Compound, preparation method therefor, and use thereof

Abstract

The present invention relates to the field of biomedicine, in particular to a compound, a preparation method therefor, and a use thereof. In particular, the present application relates to a compound represented by formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound, or polymorph thereof, a preparation method therefor, a pharmaceutical composition comprising same, and a use thereof. The compound can be used as a sodium ion channel inhibitor and has an analgesic effect. The compound of the present application also has a plurality of excellent properties.

Description

Compound, preparation method and use thereof Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a class of compounds or pharmaceutically acceptable salts, stereoisomers, solvates, isotope-labeled compounds or polymorphs thereof, preparation methods thereof, pharmaceutical compositions containing the same, and uses thereof. Background Art

[0002] Pain is one of the most common clinical symptoms and the fifth vital sign after respiration, pulse, blood pressure, and body temperature, seriously affecting patients' quality of life. According to statistics, the global analgesic market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023. Among them, acute, moderate, and severe pain mainly relies on opioids, accounting for about two-thirds of the analgesic market share and will grow steadily at a compound annual growth rate of 2.5% in the future. The number of patients with chronic pain, mainly neuropathic pain and arthritis pain, is increasing year by year, and the market is expected to show a compound annual growth rate of approximately 18%, which will be the main driving force for the continued growth of the global pain market in the next decade.

[0003] Neuropathic pain is a type of chronic pain caused by damage or disease of the peripheral somatic sensory nervous system. Its symptoms include spontaneous pain and hyperalgesia to normal, harmless stimuli. Common causes of neuropathic pain include diabetes, herpes zoster, spinal cord injury, stroke, multiple sclerosis, cancer, HIV infection, lumbar or cervical radiculopathy, and traumatic or postoperative nerve damage. Osteoarthritis, also known as degenerative arthritis, is a degeneration of the cartilage in the joints caused by various factors. It can lead to uneven joint bone surfaces and the formation of bone spurs. The main clinical manifestations are joint pain and stiffness. Long-term pain not only affects patients' sleep, work, and life abilities, but also increases the incidence of emotional disorders such as depression or anxiety, thus placing a heavy economic burden on patients' families and society.

[0004] Opioid receptors (μ, δ, and κ) are widely present in the central and peripheral nervous systems. Traditional opioid receptor agonists (such as morphine and its derivatives) are the most effective drugs for treating moderate to severe pain caused by chronic arthritis, inflammatory neuralgia, postoperative pain, and various cancers.

[0005] CN 101627049 B discloses a class of synthetic peptide amides having polypeptide chains, which can serve as ligands for kappa opioid receptors. Further research is needed to determine whether these peptides can be developed into drugs.

[0006] The inward current of voltage-gated sodium channels (Nav) is a key component in the generation and conduction of action potentials in central and peripheral neurons. Increased neuronal excitability, or increased responsiveness to stimuli, is a key mechanism in the development and progression of various pain conditions. Therefore, the role of voltage-gated sodium channels in pain transmission pathways, particularly in peripheral sensory neurons, has been a hot topic in pain research.

[0007] There are nine types of human sodium channels, namely Nav1.1 to Nav1.9. Nav1.5, Nav1.8, and Nav1.9 are tetrodotoxin (TTX)-insensitive sodium channels. Among them, Nav1.8 is mainly expressed on afferent neurons, including sensory neurons. By controlling the flow of sodium ions into and out of cells, it plays an important role in maintaining the excitability of nociceptive sensory neurons, the firing and persistence of action potentials, and the regulation of pain sensitivity. Patients with activating mutations in NaV1.8 experience paroxysmal pain caused by small fiber neuropathy (damage to Aδ fibers and unmyelinated C-type fibers, which are mainly responsible for pain transmission). Diseases such as chronic inflammation and diabetes can cause increased expression of NaV1.8 or changes in its properties, thereby sensitizing nociceptive neurons and causing various types of pain. NaV1.8 gene knockout mice are insensitive to pain.

[0008] With the established role of NaV1.8 in chronic pain, drug research targeting this target has intensified. Currently, one small molecule inhibitor is recruiting for Phase 3 clinical trials internationally, while several other small molecule inhibitors and antibodies are in preclinical development. In China, Jimin Kexin has a small molecule inhibitor in Phase 1 clinical trials. At the forefront of research and development is Vertex's small molecule NaV1.8 blocker, VX-548. Phase 2 clinical trials have yielded positive results in patients with acute pain following bunionectomy and abdominoplasty surgery, and Vertex is preparing for Phase 3 clinical trials. Furthermore, the mechanism of action and Phase 2 clinical trials of NaV1.8 blockers suggest a broad range of indications, including neuropathic pain, osteoarthritis pain, and acute injury pain. They are also relatively safe, lacking the addictive potential and the gastrointestinal and cardiovascular side effects of nonsteroidal anti-inflammatory drugs. They can be combined with other analgesics to enhance efficacy and minimize side effects. Summary of the Invention

[0009] On one hand, the present application provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof. Such compound can be used as a sodium ion channel inhibitor and has analgesic effect. The compound of the present application also has multiple excellent properties, such as not only having stronger analgesic activity in vivo and in vitro, but also having better pharmacokinetics. The compound has the following structure:

[0010] in:

[0011] R a Selected from

[0012] Y 1 、Y 2 、Y 3 、Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ;

[0013] R a1 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and -S(O)2R 1 ;

[0014] R a2 Each independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 1-6 Cycloalkyl, -NR 2 R 3 、-NHC(O)R 4 、-C(O)OR 5 、-C(O)NR 6 R 7 SR 8 、-S(O)R 9 、-S(O)2R 10 、-S(O)2NR 11 R 12 、-S(O)(NR 13 )R 14 、-P(O)R 15 R 16 and The C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 19 R 20 substituted by a substituent;

[0015] Or adjacent R a1 and R a2 Or two R a2 The carbon atom to which it is attached forms a 5-6 membered heteroaromatic ring;

[0016] R 1 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 19 、R 20 Each independently selected from H and C 1-6 alkyl;

[0017] R 2 、R 3 Each independently selected from H, C 1-6 Alkyl and carbonyl substituted C 1-6 alkyl;

[0018] R 4 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 2-6 alkenyl;

[0019] R 17 、R 18 Each independently selected from H and C 1-6 Alkyl, or R 17 、R 18 Together with the boron and oxygen atoms connected thereto, a 5-10 membered heterocyclic group is formed, wherein the 5-10 membered heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-6 substituted by an alkyl substituent;

[0020] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ;

[0021] R a3 Each independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl, -NR 21R 22 、-NHC(O)R 23 、-C(O)OR 24 、-C(O)NR 25 R 26 、-SR 27 、-S(O)R 28 、-S(O)2R 29 、-S(O)2NR 30 R 31 、-S(O)(NR 32 )R 33 、-P(O)R 34 R 35 and The C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 38 R 39 substituted by a substituent;

[0022] Or two adjacent R a3 The carbon atom to which it is connected forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally substituted by one or more OH, C 1-6 alkyl;

[0023] R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 38 、R 39 Each independently selected from H and C 1-6 alkyl;

[0024] R 21 、R 22 Each independently selected from H, C 1-6 Alkyl, carbonyl substituted C 1-6 Alkyl and -C(O)OC 1-6 alkyl;

[0025] R 23 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 2-6alkenyl;

[0026] R 36 、R 37 Each independently selected from H and C 1-6 Alkyl, or R 36 、R 37 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-6 substituted by an alkyl substituent;

[0027] V is selected from N, N + -O - and CR a4 ;

[0028] R a4 Selected from H and C 1-6 alkyl;

[0029] R a5 Selected from H and C 1-6 alkyl;

[0030] R a6 Selected from H and C 1-6 alkyl;

[0031] R b1 and R b2 are each independently selected from H and deuterium;

[0032] R b3 and R b4 Each independently selected from H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0033] R b5 and R b6 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl, or R b5 、R b6 Together with the attached carbon atom, it forms C 3-5 Cycloalkyl and 4-6 membered heterocyclic groups;

[0034] R c Selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 、C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl substituent are substituted, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl are optionally substituted with one or more halogen, C 1-6 Alkyl substitution;

[0035] R 40 、R 41 Each independently selected from H and C 1-6 alkyl;

[0036] X 1 、X 2 、X 3 、X 4 Each independently selected from N and CR c1 ;

[0037] R c1 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

[0038] The present invention also provides a compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein the compound has the following structure:

[0039] Among them, R a Selected from

[0040] Y 1 、Y 2 、Y 3 、Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ;

[0041] R a1 Each independently selected from -S(O)2-R 42 ;

[0042] R a2 Each independently selected from H and C 1-6 alkyl;

[0043] R 42 Each independently selected from C 1-6 Haloalkyl and C 3-6 Cycloalkyl; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ;

[0044] R a3 Each independently selected from

[0045] H, halogen, -N3, -NO2, -SCN, -S(F)5, -CH(O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)NR 43 R 44 、-C(O)NR 45 S(O)2NR 46 R 47 、-C(S)NR 48 R 49 、-C(=NR 50 )NR 51 R 52 、-C(=NR 53 )R 54 、-NR 55 R 56 、-NR 57 S(O)2R 58 、-NR 59 S(O)2NR 60 R 61 、-N=S(O)R 62 R 63 、-OS(O)2R 64 、-S(O)2R 65 、-S(O)2NR 66 R 67 、-Si(OR 68 )3. The C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl are optionally substituted with one or more halogen, hydroxyl, -CN, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)OR 71 、-C(O)NR 72 R 73 Substituents substituted;

[0046] Or two adjacent R a3 The carbon atom to which it is connected forms a 5-6 membered heterocyclic group or a 5-10 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-10 membered heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, amino, -CN, =O, C 1-6 Alkyl, -C 1-6 Alkyl NR 74 R 75 Substituents substituted;

[0047] R 43 、R 44 、R 50 、R 53 Each independently selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 alkoxy;

[0048] R 45 、R 46 、R 47 、R 48 、R 49 、R 51 、R 52 、R 54 、R 57 、R 59 、R 62 、R 63 、R 68 、R 71 、R 72 、R 73 、R 74 、R 75 Each independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0049] R 55 、R 56 、R 66 、R 67 Each independently selected from H, hydroxyl, -CN, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 2-6Alkenyl, -C(O)C 2-6 Alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The 3-6 membered cycloalkyl and 3-6 membered heterocyclic groups are optionally halogen, hydroxyl, amino, -CN, N3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino substitution;

[0050] R 58 independently selected from halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, N3 substituent substitution;

[0051] R 60 、R 61 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, N3 substituent substitution;

[0052] R 64 independently selected from halogen, amino and C 1-6 Alkylamino;

[0053] R 65 Independently selected from halogen, N3, C 1-6 Alkyl and C 1-6 alkyl halide;

[0054] R 69 、R 70 are independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl is optionally substituted with hydroxyl and amino; or R 69 、R 70 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-4 substituted by an alkyl group and a =O substituent;

[0055] L 1 , L 2 are each independently selected from O and N;

[0056] V is selected from N, N + -O - and CR a4 ;

[0057] R a4 Selected from H and C 1-6 alkyl;

[0058] R a5 Selected from H and C 1-6 alkyl;

[0059] R a6 Selected from H and C 1-6 alkyl;

[0060] R a7 Selected from H and C 1-6 alkyl;

[0061] R b1 and R b2 are each independently selected from H and deuterium;

[0062] R b3 and R b4 Each independently selected from H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0063] R b5 and R b6 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl, or R b5 、R b6 Together with the attached carbon atom, it forms C 3-5 Cycloalkyl and 4-6 membered heterocyclic groups;

[0064] R c Selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 、C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl substituent are substituted, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl are optionally substituted with one or more halogen, C 1-6 Alkyl substitution;

[0065] R 40 、R 41 Each independently selected from H and C 1-6 alkyl;

[0066] X 1 、X 2 、X 3 、X 4 Each independently selected from N and CR c1 ;

[0067] R c1 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

[0068] On the other hand, the present application also provides a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of a compound represented by Formula I or Formula II of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, and one or more pharmaceutically acceptable carriers.

[0069] On the other hand, the present application also provides a medicine kit comprising a compound represented by Formula I or Formula II of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, or a pharmaceutical composition of the present application.

[0070] On the other hand, the present application also provides the use of the compound represented by Formula I or Formula II of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph, or the pharmaceutical composition of the present application, or the medicine kit of the present application in the preparation of drugs for preventing and / or treating NaV1.8-related diseases. Preferably, the NaV1.8-related disease is pain.

[0071] On the other hand, the present application also provides a compound represented by Formula I or Formula II of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, or a pharmaceutical composition of the present application or a medicine kit of the present application, for preventing and / or treating NaV1.8-related diseases. Preferably, the NaV1.8-related disease is pain.

[0072] On the other hand, the present application also provides a method for preventing and / or treating NaV1.8-related diseases, comprising administering to an individual a therapeutically effective amount of a compound shown in Formula I or Formula II of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, or a pharmaceutical composition of the present application or a medicine kit of the present application. Preferably, the NaV1.8-related disease is pain.

[0073] On the other hand, the present application also provides a method for preparing the compound represented by Formula I or Formula II of the present application.

[0074] Definition and Description

[0075] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0076] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0077] Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, chemical elements are defined according to the Periodic Table of the Elements, CAS version, and the Handbook of Chemicals, 75th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0078] The term "alkyl" herein refers to a saturated straight or branched aliphatic hydrocarbon group of 1 to 20 carbon atoms, wherein the alkyl group may be independently optionally substituted with one or more substituents described herein. 1-6 "Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms. The term "C 1-4 "Alkyl" refers to a straight or branched chain group having 1 to 4 carbon atoms, which is optionally substituted with one or more (such as 1 to 4) suitable substituents such as halogen. Examples of alkyl groups also include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (-Bu, -CH2CH2CH2CH3), 2-methylpropyl or isobutyl (i-Bu, -CH2CH(CH3)2) 2), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH 2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2 -pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein include both straight and branched saturated carbon chains.

[0079] The term "alkoxy" herein refers to an alkyl group connected to a main carbon chain via an oxygen atom. The "alkyl" group is as defined above. For example, the term "C 1-12 "Alkoxy" refers to "C 1-12In one embodiment, the alkoxy group contains 1-12 carbon atoms. In another embodiment, the alkoxy group contains 1-4 carbon atoms. In yet another embodiment, the alkoxy group contains 1-3 carbon atoms. Such examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy or n-hexoxy, etc.

[0080] The term "cycloalkyl" herein refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including spirocyclic, fused or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (including cyclic, bridged or spirocyclic) hydrocarbon ring having 3 to 10 ring carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, wherein the substituents may be, but are not limited to, oxo (=O), fluorine, chlorine, bromine, iodine, hydroxyl, amino, -C(=O)-NH2, carboxyl, -S(=O) t OH,-OS(=O) t -H, -S(=O) t NH2, triazolyl, tetrazolyl, -(CR 3b R 3c ) n -NH2, alkyl, alkyl-S(=O) t -, haloalkyl, hydroxyalkyl, alkoxy, alkylamino, alkylthio, haloalkoxy, amino, aryl, heteroaryl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkanoyl, benzyl, cyclopropyl, phenyl, alkyl-C(=O)-, alkyl-C(=O)-NH-, formamido or alkoxyalkyl, etc., t is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. For example, C3-8 cycloalkyl, C3-6 cycloalkyl.

[0081] Examples of cycloalkyl groups further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like.

[0082] As used herein, the term "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.

[0083] As used herein, the term "halo" refers to substitution with one or more (such as 1 to 3) the same or different halogen atoms.

[0084] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. For example, the term "C 1-6 The term "haloalkyl" refers to a halogenated alkyl group having 1 to 6 carbon atoms, for example, -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3.

[0085] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted by one or more (such as 1 to 3) the same or different halogen atoms. For example, the term "C 1-6 The term "haloalkoxy" refers to a haloalkoxy group having 1 to 6 carbon atoms, for example, -O-CF3, -O-C2F5, -O-CHF2, -O-CH2F, -O-CH2CF3, -O-CH2Cl or -O-CH2CH2CF3, etc.

[0086] As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and one of its hydrogen atoms being replaced by a bond. Alkenyl can be a straight or branched alkenyl and contains approximately 2 to approximately 15 carbon atoms. In one embodiment, alkenyl contains approximately 2 to approximately 12 carbon atoms. In another embodiment, alkenyl contains approximately 2 to approximately 6 carbon atoms. Non-limiting examples of alkenyl include vinyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, and decenyl. Alkenyl may be unsubstituted alkenyl or substituted with one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halogen, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH2, -NH(alkyl), -N(alkyl), -NH(cycloalkyl), -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(O)OH, and -C(O)O-alkyl. The term "C2-6 "Alkenyl" refers to an alkenyl group of 2 to 6 carbon atoms.

[0087] As used herein, the term "heterocycle" or "heterocyclyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic group, for example, having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., 1, 2, 3 or 4) independently selected from N, O or S(O) in the ring. t (wherein t is 0, 1 or 2) a heteroatom, such as a 3-12 membered heterocyclyl, a 3-10 membered heterocyclyl, a 3-9 membered heterocyclyl, a 3-8 membered heterocyclyl, a 3-7 membered heterocyclyl, a 3-6 membered heterocyclyl, a 5-6 membered heterocyclyl, etc. Representative examples of heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyrrolidinyl, hexahydro-1H-pyrroline, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydropyridinyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, etc.

[0088] As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, the term "C 6-10 Aryl" or "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring). The aromatic group or aromatic ring is optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0089] In this article, term " heteroaryl " refers to a cyclic group with aromaticity, wherein at least one ring atom is a heteroatom, such as a nitrogen atom, an oxygen atom, a boron atom or a sulfur atom. Optionally, the ring atoms (such as carbon atoms, nitrogen atoms or sulfur atoms) in the ring structure can be oxoed. Specific examples include but are not limited to 5-10 yuan heteroaryl, 6-10 yuan heteroaryl, 5-10 yuan nitrogen-containing heteroaryl, 6-10 yuan oxygen-containing heteroaryl, 6-8 yuan nitrogen-containing heteroaryl, 5-8 yuan oxygen-containing heteroaryl, such as furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridinyl, 2-pyridonyl, 4-pyridonyl, pyrimidinyl, 1,4-dioxadienyl, 2H-1,2-oxazinyl, 4H-1,2-oxazinyl, 6H-1,2-oxazinyl, 4H-1,3-oxazinyl, 6H-1,3-oxazinyl, 4H-1,4-oxazinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azacycloheptatrienyl, 1,3-diazacycloheptatrienyl, azacyclooctatetraenyl, and the like.

[0090] The hydrogen in the groups involved in the present invention may be replaced by isotopes such as protium, deuterium, and tritium.

[0091] The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence in the current context is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0092] If a substituent is described as being "optionally substituted with," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected substituents or unsubstituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected substituent or unsubstituted.

[0093] If a substituent is described as being "independently selected" from a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0094] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.

[0095] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0096] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0097] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of suitable isotopes for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H. 3 H, deuterium D, tritium T); carbon isotopes (such as 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 37 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to monitor. 11 C. 18 F. 15 O and 13N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0098] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., 1, 2, 3, or 4) asymmetric centers, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0099] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0100] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0101] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases that form pharmaceutically acceptable salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.

[0102] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound. The amount of the polar solvent, especially water, may be present in a stoichiometric or non-stoichiometric ratio.

[0103] Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0104] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0105] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity, and when administered to the body or thereon, can be converted into the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (E.B. Roche, ed., American Pharmaceutical Association). The prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985)).

[0106] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P.GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0107] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0108] This application is in no way limited to the methods and materials described herein. In the event that one or more of the combined literature, patents, and similar materials differ from or contradict this application (including but not limited to defined terms, term applications, described technologies, etc.), the description of this application and the accompanying structural formula shall prevail.

[0109] Compound

[0110] One object of the present application is to provide a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof:

[0111] in:

[0112] R a Selected from

[0113] Y 1 、Y 2 、Y 3 、Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ;

[0114] R a1 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and -S(O)2R 1 ;

[0115] R a2 Each independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 1-6 Cycloalkyl, -NR 2 R 3 、-NHC(O)R 4 、-C(O)OR 5 、-C(O)NR 6 R 7 、-SR 8 、-S(O)R 9 、-S(O)2R 10 、-S(O)2NR 11 R 12、-S(O)(NR 13 )R 14 、-P(O)R 15 R 16 and The C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 19 R 20 substituted by a substituent;

[0116] Or adjacent R a1 and R a2 Or two R a2 The carbon atom to which it is attached forms a 5-6 membered heteroaromatic ring;

[0117] R 1 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 19 、R 20 Each independently selected from H and C 1-6 alkyl;

[0118] R 2 、R 3 Each independently selected from H, C 1-6 Alkyl and carbonyl substituted C 1-6 alkyl;

[0119] R 4 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 2-6 alkenyl;

[0120] R 17 、R 18 Each independently selected from H and C 1-6 Alkyl, or R 17 、R 18 Together with the boron and oxygen atoms connected thereto, a 5-10 membered heterocyclic group is formed, wherein the 5-6 membered heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-6 substituted by an alkyl substituent;

[0121] Z1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ;

[0122] R a3 Each independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl, -NR 21 R 22 、-NHC(O)R 23 、-C(O)OR 24 、-C(O)NR 25 R 26 、-SR 27 、-S(O)R 28 、-S(O)2R 29 、-S(O)2NR 30 R 31 、-S(O)(NR 32 )R 33 、-P(O)R 34 R 35 and The C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 38 R 39 substituted by a substituent;

[0123] Or two adjacent R a3 The carbon atom to which it is connected forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally substituted by one or more OH, C 1-6 alkyl;

[0124] R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33、R 34 、R 35 、R 38 、R 39 Each independently selected from H and C 1-6 alkyl;

[0125] R 21 、R 22 Each independently selected from H, C 1-6 Alkyl and carbonyl substituted C 1-6 Alkyl and -C(O)OC 1-6 alkyl;

[0126] R 23 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 2-6 alkenyl;

[0127] R 36 、R 37 Each independently selected from H and C 1-6 Alkyl, or R 36 、R 37 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-6 substituted by an alkyl substituent;

[0128] V is selected from N, N + -O - and CR a4 ;

[0129] R a4 Selected from H and C 1-6 alkyl;

[0130] R a5 Selected from H and C 1-6 alkyl;

[0131] R a6 Selected from H and C 1-6 alkyl;

[0132] R b1 and R b2 are each independently selected from H and deuterium;

[0133] R b3 and R b4 Each independently selected from H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0134] R b5 and Rb6 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl, or R b5 、R b6 Together with the attached carbon atom, it forms C 3-5 Cycloalkyl and 4-6 membered heterocyclic groups;

[0135] R c Selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 、C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl substituent are substituted, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl are optionally substituted with one or more halogen, C 1-6 Alkyl substitution;

[0136] R 40 、R 41 Each independently selected from H and C 1-6 alkyl;

[0137] X 1 、X 2 、X 3 、X 4 Each independently selected from N and CR c1 ;

[0138] R c1 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

[0139] In some embodiments, the compound of formula I of the present application, wherein:

[0140] R a Selected from

[0141] Y 1 、Y 2 、Y 3 、Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ;

[0142] R a1 Each independently selected from H, C 1-4 Alkyl (e.g. methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g., CF3, CHF2, CH2F) and -S(O)2R 1 (e.g. -S(O)2CH3);

[0143] R a2 Each is independently selected from H, halogen (such as fluorine, chlorine, bromine, iodine), hydroxyl, -CN, C 1-4 Alkyl (e.g. methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g. CF3, CHF2, CH2F), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, C 1-4 Cycloalkyl, -NR 2 R 3 、-NHC(O)R 4 、-C(O)OR 5 、-C(O)NR 6 R 7 SR 8 、-S(O)R 9 、-S(O)2R 10 、-S(O)2NR 11 R 12 、-S(O)(NR 13 )R 14 、-P(O)R 15 R 16 and The C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 19 R 20 substituted by a substituent;

[0144] Or adjacent Ra1 and R a2 Or two R a2 The carbon atom to which it is attached forms a 5-6 membered heteroaromatic ring;

[0145] R 1 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 19 、R 20 Each independently selected from H and C 1-4 alkyl;

[0146] R 2 、R 3 Each independently selected from H, C 1-4 Alkyl and carbonyl substituted C 1-4 alkyl;

[0147] R 4 Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl and C 2-6 alkenyl;

[0148] R 17 、R 18 Each independently selected from H and C 1-4 Alkyl, or R 17 、R 18 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-4 substituted by an alkyl substituent;

[0149] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ;

[0150] R a3 Each is independently selected from H, halogen (such as fluorine, chlorine, bromine, iodine), hydroxyl, -CN, C 1-4 Alkyl (e.g. methyl, ethyl, propyl, butyl), C1-4 Haloalkyl (e.g. CF3, CHF2, CH2F), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, C 1-4 Cycloalkyl, -NR 21 R 22 、-NHC(O)R 23 、-C(O)OR 24 、-C(O)NR 25 R 26 、-SR 27 、-S(O)R 28 、-S(O)2R 29 、-S(O)2NR 30 R 31 、-S(O)(NR 32 )R 33 、-P(O)R 34 R 35 and The C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 38 R 39 substituted by a substituent;

[0151] Or two adjacent R a3 The carbon atom to which it is connected forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally substituted by one or more OH, C 1-6 Alkyl substitution;

[0152] R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 38 、R 39 Each independently selected from H and C 1-4 alkyl;

[0153] R 21 、R 22 Each independently selected from H, C 1-4 Alkyl, carbonyl substituted C 1-4Alkyl and -C(O)OC 1-4 alkyl;

[0154] R 23 Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl and C 2-6 alkenyl;

[0155] R 36 、R 37 Each independently selected from H and C 1-4 Alkyl, or R 36 、R 37 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-4 substituted by an alkyl substituent;

[0156] V is selected from N, N + -O - and CR a4 ;

[0157] R a4 Selected from H and C 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl);

[0158] R a5 Selected from H and C 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl);

[0159] R a6 Selected from H and C 1-4 Alkyl (eg, methyl, ethyl, propyl, butyl).

[0160] In some embodiments, the compound of formula I of the present application, wherein:

[0161] R a Selected from

[0162] Y 1 、Y 2 、Y 3 、Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ;

[0163] R a1 Each independently selected from H, methyl, CF3, CHF2 and -S(O)2CH3;

[0164] R a2Each independently selected from H, fluorine, chlorine, methyl, CF3, CHF2, -C(O)NH2, -NH2 and

[0165] Or adjacent R a1 and R a2 Or two R a2 The carbon atom to which it is attached forms a 5-6 membered heteroaromatic ring;

[0166] R 17 、R 18 Each independently selected from H and C 1-4 Alkyl, or R 17 、R 18 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-4 substituted by an alkyl substituent;

[0167] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ;

[0168] R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -NR 21 R 22 、-NC(O)R 23 、-C(O)OR 24 、-C(O)NR 25 R 26 、-SR 27 、-S(O)R 28 、-S(O)2R 29 、-S(O)2NR 30 R 31 、-S(O)(NR 32 )R 33 、-P(O)R 34 R 35 and

[0169] Or two adjacent R a3The carbon atom to which it is attached forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the heterocyclic group is optionally substituted by one or more hydroxyl groups or methyl groups;

[0170] R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 Each independently selected from H and C 1-4 alkyl;

[0171] R 21 、R 22 Each independently selected from H, C 1-4 Alkyl and carbonyl substituted C 1-4 alkyl;

[0172] R 23 Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl and C 2-6 alkenyl;

[0173] R 36 、R 37 Each independently selected from H and C 1-4 Alkyl, or R 36 、R 37 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-4 substituted by an alkyl substituent;

[0174] V is selected from N, N + -O - and CR a4 ;

[0175] R a4 selected from H and methyl;

[0176] R a5 selected from H and methyl;

[0177] R a6 is selected from H and methyl.

