A heterocyclic compound and application thereof

Abstract

The application provides a novel heterocyclic compound, a preparation method and a pharmaceutical use, and provides a new direction for development of a Nav1.8 inhibitor drug. The compound has good Nav1.8 inhibitory activity, good drug metabolism, and good drug properties. As a Nav1.8 inhibitor, the compound can be used for preventing and / or treating diseases related to abnormal expression of Nav1.8 channel activity, and has important clinical application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to a class of heterocyclic small molecule compounds, their preparation methods, and their pharmaceutical uses. Background Technology

[0002] Pain is a complex physiological and psychological phenomenon; it is an unpleasant sensory and emotional experience resulting from potential or actual tissue damage. Pain has a complex physiological mechanism involving multiple processes. First, various pain receptors are distributed in the skin, muscles, and other tissues of the human body. These receptors can sense harmful stimuli such as mechanical, chemical, and thermal stimuli. When the intensity of these stimuli reaches a certain threshold, the receptors are activated. Once activated, the pain receptors transmit pain signals to the central nervous system (spinal cord and brain) via afferent nerve fibers. The pain signal first reaches the spinal cord, where it undergoes initial integration and modulation. Then, the signal continues to ascend to multiple areas of the brain, including the thalamus, somatic sensory cortex, and limbic system.

[0003] Sodium ion channels are protein channels on the cell membrane, primarily responsible for the transmembrane transport of sodium ions, and are crucial for various physiological functions such as cellular excitability. Based on their activation mechanism, they are classified as voltage-gated sodium ion channels, ligand-gated sodium ion channels, and mechano-gated sodium ion channels.

[0004] Voltage-gated sodium channels are the most common type of sodium ion channel. Their opening and closing are controlled by the cell membrane potential. When cell membrane depolarization reaches a certain threshold, the channel opens rapidly, allowing a rapid influx of sodium ions, leading to further depolarization of the cell membrane and generating an action potential. For example, most sodium channels in nerve and muscle cells belong to this type. They play a crucial role in nerve impulse transmission and muscle contraction. Voltage-gated sodium channels can be further divided into several subtypes based on their gene families, such as NaV1.1-NaV1.9. Different subtypes have different distributions and functions in different tissues and cells.

[0005] The NaV1.8 ion channel is a tetrodotoxin-insensitive sodium channel primarily expressed on nociceptive neurons, playing a crucial role in pain signal transduction in the peripheral nervous system. Belonging to the α-channel subunit, NaV1.8 consists of four homologous domains, each containing six transmembrane regions, one of which is a voltage sensor. It exhibits unique voltage dependence, possessing a relatively depolarized steady-state inactivation characteristic. This allows it to remain active and activated even when the neuron depolarizes to the membrane potential that inactivates other sodium channels. It exhibits slow inactivation and rapid recovery kinetics: compared to other sodium channel subtypes, the transition from an open to an inactive state in NaV1.8 channels is slower, and the recovery from inactivation is rapid, more than 10 times faster than that of tetrodotoxin-sensitive (TTX-S) sodium channels. This characteristic endows it with a special role in sensing nociceptive stimuli in nociceptors, especially nociceptive cold and mechanical stimuli at low temperatures. The NaV1.8 channel is highly expressed in small-diameter primary sensory neurons that sense pain and is an important channel for transmitting pain signals. It can be activated by noxious stimuli, generating inward currents, which in turn trigger action potentials, transmitting pain signals to the central nervous system.

[0006] NaV1.8 is mainly distributed in small-diameter C-fiber neurons of the dorsal root ganglion (DRG) and plays an important role in the development of various pain types, including inflammatory pain and neuropathic pain. For example, in an inflammatory state, inflammatory mediators can upregulate the expression and function of NaV1.8 channels, making them more sensitive to painful stimuli, thus leading to hyperalgesia and anomalous pain. In neuropathic pain caused by nerve damage, the expression and activity of NaV1.8 channels also change, participating in the generation and maintenance of pain.

[0007] Due to its crucial role in pain transmission and its non-involvement in central nervous system-related activities, NaV1.8 inhibitors do not pose addiction risks similar to opioids and do not affect motor function, making them a popular target for developing non-addictive analgesics. Currently, several selective NaV1.8 blockers exist; therefore, it is necessary to develop NaV1.8 inhibitors with higher activity, better selectivity, superior pharmacokinetic properties, and fewer side effects. Summary of the Invention

[0008] In a first aspect, the present invention provides a compound of formula (A), a stereoisomer, a tautomer, or a mixture thereof, or a pharmaceutically acceptable salt of the compound:

[0009] (A)

[0010] R a and R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. R c and R d Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. “ " indicates a single or double bond, Z" 1 -Z 5 The ring it belongs to is an aromatic ring; Z 1 Selected from N, CR Z1 Or C=O; Z 2 Selected from N, CR Z2 Or C=O; Z 3 Selected from N, CR Z3 Or C=O; Z 4 Selected from N, CR Z4 Or C=O; Z 5 Selected from N, CR Z5 Or C=O; R Z1 RZ2 R Z3 R Z4 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 The substituents of the alkylthio group are replaced; R e1 R e2 R e3 R e4Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 3-6 cycloalkyl; R g Selected from H, C 1-6 Alkyl or C 3-6 cycloalkyl; R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. L1 is a bond, -OC 1-2 Alkylene-, -NR l - C 1-2 alkylene- or -C 1-3 Alkylene, wherein the alkylene group is optionally composed of one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups; R l Selected from H, C 1-6 Alkyl or C 3-6 cycloalkyl; R h Selected from hydrogen, deuterium, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl, 5-12 heteroaryl, said C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl groups and 5-12 heteroaryl groups may be optionally substituted with 1-6 or fewer substituents: deuterium, halogen, nitro, amino, hydroxyl, -NR. h1 R h2 Oxide group, thio group, carboxyl group, cyano group, C group optionally substituted with halogen 1-6 Alkyl groups, C groups optionally substituted with halogens 1-6 Alkoxy, optional C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl, optionally C 1-3 Alkyl or halogen-substituted 5-6 membered heterocyclic groups, optionally C 1-3 Alkyl or halogen-substituted phenyl, optionally C 1-3 5-6 membered heteroaryl groups substituted with alkyl or halogen; R h1 R h2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl; X is either O or S; Unless otherwise stated, the heteroatoms in the above heterocyclic or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0011] The present invention also provides a compound of formula (I), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0012] R a and R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. R c and R dEach is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. “ " indicates a single or double bond, Z" 1 -Z 5 The ring it belongs to is an aromatic ring; Z 1 Selected from N, CR Z1 Or C=O; Z 2 Selected from N, CR Z2 Or C=O; Z 3 Selected from N, CR Z3 Or C=O; Z 4 Selected from N, CR Z4 Or C=O; Z 5 Selected from N, CR Z5 Or C=O; R Z1 R Z2 R Z3 R Z4 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2-C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 The substituents of the alkylthio group are replaced; R e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 3-6 cycloalkyl; R g Selected from H, C 1-6 Alkyl or C 3-6 cycloalkyl; R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, the C 1-6 Alkoxy, C 1-6Alkylthio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. L1 is a bond, -OC 1-2 Alkylene-, -NR l - C 1-2 alkylene- or -C 1-3 Alkylene, wherein the alkylene group is optionally composed of one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups; R l Selected from H, C 1-6 Alkyl or C 3-6 cycloalkyl; R h Selected from hydrogen, deuterium, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl, 5-12 heteroaryl, said C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl groups and 5-12 heteroaryl groups may be optionally substituted with 1-6 or fewer substituents: deuterium, halogen, nitro, amino, hydroxyl, -NR. h1 R h2 Oxide group, thio group, carboxyl group, cyano group, C group optionally substituted with halogen 1-6 Alkyl, optionally C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl, optionally C 1-3 Alkyl or halogen-substituted 5-6 membered heterocyclic groups, optionally C 1-3 Alkyl or halogen-substituted phenyl, optionally C 1-3 5-6 membered heteroaryl groups substituted with alkyl or halogen; R h1 R h2Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl; X is either O or S; Unless otherwise stated, the heteroatoms in the above heterocyclic or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

