Heterocyclic compound used as voltage-gated sodium channel inhibitor, and pharmaceutical composition, pharmaceutical preparation and application thereof

Abstract

The invention belongs to the field of medicines, and relates to a heterocyclic compound as shown in formula (I), which can be used as a voltage-gated sodium channel inhibitor, especially has an excellent inhibition effect on Nav1.8, has better selectivity and pharmacokinetic properties, and can be applied to prevention, alleviation and / or treatment of voltage-gated sodium channel related diseases.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a heterocyclic compound used as a voltage-gated sodium channel inhibitor, pharmaceutical compositions and pharmaceutical preparations containing the same, and their use in the preparation of medicaments for the prevention, relief and / or treatment of pain-related diseases. Background Technology

[0002] Pain is a complex physiological and psychological activity, usually caused by physical injury, illness, or adverse external stimuli. The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience, often accompanied by actual or potential tissue damage." Pain is a protective mechanism that prevents tissue damage in healthy animals and prevents further damage to injured tissues, playing 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 caused the pain disappears, intense or persistent pain can cause physiological dysfunction, seriously affecting the quality of life of living beings. Data shows that about one-fifth of the world's population suffers from moderate to severe chronic pain. In 2022, the global pain treatment market totaled US$77.03 billion, and it is projected to reach US$116.23 billion by 2032. However, the abuse of opioid analgesics has had a staggering impact on society. According to the WHO, an estimated 69,000 people die each year globally from opioid overdoses, and 15 million people are addicted to opioids. Therefore, the importance of developing novel analgesics that are effective, non-addictive, and do not have drug resistance is self-evident.

[0003] Pain originates from nociceptors in the peripheral nervous system. Nociceptors are free nerve endings widely distributed throughout the skin, muscles, joints, and internal organs. They convert perceived temperature, mechanical, or chemical stimuli into nerve impulses (action potentials), which are transmitted via afferent nerve fibers to the cell bodies of the dorsal root ganglia, ultimately reaching higher nerve centers and causing pain. Voltage-gated sodium channels mediating inward currents are crucial for the generation and conduction of action potentials in both central and peripheral neurons. Therefore, inhibiting abnormal sodium ion channel activity can help relieve and treat pain.

[0004] Voltage-gated sodium channels (Na v Na+ is a class of transmembrane ion channel proteins composed of α and β subunits. Based on the different α subunits, it can be divided into nine isotypes. v1.1-1.9, different subtypes exhibit different tissue distributions and electrophysiological and pharmacological characteristics. Based on whether they can be effectively inhibited by nanomolar levels of tetrodotoxin (TTX), Na... v It is divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). Na v 1.1-1.4, Na v 1.6 and Na v 1.7 is of the TTX-S type, in which Na v 1.1, Na v 1.2, Na v 1.3 and Na v 1.6 It is highly expressed in the central nervous system, Na v 1.4 It is abundant in skeletal muscle, Na v 1.7 It is present in the central nervous system and dorsal root ganglia. Na v 1.5, Na v 1.8 and Na v 1.9 is of the TTX-R type, in which Na v 1.5 is mainly found in cardiomyocytes, Na v 1.8 and Na v 1.9 It is present in the dorsal root ganglia of the peripheral nervous system. Non-selective Na... v Inhibitors (such as lamotrigine, lacosamide, mexiletine, etc.) have been successfully used to treat chronic pain. However, currently used clinically, sodium... v Inhibitors lack subtype selectivity, inhibiting sodium ion channels expressed in the heart and central nervous system, resulting in a narrow therapeutic window and limited application.

[0005] Na v The gene encoding 1.8 is SCN10A, which exhibits electrophysiological characteristics of slow inactivation and rapid recovery. In some models of neuropathic pain, nerve damage can cause Na+... v 1.8 Expression levels increased in axons and neuronal cell bodies. Using Na... v 1.8 Antisense oligonucleotides in reducing Na+ v 1.8 expression can significantly relieve pain. Na v 1.8 gene knockout mice do not exhibit normal visceral inflammatory pain. Human Na+... v 1.8 Gene mutations that produce a functional gain can lead to peripheral neuralgia. Na v 1.8 It is mainly distributed in the peripheral nervous system, so it selectively inhibits Na+. v1.8 can effectively reduce side effects and has the potential to become a novel analgesic therapy, applicable to the treatment of various pain types such as inflammatory pain, neuropathic pain, postoperative pain, and cancer pain. Therefore, highly selective Na+... v 1.8 inhibitors have become one of the key areas of research and development for voltage-gated sodium ion channels.

[0006] Na has been reported to date. v 1.8 Small molecule inhibitors include VX-548, VX-150, HRS-4800, JMKX-000623, HBW-004285, JKN23061, and LTG-001, etc. Research is underway to develop inhibitors with higher affinity and better selectivity (e.g., compared to Na+). v 1.5) and Na with better pharmacokinetic properties v 1.8 Inhibitors still have great social and economic value. Summary of the Invention

[0007] The problem the invention aims to solve

[0008] This invention aims to provide a heterocyclic compound for use as a voltage-gated sodium channel inhibitor, and also provides pharmaceutical compositions and formulations comprising the same, and their pharmaceutical uses, wherein the heterocyclic compound has excellent voltage-gated sodium channels (especially Na+). v 1.8) It has an inhibitory effect, while also exhibiting better selectivity and superior pharmacokinetic properties.

[0009] Solution for solving the problem

[0010] In a first aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof:

[0011]

[0012] in:

[0013] Ring A is a phenyl or a 6-membered heteroaryl group, wherein the heteroatom on the heteroaryl group is optionally oxidized;

[0014] R a2 The group is selected from H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CONH2 and -CONH (C1-C4 alkyl), wherein the C1-C4 alkyl or C1-C4 alkoxy is optionally substituted with a group selected from halogen, hydroxy and C1-C4 alkoxy.

[0015] R a1 Selected from

[0016] Q is either -NH- or -S-;

[0017] R 1 and R 2 Each is independently selected from H and C1-C4 alkyl groups;

[0018] R 3 Selected from H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-COOH, -CH2-CONH2, -(CH2)2-COOH, -(CH2)4-NH2, -(CH2)2-S-CH3, -(CH2)3-NHC(=NH)NH2, -(CH2)2-CONH2, -CH2-OH, -CH(CH3)-OH and -CH2-SH;

[0019] R 4 Selected from -COOH, -CONH2, and -COO (C1-C4 alkyl);

[0020] R 5 It is -OH or -NH2;

[0021] X is either O or S;

[0022] R d1 and R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl;

[0023] R c1 and R c2 Each is independently selected from H, C1-C4 alkyl, and C1-C4 haloalkyl;

[0024] R e For H or D;

[0025] L stands for -CONH-;

[0026] Ring B is a phenyl group or a 6-membered heteroaryl group containing 1-2 nitrogen atoms;

[0027] R b1 R b2 and R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups.

[0028] In some implementations, L in formula (I) above is connected to ring A via N atoms.

[0029] Specifically, the present invention provides a compound as shown in formula (I-1):

[0030]

[0031] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug.

[0032] In some embodiments of the present invention, the compound of formula (I-1) is further shown as in formula (I-1a) or (I-1b):

[0033]

[0034] In the compounds represented by formula (I-1), (I-1a) or (I-1b), ring A is a phenyl or a 6-membered heteroaryl group, and the heteroatom on the heteroaryl group is optionally oxidized.

[0035] In some embodiments, ring A is a phenyl group.

[0036] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-3 N atoms, and the N atoms are optionally oxidized.

[0037] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-2 N atoms, and the N atoms are optionally oxidized.

[0038] In some embodiments, ring A is a 6-membered heteroaryl group, which is a pyridyl group and the N atom on the pyridyl group is optionally oxidized.

[0039] In some embodiments, ring A is phenyl or a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group is pyridyl or N-pyridyl oxide, that is, ring A is phenyl, pyridyl or N-pyridyl oxide.

[0040] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0041] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0042] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0043] In the compounds represented by formulas (I-1), (I-1a), or (I-1b) above, R a2 The group is selected from H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CONH2 and -CONH (C1-C4 alkyl), wherein each of the C1-C4 alkyl or C1-C4 alkoxy groups is independently and optionally substituted with a group selected from halogen, hydroxyl and C1-C4 alkoxy groups.

[0044] In some implementations, R a2 The group is selected from H, D, halogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, -CONH2 and -CONH (C1-C2 alkyl), wherein each of the C1-C2 alkyl or C1-C2 alkoxy groups is independently and optionally substituted with a group selected from halogen, hydroxyl and C1-C2 alkoxy groups.

[0045] In some implementations, R a2 Selected from H, D, halogen, cyano, C1-C2 alkyl and C1-C2 alkoxy.

[0046] In some implementations, R a2 Selected from H, halogens, and cyano groups.

[0047] In some implementations, R a2 Selected from H, F and cyano groups.

[0048] In some implementations, R a2 For H.

[0049] In some specific embodiments, when ring A is phenyl, R a2 Selected from H, F and cyano groups.

[0050] In some specific embodiments, when ring A is a 6-membered heteroaryl group (e.g., pyridyl or N-oxypyridyl), R a2 For H.

[0051] In some specific implementations, when ring A is At that time, R a2 Let H be the number of digits. This indicates the location where ring A connects to L, and ring A also connects to... Connected.

[0052] In some implementations, when ring A is At that time, R a2 Let H be the number of digits. This indicates the location where ring A connects to L, and ring A also connects to... The ring is preferably connected via a carbon atom adjacent to the nitrogen atom. connect.

[0053] In some specific implementations, ring A is With R a2 The phenyl groups are connected to the following positions respectively: Where R a2 Selected from H, F, and cyano groups.

[0054] In some specific implementations, ring A is Pyridinyl or N-oxypyridinyl groups are attached to the positions shown below: Where R a2 For H.

[0055] In some specific implementations, ring A is Attached to the pyridinyl group at the position shown below: Where R a2 For H.

[0056] In the compounds shown by formulas (I-1), (I-1a), or (I-1b) above, Q is -NH- or -S-.

[0057] In some implementations, Q is -NH-.

[0058] In some implementations, Q is -S-.

[0059] In the compounds represented by formula (I-1), (I-1a), or (I-1b), X is O or S.

[0060] In some implementations, X is 0.

[0061] In the compounds represented by formula (I-1), (I-1a), or (I-1b), R d1 R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0062] In some implementations, R d1 R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl, and R d1 and R d2 They are not the same.

[0063] In some implementations, R d1 R d2 Each is independently selected from C1-C2 alkyl and C1-C2 haloalkyl.

[0064] In some implementations, R d1 R d2 Each is independently selected from C1-C2 alkyl and C1-C2 haloalkyl, and R d1 and Rd2 They are not the same.

[0065] In some implementations, R d1 R d2 Each is independently selected from methyl and trifluoromethyl.

[0066] In some implementations, R d1 R d2 Each is independently selected from methyl and trifluoromethyl, and R d1 and R d2 They are not the same.

[0067] In the compounds represented by formula (I-1), (I-1a), or (I-1b), R c1 R c2 Each is independently selected from H, C1-C4 alkyl, and C1-C4 haloalkyl.

[0068] In some implementations, R c1 R c2 Each is independently selected from H and C1-C4 alkyl groups, and R c1 and R c2 They are not the same.

[0069] In some implementations, R c1 R c2 Each is independently selected from H, C1-C2 alkyl, and C1-C2 haloalkyl.

[0070] In some implementations, R c1 R c2 Each is independently selected from H and C1-C2 alkyl groups, and R c1 and R c2 They are not the same.

[0071] In some implementations, R c1 R c2 Each is independently selected from H and methyl.

[0072] In some implementations, R c1 R c2 Each is independently selected from H and methyl, and R c1 and R c2 They are not the same.

[0073] In the compounds represented by formula (I-1), (I-1a), or (I-1b), R e It can be H or D.

[0074] In the compounds represented by formula (I-1), (I-1a), or (I-1b), R e For H.

[0075] In the compounds represented by formula (I-1), (I-1a), or (I-1b), L is -CONH-.

[0076] In some embodiments, L in formula (I-1), (I-1a) or (I-1b) is connected to ring A via N atoms.

[0077] In the compounds represented by formula (I-1), (I-1a) or (I-1b), ring B is a phenyl group or a 6-membered heteroaryl group containing 1-2 N atoms.

[0078] In some embodiments, ring B is phenyl or pyridyl.

[0079] In some embodiments, ring B is a phenyl group.

[0080] In the compounds represented by formula (I-1), (I-1a), or (I-1b), R b1 R b2 R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups.

[0081] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens, C1-C2 alkoxy groups, C1-C2 deuterated alkoxy groups, and C1-C2 haloalkoxy groups.

[0082] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, deuterated methoxy, and halomethoxy.

[0083] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, deuterated methoxy, and fluoromethoxy.

[0084] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, -OCD3 and difluoromethoxy.

[0085] In some implementations, R b1 R b2 For halogens, R b3 It is selected from C1-C4 alkoxy, C1-C4 deuterated alkyl and C1-C4 haloalkoxy.

[0086] In some implementations, Rb1 R b2 For halogens, R b3 It is selected from C1-C2 alkoxy, C1-C2 deuterated alkoxy and C1-C2 haloalkoxy.

[0087] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and halomethoxy.

[0088] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and fluoromethoxy.

[0089] In some implementations, R b1 R b2 For F, R b3 Selected from methoxy, -OCD3 and difluoromethoxy.

[0090] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens and C1-C4 alkoxy groups.

[0091] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens and C1-C2 alkoxy groups.

[0092] In some implementations, R b1 R b2 R b3 Each is independently selected from F and methoxy groups.

[0093] In some implementations, R b1 R b2 For halogens, R b3 Selected from C1-C4 alkoxy groups.

[0094] In some implementations, R b1 R b2 For halogens, R b3 Selected from C1-C2 alkoxy groups.

[0095] In some implementations, R b1 R b2 For F, R b3 It is a methoxy group.

[0096] In some specific implementations, ring B is R. b1 Rb2 and R b3 The phenyl groups are connected to the following positions respectively:

[0097] In some specific implementations, ring B is selected from...

[0098] In some specific implementations, ring B is

[0099] Specifically, the present invention provides a compound as shown in formula (I-2):

[0100]

[0101] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug.