[0178] In some embodiments, the compound of formula I of the present application, wherein:

[0179] R a3Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -NR 21 R 22 、-NC(O)R 23 、-C(O)OR 24 、-C(O)NR 25 R 26 、-SR 27 、-S(O)R 28 、-S(O)2R 29 、-S(O)2NR 30 R 31 、-S(O)(NR 32 )R 33 、-P(O)R 34 R 35 and

[0180] Or two adjacent R a3 The carbon atom to which it is attached forms

[0181] R 24 、R 25 、R 26 、R 27 、R 28 、R 29 、R 30 、R 31 、R 32 、R 33 、R 34 、R 35 Each independently selected from H and C 1-4 alkyl;

[0182] R 21 、R 22 Each independently selected from H, C 1-4 Alkyl and carbonyl substituted C 1-4 alkyl;

[0183] R 23 Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl and C 2-6 Alkenyl.

[0184] In some embodiments, in the compound of formula I of the present application, R a3each independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -N(CH3)-Boc, -NH(CH3), -N(CH3)2, -C(O)OCH3, -C(O)NH2, -SH, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -P(O)(CH3)2, and

[0185] Or two adjacent R a3 The carbon atom to which it is attached forms

[0186] In some embodiments, in the compound of formula I of the present application, R b3 and R b4 Each independently selected from H, deuterium, C 1-4 Alkyl (such as methyl, ethyl, propyl and butyl), C 1-4 Haloalkyl and C 3-6 Cycloalkyl.

[0187] In some embodiments, in the compound of formula I of the present application, R b3 and R b4 are each independently selected from H, deuterium and methyl.

[0188] In some embodiments, in the compound of formula I of the present application, R b5 and R b6 Each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl, or R b5 、R b6 Together with the attached carbon atom, it forms C 3-5 cycloalkyl and 4- to 6-membered heterocyclic groups (e.g., 4- to 6-membered oxygen-containing heterocyclic groups).

[0189] In some embodiments, in the compound of formula I of the present application, R b5 and R b6 are each independently selected from H, methyl, cyclopropyl and trifluoromethyl, or R b5 、R b6 The carbon atom to which it is connected forms a cyclobutyl group, a cyclopentyl group and a 4-6 membered oxygen-containing heterocyclic group.

[0190] In some embodiments, in the compound of formula I of the present application, R b5 and Rb6 are each independently selected from H, methyl, cyclopropyl and trifluoromethyl, or R b5 、R b6 The carbon atom to which it is attached forms a cyclobutyl group and

[0191] In some embodiments, in the compound of formula I of the present application, R b5 and R b6 Each is independently selected from H, methyl, cyclopropyl and trifluoromethyl.

[0192] In some embodiments, in the compound of formula I of the present application, R b5 Selected from methyl, R b6 Selected from trifluoromethyl.

[0193] In some embodiments, in the compound of formula I of the present application, R c Selected from H, hydroxy, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 、C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl substituent are substituted, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl substitution; R 40 、R 41 Each independently selected from H and C 1-4 alkyl.

[0194] In some embodiments, in the compound of formula I of the present application, X 1 、X 2 、X 3 、X 4 Each independently selected from CR c1 .

[0195] In some embodiments, in the compound of formula I of the present application, R c1 are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0196] In some embodiments, in the compound of formula I of the present application, R c1 Each is independently selected from H, F, Cl, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl, methoxy, ethoxy, propoxy, butoxy, fluoromethoxy, fluoroethoxy and fluoropropoxy.

[0197] In some embodiments, in the compound of formula I of the present application, R c1 Each is independently selected from H, F, methyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methoxy and difluoromethoxy.

[0198] In some embodiments, in the compound of formula I of the present application, wherein R a Selected from:

[0199] In some embodiments, in the compound of formula I of the present application, wherein R a Selected from:

[0200] In some embodiments, in the compound of formula I of the present application, wherein R c Selected from H, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, -OCHF2,

[0201] In some embodiments, the compound of the present invention is selected from:

[0202] In some embodiments, the compound of the present invention is selected from:

[0203] Another aspect of the present invention is to provide a compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein the compound has the following structure:

[0204] Among them, R a Selected from

[0205] Y 1 、Y 2 、Y 3 、Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ;

[0206] R a1 Each independently selected from -S(O)2-R 42 ;

[0207] R a2 Each independently selected from H and C 1-6 alkyl;

[0208] R 42 Each independently selected from C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0209] Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ;

[0210] R a3 Each independently selected from H, halogen, -N3, -NO2, -SCN, -S(F)5, -CH(O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)NR 43 R 44、-C(O)NR 45 S(O)2NR 46 R 47 、-C(S)NR 48 R 49 、-C(=NR 50 )NR 51 R 52 、-C(=NR 53 )R 54 、-NR 55 R 56 、-NR 57 S(O)2R 58 、-NR 59 S(O)2NR 60 R 61 、-N=S(O)R 62 R 63 、-OS(O)2R 64 、-S(O)2R 65 、-S(O)2NR 66 R 67 、-Si(OR 68 )3. The C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl are optionally substituted with one or more halogen, hydroxyl, -CN, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)OR 71 、-C(O)NR 72 R 73 Substituents substituted;

[0211] Or two adjacent R a3 The carbon atom to which it is connected forms a 5-6 membered heterocyclic group or a 5-10 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-10 membered heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, amino, -CN, =O, C 1-6 Alkyl, -C 1-6 Alkyl NR 74 R 75 Substituents substituted;

[0212] R 43 、R 44 、R 50 、R 53 Each independently selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 alkoxy;

[0213] R 45 、R 46 、R 47 、R 48 、R 49 、R 51 、R 52 、R 54 、R 57 、R 59 、R 62 、R 63 、R 68 、R 71 、R 72 、R 73 、R 74 、R 75 Each independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0214] R 55 、R 56 、R 66 、R 67 Each independently selected from H, hydroxyl, -CN, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 2-6 Alkenyl, -C(O)C 2-6 Alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The 3-6 membered cycloalkyl and 3-6 membered heterocyclic groups are optionally halogen, hydroxyl, amino, -CN, N3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino substitution;

[0215] R 58 independently selected from halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, N3 substituent substitution;

[0216] R 60 、R 61 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6Alkylamino, N3 substituent substitution;

[0217] R 64 independently selected from halogen, amino and C 1-6 Alkylamino;

[0218] R 65 Independently selected from halogen, N3, C 1-6 Alkyl and C 1-6 alkyl halide;

[0219] R 69 、R 70 are independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl is optionally substituted with hydroxyl and amino; or R 69 、R 70 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-4 substituted by an alkyl group and a =O substituent;

[0220] L 1 , L 2 are each independently selected from O and N;

[0221] V is selected from N, N + -O - and CR a4 ;

[0222] R a4 Selected from H and C 1-6 alkyl;

[0223] R a5 Selected from H and C 1-6 alkyl;

[0224] R a6 Selected from H and C 1-6 alkyl;

[0225] R a7 Selected from H and C 1-6 alkyl;

[0226] R b1 and R b2 are each independently selected from H and deuterium;

[0227] R b3 and Rb4 Each independently selected from H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl;

[0228] R b5 and R b6 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl, or R b5 、R b6 Together with the attached carbon atom, it forms C 3-5 Cycloalkyl and 4-6 membered heterocyclic groups;

[0229] R c Selected from H, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 、C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl substituent are substituted, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl are optionally substituted with one or more halogen, C 1-6 Alkyl substitution;

[0230] R 40 、R 41 Each independently selected from H and C 1-6 alkyl;

[0231] X 1 、X 2 、X 3 、X 4 Each independently selected from N and CR c1 ;

[0232] R c1 are each independently selected from H, halogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

[0233] In some embodiments, in the compound of formula II of the present application, R b1 and R b2 are each independently selected from H.

[0234] In some embodiments, in the compound of formula II of the present application, R b1 and R b2 are each independently selected from deuterium.

[0235] In some embodiments, in the compound of formula II of the present application, R b3 and R b4 Each is independently selected from H, deuterium, and methyl.

[0236] In some embodiments, in the compound of formula II of the present application, R b3 and R b4 All are selected from H.

[0237] In some embodiments, in the compound of formula II of the present application, R b5 and R b6 are each independently selected from H, methyl, cyclopropyl and trifluoromethyl, or R b5 、R b6 The carbon atom to which it is connected forms a cyclobutyl group, a cyclopentyl group and a 4-6 membered oxygen-containing heterocyclic group.

[0238] In some embodiments, in the compound of formula II of the present application, R b5 and R b6 are each independently selected from H, methyl, cyclopropyl and trifluoromethyl, or R b5 、R b6 The carbon atom to which it is attached forms a cyclobutyl group and

[0239] In some embodiments, in the compound of formula II of the present application, R b5 and R b6 Each is independently selected from H, methyl, cyclopropyl and trifluoromethyl.

[0240] In some embodiments, in the compound of formula II of the present application, R b5 Selected from methyl, R b6 Selected from trifluoromethyl.

[0241] In some embodiments, in the compound of formula II of the present application, R c Selected from H, hydroxy, halogen, C 1-4 Alkyl, C1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 、C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl substituent are substituted, wherein the 3-6 membered heterocyclic group and the 5-6 membered heteroaryl are optionally substituted with one or more halogen, C 1-4 Alkyl substitution; R 40 、R 41 Each independently selected from H and C 1-4 alkyl.

[0242] In some embodiments, in the compound of formula II of the present application, R c Selected from H, hydroxy, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy.

[0243] In some embodiments, in the compound of formula II of the present application, R c Selected from C 1-4 Alkoxy.

[0244] In some embodiments, in the compound of formula II of the present application, R c Selected from methoxy.

[0245] In some embodiments, in the compound of formula II of the present application, X 1 、X 2 、X 3 、X 4 Each independently selected from CR c1 .

[0246] In some embodiments, in the compound of formula II of the present application, R c1 are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4Halogenated alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

[0247] In some embodiments, in the compound of formula II of the present application, R c1 Each is independently selected from H, F, Cl, methyl, ethyl, propyl, butyl, fluoromethyl, fluoroethyl, fluoropropyl, methoxy, ethoxy, propoxy, butoxy, fluoromethoxy, fluoroethoxy and fluoropropoxy.

[0248] In some embodiments, in the compound of formula II of the present application, R c1 Each is independently selected from H, F, methyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methoxy and difluoromethoxy.

[0249] In some embodiments, in the compound of formula II of the present application, X 1 Selected from CR c1 , R c1 Selected from methoxy.

[0250] In some embodiments, in the compound of formula II of the present application, X 2 Selected from CR c1 , R c1 Selected from F.

[0251] In some embodiments, in the compound of formula II of the present application, X 3 Selected from CR c1 , R c1 Selected from F.

[0252] In some embodiments, in the compound of formula II of the present application, X 4 Selected from CR c1 , R c1 Selected from H.

[0253] In some embodiments, in the compound of formula II of the present application, Ra is selected from Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ; R a3 Each independently selected from H, halogen, -N3, -NO2, -SCN, -S(F)5, -CH(O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)NR43 R 44 、-C(O)NR 45 S(O)2NR 46 R 47 、-C(S)NR 48 R 49 、-C(=NR 50 )NR 51 R 52 、-C(=NR 53 )R 54 、-NR 55 R 56 、-NR 57 S(O)2R 58 、-NR 59 S(O)2NR 60 R 61 、-N=S(O)R 62 R 63 、-OS(O)2R 64 、-S(O)2R 65 、-S(O)2NR 66 R 67 、-Si(OR 68 )3. The C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl are optionally substituted with one or more halogen, hydroxyl, -CN, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)OR 71 、-C(O)NR 72 R 73 Substituents substituted;

[0254] Or two adjacent R a3 The carbon atom to which it is connected forms a 5-6 membered heterocyclic group or a 5-10 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-10 membered heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, amino, -CN, =O, C 1-6 Alkyl, -C 1-6 Alkyl NR 74 R 75 Substituents substituted;

[0255] R 43 、R 44 、R 50 、R 53 Each independently selected from H, hydroxyl, C 1-6 Alkyl and C1-6 alkoxy;

[0256] R 45 、R 46 、R 47 、R 48 、R 49 、R 51 、R 52 、R 54 、R 57 、R 59 、R 62 、R 63 、R 68 、R 71 、R 72 、R 73 、R 74 、R 75 Each independently selected from H, C 1-6 Alkyl and C 1-6 alkyl halide;

[0257] R 55 、R 56 、R 66 、R 67 Each independently selected from H, hydroxyl, -CN, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 2-6 Alkenyl, -C(O)C 2-6 Alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The 3-6 membered cycloalkyl and 3-6 membered heterocyclic groups are optionally halogen, hydroxyl, amino, -CN, N3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino substitution;

[0258] R 58 independently selected from halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, N3 substituent substitution;

[0259] R 60 、R 61 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C1-6 Alkylamino, N3 substituent substitution;

[0260] R 64 independently selected from halogen, amino and C 1-6 Alkylamino;

[0261] R 65 Independently selected from halogen, N3, C 1-6 Alkyl and C 1-6 alkyl halide;

[0262] R 69 、R 70 are independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl is optionally substituted with hydroxyl and amino; or R 69 、R 70 Together with the attached boron and oxygen atoms, a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group) is formed, wherein the heterocyclic group is optionally substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-4 substituted by an alkyl group and a =O substituent;

[0263] L 1 , L 2 are each independently selected from O and N.

[0264] In some embodiments, in the compound of formula II of the present application, R a Selected from one or more R 3a Substituted phenyl, pyridine and pyridazine, where R 3a Each independently selected from H, halogen, -N3, -NO2, -SCN, -S(F)5, -CH(O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)NR 43 R 44 、-C(O)NR 45 S(O)2NR 46 R 47 、-C(S)NR 48 R 49 、-C(=NR 50 )NR 51 R 52 、-C(=NR 53 )R 54、-NR 55 R 56 、-NR 57 S(O)2R 58 、-NR 59 S(O)2NR 60 R 61 、-N=S(O)R 62 R 63 、-OS(O)2R 64 、-S(O)2R 65 、-S(O)2NR 66 R 67 、-Si(OR 68 )3. The C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl are optionally substituted with one or more halogen, hydroxyl, -CN, amino, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)OR 71 、-C(O)NR 72 R 73 Substituents substituted;

[0265] Or two adjacent R a3 The carbon atom to which it is connected forms a 5-6 membered heterocyclic group or a 5-10 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-10 membered heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, amino, -CN, =O, C 1-6 Alkyl, -C 1-6 Alkyl NR 74 R 75 substituted by a substituent.

[0266] In some embodiments, in the compound of formula II of the present application, R a Selected from one or more R 3a Substituted phenyl, pyridine and pyridazine, where R 3a Each independently selected from F, N3, -SCN, N(H)CN, -S(O)2CHF2, -S(O)2CF3, SF5, -NO2, -S(O)2N(H)CN, -N=S(O)(CH3)2, -OS(O)2NH2, -NH(OH), -NHS(O)2NH2, -NHS(O)2CH2CH3, C(S)NH2, -S(O)2N3, -OS(O)2F, -NHS(O)2F, -S(O)2NH2, -CH(O), -C(O)NH(OH), Or two adjacent R a3 The carbon atom to which it is attached forms

[0267] In some embodiments, in the compound of formula II of the present application, R a Selected from one or more R 3a Replaced where R 3a Each independently selected from

[0268] In some embodiments, in the compound of formula II of the present application, R a Selected from Among them, R a7 Each selected from H.

[0269] In some embodiments, in the compound of formula II of the present application, R a Selected from Y 1 、Y 2 、Y 3 、Y 4 Each independently selected from O, S, N, NR a1 and CR a2 If present, R a1 Each independently selected from -S(O)2-C 3-6 Cycloalkyl, -S(O)2-C 1-6 Haloalkyl; R a2 Each independently selected from C 1-6 alkyl.

[0270] In some embodiments, in the compound of formula II of the present application, R a Selected from R a1 Each is independently selected from -S(O)2-cyclopropyl; R a2 are each independently selected from methyl.

[0271] In some embodiments, in the compound of formula II of the present application, wherein R a Selected from:

[0272] The groups of all embodiments of the present invention can be appropriately selected and combined in any combination to obtain different general formula ranges or specific schemes. These ranges and schemes all belong to the present invention. The present invention covers compounds obtained by any combination of the various embodiments.

[0273] In some embodiments, the compound of the present invention is selected from:

[0274] In some embodiments, the compound of the present invention is selected from:

[0275] Pharmaceutical compositions and kits

[0276] Another object of the present application is to provide a pharmaceutical composition comprising a preventive and / or therapeutically effective amount of a compound represented by Formula I or Formula II of the present application, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, and one or more pharmaceutically acceptable carriers.

[0277] Another object of the present application is to provide a kit comprising a compound of Formula I or Formula II of the present application, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound, or polymorph thereof, or a pharmaceutical composition of the present application. Optionally, the kit further comprises instructions for use.

[0278] As used herein, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with a therapeutic agent and is suitable, within the scope of sound medical judgment, for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0279] Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present application include, but are not limited to, sterile liquids. The pharmaceutical composition can be in the form of, for example, a solid preparation, a semi-solid preparation, a liquid preparation, or a gaseous preparation.

[0280] The pharmaceutical compositions of the present application can act systemically and / or locally. For this purpose, they can be administered by a suitable route, such as by injection or transdermal administration; or by oral administration or by inhalation administration.

[0281] The content or dosage of the compound of the present application in the pharmaceutical composition can be about 0.001 mg to about 5000 mg, suitably 0.01-1000 mg.

[0282] In some embodiments, the present application provides a method for preparing the pharmaceutical composition of the present application, which comprises combining the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph with one or more pharmaceutically acceptable carriers.

[0283] Treatment methods and uses

[0284] The present application also provides the use of the compound represented by Formula I or Formula II of the present application or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph, or the pharmaceutical composition of the present application or the medicine kit of the present invention in the preparation of a drug for preventing and / or treating NaV1.8-related diseases. Preferably, the NaV1.8-related diseases are pain, multiple sclerosis, Chuck-Male-Dodds syndrome, incontinence, pathological cough or arrhythmia.

[0285] The present application also provides a compound represented by Formula I or Formula II of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, or a pharmaceutical composition of the present application, or a medicine kit of the present invention for preventing and / or treating NaV1.8-related diseases. Preferably, the NaV1.8-related diseases are pain, multiple sclerosis, Chuck-Male-Dodds syndrome, incontinence, pathological cough or arrhythmia.

[0286] The present application also provides a method for preventing and / or treating NaV1.8-related diseases, comprising administering to an individual a therapeutically effective amount of a compound shown in Formula I or Formula II of the present application or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, or a pharmaceutical composition of the present application, or a medicine kit of the present invention. Preferably, the NaV1.8-related disease is pain, multiple sclerosis, Chuck-Male-Dodds syndrome, incontinence, pathological cough or arrhythmia.

[0287] In some embodiments of the invention, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, ICU analgesia, fracture or postoperative pain (e.g., bunionectomy pain, hernia repair pain, and abdominoplasty pain), neuropathic pain (e.g., neuralgia of peripheral neuropathy, postherpetic neuralgia, peripheral neuralgia, small fiber neuropathy pain, trigeminal neuralgia, idiopathic small fiber neuralgia, or diabetic neuralgia), visceral pain (e.g., intestinal pain), musculoskeletal pain, primary pain, idiopathic pain, osteoarthritis pain, gouty arthritis pain, rheumatic or rheumatoid arthritis pain, dental pain, joint pain, labor pain, fibromyalgia, chronic low back pain, painful bladder syndrome, and sciatica.

[0288] In some embodiments of the present invention, the pain is selected from postoperative pain, neuropathic pain (eg, postherpetic neuralgia, small fiber neuropathy pain, diabetic neuropathy), osteoarthritis pain, painful bladder syndrome, and cancer pain.

[0289] In some embodiments of the invention, the pain is selected from postoperative pain, such as bunionectomy pain, hernia repair pain, and abdominoplasty pain.

[0290] In some embodiments of the present invention, the pain is selected from neuropathic pain, such as postherpetic neuralgia, small fiber neuropathy pain, and diabetic neuropathy.

[0291] In some embodiments of the invention, the pain is selected from osteoarthritis pain.

[0292] In some embodiments of the invention, the pain is selected from painful bladder syndrome.

[0293] In some embodiments of the present invention, the pain is selected from cancer pain.

[0294] In some embodiments of the invention, the pain is selected from inflammatory pain.

[0295] In some embodiments of the invention, the pain is selected from neuropathic pain and inflammatory pain.

[0296] In some embodiments of the present invention, the compound of the present invention or the pharmaceutical composition of the present invention is administered once a day, twice a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, ten times a day, 11 times a day, 12 times a day, 13 times a day, 14 times a day, 15 times a day, 16 times a day, 17 times a day, 18 times a day, 19 times a day, 20 times a day, 21 times a day, 22 times a day, 23 times a day, 24 times a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, twice a week, three times a week, once every two weeks, three times every two weeks, once every three weeks, twice every three weeks, once every four weeks, or three times every four weeks.

[0297] In some embodiments, the dose of each administration of the compound of the present invention or the pharmaceutical composition of the present invention is selected from 0.1-500 mg / kg based on the body weight of the subject, for example 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg. / kg, 9mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, 105mg / kg, 110mg / kg, 115mg / kg, 12 0mg / kg, 125mg / kg, 130mg / kg, 135mg / kg, 140mg / kg, 145mg / kg, 150mg / kg, 160mg / kg, 165mg / kg, 170mg / kg, 180mg / kg , 190mg / kg, 200mg / kg, 210mg / kg, 22mg / kg, 230mg / kg, 240mg / kg, 250mg / kg, 260mg / kg, 270mg / kg, 280mg / kg, 290mg / kg, 300mg / kg, 310mg / kg, 320mg / kg, 330mg / kg, 340mg / kg, 350mg / kg, 360mg / kg, 370mg / kg, 380mg / kg, 390mg / kg, 400 mg / kg, 410mg / kg, 420mg / kg, 430mg / kg, 440mg / kg, 450mg / kg, 460mg / kg, 470mg / kg, 480mg / kg, 490mg / kg or 500mg / kg.

[0298] In some embodiments, the dosage of the compound of the invention or the pharmaceutical composition of the invention is 0.1-1000 mg, for example, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150mg, 160mg, 165mg, 170mg, 180mg, 190mg, 200mg, 210mg, 22mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg or 1000mg.

[0299] As used herein, the term "effective amount" refers to an amount sufficient to achieve the desired prophylactic or therapeutic effect, for example, to achieve relief of one or more symptoms associated with the disease being treated.

[0300] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the compounds of the present invention.

[0301] The amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In some cases, a dosage level no higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0302] As used herein, unless otherwise indicated, the terms "treat," ...

[0303] The term "prevention" refers to inhibiting and delaying the onset of a disease, and includes not only prevention before the development of a disease but also prevention of recurrence of a disease after treatment.

[0304] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0305] The ones used in this article Represents a join key. DETAILED DESCRIPTION

[0306] In order to make the purpose and technical scheme of the present invention clearer, the embodiments of the present invention are described in detail below in conjunction with embodiment.But those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.Unindicated specific conditions in the examples are all carried out according to the conditions of normal conditions or manufacturer's advice.Reagents used or instruments not indicated by manufacturer are all conventional products that can be obtained commercially.

[0307] The structures of the compounds in all examples were determined by NMR ( 1 H-NMR) was recorded on a Vian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were all by volume.

[0308] The present invention uses the following abbreviations: nuclear magnetic resonance (NMR); liquid chromatography-mass spectrometry (LC-MS); thin layer chromatography (TLC); preparative liquid chromatography (pre-HPLC); room temperature (RT, rt); equivalent (eq); gram / milligram (g / mg); mole / millimole (mol / mmol); liter / milliliter (L / mL); minute (min(s)); hour (h, hr, hrs); nitrogen (N2); aqueous solution (aq. ); petroleum ether (PE); ethyl acetate (EA); dichloromethane (DCM); methanol (MeOH); methyl tert-butyl ether (MTBE); ethanol (EtOH); trifluoroacetic acid (TFA); N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH); lithium diisopropylamide (LDA); N-methylimidazole (NMI); N,N-dimethylformamide (DMF); N,N-diisopropylethylamine (DIPEA).

[0309] Preparation method for preparative high performance liquid chromatography: instrument model: Agilent 1260, chromatographic column: Waters SunFire Prep C18 OBD (19 mm×150 mm×5.0 μm); column temperature: 25°C; flow rate: 20.0 mL / min; monitoring wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid in water.

[0310] Aluminum plates (20×20 cm) produced by Merck were used for thin layer chromatography silica gel plates (TLC), and the specifications used for thin layer chromatography separation and purification were GF 254 (1 mm) produced in Yantai.

[0311] The reaction is monitored by thin layer chromatography (TLC) or LC-MS; the developing solvent systems used include: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound or by adding triethylamine.

[0312] Microwave reaction was carried out using Biotage Initiator+ (400W, RT-300°C) microwave reactor.

[0313] Column chromatography generally uses 200-300 mesh silica gel as a carrier. Eluent systems include: dichloromethane and methanol systems, and petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.

[0314] Unless otherwise specified in the examples, the reaction temperature is room temperature (20°C to 35°C);

[0315] The reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Teber Chemical and other companies.

[0316] Intermediate 1: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid (1-7)

[0317] Step 1: Synthesis of 3-((2-ethoxy-2-oxoethyl)thio)-4,4,4-trifluoro-3-methylbutyric acid benzyl ester (1-2)

[0318] Benzyl (Z)-4,4,4-trifluoro-3-methyl-2-butenoate (10 g, 54.9 mmol) and piperidine (0.5 g) were cooled to 0°C and ethyl mercaptoacetate (6.6 g, 54.9 mmol) was added dropwise. Stirring was continued at this temperature. LC-MS monitoring confirmed the reaction was complete and the reaction solution was directly used for the next step. MS: m / z = 365.2, [M+H] + .

[0319] Step 2: Synthesis of 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid ethyl ester (1-3)

[0320] After complete dissolution of sodium ethoxide (11.2 g, 164.73 mmol) and anhydrous ethanol (120 mL), the system temperature was lowered to 0°C, and the reaction solution obtained in step 1 was slowly added dropwise to the system. After returning to room temperature naturally, stirring was continued. LC-MS monitored the reaction completion. Aqueous citric acid solution (1 M, 100 mL) was added dropwise to the reaction system under an ice bath, and the mixture was extracted with dichloromethane (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (8.7 g, 33.95 mmol, yield 61.83%) was isolated by silica gel column chromatography (EA / PE = 20 / 80). MS: m / z = 257.2, [M+H] + .

