MS (ESI, m / z) 399 [M+H] + .

[0291] Step 5: Synthesis of intermediate 39-4

[0292] The synthetic route is shown below:

[0293]

[0294] Method: 39-3 (160 mg, crude, 0.402 mmol) was dissolved in DCM (4 mL), 1 drop of DMF was added, the temperature was lowered to 0 °C, oxalyl chloride (0.1 mL, 1.206 mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 0.5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, dissolved in DCM (4 mL), and slowly added dropwise to a DCM / NMP (4:1, 5 mL) solution of 5-amino-2-fluorobenzonitrile (55 mg, 0.402 mmol) and TEA (122 mg, 1.206 mmol), and stirred at room temperature for 0.5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, dissolved in EA, quenched with water, extracted with EA, the organic phases were combined, washed once with water and saturated aqueous NaCl solution, and anhydrous Na 2 SO 4 After drying and concentration under reduced pressure, yellow oily compound 39-4 (207 mg, crude product) was obtained. MS (ESI, m / z) 517 [M+H] + .

[0295] Step 6: Synthesis of BX20-9-039

[0296] The synthetic route is shown below:

[0297]

[0298] Method: Compound 39-4 (207 mg, crude product, about 0.4 mmol) was dissolved in EtOH (5 mL) and NH 2 OH (0.1 mL, 1.608 mmol, 50% in H 2 O), heated to 80 ° C and stirred for 1 hour. After the reaction, the mixture was concentrated under reduced pressure and purified by preparative chromatography (formic acid system), and freeze-dried to obtain a white solid BX20-9-039 (112 mg, 51%). MS (ESI, m / z) 550 [M+H] + .

[0299] 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.63 (s, 1H), 7.80-7.73(m, 1H), 7.69-7.62 (m, 1H), 7.21-7.14 (m, 3H), 5.79 (s, 2H), 5.06 (d, J =10.8 Hz, 1H), 4.36-4.30 (m, 1H), 4.29-4.24 (m, 1H), 4.23-4.16 (m, 1H), 3.64-3.59 (m, 2H), 3.29 (d, J = 1.2 Hz, 3H), 2.79-2.71 (m, 1H), 1.60 (s, 3H), 0.69(d, J = 7.2 Hz, 3H).

[0300] Example 11: Synthesis of BX20-9-040

[0301] Step 1: Synthesis of intermediate 39-1

[0302] Reference Example 10 Step 1~Step 2 Synthesis of Intermediate 39-1

[0303] Step 2: Synthesis of intermediate 40-1

[0304] The synthetic route is shown below:

[0305]

[0306] Method: 39-1 (500 mg, crude, 1.55 mmol) was dissolved in DMF (5 mL) and Cs 2 CO 3 (2.1mL, 21.32 mmol) and 3-iodooxetane (1.14g, 6.2 mmol), heated to 70 °C and stirred for 16 hours. After the reaction, water was added to quench, EA was extracted, washed with saturated NaCl aqueous solution, anhydrous Na 2 SO 4 After drying and concentration under reduced pressure, yellow oily compound 40-1 (565 mg, crude product) was obtained. MS (ESI, m / z) 378 [M+H] + .

[0307] Step 3: Synthesis of intermediate 40-2

[0308] The synthetic route is shown below:

[0309]

[0310] Method: 40-1 (565 mg, crude, 1.5 mmol) was dissolved in MeOH (7.5 mL), and an aqueous solution of KOH (587 mg, 10.5 mmol, dissolved in 1.5 mL of water) was added, and the temperature was raised to 60 °C and stirred for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, diluted with water, extracted with MTBE, and the aqueous phase was added with 1 N HCl to adjust the pH to <3, extracted with EA, washed with a saturated aqueous solution of NaCl, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily compound 40-2 (330 mg, crude). MS (ESI, m / z) 397 [M+H] + .

[0311] Step 4: Synthesis of intermediate 40-3

[0312] The synthetic route is shown below:

[0313]

[0314] Method: 40-2 (330 mg, crude product, 0.83 mmol) was dissolved in DMF (6 mL), EDCI (318 mg, 1.66 mmol), HOBT (135 mg, 1.0 mmol) and DIEA (321 mg, 2.4 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Then, 5-amino-2-fluorobenzonitrile (79 mg, 0.58 mmol) was added, and the reaction was continued at room temperature for 4 hours. After the reaction was completed, water was added to quench the mixture, and EA was extracted. The mixture was washed with water and saturated NaCl aqueous solution once, and anhydrous Na 2 SO 4 After drying and concentration under reduced pressure, yellow oily compound 40-3 (400 mg, crude product) was obtained. MS (ESI, m / z) 515 [M+H] + .

[0315] Step 5: Synthesis of BX20-9-040

[0316] The synthetic route is shown below:

[0317]

[0318] Method: Compound 40-3 (400 mg, crude product, 0.78 mmol) was dissolved in EtOH (5 mL) and NH 2 OH (0.2 mL, 3.12 mmol, 50% in H 2O), heated to 80°C and stirred for 1 hour. After the reaction, the mixture was concentrated under reduced pressure and purified by preparative chromatography (formic acid system), and freeze-dried to obtain a white solid BX20-9-040 (45 mg, 11%). MS (ESI, m / z) 548 [M+H] + .

[0319] 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.65 (s, 1H), 7.76 (d, J =6.4 Hz, 1H), 7.69-7.62 (m, 1H), 7.22-7.14 (m, 3H), 5.33-5.25 (m, 1H), 5.07(d, J = 10.4 Hz, 3H), 4.90-4.82 (m, 2H), 4.73-4.66 (m, 2H), 4.29-4.22 (m,1H), 2.81-2.73 (m, 1H), 1.60 (s, 3H), 0.72 (d, J = 7.2 Hz, 3H).