[0102] In some embodiments of the present invention, the compound of formula (I-2) is further shown as in formula (I-2a) or (I-2b):

[0103]

[0104] In the compounds represented by formula (I-2), (I-2a) or (I-2b), ring A is a phenyl or a 6-membered heteroaryl group, and the heteroatom on the heteroaryl group is optionally oxidized.

[0105] In some embodiments, ring A is a phenyl group.

[0106] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-3 N atoms, and the N atoms are optionally oxidized.

[0107] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-2 N atoms, and the N atoms are optionally oxidized.

[0108] In some embodiments, ring A is a 6-membered heteroaryl group, which is a pyridyl group and the N atom on the pyridyl group is optionally oxidized.

[0109] In some embodiments, ring A is phenyl or a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group is pyridyl or N-pyridyl oxide, that is, ring A is phenyl, pyridyl or N-pyridyl oxide.

[0110] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0111] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0112] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0113] In the compounds represented by formulas (I-2), (I-2a), or (I-2b) above, R a2 The group is selected from H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CONH2 and -CONH (C1-C4 alkyl), wherein each of the C1-C4 alkyl or C1-C4 alkoxy groups is independently and optionally substituted with a group selected from halogen, hydroxyl and C1-C4 alkoxy groups.

[0114] In some implementations, R a2 The group is selected from H, D, halogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, -CONH2 and -CONH (C1-C2 alkyl), wherein each of the C1-C2 alkyl or C1-C2 alkoxy groups is independently and optionally substituted with a group selected from halogen, hydroxyl and C1-C2 alkoxy groups.

[0115] In some implementations, R a2 Selected from H, D, halogen, cyano, C1-C2 alkyl and C1-C2 alkoxy.

[0116] In some implementations, R a2 Selected from H, halogens, and cyano groups.

[0117] In some implementations, R a2 Selected from H, F and cyano groups.

[0118] In some implementations, R a2 For H.

[0119] In some specific embodiments, when ring A is phenyl, R a2 Selected from H, F and cyano groups.

[0120] In some specific embodiments, when ring A is a 6-membered heteroaryl group (e.g., pyridyl or N-oxypyridyl), R a2 For H.

[0121] In some specific implementations, when ring A is At that time, R a2 Let H be the number of digits. This indicates the location where ring A connects to L, and ring A also connects to... Connected.

[0122] In some implementations, when ring A is At that time, R a2 Let H be the number of digits. This indicates the location where ring A connects to L, and ring A also connects to... The ring is preferably connected via a carbon atom adjacent to the nitrogen atom. connect.

[0123] In some specific implementations, ring A is With R a2 The phenyl groups are connected to the following positions respectively: Where R a2 Selected from H, F, and cyano groups.

[0124] In some specific implementations, ring A is Pyridinyl or N-oxypyridinyl groups are attached to the positions shown below: Where R a2 For H.

[0125] In some specific implementations, ring A is Attached to the pyridinyl group at the position shown below: Where R a2 For H.

[0126] In the compounds represented by formulas (I-2), (I-2a), or (I-2b) above, R 1 and R 2 Each is independently selected from H and C1-C4 alkyl groups.

[0127] In some implementations, R 1 and R 2 Each is independently selected from H and C1-C3 alkyl groups.

[0128] In some implementations, R 1 and R 2 Each is independently selected from H and C1-C2 alkyl groups.

[0129] In some implementations, R 1 For H, R 2 Selected from H and C1-C4 alkyl groups.

[0130] In some implementations, R 1 For H, R 2 Selected from H and C1-C3 alkyl groups.

[0131] In some implementations, R1 For H, R 2 Selected from H and C1-C2 alkyl groups.

[0132] In some implementations, R 1 For H, R 2 It can be H or -CH3.

[0133] In the compounds represented by formula (I-2), (I-2a), or (I-2b), R 3 Selected from H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-COOH, -CH2-CONH2, -(CH2)2-COOH, -(CH2)4-NH2, -(CH2)2-S-CH3, -(CH2)3-NHC(=NH)NH2, -(CH2)2-CONH2, -CH2-OH, -CH(CH3)-OH and -CH2-SH.

[0134] In some implementations, R 3 Selected from H, -CH2-CONH2, -CH2-SH, -(CH2)2-CONH2, -CH2-OH, -CH(CH3)-OH, -CH2-COOH, -(CH2)2-COOH and

[0135] In some implementations, R 3 It can be H or -CH2-OH.

[0136] In the compounds represented by formula (I-2), (I-2a), or (I-2b), R 4 Selected from -COOH, -CONH2 and -COO (C1-C4 alkyl).

[0137] In some implementations, R 4 Selected from -COOH, -CONH2 and -COO (C1-C3 alkyl).

[0138] In some implementations, R 4 Selected from -COOH, -CONH2 and -COO (C1-C2 alkyl).

[0139] In some implementations, R 4 Selected from -COOH, -CONH2, -COOCH3 and -COOCH2CH3.

[0140] In some implementations, R 4 Selected from -COOH, -COOCH3 and -COOCH2CH3.

[0141] In some implementations, when R 2 R 3 R 4 When they are different, the R 2 R 3 R 4 The attached carbon atom is in a racemic configuration.

[0142] In some implementations, when R 2 R 3 R 4 When they are different, the R 2 R 3 R 4 The attached carbon atom has an R-configuration.

[0143] In some implementations, when R 2 R 3 R 4 When they are different, the R 2 R 3 R 4 The attached carbon atom has an S-configuration.

[0144] In the compounds shown by formulas (I-2), (I-2a), or (I-2b) above, X is O or S.

[0145] In some implementations, X is 0.

[0146] In the compounds represented by formula (I-2), (I-2a), or (I-2b), R d1 R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0147] In some implementations, R d1 R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl, and R d1 and R d2 They are not the same.

[0148] In some implementations, R d1 R d2 Each is independently selected from C1-C2 alkyl and C1-C2 haloalkyl.

[0149] In some implementations, R d1 R d2 Each is independently selected from C1-C2 alkyl and C1-C2 haloalkyl, and R d1 and R d2 They are not the same.

[0150] In some implementations, R d1 R d2 Each is independently selected from methyl and trifluoromethyl.

[0151] In some implementations, R d1 R d2 Each is independently selected from methyl and trifluoromethyl, and R d1 and R d2 They are not the same.

[0152] In the compounds represented by formula (I-2), (I-2a), or (I-2b), R c1 R c2 Each is independently selected from H, C1-C4 alkyl, and C1-C4 haloalkyl.

[0153] In some implementations, R c1 R c2 Each is independently selected from H and C1-C4 alkyl groups, and R c1 and R c2 They are not the same;

[0154] In some implementations, R c1 R c2 Each is independently selected from H, C1-C2 alkyl, and C1-C2 haloalkyl.

[0155] In some implementations, R c1 R c2 Each is independently selected from H and C1-C2 alkyl groups, and R c1 and R c2 They are not the same.

[0156] In some implementations, R c1 R c2 Each is independently selected from H and methyl;

[0157] In some implementations, R c1 R c2 Each is independently selected from H and methyl, and R c1 and R c2 They are not the same.

[0158] In the compounds represented by formula (I-2), (I-2a), or (I-2b), R e It can be H or D.

[0159] In the compounds represented by formula (I-2), (I-2a), or (I-2b), R e For H.

[0160] In the compounds represented by formula (I-2), (I-2a), or (I-2b), L is -CONH-.

[0161] In some embodiments, L in formula (I-2), (I-2a) or (I-2b) is connected to ring A via N atoms.

[0162] In the compounds represented by formula (I-2), (I-2a) or (I-2b), ring B is a phenyl group or a 6-membered heteroaryl group containing 1-2 N atoms.

[0163] In some embodiments, ring B is phenyl or pyridyl.

[0164] In some embodiments, ring B is a phenyl group.

[0165] In the compounds represented by formula (I-2), (I-2a), or (I-2b), R b1 R b2 R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups.

[0166] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens, C1-C2 alkoxy groups, C1-C2 deuterated alkoxy groups, and C1-C2 haloalkoxy groups.

[0167] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, deuterated methoxy, and halomethoxy.

[0168] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, deuterated methoxy, and fluoromethoxy.

[0169] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, -OCD3 and difluoromethoxy.

[0170] In some implementations, R b1 R b2 For halogens, R b3 Selected from C1-C4 alkoxy, C1-C4 deuterated alkoxy and C1-C4 haloalkoxy.

[0171] In some implementations, R b1 R b2 For halogens, R b3It is selected from C1-C2 alkoxy, C1-C2 deuterated alkoxy and C1-C2 haloalkoxy.

[0172] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and halomethoxy.

[0173] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and fluoromethoxy.

[0174] In some implementations, R b1 R b2 For F, R b3 Selected from methoxy, -OCD3 and difluoromethoxy.

[0175] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens and C1-C4 alkoxy groups.

[0176] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens and C1-C2 alkoxy groups.

[0177] In some implementations, R b1 R b2 R b3 Each is independently selected from F and methoxy groups.

[0178] In some implementations, R b1 R b2 For halogens, R b3 Selected from C1-C4 alkoxy groups.

[0179] In some implementations, R b1 R b2 For halogens, R b3 Selected from C1-C2 alkoxy groups.

[0180] In some implementations, R b1 R b2 For F, R b3 It is a methoxy group.

[0181] In some specific implementations, ring B is R. b1 R b2 and R b3 The phenyl groups are connected to the following positions respectively:

[0182] In some specific implementations, ring B is selected from...

[0183] In some specific implementations, ring B is

[0184] Specifically, the present invention provides a compound as shown in formula (I-3):

[0185]

[0186] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug.

[0187] In some embodiments of the present invention, the compounds of formula (I-3) are further shown as in formula (I-3a) or (I-3b):

[0188]

[0189] In the compounds represented by formula (I-3), (I-3a) or (I-3b), ring A is a phenyl or a 6-membered heteroaryl group, and the heteroatom on the heteroaryl group is optionally oxidized.

[0190] In some embodiments, ring A is a phenyl group.

[0191] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-3 N atoms, and the N atoms are optionally oxidized.

[0192] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-2 N atoms, and the N atoms are optionally oxidized.

[0193] In some embodiments, ring A is a 6-membered heteroaryl group, which is a pyridyl group and the N atom on the pyridyl group is optionally oxidized.

[0194] In some embodiments, ring A is phenyl or a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group is pyridyl or N-pyridyl oxide, that is, ring A is phenyl, pyridyl or N-pyridyl oxide.

[0195] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0196] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R.a2 and connect.

[0197] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0198] In the compounds represented by formulas (I-3), (I-3a), or (I-3b) above, R a2 The group is selected from H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CONH2 and -CONH (C1-C4 alkyl), wherein each of the C1-C4 alkyl or C1-C4 alkoxy groups is independently and optionally substituted with a group selected from halogen, hydroxyl and C1-C4 alkoxy groups.

[0199] In some implementations, R a2 The group is selected from H, D, halogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, -CONH2 and -CONH (C1-C2 alkyl), wherein each of the C1-C2 alkyl or C1-C2 alkoxy groups is independently and optionally substituted with a group selected from halogen, hydroxyl and C1-C2 alkoxy groups.

[0200] In some implementations, R a2 Selected from H, D, halogen, cyano, C1-C2 alkyl and C1-C2 alkoxy.

[0201] In some implementations, R a2 Selected from H, halogens, and cyano groups.

[0202] In some implementations, R a2 Selected from H, F and cyano groups.

[0203] In some implementations, R a2 For H.

[0204] In some specific embodiments, when ring A is phenyl, R a2 Selected from H, F and cyano groups.

[0205] In some specific embodiments, when ring A is a 6-membered heteroaryl group (e.g., pyridyl or N-oxypyridyl), R a2 For H.

[0206] In some specific implementations, when ring A is At that time, R a2 Let H be the number of digits. This indicates the location where ring A connects to L, and ring A also connects to... Connected.

[0207] In some implementations, when ring A is At that time, R a2 Let H be the number of digits. This indicates the location where ring A connects to L, and ring A also connects to... The ring is preferably connected via a carbon atom adjacent to the nitrogen atom. connect.

[0208] In some specific implementations, ring A is With R a2 The phenyl groups are connected to the following positions respectively: Where R a2 Selected from H, F, and cyano groups.

[0209] In some specific implementations, ring A is Pyridinyl or N-oxypyridinyl groups are attached to the positions shown below: Where R a2 For H.

[0210] In some specific implementations, ring A is Attached to the pyridinyl group at the position shown below: Where R a2 For H.

[0211] In the compounds represented by formulas (I-3), (I-3a), or (I-3b) above, R 4 Selected from -COOH, -CONH2 and -COO (C1-C4 alkyl).

[0212] In some implementations, R 4 Selected from -COOH, -CONH2 and -COO (C1-C3 alkyl).

[0213] In some implementations, R 4 Selected from -COOH, -CONH2 and -COO (C1-C2 alkyl).

[0214] In some implementations, R 4 Selected from -COOH, -CONH2, -COOCH3 and -COOCH2CH3.

[0215] In some implementations, R 4 Selected from -COOH and -CONH2.

[0216] In some implementations, R 4 It is -CONH2.

[0217] In the compounds represented by formula (I-3), (I-3a), or (I-3b), R5 It can be -OH or -NH2.

[0218] In some implementations, R 5 It is -OH.

[0219] In some implementations, R 5 It is -NH2.

[0220] In some implementations... Chinese R 4 R 5 The carbon atom bonded to H is in a racemic configuration.

[0221] In some implementations... Chinese R 4 R 5 The carbon atom bonded to H has an R-configuration.

[0222] In some implementations... Chinese R 4 R 5 The carbon atom bonded to H has an S-configuration.

[0223] In the compounds represented by formula (I-3), (I-3a) or (I-3b), X is O or S.

[0224] In some implementations, X is 0.

[0225] In the compounds represented by formula (I-3), (I-3a), or (I-3b), R d1 R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0226] In some implementations, R d1 R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl, and R d1 and R d2 They are not the same.

[0227] In some implementations, R d1 R d2 Each is independently selected from C1-C2 alkyl and C1-C2 haloalkyl.

[0228] In some implementations, R d1 R d2 Each is independently selected from C1-C2 alkyl and C1-C2 haloalkyl, and R d1 and R d2 They are not the same.

[0229] In some implementations, Rd1 R d2 Each is independently selected from methyl and trifluoromethyl.

[0230] In some implementations, R d1 R d2 Each is independently selected from methyl and trifluoromethyl, and R d1 and R d2 They are not the same.

