Ring-fused pyridone compound as Nav1.8 inhibitor

Abstract

The invention provides a compound as shown in a formula (I), and a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof. The compound has a relatively good Nav1.8 inhibition effect;

Description

[0001] The present invention claims:

[0002] Priority to a prior application, patent application number 202410342470.X, filed on March 22, 2024, entitled “Cyclic pyridone compounds as Nav1.8 inhibitors”;

[0003] Priority to the prior application, patent application number 202410826806.X, filed on June 25, 2024, entitled “Cyclic pyridone compounds as Nav1.8 inhibitors”;

[0004] The entire contents of the above-mentioned prior applications are incorporated into the present application by reference. Technical Field

[0005] The present invention belongs to the field of medicine and relates to substituted cyclic pyridone compounds as Nav1.8 inhibitors and their uses. Specifically, the present invention relates to substituted cyclic pyridone compounds, their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions thereof as Nav1.8 inhibitors and their use in the preparation of drugs for treating, alleviating or preventing pain. Background Art

[0006] Pain is "an unpleasant sensory and emotional feeling, accompanied by actual or potential tissue damage, and it is a subjective feeling." Pain can serve as a warning signal, alerting the body to potential dangers, and plays an indispensable protective role in the body's normal life activities. At the same time, pain is also a common clinical symptom. After the external stimulus that causes pain disappears, intense or persistent pain can cause physiological dysfunction and seriously affect the quality of life of the living organism. According to statistics, about one-fifth of the world's people suffer from moderate to severe chronic pain. In 2018, the global analgesic market was approximately US$36 billion and is expected to reach US$56 billion in 2023. Among them, acute, moderate and severe pain will grow steadily at a compound annual growth rate of 2.5% in the future, and the chronic pain market will grow at a compound annual growth rate of about 18%. Chronic pain is the main driving force for the continued growth of the global pain market in the next decade.

[0007] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings that are widely distributed throughout the skin, muscles, joints, and visceral tissues of the body. They can convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) and transmit them via afferent nerve fibers to their cell bodies located in the dorsal root ganglia (DRG), ultimately transmitting them to higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons, in turn, rely on voltage-gated sodium channels (NaV) on the cell membrane. When the cell membrane depolarizes, sodium channels activate and open, causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and relieve pain.

[0008] Human sodium channels are transmembrane ion channels composed of a 260kD α subunit and a 30-40kD β subunit. They are classified into nine subtypes based on the α subunits: Nav1.1 to Nav1.9. Nav1.5, Nav1.8, and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Nav1.5 is primarily found in cardiomyocytes, while Nav1.8 and Nav1.9 are found in the peripheral nervous system. Nav1.8 is a key ion channel involved in chronic pain, atrial fibrillation, and Budd-Chiari syndrome, making it a highly selective target for pain treatment.

[0009] The gene encoding Nav1.8, SCN10A, is located in the human chromosome 3p21-22 region and primarily encodes the α subunit. Studies have found that the human and rat Nav1.8 genes share up to 93% homology. Nav1.8 is primarily present in trigeminal ganglion neurons and DRG neurons, exhibiting electrophysiological characteristics of slow inactivation and rapid recovery. In Nav1.8-expressing neurons, the rise of the action potential is primarily composed of Nav1.8 currents. In models of neuropathic pain, nerve injury increases Nav1.8 expression in axons and neuronal cell bodies. Nav1.8 antisense oligonucleotides significantly alleviate pain while simultaneously reducing Nav1.8 expression. Intra-paw injection of carrageenan in rats increases Nav1.8 expression in DRG neurons. Nav1.8 knockout mice fail to exhibit normal visceral inflammatory pain. Gain-of-function mutations in the human Nav1.8 gene cause peripheral neuropathic pain. Based on a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy that can be used to treat various types of pain, including inflammatory pain, neuralgia, postoperative pain, and cancer pain.

[0010] The main disadvantage of some known Nav's inhibitors is their poor therapeutic window, which may be the result of their lack of isotype selectivity. Since Nav1.8 is mainly limited to neurons that perceive pain, selective Nav1.8 blockers are unlikely to induce adverse reactions common to non-selective Nav's blockers. Therefore, there is still a need to develop new Nav1.8 selective inhibitors in this area, preferably Nav channel inhibitors with better selectivity for Nav1.8, more effectiveness, increased metabolic stability, increased solubility and fewer side effects. Summary of the Invention

[0011] The present invention aims to propose a Nav1.8 inhibitor that can be used to prepare a drug for treating, alleviating or preventing pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0012] In the first aspect of the present invention, the present invention provides a compound represented by formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I):

[0013]

[0014] in,

[0015] X 3a N or CR 3a ;

[0016] X 4a N or CR 4a ;

[0017] X 5a N or CR 5a ;

[0018] X 6a N, N + -O - or CR 6a ;

[0019] R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0020] R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 5-12 membered heteroaryl, -NR3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 or -S(=O)(=NR 5 )R 3 ;

[0021] Ring A and Ring B are each independently selected from C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl;

[0022] L is -O-, -S- or -NH-;

[0023] R 1 Selected from H, halogen, hydroxy, cyano, oxo, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by;

[0024] Or, two adjacent R 1 Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R A replaced by;

[0025] R A Selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, =CR 3 R4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0026] R 2 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -OR 4 、-NR 3 R 4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by;

[0027] Or, two adjacent R 2 Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R B replaced by;

[0028] R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0029] R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R C replaced by;

[0030] Or, R 3 、R 4 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic group or a C 3-12 Cycloalkyl, the 3-12 membered heterocyclic group or C 3-12 The cycloalkyl group is optionally substituted with one or more R C replaced by;

[0031] R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0032] R 6 and R 6 ' are each independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R D replaced by;

[0033] R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0034] m is selected from 0, 1, 2, 3, 4, 5 and 6;

[0035] n is selected from 0, 1, 2, 3, 4, 5 and 6.

[0036] In an optional embodiment of the present invention, R 6 For H.

[0037] In an optional embodiment of the present invention, R 6 ' is H, F, Cl, methyl, trifluoromethyl, methoxy or trifluoromethoxy.

[0038] In an optional embodiment of the present invention, the group fragment for Among them, R 5a is halogen, R 6a For diazole, triazole, -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C The definition of is as described in the present invention; preferably, R 3 is H, hydroxy, methyl or methoxy.

[0039] In an optional embodiment of the present invention, the group fragment for

[0040] In an optional embodiment of the present invention, ring A is a 6-membered heterocycloalkenyl, a 6-membered heterocyclyl, a 6-membered heteroaryl, a 5-membered heteroaryl or a phenyl group; preferably, ring A is a pyridyl, a 1,2-dihydropyridyl, a phenyl or a thienyl group.

[0041] In an optional embodiment of the present invention, R 1 H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group; wherein, the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 The cycloalkyl and 3-12 membered heterocyclic groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy; R 3 and R 4 The definition of is as described in the present invention.

[0042] In an optional embodiment of the present invention, two adjacent R 1 Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R A Replaced by; R A The definition of is as described in the present invention.

[0043] In an optional embodiment of the present invention, the group fragment for where R 2b 、R 3b and R 4b are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy.

[0044] In an optional embodiment of the present invention, the group fragment for where R 2b 、R 3b and R 4b Each is independently selected from H, F, Cl, methyl, and trifluoromethyl.

