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

Abstract

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

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a heterocyclic compound used as a voltage-gated sodium channel inhibitor, a pharmaceutical composition and a pharmaceutical preparation containing the same, and use of the same in the preparation of a medicine for preventing, relieving and / or treating a pain-related disease. BACKGROUND

[0002] Pain is a complex physiological and psychological activity, usually caused by physical injury, illness or adverse external stimuli. The International Association for the Study of Pain (IASP) defines pain as "an unpleasant sensory and emotional experience, often accompanied by actual or potential tissue damage". Pain is a protective mechanism that 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 the pain will 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 770.3 billion US dollars, and is expected to reach 1162.3 billion US dollars in 2032. However, the abuse of opioid analgesics has had a staggering impact on society. According to the WHO, 69,000 people die from opioid overdose every year, and 15 million people are dependent on opioids (i.e., opioid addiction). Therefore, it is self-evident that it is important to develop new analgesics with good efficacy, no addiction and drug resistance.

[0003] Pain originates from nociceptors in the peripheral nervous system. Nociceptors are free nerve endings widely distributed in the skin, muscles, joints and internal organs of the whole body, which can convert the temperature, mechanical or chemical stimuli they sense into nerve impulses (action potentials) and transmit them to the soma part of the dorsal root ganglion via afferent nerve fibers, and ultimately to the high-level 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.

[0004] Voltage-gated sodium channels (Na v ) are a class of transmembrane ion channel proteins composed of alpha and beta subunits. According to the different alpha subunits, they can be divided into nine subtypes Na v1.1-1.9, different subtypes show different tissue distribution and electrophysiological, pharmacological characteristics. According to whether it can be effectively inhibited by nanomolar tetrodotoxin (TTX), Na v Is divided into TTX-sensitive (TTX-S) and TTX-insensitive (TTX-R). Na v 1.1-1.4, Na v 1.6 and Na v 1.7 are TTX-S type, in 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, Na v 1.7 is present 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 type, in which Na v 1.5 is mainly present in myocardial cells, Na v 1.8 and Na v 1.9 are present in the dorsal root ganglion of the peripheral nervous system. Non-selective Na v Inhibitors (such as lamotrigine, lacosamide, mexiletine and other drugs) have been successfully used to treat chronic pain. But the existing clinical use of Na v Inhibitors lack subtype selectivity, can inhibit sodium ion channels expressed in the heart and central nervous system, have a narrow therapeutic window, and are limited in application.

[0005] Na v 1.8 is encoded by SCN10A, which has the electrophysiological characteristics of slow inactivation and rapid recovery. In some models of studying neuropathic pain, nerve injury can increase the expression level of Na v 1.8 in axons and neuronal cell bodies. Using Na v 1.8 antisense oligonucleotide can significantly alleviate pain while reducing the expression of Na v 1.8. Na v 1.8 gene knockout mice cannot exhibit normal visceral inflammatory pain. When the Na v 1.8 gene of humans produces a functional gain-of-function mutation, it can cause peripheral neuropathic pain. Na v 1.8 is mainly distributed in the peripheral nervous system, so it is necessary to selectively inhibit Na v1.8 can effectively reduce side effects, has the potential to become a new analgesic therapy, and can be used for the treatment of various types of pain such as inflammatory pain, neuropathic pain, postoperative pain, and cancer pain. Therefore, highly selective Na v 1.8 inhibitors have become one of the focuses of the development of voltage-gated sodium ion channels.

[0006] 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 1.5) and better pharmacokinetic properties. v 1.8 inhibitors. SUMMARY

[0007] Problem to be solved by the invention

[0008] The present application aims to provide a heterocyclic compound for use as a voltage-gated sodium channel inhibitor, and to provide a pharmaceutical composition and a pharmaceutical preparation comprising the same, and a medical use thereof, which has an excellent voltage-gated sodium channel (especially Na v 1.8) inhibitory effect, while having better selectivity and better pharmacokinetic properties.

[0009] Solution to the problem

[0010] In a first aspect, the present application provides a compound as shown in formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof:

[0011]

[0012] wherein:

[0013] Ring A is phenyl or a 6-membered heteroaryl, the heteroatom in the heteroaryl being optionally oxidized;

[0014] 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), the C1-C4 alkyl or C1-C4 alkoxy being optionally substituted with a group selected from halogen, hydroxyl, and C1-C4 alkoxy;

[0015] 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 ;

[0016] 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 together with 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 optionally substituted with 1-3 groups selected from halogen and C1-C4alkyl;

[0017] R 2 is C1-C4alkyl;

[0018] or, R 1 , R 2 together with 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 halogen and C1-C4alkyl;

[0019] R 3 is selected from -L 2 -R 14 and -CH(R 16 )-COOH, or, from -L 2 -R 14 and -CH(R 16 )-COOH; L 2 is selected from C1-C4alkylene and C4-C6cycloalkylene; R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH, -COOR15 cyano, C1-C4alkoxy and C1-C4alkyl; R 16 is a natural or unnatural amino acid side chain;

[0020] with the proviso that, when L 2 is C1-C4alkylene, R 14 is not C1-C4alkoxy or C1-C4alkyl;

[0021] R 4 is selected from H and C1-C4alkyl;

[0022] or, R 3 , R 4 together with the N atom to which they are attached form a 4-7 membered heterocyclyl group, said heterocyclyl group optionally further containing 1-2 heteroatoms selected from N, O and S and being substituted with a group selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH and -COOR 15 ;

[0023] R 15 is selected from C1-C4alkyl and C1-C4haloalkyl;

[0024] R 5 and R 6 are each independently selected from C1-C4alkyl and C1-C4haloalkyl;

[0025] X is O or S;

[0026] R d1 and R d2 are each independently selected from C1-C4alkyl and C1-C4haloalkyl;

[0027] R c1 and R c2 are each independently selected from H, C1-C4alkyl and C1-C4haloalkyl;

[0028] R e is H or D;

[0029] L is -C(=O)NH-;

[0030] Ring B is phenyl or a 6-membered heteroaryl group containing 1-2 N atoms;

[0031] 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.

[0032] In some embodiments, L in the above formula (I) is connected to ring A through a N atom.

[0033] Specifically, the present application provides a compound as shown in formula (I-1):

[0034]

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

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

[0037]

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

[0039]

[0040] In some embodiments of the present application, the above compound of formula (I-1b) is further as shown in formula (I-1b-1) or formula (I-1b-2):

[0041]

[0042] In the compound of formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1) or (I-1b-2), ring A is phenyl or 6-membered heteroaryl, and the heteroatom in the heteroaryl is optionally oxidized.

[0043] In some embodiments, ring A is phenyl.

[0044] In some embodiments, ring A is 6-membered heteroaryl, and the 6-membered heteroaryl contains 1-3 N atoms and the N atoms are optionally oxidized.

[0045] In some embodiments, ring A is 6-membered heteroaryl, and the 6-membered heteroaryl contains 1-2 N atoms and the N atoms are optionally oxidized.

[0046] In some embodiments, ring A is 6-membered heteroaryl, and the 6-membered heteroaryl is pyridyl and the N atom in the pyridyl is optionally oxidized.

[0047] In some embodiments, ring A is phenyl or 6-membered heteroaryl, and the 6-membered heteroaryl is pyridyl or N-oxidized pyridyl, i.e. ring A is phenyl, pyridyl or N-oxidized pyridyl.

[0048] In some embodiments, ring A is wherein represents the point of attachment of ring A to L, and ring A is also attached to R a2 and .

[0049] In some embodiments, ring A is wherein represents the point of attachment of ring A to L, and ring A is also attached to R a2 and .

[0050] In some embodiments, 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.

[0051] 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.

[0052] In some embodiments, R a2 is selected from H, D, halogen, cyano, C1-C2 alkyl, and C1-C2 alkoxy.

[0053] In some embodiments, R a2 is selected from H, halogen, and cyano.

[0054] In some embodiments, R a2 is selected from H, F, and cyano.

[0055] In some specific embodiments, when ring A is phenyl, R a2 is selected from H, F, and cyano.

[0056] In some specific embodiments, when ring A is 6-membered heteroaryl (e.g., pyridyl or N-oxidized pyridyl), R a2 is H.

[0057] In some specific embodiments, when ring A is , R a2 is H, wherein This indicates the location where ring A connects to L, and ring A also connects to... connect.

[0058] 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.

[0059] In some specific implementations, ring A is Pyridinyl or N-oxypyridinyl groups are attached to the positions shown below: Where R a2 For H.

[0060] 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.

[0061] In some implementations, 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, -NHR 12 and -NR 12 R13 ;R 12 and R 13 Each is independently selected from C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 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 and O and optionally substituted by 1-3 halogens.

[0062] In some implementations, R 1 Selected from cyano and -L 1 -R 11 L 1 Selected from -C(=O)-(C1-C4 alkylene)- 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.

[0063] In some implementations, R 1 Selected from cyano and -L 1 -R 11 L 1 Selected from -C(=O)-(C1-C4 alkylene)- and -C1-C4 alkylene-; R 11 Selected from -NH2, -OH, -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, 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 and O and optionally substituted by 1-3 halogens.

[0064] In some implementations, L 1 It is -C(=O)-(C1-C4 alkylene)-.

[0065] In some implementations, L 1 It is -C(=O)-(C1-C2 alkylene)-.

[0066] In some implementations, L 1 It is -C(=O)-CH2-.

[0067] In some implementations, L 1 It is -C(=O)-.

[0068] In some implementations, L 1 It is -C(=O)-(C3-C6 cycloalkylene)-.

[0069] In some implementations, L 1 It is -C(=O)-(C3-C4 cycloalkylene)-.

[0070] In some implementations, L 1 for

[0071] In some implementations, L 1 It is a -C1-C4 alkylene-.

[0072] In some implementations, L 1 It is a -C1-C2 alkylene-.

[0073] In some implementations, L 1 It is -C2H4-.

[0074] In some implementations, R 11 Selected from -NH2, -OH, -OR 12 -NHR 12 and -NR 12 R 13 .

[0075] In some implementations, R 11 Selected from -NH2, -OH, -NHR 12 and -NR 12 R 13 .

[0076] In some implementations, R 12 and R 13each independently is selected from the group consisting of C1-C3alkyl, C1-C3haloalkyl, C3-C5cycloalkyl, C3-C5halocycloalkyl, and -(C1-C3alkylene)-(C3-C5cycloalkyl).

[0077] In some embodiments, R 12 and R 13 each independently is selected from the group consisting of C1-C3alkyl, C1-C3haloalkyl, C3-C5cycloalkyl, and -(C1-C3alkylene)-(C3-C5cycloalkyl).

[0078] In some embodiments, R 12 and R 13 each independently is selected from the group consisting of C1-C2alkyl, C1-C2haloalkyl, C3-C4cycloalkyl, C3-C4halocycloalkyl, and -(C1-C2alkylene)-(C3-C4cycloalkyl).

[0079] In some embodiments, R 12 and R 13 each independently is selected from the group consisting of C1-C2alkyl, C1-C2haloalkyl, C3-C4cycloalkyl, and -(C1-C2alkylene)-(C3-C4cycloalkyl).

[0080] In some embodiments, R 12 and R 13 each independently is selected from the group consisting of methyl, ethyl, -CH2CF3, cyclopropyl, and -CH2-cyclopropyl.

[0081] In some embodiments, R 12 , R 13 and the N atom to which they are attached together form a 4-6 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-C4alkyl.

[0082] In some embodiments, R 12 , R 13 and the N atom to which they are attached together form a 4-6 membered heterocyclyl group, which optionally further contains 1-2 heteroatoms selected from N and O and is optionally substituted with 1-3 groups selected from halogen and C1-C4alkyl.

[0083] In some embodiments, R 12 , R 13 and the N atom to which they are attached together form a 4-6 membered heterocyclyl group, which optionally further contains 1-2 heteroatoms selected from N and O and is optionally substituted with 1-2 groups selected from halogen and C1-C4alkyl.

[0084] In some embodiments, R 12R 13 Together with the N atoms to which they are attached, they form a 4-6 membered heterocyclic group, which optionally also contains 1-2 heteroatoms selected from N and O and optionally substituted by 1-2 halogens.

[0085] In some implementations, R 12 R 13 Together with the N atoms to which they are attached, they form a 4-6 membered heterocyclic group, which optionally also contains 1-2 heteroatoms selected from N and O and optionally substituted by 1-2 F atoms.

[0086] In some implementations, R 12 R 13 Together with the N atoms they are attached to form The It can be optionally replaced by 1-2 halogens.

[0087] In some implementations, R 12 R 13 Together with the N atoms they are attached to form The It can be replaced by 1-2 Fs.

[0088] In some implementations, R 12 R 13 Together with the N atoms they are attached to form The It is replaced by 1-2 halogens.

[0089] In some implementations, R 12 R 13 Together with the N atoms they are attached to form The Replaced by 1-2 Fs.

[0090] In some implementations, R 12 R 13 Together with the N atoms they are attached to form

[0091] In some implementations, R 11 Selected from -NH2, -OH, -NHCH3, -NHCH2CH3, -N(CH3)2,

[0092] In some specific implementations, when L 1 When R is -C(=O)-(C1-C4 alkylene)-, 11 Selected from -NH2, -OH, -OR12 -NHR 12 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, 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 group, said 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-C4alkyl.

[0093] In some embodiments, when L 1 is -C(=O)-(C1-C4alkylene)-, R 11 is selected from the group consisting of -NH2, -OH, -OR 12 , -NHR 12 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 form a 4-6 membered heterocyclyl group, said 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-C4alkyl.

[0094] In some embodiments, when L 1 is -C(=O)-(C1-C4alkylene)-, R 11 is selected from the group consisting of -NH2, -OH, -NHR 12 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 form a 4-6 membered heterocyclyl group, said 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.

[0095] In some embodiments, when L1 R is -NH2when L is -C(=O)-CH2-; 11 R is selected from -NH2, -OH, -NHCH3, -NHCH2CH3, -N(CH3)2,

[0096] In some embodiments, when L 1 R is -NH2when L is -C(=O)-(C1-C4alkylene)-; 11 R is -NH2.

[0097] In some embodiments, when L 1 R is -NH2when L is -C(=O)-CH2-; 11 R is -NH2.

[0098] In some embodiments, when L 1 R is -NH2when L is -C(=O)-; 11 R is -NH2.

[0099] In some embodiments, when L 1 R is -NH2when L is -C(=O)-(C3-C6cycloalkylene)-; 11 R is -OH.

[0100] In some embodiments, L 1 R is -NH2when L is -C(=O)-(C3-C4cycloalkylene)-; 11 R is -OH.

[0101] In some embodiments, when L 1 R is -NH2when L is R is -OH. 11 R is -OH.

[0102] In some embodiments, when L 1 R is -NH2when L is -C1-C4alkylene-; 11 R is selected from -NH2and -OH;

[0103] In some embodiments, when L 1 R is -NH2when L is -C2H4-; 11 R is -NH2.

[0104] In some embodiments, R 2 R is C1-C4alkyl.

[0105] In some embodiments, R 2 R is C1-C2alkyl.

[0106] In some embodiments, R2 is methyl.

[0107] Alternatively, in the compound represented by formula (I-1), (I-1a) or (I-1b), R 1 , R 2 and the N, S atom to which they are attached form a 5-10 membered heterocyclic group, which is optionally substituted by 1-3 groups selected from halogen and C1-C4 alkyl.

[0108] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached form a 5-7 membered heterocyclic group, which is optionally substituted by 1-3 groups selected from halogen and C1-C4 alkyl.

[0109] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached form a 5-6 membered heterocyclic group, which is optionally substituted by 1-3 groups selected from halogen and C1-C4 alkyl.

[0110] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached form a 5-6 membered heterocyclic group.

[0111] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached form p is any integer from 1-6, said is optionally substituted by 1-3 groups selected from halogen and C1-C4 alkyl.

[0112] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached form p is any integer from 1-3, said is optionally substituted by 1-2 groups selected from halogen and C1-C4 alkyl.

