Furan ring-containing compound, pharmaceutical composition thereof, and use thereof

Abstract

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

Description

A compound containing a furan ring, its pharmaceutical composition and its application

[0001] This application claims the benefit of priority to Chinese Patent Application No. 2023115572534, filed on November 21, 2023, and Chinese Patent Application No. 2024100374874, filed on January 10, 2024. The entire text of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present 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. These are free nerve endings widely distributed throughout the skin, muscles, joints, and internal organs. They convert thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are transmitted via afferent nerve fibers to the cell bodies of the dorsal root ganglia (DRG), ultimately reaching higher neural centers, causing pain sensation. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (VGSC / Nav) on the cell membrane. Nav is a key mediator for transmembrane information transmission along neurons.

[0004] According to statistics, approximately 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 projected to reach US$56 billion by 2023. The acute, moderate to severe pain market is expected to grow steadily at a compound annual growth rate of 2.5%, while the chronic pain market is projected to grow at a compound annual growth rate of approximately 18%. Chronic pain is expected to be the primary driver of continued growth in the global pain market over the next decade.

[0005] The secondary structure of voltage-gated sodium channels (VGSC / Nav) consists of four pore-forming domains (DI-DIV), each with six transmembrane α-helices (S1-S6). S4 is a voltage sensor containing positively charged ions. The intracellular loop between DIII and DIV is considered the rapid inactivation gate. Nav exists in three distinct states, with the inactivated closed state exhibiting either rapid inactivation (within milliseconds) or slow inactivation (seconds) kinetics. When the cell membrane depolarizes, the sodium channel activates and opens, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of an action potential. Therefore, inhibiting abnormal sodium channel activity may help treat and alleviate pain, making Nav a potential peripheral target for pain treatment.

[0006] There are nine major subtypes of human Nav, namely Nav1.1-Nav1.9. Based on whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), Nav is divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). 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 subtypes. Among them, Nav1.1, Nav1.2, and Nav1.3 are abundantly expressed in the central nervous system (CNS), Nav1.4 is abundant in skeletal muscle, and Nav1.6 and Nav1.7 are mainly abundant in the CNS. Nav1.5, Nav1.8 and Nav1.9 are of TTX-R type, among which Nav1.5 is mainly present in cardiomyocytes, while 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 therapeutic 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 models 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 neuropathic pain. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy that 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 a highly selective target for pain treatment because it is mainly distributed in the peripheral nervous system and confined to neurons that sense pain. Therefore, 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, their therapeutic window is narrow and their 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 shortcomings of the prior art in insufficient inhibition of Nav1.8 channels. 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 (e.g., 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 problems 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] Among them, 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;

[0014] 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 one, two or three of N, O and S, and the number of heteroatoms is one, two or three;

[0015] Each R 1-2 are each independently halogen;

[0016] Each R 1-3 Each is independently a C1-C6 alkoxy group;

[0017] X 1 N, N + -O - or CR X1 ;

[0018] R X1 is hydrogen, halogen, or C1-C6 alkyl substituted by one or more halogens;

[0019] X 2 is O or NH;

[0020] R 4 is hydrogen or C1-C6 alkyl;

[0021] R 5 C1-C6 alkoxy, -OH, -NR 5-1 R 5-2 or -CN;

[0022] R 5-1 and R 5-2 Each is independently hydrogen or C1-C6 alkyl;

[0023] n is 0, 1, 2, or 3;

[0024] R 6 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy or C1-C6 alkoxy;

[0025] R 7 is hydrogen or C1-C6 alkyl;

[0026] R 8 It is hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy or C1-C6 alkoxy.

[0027] In some embodiments, in the compound shown in Formula I, 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;

[0028] 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 one, two or three of N, O and S, and the number of heteroatoms is one, two or three;

[0029] Each R1-2 are each independently halogen;

[0030] Each R 1-3 Each is independently a C1-C6 alkoxy group;

[0031] X 1 N, N + -O - or CR X1 ;

[0032] R X1 is hydrogen, halogen, or C1-C6 alkyl substituted by one or more halogens;

[0033] X 2 is O or NH;

[0034] R 4 is hydrogen or C1-C6 alkyl;

[0035] R 5 C1-C6 alkoxy, -OH or -NR 5-1 R 5-2 ;

[0036] R 5-1 and R 5-2 Each is independently hydrogen or C1-C6 alkyl;

[0037] n is 0, 1, 2, or 3;

[0038] R 6 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy or C1-C6 alkoxy;

[0039] R 7 is hydrogen or C1-C6 alkyl;

[0040] R 8 It is hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy or C1-C6 alkoxy.

[0041] In some embodiments, R 1 、R 2 and R 3 wherein the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0042] In some embodiments, R 1 、R 2 and R 3 wherein the C1-C6 alkyl group is replaced by one or more R 1-2The C1-C6 alkyl groups in the substituted C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0043] In some embodiments, R 1 、R 2 and R 3 wherein the C3-C6 cycloalkyl groups are each independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl.

[0044] In some embodiments, R 1 、R 2 and R 3 wherein the C1-C6 alkoxy group is replaced by 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.

[0045] In some embodiments, R 1-1 In the embodiment, the C3-C6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, and is preferably a cyclopropyl group.

[0046] In some embodiments, R 1-1 wherein the heteroatoms in the 3-8 membered heterocycloalkyl group are N and / or O; the number of heteroatoms is preferably 1 or 2. The 3-8 membered heterocycloalkyl group is preferably a 4-6 membered heterocycloalkyl group; more preferably For example

[0047] In some embodiments, R 1-2 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0048] In some embodiments, R 1-3 In the embodiment, the C1-C6 alkoxy group is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

[0049] In some embodiments, R X1 wherein the halogen and the halogen in the C1-C6 alkyl group substituted by one or more halogens are each independently fluorine, chlorine, bromine or iodine, preferably fluorine.

[0050] In some embodiments, R X1 In the C1-C6 alkyl group substituted by one or more halogens, the C1-C6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0051] In some embodiments, R 5 In the embodiment, the C1-C6 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group or a tert-butoxy group, preferably a methoxy group or an ethoxy group.

[0052] In some embodiments, 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.

[0053] In some embodiments, R 6 wherein the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0054] In some embodiments, R 7 In the embodiment, the C1-C6 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, and is preferably a methyl group.

[0055] In some embodiments, R 8 In the embodiment, the C1-C6 alkyl group is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group or a tert-butyl group, and is preferably a methyl group.

[0056] In some embodiments, R 1 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.

[0057] In some embodiments, R 2 It is a halogen.

[0058] In some embodiments, R 3 It is a halogen.

[0059] In some embodiments, R 4 For hydrogen.

[0060] In some embodiments, R 5-1 For hydrogen.

[0061] In some embodiments, R 5-2 is hydrogen or C1-C6 alkyl.

[0062] In some embodiments, R 6 It is a halogen.

[0063] In some embodiments, R 7 It is a C1-C6 alkyl group.

[0064] In some embodiments, R 8 It is a C1-C6 alkyl group.

[0065] In some embodiments, in the compound shown in Formula I, 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;

[0066] 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 one, two or three of N, O and S, and the number of heteroatoms is one, two or three;

[0067] Each R 1-2 are each independently halogen;

[0068] Each R 1-3 Each is independently a C1-C6 alkoxy group;

[0069] X 1 CR X1 ;

[0070] R X1 is hydrogen, halogen, or C1-C6 alkyl substituted by one or more halogens;

[0071] X 2 for NH;

[0072] R 4 is hydrogen or C1-C6 alkyl;

[0073] R 5 -OH, -NR 5-1 R 5-2 or -CN;

[0074] R 5-1 and R 5-2 Each is independently hydrogen or C1-C6 alkyl;

[0075] n is 0, 1, 2, or 3;

[0076] R 6 is hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy or C1-C6 alkoxy;

[0077] R 7 is hydrogen or C1-C6 alkyl;

[0078] R 8 It is hydrogen, hydroxy, C1-C6 alkyl, C1-C6 alkyl-C1-C6 alkoxy or C1-C6 alkoxy.

[0079] 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:

[0080] R 1 is C1-C6 alkoxy or is replaced by one or more R 1-3 Substituted C1-C6 alkoxy;

[0081] Each R 1-3 Each is independently a C1-C6 alkoxy group;

[0082] R 2 is a halogen;

[0083] R 3 is a halogen;

[0084] X 1 N or CR X1 ;

[0085] R X1 is a halogen;

[0086] X 2 is O or NH;

[0087] R 4 is hydrogen;

[0088] R 5 is -OH or -CN;

[0089] R 7 is a C1-C6 alkyl group;

[0090] R 8 It is a C1-C6 alkyl group.