[0013] In some implementation schemes, R a and R b Each group is independently selected from hydrogen, deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, and cyano; preferably, R a and R b Each of the following groups is independently selected from hydrogen, deuterium, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from F, Cl, and Br; more preferably, R a and R b Each group is independently selected from methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from F, Cl, and Br; more preferably, R a and R b Each is independently selected from methyl groups optionally substituted with 1, 2, or 3 F, Cl, or Br; more preferably, R a Selected from methyl, R b Selected from trifluoromethyl.

[0014] In some implementation schemes, R c and R d Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, and cyano groups; preferably, R c and R d Each of the following groups is independently selected from hydrogen, deuterium, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from F, Cl, and Br; more preferably, R c and R dEach is independently selected from hydrogen, deuterium, methyl, methoxy, and cyclopropyl, wherein the methyl, methoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from F, Cl, and Br; more preferably, R c and R d Each is independently selected from hydrogen, deuterium, and methyl; more preferably, R c Selected from methyl, R d Selected from hydrogen.

[0015] In some implementation schemes, Z 1 Selected from N, CR Z1 Z 2 Selected from N, CR Z2 Z 3 Selected from N, CR Z3 Z 4 Selected from N, CR Z4 Z 5 Selected from N, CR Z5 Preferred, Z 1 -Z 5 Of these, 0-2 are selected from N; more preferably, Z 1 -Z 5 The 0 or 1 in the selection is chosen from N; more preferably, Z 3 Selected from N or CR Z3 Z 1 Selected from CR Z1 Z 2 Selected from CR Z2 Z 4 Selected from CR Z4 Z 5 Selected from CR Z5 .

[0016] In some implementation schemes, R Z1 R Z2 R Z3 R Z4 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, -S(O)-C 1-4 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NR e1R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, -S(O)-C 1-4 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 The substituents of the alkylthio group are replaced by R. e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 3-6 cycloalkyl; Preferred, R Z1 R Z2 R Z3 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, R Z4 Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, -S(O)-C 1-4 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NRe1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, -S(O)-C 1-4 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 The substituents of the alkylthio group are replaced by R. e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 3-6 cycloalkyl; More preferably, R Z1 R Z2 R Z3 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, R Z4 Selected from -S(O)-C 1-3 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NRe3 C(O)R e4 The methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, -S(O)-C 1-3 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, optionally halogen-substituted methyl, optionally halogen-substituted ethyl, optionally halogen-substituted methoxy, optionally halogen-substituted ethoxy, R e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-3 Alkyl, C 3-6 cycloalkyl; Even better, R Z1 R Z2 R Z3 R Z5 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, methyl, and methoxy groups, R. Z4 Selected from -S(O)-methyl, -S(O)-ethyl, -S(O)-cyclopropyl, -S(O)2-methyl, -S(O)2-ethyl, -S(O)2-cyclopropyl, -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 R e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, methyl, and ethyl; Even better, Z 3 Selected from N or CR Z3 Z 1 Selected from CR Z1 Z 2 Selected from CR Z2 Z 4 Selected from CR Z4 Z 5 Selected from CR Z5 R Z1 RZ2 R Z3 R Z5 Selected independently from hydrogen, deuterium, F, Cl, Br, and R Z4 Selected from -S(O)-CH3, -S(O)2-CH3, -C(O)NH2, -S(O)2NH2, -S(=NH)(O)CH3, -S(=N-CH3)(O)CH3; more preferably, Z 3 Selected from N or CR Z3 Z 1 Selected from CR Z1 Z 2 Selected from CR Z2 Z 4 Selected from CR Z4 Z 5 Selected from CR Z5 R Z1 R Z2 R Z5 Selected independently from hydrogen and deuterium, R Z3 Selected from hydrogen, deuterium, F, Cl, Br, R Z4 Selected from -S(O)2-CH3, -C(O)NH2, -S(O)2NH2, -S(=NH)(O)CH3, -S(=N-CH3)(O)CH3.

[0017] In some implementation schemes, R g Selected from H, methyl; preferably, R g Selected from H.

[0018] In some implementation schemes, R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl, C 3-6 cycloalkyl, the C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl, C 3-6 The cycloalkyl group may be optionally replaced by one, two, or three substituents selected from deuterium or halogens; preferably, R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, methyl, ethyl, methoxy, ethoxy; more preferably, R f1 R f2 R f3 R f4Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, methyl; more preferably, R f1 R f2 R f3 R f4 Independently selected from hydrogen and halogens (e.g., F, Cl, Br); more preferably, R f1 R f2 Selected from hydrogen, R f3 R f4 Selected from F, Cl, and Br.

[0019] In some implementation schemes, R f1 R f2 Selected from hydrogen, R f3 R f4 Selected from F.

[0020] In some implementations, L1 is a bond, -O-methylene-, -NR l -methylene- or ethylene, wherein the methylene or ethylene is optionally substituted with one, two, or three substituents selected from deuterium, halogen, methyl, and methoxy, R l Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl; preferably, L1 is a bond, -O-methylene-, -NR l -methylene, R l Selected from H, methyl.

[0021] In some embodiments, L1 is -O-methylene-, wherein the methylene group is optionally substituted with a substituent selected from methyl.

