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

Abstract

The present disclosure belongs to the field of medicine, and relates to a heterocyclic compound as represented in Formula (I). The heterocyclic compound can be used as a voltage-gated sodium channel inhibitor and achieves a good inhibitory effect on Nav1.8. Moreover, the heterocyclic compound has good selectivity and pharmacokinetic properties, and can be used for preventing, alleviating, and / or treating voltage-gated sodium channel-related diseases.

Description

A heterocyclic compound for use as a voltage-gated sodium channel inhibitor, and pharmaceutical compositions, pharmaceutical preparations and uses thereof

[0001] Cross-reference to Related Applications

[0002] The present disclosure claims priority to the invention patent application filed in China on June 7, 2024, entitled “A heterocyclic compound for use as a voltage-gated sodium channel inhibitor, and pharmaceutical compositions, pharmaceutical preparations and uses thereof”, application number 202410740958.8, the invention patent application filed in China on October 12, 2024, entitled “A heterocyclic compound for use as a voltage-gated sodium channel inhibitor, and pharmaceutical compositions, pharmaceutical preparations and uses thereof”, application number 202411426243.1, and the invention patent application filed in China on December 17, 2024, entitled “A heterocyclic compound for use as a voltage-gated sodium channel inhibitor, and pharmaceutical compositions, pharmaceutical preparations and uses thereof”, application number 202411864386.0, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of medicine, and in particular relates to a heterocyclic compound for use as a voltage-gated sodium channel inhibitor, a pharmaceutical composition and a pharmaceutical preparation comprising the same, and uses thereof in the preparation of a medicament for preventing, alleviating and / or treating a pain-related disease. BACKGROUND

[0004] Pain is a complex physiological and psychological activity, usually caused by physical injury, illness or adverse external stimuli. The International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience, often accompanied by actual or potential tissue damage”. Pain is a protective mechanism that enables healthy animals to avoid tissue damage and prevent further damage to injured tissue, and plays an indispensable protective role in normal life activities of the body. At the same time, pain is a common clinical symptom. Intense or persistent pain after the disappearance of the external stimulus that triggered it can cause physiological dysfunction and seriously affect the quality of life of living beings. Data shows that about one-fifth of the world's population is affected by moderate to severe chronic pain. In 2022, the global pain treatment market totaled 77.03 billion US dollars, and is expected to reach 116.23 billion US dollars by 2032. However, the abuse of opioid analgesic drugs has had a staggering impact on society. According to the WHO, 69,000 people die worldwide each year from opioid overdose, and 15 million people are dependent on opioids (i.e., opioid addiction). Therefore, it is self-evident that the development of new analgesic drugs with good efficacy, no addiction and drug resistance is of great importance.

[0005] Pain originates from nociceptors in the peripheral nervous system. Nociceptors are free nerve endings widely distributed in the skin, muscle, joint and internal organs, which can convert the temperature, mechanical or chemical stimuli into nerve impulses (action potentials) and transmit to the soma of dorsal root ganglion via afferent nerve fibers, and ultimately to the higher neural center, causing pain. Voltage-gated sodium channel-mediated inward current is an important link in the generation and conduction of action potentials in central and peripheral neurons. Therefore, inhibiting abnormal sodium channel activity helps to relieve and treat pain.

[0006] Voltage-gated sodium channels (Na v ) are a class of transmembrane ion channel proteins composed of α and β subunits. According to the different α subunits, they can be divided into nine subtypes Na v 1.1-1.9, which exhibit different tissue distribution and electrophysiological, pharmacological characteristics. According to whether they can be effectively inhibited by nanomolar tetrodotoxin (TTX), Na v can be divided into TTX-sensitive (TTX-S) and TTX-resistant (TTX-R). Na v 1.1-1.4, Na v 1.6 and Na v 1.7 are TTX-S, among which Na v 1.1, Na v 1.2, Na v 1.3 and Na v 1.6 are highly expressed in the central nervous system, Na v 1.4 is mainly present in skeletal muscle, and Na v 1.7 exists in the central nervous system and dorsal root ganglion. Na v 1.5, Na v 1.8 and Na v 1.9 are TTX-R, among which Na v 1.5 is mainly present in cardiac muscle cells, and Na v 1.8 and Na v 1.9 exist in the dorsal root ganglion of the peripheral nervous system. Non-selective Na v inhibitors (such as lamotrigine, lacosamide, mexiletine, etc.) have been successfully used to treat chronic pain. However, the existing Na v inhibitors lack subtype selectivity, can inhibit sodium channels expressed in the heart and central nervous system, have a narrow therapeutic window, and are limited in application.

[0007] Nav 1.8, which has the electrophysiological characteristics of slow inactivation and rapid recovery. In some models of studying neuropathic pain, nerve injury can cause Na v 1.8 expression levels in axons and neuronal cell bodies. Using Na v 1.8 antisense oligonucleotides can significantly alleviate pain while reducing Na v 1.8 expression. Na v 1.8 knockout mice cannot exhibit normal visceral inflammatory pain. In humans, Na v 1.8 gene produces a functional gain-of-function mutation, which can cause peripheral neuropathic pain. Na v 1.8 is mainly distributed in the peripheral nervous system, so selectively inhibiting Na v 1.8 can effectively reduce side effects and 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, and cancer pain. Therefore, Na v 1.8 inhibitors with high selectivity have become one of the key directions of voltage-gated sodium ion channel research and development.

[0008] Currently reported Na v 1.8 small molecule inhibitors include VX-548, VX-150, HRS-4800, JMKX-000623, HBW-004285, JKN23061, and LTG-001. There is still great social and economic value in developing Na v 1.8 inhibitors with higher affinity, better selectivity (for example, relative to Na v 1.5), and more optimal pharmacokinetic properties. SUMMARY

[0009] Problems to be solved

[0010] The present disclosure aims to provide a heterocyclic compound for use as a voltage-gated sodium channel inhibitor, which has excellent voltage-gated sodium channel (especially Na v 1.8) inhibition effect while having better selectivity and more optimal pharmacokinetic properties, as well as a pharmaceutical composition and a pharmaceutical preparation comprising the same and medical uses thereof.

[0011] Solution to the problem

[0012] In a first aspect, the present disclosure provides a compound as shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof:

[0013] wherein:

[0014] Ring A is phenyl or a 6-membered heteroaryl, the heteroatoms of which are optionally oxidized;

[0015] R a2 is selected from H, D, halogen, cyano, C1-C4alkyl, C1-C4alkoxy, -C(=O)NH2and -C(=O)NH(C1-C4alkyl), said C1-C4alkyl or C1-C4alkoxy being optionally substituted by a group selected from halogen, hydroxyl and C1-C4alkoxy;

[0016] R a1 is selected from -S(=O)(=NR 1 )R 2 , -C(=O)N(R 3 )R 4 and -N=S(=O)(R 5 )R 6 ;

[0017] R 1 is selected from cyano and -L 1 -R 11 ; L 1 is selected from -C(=O)-, -C(=O)-(C1-C4alkylene)-, -C(=O)-(C3-C6cycloalkylene)- and -C1-C4alkylene-, or, from -C(=O)-(C1-C4alkylene) and C1-C4alkylene; R 11 is selected from -NH2, -OH, -OR 12 , -NHR 12 and -NR 12 R 13 ; R 12 and R 13 are each independently selected from C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl and -(C1-C4alkylene)-(C3-C6cycloalkyl); or, R 12 , R 13 and the N atom to which they are attached form a 4-7 membered heterocyclyl, said heterocyclyl optionally further containing 1-2 heteroatoms selected from N, O and S and being optionally substituted by 1-3 groups selected from halogen and C1-C4alkyl;

[0018] R 2 is C1-C4alkyl;

[0019] or, R 1 , R 2 and the N, S atom to which they are attached form a 5-10 membered heterocyclyl, said heterocyclyl being optionally substituted by 1-3 groups selected from halogen and C1-C4alkyl;

[0020] R 3 is selected from the group consisting of -L 2 -R 14 and -CH(R 16 )-COOH, or is selected from the group consisting of -L 2 -R 14 and -CH(R 16 )-COOH; L 2 is selected from the group consisting of C1-C4 alkylene and C4-C6 cycloalkylene; R 14 is selected from the group consisting of -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH, -COOR 15 , cyano, C1-C4 alkoxy and C1-C4 alkyl; R 16 is a natural or unnatural amino acid side chain;

[0021] with the proviso that when L 2 is C1-C4 alkylene, R 14 is not C1-C4 alkoxy or C1-C4 alkyl;

[0022] R 4 is selected from the group consisting of H and C1-C4 alkyl;

[0023] or R 3 , R 4 and the N atom to which they are attached together form a 4-7 membered heterocyclyl group, which optionally further contains 1-2 heteroatoms selected from the group consisting of N, O and S and is substituted with a group selected from the group consisting of -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH and -COOR 15 ;

[0024] R 15 is selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl;

[0025] R 5 and R 6 are each independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl;

[0026] X is O or S;

[0027] R d1 and R d2 are each independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl;

[0028] R c1 and R c2 are each independently selected from the group consisting of H, C1-C4 alkyl and C1-C4 haloalkyl;

[0029] R e is H or D;

[0030] L is -C(=O)NH-;

[0031] Ring B is phenyl or 6-membered heteroaryl containing 1-2 N atoms;

[0032] R b1 , R b2 , and R b3 are each independently selected from halogen, C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy, or, are each independently selected from halogen and C1-C4alkoxy.

[0033] In some embodiments, L in the above formula (I) connects ring A through an N atom.

[0034] In particular, the present disclosure provides a compound as shown in formula (I-1):

[0035] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form, or prodrug thereof.

[0036] In some embodiments of the present disclosure, the above compound of formula (I-1) is further shown as formula (I-1a) or formula (I-1b):

[0037] In some embodiments of the present disclosure, the above compound of formula (I-1a) is further shown as formula (I-1a-1) or formula (I-1a-2):

[0038] In some embodiments of the present disclosure, the above compound of formula (I-1b) is further shown as formula (I-1b-1) or formula (I-1b-2):

[0039] In some embodiments of the present disclosure, the above compound of formula (I-1b) is further shown as formula (I-1b-1) or formula (I-1b-2):

[0040] In some embodiments, ring A is phenyl.

[0041] In some embodiments, ring A is 6-membered heteroaryl containing 1-3 N atoms and the N atoms are optionally oxidized.

[0042] In some embodiments, ring A is a 6-membered heteroaryl containing 1-2 N atoms and the N atoms are optionally oxidized.

[0043] In some embodiments, ring A is a 6-membered heteroaryl which is pyridyl and the N atom on the pyridyl is optionally oxidized.

[0044] In some embodiments, ring A is phenyl or a 6-membered heteroaryl which is pyridyl or N-oxidized pyridyl, i.e., ring A is phenyl, pyridyl or N-oxidized pyridyl.

[0045] In some embodiments, ring A is wherein denotes the position at which ring A is attached to L, and ring A is also attached to R a2 and .

[0046] In some embodiments, ring A is wherein denotes the position at which ring A is attached to L, and ring A is also attached to R a2 and .

[0047] In some embodiments of the compound of formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1) or (I-1b-2), R a2 is selected from H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2 and -C(=O)NH(C1-C4 alkyl), said C1-C4 alkyl or C1-C4 alkoxy being optionally substituted with a group selected from halogen, hydroxyl and C1-C4 alkoxy.

[0048] In some embodiments, R a2 is selected from H, D, halogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, -C(=O)NH2 and -C(=O)NH(C1-C2 alkyl), said C1-C2 alkyl or C1-C2 alkoxy being optionally substituted with a group selected from halogen, hydroxyl and C1-C2 alkoxy.

[0049] In some embodiments, R a2 is selected from H, D, halogen, cyano, C1-C2 alkyl and C1-C2 alkoxy.

[0050] In some embodiments, R a2 is selected from H, halogen and cyano.

[0051] In some embodiments, R a2 is selected from H, F and cyano.

[0052] In some specific embodiments, when ring A is phenyl, R a2 Selected from H, F and cyano groups.

[0053] In some specific embodiments, when ring A is a 6-membered heteroaryl group (e.g., pyridyl or N-oxypyridyl), R a2 For H.

[0054] In some specific implementations, when ring A is At that time, R a2 Let H be the number of digits. This indicates the location where ring A connects to L, and ring A also connects to... connect.

[0055] In some specific implementations, ring A is With R a2 The phenyl groups are connected to the following positions respectively: Where R a2 Selected from H, F and cyano groups.

[0056] In some specific implementations, ring A is Pyridinyl or N-oxypyridinyl groups are attached to the positions shown below: Where R a2 For H.

[0057] In the compounds represented by formulas (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), or (I-1b-2), R 1 Selected from cyano and -L 1 -R 11 L 1 Selected from -C(=O)-, -C(=O)-(C1-C4 alkylene)-, -C(=O)-(C3-C6 cycloalkylene)- and -C1-C4 alkylene; R 11 Selected from -NH2, -OH, -OR 12 -NHR 12 and -NR 12 R 13 ;R 12 and R 13 Each is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl, and -(C1-C4 alkylene)-(C3-C6 cycloalkyl); or, R 12 R 13 Together with the N atoms to which they are attached, they form a 4-7 membered heterocyclic group, which optionally also contains 1-2 heteroatoms selected from N, O and S and optionally is substituted by 1-3 groups selected from halogens and C1-C4 alkyl groups.

[0058] In some embodiments, R 1 is selected from cyano and -L 1 -R 11 ; L 1 is selected from -C(=0)-, -C(=0)-(Ci-C4alkylene)-, -C(=0)-(C3-C6cycloalkylene)-, and -Ci-C4alkylene-; R 11 is selected from -NH2, -OH, -NHR 12 , and -NR 12 R 13 ; R 12 and R 13 are each independently selected from Ci-C4alkyl, Ci-C4haloalkyl, C3-C6cycloalkyl, and -(Ci-C4alkylene)-(C3-C6cycloalkyl); or, R 12 , R 13 together with the N atom to which they are attached form a 4-7 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N and O and optionally substituted with 1-3 halogens.

[0059] In some embodiments, R 1 is selected from cyano and -L 1 -R 11 ; L 1 is selected from -C(=0)-(Ci-C4alkylene)- and -Ci-C4alkylene-; R 11 is selected from -NH2, -OH, -OR 12 , -NHR 12 , and -NR 12 R 13 ; R 12 and R 13 are each independently selected from Ci-C4alkyl, Ci-C4haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, and -(Ci-C4alkylene)-(C3-C6cycloalkyl); or, R 12 , R 13 together with the N atom to which they are attached form a 4-7 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N, O, and S and optionally substituted with 1-3 groups selected from halogen and Ci-C4alkyl.

[0060] In some embodiments, R 1 is selected from cyano and -L 1 -R 11 ; L 1 is selected from -C(=0)-(Ci-C4alkylene)- and -Ci-C4alkylene-; R 11 is selected from -NH2, -OH, -NHR12 and -NR 12 R 13 ; R 12 and R 13 are each independently selected from the group consisting of C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, and -(C1-C4alkylene)-(C3-C6cycloalkyl); or, R 12 , R 13 and the N atom to which they are attached collectively form a 4-7 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N and O and optionally substituted with 1-3 halogens.

[0061] In some embodiments, L 1 is -C(=O)-(C1-C4alkylene)-.

[0062] In some embodiments, L 1 is -C(=O)-(C1-C2alkylene)-.

[0063] In some embodiments, L 1 is -C(=O)-CH2-.

[0064] In some embodiments, L 1 is -C(=O)-.

[0065] In some embodiments, L 1 is -C(=O)-(C3-C6cycloalkylene)-.

[0066] In some embodiments, L 1 is -C(=O)-(C3-C4cycloalkylene)-.

[0067] In some embodiments, L 1 is

[0068] In some embodiments, L 1 is -C1-C4alkylene-.

[0069] In some embodiments, L 1 is -C1-C2alkylene-.

[0070] In some embodiments, L 1 is -C2H4-.

[0071] In some embodiments, R 11 is selected from the group consisting of -NH2, -OH, -OR 12 , -NHR 12 , and -NR 12 R 13 .

[0072] In some embodiments, R 11 is selected from -NH2, -OH, -NHR 12 and -NR 12 R 13 .

[0073] In some embodiments, R 12 and R 13 are each independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, C3-C5 halocycloalkyl, and -(C1-C3 alkylene)-(C3-C5 cycloalkyl).

[0074] In some embodiments, R 12 and R 13 are each independently selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 cycloalkyl, and -(C1-C3 alkylene)-(C3-C5 cycloalkyl).

[0075] In some embodiments, R 12 and R 13 are each independently selected from C1-C2 alkyl, C1-C2 haloalkyl, C3-C4 cycloalkyl, C3-C4 halocycloalkyl, and -(C1-C2 alkylene)-(C3-C4 cycloalkyl).

[0076] In some embodiments, R 12 and R 13 are each independently selected from C1-C2 alkyl, C1-C2 haloalkyl, C3-C4 cycloalkyl, and -(C1-C2 alkylene)-(C3-C4 cycloalkyl).

[0077] In some embodiments, R 12 and R 13 are each independently selected from methyl, ethyl, -CH2CF3, cyclopropyl, and -CH2-cyclopropyl.

[0078] In some embodiments, R 12 , R 13 and the N atom to which they are attached together form a 4-6 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N, O, and S and optionally substituted with 1-3 groups selected from halogen and C1-C4 alkyl.

[0079] In some embodiments, R 12 , R 13 and the N atom to which they are attached together form a 4-6 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N and O and optionally substituted with 1-3 groups selected from halogen and C1-C4 alkyl.

[0080] In some embodiments, R 12 , R 13 , taken together with the N atom to which they are attached, form a 4-6 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N and O and optionally substituted with 1-2 groups selected from halo and C1-C4 alkyl.

[0081] In some embodiments, R 12 , R 13 , taken together with the N atom to which they are attached, form a 4-6 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N and O and optionally substituted with 1-2 halo.

[0082] In some embodiments, R 12 , R 13 , taken together with the N atom to which they are attached, form a 4-6 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N and O and optionally substituted with 1-2 F.

[0083] In some embodiments, R 12 , R 13 , taken together with the N atom to which they are attached, form , taken together with the N atom to which they are attached, are optionally substituted with 1-2 halo. , taken together with the N atom to which they are attached, are optionally substituted with 1-2 F.

[0084] In some embodiments, R 12 , R 13 , taken together with the N atom to which they are attached, form , taken together with the N atom to which they are attached, are optionally substituted with 1-2 F. , taken together with the N atom to which they are attached, are optionally substituted with 1-2 F.

[0085] In some embodiments, R 12 , R 13 , taken together with the N atom to which they are attached, form , taken together with the N atom to which they are attached, are substituted with 1-2 halo. In some embodiments, R 12 , R 13 , taken together with the N atom to which they are attached, form

[0086] , taken together with the N atom to which they are attached, are substituted with 1-2 F. , taken together with the N atom to which they are attached, are substituted with 1-2 F.

[0087] In some embodiments, R 12 , R 13 , taken together with the N atom to which they are attached, form

[0088] In some embodiments, R 11 ​-NH2, -OH, -NHCH3, -NHCH2CH3, -N(CH3)2,

[0089] In some embodiments, when L 1 is -C(=O)-(C1-C4alkylene)-, R 11 is selected from -NH2, -OH, -OR 12 , -NHR 12 , and -NR 12 R 13 , R 12 , and R 13 are each independently selected from C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, C3-C6halocycloalkyl, and -(C1-C4alkylene)-(C3-C6cycloalkyl); or, R 12 , R 13 and the N atom to which they are attached together form a 4-7 membered heterocyclyl group optionally containing 1-2 heteroatoms selected from N, O, and S and optionally substituted with 1-3 groups selected from halogen and C1-C4alkyl.

[0090] In some embodiments, when L 1 is -C(=O)-(C1-C4alkylene)-, R 11 is selected from -NH2, -OH, -OR 12 , -NHR 12 , and -NR 12 R 13 , R 12 , and R 13 are each independently selected from C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, and -(C1-C4alkylene)-(C3-C6cycloalkyl); or, R 12 , R 13 and the N atom to which they are attached together form a 4-6 membered heterocyclyl group optionally containing 1-2 heteroatoms selected from N and O and optionally substituted with 1-3 groups selected from halogen and C1-C4alkyl.

[0091] In some embodiments, when L 1 is -C(=O)-(C1-C4alkylene)-, R 11 is selected from -NH2, -OH, -NHR 12 , and -NR 12 R 13 , R 12 , and R 13each independently selected from the group consisting of C1-C4alkyl, C1-C4haloalkyl, C3-C6cycloalkyl, and -(C1-C4alkylene)-(C3-C6cycloalkyl); or, R 12 , R 13 together with the N atom to which they are attached form a 4-6 membered heterocyclyl group optionally further containing 1-2 heteroatoms selected from N and O and optionally substituted with 1-2 groups selected from halogen and C1-C4alkyl.

[0092] In some embodiments, when L 1 is -C(=O)-CH2-, R 11 is selected from the group consisting of -NH2, -OH, -NHCH3, -NHCH2CH3, -N(CH3)2,

[0093] In some embodiments, when L 1 is -C(=O)-(C1-C4alkylene)-, R 11 is -NH2.

[0094] In some embodiments, when L 1 is -C(=O)-CH2-, R 11 is -NH2.

[0095] In some embodiments, when L 1 is -C(=O)-, R 11 is -NH2.

[0096] In some embodiments, when L 1 is -C(=O)-(C3-C6cycloalkylene)-, R 11 is -OH.

[0097] In some embodiments, L 1 is -C(=O)-(C3-C4cycloalkylene)-, R 11 is -OH.

[0098] In some embodiments, when L 1 is , R 11 is -OH.

[0099] In some embodiments, when L 1 is -C1-C4alkylene-, R 11 is selected from the group consisting of -NH2and -OH;

[0100] In some embodiments, when L 1 is -C2H4-, R 11 is -NH2.

[0101] In some embodiments, R1is selected from the group consisting of H, C1-C4alkyl, C1-C4alkoxy, and halogen. 2 In some embodiments, R1is C1-C4alkyl.

[0102] In some embodiments, R1is selected from the group consisting of H, C1-C4alkyl, C1-C4alkoxy, and halogen. 2 In some embodiments, R1is C1-C2alkyl.

[0103] In some embodiments, R1is selected from the group consisting of H, C1-C4alkyl, C1-C4alkoxy, and halogen. 2 In some embodiments, R1is methyl.

[0104] In some embodiments, R1is selected from the group consisting of H, C1-C4alkyl, C1-C4alkoxy, and halogen. 1 In some embodiments, R1is selected from the group consisting of H, C1-C4alkyl, C1-C4alkoxy, and halogen. 2 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-10 membered heterocyclyl group, optionally substituted with 1-3 groups selected from the group consisting of halogen and C1-C4alkyl.

[0105] In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-7 membered heterocyclyl group, optionally substituted with 1-3 groups selected from the group consisting of halogen and C1-C4alkyl. 1 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-7 membered heterocyclyl group, optionally substituted with 1-3 groups selected from the group consisting of halogen and C1-C4alkyl. 2 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group, optionally substituted with 1-3 groups selected from the group consisting of halogen and C1-C4alkyl.

[0106] In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. 1 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. 2 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group.

[0107] In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. 1 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. 2 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group.

[0108] In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. 1 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. 2 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. p is any integer from 1-6, said optionally substituted with 1-3 groups selected from the group consisting of halogen and C1-C4alkyl.

[0109] In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. 1 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. 2 In some embodiments, R1and R2together with the N, S atom to which they are attached form a 5-6 membered heterocyclyl group. p is any integer from 1-3, said optionally substituted with 1-2 groups selected from the group consisting of halogen and C1-C4alkyl.

[0110] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached together form p is 1 or 2, and said is optionally substituted with 1-2 groups selected from halogen and C1-C4 alkyl.

[0111] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached together form p is any integer between 1-3.

[0112] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached together form p is 1 or 2.

[0113] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached together form

[0114] In the compound of formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1) or (I-1b-2), X is O or S.

[0115] In some embodiments, X is O.

[0116] In the compound of formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1) or (I-1b-2), R d1 and R d2 are each independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl.

[0117] In some embodiments, R d1 and R d2 are each independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl, and R d1 and R d2 are not the same as each other.

[0118] In some embodiments, R d1 and R d2 are each independently selected from the group consisting of methyl and trifluoromethyl.

[0119] In some embodiments, R d1 and R d2 are each independently selected from the group consisting of methyl and trifluoromethyl, and Rd1 and R d2 are not identical to each other.

[0120] In some embodiments, R c1 and R c2 are each independently selected from the group consisting of H, C1-C4 alkyl, and C1-C4 haloalkyl.

[0121] In some embodiments, R c1 and R c2 are each independently selected from the group consisting of H and C1-C4 alkyl, and R c1 and R c2 are not identical to each other.

[0122] In some embodiments, R c1 and R c2 are each independently selected from the group consisting of H and methyl.

[0123] In some embodiments, R c1 and R c2 are each independently selected from the group consisting of H and methyl, and R c1 and R c2 are not identical to each other.

[0124] In some embodiments, R e is H or D.

[0125] In some embodiments, R e is H.

[0126] In some embodiments, L is -C(=O)NH- in the compound of Formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), or (I-1b-2).

[0127] In some embodiments, L in Formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), or (I-1b-2) is attached to ring A through a N atom.

[0128] In some embodiments, ring B is phenyl or 6-membered heteroaryl containing 1-2 N atoms in the compound of Formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), or (I-1b-2).

[0129] In some embodiments, ring B is phenyl or pyridyl.

[0130] In some embodiments, ring B is a phenyl group.

[0131] In the compounds represented by formulas (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), or (I-1b-2), R b1 R b2 R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups.

[0132] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens, C1-C2 alkoxy groups, C1-C2 deuterated alkoxy groups, and C1-C2 haloalkoxy groups.

[0133] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, deuterated methoxy, and halomethoxy.

[0134] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, deuterated methoxy, and fluoromethoxy.

[0135] In some implementations, R b1 R b2 R b3 Each is independently selected from F, methoxy, -OCD3 and difluoromethoxy.

[0136] In some implementations, R b1 R b2 For halogens, R b3 It is selected from C1-C4 alkoxy, C1-C4 deuterated alkyl and C1-C4 haloalkoxy.

[0137] In some implementations, R b1 R b2 For halogens, R b3 It is selected from C1-C2 alkoxy, C1-C2 deuterated alkoxy and C1-C2 haloalkoxy.

[0138] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and halomethoxy.

[0139] In some embodiments, R b1 , R b2 is F, and R b3 is selected from methoxy, deuterated methoxy, and fluorinated methoxy.

[0140] In some embodiments, R b1 , R b2 is F, and R b3 is selected from methoxy, -OCD3, and difluoromethoxy.

[0141] In some embodiments, R b1 , R b2 , and R b3 are each independently selected from halogen and C1-C4 alkoxy.

[0142] In some embodiments, R b1 , R b2 , and R b3 are each independently selected from halogen and C1-C2 alkoxy.

[0143] In some embodiments, R b1 , R b2 , and R b3 are each independently selected from F and methoxy.

[0144] In some embodiments, R b1 and R b2 are halogen, and R b3 is C1-C4 alkoxy.

[0145] In some embodiments, R b1 and R b2 are halogen, and R b3 is C1-C2 alkoxy.

[0146] In some embodiments, R b1 and R b2 are F, and R b3 is methoxy.

[0147] In some specific embodiments, ring B is b1 , R b2 , and R b3 are each attached to a phenyl group at the positions shown below:

[0148] In some specific embodiments, ring B is selected from

[0149] In some specific embodiments, ring B is

[0150] In some embodiments of this disclosure, the compound of formula (I-1) is further shown as in formula (I-1c) or formula (I-1d):

[0151] In the compounds represented by formula (I-1c) or (I-1d), ring A is in This indicates the location where ring A connects to NH, and ring A also connects to R. a2 and Connection; R a2 Selected from H, F and cyano groups.

[0152] In some specific implementations, ring A is With R a2 The phenyl groups are connected to the following positions respectively: Where R a2 Selected from H, F and cyano groups.

[0153] In some specific implementations, ring A is Attached to the pyridinyl group at the position shown below: Where R a2 For H.

[0154] In the compounds represented by formula (I-1c) or (I-1d), R 1 Selected from cyano and -L 1 -R 11 L 1 Selected from -C(=O)-, -C(=O)-(C1-C4 alkylene)-, -C(=O)-(C3-C6 cycloalkylene)- and -C1-C4 alkylene; R 11 Selected from -NH2, -OH and -NR 12 R 13 ;R 12 R 13 Together with the N atoms to which they are attached, they form 4-7 membered heterocyclic groups, which are optionally substituted with 1-3 halogens.