[0113] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached form p is 1 or 2, said is optionally substituted by 1-2 groups selected from halogen and C1-C4 alkyl.

[0114] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached form p is any integer from 1 to 3.

[0115] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached together form p is 1 or 2.

[0116] In some embodiments, R 1 , R 2 and the N, S atom to which they are attached together form

[0117] In the compound represented by 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.

[0118] In some embodiments, X is O.

[0119] In the compound represented by 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.

[0120] 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.

[0121] In some embodiments, R d1 and R d2 are each independently selected from the group consisting of methyl and trifluoromethyl.

[0122] In some embodiments, 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 the same as each other.

[0123] In the compound represented by formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1) or (I-1b-2), R c1 and R c2 are each independently selected from the group consisting of H, C1-C4 alkyl and C1-C4 haloalkyl.

[0124] In some embodiments, Rc1 and R c2 are each independently selected from H and C1-C4 alkyl, and R c1 and R c2 are not the same as each other.

[0125] In some embodiments, R c1 and R c2 are each independently selected from H and methyl.

[0126] In some embodiments, R c1 and R c2 are each independently selected from H and methyl, and R c1 and R c2 are not the same as each other.

[0127] 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 e is H or D.

[0128] In some embodiments, R e is H.

[0129] In the compound of Formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), or (I-1b-2), L is -C(=O)NH-.

[0130] 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.

[0131] In the compound of Formula (I-1), (I-1a), (I-1a-1), (I-1a-2), (I-1b), (I-1b-1), or (I-1b-2), ring B is phenyl or 6-membered heteroaryl containing 1-2 N atoms.

[0132] In some embodiments, ring B is phenyl or pyridyl.

[0133] In some embodiments, ring B is phenyl.

[0134] 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 b1 , R b2 , R b3each independently selected from halogen, C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0135] In some embodiments, R b1 , R b2 , R b3 each independently selected from halogen, C1-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0136] In some embodiments, R b1 , R b2 , R b3 each independently selected from F, methoxy, deutero-methoxy, and halo-methoxy.

[0137] In some embodiments, R b1 , R b2 , R b3 each independently selected from F, methoxy, deutero-methoxy, and fluoro-methoxy.

[0138] In some embodiments, R b1 , R b2 , R b3 each independently selected from F, methoxy, -OCD3, and difluoro-methoxy.

[0139] In some embodiments, R b1 , R b2 is halogen, R b3 is selected from C1-C4alkoxy, C1-C4deuteroalkyl, and C1-C4haloalkoxy.

[0140] In some embodiments, R b1 , R b2 is halogen, R b3 is selected from C1-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0141] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, deutero-methoxy, and halo-methoxy.

[0142] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, deutero-methoxy, and fluoro-methoxy.

[0143] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, -OCD3, and difluoro-methoxy.

[0144] In some embodiments, R b1 , R b2 and R b3 are each independently selected from halogen and C1-C4alkoxy.

[0145] In some embodiments, R b1 , R b2 and R b3 are each independently selected from halogen and C1-C2alkoxy.

[0146] In some embodiments, R b1 , R b2 and R b3 are each independently selected from F and methoxy.

[0147] In some embodiments, R b1 and R b2 are halogen, and R b3 is C1-C4alkoxy.

[0148] In some embodiments, R b1 and R b2 are halogen, and R b3 is C1-C2alkoxy.

[0149] In some embodiments, R b1 and R b2 are F, and R b3 is methoxy.

[0150] 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:

[0151] In some specific embodiments, ring B is selected from

[0152] In some specific embodiments, ring B is

[0153] In some embodiments of the present application, the above-mentioned compound of formula (I-1) is further represented by formula (I-1c) or formula (I-1d):

[0154]

[0155] In the compound of formula (I-1c) or (I-1d), ring A is wherein represents the position at which ring A is attached to NH, and ring A is further attached to R a2 and connected; R a2 is selected from H, F and cyano.

[0156] In some embodiments, ring A is connected to the phenyl group at the position indicated below: a2 wherein R a2 is selected from H, F and cyano.

[0157] In some embodiments, ring A is connected to the phenyl group at the position indicated below: wherein R a2 is H.

[0158] In the compound of formula (I-1c) or (I-1d), 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 and -NR 12 R 13 ; R 12 , R 13 and the N atom to which they are attached together form a 4-7 membered heterocyclyl group, which is optionally substituted with 1-3 halogens.

[0159] In some embodiments, L 1 is -C(=0)-CH2-.

[0160] In some embodiments, L 1 is -C(=0)-.

[0161] In some embodiments, L 1 is

[0162] In some embodiments, L 1 is -C2H4-.

[0163] In some embodiments, R 11 is selected from -NH2, -OH and

[0164] In some embodiments, when L 1 is -C(=0)-CH2-, R 11 is selected from -NH2, -OH and ​

[0165] In some embodiments, when L 1 is -C(=O)-, R 11 is -NH2.

[0166] In some embodiments, when L 1 is -C2H4-, R 11 is -OH.

[0167] In some embodiments, when L 1 is -C2H4-, R 11 is -NH2.

[0168] In the compound represented by formula (I-1c) or (I-1d), R 2 is C1-C4 alkyl.

[0169] In some embodiments, R 2 is methyl.

[0170] In the compound represented by formula (I-1c) or (I-1d), 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 identical to each other.

[0171] In some embodiments, 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.

[0172] In some embodiments, R d1 is methyl, and R d2 is trifluoromethyl.

[0173] In some embodiments, R d1 is trifluoromethyl, and R d2 is methyl.

[0174] In the compound represented by formula (I-1c) or (I-1d), 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.

[0175] 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.

[0176] In some embodiments, R c1 is H, R c2 is methyl.

[0177] In some embodiments, R c1 is methyl, R c2 is H.

[0178] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen, C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0179] In some embodiments, R b1 , R b2 , R b3 are each independently selected from F, methoxy, -OCD3, and difluoromethoxy.

[0180] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, -OCD3, and difluoromethoxy.

[0181] In some embodiments of the present application, the compound of formula (I-1) above is further represented by formula (I-1e) or formula (I-1f):

[0182]

[0183] In some embodiments, W is CR a2 or N, wherein R a2 is selected from H, F, and cyano.

[0184] In some embodiments, R b3 is selected from methoxy, -OCD3, and difluoromethoxy.

[0185] In some embodiments, W is CH, R b3 is selected from methoxy, -OCD3, and difluoromethoxy.

[0186] In some embodiments, W is CF, R b3 is methoxy.

[0187] In some embodiments, W is C(CN), R b3 is methoxy.

[0188] In some embodiments, W is N, R b3 is selected from methoxy, -OCD3, and difluoromethoxy.

[0189] In some embodiments of the present application, the above-mentioned compound of formula (I-1e) is further represented by formula (I-1e-1) or formula (I-1e-2):

[0190]

[0191] In the compound of formula (I-1e-1) or (I-1e-2), W and R b3 are as defined in formula (I-1e).

[0192] In some embodiments of the present application, the above-mentioned compound of formula (I-1f) is further represented by formula (I-1f-1) or formula (I-1f-2):

[0193]

[0194] In the compound of formula (I-1f-1) or (I-1f-2), W and R b3 are as defined in formula (I-1f).

[0195] In particular, the present application provides a compound of formula (I-2):

[0196]

[0197] or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof.

[0198] In some embodiments of the present application, the above-mentioned compound of formula (I-2) is further represented by formula (I-2a) or formula (I-2b):

[0199]

[0200] In the compound of formula (I-2), (I-2a), or (I-2b), ring A is phenyl or a 6-membered heteroaryl, the heteroatom(s) of which is optionally oxidized.

[0201] In some embodiments, ring A is phenyl.

[0202] In some embodiments, ring A is a 6-membered heteroaryl containing 1-3 N atoms, and the N atom(s) is optionally oxidized.

[0203] In some embodiments, ring A is a 6-membered heteroaryl containing 1-2 N atoms, and the N atom(s) is optionally oxidized.

[0204] In some embodiments, ring A is a 6-membered heteroaryl, which is pyridyl and the N atom of the pyridyl is optionally oxidized.

[0205] 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.

[0206] 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 .

[0207] 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 .

[0208] 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 .

[0209] 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 independently optionally substituted with a group selected from halogen, hydroxyl and C1-C4 alkoxy.

[0210] 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 independently optionally substituted with a group selected from halogen, hydroxyl and C1-C2 alkoxy.

[0211] In some embodiments, R a2 is selected from H, D, halogen, cyano, C1-C2 alkyl and C1-C2 alkoxy.

[0212] In some embodiments, R a2 is selected from H, halogen and cyano.

[0213] In some embodiments, R a2Selected from H, F and cyano groups.

[0214] In some implementations, R a2 For H.

[0215] In some specific embodiments, when ring A is phenyl, R a2 Selected from H, F and cyano groups.

[0216] In some specific embodiments, when ring A is a 6-membered heteroaryl group (e.g., pyridyl or N-oxypyridyl), R a2 For H.

[0217] 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.

[0218] 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.

[0219] In some specific implementations, ring A is Pyridinyl or N-oxypyridinyl groups are attached to the positions shown below: Where R a2 For H.

[0220] 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 16 It is a natural or non-natural α-amino acid side chain; R 4 Selected from H and C1-C4 alkyl groups;

[0221] or, in the above compounds of 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 ;

[0222] R 15 is selected from C1-C4alkyl and C1-C4haloalkyl.

[0223] In some embodiments, R 3 is selected from -L 2 -R 14 and -CH(R 16 )-COOH; L 2 is selected from C1-C4alkylene and C4-C6cycloalkylene, R 14 is selected from -S(=O)2-R 15 , -S(=O)(=NH)R 15 , -COOH, -COOR 15 , cyano, C1-C4alkoxy and C1-C4alkyl, with the proviso that when L 2 is C1-C4alkylene, R 14 is not C1-C4alkoxy or C1-C4alkyl; R 16 is the side chain of a natural or unnatural alpha-amino acid; R 4 is selected from H and C1-C4alkyl;

[0224] 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 ;

[0225] R 15 is selected from C1-C4alkyl and C1-C4haloalkyl.

[0226] In some embodiments, R 3 is selected from -L 2 -R 14 and -CH(R 16 )-COOH; L2 Selected from C1-C4 alkylene and C4-C6 cycloalkylene, R 14 Selected from -S(=O)2-R 15 -S(=O)(=NH)R 15 -COOH and C1-C4 alkoxy groups; the condition is that when L 2 When it is a C1-C4 alkylene group, R 14 Not a C1-C4 alkoxy group; R 15 It is a C1-C4 alkyl group;

[0227] R 16 It is 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.

[0228] In some implementations, 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 and C1-C4 alkoxy groups; the condition is that when L 2 When it is a C1-C4 alkylene group, R 14 Not a C1-C4 alkoxy group; R 15 It is a C1-C4 alkyl group;

[0229] R 16 It is 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.

[0230] In some implementations, when L 2 When it is a C1-C4 alkylene group, R 14 Selected from -S(=O)2-R 15 -S(=O)(=NH)R 15 -COOH, -COOR 15 and cyano.

[0231] 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, and cyano.

[0232] 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 , and -COOH.

[0233] In some embodiments, when L 2 is -C2H4-, R 14 is selected from -S(=0)2CH3, -S(=0)(=NH)CH3, -COOH, and cyano.

[0234] In some embodiments, when L 2 is C1-C4 alkylene, R 14 is -S(=0)2-R 15 .

[0235] In some embodiments, when L 2 is -C2H4-, R 14 is -S(=0)2-CH3.

[0236] In some embodiments, when L 2 is C4-C6 cycloalkylene, R 14 is selected from -S(=0)2-R 15 , -S(=0)(=NH)R 15 , -COOH, -COOR 15 , cyano, C1-C4 alkoxy, and C1-C4 alkyl.

[0237] In some embodiments, when L 2 is C4-C6 cycloalkylene, R 14 is selected from -S(=0)2-R 15 , -S(=0)(=NH)R 15 , -COOH, -COOR 15 , cyano, and C1-C4 alkoxy.

[0238] In some embodiments, when L 2 is C4-C6 cycloalkylene, R 14 is selected from -S(=0)2-R 15 , and C1-C4 alkoxy.

[0239] In some embodiments, L 2 is In some embodiments, R 14 is -S(=O)2-CH3or -OCH3.

[0240] In some embodiments, L 2 is C1-C4alkylene.

[0241] In some embodiments, L 2 is C1-C3alkylene.

[0242] In some embodiments, L 2 is -C2H4- or -CH2-.

[0243] In some embodiments, L 2 is C4-C6cycloalkylene.

[0244] In some embodiments, L 2 is cyclobutane, cyclopentane or cyclohexane.

[0245] In some embodiments, L 2 is

[0246] In some embodiments, R 15 is selected from C1-C3alkyl and C1-C3haloalkyl.

[0247] In some embodiments, R 15 is selected from C1-C2alkyl and C1-C2haloalkyl.

[0248] In some embodiments, R 15 is selected from methyl and ethyl.

[0249] 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.

[0250] 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.

[0251] In some embodiments, R 14selected from -S(=0)2-(Ci-C4alkyl), -S(=0)(=NH)(Ci-C4alkyl), -COOH, -COO(Ci-C4alkyl), and cyano.

[0252] In some embodiments, R 14 selected from -S(=0)2-(Ci-C4alkyl), -S(=0)(=NH)(Ci-C4alkyl), -COOH, -COO(Ci-C4alkyl), and cyano.

[0253] In some embodiments, R 14 selected from -S(=0)2-(Ci-C2alkyl), -S(=0)(=NH)(Ci-C2alkyl), -COOH, -COO(Ci-C2alkyl), and cyano.

[0254] In some embodiments, R 14 selected from -S(=0)2-CH3, -S(=0)(=NH)CH3, -COOH, -COOCH3, and cyano.

[0255] In some embodiments, R 16 is a natural alpha-amino acid side chain.

[0256] In some embodiments, R 16 is a natural alpha-amino acid side chain that is in the L-form.

[0257] In some embodiments, R 16 is a natural alpha-amino acid side chain that is in the D-form.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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 In some embodiments, R

[0263] 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 .

[0264] In some embodiments, R 16 is selected from H, -CH2-OH, -CH2-CONH2, and

[0265] In some embodiments, R 16 is a hydrophilic natural alpha-amino acid side chain.

[0266] In some embodiments, R 16 is a hydrophilic natural alpha-amino acid side chain that is in the L-form.

[0267] In some embodiments, R 16 is a hydrophilic natural alpha-amino acid side chain that is in the D-form.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] In some embodiments, R 16 is a side chain of a non-natural α-amino acid.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] In some embodiments, R 16 is C1-C4 alkyl, said C1-C4 alkyl being optionally substituted with one or more -NH2, -COOH, -SH, -S-CH3, -C(=O)NH2, guanidino, phenyl, 4-7 membered heterocyclyl, or 5-10 membered heteroaryl, and R 16 the absolute configuration of the attached C atom is S-type.

[0280] 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,

[0281] In some embodiments, R 4 is selected from H and C1-C3 alkyl.

[0282] In some embodiments, R 4 is selected from H and C1-C2 alkyl.

[0283] In some embodiments, R 4 is selected from H and methyl.

[0284] In some embodiments, R 3 , R 4 together with 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 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.

[0285] In some embodiments, R 3 , R 4 together with the N atom to which they are attached form a 4-6 membered heterocyclyl, said heterocyclyl optionally further containing 1-2 heteroatoms selected from N, O and S and being 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.

[0286] 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.

[0287] 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.

[0288] In some embodiments, R 3 , R 4 and the N atom to which they are attached form the is each independently 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.

[0289] In some embodiments, R 3 , R 4 and the N atom to which they are attached form the is each independently substituted with a group selected from -S(=0)2-R 15 , -COOH and -COOR 15 ; R 15 is C1-C4 alkyl.