[0091] In some embodiments, R 1 Methyl, cyclopropyl, methoxy, -CF3,

[0092] In some embodiments, R 2 For fluorine.

[0093] In some embodiments, R 3 For fluorine.

[0094] In some embodiments, X 1 N, N + -O -, CH, CF or C-CF3.

[0095] In some embodiments, R 5 It is methoxy, ethoxy, -OH, -NH2, -NH(CH3) or -CN.

[0096] In some embodiments, for

[0097] In some embodiments, the compound as shown in Formula I is any of the following compounds:

[0098] The present invention provides a pharmaceutical composition comprising:

[0099] (1) the compound represented by formula I or a pharmaceutically acceptable salt thereof, and

[0100] (2) Pharmaceutically acceptable excipients.

[0101] The present invention provides a 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;

[0102] The substance A is the compound represented by formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0103] 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.

[0104] 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.

[0105] The present invention provides an application of the substance A in the preparation of a voltage-gated sodium channel inhibitor; the voltage-gated sodium channel is preferably Na V 1.8.

[0106] In some embodiments, the voltage-gated sodium channel inhibitor can be used in mammalian organisms; 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.

[0107] 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.

[0108] The present invention also provides a method for preparing the compound shown in Formula I: it is prepared by the following route 1 or route 2:

[0109] Route 1:

[0110] General formulas (Z1) and (Z2) are condensed to obtain general formula (Z3), general formula (Z3) is reduced to obtain general formula (Z4), general formula (Z4) is reduced by DIBAL-H to obtain general formula (Z5), general formula (Z5) reacts with acetyl chloride to obtain general formula (Z6), general formula (Z6) is reacted under TMSCN / BF3OEt2 conditions to obtain general formula (Z7), general formula (Z7) is hydrolyzed to obtain general formula (Z8), general formula (Z8) is condensed with amine to obtain general formula (Z9), and general formula (Z9) is reacted with ammonia methanol or hydroxylamine to obtain the compound shown in Formula I:

[0111] Route 2:

[0112] General formula (Z7) is subjected to boron tribromide conditions to obtain general formula (Z10), general formula (D10) is subjected to nucleophilic substitution reaction with halogenated alkane or alkyl sulfonate to obtain general formula (Z11), general formula (Z11) is hydrolyzed to obtain general formula (Z12), general formula (Z12) is condensed with amine to obtain general formula (Z13), and general formula (Z13) is subjected to ammonia methanol or hydroxylamine conditions to obtain the compound shown in Formula I:

[0113] Among them, R 9 is -C(=O)OC1-C6 alkyl or CN;

[0114] 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;

[0115] When R 1 is halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or one or more R 1-2 When the C1-C6 alkyl group is substituted, the compound shown in Formula I is prepared by route 1;

[0116] When R 1 OR 1-1 or by one or more R 1-3 When the C1-C6 alkoxy group is substituted, the compound shown in Formula I is prepared by Route 2.

[0117] Terminology

[0118] As used herein, 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, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0119] In the present invention, the structural fragment This refers to the bond through which the structural fragment is connected to the rest of the molecule. For example, It refers to cyclopropyl.

[0120] 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.

[0121] In the present invention, the term "one or more" refers to 1, 2, 3, 4 or 5, such as 1, 2 or 3.

[0122] In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0123] As used herein, the term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

[0124] 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.

[0125] In the present invention, the term "cycloalkyl" refers to a cyclic, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C3-C6). Cycloalkyl groups include, but are not limited to: wait.

[0126] As used herein, the term "heterocycloalkyl" refers to a cyclic, saturated, monovalent group having a specified number of ring atoms (e.g., 3-12, 4-8, 5, 6, or 7 members), 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 groups are attached to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl groups include, but are not limited to: wait.

[0127] As used herein, the term "pharmaceutically acceptable excipients" refers to all substances contained in a pharmaceutical formulation other than the active pharmaceutical ingredient, and is generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0128] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0129] The reagents and raw materials used in the present invention are commercially available.

[0130] The positive progress of the present invention is 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, Nav1.3Nav1.4, Nav1.5, Nav1.6, Nav1.7, Nav1.9) and high safety. DETAILED DESCRIPTION

[0131] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0132] Example 1 Synthesis of BX20-9-021

[0133] Step 1: Synthesis of Intermediate A2

[0134] The synthetic route is shown below:

[0135] Method: Compound A1 (18.00 g, 95.76 mmol) was dissolved in toluene (300 mL). SM1 (13.32 g, 87.07 mmol), Pd(PPh3)4 (3.19 g, 2.76 mmol), Cu2O (0.37 g, 2.62 mmol), and K2CO3 (41.19 g, 298.06 mmol) were added sequentially. The atmosphere was replaced with nitrogen. The reaction mixture was stirred at 100°C for 16 hours. After completion, the reaction mixture was filtered through celite and washed with EA. The filtrate was collected and extracted with saturated brine. The organic phase was dried. The product was concentrated under reduced pressure and purified by column chromatography to yield Compound A2 (7.60 g, 40.4%) as a white solid.

[0136] Step 2: Synthesis of Intermediate A3

[0137] The synthetic route is shown below:

[0138] Methods: Compound A2 (7.60 g, 35.16 mmol) was dissolved in THF (80 mL), and aqueous lithium hydroxide solution (3.39 g LiOH·H2O dissolved in 40 mL H2O, 80.87 mmol) was added. The reaction mixture was stirred at 50°C for 3 h. After completion of the reaction, the mixture was diluted with DCM, separated into layers, and extracted three times with H2O. The aqueous phases were combined, the pH was adjusted to <5 with 1N HCl, and extracted three times with DCM. The organic phases were combined, dried, and concentrated under reduced pressure to yield Compound A3 (5.90 g, 83.0%) as a white solid.

[0139] Step 3: Synthesis of Intermediate S2

[0140] The synthetic route is shown below:

[0141] Methods: Compound S1 (15.50 g, 98.05 mmol) was dissolved in Et2O (155 mL). The atmosphere was replaced with N2, and the temperature was lowered to approximately 0°C. MeLi.LiBr (209 mL, 313.76 mmol, 1.5 M in Et2O) was added portionwise while maintaining the temperature at 0-10°C. After completion of the addition, the mixture was naturally warmed to room temperature and allowed to react for 12 hours. After completion of the reaction, H2O (100 mL) and saturated sodium chloride solution (20 mL) were added dropwise to quench the reaction. Citric acid (25.04 g) was added, stirred for 0.5 hour, and extracted three times with Et2O. The organic phases were combined, dried, and concentrated under reduced pressure to 30 g to obtain crude product S2 (about 35% in Et2O, 30 g).

[0142] Step 4: Synthesis of Intermediate S3

[0143] The synthetic route is shown below:

[0144] 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. The atmosphere was replaced with nitrogen and the mixture was stirred at below 10°C for 1.5 hours. S2 (about 35% in Et2O, 15 g, 30 mmol) and K2CO3 (5.00 g, 36.50 mmol) were added. The reaction mixture was stirred at 35°C for 12 hours. After the reaction, water and dilute hydrochloric acid were added to the reaction mixture and stirred until clear. The mixture was extracted with EA, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to yield S3 (7.40 g, 78.7%) as a white solid. MS (ESI, m / z) 323 [M+H] + .

[0145] Step 5: Synthesis of S4

[0146] The synthetic route is shown below:

[0147] Methods: Compound S3 (9.00 g, 28.0 mmol) was dissolved in anhydrous methanol (800 mL) and anhydrous tetrahydrofuran (160 mL) with stirring until clear. The mixture was cooled to -40°C and the first batch of NiCl2·6H2O (6.80 g, 28.6 mmol) and NaBH4 (5.60 g, 148.4 mmol) were added, followed by the second batch of NiCl2·6H2O (6.80 g, 28.6 mmol) and NaBH4 (5.60 g, 148.4 mmol). The reaction was complete upon completion. After completion of the reaction, saturated ammonium chloride was slowly added dropwise to the reaction mixture at -40°C to quench the reaction mixture. The mixture was stirred for 30 min and allowed to warm to room temperature. The mixture was filtered through celite, extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to afford compound S4 (3.57 g, 39.3%) as a colorless oil. MS (ESI, m / z) 325 [M+H] + .

