Substituted tetrahydrofuran derivative, and preparation method therefor and use thereof

Abstract

Disclosed in the present application are a compound as represented by formula (I), a pharmaceutically acceptable salt, a stereoisomer, a tautomer, or an N-oxide, and the use thereof in the preparation of a drug for treating, preventing or alleviating voltage-gated sodium ion channel-related diseases.

Description

Substituted tetrahydrofuran derivatives, preparation method and use thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry, in particular to a substituted tetrahydrofuran derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative or N-oxide thereof, a preparation method thereof, and a use thereof as a Nav1.8 inhibitor and a use thereof in the preparation of a drug for treating and / or alleviating pain and pain-related diseases. BACKGROUND

[0002] Pain is a complex psychophysiological activity, and is one of the most common symptoms in clinical practice. The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, which is a subjective experience". Pain can serve as a warning signal to alert the body to potential danger, and has an indispensable protective effect on normal life activities. At the same time, pain is also a common clinical symptom. Intense or persistent pain after the disappearance of the external stimulus that triggers pain can cause physiological dysfunction and seriously affect the quality of life of living beings. Statistical data shows that about one-fifth of the world's population suffers from moderate to severe chronic pain.

[0003] Pain originates from nociceptors in the peripheral nervous system. These are free nerve endings widely distributed in the skin, muscles, joints and internal organs of the whole body, which can convert the heat, mechanical or chemical stimuli they feel into nerve impulses (action potentials) and transmit them to their cell body part located in the dorsal root ganglion (DRG) via afferent nerve fibers, and ultimately to the high-level neural center, causing pain. The generation and conduction of action potentials in neurons, in turn, depend on voltage-gated sodium channels (Nav) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated, the channel is opened, and the sodium ion influx occurs, which causes the cell membrane to be further depolarized, leading to the generation of action potentials. Therefore, inhibiting abnormal sodium ion channel activity helps to treat and relieve pain.

[0004] Voltage-gated sodium channels (Nav) are a class of transmembrane ion channel proteins. These proteins are composed of an α subunit with a molecular weight of 260 kD and a β subunit with a molecular weight of 30-40 kD. According to the different α subunits, they can be divided into 9 subtypes, Nav1.1-Nav1.9. Different subtypes show different tissue distribution and electrophysiological and pharmacological characteristics. According to whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), sodium channels are divided into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) types. Among them, Nav1.1, Nav1.2, Nav1.3 and Nav1.7 are TTX-S type, and the encoding gene is located on human chromosome 2q23-24, which is highly expressed in neurons. Nav1.5, Nav1.8 and Navl.9 are TTX-R type, and the encoding gene is located on human chromosome 3p21-24. Among them, Nav1.5 mainly exists in myocardial cells, and Nav1.8 and Nav1.9 exist in the peripheral nervous system. Nav1.4 and Nav1.6 are both TTX-S type, and are highly expressed in skeletal muscle and central nervous system, respectively.

[0005] Nav1.8 is a TTX-R type, and its encoding gene SCN10A mainly exists in trigeminal ganglion neurons and DRG neurons, with the electrophysiological characteristics of slow inactivation and rapid recovery. In neurons expressing Nav1.8, the rising of action potential is mainly composed of Nav1.8 current. In some models of studying neuropathic pain, nerve injury can increase the expression level of Nav1.8 in axons and neuronal cell bodies. Using Nav1.8 antisense oligonucleotides can significantly alleviate pain while reducing the expression of Nav1.8. After intracapsular injection of carrageenan in rats, the expression of Nav1.8 in DRG neurons increases. Nav1.8 knockout mice cannot exhibit normal visceral inflammatory pain. After the human Nav1.8 gene produces a functional gain-of-function mutation, it can cause peripheral neuropathic pain. According to a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy, which can be used for the treatment of various types of pain such as inflammatory pain, neuropathic pain, postoperative pain, cancer pain, etc.

[0006] The Nav inhibitors used in the clinic have a narrow therapeutic window and limited application because of the lack of subtype selectivity, which can inhibit sodium ion channels expressed in the heart and central nervous system. Nav1.8 is mainly distributed in the peripheral nervous system, so selectively inhibiting Nav1.8 can effectively reduce side effects. Therefore, the application of selective Nav1.8 inhibitors is less likely to cause adverse reactions common to non-selective Nav inhibitors. Nav1.8 is not involved in central nervous system-related activities, so Nav1.8 inhibitors do not have the problem of addiction like opioids, nor do they affect motor function.

[0007] VX548 (Suzetrigine) has been approved for marketing for the treatment of moderate to severe acute pain in adults. However, it has a significant monooxygenated metabolite in the clinic, and its metabolism is greatly affected by CYP3A inhibitors or inducers, and clinical contraindications are associated with drug combination. Therefore, it is necessary to develop Nav1.8 inhibitors with higher activity, better pharmacokinetic properties, and fewer side effects. SUMMARY

[0008] The purpose of the present application is to provide a substituted tetrahydrofuran derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative or N-oxide thereof and a preparation method thereof, so as to screen out small molecule compounds used as Nav1.8 inhibitors with excellent performance in selectivity, effectiveness and safety, etc.

[0009] To achieve the purpose of the present application, the following technical solutions are adopted in the present application:

[0010] In some embodiments, the present application provides a compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative or N-oxide thereof, wherein the compound has the structure of formula (I):

[0011] wherein:

[0012] R a and R b are the same or different, and each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl or C 3-6 cycloalkoxy, wherein the C 1-4 alkyl, C 3-6 cycloalkyl or C 3-6 cycloalkoxy is each independently optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl or alkoxy;

[0013] or R a and R b together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each of said 3-6 membered hydrocarbon ring or 4-6 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, oxo, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

[0014] R c and R d are the same or different and each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, or C 1-4 haloalkyl;

[0015] or R c and R d together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each of said 3-6 membered hydrocarbon ring or 4-6 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, oxo, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

[0016] selected from substituted or unsubstituted phenyl, 5-6 membered heteroaryl containing 1 to 2 atoms selected from N, O, or S atom;

[0017] R 1 are each independently selected from halogen, cyano, -SF5, -S-C 1-6 alkyl, -S-C 1-6 haloalkyl, oxo, -NR 3 R 4 , -C(=O)-R 3 , -C(=O)-NR 3 R 4 , -NR 3 -C(=O)-R 4 , -NR 5 -C(=O)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 , -S(=O) uR 3 -S(=NR) 5 (=O)R 3 -S (=O) u -NR 3 R 4 -NR 3 -S(=O) u -R 4 , -C(=S)-NR 3 R 4 -NR 5 -C(=S)-NR 3 R 4 -P(=O)R 3 R 4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, -O-(C 3-6 cycloalkyl), C 1-6 Haloalkoxy, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl or 4-9 membered heterocyclic, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, -O-(C 3-6 cycloalkyl), C 1-6 The haloalkoxy, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclic group is unsubstituted or further optionally, each independently, is converted to one or more R groups. 01 Replaced; when R 1 When there are multiple R, each 1 Same or different;

[0018] Or two adjacent R 1 The atoms bonded to it together form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocycle, wherein each of the 5-7 membered hydrocarbon rings or 5-7 membered heterocycles is independently and optionally bonded by one or more atoms selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -NR. 3 R 4 C 1-4 Alkyl, hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Substituents of haloalkoxy groups;

[0019] R 3 R 4 R 5They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, halogenated C 1-4 Alkyl, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 Alkyl), -O-(halogenated C) 1-4 alkyl) or -O-(C 3-6 cycloalkyl), wherein the -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, halogenated C 1-4 Alkyl, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 Alkyl), -O-(halogenated C) 1-4 alkyl) or -O-(C 3-6 (Cycloalkyl) is unsubstituted or further, independently and optionally, substituted by one or more R 01 Replaced;

[0020] Or R 3 R 4 Together with the atoms they are attached to, they form 5-7 membered heterocycles, wherein each of the 5-7 membered heterocycles is independently and optionally bounded by one or more R atoms. 01 Replaced;

[0021] R 2 Each is independently selected from deuterium, halogen, hydroxyl, cyano, -SF5, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 Alkyl, -O-(C 1-4 Alkyl), -O-(halogenated C) 1-4 alkyl), -O-(C 3-6 cycloalkyl), -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl or 4-9 membered heterocyclic, wherein the -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6alkynyl, halogenated C 1-4 Alkyl, -O-(C 1-4 Alkyl), -O-(halogenated C) 1-4 alkyl), -O-(C 3-6 The cycloalkyl, 3-7-membered cycloalkyl, 4-7-membered cycloalkenyl, or 4-9-membered heterocyclic groups are unsubstituted or further, each independently and optionally, are occupied by one or more R groups. 01 Replaced; when R 2 When there are multiple R, each 2 Same or different;

[0022] Each R 01 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, oxo, and -NR. 3 R 4 -C(=O)-R 3 -C(=O)-NR 3 R 4 -NR 3 -C(=O)-R 4 -NR 5 -C(=O)-NR 3 R 4 -C(=NR) 5 )-NR 3 R 4 -S (=O) u R 3 -S(=NR) 5 (=O)R 3 -S (=O) u -NR 3 R 4 -NR 3 -S(=O) u -R 4 , -C(=S)-NR 3 R 4 -NR 5 -C(=S)-NR 3 R 4 -P(=O)R 3 R 4 C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, -O-(C 3-6 cycloalkyl), -(OC 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4alkyl), -O-(C 1-4 haloalkyl), C 3-6 cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl, wherein said C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, -O-(C 3-6 cycloalkyl), -(O-C 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), C 3-6 cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl are each independently optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -NR 3 R 4 , C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

[0023] m is 1, 2, or 3;

[0024] n is 1, 2, 3, or 4;

[0025] u is 0, 1, or 2;

[0026] v is 0, 1, 2, or 3.

[0027] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein the compound has the structure of Formula (I):

[0028] wherein:

[0029] R a and R b are the same or different and each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, or C 3-6 cycloalkoxy, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6each independently optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, or alkoxy;

[0030] or R a and R b together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, oxo, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

[0031] R c and R d are the same or different, and each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, or C 1-4 haloalkyl;

[0032] or R c and R d together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, oxo, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

[0033] selected from substituted or unsubstituted phenyl, 5-6 membered heteroaryl containing 1 to 2 atoms selected from N, O, or S atoms;

[0034] R 1 each independently selected from halogen, cyano, -SF5, oxo, -NR 3 R 4 , -C(=O)-R 3 , -C(=O)-NR 3 R 4 , -NR 3 -C(=O)-R 4 , -NR 5 -C(=O)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 , -S(=O) uR 3 -S(=NR) 5 (=O)R 3 -S (=O) u -NR 3 R 4 -NR 3 -S(=O) u -R 4 -N = S( = NR) 5 )R 3 R 4 -C(=S)-NR 3 R 4 -NR 5 -C(=S)-NR 3 R 4 -P(=O)R 3 R 4 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, -O-(C 3-6 cycloalkyl), C 1-6 Haloalkoxy, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl or 4-9 membered heterocyclic, wherein the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, -O-(C 3-6 cycloalkyl), C 1-6 The haloalkoxy, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclic group is unsubstituted or further optionally, each independently, is converted to one or more R groups. 01 Replaced; when R 1 When there are multiple R, each 1 Same or different;

[0035] Or two adjacent R 1 The atoms bonded to it together form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocycle, wherein each of the 5-7 membered hydrocarbon rings or 5-7 membered heterocycles is independently and optionally bonded by one or more atoms selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -NR. 3 R 4 C 1-4 Alkyl, hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Substituents of haloalkoxy groups;

[0036] R 3R 4 R 5 are identical or different and each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, -N-(C 1-4 alkyl)2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, halogen-C 1-4 alkyl, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(halogen-C 1-4 alkyl) or -O-(C 3-6 cycloalkyl), wherein said -N-(C 1-4 alkyl)2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, halogen-C 1-4 alkyl, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(halogen-C 1-4 alkyl) or -O-(C 3-6 cycloalkyl) is unsubstituted or further each independently optionally substituted with one or more R 01 ;

[0037] or R 3 , R 4 together with the atom to which they are attached form a 5-7 membered heterocyclic ring, wherein said 5-7 membered heterocyclic ring is each independently optionally substituted with one or more R 01 ;

[0038] R 2 is each independently selected from the group consisting of deuterium, halogen, hydroxyl, cyano, -SF5, -N-(C 1-4 alkyl)2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen-C 1-4 alkyl, -O-(C 1-4 alkyl), -O-(halogen-C 1-4 alkyl), -O-(C 3-6 cycloalkyl), 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl or 4-9 membered heterocyclyl, wherein said -N-(C 1-4 alkyl)2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen-C1-4 alkyl, -0-(C 1-4 alkyl), -0-(haloC 1-4 alkyl), -0-(C 3-6 cycloalkyl), 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl is unsubstituted or further each independently optionally substituted by one or more R 01 , when R 2 is multiple, each R 2 is the same or different;

[0039] each R 01 is each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, oxo, -NR 3 R 4 , -C(=0)-R 3 , -C(=0)-NR 3 R 4 , -NR 3 -C(=0)-R 4 , -NR 5 -C(=0)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 , -S(=0) u R 3 , -S(=NR 5 )(=0)R 3 , -S(=0) u -NR 3 R 4 , -NR 3 -S(=0) u -R 4 , -N=S(=NR 5 )R 3 R 4 , -C(=S)-NR 3 R 4 , -NR 5 -C(=S)-NR 3 R 4 , -P(=0)R 3 R 4 , C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, -0-(C 3-6 cycloalkyl), -(0-C 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4alkyl)-0-(C 1-4 alkyl), -0-(C 1-4 haloalkyl), C 3-6 cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl, wherein said C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, -0-(C 3-6 cycloalkyl), -(O-C 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-0-(C 1-4 alkyl), -0-(C 1-4 haloalkyl), C 3-6 cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl are each independently further optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -NR 3 R 4 , C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy;

[0040] m is 1, 2, or 3;

[0041] n is 1, 2, 3, or 4;

[0042] u is 0, 1, or 2;

[0043] v is 0, 1, 2, or 3.

[0044] In some embodiments, R a and R b are the same or different, and each is independently selected from hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy, or C 3-6 cycloalkyl, said C 1-4 alkyl, or C 3-6 cycloalkyl is each independently optionally substituted with one or more substituents selected from F, Cl, Br, cyano, hydroxyl, or alkoxy;

[0045] or R a and R b together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein said 3-6 membered hydrocarbon ring or 4-6 membered heterocyclic ring is each independently optionally substituted with one or more substituents selected from deuterium, F, Cl, Br, C1-4 alkyl, C 1-4 alkoxy, C 1-4 fluoroalkyl, or C 1-4 fluoroalkoxy, substituted with one or more substituents selected from F, Cl, Br, cyano, hydroxy, or alkoxy.

[0046] In some preferred embodiments, R a and R b are the same or different, and each is independently selected from C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, C 3-4 cycloalkyl, or C 3-4 cycloalkoxy, each independently optionally substituted with one or more substituents selected from F, Cl, Br, cyano, hydroxy, or alkoxy; 3-4 cycloalkyl, or C 3-4 cycloalkoxy, each independently optionally substituted with one or more substituents selected from F, Cl, Br, cyano, hydroxy, or alkoxy;

[0047] or R a and R b together with the atom to which they are attached form a 3-5 membered hydrocarbon ring or a 4-5 membered heterocyclic ring, wherein each of said 3-5 membered hydrocarbon ring or 4-5 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, fluorine, methyl, ethyl, -OMe, -OEt, -CF3, -CF2H, -CFH2, or C 1-4 fluoroalkoxy, substituted with one or more substituents selected from F, Cl, Br, cyano, hydroxy, or alkoxy.

[0048] In some preferred embodiments, R a is selected from methyl, ethyl, isopropyl, -CF3, -CF2H, -CFH2, or cyclopropyl; R b is selected from hydroxy, cyano, methyl, ethyl, isopropyl, -OMe, -OEt, -CF3, -CF2H, -CFH2, fluoroalkoxy, cyclopropyl, or -CH2OH;

[0049] or R a and R b together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each of said 3-6 membered hydrocarbon ring or 4-6 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, fluorine, methyl, ethyl, -OMe, -OEt, -CF3, -CF2H, -CFH2, or C 1-4 fluoroalkoxy, substituted with one or more substituents selected from F, Cl, Br, cyano, hydroxy, or alkoxy.