[0320] Example 12: Synthesis of BX20-9-046

[0321] Step 1: Synthesis of S9

[0322] Reference Example 7 Step 1 to Step 2 Synthesis of S9

[0323] Step 2: Synthesis of 46-1

[0324] The synthetic route is shown below:

[0325]

[0326] Method: Dissolve the compound 5-amino-2-(trifluoromethyl)benzonitrile (97 mg, 0.50 mmol) in NMP (2 mL), add TEA (85 mg, 0.84 mmol), and then slowly add S9 (crude product, diluted with 5 mL DCM, about 0.4 mmol), and stir at room temperature for 0.5 hours. After the reaction, add saturated ammonium chloride to quench, extract with DCM, combine the organic phases, wash with concentrated brine, dry the organic phases, and concentrate under reduced pressure to obtain a brown oil 46-1 (0.28 g, crude product). MS (ESI, m / z) 523 [M+H] + .

[0327] Step 3: Synthesis of BX20-9-046

[0328] The synthetic route is shown below:

[0329]

[0330] Method: Compound 46-1 (0.28 g) was dissolved in EtOH (6 mL) and NH 2 OH (0.11 g, 1.68 mmol, 50 wt % aqueous solution), the reaction mixture was heated to 80 °C and stirred for 0.5 hours. After the reaction, it was directly concentrated under reduced pressure and purified by preparative chromatography and freeze-dried to obtain a white solid BX20-9-046 (71 mg, 30.5 %). MS (ESI, m / z) 556[M+H] + .

[0331] 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (d, J = 4.4 Hz, 1H), 9.59 (s, 1H), 7.86-7.80 (m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.22-7.11 (m, 2H), 5.88 (s, 2H),5.12-5.07 (m, 1H), 4.28-4.21 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.81-2.72 (m,1H), 1.60 (s, 3H), 0.76-0.70 (m, 3H).

[0332] Example 13: Synthesis of BX20-9-047

[0333] Step 1: Synthesis of S8

[0334] Reference Example 1 Steps 1 to 9 were used to synthesize S8.

[0335] Step 2: Synthesis of 47-1

[0336] The synthetic route is shown below:

[0337]

[0338] Method: Dissolve S8 (150 mg, 0.42 mmol) in DCM (3 mL), add one drop of DMF, and dropwise add oxalyl chloride (160 mg, 1.26 mmol) at 0 °C. Stir the reaction mixture at room temperature for 0.5 h. After completion of the reaction, concentrate the reaction mixture under reduced pressure to obtain crude S9 (180 mg, crude product), which is directly used for the next step; Dissolve compound 5-amino-2,3-difluorobenzonitrile (78 mg, 0.50 mmol) in NMP (2 mL), add TEA (85 mg, 0.84 mmol), and then slowly add S9 (crude product, diluted with 5 mL DCM, about 0.42 mmol). Stir at room temperature for 0.5 h. After completion of the reaction, quench with saturated ammonium chloride, extract with EA, combine the organic phases, wash with brine, dry the organic phase, and concentrate under reduced pressure to obtain a brown oil 47-1 (0.17 g, crude product). MS (ESI, m / z) 491 [M+H] + 。

[0339] Step 3: Synthesis of BX20-9-047

[0340] The synthetic route is shown as follows:

[0341]

[0342] Method: Dissolve compound 47-1 (crude product, about 0.42 mmol) in EtOH (6 mL), add NH 2 OH (0.11 g, 1.68 mmol, 50 wt % aqueous solution), and heat the reaction mixture to 80 °C and stir for 0.5 h. After completion of the reaction, directly concentrate under reduced pressure and purify by preparative chromatography (formic acid) system to obtain white solid BX20-9-047 (52 mg, 23.6 %). MS (ESI, m / z) 524 [M+H] + 。

[0343] 1H NMR (400 MHz, DMSO-d6) δ = 9.87 (s, 1H), 9.76 (s, 1H), 7.97-7.92(m, 1H), 7.48-7.40 (m, 1H), 7.36-7.31 (m, 1H), 7.20-7.12 (m, 1H), 6.28 (s,2H), 5.19 (d, J = 11.2 Hz, 1H), 4.06-3.99 (m, 1H), 3.90 (d, J = 2.0 Hz, 3H), 2.74-2.64 (m, 1H), 1.65 (s, 3H), 0.74-0.69 (m, 3H).

[0344] Example 14: Synthesis of BX20-9-048

[0345] Step 1: Synthesis of 48-2

[0346] The synthetic route is shown below:

[0347]

[0348] Method: Compound 48-1 (0.50 g, 2.7 mmol) was dissolved in EtOH (4 mL), and AcOH (0.97 g, 16.2 mmol) and reduced iron powder (0.76 g, 13.5 mmol) were added. The mixture was stirred at room temperature for 0.5 hour, and then heated to 50 °C and stirred for 0.5 hour. After the reaction was completed, the mixture was directly filtered, extracted with water and EA, the organic phases were combined, washed with concentrated brine, dried, and concentrated under reduced pressure to obtain 48-2 (0.40 g, 96.3%). MS (ESI, m / z) 155 [M+H] + .