[0022] In some implementation schemes, R h Selected from hydrogen, deuterium, amino, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl, 5-12 heteroaryl, said C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl groups and 5-12 heteroaryl groups may be optionally substituted with 1, 2, or 3 or fewer substituents: deuterium, halogen, amino, hydroxyl, -NR. h1 R h2 Oxide group, cyano group, C group optionally substituted with halogen 1-3 Alkyl, optionally C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl, optionally C 1-3Alkyl or halogen-substituted 5-6 membered heterocyclic groups, optionally C 1-3 Alkyl or halogen-substituted phenyl, optionally C 1-3 5-6 alkyl- or halogen-substituted heteroaryl groups, R h1 R h2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl; Preferred, R h Selected from hydrogen, deuterium, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 5-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 5-membered bicyclic heterocyclic group, 6-membered anodic 6-membered bicyclic heterocyclic group, phenyl, naphthyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered anodic 6-membered bicyclic heteroaryl, 6-membered anodic 5-membered bicyclic heteroaryl, 6-membered anodic 6-membered bicyclic heteroaryl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 5-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 5-membered bicyclic heterocyclic group, 6-membered anodic 6 ...5-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 5-membered bicyclic heterocyclic group, 6-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 6-membered bicyclic heterocyclic group, 5-membered anodic 6-membered bicyclic heterocyclic group Cyclic heterocyclic groups, phenyl, naphthyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 6-membered 5-membered bicyclic heteroaryl, 6-membered 6-membered bicyclic heteroaryl, optionally substituted with 1, 2 or 3 or fewer substituents: deuterium, halogen, amino, hydroxyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)2, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl optionally substituted with methyl or halogen, 5-6-membered heterocyclic groups optionally substituted with methyl or halogen; More preferably, R h Selected from hydrogen, deuterium, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 6-membered monocyclic heterocyclic alkyl, 5-membered pheno-6-membered bicyclic heterocyclic alkyl, 6-membered pheno-5-membered bicyclic heterocyclic alkyl, 6-membered pheno-6-membered bicyclic heterocyclic alkyl, phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered pheno-6-membered bicyclic heteroaryl, 6-membered pheno-5-membered bicyclic heteroaryl, 6-membered pheno-6-membered bicyclic heteroaryl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 6-membered monocyclic heterocyclic alkyl, 5-membered pheno-6-membered bicyclic heterocyclic alkyl, 6-membered pheno-5-membered bicyclic heterocyclic alkyl, 6-membered pheno-5-membered bicyclic heterocyclic alkyl Cycloyl, 6-membered anodic-6-membered bicyclic heterocyclic, phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered anodic-6-membered bicyclic heteroaryl, 6-membered anodic-5-membered bicyclic heteroaryl, 6-membered anodic-6-membered bicyclic heteroaryl optionally substituted with 1, 2 or 3 or less substituents: deuterium, halogen, hydroxyl, amino, -NHCH3, -N(CH3)2, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, 6-membered heterocyclic alkyl optionally substituted with methyl or halogen; Even better, R h Selected from hydrogen, methyl, ethyl, cyclopropyl, pyridyl, phenyl, pyrazolyl, piperidinyl, pyrimidinyl, , , , , , , The methyl, ethyl, cyclopropyl, pyridyl, phenyl, pyrazolyl, piperidyl, pyrimidinyl, and other compounds are mentioned. , , , , , , It may be optionally substituted with 1, 2 or 3 or fewer substituents: deuterium, F, Cl, Br, hydroxyl, -N(CH3)2, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, piperazine group optionally substituted with methyl or halogen, morpholino group optionally substituted with methyl or halogen; Even better, R h Selected from hydrogen, methyl, hydroxymethyl, cyclopropyl, phenyl, piperidinyl, , , , , , , , , , , , , , , , , , , , , .

[0023] In some implementation schemes, R h Selected from 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 membered heteroaryl, said 5-12 membered heterocyclic group, C 6-10 Aryl groups and 5-12 heteroaryl groups may be optionally substituted with 1-6 or fewer substituents: deuterium, halogen, nitro, amino, hydroxyl, -NR. h1 R h2 Oxide group, thio group, carboxyl group, cyano group, C group optionally substituted with halogen 1-6 Alkyl groups, C groups optionally substituted with halogens 1-6Alkoxy, optional C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl; Preferred, R h Selected from benzo6-membered heterocyclic groups, 5-membered monocyclic heteroaryl groups, 6-membered monocyclic heteroaryl groups, and 6-5-membered bicyclic heteroaryl groups, wherein the benzo6-membered heterocyclic group, 5-membered monocyclic heteroaryl group, 6-membered monocyclic heteroaryl group, and 6-5-membered bicyclic heteroaryl group are optionally substituted with 1 to 4 or fewer substituents: deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, and C groups optionally substituted with halogens. 1-6 Alkyl groups, C groups optionally substituted with halogens 1-6 Alkoxy, optional C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl; More preferably, R h Selected from , , , , , , , And optionally substituted by 1 to 3 or fewer substituents: deuterium, F, Cl, Br, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl; More preferably, R h Selected from , , , , , , , , , , , , .

[0024] In some implementations, X is O.

[0025] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0026] The compounds described in this invention are selected from:

[0027] or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compound.

[0028] The compounds described in this invention are selected from:

[0029] or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compound.

[0030] The present invention also aims to provide a method for preparing compounds represented by the above general formula, stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts of the compounds. The compound of the general formula can be prepared by a variety of methods, including but not limited to the following:

[0031] U = -OH, -NH, -CHO, halogen, and other substituents as described above. Method a is methyl esterification under acidic conditions; method b is a substitution reaction, reductive amination, or metal-catalyzed coupling reaction in the presence of a base; method c is an ester hydrolysis reaction under basic conditions; and method d is an amide condensation reaction under dehydrating or condensing agent conditions.

[0032] The present invention also provides a pharmaceutical composition comprising the compound described herein, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound. Further, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0033] The object of this invention also includes the use of the compounds shown in this invention, stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts of the compounds, in the preparation of medicaments for treating and / or preventing NaV1.8-mediated diseases. Preferably, NaV1.8-mediated diseases are selected from acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epilepsy syndrome, neurodegenerative diseases, mental illnesses, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neurodegenerative diseases, endocrine disorders, ataxia, central nervous system pain associated with multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, and other related conditions. Radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain (including chronic cancer pain and breakthrough cancer pain), stroke (e.g., post-stroke central nervous system pain), cervical sprain-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, polymyalgia rheumatica, pyoderma gangrenosum, chronic generalized pain, diffuse idiopathic hypertrophic bone, intervertebral disc degeneration / Highlighting pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, intervertebral discitis, transverse myelitis, Ellison-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced stomatitis, Charcot's neuropathic osteoarthropathy, temporomandibular joint disorder, joint replacement surgery pain, non-cardiac chest pain, genital pain, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

[0034] The object of this invention also includes providing the use of the compounds shown in this invention, stereoisomers, tautomers, or mixtures thereof, or pharmaceutically acceptable salts of the compounds, as pharmaceuticals. The pharmaceuticals are used to treat and / or prevent the following conditions: acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epilepsy syndrome, neurodegenerative diseases, mental illness, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neurodegenerative diseases, endocrine disorders, ataxia, central nervous system pain associated with multiple sclerosis and irritable bowel syndrome, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, and other related conditions. Radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain (including chronic cancer pain and breakthrough cancer pain), stroke (e.g., post-stroke central nervous system pain), cervical sprain-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, polymyalgia rheumatica, pyoderma gangrenosum, chronic generalized pain, diffuse idiopathic hypertrophic bone, intervertebral disc degeneration / Highlighting pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, intervertebral discitis, transverse myelitis, Ellison-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced stomatitis, Charcot's neuropathic osteoarthropathy, temporomandibular joint disorder, joint replacement surgery pain, non-cardiac chest pain, genital pain, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

[0035] definition

[0036] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6"Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0037] The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group, as defined above, has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) carbon atoms. The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms, more preferably an alkylene group having 1 to 6 carbon atoms. Non-limiting examples include: -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, etc. The alkylene group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of deuterium, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0038] Unless otherwise specified, the term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl. For example, a cycloalkyl group may contain 3 to 16 carbon atoms (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4). Even further, for example, a cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms (such as 3 to 10, further such as 3 to 8, 3 to 6). Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include those having 5 to 12, more such as 7 to 12 or 5 to 10 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, or arranged in a bridging bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include rings arranged in a bicyclic arrangement selected from the [5,6] and [6,6] ring systems.

[0039] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure containing 3-20 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0040] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated "heterocyclic group" as defined above.

[0041] Unless otherwise specified, "alkoxy" refers to -O-alkyl, and the alkyl group is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0042] Unless otherwise specified, the term "alkoxy" refers to the form in which the oxygen in "alkoxy" is replaced by sulfur.

[0043] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0044] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyreneyl.

[0045] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrroloyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzoimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, and pyrazolo[1,5-a]. Pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, etc.