[0050] In some preferred embodiments, R a is selected from methyl, ethyl, isopropyl, -CF3, -CF2H, or -CFH2; R b is selected from hydroxy, cyano, methyl, ethyl, isopropyl, -OMe, -OEt, -CF3, -CF2H, or -CFH2.

[0051] In some preferred embodiments, R a and R b are the same or different, and each is independently selected from -CF3, methyl; preferably, R a is -CF3, and R b is methyl.

[0052] In some embodiments, R c and R d are the same or different, and each is independently selected from hydrogen, deuterium, fluorine, cyano, hydroxyl, methyl, ethyl, hydroxyalkyl, -OMe, -OEt, -CF3, -CF2H, or -CFH2;

[0053] or R c and R d together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, each independently optionally substituted with one or more substituents selected from deuterium, fluorine, cyano, hydroxyl, methyl, ethyl, hydroxyalkyl, -OMe, -OEt, -CF3, -CF2H, -CFH2, or CF 1-4 fluoroalkoxy.

[0054] In some preferred embodiments, R c is selected from hydrogen or deuterium; R d is selected from hydrogen, deuterium, fluorine, hydroxyl, methyl, or -OMe;

[0055] or R c and R d together with the atom to which they are attached form a 3-5 membered hydrocarbon ring or a 4-5 membered oxygen heterocyclic ring, each independently optionally substituted with one or more substituents selected from deuterium, fluorine, hydroxyl, methyl, ethyl, -OMe, or fluoromethyl.

[0056] In some preferred embodiments, R c and R d are the same or different, and each is independently selected from hydrogen, deuterium; preferably, R c and R d are both hydrogen;

[0057] or R c and R d together with the atom to which they are attached form a 3-4 membered hydrocarbon ring or a 4-5 membered oxygen heterocyclic ring, each independently optionally substituted with one or more substituents selected from deuterium, fluorine, hydroxyl, methyl, ethyl, -OMe, or fluoromethyl.

[0058] In some embodiments, The N-oxide is selected from substituted or unsubstituted phenyl, pyridine, pyridine N-oxide, pyrimidine, pyrimidine N-oxide, pyrazine, pyrazine N-oxide, pyridazine, pyridazine N-oxide, pyrazole, pyrazole N-oxide, oxazole, oxazole N-oxide, isoxazole, isoxazole N-oxide, thiophene, thiazole, or thiazole N-oxide; preferably selected from substituted or unsubstituted pyridine, pyridine N-oxide, thiazole, or thiazole N-oxide; more preferably selected from substituted or unsubstituted pyridine or pyridine N-oxide.

[0059] In some implementation schemes, It is selected from substituted or unsubstituted phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole, isoxazole, thiophene or thiazole; preferably selected from substituted or unsubstituted pyridine or thiazole.

[0060] In some preferred embodiments, R 1 Each is independently selected from -C(=O)-NR 3 R 4 -C(=NR) 5 )-NR 3 R 4 , C 1-4 Alkyl groups, preferably selected from -C(=O)-NR 3 R 4 -C(=NR) 5 )-NR 3 R 4 , C 1-3 Alkyl groups, or preferably selected from -C (=NR) 5 )-NR 3 R 4 , Wherein C 1-3 Alkyl or C 1-4 The alkyl group is unsubstituted or further optionally, independently, by one or more R groups. 01 What it replaced.

[0061] In some preferred embodiments, R 1 Each is independently selected from -C(=O)-NR 3 R 4 -C(=NR) 5 )-NR 3 R 4 , C 1-3 Alkyl groups, preferably selected from -C(=O)-NR 3 R 4 -C(=NR)5 )-NR 3 R 4 、 C 1-2 alkyl, or preferably selected from -C(=NR 5 )-NR 3 R 4 、 wherein said C 1-3 alkyl or C 1-2 alkyl is unsubstituted or further each independently optionally substituted with one or more R 01 .

[0062] In some preferred embodiments, R 1 each independently is selected from -C(=O)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 、 C 1-3 alkyl, preferably selected from -C(=NR 5 )-NR 3 R 4 、 optionally, R 3 , R 4 , R 5 are the same or different, and each independently is selected from hydrogen, cyano, C 1-3 alkyl, -(C 1-3 alkyl)-O-(C 1-3 alkyl), wherein said C 1-3 alkyl, -(C 1-3 alkyl)-O-(C 1-3 alkyl) is unsubstituted or further each independently optionally substituted with one or more R 01 , or R 3 , R 4 together with the atom to which they are attached form a 5-6 membered heterocyclic ring, wherein said 5-6 membered heterocyclic ring is each independently optionally substituted with one or more R 01 ; optionally, each R 01 is the same or different, and each independently is selected from hydrogen, deuterium, hydroxyl, -(O-C 1-3 alkyl) v -O-(C 1-3 alkyl).

[0063] In some preferred embodiments, R 1 each independently is selected from -C(=O)-NR 3 R 4 , -C(=NR 5)-NR 3 R 4 、 C 1-2 alkyl, preferably selected from -C(=NR 5 )-NR 3 R 4 、 each R 3 , R 4 , R 5 are identical or different and each independently selected from the group consisting of hydrogen, cyano, C 1-2 alkyl, -(C 1-2 alkyl)-O-(C 1-2 alkyl), wherein said C 1-2 alkyl, -(C 1-2 alkyl)-O-(C 1-2 alkyl) is unsubstituted or further each independently optionally substituted by one or more R 01 , or R 3 , R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring, wherein said 5-6 membered heterocyclic ring is each independently optionally substituted by one or more R 01 ; each R 01 is identical or different and each independently selected from the group consisting of hydroxyl, -(O-C 1-2 alkyl) v -O-(C 1-2 alkyl).

[0064] In some preferred embodiments, R 1 or R 01 substituted R 1 is each independently selected from the group consisting of -C(=O)NH-(C2H5)-O-(C2H5)-O-(C2H5)-OH, -C(=N-CN)-NH2, -C(=O)-NH2, -CH(OH)CH2OH.

[0065] In some preferred embodiments, R 1 or R 01 substituted R 1 is each independently selected from the group consisting of -C(=O)-NH2.

[0066] In some preferred embodiments, R 2 or R 01 substituted R 2 is each independently selected from the group consisting of halogen, -O-(C 1-4 alkyl), -O-(haloC 1-4 alkyl), wherein said -O-(C1-4 Alkyl) or -O- (halogenated C) 1-4 Alkyl groups are unsubstituted or further, independently and optionally, substituted with one or more R groups. 01 Replaced; optionally, each R 01 They may be the same or different, and each is independently selected from deuterium and halogen; optionally, at least one R 01 It is deuterium.

[0067] In some preferred embodiments, R 2 Or be R 01 Replacement R 2 Each is independently selected from halogens, -O-(C 1-3 Alkyl), -O-(halogenated C) 1-4 alkyl), wherein the -O-(C 1-3 Alkyl) or -O- (halogenated C) 1-4 Alkyl groups are unsubstituted or further, independently and optionally, substituted with one or more R groups. 01 Replaced; optionally, each R 01 They may be the same or different, and each is independently selected from deuterium and halogen; optionally, at least one R 01 It is deuterium.

[0068] In some preferred embodiments, R 2 R 01 Replacement, and at least one R 01 It is deuterium.

[0069] In some preferred embodiments, R 2 All the hydrogen in it was R 01 Replace, each R 01 They may be the same or different, and each is independently selected from deuterium and halogens; preferably, R 01 It is deuterium.

[0070] In some preferred embodiments, R 2 Or be R 01 Replacement R 2 Each is independently selected from F, -OCH3, -OCD3,

[0071] In some preferred embodiments, R 2 Or be R 01 Replacement R 2 Each is independently selected from F, -OCD3,

[0072] In some preferred embodiments, R 2 Or be R 01 Replacement R 2each independently selected from F, -OCD3,

[0073] In some embodiments, each R 01 each independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, oxo, -NR 03 R 04 , -C(=O)-R 03 , -C(=O)-NR 03 R 04 , -NR 03 -C(=O)-R 04 , -NR 05 -C(=O)-NR 03 R 04 , -C(=NR 05 )-NR 03 R 04 , -S(=O) u R 03 , -S(=NR 05 )(=O)R 03 , -S(=O) u -NR 03 R 04 , -NR 03 -S(=O) u -R 04 , -C(=S)-NR 03 R 04 , -NR 05 -C(=S)-NR 03 R 04 , -P(=O)R 03 R 04 , C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, -O-(C 3-6 cycloalkyl), -(O-C 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), C 3-6 cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl, wherein the C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, -O-(C3-6 cycloalkyl), -(O-C 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), C 3-6 cycloalkyl, 4-7-membered cycloalkenyl or 4-9-membered heterocyclyl are each independently further optionally substituted with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy;

[0074] R 03 , R 04 , R 05 are the same or different and each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, cyano, -N-(C 1-4 alkyl)2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, haloC 1-4 alkyl, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(haloC 1-4 alkyl) or -O-(C 3-6 cycloalkyl).

[0075] In some preferred embodiments, R a is selected from methyl, ethyl, isopropyl, -CF3, -CF2H or -CFH2;

[0076] R b is selected from hydroxyl, cyano, methyl, ethyl, isopropyl, -OMe, -OEt, -CF3, -CF2H or -CFH2;

[0077] R c is selected from hydrogen or deuterium; R d is selected from hydrogen, deuterium, fluorine, hydroxyl, methyl or -OMe;

[0078] is selected from substituted or unsubstituted pyridine, N-oxide of pyridine, thiazole or N-oxide of thiazole; preferably from substituted or unsubstituted pyridine or N-oxide of pyridine;

[0079] R 1 are each independently selected from -C(=O)-NR3 R 4 , -C(=NR 5 )-NR 3 R 4 , C 1-2 alkyl, preferably selected from -C(=O)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 , Optionally, R 3 , R 4 , R 5 are the same or different and each independently selected from the group consisting of hydrogen, cyano, C 1-2 alkyl, -(C 1-2 alkyl)-O-(C 1-2 alkyl), wherein said C 1-2 alkyl, -(C 1-2 alkyl)-O-(C 1-2 alkyl) is unsubstituted or further each independently optionally substituted with one or more R 01 ; or R 3 , R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring, wherein said 5-6 membered heterocyclic ring is each independently optionally substituted with one or more R 01 ; optionally, each R 01 is the same or different and each independently selected from the group consisting of hydroxyl, -(O-C 1-2 alkyl) v -O-(C 1-2 alkyl);

[0080] R 2 or R 01 substituted R 2 is each independently selected from the group consisting of halogen, -O-(C 1-3 alkyl), -O-(haloC 1-4 alkyl), wherein said -O-(C 1-3 alkyl) or -O-(haloC 1-4 alkyl) is unsubstituted or further each independently optionally substituted with one or more R 01 ; optionally, each R 01 is the same or different and each independently selected from the group consisting of deuterium, halogen; optionally, at least one R 01 is deuterium.

[0081] In some preferred embodiments, R a and R b are the same or different and each independently selected from the group consisting of -CF3, methyl;

[0082] R c and R d are the same or different and each independently selected from the group consisting of hydrogen, deuterium;

[0083] is selected from the group consisting of substituted or unsubstituted pyridine, N-oxide of pyridine, thiazole, or N-oxide of thiazole; preferably selected from the group consisting of substituted or unsubstituted pyridine or N-oxide of pyridine;

[0084] R 1 or R 01 substituted R 1 are each independently selected from the group consisting of -C(=0)NH-(C2H5)-0-(C2H5)-0-(C2H5)-OH, -C(=N-CN)-NH2, -C(=0)-NH2, -CH(OH)CH2OH;

[0085] R 2 or R 01 substituted R 2 are each independently selected from the group consisting of F, -OCH3, -OCD3,

[0086] In some embodiments, the present application includes the above-defined variables and embodiments thereof, and any combination thereof.

[0087] In certain specific embodiments, the present application provides a compound, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or N-oxide thereof, wherein the compound is selected from the group consisting of:

[0088] In another aspect, the present application provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, in the manufacture of a medicament for the treatment, prevention and / or alleviation of a voltage-gated sodium ion channel-associated disease. In an alternative aspect, the present application also provides a method for the treatment, prevention and / or alleviation of a voltage-gated sodium ion channel-associated disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof. In another alternative aspect, the present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, for use in the treatment, prevention and / or alleviation of a voltage-gated sodium ion channel-associated disease. In another alternative aspect, the present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, for the treatment, prevention and / or alleviation of a voltage-gated sodium ion channel-associated disease. More particularly, the voltage-gated sodium ion channel is Nav1.8.

[0089] In another aspect, the present application provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, in the manufacture of a medicament for the treatment, prevention and / or alleviation of pain and pain-associated disorders, multiple sclerosis, incontinence, pathological cough, or cardiac arrhythmia. In an alternative aspect, the present application also provides a method for the treatment, prevention and / or alleviation of pain and pain-associated disorders, multiple sclerosis, incontinence, pathological cough, or cardiac arrhythmia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof. In another alternative aspect, the present application also provides a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, for use in the treatment, prevention and / or alleviation of pain and pain-associated disorders, multiple sclerosis, incontinence, pathological cough, or cardiac arrhythmia. In another alternative aspect, the present application also provides the use of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, for the treatment, prevention and / or alleviation of pain and pain-associated disorders, multiple sclerosis, incontinence, pathological cough, or cardiac arrhythmia.

[0090] In more detail, the present application provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, in the manufacture of a medicament for the treatment, prevention and / or alleviation of pain and pain-associated disorders. In an alternative aspect, the present application also provides a method for the treatment, prevention and / or alleviation of pain and pain-associated disorders, which comprises the administration of a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, to a subject in need of such treatment, prevention and / or alleviation. In another alternative aspect, the present application also provides a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, for use in the treatment, prevention and / or alleviation of pain and pain-associated disorders. In another alternative aspect, the present application also provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, for the manufacture of a medicament for the treatment, prevention and / or alleviation of pain and pain-associated disorders. In this regard, the pain is preferably selected from the group consisting of chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain; and the postoperative pain is preferably selected from the group consisting of bunionectomy pain, herniorrhaphy pain and abdominoplasty pain.

[0091] Definitions

[0092] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to techniques used in the present application is intended to refer to those techniques generally understood by those skilled in the art, including variations or substitutions of techniques that are apparent to those skilled in the art. Although the following terms are believed to be understood by one of ordinary skill in the art, the following definitions are set forth to better explain the present application.

[0093] The compounds described in the present application are named according to the chemical structure formula. If the naming of the compound does not conform to the chemical structure formula when referring to the same compound, the chemical structure formula shall prevail.

[0094] The terms "comprising", "containing", "having" "including" or "involving" and other variants thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0095] The term "alkylene" denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, propylene or butylene.

[0096] The term "alkyl" defines a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 alkyl" refers to a linear or branched chain of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, or n-hexyl) optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halo (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCI3, CH2CF3, CH2CI, or -CH2CH2CF3, etc.). The term "C 1-4 alkyl" refers to a linear or branched chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl).

[0097] The term "alkenyl" means a linear or branched monovalent hydrocarbon radical that contains one double bond and has 2-5 carbon atoms (C 2-5 alkenyl). The alkenyl group is, for example, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the application contain an alkenylene group, the compounds can exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0098] The term "alkynyl" means a linear or branched monovalent hydrocarbon radical that contains one triple bond and has 2-5 carbon atoms (C 2-5 alkynyl). The alkynyl group is, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 2-methyl-2-propynyl, and 4-methyl-3-pentynyl.

[0099] The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including a spiro, fused, or bridged system (such as bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, etc.) optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-6"Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with 1 or more (such as up to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0100] The terms "cycloalkyl" and "cycloalkylene" refer to saturated (i.e., "cycloalkyl" and "cycloalkylene") or unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings of, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including, but not limited to, (cyclo)propyl, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, and the like.