[0290] In some embodiments, R 3 , R 4 and the N atom to which they are attached form the is each independently substituted with a group selected from -S(=0)2-CH3, -COOH and -COOCH3.

[0291] In the compound represented by formula (I-2), (I-2a) or (I-2b), X is O or S.

[0292] In some embodiments, X is O.

[0293] 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.

[0294] 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.

[0295] In some embodiments, R d1 , R d2 are each independently selected from the group consisting of methyl and trifluoromethyl.

[0296] 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.

[0297] 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.

[0298] 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.

[0299] In some embodiments, R c1 , R c2 are each independently selected from the group consisting of H and methyl.

[0300] 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.

[0301] In the compound represented by formula (I-2), (I-2a) or (I-2b), R e is H or D.

[0302] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is: e H.

[0303] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is:

[0304] In some embodiments, L in Formula (I-2), (I-2a), or (I-2b) connects ring A through a N atom.

[0305] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is:

[0306] In some embodiments, ring B is phenyl or pyridyl.

[0307] In some embodiments, ring B is phenyl.

[0308] 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.

[0309] 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-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0310] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is: b1 , R b2 , R b3 each independently selected from F, methoxy, deutero-methoxy, and halo-methoxy.

[0311] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is: b1 , R b2 , R b3 each independently selected from F, methoxy, deutero-methoxy, and halo-methoxy.

[0312] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is: b1 , R b2 , R b3 each independently selected from F, methoxy, -OCD3, and difluoromethoxy.

[0313] In some embodiments, the compound of Formula (I-2), (I-2a), or (I-2b) is: b1 , R b2 is halogen, Rb3 selected from C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0314] In some embodiments, R b1 , R b2 is halogen, R b3 is selected from C1-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0315] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, deutero-methoxy, and halo-methoxy.

[0316] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, deutero-methoxy, and fluoro-methoxy.

[0317] In some embodiments, R b1 , R b2 is F, R b3 is selected from methoxy, -OCD3, and difluoro-methoxy.

[0318] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen and C1-C4alkoxy.

[0319] In some embodiments, R b1 , R b2 , R b3 are each independently selected from halogen and C1-C2alkoxy.

[0320] In some embodiments, R b1 , R b2 , R b3 are each independently selected from F and methoxy.

[0321] In some embodiments, R b1 , R b2 is halogen, R b3 is C1-C4alkoxy.

[0322] In some embodiments, R b1 , R b2 is halogen, R b3 is C1-C2alkoxy.

[0323] In some embodiments, R b1 , R b2 is F, Rb3 It is a methoxy group.

[0324] In some specific implementations, ring B is R. b1 R b2 and R b3 The phenyl groups are connected to the following positions respectively:

[0325] In some specific implementations, ring B is selected from...

[0326] In some specific implementations, ring B is

[0327] Specifically, the present invention provides a compound as shown in formula (I-3):

[0328]

[0329] Or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug.

[0330] In some embodiments of the present invention, the compounds of formula (I-3) are further shown as in formula (I-3a) or formula (I-3b):

[0331]

[0332] 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.

[0333] In some embodiments, ring A is a phenyl group.

[0334] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-3 N atoms, and the N atoms are optionally oxidized.

[0335] In some embodiments, ring A is a 6-membered heteroaryl group containing 1-2 N atoms, and the N atoms are optionally oxidized.

[0336] 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.

[0337] 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.

[0338] In some implementations, ring A is wherein represents the site of attachment of ring A to L, and ring A is also attached to R a2 and .

[0339] In some embodiments, ring A is wherein represents the site of attachment of ring A to L, and ring A is also attached to R a2 and .

[0340] In the compounds of formula (I-3), (I-3a) or (I-3b) above, 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), 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.

[0341] 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).

[0342] In some embodiments, R a2 is selected from H, D, halogen, cyano, C1-C2 alkyl, and C1-C2 alkoxy.

[0343] In some embodiments, R a2 is selected from H, halogen, and cyano.

[0344] In some embodiments, R a2 is selected from H, F, and cyano.

[0345] In some specific embodiments, when ring A is phenyl, R a2 is selected from H, F, and cyano.

[0346] In some specific embodiments, when ring A is a 6-membered heteroaryl (e.g., pyridyl or N-oxidized pyridyl), R a2 is H.

[0347] In some specific embodiments, when ring A is , R a2 is H, wherein represents the site of attachment of ring A to L, and ring A is also attached to .

[0348] In some embodiments, ring A is and R a2 is phenyl attached to the indicated position: wherein R a2 is selected from H, F, and cyano.

[0349] In some embodiments, ring A is is pyridyl or N-oxypyridyl attached to the indicated position: wherein R a2 is H.

[0350] 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.

[0351] In some embodiments, R 5 , R 6 are each independently selected from C1-C3 alkyl and C1-C3 haloalkyl.

[0352] In some embodiments, R 5 , R 6 are each independently selected from C1-C2 alkyl and C1-C2 haloalkyl.

[0353] In some embodiments, R 5 , R 6 are each independently C1-C4 alkyl.

[0354] In some embodiments, R 5 , R 6 are each independently C1-C2 alkyl.

[0355] In some embodiments, R 5 , R 6 are each independently selected from methyl and ethyl.

[0356] In some embodiments, R 5 and R 6 are each methyl or ethyl.

[0357] In some embodiments, R 5 and R 6 are each methyl.

[0358] In the compound of formula (I-3), (I-3a), or (I-3b), X is O or S.

[0359] In some embodiments, X is O.

[0360] In the compound represented by formula (I-3), (I-3a), or (I-3b), R d1 , R d2 each is independently selected from the group consisting of C1-C4 alkyl and C1-C4 haloalkyl.

[0361] In some embodiments, R d1 , R d2 each is 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.

[0362] In some embodiments, R d1 , R d2 each is independently selected from the group consisting of methyl and trifluoromethyl.

[0363] In some embodiments, R d1 , R d2 each is independently selected from the group consisting of methyl and trifluoromethyl, and R d1 and R d2 are not the same as each other.

[0364] In the compound represented by formula (I-3), (I-3a), or (I-3b), R c1 , R c2 each is independently selected from the group consisting of H, C1-C4 alkyl, and C1-C4 haloalkyl.

[0365] In some embodiments, R c1 , R c2 each is 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.

[0366] In some embodiments, R c1 , R c2 each is independently selected from the group consisting of H and methyl.

[0367] In some embodiments, R c1 , R c2 each is independently selected from the group consisting of H and methyl, and R c1 and R c2 are not the same as each other.

[0368] In the compound represented by formula (I-3), (I-3a), or (I-3b), R e is H or D.

[0369] In the compound represented by formula (I-3), (I-3a), or (I-3b), R e is H.

[0370] In the compound represented by formula (I-3), (I-3a), or (I-3b), L is -CONH-.

[0371] In some embodiments, L in formula (I-3), (I-3a), or (I-3b) connects ring A through a N atom.

[0372] In the compound represented by formula (I-3), (I-3a), or (I-3b), ring B is phenyl or 6-membered heteroaryl containing 1-2 N atoms.

[0373] In some embodiments, ring B is phenyl or pyridyl.

[0374] In some embodiments, ring B is phenyl.

[0375] In the compound represented by formula (I-3), (I-3a), or (I-3b), R b1 , R b2 , R b3 are each independently selected from the group consisting of halogen, C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0376] In some embodiments, R b1 , R b2 , R b3 are each independently selected from the group consisting of halogen, C1-C2alkoxy, C1-C2deuteroalkoxy, and C1-C2haloalkoxy.

[0377] In some embodiments, R b1 , R b2 , R b3 are each independently selected from the group consisting of F, methoxy, deutero-methoxy, and halo-methoxy.

[0378] In some embodiments, R b1 , R b2 , R b3 are each independently selected from the group consisting of F, methoxy, deutero-methoxy, and fluoro-methoxy.

[0379] In some embodiments, R b1 , R b2 , R b3 are each independently selected from the group consisting of F, methoxy, -OCD3, and difluoromethoxy.

[0380] In some embodiments, R b1 , R b2 is halogen, and R b3 is selected from the group consisting of C1-C4alkoxy, C1-C4deuteroalkoxy, and C1-C4haloalkoxy.

[0381] In some embodiments, Rb1 R b2 For halogens, R b3 It is selected from C1-C2 alkoxy, C1-C2 deuterated alkoxy and C1-C2 haloalkoxy.

[0382] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and halomethoxy.

[0383] In some implementations, R b1 R b2 For F, R b3 It is selected from methoxy, deuterated methoxy and fluoromethoxy.

[0384] In some implementations, R b1 R b2 For F, R b3 Selected from methoxy, -OCD3 and difluoromethoxy.

[0385] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens and C1-C4 alkoxy groups.

[0386] In some implementations, R b1 R b2 R b3 Each is independently selected from halogens and C1-C2 alkoxy groups.

[0387] In some implementations, R b1 R b2 R b3 Each is independently selected from F and methoxy groups.

[0388] In some implementations, R b1 R b2 For halogens, R b3 It is a C1-C4 alkoxy group.

[0389] In some implementations, R b1 R b2 For halogens, R b3 It is a C1-C2 alkoxy group.

[0390] In some implementations, R b1 R b2 For F, R b3 It is a methoxy group.

[0391] In some specific implementations, ring B is R. b1 R b2and R b3 phenyl attached at the position shown below:

[0392] In some embodiments, ring B is selected from

[0393] In some embodiments, ring B is

[0394] In some embodiments, the present application relates to a compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof. In other embodiments, the present application relates to a compound selected from the compounds of Table 1 in a non-salt form (e.g., stereoisomer, tautomer, solvate, isotopically labeled, or prodrug).

[0395] Table 1 Compound Structures and Names

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404] In a second aspect, the present application provides a pharmaceutical composition containing a compound of the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled, or prodrug thereof.

[0405] In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient.

[0406] In some embodiments, the pharmaceutically acceptable excipient (or excipient) includes, but is not limited to, fillers, disintegrants, surfactants, solubilizers, lubricants, wetting agents, thickening agents, glidants, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, and light shielding agents, etc.

[0407] In a third aspect, the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled version or prodrug thereof, or the pharmaceutical composition of the second aspect can be administered by any of the known modes, such as orally, topically, rectally, parenterally, by inhalation, or by implant.

[0408] Therefore, the present application also provides a pharmaceutical preparation made of the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled version or prodrug thereof, or the pharmaceutical composition of the second aspect.

[0409] 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.

[0410] In a fourth aspect, the present application provides a use of the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled version or prodrug thereof, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect in medicine.

[0411] The present application provides a use of the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled version or prodrug thereof, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect in the preparation of a medicament for inhibiting voltage-gated sodium channels.

[0412] The present application provides a use of the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled version or prodrug thereof, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect in the preparation of a medicament for preventing, alleviating and / or treating a disease or disorder associated with voltage-gated sodium channels.

[0413] The present application provides a use of the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled version or prodrug thereof, or the pharmaceutical composition of the second aspect, or the pharmaceutical preparation of the third aspect in the preparation of a medicament for preventing, alleviating and / or treating pain.

[0414] The present application provides the compound of the first aspect or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically labeled version or prodrug thereof, 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).

[0415] The present application provides a compound as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled, or prodrug thereof, or a pharmaceutical composition as described in the second aspect, or a pharmaceutical preparation as described in the third aspect, for use in preventing, alleviating and / or treating a voltage-gated sodium channel-related disease or disorder.

[0416] The present application provides a compound as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled, or prodrug thereof, or a pharmaceutical composition as described in the second aspect, or a pharmaceutical preparation as described in the third aspect, for use in preventing, alleviating and / or treating pain.

[0417] The present application 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 as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled, or prodrug thereof, or a pharmaceutical composition as described in the second aspect, or a pharmaceutical preparation as described in the third aspect.

[0418] The present application 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 as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled, or prodrug thereof, or a pharmaceutical composition as described in the second aspect, or a pharmaceutical preparation as described in the third aspect.

[0419] The present application 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 as described in the first aspect, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotopically-labeled, or prodrug thereof, or a pharmaceutical composition as described in the second aspect, or a pharmaceutical preparation as described in the third aspect.

[0420] In some embodiments, the voltage-gated sodium channel described in the present application is Na v 1.8.

[0421] In some embodiments, the voltage-gated sodium channel-related disease or disorder described in the application includes, but is not limited to, pain, arthritis, epilepsy or seizure 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, cardiac palpitations, hypertension, multiple sclerosis, Charcot-Marie-Tooth syndrome, distal spinal muscular atrophy, incontinence, pathological cough, arrhythmia, and abnormal gastrointestinal motility, among others.

[0422] In some embodiments, the pain described in the application 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.

[0423] In some embodiments, the acute pain described in the application includes, but is not limited to, acute postoperative pain.

[0424] In some embodiments, the intestinal pain described in the application includes, but is not limited to, inflammatory bowel disease pain and Crohn's disease pain.

[0425] In some embodiments, the neuropathic pain described in the application includes, but is not limited to, central neuropathic postherpetic neuralgia, diabetic neuropathic pain, painful HIV-associated sensory neuropathy, trigeminal neuralgia, neuropathic pain due to causalgia, post-amputation pain, phantom limb pain, neuropathic pain due to painful neuromas, neuropathic pain due to traumatic neuromas, neuropathic pain due to Morton's neuroma, neuropathic pain due to entrapment injuries, neuropathic pain due to spinal stenosis, neuropathic pain due to carpal tunnel syndrome, radicular pain, sciatica, neuropathic pain due to nerve avulsion injuries, neuropathic pain due to brachial plexus avulsion injuries, neuropathic pain due to complex regional pain syndrome, neuropathic pain due to drug therapy, neuropathic pain due to cancer chemotherapy, neuropathic pain due to antiretroviral therapy, post-spinal cord injury pain, neuropathic pain due to small-fiber neuropathy, neuropathic pain due to idiopathic small-fiber neuropathy, neuropathic pain due to idiopathic sensory neuropathy, and neuropathic pain due to trigeminal autonomic neuropathy.

[0426] In some embodiments, the musculoskeletal pain described in the application includes, but is not limited to, osteoarthritic pain, back pain, cold pain, burning pain, and dental pain.

[0427] In some embodiments, the inflammatory pain described in the application includes, but is not limited to, rheumatoid arthritis pain, vulvodynia pain, and interstitial cystitis pain.

[0428] In some embodiments, the idiopathic pain described in the present application includes, but is not limited to, fibromyalgia.

[0429] In some embodiments, the postoperative pain described in the present application includes, but is not limited to, bunionectomy pain, herniorrhaphy pain, and abdominoplasty pain.

[0430] In some embodiments, the visceral pain described in the present application includes, but is not limited to, acute abdominal pain, intratumoral visceral pain, angina pectoris, and visceral pain caused by abdominoplasty.

[0431] Effects of the invention

[0432] The heterocyclic compound provided by the present application can be used as a voltage-gated sodium channel inhibitor, which has excellent inhibitory effect 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 has a good application prospect. v 1.8) and can be used for preventing, alleviating, and / or treating pain and other related diseases, and has a good application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0433] Figure 1 The test results of the compound of the present application in the SNI pharmacodynamic model are shown. DETAILED DESCRIPTION

[0434] Various exemplary embodiments, features, and aspects of the present application 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.

[0435] In addition, in order to better illustrate the present application, numerous specific details are given in the following detailed description. Those skilled in the art will understand that the present application can be practiced without certain specific details. In some instances, well-known methods, means, instruments, and steps have not been described in detail in order to highlight the principles of the present application.

[0436] Unless otherwise specified, the units used in the present specification are international standard units, and the numerical values and numerical value ranges appearing in the present application should be understood to include systematic errors that are inevitable in industrial production.

[0437] 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.

[0438] In this specification, reference to "some embodiments", "other embodiments", "an embodiment", "embodiments" etc. means that a particular feature, structure, property, characteristic etc. being described is included in at least one embodiment of the application, and can or can not be present in other embodiments. In addition, it is to be understood that such features, structures, properties, characteristics etc. can be included in various combinations in various embodiments.