[0046] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0047] The compounds of this invention also include their "isotope derivatives." Unless otherwise specified, the term "isotope derivative" refers to compounds of this invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive isotopes. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0048] The compounds of this invention also include their solvates. Unless otherwise specified, the terms "solvate" or "solvent" refer to the physical association of the compound of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" encompasses both solution phases and separable solvates. Solventization methods are well known in the art.

[0049] Unless otherwise specified, the compounds of this invention also include their “prodrugs.” The term “prodrug” refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited thereto, can be any compound of this invention administered as an ester (“prodrug”) to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, i.e., the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0050] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0051] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0052] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably by one, two, or three substituents, wherein the substituents are preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C 6-14 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic group, C 6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 One or more substituents in the alkoxy group are substituted, wherein the oxo group refers to two H at the same substitution position being replaced by the same O to form a double bond.

[0053] The beneficial effects of this invention are as follows: This invention designs a class of novel compounds, providing a new direction for the development of NaV1.8 inhibitors. In vitro experiments show that the compounds of this application have a significant inhibitory effect on NaV1.8 activity and can be used to treat pain-related diseases. In vivo pharmacokinetic experiments show that the compounds of this application have good pharmacokinetic properties. Detailed Implementation

[0054] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0055] The structures of the compounds in this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR measurements were performed using a Bruker AVANCE III 600 MHz instrument; the LC-MS measurements were performed using an LCMS WATERS ACQUITY UPLC H-Class PLUS and / or SQD2 instrument; and the HPLC measurements were performed using a WATERS e2695_2998 and / or an Agilent 1100 instrument.

[0056] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0057] The abbreviations used in this application are: DCM: Dichloromethane; DMF: N,N-dimethylformamide; DMSO: Dimethyl sulfoxide; PE: Petroleum ether; EA: Ethyl acetate; MeOH: Methanol; THF: Tetrahydrofuran; Example 1: Synthesis of intermediate compound A

[0058] Add starting material A-1 (100.0 mg), 1 drop of DMF, and 3 mL of DCM to a reaction flask and dissolve. Cool to 0 °C in an ice bath, then slowly add oxalyl chloride (55.9 mg). React at 25 °C for 1 h. Concentrate the reaction solution to dryness under reduced pressure to obtain the product (100 mg), which can be used directly in subsequent reactions. ESI-MS (m / z): 355.09 [M-Cl+MeOH+H] +

[0059] Example 2: Synthesis of intermediate compound B

[0060] Intermediate B-1 (800 mg, obtained by the method in Example 1 of WO2022256660A1) was added to dichloromethane (15 mL) and incubated on ice until 0°C. o After step C, boron tribromide (2.11 g) was added and the reaction mixture was stirred for 8 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (dichloromethane:methanol = 50:1, v / v) to give intermediate compound B (500 mg). ESI-MS (m / z): 460.12 [M+H] + .

[0061] Example 3: Synthesis of intermediate compound C

[0062] 3-(4-pyridyl)-2-propyn-1-ol (100.0 mg) and DCM (3 mL) were added to a reaction flask and dissolved. The mixture was cooled to 0 °C in an ice bath, and PBr3 (406.0 mg) was slowly added. After the addition was complete, the reaction was carried out at 25 °C for 2 h. Saturated NaHCO3 solution and dichloromethane were added, the mixture was stirred, and the layers were separated. The resulting organic phase was washed once with water and once with saturated brine. The organic phase was concentrated under reduced pressure to 2 mL to obtain the target product (97.6 mg). ESI-MS (m / z): 196.1 [M+H] + .

[0063] Example 4: Synthesis of intermediate compound D

[0064] (1) Preparation of intermediate D1

[0065] 4-Iodo-1-methyl-1H-pyrazole (1 g), tert-butyldimethyl(2-propynoxy)silane (818 mg), bis(triphenylphosphine)palladium dichloride (168 mg), cuprous iodide (91.5 mg), and triethylamine (971 mg) were added to N,N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), and concentrated under reduced pressure to obtain crude intermediate D1 (1.6 g).

[0066] (2) Preparation of intermediate D2

[0067] 1.6 g of crude intermediate D1 and 10 mL of 1 M tetrabutylammonium fluoride tetrahydrofuran solution were added to 20 mL of tetrahydrofuran, and the mixture was stirred at room temperature for 2 h. Water (80 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 2:1, v / v) to give intermediate D2 (500 mg). ESI-MS (m / z): 137.1 [M+H] + .

[0068] (3) Preparation of intermediate compound D

[0069] Intermediate D2 (150 mg), triphenylphosphine (347 mg), and N-bromosuccinimide (235 mg) were added to dichloromethane (5 mL) and reacted with the mixture at room temperature for 1 h. Water (50 mL) was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (100 mL × 2), concentrated under reduced pressure, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1, v / v) to give intermediate D (100 mg). ESI-MS (m / z): 199.0 [M+H] + .

[0070] Example 5: Preparation of intermediate compound E

[0071] The synthesis method was the same as in Example 4 for intermediate preparation, except that the starting material 4-iodo-1-methyl-1H-pyrazole was replaced with 8-bromoisoquinoline, yielding the target product E (205 mg). ESI-MS (m / z): 246.0 [M+H] + .

[0072] Example 1: Preparation of Compound 1

[0073] Intermediate B (260 mg), potassium carbonate (180 mg), and bromopropyne (101 mg) were added to acetonitrile (50 mL) and heated to 60°C. o The reaction mixture was stirred at C for 4 h. The reaction solution was cooled to room temperature, water (60 mL) was added, and the mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL × 2), concentrated under reduced pressure, and the mixture was purified by preparative thin-layer chromatography (dichloromethane:methanol = 20:1, v / v) to give compound 1 (180 mg), ESI-MS (m / z): 498.1 [M+H] + . 1 H NMR (600 MHz, DMSO- d6 ) δ 10.71 (s, 1H), 8.49 (d, J = 5.5Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 1.6 Hz, 1H), 7.86–7.83 (m,1H), 7.63 (d, J = 1.5 Hz, 1H), 7.27–7.16 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 4.99–4.88 (m, 2H), 4.34 (dd, J = 10.3, 7.6 Hz, 1H), 3.65 (t, J = 2.3 Hz, 1H),2.88–2.80 (m, 1H), 1.63 (s, 3H), 0.75 (d, J = 6.6 Hz, 3H).

[0074] Examples 2-10: Compounds were prepared according to the preparation method of Example 1 to obtain the following examples.

[0075] Example 11: Preparation of Compound 11

[0076] Step 1: Preparation of Intermediate 11-1: Add starting material A-1 (100.0 mg), concentrated sulfuric acid (0.15 mL), and MeOH (3 mL) to a reaction flask, and react at 60 °C for 1 h. After cooling to room temperature, concentrate under reduced pressure, add water and ethyl acetate, separate the layers, and wash the organic phase once with water and once with saturated brine. Concentrate the organic phase to dryness under reduced pressure to obtain the product (100 mg). ESI-MS (m / z): 355.09 [M+H] +

[0077] Step 2: Preparation of Intermediate 11-2: Intermediate 11-1 (100.0 mg), (3-bromo-1-propyn-1-yl)cyclopropane (50.0 mg), potassium carbonate (78.2 mg), and MeCN (3 mL) were added to a reaction flask and reacted at 40 °C for 12 h. After cooling to room temperature, water and ethyl acetate were added, and the mixture was separated. The organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (EA:PE = 1:10) to obtain the product (100 mg). ESI-MS (m / z): 433.38 [M+H] + .