[0231] In the compounds represented by formula (I-3), (I-3a), or (I-3b), R c1 R c2 Each is independently selected from H, C1-C4 alkyl, and C1-C4 haloalkyl.

[0232] In some implementations, R c1 R c2 Each is independently selected from H and C1-C4 alkyl groups, and R c1 and R c2 They are not the same.

[0233] In some implementations, R c1 R c2 Each is independently selected from H, C1-C2 alkyl, and C1-C2 haloalkyl.

[0234] In some implementations, R c1 R c2 Each is independently selected from H and C1-C2 alkyl groups, and R c1 and R c2 They are not the same.

[0235] In some implementations, R c1 R c2 Each is independently selected from H and methyl.

[0236] In some implementations, R c1 R c2 Each is independently selected from H and methyl, and R c1 and R c2 They are not the same.

[0237] In the compounds represented by formula (I-3), (I-3a), or (I-3b), R e It can be H or D.

[0238] In the compounds represented by formula (I-3), (I-3a), or (I-3b), R e For H.

[0239] In the compounds represented by formula (I-3), (I-3a), or (I-3b), L is -CONH-.

[0240] In some implementations, L in formulas (I-3), (I-3a), or (I-3b) is connected to ring A via an N atom.

[0241] In the compounds represented by formula (I-3), (I-3a) or (I-3b), ring B is a phenyl group or a 6-membered heteroaryl group containing 1-2 N atoms.

[0242] In some embodiments, ring B is phenyl or pyridyl.

[0243] In some embodiments, ring B is a phenyl group.

[0244] In the compounds represented by formula (I-3), (I-3a), or (I-3b), R b1 R b2 R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups.

[0245] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens, C1-C2 alkoxy groups, C1-C2 deuterated alkoxy groups, and C1-C2 haloalkoxy groups.

[0246] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, deuterated methoxy, and halomethoxy.

[0247] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, deuterated methoxy, and fluoromethoxy.

[0248] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, -OCD3 and difluoromethoxy.

[0249] In some implementations, R b1 R b2 For halogens, R b3 Selected from C1-C4 alkoxy, C1-C4 deuterated alkoxy and C1-C4 haloalkoxy.

[0250] In some implementations, R b1 R b2 For halogens, R b3It is selected from C1-C2 alkoxy, C1-C2 deuterated alkoxy and C1-C2 haloalkoxy.

[0251] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and halomethoxy.

[0252] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and fluoromethoxy.

[0253] In some implementations, R b1 R b2 For F, R b3 Selected from methoxy, -OCD3 and difluoromethoxy.

[0254] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens and C1-C4 alkoxy groups.

[0255] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens and C1-C2 alkoxy groups.

[0256] In some implementations, R b1 R b2 R b3 Each is independently selected from F and methoxy groups.

[0257] In some implementations, R b1 R b2 For halogens, R b3 Selected from C1-C4 alkoxy groups.

[0258] In some implementations, R b1 R b2 For halogens, R b3 Selected from C1-C2 alkoxy groups.

[0259] In some implementations, R b1 R b2 For F, R b3 It is a methoxy group.

[0260] In some specific implementations, ring B is R. b1 R b2 and R b3 The phenyl groups are connected to the following positions respectively:

[0261] In some specific implementations, ring B is selected from...

[0262] In some specific implementations, ring B is

[0263] In some embodiments, the compounds involved in this invention are selected from the compounds in Table 1 or pharmaceutically acceptable salts thereof. In other embodiments, this invention relates to compounds selected from Table 1 in non-salt form (e.g., stereoisomers, tautomers, solvates, isotope-labeled forms, or prodrugs).

[0264] Table 1. Compound Structures and Names

[0265]

[0266]

[0267] In a second aspect, the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof.

[0268] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0269] In some embodiments, the pharmaceutically acceptable excipients (or excipients) include, but are not limited to, fillers, disintegrants, surfactants, solubilizers, lubricants, wetting agents, thickeners, flow aids, flavoring agents, odor-correcting agents, preservatives, antioxidants, pH adjusters, solvents, and light-blocking agents.

[0270] Thirdly, the compounds described in the first aspect of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled substances or prodrugs, or the pharmaceutical compositions described in the second aspect of the present invention, can be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation or implantation.

[0271] Therefore, the present invention also provides a pharmaceutical formulation made from the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label or prodrug thereof, or the pharmaceutical composition described in the second aspect of the present invention.

[0272] In some embodiments, the pharmaceutical preparation is a tablet, capsule, granule, sugar-coated pill, powder, lozenge, powder for injection, liquid preparation, or suppository.

[0273] Fourthly, the present invention provides the pharmaceutical use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, or the pharmaceutical composition described in the second aspect of the present invention, or the pharmaceutical preparation described in the third aspect.

[0274] The present invention provides the use of the compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label or prodrug thereof, or the pharmaceutical composition described in the second aspect of the present invention, or the pharmaceutical formulation described in the third aspect of the present invention, in the preparation of a medicament for inhibiting voltage-gated sodium channels.

[0275] The present invention provides the use of the compounds described in the first aspect or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled substances or prodrugs thereof, or pharmaceutical compositions described in the second aspect of the present invention, or pharmaceutical formulations described in the third aspect of the present invention, in the preparation of medicaments for the prevention, relief and / or treatment of voltage-gated sodium channel-related diseases or conditions.

[0276] The present invention provides the use of the compounds described in the first aspect or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled substances or prodrugs thereof, or pharmaceutical compositions described in the second aspect of the present invention, or pharmaceutical preparations described in the third aspect of the present invention, in the preparation of medicaments for the prevention, relief and / or treatment of pain.

[0277] In some embodiments, the voltage-gated sodium channel described in this invention is Na v 1.8.

[0278] In some embodiments, the voltage-gated sodium channel-related diseases or conditions described in this invention include, but are not limited to: pain, arthritis, epilepsy or epilepsy syndrome, neurodegenerative diseases, mental disorders (such as anxiety or depression), bipolar disorder, myotonia, movement disorders, neuroendocrine disorders, ataxia, irritable bowel syndrome, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis (ALS), stress- or exercise-induced angina, palpitations, hypertension, multiple sclerosis, Sharma-Turia syndrome, peroneal muscular dystrophy, incontinence, pathological cough, arrhythmia, and abnormal gastrointestinal activity.

[0279] In some embodiments, the pain described in this invention includes, but is not limited to: migraine, cluster headache, acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain.

[0280] In some embodiments, the acute pain described in this invention includes, but is not limited to, acute postoperative pain.

[0281] In some embodiments, the intestinal pain described in this invention includes, but is not limited to, inflammatory bowel disease pain and Crohn's disease pain.

[0282] In some embodiments, the neuropathic pain described in this invention includes, but is not limited to: postherpetic neuralgia, diabetic neuropathic pain, painful HIV-related sensory neuropathic pain, trigeminal neuralgia, neuropathic pain caused by burn syndrome, post-amputation pain, phantom limb pain, neuropathic pain caused by painful neuroma, neuropathic pain caused by traumatic neuroma, neuropathic pain caused by Morton's neuroma, neuropathic pain caused by nerve entrapment injury, neuropathic pain caused by spinal stenosis, neuropathic pain caused by carpal tunnel syndrome, nerve root pain, sciatica, neuropathic pain caused by nerve tearing injury, neuropathic pain caused by brachial plexus tearing injury, neuropathic pain caused by complex regional pain syndrome, neuropathic pain caused by drug therapy, neuropathic pain caused by cancer chemotherapy, neuropathic pain caused by antiretroviral therapy, post-spinal cord injury pain, neuropathic pain caused by small fiber neuropathy, neuropathic pain caused by idiopathic small fiber neuropathy, neuropathic pain caused by idiopathic sensory neuropathy, and neuropathic pain caused by trigeminal autonomic neuropathy.

[0283] In some embodiments, the musculoskeletal pain described in this invention includes, but is not limited to: osteoarthritis pain, back pain, cold pain, burning pain, and toothache.

[0284] In some embodiments, the inflammatory pain described in this invention includes, but is not limited to: rheumatoid arthritis pain, vulvar pain, and interstitial cystitis pain.

[0285] In some embodiments, the idiopathic pain described in this invention includes, but is not limited to, fibromyalgia.

[0286] In some embodiments, the postoperative pain described in this invention includes, but is not limited to: pain from bunion removal surgery, pain from hernia repair surgery, and pain from abdominoplasty.

[0287] In some embodiments, the visceral pain described in this invention includes, but is not limited to: acute abdominal pain, visceral pain caused by tumors, angina pectoris, and visceral pain caused by abdominoplasty.

[0288] The effects of the invention

[0289] The heterocyclic compounds provided by this invention can be used as voltage-gated sodium channel inhibitors, exhibiting excellent voltage-gated sodium channel characteristics (especially Na+). v 1.8) It has an inhibitory effect, while also having better selectivity and superior pharmacokinetic properties. It can be used to prevent, relieve and / or treat pain and other related diseases, and has good application prospects. Detailed Implementation

[0290] Various exemplary embodiments, features, and aspects of the present invention will be described in detail below. The term "exemplary" as used herein means "serving as an example, embodiment, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as superior to or better than other embodiments.

[0291] Furthermore, to better illustrate the present invention, numerous specific details are set forth in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In other instances, methods, means, apparatus, and steps well known to those skilled in the art have not been described in detail in order to highlight the spirit of the present invention.

[0292] Unless otherwise stated, all units used in this specification are international standard units, and all numerical values ​​and ranges appearing in this invention should be understood to include systematic errors that are unavoidable in industrial production.

[0293] In this specification, the word "may" has two meanings: to perform a certain process and not to perform a certain process.

[0294] In this specification, references to "some specific / preferred embodiments," "other specific / preferred embodiments," "implementation," etc., mean that a particular element (e.g., feature, structure, property, and / or characteristic) related to that embodiment is included in at least one of the embodiments described herein, and may or may not be present in other embodiments. Furthermore, it should be understood that the elements may be combined in any suitable manner in various embodiments.

[0295] Terminology Explanation

[0296] In this specification, the range of values ​​referred to as "value A to value B" refers to the range including the endpoint values ​​A and B.

[0297] In this instruction manual, when "room temperature" or "room temperature" is used, the temperature can be 15℃ to 30℃, or more specifically 15℃ to 25℃, such as 20℃.

[0298] As used herein, the term "compound of the present invention" refers to compounds of formula (I), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), (I-3), (I-3a) or (I-3b) as described herein, and all embodiments thereof, as well as the compounds identified in Table 1. "Compound of the present invention" also includes pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled forms or prodrugs of compounds of formula (I), (I-1), (I-1a), (I-1b), (I-2), (I-2a), (I-2b), (I-3), (I-3a) or (I-3b) as described herein.

[0299] As used in this article, the term "D" refers to the deuterium atom.

[0300] As used herein, the term “deuterated” refers to the substitution of one or more hydrogen atoms in a defined group by a deuterium atom.

[0301] As used herein, the term "halogen" refers to F, Cl, Br, or I.

[0302] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting only of carbon and hydrogen atoms, having a specified number of carbon atoms, and connected to the rest of the molecule by single bonds.

[0303] As used herein, the term "halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, and the terms "halogen" and "alkyl" have the definitions above.

[0304] As used herein, the term "alkoxy" refers to a group of the formula -OR, where R is an alkyl group having a specified number of carbon atoms, and the "alkyl" has the definition above.

[0305] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen, and the "halogen" and "alkoxy" have the definitions above.

[0306] As used herein, the term "heteroaryl" refers to an aromatic, monocyclic, bicyclic, or polycyclic fused unsaturated cyclic group containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur as cyclic atoms.

[0307] The modifiers preceding "alkyl", "haloalkyl", "alkoxy" and other groups, such as "C1-C4" and "C3-C6", refer to the range of the number of carbon atoms contained in the defined group.

[0308] The modifiers preceding "heteroaryl" and other groups, such as "4-7" or "6-10", refer to the range of the number of cyclic atoms contained in the defined group.

[0309] As used herein, the term “optionally” means that the event described thereafter may or may not occur. For example, a group “optionally substituted with 1-2 halogens” means unsubstituted, substituted with 1 halogen, or substituted with 2 halogens.

[0310] As used herein, the term "pharmaceutically acceptable salt" means a salt that is physiologically free from undue toxicity, irritation, or allergic reactions. The substance used for salt formation can be an acid or a base, wherein the acid includes inorganic or organic acids that can form a salt with the basic group in the compounds of this invention; and the base includes inorganic or organic bases that can form a salt with the acidic group in the compounds of this invention.

[0311] Unless otherwise specified, the compounds of this invention include all possible stereoisomers and tautomers (e.g., enol and ketone forms). Stereoisomers in this invention include optical isomers (e.g., enantiomers, diastereomers, epimers), cis-trans isomers (e.g., Z-type and E-type), and conformational isomers. Furthermore, single stereoisomers or tautomers, as well as mixtures of stereoisomers and tautomers, are all within the scope of this invention.

[0312] As used herein, in any chemical structure or formula, the bold or scattered wedge-shaped bonds (respectively) attached to the stereoisomer centers of the compound ), representing the absolute stereochemistry of the stereoisomer center, and the relative stereochemistry of the stereoisomer center relative to other stereoisomer centers connected by bold or scattered wedge bonds.

[0313] As used herein, the term "optical isomer" refers to a stable isomer that, due to having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.), has a perpendicular asymmetric plane, thereby enabling the rotation of plane-polarized light. Since the compounds of this invention contain asymmetric centers and other chemical structures that may lead to stereoisomerism, this invention also includes these stereoisomers and mixtures thereof. Because the compounds of this invention and their salts include asymmetric carbon atoms, they can exist as single stereoisomers, racemates, and mixtures of enantiomers and diastereomers. The term "enantiomer" refers to a pair of stereoisomers that have mirror images of each other that cannot be superimposed. The term "diastereomer" or "diastereomer" refers to an optical isomer that does not form a mirror image of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers).

[0314] As used herein, the term "cis-trans isomer" refers to a stereoisomer formed by the different positions of atoms (or groups) on opposite sides of a double bond or ring system relative to a reference plane; in the cis isomer, the atoms (or groups) are on the same side of the double bond or ring system, and in the trans isomer, the atoms (or groups) are on opposite sides of the double bond or ring system. Unless otherwise indicated, all cis-trans isomers of the compounds of this invention are within the scope of this invention.