[0321] Step 3: Synthesis of ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene-2-carboxylate (1-4)

[0322] The product from step 2 (3.1 g, 12.1 mmol), dichloromethane (60 mL), and N,N-diisopropylethylamine (2.35 g, 18.15 mmol) were cooled to -78°C. Trifluoromethanesulfonic anhydride (4.1 g, 14.52 mmol) was slowly added dropwise to the system and maintained at this temperature until the reaction was complete. Water (50 mL) was added to quench the system, and the mixture was extracted with dichloromethane (60 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (3.5 g, 9.01 mmol, yield 74.51%) was isolated by silica gel column chromatography (EA / PE = 10 / 90). MS: m / z = 389.2, [M+H] + .

[0323] Step 4: Synthesis of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-4,5-dihydrothiophene-2-carboxylate (1-5)

[0324] The product from step 3 (3.5 g, 9.01 mmol) was added to 1,4-dioxane (50 mL) and water (5 mL). (3,4-difluoro-2-methoxyphenyl)boronic acid (2.53 g, 13.6 mmol), potassium carbonate (3.7 g, 27.2 mmol), and Pd(dppf)Cl2 (0.63 g, 0.9 mmol) were then added sequentially. After nitrogen replacement, the temperature was raised to 100°C and stirred. The reaction was monitored for completion by LC-MS. The system was returned to room temperature and concentrated under reduced pressure. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (2.8 g, 7.3 mmol, 81.25% yield) was obtained by silica gel column chromatography (EA / PE = 9 / 91). MS: m / z = 383.2, [M+H] + .

[0325] Step 5: Synthesis of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylate (1-6)

[0326] The product from step 4 (2.3 g, 6.02 mmol), methanol (50 mL), and palladium hydroxide / carbon (3.4 g) were replaced with hydrogen and pressurized to 1.5 MPa. The reaction was continued at 60°C for 16 h. The system was returned to room temperature and the pressure was released to atmospheric pressure. The reaction solution was filtered through celite and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to obtain the title compound (1.8 g, 4.8 mmol, 77.85% yield). MS: m / z = 385.2, [M+H] + .

[0327] Step 6: Synthesis of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid (1-7)

[0328] Anhydrous ethanol (80 mL) and cesium carbonate (1.7 g, 5.2 mmol) were heated to 50°C. After the system clarified, a solution of the product from step 5 (1 g, 2.6 mmol) in anhydrous ethanol (20 mL) was added and stirring continued for 2 h. The system was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The crude product was dissolved in water (25 mL) and 1M HCl aqueous solution was added dropwise to adjust the pH to 3. The product was extracted with EA (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to obtain the title compound (0.837 g, 2.35 mmol, 90.29% yield). MS: m / z = 357.1, [M+H] + .

[0329] Compound 1-7 was separated by chiral separation method: chromatographic column AD-H, column temperature 30°C, mobile phase (n-hexane-anhydrous ethanol-isopropanol-diethylamine = 80:16:4:0.05), flow rate 1 mL / min, to obtain compound 1-7-1 (retention time 3.149 min) and compound 1-7-2 (retention time 5.348 min).

[0330] Intermediate 2: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-deuterium-2-carboxylic acid (Compound 1-8)

[0331] Compound 1-6 (40 mg, 0.10 mmol), cesium carbonate (7 mg, 0.20 mmol), and deuterated methanol (2 mL) were stirred at 80°C for 3 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Water (2 mL) was added to the crude product, and 1 M aqueous hydrochloric acid was added dropwise to adjust the pH to 4. The product was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product 1-8 (35 mg, 0.098 mmol, yield 99%), which was used directly in the next reaction. MS: m / z = 358.2, [M+H] + .

[0332] Intermediate 3: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5,5-methyltetrahydrothiophene-2-carboxylic acid (2-7)

[0333] Step 1: Synthesis of ethyl 3-((2-ethoxy-2-oxoethyl)mercapto)-3-methylbutanoate (2-2)

[0334] Compound 2-1 (15 g, 125 mmol) and piperidine (0.5 g) were cooled to 0°C, and ethyl mercaptoacetate (16.3 g, 127.3 mmol) was slowly added dropwise to the system while continuing to stir at this temperature. LC-MS monitored the reaction completion, and the mixture was concentrated under reduced pressure to obtain the title compound (17.2 g, 69.1 mmol). MS: m / z = 249.2, [M+H] + .

[0335] Step 2: Synthesis of 5,5-dimethyl-3-oxotetrahydrothiophene-2-carboxylic acid ethyl ester (2-3)

[0336] The product from step 1 (17.2 g, 69.1 mmol) and anhydrous ethanol (200 mL) were cooled to 0°C, and sodium ethoxide (9.3 g, 138.2 mmol) was slowly added in portions to the system. The mixture was then returned to room temperature and stirred continuously. LC-MS monitoring confirmed the completion of the reaction. Water (100 mL) was added to quench the system, and 1 M aqueous hydrochloric acid was added dropwise to adjust the pH to 6. The mixture was extracted with DCM (200 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (13.1 g, 64.8 mmol). MS: m / z = 203.2, [M+H] + .

[0337] Step 3: Synthesis of ethyl 5,5-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrothiophene-2-carboxylate (2-4)

[0338] The product from step 2 (13.1 g, 64.8 mmol), dichloromethane (200 mL), and N,N-diisopropylethylamine (25.1 g, 194.4 mmol) were added dropwise to the mixture, and the temperature was lowered to -78°C. Trifluoromethanesulfonic anhydride (27.4 g, 97.2 mmol) was slowly added dropwise to the mixture. After the mixture returned to room temperature, stirring was continued for 5 hours. The reaction was quenched by adding water (100 mL) and extracted with DCM (200 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (EA / PE = 20 / 80) to obtain the title compound (9.1 g, 27.2 mmol, 41.9% yield). MS: m / z = 335.2, [M+H] + .

[0339] Step 4: Synthesis of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyl-4,5-dihydrothiophene-2-carboxylate (2-5)

[0340] The product from step 3 (9.1 g, 27.2 mmol), 1,4-dioxane (100 mL), and water (10 mL) were then added, followed by the sequential addition of 3,4-difluoro-2-methoxyphenylboronic acid (7.6 g, 40.8 mmol), potassium carbonate (11.2 g, 81.6 mmol), and Pd(dppf)Cl2 (1.9 g, 0.27 mmol). The atmosphere was purged with nitrogen three times, the temperature was raised to 95°C, and the mixture was stirred. The reaction was monitored for completion by LC-MS. The mixture was returned to room temperature and concentrated under reduced pressure to remove 1,4-dioxane. Water (100 mL) was added, and the mixture was extracted with DCM (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (EA / PE = 20 / 80) to afford the title compound (3.4 g, 10.3 mmol, 38.1% yield). MS: m / z = 329.2, [M+H] + .

[0341] Step 5: Synthesis of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyltetrahydrothiophene-2-carboxylate (2-6)

[0342] The product from step 4 (3.4 g, 10.3 mmol), methanol (100 mL), and palladium hydroxide on carbon (3.4 g) were added. The system was replaced with hydrogen and pressurized to 1.5 MPa. The reaction mixture was heated to 60°C for 16 h. The mixture was returned to room temperature and the pressure was released to atmospheric pressure. The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude product was isolated by silica gel column chromatography (EA / PE = 20 / 80) to obtain the title compound (2.7 g, 8.1 mmol, 79.1% yield). MS: m / z = 331.2, [M+H] + .

[0343] Step 6: Synthesis of 3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyltetrahydrothiophene-2-carboxylic acid (2-7)

[0344] The product from step 5 (2.7 g, 8.1 mmol), anhydrous ethanol (100 mL), and cesium carbonate (5.2 g, 16.2 mmol) were heated to 50°C and stirred for 5 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was dissolved in water (60 mL) and 1 M HCl aqueous solution was added dropwise to adjust the pH to 3. The product was extracted with EA (60 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to obtain the title compound (2.1 g, 7.1 mmol, 88.1% yield). MS: m / z = 303.1, [M+H] + .

[0345] Example 1: Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boric acid (Compound 9)

[0346] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 3-aminophenylboronic acid (33 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (79 mg, 0.04 mmol, yield 50%). MS: m / z = 476.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.17(s,1H),8.00(s,2H),7.76(s,1H),7.59(d,J=8.1Hz,1H),7.46(d,J=7.3Hz,1H),7.23(t,J=7.7Hz,1H),7.20- 7.11(m,2H),4.62(d,J=10.7Hz,1H),4.31-4.19(m,1H),3.96(d,J=1.6Hz,3H),2.39(t,J=12.9Hz,1H),2.35-2.25(m,1H),1.73(s,3H).

[0347] Example 2: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-methylphenyl)boric acid (Compound 13)

[0348] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 3-amino-4-methylphenylboronic acid (36 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (24.5 mg, 0.05 mmol, yield 62.50%). MS: m / z = 490.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.07(s,1H),7.96(s,2H),7.45-7.40(m,2H),7.19-7.12(m,2H),7.00(d,J=8.0Hz ,1H),4.59(d,J=10.8Hz,1H),4.34-4.22(m,1H),3.96(d,J=1.6Hz,3H),2.42-2.27(m,1H),1.72(s,3H).

[0349] Example 3: Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-5-fluorophenyl)boric acid (Compound 17)

[0350] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 3-amino-5-fluorophenylboronic acid (70 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (20.0 mg, 0.04 mmol, yield 60.40%). MS: m / z = 494.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.41(s,1H),8.19(s,2H),7.61-7.50(m,2H),7.24-7.13(m,3H),4.60(d,J=10.8 Hz,1H),4.30-4.23(m,1H),3.96(d,J=1.6Hz,3H),2.45-2.41(m,1H),2.32-2.28(m,1H),1.73(s,3H).

[0351] Example 4: Preparation of (3-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-4-fluorophenyl)boric acid (Compound 18)

[0352] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 3-amino-4-fluorophenylboronic acid (70 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (16 mg, 0.03 mmol, yield 40.50%), MS: m / z = 494.2, [M+H] + , 1 H NMR(400MHz,DMSO)δ9.92(s,1H),8.03(s,2H),7.57-7.56(m,2H),7.30-7.29(m,1H),6. 88-6.86(m,2H),4.53(s,1H),4.23(s,1H),3.83(s,3H),2.17-1.96(m,2H),1.38(s,3H).

[0353] Example 5: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-fluorophenyl)boric acid (Compound 19)

[0354] Compound 1-7 (301 mg, 0.8 mmol) was dissolved in anhydrous DMF (5 mL), and 5-amino-2-fluorophenylboronic acid (703 mg, 2.4 mmol) was added. TCFH (1.19 g, 4.1 mmol) and NMI (556 mg, 6.4 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (209 mg, 0.43 mmol, yield 53.7%), MS: m / z = 494.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.22(s,1H),8.17(s,2H),7.59-7.51(m,2H),7.22-7.14(m,2H),7.09-6.89(m,1H),4.58( d,J=10.7Hz,1H),4.33-4.24(m,1H),3.96(d,J=1.5Hz,3H),2.45-2.35(m,1H),2.32-2.25(m,1H),1.73(s,3H).

[0355] Example 6: Preparation of (3-cyano-5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 26)

[0356] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 3-amino-5-cyanophenylboronic acid (62 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (18.41 mg, 0.03 mmol, yield 46%), MS: m / z = 501.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.59(s,1H),8.41(s,2H),8.10(s,1H),8.02(s,1H),7.86(s,1H),7.26-7.14(m, 2H),4.64(d,J=10.8Hz,1H),4.36-4.25(m,1H),4.00(d,J=1.6Hz,3H),2.54-2.32(m,2H),1.76(s,3H).

[0357] Example 7: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 31)

[0358] Compound 1-7 (30.0 mg, 0.084 mmol) was dissolved in DMF (1.5 mL), and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (19.0 mg, 0.126 mmol) and NMI (55.3 mg, 0.673 mmol) were added. TCHF (94.0 mg, 0.337 mmol) was added under ice-cooling, and the mixture was allowed to warm to room temperature and the reaction was continued for 4 hours. The reaction was monitored by LC-MS. After completion of the reaction, the title compound (23.5 mg, 0.048 mmol, 57.4% yield) was obtained by Pre-HPLC separation. MS: m / z = 488.1, [M+H] + , 1H NMR (400MHz, DMSO) δ10.28(s,1H),9.20(s,1H),7.92(d,J=1.7Hz,1H),7.50(dd,J=8.3,2.0Hz,1H),7.30(d,J=8.3Hz,1H),7.2 3-7.11(m,2H),4.90(s,2H),4.62(d,J=10.7Hz,1H),4.34-4.23(m,1H),3.97(d,J=1.7Hz,3H),2.47-2.15(m,2H),1.73(s,3H).

[0359] Example 8: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)thiophen-2-yl)boronic acid (Compound 48)

[0360] Compound intermediate 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 4-aminothiophene-2-boronic acid (36 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (18 mg, 0.04 mmol, yield 46.25%), MS: m / z = 482.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.64(s,1H),8.27(s,2H),7.67(d,J=0.6Hz,1H),7.53(d,J=0.8Hz,1H),7.20-7.16( m,1H),4.62(d,J=10.8Hz,1H),4.34-4.26(m,1H),3.99(d,J=1.6Hz,3H),2.43-2.33(m,1H),1.75(s,3H).

[0361] Example 9: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)thiophen-3-yl)boronic acid (Compound 49)

[0362] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 5-aminothiophene-3-boronic acid (36 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (16 mg, 0.03 mmol, yield 41.25%). MS: m / z = 482.2, [M+H] + , 1 HNMR (400MHz, DMSO) δ10.64(s,1H),8.27(s,2H),7.67(d,J=0.6Hz,1H),7.53(d,J=0.8Hz,1H),7.20-7.16 (m,1H),4.62(d,J=10.8Hz,1H),4.34-4.26(m,1H),3.99(d,J=1.6Hz,3H),2.43-2.33(m,1H),1.75(s,3H).

[0363] Example 10: Preparation of (6-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-1H-indol-4-yl)boric acid (Compound 53)

[0364] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 6-amino-1H-indole-4-boronic acid (43 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (15.4 mg, 0.03 mmol, yield 40.50%), MS: m / z = 515.2, [M+H] + , 1 H NMR(400MHz,DMSO)δ10.85(s,1H),10.09(s,1H),7.91(s,1H),7.76(s,2H),7.23-7.11(m,4H),6.6 6(s,1H),4.67(d,J=10.8Hz,1H),4.35-4.26(m,1H),3.97(s,3H),2.42-2.28(m,2H),1.74(s,3H).

[0365] Example 11: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-1H-indazol-7-yl)boric acid (Compound 54)

[0366] Compound 1-7 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 5-amino-1H-indazole-7-boronic acid (75 mg, 0.42 mmol) was added. TCFH (196 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (5.39 mg, 0.03 mmol, yield 7.47%), MS: m / z = 516.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ12.32(s,1H),10.22(s,1H),8.36(s,2H),8.09(s,1H),7.99(s,1H),7.65(d,J=1.6Hz,1H),7. 27-7.15(m,2H),4.69(d,J=10.8Hz,1H),4.37-4.29(m,1H),4.00(d,J=1.6Hz,3H),2.46-2.33(m,2H),1.77(s,3H).

[0367] Example 12: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boric acid (Compound 82)

[0368] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 4-aminophenylboronic acid (33 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (21 mg, 0.04 mmol, yield 55%), MS: m / z = 476.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.24(s,1H),7.89(s,2H),7.68(d,J=8.3Hz,2H),7.45(d,J=8.3Hz,2H),7.22-7.09( m,2H),4.61(d,J=10.7Hz,1H),4.35-4.23(m,1H),3.97(d,J=1.4Hz,3H),2.47-2.25(m,2H),1.73(s,3H).

[0369] Example 13: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-3-fluorophenyl)boric acid (Compound 87)

[0370] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 4-amino-3-fluorophenylboronic acid (70 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (19.7 mg, 0.04 mmol, yield 50.01%), MS: m / z = 494.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.04(s,1H),8.12(s,2H),7.79(t,J=7.8Hz,1H),7.53-7.49(m,2H),7.19-7.15(m ,2H),4.84(d,J=10.8Hz,1H),4.30-4.23(m,1H),3.95(d,J=1.2Hz,3H),2.37-2.31(m,2H),1.73(s,3H).

[0371] Example 14: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-3-methoxyphenyl)boric acid (Compound 94)

[0372] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 4-amino-3-methoxyphenylboronic acid (63 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (17 mg, 0.03 mmol, yield 42.10%), MS: m / z = 506.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.42(s,1H),8.01(s,2H),7.88(d,J=8.0Hz,1H),7.42(s,1H),7.33(d,J=8.0Hz,1H),7.28-7.15(m, 2H), 5.00 (d, J = 10.7Hz, 1H), 4.29 (d, J = 8.0Hz, 1H), 3.96 (d, J = 1.2Hz, 3H), 3.81 (s, 3H), 2.36-2.31 (m, 2H), 1.75 (s, 3H).

[0373] Example 15: Preparation of (2-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyrimidin-5-yl)boronic acid (Compound 111)

[0374] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 2-aminopyrimidine-5-boronic acid (34 mg, 0.24 mmol) was added. TCFH (118 mg, 0.41 mmol) and NMI (55 mg, 0.64 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (23.9 mg, 0.05 mmol, yield 62.50%). MS: m / z = 478.2, [M+H] + , 1 H NMR(400MHz,DMSO)δ10.90(s,1H),8.83(s,2H),8.46(s,2H),7.19-7.14(m,2H),4.92(d, J=10.2Hz,1H),4.36-4.28(m,1H),3.95(d,J=1.6Hz,3H),2.40-2.28(m,2H),1.72(s,3H).

[0375] Example 16: Preparation of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyltetrahydrothiophene-2-carboxamido)picolinamide (Compound 134)

[0376] Step 1: Synthesis of methyl 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyltetrahydrothiophene-2-carboxamide)picolinate

[0377] Compound 2-7 (500 mg, 1.65 mmol), acetonitrile (10 mL), NMI (583 mg, 5.7 mmol), and methyl 4-aminopicolinate (275 mg, 1.82 mmol) were mixed and stirred thoroughly. TCFH (693 mg, 2.4 mmol) was added and the mixture was stirred at room temperature for 1 h. Water was added to quench the reaction and the mixture was concentrated under reduced pressure. The residue was added with water and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Pre-HPLC to obtain the title compound (523 mg, 1.2 mmol, 78.1% yield). MS: m / z = 437.1, [M+H] + .

[0378] Step 2: Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5,5-dimethyltetrahydrothiophene-2-carboxamide)picolinamide

[0379] The product from step 1 (523 mg, 1.2 mmol) and a 2M ammonia solution in methanol (10 mL) were heated to 60°C and stirred overnight. The system was cooled to room temperature and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to obtain the title compound (283 mg, 0.67 mmol, 56.1% yield). MS: m / z = 422.1, [M+H] + . 1 H NMR (400MHz, DMSO) δ10.60 (s, 1H), 8.45 (d, J = 5.2Hz, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.74-7.57 (m ,2H),7.29-7.12(m,2H),4.40(s,2H),3.90(s,3H),2.30-2.12(m,2H),1.60(s,3H),1.48(s,3H).

[0380] Chiral separation method: chromatographic column OJ-H, column temperature 30°C, mobile phase (n-hexane-anhydrous ethanol-isopropanol-diethylamine = 80:16:4:0.05), flow rate 0.6 mL / min. Compound 134-A (retention time 14.689 min), compound 134-B (retention time 17.899 min)

[0381] Example 17: Preparation of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinamide (Compound 139)

[0382] Step 1: Synthesis of methyl 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinate (139-1)

[0383] Intermediate 1-7 (837 mg, 2.35 mmol), DMF (30 mL), NMI (1.17 g, 11.4 mmol), and methyl 4-aminopicolinate (550 mg, 3.64 mmol) were added to TCFH (2.08 mg, 7.2 mmol) under ice-cooling. The mixture was allowed to return to room temperature and stirred for 1 h. The reaction was quenched by the addition of water (20 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to obtain the title compound (910 mg, 1.86 mmol, 78.99% yield). MS: m / z = 491.1, [M+H] + .

[0384] Step 2: Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinamide (Compound 139)

[0385] The product from step 1 (910 mg, 1.86 mmol) and a 2M ammonia solution in methanol (15 mL) were heated to 60°C and stirred overnight. The system was cooled to room temperature and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to obtain the title compound (711 mg, 1.5 mmol, 80.6% yield). MS: m / z = 476.3, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.81(s,1H),8.46(d,J=5.5Hz,1H),8.15(d,J=1.7Hz,1H),8.03(s,1H),7.67(dd,J=5.5,2.0Hz,1H),7.6 0(s,1H),7.28-7.09(m,2H),4.61(d,J=10.6Hz,1H),4.39-7.18(m,1H),3.97(d,J=1.5Hz,3H),2.47-2.13(m,2H),1.74(s,3H).

[0386] Chiral separation method: chromatographic column AD-H, column temperature 30°C, mobile phase (n-hexane-anhydrous ethanol-isopropanol-diethylamine = 80:16:4:0.05), flow rate 1 mL / min. Compound 139-A (retention time 5.387 min), compound 139-B (retention time 9.442 min)

[0387] Example 18: Preparation of N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 146).

[0388] Step 1: Synthesis of methyl 5-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-fluorobenzoate (Compound 146-1).

[0389] Compound 1-7 (50.7 mg, 0.1 mmol) was completely dissolved in 3 mL of dry DMF. Methyl 5-amino-2-fluorobenzoate (169.1 mg, 0.1 mmol), NMI (240.2 mg, 3.0 mmol), and TCFH (420 mg, 0.15 mmol) were added sequentially under ice-cooling. After the addition, the temperature was naturally restored to room temperature and the reaction was continued for 4 hours. Water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by Pre-HPLC to obtain the title compound (22.3 mg, 0.044 mmol, yield 44.0%). MS: m / z = 508.2, [M+H] + .

[0390] Step 2: Synthesis of N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 146)

[0391] The product from step 1 (22.3 mg, 0.044 mmol) was added to a 7M NH3 solution in MeOH (2 mL) and stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated to obtain a crude product. Pre-HPLC separation yielded the target compound (17 mg, 0.034 mmol, 77.2% yield). MS: m / z = 493.2, [M+H] + . 1H NMR (400MHz, DMSO) δ10.42(s,1H),7.80(dd,J=6.4,2.8Hz,1H),7.71-7.56(m,3H),7.18(dt,J=10.8,8.5H z,3H),4.57(d,J=10.7Hz,1H),4.32-4.20(m,1H),3.96(d,J=1.8Hz,3H),2.43-2.29(m,2H),1.73(s,3H).

[0392] Example 19: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 170)

[0393] Compound 1-7 (30.0 mg, 0.084 mmol) was dissolved in 1.0 mL of dry MeCN, and T3P (267.8 mg, 0.842 mmol) and Et3N (68.16 mg, 0.673 mmol) were added in sequence. The mixture was reacted at 60°C for 0.5 h. 4-Aminopyridin-2(1H)-one (13.9 mg, 0.126 mmol) was added, and the reaction was continued at 60°C for 3.0 h. Pre-HPLC separation gave the title compound (13.0 mg, 0.289 mmol, yield 34.43%). MS: m / z = 449.2, [M+H] + . 1 H NMR (400MHz, DMSO) δ11.23(s,1H),10.31(s,1H),7.24(d,J=7.2Hz,1H),7.20-7.14(m,2H),6.60(d,J=2.0Hz,1H),6.18(dd,J=7.2 ,1.9Hz,1H),4.55(d,J=10.6Hz,1H),4.29-4.18(m,1H),3.96(d,J=1.9Hz,3H),2.44-2.37(m,1H),2.33-2.26(m,1H),1.71(s,3H).

[0394] Example 20: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 172)

[0395] Compound 1-7 (30 mg, 0.084 mmol) was dissolved in anhydrous DMF (2 mL), and 4-amino-1-methylpyridin-2(1H)-one (16 mg, 0.13 mmol) and NMI (33 mg, 0.4 mmol) were added. The mixture was stirred under ice-cooling. TCFH (56 mg, 0.2 mmol) was weighed and added to the reaction flask in one portion. The mixture was moved to room temperature and stirred for 2 hours. 10 mL of water was added to the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by Pre-HPLC to obtain the target compound (13 mg, 0.028 mmol, 33% yield). MS: m / z = 463.1, [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.76 (s, 1H), 7.23 (d, J = 7.4Hz, 1H), 7.02 (d, J = 6.2Hz, 1H), 6.95-6.78 (m, 2H), 6.54 (s, 1H) ,4.49(d,J=10.7Hz,1H),4.29-4.11(m,1H),4.00(d,J=2.0Hz,3H),3.52(s,3H),2.47-2.16(m,2H),1.75(s,3H).

[0396] Example 21: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 176)

[0397] Compound 1-7 (30.0 mg, 0.084 mmol) was dissolved in DMF (1.5 mL), and 5-aminopyridin-2(1H)-one (15.0 mg, 0.126 mmol) and HOBt (24.0 mg, 0.168 mmol) were added. The reaction flask was placed in an ice-water bath, and DIC (33.0 mg, 0.252 mmol) was added. The mixture was allowed to warm to room temperature and the reaction was continued for 4 hours. The reaction solution was separated by Pre-HPLC to obtain the target compound (20.8 mg, 0.046 mmol, 55.2% yield). MS: m / z = 449.2, [M+H] + , 1H NMR (400MHz, DMSO) δ11.25(s,1H),10.06(s,1H),7.77(d,J=2.8Hz,1H),7.30(dd,J=9.7,2.9Hz,1H),7.20-7.10(m,2H),6 .30(d,J=9.7Hz,1H),4.50(d,J=10.8Hz,1H),4.29-4.16(m,1H),,3.95(d,J=1.8Hz,3H),2.45-2.23(m,2H),1.71(s,3H).

[0398] Example 22: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-deuterium-2-carboxamide (Compound 177)

[0399] Compound 1-8 (40.0 mg, 0.112 mmol) was dissolved in DMF (2.0 mL), and 5-aminopyridin-2(1H)-one (18.0 mg, 0.168 mmol) and HOBt (30.0 mg, 0.224 mmol) were added. DIC (42.0 mg, 0.336 mmol) was added at 0°C, and the mixture was allowed to warm to room temperature and the reaction was continued for 4 hours. The reaction solution was separated by Pre-HPLC to obtain the title compound (27.6 mg, 0.061 mmol, 54.8% yield). MS: m / z = 450.1, [M+H] + . 1 H NMR (400MHz, DMSO) δ11.31 (s, 1H), 10.05 (s, 1H), 7.77 (d, J = 2.8Hz, 1H), 7.36-7.25 (m, 1H), 7.22-7.01 (m,2H),6.33-6.28(m,1H),4.31-4.17(m,1H),3.95(d,J=1.9Hz,3H),2.46-2.23(m,2H),1.71(s,3H).