[0155] In some specific implementations, L 1 It is -C(=O)-CH2-.

[0156] In some specific implementations, L 1 It is -C(=O)-.

[0157] In some specific implementations, L 1 for

[0158] In some specific implementations, L 1 It is -C2H4-.

[0159] In some embodiments, R 11 is selected from -NH2, -OH and

[0160] In some embodiments, when L 1 is -C(=O)-CH2-, R 11 is selected from -NH2, -OH and

[0161] In some embodiments, when L 1 is -C(=O)-, R 11 is -NH2.

[0162] In some embodiments, when L 1 is , R 11 is -OH.

[0163] In some embodiments, when L 1 is -C2H4-, R 11 is -NH2.

[0164] In the compound represented by formula (I-1c) or (I-1d), R 2 is C1-C4 alkyl.

[0165] In some embodiments, R 2 is methyl.

[0166] In the compound represented by formula (I-1c) or (I-1d), R d1 and R d2 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl, and R d1 and R d2 are not identical to each other.

[0167] In some embodiments, R d1 and R d2 are each independently selected from methyl and trifluoromethyl, and R d1 and R d2 are not identical to each other.

[0168] In some embodiments, R d1 is methyl, and R d2 is trifluoromethyl.

[0169] In some embodiments, R d1 is trifluoromethyl, and R d2 is methyl.

[0170] In the compound represented by formula (I-1c) or (I-1d), Rc1 and R c2 each independently is selected from the group consisting of H and C1-C4 alkyl, and R c1 and R c2 are not identical to each other.

[0171] In some embodiments, R c1 and R c2 each independently is selected from the group consisting of H and methyl, and R c1 and R c2 are not identical to each other.

[0172] In some embodiments, R c1 is H, R c2 is methyl.

[0173] In some embodiments, R c1 is methyl, R c2 is H.

[0174] In compounds of formula (I-1c) or (I-1d), R b1 , R b2 , R b3 each independently is selected from the group consisting of halogen, C1-C4 alkoxy, C1-C4 deuterated alkoxy and C1-C4 halogenated alkoxy.

[0175] In some embodiments, R b1 , R b2 , R b3 each independently is selected from the group consisting of F, methoxy, -OCD3 and difluoromethoxy.

[0176] In some embodiments, R b1 , R b2 is F, R b3 is selected from the group consisting of methoxy, -OCD3 and difluoromethoxy.

[0177] In some embodiments of the present disclosure, the compound of formula (I-1) above is further represented by formula (I-1e) or formula (I-1f):

[0178] In compounds of formula (I-1e) or (I-1f), W is CR a2 or N, wherein R a2 is selected from the group consisting of H, F and cyano.

[0179] In compounds of formula (I-1e) or (I-1f), R b3 is selected from the group consisting of methoxy, -OCD3 and difluoromethoxy.

[0180] In some embodiments, W is CH, R b3 is selected from the group consisting of methoxy, -OCD3 and difluoromethoxy.selected from methoxy, -OCD3, and difluoromethoxy.

[0181] In some embodiments, W is CF, R b3 is methoxy.

[0182] In some embodiments, W is C(CN), R b3 is methoxy.

[0183] In some embodiments, W is N, R b3 selected from methoxy, -OCD3, and difluoromethoxy.

[0184] In some embodiments of the disclosure, the above-mentioned compound of formula (I-1e) is further represented by formula (I-1e-1) or formula (I-1e-2):

[0185] In the compound represented by formula (I-1e-1) or (I-1e-2), W and R b3 are as defined in formula (I-1e).

[0186] In some embodiments of the disclosure, the above-mentioned compound of formula (I-1f) is further represented by formula (I-1f-1) or formula (I-1f-2):

[0187] In the compound represented by formula (I-1f-1) or (I-1f-2), W and R b3 are as defined in formula (I-1f).

[0188] In particular, the present disclosure provides a compound represented by formula (I-2):

[0189] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof.

[0190] In some embodiments of the disclosure, the above-mentioned compound of formula (I-2) is further represented by formula (I-2a) or formula (I-2b):

[0191] In the compound represented by formula (I-2), (I-2a), or (I-2b), ring A is phenyl or 6-membered heteroaryl, and the heteroatom on the heteroaryl is optionally oxidized.

[0192] In some embodiments, ring A is phenyl.

[0193] In some embodiments, ring A is 6-membered heteroaryl containing 1-3 N atoms and the N atoms are optionally oxidized.

[0194] In some embodiments, ring A is a 6-membered heteroaryl group, said 6-membered heteroaryl group containing 1-2 N atoms and said N atoms being optionally oxidized.

[0195] In some embodiments, ring A is a 6-membered heteroaryl group, said 6-membered heteroaryl group being a pyridyl group and said N atom of the pyridyl group being optionally oxidized.

[0196] In some embodiments, ring A is a phenyl group or a 6-membered heteroaryl group, said 6-membered heteroaryl group being a pyridyl group or a N-oxidized pyridyl group, i.e. ring A is a phenyl group, a pyridyl group or a N-oxidized pyridyl group.

[0197] In some embodiments, ring A is wherein denotes the position at which ring A is attached to L, and ring A is further attached to R a2 and .

[0198] In some embodiments, ring A is wherein denotes the position at which ring A is attached to L, and ring A is further attached to R a2 and .

[0199] In some embodiments, ring A is wherein denotes the position at which ring A is attached to L, and ring A is further attached to R a2 and .

[0200] In the above compounds of formula (I-2), (I-2a) or (I-2b), R a2 is selected from H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=0)NH2 and -C(=0)NH(C1-C4 alkyl), each of said C1-C4 alkyl or C1-C4 alkoxy being independently optionally substituted with a group selected from halogen, hydroxyl and C1-C4 alkoxy.

[0201] In some embodiments, R a2 is selected from H, D, halogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, -C(=0)NH2 and -C(=0)NH(C1-C2 alkyl), each of said C1-C2 alkyl or C1-C2 alkoxy being independently optionally substituted with a group selected from halogen, hydroxyl and C1-C2 alkoxy.

[0202] In some embodiments, R a2 is selected from H, D, halogen, cyano, C1-C2 alkyl and C1-C2 alkoxy.

[0203] In some embodiments, Ra2 Selected from H, halogens, and cyano groups.

[0204] In some implementations, R a2 Selected from H, F and cyano groups.

[0205] In some implementations, R a2 For H.

[0206] In some specific embodiments, when ring A is phenyl, R a2 Selected from H, F and cyano groups.

[0207] In some specific embodiments, when ring A is a 6-membered heteroaryl group (e.g., pyridyl or N-oxypyridyl), R a2 For H.

[0208] In some specific implementations, when ring A is At that time, R a2 Let H be the number of digits. This indicates the location where ring A connects to L, and ring A also connects to... Connected.

[0209] In some specific implementations, ring A is With R a2 The phenyl groups are connected to the following positions respectively: Where R a2 Selected from H, F and cyano groups.

[0210] In some specific implementations, ring A is Pyridinyl or N-oxypyridinyl groups are attached to the positions shown below: Where R a2 For H.

[0211] In the compounds represented by formulas (I-2), (I-2a), or (I-2b) above, R 3 Selected from -L 2 -R 14 and -CH(R) 16 )-COOH, L 2 Selected from C1-C4 alkylene and C4-C6 cycloalkylene, R 14 Selected from -S(=O)2-R 15 -S(=O)(=NH)R 15 -COOH, -COOR 15 , cyano, C1-C4 alkoxy and C1-C4 alkyl, under the condition that, when L 2 When it is a C1-C4 alkylene group, R 14 Not C1-C4 alkoxy or C1-C4 alkyl; R 16is a natural or unnatural alpha-amino acid side chain; R 4 is selected from H and C1-C4 alkyl;

[0212] or, in the compounds of the above formula (I-2), (I-2a) or (I-2b), R 3 , R 4 together with the N atom to which they are attached form a 4-7 membered heterocyclyl group, which preferably further contains 1-2 heteroatoms selected from N, O and S and is substituted by a group selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH and -COOR 15 ;

[0213] R 15 is selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0214] In some embodiments, R 3 is selected from -L 2 -R 14 and -CH(R 16 )-COOH, L 2 is selected from C1-C4 alkylene and C4-C6 cycloalkylene, R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH, -COOR 15 , cyano, C1-C4 alkoxy and C1-C4 alkyl, with the proviso that, when L 2 is C1-C4 alkylene, R 14 is not C1-C4 alkoxy or C1-C4 alkyl; R 16 is a natural or unnatural alpha-amino acid side chain; R 4 is selected from H and C1-C4 alkyl;

[0215] or, R 3 , R 4 together with the N atom to which they are attached form a 4-7 membered heterocyclyl group, which preferably further contains 1-2 heteroatoms selected from N, O and S and is substituted by a group selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH and -COOR 15 ;

[0216] R 15 is selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0217] In some embodiments, R 3 is selected from - L 2 -R 14 and -CH(R 16 )-COOH; L 2 is selected from C1-C4 alkylene and C4-C6 cycloalkylene, R 14 is selected from -S(=0)2-R 15 , -S(=0)(=NH)R 15 , -COOH, and C1-C4 alkoxy; provided that when L 2 is C1-C4 alkylene, R 14 is not C1-C4 alkoxy; R 15 is C1-C4 alkyl;

[0218] R 16 is selected from a glycine side chain, an alanine side chain, an isoleucine side chain, a leucine side chain, a valine side chain, a methionine side chain, a phenylalanine side chain, a tryptophan side chain, a tyrosine side chain, an asparagine side chain, a cysteine side chain, a glutamine side chain, a serine side chain, a threonine side chain, an arginine side chain, a histidine side chain, a lysine side chain, an aspartic acid side chain, and a glutamic acid side chain.

[0219] In some embodiments, R 3 is selected from -L 2 -R 14 and -CH(R 16 )-COOH; L 2 is selected from C1-C4 alkylene and C4-C6 cycloalkylene, R 14 is selected from -S(=0)2-R 15 , -S(=0)(=NH)R 15 , -COOH, and C1-C4 alkoxy; provided that when L 2 is C1-C4 alkylene, R 14 is not C1-C4 alkoxy; R 15 is C1-C4 alkyl;

[0220] R 16 is selected from a glycine side chain, an alanine side chain, an isoleucine side chain, a leucine side chain, a valine side chain, a methionine side chain, a phenylalanine side chain, a tryptophan side chain, a tyrosine side chain, an asparagine side chain, a cysteine side chain, a glutamine side chain, a serine side chain, a threonine side chain, an arginine side chain, a histidine side chain, a lysine side chain, an aspartic acid side chain, and a glutamic acid side chain.

[0221] In some embodiments, when L 2 is C1-C4 alkylene, R 14 is selected from -S(=0)2-R 15 , -S(=0)(=NH)R 15-COOH, -COOR 15 and cyano.

[0222] In some embodiments, when L 2 is C1-C4 alkylene, R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH, and cyano.

[0223] In some embodiments, when L 2 is C1-C4 alkylene, R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , and -COOH.

[0224] In some embodiments, when L 2 is -C2H4-, R 14 is selected from -S(=O)2CH3, -S(=O)(=NH)CH3, -COOH, and cyano.

[0225] In some embodiments, when L 2 is C1-C4 alkylene, R 14 is -S(=O)2-R 15 .

[0226] In some embodiments, when L 2 is -C2H4-, R 14 is -S(=O)2-CH3.

[0227] In some embodiments, when L 2 is C4-C6 cycloalkylene, R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH, -COOR 15 , cyano, C1-C4 alkoxy, and C1-C4 alkyl.

[0228] In some embodiments, when L 2 is C4-C6 cycloalkylene, R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH, -COOR 15 , cyano, and C1-C4 alkoxy.

[0229] In some embodiments, when L 2 is C4-C6 cycloalkylene, R 14-S(=O)2-R 15 and C1-C4alkoxy.

[0230] In some embodiments, L 2 is R 14 is -S(=O)2-CH3or -OCH3.

[0231] In some embodiments, L 2 is C1-C4alkylene.

[0232] In some embodiments, L 2 is C1-C3alkylene.

[0233] In some embodiments, L 2 is -C2H4- or -CH2-.

[0234] In some embodiments, L 2 is C4-C6cycloalkylene.

[0235] In some embodiments, L 2 is cyclobutylene, cyclopentylene or cyclohexylene.

[0236] In some embodiments, L 2 is

[0237] In some embodiments, R 15 is selected from C1-C3alkyl and C1-C3haloalkyl.

[0238] In some embodiments, R 15 is selected from C1-C2alkyl and C1-C2haloalkyl.

[0239] In some embodiments, R 15 is selected from methyl and ethyl.

[0240] In some embodiments, R 14 is selected from -S(=O)2-(C1-C4alkyl), -S(=O)(=NH)(C1-C4alkyl), -COOH, -COO(C1-C4alkyl), cyano, C1-C4alkoxy and C1-C4alkyl.

[0241] In some embodiments, R 14 is selected from -S(=O)2-(C1-C2alkyl), -S(=O)(=NH)(C1-C2alkyl), -COOH, -COO(C1-C2alkyl), cyano, C1-C2alkoxy and C1-C2alkyl.

[0242] In some embodiments, R14 selected from -S(=0)2-CH3, -S(=0)(=NH)CH3, -COOH, -COOCH3, cyano, -OCH3, and -CH3.

[0243] In some embodiments, R 14 selected from -S(=0)2-(Ci-C4alkyl), -S(=0)(=NH)(Ci-C4alkyl), -COOH, -COO(Ci-C4alkyl), and cyano.

[0244] In some embodiments, R 14 selected from -S(=0)2-(Ci-C2alkyl), -S(=0)(=NH)(Ci-C2alkyl), -COOH, -COO(Ci-C2alkyl), and cyano.

[0245] In some embodiments, R 14 selected from -S(=0)2-CH3, -S(=0)(=NH)CH3, -COOH, -COOCH3, and cyano.

[0246] In some embodiments, R 16 is a natural alpha-amino acid side chain.

[0247] In some embodiments, R 16 is a natural alpha-amino acid side chain, which is in the L-form.

[0248] In some embodiments, R 16 is a natural alpha-amino acid side chain, which is in the D-form.

[0249] In some embodiments, R 16 selected from glycine side chain, alanine side chain, isoleucine side chain, leucine side chain, valine side chain, methionine side chain, phenylalanine side chain, tryptophan side chain, tyrosine side chain, asparagine side chain, cysteine side chain, glutamine side chain, serine side chain, threonine side chain, arginine side chain, histidine side chain, lysine side chain, aspartic acid side chain, and glutamic acid side chain.

[0250] In some embodiments, R 16 selected from glycine side chain, and L-alanine side chain, L-isoleucine side chain, L-leucine side chain, L-valine side chain, L-methionine side chain, L-phenylalanine side chain, L-tryptophan side chain, L-tyrosine side chain, L-asparagine side chain, L-cysteine side chain, L-glutamine side chain, L-serine side chain, L-threonine side chain, L-arginine side chain, L-histidine side chain, L-lysine side chain, L-aspartic acid side chain, and L-glutamic acid side chain.

[0251] In some embodiments, R 16 is selected from the group consisting of a glycine side chain and a D-alanine side chain, a D-isoleucine side chain, a D-leucine side chain, a D-valine side chain, a D-methionine side chain, a D-phenylalanine side chain, a D-tryptophan side chain, a D-tyrosine side chain, a D- asparagine side chain, a D-cysteine side chain, a D-glutamine side chain, a D-serine side chain, a D-threonine side chain, a D-arginine side chain, a D-histidine side chain, a D- lysine side chain, a D-aspartic acid side chain, and a D-glutamic acid side chain.

[0252] In some embodiments, R 16 is selected from the group consisting of H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-COOH, -CH2-C(=0)NH2, -(CH2)2-COOH, -(CH2)4-NH2, -(CH2)2-S-CH3, -(CH2)3- NHC(=NH)NH2, -(CH2)2-C(=0)NH2, -CH2-OH, -CH(CH3)-OH, and -CH2-SH.

[0253] In some embodiments, R 16 is selected from the group consisting of H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-COOH, -CH2-C(=0)NH2, -(CH2)2-COOH, -(CH2)4-NH2, -(CH2)2-S-CH3, -(CH2)3- NHC(=NH)NH2, -(CH2)2-C(=0)NH2, -CH2-OH, -CH(CH3)-OH, and -CH2-SH, and when R 16 is not H, R 16 is in the same absolute configuration as the C atom to which it is attached has in a naturally occurring L-a-amino acid having the side chain shown for R 16 .

[0254] In some embodiments, R 16 is selected from the group consisting of H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CH(CH3)-CH2-CH3, -CH2-COOH, -CH2-C(=O)NH2, -(CH2)2-COOH, -(CH2)4-NH2, -(CH2)2-S-CH3, -(CH2)3-NHC(=NH)NH2, -(CH2)2-C(=O)NH2, -CH2-OH, -CH(CH3)-OH, and -CH2-SH, and, when R 16 is not H, R 16 has the same absolute configuration as the natural D-alpha-amino acid having the side chain shown for R 16 .

[0255] In some embodiments, R 16 is selected from H, -CH2-OH, -CH2-CONH2, and

[0256] In some embodiments, R 16 is a hydrophilic natural alpha-amino acid side chain.

[0257] In some embodiments, R 16 is a hydrophilic natural alpha-amino acid side chain, which is of the L-form.

[0258] In some embodiments, R 16 is a hydrophilic natural alpha-amino acid side chain, which is of the D-form.

[0259] In some embodiments, R 16 is selected from a glycine side chain, an asparagine side chain, a cysteine side chain, a glutamine side chain, a serine side chain, a threonine side chain, and a tyrosine side chain.

[0260] In some embodiments, R 16 is selected from a glycine side chain and an L-asparagine side chain, an L-cysteine side chain, an L-glutamine side chain, an L-serine side chain, an L-threonine side chain, and an L-tyrosine side chain.

[0261] In some embodiments, R 16 is selected from a glycine side chain and a D-asparagine side chain, a D-cysteine side chain, a D-glutamine side chain, a D-serine side chain, a D-threonine side chain, and a D-tyrosine side chain.

[0262] In some embodiments, R 16 is selected from H, -CH2-C(=O)NH2, -CH2-SH, -(CH2)2-C(=O)NH2, -CH2-OH, -CH(CH3)-OH, and , and, when R 16 is not H, R 16the absolute configuration of the attached C atom is the same as that of a natural L-α-amino acid having the side chain shown. 16 the absolute configuration of the attached C atom is the same as that of a natural L-α-amino acid having the side chain shown.

[0263] In some embodiments, R 16 is selected from -CH2-C(=O)NH2, -CH2-SH, -(CH2)2-C(=O)NH2, -CH2-OH, -CH(CH3)-OH, and and, when R 16 is not H, R 16 the absolute configuration of the attached C atom is the same as that of a natural L-α-amino acid having the side chain shown. 16 the absolute configuration of the attached C atom is the same as that of a natural L-α-amino acid having the side chain shown.

[0264] In some embodiments, R 16 is a side chain of a non-natural α-amino acid.

[0265] In some embodiments, R 16 is a side chain of a non-natural α-amino acid, the absolute configuration of the α-position carbon atom of which is R-type.

[0266] In some embodiments, R 16 is a side chain of a non-natural α-amino acid, the absolute configuration of the α-position carbon atom of which is S-type.

[0267] In some embodiments, R 16 is C1-C6 alkyl, which is optionally substituted with one or more -NH2, -COOH, -SH, -S-CH3, -C(=O)NH2, guanidino, phenyl, 4-7 membered heterocyclyl, or 5-10 heteroaryl, and R 16 the absolute configuration of the attached C atom is R-type.

[0268] In some embodiments, R 16 is C1-C6 alkyl, which is optionally substituted with one or more -NH2, -COOH, -SH, -S-CH3, -C(=O)NH2, guanidino, phenyl, 4-7 membered heterocyclyl, or 5-10 heteroaryl, and R 16 the absolute configuration of the attached C atom is S-type.

[0269] In some embodiments, R 16 is C1-C4 alkyl, which is optionally substituted with one or more -NH2, -COOH, -SH, -S-CH3, -C(=O)NH2, guanidino, phenyl, 4-7 membered heterocyclyl, or 5-10 heteroaryl, and R 16 the absolute configuration of the attached C atom is R-type.

[0270] In some embodiments, R 16 is C1-C4 alkyl, which is optionally substituted with one or more -NH2, -COOH, -SH, -S-CH3, -C(=O)NH2, guanidinyl, phenyl, 4-7 membered heterocyclyl, or 5-10 membered heteroaryl, and R 16 the absolute configuration of the attached C atom is S-form.

[0271] In some embodiments, R 3 is -L 2 -R 14 , -L 2 -R 14 is selected from -C2H4-S(=O)2-CH3, -C2H4-S(=O)(=NH)CH3, -CH2-COOH,

[0272] In some embodiments, R 4 is selected from H and C1-C3 alkyl.

[0273] In some embodiments, R 4 is selected from H and C1-C2 alkyl.

[0274] In some embodiments, R 4 is selected from H and methyl.

[0275] In some embodiments, R 3 , R 4 together with the N atom to which they are attached form a 4-7 membered heterocyclyl, which optionally further contains 1-2 heteroatoms selected from N, O and S and is substituted with a group selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH and -COOR 15 ; R 15 is selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0276] In some embodiments, R 3 , R 4 together with the N atom to which they are attached form a 4-6 membered heterocyclyl, which optionally further contains 1-2 heteroatoms selected from N, O and S and is substituted with a group selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH and -COOR 15 ; R 15 is selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0277] In some embodiments, R3 R 4 and the N atom to which they are attached form a 4-6 membered heterocyclyl group, which optionally further contains 1-2 N atoms and is substituted with a group selected from -S(=0)2-R 15 , -S(=0)(=NH)R 15 , -COOH and -COOR 15 ; R 15 is C1-C4 alkyl.

[0278] In some embodiments, R 3 , R 4 and the N atom to which they are attached form a 4-6 membered heterocyclyl group, which optionally further contains 1-2 N atoms and is substituted with a group selected from -S(=0)2-R 15 , -COOH and -COOR 15 ; R 15 is C1-C4 alkyl.

[0279] In some embodiments, R 3 , R 4 and the N atom to which they are attached form the each independently is substituted with a group selected from -S(=0)2-R 15 , -S(=0)(=NH)R 15 , -COOH and -COOR 15 ; R 15 is C1-C4 alkyl.

[0280] In some embodiments, R 3 , R 4 and the N atom to which they are attached form the each independently is substituted with a group selected from -S(=0)2-R 15 , -COOH and -COOR 15 ; R 15 is C1-C4 alkyl.

[0281] In some embodiments, R 3 , R 4 and the N atom to which they are attached form the each independently is substituted with a group selected from -S(=0)2-CH3, -COOH and -COOCH3.

[0282] In the compound represented by formula (I-2), (I-2a) or (I-2b), X is O or S.

[0283] In some embodiments, X is O.

[0284] In the compound represented by formula (I-2), (I-2a) or (I-2b), R d1 , R d2 are each independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl.

[0285] In some embodiments, R d1 , R d2 are each independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl, and R d1 and R d2 are not the same as each other.

[0286] In some embodiments, R d1 , R d2 are each independently selected from the group consisting of methyl and trifluoromethyl.

[0287] In some embodiments, R d1 , R d2 are each independently selected from the group consisting of methyl and trifluoromethyl, and R d1 and R d2 are not the same as each other.

[0288] In the compound represented by formula (I-2), (I-2a) or (I-2b), R c1 , R c2 are each independently selected from the group consisting of H, C1-C4 alkyl and C1-C4 haloalkyl.

[0289] In some embodiments, R c1 , R c2 are each independently selected from the group consisting of H and C1-C4 alkyl, and R c1 and R c2 are not the same as each other.

[0290] In some embodiments, R c1 , R c2 are each independently selected from the group consisting of H and methyl.

[0291] In some embodiments, R c1 , R c2 are each independently selected from the group consisting of H and methyl, and R c1 and R c2 are not the same as each other.

[0292] In the compound represented by formula (I-2), (I-2a) or (I-2b), R e is H or D.

[0293] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is: e is H.

[0294] In some embodiments, L in the compound of Formula (I-2), (I-2a), or (I-2b) is -CONH-.

[0295] In some embodiments, L in the compound of Formula (I-2), (I-2a), or (I-2b) is connected to ring A through a N atom.

[0296] In some embodiments, ring B is phenyl or 6-membered heteroaryl containing 1-2 N atoms.

[0297] In some embodiments, ring B is phenyl or pyridyl.

[0298] In some embodiments, ring B is phenyl.

[0299] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is: b1 , R b2 , R b3 each independently selected from halogen, C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0300] In some embodiments, R b1 , R b2 , R b3 each independently selected from halogen, C1-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0301] In some embodiments, R b1 , R b2 , R b3 each independently selected from F, methoxy, deutero-methoxy, and halo-methoxy.

[0302] In some embodiments, R b1 , R b2 , R b3 each independently selected from F, methoxy, deutero-methoxy, and fluoro-methoxy.

[0303] In some embodiments, R b1 , R b2 , R b3 each independently selected from F, methoxy, -OCD3, and difluoromethoxy.

[0304] In some embodiments, R b1 , R b2 is halogen, Rb3 selected from C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0305] In some embodiments, R b1 , R b2 is halogen, R b3 is selected from C1-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0306] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, deutero-methoxy, and halo-methoxy.

[0307] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, deutero-methoxy, and fluoro-methoxy.

[0308] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, -OCD3, and difluoro-methoxy.

[0309] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen and C1-C4alkoxy.

[0310] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen and C1-C2alkoxy.

[0311] In some embodiments, R b1 , R b2 , R b3 are each independently selected from F and methoxy.

[0312] In some embodiments, R b1 , R b2 is halogen, R b3 is C1-C4alkoxy.

[0313] In some embodiments, R b1 , R b2 is halogen, R b3 is C1-C2alkoxy.

[0314] In some embodiments, R b1 , R b2 is F, Rb3 It is a methoxy group.

[0315] In some specific implementations, ring B is R. b1 R b2 and R b3 The phenyl groups are connected to the following positions respectively:

[0316] In some specific implementations, ring B is selected from...

[0317] In some specific implementations, ring B is

[0318] Specifically, this disclosure provides a compound as shown in formula (I-3):

[0319] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug.

[0320] In some embodiments of this disclosure, the compounds of formula (I-3) are further shown as in formula (I-3a) or formula (I-3b):

[0321] In the compounds represented by formula (I-3), (I-3a) or (I-3b), ring A is a phenyl or a 6-membered heteroaryl group, and the heteroatom on the heteroaryl group is optionally oxidized.

[0322] In some embodiments, ring A is a phenyl group.

[0323] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-3 N atoms, and the N atoms are optionally oxidized.

[0324] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-2 N atoms, and the N atoms are optionally oxidized.

[0325] In some embodiments, ring A is a 6-membered heteroaryl group, which is a pyridyl group and the N atom on the pyridyl group is optionally oxidized.

[0326] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R. a2 and connect.

[0327] In some implementations, ring A is in This indicates the location where ring A connects to L, and ring A also connects to R.a2 and is connected.

[0328] In some embodiments, ring A is wherein denotes the point of attachment of ring A to L, and ring A is also connected to R a2 and is connected.

[0329] In the compound represented by the above formula (I-3), (I-3a) or (I-3b), R a2 is selected from the group consisting of H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2, and -C(=O)NH(C1-C4 alkyl), each of said C1-C4 alkyl or C1-C4 alkoxy being independently optionally substituted with a group selected from halogen, hydroxyl, and C1-C4 alkoxy.

[0330] In some embodiments, R a2 is selected from the group consisting of H, D, halogen, cyano, C1-C2 alkyl, C1-C2 alkoxy, -C(=O)NH2, and -C(=O)NH(C1-C2 alkyl).

[0331] In some embodiments, R a2 is selected from the group consisting of H, D, halogen, cyano, C1-C2 alkyl, and C1-C2 alkoxy.

[0332] In some embodiments, R a2 is selected from the group consisting of H, halogen, and cyano.

[0333] In some embodiments, R a2 is selected from the group consisting of H, F, and cyano.

[0334] In some specific embodiments, when ring A is phenyl, R a2 is selected from the group consisting of H, F, and cyano.

[0335] In some specific embodiments, when ring A is 6-membered heteroaryl (e.g., pyridyl or N-oxidized pyridyl), R a2 is H.