[0078] Step 3: Preparation of Intermediate 11-3: Intermediate 11-2 (100.0 mg), LiOH (16.6 mg), THF (2 mL), H₂O (1 mL), and MeOH (1 mL) were added to a reaction flask and reacted at 25 °C for 1 h. The reaction solution was concentrated under reduced pressure, and 2 N HCl was added to adjust the pH to >7. Water and ethyl acetate were added, and the mixture was separated. The organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure to obtain the product (80 mg). ESI-MS (m / z): 419.35 [M+H] + .

[0079] Step 4: Preparation of Compound 11: Intermediate 11-3 (30.0 mg), 3-aminobenzamide (11.7 mg), T3P (34.4 mg), Et3N (14.5 mg), and DMF (2 mL) were added to a reaction flask and reacted at 25 °C for 12 h. The reaction solution was then added to water and ethyl acetate, and the mixture was separated. The organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: MeOH = 20:1) to obtain the product (5 mg). ESI-MS (m / z): 537.49 [M+H] + . 1 H NMR (600 MHz, DMSO-) d6) δ 10.33 (s, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.76 (d, J =7.2 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.27 – 7.15 (m,2H), 5.09 (d, J = 10.2 Hz, 1H), 4.91 – 4.82 (m, 2H), 4.35 – 4.28 (m, 1H), 2.86 – 2.83 (m, 1H), 1.62 (s, 3H), 1.23 (s, 1H), 0.79 – 0.63 (m, 5H), 0.50(s, 2H).

[0080] Example 12: Preparation of Compound 12

[0081] Step 1: Preparation of Intermediate 12-1: Intermediate A (50.0 mg), 5-amino-2-fluorobenzenesulfonamide (31.7 mg), DIEA (36.0 mg), and DCM (2 mL) were added to a reaction flask and reacted at 25 °C for 1 h. Water and dichloromethane were added, the mixture was stirred, and the layers were separated. The resulting organic phases were washed once with water and once with saturated brine. The organic phases were concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 10:1) to obtain the product (50 mg). ESI-MS (m / z): 513.42 [M+H] + .

[0082] Step 2: Preparation of Compound 12: Intermediate 12-1 (50.0 mg), (3-bromo-1-propyn-1-yl)cyclopropane (18.5 mg), potassium carbonate (27.1 mg), and acetonitrile (3 mL) were added to a reaction flask, and the reaction was carried out at 40 °C for 12 h. After cooling to room temperature, the solid was filtered off, and water and dichloromethane were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: MeOH = 10 : 1) to give the product (3 mg). ESI-MS (m / z): 591.53 [M+H] + .

[0083] Examples 13 and 14, following the preparation method of Example 12, yielded the compounds described in the following examples.

[0084] Example 15: Preparation of Compound 15

[0085] Step 1: Preparation of Intermediate 15-1: In a reaction flask, add starting material A-1 (50.0 mg), amino-2-fluorobenzamide (22.6 mg), T3P (70.3 mg), Et3N (94.1 mg), and DMF (2 mL). React at 25 °C for 2 h. Add water and ethyl acetate, separate the layers, and wash the organic phase once with water and once with saturated brine. Concentrate the organic phase to dryness under reduced pressure. Purify the concentrate by column chromatography (DCM:MeOH = 20:1) to obtain the product (30 mg). ESI-MS (m / z): 477.37 [M+H] + .

[0086] Step 2: Preparation of Compound 15: Intermediate 15-1 (30.0 mg), (3-bromo-1-propyn-1-yl)cyclopropane (14.9 mg), potassium carbonate (26.1 mg), and acetonitrile (3 mL) were added to a reaction flask, and the mixture was reacted at 40 °C for 12 h. After cooling to room temperature, the solid was filtered off, and water and ethyl acetate were added. The mixture was separated into liquid and liquid phases, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 20:1) to give the product (20 mg). ESI-MS (m / z): 555.48 [M+H] + . 1 H NMR (600 MHz, DMSO- d6 ) δ 10.35 (s, 1H), 7.95 – 7.89 (m, 1H), 7.80 –7.71 (m, 1H), 7.65 (s, 2H), 7.25 – 7.15 (m, 3H), 5.07 (d, J = 10.8 Hz, 1H),4.94 – 4.81 (m, 2H), 4.32 – 4.27 (m, 1H), 2.87 – 2.80 (m, 1H), 1.62 (s, 3H),1.35 – 1.25 (m, 1H), 0.75 – 0.68 (m, 5H), 0.58 – 0.44 (m, 2H).

[0087] Example 16: Preparation of Compound 16

[0088] Step 1: Preparation of Intermediate 16-1: 50.0 mg of tert-butyl 4-(3-hydroxyprop-1-yn-1-yl)piperidin-1-carboxylate, 65.8 mg of triphenylphosphine, 1 mL of CCl4, and 1 mL of DCM were added to a reaction flask, and the mixture was reacted at 60 °C for 4 h. After cooling to room temperature, the mixture was concentrated to dryness under reduced pressure. The concentrate was purified by column chromatography (EA:PE = 1:10) to obtain the product (50 mg). ESI-MS (m / z): 258.48 [M+H] + .

[0089] Step 2: Preparation of Intermediate 16-2: Intermediate B (50.0 mg), Intermediate 16-1 (33.7 mg), potassium carbonate (30.13 mg), and acetonitrile (3 mL) were added to a reaction flask and reacted at 80 °C for 12 h. After cooling to room temperature, the solid was filtered off, and water and dichloromethane were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM: MeOH = 20:1) to obtain the product (50 mg). ESI-MS (m / z): 681.53 [M+H] + .

[0090] Step 3: Preparation of Compound 16: Intermediate 16-2 (64.0 mg), DCM (2 mL), and dioxane hydrochloride (2 mL) were added to a reaction flask and reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and DCM and saturated NaHCO3 solution were added. The mixture was separated, and the organic phase was washed once with water and once with saturated brine. The organic phase was concentrated to dryness under reduced pressure, and the concentrate was purified by column chromatography (DCM:MeOH = 6:1) to obtain the product (20 mg). ESI-MS (m / z): 581.35 [M+H] + . 1 H NMR (600 MHz, DMSO- d6 ) δ 10.98 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 7.82 (d, J = 3.6 Hz, 1H), 7.64 (s, 1H), 7.25 – 7.21 (m, 2H), 5.20 (d, J=10.2 Hz, 1H), 4.99 – 4.90 (m, 2H), 4.40 – 4.29 (m, 1H), 3.06 – 3.00 (m, 2H), 2.85 – 2.80 (m, 3H), 2.69 (s, 1H), 1.85 (d, J = 11.4 Hz, 1H), 1.78 (d, J =11.4 Hz, 1H), 1.61 (s, 3H), 1.59 – 1.48 (m, 2H), 0.72 (d, J = 5.4 Hz, 3H).

[0091] The compounds of the following examples were prepared according to the preparation methods described in Examples 1-16.

[0092] Examples 19, 21-42: The following compounds were obtained by referring to the preparation methods of Examples 1-16.