[0315] As used herein, the term "conformal isomer," also known as "rotational isomer," refers to the different spatial arrangements of atoms or groups resulting from the rotation of single bonds. For example, cyclohexane has two conformational isomers: the boat conformation and the chair conformation. Unless otherwise stated, all conformational isomers of the compounds of this invention are within the scope of this invention.

[0316] As used herein, the term "tautomer," also known as "tautomer form," refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (or proton transfer tautomers) include (but are not limited to) interconversions via proton transfer, such as keto-enol isomerization, imine-enamine isomerization, amide-imine alcohol isomerization, etc. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0317] As used herein, the term "solvent" refers to a substance formed by the combination of a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule through non-covalent intermolecular forces. The term "solvent" includes "hydrate." Common solvates include (but are not limited to) hydrates (e.g., hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanol compounds, acetone compounds, etc.

[0318] As used herein, the term "isotope-labeled compound" refers to a compound formed by replacing specific atoms in a structure with their isotopic atoms. Unless otherwise indicated, the compounds of this invention include various isotopes of H, C, N, O, F, P, S, and Cl, such as... 2 H(D), 3 H(T), 13 C 14 C 15 N、 17 O、 18 O、 18 F, 35 S, 36 S and 37 Cl.

[0319] As used herein, the term "prodrug" refers to a derived compound that, when applied to a patient, can directly or indirectly provide the compounds of the present invention. Particularly preferred are derivative compounds or prodrugs that, when administered to a patient, can improve the bioavailability of the compounds of the present invention (e.g., facilitate absorption into the bloodstream) or promote the delivery of the parent compound to its site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the invention, and various prodrug forms are well known in the art.

[0320] The present invention further prepares specific compounds by the following methods. Unless otherwise specified, the compounds, reagents, etc. used in the embodiments of the present invention are purchased from qualified suppliers or synthesized according to methods disclosed in the prior art.

[0321] abbreviation

[0322] Unless otherwise stated or the context otherwise requires, the following abbreviations in this specification shall be understood to have the following meanings:

[0323]

[0324] Example

[0325] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products. The known starting materials of the present invention can be synthesized using or according to methods known in the art, or are commercially available.

[0326] The structure of the compound was determined by nuclear magnetic resonance and / or mass spectrometry. NMR chemical shifts (δ) were expressed in terms of 10⁻⁶. -6 The unit (ppm) is given. NMR measurements were performed using a BRUKER AVANCE NEO 400MHz NMR spectrometer, with DMSO-d6, CDCl3, and CD3OD as the solvents and TMS as the internal standard. MS measurements were performed using an Agilent 1260 / G6125C.

[0327] Example 1. Synthesis of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-serine (compound 1)

[0328]

[0329] Step 1: Synthesis of O-(tert-butyl)-N-(4-nitropyridin-2-yl)-serine tert-butyl ester (compounds 1-2)

[0330] 2-Bromo-4-nitropyridine (compound 1-1) (1 g, 4.93 mmol) was dissolved in 1,4-dioxane (15 mL), and O-(tert-butyl)-L-serine tert-butyl ester (1.61 g, 7.39 mmol), cesium carbonate (3.19 g, 9.86 mmol), BINAP (1.23 g, 1.97 mmol), and palladium acetate (0.221 g, 0.98 mmol) were added sequentially. After the addition was complete, the mixture was reacted overnight at 100 °C under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 1 / 1, v / v) to give a brown oily substance, which was O-(tert-butyl)-N-(4-nitropyridine-2-yl)-serine tert-butyl ester (compound 1-2) (300 mg, yield: 17.9%).

[0331] LC-MS m / z (ESI): 338.16 [MH] - .

[0332] 1 H NMR (400MHz, CDCl3): δ8.26(d,J=5.5Hz,1H),7.23(dd,J=5.6,1.9Hz,1H),7.19(d,J=1.9Hz,1H),5.66(d,J=8.5Hz,1H),4.72 -4.63(m,1H),3.87(dd,J=8.7,3.4Hz,1H),3.67(dd,J=8.7,3.2Hz,1H),1.46(s,9H),1.18(s,9H).

[0333] Step 2: Synthesis of N-(4-aminopyridin-2-yl)-O-(tert-butyl)-serine tert-butyl ester (compounds 1-3)

[0334] O-(tert-butyl)-N-(4-nitropyridin-2-yl)-serine tert-butyl ester (compounds 1-2) (0.3 g, 0.88 mmol) was dissolved in methanol (5 mL), 10% Pd / C (0.03 g) was added, hydrogen was purged three times, the mixture was stirred at room temperature for 3 hours, filtered, and the filtrate was concentrated to dryness to obtain a yellow oily substance, which is N-(4-aminopyridin-2-yl)-O-(tert-butyl)-serine tert-butyl ester (compounds 1-3) (0.27 g, yield: 98.9%).

[0335] LC-MS m / z (ESI): 308.21 [MH] - .

[0336] Step 3: Synthesis of O-(tert-butyl)-N-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-serine tert-butyl ester (compounds 1-5)

[0337] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compounds 1-4) (0.177 g, 0.5 mmol, prepared by the method disclosed in Example 1 of patent application "WO2022256660A1") was dissolved in anhydrous DMF (5 mL). N-(4-aminopyridin-2-yl)-O-(tert-butyl)-serine tert-butyl ester (compounds 1-3) (0.185 g, 0.6 mmol) and DIPEA (0.129 g, 1 mmol) were added, and the mixture was reacted at room temperature for 5 min. HATU (0.29 g, 0.55 mmol) was added, and the mixture was reacted overnight at room temperature under nitrogen protection. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 1 / 1, v / v) to give a pale yellow solid, which is O-(tert-butyl)-N-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-serine tert-butyl ester (compounds 1-5) (0.15 g, yield: 46.48%).

[0338] LC-MS m / z (ESI): 644.26 [MH] - .

[0339] Step 4: Synthesis of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-serine (Compound 1)

[0340] O-(tert-butyl)-N-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-serine tert-butyl ester (compounds 1-5) (0.15 g, 0.30 mmol) was dissolved in 4M dioxane hydrochloride solution (5 mL) and reacted overnight at room temperature under nitrogen protection. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to preparative high performance liquid chromatography (instrument: Hanbang NP7000; column: Phenomenex Luna 5μm C18(2)). 150*21.2mm; Mobile phase A: 0.1% v / v formic acid; Mobile phase B: acetonitrile; Gradient ratio: 30%~70% v / v acetonitrile; Flow rate: 20mL / min) After purification, lyophilization yielded a white solid, namely (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-serine (compound 1) (0.021g, yield: 16.94%).

[0341] LC-MS m / z (ESI): 534.18 [M+H] + .

[0342] 1 H NMR (400MHz, DMSO-d6): δ10.26 (s, 1H), 7.81 (d, J = 5.7Hz, 1H), 7.21-7.07 (m, 2H),6.98-6.91(m,1H),6.75-6.67(m,1H),6.55(d,J=7.9Hz,1H),5.06(d,J=1 0.3Hz,1H),4.42-4.33(m,1H),4.23(dd,J=10.3,7.6Hz,1H),3.95(d,J=2.1H z,3H),3.78-3.64(m,2H),2.82-2.67(m,1H),1.58(s,3H),0.80-0.64(m,3H).

[0343] Example 2. Synthesis of (5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-serine (compound 2)

[0344]

[0345] Step 1: Synthesis of O-(tert-butyl)-N-(5-nitropyridin-2-yl)-serine tert-butyl ester (compound 2-2)

[0346] 2-Chloro-5-nitropyridine (compound 2-1) (1 g, 6.32 mmol) was dissolved in DMF (15 mL), and O-(tert-butyl)-L-serine tert-butyl ester (1.37 g, 6.32 mmol) and potassium carbonate (2.61 g, 18.96 mmol) were added. After the addition was complete, the mixture was reacted overnight at 100 °C under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 1 / 1, v / v) to give a brown oily substance, which was O-(tert-butyl)-N-(5-nitropyridine-2-yl)-serine tert-butyl ester (compound 2-2) (600 mg, yield: 28.16%).

[0347] LC-MS m / z (ESI): 338.16 [MH] - .

[0348] 1 H NMR (400MHz, CDCl3): δ8.99(d,J=2.7Hz,1H),8.16(dd,J=9.2,2.7Hz,1H),6.47(d,J=9.3Hz,1H),5.98(d,J= 8.2Hz,1H),4.79(s,1H),3.88(dd,J=8.8,3.1Hz,1H),3.68(dd,J=8.8,3.1Hz,1H),1.47(s,9H),1.17(s,9H).

[0349] Step 2: Synthesis of N-(5-aminopyridin-2-yl)-O-(tert-butyl)-serine tert-butyl ester (compound 2-3) O-(tert-butyl)-N-(5-nitropyridin-2-yl)-serine tert-butyl ester (compound 2-2) (0.6 g, 1.77 mmol) was dissolved in methanol (5 mL), 10% Pd / C (0.06 g) was added, the mixture was purged with hydrogen three times, stirred at room temperature for 3 hours under a hydrogen atmosphere, filtered, and the filtrate was concentrated to dryness to obtain a yellow oily substance, which is N-(5-aminopyridin-2-yl)-O-(tert-butyl)-serine tert-butyl ester (compound 2-3) (0.52 g, yield: 98.06%).

[0350] LC-MS m / z (ESI): 308.21 [MH] - .

[0351] Step 3: Synthesis of O-(tert-butyl)-N-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-serine tert-butyl ester (compounds 2-4)

[0352] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compounds 1-4) (0.177 g, 0.5 mmol) was dissolved in anhydrous DMF (5 mL). N-(5-aminopyridin-2-yl)-O-(tert-butyl)-serine tert-butyl ester (compounds 2-3) (0.185 g, 0.6 mmol) and DIPEA (0.129 g, 1 mmol) were added. The mixture was reacted at room temperature for 5 min. HATU (0.29 g, 0.55 mmol) was then added, and the mixture was reacted overnight at room temperature under nitrogen protection. After the reaction was complete, water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 1 / 1, v / v) to give a pale yellow solid, which is O-(tert-butyl)-N-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-serine tert-butyl ester (compounds 2-4) (0.2 g, yield: 62.01%).

[0353] LC-MS m / z (ESI): 644.26 [MH] - .

[0354] Step 4: Synthesis of (5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-serine (compound 2)

[0355] O-(tert-butyl)-N-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)-serine tert-butyl ester (compound 2-4) (0.15 g, 0.30 mmol) was dissolved in 4M dioxane hydrochloride solution (5 mL) and reacted overnight at room temperature under nitrogen protection. The reaction solution was concentrated to dryness under reduced pressure, and the residue was subjected to preparative high performance liquid chromatography (HPLC) (instrument: Hanbang NP7000; column: Phenomenex Luna 5μm C18 (2)). 150*21.2mm; Mobile phase A: 0.1% v / v formic acid; Mobile phase B: acetonitrile; Gradient ratio: 30%~70% v / v acetonitrile; Flow rate: 20mL / min) After purification, lyophilization yielded a white solid, namely (5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)-serine (compound 2) (0.084g, yield: 50.91%).

[0356] LC-MS m / z (ESI): 532.15 [MH] - .

[0357] 1 H NMR (400MHz, DMSO-d6): δ9.94 (d, J=4.0Hz, 1H), 8.08 (dd, J=5.7, 2.6Hz, 1H), 7.61 -7.52(m,1H),7.22-7.08(m,2H),6.61(d,J=8.9Hz,1H),6.49(d,J=8.1Hz,1H),5. 01(d,J=10.4Hz,1H),4.44-4.35(m,1H),4.20(dd,J=10.1,7.8Hz,1H),3.94(d,J= 2.1Hz,3H),3.80-3.65(m,2H),2.80-2.67(m,1H),1.58(s,3H),0.75-0.67(m,3H).

[0358] Example 3. Synthetic route of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)glycine (compound 3)

[0359]

[0360] Step 1: Synthesis of 2-((2-(tert-butoxy)-2-oxoethyl)amino)-4-nitropyridine 1-oxide (compound 3-2)

[0361] 2-Chloro-4-nitropyridine 1-oxide (compound 3-1) (600 mg, 3.44 mmol), glycine tert-butyl ester (541 mg, 4.13 mmol), and DIPEA (889 mg, 6.88 mmol) were dissolved in n-butanol (10 mL) and DMF (2 mL). The mixture was stirred and heated to 120 °C for 2.5 hours until the reaction was complete. The solution was concentrated under reduced pressure and purified by column chromatography (eluent: n-heptane / ethyl acetate = 0–4 / 1, v / v) to obtain a yellow oily substance, which was 2-((2-(tert-butoxy)-2-oxoethyl)amino)-4-nitropyridine 1-oxide (compound 3-2) (500 mg, yield: 53.9%).

[0362] Step 2: Synthesis of (4-aminopyridin-2-yl)glycine tert-butyl ester (compound 3-3)

[0363] 2-((2-(tert-butoxy)-2-oxoethyl)amino)-4-nitropyridine 1-oxide (compound 3-2) (350 mg) was dissolved in methanol (10 mL), Raney nickel (200 mg) was added, hydrogen was purged, and the mixture was stirred overnight at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: n-heptane / ethyl acetate = 0-1 / 1, v / v) to give a yellow oily substance, which is (4-aminopyridin-2-yl)glycine tert-butyl ester (compound 3-3) (210 mg, yield: 72.4%).

[0364] Step 3: Synthesis of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)glycine tert-butyl ester (compounds 3-4)

[0365] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-4) (299 mg, 0.85 mmol) was dissolved in DMF (10 mL). HATU (536 mg, 1.41 mmol), DIPEA (364 mg, 2.82 mmol), and (4-aminopyridin-2-yl)glycine tert-butyl ester (compound 3-3) (210 mg, 0.94 mmol) were added sequentially to the reaction mixture. The mixture was stirred overnight at room temperature. Add water (100 mL) and EA (50 mL) to the liquid, stir and extract, collect the organic phase, wash the organic phase with saturated brine (20 mL * 2), concentrate under reduced pressure, and purify by column chromatography (eluent: n-heptane / ethyl acetate = 0 ~ 2 / 1, v / v) to obtain a yellow oily substance, which is (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)glycine tert-butyl ester (compound 3-4) (260 mg, yield: 49.4%).

[0366] LC-MS m / z(ESI):504.26[M+H-tBu] + .