[0349] Step 2: Synthesis of 48-3

[0350] The synthetic route is shown below:

[0351]

[0352] Method: S8 (150 mg, 0.42 mmol) was dissolved in DCM (3 mL), and a drop of DMF was added. Oxalyl chloride (160 mg, 1.26 mmol) was added dropwise at 0 °C, and the reaction solution was stirred at room temperature for 0.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain crude S9 (180 mg, crude), which was directly used in the next step; 5-amino-2,4-difluorobenzonitrile (78 mg, 0.50 mmol) was dissolved in NMP (2 mL), TEA (85 mg, 0.84 mmol) was added, and then S9 (crude, diluted with 5 mL DCM, 0.42 mmol) was slowly added, and stirred at room temperature for 0.5 hours. After the reaction was completed, saturated ammonium chloride was added to quench, and DCM was extracted. The organic phases were combined, washed with concentrated brine, dried, and concentrated under reduced pressure to obtain brown oil 48-3 (0.15 g, crude). MS (ESI, m / z) 491[M+H] + .

[0353] Step 3: Synthesis of BX20-9-048

[0354] The synthetic route is shown below:

[0355]

[0356] Method: Compound 48-3 (0.15 g, crude, about 0.42 mmol) was dissolved in EtOH (6 mL) and NH 2 OH (0.11 g, 1.72 mmol, 50 wt % aqueous solution), the reaction mixture was heated to 80 °C and stirred for 0.5 hours. After the reaction was completed, it was directly concentrated under reduced pressure and purified by preparative chromatography (neutral) system to obtain a white solid BX20-9-048 (56 mg, 27.2 %). MS (ESI, m / z) 524 [M+H] + .

[0357] 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 9.64 (s, 1H), 7.85-7.78 (m,1H), 7.44-7.33 (m, 1H), 7.24-7.12 (m, 2H), 5.81 (s, 2H), 5.19 (d, J = 10.4Hz, 1H), 4.24-4.17 (m, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.83-2.66 (m, 1H), 1.60 (s, 3H), 0.74-0.70 (m, 3H).

[0358] Example 15: Synthesis of BX20-9-049

[0359] Step 1: Synthesis of S8

[0360] Reference Example 1 Steps 1 to 9 were used to synthesize S8.

[0361] Step 2: Synthesis of 49-1

[0362] The synthetic route is shown below:

[0363]

[0364] Method: S8 (150 mg, 0.42 mmol) was dissolved in DCM (3 mL) solution, one drop of DMF was added, oxalyl chloride (160 mg, 1.26 mmol) was added dropwise at 0 °C, and the reaction solution was stirred at room temperature for 0.5 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain crude S9 (180 mg, crude product), which was directly used in the next step; compound 3-amino-2,6-difluorobenzonitrile (78 mg, 0.50 mmol) was dissolved in NMP (2 mL), TEA (85 mg, 0.84 mmol) was added, and then S9 (crude product, diluted with 5 mL DCM, about 0.42 mmol) was slowly added, and stirred at room temperature for 0.5 hours. After the reaction, saturated ammonium chloride was added to quench, EA was extracted, the organic phases were combined, washed with concentrated brine, the organic phases were dried, and concentrated under reduced pressure to obtain brown oil 49-1 (0.13 g, crude product). MS (ESI, m / z) 491 [M+H] + .

[0365] Step 3: Synthesis of BX20-9-049

[0366] The synthetic route is shown below:

[0367]

[0368] Method: Compound 49-1 (0.13 g, crude product, about 0.42 mmol) was dissolved in EtOH (6 mL) and NH 2 OH (0.11 g, 1.68 mmol, 50 wt % aqueous solution), the reaction mixture was heated to 80 °C and stirred for 0.5 hours. After the reaction, it was directly concentrated under reduced pressure and purified by preparative chromatography (formic acid) system to obtain a white solid BX20-9-049 (48 mg, 21.9%). MS (ESI, m / z) 524 [M+H] + .

[0369] 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 9.60 (s, 1H), 7.79-7.69 (m,1H), 7.24-7.14 (m, 2H), 7.12-7.05 (m, 1H), 5.97 (s, 2H), 5.21 (d, J = 10.4Hz, 1H), 4.23-4.16 (m, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.80-2.69 (m, 1H), 1.60(s, 3H), 0.74-0.70 (m, 3H).

[0370] Example 16: Synthesis of BX20-9-055

[0371] Step 1: Synthesis of BX20-9-029

[0372] Reference Example 3 Steps 1 to 3 complete the synthesis of BX20-9-029

[0373] Step 2: Synthesis of Intermediate 55-1

[0374]

[0375] Method: BX20-9-029 (100 mg, 0.2 mmol) was dissolved in AcOH (5 mL), Pd / C (100 mg, 50%wt water) and ammonium formate (126 mg, 2 mmol) were added, and the reaction system was replaced with nitrogen and heated at 120 °C for 3 hours. After the reaction was completed, the filtrate was filtered and concentrated under reduced pressure to obtain a yellow oily liquid 55-1 (90 mg, crude product). MS (ESI, m / z) 490 [M+H] + .

[0376] Step 3: Synthesis of BX20-9-055

[0377]

[0378] Method: 55-1 (90 mg, crude product) was dissolved in EtOH (3 mL), and NaOH (80 mg, 2 mmol) and cyanogen bromide (106 mg, 1 mmol) were added. The reaction was stirred at room temperature for 3 hours. After the reaction was completed, water was added to quench the reaction, and EA was extracted three times. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative chromatography to obtain a white solid BX20-9-055 (11 mg, yield 11%). MS (ESI, m / z) 515 [M+H] +

[0379] 1 H NMR (400 MHz, DMSO-d6) δ = 10.44 (brs, 1H), 7.83 (brs, 1H),7.77-7.73 (m, 1H), 7.32 (t, J = 9.2 Hz, 1H), 7.17-7.09 (m, 2H), 5.04 (d, J = 10.4Hz, 1H), 4.21 (dd, J = 10.4 Hz, 8.4 Hz, 1H), 3.92 (d, J = 2.0 Hz, 3H), 2.77-2.69 (m, 1H), 1.57 (s, 3H), 0.70 (d, J = 6.8 Hz, 3H).