[0045] In an optional embodiment of the present invention, the group fragment for

[0046] In an optional embodiment of the present invention, the group fragment for Where W is N or CR 4b , R 1b 、R 2b 、R 3b and R 4b independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, 3-12 membered heterocyclic group; the C 1-6Alkyl, C 2-6 Alkynyl and 3-12 membered heterocyclyl are each independently optionally substituted by one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy; R 3 and R 4 The definition of is as described in the present invention. In some embodiments, W is N, R 1b 、R 2b 、R 3b and R 4b Independently selected from H, C 1-3 Alkyl, C substituted by one or more halogen 1-3 Alkyl; in some embodiments, W is N, R 1b Selected from C 1-3 Alkyl, R 2b Selected from C substituted by one or more halogens 1-3 Alkyl, R 2b Selected from H.

[0047] In an optional embodiment of the present invention, the group fragment for Where W is N or CR 4b , R 1b 、R 2b 、R 3b and R 4b independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group; the C 1-6 Alkyl, C 2-6 Alkynyl, C 3-12 The cycloalkyl and 3-12 membered heterocyclic groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy; R 3 and R 4 The definition of is as described in the present invention.

[0048] In an optional embodiment of the present invention, the group fragment for Where W is N or CH, R 1b 、R 2b and R 3b Each independently selected from H, F, Cl, methyl, trifluoromethyl, tert-butyl,

[0049] In an optional embodiment of the present invention, the group fragment for Where W is N or CH, R 1b 、R 2b and R 3b Each independently selected from H, F, Cl, methyl, trifluoromethyl, tert-butyl,

[0050] In an optional embodiment of the present invention, the group fragment for In an optional embodiment of the present invention, the group fragment for

[0051] In an optional embodiment of the present invention, the group fragment for Wherein ring C is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkenyl, wherein W is N or CR 4b , R 1b and R 4b independently selected from H, halogen, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally replaced by one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, p is selected from 0, 1, 2, 3 and 4, R B The definition of is as described in the present invention.

[0052] In an optional embodiment of the present invention, the group fragment for Wherein ring C is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkenyl, wherein W is N or CR 4b , R 1b and R 4b independently selected from H, halogen, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more R AReplaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, p is selected from 0, 1, 2, 3 and 4.

[0053] In an optional embodiment of the present invention, the group fragment for

[0054] In an optional embodiment of the present invention, the group fragment for L is -O- or -NH-; R 1c 、R 2c 、R 3c 、R 4c and R 5c are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -OR 4 、-NR 3 R 4 、C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R B Replaced by; R 3 and R 4 Definitions of the present invention;

[0055] R B Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy.

[0056] In an optional embodiment of the present invention, L is -O-; R 2c 、R 3c 、R 4c 、R 5c are each independently selected from H, halogen; R 1c Selected from C 1-6 Alkyl, -OR 4 、C 3-12 Cycloalkyl or -NR 3 R 4 , where R 3 、R 4 Each independently selected from H, C 1-3 Alkyl or C3-6 Cycloalkyl.

[0057] In some embodiments, L is -O-; R 1c 、R 2c 、R 3c 、R 4c are each independently selected from H, halogen; R 5c Selected from-NR 3 R 4 , where R 3 、R 4 Each independently selected from H or C 1-3 In an optional embodiment of the present invention, R 1c 、R 2c 、R 3c 、R 4c and R 5c Each independently selected from H, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl,

[0058] In an optional embodiment of the present invention, the group fragment for where R 1c 、R 2c and R 3c are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 4 、-NR 3 R 4 、C 3-12 Cycloalkyl, R 3 and R 4 The definition of is as described in the present invention; preferably, R 2c 、R 3c are each independently selected from H, halogen; R 1c Selected from C 1-6 Alkyl, -OR 4 、C 3-12 Cycloalkyl, -NR 3 R 4 , where R 3 、R 4 Each independently selected from H, C 1-3 Alkyl or C 3-6 Cycloalkyl; preferably, R 1c 、R 2c and R 3c Each independently selected from H, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl,

[0059] In an optional embodiment of the present invention, the group fragment for where R 1c 、R 2c and R 3c are each independently selected from H, halogen, H, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 4 、-NR 3 R 4 , R 3 and R 4 The definition of is as described in the present invention; preferably, R 2c 、R 3c are each independently selected from H, halogen; R 1c Selected from-NR 3 R 4 , where R 3 、R 4 Each independently selected from H or C 1-3 Alkyl. Preferably, R 1c 、R 2c and R 3c Each independently selected from H, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl,

[0060] In an optional embodiment of the present invention, the group fragment for

[0061] In an optional embodiment of the present invention, the group fragment for

[0062] In an optional embodiment of the present invention, the group fragment for where R 1c 、R 2c and R 3c are each independently selected from H, halogen, H, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 4 、-NR 3 R 4 , R 3 and R 4 The definition of is as described in the present invention; preferably, R 1c 、R 2c and R 3c Each independently selected from H, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl,

[0063] In an optional embodiment of the present invention, the group fragment for

[0064] In an optional embodiment of the present invention, the compound represented by formula (I), its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is a compound represented by formula (IA), (IB) or (IC):

[0065]

[0066] in

[0067] W is N or CR 4b ;

[0068] R 1b 、R 2b 、R 3b and R 4b are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A replaced by;

[0069] Or, two adjacent R 1b 、R 2b 、R 3b and R 4b Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R A replaced by;

[0070] R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, =CR 3 R 4 、C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0071] R 1c 、R 2c 、R 3c 、R 4c and R 5c are each independently selected from H, halogen, C 1-6 Alkyl, C1-6 Alkoxy, -OR 4 、-NR 3 R 4 、C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R B replaced by;

[0072] Or, two adjacent R 1c 、R 2c 、R 3c 、R 4c and R 5c Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R B replaced by;

[0073] R B Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy;

[0074] X 4a 、R 5a 、R 6 '、R 3 and R 4 The definition of is as described in the present invention.

[0075] In an optional embodiment of the present invention, the compound has any one of the following structures, or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of any one of the structures:

[0076]

[0077]

[0078]

[0079] In the second aspect of the present invention, a pharmaceutical composition is provided, which comprises a therapeutically effective amount of the above-mentioned compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and a pharmaceutically acceptable pharmaceutical carrier, diluent or excipient.

[0080] In the third aspect of the present invention, the present invention proposes the use of the above-mentioned compound, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical composition in the preparation of drugs related to inhibiting voltage-gated sodium ion channels, wherein the voltage-gated sodium ion channels include Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8.

[0081] According to a specific embodiment of the present invention, the use of the above-mentioned compound or its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug or the above-mentioned pharmaceutical composition in the preparation of a drug, the drug can be used to treat, relieve or prevent pain, and the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0082] In a fourth aspect, the present invention provides a method for inhibiting voltage-gated sodium ion channels, or preventing and / or treating diseases related to voltage-gated sodium ion channels, comprising the steps of administering to a subject in need thereof the compound of formula I described in the first aspect of the present invention, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition described in the second aspect of the present invention.

[0083] The voltage-gated sodium ion channels include Nav1.1 to Nav1.9, Nav1.5, Nav1.8 and Nav1.9, preferably Nav1.8. The diseases associated with the voltage-gated sodium ion channels are pain, including acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0084] Beneficial effects:

[0085] According to the embodiments of the present invention, the present invention has at least one of the following technical effects:

[0086] Provided are Nav1.8 inhibitors with novel structure, excellent pharmacokinetic properties, and good efficacy or drugability, which can be used to effectively treat Nav1.8-related diseases and conditions.