[0400] Example 23: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 178)

[0401] Compound 1-7 (30.0 mg, 0.084 mmol) was dissolved in 1.0 mL of dry MeCN. T3P (267.8 mg, 0.842 mmol) and Et3N (68.16 mg, 0.673 mmol) were added sequentially. The mixture was stirred at 60°C for 0.5 h. 5-Amino-1-methylpyridin-2(1H)-one (15.6 mg, 0.126 mmol) was added and stirring continued at 60°C for 3.0 h. The reaction mixture was separated by Pre-HPLC to obtain the title compound (13.0 mg, 0.028 mmol, yield 33.45%). MS: m / z = 463.2, [M+H] + . 1 H NMR (400MHz, DMSO) δ10.42(s,1H),7.80(dd,J=6.4,2.8Hz,1H),7.71-7.56(m,3H),7.24-7.11(m,3H ),4.57(d,J=10.7Hz,1H),4.32-4.20(m,1H),3.96(d,J=1.8Hz,3H),2.43-2.31(m,2H),1.73(s,3H).

[0402] Example 24: Synthesis of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-deuterium-2-carboxamide (Compound 179)

[0403] Compound 1-8 (35 mg, 0.098 mmol) was dissolved in anhydrous DMF (2 mL), and 5-amino-1-methylpyridin-2(1H)-one (18 mg, 0.14 mmol) and NMI (33 mg, 0.4 mmol) were added. The mixture was stirred at 0°C. TCFH (56 mg, 0.2 mmol) was added to the reaction flask in one portion, and the mixture was brought to room temperature and stirred for 2 hours. The reaction mixture was separated by Pre-HPLC to obtain the title compound (15 mg, 0.032 mmol, 32% yield). MS: m / z = 464.2, [M+H] + . 1 H NMR (400MHz, DMSO) δ10.05 (s, 1H), 8.07 (d, J = 2.8Hz, 1H), 7.30-7.21 (m, 1H), 7.20-7.14 (m, 2H), 6.35 (d ,J=9.7Hz,1H),4.27-4.17(m,1H),3.96(d,J=1.8Hz,3H),3.36(s,3H),2.44-2.25(m,2H),1.71(s,3H).

[0404] Example 25: Preparation of 3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido-2-d)phenyl)boronic acid (Compound 10-A)

[0405] Compound 1-8-A (0.86 g, 2.41 mmol) was dissolved in anhydrous DMF (30 mL), and ((3-aminophenyl)boronic acid (990.5 mg, 7.23 mmol) was added. TCFH (3.37 g, 12.05 mmol) and NMI (1.58 g, 19.28 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (842.6 mg, 1.76 mmol, yield 73.3%).

[0406] MS: m / z = 477.2, [M+H] + .

[0407] 1 H NMR (400MHz, DMSO) δ10.02 (s, 1H), 7.59-7.58 (m, 3H), 7.46-7.45 (m, 1H), 7.02 (d, J = 2.0Hz, 1H), 6. 85(d,J=2.0Hz,1H),4.20(s,2H),3.83(s,3H),3.51-3.50(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0408] Example 26: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-d-2-carboxamide (Compound 177)

[0409] The experimental procedures were similar to those in Example 1 (Compound 9).

[0410] MS:m / z=450.1,[M+H]+,1H NMR (400MHz, DMSO) δ11.31(s,1H),10.05(s,1H),7.77(d,J=2.8Hz,1H),7.30(dd,J=9.7,2.9Hz,1H),7.16(dd,J=8.4,5.5Hz,2H),6.33 -6.28(m,1H),4.21(dd,J=13.1,6.1Hz,1H),3.95(d,J=1.9Hz,3H),2.39(t,J=12.9Hz,1H),2.28(dd,J=12.6,6.2Hz,1H),1.71(s,3H).

[0411] Example 27: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-((difluoromethyl)sulfonyl)phenyl)boronic acid (Compound a-1)

[0412] The experimental procedures were similar to those in Example 1 (Compound 9).

[0413] MS: m / z = 590.2 [M+H] + .

[0414] 1H NMR (400MHz, CDCl3) δ8.26(s,1H),7.99(d,J=8.8Hz,1H),7.93(d,J=8.7Hz,1H),7.70(s,1H),7.04-6.96(m,1H),6.85(dd,J=16.5,8.8Hz,1H),6.42(t ,J=53.8Hz,1H),4.47(d,J=10.6Hz,1H),4.23-4.11(m,1H),4.00(d,J=2.2 Hz, 3H), 2.61 (t, J = 13.0Hz, 1H), 2.24 (dd, J = 12.9, 5.9Hz, 1H), 1.81 (s, 3H).

[0415] Example 28: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 219)

[0416] The experimental procedures were similar to those in Example 1 (Compound 9).

[0417] MS: m / z = 488.2 [M+H] + .

[0418] 1H NMR (400MHz, CDCl3) δ7.87 (s, 1H), 7.75 (s, 1H), 7.65 (d, J = 7.9Hz, 1H), 7.21-7.1 6(m,1H),7.00(ddd,J=7.9,5.6,2.0Hz,1H),6.86(dt,J=16.3,8.2Hz,1H),5.01(d ,J=11.4Hz,2H),4.41(d,J=10.8Hz,1H),4.22-4.11(m,1H),3.98(d,J=2.5Hz,4H) ,2.60(t,J=13.0Hz,1H),2.23(dd,J=12.9,6.1Hz,1H),1.81(s,4H),1.62(s,2H).

[0419] Example 29: Preparation of (2-bromo-5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boric acid (Compound 24)

[0420] The experimental procedures were similar to those in Example 1 (Compound 9).

[0421] MS: m / z = 555.1 [M+H] + .

[0422] 1H NMR (400MHz, CDCl3) δ7.84(s,1H),7.77(dd,J=8.7,2.8Hz,1H),7.66(d,J=2.8H z,1H),7.45(d,J=8.7Hz,1H),7.01-6.96(m,1H),6.85(dt,J=16.4,8.2Hz,1H), 5.48(s,2H),4.36(dd,J=10.9,5.5Hz,1H),4.19-4.08(m,1H),3.97(d,J=2.6Hz ,3H),2.60(dd,J=22.3,9.3Hz,1H),2.22(dd,J=12.9,6.0Hz,1H),1.80(s,3H).

[0423] Example 30: Preparation of (4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido-2-d)thiophen-2-yl)boronic acid (Compound 50-A)

[0424] Compound 1-8-A (0.86 g, 2.41 mmol) was dissolved in anhydrous DMF (30 mL), and (4-aminothiophen-2-yl)boric acid (1.03 g, 7.23 mmol) was added. TCFH (3.37 g, 12.05 mmol) and NMI (1.58 g, 19.28 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (662.6 mg, 1.37 mmol, yield 56.9%).

[0425] MS: m / z = 483.2, [M+H] + .

[0426] 1 H NMR (400MHz, DMSO) δ9.92(s,1H),7.02(d,J=2.0Hz,1H),6.85(d,J=2.0Hz,1H),6.57(s,1H) ,6.32(s,1H),4.20(s,2H),3.83(s,3H),3.51-3.50(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0427] Example 31: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido-2-d)-2-fluorophenyl)boric acid (Compound 20-A)

[0428] Compound 1-8-A (0.86 g, 2.41 mmol) was dissolved in anhydrous DMF (30 mL), and (5-amino-2-fluorophenyl)boric acid (1.12 g, 7.23 mmol) was added. TCFH (3.37 g, 12.05 mmol) and NMI (1.58 g, 19.28 mmol) were added under ice bath. The mixture was allowed to return to room temperature and continued to stir. After the reaction was complete, the target compound (886.5 mg, 1.79 mmol, yield 72.3%) was obtained by Pre-HPLC separation.

[0429] MS: m / z = 495.2, [M+H] + .

[0430] 1H NMR (400MHz, DMSO) δ10.02 (s, 1H), 7.60-7.58 (m, 2H), 7.30 (d, J = 2.0Hz, 1H), 7.02 (d, J = 2.0Hz, 1H), 6.85(d,J=2.0Hz,1H),4.20(s,2H),3.83(s,3H),3.51-3.50(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0431] Example 32: Preparation of (4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-(methoxycarbonyl)phenyl)boronic acid (Compound 101-A)

[0432] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and (4-amino-2-(methoxycarbonyl)phenyl)boronic acid (82.3 mg, 0.42 mmol) was added. TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (24.6 mg, 0.05 mmol, yield 32.9%).

[0433] Ms: m / z = 534.2, [M+H] + .

[0434] 1 H NMR (400MHz, DMSO) δ10.02(s,1H),8.19(d,J=2.0Hz,1H),7.96(d,J=2.0Hz,1H),7.86(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1 H),6.85(d,J=2.0Hz,1H),4.20-4.07(m,3H),3.90(s,3H),3.83(s,3H),3.46-3.43(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0435] Example 33: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-chlorophenyl)boronic acid (Compound 92-A)

[0436] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 4-amino-2-chlorophenylboronic acid (72 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (63 mg, 0.12 mmol, yield 88%).

[0437] MS: m / z = 510.07, [M+H] + .

[0438] 1 H NMR (400 MHz, DMSO) δ 1 H NMR (400MHz, DMSO) δ9.89 (s, 1H), 8.25 (d, J = 13.8Hz, 2H), 7.88-7.64 (m, 2H), 7.56-7.44 (m, 3H), 4.61 (d, J = 10.7Hz ,1H),4.38-4.24(m,1H),3.98(d,J=1.6Hz,3H),2.45(t,J=12.9Hz,1H),2.31(dd,J=12.6,6.0Hz,1H),1.76(s,3H).

[0439] Example 34: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-trifluoromethoxyphenyl)boric acid (Compound 29-A)

[0440] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 4-amino-2-trifluoromethoxyphenylboronic acid (93 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (54 mg, 0.096 mmol, yield 69%).

[0441] MS: m / z = 560.06, [M+H] + .

[0442] 1H NMR (400MHz, DMSO) δ9.91 (s, 1H), 8.26 (d, J = 13.8Hz, 2H), 7.87-7.63 (m, 2H), 7.56-7.43 (m, 3H), 4.60 (d, J = 10.7Hz ,1H),4.38-4.24(m,1H),3.99(d,J=1.6Hz,3H),2.44(t,J=12.9Hz,1H),2.32(dd,J=12.6,6.0Hz,1H),1.77(s,3H).

[0443] Example 35: Preparation of (2R,3S,5R)-N-(2-amino-3,4-dioxocyclobut-1-en-1-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-91-A)

[0444] Compound 1-7-2 (50.0 mg, 0.140 mmol) was dissolved in anhydrous DMF (3 mL), and 3,4-diaminocyclobutane-3-ene-1,2-dione (15.7 mg, 0.140 mmol) and NMI (22.9 mg, 0.280 mmol) were added, and the mixture was stirred at 0°C. TCFH (78.7 mg, 0.280 mmol) was added to the reaction flask in one portion, and the mixture was brought to room temperature and stirred. The reaction was completed, and the reaction solution was separated by Pre-HPLC to obtain the target compound (7.5 mg, 0.017 mmol, yield 12%).

[0445] MS: m / z = 450.1, [M+H] + . 1 H NMR (400MHz, DMSO) δ11.72(s,1H),8.74(s,1H),7.43(s,1H),7.21-7.15(m,2H),4.75(d,J=10.5Hz ,1H),4.30-4.16(m,1H),3.95(d,J=2.0Hz,3H),2.36(ddd,J=17.5,12.6,9.5Hz,2H),1.72(s,3H).

[0446] Example 36: Preparation of (5-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-fluorophenyl)boronic acid (Compound 19-A)

[0447] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), (5-amino-2-fluorophenyl)boric acid (65.1 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (36.8 mg, 0.07 mmol, yield 53.27%).

[0448] MS: m / z = 494.1, [M+H] + .

[0449] 1H NMR (400MHz, DMSO) δ10.22(s,1H),8.17(s,2H),7.56(dd,J=11.5,3.9Hz,2H),7.16(dd,J=9.9,6.5Hz,2H),6.98(d,J=8.9Hz,1H),4 .58(d,J=10.7Hz,1H),4.31-4.24(m,1H),3.96(d,J=1.5Hz,3H),2.39(d,J=12.9Hz,1H),2.30(dd,J=12.5,6.1Hz,1H),1.73(s,3H).

[0450] Example 37: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 193)

[0451] The experimental procedures were similar to those in Example 1 (Compound 9).

[0452] MS: m / z = 512.2 [M+H] + .

[0453] 1 H NMR (400MHz, MeOD) δ7.90-7.84(m,1H),7.10(d,J=2.5Hz,1H),7.00(ddd,J=8.1,5.7,2.1Hz,1H),6.87(td,J=9.3,7.5Hz,1H),6.75(dd,J=6.8,2.5Hz ,1H),4.33(d,J=11.0Hz,1H),4.11-4.03(m,1H),3.91(d,J=2.0Hz,3H),2. 37(t,J=13.0Hz,1H), 2.13(dd,J=12.7,6.0Hz,1H), 1.66(d,J=9.5Hz,3H).

[0454] Example 38: Preparation of (3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 9-A)

[0455] The experimental procedures were similar to those in Example 1 (Compound 9).

[0456] MS: m / z = 476.2, [M+H] + .

[0457] 1 H NMR (400MHz, CDCl3) δ8.13 (d, J = 74.5Hz, 1H), 7.98-7.59 (m, 2H), 7.55-7.27 (m, 2H), 7.08-6.89 (m, 1H), 6.89-6.74 (m, 1H), 4 .52-4.32(m,1H),4.30-4.08(m,1H),3.95(d,J=17.6Hz,3H),2.67-2.47(m,1H),2.32-2.14(m,1H),1.79(d,J=13.0Hz,3H).

[0458] Example 39: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-fluorophenyl)boric acid (Compound 19)

[0459] Compound 1-7 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 5-amino-2-fluorophenylboronic acid (65 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (44 mg, 0.089 mmol, yield 64%).

[0460] MS: m / z = 494.10, [M+H] + .

[0461] 1H NMR (400MHz, DMSO) δ10.45(s,1H),8.00(d,J=13.8Hz,2H),7.56-7.32(m,2H),7.26-7.13(m,3H),4.61(d,J=10.7Hz ,1H),4.38-4.24(m,1H),3.99(d,J=1.6Hz,3H),2.46(t,J=12.9Hz,1H),2.34(dd,J=12.6,6.0Hz,1H),1.76(s,3H).

[0462] Example 40: Preparation of (3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 82-A)

[0463] The experimental procedures were similar to those in Example 1 (Compound 9).

[0464] MS: m / z = 476.2, [M+H] + .

[0465] 1 H NMR (400MHz, CDCl3) δ8.08-7.95(m,2H),7.94-7.66(m,1H),7.48(dd,J=16.9,8.3Hz,2H),7.00(dt,J=10.8,7.9Hz,1H),6.84(dt,J=8.8,7.9Hz,1 H),4.41(dd,J=15.4,10.8Hz,1H),4.27-4.11(m,1H),3.96(dd,J=10.7,2.4Hz,3H),2.66-2.51(m,1H),2.29-2.17(m,1H),1.81(d,J=8.9Hz,3H).

[0466] Example 41: Preparation of (2-bromo-4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 93)

[0467] The experimental procedures were similar to those in Example 1 (Compound 9).

[0468] MS: m / z = 555.2 [M+H] + .

[0469] 1H NMR (400MHz, CDCl3) δ7.88(dd,J=8.5,5.1Hz,2H),7.80(s,1H),7.31(dd,J=8.3,2.0Hz,1H),7.02-6.96(m,1H),6.87(td,J=9.1,7.3Hz,1 H),4.38(d,J=10.8Hz,1H),4.19-4.09(m,1H),3.98(d,J=2.7Hz,3H),2.60(t,J=13.0Hz,1H),2.23(dd,J=12.9,6.0Hz,1H),1.81(s,3H).

[0470] Example 42: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-(methylthio)phenyl)boric acid (Compound 37)

[0471] The experimental procedures were similar to those in Example 1 (Compound 9).

[0472] MS: m / z = 522.2 [M+H] + .

[0473] 1 H NMR (400MHz, CDCl3) δ7.93(dd,J=8.5,2.6Hz,1H),7.82(s,1H),7.69(d,J=2.6Hz,1H),7.48(d,J=8.5Hz,1H),7.02-6.96(m,1H),6.85(dd,J=16.4,9.1Hz ,1H),4.37(d,J=10.8Hz,1H),4.18-4.09(m,1H),3.97(d,J=2.6Hz,3H),2.5 9(t,J=13.0Hz,1H),2.44(s,3H),2.22(dd,J=12.9,6.0Hz,1H),1.81(s,3H).

[0474] Example 43: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-d-2-carboxamide (Compound 179)

[0475] Compound 1-8 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 5-amino-1-methylpyridin-2(1H)-one (52.1 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (35.7 mg, 0.08 mmol, yield 55.10%).

[0476] MS: m / z = 464.1, [M+H] + .

[0477] 1 H NMR (400MHz, DMSO) δ10.03(s,1H),8.06(s,1H),7.69-7.51(m,1H),7.25(d,J=7.3Hz,1H),7.15(s,1H),6.34(d,J=9.6Hz, 1H), 4.22 (d, J = 7.2Hz, 1H), 3.96 (s, 3H), 3.36 (s, 3H), 2.40 (t, J = 12.8Hz, 1H), 2.29 (dd, J = 12.2, 5.9Hz, 1H), 1.71 (s, 3H).

[0478] Example 44: Preparation of (2-((tert-Butyloxycarbonyl)amino)-5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 220)

[0479] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and (5-amino-2-((tert-butoxycarbonyl)amino)phenyl)boronic acid (60.48 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. The mixture was allowed to return to room temperature and continued to stir. After the reaction was complete, the target compound (5.91 mg, 0.01 mmol, yield 13%) was separated by Pre-HPLC.

[0480] MS: m / z = 591.2, [M+H] + .

[0481] 1H NMR(500MHz,Chloroform)δ8.37(s,1H),7.75(s,1H),7.62(s,1H),7.13(s,1H),6.86(d,J=7.5Hz,2H), 4.58(s,1H),3.93(d,J=12.5Hz,4H),3.31(s,1H),1.89(s,1H),1.70(s,2H),1.49(s,9H),1.38(s,3H).

[0482] Example 45: Preparation of (2R, 3S, 5R)-N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 146-A) and (2S, 3R, 5S)-N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 146-B)

[0483] Step 1: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-2-(methoxycarbonyl)phenyl)boronic acid (Compound 146-1)

[0484] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and methyl 5-amino-2-fluorobenzoate (71.0 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice-cooling. The mixture was allowed to return to room temperature and continued to stir. After the reaction was complete, the title compound (44.1 mg, 0.09 mmol, yield 62.10%) was separated by Pre-HPLC. MS: m / z = 508.1, [M+H] + .

[0485] Step 2: Preparation of N-(3-carbamoyl-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 146)

[0486] The product of step 1 (44.1 mg, 0.09 mmol) was dissolved in 7 M NH3.MeOH (5 mL) and stirred at room temperature. After the reaction was complete, the target compound (38.4 mg, 0.08 mmol, yield 86.71%) was separated by Pre-HPLC. MS: m / z = 493.1, [M+H] + .

[0487] Step 3: Preparation of (2R, 3S, 5R) -N- (3-carbamoyl-4-fluorophenyl) -3- (3,4-difluoro-2-methoxyphenyl) -5-methyl-5- (trifluoromethyl) tetrahydrothiophene-2-carboxamide (Compound 146-A) and (2S, 3R, 5S) -N- (3-carbamoyl-4-fluorophenyl) -3- (3,4-difluoro-2-methoxyphenyl) -5-methyl-5- (trifluoromethyl) tetrahydrothiophene-2-carboxamide (Compound 146-B)

[0488] The product of step 2 (38.4 mg, 0.08 mmol) was separated to obtain the target compounds Compound 146-A (16.2 mg, 0.03 mmol, yield 42.19%) and Compound 146-B (16.6 mg, 0.03 mmol, yield 43.22%).

[0489] Compound 146-A:

[0490] MS: m / z = 493.1, [M+H] + .

[0491] 1 H NMR (400MHz, CDCl3) δ9.39 (s, 1H), 8.37 (ddd, J = 9.0, 4.4, 2.9Hz, 1H), 8.00 (dd, J = 6.7, 2.8Hz,1H),7.10(dd,J=11.4,9.1Hz,1H),7.02-6.96(m,1H),6.91(d,J=13.3Hz,1H),6 .82(td,J=9.1,7.4Hz,1H),6.35(s,1H),4.64(d,J=10.9Hz,1H),4.33-4.23(m,1H),4. 03(d,J=2.4Hz,3H),2.58(t,J=13.1Hz,1H),2.25(dd,J=12.9,6.1Hz,1H),1.80(s,3H).

[0492] Compound 146-B:

[0493] MS: m / z = 493.1, [M+H] + .

[0494] 1H NMR (400MHz, CDCl3) δ9.42 (s, 1H), 8.38 (ddd, J=8.9, 4.4, 2.9Hz, 1H), 8.00 (dd, J=6.7, 2.8Hz,1H),7.10(dd,J=11.4,9.1Hz,1H),7.02-6.96(m,1H),6.91(d,J=13.8Hz,1H),6. 83(dt,J=16.4,8.2Hz,1H),6.36(s,1H),4.65(d,J=10.9Hz,1H),4.33-4.24(m,1H),4. 03(d,J=2.4Hz,3H),2.57(t,J=13.1Hz,1H),2.25(dd,J=12.9,6.1Hz,1H),1.80(s,3H).

[0495] Example 46: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 31-A) and (2S, 3R, 5S)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 31-B)

[0496] The experimental procedures refer to Example 45.

[0497] Compound 31-A:

[0498] MS: m / z = 488.1 [M+H] + , 1 H NMR (400MHz, CDCl3) δ7.84(s,1H),7.75(d,J=1.8Hz,1H),7.59(dd,J=8.3,2.0H z,1H),7.28(d,J=8.3Hz,1H),7.01(ddd,J=5.6,4.7,2.2Hz,1H),6.84(td,J=9.1 ,7.4Hz,1H),5.05(s,2H),4.40(t,J=10.1Hz,1H),4.21-4.11(m,1H),3.97(d,J =2.6Hz, 3H), 2.60 (t, J = 13.0Hz, 1H), 2.23 (dd, J = 12.9, 6.0Hz, 1H), 1.81 (s, 3H).

[0499] Compound 31-B:

[0500] MS: m / z = 488.1 [M+H] + , 1 H NMR (400MHz, CDCl3) δ7.84(s,1H),7.75(d,J=1.8Hz,1H),7.59(dd,J=8.3,2.0H z,1H),7.30-7.26(m,1H),7.03-6.98(m,1H),6.84(td,J=9.1,7.4Hz,1H),5.05 (s,2H),4.41(d,J=10.8Hz,1H),4.16(ddd,J=13.0,11.0,6.0Hz,1H),3.97(d,J =2.6Hz, 3H), 2.60 (t, J = 13.0Hz, 1H), 2.22 (dd, J = 12.9, 6.0Hz, 1H), 1.81 (s, 3H).

[0501] Example 47: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-hydroxy)pyridine (Compound 170-A)

[0502] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 4-amino-2-hydroxypyridine (46 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (44 mg, 0.098 mmol, yield 70%).

[0503] MS: m / z = 449.09, [M+H] + .

[0504] 1 H NMR (400 MHz, DMSO) δ 1 H NMR (400MHz, DMSO) δ9.86 (s, 2H), 7.26-7.13 (m, 3H), 5.86-5.62 (m, 2H), 4.62 (d, J = 10.7Hz, 1H), 4.35- 4.21(m,1H),3.98(d,J=1.6Hz,3H),2.45(t,J=12.9Hz,1H),2.32(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0505] Example 48: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 178-A)

[0506] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 5-amino-1-methylpyridin-2(1H)-one (29.76 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (18.48 mg, 0.04 mmol, yield 50%).

[0507] MS: m / z = 463.1, [M+H] + .

[0508] 1 H NMR (400MHz, DMSO) δ10.71(s,1H),7.84(d,J=9.3Hz,2H),7.72(d,J=9.0Hz,2H),7.24-7.14(m,2H),4.63(d,J= 10.7Hz,1H),4.38-4.21(m,1H),3.99(d,J=1.8Hz,3H),2.46(d,J=12.9Hz,1H),2.38-2.30(m,1H),1.76(s,3H).

[0509] Example 49: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 178-B)

[0510] Compound 1-7-1 (36 mg, 0.1 mmol) was dissolved in anhydrous DMF (5 mL), 5-amino-1-methylpyridin-2(1H)-one (37.5 mg, 0.3 mmol) was added, and TCFH (150 mg, 0.50 mmol) and NMI (70 mg, 0.8 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued for 1 h. The reaction was complete and the target compound (28.6 mg, 0.062 mmol, yield 62%) was obtained by Pre-HPLC separation.

[0511] MS: m / z=463.1, [M+H]+.

[0512] 1H NMR (400MHz, CDCl3) δ8.41(d,J=26.3Hz,1H),8.22(d,J=2.2Hz,1H),7.28(s ,1H),7.01(d,J=2.4Hz,1H),6.90-6.75(m,1H),6.59(d,J=9.4Hz,1H),4.50( d,J=10.8Hz,1H),4.15(d,J=2.9Hz,2H),4.01(d,J=2.5Hz,3H),3.55(s,3H), 2.54(t,J=13.0Hz,1H), 2.22(dd,J=12.9,6.1Hz,1H), 1.78(d,J=4.5Hz,3H).

[0513] Example 50: Preparation of (4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)thiophen-2-yl)boronic acid (Compound 48-A)

[0514] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), (4-aminothiophen-2-yl)boronic acid (60.1 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After returning to room temperature naturally, stirring was continued. After the reaction was complete, the target compound (18.6 mg, 0.04 mmol, yield 27.6%) was separated by Pre-HPLC.

[0515] Ms: m / z = 482.2, [M+H] + .

[0516] 1 H NMR (400MHz, DMSO) δ9.92 (s, 1H), 7.02 (d, J = 2.0Hz, 1H), 6.85 (d, J = 2.0Hz, 1H), 6.57 (s, 1H), 6. 32(s,1H),4.20-4.07(m,3H),3.83(s,3H),3.46-3.43(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0517] Example 51: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido-2-d)picolinamide (Compound 140-A)

[0518] 1-8-A (0.86 g, 2.41 mmol) was dissolved in anhydrous DMF (30 mL), and methyl 4-aminopyridine-2-carboxylate (990.5 mg, 7.23 mmol) was added. TCFH (3.37 g, 12.05 mmol) and NMI (1.58 g, 19.28 mmol) were added under ice bath. After returning to room temperature naturally, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (708.5 mg, 1.48 mmol, yield 61.6%).

[0519] MS: m / z = 477.2, [M+H] + .