[0380] Reference compound:

[0381] Reference patent CN114945566A Example 3 synthesis method, synthesis of reference compound (Compound 7)

[0382]

[0383] 1 H NMR (400 MHz, CD 3OD) δ = 8.48 (d, J = 5.6 Hz, 1H), 8.25 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 2.0 Hz, 5.2 Hz, 1H), 7.13-7.09(m, 1H), 7.00-6.94 (m,1H), 5.08 (d, J = 10.4 Hz, 1H), 4.34-4.30 (m, 1H), 3.99 (d, J = 2.4 Hz, 3H), 2.83-2.75 (m, 1H), 1.65 (s, 3H), 0.82-0.80 (m, 3H)

[0384] Biological test evaluation

[0385] The present invention is further described and explained below in conjunction with test examples.

[0386] Test Example 1 Blocking activity of the compounds of the present invention on sodium ion channel 1.8 (Nav1.8)

[0387] 1. Experimental purpose: Use patch clamp technique to detect the effect of compounds on the current of voltage-gated sodium channel (NaV) 1.8 subtype

[0388] 2. Experimental materials and equipment

[0389] 2.1. Cell line: CHO cell line stably expressing Nav1.8 sodium channel. Nav1.8 cells were constructed by the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd. Gene information: Sodium channel, voltage-gated, type8, alpha (SCN10A), cDNA strictly similar to GenBank accession number: NM_006514

[0390] 2.2. Compound: Dissolved in DMSO

[0391] 3. Experimental Methods

[0392] Cell culture

[0393] (1) Maintenance medium: The cells were cultured in HAM'S / F-12 medium containing 10% fetal bovine serum, 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B, and 100 μg / mL Zeocin at 37°C and a carbon dioxide concentration of 5%.

[0394] (2) Cell passaging: Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25%-Trypsin-EDTA solution and incubate at 37°C for about 1.5 min. When the cells detach from the bottom of the dish, add about 5 mL of complete culture medium preheated at 37°C. Gently blow the cell suspension with a pipette to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and collect the cells by centrifugation at 1000 rpm for 5 min. For expansion or maintenance culture, inoculate the cells in a 6 cm cell culture dish with 2.5×105 cells in each cell culture dish (final volume: 5 mL).

[0395] (3) To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0396] (4) Patch clamp assay: Before the test, cells were detached with 0.25%-Trypsin-EDTA, 6.5×103 cells were plated on coverslips and cultured in 24-well plates (final volume: 500 µL). After 18 hours, the test was performed.

[0397] 3.2. Patch clamp assay

[0398] (1) After the whole-cell seal is formed, the cell voltage is clamped at -120 mV. First, the voltage is stepped from -130 mV to -10 mV in 10 mV steps and maintained for 5 s, and then a 0 mV depolarization pulse is given to obtain the half-inactivated voltage (Vhalf). The resting state and half-inactivated state of the sodium current are detected using a double pulse mode. First, the first depolarization pulse (TP1) is given to 0 mV for 50 ms to detect the sodium current in the resting state. Then the voltage is adjusted to Vhalf and maintained for 5 s, and then the voltage is restored to -120 mV and maintained for 20 ms. Then a second depolarization pulse (TP2) is given to 0 mV for 50 ms to detect the sodium current in the half-inactivated state. Finally, it is restored to the clamping voltage of -120 mV. Data is collected repeatedly every 20 ms to observe the effect of the drug on the peak sodium current in the two different states. The test data were collected by EPC10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0399] (2) When performing the patch clamp operation, first use a microelectrode puller to pull the capillary glass tube into a recording electrode, then place the electrode filled with intracellular fluid into the microelectrode holder, and manipulate the microelectrode manipulator under an inverted microscope to bring the recording electrode into contact with the cell, applying negative pressure to form a GΩ seal. At this time, perform fast capacitance compensation, and then continue to apply negative pressure to break the cell membrane and form a whole-cell recording mode. Finally, perform slow capacitance compensation and record related parameters. No leakage compensation is given.

[0400] (3) When the sodium current recorded by the whole cell is stable, the drug is administered. Each drug concentration is applied for 5 min (or the current is stable) before the next concentration is detected. The coverslip with cells is placed in the recording bath under an inverted microscope. The blank control external solution and the working solution of the compound to be tested flow through the recording bath from low concentration to high concentration by gravity perfusion to act on the cells. A peristaltic pump is used for liquid exchange during recording. The current detected by each cell in the external solution without the compound serves as its own control group. Each concentration is tested twice independently. All electrophysiological experiments are performed at room temperature.

[0401] Data analysis

[0402] First, the current after each drug concentration and the blank control current were normalized, and then the inhibition rate corresponding to each drug concentration was calculated, that is, (1-Icompound / Icontrol), and the mean (Mean), standard deviation (SD) and standard error (SE) of the inhibition rate of each concentration were calculated, and the data were expressed as mean ± SE.

[0403] 4. Experimental Results

[0404] Table 1 The blocking rate of the compounds of the present invention on NaV1.8

[0405]

[0406] It can be seen that the compounds of the present invention have a significant blocking effect on the activity of NaV1.8 channels.