[0336] In some specific embodiments, when ring A is R a2 is H, wherein denotes the point of attachment of ring A to L, and ring A is also connected to .

[0337] In some specific embodiments, ring A is with R a2 phenyl attached to the following position: wherein R a2 is selected from H, F and cyano.

[0338] In some embodiments, ring A is pyridyl or N-oxypyridyl attached to the following position: wherein R a2 is H.

[0339] In the compound of formula (I-3), (I-3a) or (I-3b) above, R 5 , R 6 are each independently selected from C1-C4 alkyl and C1-C4 haloalkyl.

[0340] In some embodiments, R 5 , R 6 are each independently selected from C1-C3 alkyl and C1-C3 haloalkyl.

[0341] In some embodiments, R 5 , R 6 are each independently selected from C1-C2 alkyl and C1-C2 haloalkyl.

[0342] In some embodiments, R 5 , R 6 are each independently C1-C4 alkyl.

[0343] In some embodiments, R 5 , R 6 are each independently C1-C2 alkyl.

[0344] In some embodiments, R 5 , R 6 are each independently selected from methyl and ethyl.

[0345] In some embodiments, R 5 and R 6 are each methyl or ethyl.

[0346] In some embodiments, R 5 and R 6 are each methyl.

[0347] In the compound of formula (I-3), (I-3a) or (I-3b), X is O or S.

[0348] In some embodiments, X is O.

[0349] In the compound of formula (I-3), (I-3a) or (I-3b), Rd1 , R d2 each independently is selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl.

[0350] In some embodiments, R d1 , R d2 each independently is selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl, and R d1 and R d2 are not the same as each other.

[0351] In some embodiments, R d1 , R d2 each independently is selected from the group consisting of methyl and trifluoromethyl.

[0352] In some embodiments, R d1 , R d2 each independently is selected from the group consisting of methyl and trifluoromethyl, and R d1 and R d2 are not the same as each other.

[0353] In the compound represented by formula (I-3), (I-3a) or (I-3b), R c1 , R c2 each independently is selected from the group consisting of H, C1-C4 alkyl and C1-C4 haloalkyl.

[0354] In some embodiments, R c1 , R c2 each independently is selected from the group consisting of H and C1-C4 alkyl, and R c1 and R c2 are not the same as each other.

[0355] In some embodiments, R c1 , R c2 each independently is selected from the group consisting of H and methyl.

[0356] In some embodiments, R c1 , R c2 each independently is selected from the group consisting of H and methyl, and R c1 and R c2 are not the same as each other.

[0357] In the compound represented by formula (I-3), (I-3a) or (I-3b), R e is H or D.

[0358] In the compound represented by formula (I-3), (I-3a) or (I-3b), R e is H.

[0359] In the compound represented by formula (I-3), (I-3a) or (I-3b), L is -CONH-.

[0360] In some embodiments, L in formula (I-3), (I-3a), or (I-3b) connects ring A through a N atom.

[0361] In some embodiments, ring B is phenyl or 6-membered heteroaryl containing 1-2 N atoms.

[0362] In some embodiments, ring B is phenyl or pyridyl.

[0363] In some embodiments, ring B is phenyl.

[0364] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen, C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0365] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen, C1-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0366] In some embodiments, R b1 , R b2 , R b3 are each independently selected from F, methoxy, deutero-methoxy, and halo-methoxy.

[0367] In some embodiments, R b1 , R b2 , R b3 are each independently selected from F, methoxy, deutero-methoxy, and fluoro-methoxy.

[0368] In some embodiments, R b1 , R b2 , R b3 are each independently selected from F, methoxy, -OCD3, and difluoromethoxy.

[0369] In some embodiments, R b1 , R b2 is halogen, and R b3 is selected from C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0370] In some embodiments, R b1 , R b2 is halogen, and R b3selected from C1-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0371] In some embodiments, R b1 , R b2 is F, and R b3 is selected from methoxy, deutero-methoxy, and halo-methoxy.

[0372] In some embodiments, R b1 , R b2 is F, and R b3 is selected from methoxy, deutero-methoxy, and fluoro-methoxy.

[0373] In some embodiments, R b1 , R b2 is F, and R b3 is selected from methoxy, -OCD3, and difluoro-methoxy.

[0374] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen and C1-C4alkoxy.

[0375] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen and C1-C2alkoxy.

[0376] In some embodiments, R b1 , R b2 , R b3 are each independently selected from F and methoxy.

[0377] In some embodiments, R b1 , R b2 is halogen, and R b3 is C1-C4alkoxy.

[0378] In some embodiments, R b1 , R b2 is halogen, and R b3 is C1-C2alkoxy.

[0379] In some embodiments, R b1 , R b2 is F, and R b3 is methoxy.

[0380] In some specific embodiments, ring B is b1 , R b2 , and R b3 are each attached to a phenyl group at the positions shown below:

[0381] In some embodiments, ring B is selected from

[0382] In some embodiments, ring B is

[0383] In some embodiments, the compound of the present disclosure is selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the present disclosure relates to a compound selected from Table 1 in a non-salt form (e.g., stereoisomer, tautomer, solvate, isotopically labeled, or prodrug).

[0384] Table 1 Compound Structures and Names

[0385] In a second aspect, the present disclosure provides a pharmaceutical composition containing the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof.

[0386] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0387] In some embodiments, the pharmaceutically acceptable excipient (or excipient) includes, but is not limited to, a filler, a disintegrant, a surfactant, a solubilizer, a lubricant, a wetting agent, a thickening agent, a glidant, a flavoring agent, an odorant, a preservative, an antioxidant, a pH adjuster, a solvent, and a light shielding agent, etc.

[0388] In a third aspect, the compound of the first aspect of the present disclosure, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof, or the pharmaceutical composition of the second aspect of the present disclosure can be administered by various known means, such as orally, topically, rectally, parenterally, inhalation, or implantation.

[0389] Therefore, the present disclosure also provides a pharmaceutical preparation made from the compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof, or the pharmaceutical composition of the second aspect of the present disclosure.

[0390] In some embodiments, the pharmaceutical preparation is a tablet, a capsule, a granule, a sugar-coated pill, a powder, a lozenge, a powder injection, a liquid preparation, or a suppository.

[0391] In a fourth aspect, the present disclosure provides a use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled derivative or prodrug thereof of the first aspect, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect in the manufacture of a medicament for inhibiting voltage-gated sodium channels.

[0392] The present disclosure provides a use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled derivative or prodrug thereof of the first aspect, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect in the manufacture of a medicament for inhibiting voltage-gated sodium channels.

[0393] The present disclosure provides a use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled derivative or prodrug thereof of the first aspect, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect in the manufacture of a medicament for preventing, alleviating and / or treating a disease or disorder associated with voltage-gated sodium channels.

[0394] The present disclosure provides a use of the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled derivative or prodrug thereof of the first aspect, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect in the manufacture of a medicament for preventing, alleviating and / or treating pain.

[0395] The present disclosure provides the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled derivative or prodrug thereof of the first aspect, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect for use in inhibiting voltage-gated sodium channels or as a medicament (in particular, a voltage-gated sodium channel inhibitor).

[0396] The present disclosure provides the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled derivative or prodrug thereof of the first aspect, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect for use in preventing, alleviating and / or treating a disease or disorder associated with voltage-gated sodium channels.

[0397] The present disclosure provides the compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled derivative or prodrug thereof of the first aspect, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect for use in preventing, alleviating and / or treating pain.

[0398] The present disclosure provides a method of inhibiting a voltage-gated sodium channel, comprising administering to an individual in need thereof an inhibitory effective amount of a compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled, or prodrug thereof, or a pharmaceutical composition described in the second aspect, or a pharmaceutical preparation described in the third aspect of the present disclosure.

[0399] The present disclosure provides a method of preventing, alleviating, and / or treating a voltage-gated sodium channel-related disease or disorder, comprising administering to an individual in need thereof a prophylactically, alleviatingly, and / or therapeutically effective amount of a compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled, or prodrug thereof, or a pharmaceutical composition described in the second aspect, or a pharmaceutical preparation described in the third aspect of the present disclosure.

[0400] The present disclosure provides a method of preventing, alleviating, and / or treating pain, comprising administering to an individual in need thereof a prophylactically, alleviatingly, and / or therapeutically effective amount of a compound described in the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled, or prodrug thereof, or a pharmaceutical composition described in the second aspect, or a pharmaceutical preparation described in the third aspect of the present disclosure.

[0401] In some embodiments, the voltage-gated sodium channel described in the present disclosure is a Na v 1.8.

[0402] In some embodiments, the voltage-gated sodium channel-related disease or disorder described in the present disclosure includes, but is not limited to, pain, arthritis, epilepsy or epileptic disorders, neurodegenerative diseases, psychiatric disorders (such as anxiety or depression), bipolar disorder, myotonia, movement disorders, neuroendocrine disorders, ataxia, irritable bowel syndrome, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitations, hypertension, multiple sclerosis, Charcot-Marie-Tooth syndrome, distal spinal muscular atrophy, incontinence, pathological cough, arrhythmia, and abnormal gastrointestinal motility, etc.

[0403] In some embodiments, the pain described in the present disclosure includes, but is not limited to, migraine, cluster headache, acute pain, chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, and visceral pain.

[0404] In some embodiments, the acute pain described in the present disclosure includes, but is not limited to, acute postoperative pain.

[0405] In some embodiments, the intestinal pain described in the present disclosure includes, but is not limited to, inflammatory bowel disease pain and Crohn's disease pain.

[0406] In some embodiments, the neuropathic pain described in the present disclosure includes, but is not limited to, postherpetic neuralgia, diabetic neuropathic pain, painful HIV-related sensory neuropathy, trigeminal neuralgia, burn syndrome-induced neuropathic pain, post-amputation pain, phantom limb pain, painful neuroma-induced neuropathic pain, traumatic neuroma-induced neuropathic pain, Morton's neuroma-induced neuropathic pain, nerve entrapment injury-induced neuropathic pain, spinal stenosis-induced neuropathic pain, carpal tunnel syndrome-induced neuropathic pain, radicular pain, sciatica, nerve avulsion injury-induced neuropathic pain, brachial plexus avulsion injury-induced neuropathic pain, complex regional pain syndrome-induced neuropathic pain, drug therapy-induced neuropathic pain, cancer chemotherapy-induced neuropathic pain, antiretroviral therapy-induced neuropathic pain, post-spinal cord injury pain, small fiber neuropathy-induced neuropathic pain, idiopathic small fiber neuropathy-induced neuropathic pain, idiopathic sensory neuropathy-induced neuropathic pain, and trigeminal autonomic neuropathy-induced neuropathic pain.

[0407] In some embodiments, the musculoskeletal pain described in the present disclosure includes, but is not limited to, osteoarthritic pain, back pain, cold pain, burning pain, and dental pain.

[0408] In some embodiments, the inflammatory pain described in the present disclosure includes, but is not limited to, rheumatoid arthritis pain, vulvodynia pain, and interstitial cystitis pain.

[0409] In some embodiments, the idiopathic pain described in the present disclosure includes, but is not limited to, fibromyalgia.

[0410] In some embodiments, the postoperative pain described in the present disclosure includes, but is not limited to, bunionectomy pain, herniorrhaphy pain, and abdominoplasty pain.

[0411] In some embodiments, the visceral pain described in the present disclosure includes, but is not limited to, acute abdominal pain, tumor visceral pain, angina pectoris, and abdominoplasty-induced visceral pain. Beneficial effects

[0412] The heterocyclic compounds provided by the present disclosure can be used as voltage-gated sodium channel inhibitors, which have excellent inhibitory effects on voltage-gated sodium channels (especially Nav1.7), better selectivity, and more optimal pharmacokinetic properties, and can be used for preventing, alleviating, and / or treating pain and other related diseases, and have good application prospects. v 1.8) inhibitory effects, better selectivity, and more optimal pharmacokinetic properties, and can be used for preventing, alleviating, and / or treating pain and other related diseases, and have good application prospects. BRIEF DESCRIPTION OF DRAWINGS

[0413] FIG. 1 shows the test results of the compounds of the present disclosure in the SNI pharmacodynamic model. DETAILED DESCRIPTION

[0414] Various exemplary embodiments, features, and aspects of the present disclosure will be described in detail below. The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any implementation described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other implementations.

[0415] In addition, for the purpose of better illustrating the present disclosure, numerous specific details are set forth in the following detailed description. Those skilled in the art will appreciate that the present disclosure can be practiced without some or all of the specific details. In other instances, well known methods, apparatuses, materials and steps have not been described in detail in order to avoid obscuring the present disclosure.

[0416] Unless otherwise stated, units used in the present specification are international standard units, and the numerical values, numerical ranges appearing in the present disclosure should be understood to include systematic errors that are inevitable in industrial production.

[0417] In the present specification, the meaning of "may" includes both the meaning of performing a certain process and the meaning of not performing a certain process.

[0418] In the present specification, the terms "some specific / preferred embodiments", "other specific / preferred embodiments", "embodiments", and the like, mean that the particular element (e.g., feature, structure, property, and / or characteristic) described is included in at least one embodiment described herein, and can or can not be present in other embodiments. In addition, it should be understood that the described elements can be combined in any suitable manner in various embodiments.

[0419] Terminology

[0420] In the present specification, the numerical range expressed using "numerical value A to numerical value B" means a range including the end point values A and B.

[0421] In the present specification, when "room temperature" is used, the temperature thereof can be 15°C to 30°C, further 15°C to 25°C, for example, 20°C.

[0422] As used herein, the term "compound of the present disclosure" refers to a compound of Formula (I), (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), (I-1b-2), (I-1c), (I-1d), (I-1e), (I-1e-1), (I-1e-2), (I-1f), (I-1f-1), (I-1f-2), (I-2), (I-2a), (I-2b), (I-3), (I-3a), or (I-3b) as described herein, and all embodiments thereof, as well as the compounds identified in Table 1. "Compound of the present disclosure" also includes pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, isotopically labeled, or prodrugs of the compounds of Formula (I), (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), (I-1b-2), (I-1c), (I-1d), (I-1e), (I-1e-1), (I-1e-2), (I-1f), (I-1f-1), (I-1f-2), (I-2), (I-2a), (I-2b), (I-3), (I-3a), or (I-3b) as described herein.

[0423] As used herein, the term "D" refers to a deuterium atom.

[0424] As used herein, the term "deuterated" refers to one or more hydrogen atoms in a defined radical being replaced by a deuterium atom.

[0425] As used herein, the term "halogen" refers to F, CI, Br, or I.

[0426] As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical consisting only of carbon and hydrogen atoms, having the specified number of carbon atoms, connected by single bonds between the carbon atoms, and attached to the rest of the molecule by a single bond.

[0427] As used herein, the term "haloalkyl" refers to an alkyl radical in which one or more of the hydrogen atoms is replaced by a halogen, said "halogen" and "alkyl" having the definitions as above.

[0428] As used herein, the term "alkylene" refers to a divalent alkyl radical, which is attached to the rest of the molecule or other radical via two single bonds or one double bond, said "alkyl" having the definition as above, said two single bonds can be provided by the same carbon atom or by different carbon atoms. For example, all conform to the definition of "alkylene".

[0429] As used herein, the term "alkoxy" refers to a group of the formula -OR, wherein R is an alkyl group having the specified number of carbon atoms, said "alkyl" having the definition as above.

[0430] As used herein, the term "haloalkoxy" refers to an alkoxy group in which one or more of the hydrogen atoms is replaced by a halogen, said "halogen", "alkoxy" having the definition as above.

[0431] As used herein, the term "cycloalkyl" refers to a non-aromatic, monocyclic or bicyclic (fused, bridged or spirocyclic) saturated hydrocarbon group consisting only of carbon and hydrogen atoms, having the specified number of ring-forming atoms, which is attached to the rest of the molecule through a single bond via a ring-forming carbon atom. For the purposes of the present disclosure, "cycloalkyl" is preferably a monocyclic saturated hydrocarbon group.

[0432] As used herein, the term "halocycloalkyl" refers to a cycloalkyl group in which one or more of the hydrogen atoms is replaced by a halogen, said "halogen", "cycloalkyl" having the definition as above.

[0433] As used herein, the term "heterocyclyl" refers to a non-aromatic, monocyclic or bicyclic (fused, bridged or spirocyclic) saturated or unsaturated ring group having the specified number of ring-forming atoms, which consists of carbon and one or more heteroatoms (such as nitrogen, oxygen and sulfur), wherein a ring-forming carbon atom or a ring-forming heteroatom (such as sulfur) is optionally oxidized, and which is attached to the rest of the molecule through a single bond via a ring-forming carbon atom or a ring-forming heteroatom. For the purposes of the present disclosure, heterocyclyl is preferably a non-aromatic, monocyclic saturated or unsaturated ring group.

[0434] As used herein, the term "cycloalkylene" refers to a divalent cycloalkyl group, which is attached to the rest of the molecule or other groups via two single bonds or one double bond, said "cycloalkyl" having the definition as above, said two single bonds can be provided by the same ring-forming carbon atom or by different ring-forming carbon atoms. For example, both conform to the definition of "cycloalkylene".

[0435] As used herein, the term "heteroaryl" refers to an aromatic, monocyclic or bicyclic or polycyclic fused unsaturated ring group containing one or more heteroatoms selected from nitrogen, oxygen and sulfur as ring-forming atoms.

[0436] The attributive before the above-mentioned "alkyl", "haloalkyl", "alkylene", "alkoxy", "cycloalkyl", "halocycloalkyl" and "cycloalkylene" groups, such as "C1-C4", "C3-C6", refers to the range of the number of carbon atoms contained in the defined group.

[0437] The descriptors before the above-mentioned "heterocyclyl", "heteroaryl" and the like, such as "4-7 membered", "6-10 membered", refer to the number of ring-forming atoms contained in the defined group.

[0438] As used herein, the term "optionally" means that the event being described can or can not occur. For example, a group "optionally substituted with 1-2 halogens" means unsubstituted, substituted with 1 halogen, or substituted with 2 halogens.

[0439] As used herein, the term "a-amino acid" refers to an amino acid having the general structure H2N-CH(R)-COOH in which the amino and carboxyl groups are directly attached to the same carbon atom; the term "a-amino acid side chain" refers to the R group in the general structure H2N-CH(R)-COOH; for example, the R group of alanine (NH2-CH(CH3)-COOH) is -CH3, i.e., the side chain of alanine is -CH3.

[0440] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is not physiologically noxious, irritating, or causes an allergic reaction. The substance used for salt formation can be an acid or a base, where the acid includes an inorganic acid or an organic acid that can form a salt with a basic group in a compound of the present disclosure; the base includes an inorganic base or an organic base that can form a salt with an acidic group in a compound of the present disclosure.

[0441] Unless otherwise specified, all compounds of the present disclosure include all possible stereoisomers and tautomers thereof (e.g., enol and keto forms). Stereoisomers in the present disclosure include optical isomers (e.g., enantiomers, diastereomers, epimers), cis / trans isomers (e.g., Z- and E-forms), conformers. In addition, a single stereoisomer or tautomer, as well as mixtures of stereoisomers and tautomers, are within the scope of the present disclosure.

[0442] As used herein, in any chemical structure or formula, a bold or hashed wedge bond (respectively ) connected to a stereocenter of a compound, such as in , indicates the absolute stereochemistry of the stereocenter, and the relative stereochemistry of the stereocenter relative to other stereocenters to which the bold or hashed wedge bond is connected.

[0443] As used herein, the term "optical isomer" refers to a stable isomer capable of rotating plane-polarized light to the right or left, due to having at least one chiral element (including chiral centers, chiral axes, chiral planes, etc.) that results in a non-superimposable mirror image. Because of the presence of asymmetric centers in the compounds of the present disclosure that can lead to stereoisomers, as well as other chemical structures, the present disclosure also includes these stereoisomers and mixtures thereof. Because the compounds of the present disclosure, and salts thereof, include asymmetric carbon atoms, they can exist in single stereoisomer, racemic, enantiomeric, and diastereomeric mixtures. The term "enantiomeric" refers to a pair of stereoisomers that are non-superimposable mirror images of each other. The term "diastereomeric" or "diastereomers" refers to optical isomers that are not mirror images of each other. The term "racemic mixture" or "racemate" refers to a mixture containing equal amounts of single enantiomeric isomers (i.e., an equimolar amount of two R and S enantiomers).

[0444] As used herein, the term "cis-trans isomer" refers to stereoisomers that result from the different positioning of atoms (or groups) relative to a reference plane; in cis isomers, the atoms (or groups) are on the same side of the double bond or ring system, and in trans isomers, the atoms (or groups) are on opposite sides of the double bond or ring system. Unless otherwise indicated, all cis-trans isomer forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0445] As used herein, the term "conformational isomer" also referred to as "rotamers," refers to different spatial arrangements of atoms or groups resulting from rotation about single bonds, for example, cyclohexane has two conformational isomers, boat and chair. Unless otherwise indicated, all conformational isomer forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0446] As used herein, the term "tautomers" also referred to as "tautomer forms," refers to structural isomers that differ in the arrangement of atoms with different energy that can interconvert by low energy barriers. If tautomerization is possible (as in solution), a chemical equilibrium of tautomers can be achieved. For example, prototropic tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imidol isomerization, etc. Unless otherwise indicated, all tautomer forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0447] As used herein, the term “solvate” refers to a substance having a compound of the disclosure, or a pharmaceutically acceptable salt thereof, combined with at least one solvent molecule through non-covalent intermolecular forces. The term “solvate” includes “hydrate”. Common solvates include, but are not limited to, hydrates (e.g., hemi-hydrate, monohydrate, di-hydrate, tri-hydrate, etc.), ethanolates, acetoneates, and the like.

[0448] As used herein, the term “isotopically-labeled” refers to a compound formed by replacing a particular atom in the structure with an isotopic atom thereof. Unless otherwise indicated, various isotopes of H, C, N, O, F, P, S, Cl, such as 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 35 S, 36 S, and 37 Cl.

[0449] As used herein, the term “prodrug” refers to a derivative compound that, upon administration to a patient, is capable of providing directly or indirectly a compound of the disclosure. Particularly preferred are derivative compounds or prodrugs that increase the bioavailability of a compound of the disclosure when administered to a patient (e.g., are more readily absorbed into the blood), or that facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise specified, all prodrug forms of a compound of the disclosure are within the scope of the disclosure, and various prodrug forms are well known in the art.

[0450] The disclosure further provides specific compounds by the following methods. Unless otherwise specified, the compounds, reagents, and the like used in the examples of the disclosure are purchased from qualified suppliers or synthesized according to methods disclosed in the prior art.

[0451] Abbreviations

[0452] Unless otherwise indicated or unless otherwise apparent from context, the following abbreviations have the following meanings in the present specification:

[0453] Examples

[0454] The embodiments of the present disclosure will be described in detail below with examples, but those skilled in the art will understand that the following examples are only for illustration of the present disclosure and should not be regarded as limiting the scope of the present disclosure. The specific conditions not noted in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not noted by the manufacturer, which are all conventional products that can be obtained by purchase. The known starting materials of the present disclosure can be used or synthesized according to the methods known in the art, or commercially available.

[0455] The structure of the compound is determined by nuclear magnetic resonance or / and mass spectrometry. The NMR chemical shift (δ) is given in units of 10 -6 (ppm). The NMR is measured by BRUKER AVANCE NEO 400mHz nuclear magnetic instrument, and the measurement solvent is DMSO-d6, CDCl3, CD3OD, and the internal standard is TMS. The MS is measured by Agilent 1260 / G6125C.

[0456] The HPLC analysis uses Agilent 1260II. The chiral HPLC analysis measurement uses Shimadzu LC-20AT and Thermo UltiMate 3000.

[0457] Example 1. Synthesis of (2R,3S,4S,5R)-N-(3-(N-(2-aminoacetyl)-S-methylsulfϊnylimino)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 1)

[0458] 1.11-(S-methylsulfϊnylimino)-3-nitrobenzene (Compound 1-2) synthesis

[0459] 3-nitroanisole sulfide (Compound 1-1, 6.58 g, 38.88 mmol) was dissolved in methanol (100 mL), ammonium carbonate (5.66 g, 58.27 mmol) and iodobenzene diacetate (25.00 g, 77.72 mmol) were added to the reaction solution, and stirred at room temperature for 5 h. After the reaction solution was concentrated to dryness, dichloromethane (100 mL) was added, stirred, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, v / v) and concentrated to obtain a light yellow solid, which was Compound 1-2 (6.3 g, yield 80.97%).

[0460] 1.2 Synthesis of tert-butyl (2-((methyl(3-nitrophenyl)(oxo)-λ 6 sulfϊnyl)amino)-2-oxoethyl)carbamate (Compound 1-3)

[0461] To a solution of 1-(S-methylsulfinylimino)-3-nitrobenzene (compound 1-2, 600 mg, 2.99 mmol) and Boc-glycine (788 mg, 4.50 mmol) in dichloromethane (10 mL) was added HATU (2281 mg, 6.00 mmol) and DIEA (1163 mg, 9.00 mmol) and stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-heptane / ethyl acetate = 2 / 1, v / v) and concentrated to give a light yellow oil, which was compound 1-3 (1.03 g, yield: 96.26%).

[0462] LC-MS m / z (ESI): 356.09 [M-H] - .

[0463] 1.3 Intermediate tert-butyl (2-(((3-aminophenyl)(methyl)(oxo)-λ 6 - sulfinyl)amino)-2-oxoethyl)carbamate (compound 1-4)

[0464] To a solution of tert-butyl (2-((methyl(3-nitrophenyl)(oxo)-λ 6 - sulfinyl)amino)-2-oxoethyl)carbamate (compound 1-3, 500 mg, 1.40 mmol) in methanol (10 mL) was added palladium hydroxide on carbon (100 mg) and stirred at room temperature for 9 h under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 20 / 1, v / v) to give a light yellow solid, which was compound 1-4 (380 mg, yield: 83.15%).

[0465] 1.4 Intermediate tert-butyl (2-(((3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)phenyl)(methyl)(oxo)-λ 6 - sulfinyl)amino)-2-oxoethyl)carbamate (compound 1-6)

[0466] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, 82 mg, 0.23 mmol, prepared by the method disclosed in Example 1 of patent application “WO2022256660A1”) was dissolved in anhydrous dichloromethane (5 mL), 1 drop of DMF was added, and the mixture was protected by nitrogen and cooled to 0 °C. Oxalyl chloride (86 mg, 0.68 mmol) was added dropwise, and the mixture was allowed to warm to room temperature and react for 1 h. The reaction mixture was concentrated to dryness, the residue was dissolved in anhydrous dichloromethane (5 mL), and the solution was added dropwise to a solution of tert-butyl (2-(((3-aminophenyl)(methyl)(oxo)-λ 6 - sulfinyl)amino)-2-oxoethyl)carbamate (Compound 1-4, 113 mg, 0.34 mmol) and TEA (116 mg, 1.14 mmol) in dichloromethane (2 mL) at 0 °C. After the addition was completed, the mixture was allowed to warm to room temperature and react for 2 h. After the reaction was completed, water (10 mL) was added, and the mixture was partitioned. The aqueous phase was extracted with dichloromethane (10 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 20 / 1, v / v) to give Compound 1-6 (82 mg, yield: 53.95%) as a light yellow solid.

[0467] LC-MS m / z (ESI): 662.20 [M-H] - .

[0468] 1.5 Synthesis of (2R,3S,4S,5R)-N-(3-(N-(2-aminoacetyl)-S-methylsulfinimidoyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 1)

[0469] (2-(((3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)phenyl)(methyl)(oxo)-λ 6tert-Butyl (S)-2-((2-oxooxazolidin-5-yl)amino)-2-oxoethyl)carbamate (Compound 1-6, 82 mg, 0.12 mmol) was dissolved in 1,4-dioxane (8 mL), hydrogen chloride 1,4-dioxane solution (4 M) (8 mL) was added with stirring, stirred at room temperature for 2 h. The reaction solution was concentrated to dryness, dichloromethane (20 mL) and water (20 mL) were added with stirring, saturated sodium carbonate solution was added dropwise to adjust the pH to 9-10, separated, dichloromethane (15 mL x 2) was extracted, the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated, the crude product was separated and purified by preparative liquid phase (instrument: Hanban NP 7000; column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%~70% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm), to obtain a white solid, which was Compound 1 (28.1 mg, yield: 40.37%).

[0470] LC-MS m / z (ESI): 562.14 [M-H] - .