[0148] The NMR spectrum is:

[0149] 1 H NMR (400MHz, CDCl3) δ = 6.96-6.83 (m, 2H), 4.47 (d, J = 9.6Hz, 1H), 4.02 (d, J = 2.8Hz, 1H), 2.92-2.84 (m, 1H), 1.70 (s, 3H), 0.81-0.78 (m, 3H).

[0150] Step 6: Synthesis of S5

[0151] The synthetic route is shown below:

[0152] Method: Compound S4 (3.57 g, 11.0 mmol) was dissolved in toluene (30 mL). The atmosphere was replaced with nitrogen and the temperature was lowered to -30°C. DiBAL-H (1.5 M, 7.7 mL, 11.6 mmol) was slowly added dropwise. The reaction mixture was stirred at -25 to -30°C for 2 hours. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride, filtered through celite, extracted with EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford compound S5 (3.53 g, crude) as a colorless oil. MS (ESI, m / z) 327 [M+H] + .

[0153] Step 7: Synthesis of S6

[0154] The synthetic route is shown below:

[0155] Method: Compound S5 (3.53 g, 10.8 mmol) was dissolved in anhydrous DCM (30 mL) and stirred until clear. Et3N (2.18 g, 21.6 mmol) was added, and the temperature was cooled to 0-10°C in an ice-water bath. AcCl (1.70 g, 21.6 mmol) was slowly added dropwise. After the temperature was complete, the mixture was warmed to room temperature and stirred for 1 hour. After the reaction was complete, saturated ammonium chloride was added to quench the reaction mixture, extracted with DCM, washed with concentrated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound S6 (4.36 g, crude) as a colorless oil. MS (ESI, m / z) 369 [M+H] + .

[0156] Step 8: Synthesis of S7

[0157] The synthetic route is shown below:

[0158] Method: Compound S6 (4.36 g, 11.8 mmol) was dissolved in anhydrous DCM (40 mL) and stirred until clear. The N2 was replaced, the temperature was lowered to -78°C, and TMSCN (3.52 g, 35.5 mmol) and BF3OEt2 (5.04 g, 35.5 mmol) were added dropwise. After the addition was complete, the mixture was stirred at -60°C for 1 hour, then naturally warmed to room temperature and stirred for 12 hours. After completion of the reaction, the reaction mixture was quenched with saturated sodium carbonate solution, filtered through celite, extracted with DCM, washed with brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound S7 (2.25 g, 56.9%) as a colorless oil. MS (ESI, m / z) 336 [M+H] + .

[0159] Step 9: Synthesis of S8

[0160] The synthetic route is shown below:

[0161] Method: Compound S7 (2.25 g, 6.7 mmol) was dissolved in MeOH (50 mL), and a KOH aqueous solution (2.63 g KOH dissolved in 10 mL H2O, 46.9 mmol) was added. The reaction mixture was stirred at 60°C for 12 h. After completion of the reaction, MTBE was added for extraction. The aqueous phase was adjusted to pH <5 with hydrochloric acid and then extracted with MTBE. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated to afford compound S8 (2.20 g, crude) as a colorless oil. MS (ESI, m / z) 355 [M+H] +

[0162] Step 10: Synthesis of Intermediate S10

[0163] The synthetic route is shown below:

[0164] Methods: S8 (150 mg, 0.42 mmol) was dissolved in DCM (5 mL) and DMF (20 μL). Oxalyl chloride (0.3 mL, 3.20 mmol) was slowly added dropwise and allowed to react at room temperature for 0.5 h. The reaction solution was concentrated under reduced pressure at 40°C, redissolved in DCM (5 mL), and slowly added dropwise to a solution of methyl 4-aminopyridine-2-carboxylate (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 completion of the reaction, the solution was quenched with saturated NH₄Cl solution (30 mL) and extracted with DCM (30 mL × 3). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated to afford compound S9 (390 mg, crude) as a yellow oil. MS (ESI, m / z) 489 [M+H] + .

[0165] Step 11: Synthesis of Intermediate S11

[0166] The synthetic route is shown below:

[0167] Method: Dissolve S10 (390 mg, 0.80 mmol) in methanol (15 mL), add NaOH (1N, 15 mL), and stir at room temperature overnight. After the reaction, adjust the pH to 3-4, extract with EA, dry with sodium sulfate, and concentrate to obtain S11 (300 mg, crude product). MS (ESI, m / z) 475 [M+H] + .

[0168] Step 12: Synthesis of BX20-9-021

[0169] The synthetic route is shown below:

[0170] 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 (42 mg, 0.5 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction was quenched with water, extracted with EA, dried over sodium sulfate, and concentrated. The mixture was purified by preparative chromatography and lyophilized to afford BX20-9-021 (13 mg, 8.4% yield) as a pale yellow solid. MS (ESI, m / z) 504 [M+H] + .

[0171] 1 H NMR (400MHz, CD3OD) δ = 8.45 (d, J = 5.6Hz, 1H), 8.22 (d, J = 2.4Hz, 1H), 7.87 (dd, J = 5.6Hz, 2.4Hz, 1H), 7.13-7.09 (m, 1H), 7.00-6.94 (m, 1H), 5. 07(d,J=10.4Hz,1H),4.32(dd,J=10.4Hz,8.0Hz,1H),3.99(d,J=2.4Hz,3H),3.80(s,3H),2.83-2.75(m,1H),1.65(s,3H),0.82-0.79(m,3H).

[0172] Example 2: Synthesis of BX20-9-022

[0173] Step 1: Synthesis of intermediate S11

[0174] Reference Example 1 Step 1 to Step 11

[0175] Step 2: Synthesis of BX20-9-022

[0176] The synthetic route is shown below:

[0177] 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. The reaction mixture was stirred at room temperature for 3 hours. After completion, the reaction was quenched with water, extracted with EA, dried over sodium sulfate, and concentrated. The mixture was purified by preparative chromatography and lyophilized to afford BX20-9-021 (13 mg, 8.1% yield) as a pale yellow solid. MS (ESI, m / z) 518 [M+H]+ .

[0178] 1 H NMR (400MHz, CD3OD) δ = 8.45 (d, J = 5.6Hz, 1H), 8.22 (d, J = 2.4Hz, 1H), 7.87 (dd, J = 5.6Hz, 2.4Hz, 1H), 7.13-7.09 (m, 1H), 7.00-6. 94(m,1H),5.07(d,J=10.4Hz,1H),4.32(dd,J=10.4Hz,8.0Hz,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=6.8Hz,3H),0.82-0.79(m,3H).

[0179] Example 3: Synthesis of BX20-9-029

[0180] Step 1: Synthesis of intermediate S8

[0181] Reference Example 1 Steps 1-9

[0182] Step 2: Synthesis of intermediate S9'

[0183] The synthetic route is shown below:

[0184] 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, and oxalyl chloride (0.1 mL, 1.272 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 0.5 h. After completion of the reaction, the mixture was concentrated under reduced pressure, redissolved in DCM (5 mL), and slowly added dropwise to a solution of A1 (69 mg, 0.509 mmol) and TEA (154 mg, 1.527 mmol) in DCM / NMP (10:1, 5.5 mL). The mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, dissolved in EA, quenched with water (15 mL), and extracted with EA. The organic phases were combined, washed once with water and once with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford compound S9' (250 mg, crude) as a yellow oil. MS (ESI, m / z) 473 [M+H] + .

[0185] Step 3: Synthesis of BX20-9-029

[0186] The synthetic route is shown below:

[0187] Method: Compound S9' (250 mg, crude product, 0.424 mmol) was dissolved in EtOH (6 mL), and NH2OH (112 mg, 1.696 mmol, 50%) was added. The reaction mixture was stirred at 80°C for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by preparative chromatography (formic acid system). The product was lyophilized to afford BX20-9-029 (128 mg, 60%) as a white solid. MS (ESI, m / z) 497 [M+H] + .

[0188] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),9.62(s,1H),7.75(dd,J=6.8Hz,2.8Hz,1H),7.67-7.62(m,1H),7.21-7.12(m,3H),5.77 (s,2H),5.04(d,J=10.4Hz,3H),4.27-4.20(m,1H),3.94(d,J=2.0Hz,3H),2.79-2.71(m,1H),1.59(s,3H),0.75-0.69(m,3H).

[0189] Example 4: Synthesis of BX20-9-033

[0190] Step 1: Synthesis of intermediate S10

[0191] Reference Example 1 Step 1 to Step 10 Synthesis

[0192] Step 2: Synthesis of compound BX20-9-033

[0193] The synthetic route is shown below:

[0194] Methods: Compound S10 (180 mg, 0.37 mmol) was dissolved in MeOH (8 mL), and NH2OH (50% in water, 220 mg, 3.4 mmol) was added dropwise. The mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure at 40°C, purified by preparative chromatography (formic acid system), and lyophilized to obtain a white solid powder BX20-9-033 (58 mg, 32.2% yield). MS (ESI, m / z) 489 [M+H] + .