[0520] 1 H NMR (400MHz, DMSO) δ9.92 (s, 1H), 8.85 (s, 1H), 8.22-8.18 (m, 3H), 7.02 (d, J = 2.0Hz, 1H), 6.85 ( d,J=2.0Hz,1H),5.82(s,1H),3.83(s,3H),3.51-3.50(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0521] Example 52: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-3-oxo-2,3-dihydro-1H-benzo[c][1,2]azabor-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 221-A)

[0522] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 4H-pyrido[2,1-c][1,2,4]triazine-7-amine (62.2 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, the target compound (22.6 mg, 0.05 mmol, yield 33.1%) was obtained by Pre-HPLC separation.

[0523] Ms: m / z = 487.2, [M+H] + .

[0524] 1H NMR (400MHz, DMSO) δ9.30(s,1H),9.15(d,J=2.0Hz,1H),7.52(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),6.85(d, J=2.0Hz,1H),5.82(s,1H),4.20-4.07(m,2H),3.83(s,3H),3.46-3.43(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0525] Example 53: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-methylisoxazol-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 197)

[0526] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 3-methylisoxazol-4-amine (41.2 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (31.3 mg, 0.07 mmol, yield 51.30%).

[0527] MS: m / z = 437.1, [M+H] + .

[0528] 1 H NMR (400MHz, DMSO) δ10.09(s,1H),9.01(s,1H),7.24-7.07(m,2H),4.72(d,J=10.7Hz,1H),4.27(ddd,J=13.0,10.9 ,6.1Hz,1H),3.95(d,J=1.9Hz,3H),2.42(t,J=12.9Hz,1H),2.30(dd,J=12.6,6.1Hz,1H),2.15(s,3H),1.72(s,3H).

[0529] Example 54: Preparation of N-(6-aminopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 181)

[0530] Step 1: Preparation of tert-butyl (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyridin-2-yl)carbamate (Compound 181-1)

[0531] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and tert-butyl (5-aminopyridin-2-yl)carbamate (121.9 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. The mixture was allowed to return to room temperature and continued to stir. After the reaction was complete, the title compound (47.0 mg, 0.09 mmol, yield 61.42%) was separated by Pre-HPLC. MS: m / z = 548.2, [M+H] + .

[0532] Step 2: Preparation of N-(6-aminopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 181)

[0533] The product of step 1 (47.0 mg, 0.09 mmol) was dissolved in 1,4-dioxane (5 mL) and stirred at room temperature. After the reaction was complete, the target compound (32.4 mg, 0.07 mmol, yield 80.43%) was separated by Pre-HPLC.

[0534] MS: m / z = 448.1, [M+H] + .

[0535] 1 H NMR (400MHz, DMSO) δ9.98(s,1H),7.99(d,J=1.8Hz,1H),7.46(dd,J=8.8,2.2Hz,1H),7.15(dd,J=16.6,7.7Hz,2H),6.38(d,J=8.8Hz,1H) ,5.84(s,2H),4.54(d,J=10.7Hz,1H),4.29-4.18(m,1H),3.95(s,3H),2.39(t,J=12.9Hz,1H),2.28(dd,J=12.5,6.0Hz,1H),1.71(s,3H).

[0536] Example 55: Preparation of (4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido-2-d)phenyl)boronic acid (Compound 83-A)

[0537] Compound 1-8-A (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and (4-aminophenyl)boronic acid (32.64 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (9.52 mg, 0.02 mmol, yield 25%).

[0538] MS: m / z = 477.1, [M+H] + .

[0539] 1 H NMR (400MHz, DMSO) δ10.29(s,1H),7.94(s,2H),7.71(d,J=8.3Hz,2H),7.48(d,J=8.3Hz,2H),7.24-7.16(m,2H) ,4.30(dd,J=13.0,6.0Hz,1H),3.99(s,3H),2.44(t,J=12.9Hz,1H),2.33(dd,J=12.5,6.2Hz,1H),1.76(s,3H).

[0540] Example 56: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-chlorophenyl)boronic acid (Compound 23-A)

[0541] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 5-amino-2-chlorophenylboronic acid (72 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (52 mg, 0.10 mmol, yield 73%).

[0542] MS: m / z = 510.07, [M+H] + .

[0543] 1H NMR (400MHz, DMSO) δ9.89 (s, 1H), 8.27 (d, J = 13.8Hz, 2H), 7.86-7.62 (m, 2H), 7.56-7.43 (m, 3H), 4.61 (d, J = 10.7Hz ,1H),4.38-4.24(m,1H),3.99(d,J=1.6Hz,3H),2.45(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.76(s,3H).

[0544] Example 57: Preparation of N-(6-aminopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 222)

[0545] Step 1: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(2-methoxypyridin-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-d-2-carboxamide (Compound 222-1)

[0546] Compound 1-8 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 2-methoxypyridin-4-amine (52.1 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice-cooling. The mixture was allowed to return to room temperature and continued to stir. After the reaction was complete, the title compound (35.8 mg, 0.08 mmol, yield 55.25%) was obtained by Pre-HPLC separation. MS: m / z = 464.1, [M+H] + .

[0547] Step 2: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(2-hydroxypyridin-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-d-2-carboxamide (Compound 222)

[0548] The product of step 1 (35.8 mg, 0.08 mmol) was dissolved in DMF (5 mL), and pyridine hydrobromide (64.0 mg, 0.40 mmol) was added and stirred at room temperature. After the reaction was complete, the target compound (27.9 mg, 0.06 mmol, yield 77.62%) was obtained by Pre-HPLC separation.

[0549] MS: m / z = 450.1, [M+H] + .

[0550] 1H NMR (400MHz, DMSO) δ11.22(s,1H),10.31(s,1H),7.24(d,J=7.2Hz,1H),7.21-7.11(m,2H),6.60(d,J=1.6Hz,1H),6.18(dd,J= 7.2,1.7Hz,1H),4.23(dd,J=13.1,6.1Hz,1H),3.96(s,3H),2.42(t,J=12.9Hz,1H),2.30(dd,J=12.6,6.1Hz,1H),1.72(s,3H).

[0551] Example 58: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(tetrazolo[1,5-a]pyridin-7-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 203)

[0552] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and tetrazo[1,5-a]pyridin-7-amine (56.8 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (36.7 mg, 0.08 mmol, yield 55.38%).

[0553] MS: m / z = 474.1, [M+H] + .

[0554] 1 H NMR (400MHz, DMSO) δ11.05(s,1H),9.17(d,J=7.4Hz,1H),8.38(d,J=1.1Hz,1H),7.26-7.15(m,3H),4 .64(d,J=10.6Hz,1H),4.35-4.27(m,1H),3.99(s,3H),2.46(s,1H),2.37-2.32(m,1H),1.75(s,3H).

[0555] Example 59: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-3-oxo-2,3-dihydro-1H-benzo[c][1,2]azaborin-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-2)

[0556] 1-7 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 6-amino-1-hydroxy-1,2-dihydro-3H-benzo[c][1,2]azabor-3-one (68.0 mg, 0.42 mmol) was added. TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (22.5 mg, 0.04 mmol, yield 32.0%).

[0557] Ms: m / z = 501.2, [M+H] + .

[0558] 1 H NMR (400MHz, DMSO) δ10.02(s,1H),8.09(d,J=2.0Hz,1H),7.82-7.77(m,3H),7.02(d,J=2.0Hz,1H),6.8 5(d,J=2.0Hz,1H),4.22-4.02(m,2H),3.82(s,3H),3.48-3.45(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0559] Example 60: Preparation of (2R,3S,5R)3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-oxo-1,6-dihydropyridazin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-3-A)

[0560] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 6-aminopyridazin-3(2H)-one (26.64 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (6.74 mg, 0.015 mmol, yield 19%).

[0561] MS: m / z = 450.1, [M+H] + .

[0562] 1H NMR (400MHz, DMSO) δ12.71(s,1H),10.82(s,1H),7.84(d,J=10.1Hz,1H),7.20(t,J=6.0Hz,2H),6.90(d,J=10.1Hz,1H),4.66(d,J=1 0.6Hz,1H),4.28(td,J=12.8,6.2Hz,1H),3.97(d,J=1.7Hz,3H),2.43(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.2Hz,1H),1.75(s,3H).

[0563] Example 61: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(4-(pentafluoro-16-thio)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-4-A)

[0564] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 4-(pentafluoro-6-sulfonyl)aniline (52.56 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (11.14 mg, 0.02 mmol, yield 25%).

[0565] MS: m / z = 558.2, [M+H] + .

[0566] 1 H NMR (400MHz, DMSO) δ12.71(s,1H),10.82(s,1H),7.84(d,J=10.1Hz,1H),7.20(t,J=6.0Hz,2H),6.90(d,J=10.1Hz,1H),4.66(d,J=1 0.6Hz,1H),4.28(td,J=12.8,6.2Hz,1H),3.97(d,J=1.7Hz,3H),2.43(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.2Hz,1H),1.75(s,3H).

[0567] Example 62: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-fluorophenyl)boronic acid (Compound 88)

[0568] Compound 1-7 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 4-amino-2-fluorophenylboronic acid (65 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (48 mg, 0.097 mmol, yield 69%).

[0569] MS: m / z = 494.10, [M+H] + .

[0570] 1 H NMR (400MHz, DMSO) δ10.43(s,1H),8.00(d,J=13.8Hz,2H),7.56-7.32(m,2H),7.26-7.13(m,3H),4.62(d,J=10.7Hz ,1H),4.36-4.22(m,1H),3.99(d,J=1.6Hz,3H),2.46(t,J=12.9Hz,1H),2.34(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0571] Example 63: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-1-difluoromethyl-3-methyl)pyrazole (Compound 199)

[0572] Compound 1-7 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 1-difluoromethyl-3-methyl-4-amino-1H-pyrazole (62 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (40 mg, 0.082 mmol, yield 59%).

[0573] MS: m / z = 486.10, [M+H] + .

[0574] 1H NMR (400MHz, DMSO) δ9.84 (s, 1H), 8.27 (t, J = 114.7Hz, 1H), 7.56-7.43 (m, 3H), 4.61 (d, J = 10.7Hz, 1H), 4.38-4.2 4(m,1H),3.99(d,J=1.6Hz,3H),2.63(s,1H),2.45(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.76(s,3H).

[0575] Example 64: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxabor-5-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 119-A)

[0576] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 5-aminobenzo[c][1,2]oxaborol-1(3H)-ol (62.6 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, the target compound (44.5 mg, 0.09 mmol, yield 65.1%) was obtained by Pre-HPLC separation.

[0577] Ms: m / z = 488.2, [M+H] + .

[0578] 1 H NMR (400MHz, DMSO) δ10.02(s,1H),7.88(s,1H),7.84(d,J=2.0Hz,1H),7.62(d,J=2.0Hz,1H),7.02(d,J=2.0Hz,1H),6 .85(d,J=2.0Hz,1H),5.12(s,2H),4.22-4.02(m,2H),3.82(s,3H),3.48-3.45(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0579] Example 65: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 223-A) and (2S, 3R, 5S)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 223-B)

[0580] The experimental procedures refer to Example 45.

[0581] Compound 223-A: MS: m / z = 511.1 [M+H] +, 1H NMR(400MHz,DMSO)δ10.60(s,1H),8.07(s,1H),7.64(dd,J=12.1,10.5Hz,2H ),7.53-7.44(m,2H),7.23-7.11(m,2H),4.68(t,J=5.5Hz,1H),4.61(d,J=10. 7Hz,1H),4.33-4.23(m,1H),3.97(d,J=1.6Hz,3H),2.76(t,J=6.4Hz,2H),2. 44(t,J=12.9Hz,1H),2.31(dd,J=12.6,6.1Hz,1H),2.07(s,1H),1.73(s,3H).

[0582] Compound 223-B: MS: m / z = 511.1 [M+H] +, 1H NMR (400MHz, CDCl3) δ8.07(s,1H),8.00(t,J=1.8Hz,1H),7.74(dd,J=8.2,1.2Hz ,1H),7.66(d,J=7.9Hz,1H),7.45(t,J=8.0Hz,1H),7.02-6.96(m,1H),6.84(dt, J=16.4,8.2Hz,1H),4.92(s,2H),4.42(d,J=10.8Hz,1H),4.15(ddd,J=13.0,10. 9,6.0Hz,1H),2.60(t,J=13.0Hz,1H),2.23(dd,J=12.9,6.0Hz,1H),1.81(s,3H).

[0583] Example 66: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-(ethylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 224-A)

[0584] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 1-(ethylsulfonyl)-3-methyl-1H-pyrazol-4-amine (79.5 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After returning to room temperature naturally, stirring was continued. After the reaction was complete, the target compound (39.4 mg, 0.07 mmol, yield 53.2%) was separated by Pre-HPLC.

[0585] Ms: m / z = 528.2, [M+H] + .

[0586] 1 H NMR (400MHz, DMSO) δ9.92(s,1H),8.08(s,1H),7.02(d,J=2.0Hz,1H),6.85(d,J=2.0Hz,1H),4.22-4.02(m ,1H),3.82(s,3H),3.48-3.45(m,3H),2.75(s,3H),2.17-1.92(m,2H),1.38(s,3H),1.22(t,J=4.0Hz,1H).

[0587] Example 67: Preparation of (2-cyclopropyl-5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound 16)

[0588] The experimental steps are as in Example 1.

[0589] MS: m / z = 516.3 [M+H] +.

[0590] 1 H NMR (400MHz, CDCl3) δ8.09-7.52(m,2H),7.19-6.63(m,3H),4.73-4.34(m,1H),4.32-4.11(m,1H),4.00-3.87(m,3H),3.05-2.80(m,1H),2.6 8-2.43(m,2H),2.21(tt,J=16.4,8.2Hz,1H),1.85-1.73(m,3H),1.31(ddd,J=27.6,10.6,4.7Hz,1H),1.00-0.79(m,2H),0.77-0.49(m,2H).

[0591] Example 68: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-(dimethylamino)phenyl)boronic acid (Compound 98)

[0592] The experimental steps are as in Example 1.

[0593] MS: m / z = 519.3 [M+H] + .

[0594] 1 H NMR (400MHz, CDCl3) δ7.82(d,J=26.1Hz,3H),7.02(dd,J=15.8,7.6Hz,2H),6.86(dd,J=16.5,8.5Hz,1H),4.41(d,J=10.8Hz,1 H),4.22-4.12(m,1H),3.98(d,J=1.9Hz,3H),2.68(s,6H),2.59(t,J=13.1Hz,1H),2.23(dd,J=12.9,6.0Hz,1H),1.81(s,3H).

[0595] Example 69: Preparation of (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-vinylphenyl)boronic acid (Compound 15)

[0596] The experimental steps are as in Example 1.

[0597] MS: m / z = 502.3 [M+H] + .

[0598] 1 H NMR (400MHz, CD3OD_SPE) δ7.48-7.41(m,2H),7.36(d,J=1.2Hz,1H),7.10(ddd,J=8.2,5. 7,2.2Hz,1H),6.94(td,J=9.3,7.6Hz,1H),6.66(dd,J=17.5,11.0Hz,1H),5.61-5.53(m, 1H),5.16(d,J=11.3Hz,1H),4.53(t,J=9.3Hz,1H),4.32(ddd,J=13.2,10.9,6.0Hz,1H), 3.98(d,J=2.2Hz,3H),2.52(t,J=13.0Hz,1H),2.25(dd,J=12.7,6.0Hz,1H),1.76(s,3H).

[0599] Example 70: Preparation of 3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)benzenesulfonylfluoride (Compound a-70-A)

[0600] Compound 1-7-2 (100 mg, 0.28 mmol) was dissolved in anhydrous MeCN (5 mL), 3-aminophenyl fluorosulfonate (54 mg, 0.28 mmol) was added, and EDCI (44 mg, 0.28 mmol) was added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (83 mg, 0.16 mmol, yield 55.85%).

[0601] MS: m / z=529.1, [M+H]+.

[0602] 1 H NMR (400MHz, DMSO) δ10.67(s,1H),7.87(s,1H),7.49(s,2H),7.19(ddd,J=22.7,19.2,5.8Hz,3H),4.60(d,J=1 0.6Hz,1H),4.33-4.23(m,1H),3.96(s,3H),2.43(d,J=12.9Hz,1H),2.31(dd,J=12.4,5.9Hz,1H),1.73(s,3H).

[0603] Example 71: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonylimino)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 225)

[0604] Refer to Example 70 for the experimental procedures.

[0605] MS: m / z = 509.1 [M+H] + , 1 H NMR (400MHz, DMSO) δ7.30-7.08(m,3H),7.00(dt,J=5.8,2.0Hz,1H),6.84-6.58(m,2H),5.73(d,J=6.8Hz,2H),4.56(dd,J=11.1, 4.4Hz,1H),4.08-3.97(m,1H),3.88(dd,J=32.2,1.4Hz,3H),3.28(d,J=13.2Hz,3H),2.35-2.15(m,2H),1.65(d,J=10.7Hz,3H).

[0606] Example 72: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-(pentafluorosulfanyl)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-5)

[0607] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and (3-aminophenyl)sulfur pentafluoride (92.1 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (44.8 mg, 0.08 mmol, yield 57.48%).

[0608] MS: m / z = 558.0, [M+H] + .

[0609] 1 H NMR (400MHz, DMSO) δ10.80(s,1H),8.92(d,J=7.4Hz,1H),8.13(d,J=1.1Hz,1H),7.04-6.96(m,2H),6.98-6.80(m,2H),4.39(d ,J=10.6Hz,1H),4.07(td,J=13.0,6.1Hz,1H),3.74(d,J=1.7Hz,3H),2.21(s,1H),2.09(dt,J=11.5,5.8Hz,1H),1.50(s,3H).

[0610] Example 73: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(2,3-dihydroxypropoxy)pyridin-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 191)

[0611] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 3-((4-aminopyridin-2-yl)oxy)propane-1,2-diol (77.3 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (44.8 mg, 0.08 mmol, yield 57.48%).

[0612] MS: m / z = 523.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ7.57(d,J=5.7Hz,1H),7.35-7.23(m,1H),7.14-7.00(m,1H),6.16(dd,J=7.9,3.4Hz,1H),5.97(d,J=14.6Hz,2H),5.82-5.74(m ,1H),4.98-4.85(m,1H),4.65(td,J=11.5,3.7Hz,1H),4.11-3.97(m,3H), 3.94(d,J=1.8Hz,3H),3.90-3.78(m,1H),2.41-2.20(m,2H),1.67(s,3H).

[0613] Example 74: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(tetrazolo[1,5-a]pyridin-6-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 202)

[0614] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and tetrazo[1,5-a]pyridin-6-amine (56.7 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (31.0 mg, 0.07 mmol, yield 46.69%).

[0615] MS: m / z = 474.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.95(s,1H),9.64(s,1H),8.17(d,J=9.6Hz,1H),7.64(dd,J=9.6,1.6Hz,1H),7.28-7.05(m,2H),4.65(d ,J=10.6Hz,1H),4.32(td,J=13.0,6.1Hz,1H),3.99(d,J=1.7Hz,3H),2.45(s,1H),2.34(dd,J=12.6,6.0Hz,1H),1.74(s,3H).

[0616] Example 75: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-3-oxo-1,3-dihydrobenzo[c][1,2]oxabor-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-6-A)

[0617] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 6-amino-1-hydroxybenzo[c][1,2]oxaborol-3(1H)-one (68.5 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, the target compound (33.2 mg, 0.07 mmol, yield 42.2%) was separated by Pre-HPLC.

[0618] Ms: m / z = 502.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02(s,1H),8.27(d,J=1.6Hz,1H),7.85(d,J=1.6Hz,1H),7.79(s,1H),7.02(d,J=2.0Hz,1H),6 .85(d,J=2.0Hz,1H),4.22-4.02(m,2H),3.82(s,3H),3.47-3.46(m,1H),2.50(s,3H),2.16-1.92(m,2H),1.38(s,3H).

[0619] Example 76: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-methylsulfonyl)pyridine (Compound 192)

[0620] Compound 1-7 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 2-methylsulfonyl-4-aminopyridine (72 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (53 mg, 0.10 mmol, yield 74%).

[0621] MS: m / z = 511.07, [M+H] + , 1H NMR (400MHz, DMSO) δ9.56 (m, 2H), 7.86-7.62 (m, 2H), 7.56-7.43 (m, 2H), 4.61 (d, J = 10.7Hz, 1H), 4.38-4.24 (m ,1H),3.99(d,J=1.6Hz,3H),3.41(s,3H),2.45(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0622] Example 77: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-nitro)pyridine (Compound a-7)

[0623] Compound 1-7 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 2-nitro-4-aminopyridine (58 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (35 mg, 0.073 mmol, yield 52%) was obtained by Pre-HPLC separation.

[0624] MS: m / z = 478.08, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.87(s,1H),8.58-8.48(m,1H),7.96-7.72(m,2H),7.54-7.41(m,2H),4.61(d,J=10.7Hz,1 H),4.38-4.24(m,1H),3.99(d,J=1.6Hz,3H),2.43(t,J=12.9Hz,1H),2.31(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0625] Example 78: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-3-oxo-1,3-dihydrobenzo[c][1,2]oxabor-5-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-8-A)

[0626] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 5-amino-1-hydroxybenzo[c][1,2]oxaborol-3(1H)-one (39.12 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (10.04 mg, 0.02 mmol, yield 25%).

[0627] MS: m / z = 502.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ12.71(s,1H),10.82(s,1H),7.84(d,J=10.1Hz,1H),7.20(t,J=6.0Hz,2H),6.90(d,J=10.1Hz,1H),4.66(d,J=1 0.6Hz,1H),4.28(td,J=12.8,6.2Hz,1H),3.97(d,J=1.7Hz,3H),2.43(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.2Hz,1H),1.75(s,3H).

[0628] Example 80: Preparation of N-(3-(N-cyanosulfamoyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-9)

[0629] Refer to Example 70 for the experimental procedures.

[0630] MS: m / z = 553.1 [M+H] + , 1 H NMR (400MHz, CDCl3) δ9.10 (s, 1H), 7.68-7.38 (m, 3H), 7.08-6.59 (m, 4H), 4.49 (d, J = 10.3Hz, 1H), 4.28-4.16(m,1H),3.88(d,J=1.4Hz,3H),2.44(d,J=6.3Hz,1H),2.21-2.11(m,1H),1.69(s,4H).

[0631] Example 81: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((dimethyl(oxo)-16-sulfanylidene)amino)pyridin-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-10)

[0632] Refer to Example 70 for the experimental procedures.

[0633] MS: m / z = 524.1 [M+H] + , 1 H NMR (400MHz, CDCl3) δ8.20 (s, 1H), 8.02 (d, J = 5.9Hz, 1H), 7.08 (dd, J = 5.8, 1.7 Hz,1H),7.00(ddd,J=7.9,5.5,2.0Hz,1H),6.90-6.81(m,2H),4.43(d,J=10.8H z,1H),4.17(ddd,J=13.0,10.9,6.1Hz,1H),3.97(d,J=2.5Hz,3H),3.33(s,6H) ,2.55(t,J=13.0Hz,1H),2.21(dd,J=12.9,6.1Hz,1H),1.77(d,J=10.7Hz,3H).

[0634] Example 82: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-((dimethyl(oxo)-16-sulfonyl)amino)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-11-A)

[0635] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), ((4-aminophenyl)imino)dimethyl-6-thione (77.3 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After returning to room temperature naturally, stirring was continued. After the reaction was complete, the target compound (25.1 mg, 0.05 mmol, yield 34.3%) was separated by Pre-HPLC.

[0636] Ms: m / z = 523.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02(s,1H),7.56(d,J=1.6Hz,2H),7.34(d,J=2.0Hz,2H),7.02(d,J=2.0Hz,1H),6.85(d, J=2.0Hz,1H),4.22-4.02(m,1H),3.82(s,3H),3.47-3.46(m,1H),2.50(s,3H),2.16-1.92(m,2H),1.38(s,3H).

[0637] Example 83: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazin-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-12)

[0638] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 6-amino-2,3-dihydrophthalazine-1,4-dione (41.2 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (31.0 mg, 0.08 mmol, yield 55.03%).

[0639] MS: m / z = 516.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ11.97(s,1H),7.87(d,J=8.7Hz,1H),7.47(t,J=6.7Hz,1H),7.24-7.17(m,1H),7.04(dd,J=8.7,2.0Hz,1H), 6.46-6.37(m,3H),5.12(d,J=10.9Hz,1H),4.28(td,J=12.2,6.2Hz,1H),3.97(d,J=1.4Hz,3H),2.47-2.32(m,2H),1.78(s,3H).

[0640] Example 84: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(4-((dimethyl(oxo)-16-sulfonyl)amino)-3-fluorophenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-13)

[0641] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and (4-amino-2-fluorophenyl)dimethyl-6-sulfonic acid (84.9 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (34.0 mg, 0.06 mmol, yield 45.01%).

[0642] MS: m / z = 541.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.27(s,1H),7.47-7.38(m,1H),7.20-7.12(m,2H),7.05-6.99(m,2H),4.55(d,J=10. 8Hz, 1H), 4.25 (td, J=12.8, 6.1Hz, 1H), 3.96 (d, J=1.3Hz, 3H), 3.18 (s, 6H), 2.45-2.24 (m, 2H), 1.72 (s, 3H).

[0643] Example 85: Preparation of 4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenylsulfamate (Compound a-14)

[0644] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 4-aminophenylsulfamate (79.0 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (31.0 mg, 0.06 mmol, yield 42.13%).

[0645] MS: m / z = 527.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.38(s,1H),7.89(s,2H),7.54(d,J=9.0Hz,2H),7.16(t,J=9.0Hz,4H),4.59(d,J=10.7Hz,1H),4 .27(td,J=12.8,6.1Hz,1H),3.96(d,J=1.6Hz,3H),2.42(t,J=12.9Hz,1H),2.31(dd,J=12.6,6.1Hz,1H),1.73(s,3H).

[0646] Example 86: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-hydroxybenzoic acid (Compound 226-A)

[0647] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 4-amino-2-hydroxybenzoic acid (36.72 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (9.82 mg, 0.02 mmol, yield 25%).

[0648] MS: m / z = 492.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.17(s,1H),7.56(d,J=8.4Hz,1H),7.23-7.16(m,2H),6.97(s,1H),6.76(dd,J=8.4,1.4Hz,1H),4.62(d ,J=10.7Hz,1H),4.29(td,J=12.6,6.2Hz,1H),3.99(s,3H),2.42(t,J=12.9Hz,1H),2.32(dd,J=12.6,6.3Hz,1H),1.75(s,3H).

[0649] Example 87: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(3-((dimethyl(oxo)-16-sulfonyl))amino)-4-fluorophenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-15)

[0650] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and (5-amino-2-fluorophenyl)imino)dimethyl-6-thione (48.48 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (10.81 mg, 0.02 mmol, yield 25%).

[0651] MS: m / z = 541.3, [M+H] + , 1H NMR (400MHz, DMSO) δ10.20(s,1H),7.33(d,J=5.9Hz,1H),7.22-7.16(m,2H),7.12(d,J=8.2Hz,1H),7.01(t,J=9.7Hz,1H),4.58(d,J=1 0.7Hz,1H),4.29(td,J=12.5,6.4Hz,1H),3.99(s,3H),3.26(s,6H),2.42(t,J=12.8Hz,1H),2.32(dd,J=12.5,6.2Hz,1H),1.75(s,3H).