[0101] The terms "heterocyclyl" and "heterocyclylene" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and / or triple bonds within the ring) cyclic group of, for example, 3-10 (suitably 3-8, more suitably 3-6) ring atoms, at least one of which is a heteroatom selected from N, O, and S, and the remainder of which are C, including spiro, fused, or bridged systems. For example, a "3-10 membered (hetero)cyclyl" is a saturated or partially unsaturated (hetero)cyclyl group having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. Examples of heterocyclyl and heterocyclylene groups include, but are not limited to, (hetero)oxiranyl, (hetero)aziridinyl, (hetero)azetidinyl, (hetero)oxetanyl, (hetero)tetrahydrofuranyl, (hetero)dioxolinyl, (hetero)pyrrolidinyl, (hetero)pyrrolidinonyl, (hetero)imidazolidinyl, (hetero)pyrazolidinyl, (hetero)pyrazolinyl, (hetero)tetrahydropyranyl, (hetero)piperidinyl, (hetero)morpholinyl, (hetero)dithianyl, (hetero)thiomorpholinyl, (hetero)piperazinyl, or (hetero)trithianyl. Heterocyclyl and heterocyclylene groups can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0102] The term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0103] The term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic radical having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 carbon atoms and at least one nitrogen atom in the ring which can also optionally contain one or more (e.g., one, two, three, or four) ring members selected from N, O, C=0, S, S=0, and S(=0)2, which is attached to the remainder of the molecule through a nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atom, which is optionally benzo-fused, through a nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring to the remainder of the molecule.

[0104] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0105] If substituents are described as being "selected independently from" a group, each substituent is selected independently of the other(s). Thus, each substituent can be the same or different from the other (other) substituent(s).

[0106] The term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, or 10, under reasonable conditions.

[0107] Herein, in the case of no explicit definition, the substituents R 01 in further substitutions in R 3 , R 4 , and R 5 may be interchanged in turn with R 03 , R 04 , and R 05 , as in -C(=NR 05 )-NR 03 R 04 and -C(=NR 5 )-NR 3 R 4 , R 03 and R 3 , R 4 and R 04 , R 5 and R 05 may be interchanged.

[0108] Unless indicated otherwise, as used herein, the point of attachment of a substituent can come from any suitable position of the substituent.

[0109] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom of the substituted ring.

[0110] This application also includes all pharmaceutically acceptable isotopically labeled compounds identical to those of this application, except that one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number than the dominant atomic mass or mass number found in nature. Examples of isotopes suitable for inclusion in the compounds of this application include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., ... 11 C 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isoforms of iodine (e.g. 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g. 35 S).

[0111] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of this application can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include ketone-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0112] Solid lines may be used in this article. solid wedge Or virtual wedge Carbon-carbon bonds of the compounds of the application are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom indicates that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) are included, including at that carbon atom. The use of solid or dashed wedges to depict bonds to an asymmetric carbon indicates the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise specified, the compounds of the application are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, atropisomers, and mixtures thereof. The compounds of the application can exhibit more than one type of isomerism, and consist of mixtures (e.g., racemic mixtures and diastereomeric pairs) thereof.

[0113] The application encompasses all possible crystalline forms or polymorphs of the compounds of the application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0114] It is also to be understood that certain compounds of the application can exist in free form for treatment, or as appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which upon administration to a patient in need thereof, are capable of providing (directly or indirectly) a compound of the application or a metabolite or residue thereof. Accordingly, as used herein, reference to a "compound of the application" is intended to encompass also the various derivative forms of the compound.

[0115] Pharmaceutically acceptable salts of the compounds of the application include both acid and base addition salts thereof.

[0116] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include hydrochloride, acetate, aspartate, benzoate, bicarbonate / carbonate, gluceptate, gluconate, nitrate, orotate, palmitate, and other similar salts.

[0117] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, choline, magnesium salts, and other similar salts.

[0118] A review of suitable salts is given in "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing the pharmaceutically acceptable salts of the compounds of the application are known to those skilled in the art.

[0119] As used herein, the term "ester" means an ester derived from the various generic compounds of the present application, which includes physiologically hydrolysable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the compounds of the present application). The compounds of the present application can also be esters themselves.

[0120] The compounds of the present application can exist in solvate (preferably hydrate) form, wherein the compound of the present application contains a polar solvent, particularly, for example, water, methanol or ethanol, as a structural element of the crystal lattice of the compound. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric amounts.

[0121] It will be appreciated by those skilled in the art that not all nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize which nitrogen-containing heterocycles are capable of forming N-oxides, for example, the N-oxide of pyridine is It will also be recognized by those skilled in the art that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art. These include oxidation of heterocycles and tertiary amines with peroxy acids such as peroxyacetic acid and m-chloroperbenzoic acid (m-CPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392. A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0122] Also included within the scope of the present application are metabolites of the compounds of the present application, i.e., substances formed in vivo upon administration of a compound of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic cleavage, and the like. Accordingly, the present application includes metabolites of compounds of the present application, including those produced by the contact of a compound of the present application with a mammal to be treated.

[0123] The present application further includes within its scope prodrugs of the compounds of the present application, which are certain derivatives of the compounds of the present application that possess little or no pharmacological activity themselves but, following administration, are converted into compounds of the present application, which are pharmaceutically active, due to enzymatic or chemical processes. In general, such prodrugs will be preservatives of functional groups present in the compounds of the present application, which readily undergo transformation under in vivo conditions to yield the desired compounds of the present application. For additional information on prodrugs, see "Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present application can be prepared by replacing appropriate functionalities present in the compounds of the present application with certain moieties known to those skilled in the art as "pro-moieties" (for example, as described in "Design of Prorugs", H. Bundgaard (Elsevier, 1985).

[0124] The present application also encompasses compounds of the present application that contain protecting groups. During any of the processes for preparation of the compounds of the present application, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned, thus forming protecting groups' versions of compounds of the present application. This can be achieved by means of conventional protecting groups, for example, those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is hereby incorporated by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0125] The term "about" means within ±10% of the stated value, preferably within ±5%, more preferably within ±2%.

[0126] The term "preventing" means administering a compound described herein to prevent a disease or one or more symptoms associated with the disease described herein, including: preventing the disease or condition from occurring in a subject, particularly when such subject is predisposed to the condition but has not yet been diagnosed as having it.

[0127] The term "treating" means administering a compound described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease described herein, including: inhibiting the disease or condition, i.e., arresting its development; or, relieving the disease or condition.

[0128] The term “relief” means administering the compound described in this application to alleviate or reduce one or more symptoms of the disease described in this application or related to the disease, including: alleviating the severity of the disease described in this application, delaying the progression of the disease, or reducing the frequency or duration of the disease.

[0129] (i) suppress a disease or disease state, i.e., curb its development; (ii) alleviate a disease or disease state, or cause the disease or disease state to subside.

[0130] The term "therapeutic effective amount" means the amount of the compound of this application used to treat (i) the specific disease, condition, or disorder described herein, (ii) reduce, improve, or eliminate one or more symptoms of the specific disease, condition, or disorder described herein, or (iii) prevent or delay the onset of one or more symptoms of the specific disease, condition, or disorder described herein. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the subject to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and the present disclosure.

[0131] Unless otherwise stated, the terms “patient,” “subject,” and “individual” are used interchangeably in this document and refer to human or non-human animals (e.g., primates, rodents, etc.), such as, but not limited to, mice, rats, guinea pigs, dogs, pigs, chickens, rabbits, monkeys (e.g., rhesus monkeys, cynomolgus monkeys, etc.), humans, etc.

[0132] Unless otherwise stated, in this document, singular terms cover the plural referents, and vice versa.

[0133] For purposes of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or contents of these documents. Detailed Implementation

[0134] The following detailed description of the present application is provided in conjunction with embodiments, but is not intended to limit the present application. Any equivalent substitutions made in the art based on the disclosure of the present application shall fall within the protection scope of the present application.

[0135] The structure of the compound was determined by mass spectrometry (MS) or nuclear magnetic resonance (NMR). 1 It was determined by HNMR.

[0136] In cases where the wording of compounds in this application conflicts with their structural formulas, the structural formulas shall prevail, unless the structural formulas contain obvious errors.

[0137] Nuclear magnetic resonance (NMR) 1 The ¹H NMR (hydrocarbon NMR) measurements were performed using a Bruker Avance-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard. Chemical shifts were expressed as 10⁻¹⁰ NMR values. -6 (ppm) is given as the unit.

[0138] Mass spectrometry (MS) measurements were performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX).

[0139] Thin-layer silicone uses Yantai Huanghai HSGF254 or Qingdao GF254 silicone sheets.

[0140] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0141] The intermediate SM-1 used in the examples was purchased from Chengdu Ammabio Biopharmaceutical Co., Ltd.

[0142] Unless otherwise specified in this application, all reactions mentioned herein are carried out under N2 protection or a nitrogen atmosphere.

[0143] In the terminology of this application, "N2 protection" or "nitrogen atmosphere" refers, for example, connecting a reaction flask to a 1L nitrogen balloon.

[0144] Unless otherwise specified in this application, the solutions mentioned in the reactions described herein are aqueous solutions.

[0145] In this application, the term "room temperature" refers to a temperature between 10°C and 25°C.

[0146] The abbreviations used in this article have the following meanings:

[0147] Example A: Synthesis of intermediates A-P1(S)-6-(2,2-dimethyl-1,3-dioxolane-4-yl)pyridine-3-amine and A-P2(R)-6-(2,2-dimethyl-1,3-dioxolane-4-yl)pyridine-3-amine

[0148] Step 1: Preparation of compound 5-nitro-2-vinylpyridine (A-1).

[0149] Compound 2-bromo-5-nitropyridine (2 g, 9.85 mmol) was dissolved in a mixture of 1,4-dioxane (40 mL) and water (10 mL), and potassium trifluorovinylborate (3.96 g, 29.56 mmol), potassium carbonate (4.08 g, 29.56 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (357 mg, 0.49 mmol) were added. The reaction system was stirred at 100 °C under a nitrogen atmosphere for 8 hours. After the reaction was completed, water and ethyl acetate were added to dilute the reaction system, and the mixture was separated. The aqueous phase was extracted with ethyl acetate three times, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound A-1 (1.26 g, yield: 85%).

[0150] MS (ESI) m / z: 151.0 [M+H] +

[0151] Second step: Preparation of compound rac-1-(5-nitropyridin-2-yl)ethane-1,2-diol (A-2).

[0152] Compound A-1 (1.26 g, 8.39 mmol) was dissolved in tetrahydrofuran (30 mL), and potassium osmate dihydrate (309 mg, 0.84 mmol) and N-methylmorpholine oxide (2.95 g, 25.18 mmol) were added. The reaction system was stirred at room temperature for 4 hours. After the reaction was completed, the reaction was quenched by adding a saturated sodium thiosulfate solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound A-2 (1.28 g, yield: 83%).

[0153] MS (ESI) m / z: 185.0 [M+H] +

[0154] Third step: Preparation of compound rac-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-5-nitropyridine (A-3).

[0155] Compound A-2 (1.28 g, 6.97 mmol) was dissolved in dichloromethane (30 mL), and p-toluenesulfonic acid (240 mg, 1.39 mmol) and 2,2-dimethoxypropane (3.63 g, 34.83 mmol) were added under ice bath conditions. The reaction system was stirred at room temperature. After the reaction was completed, the reaction system was concentrated to obtain a crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound A-3 (1.43 g, yield: 76%).

[0156] MS (ESI) m / z: 225.0 [M+H] +

[0157] Fourth Step: Preparation of compound rac-6-(2,2-dimethyl-l,3-dioxolan-4-yl)pyridin-3-amine (A).

[0158] Compound A-3 (1.43 g, 6.38 mmol) was dissolved in methanol (10 mL), then 5% palladium on carbon (100 mg) was added, and the reaction system was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered to remove the palladium on carbon, and the filtrate was concentrated to obtain a crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound A (1.14 g, yield: 92%).

[0159] MS (ESI) m / z: 195.0 [M+H] +

[0160] Fifth Step: Preparation of the synthesis of compounds A-P1 (S)-6-(2,2-dimethyl-l,3-dioxolan-4-yl)pyridin-3-amine and A-P2 (R)-6-(2,2-dimethyl-l,3-dioxolan-4-yl)pyridin-3-amine.

[0161] The compound rac-6-(2,2-dimethyl-l,3-dioxolan-4-yl)pyridin-3-amine (A) was prepared by chiral resolution, and the preparation method was as follows:

[0162] Instrument: Prep SFC 150Mgm.

[0163] Column: Daicel CHIRALPAK OD-H 250*30mm 5um.

[0164] Mobile phase: EtOH:CO2-32:68

[0165] Flow rate: 60.0 mL / min.

[0166] Obtained A-P1: (S)-6-(2,2-dimethyl-l,3-dioxolan-4-yl)pyridin-3-amine (retention time 2.952).

[0167] MS (ESI) m / z: 195.0 [M+H] +

[0168] A-P2: (R)-6-(2,2-dimethyl-l,3-dioxolan-4-yl)pyridin-3-amine (retention time 5.034).

[0169] MS (ESI) m / z: 195.0 [M+H] +

[0170] Example B: Synthesis of intermediate N'-(4-aminopyridin-2-yl)-N-(4- methoxybenzyl)-N-methylmethanesulfonimidamide (B)

[0171] First step: Preparation of compound N-(tert-butyldimethylsilyl)methanesulfonamide (B-2).

[0172] Compound B-1 (6.00 g, 63.1 mmol) was dissolved in tetrahydrofuran (60 mL), sodium hydride (1.82 g, 75.7 mmol) was added, stirred at room temperature for 30 minutes, tert-butyldimethylsilyl chloride (11.41 g, 75.7 mmol) was added, and stirring was continued overnight. After the reaction was completed, water (10 mL) was added to the reaction system under ice bath environment to quench the reaction, then water and ethyl acetate were continuously added to the reaction system to dilute, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound B-2 (11.70 g, yield: 89%).

[0173] MS m / z (ES): 210.1 [M+H] +

[0174] Second step: Preparation of compound N'-(tert-butyldimethylsilyl)-N-(4- methoxybenzyl)-N-methylmethanesulfonimidamide (B-3).

[0175] Triphenylphosphine dichloride (9.55 g, 28.7 mmol) was dissolved in chloroform (50 mL), then N,N-diisopropylethylamine (7.28 g, 56.4 mmol) was added under nitrogen atmosphere and at 0°C, stirring was continued for 2 hours, then compound B-2 (2.00 g, 9.55 mmol) was added, stirring was continued under nitrogen atmosphere and at 0°C for 3 hours, then a solution of N-methyl-4-methoxybenzylamine (1.73 g, 11.5 mmol) in chloroform (20 mL) was added, the reaction system was raised to room temperature and stirred overnight. After the reaction was completed, water and dichloromethane were added to the reaction system to dilute, the liquid was separated, the aqueous phase was extracted with dichloromethane three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound B-3 (2.80 g, yield: 86%).

[0176] MS m / z (ES): 343.2 [M+H] +

[0177] Third step: Preparation of compound N-(4-methoxybenzyl)-N-methylmethanesulfonimidamide (B-4).

[0178] Compound B-3 (2.80 g, 8.17 mmol) was dissolved in tetrahydrofuran (5 mL), water (5 mL) and glacial acetic acid (15 mL) were added, and the reaction was stirred at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution was added to the reaction system under ice bath, the pH of the reaction system was adjusted to basic, and stirring was continued for 2 hours. The reaction mixture was extracted with ethyl acetate three times, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound B-4 (1.80 g, yield: 96%).

[0179] MS m / z (ES): 229.1 [M+H] +

[0180] Fourth step: Preparation of compound N-(4-methoxybenzyl)-N-methyl-N'-(4-nitropyridin-2- yl)thiosemicarbazide (B-5).

[0181] Compound B-4 (1.80 g, 7.88 mmol) was dissolved in 1,4-dioxane (30 mL), 2-bromo-4-nitropyridine (1.60 g, 7.88 mmol), cesium carbonate (5.14 g, 15.8 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.91 g, 1.58 mmol), and tris(dibenzylideneacetone)dipalladium (0.72 g, 0.788 mmol) were added, and the reaction was stirred at 100°C under nitrogen protection overnight. After the reaction was completed, water and ethyl acetate were added to dilute the reaction system, and the reaction mixture was separated. The aqueous phase was extracted with ethyl acetate three times, the organic phase was combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound B-5 (2.05 g, yield: 74%).