[0471] 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.40 (s, 1H), 8.37 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.75-7.60 (m, 2H), 7.26-7.16 (m, 2H), 5.17 (d, J = 10.4 Hz, 1H), 4.32-4.28 (m, 1H), 3.999-3.994 (m, 5H), 3.49 (s, 3H), 2.87-2.76 (m, 1H), 1.64 (s, 3H), 0.77 (d, J = 6.1 Hz, 3H).

[0472] Compound 1 (14 mg) was resolved by chiral SFC (Waters PrepSFC 150Mgm; column: Daicel ChiralPak OZ, 40 mm I.D. x 250 mm, 10 μm; mobile phase A: CO2; mobile phase B: MeOH (0.1% NH3·H2O); gradient ratio: 50% v / v mobile phase B; flow rate: 140 mL / min), to obtain Compound 1-a (4 mg, RT = 2.0 min) and Compound 1-b (6 mg, RT = 4.9 min).

[0473] Example 2. Synthesis of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(3-(N-(2-(3, 3-difluoroazetidin-l-yl)acetyl)-S-methylsulfmylimino)phenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 2)

[0474] 2.1 Synthesis of 2-chloro-N-(methyl(3-nitrophenyl)(oxo)-lambda 6 -sulfenyl)acetamide (Compound 2-1)

[0475] S-methyl-S-(3-nitrophenyl)-sulfmylimine (Compound 1-2, 200 mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol) were dissolved in dichloromethane (10 mL) and stirred under nitrogen protection at 0 °C. Chloroacetyl chloride (135 mg, 1.2 mmol) was added dropwise and the reaction was allowed to proceed at room temperature for 2 h. The reaction was terminated by adding water (20 mL) dropwise after TLC detection. The organic phase was separated and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oil, which was Compound 2-1 (250 mg, yield: 90.5%).

[0476] LC-MS m / z (ESI): 274.9 [M-H] - .

[0477] 2.2 Synthesis of 2-(3, 3-difluoroazetidin-l-yl)-N-(methyl(3-nitrophenyl)(oxo)-lambda 6 -sulfenyl)acetamide (Compound 2-2)

[0478] 2-chloro-N-(methyl(3-nitrophenyl)(oxo)-lambda 6 -sulfenyl)acetamide (Compound 2-1, 250 mg, 0.9 mmol), KI (298 mg, 1.8 mmol), 3, 3-difluoroazetidine hydrochloride (233 mg, 1.8 mmol) were dissolved in DMF (10 mL) and K2CO3 (233 mg, 1.8 mmol) was added. The reaction was stirred at room temperature overnight. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain an oil, which was Compound 2-2 (244 mg, yield: 81.0%).

[0479] LC-MS m / z (ESI): 378.05 [M+HCOO] + .

[0480] 2.3 N-((3-aminophenyl)(methyl)(oxo)-lambda 6 - sulfinyl)-2-(3,3-difluoroazetidin-l-yl)acetamide (Compound 2-3)

[0481] N-((3-aminophenyl)(methyl)(oxo)-lambda 6 - sulfinyl)-2-(3,3-difluoroazetidin-l-yl)acetamide (Compound 2-3, 180 mg, 0.59 mmol) and DIEA (381 mg, 2.95 mmol) were dissolved in tetrahydrofuran (5 mL), and the mixture was cooled to 0 °C under nitrogen protection. The above acyl chloride solution in tetrahydrofuran was added dropwise, and the mixture was warmed to 70 °C and reacted for 2 h. The reaction was terminated by dropwise addition of water (20 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative separation (instrument: Hanbon NP 7000; column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 40%~84% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to give Compound 2 as a white solid (113.62 mg, yield: 44.96%).

[0482] 2.4 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-(2-(3,3- difluoroazetidin-l-yl)acetyl)-S-methylsulfmylimino)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 2)

[0483] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, 140 mg, 0.4 mmol) was dissolved in sulfurous acid (5 mL). The mixture was warmed to 80 °C under nitrogen protection and refluxed for 2 h. The mixture was concentrated under reduced pressure, dissolved in tetrahydrofuran (3 mL), and used as prepared.

[0484] N-((3-aminophenyl)(methyl)(oxo)-lambda 6 - sulfinyl)-2-(3,3-difluoroazetidin-l-yl)acetamide (Compound 2-3, 180 mg, 0.59 mmol) and DIEA (381 mg, 2.95 mmol) were dissolved in tetrahydrofuran (5 mL), and the mixture was cooled to 0 °C under nitrogen protection. The above acyl chloride solution in tetrahydrofuran was added dropwise, and the mixture was warmed to 70 °C and reacted for 2 h. The reaction was terminated by dropwise addition of water (20 mL), and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative separation (instrument: Hanbon NP 7000; column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 40%~84% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to give Compound 2 as a white solid (113.62 mg, yield: 44.96%).

[0485] LC-MS m / z (ESI): 640.16 [M+H] + .

[0486] 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (d, J = 3.3 Hz, 1H), 8.33 (s, 1H), 7.90 (dd, J = 7.1, 1.3 Hz, 1H), 7.68 - 7.59 (m, 2H), 7.22 - 7.09 (m, 2H), 5.11 (d, J = 10.3 Hz, 1H), 4.27 (dd, J = 10.2, 7.7 Hz, 1H), 3.96 (s, 3H), 3.67 - 3.59 (m, 4H), 3.35 - 3.32 (m, 5H), 2.78 (p, J = 7.4 Hz, 1H), 1.61 (s, 3H), 0.74 (d, J = 6.1 Hz, 3H).

[0487] Compound 2 (86 mg) was resolved by chiral SFC (Waters Prep SFC 150Mgm; Column: Daicel ChiralPak IC, 40 mm I.D. x 250 mm, 10 pm; Mobile Phase A: C02; Mobile Phase B: MeOH; Gradient Ratio: 20% v / v Mobile Phase B; Flow Rate: 140 mL / min) to give compound 2-a (38 mg, RT = 2.3 min) and compound 2-b (27 mg, RT = 3.0 min).

[0488] Compound 2-a:

[0489] LC-MS m / z (ESI): 640.1 [M+H] + .

[0490] 1 H NMR (400 MHz, MeOD) δ 8.40 - 8.39 (m, 1H), 7.85 - 7.82 (m, 1H), 7.75 - 7.72 (m, 1H), 7.60 (t, J = 8.0 Hz, 1H), 7.16 - 7.08 (m, 1H), 7.00 - 6.94 (m, 1H), 5.07 (d, J = 10.5 Hz, 1H), 4.34 - 4.29 (m, 1H), 4.00 (d, J = 2.3 Hz, 3H), 3.72 (t, J = 12.3 Hz, 4H), 3.46 (q, J = 1.4 Hz, 2H), 3.38 (s, 3H), 2.83 - 2.76 (m, 1H), 1.66 (s, 3H), 0.85 - 0.77 (m, 3H).

[0491] Compound 2-b:

[0492] LC-MS m / z (ESI): 640.1 [M+H] + .

[0493] 1 H NMR (400 MHz, MeOD) δ 8.40-8.39 (m, 1H), 7.85-7.82 (m, 1H), 7.75-7.72 (m, 1H), 7.60 (t, J = 8.1 Hz, 1H), 7.17-7.08 (m, 1H), 7.03-6.92 (m, 1H), 5.08 (d, J = 10.5 Hz, 1H), 4.34-4.29 (m, 1H), 3.99 (d, J = 2.3 Hz, 3H), 3.76-3.70 (m, 4H), 3.47-3.46 (m, 2H), 3.38 (s, 3H), 2.83-2.75 (m, 1H), 1.66 (d, J = 1.3 Hz, 3H), 0.83-0.80 (m, 3H).

[0494] Example 3. Synthesis of (2R,3S,4S,5R)-N-(3-(N-cyano-S-methylsulfϊnylimino)- phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 3)

[0495] 3.1 Synthesis of N-(methyl(3-nitrophenyl)(carbonyl)-lambda 6 -sulfanylidenyl)cyanamide (Compound 3-1)

[0496] (1-(S-methylsulfϊnylimino)-3-nitrobenzene (Compound 1-2, 750 mg, 3.74 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, DMAP (549 mg, 4.49 mmol) and cyanogen bromide (595 mg, 5.62 mmol) were added to the reaction solution, stirred at room temperature for 2 h, TLC detection showed that the reaction was complete, saturated ammonium chloride solution (20 mL) and dichloromethane (100 mL) were added and stirred to separate the organic phase, washed successively with saturated brine (50 mL) and water (50 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a light yellow oil, which was Compound 3-1 (640 mg, yield: 75.9%), the crude product was directly used in the next step.

[0497] LC-MS m / z (ESI): 224.01 [M-H] - .

[0498] 3.2 Synthesis of N-((3-aminophenyl)(methyl)(carbonyl)-lambda 6Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-cyano-S-methylsulfϊnylimino)phenyl)-3-(3,4- difluoro-2-methoxyphenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 3-2)

[0499] N-((3-aminophenyl)(methyl)(carbonyl)-λ 6 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-cyano-S-methylsulfϊnylimino)phenyl)-3-(3,4- difluoro-2-methoxyphenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 3-2)

[0500] LC-MS m / z (ESI): 240.04 [M+HCOO] + .

[0501] 3.3 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-cyano-S-methylsulfϊnylimino)phenyl)-3-(3,4- difluoro-2-methoxyphenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 3)

[0502] Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-cyano-S-methylsulfϊnylimino)phenyl)-3-(3,4- difluoro-2-methoxyphenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 3-2) 6 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-cyano-S-methylsulfϊnylimino)phenyl)-3-(3,4- difluoro-2-methoxyphenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 3-2) 6A solution of (thioalkylidene)cyanamide (compound 3-2) in dichloromethane was added dropwise, raised to room temperature and stirred overnight, concentrated under reduced pressure and the crude was purified by preparative separation (instrument: Hanbon NP 7000; column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 50% to 85% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to give compound 3 as a white solid (44.85 mg, yield: 29.9%).

[0503] LC-MS m / z (ESI): 531.99 [M+H] + .

[0504] 1 H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.35 (t, J = 2.0 Hz, 1H), 7.98-7.93 (m, 1H), 7.73-7.63 (m, 2H), 7.15-7.05 (m, 2H), 5.05 (d, J = 10.3 Hz, 1H), 4.20 (dd, J = 10.3, 7.6 Hz, 1H), 3.89 (d, J = 2.2 Hz, 3H), 3.63 (s, 3H), 2.71 (p, J = 7.5 Hz, 1H), 1.55 (s, 3H), 0.67 (dd, J = 7.3, 2.5 Hz, 3H).

[0505] Compound 3 (22 mg) was resolved by chiral SFC (Waters PrepSFC 150Mgm; column: Daicel ChiralPak IC, 40 mm I.D. x 250 mm, 10 pm; mobile phase A: C02; mobile phase B: MeOH; gradient ratio: 30% v / v mobile phase B; flow rate: 120 mL / min) to give compound 3-a (15 mg, RT = 2.9 min) and compound 3-b (9 mg, RT = 5.2 min).

[0506] Compound 3-a:

[0507] LC-MS m / z (ESI): 532.1 [M+H] + .

[0508] 1H NMR (400 MHz, MeOD) δ 8.43 (t, J = 2.0 Hz, 1H), 7.00 - 7.97 (m, 1H), 7.81 - 7.78 (m, 1H), 7.69 (t, J = 8.1 Hz, 1H), 7.16 - 7.12 (m, 1H), 7.01 - 6.95 (m, 1H), 5.09 (d, J = 10.5 Hz, 1H), 4.32 (dd, J = 10.5, 8.0 Hz, 1H), 4.00 (d, J = 2.3 Hz, 3H), 3.33 (s, 3H), 2.83 - 2.76 (m, 1H), 1.67 (d, J = 1.3 Hz, 3H), 0.82 (m, 3H).

[0509] Compound 3-b:

[0510] LC-MS m / z (ESI): 532.1 [M+H] + .

[0511] 1 H NMR (400 MHz, MeOD) δ 8.44 (t, J = 2.0 Hz, 1H), 7.00 - 7.97 (m, 1H), 7.81 - 7.78 (m, 1H), 7.69 (t, J = 8.1 Hz, 1H), 7.16 - 7.11 (m, 1H), 7.01 - 6.95 (m, 1H), 5.09 (d, J = 10.5 Hz, 1H), 4.32 (dd, J = 10.5, 8.0 Hz, 1H), 4.00 (d, J = 2.3 Hz, 3H), 3.33 (s, 3H), 2.84 - 2.76 (m, 1H), 1.67 (d, J = 1.3 Hz, 3H), 0.84 - 0.80 (m, 3H).

[0512] Example 4. Synthesis of (2R,3S,4S,5R)-N-(3-(N-(2-aminoethyl)-S- methylsulfϊnylimino)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 4)

[0513] 4.1 Synthesis of tert-butyl (2-((methyl(3-nitrophenyl)(oxo)-λ 6 sulfmyl)amino)ethyl)carbamate (Compound 4-1)

[0514] (2-((methyl(3-nitrophenyl)(oxo)-λ 6tert-Butyl (2-(((3-amino-4-(2-(methoxycarbonyl)ethyl)phenyl)(methyl)(oxo)- lambda-6-sulfanylidene)amino)ethyl)carbamate (Compound 4-2) was synthesized according to the procedure described in Scheme 4.

[0515] 4.2 tert-Butyl (2-(((3-amino-4-(2-(methoxycarbonyl)ethyl)phenyl)(methyl)(oxo)- lambda-6-sulfanylidene)amino)ethyl)carbamate (Compound 4-2) 6 tert-Butyl (2-(((3-amino-4-(2-(methoxycarbonyl)ethyl)phenyl)(methyl)(oxo)- lambda-6-sulfanylidene)amino)ethyl)carbamate (Compound 4-2) was synthesized according to the procedure described in Scheme 4.

[0516] tert-Butyl (2-(((3-amino-4-(2-(methoxycarbonyl)ethyl)phenyl)(methyl)(oxo)- lambda-6-sulfanylidene)amino)ethyl)carbamate (Compound 4-2) was synthesized according to the procedure described in Scheme 4. 6 tert-Butyl (2-(((3-amino-4-(2-(methoxycarbonyl)ethyl)phenyl)(methyl)(oxo)- lambda-6-sulfanylidene)amino)ethyl)carbamate (Compound 4-2) was synthesized according to the procedure described in Scheme 4.

[0517] LC-MS m / z (ESI): 358.14 [M+HCOO] + .

[0518] 4.3 tert-Butyl (2-(((3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)phenyl)(methyl)(oxo)- lambda-6-sulfanylidene)amino)ethyl)carbamate (Compound 4-3) 6 tert-Butyl (2-(((3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)phenyl)(methyl)(oxo)- lambda-6-sulfanylidene)amino)ethyl)carbamate (Compound 4-3)

[0519] tert-Butyl (2-(((3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)phenyl)(methyl)(oxo)- lambda-6-sulfanylidene)amino)ethyl)carbamate (Compound 4-3) 6- Sulfinyl) amino) ethyl) carbamate (compound 4-3, 90 mg, 0.14 mmol) was dissolved in 1,4-dioxane (5 mL), and a solution of 1,4-dioxane hydrogen chloride (4 M) (5 mL) was added dropwise slowly with stirring at room temperature overnight. A 10% sodium carbonate solution was added dropwise to pH 9-10, and extraction was performed with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative separation (instrument: Hanbon NP 7000; column: Phenomenex Luna 5 pm C18(2), 110 A, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to obtain a white solid, which was compound 4 (31.83 mg, yield: 41.81%).

[0520] LC-MS m / z (ESI): 648.21 [M-H] - .

[0521] 4.4 Synthesis of (2R,3S,4S,5R)-N-(3-(N-(2-aminoethyl)-S-methylsulfinylimino)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 4)

[0522] (tert-butyl (2-(((3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)phenyl)(methyl)(oxo)-lambda 6 - Sulfinyl) amino) ethyl) carbamate (compound 4-3, 90 mg, 0.14 mmol) was dissolved in 1,4-dioxane (5 mL), and a solution of 1,4-dioxane hydrogen chloride (4 M) (5 mL) was added dropwise slowly with stirring at room temperature overnight. A 10% sodium carbonate solution was added dropwise to pH 9-10, and extraction was performed with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative separation (instrument: Hanbon NP 7000; column: Phenomenex Luna 5 pm C18(2), 110 A, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%-70% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to obtain a white solid, which was compound 4 (31.83 mg, yield: 41.81%).

[0523] LC-MS m / z (ESI): 550.18 [M+H] + .

[0524] 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.46 (s, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.61-7.55 (m, 2H), 7.24-7.13 (m, 2H), 5.16 (d, J = 10.5 Hz, 1H), 4.32-4.19 (m, 1H), 3.96 (s, 3H), 3.14 (s, 3H), 2.99-2.92 (m, 1H), 2.86-2.70 (m, 4H), 1.60 (s, 3H), 0.73 (d, J = 6.1 Hz, 3H).

[0525] Compound 4 (16 mg) was resolved by chiral SFC (Waters PrepSFC 150Mgm; Column: Daicel ChiralPak IH, 40 mm I.D. x 250 mm, 10 pm; Mobile Phase A: CO2; Mobile Phase B: 0.8 MeOH (0.1% NH3-H2O) + 0.2 ACN; Gradient Ratio: 20% v / v Mobile Phase B; Flow Rate: 140 mL / min) to give compound 4-a (5 mg, RT = 3.8 min) and compound 4-b (8 mg, RT = 5.0 min).

[0526] Compound 4-a:

[0527] LC-MS m / z (ESI): 550.1 [M+H] + .

[0528] 1 H NMR (400 MHz, MeOD) δ 8.30 (t, J = 1.9 Hz, 1H), 7.80-7.77 (m, 1H), 7.68-7.66 (m, 1H), 7.61-7.57 (m, 1H), 7.15-7.10 (m, 1H), 7.01-6.94 (m, 1H), 5.07 (d, J = 10.6 Hz, 1H), 4.32 (dd, J = 10.5, 7.9 Hz, 1H), 4.00 (d, J = 2.3 Hz, 3H), 3.17 (s, 3H), 3.06-2.97 (m, 2H), 2.95-2.73 (m, 3H), 1.66 (d, J = 1.4 Hz, 3H), 0.88-0.80 (m, 3H).

[0529] Compound 4-b:

[0530] LC-MS m / z (ESI): 550.1 [M+H] + .

[0531] 1H NMR (400 MHz, MeOD) δ 8.27 (t, J = 1.9 Hz, 1H), 7.83-7.80 (m, 1H), 7.68-7.57 (m, 2H), 7.15-7.11 (m, 1H), 7.01-6.94 (m, 1H), 5.07 (d, J = 10.5 Hz, 1H), 4.32 (dd, J = 10.5, 8.0 Hz, 1H), 4.00 (d, J = 2.3 Hz, 3H), 3.16 (s, 3H), 2.97-2.86 (m, 2H), 2.79-2.74 (m, 3H), 1.66 (d, J = 1.4 Hz, 3H), 0.88-0.80 (m, 3H).

[0532] Example 5. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-(2- hydroxyacetyl)-S-methylsulfϊnimidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 5)

[0533] 5.1 Synthesis of butyl 2-((tert-butyldimethylsilyl)oxy)acetate (Compound 5-2)

[0534] Butyl hydroxyacetate (Compound 5-1, 5.00 g, 37.83 mmol) and imidazole (6.41 g, 94.58 mmol) were added to DMF (20 mL), and tert-butyldimethylsilyl chloride (6.80 g, 45.40 mmol) was added to the reaction solution, which was stirred at 20-25 °C for 1.5 hours. Water (50 mL) and methyl tert-butyl ether (50 mL) were added to the reaction solution, which was stirred, separated, extracted with methyl tert-butyl ether (30 mL x 2), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless oil, which was Compound 5-2 (9.32 g, yield: 90.31%).

[0535] 5.2 Synthesis of butyl 2-((tert-butyldimethylsilyl)oxy)acetate (Compound 5-3)

[0536] Potassium hydroxide (2.14 g, 38.09 mmol) was weighed into methanol (8 mL) and water (4 mL). Butyl 2-((tert-butyldimethylsilyl)oxy)acetate (compound 5-2, 9.32 g, 37.82 mmol) was added to tetrahydrofuran (20 mL), stirred and cooled to -10 °C, and the potassium hydroxide solution was added dropwise, then warmed to 5 °C and stirred for 6 h. Methyl tert-butyl ether (50 mL) and water (10 mL) were added, stirred, separated, and the organic phase was taken, and the aqueous phase was further extracted with methyl tert-butyl ether (50 mL). The aqueous phase was cooled to 0-5 °C, 1 M hydrochloric acid solution was added dropwise to adjust the pH to 5-6, methyl tert-butyl ether was added (50 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to give a colorless solid, which was compound 5-3 (4.6 g, yield: 63.91%).

[0537] 5.3 2-((tert-butyldimethylsilyl)oxy)-N-(methyl(3-nitrophenyl)(oxo)-λ 6 sulfanylidene)acetamide (compound 5-4)

[0538] 1-(S-methylsulfonimidoyl)-3-nitrobenzene (compound 1-2, 600 mg, 2.99 mmol) and butyl 2-((tert-butyldimethylsilyl)oxy)acetate (compound 5-3, 859 mg, 4.50 mmol) were dissolved in dichloromethane (10 mL), HATU (2281 mg, 6.00 mmol) and DIEA (1163 mg, 9.00 mmol) were added to the reaction solution, and the reaction was stirred at room temperature for 20 h. After the reaction was completed, the reaction solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-heptane / ethyl acetate = 2 / 1, v / v) and concentrated to give a light yellow oil, which was compound 5-4 (570 mg, yield: 51.12%).

[0539] LC-MS m / z (ESI): 371.10 [M-H] - .

[0540] 5.4 N-((3-aminophenyl)(methyl)(oxo)-λ 6 sulfanylidene)-2-((tert-butyldimethylsilyl)oxy)acetamide (compound 5-5)

[0541] 2-((tert-butyldimethylsilyl)oxy)-N-(methyl(3-nitrophenyl)(oxo)-λ 6- Sulfinyl)acetamide (compound 5-4, 570 mg, 1.53 mmol) and palladium hydroxide on carbon (75 mg) were added to methanol (10 mL) and stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered using celite, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 20 / 1, v / v) and concentrated to obtain a yellowish solid, which was compound 5-5 (400 mg, yield: 76.34%).

[0542] 5.5 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S- methylsulfinimidoyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 5-6)

[0543] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-5, 90 mg, 0.25 mmol) was dissolved in anhydrous dichloromethane (5 mL), and HATU (145 mg, 0.38 mmol) and DIEA (98 mg, 0.76 mmol) were added to the reaction solution. After stirring for 10 minutes, N-((3- aminophenyl)(methyl)(oxo)-lambda 6 Sulfinyl)-2-((tert-butyldimethylsilyl)oxy)acetamide (compound 5-5, 150 mg, 0.44 mmol) was added to the reaction solution, and stirred overnight under nitrogen atmosphere. The reaction solution was added to water (10 mL), and separated. The dichloromethane layer was extracted (10 mL x 2), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane / methanol = 20 / 1, v / v) to obtain a yellowish solid, which was compound 5-6 (120 mg, yield: 69.77%).

[0544] 5.6 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-(2- hydroxyacetyl)-S-methylsulfinimidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 5)

[0545] (2R,3S,4S,5R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S- methylsulfϊnamidyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 5-6, 120 mg, 0.15 mmol) was dissolved in tetrahydrofuran (8 mL) followed by the addition of water (5 mL) and acetic acid (2 mL) and stirred at room temperature overnight. The reaction was added to ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (20 mL x 2), water (20 mL), the organic phase was dried and concentrated, the crude was separated by preparative liquid chromatography (Instrument: Hanbon NP 7000; Column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; Mobile Phase A: 0.1% formic acid; Mobile Phase B: acetonitrile; Gradient: 30% to 70% v / v acetonitrile; Flow rate: 20 mL / min; Wavelength: 210 / 254 nm) to give Compound 5 as a white solid (42.62 mg, yield: 53.95%).

[0546] LC-MS m / z (ESI): 587.14 [M+Na] + .

[0547] 1 H NMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.32 (d, J = 6.7 Hz, 1H), 8.03 - 7.93 (m, 1H), 7.74 - 7.57 (m, 2H), 7.25 - 7.13 (m, 2H), 5.14 (d, J = 10.3 Hz, 1H), 4.38 - 4.13 (m, 1H), 4.00 (d, J = 1.9 Hz, 3H), 3.97 (s, 2H), 3.45 (d, J = 7.0 Hz, 3H), 2.86 - 2.75 (m, 1H), 1.65 (s, 3H), 0.77 (d, J = 6.2 Hz, 3H).

[0548] Example 6. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N- glycyl-S-methylsulfϊnamidyl)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 6)

[0549] 6.1 Synthesis of 2-(methylthio)pyridin-4-amine (Compound 6-2)

[0550] To a solution of 4-amino-2-fluoropyridine (compound 6-1, 2.00 g, 0.018 mol) in NMP (20 mL) was added sodium thiomethoxide (3.00 g, 0.042 mol) and the reaction mixture was heated to 130 °C. The reaction was monitored by TLC and was completed after 2 hours. The reaction mixture was cooled to room temperature and water (80 mL) was added. The mixture was extracted with dichloromethane (80 mL x 3). The organic layers were combined, washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 80 / 1 to 40 / 1, v / v) to give compound 6-2 (1.84 g, yield: 73.6%) as an oil.

[0551] 6.2 (tert-Butyl (2-(methylthio)pyridin-4-yl)carbamate (compound 6-3)

[0552] To a solution of 4-amino-2-fluoropyridine (compound 6-1, 2.00 g, 0.018 mol) in NMP (20 mL) was added sodium thiomethoxide (3.00 g, 0.042 mol) and the reaction mixture was heated to 130 °C. The reaction was monitored by TLC and was completed after 2 hours. The reaction mixture was cooled to room temperature and water (80 mL) was added. The mixture was extracted with dichloromethane (80 mL x 3). The organic layers were combined, washed with saturated brine (80 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 80 / 1 to 40 / 1, v / v) to give compound 6-2 (1.84 g, yield: 73.6%) as an oil.

[0553] LC-MS m / z (ESI): 239.07 [M-H] - .

[0554] 6.3 (tert-Butyl (2-(S-methylsulfinimidoyl)pyridin-4-yl)carbamate (compound 6-4)

[0555] To a solution of tert-butyl (2-(methylthio)pyridin-4-yl)carbamate (compound 6-3, 1.80 g, 0.0075 mol) in methanol (10 mL) was added ammonium carbonate (2.16 g, 0.022 mol) and iodoxybenzene diacetate (9.65 g, 0.030 mol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and dichloromethane (30 mL) was added. The mixture was filtered and the filtrate was stirred with water (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 6-4 (1.90 g, yield: 93.5%) as a yellow oil. The crude product was used directly in the next step.

[0556] LC-MS m / z (ESI): 270.09 [M-H] - .

[0557] 6.4 Synthesis of tert-butyl (2-(N-((tert-butoxycarbonyl)glycyl)-S- methylsulfmimidoyl)pyridin-4-yl)carbamate (compound 6-5)

[0558] Boc-glycine (1.35 g, 0.0077 mol) was dissolved in DMF (5 mL), DIEA (1.81 g, 0.014 mol) and HATU (3.46 g, 0.091 mol) were added, stirred at room temperature for 0.5 h, tert-butyl (2-(S-methylsulfmimidoyl)pyridin-4-yl)carbamate (compound 6-4, 1.90 g, 0.0070 mol) was added, stirred at room temperature overnight, saturated sodium bicarbonate solution (30 mL) was added, dichloromethane (30 mL x 2) was extracted, the organic phase was combined, concentrated under reduced pressure, and yellow-brown oil was obtained, which was compound 6-5 (3.50 g). The crude product was directly used in the next step.

[0559] LC-MS m / z (ESI): 427.16 [M-H] - .

[0560] 6.5 Synthesis of 2-amino-N-((4-aminopyridin-2-yl)(methyl)(oxo)-lambda 6 -amino-sulfmimidate)acetamide (compound 6-6)

[0561] Tert-butyl (2-(N-((tert-butoxycarbonyl)glycyl)-S-methylsulfmimidoyl)pyridin-4- yl)carbamate (compound 6-5, 3.50 g, 0.0082 mol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (10 mL) was added, stirred at room temperature for 1 h, concentrated under reduced pressure, stirred with water (30 mL) to dissolve, washed with dichloromethane (15 mL x 2), the aqueous phase was adjusted to pH 9-10 with 10% sodium carbonate solution, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 20 / 1-5 / 1, v / v) to obtain an oil, which was compound 6-6 (5.08 g). The crude product was directly used in the next step.