[0087] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0088] Terms and Definitions

[0089] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0090] Those skilled in the art will understand that, according to the conventions used in the art, in the structural formula of this application, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0091] Unless otherwise specified, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0092] Unless otherwise specified, the term "pharmaceutically acceptable salts" refers to salts of pharmaceutically acceptable non-toxic acids or bases including salts of inorganic acids and bases, and organic acids and bases.

[0093] In addition to pharmaceutically acceptable salts, the present invention also contemplates other salts that may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or that may be useful in the identification, characterization, or purification of the compounds of the present invention.

[0094] Unless otherwise specified, the term "pharmaceutical composition" means a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0095] Unless otherwise specified, the term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression.

[0096] Unless otherwise specified, the term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl or amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or free amino group, respectively.

[0097] Unless otherwise specified, the term "stereoisomer" refers to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0098] Depending on the choice of raw materials and methods, the compounds of the present invention may exist in the form of one of the possible isomers or a mixture thereof, for example as pure optical isomers, or as a mixture of isomers, such as a racemic and diastereomeric mixture, depending on the number of asymmetric carbon atoms. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to the chiral center (or multiple chiral centers) in the molecule. The prefixes D and L or (+) and (–) are the symbols used to specify the rotation of plane polarized light caused by the compound, where (–) or L indicates that the compound is left-handed. Compounds prefixed with (+) or D are right-handed. With respect to a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of the isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. Many geometric isomers of alkenes, C=N double bonds, etc. can also exist in the compounds described herein, and all such stable isomers are contemplated by the present invention. When the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may be in either the cis- or trans- configuration.

[0099] When the bonds to the chiral carbon atoms in the present formulae are depicted as straight lines, it is understood that both the (R) and (S) configurations of the chiral carbon atoms and the enantiomerically pure compounds and mixtures thereof are encompassed within the scope of the formulae. The notation for racemates or enantiomerically pure compounds herein is adapted from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to represent the absolute configuration of a stereocenter.

[0100] Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. Compounds of the invention containing asymmetrically substituted carbon atoms can be separated in optically active form or racemic form. Resolution of a racemic mixture of a compound can be carried out by any of a number of methods known in the art. An exemplary method includes fractional recrystallization using a chiral resolving acid that is an optically active, salified organic acid. Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include α-methyl-benzylamine (e.g., S and R forms or diastereoisomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. The resolution of the racemic mixture can also be carried out by eluting on a chromatographic column filled with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). High performance liquid chromatography (HPLC) can also be used to carry out supercritical fluid chromatography (SFC). The selection of specific methods and elution conditions, chromatographic column selection can be selected by those skilled in the art according to the structure of the compound and test results. Further, optically pure starting materials or reagents of known configuration can also be used to obtain any enantiomer or diastereomer of the compound described in the present invention through stereoorganic synthesis.

[0101] Unless otherwise specified, the term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Prototropic tautomers arise from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0102] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter.

[0103] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0104] In embodiments of the present invention, protons can occupy two or more positions of the cyclic form of the heterocyclic ring system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, tetrazole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically fixed to one form by appropriate substitution. For example:

[0105]

[0106] Due to resonance, the hydrogen atoms of the nitrogen atoms of tetrazole can be on any of the four nitrogen atoms.

[0107] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0108] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0109] Unless otherwise specified, the terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0110] Unless otherwise specified, the term "substituted" means that any one or more (two, three or more) hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. When the substituent is limited to one or more, the plurality includes two, three or more.

[0111] Unless otherwise specified, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0112] The term "optionally substituted" means that the group may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any based on chemical feasibility.

[0113] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. For example, R 1 Be g R a When g is 2, 3 or 4, each R a Are independent options and can be the same or different.

[0114] In addition, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. In addition, when multiple rings (parallel rings, spiro rings, or bridged rings) are substituted with substituents, each hydrogen atom on the ring may be substituted.

[0115] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Examples of C1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.

[0116] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0117] The term "halo" by itself or as part of another substituent is used interchangeably with the term "halogen-substituted."

[0118] Unless otherwise specified, "haloalkyl" or "halo-substituted alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens.

[0119] Unless otherwise specified, the term "haloalkoxy" means that one or more hydrogen atoms of an alkoxy group are replaced by halogen, specifically including monohaloalkoxy, dihaloalkoxy and polyhaloalkoxy. For example, "C 1-6 "Haloalkoxy" means monohaloalkoxy and polyhaloalkoxy containing 1 to 6 carbon atoms. For example, C 1-3 Haloalkoxy includes C 1-2 、C 2-3 , C3, C2 and C1 haloalkoxy, etc. 1-3 Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, 3-bromopropoxy, and the like.

[0120] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0121] Unless otherwise specified, “C 2-3"Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0122] Unless otherwise specified, “C 2-6 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-6 Alkynyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.

[0123] Unless otherwise specified, “C 2-3 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0124] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0125] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0126] Unless otherwise specified, the term “C 3-12 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-12 Cycloalkyl groups include C 3-10 、C 3-8 、C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0127] Unless otherwise specified, the term “C 3-8 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. 3-8 Cycloalkyl groups include C 3-6 、C 3-5 、C 4-8 、C 4-6 、C 4-5 、C 5-8 or C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, and the like.

[0128] Unless otherwise specified, the term “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0129] Unless otherwise specified, the term "C6-12 Aromatic ring" and "C 6-12 Aryl" can be used interchangeably, the term "C 6-12 Aromatic ring" or "C 6-12 "Aryl" refers to a cyclic hydrocarbon group composed of 6 to 12 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein at least one ring is aromatic and the other rings are any rings, which can be cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl. It can be monovalent, divalent or polyvalent, C 6-12 Aryl groups include C 6-10 、C 6-9 、C 6-8 、C 12 、C 10 and C6 aryl, etc. 6-12 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0130] Unless otherwise specified, the term "4-12 membered heterocycloalkenyl" refers to a stable non-aromatic ring structure (monocyclic or polycyclic) containing at least one double bond, one or more heteroatoms independently selected from O, N and S and the specified number of ring atoms. The non-aromatic ring structure may have 4 to 12 ring members, and particularly 4 to 7 ring members. The fused heterocyclic ring system may contain carbocyclic rings and need only contain one heterocyclic ring.

[0131] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any one of n to n+m carbons, e.g., C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12 Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0132] Unless otherwise specified, the terms "3-12 membered heterocyclyl" and "3-12 membered heterocycloalkyl" are used interchangeably. "3-12 membered heterocyclyl" or "3-12 membered heterocycloalkyl" by themselves or in combination with other terms refer to a saturated cyclic group consisting of 3 to 12 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-12 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is attached to the rest of the molecule. For example, 3-12 membered heterocycloalkyl groups include, but are not limited to, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, 12-membered, 3-10-membered, 3-8-membered, 4-6-membered, etc. Examples of “3-12 membered heterocycloalkyl” include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0133] Unless otherwise specified, the term "4-8 membered heterocyclyl" or "4-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 4 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, annelated and bridged rings. In addition, with respect to the "6-8 membered heterocycloalkyl", heteroatoms can occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. For example, 4-8 membered heterocycloalkyl includes, but is not limited to, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 4-6-membered, etc. Examples of 4-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, and hexahydropyridazinyl.

[0134] Unless otherwise specified, the terms "5-12 membered heteroaromatic ring" and "5-12 membered heteroaryl" are used interchangeably herein, and the term "5-12 membered heteroaryl" refers to a cyclic group consisting of 5 to 12 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-12 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-12 membered heteroaryl includes 5-10 membered, 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups, etc. Examples of the 5-12 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl) 1-oxazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-1-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0135] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably herein, and the term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl), and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0136] Unless otherwise specified, the term "5,6-membered ring" refers to a 5-membered ring and a 6-membered ring.