[0439] Explanation of terms

[0440] In this specification, a numerical range expressed using "numerical value A ~ numerical value B" means a range including the end point numerical values A, B.

[0441] In this specification, when "ordinary temperature" or "room temperature" is used, the temperature thereof can be 15°C to 30°C, further 15°C to 25°C, for example, 20°C.

[0442] As used herein, the term "compound of the application" 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 application" 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.

[0443] As used herein, the term "D" refers to a deuterium atom.

[0444] As used herein, the term "deuterated" refers to one or more hydrogen atoms in a defined group being replaced by a deuterium atom.

[0445] As used herein, the term "halogen" refers to F, Cl, Br, or I.

[0446] As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group consisting solely of carbon and hydrogen atoms, having the number of carbon atoms designated, and which is attached to the rest of the molecule by a single bond.

[0447] As used herein, the term "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms is replaced by a halogen, the "halogen", "alkyl" having the definition as above.

[0448] As used herein, the term "alkylene" refers to a divalent alkyl group, the "alkyl" having the definition as above, attached to the rest of the molecule or other group via two single bonds or one double bond, the 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".

[0449] As used herein, the term "alkoxy" refers to a group of the formula -OR, wherein R is an alkyl group having the number of carbon atoms designated, the "alkyl" having the definition as above.

[0450] 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, the "halogen", "alkoxy" having the definition as above.

[0451] As used herein, the term "cycloalkyl" refers to a non-aromatic, monocyclic or bicyclic (fused, bridged or spirocyclic) saturated hydrocarbon group consisting solely of carbon and hydrogen atoms, having the number of ring-forming atoms designated, which is attached to the rest of the molecule by a single bond through a ring-forming carbon atom. For the purposes of the present invention, "cycloalkyl" is preferably a monocyclic saturated hydrocarbon group.

[0452] 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, the "halogen", "cycloalkyl" having the definition as above.

[0453] 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 number of ring-forming atoms designated, which ring-forming atoms consist 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 by oxo, and which is attached to the rest of the molecule by a single bond through a ring-forming carbon atom or a ring-forming heteroatom. For the purposes of the present invention, heterocyclyl is preferably a non-aromatic, monocyclic saturated or unsaturated ring group.

[0454] As used herein, the term "cycloalkyl" refers to a saturated, monovalent, monocyclic hydrocarbon ring radical having the number of carbon atoms designated and having a single ring (i.e., 3 to 6 carbon atoms for C3-C6cycloalkyl). For example, All conform to the definition of "cycloalkyl" as described above.

[0455] As used herein, the term "heteroaryl" refers to an aromatic, monocyclic or bicyclic or polycyclic, fused unsaturated cyclic radical containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur as ring-forming atoms.

[0456] The numerical designations before the above "alkyl", "haloalkyl", "alkylene", "alkoxy", "cycloalkyl", "halocycloalkyl", and "cycloalkylene" groups, such as "C1-C4", "C3-C6", refer to the range of the number of carbon atoms that the defined group can contain.

[0457] The numerical designations before the above "heterocyclyl", "heteroaryl" groups, and the like, such as "4-7 membered", "6-10 membered", refer to the range of the number of ring-forming atoms that the defined group can contain.

[0458] As used herein, the term "optionally" means that an event, either described after the term or not, 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.

[0459] As used herein, the term "alpha-amino acid" means 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 "alpha-amino acid side chain" means 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.

[0460] As used herein, the term "pharmaceutically acceptable salt" means a salt that is not physiologically undesirable, irritating, or causes an allergic reaction. The substance used for salt formation can be an acid or a base, wherein the acid includes an inorganic acid or an organic acid, which can form a salt with a basic group in the compound of the present application; the base includes an inorganic base or an organic base, which can form a salt with an acidic group in the compound of the present application.

[0461] Unless otherwise specified, all compounds of the application encompass all possible stereoisomers and tautomers (e.g., enol and keto forms) of the compounds of the present application. Stereoisomers in the present application include optical isomers (e.g., enantiomers, diastereomers, epimers), cis- and trans-isomers (e.g., Z- and E-isomers), conformational isomers. In addition, single stereoisomers or tautomers, as well as mixtures of stereoisomers and tautomers are within the scope of the present application.

[0462] As used herein, in any chemical structure or formula, a bold or hashed wedge-shaped bond (respectively ), connected to a stereocenter of a compound, such as in , represents the absolute stereochemistry of the stereocenter, and the relative stereochemistry of the stereocenter relative to other stereocenters connected by the bold or hashed wedge-shaped bond.

[0463] As used herein, the term "optical isomer" refers to a stable isomer capable of rotating the plane of polarized light due to having at least one chiral element (including chiral centers, chiral axes, chiral faces, etc.) that results in a non-superimposable mirror image. Because of the presence of asymmetric centers in the compounds of the present application that can lead to stereoisomers, as well as other chemical structures, the present application also includes these stereoisomers and mixtures thereof. Because the compounds of the present application 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 one another. The term "diastereomeric" or "diastereomer" refers to optical isomers that are not mirror images of one another. The term "racemic mixture" or "racemate" refers to a mixture containing equal amounts of a single pair of enantiomeric isomers (i.e., an equimolar mixture of two R and S enantiomers).

[0464] 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 application are within the scope of the present application.

[0465] As used herein, the term "conformational isomer" also known 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 application are within the scope of the present application.

[0466] As used herein, the term "tautomer" also referred to as "tautomeric form," refers to structural isomers that have different energies and can interconvert by a low energy barrier. If tautomerization is possible (e.g., in solution), a chemical equilibrium of the tautomers can be achieved. For example, prototropic tautomers (or proton-shift tautomers) include, but are not limited to, interconversions by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imidol isomerization, and the like. Unless otherwise specified, all tautomeric forms of the compounds of the application are within the scope of the application.

[0467] As used herein, the term "solvate" refers to a molecular complex of a compound of the application or a pharmaceutically acceptable salt thereof with one or more solvent molecules. 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.

[0468] As used herein, the term "isotopically-labeled" refers to compounds formed by replacing a specific atom in the structure with an isotopic atom thereof. Unless otherwise specified, all isotopes of H, C, N, O, F, P, S, CI, 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 CI.

[0469] 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 application. Particularly preferred are derivative compounds or prodrugs that, when administered to a patient, increase the bioavailability of a compound of the application (e.g., are more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise specified, all prodrug forms of the compounds of the application are within the scope of the application, and various prodrug forms are well known in the art.

[0470] The present application further provides methods for preparing specific compounds. Unless otherwise specified, the compounds, reagents, and the like used in the examples of the present application are purchased from qualified suppliers or synthesized according to methods disclosed in the prior art.

[0471] Abbreviations

[0472] The following abbreviations in the present specification shall have the following meanings unless otherwise specified or made clear from the context:

[0473]

[0474] Examples

[0475] Embodiments of the present application will now be described in detail in the following Examples, but a person skilled in the art will understand that the following Examples are for illustration of the present application only and should not be construed as limiting the scope of the present application. Where specific conditions are not mentioned in the Examples, they are carried out under conventional conditions or conditions recommended by the manufacturer. Where the manufacturer of the reagent or instrument is not mentioned, it is a conventional product that can be obtained commercially. Known starting materials of the present application can be used or synthesized according to methods known in the art, or are commercially available.

[0476] The structure of the compound is determined by nuclear magnetic resonance or / and mass spectrometry. NMR chemical shifts (δ) are given in units of 10 -6 (ppm). NMR is measured with a BRUKER AVANCE NEO 400mHz nuclear magnetic instrument, and the measurement solvent is DMSO-d6, CDCl3, CD3OD, and the internal standard is TMS. MS is measured with Agilent 1260 / G6125C.

[0477] HPLC analysis uses Agilent 1260II. Chiral HPLC analysis measurement uses Shimadzu LC-20AT and Thermo UltiMate 3000.

[0478] Example 1. Synthesis of (2R,3S,4S,5R)-N-(3-(N-(2-aminoacetyl)-S-methylsulfϊnimidyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 1)

[0479]

[0480] 1.11 Synthesis of 1-(S-methylsulfϊnimidyl)-3-nitrobenzene (Compound 1-2)

[0481] To a solution of 3-nitrothiophene (compound 1-1, 6.58 g, 38.88 mmol) in methanol (100 mL) was added ammonium carbonate (5.66 g, 58.27 mmol) and iodobenzene diacetate (25.00 g, 77.72 mmol) and stirred at room temperature for 5 h. The reaction mixture was concentrated to dryness, then dichloromethane (100 mL) was added, stirred and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 10 / 1, v / v) and concentrated to give a yellow solid, which was compound 1-2 (6.3 g, yield 80.97%).

[0482] 1.2 (2-((methyl(3-nitrophenyl)(oxo)-λ 6 Synthesis of tert-butyl (2-((methyl(3-nitrophenyl)(oxo)-λ

[0483] To a solution of 1-(S-methylsulfonimidoyl)-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), saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-heptane / ethyl acetate = 2 / 1, v / v) and concentrated to give a yellow oil, which was compound 1-3 (1.03 g, yield: 96.26%).

[0484] LC-MS m / z (ESI): 356.09 [M-H] - .

[0485] 1.3 intermediate (tert-butyl (2-((methyl(3-aminophenyl)(oxo)-λ 6 Synthesis of tert-butyl (2-((methyl(3-aminophenyl)(oxo)-λ

[0486] To a solution of tert-butyl (2-((methyl(3-nitrophenyl)(oxo)-λ 6 - sulfonimidoyl)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, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to give a yellow solid, which was compound 1-4 (380 mg, yield: 83.15%).

[0487] 1.4 Synthesis of 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)-2-oxoethyl)carbamate (Compound 1-6)

[0488] (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 reaction was protected by nitrogen. The reaction was cooled to 0 °C. Oxalyl chloride (86 mg, 0.68 mmol) was added dropwise, and the reaction was allowed to warm to room temperature and react for 1 h. The reaction 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-amino phenyl)(methyl)(oxo)-lambda 6 - sulfinyl)amino)-2-oxoethyl)carbamate (Compound 1-6)

[0489] LC-MS m / z (ESI): 662.20 [M-H] - .

[0490] 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)

[0491] (2-(((3-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamido)phenyl)(methyl)(oxo)-lambda 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 combined organic phase was 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%).

[0492] LC-MS m / z (ESI): 562.14 [M-H] - .

[0493] 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).

[0494] 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).

[0495] Example 2. Synthesis of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(3-(N-(2-(3, 3-difluoroazetidin-1-yl)acetyl)-S-methylsulfmylimino)phenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 2)

[0496]

[0497] 2.1 Synthesis of 2-chloro-N-(methyl(3-nitrophenyl)(oxo)-lambda 6 -sulfenyl)acetamide (Compound 2-1)

[0498] 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), 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. TLC detection showed that the reaction was complete, water (20 mL) was added to terminate the reaction, the organic phase was separated, 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%).

[0499] LC-MS m / z (ESI): 274.9 [M-H] - .

[0500] 2.2 Synthesis of 2-(3, 3-difluoroazetidin-1-yl)-N-(methyl(3-nitrophenyl)(oxo)-lambda 6 -sulfenyl)acetamide (Compound 2-2)

[0501] 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), K2CO3 (233 mg, 1.8 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. The reaction solution was added to 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, and concentrated under reduced pressure to obtain an oil, which was Compound 2-2 (244 mg, yield: 81.0%).

[0502] LC-MS m / z (ESI): 378.05 [M+HCOO] + .

[0503] 2.3N-((3-aminophenyl)(methyl)(oxo)-λ 6 - sulfinyl)acetamide (compound 2-2, 244 mg, 0.73 mmol), hydrazine hydrate (352 mg, 11.0 mmol) and Raney nickel (24 mg) were added into methanol (10 mL), warmed to 70 °C for 2 hours, filtered hot, concentrated under reduced pressure to get an oil, which was compound 2-3 (180 mg, yield: 81.0%), crude was used directly for next step.

[0504] 2.3N-((3-aminophenyl)(methyl)(oxo)-λ 6 - sulfinyl)acetamide (compound 2-2, 244 mg, 0.73 mmol), hydrazine hydrate (352 mg, 11.0 mmol) and Raney nickel (24 mg) were added into methanol (10 mL), warmed to 70 °C for 2 hours, filtered hot, concentrated under reduced pressure to get an oil, which was compound 2-3 (180 mg, yield: 81.0%), crude was used directly for next step.

[0505] 2.4 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-(2-(3,3- difluoroazetidin-1-yl)acetyl)-S-methylsulfinimidoyl)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 2)

[0506] (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 chloride (5 mL). Warmed to 80 °C under nitrogen protection, refluxed for 2 hours, concentrated under reduced pressure, dissolved in tetrahydrofuran (3 mL) for standby.

[0507] 2.3N-((3-aminophenyl)(methyl)(oxo)-λ 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), 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), 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: 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 a white solid, i.e., compound 2 (113.62 mg, yield: 44.96%).

[0508] LC-MS m / z (ESI): 640.16 [M+H] + .

[0509] 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).

[0510] Compound 2 (86 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: CO2; mobile phase B: MeOH; gradient ratio: 20% v / v mobile phase B; flow rate: 140 mL / min) to obtain compound 2-a (38 mg, RT = 2.3 min) and compound 2-b (27 mg, RT = 3.0 min).

[0511] Compound 2-a:

[0512] LC-MS m / z (ESI): 640.1 [M+H] + .

[0513] 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).

[0514] Compound 2-b:

[0515] LC-MS m / z (ESI): 640.1 [M+H] + .

[0516] 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).

[0517] Example 3. Synthesis of (2R,3S,4S,5R)-N-(3-(N-cyano-S-methylsulfϊnimido)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 3)

[0518]

[0519] 3.1 Synthesis of N-(methyl(3-nitrophenyl)(carbonyl)-lambda 6 -sulfanylidenyl)cyanoamide (Compound 3-1)

[0520] (1-(S-methylsulfinimide)-3-nitrobenzene (compound 1-2, 750 mg, 3.74 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 °C, and DMAP (549 mg, 4.49 mmol) and cyanogen bromide (595 mg, 5.62 mmol) were added to the reaction solution. The mixture was heated to room temperature and stirred for 2 h. The reaction was confirmed to be complete by TLC. Saturated ammonium chloride solution (20 mL) and dichloromethane (100 mL) were added, and the mixture was stirred and separated. The organic phase was separated and washed successively with saturated brine (50 mL) and water (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a pale yellow oil, namely compound 3-1 (640 mg, yield: 75.9%). The crude product was used directly in the next reaction.

[0521] LC-MSm / z(ESI): 224.01 [MH] - .

[0522] 3,2N-((3-aminophenyl)(methyl)(carbonyl)-λ 6 Synthesis of 3-thionyl)cyanoamide (compound 3-2)

[0523] N-(methyl(3-nitrophenyl)(carbonyl)-λ 6 (-thionyl)cyanoamide (compound 3-1, 640 mg, 2.84 mmol) was dissolved in ethanol (15 mL) and water (5 mL), and Fe powder (796 mg, 14.20 mmol) and ammonium chloride (1520 mg, 28.40 mmol) were added. The mixture was heated to 80 °C and refluxed for 4 h. The reaction was completed by TLC. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (eluent: dichloromethane / methanol = 80 / 1~20 / 1, v / v) to give a pale yellow oil, namely compound 3-2 (540 mg, yield: 97.3%).

[0524] LC-MSm / z(ESI): 240.04 [M+HCOO] + .

[0525] Synthesis of 3,3(2R,3S,4S,5R)-N-(3-(N-cyano-S-methylsulfinimide)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 3)

[0526] (2R,3S,4S,5R)-4,5-Dimethyl-5-trifluoromethyl-3-(3,4-difluoro-2-methoxyphenyl)- tetrahydrofuran-2-carboxylic acid (Compound 1-5, 100 mg, 0.28 mmol) was dissolved in dichloromethane (5 mL), DMF (20 mg) was added, and oxalyl chloride (106 mg, 0.84 mmol) was added to the reaction solution. The solution was stirred at 40 °C for 1 h, and the solvent was removed under reduced pressure. The resulting solution was dissolved in dichloromethane (3 mL) and used as is. 6 -((3-aminophenyl)(methyl)(carbonyl)-λ 6 -((3-aminophenyl)(methyl)(carbonyl)-λ

[0527] LC-MS m / z (ESI): 531.99 [M+H] + .