[0562] LC-MS m / z (ESI): 251.06 [M+Na] + .

[0563] 6.6 Synthesis of tert-butyl (2-(((4-aminopyridin-2-yl)(methyl)(oxo)-lambda 6 -amino-sulfmimidateamino)-2-oxoethyl)carbamate (compound 6-7)

[0564] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, 100 mg, 0.28 mmol) was added to sulfurous acid chloride (5 mL) and warmed to reflux for 2 hours. The reaction was concentrated under reduced pressure and diluted with dichloromethane (5 mL). (2-(((4-amino-pyridin-2-yl)(methyl)(oxo)-λ 6 -aminosulfinylimine)acetamide (Compound 6-6, 5.08 g, 0.022 mol) was dissolved in dichloromethane (15 mL) and sodium bicarbonate (1.76 g, 0.021 mol) was added. The reaction was cooled to 0-5 °C and Boc20 (1.53 g, 0.0070 mol) was dissolved in dichloromethane (5 mL) and added dropwise to the reaction. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched by the addition of water (20 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (15 mL x 2) and the organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 80 / 1 to 20 / 1, v / v) to give a white solid, which was Compound 6-7 (0.42 g). The crude product was used directly in the next reaction.

[0565] LC-MS m / z (ESI): 329.12 [M+H] + .

[0566] 6.7 (2-(((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)(methyl)(oxo)-λ 6 -aminosulfinylimine)amino)-2-oxoethyl)tert-butyl carbamate (Compound 6-8)

[0567] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, 100 mg, 0.28 mmol) was added to sulfurous acid chloride (5 mL) and warmed to reflux for 2 hours. The reaction was concentrated under reduced pressure and diluted with dichloromethane (5 mL). (2-(((4-amino-pyridin-2-yl)(methyl)(oxo)-λ 6 -aminosulfinylimine)amino)-2-oxoethyl)tert-butyl carbamate (Compound 6-7, 220 mg, 0.67 mmol) was dissolved in dichloromethane (10 mL) and DIEA (110 mg, 0.85 mmol) was added. The acyl chloride in dichloromethane was added dropwise slowly and the reaction was stirred at room temperature overnight. The reaction was quenched by the addition of water (15 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (15 mL) and the organic phases were combined and concentrated under reduced pressure to give an oil, which was Compound 6-8 (421 mg). The crude product was used directly in the next reaction.

[0568] 6.8 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N- glycyl-S-methylsulfmimidoyl)pyridin-4-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 6)

[0569] tert-Butyl (2-(((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)(methyl)(oxo)- lambda 6 tert-Butyl (2-(((4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)(methyl)(oxo)- lambda

[0570] LC-MS m / z (ESI): 563.13 [M-H] - .

[0571] 1 H NMR (400 MHz, DMSO-d6) d 11.24 (s, 1H), 8.55 (d, J = 5.5 Hz, 1H), 8.49 (t, J = 2.1 Hz, 1H), 7.88 (dd, J = 5.5, 2.1 Hz, 1H), 7.19 - 7.04 (m, 2H), 5.14 (d, J = 10.2 Hz, 1H), 4.20 (dd, J = 10.2, 7.6 Hz, 1H), 3.89 (d, J = 2.0 Hz, 3H), 3.37 (d, J = 3.3 Hz, 3H), 3.29 (d, J = 2.0 Hz, 2H), 2.77 - 2.65 (m, 1H), 1.55 (s, 3H), 0.67 (dd, J = 7.6, 2.7 Hz, 3H).

[0572] Compound 6 (29 mg) was resolved by chiral SFC (Waters PrepSFC 150Mgm; Column: Daicel ChiralPak IC, 40 mm I.D. x 250 mm, 10 pm; Mobile Phase A: C02; Mobile Phase B: 0.8 MeOH (0.1% NH3-H20) + 0.2 ACN; Gradient Ratio: 20% v / v Mobile Phase B; Flow Rate: 140 mL / min) to give compound 6-a (9 mg, RT = 3.3 min) and compound 6-b (12 mg, RT = 4.3 min).

[0573] Compound 6-a:

[0574] LC-MS m / z (ESI): 563.0 [M-H] - .

[0575] 1 H NMR (400 MHz, MeOD) d 8.56 (d, J = 5.5 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 5.5, 2.1 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.99 - 6.95 (m, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 10.4, 8.0 Hz, 1H), 4.00 (d, J = 2.3 Hz, 3H), 3.42 (s, 3H), 3.34 (s, 2H), 2.80 (p, J = 7.7 Hz, 1H), 1.66 (d, J = 1.4 Hz, 3H), 0.82 (dq, J = 7.4, 2.3 Hz, 3H).

[0576] Compound 6-b:

[0577] LC-MS m / z (ESI): 563.0 [M-H] - .

[0578] 1 H NMR (400 MHz, MeOD) d 8.56 (d, J = 5.5 Hz, 1H), 8.54 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 5.5, 2.1 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.99 - 6.95 (m, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.33 (dd, J = 10.4, 8.0 Hz, 1H), 4.00 (d, J = 2.3 Hz, 3H), 3.42 (s, 3H), 3.34 (s, 2H), 2.80 (p, J = 7.7 Hz, 1H), 1.66 (d, J = 1.4 Hz, 3H), 0.82 (dq, J = 7.4, 2.3 Hz, 3H).

[0579] Example 7. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2- ((dimethyl(oxo)-lambda 6 -6-sulfonamide (Compound 7-2) Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-N-(2-((dimethyl(oxo)-lambda

[0580] 7.1 dimethyl(4-nitropyridin-2-yl)imino- lambda 6 -6-sulfonamide (Compound 7-2) Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-N-(2-((dimethyl(oxo)-lambda

[0581] Into a reaction flask was placed 2-chloro-4-nitropyridine (Compound 7-1, 500 mg, 3.15 mmol), dimethylsulfinimidate (440 mg, 4.73 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (365 mg, 631 μmol), tris[dibenzylideneacetone]dipalladium (289 mg, 630 μmol), cesium carbonate (3.08 g, 9.46 mmol) and 1,4-dioxane (10 mL), stirred at 100 °C overnight. TLC detection showed the reaction was completed, added 1,4-dioxane (20 mL), stirred, filtered, the filtrate was concentrated under reduced pressure, purified by column chromatography (eluent: DCM) to give yellow solid, which was Compound 7-2 (600 mg, yield: 88%).

[0582] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 5.6 Hz, 1H), 7.45 (dd, J = 5.6, 2.1 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 3.44 (s, 6H).

[0583] 7.2 dimethyl(4-aminopyridin-2-yl)imino- lambda 6 -6-sulfonamide (Compound 7-2) Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-N-(2-((dimethyl(oxo)-lambda

[0584] Into a reaction flask was placed dimethyl(4-aminopyridin-2-yl)imino- lambda 6 -6-sulfonamide (Compound 7-2, 600 mg, 2.79 mmol) and Pd / C (10%) (120 mg) into methanol (10 mL), replaced with H2, stirred at room temperature overnight. TLC detection showed the reaction was completed, filtered, the filtrate was concentrated under reduced pressure, purified by column chromatography (eluent: DCM / MeOH = 20 / 1 ~ 8 / 1, v / v), concentrated under reduced pressure to give off-white solid, which was Compound 7-3 (430 mg, yield: 83%).

[0585] 1H NMR (400 MHz, DMSO-d6) δ 7.61 (d, J = 5.7 Hz, 1H), 6.04 (dd, J = 5.7, 2.1 Hz, 1H), 5.80 (d, J = 2.1 Hz, 1H), 5.68 (s, 2H), 3.31 (s, 6H).

[0586] 7.3 (2R, 3S, 4S, 5R)-3-(3,4-Difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)-lambda 6 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)- lambda

[0587] (2R, 3S, 4S, 5R)-4, 5-dimethyl-5-trifluoromethyl-3-(3, 4-difluoro-2- methoxyphenyl)-tetrahydrofuran-2-carboxylic acid (Compound 1-5, 70 mg, 198 pmol) was dissolved with dichloromethane (5 mL), DMF (20 mg) was added, oxalyl chloride (75 mg, 593 pmol) was added, stirred at room temperature for 1.5 h, the solvent was removed by concentration under reduced pressure, dissolved with dichloromethane (5 mL), and cooled to 0 °C for standby. Dimethyl(4-aminopyridin-2-yl)imino- lambda 6 (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)- lambda

[0588] LC-MS m / z (ESI): 522.16 [M+H] + .

[0589] 1H NMR (400 MHz, CDC13) δ 8.30 (s, 1H), 8.08 (d, J = 5.7 Hz, 1H), 7.12 (dd, J = 5.8, 2.0 Hz, 1H), 7.09-7.07 (m, 1H), 6.92-6.85 (m, 1H), 6.82 (d, J = 1.9 Hz, 1H), 4.96 (d, J = 10.8 Hz, 1H), 4.07 (dd, J = 10.8, 8.0 Hz, 1H), 3.99 (d, J = 2.7 Hz, 3H), 3.33 (s, 6H), 2.73 (p, J = 7.7 Hz, 1H), 1.71 (s, 3H), 0.77 (dt, J = 7.7, 2.5 Hz, 3H).

[0590] Example 8. Synthesis of 4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-methyl-N-(2-(methylsulfonyl)ethyl)picolinamide (Compound 8)

[0591] 8.1 Synthesis of methyl 4-((tert-butoxycarbonyl)amino)picolinate (Compound 8-2)

[0592] Methyl 4-aminopicolinate (Compound 8-1, 6 g, 39.46 mmol) was dissolved in DCM (20 mL), DMAP (0.48 g, 3.95 mmol) was added, followed by BOC anhydride (9.47 g, 43.40 mmol), and the mixture was stirred at room temperature under nitrogen protection overnight. Water (20 mL) was added to the reaction solution, and the mixture was separated. The organic phase was extracted with DCM (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-heptane / ethyl acetate = 1 / 1, v / v) to give methyl 4-((tert-butoxycarbonyl)amino)picolinate (Compound 8-2, 7 g, yield: 70.42%) as a light yellow solid.

[0593] LC-MS m / z (ESI): 253.12 [M+H] + .

[0594] 8.2 Synthesis of 4-((tert-butoxycarbonyl)amino)picolinic acid (Compound 8-3)

[0595] Methyl 4-((tert-butoxycarbonyl)amino)picolinate (compound 8-2, 7 g, 27.77 mmol) was dissolved in methanol (70 mL), 2N sodium hydroxide solution (70 mL) was added, stirred at room temperature overnight, concentrated under reduced pressure, then added pure water (100 mL) and ethyl acetate (150 mL), adjusted to pH 5-6 using 2N dilute hydrochloric acid in an ice bath, suction filtered, and white solid was obtained, which was dried to obtain 4-((tert-butoxycarbonyl)amino)picolinic acid, i.e. compound 8-3 (4.30 g, yield: 65.34%).

[0596] LC-MS m / z (ESI): 237.08 [M-H] - .

[0597] 8.3 Synthesis of N-methyl-2-(methylsulfonyl)ethane-1-amine (compound 8-5)

[0598] Methylamine hydrochloride (6.36 g, 94 mmol) was dissolved in methanol (25 mL), TEA (9.51 g, 94 mmol) was added, then methyl vinyl sulfone (compound 8-4, 1 g, 9.43 mmol) was added, and after addition, it was reacted at room temperature overnight. The reaction solution was suction filtered, and the filtrate was evaporated to dryness, then ethyl acetate (10 mL) was added and stirred for 10 minutes, then suction filtered again, and the filtrate was evaporated to dryness to obtain a light yellow solid, i.e. N-methyl-2-(methylsulfonyl)ethane-1-amine (compound 8-5, 1 g, yield: 77.52%).

[0599] LC-MS m / z (ESI): 138.05 [M+H] + .

[0600] 8.4 Synthesis of tert-butyl (2-(methyl(2-(methylsulfonyl)ethyl)carbamate)pyridin-4-yl)carbamate (compound 8-6)

[0601] To a solution of 4-((tert-butoxycarbonyl)amino)picolinic acid (compound 8-3, 0.5 g, 2.10 mmol) in DMF (10 mL) was added N-methyl-2-(methylsulfonyl)ethane-1- amine (compound 8-5, 0.58 g, 4.23 mmol), DIEA (0.82 g, 6.34 mmol) and HATU (0.96 g, 2.52 mmol). After addition, the reaction solution was purged with nitrogen for three times and stirred at room temperature overnight. The reaction solution was added with water (20 mL) and ethyl acetate (10 mL), and the mixture was separated. The aqueous phase was extracted with ethyl acetate (10 mL x 2), and the organic phases were combined, washed with water (10 mL x 2), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 1 / 4, v / v) to obtain tert-butyl (2-(methyl(2-(methylsulfonyl)ethyl)carbamate)pyridin-4-yl)carbamate (compound 8-6, 0.62 g, yield: 82.67%) as a white solid.

[0602] LC-MS m / z (ESI): 358.14 [M+H] + .

[0603] 8.5 Synthesis of 4-amino-N-methyl-N-(2-(methylsulfonyl)ethyl)picolinamide hydrochloride (compound 8-7)

[0604] Tert-butyl (2-(methyl(2-(methylsulfonyl)ethyl)carbamate)pyridin-4-yl)carbamate (compound 8-6, 0.62 g, 1.74 mmol) was dissolved in 4N HCl in dioxane (10 mL) and stirred at room temperature for 2 hours. The reaction solution was filtered to obtain a white solid, which was dried to obtain 4-amino-N-methyl-N-(2-(methylsulfonyl)ethyl)picolinamide hydrochloride (compound 8-7, 0.80 g, yield: 100%).

[0605] LC-MS m / z (ESI): 258.08 [M+H] + .

[0606] 8.6 Synthesis of 4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-methyl-N-(2-(methylsulfonyl)ethyl) picolinamide (compound 8)

[0607] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, CAS: 2649469-37-2, 0.071 g, 0.20 mmol) was dissolved in anhydrous dichloromethane (3 mL), 1 drop of DMF was added, and the mixture was stirred at 0 °C under nitrogen protection. Oxalyl chloride (0.076 g, 0.60 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and react for 1 h. The reaction mixture was evaporated to dryness, and the residue was dissolved in anhydrous dichloromethane (3 mL). The solution was cooled to 0 °C, and a solution of 4-amino-N-methyl-N-(2-(methylsulfonyl)ethyl)picolinamide (Compound 8-7, 0.088 g, 0.30 mmol) and TEA (0.60 g, 6.00 mmol) in anhydrous dichloromethane (2 mL) was added dropwise. After the addition was completed, the reaction mixture was allowed to warm to room temperature and react for 2 h. After the reaction was completed, water (10 mL) was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-heptane / ethyl acetate = 3 / 1, v / v) to obtain a crude product. The crude product was purified by high-performance liquid chromatography (instrument: Hanbon NP 7000; column: Phenomenex Luna 5 μm C18(2), 110 A, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient ratio: 30% to 70% v / v acetonitrile; flow rate: 20 mL / min), and then lyophilized to obtain a white solid, which was 4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carbonyl)-N-methyl-N-(2-(methylsulfonyl)ethyl)picolinamide (Compound 8, 0.034 g, yield: 28.59%).

[0608] LC-MS m / z (ESI): 594.17 [M+H] + .

[0609] 1H NMR (400 MHz, DMSO-d6) δ 10.69 (d, J = 2.8 Hz, 1H), 8.46 (dd, J = 5.6, 1.2 Hz, 1H), 7.86 (dd, J = 22.7, 2.1 Hz, 1H), 7.74 - 7.63 (m, 1H), 7.23 - 7.09 (m, 2H), 5.10 (d, J = 10.2 Hz, 1H), 4.25 (dd, J = 10.2, 7.7 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.84 (t, J = 7.1 Hz, 1H), 3.75 - 3.66 (m, 1H), 3.62 - 3.53 (m, 1H), 3.47 (t, J = 7.1 Hz, 1H), 3.04 (d, J = 27.5 Hz, 3H), 2.94 (d, J = 20.2 Hz, 3H), 2.81 - 2.72 (m, 1H), 1.60 (s, 3H), 0.77 - 0.69 (m, 3H).

[0610] Example 9. Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-(2-(methylsulfonyl) ethyl)picolinamide (Compound 9)

[0611] 9.1 Synthesis of methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (Compound 9-1)

[0612] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, CAS: 2649469-37-2) (0.213 g, 0.60 mmol) was dissolved in anhydrous dichloromethane (5 mL), 3 drops of DMF was added dropwise, and the reaction was stirred at 0 °C under nitrogen protection. Oxalyl chloride (0.228 g, 1.80 mmol) was added dropwise, and after the addition was completed, the reaction was allowed to react at room temperature for 1 h. After the reaction was completed, the reaction was rotary evaporated to dryness, and the residue was dissolved in anhydrous dichloromethane (5 mL). A solution of methyl 4-aminopicolinate (Compound 8-1, 0.137 g, 0.90 mmol) and TEA (0.304 g, 3.00 mmol) in dichloromethane (2 mL) was added dropwise to the reaction at 0 °C. After the addition was completed, the reaction was allowed to react at room temperature for 2 h. After the reaction was completed, water (10 mL) was added to the reaction, and the mixture was separated. The aqueous phase was extracted with dichloromethane (10 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 80, v / v) to obtain methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (Compound 9-1, 0.190 g, yield: 64.87%) as a light yellow oil.

[0613] LC-MS m / z (ESI): 489.15 [M+H] + .

[0614] 9.2 Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinic acid (Compound 9-2)

[0615] Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylate (compound 9-1, 190 mg, 0.40 mmol) was dissolved in tetrahydrofuran (5 mL), 2N lithium hydroxide solution (3 mL) was added, stirred at room temperature for 2 hours, the reaction solution was adjusted to pH 2-3 using 1N dilute hydrochloric acid, separated, the aqueous phase was extracted with dichloromethane (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, suction filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20, v / v) to obtain 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxylic acid (compound 9-2, 0.10 g, yield: 52.73%) as a white foamy solid.

[0616] LC-MS m / z (ESI): 475.13 [M+H] + .

[0617] 9.3 Synthesis of 4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-(2-(methylsulfonyl)ethyl)pyridinecarboxamide (compound 9)

[0618] (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarboxamide (Compound 9-2, 0.100 g, 0.21 mmol) was dissolved in DMF (3 mL), 2-(methylsulfonyl)ethane-1- amine (0.028 g, 0.23 mmol), DIEA (0.082 g, 0.63 mmol) and HATU (0.096 g, 0.25 mmol) were added, after addition, the reaction was carried out at room temperature for 4 hours under nitrogen protection. The reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the liquid was separated, the aqueous phase was extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with water (5 mL x 2), then washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 1 / 4, v / v) to obtain a crude product, which was freeze-dried after purification by high performance liquid preparative chromatography (instrument: Hanban NP 7000; column: Phenomenex Luna 5 μm C18(2), 110 A, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient ratio: 30% to 70% v / v acetonitrile; flow rate: 20 mL / min) to obtain a white solid, which was 4-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)-N-(2-(methylsulfonyl)ethyl)pyridinecarboxamide (Compound 9, 0.052 g, yield: 42.64%).

[0619] LC-MS m / z (ESI): 580.17 [M+H] + .

[0620] 1 H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.98 (t, J = 6.0 Hz, 1H), 8.52 (d, J = 5.5 Hz, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.87 (dd, J = 5.5, 2.2 Hz, 1H), 7.21 - 7.12 (m, 2H), 5.11 (d, J = 10.1 Hz, 1H), 4.26 (dd, J = 10.2, 7.7 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.79 - 3.68 (m, 2H), 3.39 (t, J = 6.8 Hz, 2H), 3.03 (s, 3H), 2.84 - 2.72 (m, 1H), 1.61 (s, 3H), 0.77 - 0.70 (m, 3H).

[0621] Example 10. Synthesis of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 5- dimethyl-N-(2-(3-(methylsulfonyl)azetidine-l-carbonyl)pyridin-4-yl)-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 10)

[0622] 10.1 Synthesis of tert-butyl (2-(3-(methylsulfonyl)azetidine-l-carbonyl)pyridin-4- yl)carbamate (Compound 10-2)

[0623] Tert-butyl 4-((tert-butoxycarbonyl)amino)picolinate (Compound 8-3, 200 mg, 1.17 mmol), 3-methylsulfonylazetidine (Compound 10-1, 305 mg, 1.28 mmol) and HATU (576 mg, 1.51 mmol) were dissolved in DMF (10 mL), stirred, DIEA (452 mg, 3.50 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 h. The reaction was completed as detected by TLC, and the reaction was terminated by adding saturated aqueous sodium bicarbonate solution (15 mL) dropwise, and the mixture was filtered under suction, the filter cake was washed with a small amount of water, and the solid was dried in a vacuum at 50°C to obtain a beige solid, which was Compound 10-2 (400 mg, yield: 96.6%).

[0624] LC-MS m / z (ESI): 354.11 [M-H] - .

[0625] 10.2 Synthesis of (4-aminopyridin-2-yl)(3-(methylsulfonyl)azetidin-l-yl)methanone (Compound 10-3)

[0626] Tert-butyl (2-(3-(methylsulfonyl)azetidine-l-carbonyl)pyridin-4-yl)carbamate (Compound 10-2, 400 mg, 1.13 mmol) was dissolved in DCM (10 mL), and TFA (10 mL) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 h. The reaction was completed as detected by TLC, and the reaction mixture was concentrated to dryness under reduced pressure. Water (5 mL) was added to the residue, and the mixture was stirred to dissolve, the pH was adjusted to 9-10 using saturated aqueous sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 3 / 1-1 / 1, v / v) to obtain an oil, which was Compound 10-3 (200 mg, yield: 69.6%).

[0627] LC-MS m / z (ESI): 256.07 [M+H] + .

[0628] 10.3 Synthesis of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 5- dimethyl-N-(2-(3-(methylsulfonyl)azetidine-l-carbonyl)pyridin-4-yl)-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 10)

[0629] (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, 90 mg, 0.25 mmol) was dissolved in thionyl chloride (5 mL). The reaction was refluxed at 80 °C for 2 h under nitrogen protection, concentrated under reduced pressure, and dissolved in tetrahydrofuran (3 mL) for standby.

[0630] (4-aminopyridin-2-yl)(3-(methylsulfonyl)azetidin-l-yl)methanone (Compound 10-3, 200 mg, 0.78 mmol) and DIEA (100 mg, 0.77 mmol) were dissolved in tetrahydrofuran (5 mL) under nitrogen protection, cooled to 0 °C, and the above acyl chloride tetrahydrofuran solution was added dropwise. The reaction was warmed to 65 °C for 2 h. The reaction was terminated by adding water (20 mL) dropwise, extracted with ethyl acetate (30 mL x 3), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative separation (Instrument: Hanbon NP 7000; Column: Phenomenex Luna 5 pm C18(2), 110 A, 150*21.2 mm; Mobile phase A: 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 40%~84% v / v acetonitrile; Flow rate: 20 mL / min; Wavelength: 210 / 254 nm) to obtain white solid, which was Compound 10 (58.49 mg, yield: 38.9%).

[0631] LC-MS m / z (ESI): 592.16 [M+H] + .

[0632] 1H NMR (400 MHz, CDC13) δ 8.61 (s, 1H), 8.44 (d, J = 5.5 Hz, 1H), 8.09-8.03 (m, 1H), 7.85 (dd, J = 15.3, 2.2 Hz, 1H), 7.09-7.05 (m, 1H), 6.98-6.81 (m, 1H), 5.13-5.03 (m, 2H), 5.01 (dd, J = 11.0, 2.7 Hz, 1H), 4.56-4.51 (m, 2H), 4.14-4.02 (m, 2H), 4.00-3.98 (m, 3H), 2.93 (s, 3H), 2.80-2.68 (m, 1H), 1.68-1.60 (m, 3H), 0.80-0.74 (m, 3H).

[0633] Example 11. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-N-(2-(3-(methylsulfonyl)pyrrolidine-1-carbonyl)pyridin-4-yl)-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 11)

[0634] 11.1 Synthesis of tert-butyl (2-(3-(methylsulfonyl)pyrrolidine-1-carbonyl)pyridin-4- yl)carbamate (Compound 11-2)

[0635] tert-Butyl 4-((tert-butoxycarbonyl)amino)picolinate (Compound 8-3, 238 mg, 1 mmol), 3-(methylsulfonyl)pyrrolidine (Compound 11-1, 164 mg, 1.1 mmol) and HATU (494 mg, 1.3 mmol) were dissolved in DMF (10 mL) and stirred. DIEA (258 mg, 2 mmol) was added dropwise, and after the dropwise addition was completed, the reaction was allowed to proceed at room temperature for 4 h. After the reaction was completed as determined by TLC, saturated NaHCO3solution (15 mL) was added, the mixture was separated, dichloromethane (30 mL x 3) was added for extraction, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a light yellow oil, which was Compound 11-2 (323 mg, yield: 87.4 %), and the crude product was used directly in the next step.

[0636] 11.2 Synthesis of (4-aminopyridinyl)(3-(methylsulfonyl)pyrrolidinyl)methanone (Compound 11-3)

[0637] Tert-butyl (2-(3-(methylsulfonyl)pyrrolidine-1-carbonyl)pyridin-4-yl)carbamate (compound 11-2, 310 mg, 0.84 mmol) was dissolved in 1,4-dioxane (5 mL), stirred, slowly added dropwise with hydrogen chloride in 1,4-dioxane (4 M) (5 mL), reacted at room temperature overnight, added with water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, to obtain a light yellow oil, which was compound 11-3 (244 mg, yield: 81.0%).

[0638] LC-MS m / z (ESI): 270.09 [M+H] + .

[0639] 11.3 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(3- (methylsulfonyl)pyrrolidine-1-carbonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (compound 11)

[0640] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-5, 60 mg, 0.17 mmol) was dissolved in thionyl chloride (5 mL). The temperature was raised to reflux for 2 hours. Concentrated under reduced pressure, diluted with tetrahydrofuran (3 mL) for standby.

[0641] (4-aminopyridinyl)(3-(methylsulfonyl)pyrrolidinyl)methanone (compound 11-3, 200 mg, 0.74 mmol) and DIEA (478 mg, 3.7 mmol) were dissolved in tetrahydrofuran (5 mL), slowly added dropwise with the prepared acyl chloride solution, raised to reflux for 2 h. Added with water (20 mL), extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the crude product was purified by preparative separation (instrument: Hanban NP 7000; column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30%~70% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm), to obtain a white solid, which was compound 11 (12.92 mg, yield: 12.6%).

[0642] LC-MS m / z (ESI): 606.18 [M+H] + .

[0643] 1H NMR (400 MHz, DMSO-d6) δ 10.70 (d, J = 5.8 Hz, 1H), 8.49 (dd, J = 12.4, 5.6 Hz, 1H), 8.07 - 8.00 (m, 1H), 7.79 - 7.70 (m, 1H), 7.18 - 7.12 (m, 2H), 5.10 (d, J = 10.1 Hz, 1H), 4.25 (dd, J = 10.2, 7.7 Hz, 1H), 4.06 - 4.05 (m, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.92 - 3.87 (m, 2H), 3.03 (d, J = 26.7 Hz, 3H), 2.76 (q, J = 7.5 Hz, 1H), 2.32 - 2.24 (m, 2H), 1.61 (s, 3H), 1.27 - 1.22 (m, 2H), 0.76 - 0.69 (m, 3H).

[0644] Example 12. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-N-(2-(4-(methylsulfonyl)piperidine-l-carbonyl)pyridin-4-yl)-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 12)

[0645] 12.1 Synthesis of tert-butyl (2-(4-(methylsulfonyl)piperidine-l-carbonyl)pyridin-4- yl)carbamate (Compound 12-2)

[0646] Tert-butyl 4-((tert-butoxycarbonyl)amino)picolinate (Compound 8-3, 321 mg, 1.35 mmol), 4-(methylsulfonyl)piperidine (Compound 12-1, 200 mg, 1.23 mmol) and HATU (606 mg, 1.59 mmol) were dissolved in DMF (5 mL), stirring was started, DIEA (317 mg, 2.45 mmol) was added dropwise, and the reaction was warmed to room temperature for 2 h. The reaction was complete as detected by TLC, and the reaction was terminated by the addition of saturated aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give yellow oil, which was Compound 12-2 (1.5 g), and the crude product was used directly in the next step.