[0093] Experimental Example 1: In vitro activity test

[0094] HEK293 cell lines (stable expression of hNav1.8 / β3 channels) were cultured in specific media and maintained at appropriate confluence. In the experiments, cells were seeded on coverslips and whole-cell patch-clamp recordings were performed. Yangshen compounds were serially diluted and tested at concentrations of 1, 0.2, 0.04, 0.008, and 0.0016 μM. Initial screening of test compounds was performed at serial concentrations of 1, 0.2 nM or 5, 0.2 nM. All samples were dissolved in DMSO, and the final DMSO concentration after stock dilution was 0.1%. During testing, the cell holding potential was set to -80 mV for 200 ms; current was recorded at a frequency of 20 kHz with a filter frequency of 10 kHz. Leakage current was measured at -80 mV. hNav1.8 current was excited every 10 seconds by applying a -10 mV voltage pulse for 20 ms starting from the -80 mV holding potential. The magnitude of the maximum peak current was used to determine the hNav1.8 current amplitude. The current was recorded for 120 seconds to assess current stability. Only stable cells meeting specific criteria were used for compound perfusion experiments. Using a liquid perfusion system, cells were sequentially perfused with a series of test buffers containing the test substance, and the hNav1.8 current was recorded at different doses from low to high. Peak currents were extracted from the raw data, and the percentage of hNav1.8 current inhibition was calculated.

[0095] Table 1. In vitro inhibition test of NaV1.8 activity

[0096] Comparative compound 1 is a yang-ginseng compound, selected from compound I in patent WO2022256660A1.

[0097] Experimental Example 2: Mouse PK Test

[0098] Mice (Beijing Vitonda Biotechnology Co., Ltd.), approximately 4 weeks old, weighing 25-30g, male. Pharmacokinetic study: ICR mice were fasted overnight and then administered the compound intravenously at 2 mg / kg or by gavage at 10 mg / kg, with 3 mice in each group. At different time points after administration (0.083 h (intravenous only), 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h), approximately 0.1 mL of blood was collected from the mouse orbital sinus and placed in EDTA anticoagulant tubes. Plasma samples were obtained by centrifugation at 3000 g for 10 min within 2 h. Methanol protein precipitation was used, and the drug concentration in mouse plasma after administration was determined by HPLC-MS / MS. Drug-time curves were plotted, and pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compound in rats after administration was described by statistical moment parameters of a non-compartmental model.

[0099] Table 2

[0100] The results showed that the compounds of the present invention have good pharmacokinetic properties, such as good oral bioavailability and oral exposure, and good drug-likeness. Exemplary compounds are shown in Table 2.

[0101] Experiment Example 3: Monkey PK Experiment

[0102] Pharmacokinetic Study in Cynomolgus Monkeys: After fasting overnight, cynomolgus monkeys were administered the compound by gavage at a dose of 10 mg / kg. Two monkeys (half male and half female) were administered the compound at different time points after administration: 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h. Approximately 0.5 mL of blood was collected from the forelimb vein and placed in EDTA-K2 anticoagulant tubes. The tubes were gently shaken to mix and immediately placed in an ice-water bath. Plasma samples were obtained by centrifugation at 3000 g for 10 min at 4°C within 30 min. Methanol protein precipitation was used, and the drug concentration in the plasma of the cynomolgus monkeys after administration was determined by HPLC-MS / MS. Drug-time curves were plotted, and pharmacokinetic parameters were calculated. The pharmacokinetic behavior of the compound in cynomolgus monkeys after administration was described by statistical moment parameters of a non-compartmental model.

[0103] The results showed that the example compounds had good oral bioavailability and oral exposure, and good drug-like properties.

Claims

1. A compound of formula (A), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound: （A） R a and R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. R c and R d Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. " " indicates a single or double bond, Z" 1 -Z 5 The ring it belongs to is an aromatic ring; Z 1 Selected from N, CR Z1 Or C=O; Z 2 Selected from N, CR Z2 Or C=O; Z 3 Selected from N, CR Z3 Or C=O; Z 4 Selected from N, CR Z4 Or C=O; Z 5 Selected from N, CR Z5 Or C=O; R Z1 R Z2 R Z3 R Z4 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 The substituents of the alkylthio group are replaced; R e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 3-6 cycloalkyl; R g Selected from H, C 1-6 Alkyl or C 3-6 cycloalkyl; R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. L1 is a bond, -OC 1-2 Alkylene-, -NR l - C 1-2 alkylene- or -C 1-3 Alkylene, wherein the alkylene group is optionally composed of one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups; R l Selected from H, C 1-6 Alkyl or C 3-6 cycloalkyl; R h Selected from hydrogen, deuterium, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl, 5-12 heteroaryl, said C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl groups and 5-12 heteroaryl groups may be optionally substituted with 1-6 or fewer substituents: deuterium, halogen, nitro, amino, hydroxyl, -NR. h1 R h2 Oxide group, thio group, carboxyl group, cyano group, C group optionally substituted with halogen 1-6 Alkyl groups, C groups optionally substituted with halogens 1-6 Alkoxy, optional C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl, optionally C 1-3 Alkyl or halogen-substituted 5-6 membered heterocyclic groups, optionally C 1-3 Alkyl or halogen-substituted phenyl, optionally C 1-3 5-6 membered heteroaryl groups substituted with alkyl or halogen; R h1 R h2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl; X is either O or S; Unless otherwise stated, the heteroatoms in the above heterocyclic or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

2. A compound of formula (I), a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound: R a and R b Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. R c and R d Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. " " indicates a single or double bond, Z" 1 -Z 5 The ring it belongs to is an aromatic ring; Z 1 Selected from N, CR Z1 Or C=O; Z 2 Selected from N, CR Z2 Or C=O; Z 3 Selected from N, CR Z3 Or C=O; Z 4 Selected from N, CR Z4 Or C=O; Z 5 Selected from N, CR Z5 Or C=O; R Z1 R Z2 R Z3 R Z4 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, oxo, thio, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 cycloalkyl, 5-6 membered heterocyclic, C 6-10 Aryl, 5-6 quinone heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-6 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 The substituents of the alkylthio group are replaced; R e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-6 Alkyl, C 3-6 cycloalkyl; R g Selected from H, C 1-6 Alkyl or C 3-6 cycloalkyl; R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, the C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 The cycloalkyl group may be optionally replaced by one, two or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl or cyano. L1 is a bond, -OC 1-2 Alkylene-, -NR l - C 1-2 alkylene- or -C 1-3 Alkylene, wherein the alkylene group is optionally composed of one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, cyano, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups; R l Selected from H, C 1-6 Alkyl or C 3-6 cycloalkyl; R h Selected from hydrogen, deuterium, amino, cyano, nitro, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl, 5-12 heteroaryl, said C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl groups and 5-12 heteroaryl groups may be optionally substituted with 1-6 or fewer substituents: deuterium, halogen, nitro, amino, hydroxyl, -NR. h1 R h2 Oxide group, thio group, carboxyl group, cyano group, C group optionally substituted with halogen 1-6 Alkyl, optionally C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl, optionally C 1-3 Alkyl or halogen-substituted 5-6 membered heterocyclic groups, optionally C 1-3 Alkyl or halogen-substituted phenyl, optionally C 1-3 5-6 membered heteroaryl groups substituted with alkyl or halogen; R h1 R h2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl; X is either O or S; Unless otherwise stated, the heteroatoms in the above heterocyclic or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4.

3. The compound of claim 1 or 2, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R a and R b Each group is independently selected from hydrogen, deuterium, F, Cl, Br, amino, hydroxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from deuterium, F, Cl, Br, amino, hydroxyl, and cyano; preferably, R a and R b Each of the following groups is independently selected from hydrogen, deuterium, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from F, Cl, and Br; more preferably, R a and R b Each group is independently selected from methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from F, Cl, and Br; more preferably, R a and R b Each is independently selected from methyl groups optionally substituted with 1, 2, or 3 F, Cl, or Br; more preferably, R a Selected from methyl, R b Selected from trifluoromethyl.