[0195] 1H NMR (400MHz, DMSO-d6) δ = 11.39 (s, 1H), 10.74 (s, 1H), 9.09 (s, 1H), 8.45 (d, J = 5.2Hz, 1H), 8.23 ​​(d, J = 2.0Hz, 1H), 7.81 (dd, J = 5.2Hz, J = 2.0Hz, 1H), 7. 21-7.13(m,2H),5.11(d,J=10.4Hz,1H),4.22(dd,J=10.4Hz,J=8.0Hz,1H) ,3.95(d,J=2.0Hz,3H),2.81-2.73(m,1H),1.61(s,3H),0.74-0.72(m,3H).

[0196] Example 5: Synthesis of BX20-9-034

[0197] Step 1: Synthesis of intermediate S10

[0198] Reference Example 1 Step 1 to Step 10 Synthesis

[0199] Step 2: Synthesis of compound BX20-9-034

[0200] The synthetic route is shown below:

[0201] Methods: Compound S10 (180 mg, 0.37 mmol) was dissolved in EtOH (2 mL), and N₂H₄·H₂O (50 mg, 1.0 mmol) was added dropwise. The mixture was stirred at 85°C for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography. After lyophilization, a white solid powder BX20-9-034 (62 mg, 34.4% yield) was obtained. MS (ESI, m / z) 488 [M+H] + .

[0202] 1 H NMR (400MHz, DMSO-d6) δ = 10.78 (s, 1H), 9.84 (s, 1H), 8.47 (d, J = 5.6Hz, 1H), 8.25 (s, 1H), 7.82 (dd, J = 5.6Hz, J = 2.0Hz, 1H), 7.20-7 .16(m,2H),5.11(d,J=10.0Hz,1H),4.28-4.23(m,1H),3.95(d,J=2.0Hz,3H),2.79-2.76(m,1H),1.61(s,3H),0.74-0.72(m,3H).

[0203] Example 6: Synthesis of BX20-9-035

[0204] Step 1: Synthesis of intermediate S11

[0205] Reference Example 1 Step 1 to Step 11 Synthesis

[0206] Step 2: Synthesis of Intermediate 35-3

[0207] The synthetic route is shown below:

[0208] Methods: 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 sequentially. The mixture was stirred at room temperature for 10 min. SM1 (53 mg, 0.3 mmol) was then added and stirred at room temperature for 16 h. After the reaction, the reaction mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 35-3 (210 mg, crude) as a yellow oil. MS (ESI, m / z) 602 [M+H] + .

[0209] Step 3: Synthesis of compound BX20-9-035

[0210] The synthetic route is shown below:

[0211] Method: Compound 35-3 (210 mg, 0.35 mmol) was dissolved in DCM (2 mL) and HCl / 1,4-dioxane (1.75 mL, 6.98 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative chromatography. After lyophilization, a white solid powder BX20-9-035 (23 mg, 13.1% yield) was obtained. MS (ESI, m / z) 502.2 [M+H] +

[0212] 1 H NMR (400MHz, DMSO-d6) δ = 10.76 (s, 1H), 10.13 (s, 1H), 8.47 (d, J = 5.6Hz, 1H), 8.24 (d,J=2.0Hz,1H),7.83(dd,J=5.6Hz,J=2.0Hz,1H),7.21-7.13(m,2H),5.11(d,J= 10.4Hz,1H),4.25(dd,J=10.4Hz,J=8.0Hz,1H),3.95(d,J=2.0Hz,3H),2.81-2.73(m,1H),2.52(s,3H),1.61(s,3H),0.74-0.72(m,3H).

[0213] Example 7: Synthesis of BX20-9-036

[0214] Step 1: Synthesis of S8

[0215] Reference Example 1 Step 1 to Step 9 Synthesis

[0216] Step 2: Synthesis of S9

[0217] The synthetic route is shown below:

[0218] Method: Compound S8 (0.15 g, 0.42 mmol) was dissolved in DCM (4 mL) and stirred until clear. 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 warmed to room temperature and stirred for 0.5 h. The reaction solution was concentrated under reduced pressure to obtain crude product S9 which was used directly in the next step.

[0219] Step 3: Synthesis of 36-1

[0220] The synthetic route is shown below:

[0221] Method: Compound SM1 (76 mg, 0.64 mmol) was dissolved in NMP (2 mL), and TEA (86 mg, 0.85 mmol) was added. S9 (crude, diluted with 5 mL of DCM, 0.42 mmol) was then slowly added and stirred at room temperature for 0.5 h. After completion of the reaction, saturated ammonium chloride was added to quench the reaction, followed by extraction with DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford 36-1 (0.33 g, crude) as a brown oil. MS (ESI, m / z) 456 [M+H] + .

[0222] Step 4: Synthesis of BX20-9-036

[0223] The synthetic route is shown below:

[0224] Method: Compound 36-1 (0.33 g, crude, approximately 0.4 mmol) was dissolved in EtOH (6 mL). NH2OH (0.11 g, 1.72 mmol, 50 wt% aqueous solution) was added. The reaction mixture was heated to 80°C and stirred for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by preparative chromatography (neutral system). After lyophilization, a white solid BX20-9-036 (102 mg, 49.7%) was obtained. MS (ESI, m / z) 489 [M+H] + .

[0225] 1 H NMR (400MHz, DMSO-d6) δ10.07(s,2H),8.42(d,J=5.6Hz,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=10.0Hz,1H),4.27-4.22(m,1H),3.94(d,J=2.0Hz,3H),2.81–2.72(m,1H),1.60(s,3H),0.74-0.70(m,3H).

[0226] Example 8: Synthesis of BX20-9-037

[0227] Step 1: Synthesis of 36-1

[0228] Reference Example 7 Steps 1 to 3

[0229] Step 2: Synthesis of 37-1

[0230] The synthetic route is shown below:

[0231] Method: Compound 36-1 (220 mg, crude, approximately 0.4 mmol) was dissolved in DCE (5 mL) and stirred until clear. The temperature was then 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 quenched with NaHCO₃. The mixture was extracted with DCM / MeOH, and the organic phases were combined, washed with brine, dried, and concentrated under reduced pressure to yield 37-1 (0.26 g, crude) as a brown oil. MS (ESI, m / z) 472 [M+H] + .

[0232] Step 3: Synthesis of BX20-9-037

[0233] The synthetic route is shown below:

[0234] Method: Compound 37-1 (0.26 g, crude) was dissolved in EtOH (6 mL), and NH2OH (0.11 g, 1.72 mmol, 50 wt% aqueous solution) was added. The reaction mixture was heated to 80°C and stirred for 0.5 hours. After completion of the reaction, the mixture was directly concentrated under reduced pressure and purified by preparative chromatography (alkaline system). After lyophilization, a pale yellow solid BX20-9-037 (22 mg, 10.4%) was obtained. MS (ESI, m / z) 505 [M+H] + .

[0235] 1 H NMR(400MHz,DMSO-d6)δ10.72(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,2 H),5.07(d,J=10.0Hz,1H),4.26-4.20(m,1H),3.94(d,J=2.0Hz,3H),2.80-2.71(m,1H),1.60(s,3H),0.74-0.70(m,3H).

[0236] Example 9: Synthesis of BX20-9-038

[0237] Step 1: Synthesis of intermediate S8

[0238] Reference Example 1 Steps 1 to 9

[0239] Step 2: Synthesis of Intermediate 38-1

[0240] Method: S8 (150 mg, 0.42 mmol) was dissolved in DCM (3 mL), one drop of DMF was added, and oxalyl chloride (160 mg, 1.26 mmol) was added dropwise at 0°C. 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 product S9 (170 mg, crude product), 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 solution of S9 (170 mg, crude product) in DCM (2 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 h. After the reaction, the product was extracted with water and DCM, washed with brine, and concentrated under reduced pressure to obtain a yellow oily liquid 38-1 (197 mg, crude product). MS (ESI, m / z) 506 [M+H] + .

[0241] Step 3: Synthesis of intermediate BX20-9-038

[0242] Method: Compound 38-1 (180 mg, 0.37 mmol) was dissolved in MeOH (2 mL), and NH2OH (100 mg, 1.5 mmol, 50 wt% aqueous solution) was added dropwise. The mixture was stirred at room temperature for 72 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, purified by preparative chromatography (prepared with formic acid), and lyophilized to obtain a light yellow solid powder BX20-9-038 (62 mg, 34.4% yield). MS (ESI, m / z) 507 [M+H] + .