[0407] Test Example 2 Blocking activity (IC 50 )

[0408] 1. Research objectives

[0409] Manual patch clamp technique was used to evaluate whether the test compound had a potential inhibitory effect on the voltage-gated sodium channel hNav1.8. This experiment detected the effect of the compound at 5 concentrations or at a single point or at two concentrations on the hNav1.8 channel current, obtained the dose-effect curve of the compound and calculated the IC 50 This experiment included 2 parallel sample measurements.

[0410] 2. Test methods

[0411] 2.1. Test materials

[0412] 1) Cells: The HEK293 cell line stably expressing hNav1.8 / β3 ion channel was prepared by the Biology Department of Kanglong Chemical (Beijing) Pharmaceutical Technology Co., Ltd. (the lentiviral vectors expressing human Nav1.8 and β3 were transduced into HEK293 cells and prepared after screening. For details, please refer to: Proc Natl Acad Sci US A. 2022 Jul 26;119(30):e2208211119. doi: 10.1073 / pnas.2208211119. and Cell Lines / BSYS CHONaV1.8 / β3 Cell Line Instructions). The cell line was cultured in a medium containing 90% DMEM, 10% fetal bovine serum, 100U / mL penicillin-streptomycin solution, 0.75μg / mL puromycin and 100μg / mL hygromycin. When the cell density grew to 40%-80% of the bottom area of ​​the culture dish, the cells were digested by trypsin and passaged three times a week. Before the experiment, the cells were cultured in a 6 cm culture dish at a total number of 5×105 and seeded on a glass slide for subsequent manual patch clamp experiments.

[0413] 2) Compounds: The test compound is dissolved in DMSO and prepared into a stock solution with a final concentration of 10 or 30 mM. The stock solution is diluted into the required intermediate solution using DMSO as the solvent. Before the experiment begins, the gradient intermediate solution of the test compound is diluted again with extracellular fluid at a ratio of 1:1000 to form a series of working solutions at the concentration. The content of DMSO in the working solution is 0.1% (volume ratio). Working solutions with different concentration gradients are used to determine the potential inhibitory effect of the compound on the hNav1.8 channel and to fit the dose-effect curve and calculate the IC 50 .

[0414] 2.2. Experimental procedures

[0415] 1) Place the small glass slide containing HEK293 cells in the culture dish into the perfusion tank of the microscope operation table.

[0416] 2) Place the appropriate cell in the center of the field of view under an Olympus IX71 or IX73 inverted microscope, use a ×10 objective lens to find the tip of the glass electrode and place it in the center of the field of view. Then use the micromanipulator to move the electrode down while adjusting the coarse focus knob to slowly bring the electrode closer to the cell.

[0417] 3) When approaching the cell, switch to a ×40 objective lens for observation and use the micromanipulator to fine-tune the gear to gradually bring the electrode closer to the cell surface.

[0418] 4) Apply negative pressure to form a seal with a resistance higher than 1 GΩ between the electrode tip and the cell membrane.

[0419] 5) Compensate the instantaneous capacitance current Cfast in voltage clamp mode, then repeatedly apply short negative pressure to break the membrane, and finally form a whole-cell recording mode.

[0420] 6) Under the condition that the membrane potential is clamped at -60 mV, the slow capacitive current Cslow, cell membrane capacitance (Cm) and input membrane resistance (Ra) are compensated separately.

[0421] 7) After the cells are stable, the clamp voltage is changed to -80mV, the sampling frequency is set to 20kHz, and the filtering frequency is

[0422] The leakage current detection condition is that the clamping voltage is changed to -80mV and the time course is 200ms.

[0423] 8) The hNav1.8 current test method is as follows: apply a 20 millisecond depolarization command voltage to depolarize the membrane potential from -80mV to -10mV, and then repolarize the membrane potential to -80mV to close the channel. Stimulate once every 15 seconds. The instantaneous current peak under the depolarization voltage is the magnitude of the Nav1.8 sodium channel current.

[0424] 9) The hNav1.8 current used to detect the test compound was recorded for 120 seconds before administration to evaluate the stability of the hNav1.8 current generated by the test cells. Only stable cells within the acceptable range of the evaluation criteria can enter the subsequent compound testing.

[0425] 10) Test of the inhibitory effect of the test compound on hNav1.8 current: First, the hNav1.8 current measured in the extracellular solution containing 0.1% DMSO is used as the detection baseline. After the hNav1.8 current remains stable for at least 5 minutes, the solution containing the test compound is perfused around the cells from low concentration to high concentration. After each perfusion, wait for about 5 minutes to allow the compound to fully act on the cell and record the hNav1.8 current simultaneously. After the recorded current tends to stabilize, record the last 5 hNav1.8 current values, and take the average value as its final current value at a specific concentration. After the test compound is completed, add 5nM reference compound to the same cell to completely inhibit its current as a positive control for the cell. At the same time, the positive compound reference compound is synchronously detected using the same patch clamp system before and after the test drug experiment to ensure the reliability and sensitivity of the entire detection system. The above test steps will be repeated on two separate test cells (n=2).

[0426] Data analysis

[0427] 1) The data must meet the following standards: initial sealing resistance greater than 1GΩ; membrane rupture resistance Ra less than 15MΩ; leakage current under the detection voltage is less than 50% of the current value under this condition; Nav1.8 peak current is at least greater than 200pA;

[0428] 2) The data were analyzed according to the following steps (data were output by PatchMaster software):

[0429] ① After perfusing the blank solvent or compound gradient solution, the average value of the 5 consecutive current values ​​obtained was calculated and used as the "current magnitude" 空白 ” and “ Current Size 化合物 The current suppression percentage is calculated by the following formula.