[0182] MS m / z (ES): 351.1 [M+H] +

[0183] Fifth step: Preparation of compound N'-(4-aminopyridin-2-yl)-N-(4-methoxybenzyl)-N- methylthiosemicarbazide (B).

[0184] Compound B-5 (2.05 g, 5.85 mmol) was dissolved in methanol (20 mL), and then 5% palladium-carbon (0.41 g) was added. The reaction system was stirred at 40°C under a hydrogen atmosphere for 12 hours. The reaction solution was filtered to remove the palladium-carbon, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The title compound B (0.67 g, yield: 36%) was obtained by column chromatography.

[0185] MS m / z (ES): 321.1 [M+H] +

[0186] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 5.6 Hz, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.11 (dd, J = 5.6, 2.0 Hz, 1H), 6.04 (d, J = 2.0 Hz, 1H), 5.89 (br s, 2H), 4.31 (d, J = 14.0 Hz, 1H), 4.14 (d, J = 14.0 Hz, 1H), 3.73 (s, 3H), 3.10 (s, 3H), 2.62 (s, 3H).

[0187] Example C: Synthesis of intermediate N'-(4-aminopyridin-2-yl)-N,N-bis(4- methoxybenzyl)thiosemicarbazide (C)

[0188] Intermediate C was synthesized by replacing N-methyl-4-methoxybenzylamine with bis(4-methoxybenzyl)amine in the second step of Example B, using a similar procedure as described in Example B.

[0189] MS m / z (ES): 427.3 [M+H] +

[0190] Example 1: Preparation of compound (2R,3S,4S,5R)-N-(2-aminothiazol-5-yl)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (1).

[0191] First step: Preparation of compound ethyl 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)thiazole- 2-carboxylate (1-2).

[0192] Compound SM-1 (100 mg, 0.28 mmol) was dissolved in thionyl chloride (3 mL) and refluxed at 80 °C for 1 h. Excess thionyl chloride was removed and diluted with 4 mL of dry dichloromethane and added drop wise to a solution of 5-aminothiazole-2-carboxylic acid ethyl ester (1-1) (73 mg, 0.42 mmol) and triethylamine (86 mg, 0.85 mmol) in dry dichloromethane (3 mL) and the reaction mixture was allowed to react at room temperature. The reaction was monitored by TLC and upon completion, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate three times, the organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to get the crude compound. The crude compound was purified by column chromatography to get the title compound (1-2) (107 mg, yield: 74%).

[0193] MS (ESI) m / z: 509.1 [M+H] + ;

[0194] Second Step: Preparation of compound 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)thiazole- 2-carboxamide (1-3).

[0195] Compound 1-2 (107 mg, 0.21 mmol) was dissolved in ammonia in methanol solution (7 M, 5 mL) and allowed to react at room temperature. The reaction was monitored by TLC and upon completion, the reaction mixture was concentrated under reduced pressure to get the crude compound. The crude compound was purified by column chromatography to get the title compound 1-3 (95 mg, yield: 94%).

[0196] MS (ESI) m / z: 480.0 [M+H] +

[0197] 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.22 - 7.10 (m, 2H), 5.22 (d, J = 10.8 Hz, 1H), 4.26 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.76 (p, J = 7.2 Hz, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.8 Hz, 3H).

[0198] Third Step: Preparation of compound (2R,3S,4S,5R)-N-(2-aminothiazol-5-yl)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (1).

[0199] Compound 1-3 (95 mg, 0.20 mmol) was dissolved in toluene (5 mL), Lawesson’s reagent (80 mg, 0.20 mmol) was added and the reaction mixture was warmed to 100 °C overnight. After completion of the reaction, the solvent was removed by concentration. The crude compound was purified by column chromatography to obtain the title compound 1 (65 mg, yield: 66%).

[0200] MS (ESI) m / z: 496.0 [M+H] + .

[0201] 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.21 (s, 1H), 9.45 (s, 1H), 7.88 (s, 1H), 7.24 - 7.09 (m, 2H), 5.22 (d, J = 10.4 Hz, 1H), 4.26 (dd, J = 10.4, 5.2 Hz, 1H), 3.95 (d, J = 2.4 Hz, 3H), 2.83 - 2.70 (m, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.4 Hz, 3H).

[0202] Example 2: Preparation of compound 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N- (2,5,8,11-tetraoxotridec-13-yl)picolinamide (2).

[0203] First step: Preparation of compound methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (2-1).

[0204] Compound SM-1 (50 mg, 0.14 mmol) was dissolved in sulfurous chloride (3 mL) and refluxed at 80 °C for 1 h. Excess sulfurous chloride was removed by distillation and the residue was diluted with 3 mL of dry dichloromethane. This was added dropwise to a solution of methyl 4- aminopicolinate (32 mg, 0.21 mmol) and triethylamine (42 mg, 0.42 mmol) in dry dichloromethane (3 mL) and the reaction mixture was allowed to react at room temperature. After completion of the reaction as monitored by TLC, the reaction mixture was quenched by the addition of water (5 mL) and then extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to obtain the crude compound. The crude compound was purified by column chromatography to obtain the title compound (2-1) (64 mg, yield: 93%).

[0205] MS (ESI) m / z: 489.1 [M+H] +

[0206] Step 2: Preparation of compound 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinic acid (2-2).

[0207] Compound 2-1 (64 mg, 0.13 mmol) was dissolved in a mixture of methanol (3 mL) and water (1 mL), and lithium hydroxide (5 mg, 0.20 mmol) was added. The reaction system was allowed to react at room temperature. After the reaction was completed as monitored by TLC, the pH of the reaction system was adjusted to 4-6 with 2M hydrochloric acid, and then extracted with ethyl acetate three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound 2-2 (58 mg, yield: 92%).

[0208] MS (ESI) m / z: 475.1 [M+H] +

[0209] Step 3: Preparation of compound 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-(2,5,8,11- tetraoxatridecan-13-yl)picolinamide (2).

[0210] Compound 2-2 (58 mg, 0.12 mmol) was dissolved in anhydrous DMF (3 mL), and DIPEA (46 mg, 0.36 mmol), HATU (91 mg, 0.24 mmol), and 2,5,8,11- tetraoxatridecan-13-amine (37 mg, 0.18 mmol) were sequentially added. After the addition was completed, the reaction system was allowed to react at room temperature. After the reaction was completed as monitored by TLC, the reaction system was diluted with water (10 mL), and then extracted with ethyl acetate three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound 2 (68 mg, yield: 83%).

[0211] MS (ESI) m / z: 664.2 [M+H] + .

[0212] 1H NMR (400 MHz, CDC13) δ 8.62 (s, 1H), 8.44 (d, J = 5.6 Hz, 1H), 8.40 - 8.31 (m, 1H), 8.13 (dd, J = 5.6, 2.0 Hz, 1H), 7.86 (d, J = 2.0 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.96 - 6.85 (m, 1H), 5.01 (d, J = 10.8 Hz, 1H), 4.08 (dd, J = 10.8, 8.4 Hz, 1H), 4.00 (d, J = 2.8 Hz, 3H), 3.78 - 3.59 (m, 14H), 3.58 - 3.51 (m, 2H), 3.37 (s, 3H), 2.81 - 2.70 (m, 1H), 1.69 (s, 3H), 0.79 (d, J = 7.6 Hz, 3H).

[0213] Example 3: Preparation of (2R,3S,4S,5R)-N-(2-((Z)-N'-cyanocarbamimidoyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (3)

[0214] First Step: Preparation of compound 4-aminopyridinecarbonitrile (3-2)

[0215] Compound 3-1 (0.5 g, 3.3 mmol), NH4CI (0.9 g, 16.8 mmol), iron powder (0.9 g, 16.8 mmol) were added into a mixture of ethanol (25 mL) and water (2.5 mL) at room temperature, and the reaction system was raised to 60 °C under N2protection. The reaction was carried out for 6 hours. After the reaction was completed, the reaction system was lowered to 25 °C and filtered. The filtrate was concentrated to obtain a crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound 3-2 (120 mg, yield: 30%).

[0216] MS (ESI) m / z: 120.0 [M+H] +

[0217] Second Step: Preparation of compound (2R,3S,4S,5R)-N-(2-cyanopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (3-3)

[0218] Compound SM-1 (50 mg, 0.14 mmol) was dissolved in dichloromethane (3 mL) and cooled to 0 °C under N2protection, then oxalyl chloride (0.1 mL) and DMF (2 drops) were added slowly into the reaction system. After the addition, the reaction was carried out at 25 °C for 1 h. The reaction solution was concentrated, compound 3-2 (20 mg, 0.17 mmol) and DIPEA (0.5 mL) were added, and the reaction was carried out at 25 °C for 2 h under N2protection. After the reaction was completed, the reaction solution was diluted with water (5 mL), extracted with dichloromethane for three times, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude compound. The obtained crude compound was purified by column chromatography to give the title compound 3-3 (25 mg, yield: 39%).

[0219] MS (ESI) m / z: 456.1 [M+H]+

[0220] Step 3: Preparation of compound (2R,3S,4S,5R)-N-(2-((Z)-N'-cyanocarbamimidoyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (3)

[0221] Compound 3-3 (25 mg, 0.05 mmol) was dissolved in methanol (2 mL) and cooled to 0 °C under N2protection, then sodium methoxide (0.3 mg, 0.005 mmol) was added, and the temperature was raised to 25 °C. The reaction was carried out at 25 °C for 4 h, then cyanamide (4 mg, 0.08 mmol) was added at room temperature. After the reaction was completed, the reaction solution was diluted with water (5 mL) at 0 °C, separated into layers, and the aqueous phase was extracted with ethyl acetate for three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude compound. The obtained crude compound was purified by Pre-TLC to give the title compound 3 (7.6 mg, yield: 30%).

[0222] MS (ESI) m / z: 498.1 [M+H] +

[0223] 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.11 (s, 1H), 9.00 (s, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.91 (dd, J = 5.6, 2.4 Hz, 1H), 7.20 - 7.12 (m, 2H), 5.12 (d, J = 10.0 Hz, 1H), 4.25 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.83 - 2.72 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.4 Hz, 3H).

[0224] Example 4: Preparation of compound 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-(2-(2- (2-hydroxyethoxy)ethoxy)ethyl)picolinamide (4).

[0225] The title compound 4 (50 mg, yield: 83%) was prepared by following the procedure of Reference Example 2, Step 3 using similar method.

[0226] MS (ESI) m / z: 606.2 [M+H] + .

[0227] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.66 (t, J = 6.0 Hz, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 5.6, 2.0 Hz, 1H), 7.26 - 7.09 (m, 2H), 5.10 (d, J = 10.0 Hz, 1H), 4.56 (t, J = 5.2 Hz, 1H), 4.25 (dd, J = 10.4, 7.6 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 3.58 - 3.38 (m, 12H), 2.77 (p, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.4 Hz, 3H).

[0228] Example 5: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-N-(5-((methylsulfonyl)methyl)thiazol-2-yl)-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (5).

[0229] First Step: Preparation of compound ethyl 2-((tert-butoxycarbonyl)amino)thiazole-5- carboxylate (5-2).

[0230] Compound 5-1 (1.00 g, 5.81 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), DIPEA (2.25 g, 17.43 mmol), di-tert-butyl dicarbonate (1.90 g, 8.72 mmol) and DMAP (71 mg, 0.58 mmol) were added successively, and the reaction was carried out at 40 °C. After the reaction was completed, water (15 mL) was added to dilute the reaction system, and then extracted with ethyl acetate three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude product was purified by column chromatography to obtain the title compound (5-2) (1.55 g, yield: 98%).

[0231] MS m / z (ES): 273.0 [M+H] +

[0232] Second step: preparation of compound tert-butyl (5-(hydroxymethyl)thiazol-2-yl)carbamate (5-3).

[0233] Compound 5-2 (500 mg, 1.84 mmol) was dissolved in anhydrous dichloromethane (10 mL), and the temperature was lowered to -40 °C, DIBAL-H (1 M n-hexane solution, 5.52 mL, 5.52 mmol) was added under nitrogen protection, and the reaction was carried out after the temperature was raised to room temperature. After the reaction was completed, a saturated aqueous solution of sodium potassium tartrate (10 mL) was added at 0 °C to quench the reaction, and then extracted with dichloromethane three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude product was purified by column chromatography to obtain the title compound 5-3 (410 mg, yield: 97%).

[0234] MS (ESI) m / z: 231.0 [M+H] +

[0235] Third step: preparation of compound tert-butyl (5-((methylthio)methyl)thiazol-2-yl)carbamate (5-4).

[0236] Compound 5-3 (410 mg, 1.78 mmol) was dissolved in anhydrous dichloromethane (5 mL), and sulfuric chloride (635 mg, 5.34 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 h. After the reaction was completed, it was concentrated to dryness, anhydrous dichloromethane (3 mL) was added to dilute the reaction system, and then sodium methyl mercaptide (20% aqueous solution, 1.87 mL, 5.34 mmol) was added at 0 °C, and the reaction was carried out at 0 °C for 1 h. After the reaction was completed, a saturated aqueous solution of sodium bicarbonate (3 mL) was added to dilute the reaction system, and then extracted with ethyl acetate three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude product was purified by column chromatography to obtain the title compound 5-4 (400 mg, yield: 87%).

[0237] MS (ESI) m / z: 261.0 [M+H] + .

[0238] Fourth Step: Preparation of compound 5-((methylthio)methyl)thiazol-2-amine (5-5).

[0239] Compound 5-4 (400 mg, 1.54 mmol) was dissolved in dichloromethane (3 mL), TFA (3 mL) was added, and the reaction was allowed to proceed at room temperature. After the reaction was completed, the excess solvent was removed, saturated sodium bicarbonate solution (10 mL) was added to the reaction system for dilution, and then extracted with ethyl acetate three times, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude product was purified by column chromatography to obtain the title compound 5-5 (240 mg, yield: 97%).

[0240] MS (ESI) m / z: 161.0 [M+H] + .

[0241] Fifth Step: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-((methylthio)methyl)thiazol-2-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (5-6).

[0242] Compound SM-1 (50 mg, 0.14 mmol) was dissolved in sulfurous chloride (3 mL) and refluxed at 80°C for 1 h. After the reaction was completed, it was concentrated to dryness, 2 mL of anhydrous dichloromethane was added for dilution, and then it was added dropwise to a solution of compound 5-5 (34 mg, 0.21 mmol) and TEA (42 mg, 0.42 mmol) in anhydrous dichloromethane (4 mL) and reacted at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate solution (5 mL) was added to the reaction system to quench the reaction, and then extracted with dichloromethane three times, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude product was purified by column chromatography to obtain the title compound 5-6 (65 mg, yield: 93%).

[0243] MS (ESI) m / z: 497.0 [M+H] + .

[0244] Sixth Step: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(5-((methylsulfonyl)methyl)thiazol-2-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (5).

[0245] Compound 5-6 (65 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL), m-CPBA (67 mg, 0.39 mmol) was added at 0 °C, and the reaction was carried out at 0 °C. After the reaction was completed, the reaction system was quenched by adding an aqueous solution of sodium thiosulfate (5 mL), and then extracted with dichloromethane three times, the organic phase was combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude product was purified by column chromatography to obtain the title compound 5 (30 mg, yield: 44%).

[0246] MS (ESI) m / z: 529.0 [M+H] + .

[0247] 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.49 (s, 1H), 7.24 - 7.09 (m, 2H), 5.19 (d, J = 10.4 Hz, 1H), 4.72 (s, 2H), 4.26 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.94 (s, 3H), 2.78 (p, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.4 Hz, 3H).

[0248] Example 6: Preparation of compound (2R,3S,4S,5R)-N-(2-cyanothiazol-5-yl)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (6)

[0249] First Step: Preparation of ethyl 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)thiazole- 2-carboxylate (1-2)

[0250] Compound SM-1 (100 mg, 0.28 mmol) was dissolved in dichloromethane (6 mL) and cooled to 0 °C under N2protection, then oxalyl chloride (0.2 mL) and DMF (2 drops) were added slowly into the reaction system, after addition, the reaction was carried out at 25 °C for 1 h. The reaction solution was concentrated to dryness, the residue was dissolved in dichloromethane (6 mL) and added into a solution of compound 1-1 (58 mg, 0.34 mmol) and DIPEA (1.0 mL) in dichloromethane (6 mL), the reaction was carried out at 25 °C for 2 h under N2protection. After the reaction was completed, the reaction solution was diluted with water (7 mL) and extracted with dichloromethane for three times, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound. The obtained crude compound was purified by column chromatography to give the title compound 1-2 (110 mg, yield: 77%).