[0652] Example 88: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-amino)pyridine (Compound 175)

[0653] Compound a-7 (20 mg, 0.14 mmol) was dissolved in anhydrous EtOH (5 mL), and Pd / C (20 mg) was added. The mixture was stirred at room temperature under the protection of hydrogen. After the reaction was complete, the target compound (10 mg, 0.022 mmol, yield 53%) was separated by Pre-HPLC.

[0654] MS: m / z = 448.10, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.87 (s, 1H), 7.88-7.64 (m, 2H), 7.56-7.43 (m, 3H), 4.61 (d, J = 10.7Hz, 1H), 4.38-4.24 (m ,1H),3.98(d,J=1.6Hz,3H),2.45(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.98(s,2H),1.75(s,3H).

[0655] Example 89: Preparation of 4-(3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinamide (Compound 136)

[0656] Step 1: Synthesis of methyl 4-(3-(3,4-difluoro-2-methoxyphenyl)-4,5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinate (136-1)

[0657] Compound 1-7 (37 mg, 0.1 mmol), anhydrous acetonitrile (3 mL), NMI (65 mg, 0.8 mmol) and methyl 4-aminopicolinate (41 mg, 0.3 mmol) were added with TCFH (140 mg, 0.5 mmol) under ice bath. After returning to room temperature, stirring was continued. Water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water and saturated brine, and the crude product was separated by Pre-HPLC to obtain the title compound (38 mg, 0.075 mmol, yield 75.24%). MS: m / z = 505.1, [M+H] + .

[0658] Step 2: Synthesis of 4-(3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)picolinamide (Compound 136)

[0659] The product of step 2 (38 mg, 0.075 mmol) and 7 M ammonia in methanol solution (2 mL) were stirred at 25°C and concentrated under reduced pressure. The crude product was separated by Pre-HPLC to obtain the title compound (21 mg, 0.043 mmol, yield 57.33%).

[0660] MS: m / z = 490.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.79(s,1H),8.48(d,J=5.5Hz,1H),8.17(d,J=1.8Hz,1H),8.12-8.04(m,1H),7.70-7.59(m,2H),7.24-7.16 (m,2H),4.49(d,J=10.5Hz,1H),3.98(d,J=1.2Hz,3H),3.96-3.86(m,2H),2.90-2.72(m,1H),1.63(s,3H),0.85(d,J=6.7Hz,3H).

[0661] Example 90: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-(S-methylsulfonylimino)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 227)

[0662] Refer to Example 70 for the experimental procedures.

[0663] MS: m / z=527.2[M+H]+, 1H NMR (400MHz, DMSO) δ10.60(d,J=22.1Hz,1H),8.08(ddd,J=12.9,6.4,2.7Hz ,1H),7.81-7.72(m,1H),7.35(t,J=9.3Hz,1H),7.23-7.10(m,1H),4.65(t,J =8.1Hz,1H),4.59(d,J=10.7Hz,1H),4.31-4.22(m,1H),3.97(s,1H),3.13( d,J=6.6Hz,1H),2.41(d,J=13.0Hz,1H),2.29(s,1H),1.72(d,J=8.1Hz,1H).

[0664] Example 91: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(4-(S-methylsulfonylimino)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 228)

[0665] Refer to Example 70 for the experimental procedures.

[0666] MS: m / z=509.1[M+H]+,1H NMR (400MHz, DMSO) δ10.64(s,1H),7.85-7.80(m,1H),7.68(dd,J=7.7,6.0Hz,1H),7.17(dt,J=16.2,7.4Hz,1H),4.62(d,J=10.7Hz,1H ),4.33-4.24(m,1H),4.11(s,1H),3.97(d,J=1.7Hz,1H),2.98(d,J=6.2Hz,1H),2.36-2.28(m,1H),1.74(s,1H),1.51(d,J=2.6Hz,1H).

[0667] Example 92: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-hydroxylamine)pyridine (Compound a-16)

[0668] Compound a-7 (20 mg, 0.14 mmol) was dissolved in hydrazine hydrate (5 mL), and Rh / C (20 mg) was added. The mixture was stirred at room temperature under the protection of hydrogen. After the reaction was complete, the target compound (13 mg, 0.028 mmol, yield 67%) was separated by Pre-HPLC.

[0669] MS: m / z = 464.10, [M+H] + , 1H NMR (400MHz, DMSO) δ9.89 (s, 1H), 7.89-7.63 (m, 2H), 7.56-7.41 (m, 3H), 4.62 (d, J = 10.7Hz, 1H), 4.38-4.24 (m, 1 H),3.99(d,J=1.6Hz,3H),2.45(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),2.21-1.99(m,2H),1.75(s,3H).

[0670] Example 93: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-methylsulfonylpyridin-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 192-A)

[0671] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 2-methylsulfonyl-4-aminopyridine (72 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (53 mg, 0.10 mmol, yield 74%).

[0672] MS: m / z = 511.07, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.57(m,2H),7.86-7.62(m,2H),7.56-7.43(m,2H),4.61(d,J=10.7Hz,1H),4.37-4.23(m ,1H),3.99(d,J=1.6Hz,3H),3.42(s,3H),2.45(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.76(s,3H).

[0673] Example 94: Preparation of (2S,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-nitropyridin-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-7-A)

[0674] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 2-nitropyridine-4-amine (58.4 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (41.6 mg, 0.09 mmol, yield 62.23%).

[0675] MS: m / z = 478.1, [M+H] + ,1H NMR (400MHz, DMSO) δ9.52(s,1H),8.82(d,J=8.0Hz,1H),8.47(s,1H),7.62(dt,J=8.1,4.0Hz,1H),7.23-7.01(m,1H),6.93-6.72(m,1H ),4.59(d,J=10.7Hz,1H),4.31-4.25(m,1H),4.00(d,J=2.5Hz,3H),2.49(t,J=13.1Hz,1H),2.24(dd,J=12.9,6.2Hz,1H),1.78(s,3H).

[0676] Example 95: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 229-A)

[0677] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (99.6 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (38.8 mg, 0.07 mmol, yield 48.2%).

[0678] Ms: m / z = 576.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.02(s,1H),7.82-7.75(m,2H),7.41(d,J=1.6Hz,1H),7.01(d,J=2.0Hz,1H),6.85(d,J=2.0Hz ,1H),4.22-4.02(m,1H),3.82(s,3H),3.47-3.46(m,1H),2.63(s,3H),2.16-1.92(m,2H),1.37(s,3H),1.20(s,3H).

[0679] Example 96: Preparation of (4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-fluorophenyl)boronic acid (Compound 88-A)

[0680] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), (4-amino-2-fluorophenyl)boric acid (71.4 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (45.8 mg, 0.09 mmol, yield 64.2%).

[0681] Ms: m / z = 494.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02(s,1H),7.83-7.75(m,2H),7.42(d,J=1.6Hz,1H),7.02(d,J=2.0Hz,1H),6.86(d,J =2.0Hz,1H),4.23-4.02(m,3H),3.83(s,3H),3.48-3.46(m,1H),2.64(s,3H),2.17-1.92(m,2H),1.38(s,3H).

[0682] Example 97: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-(dimethylphosphoryl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (230-A)

[0683] The experimental steps are as in Example 1.

[0684] MS: m / z = 508.2 [M+H] +, 1 H NMR (400MHz, CDCl3) δ10.03(s,1H),7.73(d,J=7.0Hz,2H),7.57(dd,J=11.2,8.6Hz,2H),7.03-6.97(m,1H),6.78(dt,J=16.5,8.3Hz,1H),4.65(d,J =10.8Hz,1H),4.29(ddd,J=13.2,10.9,6.1Hz,1H),4.00(d,J=2.3Hz,3H) ,2.49(t,J=13.0Hz,1H),2.24(dd,J=12.8,6.1Hz,2H),1.81-1.69(m,9H).

[0685] Example 98: Preparation of (2R,3S,5R)-N-(3-((Z)-2-cyano-3-hydroxybut-2-enyl)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-17-A)

[0686] The experimental steps are as in Example 1.

[0687] MS: m / z = 573.1 [M+H] + , 1 H NMR (400MHz, DMSO) δ12.16(s,1H),10.32(s,1H),8.51-8.46(m,1H),7.36-7.27(m,2H),7.25-7.14(m,3H),7.12-7.01(m,2H),4.67(d,J =10.8Hz,1H),4.37-4.27(m,1H),4.02(d,J=1.7Hz,3H),2.43(t,J=12.8Hz,1H),2.34(dd,J=12.6,6.3Hz,1H),2.08(s,3H),1.78(s,3H).

[0688] Example 99: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-(sulfamoylamino)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-18-A)

[0689] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 4-aminophenylsulfamate (78.6 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (29.4 mg, 0.06 mmol, yield 40.00%).

[0690] MS: m / z = 526.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.22(s,1H),7.29(s,1H),7.24-6.91(m,6H),6.88(d,J=8.3Hz,1H),4.62(d,J =10.7Hz,1H),4.27(td,J=12.9,6.2Hz,1H),3.96(d,J=1.5Hz,3H),2.43-2.27(m,2H),1.72(s,3H).

[0691] Example 100: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-(S-methylsulfonylimino)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 225-A)

[0692] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL) and (3-aminophenyl)(imino)(methyl)-λ was added. 6 -thioketone (71.4 mg, 0.42 mmol), TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath, and the mixture was naturally restored to room temperature and continued to stir. After the reaction was complete, Pre-HPLC separation gave the target compound (45.8 mg, 0.09 mmol, yield 64.2%).

[0693] Ms: m / z = 509.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.02(s,1H),7.75-7.66(m,3H),7.33(d,J=1.6Hz,1H),7.02(d,J=2.0Hz,1H),6.86(d,J =2.0Hz,1H),4.23-4.02(m,2H),3.83(s,3H),3.48-3.46(m,1H),2.64(s,3H),2.17-1.92(m,2H),1.38(s,3H).

[0694] Example 101: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-(methylthio)pyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 231-A)

[0695] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 6-(methylthio)pyridin-3-amine (33.62 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (9.56 mg, 0.02 mmol, yield 25%).

[0696] MS: m / z = 479.3, [M+H] + , 1 H NMR (400 MHz, DMSO) δ 1 H NMR: δ8.07(dd,J=1.8,0.5Hz,1H),7.34(dd,J=8.6,1.8Hz)),7.15-7.40(2H,7.22(dd,J=8.6,0.5Hz),7.09(d,J=8.1Hz,1H),6.87(d,J=8 .1Hz,1H),3.98(d,J=5.5Hz,1H),3.77(s,3H),3.61(1H,ddd,J=8.1,6.1,5.5Hz),2.44(3H,s),1.93(2H,dd,J=16.0,7.1Hz),1.75(s,3H).

[0697] Example 102: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-[3-fluoro-4-(sulfamoylamino)phenyl]-5-methyl-5-(trifluoromethyl)thiolane-2-carboxamide (Compound a-19-A)

[0698] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 2-fluoro-4-aminosulfonamide (86 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (45 mg, 0.083 mmol, yield 59%).

[0699] MS: m / z = 544.07, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.87 (s, 1H), 7.88-7.54 (m, 3H), 7.36-7.23 (m, 2H), 5.62 (s, 1H), 4.61 (d, J = 10.7Hz, 1H), 4.47 ( s,2H),4.38-4.24(m,1H),3.98(d,J=1.6Hz,3H),2.43(t,J=12.9Hz,1H),2.32(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0700] Example 103: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-3-oxo-2,3-dihydro-1H-benzo[c][1,2]azaborin-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-2-A)

[0701] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 6-amino-1-hydroxy-1,2-dihydro-3H-benzo[c][1,2]azabor-3-one (68.0 mg, 0.42 mmol) was added. TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, the target compound (40.1 mg, 0.08 mmol, yield 51.1%) was obtained by Pre-HPLC separation.

[0702] Ms: m / z = 501.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.02(s,1H),8.09(d,J=2.0Hz,1H),7.82-7.70(m,3H),7.07(d,J=1.6Hz,1H),6.8 6(d,J=2.0Hz,1H),4.23-4.02(m,2H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0703] Example 104: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(tetrazolo[1,5-a]pyridin-6-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 202-A)

[0704] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), tetrazo[1,5-a]pyridin-6-amine (56.7 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (31.3 mg, 0.07 mmol, yield 47.23%).

[0705] MS: m / z = 474.1, [M+H] + ,1H NMR (400MHz, DMSO) δ10.85(s,1H),9.54(s,1H),8.07(d,J=9.6Hz,1H),7.54(dd,J=9.6,1.6Hz,1H),7.18-7.03(m,2H),4.57(d ,J=10.6Hz,1H),4.22(td,J=13.0,6.1Hz,1H),3.89(d,J=1.7Hz,3H),2.35(s,1H),2.24(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0706] Example 105: Preparation of (2R,3S,5R)-N-(2-aminopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 175-A)

[0707] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and pyridine-2,4-diamine (26.16 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (4.93 mg, 0.02 mmol, yield 14%).

[0708] MS: m / z = 448.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.17(s,1H),7.50(dd,J=5.2,0.4Hz,1H),7.28(s,2H),7.23-7.16(m,2H),6.14(dd,J=5.2,1.8Hz,1H),5.99(dd,J=1.8,0.4Hz, 1H),4.66(d,J=10.6Hz,1H),4.28(td,J=12.8,6.2Hz,1H),3.97(d,J=1.7H z,3H),2.43(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.2Hz,1H),1.75(s,3H).

[0709] Example 106: Preparation of (2R,3S,5R)-N-(2-azidopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-20-A)

[0710] The experimental steps are as in Example 1.

[0711] MS: m / z=472.4[M+H]+, 1 H NMR (400MHz, CDCl3) δ9.32 (s, 1H), 8.72 (d, J = 7.4Hz, 1H), 8.43 (s, 1H), 7.54 (d t,J=8.1,4.0Hz,1H),7.01(ddd,J=7.8,5.5,1.9Hz,1H),6.83(dt,J=16.4,8.2H z,1H),4.59(d,J=10.7Hz,1H),4.27(ddd,J=13.1,10.8,6.1Hz,1H),4.00(d,J= 2.5Hz, 3H), 2.56 (t, J = 13.1Hz, 1H), 2.24 (dd, J = 12.9, 6.2Hz, 1H), 1.78 (s, 3H).

[0712] Example 107: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(2,3-dihydroxypropoxy)pyridin-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 191-A)

[0713] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-((4-aminopyridin-2-yl)oxy)propane-1,2-diol (77.3 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (40.9 mg, 0.08 mmol, yield 55.98%) was obtained by Pre-HPLC separation.

[0714] MS: m / z = 523.1, [M+H] + ,1H NMR (400MHz, DMSO) δ10.57 (s, 1H), 7.97 (d, J = 5.7Hz, 1H), 7.23-7.11 (m, 2H), 7.0 4(s,1H),6.95(dd,J=5.7,1.4Hz,1H),4.88(d,J=5.1Hz,1H),4.65-4.53(m,2H), 4.31-4.18(m,2H),4.09-4.02(m,1H),3.96(s,3H),3.78-3.68(m,1H),3.38(t,J =5.6Hz,2H),2.44(t,J=12.9Hz,1H),2.31(dd,J=12.6,6.1Hz,1H),1.72(s,3H).

[0715] Example 108: Preparation of (2R,3S,5R)-N-(1-(cyclopropylsulfonyl)-3-methyl-1H-pyrazol-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-21-A)

[0716] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 1-(cyclopropylsulfonyl)-3-methyl-1H-pyrazol-4-amine (84.4 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (37.9 mg, 0.07 mmol, yield 50.18%) was obtained by Pre-HPLC separation.

[0717] MS: m / z = 540.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.21(s,1H),8.14(s,1H),7.13(dd,J=15.0,10.0Hz,1H),6.90-6.79(m,1H),4.45(d,J=3.3Hz,1H),4.23(td,J=7.9,3.2Hz ,1H),3.92(s,3H),3.76(dd,J=24.7,7.9Hz,1H),2.43(s,3H),2.11(dd, J=24.7,7.9Hz,1H),1.82-1.61(m,1H),1.38(s,3H),1.12-0.85(m,4H).

[0718] Example 109: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-(methylsulfinyl)pyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 232)

[0719] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 6-(methylsulfinyl)pyridin-3-amine (37.44 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (14.86 mg, 0.03 mmol, yield 37%) was obtained by Pre-HPLC separation.

[0720] MS: m / z = 495.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.33 (s, 1H), 7.27 (d, J = 7.1Hz, 1H), 7.21-7.06 (m, 2H), 6 .63(s,1H),6.21(d,J=7.0Hz,1H),4.58(d,J=10.6Hz,1H),4.39-4.19(m,1H),4 .02(dd,J=20.4,1.7Hz,3H),3.63(dd,J=61.8,11.1Hz,1H),2.46(t,J=12.9Hz, 1H),2.39-2.24(m,1H),1.73(d,J=8.8Hz,3H),1.48(s,1H),1.43-1.31(m,1H).

[0721] Example 110: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(3-((dimethyl(oxo)-16-sulfonyl)amino)-4-fluorophenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-22)

[0722] Compound 1-7 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and (5-amino-2-fluorophenyl)imino)dimethyl-6-thione (48.48 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (21.60 mg, 0.04 mmol, yield 50%) was obtained by Pre-HPLC separation.

[0723] MS: m / z = 541.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.20(s,1H),7.33(d,J=5.9Hz,1H),7.22-7.16(m,2H),7.12(d,J=8.2Hz,1H),7.01(t,J=9.7Hz,1H),4.58(d,J=1 0.7Hz,1H),4.29(td,J=12.5,6.4Hz,1H),3.99(s,3H),3.26(s,6H),2.42(t,J=12.8Hz,1H),2.32(dd,J=12.5,6.2Hz,1H),1.75(s,3H).

[0724] Example 111: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,3-dioxoindole-5-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-23-A)

[0725] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 5-aminoisoindoline-1,3-dione (68.0 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (43.5 mg, 0.09 mmol, yield 62.0%) was obtained by Pre-HPLC separation.

[0726] Ms: m / z = 501.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ13.51(s,1H),10.02(s,1H),8.35(s,1H),8.27(d,J=2.0Hz,1H),8.07(d,J=2.0Hz,1H),7.07(d,J= 1.6Hz,1H),6.86(d,J=2.0Hz,1H),4.23-4.02(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0727] Example 112: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-sulfamoylpyridin-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 234-A)

[0728] The experimental steps are as in Example 1.

[0729] MS: m / z = 512.3 [M+H] + , 1 H NMR(400MHz,DMSO)δ7.86(d,J=6.0Hz,1H),7.29(s,1H),7.14-6.96(m,3H),6.59(d,J=4.7Hz, 1H), 4.29 (d, J = 10.8Hz, 1H), 4.01-3.90 (m, 1H), 3.84 (s, 3H), 2.24-2.09 (m, 2H), 1.60 (s, 3H).

[0730] Example 113: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(3-fluoro-4-(S-methylsulfonylimino)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 235)

[0731] The experimental steps are as in Example 1.

[0732] MS: m / z = 527.1 [M+H] + , 1 H NMR (400MHz, DMSO) δ10.79(s,1H),7.76(t,J=8.5Hz,1H),7.64(d,J=12.2Hz,1H),7.36(dd,J=8.7,1.7Hz,1H),7.23-7.11(m,2H),4.62 -4.57(m,2H),4.32-4.22(m,1H),3.96(d,J=1.7Hz,3H),3.10(d,J=0.8Hz,3H),2.44(d,J=12.9Hz,1H),2.35-2.29(m,1H),1.73(s,3H).

[0733] Example 114: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(4-(sulfamoylamino)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-24-A)

[0734] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 4-aminobenzenesulfonamide (78.5 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After returning to room temperature naturally, stirring was continued. The reaction was complete and the target compound (44.6 mg, 0.08 mmol, yield 55.2%) was obtained by Pre-HPLC separation.

[0735] Ms: m / z = 526.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.58(s,1H),10.02(s,1H),7.37(d,J=2.0Hz,1H),7.07(d,J=1.6Hz,1H),6.90-6.86 (m,2H),5.51(s,1H),4.23-4.02(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0736] Example 115: Preparation of N-(2-aminopyrimidin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 236)

[0737] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and pyrimidine-2,4-diamine (46.2 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (27.0 mg, 0.06 mmol, yield 43.06%) was obtained by Pre-HPLC separation.

[0738] MS: m / z = 449.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.18(s,1H),7.87(d,J=5.8Hz,1H),7.17(d,J=7.8Hz,2H),6.92-6.81(m,2H),6.12(d,J= 5.8Hz, 1H), 4.28 (dd, J=17.8, 11.5Hz, 1H), 3.95 (d, J=1.4Hz, 3H), 3.74 (s, 1H), 2.38-2.18 (m, 2H), 1.70 (s, 3H).

[0739] Example 116: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(6-(methylsulfinyl)pyridin-3-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 238-A)

[0740] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 6-(methylsulfinyl)pyridin-3-amine (37.44 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (14.86 mg, 0.03 mmol, yield 37%) was obtained by Pre-HPLC separation.

[0741] MS: m / z = 495.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.33 (s, 1H), 7.27 (d, J = 7.1Hz, 1H), 7.21-7.06 (m, 2H), 6 .63(s,1H),6.21(d,J=7.0Hz,1H),4.58(d,J=10.6Hz,1H),4.39-4.19(m,1H),4 .02(dd,J=20.4,1.7Hz,3H),3.63(dd,J=61.8,11.1Hz,1H),2.46(t,J=12.9Hz, 1H),2.39-2.24(m,1H),1.73(d,J=8.8Hz,3H),1.48(s,1H),1.43-1.31(m,1H).

[0742] Example 117: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N-isopropylsulfamoyl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 239-A)

[0743] Refer to Example 70 for the experimental procedures.

[0744] MS: m / z=553.3[M+H]+, 1H NMR (400MHz, DMSO) δ10.59 (s, 1H), 8.11-8.07 (m, 1H), 7.63 (ddd, J = 7.3, 4.6, 2.5Hz, 2H),7.52-7.45(m,2H),7.24-7.10(m,2H),4.60(d,J=10.7Hz,1H),4.28(ddd,J=13. 1,10.9,6.1Hz,1H),3.96(d,J=1.9Hz,3H),3.19(dq,J=13.3,6.6Hz,1H),2.44(t,J= 12.9Hz, 1H), 2.31 (dd, J=12.6, 6.1Hz, 1H), 1.73 (s, 3H), 0.92 (dd, J=6.5, 0.6Hz, 6H).

[0745] Example 118: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(N,N-dimethylsulfamoyl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 240-A)

[0746] Refer to Example 70 for the experimental procedures.

[0747] MS: m / z = 539.3 [M+H] + , 1 H NMR (400MHz, DMSO) δ10.65 (s, 1H), 7.99 (t, J = 1.8Hz, 1H), 7.77-7.73 (m, 1H ),7.55(t,J=8.0Hz,1H),7.43-7.39(m,1H),7.24-7.11(m,2H),4.59(d,J= 10.7Hz,1H),4.27(ddd,J=13.1,10.9,6.1Hz,1H),3.96(d,J=1.9Hz,3H),2 .58(s,6H),2.48-2.40(m,1H),2.31(dd,J=12.6,6.1Hz,1H),1.73(s,3H).

[0748] Example 119: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-(N-methylsulfamoyl)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 241-A)

[0749] Refer to Example 70 for the experimental procedures.

[0750] MS: m / z = 542.3 [M+H] +, 1 H NMR (400MHz, DMSO) δ10.61(s,1H),8.07(t,J=1.8Hz,1H),7.68-7.64(m,1H),7.54-7.42(m,3H),7.23-7.11(m,2H),4.61(d,J=10.7Hz,1H),4.28 (ddd,J=13.1,10.9,6.1Hz,1H),3.97(d,J=1.9Hz,3H),2.44(t,J=12.9Hz,1H),2.38(d,J=4.9Hz,3H),2.31(dd,J=12.6,6.1Hz,1H),1.73(s,3H).

[0751] Example 120: Preparation of (2R,3S,5R)-N-(2-cyanopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 242-A)

[0752] Refer to Example 70 for the experimental procedures.

[0753] MS: m / z = 458.2 [M+H] + , 1 H NMR (400MHz, DMSO) δ11.03(s,1H),8.56(d,J=5.6Hz,1H),8.03(d,J=1.8Hz,1H),7.70(dd,J=5.6,2.1Hz,1H),7.24-7.10(m,2H),4. 61(d,J=10.6Hz,1H),4.32-4.22(m,1H),3.97(d,J=1.8Hz,3H),2.45(d,J=13.0Hz,1H),2.32(dd,J=12.6,6.1Hz,1H),1.73(s,3H).

[0754] Example 121: Preparation of N-(3-((2-aminoethyl)sulfonamido)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-25)

[0755] Step 1: Preparation of tert-butyl (5-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyridin-2-yl)carbamate (Compound a-25-1)

[0756] Compound 1-7 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and tert-butyl (2-(N-(3-aminophenyl)sulfamoyl)ethyl)carbamate (132.4 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After returning to room temperature, stirring was continued. The reaction was completed. Pre-HPLC separation gave the title compound (60.7 mg, 0.09 mmol, yield 66.42%). MS: m / z = 654.2, [M+H] + .

[0757] Step 2: Preparation of N-(3-((2-aminoethyl)sulfonamido)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-25)

[0758] The product of step 1 (60.7 mg, 0.09 mmol) was dissolved in 1,4-dioxane (5 mL) and stirred at room temperature. The reaction was completed and the target compound (40.5 mg, 0.07 mmol, yield 81.29%) was obtained by Pre-HPLC separation.

[0759] MS: m / z = 554.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.37(s,1H),8.25(s,1H),7.44(s,1H),7.27-7.14(m,4H),6.87(d,J=7.8Hz,1H),4.61(d,J=10.7Hz,1H),4.31-4.24(m,1H),3 .96(d,J=1.6Hz,3H),3.20(d,J=7.3Hz,2H),2.93(t,J=7.0Hz,2H),2.40( t,J=12.9Hz,1H),2.30(dd,J=12.6,6.2Hz,1H),1.98(s,2H),1.72(s,3H).

[0760] Example 122: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazin-7-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-26-A)

[0761] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 7-amino-3,4-dihydro-2H-benzo[e][1,2,4]thiadiazine-1,1-dioxide (47.76 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (10.76 mg, 0.02 mmol, yield 25%) was obtained by Pre-HPLC separation.

[0762] MS: m / z = 538.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.19(s,1H),7.83(d,J=2.4Hz,1H),7.64(t,J=7.7Hz,1H),7.30(dd,J=9.0,2.5Hz,1H),7.24-7.09(m,2H),7.03(s,1H),6.72( d,J=9.0Hz,1H),4.57(t,J=9.3Hz,3H),4.36-4.19(m,1H),3.99(d,J=1.7H z,3H),2.44(t,J=12.9Hz,1H),2.32(dd,J=12.6,6.1Hz,1H),1.75(s,3H).