[0243] 1 H NMR (400MHz, DMSO-d6) 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=10.4Hz,1H),4.23(dd,J=10.4Hz, J=7.6Hz,1H),3.95(d,J=2.0Hz,3H),2.79-2.72(m,1H),1.60(s,3H),0.74-0.70(m,3H).

[0244] Example 10: Synthesis of BX20-9-039

[0245] Step 1: Synthesis of intermediate S7

[0246] Reference Example 1 Steps 1 to 8 to synthesize intermediate S7.

[0247] Step 2: Synthesis of Intermediate 39-1

[0248] The synthetic route is shown below:

[0249] Method: S7 (1.1 g, 3.28 mmol) was dissolved in DCM (15 mL), the atmosphere was replaced with N2, the temperature was lowered to -78°C, and BBr3 (2.1 mL, 21.32 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to 0°C and the reaction was stirred for 3 hours. After the reaction was complete, the reaction solution was slowly added dropwise to ice water, extracted with DCM, washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 39-1 (1.0 g, crude) as a yellow oil. MS (ESI, m / z) 322 [M+H] + .

[0250] Step 3: Synthesis of Intermediate 39-2

[0251] The synthetic route is shown below:

[0252] Method: Dissolve 39-1 (500 mg, crude, approximately 1.5 mmol) in DMF (5 mL), add Cs2CO3 (2.1 mL, 21.32 mmol) and 1-iodo-2-methoxyethane (1.15 g, 6.2 mmol), and heat to 70°C with stirring for 16 hours. After completion of the reaction, quench with water, extract with EA, wash with saturated aqueous NaCl, dry over anhydrous Na2SO4, and concentrate under reduced pressure to obtain compound 39-2 (450 mg, crude) as a yellow oil. MS (ESI, m / z) 380 [M+H] + .

[0253] Step 4: Synthesis of intermediate 39-3

[0254] The synthetic route is shown below:

[0255] Method: Dissolve 39-2 (450 mg, crude, 1.18 mmol) in MeOH (7.5 mL) and add an aqueous solution of KOH (462 mg, 8.26 mmol, dissolved in 1.5 mL of water). Heat to 60°C and stir for 16 hours. After completion of the reaction, concentrate under reduced pressure, dilute with water, extract with MTBE, and adjust the aqueous phase to pH <3 by dropwise addition of 1N HCl. Extract with EA, wash with saturated aqueous NaCl, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to yield compound 39-3 (430 mg, crude) as a yellow oil. MS (ESI, m / z) 399 [M+H] + .

[0256] Step 5: Synthesis of Intermediate 39-4

[0257] The synthetic route is shown below:

[0258] 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, and oxalyl chloride (0.1 mL, 1.206 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 0.5 h. After completion of the reaction, the mixture was concentrated under reduced pressure, redissolved in DCM (4 mL), and slowly added dropwise to a solution of 5-amino-2-fluorobenzonitrile (55 mg, 0.402 mmol) and TEA (122 mg, 1.206 mmol) in DCM / NMP (4:1, 5 mL). The mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, dissolved in EA, quenched with water, and extracted with EA. The organic phases were combined, washed once with water and once with saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford compound 39-4 (207 mg, crude) as a yellow oil. MS (ESI, m / z) 517 [M+H] + .

[0259] Step 6: Synthesis of BX20-9-039

[0260] The synthetic route is shown below:

[0261] Methods: Compound 39-4 (207 mg, crude product, approximately 0.4 mmol) was dissolved in EtOH (5 mL), and NH2OH (0.1 mL, 1.608 mmol, 50% in H2O) was added. The reaction was heated to 80°C and stirred for 1 hour. After completion of the reaction, the product was concentrated under reduced pressure and purified by preparative chromatography (formic acid system). The product was lyophilized to obtain BX20-9-039 (112 mg, 51%) as a white solid. MS (ESI, m / z) 550 [M+H] + .

[0262] 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.63(s,1H),7.80-7.73(m,1H),7.6 9-7.62(m,1H),7.21-7.14(m,3H),5.79(s,2H),5.06(d,J=10.8Hz,1H),4.3 6-4.30(m,1H),4.29-4.24(m,1H),4.23-4.16(m,1H),3.64-3.59(m,2H),3. 29(d,J=1.2Hz,3H),2.79-2.71(m,1H),1.60(s,3H),0.69(d,J=7.2Hz,3H).

[0263] Example 11: Synthesis of BX20-9-040

[0264] Step 1: Synthesis of Intermediate 39-1

[0265] Reference Example 10 Step 1 to Step 2 Synthesis of Intermediate 39-1

[0266] Step 2: Synthesis of Intermediate 40-1

[0267] The synthetic route is shown below:

[0268] Method: Dissolve 39-1 (500 mg, crude, 1.55 mmol) in DMF (5 mL), add Cs2CO3 (2.1 mL, 21.32 mmol) and 3-iodooxetane (1.14 g, 6.2 mmol), and heat to 70°C with stirring for 16 hours. After completion of the reaction, quench with water, extract with EA, wash with saturated aqueous NaCl, dry over anhydrous Na2SO4, and concentrate under reduced pressure to obtain compound 40-1 (565 mg, crude) as a yellow oil. MS (ESI, m / z) 378 [M+H] + .

[0269] Step 3: Synthesis of Intermediate 40-2

[0270] The synthetic route is shown below:

[0271] Method: Dissolve 40-1 (565 mg, crude product, 1.5 mmol) in MeOH (7.5 mL) and add an aqueous solution of KOH (587 mg, 10.5 mmol, dissolved in 1.5 mL of water). Heat to 60°C and stir for 16 hours. After completion of the reaction, concentrate under reduced pressure, dilute with water, extract with MTBE, and adjust the aqueous phase to pH <3 by dropwise addition of 1N HCl. Extract with EA, wash with saturated aqueous NaCl, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to yield compound 40-2 (330 mg, crude product) as a yellow oil. MS (ESI, m / z) 397 [M+H] + .

[0272] Step 4: Synthesis of intermediate 40-3

[0273] The synthetic route is shown below:

[0274] Method: 40-2 (330 mg, crude, 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. After stirring at room temperature for 10 minutes, 5-amino-2-fluorobenzonitrile (79 mg, 0.58 mmol) was added and the reaction was continued at room temperature for 4 hours. After completion of the reaction, the reaction was quenched with water, extracted with EA, and washed once with water and once with saturated aqueous NaCl solution. The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford compound 40-3 (400 mg, crude) as a yellow oil. MS (ESI, m / z) 515 [M+H] + .

[0275] Step 5: Synthesis of BX20-9-040

[0276] The synthetic route is shown below:

[0277] Method: Compound 40-3 (400 mg, crude product, 0.78 mmol) was dissolved in EtOH (5 mL), and NH2OH (0.2 mL, 3.12 mmol, 50% in H2O) was added. The reaction mixture was heated to 80°C and stirred for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by preparative chromatography (formic acid system). The product was lyophilized to obtain BX20-9-040 (45 mg, 11%) as a white solid. MS (ESI, m / z) 548 [M+H] + .

[0278] 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.65(s,1H),7.76(d,J=6.4Hz,1H),7.69-7.62(m,1H),7.22-7.14(m,3H),5.33-5.25(m,1H),5. 07(d,J=10.4Hz,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=7.2Hz,3H).

[0279] Example 12: Synthesis of BX20-9-046

[0280] Step 1: Synthesis of S9

[0281] Reference Example 7 Step 1 to Step 2 Synthesis of S9

[0282] Step 2: Synthesis of 46-1

[0283] The synthetic route is shown below:

[0284] Method: Dissolve 5-amino-2-(trifluoromethyl)benzonitrile (97 mg, 0.50 mmol) in NMP (2 mL), add TEA (85 mg, 0.84 mmol), and slowly add S9 (crude product, diluted with 5 mL of DCM, approximately 0.4 mmol). Stir at room temperature for 0.5 hour. After completion of the reaction, saturated ammonium chloride was added to quench the reaction, followed by extraction with DCM. The combined organic phases were washed with brine, dried, and concentrated under reduced pressure to afford 46-1 (0.28 g, crude) as a brown oil. MS (ESI, m / z) 523 [M+H] + .