[0647] 12.2 Synthesis of (4-aminopyridin-2-yl)(4-(methylsulfonyl)piperidin-l-yl)methanone hydrochloride (Compound 12-3)

[0648] To (2-(4-(methylsulfonyl)piperidine-l-carbonyl)pyridin-4-yl)carbamic acid tert-butyl ester (compound 12-2, 1.5 g) was added hydrogen chloride in 1,4-dioxane (4 M) (10 mL) with stirring, and the reaction was allowed to proceed at room temperature overnight. The reaction was monitored by TLC, and the reaction was completed. The yellow oil was concentrated under reduced pressure to give compound 12-3 (2.50 g), which was used directly in the next step.

[0649] 12.3 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(4- (methylsulfonyl)piperidine-l-carbonyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (compound 12)

[0650] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-5, 100 mg, 0.3 mmol) was dissolved in thionyl chloride (5 mL). The reaction was allowed to proceed at 80 °C under nitrogen for 2 h. The reaction was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL).

[0651] (4-aminopyridin-2-yl)(4-(methylsulfonyl)piperidin-l-yl)methanone hydrochloride (compound 12-3, 2.5 g) and DIEA (3.03 g, 23.44 mmol) were dissolved in tetrahydrofuran (5 mL), and the reaction was allowed to proceed at 0 °C under nitrogen for 2 h. The reaction was quenched by the dropwise addition of water (20 mL), and the reaction was extracted with ethyl acetate (30 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative separation (instrument: Hanbon NP 7000; column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile; gradient: 30% to 70% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to give compound 12 as a white solid (72.26 mg, yield: 41.3%).

[0652] LC-MS m / z (ESI): 620.20 [M+H] + .

[0653] 1H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.69 (dd, J = 5.6, 2.2 Hz, 1H), 7.20 - 7.12 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H), 4.60 (d, J = 13.1 Hz, 1H), 4.28 - 4.23 (m, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.86 (d, J = 13.5 Hz, 1H), 3.44 - 3.40 (m, 1H), 3.11 - 3.05 (m, 1H), 2.95 (s, 3H), 2.88 - 2.73 (m, 2H), 2.14 (d, J = 12.9 Hz, 1H), 1.98 (d, J = 12.7 Hz, 1H), 1.63 - 1.49 (m, 5H), 0.73 (dd, J = 7.3, 2.6 Hz, 3H).

[0654] Example 13. Synthesis of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinoyl)glycine (Compound 13)

[0655] 13.1 Synthesis of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinoyl)glycine tert-butyl ester (Compound 13-1)

[0656] Methyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinate (Compound 9-1, 100 mg, 0.20 mmol), glycine tert-butyl ester (269 mg, 2.05 mmol) and 2-MeTHF (5 mL) were added to a reaction flask, which was warmed to 60 °C and stirred overnight. TLC detection showed that the reaction was complete. Column chromatography (eluent: dichloromethane / methanol = 80 / 1 ~ 20 / 1, v / v) was used to purify the organic phase, which was concentrated under reduced pressure to obtain a white solid, i.e. Compound 13-1 (59 mg, yield: 49.04%).

[0657] LC-MS m / z (ESI): 586.19 [M-H] - .

[0658] 13.2 Synthesis of (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinoyl) glycine (Compound 13)

[0659] tert-Butyl (4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinoyl)glycinate (Compound 13-1, 59 mg, 0.1 mmol) was taken in a reaction flask, 4M HCI (1,4-dioxane solution) (4 mL) was added dropwise, the reaction was stirred at room temperature for 2 h, the reaction was monitored by TLC, concentrated under reduced pressure, the crude was purified by preparative separation (Instrument: Hanban NP 7000; Column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; Mobile phase A: 0.1% formic acid; Mobile phase B: Acetonitrile; Gradient: 40% to 84% v / v acetonitrile; Flow rate: 20 mL / min; Wavelength: 210 / 254 nm) to get white solid, which was Compound 13 (24.28 mg, yield: 45.49%).

[0660] LC-MS m / z (ESI): 532.17 [M+H] + .

[0661] 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.91-8.88 (m, 1H), 8.53 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 5.5, 2.1 Hz, 1H), 7.21-7.13 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H), 4.26 (dd, J = 10.0, 7.9 Hz, 1H), 3.95-3.93 (m, 5H), 2.81-2.74 (m, 1H), 1.61 (s, 3H), 0.73 (d, J = 6.2 Hz, 3H).

[0662] Example 14. Synthesis of methyl 4-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido) picolinoyl)piperazine-1-carboxylate (Compound 14)

[0663] 14.1 Synthesis of methyl 4-(4-((tert-butoxycarbonyl)amino)picolinoyl)piperazine-1- carboxylate (Compound 14-1)

[0664] To a stirred solution of 4-((tert-butoxycarbonyl)amino)picolinic acid (compound 8-3, 300 mg, 1.26 mmol), methyl piperazine-1-carboxylate (217.9 mg, 1.51 mmol) and HATU (622.3 mg, 1.64 mmol) in DMF (5 mL) was added DIEA (244.1 mg, 1.89 mmol) dropwise. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The reaction mixture was diluted with saturated aqueous NaHCO3solution (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic extracts were washed with saturated aqueous NaCl, dried over anhydrous Na2SO4and concentrated under reduced pressure to give an oil, which was compound 14-1 (365.1 mg, yield: 79.6%).

[0665] 14.2 Synthesis of methyl 4-(4-aminopicolinoyl)piperazine-1-carboxylate hydrochloride (compound 14-2)

[0666] To a stirred solution of methyl 4-(4-((tert-butoxycarbonyl)amino)picolinoyl)piperazine-1-carboxylate (compound 14-1, 365.1 mg, 1 mmol) in 1,4-dioxane (5 mL) was added hydrogen chloride solution in 1,4-dioxane (5 mL) dropwise. The reaction mixture was stirred at room temperature for overnight. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to give a yellow oil, which was compound 14-2 (215.3 mg, yield: 71.59%).

[0667] LC-MS m / z (ESI): 265.14 [M+H] + .

[0668] 14.3 Synthesis of methyl 4-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinoyl)piperazine-1-carboxylate (compound 14)

[0669] To a stirred solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-5, 150 mg, 0.42 mmol) in thionyl chloride (5 mL) was heated to 80 °C under nitrogen atmosphere for 2 h. The reaction mixture was concentrated under reduced pressure and dissolved in tetrahydrofuran (3 mL) for further use.

[0670] Methyl 4-(4-aminopyridinecarbonyl)piperazine-1-carboxylate hydrochloride (compound 14-2, 243.3 mg, 0.81 mmol) and DIEA (523.4 mg, 4.1 mmol) were dissolved in tetrahydrofuran (5 mL), protected by nitrogen, cooled to 0 °C, and the above acyl chloride tetrahydrofuran solution was added dropwise, and then warmed to 70 °C for 2 h. The reaction was terminated by adding water (20 mL) dropwise, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative separation (instrument: Hanban NP 7000; column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; mobile phase A: purified water; mobile phase B: acetonitrile; gradient: 40%~84% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to obtain a white solid, i.e., compound 14 (180.36 mg, yield: 70.93%).

[0671] LC-MS m / z (ESI): 601.21 [M+H] + .

[0672] 1 H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.46 (d, J = 5.6 Hz, 1H), 7.76 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 1.6 Hz, 1H), 7.09-7.03 (m, 1H), 6.89 (dd, J = 16.7, 9.2 Hz, 1H), 5.00 (d, J = 11.0 Hz, 1H), 4.07 (dd, J = 11.0, 8.1 Hz, 1H), 4.00 (d, J = 2.8 Hz, 3H), 3.78-3.70 (m, 5H), 3.63-3.56 (m, 4H), 3.50-3.49 (m, 2H), 2.78-2.70 (m, 1H), 1.66 (s, 3H), 0.83-0.73 (m, 3H).

[0673] Example 15. Synthesis of 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-(4-(methoxycarbonyl)piperazine- 1-carbonyl)pyridine-1-oxide (compound 15)

[0674] Methyl 4-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridinecarbonyl)piperazine-1- carboxylate (Compound 14, 150 mg, 0.25 mmol), m-chloroperbenzoic acid (86.28 mg, 0.5 mmol) were added successively into chloroform (5 mL) and the reaction was carried out at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative separation (instrument: Hanbon NP 7000; column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; mobile phase A: purified water; mobile phase B: acetonitrile; gradient: 40%~84% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to obtain white solid, i.e. Compound 15 (33.7 mg, yield: 21.9%).

[0675] LC-MS m / z (ESI): 617.21 [M+H] + .

[0676] 1 H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.06 (d, J = 7.2 Hz, 1H), 7.78-7.50 (m, 2H), 7.09-6.99 (m, 1H), 6.89 (dd, J = 16.6, 9.0 Hz, 1H), 5.02 (d, J = 11.1 Hz, 1H), 4.16-4.05 (m, 1H), 4.01 (d, J = 2.8 Hz, 3H), 3.73 (d, J = 6.5 Hz, 3H), 3.58-3.56 (m, 6H), 3.30-3.14 (m, 2H), 2.74 (p, J = 7.6 Hz, 1H), 1.65 (s, 3H), 0.79-0.77 (m, 3H).

[0677] Example 16. Synthesis of (2R,3S,4S,5R)-N-[2-({[amino(nitroso)methyl]amino}carbonyl)pyridin-4-yl]-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 16)

[0678] 16.1 Synthesis of N-(N-tert-butoxycarbonylaminocarbonylimino)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (Compound 16-1)

[0679] N-(N-tert-butoxycarbonylaminocarbamimidoyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (Compound 16-1, 100 mg, 0.16 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane solution (5 mL) and stirred at room temperature overnight. Concentrated to dryness under reduced pressure, the residue was purified by preparative separation (Instrument: SHIMADZU RFC-40; Column: Kromasil classic C18 250 x 50 mm, 5 μm; Mobile phase: aqueous phase (10 mmol / L ammonium formate) and acetonitrile; Gradient ratio: 30%-90% v / v acetonitrile; Flow rate: 80 mL / min) to give a white solid, which was Compound 16 (66.50 mg, yield: 67.44%).

[0680] LC-MS m / z (ESI): 616.33 [M+H] + .

[0681] 16.2 Synthesis of (2R,3S,4S,5R)-N-[2-({[amino(nitroso)methyl]amino}carbonyl)pyridin-4-yl]-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 16)

[0682] N-(N-tert-butoxycarbonylaminocarbamimidoyl)-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)picolinamide (Compound 16-1, 100 mg, 0.16 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane solution (5 mL) and stirred at room temperature overnight. Concentrated to dryness under reduced pressure, the residue was purified by preparative separation (Instrument: SHIMADZU RFC-40; Column: Kromasil classic C18 250 x 50 mm, 5 μm; Mobile phase: aqueous phase (10 mmol / L ammonium formate) and acetonitrile; Gradient ratio: 30%-90% v / v acetonitrile; Flow rate: 80 mL / min) to give a white solid, which was Compound 16 (66.50 mg, yield: 67.44%).

[0683] LC-MS m / z (ESI): 516.20 [M+H] + .

[0684] 1H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.33 (s, 2H), 8.29 (d, J = 1.9 Hz, 1H), 7.74 (dd, J = 5.4, 2.1 Hz, 1H), 7.19 - 7.12 (m, 2H), 5.12 (d, J = 10.3 Hz, 1H), 4.28 - 4.22 (m, 2H), 3.95 (d, J = 2.1 Hz, 3H), 2.82 - 2.71 (m, 1H), 1.60 (s, 3H), 0.73 (d, J = 6.0 Hz, 3H).

[0685] Example 17. Synthesis of 2-{[dimethyl(oxido)-λ 6 sulfanyl]amino}-4-({[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)pyridine-1- oxide (Compound 17)

[0686] 17.1 2-{[dimethyl(oxido)-λ 6 sulfanyl]amino}-4-({[(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl]carbonyl}amino)pyridine-1- oxide (Compound 17)

[0687] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)-λ 6 sulfimide)amino)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 7, 120 mg, 0.23 mmol) was dissolved in dichloromethane (4 mL) and m-CPBA (79 mg, 0.46 mmol) was added to the reaction mixture. It was stirred at room temperature for 2 h. It was concentrated under reduced pressure and the residue was purified by preparative separation (Instrument: Hanbon NP 7000; Column: YMC-Actus Triart C18 ExRS, 150*21.2 mm; Mobile phase A: 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 30%~70% v / v acetonitrile; Flow rate: 20 mL / min; Wavelength: 254 nm) to give Compound 17 (33.77 mg, yield: 27.3%) as a white solid.

[0688] LC-MS m / z (ESI): 538.14 [M+H] + .

[0689] LC-MS m / z (ESI): 538.14 [M+H]1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 2.9 Hz, 1H), 7.19 - 7.09 (m, 3H), 5.03 (d, J = 10.2 Hz, 1H), 4.23 (dd, J = 10.2, 7.6 Hz, 1H), 3.95 (d, J = 2.2 Hz, 3H), 3.32 (s, 6H), 2.76 (p, J = 7.5 Hz, 1H), 1.59 (s, 3H), 0.72 (dd, J = 7.7, 2.5 Hz, 3H).

[0690] Example 18. Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-carbamoyl-S-methylsulfϊnylimino) phenyl)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 18)

[0691] 18.1 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-carbamoyl-S-methylsulfϊnylimino) phenyl)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 18)

[0692] (2R, 3S, 4S, 5R)-N-(3-(N-cyano-S-methylsulfϊnylimino) phenyl)-3-(3, 4-difluoro-2- methoxyphenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 3, 200 mg, 0.38 mmol) was dissolved in DCM (15 mL), cooled to 0 °C, TFA (343 mg, 3.04 mmol) was added and stirred, slowly warmed to room temperature, stirred overnight, TLC monitored the reaction was complete, saturated sodium bicarbonate solution was added to adjust pH to 8-9, dichloromethane (40 mL) was added, stirred, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a white solid crude. The crude was purified by preparative liquid chromatography (instrument: SHIMADZU RFC-40; column: Kromasil ET C18 10 μm 250*50 mm I.D; mobile phase A: 10 mM ammonium formate; mobile phase B: acetonitrile; gradient: 30% to 90% v / v acetonitrile; flow rate: 80 mL / min; wavelength: 210 / 254 nm), and lyophilized to give a white solid, which was Compound 18 (107 mg, yield: 51.7%).

[0693] LC-MS m / z (ESI): 550.30 [M+1] + .

[0694] 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (d, J = 4.3 Hz, 1H), 8.28 (t, J = 1.9 Hz, 1H), 7.93-7.90 (m, 1H), 7.69-7.55 (m, 2H), 7.27-7.08 (m, 2H), 6.41 (s, 1H), 6.04 (s, 1H), 5.12 (dd, J = 10.4, 1.6 Hz, 1H), 4.38-4.23 (m, 1H), 3.98 (d, J = 2.1 Hz, 3H), 3.32-3.30 (m, 3H), 2.80 (p, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.84-0.63 (m, 3H).

[0695] Compound 18 was purified by chiral separation (Instrument: SHIMADZU RFC-40; Column: CHIRALPAK AD-H, 5 pm 250*10 mm I.D; Mobile phase A: n-hexane-ethanol-ethanolamine (90:10:0.1, v / v), Mobile phase B: Ethanol; Gradient: Isocratic ratio 10% v / v mobile phase B; Flow rate: 5 mL / min) to give compound 18-a (46 mg, RT = 9.5 min) and 18-b (61 mg, RT = 13.4 min) after lyophilization.

[0696] 18-a:

[0697] LC-MS m / z (ESI): 550.30 [M+H] + .

[0698] 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.25 (t, J = 1.9 Hz, 1H), 7.91-7.88 (m, 1H), 7.65-7.51 (m, 2H), 7.22-7.09 (m, 2H), 6.37 (s, 1H), 6.01 (s, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.29-4.24 (m, 1H), 3.96 (d, J = 2.2 Hz, 3H), 3.29 (s, 3H), 2.77 (p, J = 7.4 Hz, 1H), 1.61 (s, 3H), 0.81-0.61 (m, 3H).

[0699] 18-b:

[0700] LC-MS m / z (ESI): 550.30 [M+H] + .

[0701] 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.25 (t, J = 1.9 Hz, 1H), 7.88 (dt, J = 7.2, 2.0 Hz, 1H), 7.67 - 7.50 (m, 2H), 7.16 (dd, J = 9.0, 6.3 Hz, 2H), 6.37 (s, 1H), 6.01 (s, 1H), 5.09 (d, J = 10.4 Hz, 1H), 4.26 (dd, J = 10.4, 7.6 Hz, 1H), 3.96 (d, J = 2.1 Hz, 3H), 3.29 (s, 3H), 2.77 (p, J = 7.3 Hz, 1H), 1.61 (s, 3H), 0.80 - 0.65 (m, 3H).

[0702] Example 19. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-(1- hydroxycyclopropane-1-carbonyl)-S-methylsulfmylimino)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 19)

[0703] 19.1 Synthesis of 1-((tert-butyldimethylsilyl)oxy)cyclopropane-1-carboxylic acid (Compound 19-2)

[0704] 1-hydroxycyclopropane-1-carboxylic acid (Compound 19-1, 3 g, 29.4 mmol) and imidazole (4.6 g, 67.6 mmol) were dissolved in DCM (300 mL), TBSC1 (8.86 g, 58.8 mmol) was added to the reaction solution, after addition, it was reacted at room temperature overnight. The reaction solution was rotary evaporated to dryness under reduced pressure, methanol and tetrahydrofuran (V MeOH THF = 3 / 1) (240 mL) to dissolve the residue, saturated potassium carbonate solution (120 mL) was added, stirred at room temperature for 1 h, after most of the organic solvent was rotary evaporated under reduced pressure, the pH was adjusted to 3 with half-saturated aqueous citric acid solution, the aqueous phase was extracted with diethyl ether (150 mL x 3), the organic phase was combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a colorless oil, which was Compound 19-2 (2.7 g, yield: 45.92%).

[0705] 19.2 Synthesis of 1-((tert-butyldimethylsilyl)oxy)-N-(methyl(3-nitrophenyl)(oxo)-λ 6 sulfanilyl)cyclopropane-1-carboxamide (Compound 19-3)

[0706] ​1-(S-methylsulfinimide)-3-nitrobenzene (compound 1-2, 0.50 g, 2.50 mmol), 1-((tert-butyldimethylsilyl)oxy)cyclopropane-1-carboxylic acid (compound 19-2, 0.51 g, 2.36 mmol) and DIEA (0.90 g, 6.93 mmol) were dissolved in DMF (5 mL), and HATU (0.97 g, 2.54 mmol) was added to the reaction solution. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water (15 mL) and ethyl acetate (30 mL) were added to the reaction solution. The mixture was separated, and the organic phase was washed three times with water (20 mL × 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0–20%, v / v) to give an off-white solid, namely compound 19-3 (0.21 g, yield: 22.35%).

[0707] 1 H NMR (400MHz, DMSO-d6) δ8.63(t,J=2.0Hz,1H),8.60-8.55(m,1H),8.39-8.31(m,1H),7.99(t,J=8.1 Hz,1H),3.55(s,3H),1.41-1.28(m,2H),1.04-0.89(m,2H),0.79(s,9H),0.05(s,3H),0.00(s,3H).

[0708] 19.3 N-((3-aminophenyl)(methyl)(oxo)-λ 6 Synthesis of (-thionyl)-1-((tert-butyldimethylsilyl)oxy)cyclopropane-1-carboxamide (compound 19-4)

[0709] 1-((tert-butyldimethylsilyl)oxy)-N-(methyl(3-nitrophenyl)(oxo)-λ 6 (-Thionyl)cyclopropane-1-carboxamide (compound 19-3, 0.21 g, 0.53 mmol) was dissolved in methanol (5 mL) and THF (5 mL), and Pd / C (wet group, 10%) (0.15 g) was added. After the addition was complete, the reaction was carried out overnight under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain compound 19-4 (200 mg), which was directly added to the next step without purification.

[0710] LC-MS m / z (ESI): 369.16 [M+H] + .

[0711] 19.4 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-(1-((tert-butyldimethylsilyl)oxy)cyclopropane-1- carbonyl)-S-methylsulfmylimino)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 19-5)

[0712] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, 0.14 g, 0.40 mmol) was dissolved in acetonitrile (5 mL), and N-((3-aminophenyl)(methyl)(oxo)-lambda 6 - sulfanylidene)-1-((tert-butyldimethylsilyl)oxy)cyclopropane-1-carboxamide (Compound 19-4, 0.16 g, 0.43 mmol), TCFH (0.133 g, 0.47 mmol), and NMI (80 mg, 1.00 mmol) were added successively, and stirred at room temperature overnight under a nitrogen atmosphere. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate / n-hexane = 0-50%, v / v) to obtain Compound 19-5 (0.17 g, yield: 60.28%) as a light yellow oil.

[0713] LC-MS m / z (ESI): 705.15 [M+H] + .

[0714] 19.5 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-(1- hydroxycyclopropane-1-carbonyl)-S-methylsulfmylimino)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 19)

[0715] (2R,3S,4S,5R)-N-(3-(N-(1-((tert-butyldimethylsilyl)oxy)cyclopropane-1- carbonyl)-S-methylsulfmylimino)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 19-5, 0.17 g, 0.24 mmol) was dissolved in THF (5 mL), 1 N TBAF tetrahydrofuran solution (1 mL) was added, and the reaction was stirred at room temperature for 2 h under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-70%, v / v) to obtain a yellow solid crude product, which was further purified by preparative separation (column: Waters AcQuiTYC SH, C18, 1.7 μm, 2.1*100 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile) to obtain white solid, which was Compound 19 (54 mg, yield: 37.91%).

[0716] LC-MS m / z (ESI): 591.30 [M+H] + .

[0717] 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.29 (s, 1H), 7.94-7.85 (m, 1H), 7.65-7.58 (m, 2H), 7.19-7.12 (m, 2H), 5.64 (s, 1H), 5.10 (d, J = 10.2 Hz, 1H), 4.32-4.22 (m, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.41-3.36 (m, 3H), 2.83-2.71 (m, 1H), 1.61 (s, 3H), 1.22-1.15 (m, 2H), 0.90-0.82 (m, 2H), 0.77-0.70 (m, 3H).

[0718] Example 20. Synthesis of (2R,3S,4S,5R)-N-(2-(N-carbamoyl-S-methylsulfmylimino)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 20)

[0719] 20.1 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-[2- (methylthio)pyridin-4-yl]-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 20-1)

[0720] To a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-5, 142 mg, 0.40 mmol), HATU (182 mg, 0.48 mmol), Et3N (122 mg, 1.2 mmol) in DCM (5 mL) was stirred at room temperature for 30 min, then 2-(methylthio)-pyridin-4-amine (112 mg, 0.80 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 0-1 / 9, v / v) to give compound 20-1 (72 mg, yield: 37.7%) as a yellow solid.

[0721] LC-MS m / z (ESI): 477.15 [M+H] + .

[0722] 20.2 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(S- methylsulfinimidoyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 20-2)

[0723] To a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-[2-(methylthio)pyridin-4-yl]-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 20-1, 70 mg, 0.15 mmol) in ethanol (10 mL) was added ammonium carbonate (28 mg, 0.29 mmol) and iodobenzene diacetate (142 mg, 0.44 mmol) portionwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: methanol / dichloromethane = 0-1 / 40, v / v) to give compound 20-2 (69 mg, yield: 92.5%) as a yellow solid.

[0724] LC-MS m / z (ESI): 508.16 [M+H] + .

[0725] 20.3 Synthesis of (2R,3S,4S,5R)-N-(2-(N-carbamoyl-S-methylsulfinimidoyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 20)

[0726] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(S- methylsulfinimidoyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 20-2, 69 mg, 0.14 mmol) was dissolved in acetic acid (10 mL), sodium cyanate (88 mg, 1.36 mmol) was added and the reaction was stirred at room temperature for 72 hours. The reaction was checked by TLC and when it was complete, saturated sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL) were added. The aqueous phase was extracted once more with ethyl acetate (30 mL) and the organic phases were combined and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (instrument: SHIMADZU RFC-40; column: Kromasil ET C18 10 μm 250*50 mm I.D; mobile phase A: 10 mM ammonium formate; mobile phase B: acetonitrile; gradient: 25% to 85% v / v acetonitrile; flow rate: 80 mL / min; wavelength: 210 / 254 nm) to give compound 20 as a white solid (16 mg, yield: 21.4%).

[0727] LC-MS m / z (ESI): 549.10 [M-H] - .

[0728] 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.61 (d, J = 5.5 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.96 - 7.83 (m, 1H), 7.19 (dd, J = 10.9, 4.8 Hz, 2H), 6.38 (s, 1H), 5.95 (s, 1H), 5.15 (d, J = 10.1 Hz, 1H), 4.28 (t, J = 8.9 Hz, 1H), 3.97 (d, J = 2.1 Hz, 3H), 3.28 (d, J = 2.8 Hz, 3H), 2.79 (p, J = 7.7 Hz, 1H), 1.63 (s, 3H), 0.86 - 0.63 (m, 3H).

[0729] Compound 20 (201 mg) was rescaled and separated by chiral resolution (instrument: SHIMADZU RFC-40; column: AD-H 5 μm 250*10 mm I.D; mobile phase: n-hexane / absolute ethanol (0.1% diethylamine); gradient elution, n-hexane content from 100% to 85% v / v; flow rate: 7 mL / min; wavelength: 210 / 254 nm) to give white solid 20-a (73.0 mg, RT = 9.755 min) and 20-b (36.9 mg, RT = 13.873 min).

[0730] 20-a:

[0731] LC-MS m / z (ESI): 549.20 [M-H] - .

[0732] 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.61 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 5.5, 2.1 Hz, 1H), 7.21 - 7.14 (m, 2H), 6.37 (s, 1H), 5.94 (s, 1H), 5.14 (d, J = 10.2 Hz, 1H), 4.28 (dd, J = 10.1, 7.7 Hz, 1H), 3.97 (d, J = 2.1 Hz, 3H), 3.28 (s, 3H), 2.79 (p, J = 7.6 Hz, 1H), 1.63 (s, 3H), 0.80 - 0.69 (m, 3H).

[0733] 20-b:

[0734] LC-MS m / z (ESI): 549.20 [M-H] - .

[0735] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 5.5 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 5.5, 2.1 Hz, 1H), 7.22 - 7.15 (m, 2H), 6.37 (s, 1H), 5.95 (s, 1H), 5.16 (d, J = 10.2 Hz, 1H), 4.28 (dd, J = 10.2, 7.6 Hz, 1H), 3.97 (d, J = 2.1 Hz, 3H), 3.28 (s, 3H), 2.79 (p, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.82 - 0.67 (m, 3H).

[0736] Example 21. Synthesis of (2R,3S,4S,5R)-N-(3-(N-carbamoyl-S-methylsulfϊnimido)-4- fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 21)

[0737] 21.1 Synthesis of 4-fluoro-3-methylsulfanyl aniline (Compound 21-2)

[0738] To a solution of 3-bromo-4-fluoroaniline (compound 21-1, 5.0 g, 26.46 mmol), Pd2(dba)3(242.5 mg, 2.65 mmol), Xantphos (3045 mg, 5.26 mmol) and sodium thiomethoxide (2845 mg, 40.64 mmol) in 1,4-dioxane (100 mL) was added under nitrogen protection. The mixture was heated to 100-110 °C overnight. The reaction was monitored by TLC. After cooling to room temperature, the mixture was filtered, and the filter cake was washed with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, and the residue was separated by preparative chromatography (instrument: Hanbon NP 7000; column: YMC-Actus Triart C18 ExRS, 250*21.2 mm; mobile phase A: 0.05% ammonia water; mobile phase B: acetonitrile; gradient: 50%-100% v / v acetonitrile; flow rate: 16 mL / min; wavelength: 214 nm) to give compound 21-2 (300 mg, yield: 7.2%) as a brown oil.

[0739] LC-MS m / z (ESI): 158.04 [M+H] + .

[0740] 21.2 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3- (methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 21-3)

[0741] To a solution of 4-fluoro-3-methylthioaniline (compound 21-2, 157 mg, 1 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-5, 354.27 mg, 1 mmol) in pyridine (8 mL) was added POCl3(460 mg, 3 mmol) dropwise slowly under stirring at 0-10 °C. The mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate / n-hexane = 0-2 / 5, v / v) to give compound 21-3 (260 mg, yield: 52.7%) as a white solid.

[0742] LC-MS m / z (ESI): 492.11 [M-H] - .