[0251] MS (ESI) m / z: 509.1 [M+H] +

[0252] Second Step: Preparation of compound 5-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide)thiazole- 2-carboxamide (1-3).

[0253] Compound 1-2 (110 mg, 0.22 mmol) was dissolved in ammonia in methanol solution (7 M, 10 mL) and the reaction was carried out at room temperature. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure to give the crude compound. The obtained crude compound was purified by column chromatography to give the title compound 1-3 (100 mg, yield: 95%).

[0254] MS (ESI) m / z: 480.0 [M+H] +

[0255] 1 H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.22 - 7.10 (m, 2H), 5.22 (d, J = 10.8 Hz, 1H), 4.26 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.76 (p, J = 7.2 Hz, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.8 Hz, 3H).

[0256] Third Step: Preparation of compound (2R,3S,4S,5R)-N-(2-cyanothiazol-5-yl)-3-(3,4- difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (6)

[0257] Compound 1-3 (85 mg, 0.18 mmol) and boron reagent (107 mg, 0.45 mmol) were dissolved in DCM (6 mL) and reacted at 25 °C for 4 hours under N2protection. After the reaction was completed, water (5 mL) was added at 0 °C to quench the reaction, the aqueous phase was extracted with DCM three times, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude compound. The obtained crude product was purified by column chromatography to give the title compound 6 (40 mg, yield: 48%).

[0258] MS (ESI) m / z: 462.0 [M+H] +

[0259] 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.16 (s, 1H), 7.26 - 7.07 (m, 2H), 5.16 (d, J = 10.8 Hz, 1H), 4.25 (dd, J = 10.4, 7.6 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 2.76 (p, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.71 (d, J = 6.0 Hz, 3H).

[0260] Example 7: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-N'- hydroxyaminocarbonyl)thiazol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (7)

[0261] Compound 6 (20 mg, 0.04 mmol) and hydroxylamine hydrochloride (16 mg, 0.2 mmol) were dissolved in MeOH (4 mL), DIPEA (0.1 mL) was added, and reacted at 45 °C for 4 hours under N2protection. After the reaction was completed, the crude compound was concentrated. The obtained crude product was purified by column chromatography to give the title compound 7 (8.91 mg, yield: 45%).

[0262] MS (ESI) m / z: 495.1 [M+H] +

[0263] 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 10.22 (s, 1H), 7.57 (s, 1H), 7.24 - 7.11 (m, 2H), 5.78 (s, 2H), 5.18 (d, J = 10.4 Hz, 1H), 4.25 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.75 (p, J = 7.2 Hz, 1H), 1.60 (s, 3H), 0.70 (d, J = 7.2 Hz, 3H).

[0264] Example 8: Preparation of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-N'- methoxycarbamoyl)thiazol-5-yl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (8)

[0265] Compound 6 (10 mg, 0.02 mmol), O-methylhydroxylamine hydrochloride (6 mg, 0.06 mmol) and mercaptoacetic acid (4 mg, 0.04 mmol) were dissolved in isopropanol (2 mL), DIPEA (0.05 mL) was added, and the reaction was carried out at 85 °C for 3 hours under N2protection. After the reaction was completed, the crude compound was concentrated. The obtained crude product was purified by column chromatography to obtain the title compound 8 (9.33 mg, yield: 92%).

[0266] MS (ESI) m / z: 509.1 [M+H] +

[0267] 1 H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 10.22 (s, 1H), 7.57 (s, 1H), 7.24 - 7.11 (m, 2H), 5.78 (s, 2H), 5.18 (d, J = 10.4 Hz, 1H), 4.25 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 2.75 (p, J = 7.2 Hz, 1H), 1.60 (s, 3H), 0.70 (d, J = 7.2 Hz, 3H).

[0268] Example 9: Preparation of compound (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2- ((dimethyl(oxo)-lambda 6 - sulfoxidane)amino)pyridin-4-yl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (9).

[0269] Step 1: Preparation of compound dimethyl(4-nitropyridin-2-yl)imino)-λ 6 - Preparation of sulfonamidone (9-2).

[0270] Compound 9-1 (550 mg, 2.71 mmol) was dissolved in 1,4-dioxane (10 mL), dimethylsulfinylimine (252 mg, 2.71 mmol) was added, followed by cesium carbonate (1.77 g, 5.42 mmol) and RuPhos-Pd-G3 (227 mg, 0.27 mmol), and the reaction system was stirred at 100 °C for 4 h under a nitrogen atmosphere. After the reaction was completed, water and ethyl acetate were added to the reaction system for dilution, the liquid was separated, the aqueous phase was extracted with ethyl acetate three times, the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound 9-2 (450 mg, yield: 77%).

[0271] MS (ESI) m / z: 216.0 [M+H] + .

[0272] Step 2: Preparation of compound ((4-aminopyridin-2-yl)imino)dimethyl-λ 6 - Preparation of sulfonamidone (9-3).

[0273] Compound 9-2 (250 mg, 1.16 mmol) was dissolved in methanol (10 mL), followed by the addition of 10% palladium-carbon (50 mg), and the reaction system was stirred at room temperature for 12 h under a hydrogen atmosphere. The reaction solution was filtered to remove the palladium-carbon, and the filtrate was concentrated under reduced pressure to obtain the title compound 9-3 (220 mg, yield: 93%).

[0274] MS (ESI) m / z: 186.1 [M+H] + .

[0275] Step 3: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2- ((dimethyl(oxo)-λ 6 - Preparation of sulfonamidone (9-2).

[0276] Compound SM-1 (50 mg, 0.14 mmol) was dissolved in dichloromethane (10 mL), oxalyl chloride (27 mg, 0.21 mmol) and N,N-dimethylformamide (2 drops) were added and the reaction mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The excess oxalyl chloride was removed by concentrating the reaction mixture under reduced pressure. The residue was diluted with 3 mL of dry dichloromethane and added dropwise to a solution of compound 9-3 (26 mg, 0.14 mmol) and triethylamine (43 mg, 0.42 mmol) in dry dichloromethane (2 mL) at room temperature. The reaction was allowed to complete and the reaction mixture was quenched by adding water (5 mL) followed by extracting with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to get the crude compound. The crude compound was purified by column chromatography to get the title compound 9 (62 mg, yield: 84%).

[0277] MS (ESI) m / z: 522.1 [M+H] + .

[0278] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.96 (d, J = 6.0 Hz, 1H), 7.22 - 7.07 (m, 2H), 7.00 (dd, J = 5.6, 2.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.04 (d, J = 10.0 Hz, 1H), 4.22 (dd, J = 10.0, 8.0 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 3.32 (s, 6H), 2.76 (p, J = 7.6 Hz, 1H), 1.58 (s, 3H), 0.72 (d, J = 5.6 Hz, 3H).

[0279] Example 10: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-N-(2-((1-oxotetrahydro-1 lambda 6 thiophene-1-ylidene)amino)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (10).

[0280] The title compound 10 (5.5 mg) was prepared by following the procedure described in Reference Example 9 using similar method.

[0281] MS (ESI) m / z: 548.2 [M+H] + .

[0282] 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.22 - 7.07 (m, 2H), 7.01 (dd, J = 5.6, 2.0 Hz, 1H), 6.99 (d, J = 1.6 Hz, 1H), 5.05 (d, J = 10.0 Hz, 1H), 4.23 (dd, J = 10.4, 8.0 Hz, 1H), 3.94 (d, J = 2.0 Hz, 3H), 3.55 - 3.42 (m, 2H), 3.31 - 3.21 (m, 2H), 2.76 (p, J = 7.6 Hz, 1H), 2.24 - 2.11 (m, 2H), 2.11 - 2.00 (m, 2H), 1.58 (s, 3H), 0.72 (d, J = 5.6 Hz, 3H).

[0283] Example 11: Preparation of compound 4-((2R,3S,4S,5R)-3-(2-(ethoxy-d5)-3,4- difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (11).

[0284] First step: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2- hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (11-1).

[0285] Compound SM-1 (200 mg, 0.56 mmol) was dissolved in anhydrous DCM (5 mL), cooled to -78 °C, and boron tribromide (0.54 mL, 5.6 mmol) was added dropwise under nitrogen protection. After the addition was completed, the reaction was allowed to react at -78 °C. After the reaction was completed, water (5 mL) was added to quench the reaction, and then extracted with ethyl acetate three times, combined the organic phase, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude compound. The obtained crude product was purified by column chromatography to give the title compound 11-1 (188 mg, yield 98%).

[0286] MS (ESI) m / z: 341.0 [M+H] +

[0287] Second step: Preparation of compound (2R,3S,4S,5R)-3-(2-(ethoxy-d5)-3,4- difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester-d5 (11-2).

[0288] Compound 11-1 (188 mg, 0.55 mmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (228 mg, 1.65 mmol) and 1-iodoethane-1,1,2,2,2-d5 (0.13 mL, 1.65 mmol) were added successively, and the reaction was performed at 80 °C. After the reaction was completed, water (5 mL) was added to dilute the reaction system, and then extracted with ethyl acetate three times, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound 11-2 (200 mg, yield: 89%).

[0289] MS (ESI) m / z: 407.2 [M+H] +

[0290] Step 3: Preparation of compound (2R,3S,4S,5R)-3-(2-(ethoxy-d5)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (11-3).

[0291] Compound 11-2 (200 mg, 0.49 mmol) was dissolved in a mixed solution of lithium hydroxide (59 mg, 2.45 mmol) in THF (6 mL) and water (2 mL), and the reaction was performed at room temperature. After the reaction was completed, the pH of the reaction system was adjusted to 2-3 with 4 M aqueous hydrochloric acid solution, and then extracted with ethyl acetate three times, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude compound. The obtained crude compound was purified by column chromatography to obtain the title compound 11-3 (153 mg, yield: 84%).

[0292] MS (ESI) m / z: 374.1 [M+H] + .

[0293] Step 4: Preparation of methyl 4-((2R,3S,4S,5R)-3-(2-(ethoxy-d5)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (11-4).

[0294] Compound 11-3 (54 mg, 0.14 mmol) was dissolved in dry DCM (5 mL) and cooled to 0 °C. Oxalyl chloride (0.04 mL, 0.42 mmol) and DMF (2 drops) were added dropwise under nitrogen protection and the reaction was allowed to proceed at 0 °C. When the reaction was complete, the excess solvent was removed and the residue was diluted with dry DCM (5 mL) and added dropwise to a solution of methyl 4-aminopicolinate (32 mg, 0.21 mmol) and TEA (0.06 mL, 0.42 mmol) in dry DCM (5 mL) and the reaction was allowed to proceed at room temperature. When the reaction was complete, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate three times. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give the crude compound. The crude compound was purified by column chromatography to give the title compound 11-4 (55 mg, yield: 77%).

[0295] MS (ESI) m / z: 508.1 [M+H] + .

[0296] Fifth step: Preparation of compound 4-((2R,3S,4S,5R)-3-(2-(ethoxy-d5)-3,4- difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (11).

[0297] Compound 11-4 (12 mg, 0.024 mmol) was dissolved in a solution of ammonia in methanol (7 M, 3 mL) and the reaction was allowed to proceed at room temperature. When the reaction was complete, the crude compound was concentrated. The crude compound was purified by column chromatography to give the title compound 11 (8 mg, yield: 68%).

[0298] MS (ESI) m / z: 493.1 [M+H] + .

[0299] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.49 (d, J = 5.2 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 7.82 (dd, J = 5.6, 2.4 Hz, 1H), 7.62 (s, 1H), 7.22 - 7.11 (m, 2H), 5.11 (d, J = 10.4 Hz, 1H), 4.29 (dd, J = 10.4, 7.6 Hz, 1H), 2.84 - 2.70 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H).

[0300] Example 12: Preparation of compound 4-((2R,3S,4S,5R)-3-(2-(ethoxy-d5)-3,4- difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (12).

[0301] The title compound 12 (32 mg) was prepared by following the procedure described in Reference Example 11 using similar method.

[0302] MS (ESI) m / z: 493.1 [M+H] + .

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.81 (dd, J = 5.6, 2.4 Hz, 1H), 7.63 (d, J = 2.8 Hz, 1H), 7.20 - 7.09 (m, 2H), 5.10 (d, J = 10.8 Hz, 1H), 4.30 (dd, J = 10.4, 7.6 Hz, 1H), 2.74 (p, J = 7.6 Hz, 1H), 1.62 (s, 3H), 0.71 (d, J = 6.4 Hz, 3H).

[0304] Example 13: Preparation of compound (2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4- difluorophenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (13).

[0305] First Step: Synthesis of compound (2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4- difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (13-1)

[0306] Compound 11-1 (90 mg, 0.26 mmol) was dissolved in anhydrous tetrahydrofuran, NaH (105 mg, 2.6 mmol) was added under ice bath, and the reaction was continued at room temperature for 30 minutes. D2O (26 mg, 1.3 mmol) was added, and the reaction was continued at room temperature for another 30 minutes. Bromodifluoromethyl phosphonic acid diethyl ester (141 mg, 0.53 mmol) was added, and the reaction was continued at room temperature overnight. LC-MS detection showed that the reaction was completed. After quenching with water, the reaction mixture was extracted with ethyl acetate three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography to give the title compound 13-1 (85 mg, yield: 82%).

[0307] MS (ESI) m / z: 390.1 [M-H] - .

[0308] Second Step: Synthesis of compound (2R, 3S, 4S, 5R)-3-(2-(difluoromethoxy-d)-3, 4-difluorophenyl)-N-(6-((R)-2, 2-dimethyl-1, 3-dioxolan-4-yl)pyridin-3-yl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (13-2)

[0309] Compound 13-1 (80 mg, 0.2 mmol) was dissolved in DCM (5 ml), and oxalyl chloride (127 mg, 1 mmol) and 2 drops of DMF were added under ice bath. The reaction was continued at room temperature. After the reaction was completed, the excess solvent was removed by rotary evaporation. The residue was diluted with anhydrous DCM (5 mL), and the solution was added dropwise to a solution of (R)-6-(2, 2-dimethyl-1, 3-dioxolan-4-yl)pyridin-3-amine (A-P2) (58 mg, 0.3 mmol) and TEA (81 mg, 0.8 mmol) in anhydrous DCM (5 mL) at room temperature. After the reaction was completed, water (10 mL) was added to dilute the reaction mixture, which was then extracted with ethyl acetate three times. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography to give the title compound 13-2 (40 mg, yield: 35%).

[0310] MS (ESI) m / z: 566.1 [M-H] - .

[0311] Third Step: Synthesis of compound (2R, 3S, 4S, 5R)-3-(2-(difluoromethoxy-d)-3, 4-difluorophenyl)-N-(6-((R)-1, 2-dihydroxyethyl)pyridin-3-yl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (13)

[0312] Compound 13-2 (30 mg, 0.05 mmol) was dissolved in a mixture of THF (3 ml) and water (0.5 ml), TFA (0.1 ml) was added at room temperature, and the reaction was carried out at 60 °C for 16 h. LC-MS detection showed that the reaction was complete. The system was diluted with DCM, and the pH was adjusted to basic with saturated aqueous sodium carbonate solution. The aqueous phase was extracted with DCM three times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude compound. The title compound 13 (11 mg, yield: 39%) was obtained by purifying the crude product by high-pressure preparative liquid chromatography.

[0313] MS (ESI) m / z: 528.1 [M+H] + .

[0314] 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.8, 2.4 Hz, 1H), 7.52 - 7.30 (m, 3H), 5.13 (d, J = 10.0 Hz, 1H), 4.56 - 4.51 (m, 1H), 4.29 - 4.23 (m, 1H), 3.65 - 3.59 (m, 1H), 3.47 - 3.37 (m, 1H), 2.74 (p, J = 7.6 Hz, 1H), 1.59 (s, 3H), 0.79 - 0.72 (m, 3H).