[0528] 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).

[0529] 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: CO2; 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).

[0530] Compound 3-a:

[0531] LC-MS m / z (ESI): 532.1 [M+H] + .

[0532] 1 H NMR (400 MHz, MeOD) d 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).

[0533] Compound 3-b:

[0534] LC-MS m / z (ESI): 532.1 [M+H] + .

[0535] 1 H NMR (400 MHz, MeOD) d 8.44 (t, J = 2.0 Hz, 1H), 8.00 - 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).

[0536] Example 4. Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-(2-aminoethyl)-S- methylsulfinimidoyl)phenyl)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 4)

[0537]

[0538] 4.1 Synthesis of tert-butyl (2-((methyl(3-nitrophenyl)(oxo)-lambda 6 - sulfinyl)amino)ethyl)carbamate (Compound 4-1)

[0539] Tert-butyl (2-((methyl(3-nitrophenyl)(oxo)-lambda 6 - sulfinyl)amino)-2-oxoethyl)carbamate (Compound 1-3, 589 mg, 1.65 mmol) was dissolved in tetrahydrofuran (10 mL), and the solution was cooled to 0 °C in an ice water bath. Borane tetrahydrofuran (6 mL, 1 mol / L) was added dropwise slowly. After the dropwise addition was completed, the reaction was stirred at room temperature for 4 h. TLC detection showed that the reaction was complete. The reaction was terminated by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was combined and dried over anhydrous sodium sulfate. The oil obtained after concentration under reduced pressure was Compound 4-1 (230 mg, yield: 40.6%). The crude product was directly used in the next reaction.

[0540] 4.2 Synthesis of tert-butyl (2-(((3-aminophenyl)(methyl)(oxo)-lambda 6 - sulfinyl)amino)ethyl)carbamate (Compound 4-2)

[0541] Tert-butyl (2-((methyl(3-nitrophenyl)(oxo)-lambda 6 - sulfinyl)amino)ethyl)carbamate (Compound 4-1, 230 mg, 0.65 mmol) was added to methanol (10 mL) and stirred to dissolve. Raney nickel (23 mg) and hydrazine hydrate (312 mg, 9.75 mmol) were added. The reaction was stirred at 70 °C for 2 h. TLC detection showed that the reaction was complete. The nickel powder was removed by filtration. Concentration under reduced pressure gave Compound 4-2 (200 mg, yield: 95.27%) as an oil. The crude product was directly used in the next reaction.

[0542] LC-MS m / z (ESI): 358.14 [M+HCOO] + .

[0543] 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 Synthesis of 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

[0544] (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 added into sulfurous chloride (5 mL), and the reaction was warmed to 80 °C and refluxed for 2 h, concentrated under reduced pressure, and dissolved in tetrahydrofuran (3 mL) for use. tert-butyl(2-(((3-aminophenyl)(methyl)(oxo)-lambda 6 Synthesis of 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

[0545] LC-MS m / z (ESI): 648.21 [M-H] - .

[0546] 4.4 Synthesis of (2R,3S,4S,5R)-N-(3-(N-(2-aminoethyl)-S-methylsulfinimidoyl)phenyl)- 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (compound 4)

[0547] Synthesis of 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(Compound 4-3, 90 mg, 0.14 mmol) was dissolved in 1,4-dioxane (5 mL), 1,4-dioxane hydrogen chloride (4 M) (5 mL) was added dropwise slowly with stirring, stirred at room temperature overnight, 10% sodium carbonate solution was added dropwise to pH 9-10, 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: Phenomenex Luna5μm C18(2), 110 A, 150*21.2mm; 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%).

[0548] LC-MS m / z (ESI): 550.18 [M+H] + .

[0549] 1 H 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).

[0550] Compound 4 (16 mg) was resolved by chiral SFC (Waters PrepSFC 150Mgm; column: Daicel ChiralPak IH, 40 mm I.D. x 250 mm, 10 μm; 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 obtain compound 4-a (5 mg, RT = 3.8 min) and compound 4-b (8 mg, RT = 5.0 min).

[0551] Compound 4-a:

[0552] LC-MS m / z (ESI): 550.1 [M+H] + .

[0553] 1H 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).

[0554] Compound 4-b:

[0555] LC-MS m / z (ESI): 550.1 [M+H] + .

[0556] 1 H 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).

[0557] Example 5. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-(2- hydroxyacetyl)-S-methylsulfmylimino)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 5)

[0558]

[0559] 5.1 Synthesis of 5-butyl 2-((tert-butyldimethylsilyl)oxy)acetate (Compound 5-2)

[0560] 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 and separated, and the methyl tert-butyl ether layer was extracted (30 mL x 2). 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%).

[0561] 5.2 Synthesis of butyl 2-((tert-butyldimethylsilyl)oxy)acetate (compound 5-3)

[0562] Potassium hydroxide (2.14 g, 38.09 mmol) was weighed and dissolved in 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), which was stirred and cooled to -10°C, and the potassium hydroxide solution was added dropwise, followed by warming to 5°C and stirring for 6 hours. Methyl tert-butyl ether (50 mL) and water (10 mL) were added, which was 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, and 1M hydrochloric acid solution was slowly added dropwise to adjust the pH to 5-6, and methyl tert-butyl ether was added to extract (50 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to obtain a colorless solid, which was compound 5-3 (4.6 g, yield: 63.91%).

[0563] 5.3 Synthesis of 2-((tert-butyldimethylsilyl)oxy)-N-(methyl(3-nitrophenyl)(oxo)-λ 6 -sulfenyl)acetamide (compound 5-4)

[0564] 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), and HATU (2281 mg, 6.00 mmol) and DIEA (1163 mg, 9.00 mmol) were added to the reaction solution, which was stirred at room temperature for 20 hours. 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 obtain a light yellow oil, which was compound 5-4 (570 mg, yield: 51.12%).

[0565] LC-MS m / z (ESI): 371.10 [M-H] - .

[0566] 5.4 Synthesis of N-((3-aminophenyl)(methyl)(oxo)-λ 6 - sulfinyl)-2-((tert-butyldimethylsilyl)oxy)acetamide (Compound 5-5)

[0567] To a solution of 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) was added methanol (10 mL) and stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered using celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) and concentrated to give a yellow solid, which was Compound 5-5 (400 mg, yield: 76.34%).

[0568] 5.5 Synthesis of (2R,3S,4S,5R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S- methylsulfmylimino)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 5-6)

[0569] 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, 90 mg, 0.25 mmol) was added anhydrous dichloromethane (5 mL), and HATU (145 mg, 0.38 mmol) and DIEA (98 mg, 0.76 mmol) were added to the reaction mixture. After stirring for 10 minutes, N-((3- aminophenyl)(methyl)(oxo)-λ 6 - sulfinyl)-2-((tert-butyldimethylsilyl)oxy)acetamide (Compound 5-5, 150 mg, 0.44 mmol) was added to the reaction mixture and stirred overnight under nitrogen atmosphere. Water (10 mL) was added to the reaction mixture, and the mixture was separated. The organic layer 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 the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 20 / 1, v / v) to give a yellow solid, which was Compound 5-6 (120 mg, yield: 69.77%).

[0570] 5.6 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-(2- hydroxyacetyl)-S-methylsulfmimidoyl)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 5)

[0571] (2R, 3S, 4S, 5R)-N-(3-(N-(2-((tert-butyldimethylsilyl)oxy)acetyl)-S- methylsulfmimidoyl)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 solution was added to ethyl acetate (20 mL), washed with saturated sodium bicarbonate solution (20 mL x 2), washed with water (20 mL), and the organic phase was dried and concentrated. The crude product 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%~70% v / v acetonitrile; flow rate: 20 mL / min; wavelength: 210 / 254 nm) to obtain white solid, which was Compound 5 (42.62 mg, yield: 53.95%).

[0572] LC-MS m / z (ESI): 587.14 [M+Na] + .

[0573] 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).

[0574] Example 6. 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)

[0575]

[0576] 6.1 Synthesis of 2-(methylthio)pyridin-4-amine (Compound 6-2)

[0577] 4-Amino-2-fluoropyridine (Compound 6-1, 2.00 g, 0.018 mol) was dissolved in NMP (20 mL), sodium methanethiolate (3.00 g, 0.042 mol) was added, and the reaction was allowed to proceed at 130 °C, with TLC monitoring until completion. The reaction mixture was allowed to cool to room temperature, water (80 mL) was added, and the mixture was extracted with dichloromethane (80 mL x 3). The organic phase was 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 ~ 40 / 1, v / v) to obtain an oil, which was Compound 6-2 (1.84 g, yield: 73.6%).

[0578] 6.2 Synthesis of tert-butyl (2-(methylthio)pyridin-4-yl)carbamate (Compound 6-3)

[0579] 2-(Methylthio)pyridin-4-amine (Compound 6-2, 1.84 g, 0.13 mol) was dissolved in dichloromethane (10 mL), DMAP (0.16 g, 0.0013 mol) and DIEA (2.04 g, 0.011 mol) were added, and the reaction mixture was cooled to 0~5 °C in an ice bath. Boc2O (3.00 g, 0.014 mol) was dissolved in dichloromethane (5 mL) and added dropwise to the reaction mixture, which was then allowed to warm to room temperature and stirred overnight. The reaction was terminated by adding water (30 mL), and the mixture was extracted with dichloromethane (15 mL x 2). The organic phase was combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 60 / 1 ~ 20 / 1, v / v) to obtain an oil, which was Compound 6-3 (1.80 g, yield: 42.0%).

[0580] LC-MS m / z (ESI): 239.07 [M-H] - .

[0581] 6.3 Synthesis of tert-butyl (2-(S-methylsulfonimidoyl)pyridin-4-yl)carbamate (Compound 6-4)

[0582] tert-Butyl (2-(methylthio)pyridin-4-yl)carbamate (compound 6-3, 1.80 g, 0.0075 mol) was dissolved in methanol (10 mL), ammonium carbonate (2.16 g, 0.022 mol) and iodobenzene diacetate (9.65 g, 0.030 mol) were added, stirred at room temperature for 1 hour, concentrated under reduced pressure, dichloromethane (30 mL) was added, filtered, the filtrate was stirred with water (15 mL), separated, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain a yellow oil, which was compound 6-4 (1.90 g, yield: 93.5%), which was used directly in the next step.

[0583] LC-MS m / z (ESI): 270.09 [M-H] - .

[0584] Synthesis of tert-butyl 6-(2-(N-((tert-butoxycarbonyl)glycyl)-S- methylsulfonimidoyl)pyridin-4-yl)carbamate (compound 6-5)

[0585] 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-methylsulfonimidoyl)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 phases were combined, concentrated under reduced pressure to obtain a yellow-brown oil, which was compound 6-5 (3.50 g), which was used directly in the next step.

[0586] LC-MS m / z (ESI): 427.16 [M-H] - .

[0587] Synthesis of 2-amino-N-((4-aminopyridin-2-yl)(methyl)(oxo)-λ 6 -amino sulfonimidate)acetamide (compound 6-6)

[0588] To a solution of tert-butyl (2-(N-((tert-butoxycarbonyl)glycyl)-S-methylsulfmimidoyl)pyridin-4-yl)carbamate (compound 6-5, 3.50 g, 0.0082 mol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, dissolved in water (30 mL) and 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 to 5 / 1, v / v) to give compound 6-6 (5.08 g) as an oil. The crude product was used directly in the next reaction.

[0589] LC-MS m / z (ESI): 251.06 [M+Na] + .

[0590] 6.6 (2-(((4-amino pyridin-2-yl)(methyl)(oxo)-λ 6 -aminosulfmimidoyl)amino)-2-oxoethyl)carbamate (compound 6-7)

[0591] To a solution of 2-amino-N-((4-amino pyridin-2-yl)(methyl)(oxo)-λ 6 -aminosulfmimidoyl)acetamide (compound 6-6, 5.08 g, 0.022 mol) in dichloromethane (15 mL) was added sodium bicarbonate (1.76 g, 0.021 mol) and the reaction mixture was cooled to 0-5 °C. Boc20 (1.53 g, 0.0070 mol) was dissolved in dichloromethane (5 mL) and added dropwise to the reaction mixture. The reaction mixture was stirred at room temperature overnight, quenched with water (20 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (15 mL x 2) and the combined organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: dichloromethane / methanol = 80 / 1 to 20 / 1, v / v) to give compound 6-7 (0.42 g) as a white solid. The crude product was used directly in the next reaction.

[0592] LC-MS m / z (ESI): 329.12 [M+H] + .

[0593] 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 -aminosulfmimidoyl)amino)-2-oxoethyl)carbamate (compound 6-8)

[0594] (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 a solution of thionyl chloride (5 mL) and warmed to reflux for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (5 mL). (2-(((4-aminopyridin-2-yl)(methyl)(oxo)-λ 6 tert-butyl (2-(((4-aminopyridin-2-yl)(methyl)(oxo)-λ

[0595] 6.8 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(N- glycyl-S-methylsulfϊnylimino)pyridin-4-yl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 6)

[0596] 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)- λ 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)- λ

[0597] LC-MS m / z (ESI): 563.13 [M-H] - .

[0598] 1 H NMR (400 MHz, DMSO-d6) δ 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).

[0599] 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: 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 6-a (9 mg, RT = 3.3 min) and compound 6-b (12 mg, RT = 4.3 min).

[0600] Compound 6-a:

[0601] LC-MS m / z (ESI): 563.0 [M-H] - .

[0602] 1 H NMR (400 MHz, MeOD) δ 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).

[0603] Compound 6-b:

[0604] LC-MS m / z (ESI): 563.0 [M-H]- .

[0605] 1 H NMR (400 MHz, MeOD) δ 8.59-8.53 (m, 2H), 7.94 (dd, J = 5.4, 2.2 Hz, 1H), 7.13-7.10 (m, 1H), 7.03-6.92 (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), 3.35 (s, 2H), 2.80 (p, J = 7.7 Hz, 1H), 1.66 (s, 3H), 0.85-0.78 (m, 3H).

[0606] Example 7. Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)-λ 6 - sulfinimidate)amino)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 7)

[0607]

[0608] 7.1 Synthesis of dimethyl(4-nitropyridin-2-yl)imino-λ 6 -6-sulfone (Compound 7-2)

[0609] Compound 7-2 (600 mg, yield: 88%) was obtained by stirring 2-chloro-4-nitropyridine (Compound 7-1, 500 mg, 3.15 mmol), dimethyl sulfinimidate (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) in a reaction flask at 100 °C overnight. TLC detection showed that the reaction was completed. 1,4-Dioxane (20 mL) was added, stirred, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (eluent: DCM) to obtain Compound 7-2 (600 mg, yield: 88%) as a yellow solid.

[0610] 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).

[0611] 7.2 Dimethyl(4-aminopyridin-2-yl)imino-λ 6 - Synthesis of thiooxime (compound 7-3)

[0612] Dimethyl(4-aminopyridin-2-yl)imino-λ 6 - 6-Thiooxime (compound 7-2, 600 mg, 2.79 mmol) and Pd / C (10%) (120 mg) were added into methanol (10 mL) and replaced with H2, stirred at room temperature overnight. TLC detected that 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 obtain a white solid, which was compound 7-3 (430 mg, yield: 83%).

[0613] 1 H 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).