[0137] Unless otherwise specified, the term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0138] Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other.

[0139] Unless otherwise specified, the term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0140] Unless otherwise specified, the term "therapeutically effective amount" means the amount of an active compound or drug that will elicit the biological or medical response that a researcher, veterinarian, physician, or other clinician is seeking in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) prevent disease, e.g., prevent a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who is not yet experiencing or developing the pathology or symptoms of the disease. (2) inhibit disease, e.g., inhibit the disease, disorder, or condition (i.e., prevent further development of the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. (3) alleviate disease, e.g., alleviate the disease, disorder, or condition (i.e., reverse the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition.

[0141] As used herein, the term "treatment" and other similar synonyms include the following meanings:

[0142] (i) preventing a disease or condition from occurring in a mammal, particularly where such mammal is susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition;

[0143] (ii) inhibiting the disease or condition, i.e., curbing its development;

[0144] (iii) alleviate the disease or condition, that is, cause regression of the disease or condition; or

[0145] (iv) Alleviate the symptoms of the disease or condition.

[0146] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0147] Additionally, it should be noted that, unless otherwise expressly stated, the term "independently" used in the present invention should be broadly construed to mean that the individual entities described are independent of one another and may independently represent the same or different specific groups. More specifically, the term "independently" can mean that specific options expressed by identical symbols in different groups do not affect each other, or that specific options expressed by identical symbols in the same group do not affect each other. DETAILED DESCRIPTION

[0148] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0149] Unless otherwise specified, the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and tetramethylsilane (TMS) is the internal standard.

[0150] The abbreviations of the present invention are defined as follows:

[0151] TLC: Thin layer chromatography

[0152] LC-MS: Liquid chromatography-mass spectrometry

[0153] N: equivalent concentration, for example, 2N hydrochloric acid means 2 mol / L hydrochloric acid solution

[0154] IC 50 : Half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved

[0155] Example 1: Preparation of target compound I-9

[0156] Synthesis of 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-9)

[0157]

[0158] The synthetic route of target compound I-9 is as follows:

[0159]

[0160]

[0161] Step 1: Synthesis of 2,3-difluoro-6-methoxybenzaldehyde

[0162]

[0163] Under nitrogen at -65°C, n-butyllithium (2.5 M, 90.2 mL) was slowly added dropwise to a solution of 1,2-difluoro-4-methoxybenzene (25.0 g, 173 mmol) and magnesium chloride (18.2 g, 190 mmol) in dimethyltetrahydrofuran (150 mL). The mixture was stirred at -65°C for 1 hour. After completion of the reaction, the reaction mixture was quenched with 0.1 N hydrochloric acid (300 mL) at 0°C. The mixture was extracted with ethyl acetate (200 mL), and the organic phase was dried and concentrated to yield 2,3-difluoro-6-methoxybenzaldehyde (27.0 g, 90.4% yield).

[0164] Step 2: Synthesis of 2,3-difluoro-6-methoxybenzoic acid

[0165]

[0166] To a solution of 2,3-difluoro-6-methoxybenzaldehyde (27.0 g, 157 mmol) and 2-methylbut-2-ene (44.0 g, 628 mmol) in tetrahydrofuran (250 mL) and water (100 mL) were added potassium dihydrogen phosphate (85.4 g, 627 mmol) and sodium chlorite (38.3 g, 423 mmol) at room temperature. The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (300 mL), and the organic phase was washed with 1% NaHSO3 solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2,3-difluoro-6-methoxybenzoic acid (26.1 g, crude).

[0167] Step 3: Synthesis of 2,3-difluoro-6-methoxyaniline

[0168]

[0169] To a toluene solution (300 mL) of 2,3-difluoro-6-methoxybenzoic acid (26.1 g, 138 mmol), tert-butyl alcohol (30.7 g, 414 mmol), and triethylamine (26.8 g, 207 mmol) was added diphenylphosphoryl azide (38.0 g, 138 mmol) dropwise at 70°C. The reaction mixture was stirred at 80°C for 12 hours. After completion of the reaction, sodium bicarbonate solution (500 mL) was added, filtered, extracted with ethyl acetate (200 mL), dried over sodium sulfate, and concentrated to obtain a crude product. The crude product was then dispersed in 2 M hydrochloric acid and dioxane and reacted for 2 hours. Filtered, and the filter cake was rinsed with ethyl acetate (150 mL) to obtain 2,3-difluoro-6-methoxyaniline (13.3 g, crude product).

[0170] LC-MS, M / Z (ESI): 160.2 (M+H + ).

[0171] Step 4: Synthesis of 2,3-difluoro-6-methoxy-N,N-dimethylaniline

[0172]

[0173] To a solution of 2,3-difluoro-6-methoxyaniline (7.30 g, 37.3 mmol) and potassium carbonate (20.6 g, 149 mmol) in dimethyl sulfoxide (40 mL) was added iodomethane (21.2 g, 149 mmol). The reaction mixture was sealed and reacted at 70°C for 12 hours. After completion of the reaction, the mixture was diluted with water (300 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2,3-difluoro-6-methoxy-N,N-dimethylaniline (6.52 g, 93.1% yield).

[0174] LC-MS, M / Z (ESI): 188.2 (M+H + ).

[0175] Step 5: Synthesis of 2-(dimethylamino)-3,4-difluorophenol

[0176]

[0177] To a solution of 2,3-difluoro-6-methoxy-N,N-dimethylaniline (6.21 g, 33.1 mmol) in dichloromethane (50 mL) was slowly added dropwise boron tribromide (1 M, 66 mL) at 0°C. The reaction was stirred at 25°C for 12 hours. After completion of the reaction, the reaction solution was quenched with sodium bicarbonate solution (100 mL) and extracted with dichloromethane (100 mL). The organic phase was dried and concentrated to yield 2-(dimethylamino)-3,4-difluorophenol (4.2 g, 73.2% yield).

[0178] LC-MS, M / Z (ESI): 174.2 (M+H + ).

[0179] Step 6: Synthesis of 6-((3-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-difluoro-N,N-dimethylaniline

[0180]

[0181] At room temperature, cesium carbonate (2.97 g, 9.11 mmol) was added to 2-(dimethylamino)-3,4-difluorophenol (1.10 g, 6.38 mmol) and 3-bromo-2-chloro-4-methyl-5-(trifluoromethyl)pyridine (1.25 g, 4.55 mmol) in dimethyl sulfoxide (15 mL), and the reaction solution was stirred at 90°C for 2 hours. After the reaction was completed, water (100 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1, R fP1 =0.40) to give 6-((3-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-difluoro-N,N-dimethylaniline (1.7 g, 90.7% yield).

[0182] LC-MS, M / Z (ESI): 411.2 (M+H + ).

[0183] Step 7: Synthesis of (2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)boronic acid

[0184]

[0185] To a solution of 6-((3-bromo-4-methyl-5-(trifluoromethyl)pyridin-2-yl)oxy)-2,3-difluoro-N,N-dimethylaniline (450 mg, 1.09 mmol) in tetrahydrofuran (3 mL) at -10°C was added isopropylmagnesium chloride and lithium chloride solution (1.3 M, 1.68 mL). The mixture was stirred at -10°C for 0.5 hour. Trimethyl borate (227 mg, 2.19 mmol) was added to the reaction solution, and the mixture was stirred at 25°C for 0.5 hour. After the reaction, 0.1N HCl (6 mL) and ethyl acetate (5 mL) were added, and the organic phase was dried over anhydrous sodium sulfate to provide (2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)boronic acid (392 mg, 88.6% yield).