[0743] 21.3 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-(S- methylsulfinimidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 21-4)

[0744] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-(methylthio)phenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 21-3, 260 mg, 0.55 mmol), ammonium carbonate (152.78 mg, 1.59 mmol) and PhI(OAc)2(682.85 mg, 2.12 mmol) were dissolved in methanol (10 mL) and reacted at room temperature overnight. The reaction was detected by TLC and concentrated to dryness under reduced pressure. The reaction was quenched by dropwise addition of water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: methanol / dichloromethane = 0-1 / 20, v / v) to obtain white solid, which was Compound 21-4 (204 mg, yield: 73.7%).

[0745] LC-MS m / z (ESI): 523.12 [M-H] - .

[0746] 21.4 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-carbamoyl-S-methylsulfinimidoyl)-4- fluoro phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 21)

[0747] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-(S- methylsulfinimidoyl)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 21-4, 300 mg, 0.57 mmol) and NaOCN (372 mg, 5.7 mmol) were dissolved in acetic acid (10 mL) and reacted at room temperature overnight. The reaction was completed by TLC detection, concentrated to dryness under reduced pressure, and a saturated NaHCO3 solution was slowly added dropwise to the residue to pH 9-10, extracted with ethyl acetate (30 mL x 3), the organic phase was combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by preparative liquid phase separation (instrument: SHIMADZU RFC-40; column: Kromasil ET C18 10 μm 250*50 mm I.D; mobile phase A: 10 mmol ammonium formate; mobile phase B: acetonitrile; gradient: 25% to 85% v / v acetonitrile; flow rate: 80 mL / min; wavelength: 210 / 254 nm) to obtain white solid, i.e. Compound 21 (157 mg, yield: 48.4%).

[0748] LC-MS m / z (ESI): 568.10 [M+H] + .

[0749] 1 H NMR (400 MHz, CDC13) δ 8.52 (s, 1H), 8.34-8.07 (m, 1H), 7.94-7.79 (m, 1H), 7.19 (td, J = 9.2, 3.6 Hz, 1H), 7.12-7.04 (m, 1H), 6.89 (td, J = 9.4, 2.1 Hz, 1H), 5.00 (dd, J = 11.0, 7.9 Hz, 1H), 4.83 (s, 2H), 4.07 (dt, J = 11.1, 7.8 Hz, 1H), 4.01 (d, J = 1.2 Hz, 3H), 3.38 (d, J = 5.6 Hz, 3H), 2.75 (p, J = 7.3 Hz, 1H), 1.68 (d, J = 5.1 Hz, 3H), 0.78 (d, J = 7.1 Hz, 3H).

[0750] Example 22. Synthesis of (2R,3S,4S,5R)-N-(3-(N-carbamoyl-S- methylsulfinimidoyl)-4-cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 22)

[0751] 22.1 Synthesis of 4-amino-2-chlorobenzonitrile (Compound 22-2)

[0752] Compound 22-2 (4.10 g, yield: 98.3%) as a light yellow solid was obtained by dissolving 2-chloro-4-nitrobenzonitrile (compound 22-1, 5.00 g, 27.47 mmol) in ethanol (90 mL) and water (30 mL), adding Fe powder (7.67 g, 137.37 mmol) and ammonium chloride (14.70 g, 274.74 mmol), and refluxing at 75-80°C for 4 hours. The reaction was confirmed to be complete by TLC, and the reaction mixture was filtered while hot, and the filtrate was concentrated under reduced pressure. Compound 22-2 was obtained as a light yellow solid by column chromatography (eluent: methanol / dichloromethane = 0-1 / 20, v / v).

[0753] LC-MS m / z (ESI): 151.01 [M-H] - .

[0754] 22.2 Synthesis of 4-amino-2-(methylthio)benzonitrile (compound 22-3)

[0755] Compound 22-3 (2.73 g, yield: 63.2%) as a light yellow solid was obtained by dissolving 4-amino-2-chlorobenzonitrile (compound 22-2, 4.00 g, 26.31 mmol) in DMF (10 mL), adding sodium thiomethoxide (7.37 g, 105.26 mmol), and stirring at 130-135°C overnight. The reaction was confirmed to be complete by TLC, and the reaction mixture was concentrated under reduced pressure. Compound 22-3 was obtained as a light yellow solid by column chromatography (eluent: ethyl acetate / n-hexane = 1:1, v / v).

[0756] LC-MS m / z (ESI): 165.05 [M+H] + .

[0757] 22.3 Synthesis of (2R,3S,4S,5R)-N-[4-cyano-3-(methylthio)phenyl]-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 22-4)

[0758] Compound 22-4 (510 mg, yield: 83.7%) as a white solid was obtained by dissolving 4-amino-2-(methylthio)benzonitrile (compound 22-3, 200 mg, 1.22 mmol) and (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-5, 431 mg, 1.22 mol) in pyridine (10 mL), slowly adding phosphorus oxychloride (561 mg, 3.66 mmol) dropwise under nitrogen, and stirring at room temperature overnight after the addition was completed. The reaction was confirmed to be complete by TLC, and the reaction mixture was concentrated under reduced pressure. Compound 22-4 was obtained as a white solid by column chromatography (eluent: methanol / dichloromethane = 0-1 / 20, v / v).

[0759] 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.78 (d, J = 1.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.5, 1.9 Hz, 1H), 7.17 - 7.11 (m, 2H), 5.11 (d, J = 10.2 Hz, 1H), 4.27 (dd, J = 10.2, 7.6 Hz, 1H), 3.96 (d, J = 2.2 Hz, 3H), 2.78 (p, J = 7.5 Hz, 1H), 2.56 (s, 3H), 1.60 (s, 3H), 0.74 (dd, J = 7.8, 2.6 Hz, 3H).

[0760] 22.4 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(S-methylsulfinimidoyl)-4-cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 22-5)

[0761] (2R, 3S, 4S, 5R)-N-[4-cyano-3-(methylthio)phenyl]-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 22-4, 500 mg, 1.00 mmol) was dissolved in methanol (20 mL), ammonium carbonate (290 mg, 3.00 mmol) was added, and iodobenzene diacetate (1290 mg, 4.00 mmol) was added portionwise with stirring. The reaction was stirred at room temperature for 4 hours, and TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and column chromatography (eluent: methanol / dichloromethane = 0-1 / 40, v / v) gave a light yellow solid, which was Compound 22-5 (340 mg, yield: 64.0%).

[0762] LC-MS m / z (ESI): 530.12 [M-H] - .

[0763] 22.5 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-carbamoyl-S-methylsulfinimidoyl)-4-cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 22)

[0764] A solution of (2R,3S,4S,5R)-N-(3-(S-methylsulfinimidoyl)-4- cyanophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 22-5, 300 mg, 0.57 mmol) in THF (10 mL) was prepared under nitrogen. Trimethylsilyl isocyanate (98 mg, 0.85 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The reaction mixture was diluted with saturated sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL). The mixture was stirred and the phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL). The combined organic phases were concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (instrument: SHIMADZU RFC-40; column: Kromasil ET C18 10 μm 250*50 mm I.D; mobile phase A: 10 mM ammonium formate; mobile phase B: acetonitrile; gradient: 30% to 90% v / v acetonitrile; flow rate: 80 mL / min; wavelength: 210 / 254 nm) to give compound 22 as a white solid (105 mg, yield: 32.4%).

[0765] Compound 22 was purified by chiral resolution (instrument: SHIMADZU RFC-40; column: AD-H 5 μm 250*10 mm I.D; mobile phase: n-hexane / absolute ethanol; gradient elution, n-hexane content from 100% to 87% v / v; flow rate: 7 mL / min; wavelength: 210 / 254 nm) to give compound 22-a (26.4 mg, yield: 50.3%, RT = 15.402 min) and 22-b (31.8 mg, yield: 60.6%, RT = 21.832 min) as white solids.

[0766] 22-a:

[0767] LC-MS m / z (ESI): 575.20 [M+1] + .

[0768] 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.71 (s, 1H), 7.91 (s, 2H), 7.19 (dd, J = 8.5, 4.7 Hz, 2H), 6.60 (d, J = 32.1 Hz, 2H), 5.18 (d, J = 10.3 Hz, 1H), 4.31 (dd, J = 10.3, 7.5 Hz, 1H), 3.98 (d, J = 2.2 Hz, 3H), 3.74 (s, 3H), 2.81 (q, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.79 - 0.72 (m, 3H).

[0769] 22-b:

[0770] LC-MS m / z (ESI): 575.20 [M+1] + .

[0771] 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.72 (s, 1H), 7.91 (s, 2H), 7.23 - 7.16 (m, 2H), 6.60 (d, J = 30.4 Hz, 2H), 5.17 (d, J = 10.4 Hz, 1H), 4.31 (dd, J = 10.4, 7.5 Hz, 1H), 3.97 (d, J = 2.1 Hz, 3H), 3.75 (s, 3H), 2.80 (p, J = 7.4 Hz, 1H), 1.64 (s, 3H), 0.79 - 0.72 (m, 3H).

[0772] Example 23. Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N- carbamoyl-S-methylsulfmido)phenyl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 23)

[0773] 23.1 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 23-1)

[0774] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 1-5, 1.00 g, 2.82 mmol) was dissolved in dichloromethane (20 mL), stirred, cooled to below 0 °C under nitrogen, and a 2 M solution of boron tribromide (3 mL, 6.00 mmol) was added dropwise, after which the temperature was allowed to rise to room temperature and the reaction was allowed to proceed for 4 h. The reaction solution was washed with water and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give a light yellow oil (1.02 g). The crude product was used directly in the next step.

[0775] LC-MS m / z (ESI): 339.10 [M-H] - .

[0776] 23.2 Synthesis of methyl-d3 (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)- 4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (Compound 23-2)

[0777] (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 23-1, 1.02 g, crude, based on 2.82 mmol) was dissolved in DMF (20 mL), and deuterated methyl iodide (1.43 g, 9.86 mmol) and potassium carbonate (1.36 g, 9.86 mmol) were added successively with stirring. The reaction was heated to 60 ± 5 °C under nitrogen overnight. The reaction solution was added to water (10 mL) and ethyl acetate (10 mL), stirred, and separated. The organic phase was extracted with ethyl acetate (10 mL x 3), combined, and washed successively with water, saturated aqueous ammonium chloride, and saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give a light yellow oil (3.02 g). The crude product was directly used in the next step.

[0778] LC-MS m / z (ESI): 392.20 [M + H2O] + .

[0779] 23.3 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 23-3)

[0780] Methyl-d3 (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl- 5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (compound 23-2, 3.00 g, 8.01 mmol) and lithium hydroxide (499 mg, 20.84 mmol) were added to a mixture of tetrahydrofuran (20 mL) and water (10 mL), and the reaction was heated to 60 ± 5 °C for 1.5 h. After the tetrahydrofuran was removed by evaporation under reduced pressure, the substrate was concentrated and the pH was adjusted to 1-2 with 1 M hydrochloric acid solution. The product was extracted with dichloromethane (10 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give a light yellow oil (1.01 g).

[0781] LC-MS m / z (ESI): 356.10 [M - H] - .

[0782] 23.4 Synthesis of (2R,3S,4S,5R)-N-(3-(N-cyano-S-methylsulfϊnylimino)phenyl)-3-(3,4- difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (compound 23-4)

[0783] (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 23-3, 0.36 g, 1.00 mmol) was dissolved in DCM (10 mL), and Compound 3-2 (0.22 g, 1.10 mmol), DIEA (0.39 g, 3.00 mmol), and HATU (0.46 g, 1.20 mmol) were added sequentially. The reaction was stirred at room temperature overnight. After the reaction was completed, water (10 mL) and dichloromethane (20 mL) were added to the reaction solution, and the mixture was separated. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-1 / 2, v / v) to obtain Compound 23-4 (0.38 g, yield: 71.56%) as a white solid.

[0784] 23.5 Synthesis of (2R,3S,4S,5R)-N-(3-(N-carbamoyl-S-methylsulfϊnylimino)phenyl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 23)

[0785] (2R,3S,4S,5R)-N-(3-(N-carbamoyl-S-methylsulfϊnylimino)phenyl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 23-4, 0.38 g, 0.72 mmol) was dissolved in DCM (10 mL), and TFA (1 mL) was added. The reaction was stirred at room temperature overnight under nitrogen. The reaction solution was concentrated to dryness under reduced pressure, and the pH was adjusted to 8-9 by adding a saturated sodium bicarbonate solution. The reaction solution was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-3 / 4, v / v) to obtain a crude product. The crude product was purified by high-performance liquid chromatography (column: Waters AcQuiTYC SH, C18, 1.7 μm, 2.1 x 100 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile) to obtain Compound 23 as a white solid.

[0786] Compound 23 was resolved by chiral separation (SHIMADZU RFC-40; Column: AD-H 5 pm 250*10 mm I.D; Mobile phase: n-hexane / absolute ethanol; Gradient elution, n-hexane content from 100% to 80%; Flow rate: 7 mL / min; Wavelength: 210 / 254 nm) to give white solid 23-a (65 mg, yield: 16.55%, RT = 7.073 min) and 23-b (63 mg, yield: 16.04%, RT = 8.997 min).

[0787] 23-a:

[0788] LC-MS m / z (ESI): 553.30 [M+H] + .

[0789] 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.28-8.22 (m, 1H), 7.93-7.85 (m, 1H), 7.65-7.54 (m, 2H), 7.23-7.09 (m, 2H), 6.39 (s, 1H), 6.02 (s, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.26 (dd, J = 10.3, 7.6 Hz, 1H), 3.29 (s, 3H), 2.84-2.71 (m, 1H), 1.61 (s, 3H), 0.77-0.70 (m, 3H).

[0790] 23-b:

[0791] LC-MS m / z (ESI): 553.30 [M+H] + .

[0792] 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.28-8.22 (m, 1H), 7.93-7.85 (m, 1H), 7.65-7.54 (m, 2H), 7.23-7.09 (m, 2H), 6.39 (s, 1H), 6.02 (s, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.26 (dd, J = 10.3, 7.6 Hz, 1H), 3.29 (s, 3H), 2.84-2.71 (m, 1H), 1.61 (s, 3H), 0.77-0.70 (m, 3H).

[0793] Example 24. Synthesis of (2R, 3S, 4S, 5R)-N-(2-(N- carbamoyl-S-methylsulfinimidoyl)pyridin-4-yl)-3-(3,4-difluoro-2- (methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 24)

[0794] 24.1 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5- dimethyl-N-(2-(methylthio)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 24-1)

[0795] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 23-3, 620 mg, 1.74 mmol) and 2-(methylthio)pyridin-4-amine (268 mg, 1.91 mmol) were dissolved in pyridine (10 mL), and phosphorus oxychloride (799 mg, 5.21 mmol) was added under ice bath. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the addition of 5 drops of water, and concentrated under reduced pressure. Saturated sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL) were added to the residue, stirred, and separated. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phase was concentrated under reduced pressure, and purified by column chromatography (eluent: ethyl acetate / n-hexane = 0-1 / 10, v / v) to give Compound 24-1 (620 mg, yield: 74.5%) as a white solid.

[0796] 24.2 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5- dimethyl-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 24-2)

[0797] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-N-(2-(methylthio)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 24-1, 616 mg, 1.28 mmol) was dissolved in methanol (15 mL), and ammonium carbonate (1.74 g, 5.4 mmol) and iodobenzenedicarboxylic acid (383 mg, 3.98 mmol) were added. The reaction was stirred at room temperature for 2 hours, concentrated, and purified by column chromatography (eluent: ethyl acetate / n-hexane = 0-1 / 2, v / v) to give Compound 24-2 (495 mg, yield: 75.5%) as a white solid.

[0798] 24.3 (2R, 3S, 4S, 5R)-N-(2-(N-aminoformyl-S-methylsulfmylimino)pyridin-4-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 24) synthesis

[0799] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-N-(2-(S- methylsulfmylimino)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 24-2, 490 mg, 0.96 mmol) was dissolved in acetic acid (10 mL), sodium cyanate (624 mg, 9.60 mmol) was added to the reaction solution under nitrogen protection, and the reaction was stirred at room temperature for 20 hours. The reaction solution was added to saturated sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL), stirred, separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light yellow oil, which was purified by preparation (instrument: SHIMADZU RFC-40; column: Kromasil ET C18 10 μm 250*50 mm I.D; mobile phase A: 10 mM ammonium formate; mobile phase B: acetonitrile; gradient: 30% to 90% v / v acetonitrile; flow rate: 80 mL / min; wavelength: 210 / 254 nm) to obtain a white solid, which was Compound 24.

[0800] Chiral resolution of Compound 24 (instrument: SHIMADZU RFC-40; column: AD-H 5 μm 250*10 mm I.D; mobile phase: n-hexane / anhydrous ethanol (0.1% diethylamine); gradient elution, n-hexane content from 100% to 85% v / v; flow rate: 7 mL / min; wavelength: 210 / 254 nm) gave white solids 24-a (82.6 mg, yield: 31.1%, RT = 9.792 min) and 24-b (80.6 mg, yield: 30.3%, RT = 13.898 min).

[0801] 24-a:

[0802] LC-MS m / z (ESI): 554.20 [M+H] + .

[0803] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.60 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 5.5, 2.1 Hz, 1H), 7.19 - 7.16 (m, 2H), 6.37 (s, 1H), 5.94 (s, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.27 (dd, J = 10.2, 7.7 Hz, 1H), 3.28 (s, 3H), 2.79 (t, J = 7.6 Hz, 1H), 1.63 (s, 3H), 0.76 - 0.73 (m, 3H).

[0804] 24-b:

[0805] LC-MS m / z (ESI): 554.20 [M+H] + .

[0806] 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.61 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.90 (dd, J = 5.5, 2.0 Hz, 1H), 7.18 - 7.16 (m, 2H), 6.36 (s, 1H), 5.94 (s, 1H), 5.14 (d, J = 10.2 Hz, 1H), 4.28 (dd, J = 10.2, 7.7 Hz, 1H), 3.28 (s, 3H), 2.79 (p, J = 7.5 Hz, 1H), 1.63 (s, 3H), 0.77 - 0.73 (m, 3H).

[0807] Example 25. Synthesis of (2R,3S,4S,5R)-N-(3-(N-carbamoyl-S-methylsulfϊnylimino)phenyl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 25)

[0808] 25.1 Synthesis of (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 25-1)

[0809] (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 23-1, 0.92 g, 2.71 mmol) was dissolved in dichloromethane (6 mL), and potassium hydroxide aqueous solution (1.82 g, 32.47 mmol) (5 mL) and TMSCBrF2(2.19 g, 10.82 mmol) were added dropwise at 0 °C, and the mixture was allowed to warm to room temperature and reacted for 6 hours. TLC showed that the reaction was completed, 1M hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 6, dichloromethane (25 mL x 3) was added, the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the obtained oily residue was dissolved in n-butanol (6 mL), and potassium tert-butoxide (0.74 g, 6.60 mmol) was added at room temperature, and the mixture was reacted at room temperature for 2 hours. TLC showed that the reaction was completed, 1M hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 6, dichloromethane (25 mL x 3) was added, the organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0~1 / 4, v / v) to obtain an oily residue, which was compound 25-1 (496 mg, yield: 47.01%).

[0810] LC-MS m / z (ESI): 389.07 [M-H] - .

[0811] 1 H NMR (400 MHz, CDCl3) δ 7.17-7.05 (m, 2H), 6.88-6.34 (m, 1H), 4.92 (d, J = 10.5 Hz, 1H), 4.22 (dd, J = 10.5, 8.2 Hz, 1H), 2.85-2.72 (m, 1H), 1.63 (s, 3H), 0.83-0.77 (m, 3H).

[0812] 25.2 (2R,3S,4S,5R)-N-(3-(N-cyano-S-methylsulfϊnylimino)phenyl)-3-(2- (difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (compound 25-2) synthesis

[0813] (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 25-1, 0.36 g, 0.92 mmol) was dissolved in dichloromethane (10 mL), and compound 3-2 (0.20 g, 1.01 mmol), DIEA (0.36 mg, 2.76 mmol), and HATU (0.42 g, 1.10 mmol) were added sequentially at room temperature. The reaction was allowed to proceed overnight at room temperature under a N2 atmosphere. After the reaction was completed, the reaction solution was partitioned with water (10 mL), and dichloromethane (10 mL x 2). The organic phase was combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-1 / 2, v / v) to obtain a white solid, which was Compound 25-2 (0.44 g, yield: 84.45%).

[0814] LC-MS m / z (ESI): 566.10 [M-H] - .

[0815] 25.3 Synthesis of (2R,3S,4S,5R)-N-(3-(N-carbamoyl-S-methylsulfϊnylimino)phenyl)-3-(2- (difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 25)

[0816] (2R,3S,4S,5R)-N-(3-(N-cyanomethylsulfϊnylimino)phenyl)-3-(2-(difluoromethoxy)-3,4- difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 25-2, 0.44 g, 0.77 mmol) was dissolved in dichloromethane (10 mL), and TFA (2 mL) was added at room temperature. The reaction was allowed to proceed overnight at room temperature under a N2 atmosphere. After the reaction solution was concentrated under reduced pressure, it was purified by high performance liquid chromatography (column: Waters AcQuiTYC SH, C18, 1.7 μm, 2.1*100 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile) to obtain a white solid, which was Compound 25.

[0817] Compound 25 was subjected to chiral resolution (Instrument: SHIMADZU RFC-40; Column: AD-H 5 pm 250*10 mm I.D; Mobile phase: n-hexane / absolute ethanol; Gradient elution, n-hexane content from 100% to 80% v / v; Flow rate: 7 mL / min; Wavelength: 210 / 254 nm) to give 25-a (65 mg, yield: 14.32%, RT = 16.993 min) and 25-b (77 mg, yield: 16.96%, RT = 20.143 min) as white solids.

[0818] 25-a:

[0819] LC-MS m / z (ESI): 586.30 [M+H] + .

[0820] 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.24 (t, J = 1.9 Hz, 1H), 7.96-7.86 (m, 1H), 7.66-7.56 (m, 2H), 7.55-7.09 (m, 3H), 6.39 (s, 1H), 6.03 (s, 1H), 5.16 (d, J = 10.3 Hz, 1H), 4.30 (dd, J = 10.3, 7.6 Hz, 1H), 3.30 (s, 3H), 2.84-2.71 (m, 1H), 1.61 (s, 3H), 0.77 (d, J = 6.4 Hz, 3H).

[0821] 25-b:

[0822] LC-MS m / z (ESI): 586.20 [M+H] + .

[0823] 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.24 (s, 1H), 7.90-7.81 (m, 1H), 7.64-7.53 (m, 2H), 7.51-7.07 (m, 3H), 6.36 (s, 1H), 6.01 (s, 1H), 5.13 (d, J = 10.3 Hz, 1H), 4.28 (dd, J = 10.4, 7.6 Hz, 1H), 3.28 (s, 3H), 2.81-2.69 (m, 1H), 1.59 (s, 3H), 0.75 (d, J = 6.4 Hz, 3H).

[0824] Example 26. Synthesis of (2R, 3S, 4S, 5R)-N-(2-(N-carbamoyl-S- methylsulfϊnylimino)pyridin-4-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 26)

[0825] 26.1 Synthesis of (2R, 3S, 4S, 5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5- dimethyl-N-(2-(methylthio)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 26-1)

[0826] (2R, 3S, 4S, 5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 25-1, 0.30 g, 0.84 mmol) was dissolved in pyridine (10 mL), 2-(methylthio)pyridin-4-amine (0.17 g, 1.27 mmol) was added, and POCl3(0.39 g, 2.54 mmol) was slowly added dropwise in an ice water bath. After the addition was completed, the reaction was allowed to proceed at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, water (20 mL) was added, and extraction was performed with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 0-1 / 2, v / v) to give Compound 26-1 (0.32 g, yield: 73.98%) as a light yellow solid.

[0827] LC-MS m / z (ESI): 511.10 [M-H] - .

[0828] 26.2 Synthesis of (2R, 3S, 4S, 5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5- dimethyl-N-(2-(S-methylsulfϊnylimino)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 26-2)

[0829] (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(2-(methylsulfinyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 26-2, 0.30 g, 0.55 mmol) was dissolved in acetic acid (6 mL), NaOCN (0.36 g, 5.52 mmol) was added, and the reaction was allowed to proceed under a nitrogen atmosphere at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, saturated aqueous sodium bicarbonate solution (20 mL) was added, and extraction was performed with ethyl acetate (15 mL x 3), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Waters AcQuiTYC SH, C18, 1.7 μm, 2.1*100 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile) to obtain Compound 26 as a white solid.

[0830] LC-MS m / z (ESI): 542.10 [M-H] - .

[0831] 26.3 (2R,3S,4S,5R)-N-(2-(N-carbamoyl-S-methylsulfϊnylimino)pyridin-4-yl)-3-(2- (difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 26) was synthesized

[0832] (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-N-(2-(S- methylsulfϊnylimino)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 26-2, 0.30 g, 0.55 mmol) was dissolved in acetic acid (6 mL), NaOCN (0.36 g, 5.52 mmol) was added, and the reaction was allowed to proceed under a nitrogen atmosphere at room temperature overnight. The reaction solution was concentrated to dryness under reduced pressure, saturated aqueous sodium bicarbonate solution (20 mL) was added, and extraction was performed with ethyl acetate (15 mL x 3), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Waters AcQuiTYC SH, C18, 1.7 μm, 2.1*100 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile) to obtain Compound 26 as a white solid.

[0833] Compound 26 was subjected to chiral resolution (Instrument: SHIMADZU RFC-40; Column: AD-H 5 pm 250*10 mm I.D; Mobile phase: n-hexane / absolute ethanol; Gradient elution, n-hexane content from 100% to 85% v / v; Flow rate: 7 mL / min; Wavelength: 210 / 254 nm) to give 26-a (65 mg, yield: 20.08%, RT = 14.247 min) and 26-b (65 mg, yield: 20.08%, RT = 22.265 min) as white solids.

[0834] 26-a:

[0835] LC-MS m / z (ESI): 587.10 [M+H] + .

[0836] 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.59 (d, J = 5.5 Hz, 1H), 8.42 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 5.5, 2.0 Hz, 1H), 7.53 - 7.07 (m, 3H), 6.34 (s, 1H), 5.92 (s, 1H), 5.17 (d, J = 10.2 Hz, 1H), 4.29 (dd, J = 10.2, 7.7 Hz, 1H), 3.26 (s, 3H), 2.83 - 2.70 (m, 1H), 1.60 (s, 3H), 0.79 - 0.72 (m, 3H).

[0837] 26-b:

[0838] LC-MS m / z (ESI): 587.10 [M+H] + .

[0839] 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 5.5 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 7.93 (dd, J = 5.5, 2.1 Hz, 1H), 7.59 - 7.01 (m, 3H), 6.40 (s, 1H), 5.96 (s, 1H), 5.27 (d, J = 10.3 Hz, 1H), 4.31 (dd, J = 10.2, 7.6 Hz, 1H), 3.28 (s, 3H), 2.88 - 2.70 (m, 1H), 1.62 (s, 3H), 0.88 - 0.68 (m, 3H).

[0840] Biological evaluation

[0841] Experimental Example 1. Compound on human Na v1.8 Determination of inhibitory activity

[0842] The purpose of the experiment is to detect the effect of the compound on human Na v 1.8 Effect on ion channel. Human Na v 1.8 ion channel is stably expressed on CHO (Chinese hamster ovary) cells. After Na v 1.8 current is stable, the size of Na v 1.8 current before and after the application of the compound, the effect of the compound on Na v 1.8 ion channel can be obtained.

[0843] 1. Experimental materials and instruments

[0844] 1) Patch clamp amplifier HEKA (Germany) EPC 10

[0845] 2) Micro manipulator Sutter Instrument (USA) MP225

[0846] 3) Electrode puller Sutter Instrument (USA) P97

[0847] 4) Glass capillary Sutter Instrument (USA) BF150-86-10

[0848] 5) Inverted microscope Mshot (China) MF53

[0849] 6) Peristaltic pump Longer Pump (China) BT100-2J

[0850] 7) Dimethyl sulfoxide (DMSO) Sigma D4540

[0851] 2. Experimental steps

[0852] 2.1 Compound preparation

[0853] The reagents for preparing the intracellular and extracellular solutions are purchased from Amresco, cesium fluoride is purchased from Innochem, and the rest are purchased from Sigma.

[0854] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O; adjust pH to 7.4 with NaOH;

[0855] Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA; pH = 7.2 adjusted with CsOH.

[0856] The test compounds were stored at a concentration of 10 mM in dimethyl sulfoxide. On the day of the experiment, they were dissolved in extracellular solution to the desired concentration.