[0367] Step 4: Synthesis of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)glycine (compound 3)

[0368] (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)glycine tert-butyl ester (compounds 3-4) (210 mg) was dissolved in DCM (4 mL). 4M 1,4-dioxane hydrochloride solution (5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 7 hours. After concentration under reduced pressure, the reaction solution was purified by preparative chromatography (instrument: SHIMADZU RFC-40; column: Kromasil classic C18 250*50 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium formate) and acetonitrile, gradient ratio: acetonitrile 30%-90% v / v, flow rate: 80 mL / min) to obtain a white solid (compound 3) (30.9 mg, yield: 16.4%).

[0369] LC-MS m / z (ESI): 504.20 [M+H] + .

[0370] 1 H NMR (400MHz, DMSO-d6): δ10.26 (s, 1H), 7.82 (d, J = 5.7Hz, 1H), 7.21-7.14 (m, 1H), 7.10(t,J=7.6Hz,1H),6.93(d,J=1.8Hz,1H),6.84-6.82(m,1H),6.67(dd,J=5.7,1 .8Hz,1H),5.05(d,J=10.3Hz,1H),4.23(dd,J=10.3,7.6Hz,1H),3.95(d,J=2.1Hz, 3H), 3.87 (d, J = 5.4Hz, 2H), 2.76 (q, J = 7.4Hz, 1H), 1.58 (s, 3H), 0.76-0.67 (m, 3H).

[0371] Example 4. Synthetic route of (2R,3S,4S,5R)-N-(6-(2-amino-1-hydroxy-2-oxoethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 4)

[0372]

[0373] Step 1: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-iodopyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 4-1)

[0374] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compounds 1-4) (427 mg, 1.21 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (535 mg, 4.22 mmol) and 1 drop of DMF were added under ice bath conditions. The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (10 mL) and cooled to 0 °C for later use. 2-Iodo-5-aminopyridine (318 mg, 1.45 mmol) and triethylamine (610 mg, 6.0 mmol) were dissolved in dichloromethane (5 mL) and added dropwise to the prepared dichloromethane solution at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: n-heptane / ethyl acetate = 0-4 / 1, v / v) to give a white solid (compound 4-1) (480 mg, yield: 71.6%).

[0375] LC-MS m / z (ESI): 557.03 [M+H] + .

[0376] Step 2: Synthesis of methyl 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-oxoacetate (compound 4-2)

[0377] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-iodopyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 4-1) (480 mg, 0.82 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, a 1 M solution of magnesium isopropyl bromide in tetrahydrofuran (5 mL) was added, and the reaction was carried out at room temperature for 1 hour. Dimethyl oxalate (1.02 g, 8.63 mmol) was added under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined. The organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: n-heptane / ethyl acetate = 0-4 / 1, v / v) to give a white solid (compound 4-2) (195 mg, yield: 43.8%).

[0378] Step 3: Synthesis of methyl 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-hydroxyacetate (compound 4-3)

[0379] Methyl 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-oxoacetate (compound 4-2) (190 mg, 0.37 mmol) was dissolved in methanol (30 mL). Sodium triacetoxyborohydride (1.17 g, 5.52 mmol) was added to the reaction solution under ice bath conditions, and the mixture was stirred for 30 minutes. After quenching the reaction solution with saturated ammonium chloride solution, the organic phase was removed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (20 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: n-heptane / ethyl acetate = 0-1 / 1, v / v) to give a white solid (compound 4-3) (150 mg, yield: 78.9%).

[0380] LC-MS m / z (ESI): 519.15 [M+H] + .

[0381] 1 H NMR (400MHz, DMSO-d6): δ10.48 (s, 1H), 8.69 (dd, J = 4.3, 2.5Hz, 1H), 8.09-8.05 (m,1H),7.48(d,J=8.5Hz,1H),7.22-7.14(m,2H),6.25(d,J=6.1Hz,1H),5.16(d ,J=5.7Hz,1H),5.12(d,J=10.3Hz,1H),4.26(dd,J=10.3,7.7Hz,1H),3.97(d,J= 2.1Hz,3H),3.62(s,3H),2.78(p,J=7.5Hz,1H),1.62(s,3H),0.77-0.73(m,3H).

[0382] Step 4: Synthesis of (2R,3S,4S,5R)-N-(6-(2-amino-1-hydroxy-2-oxoethyl)pyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 4)

[0383] Methyl 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)-2-hydroxyacetate (compound 4-3) (50 mg, 0.09 mmol) was dissolved in 7 M ammonia-methanol solution (6 mL) and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative chromatography (instrument: SHIMADZU RFC-40, column: Kromasil classic C18 250*50 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium formate) and acetonitrile, gradient ratio: acetonitrile 30%-90% v / v, flow rate: 80 mL / min) to give a white solid (compound 4) (10 mg, yield: 20.1%).

[0384] LC-MS m / z (ESI): 504.30 [M+H] + .

[0385] 1H NMR (400MHz, DMSO-d6): δ10.46(s,1H),8.71(t,J=2.7Hz,1H),8.03(dt,J=8.5,2 .6Hz,1H),7.44(d,J=8.5Hz,1H),7.39(s,1H),7.26(s,1H),7.19(t,J=5.5Hz,2H) ,5.97(s,1H),5.12(d,J=10.3Hz,1H),4.90(s,1H),4.26(dd,J=10.2,7.7Hz,1H), 3.97(d,J=2.1Hz,3H),2.79(p,J=7.6Hz,1H),1.63(s,3H),0.76(d,J=6.0Hz,3H).

[0386] Example 5.2 Synthetic route of 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-hydroxyacetic acid (compound 5)

[0387]

[0388] Step 1: Synthesis of 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-hydroxyacetic acid (compound 5)

[0389] Methyl 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-hydroxyacetate (compound 4-3) (50 mg, 0.09 mmol) was dissolved in dichloroethane. Trimethyltin hydroxide (52 mg, 0.29 mmol) was added to the reaction solution, and the mixture was heated to 80 °C and reacted for 8 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), and the pH was adjusted to 3-4 by adding 5% hydrochloric acid solution. The organic phase was collected. The organic phase was washed with saturated brine (10 mL * 2) and concentrated under reduced pressure to obtain an oily substance. The oily substance was purified by preparative chromatography (instrument: SHIMADZU RFC-40, column: Kromasil classic C18 250*50mm, 5μm; mobile phase: aqueous phase (10mmol / L ammonium formate) and acetonitrile, gradient ratio: acetonitrile 30%-90% v / v, flow rate: 80mL / min) to give a white solid (compound 5) (8mg, yield: 16.3%).

[0390] LC-MS m / z (ESI): 505.30 [M+H] + .

[0391] 1 H NMR (400MHz, DMSO-d6): δ10.43(d,J=18.8Hz,1H),8.74-8.56(m,1H),7.99(dd,J=34.3,8.5Hz,1H),7.36(dd,J=55.7,8.5Hz,1H),7.21-7.15(m,2H) ,5.11(d,J=10.3Hz,1H),4.57(d,J=37.8Hz,1H),4.31-4.22(m,1H),3.968 -3.963(m,4H),2.78(p,J=7.4Hz,1H),1.62(s,3H),0.75(d,J=6.3Hz,3H).

[0392] Example 6. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-guanidinopyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 6)

[0393]

[0394] Step 1: Synthesis of (4-nitropyridin-2-yl)tert-butyl carbamate (compound 6-2)

[0395] 4-Nitropyridine-2-amine (compound 6-1) (5.00 g, 35.94 mmol) was added to acetonitrile (50 mL) and stirred. Then, 4-dimethylaminopyridine (4.39 g, 35.94 mmol), triethylamine (4.36 g, 43.12 mmol), and di-tert-butyl dicarbonate (9.41 g, 43.12 mmol) were added sequentially, and the mixture was stirred overnight at room temperature under nitrogen atmosphere. Dichloromethane (50 mL) was added to the reaction mixture, and the mixture was washed successively with water, saturated ammonium chloride solution, saturated sodium bicarbonate solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a pale yellow oil (compound 6-2) (3.27 g, yield: 38.03%). The crude product was directly added to the next reaction step.

[0396] Step 2: Synthesis of (4-aminopyridin-2-yl)carbamate tert-butyl ester (compound 6-3)

[0397] (4-Nitropyridin-2-yl)tert-butyl carbamate (compound 6-2) (3.00 g, 12.54 mmol) was added to methanol (50 mL), followed by the addition of 10% Pd / C (1.00 g). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to give a grayish-white solid (compound 6-3) (1.90 g, yield: 72.41%).

[0398] Step 3: Synthesis of (E)-((1H-pyrazol-1-yl)(2,2,2-trifluoroacetamido)methylene)tert-butyl carbamate (compound 6-5)

[0399] (E)-(amino(1H-pyrazol-1-yl)methylene)tert-butyl carbamate (compound 6-4) (2.00 g, 9.51 mmol) was added to dichloromethane (10 mL), and the mixture was cooled and stirred in an ice-water bath under nitrogen atmosphere. Trifluoroacetic anhydride (2.00 g, 9.52 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated to dryness under reduced pressure. The concentrated substrate was then stirred and slurried in dichloromethane (4 mL) at room temperature, filtered, and washed to give a white solid (compound 6-5) (743 mg, yield: 25.50%).

[0400] LC-MS m / z (ESI): 305.10 [MH] - .

[0401] Step 4: Synthesis of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)tert-butyl carbamate (compound 6-6)

[0402] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compounds 1-4) (400 mg, 1.13 mmol) and (4-aminopyridin-2-yl)carbamate tert-butyl ester (compound 6-3) (307 mg, 1.47 mmol) were added to acetonitrile (20 mL) and stirred. Then, N-methylimidazolium (325 mg, 3.96 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (380 mg, 1.35 mmol) were added to the reaction mixture, and the mixture was stirred overnight at room temperature under nitrogen. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed with water, saturated ammonium chloride solution, and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 5 / 1, v / v) and concentrated to give a light white solid (compound 6-6) (196 mg, yield: 31.82%).

[0403] LC-MS m / z (ESI): 546.30 [M+H] + .

[0404] Step 5: Synthesis of (2R,3S,4S,5R)-N-(2-aminopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compounds 6-7)

[0405] (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)tert-butyl carbamate (compound 6-6) (190 mg, 0.35 mmol) was added to 1,4-dioxane (10 mL), and 4M 1,4-dioxane hydrochloride solution (20 mL) was slowly added dropwise with stirring. The mixture was stirred overnight at room temperature. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed with 7% sodium carbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a pale yellow oil (compound 6-7) (250 mg). The crude product was directly added to the next reaction step.

[0406] LC-MS m / z (ESI): 444.10 [MH] - .

[0407] Step 6: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-guanidino(tert-butoxycarbonyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compounds 6-8)

[0408] (2R,3S,4S,5R)-N-(2-aminopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 6-7) (250 mg, 0.15 mmol) and (E)-((1H-pyrazol-1-yl)(2,2,2-trifluoroacetamido)methylene)tert-butyl carbamate (compound 6-5) (214 mg, 0.70 mmol) were added to tetrahydrofuran (10 mL) and stirred overnight at room temperature under nitrogen. The above reaction solution was added dropwise to a methanol (10 mL) solution of potassium bicarbonate (701 mg, 7.00 mmol) and stirred at room temperature for 4 h. The reaction solution was then added to ethyl acetate (30 mL), washed first with saturated ammonium chloride solution and then with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 3 / 1, v / v) and concentrated to give a light white solid (compounds 6-8) (91 mg, yield: 27.60%).

[0409] LC-MS m / z (ESI): 588.40 [M+H] + .

[0410] Step 7: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-guanidinopyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 6)

[0411] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-guanidino(tert-butyloxycarbonyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compounds 6-8) (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane (10 mL), and then slowly added dropwise to a 4M solution of 1,4-dioxane hydrogen chloride (25 mL). The mixture was stirred overnight at room temperature. The reaction solution was concentrated to dryness and purified by preparative liquid chromatography (instrument: SHIMADZU RFC-40; column: Kromasil ETC18 10μm 250*30mm I.D; mobile phase A: 0.1% v / v trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 55%–95% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to obtain a white solid (compound 6) (9 mg, yield: 12.05%).

[0412] LC-MS m / z (ESI): 488.30 [M+H] + .

[0413] 1 H NMR (400MHz, DMSO-d6): δ10.77(s,1H),10.70(s,1H),8.20-8.13(m,4H),8.13(3H),7.59(d,J=1.6Hz,1H),7.23(dd,J=5.8,1.8Hz,1H),7.20-7 .08(m,2H),5.10(d,J=10.1Hz,1H),4.26(dd,J=10.1,7.7Hz,1H),3.95(t,J=4.9Hz,3H),2.82-2.72(m,1H),1.59(s,3H),0.74(d,J=6.4Hz,3H).

[0414] Example 7. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-guanidinylpyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 7)

[0415]

[0416] Step 1: Synthesis of (5-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)tert-butyl carbamate (compound 7-1)

[0417] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compounds 1-4) (200 mg, 0.56 mmol), tert-butyl (5-aminopyridin-2-yl)carbamate (153 mg, 0.73 mmol) were added to acetonitrile (20 mL) and stirred. N-methylimidazolium (160 mg, 1.95 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (189 mg, 0.67 mmol) were added and stirred at room temperature under nitrogen atmosphere for 4 h. Ethyl acetate (30 mL) was added to the reaction solution, and the mixture was washed with water, saturated ammonium chloride solution, and saturated brine. The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a pale yellow oily substance (compound 7-1) (302 mg, yield: 98.06%). The crude product was directly added to the next reaction step.

[0418] LC-MS m / z (ESI): 544.30 [MH] - .

[0419] Step 2: Synthesis of (2R,3S,4S,5R)-N-(6-aminopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 7-2)

[0420] (5-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)tert-butyl carbamate (compound 7-1) (300 mg, 0.55 mmol) was added to 1,4-dioxane (10 mL), and a 4M solution of 1,4-dioxane hydrogen chloride (30 mL) was slowly added dropwise with stirring. The mixture was stirred overnight at room temperature. Ethyl acetate (30 mL) was added to the reaction mixture, and the mixture was washed with 7% sodium carbonate solution and saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give a pale yellow oil (compound 7-2) (240 mg, yield: 95.83%). The crude product was directly added to the next reaction step.

[0421] LC-MS m / z (ESI): 444.20 [MH] - .