[0315] Example 14: Preparation of compound (2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4- difluorophenyl)-N-(6-((S)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (14).

[0316] Using (S)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (A-P1) instead of (R)-6-(2,2-dimethyl-1,3-dioxolan-4-yl)pyridin-3-amine (A-P2) in the second step of Example 13, the title compound 14 (32 mg) was prepared by referring to the operation of the second to third steps in Example 13 using a similar method.

[0317] MS (ESI) m / z: 528.1 [M+H] + .

[0318] 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8, 2.8 Hz, 1H), 7.52 - 7.28 (m, 3H), 5.34 (d, J = 4.8 Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H), 4.70 - 4.59 (m, 1H), 4.58 - 4.49 (m, 1H), 4.26 (dd, J = 10.0, 7.6 Hz, 1H), 3.68 - 3.56 (m, 1H), 3.49 - 3.39 (m, 1H), 2.74 (p, J = 7.6 Hz, 1H), 1.59 (s, 3H), 0.76 (d, J = 7.6 Hz, 3H).

[0319] Example 15: Preparation of compound (2R,3S,4S,5R)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-3-(2-(ethoxy-d5)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (15).

[0320] The title compound 15 (3.5 mg) was prepared in a similar manner as described in the second to third steps of Reference Example 13.

[0321] MS (ESI) m / z: 510.2 [M+H] + .

[0322] 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8, 2.8 Hz, 1H), 7.52 - 7.28 (m, 3H), 5.34 (d, J = 4.8 Hz, 1H), 5.14 (d, J = 10.0 Hz, 1H), 4.70 - 4.59 (m, 1H), 4.58 - 4.49 (m, 1H), 4.26 (dd, J = 10.0, 7.6 Hz, 1H), 3.68 - 3.56 (m, 1H), 3.49 - 3.39 (m, 1H), 2.74 (p, J = 7.6 Hz, 1H), 1.59 (s, 3H), 0.76 (d, J = 7.6 Hz, 3H).

[0323] Example 16: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-((propan-2-yl- d7)oxy)phenyl)-N-(6-((R)-1,2-dihydroxyethyl)pyridin-3-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (16).

[0324] The title compound 16 (10.6 mg) was prepared in analogy to the procedure described for the second to third step in Reference Example 13.

[0325] MS (ESI) m / z: 526.2 [M+H] + .

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.62 (d, J = 2.4 Hz, 1H), 7.99 (dd, J = 8.4, 2.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.18 - 7.11 (m, 2H), 5.08 (d, J = 10.8 Hz, 1H), 4.54 (dd, J = 6.8, 4.0 Hz, 1H), 4.28 (dd, J = 10.8, 7.6 Hz, 1H), 3.62 (dd, J = 10.8, 4.0 Hz, 1H), 3.44 (dd, J = 11.2, 6.8 Hz, 1H), 2.77 - 2.68 (m, 1H), 1.60 (s, 3H), 0.70 (d, J = 6.0 Hz, 3H).

[0327] Example 17: Preparation of compound (2R,3S,4S,5R)-N-(6-((S)-1,2-dihydroxyethyl)pyridin- 3-yl)-3-(2-(ethoxy-d5)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (17).

[0328] The title compound 17 (21.2 mg) was prepared in analogy to the procedure described for the second to third step in Reference Example 13.

[0329] MS (ESI) m / z: 510.2 [M+H] + .

[0330] 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.4, 2.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.19 - 7.11 (m, 2H), 5.34 (d, J = 5.2 Hz, 1H), 5.09 (d, J = 10.8 Hz, 1H), 4.65 (t, J = 6.0 Hz, 1H), 4.57 - 4.50 (m, 1H), 4.27 (dd, J = 10.4, 7.6 Hz, 1H), 3.67 - 3.58 (m, 1H), 3.48 - 3.39 (m, 1H), 2.74 (p, J = 7.6 Hz, 1H), 1.60 (s, 3H), 0.73 (d, J = 7.6 Hz, 3H).

[0331] Example 18: Preparation of compound (2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4- difluorophenyl)-N-(2-((dimethyl(oxo)-lambda 6 Preparation of compound (2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4- difluorophenyl)-N-(2-((dimethyl(oxo)-lambda

[0332] The title compound 18 (7.8 mg) was prepared in a similar manner as described in the procedure of the third step in Reference Example 9.

[0333] MS (ESI) m / z: 559.1 [M+H] + .

[0334] 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 7.96 (d, J = 5.6 Hz, 1H), 7.52 - 7.42 (m, 1H), 7.33 - 7.25 (m, 1H), 6.99 (dd, J = 5.6, 2.0 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.09 (d, J = 10.0 Hz, 1H), 4.25 (dd, J = 10.0, 7.6 Hz, 1H), 3.32 (s, 6H), 2.80 - 2.69 (m, 1H), 1.57 (s, 3H), 0.75 (d, J = 6.8 Hz, 3H).

[0335] Example 19: Preparation of compound (2R,3S,4S,5R)-N-(2-((dimethyl(oxo)-lambda 6Preparation of (2R, 3S, 4S, 5R)-N-(2-((Z)-N'-cyanoaminocarbimidoimidoyl)pyridin-4-yl)-3-(2- (ethoxy-d5)-3, 4-difluorophenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20).

[0336] The title compound 19 (36.9 mg) was prepared using a similar method to the procedure in Reference Example 9, third step.

[0337] MS (ESI) m / z: 541.1 [M+H] + .

[0338] 1 H NMR (400 MHz, CDC13) δ 8.29 (s, 1H), 8.09 (d, J = 6.0 Hz, 1H), 7.12 (dd, J = 6.0, 2.0 Hz, 1H), 7.11 - 7.04 (m, 1H), 6.93 - 6.84 (m, 1H), 6.82 (d, J = 2.0 Hz, 1H), 4.96 (d, J = 11.2 Hz, 1H), 4.09 (dd, J = 10.8, 7.6 Hz, 1H), 3.33 (s, 6H), 2.74 (p, J = 7.6 Hz, 1H), 1.64 (s, 3H), 0.82 - 0.73 (m, 3H).

[0339] Preparation of (2R, 3S, 4S, 5R)-N-(2-((Z)-N'-cyanoaminocarbimidoimidoyl)pyridin-4-yl)-3-(2- (ethoxy-d5)-3, 4-difluorophenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (20).

[0340] The title compound 20 (8.9 mg) was prepared using a similar method to Example 3, using compound 11-3 instead of compound SM-1 in Example 3.

[0341] MS (ESI) m / z: 517.2 [M+H] + .

[0342] 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.10 (s, 1H), 9.00 (s, 1H), 8.56 (d, J = 5.6 Hz, 1H), 8.39 (s, 1H), 7.90 (dd, J = 5.6, 2.0 Hz, 1H), 7.20 6, 2.0 Hz, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.28 (dd, J = 10.4, 7.2 Hz, 1H), 2.82 - 2.70 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 7.6 Hz, 3H).

[0343] Example 21: Preparation of compound (2R, 3S, 4S, 5R)-N-(2-((Z)-N'-cyanocarbamimidoyl)pyridin-4-yl)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (21).

[0344] The title compound 21 (10.8 mg) was prepared using compound 13-1 instead of compound SM-1 in Example 3, in a similar manner as in Example 3.

[0345] MS (ESI) m / z: 535.1 [M+H] + .

[0346] 1 H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.50 (d, J = 5.2 Hz, 1H), 8.34 (s, 1H), 8.12 - 8.01 (m, 2H), 7.26 - 7.09 (m, 2H), 6.57 (s, 1H), 4.98 (d, J = 11.2 Hz, 1H), 4.15 (dd, J = 11.2, 8.0 Hz, 1H), 2.81 (p, J = 7.6 Hz, 1H), 1.71 (s, 3H), 0.87 - 0.81 (m, 3H).

[0347] Example 22: Preparation of compound (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-((methyl(methylamino)(oxo)-λ 6 -sulfanylidene)amino)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (22).

[0348] Step 1 : Preparation of compound (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2- methoxyphenyl)-N-(2-((((4-methoxybenzyl)(methyl)amino)(methyl)(oxo)- lambda 6 Step 1 : Preparation of compound (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2- methoxyphenyl)-N-(2-((((4-methoxybenzyl)(methyl)amino)(methyl)(oxo)- lambda

[0349] Compound SM-1 (0.41 g, 1.15 mmol) was dissolved in dichloromethane (10 mL), oxalyl chloride (0.22 g, 1.73 mmol) and two drops of N,N- dimethylformamide were added and the reaction mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The excess oxalyl chloride was removed by concentration under reduced pressure. The residue was diluted with 5 mL of dry dichloromethane and added drop wise to a solution of intermediate B (0.37 g, 1.15 mmol) and TEA (0.35 g, 3.46 mmol) in dry dichloromethane (10 mL) at room temperature. After completion of the reaction, the reaction mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to get the crude compound. The crude compound was purified by column chromatography to get the title compound 22-1 (0.52 g, yield: 69%).

[0350] MS m / z (ES): 657.3 [M+H] + .

[0351] Step 2: Preparation of compound (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2- methoxyphenyl)-4, 5-dimethyl-N-(2-((methyl(methylamino)(oxo)-lambda 6 Step 1 : Preparation of compound (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2- methoxyphenyl)-N-(2-((((4-methoxybenzyl)(methyl)amino)(methyl)(oxo)- lambda

[0352] Compound 22-1 (0.22 g, 0.335 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (6 mL) was added. The reaction mixture was stirred at 50 °C for 12 h. After completion of the reaction, the excess trifluoroacetic acid was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and the pH was made basic by the addition of saturated aqueous sodium carbonate solution. The reaction mixture was stirred for 2 h and the layers were separated. The aqueous layer was extracted with ethyl acetate three times and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to get the crude compound. The crude compound was purified by column chromatography to get the title compound 22 (0.13 g, yield: 72%).

[0353] MS m / z (ES): 537.3 [M+H] +

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.22 - 7.13 (m, 1H), 7.13 - 7.07 (m, 1H), 7.07 - 7.02 (m, 1H), 7.00 (s, 1H), 6.85 (q, J = 5.2 Hz, 1H), 5.05 (d, J = 10.0 Hz, 1H), 4.27 - 4.19 (m, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.15 (s, 3H), 2.76 (p, J = 7.2 Hz, 1H), 2.59 (d, J = 4.8 Hz, 3H), 1.58 (s, 3H), 0.72 (d, J = 6.8 Hz, 3H).

[0355] Example 23: Compound (2R,3S,4S,5R)-N-(2-((amino(methyl)(oxo)-lambda 6 Preparation of compound (2R,3S,4S,5R)-N-(2-((amino(methyl)(oxo)-lambda

[0356] The title compound 23 (16.8 mg) was prepared using a similar method to that described in Example 22, using Intermediate C instead of Intermediate B in Example 22.

[0357] MS m / z (ES): 523.1 [M+H] +

[0358] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.22 - 7.07 (m, 2H), 7.05 - 6.99 (m, 1H), 6.98 - 6.82 (m, 3H), 5.05 (d, J = 10.4 Hz, 1H), 4.23 (dd, J = 10.4, 7.6 Hz, 1H), 3.95 (d, J = 2.0 Hz, 3H), 3.24 (s, 3H), 2.76 (p, J = 7.6 Hz, 1H), 1.58 (s, 3H), 0.73 (d, J = 6.8 Hz, 3H).

[0359] Example 24: Compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d)phenyl)-4,5- dimethyl-N-(2-((methyl(methylamino)(oxo)-lambda 6 Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d)phenyl)-4,5- dimethyl-N-(2-((methyl(methylamino)(oxo)-lambda

[0360] Step 1: Preparation of compound methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2- hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (24-1).

[0361] Compound SM-1 (5.04 g, 14.23 mmol) was dissolved in anhydrous DCM, cooled to 0 °C, and boron tribromide (10.69 g, 42.69 mmol) was added dropwise under nitrogen protection. After the addition was completed, the reaction was allowed to warm to room temperature. When the reaction was complete, the reaction system was cooled to -10 °C, methanol was added, the pH of the reaction system was adjusted to 7-8 with saturated aqueous sodium bicarbonate solution, and then extracted with DCM. The organic phases were combined and concentrated to give the crude compound 24-1. The obtained crude compound was used directly in the next step without purification.

[0362] MS m / z (ES): 353.3 [M-H] -

[0363] Step 2: Preparation of compound methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (24-2).

[0364] Compound 24-1 (5.03 g, 14.23 mmol) was dissolved in acetonitrile (100 mL), and potassium carbonate (2.83 g, 20.44 mmol) and deuterated methyl iodide-d3 (2.37 g, 16.36 mmol) were added successively. After the addition was completed, the reaction was allowed to proceed at 65 °C. When the reaction was complete, water was added to dilute the reaction system, which was then extracted with EA. The organic phases were combined and concentrated to give the crude compound 24-2. The obtained crude compound was used directly in the next step without purification.

[0365] MS m / z (ES): 370.1 [M-H] -

[0366] Step 3: Preparation of compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (24-3).

[0367] Compound 24-2 (5.28 g, 14.23 mmol) was dissolved in a mixture of methanol and water (3: 1, 100 mL), lithium hydroxide (493 mg, 20.60 mmol) was added, and the reaction was allowed to proceed at room temperature. After the reaction was completed, the pH of the reaction system was adjusted to 2-3 with 4 M aqueous hydrochloric acid solution, and then extracted with EA, and the organic phases were combined and concentrated to obtain the crude product compound, which was purified by column chromatography to obtain the title compound 24-3 (4.83 g, three-step yield: 95%).

[0368] MS m / z (ES): 356.2 [M-H] - .

[0369] Fourth to fifth steps: Preparation of compound (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2- (methoxy-d3) phenyl)-4, 5-dimethyl-N-(2-((methyl(methylamino) (oxo)-λ 6 - thiaalkyl) amino) pyridin-4-yl)-5- (trifluoromethyl) tetrahydrofuran-2-carboxamide (24).

[0370] The title compound 24 (45.3 mg) was prepared using a method similar to the first and second steps in Example 22.

[0371] MS m / z (ES): 540.3 [M+H] +

[0372] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.23 - 7.07 (m, 2H), 7.07 - 7.02 (m, 1H), 7.00 (s, 1H), 6.85 (q, J = 5.2 Hz, 1H), 5.05 (d, J = 10.4 Hz, 1H), 4.23 (dd, J = 10.4, 8.0 Hz, 1H), 3.15 (s, 3H), 2.76 (p, J = 7.6 Hz, 1H), 2.59 (d, J = 4.8 Hz, 3H), 1.58 (s, 3H), 0.72 (d, J = 6.8 Hz, 3H).

[0373] Example 25: Preparation of compound (2R, 3S, 4S, 5R)-3-(2-(ethoxy-d5)-3, 4-difluoro phenyl)-4, 5-dimethyl-N-(2-((methyl(methylamino) (oxo)-λ 6 - thiaalkyl) amino) pyridin-4-yl)-5- (trifluoromethyl) tetrahydrofuran-2-carboxamide (25).

[0374] The title compound 25 (40.2 mg) was prepared using intermediate 11-3 instead of intermediate SM-1 in example 22, by a similar method as in example 22.

[0375] MS m / z (ES): 556.4 [M+H] +

[0376] 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.21 - 7.06 (m, 2H), 7.06 - 7.01 (m, 1H), 6.99 (s, 1H), 6.85 (q, J = 4.8 Hz, 1H), 5.05 (d, J = 10.4 Hz, 1H), 4.26 (dd, J = 10.4, 7.2 Hz, 1H), 3.15 (s, 3H), 2.74 (p, J = 7.2 Hz, 1H), 2.59 (d, J = 4.8 Hz, 3H), 1.58 (s, 3H), 0.72 (d, J = 6.8 Hz, 3H).

[0377] Example 26: Preparation of compound 2-carbamoyl-4-[(2R,3S,4S,5R)-3-(2-(ethoxy-d5)-3,4- difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonylamido]pyridine 1-oxide (26).

[0378] Compound 11 (8 mg, 0.016 mmol) was dissolved in dry DCM (5 mL), m-CPBA (4 mg, 0.024 mmol) was added, and the reaction was allowed to proceed at room temperature. Upon completion of the reaction, the crude compound was concentrated. The obtained crude compound was purified by column chromatography to yield the title compound 26 (7 mg, yield: 86%).