[0285] Step 3: Synthesis of BX20-9-046

[0286] The synthetic route is shown below:

[0287] Method: Compound 46-1 (0.28 g) was dissolved in EtOH (6 mL), and NH2OH (0.11 g, 1.68 mmol, 50 wt% aqueous solution) was added. The reaction mixture was heated to 80°C and stirred for 0.5 hours. After the reaction, the mixture was directly concentrated under reduced pressure and purified by preparative chromatography and lyophilized to obtain a white solid BX20-9-046 (71 mg, 30.5%). MS (ESI, m / z) 556 [M+H] + .

[0288] 1H NMR (400MHz, DMSO-d6) δ10.62(d,J=4.4Hz,1H),9.59(s,1H),7.86-7.80(m,2H),7.70(d,J=8.4Hz,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=2.0Hz,3H),2.81-2.72(m,1H),1.60(s,3H),0.76-0.70(m,3H).

[0289] Example 13: Synthesis of BX20-9-047

[0290] Step 1: Synthesis of S8

[0291] Reference Example 1 Steps 1 to 9 were used to synthesize S8.

[0292] Step 2: Synthesis of 47-1

[0293] The synthetic route is shown below:

[0294] 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 mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude S9 (180 mg, crude), which was used directly in the next step. 5-Amino-2,3-difluorobenzonitrile (78 mg, 0.50 mmol) was dissolved in NMP (2 mL), and TEA (85 mg, 0.84 mmol) was added. S9 (crude, diluted with 5 mL of DCM, approximately 0.42 mmol) was then slowly added and stirred at room temperature for 0.5 h. After completion of the reaction, the mixture was quenched with saturated ammonium chloride and extracted with EA. The organic phases were combined, washed with brine, dried, and concentrated under reduced pressure to afford 47-1 (0.17 g, crude) as a brown oil. MS (ESI, m / z) 491 [M+H] + .

[0295] Step 3: Synthesis of BX20-9-047

[0296] The synthetic route is shown below:

[0297] Method: Compound 47-1 (crude, approximately 0.42 mmol) was dissolved in EtOH (6 mL), and NH2OH (0.11 g, 1.68 mmol, 50 wt% aqueous solution) was added. The reaction mixture was heated to 80°C and stirred for 0.5 hours. After completion of the reaction, the mixture was directly concentrated under reduced pressure and purified by preparative chromatography (formic acid) to afford BX20-9-047 (52 mg, 23.6%) as a white solid. MS (ESI, m / z) 524 [M+H] + .

[0298] 1 H NMR (400MHz, 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=11.2Hz,1H),4.06-3.99(m,1H),3.90(d,J=2.0Hz,3H),2.74-2.64(m,1H),1.65(s,3H),0.74-0.69(m,3H).

[0299] Example 14: Synthesis of BX20-9-048

[0300] Step 1: Synthesis of 48-2

[0301] The synthetic route is shown below:

[0302] 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, then at 50°C for 0.5 hour. After completion of the reaction, the mixture was filtered, extracted with water and EA, and the organic phases were combined, washed with brine, dried, and concentrated under reduced pressure to yield 48-2 (0.40 g, 96.3%). MS (ESI, m / z) 155 [M+H] + .

[0303] Step 2: Synthesis of 48-3

[0304] The synthetic route is shown below:

[0305] Methods: 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 then added dropwise at 0°C. The reaction mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude S9 (180 mg, crude), which was used directly in the next step. 5-Amino-2,4-difluorobenzonitrile (78 mg, 0.50 mmol) was dissolved in NMP (2 mL), and TEA (85 mg, 0.84 mmol) was added. S9 (crude, diluted with 5 mL of DCM, 0.42 mmol) was then slowly added and stirred at room temperature for 0.5 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride and extracted with DCM. The organic phases were combined, washed with brine, dried, and concentrated under reduced pressure to afford 48-3 (0.15 g, crude) as a brown oil. MS (ESI, m / z) 491 [M+H] + .

[0306] Step 3: Synthesis of BX20-9-048

[0307] The synthetic route is shown below:

[0308] Method: Compound 48-3 (0.15 g, crude, approximately 0.42 mmol) was dissolved in EtOH (6 mL), and NH2OH (0.11 g, 1.72 mmol, 50 wt% aqueous solution) was added. The reaction mixture was heated to 80°C and stirred for 0.5 hours. After completion of the reaction, the mixture was directly concentrated under reduced pressure and purified by preparative chromatography (neutral) to afford BX20-9-048 (56 mg, 27.2%) as a white solid. MS (ESI, m / z) 524 [M+H] + .

[0309] 1 H NMR(400MHz,DMSO-d6)δ9.96(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=2.0Hz,3H),2.83-2.66(m,1H),1.60(s,3H),0.74-0.70(m,3H).

[0310] Example 15: Synthesis of BX20-9-049

[0311] Step 1: Synthesis of S8

[0312] Reference Example 1 Steps 1 to 9 were used to synthesize S8.

[0313] Step 2: Synthesis of 49-1

[0314] The synthetic route is shown below:

[0315] Methods: 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 then added dropwise at 0°C. The reaction mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford crude S9 (180 mg, crude), which was used directly in the next step. 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 S9 (crude, diluted with 5 mL of DCM, approximately 0.42 mmol) was slowly added. The mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the mixture was quenched with saturated ammonium chloride and extracted with EA. The organic phases were combined, washed with brine, dried, and concentrated under reduced pressure to afford 49-1 (0.13 g, crude) as a brown oil. MS (ESI, m / z) 491 [M+H] + .

[0316] Step 3: Synthesis of BX20-9-049

[0317] The synthetic route is shown below:

[0318] Method: Compound 49-1 (0.13 g, crude product, approximately 0.42 mmol) was dissolved in EtOH (6 mL), and NH2OH (0.11 g, 1.68 mmol, 50 wt% aqueous solution) was added. The reaction mixture was heated to 80°C and stirred for 0.5 hours. After completion of the reaction, the mixture was directly concentrated under reduced pressure and purified by preparative chromatography (formic acid) to afford BX20-9-049 (48 mg, 21.9%) as a white solid. MS (ESI, m / z) 524 [M+H] + .

[0319] 1 H NMR(400MHz,DMSO-d6)δ9.98(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=2.0Hz,3H),2.80-2.69(m,1H),1.60(s,3H),0.74-0.70(m,3H).

[0320] Example 16: Synthesis of BX20-9-055

[0321] Step 1: Synthesis of BX20-9-029

[0322] Reference Example 3 Steps 1 to 3 complete the synthesis of BX20-9-029

[0323] Step 2: Synthesis of Intermediate 55-1

[0324] Method: BX20-9-029 (100 mg, 0.2 mmol) was dissolved in AcOH (5 mL), and Pd / C (100 mg, 50% wt water) and ammonium formate (126 mg, 2 mmol) were added. The reaction system was purged with nitrogen and heated at 120°C with stirring under reflux for 3 hours. After completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford 55-1 (90 mg, crude) as a yellow oil. MS (ESI, m / z) 490 [M+H] + .

[0325] Step 3: Synthesis of BX20-9-055

[0326] Method: Dissolve 55-1 (90 mg, crude) in EtOH (3 mL), add NaOH (80 mg, 2 mmol) and cyanogen bromide (106 mg, 1 mmol), and stir at room temperature for 3 hours. After completion, the reaction was quenched with water and extracted three times with EA. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative chromatography to afford BX20-9-055 (11 mg, 11% yield) as a white solid. MS (ESI, m / z) 515 [M+H] +

[0327] 1 H NMR (400MHz, DMSO-d6) δ=10.44(brs,1H),7.83(brs,1H),7.77-7.73(m,1H),7.32(t,J=9.2Hz,1H),7.17-7.09(m,2H),5.04(d ,J=10.4Hz,1H),4.21(dd,J=10.4Hz,8.4Hz,1H),3.92(d,J=2.0Hz,3H),2.77-2.69(m,1H),1.57(s,3H),0.70(d,J=6.8Hz,3H).

[0328] Reference compound:

[0329] Reference patent CN114945566A Example 3 synthesis of the reference compound (Compound 7)

[0330] 1 H NMR (400MHz, CD3OD) δ = 8.48 (d, J = 5.6Hz, 1H), 8.25 (d, J = 2.0Hz, 1H), 7.89 (dd, J = 2.0Hz, 5.2Hz, 1H), 7.13-7.09 (m, 1H), 7.00-6. 94(m,1H),5.08(d,J=10.4Hz,1H),4.34-4.30(m,1H),3.99(d,J=2.4Hz,3H),2.83-2.75(m,1H),1.65(s,3H),0.82-0.80(m,3H)

[0331] Biological test evaluation

[0332] The present invention is further described below in conjunction with test examples.