[0763] Example 123: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-((Z)-3-ethoxybut-2-enyl)-4-fluorophenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-27-A)

[0764] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and (Z)-N-(5-amino-2-fluorophenyl)-3-ethoxybut-2-enamide (100.1 mg, 0.42 mmol) was added. TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (44.6 mg, 0.08 mmol, yield 55.2%) was obtained by Pre-HPLC separation.

[0765] MS: m / z = 577.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.08-10.02(m,2H),7.75(s,1H),7.44-7.40(m,2H),7.07(d,J=1.6Hz,1H),6.86(d,J=1.6Hz,1H),5 .05(s,1H),4.23-4.02(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.29(s,3H),2.17-1.92(m,2H),1.38(s,3H),1.23(s,3H).

[0766] Example 124: Preparation of 7-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (Compound a-28-A)

[0767] Compound 1-7-1 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 7-amino-4H-benzo[e][1,2,4]thiadiazine 1,1-dioxide (83 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (48 mg, 0.090 mmol, yield 64%) was obtained by Pre-HPLC separation.

[0768] MS: m / z = 536.07, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.86 (s, 1H), 9.29 (s, 1H), 7.86-7.62 (m, 2H), 7.56-7.43 (m, 3H), 4.62 (d, J = 10.7Hz, 1H), 4.38- 4.24(m,1H),3.98(d,J=1.6Hz,3H),2.43(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),2.11(s,1H),1.76(s,3H).

[0769] Example 125: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(difluoromethyl)pyridin-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 244-A)

[0770] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 2-(difluoromethyl)pyridin-4-amine (60.5 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (38.6 mg, 0.08 mmol, yield 57.18%) was obtained by Pre-HPLC separation.

[0771] MS: m / z = 483.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.89(s,1H),8.51(d,J=5.5Hz,1H),7.86(d,J=1.8Hz,1H) ,7.56(dd,J=5.3,1.5Hz,1H),7.17(ddd,J=17.0,7.9,4.5Hz,2H),6.88(t,J=55. 0Hz,1H),4.61(d,J=10.6Hz,1H),4.28(ddd,J=13.1,10.8,6.0Hz,1H),3.97(t,J =3.8Hz, 3H), 2.45 (d, J = 12.9Hz, 1H), 2.32 (dd, J = 12.6, 6.1Hz, 1H), 1.73 (s, 3H).

[0772] Example 126: Preparation of (2R, 3S, 5R)-N-(3-azidophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-29-A)

[0773] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-azidoaniline (56.3 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (34.4 mg, 0.07 mmol, yield 51.98%) was obtained by Pre-HPLC separation.

[0774] MS: m / z = 483.1, [M+H] + , 1H NMR (400MHz, DMSO) δ10.42(s,1H),7.42(t,J=1.9Hz,1H),7.32-7.09(m,4H),6.77(dd,J=7.7,1.0Hz,1H),4.59(d,J=10 .7Hz,1H),4.34-4.18(m,1H),3.96(d,J=1.7Hz,3H),2.42(t,J=12.9Hz,1H),2.29(dd,J=12.6,6.1Hz,1H),1.72(s,3H).

[0775] Example 127: Preparation of (2R,3S,5R)-(4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-6-azido)pyridazine (Compound a-30-A)

[0776] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 6-azidopyridazine-4-amine (57 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (61 mg, 0.128 mmol, yield 91%).

[0777] MS: m / z = 475.09, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.68 (s, 1H), 8.93 (s, 1H), 7.76 (s, 1H), 7.56-7.43 (m, 2H), 4.62 (d, J = 10.7Hz, 1H), 4. 38-4.25(m,1H),3.97(d,J=1.6Hz,3H),2.43(t,J=12.9Hz,1H),2.35(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0778] Example 128: Preparation of (2R,3S,5R)-N-(3-azido-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-31-A)

[0779] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 3-azido-4-fluoroaniline (64 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. After the reaction was complete, Pre-HPLC separation gave the target compound (40 mg, 0.082 mmol, yield 58%).

[0780] MS: m / z = 491.09, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.41(s,1H),7.57-7.33(m,2H),7.26-7.13(m,3H),4.63(d,J=10.7Hz,1H),4.35- 4.21(m,1H),3.99(d,J=1.6Hz,3H),2.47(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0781] Example 129: Preparation of (2R, 3S, 5R)-N-(4-azidophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-32-A)

[0782] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 5-amino-2-fluorophenylsulfamate (86.6 mg, 0.42 mmol) was added, TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath, and the mixture was allowed to return to room temperature and continued to stir. The reaction was complete and the target compound (26.4 mg, 0.05 mmol, yield 34.6%) was obtained by Pre-HPLC separation.

[0783] MS: m / z = 545.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02 (s, 1H), 7.16-7.07 (m, 6H), 6.86 (d, J = 1.6Hz, 1H), 4.2 3-4.02(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0784] Example 130: Preparation of (2R, 3S, 5R)-N-(4-azidophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-33-A)

[0785] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 4-azidoaniline (56.3 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After returning to room temperature naturally, stirring was continued. The reaction was complete and the target compound (42.2 mg, 0.09 mmol, yield 63.7%) was obtained by Pre-HPLC separation.

[0786] MS: m / z = 473.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02(s,1H),7.56(d,J=2.4Hz,2H),7.34(d,J=2.4Hz,2H),7.02-6.86 (m,2H),4.23-4.02(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0787] Example 131: Preparation of (2R,3S,5R)-N-(6-aminopyridazin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 245-A)

[0788] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and pyridazine-3,5-diamine (26.41 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (14.37 mg, 0.03 mmol, yield 40%) was obtained by Pre-HPLC separation.

[0789] MS: m / z = 449.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.83(s,1H),8.27(d,J=2.4Hz,1H),7.36(d,J=1.9Hz,1H),7.21(dd,J=8.5,4.4 Hz,2H),6.52(s,2H),4.83(d,J=10.6Hz,1H),4.49-4.18(m,1H),3.97(d,J=1.4Hz,3H),1.75(s,3H).

[0790] Example 132: Preparation of (2R, 3S, 5R)-N-(2-cyanoaminopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-34-A)

[0791] The experimental steps are as in Example 1.

[0792] MS: m / z=473.2[M+H]+,1H NMR (400MHz, DMSO) δ10.85(s,1H),7.62(d,J=6.9Hz,1H),7.40(d,J=1.8Hz, 1H),7.24-7.09(m,2H),6.70-6.62(m,1H),4.59(d,J=10.5Hz,1H),4.25(dd d,J=13.1,10.7,6.1Hz,1H),3.97(d,J=2.0Hz,3H),3.16(d,J=4.9Hz,1H),2 .46(d,J=12.9Hz,1H),2.32(dd,J=12.5,6.1Hz,1H),1.74(d,J=9.9Hz,3H).

[0793] Example 133: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-(6-methyl-4,8-dioxo-1,3,6,2-diazaborolan-2-yl)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-35-A)

[0794] Step 1: Preparation of (3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)boronic acid (Compound a-35-1)

[0795] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and (3-aminophenyl)boronic acid (57.6 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After returning to room temperature, stirring was continued. The reaction was complete. Pre-HPLC separation gave the title compound (46.1 mg, 0.10 mmol, yield 69.33%). MS: m / z = 476.1, [M+H] + .

[0796] Step 2: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-(6-methyl-4,8-dioxo-1,3,6,2-diazaborolan-2-yl)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-35-A)

[0797] The product of step 1 (46.1 mg, 0.10 mmol) and 2,2'-(methylnitrodiyl)diacetic acid (22.1 mg, 0.15 mmol) were dissolved in toluene (30 mL) and dimethyl sulfoxide (3 mL), heated to 160°C with stirring. The reaction was complete, and the target compound (26.9 mg, 0.05 mmol, yield 45.87%) was obtained by Pre-HPLC separation.

[0798] MS: m / z = 587.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.25(d,J=23.2Hz,1H),7.88-6.98(m,6H),4.65(d,J=7.8Hz,1H),4.36(d,J =17.1Hz,2H),4.11(d,J=16.7Hz,1H),4.00(s,3H),3.39(s,3H),2.53-2.31(m,4H),1.76(s,3H).

[0799] Example 134: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,1-dioxide-3-oxo-2,3-dihydrobenzo[d]isothiazol-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-36-A)

[0800] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 6-aminobenzo[d]isothiazol-3(2H)-one-1,1-dioxide (83.2 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (45.6 mg, 0.09 mmol, yield 60.77%) was obtained by Pre-HPLC separation.

[0801] MS: m / z = 537.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.65(s,1H),8.21(s,1H),7.90(d,J=1.2Hz,1H),7.52(dt,J=20.0,4.9Hz,2H),7.22-7.06(m,2H),4.61( d,J=10.7Hz,1H),4.36-4.20(m,1H),3.98(d,J=1.6Hz,3H),2.44(t,J=12.9Hz,1H),2.32(dd,J=12.6,6.1Hz,1H),1.74(s,3H).

[0802] Example 135: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-((1,2,3)triazolo(1,5-a)pyridin-5-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 246-A)

[0803] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and [1,2,3]triazolo[1,5-a]pyridine-5-amine (56 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (47 mg, 0.10 mmol, yield 71%) was obtained by Pre-HPLC separation.

[0804] MS: m / z = 473.10, [M+H] + , 1H NMR (400MHz, DMSO) δ9.53(m,2H),7.87-7.63(m,2H),7.36-7.23(m,3H),4.63(d,J=10.7Hz,1H),4.35- 4.21(m,1H),3.98(d,J=1.6Hz,3H),2.46(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0805] Example 136: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,1-dioxide-2,3-dihydrobenzo[d]isothiazol-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-37-A)

[0806] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), ethyl 2-(4-aminopyridin-2-yl)acetate (75.7 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (28.8 mg, 0.05 mmol, yield 39.6%) was obtained by Pre-HPLC separation.

[0807] MS: m / z = 523.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.92 (s, 1H), 8.85 (d, J = 2.4Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 2.4Hz, 1H), 7.02-6.86 ( m,2H),4.23-4.02(m,5H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H),1.21(s,3H).

[0808] Example 137: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(6-mercaptopyridin-3-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 247-A)

[0809] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 5-aminopyridine-2-thiol (30.24 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (9.28 mg, 0.02 mmol, yield 25%) was obtained by Pre-HPLC separation.

[0810] MS: m / z = 465.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ13.38(s,1H),10.43(s,1H),8.15(d,J=3.2Hz,1H),7.23(dtd,J=13.1,9.5,4.6Hz,4H),4.55(d,J=1 0.7Hz,1H),4.32-4.19(m,1H),3.99(d,J=1.9Hz,3H),2.46(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.1Hz,1H),1.74(s,3H).

[0811] Example 138: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-N-(3-(3-(trifluoromethane)-3H-diazin-3-yl)phenyl)tetrahydrothiophene-2-carboxamide (Compound a-38-A)

[0812] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 3-(3-(trifluoromethyl)-3H-diazoxide-3-yl)aniline (84.6 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (41.8 mg, 0.08 mmol, yield 57.37%) was obtained by Pre-HPLC separation.

[0813] MS: m / z = 537.1, [M+H] +,1H NMR (400MHz, DMSO) δ10.52(s,1H),7.64-7.54(m,2H),7.43-7.36(m,1H),7.24-7.08(m,2H),6.89(d,J=7.8Hz,1H),4.58(d,J=1 0.7Hz,1H),4.35-4.20(m,1H),3.98(dd,J=12.1,5.0Hz,3H),2.44(t,J=12.9Hz,1H),2.30(dd,J=12.6,6.1Hz,1H),1.73(s,3H).

[0814] Example 139: Preparation of (3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenylsulfamate (Compound a-39-A)

[0815] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-aminophenylsulfamate (79.0 mg, 0.42 mmol) was added, TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath, and the mixture was allowed to return to room temperature and continued to stir. The reaction was complete and the target compound (35.1 mg, 0.07 mmol, yield 47.62%) was obtained by Pre-HPLC separation.

[0816] MS: m / z = 527.1, [M+H] + ,1H NMR (400MHz, DMSO) δ10.46(s,1H),7.98(s,2H),7.58(s,1H),7.46-7.29(m,2H),7.25-7.08(m,2H),6.97(t,J=11.9Hz,1H),4.60 (d,J=10.7Hz,1H),4.28(td,J=12.7,6.1Hz,1H),3.97(s,3H),2.43(t,J=12.9Hz,1H),2.30(dd,J=12.5,6.1Hz,1H),1.73(s,3H).

[0817] Example 140: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyridin-2-ylaminosulfonate (Compound a-40-A)

[0818] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 4-aminopyridine-2-aminosulfonate (79.4 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (33.8 mg, 0.06 mmol, yield 45.79%) was obtained by Pre-HPLC separation.

[0819] MS: m / z = 527.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.00(s,1H),7.46(s,1H),7.35-7.04(m,2H),5.95(d,J=5.2Hz,1H),4.52(d,J =11.1Hz,1H),4.08(td,J=12.3,6.1Hz,1H),3.95(d,J=1.2Hz,3H),2.33-2.18(m,2H),1.67(s,3H).

[0820] Example 141: Preparation of (2R, 3S, 5R)-N-(3-(3H-diazin-3-yl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-41-A)

[0821] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-(3H-diazoxide-3-yl)aniline (55.9 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (18.9 mg, 0.04 mmol, yield 28.6%) was obtained by Pre-HPLC separation.

[0822] MS: m / z = 472.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.02(s,1H),7.72(s,1H),7.63(d,J=2.4Hz,1H),7.29(d,J=2.0Hz,1H),7.02-6.86 (m,3H),4.23-4.21(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.79(s,1H),2.17-1.92(m,2H),1.38(s,3H).

[0823] Example 142: Preparation of (2R, 3S, 5R)-N-(3-(1,2,4-oxadiazol-3-yl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-42-A)

[0824] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-(1,2,4-oxadiazol-3-yl)aniline (67.6 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (22.9 mg, 0.05 mmol, yield 32.7%) was obtained by Pre-HPLC separation.

[0825] MS: m / z = 500.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02(s,1H),8.12(d,J=2.0Hz,1H),7.74-7.68(m,3H),7.07(d,J=2.4Hz,1H),6.8 6(d,J=2.4Hz,1H),4.23-4.21(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0826] Example 143: Preparation of (2R,3S,5R)-N-(benzo[c][1,2,5]oxadiazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 248-A)

[0827] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and benzo[c][1,2,5]oxadiazole-5-amine (56.7 mg, 0.42 mmol) was added. TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (28.1 mg, 0.06 mmol, yield 42.3%) was obtained by Pre-HPLC separation.

[0828] MS: m / z = 474.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02(s,1H),7.89-7.88(m,2H),7.37(d,J=2.0Hz,1H),7.07(d,J=2.0Hz,1H),6.8 6(d,J=2.0Hz,1H),4.23-4.21(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0829] Example 144: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(4-methyl-1-((trifluoromethyl)sulfonyl)-1H-pyrazol-3-yl)-5-(trifluoromethane)tetrahydrothiophene-2-carboxamide (Compound a-43-A)

[0830] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 4-methyl-1-((trifluoromethyl)sulfonyl)-1H-pyrazole-3-amine (57.96 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (11.35 mg, 0.02 mmol, yield 25%) was obtained by Pre-HPLC separation.

[0831] MS: m / z = 567.8, [M+H] + , 1H NMR (400MHz, DMSO) δ10.46(s,1H),8.53(s,1H),7.20(dd,J=10.2,6.7Hz,2H),4.80(d,J=10.7Hz,1H),4.36 -4.26(m,1H),3.99(d,J=1.8Hz,3H),2.48(t,J=12.9Hz,1H),2.38-2.33(m,1H),2.30(s,3H),1.75(s,3H).

[0832] Example 145: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(ethylsulfonamido)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-44-A)

[0833] Refer to Example 70 for the experimental procedures.

[0834] MS: m / z=539.1[M+H]+, 1 H NMR (400MHz, DMSO) δ10.85(s,1H),7.62(d,J=6.9Hz,1H),7.40(d,J=1.8Hz, 1H),7.24-7.09(m,2H),6.70-6.62(m,1H),4.59(d,J=10.5Hz,1H),4.25(dd d,J=13.1,10.7,6.1Hz,1H),3.97(d,J=2.0Hz,3H),3.16(d,J=4.9Hz,1H),2 .46(d,J=12.9Hz,1H),2.32(dd,J=12.5,6.1Hz,1H),1.74(d,J=9.9Hz,3H).

[0835] Example 146: Preparation of (2R,3S,5R)-N-(3-(N-(2-aminoethyl)sulfamoyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-45-A)

[0836] Step 1: Preparation of tert-butyl (2-(3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenylsulfonamido)ethyl)carbamate (Compound a-45-1)

[0837] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and tert-butyl (2-((3-aminophenyl)sulfonamido)ethyl)carbamate (132.4 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After returning to room temperature, stirring was continued. The reaction was completed. Pre-HPLC separation gave the title compound (50.6 mg, 0.08 mmol, yield 55.31%), MS: m / z = 654.2, [M+H] + .

[0838] Step 2: Preparation of (2R, 3S, 5R)-N-(3-(N-(2-aminoethyl)sulfamoyl)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-45-A)

[0839] The product of step 1 (50.6 mg, 0.08 mmol) was dissolved in 1,4-dioxane (5 mL) and stirred at room temperature. The reaction was completed and the target compound (36.8 mg, 0.07 mmol, yield 83.19%) was obtained by Pre-HPLC separation.

[0840] MS: m / z = 554.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.71 (s, 1H), 8.18 (s, 1H), 7.90 (dd, J = 16.8, 11.1Hz, 4H), 7. 65(d,J=8.1Hz,1H),7.52(dd,J=17.0,9.1Hz,2H),7.25-7.12(m,2H),4.64(d,J=1 0.7Hz,1H),4.28(td,J=12.9,6.1Hz,1H),3.97(d,J=1.5Hz,3H),2.89(dd,J=18.2 ,12.6Hz,4H),2.44(t,J=12.9Hz,1H),2.32(dt,J=12.5,6.3Hz,1H),1.73(s,3H).

[0841] Example 147: Preparation of (2R, 3S, 5R) -N- (2- (1,2,4-oxadiazol-3-yl) pyridin-4-yl) -3- (3,4-difluoro-2-methoxyphenyl) -N-hydroxy-5-methyl-5- (trifluoromethyl) tetrahydrothiophene-2-carboxamide (Compound a-46-A)

[0842] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and N-(2-(1,2,4-oxadiazol-3-yl)pyridin-4-yl)hydroxylamine (42.72 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (15.48 mg, 0.03 mmol, yield 37%) was obtained by Pre-HPLC separation.

[0843] MS: m / z = 516.9, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.94(s,1H),9.79(d,J=7.0Hz,1H),8.62(d,J=5.5Hz,1H),8.36(d,J=1.3Hz,1H),7.66(dd,J=5.5,1.7Hz,1H),7.36 -7.08(m,2H),4.65(d,J=10.6Hz,1H),4.42-4.22(m,1H),3.99(d,J=11.6Hz,3H),2.49(d,J=13.0Hz,1H),2.38-2.28(m,1H),1.77(s,3H).

[0844] Example 148: Preparation of (2R,3S,5R)-N-(4-amino-3-sulfamoylphenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 249-A)

[0845] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 2,5-diaminobenzenesulfonamide (78.6 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (26.3 mg, 0.05 mmol, yield 35.73%) was obtained by Pre-HPLC separation.

[0846] MS: m / z = 526.1, [M+H] +,1H NMR (400MHz, DMSO) δ10.08(s,1H),7.79(s,1H),7.36-7.10(m,5H),6.70(d,J=8.7Hz,1H),5.69(s,1H),4.54(d,J=1 0.7Hz,1H),4.26(d,J=12.1Hz,1H),3.96(s,3H),2.39(t,J=12.8Hz,1H),2.28(dd,J=12.3,5.8Hz,1H),1.72(s,3H).

[0847] Example 149: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-N-[2-(1,2,4-oxadiazol-3-yl)-4-pyridinyl]-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-48-A)

[0848] The experimental steps are as in Example 1.

[0849] MS: m / z=501.3[M+H]+,1H NMR (400MHz, DMSO) δ10.93(s,1H),9.75(s,1H),8.59(d,J=5.5Hz,1H),8.33(d,J=1.9Hz,1H),7.64(dd,J=5.5,2.1Hz,1H),7.26-7.09(m,2H),4.63 (d,J=10.6Hz,1H),4.29(ddd,J=13.1,10.8,6.1Hz,1H),3.98(d,J=1.9Hz,3H),2.46(d,J=12.9Hz,1H),2.33(dd,J=12.6,6.1Hz,1H),1.74(s,3H).

[0850] Example 150: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxy-phenyl)-N-[3-(2-hydroxyethylsulfonylamino)phenyl]-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-49-A)

[0851] Refer to Example 70 for the experimental procedures.

[0852] MS: m / z=555.3[M+H]+, 1H NMR (400MHz, DMSO) δ10.32 (s, 1H), 7.42 (t, J = 1.9Hz, 1H), 7.31-7.26 (m, 1H) ,7.23-7.14(m,3H),6.87(dd,J=8.0,1.1Hz,1H),4.60(d,J=10.7Hz,1H),4. 32-4.22(m,1H),3.97(d,J=1.8Hz,3H),3.70(t,J=6.7Hz,2H),3.20(t,J=6. 8Hz, 2H), 2.40 (t, J=12.9Hz, 1H), 2.30 (dd, J=12.6, 6.2Hz, 1H), 1.72 (s, 3H).

[0853] Example 151: Preparation of tert-butyl N-(2-((3-(((2R,3S,5R)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carbonyl)amino)phenyl)sulfamoyl)ethyl)-N-methylcarbamate (Compound a-50-A)

[0854] Refer to Example 70 for the experimental procedures.

[0855] MS: m / z=668.4[M+H]+, 1 H NMR(400MHz,DMSO)δ10.31(s,1H),9.92(s,1H),7.46(s,1H),7.30-7.11(m ,4H),6.88(d,J=7.6Hz,1H),4.60(d,J=10.7Hz,1H),4.33-4.22(m,1H),3.9 6(d,J=1.8Hz,3H),3.44(s,2H),3.28(s,2H),2.73(s,3H),2.40(t,J=12.9 Hz,1H),2.30(dd,J=12.6,6.2Hz,1H),1.72(s,3H),1.23(d,J=77.2Hz,9H).

[0856] Example 152: Preparation of (2R, 3S, 5R)-N-(2-aminomethylthio-4-pyridyl)-3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-51-A)

[0857] Compound 242-A (85 mg, 185.83 μmol) was added to a pressure tube and dissolved in EtOH (2 mL). Lawesson's reagent (375.80 mg, 929.13 μmol) was added and refluxed at 90°C. After the reaction was complete, the crude product was used to obtain the target compound (36 mg, 73.25 μmol, yield 39.42%).

[0858] MS:m / z=492.2[M+H]+, 1 H NMR (400MHz, DMSO) δ10.92(s,1H),10.17(d,J=2.3Hz,1H),9.89(d,J=2.6Hz,1H ),8.57(d,J=2.0Hz,1H),8.43(d,J=5.5Hz,1H),7.78(dd,J=5.5,2.1Hz,1H),7. 24-7.10(m,2H),4.63(d,J=10.6Hz,1H),4.34-4.23(m,1H),3.97(d,J=1.9Hz,3 H), 2.44 (d, J = 12.9Hz, 1H), 2.32 (dd, J = 12.6, 6.1Hz, 1H), 1.74 (d, J = 8.3Hz, 3H).

[0859] Example 153: Preparation of 6-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-1-methoxybenzo[c][1,2]oxabor-3(1H)-one (Compound a-52)

[0860] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 6-amino-1-methoxybenzo[c][1,2]oxaborol-3(1H)-one (74 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After returning to room temperature, stirring was continued for 1 h. The reaction was complete. Pre-HPLC separation gave the title compound (35 mg, 0.068 mmol, yield 49%), MS: m / z=516.10, [M+H] + , 1H NMR (400MHz, DMSO) δ9.98 (s, 1H), 7.57-7.33 (m, 3H), 7.26-7.13 (m, 2H), 4.63 (d, J = 10.7Hz, 1H), 4.35-4.21 (m ,1H),3.99(d,J=1.6Hz,3H),3.42(s,3H),2.47(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0861] Example 154: Preparation of 3-(1-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxyl)hydrazino)benzenesulfonamide (Compound a-83-A)

[0862] Compound a-81-A (30 mg, 0.05 mmol) was dissolved in anhydrous DCM (2 mL). A solution of hydrochloric acid in dioxane (2 mL) was added under ice-bath. The mixture was allowed to return to room temperature and continued to stir. The reaction was complete. Pre-HPLC separation gave the target compound (15 mg, 0.03 mmol, 57.62% yield).

[0863] MS: m / z = 525.1, 1 H NMR (400MHz, DMSO) δ7.85(s,1H),7.69(d,J=7.7Hz,1H),7.59(d,J=6.5Hz,1H),7.47(s,3H),7.15( t,J=8.1Hz,1H),4.27(s,1H),4.00(d,J=13.2Hz,4H),2.41-2.26(m,2H),2.08(s,2H),1.73(s,3H).

[0864] Example 155: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-((2-(methylamino)ethyl)sulfonamido)phenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-54-A)

[0865] Refer to Example 154 for the experimental procedures.

[0866] MS: m / z=568.2[M+H]+, 1H NMR (400MHz, DMSO) δ10.36 (s, 1H), 8.24 (s, 1H), 7.44 (s, 1H), 7.28 (d, J = 8.4Hz, 1H) ,7.18(dt,J=9.5,7.2Hz,3H),6.87(d,J=7.9Hz,1H),4.60(d,J=10.7Hz,1H),4.30-4 .24(m,1H),3.96(d,J=1.7Hz,4H),3.23(t,J=7.2Hz,2H),2.87(t,J=7.2Hz,2H),2. 40(dd,J=16.9,8.9Hz,1H),2.30(dd,J=12.6,6.2Hz,1H),2.25(s,3H),1.72(s,3H).

[0867] Example 156: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-(3-oxetane)amino)pyridine (Compound a-53-A)

[0868] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 4-amino-2-(3-oxetane)aminopyridine (69 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (25 mg, 0.050 mmol, yield 35%) was obtained by Pre-HPLC separation.

[0869] MS: m / z = 504.13, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.85 (s, 1H), 7.88-7.64 (m, 2H), 7.56-7.43 (m, 3H), 5.03-4.81 (m, 4H), 4.61 (d, J = 10.7Hz, 1H), 4.38-4.24 (m ,1H),4.11(s,1H),3.97(d,J=1.6Hz,3H),3.87-3.74(m,1H),2.43(t,J=12.9Hz,1H),2.31(dd,J=12.6,6.0Hz,1H),1.76(s,3H).

[0870] Example 157: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinden-7-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-55-A)

[0871] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 7-amino-3,4-dihydro-1H-benzo[c][1,2]oxaborolan-1-ol (68.5 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued for 1 h. The reaction was complete and the target compound (46.2 mg, 0.09 mmol, yield 65.88%) was obtained by Pre-HPLC separation.