[0430]

[0431] ②The dose-effect curve was fitted using Graphpad Prism 8.0 software and the IC50 value was calculated.

[0432] The standard deviation of the two sets of data is less than 15 (SD<15)

[0433] 3. Test results

[0434] Table 2 The blocking activity of the compounds of the present invention on NaV1.8

[0435]

[0436] It can be seen that the compounds of the present invention have strong inhibitory activity on NaV1.8 channels, which is better than the reference compounds.

[0437] Test Example 3 Selective test of the compounds of the present invention on sodium ion channels

[0438] 1. Experimental purpose: Use patch clamp technique to detect the effect of compounds on the current of voltage-gated sodium ion channel (NaV) 1.1~1.7 subtypes

[0439] 2. Experimental materials and equipment

[0440] 2.1. Cell line: CHO / HEK293 cell line stably expressing Nav1.1-1.7 sodium channel, which was constructed by the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd. (refer to Jarvis MF, Honore P, Shieh CC,Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, ThomasJ, Liu D, Krambis M, Liu Y, McGaraughty S, Chu K, Roeloffs R, Zhong C, MikusaJP, Hernandez G, Gauvin D, Wade C, Zhu C, Pai M, Scanio M, Shi L, Drizin I,Gregg R, Matulenko M, Hakeem A, Gross M, Johnson M, Marsh K, Wagoner PK,Sullivan JP, Faltynek CR, Krafte DS. A-803467, a potent and selective Nav1.8sodium channel blocker, attenuates neuropathic and inflammatory pain in therat. Proc Natl Acad Sci US A. 2007 May 15;104(20):8520-5. doi: 10.1073 / pnas.0611364104. Epub 2007 May 2. PMID: 17483457; PMCID: PMC1895982.), gene information Nav1.1: NM_006920; Nav1.2: NM_001040142; Nav1.3: NM_006922; Nav1.4: NM_000334; Nav1.5: NM198056; Nav1.6: NM014191; Nav1.7: NM006922.

[0441] 2.2. Compounds: Dissolved in DMSO, and the sample concentration was prepared to 30µM.

[0442] 3. Experimental Methods

[0443] Cell culture

[0444] (1) Maintenance medium: CHO cells were cultured in HAM'S / F-12 medium containing 10% fetal bovine serum, 100 µg / mL Zeocin and 10 µg / mL Blasticidin at 37°C and a carbon dioxide concentration of 5%. HEK-293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 800 µg / mL G418 at 37°C and a carbon dioxide concentration of 5%.

[0445] (2) Cell passaging: Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25%-Trypsin-EDTA solution and incubate at 37°C for about 1.5 min. When the cells detach from the bottom of the dish, add about 5 mL of complete culture medium preheated at 37°C. Gently blow the cell suspension with a pipette to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and collect the cells by centrifugation at 1000 rpm for 5 min. For expansion or maintenance culture, inoculate the cells in a 6 cm cell culture dish with 2.5×10 cells in each cell culture dish. 5 Cells (final volume: 5 mL).

[0446] (3) To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0447] (4) Patch clamp assay: Before the experiment, cells were separated with 0.25%-Trypsin-EDTA and 6.5×10 3 Cells were plated onto coverslips and cultured in 24-well plates (final volume: 500 µL) and assayed 18 hours later.

[0448] 3.2. Patch clamp assay

[0449] Same as test case 1 3.2

[0450] Data analysis

[0451] Same as test case 1 3.3

[0452] 4. Experimental Results

[0453] Table 3 The blocking rate of the compounds of the present invention on NaV1.1-1.7 at 30 μM

[0454]

[0455] Conclusion: It can be seen that the compounds of the present invention have no obvious activity on NaV1.1-1.7 channels. At the same concentration, the inhibitory activity on NaV1.1-1.6 channels is lower than that of the reference compound, and the target selectivity is better, indicating that the compounds of the present invention are safer.

[0456] Test Example 4 Pharmacokinetics Determination in SD Rats

[0457] 1. Purpose of the study

[0458] SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 10 mg / kg.

[0459] 2. Test methods

[0460] 2.1. Investigational Drugs

[0461] The examples and reference compounds of the present invention were prepared in-house.

[0462] 2.2. Experimental animals

[0463] Male SPF SD rats, weighing (200±20) g.

[0464] 2.3. Preparation of test drugs

[0465] Drug preparation: The drug concentration was prepared to 1 mg / mL, and the preparation solvent was Tween80+0.5% MC (v / v 1:99).

[0466] 2.4. Administration:

[0467] Male SPF SD rats were fed adaptively for 3-4 days and then given the drug by gavage at a dose of 10 mg / kg in a volume of 10 mL / kg.

[0468] 2.5. Sample collection

[0469] Before administration (0h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h after administration, blood was collected from rats by fundus puncture. The blood volume was about 0.2mL and placed in a labeled EDTA-K2 anticoagulant tube. Immediately after blood collection, the blood collection tube was gently and completely inverted 3 times to mix with the anticoagulant, and immediately centrifuged at 4500rpm in an ice water bath at 4℃ for 10 min. After the centrifugation operation was completed, the plasma was promptly dispensed into EP tubes with corresponding labels and stored in a -80℃ refrigerator.