[0614] 7.3 (2R, 3S, 4S, 5R)-3-(3, 4-Difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)-λ 6 - Synthesis of (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)-λ

[0615] (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 μmol) was dissolved in dichloromethane (5 mL), DMF (20 mg) was added, oxalyl chloride (75 mg, 593 μmol) was added, stirred at room temperature for 1.5 h, the solvent was removed by concentration under reduced pressure, dissolved in dichloromethane (5 mL), and cooled to 0°C for standby. Dimethyl(4-aminopyridin-2-yl)imino-λ 6-6-sulfonyl ketone (compound 7-3, 55 mg, 296 μmol) and triethylamine (99 mg, 988 μmol) were dissolved with dichloromethane (2 mL) and N,N-dimethylformamide (2 mL) and added dropwise to the above prepared dichloromethane solution, after dropwise addition, it was stirred at room temperature for 3 h, stirred with water (10 mL), extracted with dichloromethane (20 mL x 2), the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which 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 obtain a white solid, which was compound 7 (58.57 mg, yield: 56.8%).

[0616] LC-MS m / z (ESI): 522.16 [M+H] + .

[0617] 1 H NMR (400 MHz, CDCl3) 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).

[0618] 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)

[0619]

[0620] 8.1 Synthesis of methyl 4-((tert-butoxycarbonyl)amino)picolinate (compound 8-2)

[0621] Methyl 4-aminopyridine-2-carboxylate (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 overnight under nitrogen protection. 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 the filtrate was 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)pyridine-2-carboxylate (compound 8-2, 7 g, yield: 70.42%) as a light yellow solid.

[0622] LC-MS m / z (ESI): 253.12 [M+H] + .

[0623] 8.2 Synthesis of 4-((tert-butoxycarbonyl)amino)pyridine-2-carboxylic acid (compound 8-3)

[0624] Methyl 4-((tert-butoxycarbonyl)amino)pyridine-2-carboxylate (compound 8-2, 7 g, 27.77 mmol) was dissolved in methanol (70 mL), and 2N sodium hydroxide solution (70 mL) was added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and then water (100 mL) and ethyl acetate (150 mL) were added. The pH was adjusted to 5-6 using 2N dilute hydrochloric acid under ice bath, and the mixture was filtered under suction to give a white solid, which was dried to give 4-((tert-butoxycarbonyl)amino)pyridine-2-carboxylic acid, i.e., compound 8-3 (4.30 g, yield: 65.34%).

[0625] LC-MS m / z (ESI): 237.08 [M-H] - .

[0626] 8.3 Synthesis of N-methyl-2-(methylsulfonyl)ethan-1-amine (compound 8-5)

[0627] Methylamine hydrochloride (6.36 g, 94 mmol) was dissolved in methanol (25 mL), and TEA (9.51 g, 94 mmol) was added, followed by methyl vinyl sulfone (compound 8-4, 1 g, 9.43 mmol). The mixture was stirred at room temperature overnight. The reaction solution was filtered under suction, and the filtrate was evaporated to dryness. The residue was resuspended in ethyl acetate (10 mL) and filtered under suction again. The filtrate was evaporated to dryness to give N-methyl-2-(methylsulfonyl)ethan-1-amine (compound 8-5, 1 g, yield: 77.52%) as a light yellow solid.

[0628] LC-MS m / z (ESI): 138.05 [M+H] + .

[0629] 8.4 Synthesis of tert-butyl (2-(methyl(2-(methylsulfonyl)ethyl)carbamate)pyridin-4- yl)carbamate (Compound 8-6)

[0630] 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 suction filtered to obtain a white solid, which was dried to obtain 4-amino-N-methyl-N-(2-(methylsulfonyl)ethyl)pyridine amide hydrochloride, Compound 8-7 (0.80 g, yield 100%).

[0631] LC-MS m / z (ESI): 358.14 [M+H] + .

[0632] 8.5 Synthesis of 4-amino-N-methyl-N-(2-(methylsulfonyl)ethyl)pyridine amide hydrochloride (Compound 8-7)

[0633] 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 suction filtered to obtain a white solid, which was dried to obtain 4-amino-N-methyl-N-(2-(methylsulfonyl)ethyl)pyridine amide hydrochloride, Compound 8-7 (0.80 g, yield 100%).

[0634] LC-MS m / z (ESI): 258.08 [M+H] + .

[0635] 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)pyridine amide (Compound 8)

[0636] (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, 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 give a crude product. The crude product was purified by high-performance liquid preparative chromatography (instrument: Hanbon NP7000; 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 give 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%) as a white solid.

[0637] LC-MS m / z (ESI): 594.17 [M+H] + .

[0638] 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).

[0639] 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)

[0640]

[0641] 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)

[0642] (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 give 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.

[0643] LC-MS m / z (ESI): 489.15 [M+H] + .

[0644] 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)

[0645] 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.

[0646] LC-MS m / z (ESI): 475.13 [M+H] + .

[0647] 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)

[0648] (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%).

[0649] LC-MS m / z (ESI): 580.17 [M+H] + .

[0650] 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).

[0651] 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)

[0652]

[0653] 10.1 Synthesis of tert-butyl (2-(3-(methylsulfonyl)azetidine-l-carbonyl)pyridin-4- yl)carbamate (Compound 10-2)

[0654] 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. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. 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 with saturated aqueous sodium bicarbonate solution. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / methanol = 3 / 1 to 1 / 1, v / v) to give Compound 10-3 (200 mg, yield: 69.6%) as an oil.

[0655] LC-MS m / z (ESI): 354.11 [M-H] - .

[0656] 10.2 Synthesis of (4-aminopyridin-2-yl)(3-(methylsulfonyl)azetidin-l-yl)methanone (Compound 10-3)

[0657] 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. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. 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 with saturated aqueous sodium bicarbonate solution. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: dichloromethane / methanol = 3 / 1 to 1 / 1, v / v) to give Compound 10-3 (200 mg, yield: 69.6%) as an oil.

[0658] LC-MS m / z (ESI): 256.07 [M+H] + .

[0659] 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)

[0660] (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.

[0661] (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%).

[0662] LC-MS m / z (ESI): 592.16 [M+H] + .

[0663] 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).

[0664] 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)

[0665]

[0666] 11.1 Synthesis of tert-butyl (2-(3-(methylsulfonyl)pyrrolidine-1-carbonyl)pyridin-4- yl)carbamate (Compound 11-2)

[0667] 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 dropwise, 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.

[0668] 11.2 Synthesis of (4-aminopyridinyl)(3-(methylsulfonyl)pyrrolidinyl)methanone (Compound 11-3)

[0669] 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%).

[0670] LC-MS m / z (ESI): 270.09 [M+H] + .

[0671] 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)

[0672] (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.

[0673] (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%).

[0674] LC-MS m / z (ESI): 606.18 [M+H] + .

[0675] 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).

[0676] 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)

[0677]

[0678] 12.1 Synthesis of tert-butyl (2-(4-(methylsulfonyl)piperidine-l-carbonyl)pyridin-4- yl)carbamate (Compound 12-2)

[0679] To a solution of tert-butyl (2-(4-(methylsulfonyl)piperidin-l-yl)pyridin-4- yl)carbamate (Compound 12-2, 1.5 g, 3.87 mmol) in DCM (20 mL) was added TFA (2 mL) dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and saturated aqueous NaHC03solution (20 mL) was added. The mixture was stirred at room temperature for 10 min. The organic layer was separated and the aqueous layer was extracted with DCM (20 mL x 3). The combined organic extracts were dried over anhydrous Na2S04and concentrated under reduced pressure to give Compound 12-3 (1.2 g) as a yellow solid, which was used directly in the next step without further purification.

[0680] 12.2 Synthesis of (4-aminopyridin-2-yl)(4-(methylsulfonyl)piperidin-l-yl)methanone hydrochloride (Compound 12-3)

[0681] 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.

[0682] 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)

[0683] (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).

[0684] (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%).

[0685] LC-MS m / z (ESI): 620.20 [M+H] + .

[0686] 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).

[0687] 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)

[0688]

[0689] 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)

[0690] 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 into a reaction flask, the reaction was stirred at 60 °C overnight, TLC detection showed the reaction was complete, column chromatography purification (eluent: dichloromethane / methanol = 80 / 1 ~ 20 / 1, v / v), the organic phase was collected and concentrated under reduced pressure to obtain a white solid, which was Compound 13-1 (59 mg, yield: 49.04%).

[0691] LC-MS m / z (ESI): 586.19 [M-H] - .

[0692] 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)

[0693] 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 HC1 (1,4-dioxane solution) (4 mL) was added drop wise, the reaction was stirred at room temperature for 2 h, TLC indicated the completion of the reaction, concentrated under reduced pressure, 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: 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%).

[0694] LC-MS m / z (ESI): 532.17 [M+H] + .

[0695] 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).

[0696] 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)

[0697]

[0698] 14.1 Synthesis of methyl 4-(4-((tert-butoxycarbonyl)amino)picolinoyl)piperazine- 1 -carboxylate (Compound 14-1)

[0699] Methyl piperazine-1-carboxylate (217.9 mg, 1.51 mmol) and HATU (622.3 mg, 1.64 mmol) were dissolved in DMF (5 mL), stirring was started, DIEA (244.1 mg, 1.89 mmol) was added dropwise, and the reaction was allowed to proceed at room temperature for 2 h. TLC detection showed that the reaction was complete, saturated aqueous sodium bicarbonate solution (20 mL) was added, dichloromethane (20 mL x 3) was used for extraction, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain an oil, which was Compound 14-1 (365.1 mg, yield: 79.6%).

[0700] 14.2 Synthesis of methyl 4-(4-aminopicolinoyl)piperazine-1-carboxylate hydrochloride (Compound 14-2)

[0701] Methyl 4-(4-((tert-butoxycarbonyl)amino)picolinoyl)piperazine-1-carboxylate (Compound 14-1, 365.1 mg, 1 mmol) was added dropwise to a solution of hydrogen chloride in 1,4-dioxane (5 mL), and the reaction was allowed to proceed at room temperature overnight. TLC detection showed that the reaction was complete, and the reaction mixture was concentrated to dryness under reduced pressure to obtain a yellow oil, which was Compound 14-2 (215.3 mg, yield: 71.59%).

[0702] LC-MS m / z (ESI): 265.14 [M+H] + .

[0703] 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)

[0704] (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) was dissolved in thionyl chloride (5 mL). The reaction was allowed to proceed at 80°C under nitrogen protection for 2 h, concentrated under reduced pressure, and dissolved in tetrahydrofuran (3 mL) for standby.

[0705] 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%).

[0706] LC-MS m / z (ESI): 601.21 [M+H] + .

[0707] 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).

[0708] 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)

[0709]

[0710] 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-chloroperoxybenzoic 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%).

[0711] LC-MS m / z (ESI): 617.21 [M+H] + .

[0712] 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).

[0713] 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)

[0714]

[0715] 16.1 Synthesis of 16-1 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)

[0716] 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 (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%).

[0717] LC-MS m / z (ESI): 616.33 [M+H] + .

[0718] 16.2 (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) synthesis

[0719] 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 (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%).

[0720] LC-MS m / z (ESI): 516.20 [M+H] + .

[0721] 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).

[0722] Example 17. 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) was synthesized

[0723]

[0724] 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) was synthesized

[0725] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)-λ 6 - sulfenyl)imino)pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 7, 120 mg, 0.23 mmol) was dissolved in dichloromethane (4 mL), m-CPBA (79 mg, 0.46 mmol) was added to the reaction solution, and stirring was performed at room temperature for 2 hours. Concentration under reduced pressure was performed, 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 obtain a white solid, which was Compound 17 (33.77 mg, yield: 27.3%).

[0726] LC-MS m / z (ESI): 538.14 [M+H] + .

[0727] 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).

[0728] 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)

[0729]

[0730] 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)

[0731] (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%).

[0732] LC-MS m / z (ESI): 550.30 [M+H] + .

[0733] 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).

[0734] 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), and compound 18-a (46 mg, RT = 9.5 min) and 18-b (61 mg, RT = 13.4 min) were obtained after lyophilization.

[0735] 18-a:

[0736] LC-MS m / z (ESI): 550.30 [M+H] + .

[0737] 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).

[0738] 18-b:

[0739] LC-MS m / z (ESI): 550.30 [M+H]+ .

[0740] 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).

[0741] 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)

[0742]

[0743] 19.1 Synthesis of 1-((tert-butyldimethylsilyl)oxy)cyclopropane-1-carboxylic acid (Compound 19-2)

[0744] Dissolve 1-hydroxycyclopropane-1-carboxylic acid (Compound 19-1, 3 g, 29.4 mmol) and imidazole (4.6 g, 67.6 mmol) in DCM (300 mL), add TBSCl (8.86 g, 58.8 mmol) to the reaction solution, after adding, react at room temperature overnight. The reaction solution is rotary evaporated to dryness under reduced pressure, the residue is dissolved in methanol and tetrahydrofuran (V MeOH / V THF = 3 / 1) (240 mL), add saturated potassium carbonate solution (120 mL), stir at room temperature for 1 h, after most of the organic solvent is rotary evaporated under reduced pressure, adjust the pH to 3 with half-saturated aqueous citric acid solution, extract the aqueous phase with diethyl ether (150 mL x 3), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a colorless oil, which is Compound 19-2 (2.7 g, yield: 45.92%).

[0745] 19.2 Synthesis of 1-((tert-butyldimethylsilyl)oxy)-N-(methyl(3-nitrophenyl)(oxo)- lambda 6Synthesis of (-thionyl)cyclopropane-1-carboxamide (compound 19-3)

[0746] 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%).

[0747] 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).

[0748] 19.3N-((3-aminophenyl)(methyl)(oxo)-λ 6 Synthesis of (-thionyl)-1-((tert-butyldimethylsilyl)oxy)cyclopropane-1-carboxamide (compound 19-4)

[0749] 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.

[0750] LC-MSm / z(ESI): 369.16 [M+H] + .

[0751] 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)

[0752] (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 - sulfmylimino)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 19-5, 0.17 g, 60.28% yield) as a yellowish oil was obtained by purification on a silica gel column (eluent: ethyl acetate / n-hexane = 0~50%, v / v) after concentration to dryness under reduced pressure.

[0753] LC-MS m / z (ESI): 705.15 [M+H] + .

[0754] 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)

[0755] (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%).

[0756] LC-MS m / z (ESI): 591.30 [M+H] + .

[0757] 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).

[0758] 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)

[0759]

[0760] 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)

[0761] 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.

[0762] LC-MS m / z (ESI): 477.15 [M+H] + .

[0763] 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)

[0764] 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 iodobenzenediacetic acid (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.

[0765] LC-MS m / z (ESI): 508.16 [M+H] + .

[0766] 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)

[0767] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(S-methylsulfmylimino)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, the reaction was stirred at room temperature for 72 hours, TLC showed the reaction was complete, saturated sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL) were added, the mixture was stirred and separated, the aqueous phase was extracted once more with ethyl acetate (30 mL), 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%).

[0768] LC-MS m / z (ESI): 549.10 [M-H] - .

[0769] 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).

[0770]

[0771] Re-amplification of the synthesis of compound 20 (201 mg) 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 (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).

[0772] 20-a:

[0773] LC-MS m / z (ESI): 549.20 [M-H] - .

[0774] 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).

[0775] 20-b:

[0776] LC-MS m / z (ESI): 549.20 [M-H] - .

[0777] 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).

[0778] Example 21. Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N- carbamoyl-S-methylsulfinimidoyl)-4-fluorophenyl)-3-(3,4-difluoro-2- methoxyphenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 21)

[0779]

[0780] 21.1 Synthesis of 4-fluoro-3-methylsulfanyl aniline (Compound 21-2)

[0781] Dissolve 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) under nitrogen protection, and warm to 100-110 °C for overnight. Control the reaction completion by TLC, cool to room temperature, filter, rinse the filter cake with dichloromethane (50 mL), concentrate the filtrate under reduced pressure, and prepare the separation of the residue (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 brown oil, which is Compound 21-2 (300 mg, yield: 7.2%).

[0782] LC-MS m / z (ESI): 158.04 [M+H] + .