[0422] Step 3: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-guanidino(tert-butoxycarbonyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 7-3)

[0423] (2R,3S,4S,5R)-N-(6-aminopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 7-2) (230 mg, 0.52 mmol) and (E)-((1H-pyrazol-1-yl)(2,2,2-trifluoroacetamido)methylene)carbamate tert-butyl ester (203 mg, 0.66 mmol) were added to tetrahydrofuran (10 mL), and the mixture was stirred overnight at room temperature under nitrogen. The above reaction solution was then added dropwise to a methanol (10 mL) solution of potassium bicarbonate (652 mg, 6.50 mmol), and the mixture was stirred at room temperature for 4 h. The reaction solution was first washed with saturated ammonium chloride solution and saturated brine, then the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain a pale yellow oily substance (compound 7-3) (298 mg, yield: 98.22%). The crude product was directly added to the next step of the reaction.

[0424] LC-MS m / z (ESI): 586.30 [MH] - .

[0425] Step 4: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-guanidinylpyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 7)

[0426] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-guanidino(tert-butoxycarbonyl)pyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 7-3) (295 mg, 0.50 mmol) was dissolved in dichloromethane (10 mL) and stirred in an ice-water bath under nitrogen protection. Trifluoroacetic acid (1.76 g, 15.44 mmol) was added dropwise, and the mixture was allowed to react overnight at room temperature. The reaction solution was concentrated to dryness and purified by preparative liquid chromatography (instrument: SHIMADZU RFC-40; column: Kromasil W C18 10μm 250*50mm ID; mobile phase A: 0.1% v / v trifluoroacetic acid; mobile phase B: acetonitrile; gradient: 35%–75% v / v acetonitrile; flow rate: 80 mL / min; wavelength: 210 / 254 nm) to give a white solid (compound 7) (71 mg, yield: 29.01%).

[0427] LC-MS m / z (ESI): 488.30 [M+H] + .

[0428] 1 H NMR (400MHz, DMSO-d6): δ10.88(s,1H),10.48(s,1H),8.58(d,J=2.5Hz,1H),8.24-8.04(m,3H),8.06(dd,J=8.9,2.6Hz,1H),7.17(m,2H),7.04 (d,J=8.9Hz,1H),5.08(d,J=10.3Hz,1H),4.24(dd,J=10.2,7.8Hz,1H),3.95(d,J=2.0Hz,3H),2.76(m,1H),1.60(s,3H),0.73(d,J=6.1Hz,3H).

[0429] Example 8. Synthesis of (2R,3S,4S,5R)-N-(2-(2-amino-1-hydroxy-2-oxoethyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 8)

[0430]

[0431] Step 1: Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-iodopyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 8-1)

[0432] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compounds 1-4) (700 mg, 1.98 mmol) was dissolved in dichloromethane (15 mL), and oxaloyl chloride (877 mg, 6.92 mmol) and 5 drops of DMF were added under ice bath conditions. The reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (15 mL) and cooled to 0 °C for later use. 2-Iodo-4-aminopyridine (522 mg, 2.37 mmol) and triethylamine (1.0 g, 9.88 mmol) were dissolved in dichloromethane (10 mL) and added dropwise to the prepared dichloromethane solution. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (eluent: n-heptane / ethyl acetate = 0-4 / 1, v / v) to give a white solid (compound 8-1) (880 mg, yield: 80.1%).

[0433] Step 2: Synthesis of methyl 2-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-oxoacetate (compound 8-2)

[0434] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-iodopyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 8-1) (880 mg, 1.58 mmol) was dissolved in tetrahydrofuran (10 mL). Under nitrogen protection, the reaction solution was cooled to zero degrees Celsius, and 1 M isopropyl magnesium bromide solution in tetrahydrofuran (10 mL) was added dropwise. The reaction was allowed to return to room temperature for 1 hour, then cooled to zero degrees Celsius, and the solution was added dropwise. Add dimethyl oxalate (2.24 g, 19 mmol), raise the temperature to room temperature and react for 2 hours. After the reaction is complete, add saturated ammonium chloride solution dropwise to quench the reaction mixture. Extract with ethyl acetate (20 mL * 3), combine the organic phases, wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and purify by column chromatography (eluent: n-heptane / ethyl acetate = 0–4 / 1, v / v) to give a white solid (compound 8-2) (440 mg, yield: 53.6%).

[0435] Step 3: Synthesis of methyl 2-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-hydroxyacetate (compound 8-3)

[0436] Methyl 2-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridin-2-yl)-2-oxoacetate (compound 8-2) (440 mg, 0.85 mmol) was dissolved in methanol (30 mL). Sodium triacetoxyborohydride (3.62 g, 17 mmol) was added to the reaction solution under ice bath conditions, and the mixture was stirred for 30 minutes. The reaction solution was quenched with saturated ammonium chloride solution, and the organic phase was removed by concentration under reduced pressure. The solution was extracted with ethyl acetate (20 mL x 2), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: n-heptane / ethyl acetate = 0–1 / 1, v / v) to give a white solid (compound 8-3) (330 mg, yield: 74.7%).

[0437] LC-MS m / z (ESI): 519.16 [M+H] + .

[0438] Step 4: Synthesis of (2R,3S,4S,5R)-N-(2-(2-amino-1-hydroxy-2-oxoethyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 8)

[0439] Methyl 2-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamate)pyridin-2-yl)-2-hydroxyacetic acid (compound 8-3) (330 mg, 0.62 mmol) was dissolved in 7M ammonia-methanol solution (10 mL) and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain an oily substance. The oily substance was purified by preparation (instrument: SHIMADZU RFC-40; chromatographic column: Kromasil ET C18 10 μm 250*50 mm I.D; mobile phase A: 10 mM ammonium formate; mobile phase B: acetonitrile; gradient: 30%–90% v / v acetonitrile; flow rate: 80 mL / min; wavelength: 210 / 254 nm), and lyophilized to obtain a white solid, namely compound 8.

[0440] Compound 8 was chirally resolved (instrument: SHIMADZU RFC-40; column: AD-H 5μm 250*10mm I.D; mobile phase A: n-hexane; mobile phase B: anhydrous ethanol; A:B = 85:15, v / v; flow rate: 7 mL / min; wavelength: 210 / 254 nm) to give white solids, namely compound 8-a (30 mg, RT = 8.2 min) and compound 8-b (40 mg, RT = 10.9 min).

[0441] 8-a:

[0442] LC-MS m / z (ESI): 504.20 [M+H] + .

[0443] 1 H NMR (400MHz, DMSO-d6): δ10.62(s,1H),8.37(d,J=5.5Hz,1H),7.72(d,J=2.0Hz,1H),7.5 6(dd,J=5.6,2.1Hz,1H),7.38(d,J=2.5Hz,1H),7.26(d,J=2.7Hz,1H),7.17-7.12(m,2H) ,5.95(d,J=5.2Hz,1H),5.08(d,J=10.3Hz,1H),4.87(d,J=5.2Hz,1H),4.24(dd,J=10.3, 7.6Hz,1H),3.95(d,J=2.1Hz,3H),2.77(p,J=7.5Hz,1H),1.60(s,3H),0.76-0.69(m,3H).

[0444] 8-b:

[0445] LC-MS m / z (ESI): 504.30 [M+H] + .

[0446] 1H NMR (400MHz, DMSO-d6): δ10.61(s,1H),8.37(d,J=5.6Hz,1H),7.72(d,J=2.1Hz,1H),7 .56(dd,J=5.6,2.1Hz,1H),7.38(s,1H),7.28-7.23(m,1H),7.19-7.10(m,2H),5.95(d, J=5.2Hz,1H),5.08(d,J=10.2Hz,1H),4.87(d,J=5.2Hz,1H),4.24(dd,J=10.2,7.6Hz, 1H),3.95(d,J=2.1Hz,3H),2.77(p,J=6.9,6.3Hz,1H),1.60(s,3H),0.76-0.69(m,3H).

[0447] Example 9. Synthesis of 2-(2-amino-1-hydroxy-2-oxoethyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine 1-oxide (compound 9)

[0448]

[0449] Step 1: Synthesis of (2-iodopyridin-4-yl)tert-butyl carbamate (compound 9-2)

[0450] 2-Iodopyridine-4-amine (compound 9-1) (2 g, 9.09 mmol) was dissolved in dichloromethane (40 mL), and triethylamine (1.38 g, 13.63 mmol) and Boc2O (5.95 g, 27.27 mmol) were added sequentially. After the addition was complete, the mixture was stirred at 50 °C for 16 hours. The mixture was then cooled to room temperature, and water (40 mL) was added. The mixture was separated, extracted with dichloromethane (30 mL × 2), and the organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0–1 / 2, v / v) to give an off-white solid (compound 9-2) (2.58 g, yield: 88.67%).

[0451] LC-MS m / z (ESI): 319.22 [MH] - .

[0452] Step 2: Synthesis of methyl 2-(4-(tert-butoxycarbonyl)amino)pyridin-2-yl)-2-oxoacetate (compound 9-3)

[0453] (2-Iodopyridin-4-yl)carbamate tert-butyl ester (compound 9-2) (2.58 g, 8.06 mmol) was dissolved in tetrahydrofuran (30 mL). Under nitrogen protection, a 1 M isopropyl magnesium bromide tetrahydrofuran solution (40 mL, 40 mmol) was slowly added dropwise in an ice-water bath. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 1 hour. Then, the mixture was placed back in an ice-water bath, and a tetrahydrofuran solution of dimethyl oxalate (9.51 g, 80.63 mmol) was slowly added. 10 mL was added dropwise, and the mixture was allowed to return to room temperature for 2 hours. The reaction was then quenched with saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0–1 / 1, v / v) to give an off-white solid (compound 9-3) (920 mg, yield: 40.69%).

[0454] LC-MS m / z (ESI): 279.10 [MH] - .

[0455] Step 3: Synthesis of methyl 2-(4-(tert-butoxycarbonyl)amino)pyridin-2-yl)-2-hydroxyacetate (compound 9-4)

[0456] Methyl 2-(4-(tert-Butoxycarbonyl)amino)pyridin-2-yl)-2-oxoacetate (compound 9-3) (920 mg, 3.28 mmol) was dissolved in methanol (10 mL). Sodium triacetoxyborohydride (2.08 g, 9.85 mmol) was added under an ice-water bath, and the mixture was stirred at room temperature for 1 h after the addition was complete. The reaction was quenched by adding a small amount of saturated ammonium chloride solution, concentrated to dryness under reduced pressure, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0–4 / 1, v / v) to give an off-white solid (compound 9-4) (450 mg, yield: 48.56%).

[0457] 1 H NMR (400MHz, DMSO-d6): δ9.89(s,1H),8.24(d,J=5.6Hz,1H),7.65(d,J=2.1Hz,1H),7.30(dd ,J=5.6,2.1Hz,1H),6.20(d,J=6.0Hz,1H),5.09(d,J=5.9Hz,1H),3.61(s,3H),1.49(s,9H).

[0458] LC-MS m / z (ESI): 281.11 [MH] - .

[0459] Step 4: Synthesis of methyl 2-(4-((tert-butyloxycarbonyl)amino)pyridin-2-yl)-2-((tert-butyldimethylsilyl)oxy)acetate (compounds 9-5)

[0460] Methyl 2-(4-(tert-Butoxycarbonyl)amino)pyridin-2-yl)-2-hydroxyacetate (compound 9-4) (0.45 g, 1.59 mmol) was dissolved in DMF (10 mL), and TBSCl (0.78 g, 4.78 mmol) and imidazole (0.54 g, 7.97 mmol) were added sequentially. The reaction was carried out at room temperature for 3 h under nitrogen protection. After the reaction was completed, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0–1 / 1, v / v) to give a white solid (compound 9-5) (0.56 g, yield: 88.61%).

[0461] LC-MS m / z (ESI): 395.20 [MH] - .

[0462] Step 5: Synthesis of 4-((tert-butyloxycarbonyl)amino)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methoxy-2-oxoethyl)pyridine 1-oxide (compound 9-6)

[0463] 2-(4-((tert-Butoxycarbonyl)amino)pyridin-2-yl)-2-((tert-Butyldimethylsilyl)oxy)methyl acetate (compound 9-5) (0.56 g, 1.41 mmol) was dissolved in dichloromethane (6 mL). M-chloroperoxybenzoic acid (0.72 g, 4.24 mmol) was added under ice-water bath conditions. After addition, the mixture was allowed to return to room temperature for 1 h. The reaction was quenched with sodium thiosulfate aqueous solution (5 mL), followed by the addition of water (10 mL). The mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0–1 / 9, v / v) to give an off-white solid (compound 9-6) (0.42 g, yield: 72.09%).

[0464] 1H NMR (400MHz, DMSO-d6): δ10.11(s,1H),8.11(d,J=7.1Hz,1H),7.73(d,J=3.0Hz,1H),7.50(dd, J=7.1,3.1Hz,1H),5.35(s,1H),3.60(s,3H),1.49(s,9H),0.92(s,9H),0.13(d,J=13.7Hz,6H).

[0465] LC-MS m / z (ESI): 411.20 [MH] - .

[0466] Step 6: Synthesis of 4-amino-2-(1-((tert-butyldimethylsilyl)oxy)-2-methoxy-2-oxoethyl)pyridine 1-oxide (compounds 9-7)

[0467] 4-((tert-Butoxycarbonyl)amino)-2-(1-((tert-Butyldimethylsilyl)oxy)-2-methoxy-2-oxoethyl)pyridine 1-oxide (compound 9-6) (0.42 g, 1.02 mmol) was dissolved in dichloromethane (5 mL), and TFA (1 mL) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed, the solution was concentrated under reduced pressure to dryness to obtain crude product (0.49 g), which was directly added to the next step without purification.

[0468] LC-MS m / z (ESI): 313.15 [M+H] + .

[0469] Step 7: Synthesis of 2-(1-((tert-butyldimethylsilyl)oxy)-2-methoxy-2-oxoethyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine 1-oxide (compounds 9-8)

[0470] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compounds 1-4) (0.33 g, 0.93 mmol) was dissolved in acetonitrile (10 mL), and crude trifluoroacetate of 4-amino-2-(1-((tert-butyldimethylsilyl)oxy)-2-methoxy-2-oxoethyl)pyridine 1-oxide (compounds 9-7) (0.49 g) and TCFH (0.3 g, 0.3 mmol) were added sequentially. 9 g (1.39 mmol) and NMI (0.38 g, 4.65 mmol) were stirred at room temperature for 3 h. The reaction solution was concentrated to dryness under reduced pressure, water (10 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0–1 / 9, v / v) to give a pale yellow solid (compound 9-8) (0.30 g, yield 49.66%).