[0470] 2.6. Sample testing

[0471] Take 20 μL of rat plasma after administration, add 400 μL of precipitant methanol to a 96-deep-well plate pre-added with 20 μL of internal standard working solution, vortex for 10 min, centrifuge at 4000 rpm for 15 min, take 200 μL of supernatant and put it into another 96-deep-well plate pre-added with 200 μL of ultrapure water, vortex for 5 min, centrifuge at 4000 rpm for 3 min, take 5 μL of supernatant and analyze plasma drug concentration by LC-MS / MS.

[0472] 3. Experimental results and analysis

[0473] The main pharmacokinetic parameters were calculated using WinNonlin 7.0. The results of the rat pharmacokinetic experiment are shown in Table 4 below.

[0474] Table 4 Results of rat pharmacokinetic test

[0475]

[0476] 4. Experimental Conclusion

[0477] It can be seen from the above data that, at the same dosage, the exposure of the compound of the present invention is higher than that of the reference compound, which shows that the compound of the present invention exhibits better absorption characteristics.

[0478] Test Example 5 Pharmacokinetics in KM mice

[0479] 1. Purpose of the study

[0480] KM mice were used as test animals. The compounds of the examples were administered orally at a dose of 10 mg / kg / 1 mg / kg

[0481] Pharmacokinetic behavior of the drug in plasma in mice after intravenous administration.

[0482] 2. Test methods

[0483] 2.1. Investigational Drugs

[0484] The examples and reference compounds of the present invention were prepared in-house.

[0485] 2.2. Experimental animals

[0486] Male SPF KM mice, weighing (20±2) g.

[0487] 2.3. Preparation of test drugs

[0488] Drug preparation for the oral administration group: the drug concentration was 1 mg / mL, and the solvent was Tween80+0.5% MC (v / v 1:99).

[0489] Drug preparation for intravenous administration group: The drug concentration was 0.2 mg / mL, and the preparation solvent was 5% DMA + 5% Solutol HS-15 + 90% normal saline.

[0490] 2.4. Administration:

[0491] Male SPF KM mice were fed adaptively for 3-4 days.

[0492] Intragastric administration group: the dosage was 10 mg / kg, and the administration volume was 10 mL / kg.

[0493] Intravenous administration group: the dosage was 1 mg / kg and the administration volume was 5 mL / kg.

[0494] 2.5. Sample collection

[0495] Intragastric administration: Blood samples were collected from mice before (0h) and after administration at 0, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 24h. Blood samples were collected before (0h) and after intravenous administration at 5, 15, 30 min, 1, 2, 4, 6, 8, and 24h.

[0496] Blood was collected by fundus puncture, with a blood volume of about 0.1 mL, and placed in a labeled EDTA-K2 anticoagulant tube. Immediately after blood collection, the tube was gently and completely inverted 3 times to mix with the anticoagulant, and immediately centrifuged at 4500 rpm for 10 min at 4°C in an ice water bath. After the centrifugation operation was completed, the plasma was promptly dispensed into EP tubes with corresponding labels and stored in a -80°C refrigerator.

[0497] 2.6. Sample testing

[0498] Take 20 μL of mouse plasma after administration, add 400 μL of precipitant methanol to a 96-deep-well plate pre-added with 20 μL of internal standard working solution, vortex for 10 min, centrifuge at 4000 rpm for 15 min, take 200 μL of supernatant and put it into another 96-deep-well plate pre-added with 200 μL of ultrapure water, vortex for 5 min, centrifuge at 4000 rpm for 3 min, take 5 μL of supernatant and analyze plasma drug concentration by LC-MS / MS.

[0499] 3. Experimental results and analysis

[0500] The main pharmacokinetic parameters were calculated using WinNonlin 7.0. The results of the mouse pharmacokinetic experiment are shown in Table 5 below.

[0501] Table 5 Results of mouse pharmacokinetic test

[0502]

[0503] 4. Experimental Conclusion

[0504] It can be seen from the above data that at the same dosage, the exposure amount of the compound of the present invention is higher than that of the reference compound, and the bioavailability is also higher, which shows that the compound of the present invention exhibits better absorption characteristics.

[0505] Test Example 6: Drug efficacy test in the mouse sodium acetate model

[0506] 1. Objective: To evaluate the analgesic efficacy of the examples in the acetic acid writhing model in KM mice.

[0507] 2. Test methods:

[0508] 2.1. Test drugs: Examples of the present invention and reference compounds, homemade. Naproxen, Shanghai Yuanye Biotechnology Co., Ltd., product number S63435. Prepared using solvent (Tween 80 + 0.5% MC (v:v = 1:99 PH=3)).

[0509] 2.2. Experimental animals: Male KM mice were purchased from Hubei Provincial Center for Disease Control and Prevention (Hubei Academy of Preventive Medicine), weighing 20-25 g at the time of purchase.

[0510] 2.3. Experimental groups:

[0511] Table 6 Grouping of compounds in the acetic acid writhing model

[0512]

[0513] 2.4. Drug administration and modeling

[0514] One hour after each group completed the administration of the corresponding drugs, 0.6% acetic acid (0.15mL / 10g (0.1mL / 10g is also acceptable)) was injected intraperitoneally, and the writhing latency (the time when the mouse first showed a writhing reaction after the injection of glacial acetic acid) was recorded. The number of writhing reactions of the mice within 20 minutes was observed and recorded.

[0515] · Twist index: The mouse shows typical abdominal concavity, accompanied by characteristic reactions such as trunk twisting and hip lifting, which is considered to have occurred.

[0516] Data collection and analysis

[0517] Data were collected using Excel software.

[0518] Data were analyzed using Prism (Graph pad software, Inc.) software.