[0186] LC-MS, M / Z (ESI): 377.0 (M+H + ).

[0187] Step 8: Synthesis of 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-((4-methoxybenzyl)oxy)-1,6-naphthyridine-5-carbonitrile

[0188]

[0189] At room temperature, Sphos-G3 (29.0 mg, 37.1 μmol) was added to a solution of (2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)boronic acid (150 mg, 371 μmol), 2-chloro-4-((4-methoxybenzyl)oxy)-1,6-naphthyridine-5-carbonitrile (121 mg, 371 μmol), and potassium phosphate (315 mg, 1.48 mmol) in tetrahydrofuran (4 mL). The reaction solution was stirred at 70 ° C for 16 hours. After the reaction was completed, it was directly concentrated to obtain a crude product, which was purified by thin layer chromatography (mobile phase: petroleum ether / ethyl acetate = 3:1, R fp1 =0.40) to give 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-((4-methoxybenzyl)oxy)-1,6-naphthyridine-5-carbonitrile (220 mg, 47.7% yield).

[0190] LC-MS, M / Z (ESI): 622.2 (M+H + ).

[0191] Step 9: Synthesis of 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile

[0192]

[0193] To a solution of 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-((4-methoxybenzyl)oxy)-1,6-naphthyridine-5-carbonitrile (110 mg, 177 μmol) in dichloromethane (1.50 mL) was added trifluoroacetic acid (403 mg, 3.54 mmol) at room temperature, and the reaction mixture was stirred at 25°C for 0.5 h. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution (50 mL) and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated to afford 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (100 mg, crude).

[0194] LC-MS, M / Z (ESI): 502.2 (M+H + ).

[0195] Step 10: Synthesis of 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

[0196]

[0197] To a solution of 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (90.0 mg, 179 μmol) and potassium carbonate (74.4 mg, 538 μmol) in dimethyl sulfoxide (2 mL) was added hydrogen peroxide (305 mg, 2.69 mmol) at room temperature. The reaction mixture was stirred at 60°C for 16 hours. After completion of the reaction, the filtrate was directly filtered. The product was purified by high performance liquid chromatography (chromatographic column: Phenomenex lunaC18 150*25mm*10um; mobile phase: solvent A = water + 0.1% formic acid, B = acetonitrile; gradient: 32%-62%, 15min) to obtain 2-(2-(2-(dimethylamino)-3,4-difluorophenoxy)-4-methyl-5-(trifluoromethyl)pyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-9) (13.0 mg, 13.6% yield).

[0198] 1 H NMR (400MHz, CDCl3) δ15.7(s,1H),8.98(s,1H),8.69(d,J=5.6Hz,1H),8.41(s,1H),8.14(d,J=5.5Hz,1H) ,7.23(s,1H),6.91-6.81(m,1H),6.78-6.71(m,1H),6.15-6.18(m,1H),2.69(d,J=1.8Hz,6H),2.34(s,3H)

[0199] LC-MS, M / Z (ESI): 520.1 (M+H + )

[0200] Example 2: Preparation of target compound I-20

[0201] 2-(2-((3,4-difluoro-2-methylphenyl)amino)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (target compound I-20)

[0202]

[0203] The synthetic route of target compound I-20 is as follows:

[0204]

[0205] Step 1: Synthesis of 3,6-dichloro-5-methylpyridin-2-amine

[0206]

[0207] 6-Chloro-5-methylpyridin-2-amine (20.0 g, 140 mmol) and N-chlorosuccinimide (24.3 g, 182 mmol) were dissolved in acetonitrile (200 mL). The temperature was then lowered to 0°C. Under nitrogen, trifluoromethanesulfonic acid (23.1 g, 154 mmol) was added. After complete addition, the mixture was allowed to react at 25°C for 12 hours until the starting material disappeared. The reaction mixture was adjusted to pH 7 with saturated sodium bicarbonate and extracted with ethyl acetate (150 mL). The organic phase was washed with water (40 mL) and dried over sodium sulfate to obtain the crude product, which was then purified on a silica gel column (petroleum ether:ethyl acetate (v / v) = 100:1-20:1) to afford 3,6-dichloro-5-methylpyridin-2-amine (5.00 g, 20.1% yield).

[0208] LC-MS, M / Z (ESI): 176.1 (M+H + )

[0209] Step 2: Synthesis of 3,6-dichloro-N-(3,4-difluoro-2-methylphenyl)-5-methylpyridin-2-amine

[0210]

[0211] 3,6-Dichloro-5-methylpyridin-2-amine (1.20 g, 6.78 mmol), 1-bromo-3,4-difluoro-2-methylbenzene (2.10 g, 10.1 mmol), sodium tert-butoxide (1.30 g, 13.5 mmol), tris(dibenzylideneacetone)dipalladium (620 mg, 677 μmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (646 mg, 1.36 mmol) were dissolved in toluene (10 mL), replaced with nitrogen three times, and then reacted at 100 ° C for 12 hours until the raw materials disappeared. The reaction solution was directly filtered and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1-10:1) to give 3,6-dichloro-N-(3,4-difluoro-2-methylphenyl)-5-methylpyridin-2-amine (1.40 g, yield 68.1%).

[0212] LC-MS, M / Z (ESI): 303.0 (M+H + )

[0213] Step 3: Synthesis of 3-chloro-N-(3,4-difluoro-2-methylphenyl)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-2-amine

[0214]

[0215] 3,6-Dichloro-N-(3,4-difluoro-2-methylphenyl)-5-methylpyridin-2-amine (1.40 g, 4.62 mmol), 3,3-difluoroazetidine hydrochloride (1.20 g, 9.24 mmol), cesium carbonate (6.02 g, 18.4 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (267 mg, 461 μmol) and tris(dibenzylideneacetone)dipalladium (211 mg, 230 μmol) were dissolved in dioxane (12 mL), replaced with nitrogen three times, and then reacted at 100 ° C for 12 hours until the reaction was complete. The reaction solution was directly filtered and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V / V) = 100:1-10:1) to obtain 3-chloro-N-(3,4-difluoro-2-methylphenyl)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-2-amine (550 mg, 1.53 mmol) (550 mg, 33.1% yield).

[0216] LC-MS, M / Z (ESI): 360.1 (M+H + )

[0217] Step 4: Synthesis of N-(3,4-difluoro-2-methylphenyl)-6-(3,3-difluoroazetidin-1-yl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine

[0218]

[0219] 3-Chloro-N-(3,4-difluoro-2-methylphenyl)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-2-amine (550 mg, 1.53 mmol) was dissolved in dioxane (20 mL), and then bis-naphthalene alcohol borate (776 mg, 3.06 mmol), potassium acetate (600 mg, 6.12 mmol), tricyclohexylphosphine (51.4 mg, 183 μmol), tris(dibenzylideneacetone)dipalladium (140 mg, 152 μmol) were added under nitrogen protection, and nitrogen was replaced, and then the reaction was carried out at 100 ° C for 6 hours until the raw material disappeared. The reaction solution was quenched with water (20 mL), then extracted with ethyl acetate (60 mL), the organic phase was washed with water (40 mL), dried over sodium sulfate, and then separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18150*40mm*15μm; mobile phase: A=water+0.05% formic acid, B=acetonitrile; gradient: 80%-100%, 22 min), and then N-(3,4-difluoro-2-methylphenyl)-6-(3,3-difluoroazetidin-1-yl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (220 mg, yield 31.9%) was obtained.