[0379] MS m / z (ES): 509.5 [M+H] + .

[0380] 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.59 (d, J = 4.4 Hz, 1H), 8.53 (d, J = 3.2 Hz, 1H), 8.31 (d, J = 7.2 Hz, 1H), 8.22 (d, J = 4.4 Hz, 1H), 7.88 (dd, J = 7.2, 3.2 Hz, 1H), 7.23 - 7.08 (m, 2H), 5.10 (d, J = 10.4 Hz, 1H), 4.28 (dd, J = 10.4, 7.6 Hz, 1H), 2.75 (p, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.72 (d, J = 7.6 Hz, 3H).

[0381] Biological test evaluation

[0382] The control 1 in the biological test is compound VX-548, which is purchased from MCE;

[0383] The control 2 is compound 1 in the patent WO2022256622A1 example 1; using the intermediates SM-1 and A-P2 in this patent, the similar method described in the patent WO2022256622A1 example 1 is used to prepare.

[0384] Test example 1: human Nav1.8 inhibitory activity test

[0385] 1. Test purpose

[0386] The effect of the compound on Nav1.8 current is determined by manual patch clamp test using a stable CHO cell line transfected with a specific ion channel, and then the strength of the inhibition of Nav1.8 is evaluated.

[0387] 2. Test materials

[0388] 2.1 Compound

[0389] Test drug: the example compounds 1-26 in the present application are respectively prepared by the synthesis method of examples 1-26;

[0390] 3. Test method

[0391] 3.1 Compound preparation

[0392] Compound 10 mM stock solution preparation: dissolve the compound powder in 100% DMSO to prepare 10 mM compound stock solution.

[0393] 3.2 Cells

[0394] (1) The CHO cell line stably expressing human Nav1.8 channel was used, and the cells were cultured in Ham's F-12 nutrient mixture containing 10% fetal bovine serum and 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B, 0.8 mg / mL G418, and 100 μg / mL Zeocin at 37°C in a 5% CO2 atmosphere.

[0395] (2) Before patch-clamp recording, the cells were dissociated with 0.25% Trypsin-EDTA, and 6.5 x 105cells were plated onto coverslips in 24-well plates (final volume: 500 μL). After 18 hours, the cells were used for recording. 3

[0396] 3.3 Patch-clamp recording

[0397] The voltage protocol for recording Nav1.8 currents in the whole-cell configuration was as follows: After the whole-cell configuration was formed, the cells were voltage clamped at -120 mV. First, the voltage was stepped from -110 mV to -20 mV in 10 mV steps for 5 s, and then a 0 mV depolarizing pulse was given to measure the peak inward current for the half-inactivation voltage (Vhalf).

[0398] The resting state and half-inactivated state of sodium currents were recorded using a double-pulse protocol. First, a 50 ms 0 mV depolarizing pulse (TP1) was given to measure the resting state of sodium currents. Then, the conditioning voltage was adjusted to Vhalffor 5 s, and then the voltage was returned to -120 mV for 20 ms to allow the channels that were not bound to the compound and were in the inactivated state to recover. A second 50 ms 0 mV depolarizing pulse (TP2) was given to measure the half-inactivated state of sodium currents. Finally, the voltage was returned to the clamping voltage of -120 mV, and the data were collected at intervals of 20 s to observe the effects of the drug on the peak currents of sodium currents in the two different states.

[0399] The drug was administered when the current amplitude was stable in the control extracellular solution, and the next concentration was tested after the current reached a steady-state block (about 5 minutes) at each drug concentration. The control extracellular solution and the working solution of the test compound were gravity perfused from low to high concentrations through the recording bath to act on the cells, and a peristaltic pump was used for liquid displacement in the recording. Each concentration was independently tested several times. All electrophysiological tests were performed at room temperature.

[0400] 3.4 Data analysis

[0401] ​The experimental data were collected by EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software. During data analysis, the peak current of sodium compound (Peak current compound) and the peak current of control (Peak current Control) were first normalized, and then the inhibition rate of each drug concentration in different states was calculated, i.e. Inhibition% = (1-(Peak current compound / Peak current Control)*100%. The mean (Mean), standard deviation (SD) and standard error (SE) of the inhibition rate of each concentration were calculated, and the data were expressed as Mean±SE. The half maximal inhibitory concentration (IC 50 ) was calculated by the formula of log(inhibitor) vs. response-Variable slope of GraphPad Prism software: Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hillslope)).

[0402] 4. Test results

[0403] The Nav1.8 inhibitory activity of the compound of the present application is shown in Table 1.

[0404] Table 1 Nav1.8 inhibitory activity of exemplary compounds of the present application

[0405] Conclusion: From the test data of the Nav1.8 inhibitory activity of the exemplary compounds of the present application in Table 1, it can be seen that the compound of the present application has good inhibitory activity on Nav1.8 in resting state and semi-inactivated state at a concentration of 10 nM, wherein the IC 50 of compound 11 on Nav1.8 in resting state and semi-inactivated state is 0.1181 nM and 0.1547 nM, respectively.

[0406] Test Example 2: Rat pharmacokinetic evaluation

[0407] 1. Purpose of the test

[0408] In this test, SD rats were used as test animals, and the concentration of the compound in the plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS), and the pharmacokinetic characteristics of the compound described in the present application in rats of different genders were studied.

[0409] 2. Test scheme

[0410] 2.1 Test animals

[0411] Healthy SD rats, 7-8 weeks old, weighing 180-200 g, were purchased from Chengdu Doo Lab Animal Health Technology Co., Ltd. and divided into groups, 3 males and 3 females per group.

[0412] 2.2 Compound preparation

[0413] Gavage: the test compound was prepared into a 2 mg / mL solution using 5% DMSO + 10% Solutol HS15 + 85% physiological saline as a solvent.

[0414] 2.3 Drug administration and plasma sample collection

[0415] All rats were fasted for at least 12 hours before administration, and food was restored 4 hours after administration. Water was freely available throughout the experiment. The compound was administered by gavage at a dose of 10 mg / kg. Whole blood samples (about 0.2 mL) were collected at the specified times by jugular vein puncture before administration, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, and 48 h after administration. The blood samples were immediately transferred to labeled K2-EDTA-containing centrifuge tubes. After centrifugation at 4°C and 3200g for 10 min, the supernatant plasma was aspirated and stored at -80°C for LC-MS / MS analysis.

[0416] 3. Data processing and analysis

[0417] The plasma concentration data were analyzed using pharmacokinetic data analysis software WinNonlin (8.3.5). The main pharmacokinetic parameters were calculated using non-compartmental analysis (NCA).

[0418] 4. Results of main pharmacokinetic parameters

[0419] Table 2 Main pharmacokinetic parameters of exemplary compounds of the application in rats

[0420] Conclusion: From the main pharmacokinetic parameters of the compounds in rats in Table 2, it can be seen that the exemplary compounds of the application have good pharmacokinetic properties in female and male rats, have longer half-lives, smaller clearance rates, and higher exposure amounts compared to control 1 and control 2, and the advantage of exposure amount is more obvious in males. In rats, control 1 has a serious difference between males and females, and the exemplary compounds of the application have a smaller difference between males and females.

[0421] Test Example 3: Evaluation of canine pharmacokinetics

[0422] 1. Purpose of the test

[0423] The experiment takes Beagle dogs as the test animals, and uses high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the concentration of the compound in the blood plasma, to study the pharmacokinetic characteristics of the compound in different gender Beagle dogs.

[0424] 2. Test scheme

[0425] 2.1 Test animals

[0426] Healthy Beagle dogs, male and female, weighing 10-12 kg, were evenly divided into groups, 3 males and 3 females per group.

[0427] 2.2 Compound preparation

[0428] Gavage: The test compound was prepared with 0.5% CMC-Na physiological saline solution to prepare a solution with a drug concentration of 0.4 mg / mL.

[0429] 2.3 Dosing and plasma sample collection

[0430] All Beagle dogs were fasted for at least 12 hours before dosing, and food was restored 4 hours after dosing, and water was freely available throughout the experiment. The compound was administered by gavage at a dose of 2 mg / kg. Whole blood samples were collected through the forelimb vein at the specified times before and after dosing 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, 72, 96 h. After blood sampling, the samples were placed in EDTA-K2 anticoagulant tubes, centrifuged at 4500 r / min for 10 min, and 50 μl of separated plasma was placed in a centrifuge tube and frozen at -80°C for LC-MS / MS analysis.

[0431] 3. Data processing and analysis

[0432] The pharmacokinetic data analysis software WinNonlin (8.3.5) was used to analyze the plasma concentration data. The non-compartment model method (NCA) was used to calculate the main pharmacokinetic parameters.

[0433] 4. Results of main pharmacokinetic parameters

[0434] Table 3 Main pharmacokinetic parameters of the exemplary compound of the application in Beagle dogs

[0435] Conclusion: From the main pharmacokinetic parameters of the compounds in Table 3 in Beagle dogs, it can be seen that the exemplary compounds of the present application have good pharmacokinetic properties in female and male Beagle dogs, and have higher exposure than the control product 1, especially in male dogs. In Beagle dogs, there is a serious difference between female and male dogs for the control product 1, and the difference between female and male dogs for the exemplary compounds of the present application is smaller. The Tmax of the exemplary compounds of the present application is shorter, and in the process of analgesia, it can act faster.

[0436] Test Example 4: Inhibition test of CYP450 enzymes

[0437] The purpose of this study is to evaluate the effect of the test substance on the activity of seven isozymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.

[0438] Table 4.1. Probe substrate compound information

[0439] The specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and the test substance at concentrations of 50, 16.7, 5.56, 1.85, 0.617, 0.206, 0.0686 μM, respectively, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction was completed, the samples were treated and analyzed by liquid chromatography tandem mass spectrometry (LC-MS / MS).

[0440] Table 4.2. Enzyme inhibitor compound information

[0441] The percentage of residual activity was obtained from the ratio of the amount of characteristic metabolite of the probe substrate generated to the amount generated in the absence of the test compound or enzyme inhibitor at different concentration points of the test compound or enzyme inhibitor. If a significant decrease in the amount of metabolite generated is found at the highest concentration setting point, the half-inhibitory concentration (IC 50 ) will be calculated using the log(inhibitor) vs. response--Variable slope formula of GraphPad Prism software: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*Hillslope))

[0442] X: Log(concentration of the test compound or enzyme inhibitor);

[0443] Y: percentage of residual activity;

[0444] Top and Bottom: Theoretical maximum and minimum residual activity percentage, respectively.

[0445] Hillslope: Slope coefficient or slope.

[0446] If there is no significant decrease in metabolite production at the highest concentration set point (residual activity percentage of enzyme > 50%), the half-inhibitory concentration (IC 50 ) cannot be accurately calculated, and the IC 50 is reported to be greater than the highest concentration tested.

[0447] Table 4 Inhibitory activity IC 50 values of exemplary compounds of the application on CYP enzymes

[0448] Conclusion: From the data in Table 4, it can be seen that the exemplary compounds of the application have weak CYP inhibition, especially for the CYP 2C19 subtype, which is weaker than the control 1, suggesting that the exemplary compounds of the application have better safety in drug-drug interactions than the control 1.

[0449] 1. Incubation conditions:

[0450] Incubation time of test substance: 0, 30, 60, 120 minutes;

[0451] Final concentration of test substance in incubation: 0.5 μM;

[0452] Concentration of liver microsomal protein: 0.5 mg / mL;

[0453] Concentration of NADPH and UDPGA: 1.0 mM

[0454] 2. Test procedure:

[0455] 2.1. Prepare the working solution of testosterone and 7-hydroxycoumarin mixture.

[0456] 2.2. Prepare the solution of NADPH and UDPGA mixture, and pre-warm at 37°C in a water bath shaker before use.

[0457] 2.3. Thaw the liver microsomes and dilute with buffer.

[0458] 2.4. Add the prepared test substance and liver microsomal solution to each well in the incubation plate.

[0459] 2.5. Divide the test into 3 groups and perform sample addition. Test substance test group = test substance + microsomes + coenzyme. Test substance negative control group (NC) = test substance + microsomes + buffer. Positive control group (PC) = phase I and phase II substrates + microsomes + coenzyme.

[0460] 2.6. All samples were incubated at 37°C, and pre-cooled methanol solution was added to terminate the reaction at each termination time and the time was recorded.

[0461] 2.7. After all samples were mixed, the supernatant was analyzed by LC-MS / MS after centrifugation at 4000 rpm for 5 minutes.

[0462] 3. Test results:

[0463] Table 5. Liver microsomal stability results of exemplary compounds of the present application

[0464] Conclusion: From the data in Table 5, it can be seen that the exemplary compounds of the present application are more stable than the control 1 in rat and human liver microsomal stability tests.

[0465] Test Example 6: Metabolite identification test in hepatocytes

[0466] 1. Incubation conditions:

[0467] Incubation time of test substance: 0, 240 minutes;

[0468] Final concentration of test substance for incubation: 10 μM;

[0469] Final concentration of hepatocytes: 1.0 x 10 6 cells / mL;

[0470] Temperature: 37.0°C;

[0471] 2. Test steps:

[0472] 2.1. Prepare the dosing solution of test substance and 7-hydroxycoumarin with DMSO.

[0473] 2.2. Dilute CD1 mice, SD rats, beagle dogs, cynomolgus monkeys and human primary hepatocytes with Incubation Medium cell culture medium to a concentration of 2 x 10 6 cells / mL (2 times the final concentration for incubation) and place in a carbon dioxide incubator for pre-incubation for 5 minutes.

[0474] 2.3. Add test substance to the test groups for incubation for 0 and 240 minutes, respectively, and add midazolam and 7-hydroxycoumarin to the positive control groups for incubation for 0 and 120 minutes, respectively; add the same volume of cell culture medium to the blank control groups for incubation for 240 minutes; and incubate each test substance with cell culture medium without cells for 240 minutes in the negative control groups.

[0475] 2.4. Terminate the reaction: add 2 times the volume of pre-cooled acetonitrile solution to precipitate the protein, terminate the reaction and record the time, centrifuge, and take 200 μL of the supernatant for analysis.

[0476] 3. Test results:

[0477] Table 6 Summary of Compound 11 and its metabolites in hepatocyte incubation system

[0478] Conclusion: From the data in Table 6, it can be seen that the exemplary compound of the present application has a small percentage of monooxygenated metabolites in mouse, rat, cynomolgus monkey and human hepatocyte incubation systems, especially no obvious monooxygenated metabolites in human hepatocyte metabolites, and its metabolic pathway is obviously different from that of the known reference substance 1.

[0479] Test Example 7: Rat SNI efficacy test

[0480] 1. Purpose of the experiment: This experiment explores the efficacy of the test substance in the SNI pain model of SD rats, and evaluates the analgesic effect of the exemplary compound of the present application.

[0481] 2. Experimental design

[0482] 2.1 Experimental animals: Female SD rats were used in this experiment.

[0483] 2.2 Compound preparation: Gavage: The test compound was prepared using 5% DMSO + 10% Solutol HS15 + 85% physiological saline.

[0484] 2.3 Experimental method: The mechanical pain threshold of the animals was detected one day before modeling D0, and the mechanical pain threshold of male animals was detected on D8 after modeling as the baseline. According to the baseline, the animals were grouped, and D9 was administered. The mechanical pain threshold of female animals was detected on D12 after modeling as the baseline. According to the baseline, the animals were grouped, and D13 was administered. The mechanical pain threshold was detected at 0.5h, 1h, 2h, 4h, 8h after administration. The mechanical pain threshold was measured by a foot tester, and the measurement position was at the lateral one-third of the foot. Each animal was measured 3 times with an interval of 3-5 minutes, and the average value was taken.

[0485] 2.4 Experimental grouping: Group-1 Vehicle group (n=10), Group-2 Sham group (n=6), Group-3 Example 11 3mg / kg group (n=10), Group-4 Example 11 10mg / kg group (n=10), Group-5 Example 11 30mg / kg group (n=10), Group-6 Example 19 30mg / kg group (n=10).

[0486] 2.5 Data processing and analysis: Data were processed in Office Excel 2013 and GraphPad Prism 10.0, and were expressed as Mean ± SEM (standard error). Two-way ANOVA was used for analysis, and Tukey was used for inter-group comparison. T-test was used for two-tailed test between two groups. When p < 0.05, there was a significant difference between two groups.