[0519] 3. Results

[0520] Table 7 Analgesic efficacy of compounds in the acetic acid writhing pain model in mice

[0521]

[0522] 4. Conclusion

[0523] It can be seen from the above data that, at the same dosage, the compounds of Example 10 and Example 11 of the present invention can inhibit the pain of mice caused by acetic acid and reduce the number of twisting of the mice, and the analgesic effect of Example 11 is obviously dose-dependent, and the efficacy is stronger than that of the reference compound.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt thereof, ； in, R 1 , R 2 and R 3 Each is independently halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, -OR 1-1 , by one or more R 1-2 Substituted C1-C6 alkyl or one or more R 1-3 Substituted C1-C6 alkoxy; R 1-1 is a C3-C6 cycloalkyl group or a 3-8 membered heterocycloalkyl group; in the 3-8 membered heterocycloalkyl group, the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3; Each R 1-2 are each independently a halogen; Each R 1-3 Each is independently a C1-C6 alkoxy group; X 1 is N, N + -O - , CR X1 ; R X1 is hydrogen, halogen or C1-C6 alkyl substituted by one or more halogens; X 2 is O or NH; R 4 is hydrogen or C1-C6 alkyl; R 5 C1-C6 alkoxy, -OH, -NR 5-1 R 5-2 or -CN; R 5-1 and R 5-2 Each is independently hydrogen or C1-C6 alkyl; n is 0, 1, 2 or 3; R 6 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy or C1-C6 alkoxy; R 7 is hydrogen or C1-C6 alkyl; R 8 It is hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy or C1-C6 alkoxy.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) R 1 , R 2 and R 3 wherein the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine; (2) R 1 , R 2 and R 3 wherein the C1-C6 alkyl group and one or more R 1-2 The C1-C6 alkyl in the substituted C1-C6 alkyl is each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (3) R 1 , R 2 and R 3 In the above, the C3-C6 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; (4) R 1 , R 2 and R 3 wherein the C1-C6 alkoxy group and one or more R 1-3 The C1-C6 alkoxy groups in the substituted C1-C6 alkoxy groups are each independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy or ethoxy; (5) R 1-1 In the above, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; (6) R 1-1 wherein the heteroatom in the 3-8 membered heterocycloalkyl is N and / or O; the number of heteroatoms is preferably 1 or 2; the 3-8 membered heterocycloalkyl is preferably a 4-6 membered heterocycloalkyl; more preferably ;For example ; (7) R 1-2 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (8) R 1-3 In the above, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy; (9) R X1 wherein the halogen and the halogen in the C1-C6 alkyl substituted by one or more halogens are each independently fluorine, chlorine, bromine or iodine, preferably fluorine; (10) R X1 wherein the C1-C6 alkyl group substituted by one or more halogens is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (11) R 5 wherein the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy or ethoxy; (12) R 5-1 and R 5-2 wherein the C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (13) R 6 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine; (14) R 7 wherein the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; and (15) R 8 In the above, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, -OR 1-1 , by one or more R 1-2 Substituted C1-C6 alkyl or one or more R 1-3 Substituted C1-C6 alkoxy; (2) R 2 is a halogen; (3) R 3 is a halogen; (4) R 4 is hydrogen; (5) R 5-1 is hydrogen; (6) R 5-2 is hydrogen or C1-C6 alkyl; (7) R 6 is a halogen; (8) R 7 is a C1-C6 alkyl group; and (9) R 8 It is a C1-C6 alkyl group.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound as shown in formula I or a pharmaceutically acceptable salt thereof is a compound as shown in formula I-1 or a pharmaceutically acceptable salt thereof: ； R 1 is C1-C6 alkoxy or is replaced by one or more R 1-3 Substituted C1-C6 alkoxy; Each R 1-3 Each is independently a C1-C6 alkoxy group; R 2 is a halogen; R 3 is a halogen; X 1 N or CR X1 ; R X1 is a halogen; X 2 is O or NH; R 4 is hydrogen; R 5 is -OH or -CN; R 7 is a C1-C6 alkyl group; R 8 It is a C1-C6 alkyl group.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: It meets one or more of the following conditions: (1) R 1 Methyl, cyclopropyl, methoxy, -CF3, , or ; (2) R 2 For fluorine; (3) R 3 For fluorine; (4) X 1 N, N + -O - , CH, CF or C-CF3; and (5) R 5 It is methoxy, ethoxy, -OH, -NH2, -NH(CH3) or -CN.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that: for , , , , , or .

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: The compound as shown in formula I is any of the following compounds: 。 8. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: (1) a compound of formula I as claimed in any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

9. Use of a substance A in the preparation of a medicament for treating a disease; the disease may be pain, a pain-related disease, multiple sclerosis, incontinence or arrhythmia; the pain is preferably one or more of acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; Alternatively, the disease may be a disease for treatment by inhibiting voltage-gated sodium channels; the voltage-gated sodium channels are preferably Na V 1.8; The substance A is a compound as shown in formula I or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, or a pharmaceutical composition as described in claim 8.

10. Use of substance A in the preparation of a voltage-gated sodium channel inhibitor; the voltage-gated sodium channel is preferably Na V 1.8; The substance A is as described in claim 9.

11. Use of a substance A in the preparation of a drug for a disease caused by abnormal activation of a voltage-gated sodium channel; the voltage-gated sodium channel is preferably Na V 1.8; The disease may be pain, a pain-related disease, multiple sclerosis, incontinence or cardiac arrhythmia; The substance A is as described in claim 9.

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