[0220] LC-MS, M / Z (ESI): 452.0 (M+H + )

[0221] Step 5: Synthesis of 2-{2-[(3,4-difluoro-2-methylphenyl)amino]-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl}-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine-5-carbonitrile

[0222]

[0223] N-(3,4-difluoro-2-methylphenyl)-6-(3,3-difluoroazetidin-1-yl)-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (200 mg, 443 μmol) and 2-chloro-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine-5-carbonitrile (120 mg, 369 μmol) were added to the mixture. ol) was dissolved in dioxane (4 mL) and water (1 mL), and then potassium phosphate (158 mg, 738 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl) palladium (II) (43.2 mg, 55.4 μmol) were added under nitrogen protection, and then reacted at 80 ° C for 1 hour until the starting material disappeared. The reaction solution was quenched with water (10 mL), then extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine (30 mL), dried over sodium sulfate, and then separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18150*40mm*15μm; mobile phase: A=water+0.05% formic acid, B=acetonitrile; gradient: 80%-100%, 15 min), and then 2-{2-[(3,4-difluoro-2-methylphenyl)amino]-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl}-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine-5-carbonitrile (160 mg, yield 70.4%) was obtained.

[0224] LC-MS, M / Z (ESI): 615.2 (M+H + )

[0225] Step 6: Synthesis of 2-{2-[(3,4-difluoro-2-methylphenyl)amino]-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl}-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile

[0226]

[0227] 2-{2-[(3,4-difluoro-2-methylphenyl)amino]-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl}-4-[(4-methoxyphenyl)methoxy]-1,6-naphthyridine-5-carbonitrile (150 mg, 224 μmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL), and then reacted at 25° C. for 10 minutes until the starting material disappeared. The reaction solution was quenched with 1 M aqueous sodium bicarbonate solution (5 mL), then extracted with dichloromethane (60 mL), dried over sodium sulfate, and concentrated to give compound 2-{2-[(3,4-difluoro-2-methylphenyl)amino]-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl}-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (100 mg, yield 82.8%).

[0228] LC-MS, M / Z (ESI): 495.1 (M+H + )

[0229] Step 7: Synthesis of 2-{2-[(3,4-difluoro-2-methylphenyl)amino]-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl}-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (target compound I-20)

[0230]

[0231] 2-{2-[(3,4-difluoro-2-methylphenyl)amino]-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl}-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carbonitrile (100 mg, 202 μmol) was dissolved in dimethyl sulfoxide (2 mL), and potassium carbonate (83.8 mg, 606 μmol) and hydrogen peroxide (343 mg, 3.03 mmol) were added, and the mixture was stirred at 60 ° C for 8 hours until the starting material disappeared. The reaction solution was quenched with 1 M aqueous sodium sulfite solution (5.00 mL), then extracted with ethyl acetate (20 mL), the organic phase was washed with brine (20 mL), dried over sodium sulfate, and then separated by reverse-phase high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: A=water+0.05% formic acid, B=acetonitrile; gradient: 70%-100%, 15 minutes), and then the compound 2-{2-[(3,4-difluoro-2-methylphenyl)amino]-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl}-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (target compound I-20) (2.00 mg, yield 1.93%) was obtained.

[0232] LC-MS, M / Z (ESI): 513.1 (M+H + )

[0233] 1 H NMR (400MHz, CDCl3) δ15.29 (s, 1H), 8.96 (s, 1H), 8.59 (d, J = 5.2Hz, 1H), 7.96 (br d,J=5.3Hz,1H),7.82(s,1H),7.73-7.80(m,1H),7.46(s,1H),6.93-7.09(m,1H),6.09-6.22(m,1H),4.45(br t,J=12.1Hz,4H),2.44(br s,3H),2.22(s,3H)

[0234] Example 3: Preparation of target compound I-25

[0235] Synthesis of 2-(2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-25)

[0236]

[0237] The synthetic route of target compound I-25 is as follows:

[0238]

[0239] Step 1: Synthesis of 2-chloro-5-cyano-3-methylpyridine-1-oxide

[0240]

[0241] To a solution of 6-chloro-5-methylnicotinonitrile (5.00 g, 32.8 mmol) in dichloromethane (50 mL) was added trifluoroacetic anhydride (7.57 g, 36.1 mmol) and urea hydrogen peroxide (4.01 g, 42.6 mmol) at room temperature. The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, water (80 mL) was added, the mixture was separated, and the mixture was extracted with dichloromethane (30 mL x 2). The organic phase was washed with water (30 mL), dried over anhydrous sodium sulfate, and concentrated to yield 2-chloro-5-cyano-3-methylpyridine-1-oxide (4.82 g, 86.9% yield).

[0242] LC-MS, M / Z(ESI):169.1[M+H + ]

[0243] Step 2: Synthesis of 2,6-dichloro-5-methylnicotinonitrile

[0244]

[0245] Phosphorus oxychloride (5.00 g, 32.6 mmol) was added to a solution of 2-chloro-5-cyano-3-methylpyridine-1-oxide (2.20 g, 13.1 mmol) in dichloroethane (15 mL) at room temperature. The reaction mixture was stirred at 80°C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with sodium bicarbonate (100 mL). The mixture was extracted with dichloromethane (40 mL x 2). The organic phase was dried over sodium sulfate, filtered, and concentrated to afford 2,6-dichloro-5-methylnicotinonitrile (2.23 g, crude product).

[0246] LC-MS, M / Z(ESI):187.1[M+H + ]

[0247] Step 3: Synthesis of 2-chloro-6-(3,3-difluoroazetidin-1-yl)-5-methylnicotinonitrile

[0248]

[0249] To a solution of 2,6-dichloro-5-methylnicotinonitrile (2.20 g, 11.8 mmol) and 3,3-difluoroazetidine hydrochloride (1.68 g, 13.0 mmol) in tetrahydrofuran (15 mL) was added triethylamine (2.98 g, 29.4 mmol) at room temperature. The reaction mixture was stirred at 60°C for 2 hours. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (40 mL x 2). The organic phase was dried over sodium sulfate and concentrated to yield the crude product, which was then slurried with 20 mL of methyl tert-butyl ether for 0.5 hour. Filtration afforded 2-chloro-6-(3,3-difluoroazetidine-1-yl)-5-methylnicotinonitrile (1.23 g, 41.8% yield).

[0250] LC-MS, M / Z(ESI):224.0[M+H + ]

[0251] Step 4: Synthesis of 2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylnicotinonitrile

[0252]

[0253] To a solution of 3,4-difluoro-2-methylphenol (1.21 g, 8.37 mmol) and 2-chloro-6-(3,3-difluoroazetidin-1-yl)-5-methylnicotinonitrile (1.20 g, 4.93 mmol) in N,N-dimethylformamide (15 mL) was added cesium carbonate (3.21 g, 9.85 mmol) at room temperature. The reaction mixture was stirred at 100°C for 3 hours. After completion of the reaction, water (70 mL) was added for separation, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to yield 2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylnicotinonitrile (1.81 g, crude product).

[0254] LC-MS, M / Z(ESI):352.1[M+H + ]

[0255] Step 5: Synthesis of 2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylnicotinamide

[0256]

[0257] 30% hydrogen peroxide (3.49 g, 30.74 mmol) was added to 2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylnicotinonitrile (1.81 g, 5.12 mmol) and potassium carbonate (2.12 g, 15.4 mmol) in dimethyl sulfoxide (18 mL). The reaction mixture was stirred at 60°C for 5 hours. After completion of the reaction, the mixture was diluted with water (200 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (120 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylnicotinamide (2.04 g, crude product).