[0333] Test Example 1 Blocking activity of the compound of the present invention on sodium ion channel 1.8 (Nav1.8)

[0334] 1. Experimental purpose: To detect the effect of compounds on the current of voltage-gated sodium channel (NaV) 1.8 subtype using patch clamp technique

[0335] 2. Experimental materials and equipment

[0336] 2.1. Cell Line: A CHO cell line stably expressing the Nav1.8 sodium channel. Nav1.8 cells were constructed in-house by Beijing Aisiyipu Biotechnology Co., Ltd. Gene information: Sodium channel, voltage-gated, type 8, alpha (SCN10A), cDNA strictly similar to GenBank accession number: NM_006514

[0337] 2.2. Compound: Dissolved in DMSO

[0338] 3. Experimental Methods

[0339] Cell culture

[0340] (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 5% carbon dioxide.

[0341] (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 minutes. 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 centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, inoculate the cells into 6 cm cell culture dishes, with 2.5×105 cells in each cell culture dish (final volume: 5 mL).

[0342] (3) To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0343] (4) Patch clamp assay: Before the test, cells were detached with 0.25%-Trypsin-EDTA, 6.5×10 3 cells were plated on a coverslip, and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, the test was performed.

[0344] 3.2. Patch clamp assay

[0345] (1) After the whole-cell seal is formed, the cell voltage is clamped at -120mV. First, the voltage is stepped from -130mV to -10mV in 10mV steps and maintained for 5s, and then a 0mV depolarizing pulse is given to obtain the half-inactivated voltage (Vhalf). The resting state (Resting state) and half-inactivated state (Half-inactivated state) of the sodium current are detected using a double pulse mode. First, the first depolarizing pulse (TP1) is given to 0mV for 50ms to detect the resting state sodium current. Then the voltage is adjusted to Vhalf and maintained for 5s, and then the voltage is restored to -120mV and maintained for 20ms. Then a second depolarizing pulse (TP2) is given to 0mV for 50ms to detect the half-inactivated state sodium current. Finally, it is restored to the clamping voltage of -120mV. Data are repeatedly collected every 20ms to observe the effect of the drug on the peak sodium current in the two different states. The experimental data were collected by EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0346] (2) During patch clamping, a microelectrode puller is first used to pull a capillary glass tube into a recording electrode. The electrode, filled with intracellular fluid, is then placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to bring the recording electrode into contact with the cell. Negative pressure is applied to form a GΩ seal. Fast capacitance compensation is then performed, and negative pressure is continued to be applied to rupture the cell membrane, forming a whole-cell recording mode. Finally, slow capacitance compensation is performed and the relevant parameters are recorded. No leakage compensation is performed.

[0347] (3) When the sodium current recorded in the whole cell is stable, the drug is administered. Each drug concentration is applied for 5 minutes (or the current is stable) before the next concentration is detected. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the compound to be tested are flowed through the recording bath in sequence from low concentration to high concentration by gravity perfusion to act on the cells. A peristaltic pump is used for liquid exchange during the recording. The current detected for 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.

[0348] Data analysis

[0349] First, the current after each drug concentration was normalized to the blank control current, and then the inhibition rate corresponding to each drug concentration was calculated, that is, (1-Icompound / Icontrol). The mean (Mean), standard deviation (SD) and standard error (SE) of the inhibition rate at each concentration were calculated, and the data were expressed as mean±SE.

[0350] 4. Experimental Results

[0351] Table 1 The blocking rate of the compounds of the present invention on NaV1.8

[0352] It can be seen that the compound of the present invention has a significant blocking effect on the activity of NaV1.8 channels.

[0353] Test Example 2 Blocking activity (IC) of the compounds of the present invention on sodium ion channel 1.8 (Nav1.8) 50 )

[0354] 1. Research Objectives

[0355] Manual patch clamp technique is used to evaluate whether the test compound has a potential inhibitory effect on the voltage-gated sodium channel hNav1.8. This experiment measures the effect of the compound at 5 concentrations or at a single or dual concentration point on the hNav1.8 channel current to obtain a dose-effect curve and calculate the IC 50 This experiment included 2 parallel sample measurements.

[0356] 2. Test methods

[0357] Test materials

[0358] 1) Cells: The HEK293 cell line stably expressing the 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 screened. For details, see: Proc Natl Acad Sci US A. 2022 Jul 26; 119(30): e2208211119. doi: 10.1073 / pnas.2208211119. and Cell Lines / BSYS CHO NaV1.8 / β3Cell Line instructions). The cell line was cultured in a medium containing 90% DMEM, 10% fetal bovine serum, 100 U / mL penicillin-streptomycin solution, 0.75 μg / mL puromycin, and 100 μg / mL hygromycin. When the cell density reached 40% to 80% of the bottom area of ​​the culture dish, the cells were digested with 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 glass slides for subsequent manual patch clamp experiments.

[0359] 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 with DMSO as a solvent to the required intermediate solution. 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 .

[0360] 2.2. Experimental steps

[0361] 1) Place the small glass slide containing HEK293 cells in the culture dish into the perfusion tank on the microscope stage.

[0362] 2) Using an Olympus IX71 or IX73 inverted microscope, center the field of view of an appropriate cell. Using a ×10 objective lens, locate the tip of the glass electrode and position it in the center of the field of view. Then, use the micromanipulator to lower the electrode while adjusting the coarse focus knob to gradually bring the electrode closer to the cell.

[0363] 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.

[0364] 4) Apply negative pressure to form a seal with a resistance higher than 1 GΩ between the electrode tip and the cell membrane.

[0365] 5) Compensate for the transient capacitive current Cfast in voltage clamp mode. Repeated short negative pressures are then applied to rupture the membrane, ultimately establishing whole-cell recording mode.

[0366] 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.

[0367] 7) After the cells are stable, the clamp voltage is changed to -80mV, the sampling frequency is set to 20kHz, and the filter frequency is set to

[0368] The leakage current was detected at a frequency of 10 kHz and a clamping voltage of -80 mV for a duration of 200 ms.

[0369] 8) hNav1.8 current measurement method is as follows: Depolarize the membrane potential from -80 mV to -10 mV by applying a 20 ms depolarizing command voltage, followed by repolarization to -80 mV to close the channel. Stimulation is repeated every 15 seconds. The instantaneous peak current at the depolarizing voltage is the magnitude of the Nav1.8 sodium channel current.

[0370] 9) The hNav1.8 current used to detect the test compound was recorded continuously for 120 seconds before administration to assess the stability of the hNav1.8 current generated by the test cells. Only stable cells within the acceptable range of the evaluation criteria were used for subsequent compound testing.

[0371] 10) Testing the inhibitory effect of the test compound on hNav1.8 current: First, the hNav1.8 current measured in extracellular solution containing 0.1% DMSO is used as the detection baseline. After the hNav1.8 current remains stable for at least 5 minutes, solutions containing the test compound are sequentially perfused around the cells from low to high concentrations. After each perfusion, wait approximately 5 minutes to allow the compound to fully act on the cells and simultaneously record the hNav1.8 current. After the recorded current stabilizes, record the last 5 hNav1.8 current values ​​and take the average as the final current value at the specific concentration. After the compound is tested, add 5nM of the reference compound to the same cell to completely inhibit its current and serve as a positive control for the cell. Simultaneously, the positive compound and the reference compound are simultaneously 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).

[0372] Data Analysis

[0373] 1) Data must meet the following criteria: initial sealing resistance greater than 1GΩ; membrane rupture resistance Ra less than 15MΩ; leakage current at the test voltage less than 50% of the current value under that condition; Nav1.8 peak current at least greater than 200pA;

[0374] 2) Data were analyzed according to the following steps (data were output by PatchMaster software):

[0375] 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 magnitude 化合物 The current suppression percentage is calculated using the following formula.

[0376] ②The dose-effect curve was fitted using Graphpad Prism 8.0 software and the IC50 value was calculated.

[0377] The standard deviation of the two sets of data is less than 15 (SD<15)

[0378] 3. Test results

[0379] Table 2 The inhibitory activity of the compounds of the present invention on NaV1.8

[0380] It can be seen that the compound of the present invention has a strong inhibitory activity on NaV1.8 channels, which is better than the reference compound.