4. The compound according to any one of claims 1-3, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R c and R d Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, and cyano groups; preferably, R c and R d Each of the following groups is independently selected from hydrogen, deuterium, F, Cl, Br, methyl, ethyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, methoxy, ethoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from F, Cl, and Br; more preferably, R c and R d Each is independently selected from hydrogen, deuterium, methyl, methoxy, and cyclopropyl, wherein the methyl, methoxy, and cyclopropyl groups are optionally substituted by one, two, or three substituents selected from F, Cl, and Br; more preferably, R c and R d Each is independently selected from hydrogen, deuterium, and methyl; more preferably, R c Selected from methyl, R d Selected from hydrogen.

5. The compound according to any one of claims 1-4, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, Z 1 Selected from N, CR Z1 Z 2 Selected from N, CR Z2 Z 3 Selected from N, CR Z3 Z 4 Selected from N, CR Z4 Z 5 Selected from N, CR Z5 Preferred, Z 1 -Z 5 Of these, 0-2 are selected from N; more preferably, Z 1 -Z 5 The 0 or 1 in the selection is chosen from N; more preferably, Z 3 Selected from N or CR Z3 Z 1 Selected from CR Z1 Z 2 Selected from CR Z2 Z 4 Selected from CR Z4 Z 5 Selected from CR Z5 .

6. The compound according to any one of claims 1-5, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R Z1 R Z2 R Z3 R Z4 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, -S(O)-C 1-4 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, -S(O)-C 1-4 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 The substituents of the alkylthio group are replaced by R. e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 3-6 cycloalkyl; Preferred, R Z1 R Z2 R Z3 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, and C. 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, R Z4 Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, -S(O)-C 1-4 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, -S(O)-C 1-4 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-4 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally surrounded by one, two, or three groups selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl thiols, halogenated C 1-4 Alkyl, Halogenated C 1-4 Alkoxy, halogenated C 1-4 The substituents of the alkylthio group are replaced by R. e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-4 Alkyl, C 3-6 cycloalkyl; More preferably, R Z1 R Z2 R Z3 R Z5 Each group is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, R Z4 Selected from -S(O)-C 1-3 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-C 3-6 cycloalkyl, -NR e1 R e2 -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 The methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, cyclopropyl, -S(O)-C 1-3 Alkyl, -S(O)-C 3-6 cycloalkyl, -S(O)2-C 1-3 Alkyl, -S(O)2-C 3-6 The cycloalkyl group is optionally substituted by one, two, or three substituents selected from deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, optionally halogen-substituted methyl, optionally halogen-substituted ethyl, optionally halogen-substituted methoxy, optionally halogen-substituted ethoxy, R e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, halogen, cyano, and C. 1-3 Alkyl, C 3-6 cycloalkyl; Even better, R Z1 R Z2 R Z3 R Z5 Each of the following groups is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, methyl, and methoxy groups, R. Z4 Selected from -S(O)-methyl, -S(O)-ethyl, -S(O)-cyclopropyl, -S(O)2-methyl, -S(O)2-ethyl, -S(O)2-cyclopropyl, -C(O)NR e1 R e2 -S(O)NR e1 R e2 -S(O)2NR e1 R e2 -S(=NR) e3 )(O)R e4 -NR e3 C(O)R e4 R e1 R e2 R e3 R e4 Each time it appears, it is independently selected from hydrogen, deuterium, methyl, and ethyl.

7. The compound according to any one of claims 1-6, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, Z 3 Selected from N or CR Z3 Z 1 Selected from CR Z1 Z 2 Selected from CR Z2 Z 4 Selected from CR Z4 Z 5 Selected from CR Z5 R Z1 R Z2 R Z3 R Z5 Selected independently from hydrogen, deuterium, F, Cl, Br, and R Z4 Selected from -S(O)-CH3, -S(O)2-CH3, -C(O)NH2, -S(O)2NH2, -S(=NH)(O)CH3, -S(=N-CH3)(O)CH3; more preferably, Z 3 Selected from N or CR Z3 Z 1 Selected from CR Z1 Z 2 Selected from CR Z2 Z 4 Selected from CR Z4 Z 5 Selected from CR Z5 R Z1 R Z2 R Z5 Selected independently from hydrogen and deuterium, R Z3 Selected from hydrogen, deuterium, F, Cl, Br, R Z4 Selected from -S(O)2-CH3, -C(O)NH2, -S(O)2NH2, -S(=NH)(O)CH3, -S(=N-CH3)(O)CH3.

8. The compound according to any one of claims 1-7, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R g Selected from H, methyl; preferably, R g Selected from H.

9. The compound according to any one of claims 1-8, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl, C 3-6 cycloalkyl, the C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkyl, C 3-6 The cycloalkyl group may be optionally replaced by one, two, or three substituents selected from deuterium or halogens; preferably, R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, methyl, ethyl, methoxy, ethoxy; more preferably, R f1 R f2 R f3 R f4 Independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and methyl; more preferably, R f1 R f2 R f3 R f4 Independently selected from hydrogen and halogens (e.g., F, Cl, Br); further preferably, R f1 R f2 Selected from hydrogen, R f3 R f4 Selected from F, Cl, Br, or R f1 R f2 Selected from hydrogen, R f3 R f4 Selected from F.

10. The compound according to any one of claims 1-9, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, L1 is a bond, -O-methylene-, -NR l -methylene- or ethylene, wherein the methylene or ethylene is optionally substituted with one, two, or three substituents selected from deuterium, halogen, methyl, and methoxy, R l Selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl; preferably, L1 is a bond, -O-methylene-, -NR l -methylene, R l Selected from H, methyl.