[0258] LC-MS, M / Z(ESI):370.0[M+H + ]

[0259] Step 6: Synthesis of N-(tert-butyl)-2-(2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide

[0260]

[0261] At room temperature, 2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylnicotinamide (400 mg, 1.08 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-methylamino-1,1-biphenyl-2-yl)palladium(II) (92.0 mg, 108 μmol), and cesium carbonate (1.41 g, 4.33 mmol) were dissolved in sec-butanol (7 mL). The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 36 hours. After completion of the reaction, the mixture was concentrated to obtain the crude product. It was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10:1 to 2:1) to give N-(tert-butyl)-2-(2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (183 mg, 29.7% yield).

[0262] LC-MS, M / Z(ESI):570.2[M+H + ]

[0263] Step 7: Synthesis of 2-(2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidine-1-yl)-5-methylpyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-25)

[0264]

[0265] To a solution of N-(tert-butyl)-2-(2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (90.0 mg, 158 μmol) in toluene (5 mL) was added tert-butyldimethylsilyl trifluoromethylsulfonate (418 mg, 1.58 mmol) at room temperature. The reaction mixture was stirred at 85°C for 16 hours. After completion of the reaction, the mixture was concentrated to obtain the crude product. The product was purified by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: solvent A = water + 0.225% formic acid, B = acetonitrile; gradient: 2%-28%, 15min) to obtain 2-(2-(3,4-difluoro-2-methylphenoxy)-6-(3,3-difluoroazetidin-1-yl)-5-methylpyridin-3-yl)-4-oxo-1,4-dihydro-1,6-naphthyridine-5-carboxamide (I-25) (23.2 mg, 28.1% yield).

[0266] 1 H NMR(400MHz,MeOD)δ8.56(d,J=5.6Hz,1H),8.01(s,1H),7.62-7.52(m,1H),6.98-6.87(m, 1H),6.58(d,J=8.5Hz,2H),4.76-4.58(m,2H),4.10-4.01(m,2H),2.35(d,J=16.0Hz,6H).

[0267] LC-MS, M / Z(ESI):514.1[M+H + ]

[0268] Test Example 1: Detection of the inhibitory activity of compounds on Nav1.8 ion channels

[0269] All reagents, except NaOH and KOH for acid-base titration, were purchased from Sigma (St. Louis, MO). Final concentrations of test compounds were prepared on the day of the experiment and dissolved in extracellular fluid. The extracellular fluid (mM) consisted of: NaCl, 137; KCl, 4; CaCl₂, 1.8; MgCl₂, 1; HEPES, 10; glucose, 10; pH 7.4 (NaOH titration). All test and control compound solutions contained 1 μM TTX. The intracellular fluid (mM) consisted of: aspartic acid, 140; magnesium chloride, 2; ethylene glycol tetraacetic acid (EGTA), 11; and N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), 10. The pH was adjusted to 7.4 with cesium hydroxide.

[0270] The test compound was dissolved in dimethyl sulfoxide (DMSO) at a concentration of 9 mM and redissolved in the extracellular fluid on the day of the test to prepare the required concentration.

[0271] Electrophysiological experimental steps:

[0272] Transfer the cells to a perfusion tank and perfuse with extracellular solution. Thaw the intracellular solution on the day of the experiment. Electrodes were pulled using PC-10 (Narishige, Japan). Whole-cell patch clamp recordings were performed, with noise filtered at one-fifth the sampling frequency. Fill the electrode with intracellular solution to a quarter of the length of the electrode tube and install the electrode on the probe. Set the desired protocol, adjust the interface to Membrane test, and the Stage to Bath. Apply positive pressure to the electrode, touch the electrode tip to the cell, adjust the three-way valve of the aspirator to the three-way position, and then apply negative pressure to the electrode to form a high-resistance seal between the electrode and the cell. Adjust the Stage to Patch, control the leak to -200pA, and continue to apply negative pressure to rupture the cell membrane, establishing a current path. Open the aspirator and extracellular solution valves to allow perfusion, observe the cell current, and begin drug addition after the cell current stabilizes (at least three sweeps of overlapping current curves). Add drug from low to high concentrations, with each dose lasting at least 2 minutes. Wait until the current stabilizes before changing concentrations.

[0273] The test article is administered using a gravity-fed perfusion system. During the initial recording period, the peak current amplitude is observed for at least 1 minute until it stabilizes. During this period, the CV% of all peak current amplitudes should be less than 10% to exclude fluctuations in the initial current. The average of the peak current amplitudes recorded during the last 10 recordings during the initial recording period is used as the peak current of the negative control. After the initial current stabilizes, the test article is administered starting at a low concentration until the peak currents of the 10 recordings stabilize again or, after 5 minutes of continuous administration, the peak current remains unchanged after administration. "Stable" or "unchanged" is defined as follows: 1) if the absolute average of the peak current for 10 consecutive scans exceeds 200pA with a CV value of less than 10%, or 2) if the average of the peak current for 10 consecutive scans is between 200pA and 50pA with a CV value of less than 30%. The next higher concentration is then administered.

[0274] The average peak current of the last 10 scans for each concentration was used as the peak current for that concentration and was used for data analysis. If steady state was not achieved within 5 minutes, the average peak current of the last 10 scans at that time was used as the peak current for that concentration and was used for data analysis. The cell was discarded and not used for testing at higher concentrations. At least two cells were tested for each compound concentration.

[0275] Voltage pulse program:

[0276] The cell is clamped at –80 mV and then depolarized to 10 mV with a 10-ms square wave to elicit a NaV1.8 current. This procedure is repeated every 5 seconds. The maximum current evoked by the square wave is measured and, after stabilization, the test compound is perfused. Once the response stabilizes, the magnitude of the blockade is calculated.

[0277] Data processing and fitting

[0278] Data acquisition and analysis will be performed using pCLAMP 10 (Molecular Devices, Union City, CA). Current stability refers to the fact that the current changes within a limited range over time. The dose-response relationship between the drug's serial dilution concentration and the stable current value generated by its action on HEK293 / Nav1.8 cells was plotted.

[0279] Then the inhibitory activity of the drug on Nav1.8 ion channel (IC 50 ).

[0280] Table 1: Inhibitory activity of compounds on Nav1.8 ion channels

[0281] Compound number <![CDATA[IC 50 (nM)]]> I-9 3.13

[0282] In addition to the compounds in Table 1, the results are as follows:

[0283] Inhibitory activity IC of Nav1.8 ion channel 50 Compounds (nM) less than 20nM include: I-11, I-12, I-13, I-14, I-15, I-16, I-17, I-18, I-19.

[0284] Inhibitory activity IC of Nav1.8 ion channel 50 Compounds with a (nM) concentration less than 10 μM and greater than or equal to 20 nM include: I-7, I-8, I-10, I-20, I-21, I-22, I-23, I-24, and I-25.

[0285] Inhibitory activity IC of Nav1.8 ion channel 50 Compounds with an activity (nM) greater than or equal to 10 μM include: I-1, I-2, I-3, I-4, I-5, and I-6.

[0286] The test results show that the compound of the present invention has strong inhibitory activity on Nav1.8 ion channel.