[0471] LC-MS m / z (ESI): 647.23 [MH] - .

[0472] Step 8: Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-(1-hydroxy-2-methoxy-2-oxoethyl)pyridine 1-oxide (compound 9-9)

[0473] 2-(1-((tert-butyldimethylsilyl)oxy)-2-methoxy-2-oxoethyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine 1-oxide (compound 9-8) (0.30 g, 0.46 mmol) was dissolved in THF (10 mL), and TBAF (1.20 g) was added. The mixture was stirred at room temperature for 3 hours (4.62 mmol). After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0–1 / 3, v / v) to give a pale yellow solid (compound 9-9) (0.17 g, yield: 68.77%).

[0474] LC-MS m / z (ESI): 533.20 [MH] - .

[0475] Step 9: Synthesis of 2-(2-amino-1-hydroxy-2-oxoethyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbamoyl)pyridine 1-oxide (compound 9)

[0476] 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-(1-hydroxy-2-methoxy-2-oxoethyl)pyridine 1-oxide (compound 9-9) (0.17 g, 0.32 mmol) was dissolved in methanol (4 mL). 7 M ammonia-methanol solution (4 mL) was added in an ice-water bath. After the addition was complete, the mixture was allowed to return to room temperature and reacted overnight. The reaction solution was concentrated to dryness under reduced pressure. The solution was then purified by preparative separation (chromatographic column: WatersAcQuiTYCSH, C18, 1.7 μm, 2.1*100 mm; mobile phase A: 0.1% v / v formic acid; mobile phase B: acetonitrile) to give a white solid (compound 9) (24.5 mg, yield: 14.83%).

[0477] 1 H NMR (400MHz, DMSO-d6): δ10.78 (s, 1H), 8.23 ​​(d, J = 7.1Hz, 1H), 8.16-8.09 (m, 1H), 7.89(dd,J=6.5,3.1Hz,1H),7.72-7.63(m,1H),7.35-7.30(m,1H),7.22-7.08(m,2 H),6.09(s,1H),5.46-5.40(m,1H),5.09(d,J=10.2Hz,1H),4.24(dd,J=10.2,7.7 Hz,1H),3.95(d,J=2.0Hz,3H),2.82-2.70(m,1H),1.60(s,3H),0.76-0.68(m,3H).

[0478] LC-MS m / z (ESI): 518.40 [MH] - .

[0479] Biological evaluation

[0480] Experimental Example 1. The effect of the compound on human Na v 1.8 Determination of inhibitory activity

[0481] The purpose of the experiment was to detect the effect of the compound on human-derived sodium in in vitro experiments. v 1.8 Effect of ion channels. Human Na+... v1.8 Ion channels were stably expressed on CHO (Chinese hamster ovary cells) cells. In Na... v 1.8 After the current stabilizes, compare the Na before and after the application of the compound. v 1.8 The magnitude of the current can be used to obtain the reaction of the compound with Na. v 1.8 The effect of ion channels.

[0482] 1. Experimental Materials and Instruments

[0483] 1) Patch clamp amplifier HEKA (Germany) EPC 10

[0484] 2) Micromanipulator Sutter Instrument (USA) MP225

[0485] 3) Electrode drawing instrument Sutter Instrument (USA) P97

[0486] 4) Glass capillary tube Sutter Instrument (USA) BF150-86-10

[0487] 5) Inverted microscope Mshot (China) MF53

[0488] 6) Longer Pump (China) BT100-2J peristaltic pump

[0489] 7) Dimethyl sulfoxide (DMSO) Sigma D4540

[0490] 2 Experimental Procedure

[0491] 2.1 Compound Preparation

[0492] The reagents for preparing intracellular and extracellular fluids were purchased from Amresco, cesium fluoride from Innochem, and the rest from Sigma.

[0493] Extracellular fluid: 140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O; pH adjusted to 7.4 with NaOH.

[0494] Intracellular fluid: 50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, 20mM EGTA; pH adjusted to 7.2 with CsOH.

[0495] The test compound was stored at a concentration of 10 mM and dissolved in dimethyl sulfoxide. It was then dissolved in extracellular fluid on the day of testing to prepare the required concentration.

[0496] 2.2 Cell Culture

[0497] Prior to patch-clamp assay, cells were separated using 0.25% trypsin-EDTA, and 6.5 × 10⁶ cells were collected. 3 The cells were seeded onto a coverslip and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, the cells were tested.

[0498] 2.3 Manual Patch Clamp Test Procedure

[0499] Whole-cell patch-clamp recording of Na v The voltage stimulation protocol for 1.8 current is as follows: After whole-cell sealing is achieved, the cell voltage is clamped at -120mV. First, the voltage is stepped from -110mV to -20mV in 10mV increments and maintained for 5 seconds. Then, a 0mV depolarization pulse is applied, and the peak value of the inward current is measured to obtain the half-inactivation voltage (V). half The resting state and half-inactivated state of sodium current were detected using a dual-pulse mode. First, a depolarization pulse (TP1) was applied to 0 mV for 50 ms to detect the sodium current in the resting state. Then, a conditional voltage of V was adjusted between the two depolarization pulses. half The voltage was maintained for 5 seconds, then restored to -120 mV and maintained for 20 ms to allow the unbound and inactive channels to recover. A second depolarization pulse (TP2) was then applied to 0 mV for 50 ms to detect the sodium current in the semi-inactive state. Finally, the voltage was restored to the clamp voltage of -120 mV, and data were collected repeatedly at 20-second intervals to observe the effect of the drug on the peak sodium current in the two different states.

[0500] The patch-clamp procedure begins by using a microelectrode puller to draw a capillary glass tube into a recording electrode. The electrode, filled with intracellular fluid, is then inserted into a microelectrode holder. A coverslip containing cells is placed in a recording bath under an inverted microscope. Under the microscope, the microelectrode manipulator is manipulated to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ high-resistance seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded.

[0501] Once the current amplitude stabilized in the control extracellular solution, drug administration began. After each drug concentration reached equilibrium (approximately 5 minutes), the next concentration was measured. The control extracellular solution and the working solution of the test compound were sequentially flowed through the recording bath from low to high concentration using gravity perfusion, thereby acting on the cells. Simultaneously, a peristaltic pump was used for fluid replacement during recording. Each concentration was measured independently and repeatedly. All electrophysiological experiments were performed at room temperature.

[0502] All experiments were conducted in the presence of 100 nM TTX in the extracellular fluid to block endogenous TTX-S (tetrodotoxin-sensitive type) Na+ in cells. + Electric current.

[0503] 2.4 Data Analysis

[0504] The test data were acquired by the EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0505] During data analysis, the peak sodium current after each drug concentration was first determined. compound Peak current of blank control Control Normalized, then calculate the inhibition rate corresponding to each drug concentration under different conditions, i.e., Inhibition% = (1 - (Peak current)) / (Peak current) compound / Peakcurrent Control *100%. The mean (Mean), standard deviation (SD), and standard error (SE) of the inhibition rate were calculated for each concentration, and the data are expressed as Mean ± SE. Based on different drug concentrations and their corresponding inhibition rates, IC50 was performed using GraphPad Prism software. 50 Curve plotting, data analysis, and final IC calculation. 50 value.

[0506] The compounds of this invention have effects on human Na+. v The inhibitory activity of 1.8 was determined by the above experiments, and the results are shown in Table 2.

[0507] Table 2. Effects of the compounds of this invention on human Na+ v 1.8% inhibitory activity

[0508] Compound numbering Inhibition rate (%) @ 1 nM Inhibition rate (%) @ 10 nM <![CDATA[Na v 1.8 IC 50 (nM)]]> 1 / / 9.3 2 / / 10.1 3 4.6 24.8 / 4 0.67 12.4 / 5 5.9 31.9 / 6 / / 1.2 7 21.6 73.9 / 8 51.21 92.91 / 8-a / / 1.6 8-b / / 0.8

[0509] Conclusion: The compounds in this invention are effective against human Na+. v The 1.8 channel activity was significantly inhibited, and the IC50 of some compounds was significantly reduced. 50 It can reach the 1nm level.

[0510] Experimental Example 2. Compound's effect on Na v Ion channel subtype selectivity test

[0511] The purpose of this experiment was to detect the effects of the compound on human sodium ion channel cells (Na+) in vitro. v 1.1,Na v 1.2,Na v 1.3,Na v 1.4,Na v 1.5,Na v 1.6,Na v 1.7) Effect. After the Na current stabilizes, comparing the magnitude of the Na current before and after the application of the compound can reveal the compound's effect on the Na ion channel.

[0512] 1. Experimental Materials and Instruments

[0513] 1) Patch clamp amplifier HEKA (Germany) EPC 10

[0514] 2) Micromanipulator Sutter Instrument (USA) MP285

[0515] 3) Electrode drawing instrument Sutter Instrument (USA) P97

[0516] 4) Glass capillary tube Sutter Instrument (USA) BF150-86-10

[0517] 5) Inverted microscope Mshot (China) MF53

[0518] 6) Longer Pump (China) BT100-2J peristaltic pump

[0519] 7) Data acquisition software HEKA (Germany) PatchMaster

[0520] 8) Dimethyl sulfoxide (DMSO) Sigma D4540

[0521] 2 Experimental Procedure

[0522] 2.1 Compound Preparation

[0523] The reagents used to prepare intracellular and extracellular fluids were cesium chloride purchased from Amresco, cesium fluoride from Innochem, and the rest from Sigma.

[0524] Extracellular fluid: 140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O; pH adjusted to 7.4 with NaOH.

[0525] Intracellular fluid: 50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, 20mM EGTA; pH adjusted to 7.2 with CsOH.

[0526] The test compound was stored at a concentration of 10 mM and dissolved in dimethyl sulfoxide. It was then dissolved in extracellular fluid on the day of testing to prepare the required concentration.

[0527] 2.2 Cell Culture

[0528] Prior to patch-clamp assay, cells were separated using 0.25% trypsin-EDTA, and 6.5 × 10⁶ cells were collected. 3 The cells were seeded onto a coverslip and cultured in a 24-well plate (final volume: 500 μL). After 18 hours, the cells were tested.

[0529] 2.3 Manual Patch Clamp Test Procedure

[0530] The voltage stimulation protocol for whole-cell patch-clamp recording of Na currents is as follows: After whole-cell sealing, the cell voltage is clamped at -120 mV. First, the voltage is stepped from -110 mV to -20 mV in 10 mV increments and held for 5 s. Then, a 0 mV depolarization pulse is applied, and the peak value of the inward current is measured to obtain the half-inactivation voltage (Vhalf). The resting state and half-inactivated state of the sodium current are detected using a dual-pulse mode. First, a first depolarization pulse (TP1) is applied to 0 mV for 20 ms to detect the resting state sodium current. Then, between the two depolarization pulses, the conditional voltage is adjusted to Vhalf and held for 5 s. Next, the voltage is restored to -120 mV and held for 20 ms to allow the unbound and inactivated channels to recover. A second depolarization pulse (TP2) is then applied to 0 mV for 20 ms to detect the half-inactivated sodium current. Finally, the voltage was restored to the clamping voltage of -120mV, and data was collected repeatedly at 20s intervals to observe the effect of the drug on the peak sodium current in the two different states.

[0531] The patch-clamp procedure begins by using a microelectrode puller to draw a capillary glass tube into a recording electrode. The electrode, filled with intracellular fluid, is then inserted into a microelectrode holder. A coverslip containing cells is placed in a recording bath under an inverted microscope. Under the microscope, the microelectrode manipulator is manipulated to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ high-resistance seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded.

[0532] Once the current amplitude stabilized in the control extracellular solution, drug administration began. After each drug concentration reached equilibrium (approximately 5 minutes), the next concentration was measured. The control extracellular solution and the working solution of the test compound were sequentially flowed through the recording bath from low to high concentration using gravity perfusion, thereby acting on the cells. Simultaneously, a peristaltic pump was used for fluid replacement during recording. Each concentration was measured independently and repeatedly. All electrophysiological experiments were performed at room temperature.

[0533] 2.4 Data Analysis

[0534] The test data were acquired by the EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0535] During data analysis, the peak sodium current after each drug concentration was first determined. compound Peak current of blank control Control Normalized, then calculate the inhibition rate corresponding to each drug concentration under different conditions, i.e., Inhibition% = (1 - (Peak current)) / (Peak current) compound / Peakcurrent Control *100%. The mean, standard deviation (SD), and standard error (SE) of the inhibition rate were calculated for each concentration, and the data are expressed as Mean ± SE. Based on different drug concentrations and their corresponding inhibition rates, IC50 was performed using GraphPad Prism software. 50 Curve plotting, data analysis, and final IC calculation. 50 value.

[0536] The compounds of this invention have effects on human Na+. v The inhibitory activity of the ion channels was determined by the above experiments, and the results are shown in Table 3.

[0537] Table 3. Effects of the compounds of this invention on human sodium at a concentration of 10 μM. v Inhibition rate of subtype

[0538] Compound numbering <![CDATA[Na v 1.5 Inhibition rate (%) 8-a 32.97％ 8-b 30.65％

[0539] Conclusion: The compound in this invention is effective against Na. v Ion channels exhibit good subtype selectivity, particularly for Na+, which may cause cardiac side effects. v 1.5.

[0540] Experimental Example 3. Thermodynamic Solubility

[0541] Take an appropriate amount of the analyte and place it in buffer solutions of different pH values. Shake in a 37°C water bath for 24 hours. After 24 hours, remove the solution, filter it through a filter membrane, collect the filtrate, and dilute the filtrate 1000 times with 50% v / v acetonitrile aqueous solution to obtain the test solution. Take an appropriate amount of the analyte, dissolve and dilute it with 50% v / v acetonitrile aqueous solution to obtain the control solution. The dilution factor of the control solution should be adjusted according to the LC-MS response of the test solution. Detection is performed using LC-MS, and the external standard method is used for calculation. The calculation formula is as follows:

[0542]

[0543] In the formula:

[0544] W STD : Control sample weight, mg;

[0545] A STD : Average peak area of ​​the main peak in the control solution;

[0546] V STD : The dilution factor of the control solution;

[0547] A SPM : Peak area of ​​the main peak in the test solution;

[0548] V SPM The dilution factor of the test solution;

[0549] 1000: Conversion factor between mg and μg.

[0550] The thermodynamic solubility of the compounds of the present invention was tested using the above method, and the results are shown in Table 4.