11. The compound according to any one of claims 1-10, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, R h Selected from hydrogen, deuterium, amino, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl, 5-12 heteroaryl, said C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, 5-12 membered heterocyclic, C 6-10 Aryl groups and 5-12 heteroaryl groups may be optionally substituted with 1, 2, or 3 or fewer substituents: deuterium, halogen, amino, hydroxyl, -NR. h1 R h2 Oxide group, cyano group, C group optionally substituted with halogen 1-3 Alkyl, optionally C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl, optionally C 1-3 Alkyl or halogen-substituted 5-6 membered heterocyclic groups, optionally C 1-3 Alkyl or halogen-substituted phenyl, optionally C 1-3 5-6 alkyl- or halogen-substituted heteroaryl groups, R h1 R h2 Each is independently selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl; Preferred, R h Selected from hydrogen, deuterium, methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 5-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 5-membered bicyclic heterocyclic group, 6-membered anodic 6-membered bicyclic heterocyclic group, phenyl, naphthyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered anodic 6-membered bicyclic heteroaryl, 6-membered anodic 5-membered bicyclic heteroaryl, 6-membered anodic 6-membered bicyclic heteroaryl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered monocyclic heterocyclic group, 6-membered monocyclic heterocyclic group, 5-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 5-membered bicyclic heterocyclic group, 6-membered anodic 6 ...5-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 5-membered bicyclic heterocyclic group, 6-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 6-membered bicyclic heterocyclic group, 6-membered anodic 6-membered bicyclic heterocyclic group, 5-membered anodic 6-membered bicyclic heterocyclic group Cyclic heterocyclic groups, phenyl, naphthyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered 6-membered bicyclic heteroaryl, 6-membered 5-membered bicyclic heteroaryl, 6-membered 6-membered bicyclic heteroaryl, optionally substituted with 1, 2 or 3 or fewer substituents: deuterium, halogen, amino, hydroxyl, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)2, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl optionally substituted with methyl or halogen, 5-6-membered heterocyclic groups optionally substituted with methyl or halogen; More preferably, R h Selected from hydrogen, deuterium, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 6-membered monocyclic heterocyclic alkyl, 5-membered pheno-6-membered bicyclic heterocyclic alkyl, 6-membered pheno-5-membered bicyclic heterocyclic alkyl, 6-membered pheno-6-membered bicyclic heterocyclic alkyl, phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered pheno-6-membered bicyclic heteroaryl, 6-membered pheno-5-membered bicyclic heteroaryl, 6-membered pheno-6-membered bicyclic heteroaryl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 6-membered monocyclic heterocyclic alkyl, 5-membered pheno-6-membered bicyclic heterocyclic alkyl, 6-membered pheno-5-membered bicyclic heterocyclic alkyl, 6-membered pheno-5-membered bicyclic heterocyclic alkyl Cycloyl, 6-membered anodic-6-membered bicyclic heterocyclic, phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, 5-membered anodic-6-membered bicyclic heteroaryl, 6-membered anodic-5-membered bicyclic heteroaryl, 6-membered anodic-6-membered bicyclic heteroaryl optionally substituted with 1, 2 or 3 or less substituents: deuterium, halogen, hydroxyl, amino, -NHCH3, -N(CH3)2, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, 6-membered heterocyclic alkyl optionally substituted with methyl or halogen; Even better, R h Selected from hydrogen, methyl, ethyl, cyclopropyl, pyridyl, phenyl, pyrazolyl, piperidinyl, pyrimidinyl, , , , , , , The methyl, ethyl, cyclopropyl, pyridyl, phenyl, pyrazolyl, piperidyl, pyrimidinyl, and other compounds are mentioned. , , , , , , It may be optionally substituted with 1, 2 or 3 or fewer substituents: deuterium, F, Cl, Br, hydroxyl, -N(CH3)2, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, cyclopropyl, piperazine group optionally substituted with methyl or halogen, morpholino group optionally substituted with methyl or halogen; Even better, R h Selected from hydrogen, methyl, hydroxymethyl, cyclopropyl, phenyl, piperidinyl, , , , , , , , , , , , , , , , , , , , , ; Or, R h Selected from 5-12 membered heterocyclic groups, C 6-10 Aryl, 5-12 membered heteroaryl, said 5-12 membered heterocyclic group, C 6-10 Aryl groups and 5-12 heteroaryl groups may be optionally substituted with 1-6 or fewer substituents: deuterium, halogen, nitro, amino, hydroxyl, -NR. h1 R h2 Oxide group, thio group, carboxyl group, cyano group, C group optionally substituted with halogen 1-6 Alkyl groups, C groups optionally substituted with halogens 1-6 Alkoxy, optional C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl; Preferred, R h Selected from benzo6-membered heterocyclic groups, 5-membered monocyclic heteroaryl groups, 6-membered monocyclic heteroaryl groups, and 6-5-membered bicyclic heteroaryl groups, wherein the benzo6-membered heterocyclic group, 5-membered monocyclic heteroaryl group, 6-membered monocyclic heteroaryl group, and 6-5-membered bicyclic heteroaryl group are optionally substituted with 1 to 4 or fewer substituents: deuterium, halogen, nitro, amino, hydroxyl, oxo, thio, carboxyl, cyano, and C groups optionally substituted with halogens. 1-6 Alkyl groups, C groups optionally substituted with halogens 1-6 Alkoxy, optional C 1-3 alkyl or halogen-substituted C 3-6 cycloalkyl; More preferably, R h Selected from , , , , , , , And optionally substituted by 1 to 3 or fewer substituents: deuterium, F, Cl, Br, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl; More preferably, R h Selected from , , , , , , , , , , , , .

12. The compound according to any one of claims 1-11, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, wherein, X is O.

13. Compounds, selected from: Or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compound.

14. Compounds, selected from: Or its stereoisomers, tautomers or mixtures thereof, or pharmaceutically acceptable salts of the compound.

15. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a compound as shown in any one of claims 1-14, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound; further, the pharmaceutical composition also comprises a pharmaceutically acceptable excipient.

16. The use of the compound shown in any one of claims 1-14, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, or the pharmaceutical composition of claim 15, in the preparation of a medicament for treating and / or preventing NaV1.8-mediated diseases; preferably, the NaV1.8-mediated diseases are selected from acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epilepsy syndrome, neurodegenerative diseases, mental illness, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neurodegenerative diseases, endocrine disorders, ataxia, multiple sclerosis, and intestinal disorders. Irritable bowel syndrome (IBS) can cause a wide range of pain including: central nervous system pain, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain (including chronic and breakthrough cancer pain), stroke (e.g., post-stroke central nervous system pain), cervical spine sprain-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, polymyalgia rheumatica, pyoderma gangrenosum, chronic generalized pain, diffuse idiopathic hypertrophic bone, and intervertebral disc degeneration. Highlighting pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, intervertebral discitis, transverse myelitis, Ellison-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced stomatitis, Charcot's neuropathic osteoarthropathy, temporomandibular joint disorder, joint replacement surgery pain, non-cardiac chest pain, genital pain, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

17. The use of the compound shown in any one of claims 1-14, a stereoisomer, tautomer, or mixture thereof, or a pharmaceutically acceptable salt of the compound, or the pharmaceutical composition of claim 15, in the preparation of a medicament for the treatment and / or prevention of the following diseases: acute pain, subacute and chronic pain, nociceptive pain, neuropathic pain, inflammatory pain, arthritis, migraine, cluster headache, trigeminal neuralgia, herpetic neuralgia, generalized neuralgia, epilepsy, epilepsy syndrome, neurodegenerative diseases, mental illness, anxiety, depression, bipolar disorder, myotonia, arrhythmia, movement disorders, neurodegenerative diseases, endocrine disorders, ataxia, multiple sclerosis, and irritable bowel syndrome. Menstrual pain, incontinence, pathological cough, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, nonspecific chronic back pain, headache, neck pain, moderate pain, severe pain, intractable pain, nociceptive pain, breakthrough pain, postoperative pain, cancer pain (including chronic cancer pain and breakthrough cancer pain), stroke (e.g., post-stroke central nervous system pain), cervical sprain-related disorders, fragility fractures, spinal fractures, ankylosing spondylitis, pemphigus, Raynaud's disease, scleroderma, systemic lupus erythematosus, epidermolysis bullosa, gout, juvenile idiopathic arthritis, polymyalgia rheumatica, pyoderma gangrene, chronic generalized pain, diffuse idiopathic hypertrophic bone, intervertebral disc degeneration / Highlighting pain, radiculopathy, facet joint syndrome, failed back surgery syndrome, burns, carpal tunnel syndrome, Paget's disease pain, spinal stenosis, intervertebral discitis, transverse myelitis, Ellison-Danlos syndrome, Fabry disease, mastocytosis, neurofibromatosis, ocular neuropathic pain, sarcoidosis, spondylolysis, spondylolisthesis, chemotherapy-induced stomatitis, Charcot's neuropathic osteoarthropathy, temporomandibular joint disorder, joint replacement surgery pain, non-cardiac chest pain, genital pain, renal colic, biliary tract disease, vascular leg ulcers, Parkinson's disease pain, Alzheimer's disease pain, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress-induced angina, exercise-induced angina, palpitations, hypertension, or gastrointestinal motility disorders.

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