[0287] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A compound, which is a compound represented by formula (I), or a tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I): in, X 3a N or CR 3a ; X 4a N or CR 4a ; X 5a N or CR 5a ; X 6a N, N + -O - or CR 6a ; R 3a 、R 4a 、R 5a are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy; R 6a H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 5-12 membered heteroaryl, -NR 3 R 4 、-C(=O)NR 3 R 4 、-C(=NR 5 )NR 3 R 4 、-OR 4 、-S(=O)2R 3 or -S(=O)(=NR 5 )R 3 ; Ring A and Ring B are each independently selected from C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl; L is -O-, -S- or -NH-; R 1 Selected from H, halogen, hydroxy, cyano, oxo, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NR 3 R 4 、-C(=O)NR 3 R 4 、C 3-12 Cycloalkyl, 4-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R A replaced by; Or, two adjacent R 1 Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R A replaced by; R A Selected from H, halogen, hydroxy, amino, cyano, nitro, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; R 2 Selected from H, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -OR 4 、-NR 3 R 4 、C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R B replaced by; Or, two adjacent R 2 Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R B replaced by; R B Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; R 3 、R 4 and R 5 Each independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R C replaced by; Or, R 3 、R 4 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic group or a C 3-12 Cycloalkyl, the 3-12 membered heterocyclic group or C 3-12 The cycloalkyl group is optionally substituted with one or more R C replaced by; R C Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; R 6 and R 6 ' are each independently selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl, 5-12 membered heteroaryl; wherein, the C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, 4-12 membered heterocycloalkenyl, C 6-12 Aryl and 5-12 heteroaryl are each independently optionally substituted by one or more R D replaced by; R D Selected from H, halogen, hydroxy, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; m is selected from 0, 1, 2, 3, 4, 5 and 6; n is selected from 0, 1, 2, 3, 4, 5 and 6.

2. The compound of formula (I) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: R 6 is H; and / or, R 6 ' is H, F, Cl, methyl, trifluoromethyl, methoxy or trifluoromethoxy.

3. The compound of formula (I) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: Group fragment for Among them, R 5a is halogen, R 6a For diazole, triazole, -OCH2CH(OH)CH2OH, -C(=O)NHR 3 、-C(=NH)NHR 3 、-S(=O)2R 3 、-S(=O)(=NH)R 3 , R 3 H, hydroxyl, C 1-6 Alkyl or C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy group is optionally substituted with one or more R C Replaced by R C The definition as claimed in claim 1; preferably, R 3 is H, hydroxy, methyl or methoxy; and / or, group fragments for 4. The compound of formula (I) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: Ring A is a 6-membered heterocycloalkenyl, a 6-membered heterocyclyl, a 6-membered heteroaryl, a 5-membered heteroaryl or a phenyl group; preferably, Ring A is a pyridyl, a 1,2-dihydropyridyl, a phenyl or a thienyl group; and / or, R 1 H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group; wherein, the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 The cycloalkyl and 3-12 membered heterocyclic groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy; R 3 and R 4 The definition of as claimed in claim 1; and / or, two adjacent R 1 Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R A Replaced by; R A The definition of as claimed in claim 1; and / or, group fragments for where R 2b 、R 3b and R 4b are each independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; and / or, group fragments for where R 2b 、R 3b and R 4b Each independently selected from H, F, Cl, methyl, trifluoromethyl; and / or, group fragments for and / or, group fragments for Where W is N or CR 4b , R 1b 、R 2b 、R 3b and R 4b independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclic group; the C 1-6 Alkyl, C 2-6 Alkynyl, C 3-12 The cycloalkyl and 3-12 membered heterocyclic groups are each independently optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, =CR 3 R 4 、C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy; R 3 and R 4 The definition of as claimed in claim 1; and / or, group fragments for Where W is N or CH, R 1b 、R 2b and R 3b Each independently selected from H, F, Cl, methyl, trifluoromethyl, tert-butyl, Preferably, W is N, R 1b 、R 2b 、R 3b and R 4b Independently selected from H, C 1-3 Alkyl, C substituted by one or more halogen 1-3 alkyl; and / or, group fragments for and / or, group fragments for Wherein ring C is phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkenyl, wherein W is N or CR 4b , R 1b and R 4b independently selected from H, halogen, C 1-6 Alkyl; the C 1-6 The alkyl group is optionally substituted with one or more R A Replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Haloalkoxy, p is selected from 0, 1, 2, 3 and 4; and / or, group fragments for 5. The compound of formula (I) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: Group fragment for L is -O- or -NH-; R 1c 、R 2c 、R 3c 、R 4c and R 5c are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -OR 4 、-NR 3 R 4 、C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R B Replaced by; R 3 and R 4 The definition of as claimed in claim 1; R B Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; Preferably, L is -O-; R 2c 、R 3c 、R 4c 、R 5c are each independently selected from H, halogen; R 1c Selected from C 1-6 Alkyl, -OR 4 、C 3-12 Cycloalkyl or -NR 3 R 4 , where R 3 、R 4 Each independently selected from H, C 1-3 Alkyl or C 3-6 Cycloalkyl; and / or, R 1c 、R 2c 、R 3c 、R 4c and R 5c Each independently selected from H, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, and / or, group fragments for where R 1c 、R 2c and R 3c are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 4 、-NR 3 R 4 、C 3-12 Cycloalkyl, R 3 and R 4 The definition as claimed in claim 1; preferably, R 2c 、R 3c are each independently selected from H, halogen; R 1c Selected from C 1-6 Alkyl, -OR 4 、C 3-12 Cycloalkyl, -NR 3 R 4 , where R 3 、R 4 Each independently selected from H, C 1-3 Alkyl or C 3-6 Cycloalkyl; preferably, R 1c 、R 2c and R 3c Each independently selected from H, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, and / or, group fragments for and / or, group fragments for and / or, group fragments for where R 1c 、R 2c and R 3c are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 4 、-NR 3 R 4 , R 3 and R 4 The definition as claimed in claim 1; preferably, R 1c 、R 2c and R 3c Each independently selected from H, F, Cl, methyl, trifluoromethyl, methoxy, trifluoromethoxy, cyclopropyl, and / or, group fragments for 6. The compound of formula (I) according to claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs, characterized in that: It is a compound represented by formula (IA), (IB) or (IC): in, W is N or CR 4b ; R 1b 、R 2b 、R 3b and R 4b are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R A replaced by; Or, two adjacent R 1b 、R 2b 、R 3b and R 4b Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R A replaced by; R A Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, =CR 3 R 4 、C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; R 1c 、R 2c 、R 3c 、R 4c and R 5c are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -OR 4 、-NR 3 R 4 、C 3-12 Cycloalkyl; wherein said C 1-6 Alkyl, C 1-6 Alkoxy and C 3-12 The cycloalkyl groups are each independently optionally substituted with one or more R B replaced by; Or, two adjacent R 1c 、R 2c 、R 3c 、R 4c and R 5c Together with the carbon atoms to which they are attached, they form a 4-6 membered cycloalkenyl, a 4-6 membered heterocycloalkenyl, a 5-6 membered heteroaryl or a phenyl group; the 4-6 membered cycloalkenyl, the 4-6 membered heterocycloalkenyl, the 5-6 membered heteroaryl or the phenyl group are each independently optionally substituted with one or more R B replaced by; R B Selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 haloalkoxy; X 4a 、R 5a 、R 6 '、R 3 and R 4 The definition as in claim 1.

7. The compound of formula (I) according to claim 1, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, wherein: The compound represented by formula (I) is selected from the following compounds:

8. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug and a pharmaceutically acceptable excipient.

9. a compound as described in any one among claims 1-7, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the purposes of the composition as described in claim 8 in preparing an inhibitory voltage-gated sodium channel medicine; and / or, in preparing a treatment, alleviation or prevention pain medicine.

10. The use according to claim 9, characterized in that The voltage-gated sodium ion channel is Nav1.8; and / or, the pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

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