[0487] 3. Experimental results

[0488] Table 7. Changes in mechanical pain in SNI model of rats

[0489] Note: Two-way ANOVA: **** p < 0.0001, *** p < 0.001, ** p < 0.01, * p < 0.05 vs G1-Vehicle.

[0490] 4. Experimental conclusion

[0491] In SD rats, the exemplary compounds of the present application showed significant analgesic effect at each dose, and showed a good dose-effect relationship.

[0492] Test Example 8: Incisional pain pharmacodynamic test in rats

[0493] 1. Experimental purpose: This experiment explores the pharmacodynamics of the test substance in the SD rat incisional pain model, and evaluates the analgesic effect of the candidate compound.

[0494] 2. Experimental scheme

[0495] 2.1 Experimental animals: female SD rats,

[0496] 2.2 Compound preparation: gavage: the test compound is prepared using a solvent of 5% DMSO + 10% Solutol HS15 + 85% physiological saline.

[0497] 2.3 Experimental method: The animals were anesthetized with isoflurane, routinely disinfected, and a 1-cm-long longitudinal skin incision was made on the right hind foot sole about 0.5 cm distal to the tibial joint, reaching the toes; the plantar muscle was separated, slightly elevated, and then cut longitudinally, taking care not to damage the muscle origin and insertion. The incision was sutured with 5-0 nylon thread, and a rat incisional pain model was established. The mechanical pain threshold was detected 24 h after modeling. The mechanical pain threshold was measured by a plantar tester, and the measurement position was at the position of the first suture needle on the medial side of the rat. Each animal was measured 3 times with an interval of 3-5 minutes, and the average value was taken.

[0498] 2.4 Experimental grouping: Group-1 normal group (n=9), Group-2 model group (n=11), Group-3 control product 1 50mg / kg group (n=12) Group-4 Example 11 50mg / kg (n=12).

[0499] 2.5 Data processing and analysis: Data were arranged in Office Excel 2013 and GraphPad Prism 10.0, and the data were expressed as Mean ± SEM (standard error). Two-way ANOVA was used for analysis, and Tukey was used for inter-group comparison difference significance test method; when comparing two groups, T-test was used for two-tailed test between the two groups, and when p<0.05, there was a significant difference between the two groups.

[0500] 3. Experimental results

[0501] Table 8. Change table of mechanical pain in rat incision pain model

[0502] 4. Experimental conclusion

[0503] In SD rats, the analgesic effect of the exemplified compound 11 at a dose of 50mg / kg is better than that of control product 1.

Claims

1. A compound of Formula (I), a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide: wherein: R a and R b are the same or different and each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, or C 3-6 cycloalkoxy, wherein said C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkoxy is each independently optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, or alkoxy; or R a and R b together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each of said 3-6 membered hydrocarbon ring or 4-6 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, oxo, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; R c and R d are the same or different and each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, or C 1-4 haloalkyl; or R c and R d together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each of said 3-6 membered hydrocarbon ring or 4-6 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, oxo, C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; is selected from substituted or unsubstituted phenyl, 5-6 membered heteroaryl containing 1 to 2 atoms selected from N, O, or S atoms; R 1 each independently is selected from the group consisting of halogen, cyano, -SF5, -S-C 1-6 alkyl, -S-C 1-6 haloalkyl, oxo, -NR 3 R 4 , -C(=O)-R 3 , -C(=O)-NR 3 R 4 , -NR 3 -C(=O)-R 4 , -NR 5 -C(=O)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 , -S(=O) u R 3 , -S(=NR 5 )(=O)R 3 , -S(=O) u -NR 3 R 4 , -NR 3 -S(=O) u -R 4 , -C(=S)-NR 3 R 4 , -NR 5 -C(=S)-NR 3 R 4 , -P(=O)R 3 R 4 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -O-(C 3-6 cycloalkyl), C 1-6 haloalkoxy, 3- to 7-membered cycloalkyl, 4- to 7-membered cycloalkenyl, or 4- to 9-membered heterocyclyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, -O-(C 3-6 cycloalkyl), C 1-6 haloalkoxy, 3- to 7-membered cycloalkyl, 4- to 7-membered cycloalkenyl, or 4- to 9-membered heterocyclyl is unsubstituted or further each independently optionally substituted with one or more R 01 , when R 1 is plural, each R 1 is the same or different; or two R 1 together with the atom to which they are attached form a 5-7 membered hydrocarbon ring or a 5-7 membered heterocyclic ring, wherein each of said 5-7 membered hydrocarbon ring or 5-7 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -NR 3 R 4 , C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; R 3 R 4 R 5 They may be the same or different, and each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, halogenated C 1-4 Alkyl, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 Alkyl), -O-(halogenated C) 1-4 alkyl) or -O-(C 3-6 cycloalkyl), wherein the -N-(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, halogenated C 1-4 Alkyl, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 Alkyl), -O-(halogenated C) 1-4 alkyl) or -O-(C 3-6 (Cycloalkyl) is unsubstituted or further, independently and optionally, substituted by one or more R 01 Replaced; or R 3 , R 4 and the atom to which they are attached together form a 5-7 membered heterocyclyl, wherein each said 5-7 membered heterocyclyl is independently optionally substituted with one or more R 01 ; R 2 each independently selected from deuterium, halogen, hydroxyl, cyano, -SF5, -N-(C 1-4 alkyl)2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-4 alkyl, -O-(C 1-4 alkyl), -O-(haloC 1-4 alkyl), -O-(C 3-6 cycloalkyl), -S-C 1-6 alkyl, -S-C 1-6 haloalkyl, 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl, wherein said -N-(C 1-4 alkyl)2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-4 alkyl, -O-(C 1-4 alkyl), -O-(haloC 1-4 alkyl), -O-(C 3-6 cycloalkyl), 3-7 membered cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl is unsubstituted or further each independently optionally substituted with one or more R 01 , when R 2 is multiple, each R 2 is the same or different; each R 01 is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, oxo, -NR 3 R 4 , -C(=O)-R 3 , -C(=O)-NR 3 R 4 , -NR 3 -C(=O)-R 4 , -NR 5 -C(=O)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 , -S(=O) u R 3 , -S(=NR 5 )(=O)R 3 , -S(=O) u -NR 3 R 4 , -NR 3 -S(=O) u -R 4 , -C(=S)-NR 3 R 4 、-NR 5 -C(=S)-NR 3 R 4 、-P(=O)R 3 R 4 、C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, -O-(C 3-6 cycloalkyl), -(O-C 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), C 3-6 cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl, wherein said C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, -O-(C 3-6 cycloalkyl), -(O-C 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(C 1-4 haloalkyl), C 3-6 cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclyl are further each independently optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -NR 3 R 4 , C 1-4 alkyl, hydroxyalkyl, C 1-4 alkoxy, C 1-4 haloalkyl, or C 1-4 haloalkoxy; m is 1, 2, or 3; n is 1, 2, 3, or 4; u is 0, 1, or 2; v is 0, 1, 2, or 3.

2. The compound of Formula (I) according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: R a and R b are the same or different and each is independently selected from the group consisting of hydroxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluoroalkyl, C 1-4 fluoroalkoxy or C 3-6 cycloalkyl, each of said C 1-4 alkyl or C 3-6 cycloalkyl being independently optionally substituted with one or more substituents selected from F, Cl, Br, cyano, hydroxy or alkoxy; or R a and R b together with the atom to which they are attached form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each of said 3-6 membered hydrocarbon ring or 4-6 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, F, CI, Br, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 fluoroalkyl, or C 1-4 fluoroalkoxy.

3. The compound of Formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: R a and R b The same or different, and each independently selected from C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-4 cycloalkyl or C 3-4 Cycloalkoxy, the C 3-4 cycloalkyl or C 3-4 Each cycloalkoxy group is independently and optionally substituted by one or more substituents selected from F, Cl, Br, cyano, hydroxyl or alkoxy; or R a and R b with the atom to which they are attached, form a 3-5 membered hydrocarbon ring or a 4-5 membered heterocyclic ring, wherein each of said 3-5 membered hydrocarbon ring or 4-5 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, fluorine, methyl, ethyl, -OMe, -OEt, -CF3, -CF2H, -CFH2, or C 1-4 substituted with a substituent selected from halo, deuterium, -OR, -SR, -N(R)2, -C(O)R, -C(O)OR, -C(O)N(R)2, -CN, -S(O)R, -S(O)2R, -S(O)2N(R)2, -OC(O)N(R)2, -C(O)N(OR)2, -N(C(O)R)2, -N(C(O)OR)2, -N(S(O)2R)2, -N(C(O)N(R)2 4. The compound of Formula (I) according to any one of claims 1-3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: R c and R d are the same or different and each is independently selected from hydrogen, deuterium, fluorine, cyano, hydroxyl, methyl, ethyl, hydroxyalkyl, -OMe, -OEt, -CF3, -CF2H, or -CFH2; or R c and R d with the atom to which they are attached to form a 3-6 membered hydrocarbon ring or a 4-6 membered heterocyclic ring, wherein each of said 3-6 membered hydrocarbon ring or 4-6 membered heterocyclic ring is independently optionally substituted with one or more substituents selected from deuterium, fluoro, cyano, hydroxyl, methyl, ethyl, hydroxyalkyl, -OMe, -OEt, -CF3, -CF2H, -CFH2, or C 1-4 substituted with a substituent selected from fluoroalkoxy.

5. The compound of Formula (I) according to any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: R c selected from hydrogen or deuterium; R d selected from hydrogen, deuterium, fluorine, hydroxyl, methyl or -OMe; or R c and R d together with the atom to which they are attached form a 3-5 membered hydrocarbon ring or a 4-5 membered oxygen heterocycle, each independently optionally substituted with one or more substituents selected from deuterium, fluorine, hydroxyl, methyl, ethyl, -OMe, or fluoromethyl.

6. The compound of Formula (I) according to any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: is selected from substituted or unsubstituted phenyl, pyridine, N-oxide of pyridine, pyrimidine, N-oxide of pyrimidine, pyrazine, N-oxide of pyrazine, pyridazine, N-oxide of pyridazine, pyrazole, N-oxide of pyrazole, oxazole, N-oxide of oxazole, isoxazole, N-oxide of isoxazole, thiophene, thiazole, or N-oxide of thiazole.

7. The compound of Formula (I) according to any one of claims 1-6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: is selected from substituted or unsubstituted phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrazole, oxazole, isoxazole, thiophene, or thiazole.

8. The compound of Formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: R 1 are each independently selected from the group consisting of -C(=0)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 , C 1-4 alkyl, wherein the C 1-4 alkyl groups are unsubstituted or further each independently optionally substituted by one or more R 01 substituents.

9. The compound of Formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: R 2 Or be R 01 Replacement R 2 Each is independently selected from halogens, -O-(C 1-4 Alkyl), -O-(halogenated C) 1-4 alkyl), wherein the -O-(C 1-4 Alkyl) or -O- (halogenated C) 1-4 Alkyl groups are unsubstituted or further, independently and optionally, substituted with one or more R groups. 01 Replaced; optionally, each R 01 They may be the same or different, and each is independently selected from deuterium and halogen; optionally, at least one R 01 It is deuterium.

10. The compound of Formula (I) according to any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof, wherein: each R 01 is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, oxo, -NR 03 R 04 , -C(=O)-R 03 , -C(=O)-NR 03 R 04 , -NR 03 -C(=O)-R 04 , -NR 05 -C(=O)-NR 03 R 04 , -C(=NR 05 )-NR 03 R 04 , -S(=O) u R 03 , -S(=NR 05 )(=O)R 03 , -S(=O) u -NR 03 R 04 , -NR 03 -S(=O) u -R 04 , -C(=S)-NR 03 R 04 -NR 05 -C(=S)-NR 03 R 04 -P(=O)R 03 R 04 C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, -O-(C 3-6 cycloalkyl), -(OC 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(C 1-4 (halogenated alkyl), C 3-6 Cycloalkyl, 4-7 membered cycloalkenyl or 4-9 membered heterocyclic, wherein the C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-4 Haloalkyl, -O-(C 3-6 cycloalkyl), -(OC 1-4 alkyl) v -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(C 1-4 (halogenated alkyl), C 3-6 The cycloalkyl, 4-7 membered cycloalkenyl, or 4-9 membered heterocyclic groups are further optionally and independently composed of one or more groups selected from hydrogen, deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Substituents of haloalkoxy groups; R 03 , R 04 , R 05 are the same or different and each is independently selected from hydrogen, deuterium, halogen, hydroxyl, cyano, -N-(C 1-4 alkyl)2, C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, halogenated C 1-4 alkyl, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-O-(C 1-4 alkyl), -O-(halogenated C 1-4 alkyl), or -O-(C 3-6 cycloalkyl).

11. The compound, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof according to any one of claims 1-10, wherein: R a is selected from methyl, ethyl, isopropyl, -CF3, -CF2H, or -CFH2; R b selected from hydroxyl, cyano, methyl, ethyl, isopropyl, -OMe, -OEt, -CF3, -CF2H, or -CFH2; R c selected from hydrogen or deuterium; R d selected from hydrogen, deuterium, fluorine, hydroxyl, methyl or -OMe; is selected from substituted or unsubstituted pyridine, N-oxide of pyridine, thiazole, or N-oxide of thiazole; R 1 are each independently selected from the group consisting of -C(=0)-NR 3 R 4 , -C(=NR 5 )-NR 3 R 4 , C 1-2 alkyl; optionally, R 3 , R 4 , R 5 are the same or different and each independently selected from the group consisting of hydrogen, cyano, C 1-2 alkyl, -(C 1-2 alkyl)-O-(C 1-2 alkyl), wherein said C 1-2 alkyl, -(C 1-2 alkyl)-O-(C 1-2 alkyl) is unsubstituted or further each independently optionally substituted with one or more R 01 ; or R 3 , R 4 together with the atoms to which they are attached form a 5-6 membered heterocyclic ring, wherein said 5-6 membered heterocyclic ring is each independently optionally substituted with one or more R 01 ; optionally, each R 01 is the same or different and each independently selected from the group consisting of hydroxy, -(O-C 1-2 alkyl) v -O-(C 1-2 alkyl); R 2 or R 01 substituted R 2 each independently is selected from halogen, -O-(C 1-3 alkyl), -O-(haloC 1-4 alkyl), wherein said -O-(C 1-3 alkyl) or -O-(haloC 1-4 alkyl) is unsubstituted or further each independently optionally substituted with one or more R 01 each R 01 is the same or different, and each independently is selected from deuterium, halogen; optionally, at least one R 01 is deuterium.

12. The compound, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide thereof according to any one of claims 1-11, wherein: R a and R b are the same or different and each independently selected from -CF3, methyl; R c and R d are the same or different and each is independently selected from hydrogen, deuterium; is selected from substituted or unsubstituted pyridine, N-oxide of pyridine, thiazole, or N-oxide of thiazole; R 1 or R 01 substituted R 1 are each independently selected from the group consisting of -C(=O)NH-(C2H5)-O-(C2H5)-O-(C2H5)-OH, -C(=N-CN)-NH2, -C(=O)-NH2, -CH(OH)CH2OH; R 2 or R 01 substituted R 2 are each independently selected from F, -OCH3, -OCD3, 13. The compound, pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, or N-oxide of any one of claims 1-12, wherein, The compound is selected from:

14. A compound, pharmaceutically acceptable salt, stereoisomer, tautomer, or N-oxide of any one of claims 1-13 for use in the treatment, prevention, or reduction of a voltage-gated sodium ion channel associated disease; preferably, the voltage-gated sodium ion channel is Navl.

8.

15. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, or N-oxide thereof of claim 14, wherein the voltage-gated sodium ion channel associated disease is selected from the group consisting of pain and pain related diseases, multiple sclerosis, incontinence, pathological cough, or cardiac arrhythmia; preferably, the pain is selected from the group consisting of chronic pain, acute pain, inflammatory pain, cancer pain, postoperative pain, neuropathic pain, musculoskeletal pain, idiopathic pain, intestinal pain, and idiopathic pain; the postoperative pain is preferably selected from the group consisting of bunionectomy pain, hernia repair pain, and abdominal plastic surgery pain.

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