[0551] Table 4. Thermodynamic solubility of the compounds of this invention in different media (unit: μg / ml)

[0552] Compound numbering PBS (pH 1.2) PBS (pH 3.0) PBS (pH 4.5) PBS (pH 7.4) 8 / / / 40.4 8-b 903.5 158.2 10.8 3.3

[0553] Conclusion: The compounds in this invention have good solubility in different media.

[0554] Experimental Example 4. Caco-2 Permeability Test

[0555] The experiment used monolayers of Caco-2 (ATCC) cells, incubated in 96-well Corning Insert plates. A transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing either the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), naldolol (2 μM), and metoprolol (2 μM) was added to the dosing well on the apical or basal side. A transport buffer solution containing DMSO was added to the corresponding receiving well. The plate was incubated for 2 hours at 37.0 °C, 5% CO2, and saturated humidity in a CO2 incubator without shaking. All samples were mixed with stop solution and centrifuged at 3220 × g for 10 minutes. The samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the present invention and the control compounds. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to the basal side and from the basal to the apical side of the monolayer cells, thereby calculating the efflux ratio (ER). The integrity of the monolayer cells after 2 hours of incubation was evaluated by the leakage of fluorescein.

[0556] The permeability of the compounds of the present invention was tested using the methods described above, and the results are shown in Table 5.

[0557] Table 5. Caco-2 permeability of the compounds of this invention

[0558]

[0559] Conclusion: The compounds in this invention have good permeability.

[0560] Experimental Example 5. Liver Microsomal Metabolic Stability Test

[0561] 1. Transfer the microparticle solution (100 μL) to all reaction plates (blank, T0, T5, T15, T30, T45, T60, NCF60).

[0562] 2. Add the compound working solution (2 μL) to all 96-well reaction plates (T0, T5, T15, T30, T45, T60, NCF60) except for the blank.

[0563] 3. Pre-incubate all reaction plates containing the mixture of compounds and microparticles at 37°C for 10 minutes.

[0564] 4. Add 100mM potassium phosphate buffer (98μL) to the NCF60 reaction plate.

[0565] 5. Incubate the NCF60 reaction plate at 37°C for 60 minutes.

[0566] 6. After pre-incubation, except for NCF60, add 98 μL of cofactor NADPH working solution to each reaction plate (blank, T0, T5, T15, T30, T45 and T60).

[0567] 7. Incubate the reaction plate at 37°C.

[0568] 8. At the appropriate end time, add 600 μL of stop solution to each reaction plate to terminate the reaction.

[0569] 9. Shake all sample plates for 10 minutes, then centrifuge at 3220×g for 20 minutes at 4℃.

[0570] 10. Transfer the supernatant (600 μL) from each reaction plate to eight new 96-well plates for LC-MS / MS analysis.

[0571] 11. Data analysis: Calculate T based on first-order elimination kinetics. 1 / 2 .

[0572] C t =C0·e -k·t

[0573]

[0574] The microparticle stability of the compounds of the present invention was tested using the methods described above, and the results are shown in Table 6.

[0575] Table 6 Results of liver microsomal stability tests of the compounds of this invention.

[0576]

[0577] Tests have shown that the compounds in this invention exhibit good stability in liver microparticles.

[0578] Experimental Example 6. CYP450 Enzyme Inhibition Test

[0579] The aim of this study was to evaluate the effects of test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro assay system. Specific probe substrates for CYP450 isoenzymes were co-incubated with human liver microsomes and different concentrations of the test substances. Reduced nicotinamide adenine dinucleotide (NADPH) was added to initiate the reaction. After the reaction, the changes in CYP enzyme activity were measured by processing the samples and quantitatively detecting the metabolites produced by the specific substrates using LC-MS / MS, and the IC50 was calculated. 50 The value is used to evaluate the inhibitory potential of the test substance against each CYP enzyme subtype.

[0580] The inhibitory activity of the compounds of the present invention against CYP450 enzymes was tested using the methods described above, and the results are shown in Table 7.

[0581] Table 7 Inhibitory activity of the compounds of the present invention against CYP450 enzyme

[0582] Compound numbering CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A4 8-b ＞50 ＞50 2.98 ＞50 ＞50 VX548 ＞50 17.4 3.74 49.7 ＞50

[0583] Note: The chemical structure of the control compound VX-548 (synthesized according to the method in Example 7 of WO2021113627A1) is shown below.

[0584]

[0585] Testing revealed that the compounds in this invention exhibit weak CYP inhibition and a low risk of drug-drug interactions. Specifically, compound 8-b shows weaker inhibition of CYP2C19 than VX548, suggesting that compound 8-b has better drug-drug interaction safety.

[0586] Experimental Example 7. Pharmacokinetic Test in Mice

[0587] Experimental animals: Male CD-1 (ICR) mice, 6-9 weeks old, 6 mice / compound.

[0588] Experimental Design:

[0589]

[0590] Note: The name of the control compound is (2R,3S,4S,5R)-N-(2-(2-amino-2-oxoacetyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (synthesized according to the method of Example 26 of WO2024041613A1).

[0591] Animals were euthanized with CO2 after the last PK sample was collected. Approximately 0.025 mL of whole blood was collected at specified times via the saphenous vein or other suitable method. The blood collection time points for the intravenous group and the gavage group were as follows:

[0592] Intravenous group: 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours;

[0593] Gavage groups: 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours;

[0594] After collection, all blood samples were transferred to commercially available tubes containing K2-EDTA and placed on wet ice. Within 60 minutes of blood collection, the supernatant plasma was centrifuged at 3200×g for 10 minutes at approximately 4°C (2-8°C) and immediately placed on dry ice. The samples were then stored at -60°C or lower for LC-MS / MS analysis.

[0595] The test results are shown in Table 8.

[0596] Table 8. Pharmacokinetic parameters of the compounds of the present invention in mice.

[0597]

[0598] Conclusion: The compounds in this invention exhibit high blood concentrations, high exposure, low clearance, and high bioavailability in CD-1 mice, demonstrating pharmacokinetic advantages. Compared to the control compound, compound 8-b shows better oral absorption and exposure in mice.

[0599] It should be noted that although the technical solution of the present invention has been described with specific examples, those skilled in the art will understand that the present invention should not be limited thereto.

[0600] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments. The terminology used herein is chosen to best explain the principles, practical application, or technical improvements to the embodiments in the market, or to enable others skilled in the art to understand the embodiments disclosed herein.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof: in: Ring A is a phenyl or a 6-membered heteroaryl group, wherein the heteroatom on the heteroaryl group is optionally oxidized; R a2 The group is selected from H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -CONH2 and -CONH (C1-C4 alkyl), wherein the C1-C4 alkyl or C1-C4 alkoxy is optionally substituted with a group selected from halogen, hydroxy and C1-C4 alkoxy. R a1 Selected from Q is either -NH- or -S-; R 1 and R 2 Each is independently selected from H and C1-C4 alkyl groups; R 3 Selected from H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-COOH, -CH2-CONH2, -(CH2)2-COOH, -(CH2)4-NH2, -(CH2)2-S-CH3, -(CH2)3-NHC(=NH)NH2, -(CH2)2-CONH2, -CH2-OH, -CH(CH3)-OH and -CH2-SH; R 4 Selected from -COOH, -CONH2, and -COO (C1-C4 alkyl); R 5 It is -OH or -NH2; X is either O or S; R d1 and R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl; R c1 and R c2 Each is independently selected from H, C1-C4 alkyl, and C1-C4 haloalkyl; R e For H or D; L is -C(=O)NH-; preferably, the N atom in -C(=O)NH- is connected to ring A; Ring B is a phenyl group or a 6-membered heteroaryl group containing 1-2 nitrogen atoms; R b1 R b2 and R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups, with halogens and C1-C4 alkoxy groups being preferred.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (I-1): Preferably, the compound is as shown in formula (I-1a) or formula (I-1b): Among them, rings A and R a2 Q, X, R d1 R d2 R c1 R c2 R e L, ring B, R b1 R b2 and R b3 As defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, Q is -NH-.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (I-2): Preferably, the compound is as shown in formula (I-2a) or (I-2b): Among them, rings A and R a2 R 1 R 2 R 3 R 4 X, R d1 R d2 R c1 R c2 R e L, ring B, R b1 R b2 and R b3 As defined in claim 1.

5. The compound according to claim 1 or 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, R 1 For H; R 2 Selected from H and C1-C4 alkyl groups; R 3 Selected from H, -CH2-COOH, -CH2-CONH2, -(CH2)2-COOH, -(CH2)2-CONH2, -CH2-OH, -CH(CH3)-OH and -CH2-SH; R 4 Selected from -COOH, -CONH2, and -COO (C1-C4 alkyl); Preferably, R 1 For H; R 2 For H or -CH3; R 3 For H or -CH2-OH; R 4 Selected from -COOH, -CONH2, -COOCH3, and -COOCH2CH3; More preferably, R 1 For H; R 2 For H; R 3 For H or -CH2-OH; R 4 Selected from -COOH, -COOCH3 and -COOCH2CH3.

6. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, The compounds are those shown in formula (I-3): Preferably, the compound is as shown in formula (I-3a) or formula (I-3b): Among them, rings A and R a2 R 4 R 5 X, R d1 R d2 R c1 R c2 R e L, ring B, R b1 R b2 and R b3 As defined in claim 1.

7. The compound according to claim 1 or 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, R 4 Selected from -COOH, -CONH2, -COOCH3, and -COOCH2CH3; R 5 It is -OH; Preferably, R 4 Selected from -COOH and -CONH2; R 5 It is -OH; More preferably, R 4 -CONH2; R 5 It is -OH.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, Ring A is phenyl, pyridyl, or N-oxypyridyl; preferably, ring A is... Preferred in This indicates the location where ring A connects to L, and ring A also connects to R. a1 and R a2 The preferred connection is that ring A is connected to R via a carbon atom adjacent to the nitrogen atom. a1 connect; R a2 Selected from H, halogens, and cyano groups; preferably, R a2 Selected from H, F and cyano; more preferably, R a2 For H; X is O or S; preferably, X is O; R d1 and R d2 Each is independently selected from C1-C2 alkyl and C1-C2 haloalkyl; preferably, R d1 and R d2 Each is independently selected from methyl and trifluoromethyl, and R d1 and R d2 They are not the same; R c1 and R c2 Each is independently selected from H, C1-C2 alkyl, and C1-C2 haloalkyl; preferably, R c1 and R c2 Each is independently selected from H and methyl, and R c1 and R c2 They are not the same; R e For H; Ring B is phenyl or pyridyl; preferably, ring B is phenyl. R b1 R b2 and R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups; preferably, R b1 R b2 and R b3 Each is independently selected from halogens and C1-C4 alkoxy groups; more preferably, R b1 R b2 and R b3 Each is independently selected from F and methoxy; more preferably, R b1 R b2 For F, R b3 It is a methoxy group; Preferably, ring B is R b1 R b2 and R b3 The phenyl groups are connected to the following positions respectively:

9. The following compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotope-labeled substances, or prodrugs:

10. A pharmaceutical composition comprising the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient; More preferably, the pharmaceutically acceptable excipients include one or more of the following: fillers, disintegrants, surfactants, solubilizers, lubricants, wetting agents, thickeners, flow aids, flavoring agents, odor-correcting agents, preservatives, antioxidants, pH adjusters, solvents, and light-blocking agents.

11. A pharmaceutical preparation comprising a compound according to any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label or prodrug, or a pharmaceutical composition according to claim 10; Preferably, the pharmaceutical preparation is a tablet, capsule, granule, sugar-coated pill, powder, lozenge, powder for injection, liquid preparation or suppository.

12. Use of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, or the pharmaceutical composition of claim 10, or the pharmaceutical formulation of claim 11, in the preparation of a medicament for inhibiting voltage-gated sodium channels; Preferably, the voltage-gated sodium channel is Na v 1.

8.

13. Use of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label or prodrug thereof, or the pharmaceutical composition of claim 10 or the pharmaceutical formulation of claim 11 in the preparation of a medicament for the prevention, relief and / or treatment of voltage-gated sodium channel-related diseases or conditions; Preferably, the voltage-gated sodium channel is Na v 1.8; and / or, Preferably, the voltage-gated sodium channel-related diseases or conditions include pain, arthritis, epilepsy or epilepsy symptoms, neurodegenerative diseases, mental disorders (preferably anxiety or depression), bipolar disorder, myotonia, movement disorders, neuroendocrine disorders, ataxia, irritable bowel syndrome, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis (ALS), stress- or exercise-induced angina, palpitations, hypertension, multiple sclerosis, Sharma-Turia syndrome, peroneal muscular atrophy, incontinence, pathological cough, arrhythmia, and abnormal gastrointestinal activity.

14. Use of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, or the pharmaceutical composition of claim 10, or the pharmaceutical formulation of claim 11, in the preparation of a medicament for the prevention, relief, and / or treatment of pain.

15. The use according to claim 13 or 14, characterized in that, The pain includes migraine, cluster headache, acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain; Preferably, the acute pain includes acute postoperative pain; Preferably, the intestinal pain includes inflammatory bowel disease pain and Crohn's disease pain; Preferably, the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuralgia, trigeminal neuralgia, neuralgia caused by burn syndrome, post-amputation pain, phantom limb pain, neuralgia caused by painful neuroma, neuralgia caused by traumatic neuroma, neuralgia caused by Morton's neuroma, neuralgia caused by nerve entrapment injury, neuralgia caused by spinal stenosis, neuralgia caused by carpal tunnel syndrome, nerve root pain, sciatica, neuralgia caused by nerve tearing injury, neuralgia caused by brachial plexus tearing injury, neuralgia caused by complex regional pain syndrome, neuralgia caused by drug therapy, neuralgia caused by cancer chemotherapy, neuralgia caused by antiretroviral therapy, pain after spinal cord injury, neuralgia caused by small fiber neuropathy, neuralgia caused by idiopathic small fiber neuropathy, neuralgia caused by idiopathic sensory neuropathy, and neuralgia caused by trigeminal autonomic neuropathy. Preferably, the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burning pain, and toothache; Preferably, the inflammatory pain includes rheumatoid arthritis pain, vulvar pain, and interstitial cystitis pain; Preferably, the idiopathic pain includes fibromyalgia; Preferably, the postoperative pain includes pain from bunion removal surgery, hernia repair surgery, and abdominoplasty. Preferably, the visceral pain includes acute abdominal pain, tumor-related visceral pain, angina pectoris, and visceral pain caused by abdominoplasty.

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