[0857] 2.2 Cell culture

[0858] Before patch-clamp recording, cells were dissociated with 0.25% trypsin-EDTA and 6.5 x 10 3 cells were plated onto coverslips in 24-well plates (final volume: 500 μL) and incubated for 18 h before recording.

[0859] 2.3 Manual patch-clamp recording procedure

[0860] Whole-cell patch-clamp recording of Na v 1.8 Voltage protocol for current recording: After the formation of the whole-cell configuration, the cell was 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 obtaining the half-inactivation voltage (V half ). The resting state and half-inactivated state of sodium current were detected using a double-pulse protocol. First, a 50 ms depolarizing pulse (TP1) to 0 mV was given to detect the resting state of sodium current. Then, the conditioning voltage was adjusted to V half for 5 s, and then the voltage was returned to -120 mV for 20 ms to allow the channels that were not bound by the compound and were in the inactivated state to recover. A second depolarizing pulse (TP2) to 0 mV for 50 ms was given to detect the half-inactivated state of sodium current. Finally, it was returned to the clamped voltage of -120 mV, and the data were collected repeatedly with an interval of 20 s to observe the effect of the drug on the peak of sodium current in two different states.

[0861] Patch-clamp operation First, the capillary glass tube was pulled into a recording electrode by a microelectrode puller. Then, the electrode filled with intracellular solution was installed into a microelectrode holder. Next, the cover glass with cells was placed in a recording bath under an inverted microscope. Then, the microelectrode manipulator was operated under the inverted microscope to immerse the electrode into extracellular solution and record the electrode resistance (Rpip). Then, the electrode was slowly contacted with the cell surface, and negative pressure was given to form a GΩ high resistance seal. At this time, fast capacitance compensation was performed, and negative pressure was continuously given to break the cell membrane to form a whole-cell recording mode. Finally, slow capacitance compensation was performed, and experimental parameters such as series resistance (Rs) were recorded.

[0862] When the current amplitude of the cell was stable in the control extracellular solution, the drug was administered. After the current reached a steady state of block (about 5 minutes) at each drug concentration, the next concentration was tested. The control extracellular solution and the working solution of the test compound were sequentially flowed through the recording bath from low concentration to high concentration by gravity perfusion, thereby acting on the cells. At the same time, liquid displacement was performed in the recording by using a peristaltic pump. Each concentration was independently tested several times. All electrophysiological tests were performed at room temperature.

[0863] All tests were performed in the presence of 100 nM TTX in the extracellular solution to block the endogenous TTX-S (tetrodotoxin-sensitive) Na + current.

[0864] 2.4 Data analysis

[0865] The experimental data were collected by an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0866] When analyzing the data, first, the peak sodium current (Peak current compound ) after each drug concentration was normalized with the blank control peak current (Peak current Control ). Then, the inhibition rate corresponding to 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 at each concentration were calculated, and the data were expressed as Mean±SE. According to different drug concentrations and their corresponding inhibition rates, the GraphPad Prism software was used to draw IC 50 curves, analyze the data, and obtain the final IC 50 value.

[0867] The compounds of the present disclosure have an inhibitory effect on human Na v1.8 were determined by the above test, and the results are shown in Table 2.

[0868] Table 2 Inhibition of human Na v 1.8 were determined by the above test, and the results are shown in Table 2.

[0869] Conclusion: The compounds of the present disclosure have obvious inhibitory effect on the activity of human Na v 1.8 channels, and the IC 50 of some compounds can reach the level of 1 nM, and the IC

[0870] Experimental Example 2. Inhibition of Na v Ion channel subtype selectivity test

[0871] The purpose of the experiment is to detect the effect of the compound on human sodium ion channel cells (Na v 1.1, Na v 1.2, Na v 1.3, Na v 1.4, Na v 1.5, Na v 1.6, Na v 1.7) in vitro experiment. After the Na current is stable, the size of the Na current before and after the application of the compound can be compared to obtain the effect of the compound on the Na ion channel.

[0872] 1. Experimental materials and instruments

[0873] 1) Patch clamp amplifier HEKA (Germany) EPC 10

[0874] 2) Micro manipulator Sutter Instrument (USA) MP285

[0875] 3) Electrode puller Sutter Instrument (USA) P97

[0876] 4) Glass capillary Sutter Instrument (USA) BF150-86-10

[0877] 5) Inverted microscope Mshot (China) MF53

[0878] 6) Peristaltic pump Longer Pump (China) BT100-2J

[0879] 7) Data acquisition software HEKA (Germany) PatchMaster

[0880] 8) Dimethyl sulfoxide (DMSO) Sigma D4540

[0881] 2. Experimental procedure

[0882] 2.1 Compound preparation

[0883] Reagents for the preparation of the intracellular and extracellular solutions were purchased from Amresco, Cesium fluoride from Innochem and the rest from Sigma.

[0884] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2-6H2O, 2 mM CaCl2-2H2O, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH2PO4-2H2O; pH 7.4 adjusted with NaOH;

[0885] Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA; pH 7.2 adjusted with CsOH.

[0886] Test compounds were stored at a concentration of 10 mM in dimethyl sulfoxide. On the day of the experiment they were dissolved in extracellular solution to the required concentration.

[0887] 2.2 Cell culture

[0888] Before patch-clamp recording, cells were dissociated with 0.25% trypsin-EDTA and 6.5 x 105cells were plated on coverslips in 24-well plates (final volume: 500 μL). After 18 hours, experiments were performed. 3

[0889] 2.3 Manual patch-clamp test procedure

[0890] The voltage protocol for recording Na currents in the whole-cell configuration was as follows: after the formation of the whole-cell seal, the cell was voltage clamped at -120 mV. First, the voltage was stepped from -110 mV to -20 mV in 10 mV steps for 5 s, then a 0 mV depolarizing pulse was given to measure the peak of the inward current, to obtain the half-inactivation voltage (V half ). The resting state and the half-inactivated state of the sodium current were detected using a double-pulse protocol. First, a first depolarizing pulse (TP1) to 0 mV for 20 ms was given to detect the sodium current in the resting state. Then, the conditioning voltage was adjusted to V half ​, then the voltage was returned to -120 mV for 20 ms to allow recovery of channels that were not bound to the drug and were in the inactivated state. A second depolarizing pulse (TP2) was given to 0 mV for 20 ms to detect the sodium current in the inactivated state. Finally, the voltage was returned to the holding voltage of -120 mV. The data were collected at intervals of 20 s, and the effects of the drug on the peak current in the two different states were observed.

[0891] The patch-clamp operation was first to draw the capillary glass tube into a recording electrode with a microelectrode puller, then the electrode filled with intracellular solution was installed in the microelectrode holder, and then the cover glass with cells was placed in the recording bath under the inverted microscope. Then the microelectrode manipulator was operated under the inverted microscope to immerse the electrode in the extracellular solution and record the electrode resistance (Rpip). Then the electrode was slowly contacted to the cell surface, and negative pressure was given to form a GΩ high resistance seal. At this time, fast capacitance compensation was performed, and negative pressure was continued to suck the cell membrane to form a whole-cell recording mode. Finally, slow capacitance compensation was performed and experimental parameters such as series resistance (Rs) were recorded.

[0892] When the current amplitude of the cell in the control extracellular solution was stable, the drug was started to be given, and after each drug concentration reached a stable block (about 5 minutes), the next concentration was detected. The control extracellular solution and the working solution of the test compound were sequentially flowed through the recording bath from low concentration to high concentration by gravity perfusion method, so as to act on the cells, while the liquid displacement was carried out by using a peristaltic pump in the recording. Each concentration was independently detected several times. All electrophysiological tests were carried out at room temperature.

[0893] 2.4 Data analysis

[0894] The experimental data were collected by EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0895] When analyzing the data, first, the peak current of sodium current (Peak current compound ) after each drug concentration was normalized (Normalized) with the peak current of blank control (Peak current Control ), and then the inhibition rate corresponding to each drug concentration in different states was calculated, that is, 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. According to different drug concentrations and their corresponding inhibition rates, IC 50 curve was drawn using GraphPad Prism software, and the data were analyzed to obtain the final IC50 Values.

[0896] The compounds of the present disclosure have inhibitory activity against human Na v The inhibitory activity against ion channels was measured by the above test, and the results are shown in Table 3.

[0897] Table 3 Inhibition rate of the compounds of the present disclosure against human Na v subtypes at a concentration of 10 μM

[0898] Conclusion: The compounds of the present disclosure have good subtype selectivity against Na v ion channels, particularly against Na v 1.5.

[0899] Experimental Example 3. Test of metabolic stability in liver microsomes

[0900] 1. Experimental materials

[0901] 1.1 Liver microsomes: Human and animal microsomes were purchased from a qualified supplier and stored in a -80°C freezer

[0902] 1.2 Reduced nicotinamide adenine dinucleotide phosphate (NADPH)

[0903] 1.3 Control compounds: Testosterone, diclofenac and propafenone

[0904] 2. Experimental procedure

[0905] 2.1 Preparation of working solutions

[0906] Stock solution: 10 mM DMSO solution

[0907] Working concentration preparation: Dilution of 100% acetonitrile to 100 μM (organic phase content: 99% ACN, 1% DMSO)

[0908] 2.2 Experimental procedure

[0909] Two 96-well incubation plates were prepared, designated T60 incubation plate and NCF60 incubation plate, respectively.

[0910] 445 μL of microsomal working solution (liver microsomal protein concentration of 0.56 mg / mL) was added to the T60 incubation plate and the NCF60 incubation plate, respectively, and the incubation plates were then placed in a 37°C water bath for pre-incubation for about 10 minutes.

[0911] After the pre-incubation, 5 μL of the test sample or control compound working solution was added to the T60 incubation plate and the NCF60 incubation plate, respectively, and mixed well. 50 μL of potassium phosphate buffer was added to each well of the NCF60 incubation plate to start the reaction.

[0912] To each well of the T0 stop plate, 180 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH Regeneration System Working Solution were added, and 54 μL of sample was taken from the T60 incubation plate to the T0 stop plate (T0 sample generation). To the blank control plate, only 54 μL of microsomal working solution, 6 μL of NADPH Regeneration System Working Solution and 180 μL of stop solution were added.

[0913] To each well of the T60 incubation plate, 44 μL of NADPH Regeneration System Working Solution was added to initiate the reaction. Thus, in the samples of test or control compounds, the final concentrations of compound, testosterone, diclofenac and propafenone were 1 μM, the concentration of liver microsomes was 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0914] After incubation for an appropriate time (e.g., 5, 15, 30, 45 and 60 minutes), 180 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) was added to each sample well of the stop plate, and then 60 μL of sample was taken from the T60 incubation plate or NCF60 incubation plate to stop the reaction.

[0915] All sample plates were shaken and centrifuged at 3220 x g for 20 minutes, and then 80 μL of supernatant was taken from each well and diluted into 240 μL of pure water for liquid chromatography tandem mass spectrometry analysis.

[0916] 3. Liquid chromatography tandem mass spectrometry analysis

[0917] All samples were injected for analysis.

[0918] 4. Sample analysis

[0919] In this study, the sample analysis of test and control compounds, testosterone, diclofenac and propafenone, was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) method.

[0920] 5. Data analysis

[0921] The in vitro elimination rate constant k of test and control compounds was obtained by converting the ratio of the peak area of the compound to the internal standard in the following formula into the percentage remaining e :

[0922] When

[0923] The in vitro liver microsomal stability data of the compounds of the present disclosure were tested by the above method, and the results are shown in Table 4.

[0924] Table 4 In vitro liver microsomal stability of the compounds of the present disclosure

[0925] Note: The control compounds are the compounds numbered 528 and 530 in WO2022256702A1 (single enantiomers of unknown absolute configuration), whose compound name is rel-(2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N,S-dimethylsulfϊnylimino)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (synthesized according to the method of Example 13 of WO2022256702A1).

[0926] Conclusion: The compounds of the present disclosure have better liver microsomal stability than the control compounds.

[0927] Experimental Example 4. Mouse pharmacokinetic test

[0928] Test animals: CD-1 (ICR) mice, male, 6-9 weeks old, 6 per compound.

[0929] Solvent: 5% DMSO / 5% solutol / 90% pure water.

[0930] Test design:

[0931] The animals used were CO2 euthanized after collecting the last time point of PK samples. About 0.025 mL of whole blood samples were collected at the specified time through the saphenous vein or other suitable ways.

[0932] The blood sampling time points of the intravenous group and the gavage group were:

[0933] Intravenous group: 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours;

[0934] Gavage group: 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours.

[0935] After all blood samples were collected, they were transferred to commercialized tubes containing K2-EDTA, placed on wet ice, and within 60 minutes after blood collection, the supernatant plasma was aspirated after centrifugation at 3200 x g for 10 minutes at about 4°C (2-8°C), quickly placed on dry ice, and then stored at -60°C or lower temperature for LC-MS / MS analysis.

[0936] The test results obtained are shown in Table 5.

[0937] Table 5 Mouse pharmacokinetic parameters of the compounds of the present disclosure

[0938] Conclusion: The compound of the present disclosure has high blood concentration, large exposure, low clearance rate, high bioavailability and pharmacokinetic advantages in CD-1 mice.

[0939] Example 5. Test in SNI efficacy model of ICR mice

[0940] Test animals: ICR mice, male, 25-30 g.

[0941] Solvent: 5% DMSO / 5% solutol / 90% pure water.

[0942] Test design:

[0943] [Model establishment]

[0944] ICR mice were anesthetized with isoflurane, the hair on the surgical area was shaved, the skin was disinfected with iodophor and 70% ethanol three times, and the operation was started after the skin was dry. Under sterile conditions, the skin of the middle of the left thigh of the mouse was incised with a surgical knife, the sciatic nerve and its distal sciatic nerve three branches: tibial nerve, common peroneal nerve and sural nerve were exposed, the tibial nerve and common peroneal nerve were cut off with ophthalmic scissors, and the sural nerve was reserved. Suture the wound. After the operation, the animals were placed on an electric blanket, and after the animals completely woke up (free movement), the animals were put back into the cage for feeding, and the behavior was observed after the operation.

[0945] [Drug test]

[0946] The day of the operation was recorded as day 0, and on day 10-12 after the operation, all animals were placed in a plexiglass box and adapted to 3.84 (0.6 g) and 4.08 (1 g) test fibers for 15 minutes per day. On day 13, all animals were tested for mechanical pain threshold (PWT), and after excluding the modeling animals that did not show mechanical pain hypersensitivity (PWT greater than 0.6 g), 24 were selected and randomly divided into 3 groups, 8 in each group. On day 14, the body weight of all groups of animals was measured, and each group was given a single oral dose of the corresponding drug at 10 mL / kg. The 50% PWT of the animals was tested before administration, 1, 2 and 8 h after administration, respectively. The curve was drawn by GraphPad software, and statistical analysis was performed.

[0947] The test results are shown in Table 6 and Figure 1.

[0948] Table 6 50% PWT values (g, Mean ± SEM, n = 8) of the compound of the present disclosure at different time points in each group of mice

[0949] Note: The chemical structure of the control compound VX-548 (synthesized according to the method of Example 7 of WO2021113627A1) is shown below.

[0950] Conclusion: The compound 20-b of the present disclosure (dose of 30 mg / kg) has a similar effect to VX-548 (dose of 30 mg / kg) in the SNI model of mice, and has a good analgesic effect.

[0951] It should be noted that although the technical solutions of the present disclosure are described with specific examples, those skilled in the art can understand that the present disclosure should not be limited thereto.

[0952] The above has described various embodiments of the present disclosure, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes are obvious to those skilled in the art without departing from the scope and spirit of the described embodiments. The selection of terms used herein is intended to best explain the principles, practical applications, or technical improvements in the market of the embodiments, or to enable other ordinary skilled persons in the art to understand the embodiments disclosed herein.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof: wherein: Ring A is phenyl or 6-membered heteroaryl, the heteroatom of which is optionally oxidized; R a2 selected from H, D, halogen, cyano, C1-C4alkyl, C1-C4alkoxy, -C(=O)NH2, and -C(=O)NH(C1-C4alkyl), said C1-C4alkyl or C1-C4alkoxy being optionally substituted by a group selected from halogen, hydroxyl, and C1-C4alkoxy; R a1 selected from -S(=O)(=NR 1 )R 2 , -C(=O)N(R 3 )R 4 , and -N=S(=O)(R 5 )R 6 ; R 1 is selected from cyano and -L 1 -R 11 ; L 1 is selected from -C(=O)-, -C(=O)-(C1-C4 alkylene)-, -C(=O)-(C3-C6 cycloalkylene)- and -C1-C4 alkylene-, or, from -C(=O)-(C1-C4 alkylene) and C1-C4 alkylene; R 11 is selected from -NH2, -OH, -OR 12 , -NHR 12 and -NR 12 R 13 ; R 12 and R 13 are each independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 halocycloalkyl and -(C1-C4 alkylene)-(C3-C6 cycloalkyl); or, R 12 , R 13 and the N atom to which they are attached together form a 4-7 membered heterocyclyl group, which optionally further contains 1-2 heteroatoms selected from N, O and S and is optionally substituted with 1-3 groups selected from halogen and C1-C4 alkyl; R 2 is C1-C4 alkyl; or R 1 , R 2 and the N, S atom to which they are attached form a 5-10 membered heterocyclyl group, which is optionally substituted with 1-3 groups selected from halo and C1-C4alkyl; R 3 selected from -L 2 -R 14 and -CH(R 16 )-COOH, or, selected from -L 2 -R 14 and -CH(R 16 )-COOH; L 2 is selected from C1-C4 alkylene and C4-C6 cycloalkylene; R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH, -COOR 15 , cyano, C1-C4 alkoxy, and C1-C4 alkyl; R 16 is a natural or unnatural amino acid side chain; The condition is that when L 2 When it is a C1-C4 alkylene group, R 14 Not C1-C4 alkoxy or C1-C4 alkyl; R 4 selected from H and C1-C4alkyl; or R 3 , R 4 and the N atom to which they are attached form a 4-7 membered heterocyclyl group, which optionally further contains 1-2 heteroatoms selected from N, O and S and is substituted with a group selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH and -COOR 15 ; R 15 selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; R 5 and R 6 each independently is selected from the group consisting of C1-C4alkyl and C1-C4haloalkyl; X is O or S; R d1 and R d2 each independently is selected from the group consisting of C1-C4alkyl and C1-C4haloalkyl; R c1 and R c2 are each independently selected from the group consisting of H, C1-C4 alkyl and C1-C4 haloalkyl; R e is H or D; L is -C(=O)NH-; preferably, the N atom in -C(=O)NH- is attached to ring A; Ring B is phenyl or 6-membered heteroaryl containing 1-2 N atoms; R b1 , R b2 , and R b3 are each independently selected from the group consisting of halogen, Ci-C4-alkoxy, Ci-C4-deuteroalkoxy, and Ci-C4-haloalkoxy, or, are each independently selected from the group consisting of halogen and Ci-C4-alkoxy.

2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof, wherein, The compound is as shown in formula (I-1): Preferably, the compound is as shown in formula (I-la) or formula (I-lb): More preferably, the compound is according to Formula (I-1a-1), Formula (I-1a-2), Formula (I-1b-1), or Formula (I-1b-2): wherein ring A, R a2 , R 1 , R 2 , X, R d1 , R d2 , R c1 , R c2 , R e , L, ring B, R b1 , R b2 and R b3 are as defined in claim 1.

3. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to claim 1 or 2, wherein R 1 is selected from cyano and -L 1 -R 11 ; L 1 is selected from -C(=0)-, -C(=0)-(Ci-C4alkylene)-, -C(=0)-(C3-C6cycloalkylene)- and -Ci-C4alkylene-, or, is selected from -C(=0)-(Ci-C4alkylene)- and -Ci-C4alkylene-; R 11 is selected from -NH2, -OH, -NHR 12 and -NR 12 R 13 ; R 12 and R 13 are each independently selected from Ci-C4alkyl, Ci-C4haloalkyl, C3-C6cycloalkyl and -(Ci-C4alkylene)-(C3-C6cycloalkyl); or, R 12 , R 13 and the N atom to which they are attached form a 4-7 membered heterocyclyl group, which optionally further contains 1-2 heteroatoms selected from N and O and is optionally substituted with 1-3 halogens; Preferably, R 1 Selected from cyano and -L 1 -R 11 L 1 Selected from -C(=O)-, -C(=O)-(C1-C4 alkylene)-, -C(=O)-(C3-C6 cycloalkylene)- and -C1-C4 alkylene-, or selected from -C(=O)-(C1-C4 alkylene)- and -C1-C4 alkylene-; R 11 Selected from -NH2, -OH, -NHCH3, -NHCH2CH3, -N(CH3)2, More preferably, R 1 is -L 1 -R 11 ; L 1 is -C(=O)-(C1-C4alkylene); R 11 is -NH2.

4. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof, wherein, The compound is as shown in formula (I-2): Preferably, the compound is as shown in formula (I-2a) or formula (I-2b): wherein ring A, R a2 , R 3 , R 4 , X, R d1 , R d2 , R c1 , R c2 , R e , L, ring B, R b1 , R b2 and R b3 are as defined in claim 1.

5. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to claim 1 or 4, wherein R 3 selected from -L 2 -R 14 and -CH(R 16 )-COOH, or, selected from -L 2 -R 14 and -CH(R 16 )-COOH; L 2 is selected from C1-C4 alkylene and C4-C6 cycloalkylene, R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH and C1-C4 alkoxy; with the proviso that, when L 2 is C1-C4 alkylene, R 14 is not C1-C4 alkoxy; R 15 is C1-C4 alkyl; preferably, L 2 is C1-C4 alkylene, R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 and -COOH; or, L 2 is C4-C6 cycloalkylene, R 14 is selected from -S(=O)2-R 15 and C1-C4 alkoxy; R 15 is C1-C4 alkyl; more preferably, -L 2 -R 14 is selected from -C2H4-S(=O)2-CH3, -C2H4-S(=O)(=NH)CH3, -CH2-COOH, R 16 is selected from the group consisting of a glycine side chain, an alanine side chain, an isoleucine side chain, a leucine side chain, a valine side chain, a methionine side chain, a phenylalanine side chain, a tryptophan side chain, a tyrosine side chain, an asparagine side chain, a cysteine side chain, a glutamine side chain, a serine side chain, a threonine side chain, an arginine side chain, a histidine side chain, a lysine side chain, an aspartic acid side chain, and a glutamic acid side chain; preferably, R 16 is selected from the group consisting of a glycine side chain, an asparagine side chain, a cysteine side chain, a glutamine side chain, a serine side chain, a threonine side chain, and a tyrosine side chain.

6. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to claim 1 or 4, wherein R 3 , R 4 and the N atom to which they are attached form a 4-6 membered heterocyclyl group, which optionally further contains 1-2 N atoms and is substituted with a group selected from the group consisting of -S(O)2-R 15 , -S(O)(=NH)R 15 , -COOH and -COOR 15 ; R 15 is C1-C4 alkyl; Preferably, R 3 , R 4 and the N atom to which they are attached The each independently is substituted with a group selected from -S(O)2-R 15 , -COOH and -COOR 15 ; R 15 is C1-C4 alkyl.

7. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof, wherein, The compound is a compound as shown in formula (I-3): Preferably, the compound is as shown in formula (I-3a) or formula (I-3b): wherein ring A, R a2 , R 5 , R 6 , X, R d1 , R d2 , R c1 , R c2 , R e , L, ring B, R b1 , R b2 and R b3 are as defined in claim 1.

8. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to claim 1 or 7, wherein R 5 and R 6 each independently is C1-C4alkyl; Preferably, R 5 and R 6 are each independently selected from the group consisting of methyl and ethyl.

9. The compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to any one of claims 1-8, wherein Ring A is phenyl or 6-membered heteroaryl, which is pyridyl or N-oxidized pyridyl; preferably, ring A is wherein denotes the site of attachment of ring A to L, and ring A is also attached to R a1 and R a2 ; R a2 is selected from H, halogen and cyano; preferably, R a2 is selected from H, F and cyano; more preferably, when ring A is phenyl, R a2 is selected from H, F and cyano; when ring A is At that time, R a2 For H; X is O or S; preferably, X is O; R d1 and R d2 are each independently selected from the group consisting of Ci-C4-alkyl and Ci-C4-haloalkyl; preferably R d1 and R d2 are each independently selected from the group consisting of methyl and trifluoromethyl, and R d1 and R d2 are not identical to each other; R c1 and R c2 are each independently selected from the group consisting of H, C1-C4 alkyl and C1-C4 haloalkyl; preferably, R c1 and R c2 are each independently selected from the group consisting of H and methyl, and R c1 and R c2 are not identical to each other; R e is H or D; preferably, R e is H; Ring B is phenyl or pyridyl; preferably, ring B is phenyl; more preferably, ring B is R b1 , R b2 , and R b3 are each attached to the phenyl group at the positions shown below: R b1 , R b2 and R b3 are each independently selected from the group consisting of halogen, Ci-C4-alkoxy, Ci-C4-deuteroalkoxy and Ci-C4-haloalkoxy, or, are each independently selected from the group consisting of halogen and Ci-C4-alkoxy; preferably, R b1 , R b2 and R b3 are each independently selected from the group consisting of F and methoxy; more preferably, R b1 and R b2 are F and R b3 is methoxy.

10. The following compounds or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof:

11. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to any one of claims 1-10; Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient; More preferably, the pharmaceutically acceptable excipient comprises one or more of a filler, a disintegrant, a surfactant, a solubilizer, a lubricant, a wetting agent, a thickening agent, a glidant, a flavoring agent, a flavoring odorant, a preservative, an antioxidant, a pH adjusting agent, a solvent and a light shielding agent.

12. A pharmaceutical preparation made from a compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to any one of claims 1-10 or a pharmaceutical composition according to claim 11; Preferably, the pharmaceutical preparation is a tablet, a capsule, a granule, a sugar-coated pill, a powder, a lozenge, a powder injection, a liquid preparation or a suppository.

13. Use of a compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to any one of claims 1-10 or a pharmaceutical composition according to claim 11 or a pharmaceutical preparation according to claim 12 in the manufacture of a medicament for inhibiting voltage-gated sodium channels. Preferably, the voltage-gated sodium channel is Na v 1.

8.

14. Use of a compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled form or prodrug thereof according to any one of claims 1-10 or a pharmaceutical composition according to claim 11 or a pharmaceutical preparation according to claim 12 in the manufacture of a medicament for preventing, alleviating and / or treating a voltage-gated sodium channel related disease or disorder. Preferably, the voltage-gated sodium channel is Na v 1.8; and / or, Preferably, the voltage-gated sodium channel-related disease or disorder comprises pain, arthritis, epilepsy or seizure disorders, neurodegenerative diseases, psychiatric disorders (preferably anxiety or depression), bipolar disorder, myotonia, movement disorders, neuroendocrine disorders, ataxia, irritable bowel syndrome, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, stress- or exercise-induced angina, palpitations, hypertension, multiple sclerosis, Charcot-Marie-Tooth syndrome, distal spinal muscular atrophy, incontinence, pathological cough, arrhythmia, and abnormal gastrointestinal motility.

15. Use of a compound or pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labelled, or prodrug thereof according to any one of claims 1-10 or a pharmaceutical composition according to claim 11 or a pharmaceutical preparation according to claim 12 in the manufacture of a medicament for the prevention, alleviation and / or treatment of pain.

16. Use according to claim 14 or 15, characterized in that, The pain comprises migraine, cluster headache, acute pain, chronic pain, gut pain, neuropathic pain, musculoskeletal pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain and visceral pain; Preferably, the acute pain comprises acute postoperative pain; Preferably, the gut pain comprises inflammatory bowel disease pain and Crohn's disease pain; Preferably, the neuropathic pain comprises postherpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, causalgia, postamputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy, cancer chemotherapy, antiretroviral therapy, post-spinal cord injury pain, small-fiber neuropathy, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy, and trigeminal autonomic neuropathy; Preferably, the musculoskeletal pain comprises osteoarthritic pain, back pain, cold pain, burning pain and dental pain; Preferably, the inflammatory pain comprises rheumatoid arthritis pain, vulvodynia pain and interstitial cystitis pain; Preferably, the idiopathic pain comprises fibromyalgia; Preferably, the postoperative pain comprises bunionectomy pain, herniorrhaphy pain and abdominoplasty pain; Preferably, the visceral pain comprises acute abdominal pain, tumor visceral pain, angina pectoris and visceral pain caused by abdominoplasty.

Images