[0783] 21.2 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3- (methylsulfanyl)phenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2- carboxamide (Compound 21-3)

[0784] (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) was synthesized by dissolving (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) in methanol (10 mL) and stirring at room temperature overnight. The reaction was monitored 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. The residue was purified by column chromatography (eluent: methanol / dichloromethane = 0-1 / 20, v / v) to give Compound 21-4 (204 mg, yield: 73.7%) as a white solid.

[0785] LC-MS m / z (ESI): 492.11 [M-H] - .

[0786] 21.3 (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) was synthesized by dissolving (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) in methanol (10 mL) and stirring at room temperature overnight. The reaction was monitored 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. The residue was purified by column chromatography (eluent: methanol / dichloromethane = 0-1 / 20, v / v) to give Compound 21-4 (204 mg, yield: 73.7%) as a white solid.

[0787] 21.3 (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) was synthesized by dissolving (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) in methanol (10 mL) and stirring at room temperature overnight. The reaction was monitored 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. The residue was purified by column chromatography (eluent: methanol / dichloromethane = 0-1 / 20, v / v) to give Compound 21-4 (204 mg, yield: 73.7%) as a white solid.

[0788] LC-MS m / z (ESI): 523.12 [M-H] - .

[0789] 21.4 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-carbamoyl-S-methylsulfmylimino)-4- fluorophenyl)-3-(3, 4-difluoro-2-methoxyphenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 21)

[0790] (2R, 3S, 4S, 5R)-3-(3, 4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-(S- methylsulfmylimino)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. TLC detected that the reaction was completed, concentrated to dryness under reduced pressure, slowly added saturated NaHC03 solution to the residue to pH 9-10, extracted with ethyl acetate (30 mL x 3), combined the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by preparative liquid phase (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% ~ 85% v / v acetonitrile; flow rate: 80 mL / min; wavelength: 210 / 254 nm) to obtain white solid, which was Compound 21 (157 mg, yield: 48.4%).

[0791] LC-MS m / z (ESI): 568.10 [M+H] + .

[0792] 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).

[0793] 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)

[0794]

[0795] 22.1 Synthesis of 4-amino-2-chlorobenzonitrile (Compound 22-2)

[0796] Compound 22-1 (5.00 g, 27.47 mmol) was dissolved in ethanol (90 mL) and water (30 mL), and Fe powder (7.67 g, 137.37 mmol) and ammonium chloride (14.70 g, 274.74 mmol) were added. The reaction was heated to 75-80 °C and refluxed for 4 h. TLC control showed that the reaction was complete. The reaction was filtered while hot, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (eluent: methanol / dichloromethane = 0-1 / 20, v / v) gave Compound 22-2 (4.10 g, yield: 98.3%) as a light yellow solid.

[0797] LC-MS m / z (ESI): 151.01 [M-H] - .

[0798] 22.2 Synthesis of 4-amino-2-(methylthio)benzonitrile (Compound 22-3)

[0799] Compound 22-2 (4.00 g, 26.31 mmol) was dissolved in DMF (10 mL), and sodium methanethiolate (7.37 g, 105.26 mmol) was added. The reaction was heated to 130-135 °C and stirred overnight. TLC control showed that the reaction was complete. The reaction was concentrated under reduced pressure, and purification by column chromatography (eluent: ethyl acetate / n-hexane = 1:1, v / v) gave Compound 22-3 (2.73 g, yield: 63.2%) as a light yellow solid.

[0800] LC-MS m / z (ESI): 165.05 [M+H] + .

[0801] 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)

[0802] 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, 431 mg, 1.22 mmol) and 4-amino-2-(methylthio)benzonitrile (compound 22-3, 200 mg, 1.22 mmol) in pyridine (10 mL) was added phosphorus oxychloride (561 mg, 3.66 mmol) dropwise under nitrogen. After the addition was completed, the mixture was stirred at room temperature overnight. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methanol / methylene chloride = 0-1 / 20, v / v) to give compound 22-4 (510 mg, yield: 83.7%) as a white solid.

[0803] 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).

[0804] 22.4 (2R,3S,4S,5R)-N-(3-(S-methylsulfinamido)-4-cyanophenyl)-3-(3,4-difluoro-2- methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 22-5) synthesis

[0805] To a solution 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, 500 mg, 1.00 mmol) in methanol (20 mL) was added ammonium carbonate (290 mg, 3.00 mmol) and iodobenzene diacetate (1290 mg, 4.00 mmol) portionwise with stirring. The mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: methanol / methylene chloride = 0-1 / 40, v / v) to give compound 22-5 (340 mg, yield: 64.0%) as a light yellow solid.

[0806] LC-MS m / z (ESI): 530.12 [M-H]- .

[0807] 22.5 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-carbamoyl-S-methylsulfϊnimidoyl)-4- cyano phenyl)-3-(3, 4-difluoro-2-methoxy phenyl)-4, 5-dimethyl-5- (trifluoromethyl) tetrahydrofuran-2-carboxamide (Compound 22)

[0808] Weigh (2R, 3S, 4S, 5R)-N-(3-(S-methylsulfϊnimidoyl)-4-cyano phenyl)-3-(3, 4- difluoro-2-methoxy phenyl)-4, 5-dimethyl-5-(trifluoromethyl) tetrahydrofuran-2- carboxamide (Compound 22-5, 300 mg, 0.57 mmol) dissolved in THF (10 mL), trimethylsilyl isocyanate (98 mg, 0.85 mmol) was added under nitrogen protection, stirred at room temperature overnight, TLC control reaction complete, saturated sodium bicarbonate solution (30 mL) and ethyl acetate (30 mL) were added, stirred and separated into water and organic phases, the organic phase was extracted with ethyl acetate (30 mL), combined and concentrated under reduced pressure, then purified by preparative liquid phase (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 a white solid, which was Compound 22 (105 mg, yield: 32.4%).

[0809] 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 white solid 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).

[0810] 22-a:

[0811] LC-MS m / z (ESI): 575.20 [M+1] + .

[0812] 1H 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).

[0813] 22-b:

[0814] LC-MS m / z (ESI): 575.20 [M+1] + .

[0815] 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).

[0816] Example 23. 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)

[0817]

[0818] 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)

[0819] (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 2M solution of boron tribromide (3 mL, 6.00 mmol) was added dropwise, and then warmed to room temperature and reacted 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 directly used in the next reaction.

[0820] LC-MS m / z (ESI): 339.10 [M-H] - .

[0821] 23.2 Synthesis of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid ester (compound 23-2)

[0822] (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 sequentially with stirring, and the reaction was warmed to 60 ± 5°C under nitrogen overnight. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, stirred, and the liquid was separated. The ethyl acetate layer was extracted (10 mL x 3), and the combined organic phase was washed sequentially with water, saturated aqueous ammonium chloride, and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give a light yellow oil (3.02 g). The crude product was directly used in the next reaction.

[0823] LC-MS m / z (ESI): 392.20 [M+H2O] + .

[0824] 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)

[0825] 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 mixture was warmed to 60 ± 5 °C for 1.5 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the residue was adjusted to pH 1-2 with 1 M hydrochloric acid solution, extracted with dichloromethane (10 mL x 2), and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellowish oil (1.01 g).

[0826] LC-MS m / z (ESI): 356.10 [M-H] - .

[0827] 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)

[0828] (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 sequentially added thereto, and the mixture was stirred at room temperature overnight. After the reaction was completed, water (10 mL) and dichloromethane (20 mL) were added to the reaction mixture, and the mixture was separated, and the 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 column chromatography on silica gel (eluent: ethyl acetate / n-hexane = 0-1 / 2, v / v) to give compound 23-4 as a white solid (0.38 g, yield: 71.56%).

[0829] 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)

[0830] (2R,3S,4S,5R)-N-(3-(N-cyano-S-methylsulfmimidoyl)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), TFA (1 mL) was added, and the reaction was stirred at room temperature under nitrogen overnight. The reaction was concentrated to dryness under reduced pressure, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with water (10 mL), 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*100 mm; mobile phase A: 0.1% formic acid; mobile phase B: acetonitrile) to obtain white solid, which was Compound 23.

[0831] Compound 23 was chiral resolution (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 80%; flow rate: 7 mL / min; wavelength: 210 / 254 nm) to obtain 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).

[0832] 23-a:

[0833] LC-MS m / z (ESI): 553.20 [M+H] + .

[0834] 1 H NMR (400 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.28-8.22 (m, 1H), 7.94-7.86 (m, 1H), 7.66-7.52 (m, 2H), 7.23-7.08 (m, 2H), 6.38 (s, 1H), 6.02 (s, 1H), 5.10 (d, J = 10.4 Hz, 1H), 4.27 (dd, J = 10.4, 7.6 Hz, 1H), 3.29 (s, 3H), 2.84-2.71 (m, 1H), 1.61 (s, 3H), 0.77-0.70 (m, 3H).

[0835] 23-b:

[0836] LC-MS m / z (ESI): 553.30 [M+H] + .

[0837] 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).

[0838] 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)

[0839]

[0840] 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)

[0841] (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. After the reaction was allowed to recover to room temperature for 2 hours, 5 drops of water were added to quench the reaction, and the reaction was concentrated under reduced pressure. Saturated sodium bicarbonate solution (20 mL) and ethyl acetate (20 mL) were added to the residue, which was stirred and separated. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate (20 mL x 2). The combined organic phases were concentrated under reduced pressure, and column chromatography (eluent: ethyl acetate / n-hexane = 0-1 / 10, v / v) was performed to obtain Compound 24-1 (620 mg, yield: 74.5%) as a white solid.

[0842] 24.2 Synthesis of (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5- dimethyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 24-2)

[0843] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-N-(2-(S- methylsulfonimidoyl)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 combined 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 yellowish oil. The oil was purified by preparative purification (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 white solid, which was Compound 24.

[0844] 24.3 Synthesis of (2R, 3S, 4S, 5R)-N-(2-(N-carbamoyl-S-methylsulfonimidoyl)pyridin-4-yl)- 3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 24)

[0845] (2R, 3S, 4S, 5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-N-(2-(S- methylsulfonimidoyl)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 combined 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 yellowish oil. The oil was purified by preparative purification (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 white solid, which was Compound 24.

[0846] Compound 24 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 (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 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).

[0847] 24-a:

[0848] LC-MS m / z (ESI): 554.20 [M+H] + .

[0849] 1 H 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).

[0850] 24-b:

[0851] LC-MS m / z (ESI): 554.20 [M+H] + .

[0852] 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).

[0853] Example 25. Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-carbamoyl-S- methylsulfmido)phenyl)-3-(2-(difluoromethoxy)-3, 4-difluorophenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound 25)

[0854]

[0855] 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)

[0856] (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 for extraction, the organic phase was combined, saturated brine (10 mL) was added for washing, anhydrous sodium sulfate was added for drying, filtered, and the obtained oily residue was dissolved in n-butanol (6 mL), 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 for extraction, the organic phase was combined, saturated brine (10 mL) was added for washing, anhydrous sodium sulfate was added for drying, filtered, and 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 (2R, 3S, 4S, 5R)-3-(2-(difluoromethoxy)-3, 4-difluorophenyl)-4, 5-dimethyl-5- (trifluoromethyl)tetrahydrofuran-2-carboxylic acid (Compound 25-1, 496 mg, yield: 47.01%).

[0857] LC-MS m / z (ESI): 389.07 [M-H] - .

[0858] 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).

[0859] 25.2 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-cyano-S-methylsulfmimidoyl)phenyl)-3-(2- (difluoromethoxy)-3, 4-difluorophenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 25-2)

[0860] (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 sequentially added 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 the organic layer was extracted with dichloromethane (10 mL x 2). The combined 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 column chromatography on silica gel (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%).

[0861] LC-MS m / z (ESI): 566.10 [M-H] - .

[0862] 25.3 Synthesis of (2R, 3S, 4S, 5R)-N-(3-(N-carbamoyl-S-methylsulfmimidoyl)phenyl)-3-(2- (difluoromethoxy)-3, 4-difluorophenyl)-4, 5-dimethyl-5-(trifluoromethyl)tetrahydrofuran- 2-carboxamide (Compound 25)

[0863] (2R, 3S, 4S, 5R)-N-(3-(N-cyano-S-methylsulfmimidoyl)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.

[0864] 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.

[0865] 25-a:

[0866] LC-MS m / z (ESI): 586.30 [M+H] + .

[0867] 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).

[0868] 25-b:

[0869] LC-MS m / z (ESI): 586.20 [M+H] + .

[0870] 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).

[0871] 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)

[0872]

[0873] 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)

[0874] (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 column chromatography on silica gel (eluent: ethyl acetate / n-hexane = 0-1 / 2, v / v) to give Compound 26-1 as a light yellow solid (0.32 g, yield: 73.98%).

[0875] LC-MS m / z (ESI): 511.10 [M-H] - .

[0876] 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)

[0877] (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.

[0878] LC-MS m / z (ESI): 542.10 [M-H] - .

[0879] 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

[0880] (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.

[0881] 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.

[0882] 26-a:

[0883] LC-MS m / z (ESI): 587.10 [M+H] + .

[0884] 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).

[0885] 26-b:

[0886] LC-MS m / z (ESI): 587.10 [M+H] + .

[0887] 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).

[0888] Biological evaluation

[0889] Experimental Example 1. Effect of compounds on human Nav 1.8 Determination of inhibitory activity

[0890] The purpose of the experiment is to detect the effect of the compound on human Na v 1.8 ion channel in vitro experiment. 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.

[0891] 1. Experimental materials and instruments

[0892] 1) Patch clamp amplifier HEKA (Germany) EPC 10

[0893] 2) Micro manipulator Sutter Instrument (USA) MP225

[0894] 3) Electrode puller Sutter Instrument (USA) P97

[0895] 4) Glass capillary Sutter Instrument (USA) BF150-86-10

[0896] 5) Inverted microscope Mshot (China) MF53

[0897] 6) Peristaltic pump Longer Pump (China) BT100-2J

[0898] 7) Dimethyl sulfoxide (DMSO) Sigma D4540

[0899] 2. Experimental steps

[0900] 2.1 Compound preparation

[0901] 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.

[0902] 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;

[0903] Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA; pH = 7.2 adjusted with CsOH.

[0904] 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.

[0905] 2.2 Cell culture

[0906] 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.

[0907] 2.3 Manual patch-clamp recording procedure

[0908] Whole-cell patch-clamp recording of Na v 1.8 Voltage protocol for current recording: After the whole-cell configuration was formed, 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.

[0909] Patch-clamp operation First, the capillary glass tube was drawn into a recording electrode by a microelectrode puller. Then, the electrode filled with intracellular solution was installed into a microelectrode holder. Subsequently, 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.

[0910] When the current amplitude of the cell in the control extracellular solution was stable, the drug was administered. After the current reached a steady state (about 5 minutes) at each drug concentration, 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, so as to act on the cell, while the liquid displacement was performed by using a peristaltic pump in the recording. Each concentration was independently detected several times. All electrophysiological tests were performed at room temperature.

[0911] All tests were performed in the presence of 100 nM TTX in extracellular solution to block the endogenous TTX-S (tetrodotoxin-sensitive) Na + current.

[0912] 2.4 Data analysis

[0913] The test data were collected by an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0914] When analyzing the data, first, the peak current (Peak current compound ) after each drug concentration was normalized (Normalized) with the blank control peak current (Peak current Control ). 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 represented as Mean±SE. According to different drug concentrations and the corresponding inhibition rates, the IC 50 curve was drawn by using GraphPad Prism software, and the final IC 50 value was obtained by analyzing the data.

[0915] The compound of the present application has an effect of inhibiting human Na v1.8 were determined by the above test, and the results are shown in Table 2.

[0916] Table 2 Inhibition activity of compounds of the present application on human Na v 1.8 were determined by the above test, and the results are shown in Table 2.