[0381] Test Example 3 Selectivity test of the compound of the present invention for sodium ion channels

[0382] 1. Experimental purpose: To detect the effect of compounds on the current of voltage-gated sodium ion channel (NaV) 1.1-1.7 subtypes using patch clamp technique

[0383] 2. Experimental materials and equipment

[0384] 2.1. Cell Line: CHO / HEK293 cell lines stably expressing Nav1.1-1.7 sodium channels were constructed in-house by Beijing Aisiyipu Biotechnology Co., Ltd. (referring to Jarvis MF, Honore P, Shieh CC, Chapman M, Joshi S, Zhang XF, Kort M, Carroll W, Marron B, Atkinson R, Thomas J, Liu D, Krambis M, Liu Y, McGaraughty S, Chu K, Roeloffs R, Zhong C, Mikusa JP, 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 the rat. Proc Natl Acad Sci US A.2007May 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; Nav 1.3:NM_006922;Nav1.4:NM_000334;Nav1.5:NM198056;Nav1.6:NM014191;Nav1.7:NM006922.

[0385] 2.2. Compounds: Dissolve in DMSO and prepare the sample at a concentration of 30 μM.

[0386] 3. Experimental Methods

[0387] Cell culture

[0388] (1) Maintenance medium: CHO cells were cultured in HAM'S / F-12 medium supplemented with 10% fetal bovine serum, 100 μg / mL Zeocin, and 10 μg / mL Blasticidin at 37°C and 5% CO2. HEK-293 cells were cultured in DMEM supplemented with 10% fetal bovine serum and 800 μg / mL G418 at 37°C and 5% CO2.

[0389] (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 minutes. 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 centrifuge at 1000 rpm for 5 minutes to collect the cells. 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).

[0390] (3) To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0391] (4) Patch clamp assay: Before the test, cells were separated with 0.25%-Trypsin-EDTA and 6.5×10 3 The cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the assay was performed.

[0392] 3.2. Patch clamp assay

[0393] Same as test case 1 3.2

[0394] Data analysis

[0395] Same as test case 1 3.3

[0396] 4. Experimental Results

[0397] Table 3 Blockade rate of the compounds of the present invention on NaV1.1-1.7 at 30 μM

[0398] 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, suggesting that the compounds of the present invention have better safety.

[0399] Test Example 4 Pharmacokinetic Determination in SD Rats

[0400] 1. Purpose of the study

[0401] 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.

[0402] 2. Test methods

[0403] 2.1. Investigational Drugs

[0404] The examples and reference compounds of the present invention were prepared in-house.

[0405] 2.2. Experimental animals

[0406] Male SPF SD rats, weighing (200±20) g.

[0407] 2.3. Preparation of experimental drugs

[0408] Drug preparation: The drug concentration was 1 mg / mL, and the preparation solvent was Tween 80 + 0.5% MC (v / v 1:99).

[0409] 2.4. Administration:

[0410] Male SPF SD rats were fed adaptively for 3-4 days and then orally administered with a dose of 10 mg / kg and a volume of 10 mL / kg.

[0411] 2.5. Sample collection

[0412] Before administration (0h) and after administration, blood was collected from rats at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, and 24h. Blood was collected by fundus puncture, and the blood volume was about 0.2mL. The blood was 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 4500rpm in an ice water bath at 4°C for 10min. After the centrifugation operation, the plasma was promptly divided into EP tubes with corresponding labels and stored in a -80°C refrigerator.

[0413] 2.6. Sample testing

[0414] After administration, 20 μL of rat plasma was taken and placed in a 96-deep-well plate pre-added with 20 μL of internal standard working solution. 400 μL of precipitant methanol was added, vortexed for 10 minutes, and centrifuged at 4000 rpm for 15 minutes. 200 μL of the supernatant was taken and placed in another 96-deep-well plate pre-added with 200 μL of ultrapure water. The supernatant was vortexed for 5 minutes and centrifuged at 4000 rpm for 3 minutes. 5 μL of the supernatant was taken for LC-MS / MS analysis of plasma drug concentration.

[0415] 3. Test results and analysis

[0416] The main pharmacokinetic parameters were calculated using WinNonlin 7.0. The results of the rat pharmacokinetic experiment are shown in Table 4 below.

[0417] Table 4 Results of rat pharmacokinetic test

[0418] 4. Experimental Conclusion

[0419] 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, which shows that the compound of the present invention exhibits better absorption characteristics.

[0420] Test Example 5: Pharmacokinetic Determination in KM Mice

[0421] 1. Purpose of the study

[0422] KM mice were used as test animals, and the example compounds were administered orally at a dose of 10 mg / kg / 1 mg / kg

[0423] Pharmacokinetic behavior of the drug in plasma of mice after intravenous administration.

[0424] 2. Test methods

[0425] 2.1. Investigational Drugs

[0426] The examples and reference compounds of the present invention were prepared in-house.

[0427] 2.2. Experimental animals

[0428] Male SPF KM mice, weighing (20±2) g.

[0429] 2.3. Preparation of experimental drugs

[0430] Drug preparation for the oral administration group: the drug concentration was 1 mg / mL, and the solvent was Tween 80 + 0.5% MC (v / v 1:99).

[0431] Drug preparation for the intravenous administration group: the drug concentration was 0.2 mg / mL, and the solvent was 5% DMA + 5% Solutol HS-15 + 90% normal saline.

[0432] 2.4. Administration:

[0433] Male SPF KM mice were fed adaptively for 3-4 days.

[0434] Oral gavage group: the dosage was 10 mg / kg, and the administration volume was 10 mL / kg.

[0435] Intravenous administration group: the dosage was 1 mg / kg, and the administration volume was 5 mL / kg.

[0436] 2.5. Sample collection

[0437] Oral administration: Blood samples were collected from mice before (0 h) and at 0, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 h after administration. Blood samples were collected before (0 h) and at 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h after intravenous administration.

[0438] Blood was collected by fundus puncture, with a 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 three 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 divided into EP tubes with corresponding labels and stored in a -80°C refrigerator.

[0439] 2.6. Sample testing

[0440] After administration, 20 μL of mouse plasma was taken and placed in a 96-deep-well plate pre-added with 20 μL of internal standard working solution. 400 μL of precipitant methanol was added, vortexed for 10 minutes, and centrifuged at 4000 rpm for 15 minutes. 200 μL of the supernatant was taken and placed in another 96-deep-well plate pre-added with 200 μL of ultrapure water. The supernatant was vortexed for 5 minutes and centrifuged at 4000 rpm for 3 minutes. 5 μL of the supernatant was taken for LC-MS / MS analysis of plasma drug concentration.

[0441] 3. Test results and analysis

[0442] The main pharmacokinetic parameters were calculated using WinNonlin 7.0. The results of the mouse pharmacokinetic experiment are shown in Table 5 below.

[0443] Table 5 Results of mouse pharmacokinetic test

[0444] 4. Experimental Conclusion

[0445] 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.

[0446] Test Example 6: Drug Efficacy Test in Sodium Acetate Mouse Model

[0447] 1. Objective: To evaluate the analgesic efficacy of the examples in the acetic acid writhing model in KM mice.

[0448] 2. Test method:

[0449] 2.1. Test drugs: Examples of the present invention and reference compounds, homemade. Naproxen, Shanghai Yuanye Biotechnology Co., Ltd., product number S63435, prepared using a solvent (Tween 80 + 0.5% MC (v:v = 1:99, pH = 3)).

[0450] 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.

[0451] 2.3. Experimental Grouping:

[0452] Table 6: Grouping of compounds in the acetic acid writhing model

[0453] 2.4. Drug administration and modeling

[0454] One hour after each group completed the administration of the corresponding drugs, 0.6% acetic acid (0.15 mL / 10 g (0.1 mL / 10 g is also acceptable)) was injected intraperitoneally, and the writhing latency (the time when the mouse first writhes after the injection of glacial acetic acid) was recorded. The number of writhing reactions of the mice within 20 minutes was observed and recorded.

[0455] Writhing index: The mouse shows typical abdominal concavity, accompanied by characteristic reactions such as trunk twisting and hip elevation, which is considered to be writhing.

[0456] Data Collection and Analysis

[0457] Data were collected using Excel software.

[0458] Data were analyzed using Prism (Graph pad software, Inc.) software.

[0459] 3. Results

[0460] Table 7 Analgesic efficacy of compounds in the acetic acid writhing pain model in mice

[0461] 4. Conclusion

[0462] From the above data, it can be seen that at the same dosage, the compounds of Example 10 and Example 11 of the present invention can inhibit the pain caused by acetic acid in mice and reduce the number of writhing times of mice. In addition, the analgesic effect of Example 11 is significantly dose-dependent and its 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 groups in the substituted C1-C6 alkyl groups are 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, (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 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 as defined 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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