[0917] Compound No. Inhibition rate (%) @ 1 nM Inhibition rate (%) @ 10 nM Na v 1.8 IC 50 (nM)]]> 1 / / 0.048 2 91.89 97.31 0.120 3 72.44 97.74 0.487 4 90.38 99.66 0.172 5 / / 0.199 6 76.12 98.57 0.339 7 / / 4.742 8 20.20 52.31 / 9 / / 9.828 10 16.12 57.82 / 11 21.97 23.95 12 30.39 67.52 / 13 / / 7.345 14 / / 5.348 15 / / 7.184 16 / 89.86 1.329 17 21.47 74.73 / 18 83.28 99.49 / 19 81.11 80.52 / 20 57.77 56.94 / 20-a / / 0.475 20-b / / 0.849 21 87.80 87.71 / 22-a 47.34 44.61 / 22-b 26.12 24.13 / 23-a 31.85 30.72 / 23-b 90.67 89.62 / 24-a 77.50 76.82 / 24-b 51.69 52.00 / 25-a 44.23 44.96 / 25-b 82.68 86.63 / 26-a 64.56 63.85 / 26-b 41.78 42.01 /

[0918] Conclusion: The compounds of the present application have obvious inhibitory effect on human Na v 1.8 channel activity, and the IC 50 of some compounds can reach 1 nM level, and even 0.1 nM level or below for individual compounds.

[0919] Experimental Example 2. Inhibition activity of compounds on Na v Ion channel subtype selectivity test

[0920] The experimental purpose is to detect the effect of the compounds 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 experiments. 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.

[0921] 1. Experimental materials and instruments

[0922] 1) Patch clamp amplifier HEKA (Germany) EPC 10

[0923] 2) Micro manipulator Sutter Instrument (USA) MP285

[0924] 3) Electrode puller Sutter Instrument (USA) P97

[0925] 4) Glass capillary Sutter Instrument (USA) BF150-86-10

[0926] 5) Inverted microscope Mshot (China) MF53

[0927] 6) Peristaltic pump Longer Pump (China) BT100-2J

[0928] 7) Data acquisition software HEKA (Germany) PatchMaster

[0929] 8) Dimethyl sulfoxide (DMSO) Sigma D4540

[0930] 2. Experimental procedure

[0931] 2.1 Compound preparation

[0932] Reagents for the preparation of the extracellular solution were purchased from Amresco, cesium fluoride from Innochem and the rest from Sigma.

[0933] 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;

[0934] Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA; pH 7.2 adjusted with CsOH.

[0935] 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.

[0936] 2.2 Cell culture

[0937] 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

[0938] 2.3 Manual patch-clamp procedure

[0939] The voltage protocol for recording Na currents was as follows: after the whole-cell configuration was obtained, 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 drugs on the peak currents in the two different states were observed.

[0940] 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.

[0941] 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.

[0942] 2.4 Data analysis

[0943] The experimental data were collected by EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0944] 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, the IC 50 curve was drawn using GraphPad Prism software, and the data were analyzed to obtain the final IC50 Values.

[0945] The compounds of the present application 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.

[0946] Table 3 Inhibition rate of the compounds of the present application against human Na v subtypes at a concentration of 10 μM

[0947]

[0948] Conclusion: The compounds of the present application have good subtype selectivity against Na v ion channels, particularly against Na v 1.5.

[0949] Experimental Example 3. Test of metabolic stability in liver microsomes

[0950] 1. Experimental materials

[0951] 1.1 Liver microsomes: Human and animal microsomes were purchased from a qualified supplier and stored in a -80 °C refrigerator

[0952] 1.2 Reduced nicotinamide adenine dinucleotide phosphate (NADPH)

[0953] 1.3 Control compounds: Testosterone, diclofenac and propafenone

[0954] 2. Experimental procedure

[0955] 2.1 Preparation of working solutions

[0956] Stock solution: 10 mM DMSO solution

[0957] Working concentration preparation: Dilution of 100% acetonitrile to 100 μM (organic phase content: 99% ACN, 1% DMSO)

[0958] 2.2 Experimental procedure

[0959] Two 96-well incubation plates were prepared, designated T60 incubation plate and NCF60 incubation plate, respectively.

[0960] 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 then the incubation plates were placed in a 37 °C water bath for pre-incubation for about 10 minutes.

[0961] After the pre-incubation, 5 μL of test or control compound working solution was added to each well of the T60 incubation plate and the NCF60 incubation plate, respectively, and mixed well. The reaction was initiated by adding 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate.

[0962] The reaction was terminated by adding 180 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regenerating system working solution to each well of the T0 termination plate. 54 μL of sample was removed from the T60 incubation plate to the T0 termination plate (T0 sample generation). In the blank control plate, only 54 μL of microsomal working solution, 6 μL of NADPH regenerating system working solution and 180 μL of stop solution were added.

[0963] The reaction was initiated by adding 44 μL of NADPH regenerating system working solution to each well of the T60 incubation plate. 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.

[0964] 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 well of the sample well of the termination plate, and then 60 μL of sample was removed from the T60 incubation plate or the NCF60 incubation plate to terminate the reaction.

[0965] 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.

[0966] 3. Liquid chromatography tandem mass spectrometry analysis

[0967] All samples were injected for analysis.

[0968] 4. Sample analysis

[0969] 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.

[0970] 5. Data analysis

[0971] 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 :

[0972]

[0973] When

[0974]

[0975] The in vitro liver microsomal stability data of the compounds of the present application were tested by the above method, and the results are shown in Table 4.

[0976] Table 4 In vitro liver microsomal stability of the compounds of the present application

[0977]

[0978] Note: The control compounds are compounds numbered 528 and 530 in WO2022256702A1 (single enantiomers of unknown absolute configuration), and the 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).

[0979] Conclusion: The compounds of the present application have better liver microsomal stability than the control compounds.

[0980] Experimental Example 4. Mouse pharmacokinetic test

[0981] Test animals: CD-1 (ICR) mice, male, 6-9 weeks old, 6 per compound.

[0982] Solvent: 5% DMSO / 5% solutol / 90% pure water.

[0983] Test design:

[0984]

[0985] The animals used were CO2 euthanized after collecting the PK sample at the last time point. About 0.025 mL of whole blood sample was collected at the specified time through the saphenous vein or other suitable means.

[0986] The blood sampling time points of the intravenous group and the gavage group were:

[0987] Intravenous group: 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours;

[0988] Gavage group: 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours.

[0989] All blood samples were transferred to commercial 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 approximately 4°C (2-8°C), rapidly placed on dry ice, and then stored at -60°C or lower for LC-MS / MS analysis.

[0990] The test results are shown in Table 5.

[0991] Table 5 Pharmacokinetic parameters of the compound of the application in mice

[0992]

[0993] Conclusion: The compound of the application has high blood concentration, large exposure, low clearance rate, high bioavailability, and pharmacokinetic advantages in CD-1 mice.

[0994] Example 5. Test in SNI efficacy model of ICR mice

[0995] Test animals: ICR mice, male, 25-30 g.

[0996] Solvent: 5% DMSO / 5% solutol / 90% pure water.

[0997] Test design:

[0998] [Model establishment]

[0999] 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 using a surgical knife, the sciatic nerve and its distal sciatic nerve branches: tibial nerve, common peroneal nerve and sural nerve were exposed, the tibial nerve and common peroneal nerve were cut off using ophthalmic scissors, and the sural nerve was reserved. The wound was sutured. After the operation, the animals were placed on an electric blanket, and after the animals completely woke up (could move freely), the animals were placed back in the cage for feeding, and the behavior was observed after the operation.

[1000] [Drug test]

[1001] The day of surgery is recorded as day 0, and on day 10-12 after surgery, all animals are placed in a Perspex box and acclimatized to 3.84 (0.6 g) and 4.08 (1 g) test filaments for 3 days, 15 minutes per day. On day 13, all animals are tested for mechanical pain threshold (PWT) and 24 animals that do not show mechanical pain hypersensitivity (PWT greater than 0.6 g) are selected and randomly divided into 3 groups, 8 animals in each group. On day 14, the body weight of animals in each group is measured, and each group is orally administered with corresponding drugs at a single dose of 10 mL / kg. The 50% PWT of animals is tested before administration, 1 h, 2 h and 8 h after administration, respectively. The curve is drawn by using GraphPad software, and statistical analysis is performed.

[1002] The test results are shown in Table 6 and Figure 1 .

[1003] Table 6 50% PWT values (g, Mean ± SEM, n = 8) of compounds of the present application at different time points in each group of mice

[1004]

[1005] Note: The chemical structural formula of the control compound VX-548 (synthesized according to the method of Example 7 of WO2021113627A1) is as follows.

[1006]

[1007] Conclusion: The compound 20-b (dose 30 mg / kg) of the present application has a similar analgesic effect to VX-548 (dose 30 mg / kg) in the SNI model of mice, and has a good analgesic effect.

[1008] It should be noted that although the technical solutions of the present application are described with specific examples, those skilled in the art can understand that the present application should not be limited thereto.

[1009] The above has described various embodiments of the present application, 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 choice of terms used herein is intended to best explain the principles, practical applications or improvements in the art of the market, 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: in: Ring A is a phenyl or a 6-membered heteroaryl group, wherein the heteroatom on the heteroaryl group is optionally oxidized; R a2 The group is selected from H, D, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, -C(=O)NH2 and -C(=O)NH (C1-C4 alkyl), wherein the C1-C4 alkyl or C1-C4 alkoxy is optionally substituted with a group selected from halogen, hydroxy and C1-C4 alkoxy. R a1 Selected from -S(=O)(=NR) 1 )R 2 -C(=O)N(R) 3 )R 4 and -N = S(=O)(R 5 )R 6 ; 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, -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; R 2 It is a C1-C4 alkyl group; Or, R 1 R 2 Together with the N and S atoms to which they are attached, they form 5-10 membered heterocyclic groups, which are optionally substituted by 1-3 groups selected from halogens and C1-C4 alkyl groups; 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 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; R 16 It consists of natural or non-natural amino acid side chains; 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-C4 alkyl groups; Or, R 3 R 4 Together with the N atoms they are attached to, they form a 4-7 membered heterocyclic group, which optionally also contains 1-2 heteroatoms selected from N, O, and S and selected from -S(=O)2-R. 15 -S(=O)(=NH)R 15 -COOH and -COOR 15 Substitution of groups; R 15 Selected from C1-C4 alkyl and C1-C4 haloalkyl; R 5 and R 6 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl; X is either O or S; R d1 and R d2 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl; R c1 and R c2 Each is independently selected from H, C1-C4 alkyl, and C1-C4 haloalkyl; R e For H or D; L is -C(=O)NH-; preferably, the N atom in -C(=O)NH- is connected to ring A; Ring B is a phenyl group or a 6-membered heteroaryl group containing 1-2 nitrogen atoms; R b1 R b2 and R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups, or each is independently selected from halogens and C1-C4 alkoxy groups.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (I-1): Preferably, the compound is as shown in formula (I-1a) or formula (I-1b): More preferably, the compound is as shown in formula (I-1a-1), formula (I-1a-2), formula (I-1b-1), or formula (I-1b-2): Among them, rings A and 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 As defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, 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, -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, 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 and O and optionally substituted by 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 -L 1 -R 11 L 1 -C(=O)-(C1-C4 alkylene); R 11 It is -NH2.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, The compound is shown in formula (I-2): Preferably, the compound is as shown in formula (I-2a) or formula (I-2b): Among them, rings A and 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 As defined in claim 1.

5. The compound according to claim 1 or 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, R 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 Selected from C1-C4 alkylene and C4-C6 cycloalkylene, R 14 Selected from -S(=O)2-R 15 -S(=O)(=NH)R 15 -COOH and C1-C4 alkoxy groups; the condition is that when L 2 When it is a C1-C4 alkylene group, R 14 Not a C1-C4 alkoxy group; R 15 It is a C1-C4 alkyl group; preferably, L 2 It is a C1-C4 alkylene group, R 14 Selected from -S(=O)2-R 15 -S(=O)(=NH)R 15 and -COOH; or, L 2 It is a C4-C6 cycloalkylene group, R 14 Selected from -S(=O)2-R 15 and C1-C4 alkoxy groups; R 15 It is a C1-C4 alkyl group; more preferably, -L 2 -R 14 Selected from -C2H4-S(=O)2-CH3, -C2H4-S(=O)(=NH)CH3, -CH2-COOH, R 16 Selected from glycine side chains, alanine side chains, isoleucine side chains, leucine side chains, valine side chains, methionine side chains, phenylalanine side chains, tryptophan side chains, tyrosine side chains, asparagine side chains, cysteine ​​side chains, glutamine side chains, serine side chains, threonine side chains, arginine side chains, histidine side chains, lysine side chains, aspartic acid side chains, and glutamic acid side chains; preferably, R 16 It is selected from glycine side chain, asparagine side chain, cysteine ​​side chain, glutamine side chain, serine side chain, threonine side chain and tyrosine side chain.

6. The compound according to claim 1 or 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, R 3 R 4 Together with the N atoms they are attached to, they form a 4-6 membered heterocyclic group, which optionally also contains 1-2 N atoms selected from -S(O)2-R 15 -S(O)(=NH)R 15 -COOH and -COOR 15 Group substitution; R 15 It is a C1-C4 alkyl group; Preferably, R 3 R 4 Together with the N atoms they are attached to form The Each is independently selected from -S(O)2-R 15 -COOH and -COOR 15 Group substitution; R 15 It is a C1-C4 alkyl group.

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

8. The compound according to claim 1 or 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, R 5 and R 6 Each is independently a C1-C4 alkyl group; Preferably, R 5 and R 6 Each is independently selected from methyl and ethyl.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, characterized in that, Ring A is a phenyl or a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group is pyridyl or N-oxypyridyl; preferably, ring A is... in This indicates the location where ring A connects to L, and ring A also connects to R. a1 and R a2 connect; R a2 Selected from H, halogens, and cyano groups; preferably, R a2 Selected from H, F and cyano; more preferably, when ring A is phenyl, R a2 Selected from H, F, and cyano groups; 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 Each is independently selected from C1-C4 alkyl and C1-C4 haloalkyl; preferably, R d1 and R d2 Each is independently selected from methyl and trifluoromethyl, and R d1 and R d2 They are not the same; R c1 and R c2 Each is independently selected from H, C1-C4 alkyl, and C1-C4 haloalkyl; preferably, R c1 and R c2 Each is independently selected from H and methyl, and R c1 and R c2 They are not the same; R e For H or D; preferably, R e For H; Ring B is phenyl or pyridyl; preferably, ring B is phenyl; more preferably, ring B is R. b1 R b2 and R b3 The phenyl groups are connected to the following positions respectively: R b1 R b2 and R b3 Each is independently selected from halogens, C1-C4 alkoxy groups, C1-C4 deuterated alkoxy groups, and C1-C4 haloalkoxy groups, or each is independently selected from halogens and C1-C4 alkoxy groups; preferably, R b1 R b2 and R b3 Each is independently selected from F and methoxy; more preferably, R b1 and R b2 For F, R b3 It is a methoxy group.

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

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

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

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

8.

14. Use of the compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label or prodrug thereof, or the pharmaceutical composition of claim 11 or the pharmaceutical formulation of claim 12 in the preparation of a medicament for the prevention, relief and / or treatment of voltage-gated sodium channel-related diseases or conditions; Preferably, the voltage-gated sodium channel is Na v 1.8; and / or, Preferably, the voltage-gated sodium channel-related diseases or conditions include pain, arthritis, epilepsy or epilepsy symptoms, neurodegenerative diseases, mental disorders (preferably anxiety or depression), bipolar disorder, myotonia, movement disorders, neuroendocrine disorders, ataxia, irritable bowel syndrome, stroke, cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis (ALS), stress- or exercise-induced angina, palpitations, hypertension, multiple sclerosis, Sharma-Turia syndrome, peroneal muscular atrophy, incontinence, pathological cough, arrhythmia, and abnormal gastrointestinal activity.

15. Use of the compound of any one of claims 1-10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, isotope label, or prodrug thereof, or the pharmaceutical composition of claim 11, or the pharmaceutical formulation of claim 12, in the preparation of a medicament for the prevention, relief, and / or treatment of pain.

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

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