[0872] MS: m / z = 526.1, [M+H] + ,1H NMR (400MHz, DMSO) δ10.16 (s, 1H), 8.40 (s, 1H), 7.73 (d, J = 2.1Hz, 1H), 7.51 ( dd,J=8.2,2.2Hz,1H),7.22-7.09(m,3H),4.60(d,J=10.7Hz,1H),4.27(td,J =12.8,6.1Hz,1H),4.01(t,J=5.8Hz,2H),3.96(d,J=1.5Hz,3H),2.78(t,J=5 .8Hz,2H),2.40(t,J=12.9Hz,1H),2.30(dd,J=12.6,6.2Hz,1H),1.73(s,3H).

[0873] Example 158: Preparation of (2R,3S,5R)-N-(3-((2-aminopropyl)sulfonamido)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-56-A)

[0874] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and 2-amino-N-(3-aminophenyl)propane-1-sulfonamide (54.96 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (17.01 mg, 0.03 mmol, yield 37%) was obtained by Pre-HPLC separation.

[0875] MS: m / z = 568.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.33 (s, 1H), 8.26 (s, 1H), 7.40 (dt, J = 3.9, 2.0Hz, 1H), 7.31-7.21 (m, 1H ),7.22-7.05(m,3H),6.86(dd,J=8.0,1.0Hz,1H),4.61(d,J=10.7Hz,1H),4.36-4.21(m,1H),4 .03(d,J=7.1Hz,1H),3.97(d,J=1.8Hz,3H),3.31(td,J=12.6,6.3Hz,2H),3.13-2.99(m,2H),2 .39(d,J=12.9Hz,1H),2.30(dd,J=12.6,6.2Hz,1H),1.73(s,3H),1.09(dd,J=6.5,1.3Hz,3H).

[0876] Example 159: Preparation of (5-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-((dimethylamino)methyl)phenyl)boronic acid (Compound 250-A)

[0877] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and (5-amino-2-((dimethylamino)methyl)phenyl)boronic acid (46.56 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (21.33 mg, 0.04 mmol, yield 50%) was obtained by Pre-HPLC separation.

[0878] MS: m / z = 533.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.17(s,1H),7.23-7.16(m,2H),4.66(d,J=10.6Hz,1H),4.28(td,J=12.8,6. 2Hz, 1H), 3.97 (d, J = 1.7Hz, 3H), 2.43 (t, J = 12.9Hz, 1H), 2.33 (dd, J = 12.6, 6.2Hz, 1H), 1.75 (s, 3H).

[0879] Example 160: Preparation of 2-cyano-4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyridine 1-oxide (Compound 251-A)

[0880] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), 4-amino-2-cyanopyridine 1-oxide (32.40 mg, 0.24 mmol) was added, and TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (9.48 mg, 0.02 mmol, yield 25%) was obtained by Pre-HPLC separation.

[0881] MS: m / z = 474.3, 1 H NMR (400MHz, DMSO) δ10.19(s,1H),8.17(d,J=7.2Hz,1H),8.10(d,J=3.1Hz,1H),7.53(dd,J=7.2,3.1Hz,1H),7.20(dt,J=9.3,8.5Hz,2H),4. 58(d,J=10.6Hz,1H), 4.28(td,J=13.0,6.1Hz,1H), 3.99(d,J=1.7Hz,3H), 2.48(d,J=13.0Hz,1H), 2.34(dd,J=12.6,6.0Hz,1H), 1.75(s,3H).

[0882] Example 161: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-((Z)-N'-methoxycarbamoyl)pyridin-4-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-57-A)

[0883] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and (Z)-4-amino-N'-methoxypicolinamide (39.84 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (10.11 mg, 0.02 mmol, yield 25%) was obtained by Pre-HPLC separation.

[0884] MS: m / z = 505.3, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.19(s,1H),8.17(d,J=7.2Hz,1H),8.10(d,J=3.1Hz,1 H),7.53(dd,J=7.2,3.1Hz,1H),7.20(dt,J=9.3,8.5Hz,2H),6.79(s,2H),4. 58(d,J=10.6Hz,1H),4.32(s,3H),4.28(td,J=13.0,6.1Hz,1H),3.99(d,J=1 .7Hz,3H),2.48(d,J=13.0Hz,1H),2.34(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0885] Example 162: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-2-((E)-N'-hydroxycarbamoyl)pyridine 1-oxide (Compound a-58-A)

[0886] Compound 1-7-2 (30 mg, 0.08 mmol) was dissolved in anhydrous DMF (5 mL), and (E)-4-amino-2-(N'-hydroxyaminocarbamimidoyl)pyridine 1-oxide (40.32 mg, 0.24 mmol) was added. TCFH (120 mg, 0.40 mmol) and NMI (56 mg, 0.64 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (10.15 mg, 0.02 mmol, yield 25%) was obtained by Pre-HPLC separation.

[0887] MS: m / z = 507.3, [M+H] + , 1H NMR (400MHz, DMSO) δ10.83 (s, 1H), 10.19 (s, 1H), 8.17 (d, J = 7.2Hz, 1H), 8.10 (d,J=3.1Hz,1H),7.53(dd,J=7.2,3.1Hz,1H),7.20(dt,J=9.3,8.5Hz,2H),6. 79(s,2H),4.58(d,J=10.6Hz,1H),4.28(td,J=13.0,6.1Hz,1H),3.99(d,J=1 .7Hz,3H),2.48(d,J=13.0Hz,1H),2.34(dd,J=12.6,6.0Hz,1H),1.75(s,3H).

[0888] Example 163: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1H-benzo[d][1,2,6]oxazolin-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-59-A)

[0889] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 6-amino-1H-benzo[d][1,2,6]oxazolin-1-ol (68.1 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (47.1 mg, 0.09 mmol, yield 67.32%) was obtained by Pre-HPLC separation.

[0890] MS: m / z = 501.1, [M+H] + ,1H NMR (400MHz, DMSO) δ10.66(s,1H),9.25(s,1H),8.59(s,1H),8.05-7.94(m,2H),7.69(dd,J=8.2,1.4Hz,1H),7.21-7.12(m,2H),4.66(d ,J=10.6Hz,1H),4.30(td,J=12.9,6.1Hz,1H),3.97(d,J=1.5Hz,3H),2.45(t,J=13.0Hz,1H),2.32(dd,J=12.6,6.1Hz,1H),1.74(s,3H).

[0891] Example 164: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborin-7-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-60-A)

[0892] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 7-aminobenzo[d][1,2,3]diazaborolcyclohexane-1(2H)-ol (67.7 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (41.8 mg, 0.08 mmol, yield 59.77%) was obtained by Pre-HPLC separation.

[0893] MS: m / z = 500.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.46(s,1H),9.71(s,1H),8.26(d,J=2.0Hz,1H),8.08(s,1H),7.88(s,1H),7.73(dd,J=8.5,2.2Hz,1H),7.63(d ,J=8.6Hz,1H),7.24-7.10(m,2H),4.67(d,J=10.7Hz,1H),4.35-4.25(m,1H),3.98(d,J=1.8Hz,3H),2.48-2.27(m,2H),1.74(s,3H).

[0894] Example 165: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(1,1-dioxide-4-oxo-1,2,5-thiadiazolidin-2-yl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-61-A)

[0895] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 5-(3-aminophenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (95.4 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (45.5 mg, 0.08 mmol, yield 44.73%) was obtained by Pre-HPLC separation.

[0896] MS: m / z = 566.1, [M+H] + ,1H NMR (400MHz, DMSO) δ9.95(s,1H),8.85(d,J=3.2Hz,2H),7.49(s,1H),7.41(d,J=2.4Hz,1H),7.02-6.86(m,2H ),4.65(d,J=10.0Hz,1H),4.23-4.02(m,3H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.71(s,3H).

[0897] Example 166: Preparation of tert-butyl (6-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborin-3-yl)methyl)carbamate (Compound a-62-A)

[0898] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and tert-butyl (6-amino-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)methyl)carbamate (116.8 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (43.4 mg, 0.07 mmol, yield 50.27%) was obtained by Pre-HPLC separation.

[0899] MS: m / z = 617.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.27(s,1H),9.22(s,1H),7.89(dd,J=4.5,1.7Hz,1H),7.48(dd,J=1 0.2,3.9Hz,1H),7.28(d,J=8.3Hz,1H),7.20-7.13(m,2H),6.91(t,J=5.3Hz,1H),5.05(dd ,J=6.8,4.6Hz,1H),4.62(d,J=10.7Hz,1H),4.27(tt,J=18.3,9.1Hz,1H),3.96(d,J=1.6H z,3H),3.31-3.26(m,1H),3.06-2.94(m,1H),2.44-2.27(m,2H),1.73(s,3H),1.34(s,9H).

[0900] Example 167: Preparation of (2R,3S,5R)-N-(3-(aminomethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborolan-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide hydrochloride (Compound a-63-A)

[0901] Compound a-62-A (30.0 mg, 0.05 mmol) was dissolved in 1,4-dioxane (5 mL) and stirred at room temperature for 1 h. The reaction was complete and the title compound (22.2 mg, 0.04 mmol, yield 80.27%) was obtained by spin drying. MS: m / z = 517.1, [M+H] + ,1H NMR (400MHz, DMSO) δ10.25(s,1H),9.45(s,1H),7.90(dd,J=4.4,1.6Hz,1H),7.48(d d,J=10.2,3.9Hz,1H),7.42(d,J=8.4Hz,1H),7.25-7.11(m,2H),5.11(s,2H),5.35(d d,J=6.8,4.4Hz,1H),4.64(d,J=10.7Hz,1H),4.15(tt,J=18.4,9.6Hz,1H),3.66(d, J=1.6Hz,3H),3.30-3.15(m,1H),3.07-2.94(m,1H),2.50-2.27(m,2H),1.75(s,3H).

[0902] Example 168: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazepine-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-64-A)

[0903] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 6-aminobenzo[d][1,2,3]diazaborolcyclohexane-1(2H)-ol (67.6 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (28.2 mg, 0.06 mmol, yield 40.2%) was obtained by Pre-HPLC separation.

[0904] MS: m / z = 500.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02(s,1H),8.59(s,1H),8.05(s,1H),7.73-7.53(m,2H),7.02(d,J=2.0Hz,1H),6 .88(d,J=2.0Hz,1H),4.23-4.21(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0905] Example 169: Preparation of 3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)benzenesulfonyl azide (Compound a-65-A)

[0906] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-aminobenzenesulfonyl azide (83.6 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (34.2 mg, 0.06 mmol, yield 45.5%) was obtained by Pre-HPLC separation.

[0907] MS: m / z = 537.2, [M+H] + , 1H NMR (400MHz, DMSO) δ10.02 (s, 1H), 8.03-7.97 (m, 2H), 7.80-7.64 (m, 2H), 7.07 (d, J = 2.0Hz, 1H), 6.88 (d,J=2.0Hz,1H),4.23-4.21(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0908] Example 170: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)pyridine-2-sulfonyl azide (Compound a-66-A)

[0909] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 4-aminopyridine-2-sulfonyl azide (83.6 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (6.8 mg, 0.01 mmol, yield 9.0%) was obtained by Pre-HPLC separation.

[0910] MS: m / z = 538.2, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.92 (s, 1H), 8.70 (d, J = 2.0Hz, 1H), 8.37 (s, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.07 (d, J = 2.0Hz, 1H), 6.88 (d, J = 2.0Hz, 1H), 4.07-4.06 (m, 1H), 3.83 (s, 3H), 3.48-3.46 (m, 1H), 2.17-1.92 (m, 2H), 1.38 (s, 3H).

[0911] Example 171: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-67-A)

[0912] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 2,2-difluorobenzo[d][1,3]dioxolane-5-amine (72.7 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (36.2 mg, 0.07 mmol, yield 50.5%) was obtained by Pre-HPLC separation.

[0913] MS: m / z = 512.2, [M+H] + , 1 H NMR(400MHz,DMSO)δ10.02(s,1H),7.23(s,1H),7.03-7.02(m,2H),6.87-6.86(m,2H) ,4.23-4.21(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H).

[0914] Example 172: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-1H-2,3,1-benzoxazolidin-7-yl)-5-methyl-5-(trifluoromethyl)thiolane-2-carboxamide (Compound a-68-A)

[0915] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), 7-amino-1H-benzo[d][1,2,6]oxazolin-1-ol (68 mg, 0.42 mmol) was added, and TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (51 mg, 0.102 mmol, yield 73%) was obtained by Pre-HPLC separation.

[0916] MS: m / z = 501.10, [M+H] + , 1H NMR (400MHz, DMSO) δ9.93 (s, 1H), 8.00 (s, 1H), 7.56-7.32 (m, 3H), 7.25-7.12 (m, 3H), 4.62 (d, J = 10.7Hz, 1H), 4.36-4.22(m,1H),3.99(d,J=1.6Hz,3H),2.44(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.76(s,3H).

[0917] Example 173: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1,1-dioxide-3,4-dihydro-2H-benzo[e][1,2]thiazin-7-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-69-A)

[0918] The experimental steps are as in Example 1.

[0919] MS: m / z=554.1[M+H]+, 1 H NMR (400MHz, DMSO) δ10.53(s,1H),8.03(d,J=2.2Hz,1H),7.50(dd,J=8.5,2.2Hz ,1H),7.26(d,J=8.6Hz,1H),7.23-7.10(m,2H),4.58(d,J=10.7Hz,1H),4.27(ddd ,J=13.1,10.9,6.1Hz,1H),3.97(d,J=1.9Hz,3H),3.52(t,J=6.0Hz,2H),2.82(t, J=5.9Hz,2H),2.45(t,J=12.9Hz,1H),2.31(dd,J=12.6,6.1Hz,1H),1.73(s,3H).

[0920] Example 174: Preparation of (2R,3S,5R)-N-(2-acrylamidopyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 252-A)

[0921] Compound 1-7-2 (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (5 mL), and N-(4-aminopyridin-2-yl)acrylamide (64 mg, 0.28 mmol) was added. TCFH (395 mg, 1.40 mmol) and NMI (184 mg, 2.25 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (76 mg, 0.05 mmol, yield 54.00%) was obtained by Pre-HPLC separation.

[0922] MS: m / z=501.1,[M+H]+, 1 H NMR (400MHz, DMSO) δ10.70(d,J=34.7Hz,2H),8.33(d,J=1.5Hz,1H),8.19(d,J=5.6Hz,1H),7 .42(dd,J=5.6,1.8Hz,1H),7.17(ddd,J=26.6,11.9,5.9Hz,3H),6.60(dt,J=21.2,10.5Hz,1 H),6.32(dd,J=17.0,1.8Hz,1H),5.84-5.72(m,1H),4.67(d,J=10.6Hz,1H),4.31(td,J=12. 5,6.1Hz,1H),4.00(d,J=1.7Hz,4H),2.35(dd,J=12.7,6.1Hz,2H),1.76(s,4H),1.69(s,1H).

[0923] Example 175: Preparation of (4-(3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)phenyl)sulfonyl fluoride (Compound a-71-A)

[0924] Compound 1-7-2 (39 mg, 0.11 mmol) was dissolved in anhydrous DMF (2 mL), and (4-aminophenyl)sulfonyl fluoride (65.51 mg, 0.35 mmol) was added. TCFH (154 mg, 0.55 mmol) and NMI (65.6 mg, 0.88 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (38 mg, 0.07 mmol, yield 65.60%) was obtained by Pre-HPLC separation.

[0925] MS: m / z = 529.06, [M+H] + , 1HNMR(400MHZ,DMSO)δ10.11(s,1H),7.87(s,1H),7.16(dd,J=8.7,3.8Hz,2H),7.11(d,J=8.1Hz,1H),7.05(t J=1.9Hz,1H),6.93(t J=8.1Hz,1H),6.71-6.59(m,1H),4.66(d J=10.8Hz,1H),4.31-4.20(m,1H),3.96(d,J=1.6Hz,3H),2.31(dd,J=11.8,9.9Hz,2H),1.72(s,3H).

[0926] Example 176: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-((E)-(hydroxy(methyl)-14-azaylidene)methyl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-72-A)

[0927] Step 1: Synthesis of methyl 3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)benzoate (a-72-1)

[0928] Compound 1-7-2 (450 mg, 1.26 mmol) and HATU (720.32 mg, 1.89 mmol) were dissolved in DCM (5 mL), DIEA (326.45 mg, 2.53 mmol) was added, and finally methyl 3-aminobenzoate (229.09 mg, 1.52 mmol) was added and reacted at room temperature. After the reaction was complete, the crude product was purified to obtain the title compound (600 mg, 1.23 mmol, yield 97.06%), MS: m / z = 507.1 [M+H] +

[0929] Step 2: Synthesis of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(hydroxymethyl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-72-2)

[0930] Methyl 3-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)benzoate (600 mg, 1.23 mmol) was dissolved in THF (5 mL), replaced with nitrogen, and cooled to -40°C. Lithium aluminum hydride (69.79 mg, 1.84 mmol) was added and reacted at -40°C. The mixture was quenched by adding LiAlH4:15% NaOH:H2O=1:3:1 at low temperature. The mixture was filtered, concentrated, and purified to give the title compound (300 mg, 650.13 μmol, yield 53.04%). MS: m / z=462.1 [M+H] +

[0931] Step 3: Synthesis of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-formylphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-72-3)

[0932] To (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(hydroxymethyl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (105 mg, 227.55 μmol) was added DMSO (2.0 mL) and acetone (0.5 mL) for dissolution, and the temperature was cooled to 0°C. Dess-Martin periodinane (193.02 mg, 455.09 μmol) was added and stirred at 0°C. The mixture was quenched with saturated sodium thiosulfate at low temperature, extracted with DCM, and concentrated at low temperature to give the crude title compound (100 mg, 217.66 μmol, yield 95.66%), which was directly used in the next step.

[0933] Step 4: Synthesis of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-((E)-(hydroxy(methyl)-14-azaylidene)methyl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (a-72-A)

[0934] Methanol (5 mL) was added to (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-formylphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (100 mg, 217.66 μmol) to dissolve the product. Potassium acetate (42.72 mg, 435.32 μmol) and N-methylhydroxylamine hydrochloride (23.63 mg, 282.96 μmol) were added and the reaction was carried out at 65°C. The crude product was purified to obtain the title compound (56 mg, 114.41 μmol, yield 52.56%).

[0935] MS: m / z=490.1[M+H]+,1 H NMR(400MHz,DMSO)δ10.40(s,1H),8.48(s,1H),7.80(s,1H),7.74-7.64(m ,2H),7.32(t,J=8.0Hz,1H),7.22-7.11(m,2H),4.63(d,J=10.7Hz,1H),4.2 8(ddd,J=13.0,10.9,6.2Hz,1H),3.96(d,J=1.8Hz,3H),3.76(s,3H),2.40 (t,J=12.9Hz,1H),2.30(dd,J=12.6,6.2Hz,1H),2.07(s,1H),1.73(s,3H).

[0936] Example 177: Preparation of (2R,3S,5R)-N-(2-(1-cyanocyclopropyl)pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-73-A)

[0937] Compound 1-7-2 (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (5 mL), 1-(3-aminophenyl)cyclopropanecarbonitrile (44 mg, 0.28 mmol) was added, and TCFH (395 mg, 1.40 mmol) and NMI (184 mg, 2.25 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (68 mg, 0.05 mmol, yield 48.32%) was obtained by Pre-HPLC separation.

[0938] MS:m / z=497.1,[M+H]+, 1 H NMR (400MHz, DMSO) δ10.81(s,1H),8.33(d,J=5.5Hz,1H),7.83(d,J=1.7Hz,1H),7.46(dd,J=5.6,1.9Hz,1H),7.27-7.11(m,2H),4.64(d,J=10.6Hz,1H) ,4.30(tt,J=20.5,7.9Hz,1H),4.03-3.98(m,3H),2.47(d,J=12.9Hz,1H),2 .35(dd,J=12.6,6.1Hz,1H),1.79-1.73(m,6H),1.65(dd,J=7.8,4.3Hz,2H).

[0939] Example 178: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)benzenesulfonyl azide (Compound a-74-A)

[0940] Compound 4-aminobenzenesulfonyl azide (300 mg, 0.84 mmol) was dissolved in anhydrous MeCN (5 mL), 1-7-2 (189 mg, 0.92 mmol) was added, and EDCI (177 mg, 0.92 mmol) was added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (114 mg, 0.21 mmol, yield 22.82%) was obtained by Pre-HPLC separation.

[0941] MS: m / z = 537.06, [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.70 (d, J = 5.5Hz, 1H), 8.17 (s, 1H), 8.09 (dd, J = 5.5, 1.9Hz, 1H), 7.13 (t, J = 7.1Hz, 1H), 6.96 (dd, J = 16.6, 9.0Hz,1H),4.67(d,J=10.7Hz,1H),4.17(d,J=2.9Hz,1H),4.14(d,J=2.2Hz,1H),4.11(d,J=2.5Hz,3H),2.68(t,J=12.9Hz,1H),1.91(s,3H).

[0942] Example 179: Preparation of N-(4-(2-azidoacetylamino)phenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-75-A)

[0943] The experimental steps are as in Example 1.

[0944] MS: m / z = 530.12, [M+H] + , 1HNMR(400MHZ,DMSO)δ9.33(s,1H),7.87(s,1H),7.07(dd,J=5.6,3.8Hz,2H),7.01(d,J=7.7Hz,1H).6.93(t J=3.7Hz,1H),6.81(t J=6.3Hz,1H),6.65-6.48(m,1H),4.57(d J=9.7Hz,1H),4.44-4.31(m,1H),3.83(d,J=1.6Hz,3H),2.57(s,1H),2.24(dd,J=11.8,9.9Hz,2H),1.63(s,3H).

[0945] Example 180: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-((dimethylamino)methyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-76-A)

[0946] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 6-amino-3-((dimethylamino)methyl)benzo[c][1,2]oxaborin-1(3H)-ol (86.5 mg, 0.42 mmol) was added. TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (43.5 mg, 0.08 mmol, yield 57.1%) was obtained by Pre-HPLC separation.

[0947] MS: m / z = 545.1, [M+H] + , 1 H NMR(400MHz,DMSO)δ9.98(s,1H),7.61-7.38(m,3H),7.05-7.02(m,1H),6.91-6.86(m,1H),4.85-4.83(m,1H), 4.20(s,1H),3.82(s,3H),3.48-3.46(m,1H),2.98-2.73(m,2H),2.25(s,6H),2.17-1.92(m,2H),1.38(s,3H).

[0948] Example 181: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(3-(1-(dimethylamino)ethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-77-A)

[0949] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 6-amino-3-(1-(dimethylamino)ethyl)benzo[c][1,2]oxaborin-1(3H)-ol (92.5 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (46.0 mg, 0.08 mmol, yield 58.92%) was obtained by Pre-HPLC separation.

[0950] MS: m / z = 559.2, [M+H] + ,1H NMR (400MHz, DMSO) δ8.23(s,1H),7.54(d,J=15.0Hz,1H),7.42(d,J=15.0Hz,1H),7.11(dd,J=15.0, 9.9Hz,1H),6.83(ddd,J=15.7,15.1,10.1Hz,1H),5.35(dt,J=21.2,16.5Hz,1H),4.72(d,J=14.5Hz ,1H),4.04(d,J=21.4Hz,1H),3.91(s,3H),2.87(dd,J=24.8,16.6Hz,1H),2.51(dq,J=14.2,12.5Hz ,1H),2.25(s,6H),2.13(dd,J=24.8,16.6Hz,1H),1.60(s,1H),1.38(s,3H),1.06(d,J=12.5Hz,3H).

[0951] Example 182: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(3-thiocyanatophenyl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-78-A)

[0952] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-thiocyanatoaniline (63.0 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (48 mg, 0.10 mmol, yield 70.11%) was obtained by Pre-HPLC separation.

[0953] MS: m / z = 489.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ10.02(s,1H),8.21(s,1H),7.66-7.21(m,3H),7.07-7.02(m,1H),6.92-6. 86(m,1H),4.25-4.23(m,1H),3.83(s,3H),3.48-3.46(m,1H),2.21-1.96(m,2H),1.38(s,3H).

[0954] Example 183: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-sulfamoylphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 233-A)

[0955] The experimental steps are as in Example 1.

[0956] MS: m / z=529.3[M+H]+, 1 H NMR(400MHz, CDCl3)δ8.19(s,1H),8.03-7.93(m,1H),7.76-7.68(m,1H),7.20-7.10(m,1H),7.05-6.91(m,1H),6.92-6.78(m,1H), 5.22(s,2H),4.45(d,J=10.8Hz,1H),4.23-4.12(m,1H),4.00(d,J=2.5Hz,3H),2.67-2.51(m,1H),2.30-2.16(m,1H),1.80(s,3H).

[0957] Example 184: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-N-(3-(trimethoxysilyl)phenyl)tetrahydrothiophene-2-carboxamide (Compound a-79-A)

[0958] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 3-(trimethoxysilyl)aniline (89.5 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (38.5 mg, 0.07 mmol, yield 48.33%) was obtained by Pre-HPLC separation.

[0959] MS: m / z = 552.1, [M+H] + ,1H NMR (400MHz, DMSO) δ10.30(s,1H),7.72-7.63(m,2H),7.33(t,J=7.6Hz,1H),7.23-7.13(m,3H),4.60(d,J=10.7H z,1H),4.27(d,J=4.5Hz,1H),3.97(s,3H),3.51(s,9H),2.40(d,J=13.0Hz,1H),2.33-2.28(m,1H),1.73(s,3H).

[0960] Example 185: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-N-(2-thiocyanatopyridin-4-yl)-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-80-A)

[0961] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 2-thiocyanatopyridin-4-amine (63.4 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued for 1 h. The reaction was complete and the target compound (26.3 mg, 0.05 mmol, yield 38.42%) was obtained by Pre-HPLC separation.

[0962] MS: m / z = 490.1, [M+H] + , 1H NMR (400MHz, DMSO) δ10.94(s,1H),8.38(d,J=5.6Hz,1H),7.91(d,J=1.0Hz,1H),7.44(dd,J=5.5,1.4Hz,1H),7.28-7.01(m,2H),4.60(d ,J=10.6Hz,1H),4.27(td,J=12.9,6.1Hz,1H),3.97(d,J=1.4Hz,3H),2.45(d,J=13.0Hz,1H),2.32(dd,J=12.6,6.0Hz,1H),1.73(s,3H).

[0963] Example 186: Preparation of tert-butyl 2-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxyl)-2-(3-aminosulfonylphenyl)hydrazinecarboxylate (Compound a-81-A)

[0964] The experimental steps are as in Example 1.

[0965] MS: m / z = 625.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ7.85 (s, 1H), 7.69 (d, J = 7.7Hz, 1H), 7.59 (d, J = 6.5Hz, 1H), 7.47 (s, 3H), 7.15 (t, J = 8.1Hz, 1H),4.27(s,1H),4.00(d,J=13.2Hz,4H),2.41-2.26(m,2H),2.08(s,2H),1.73(s,3H),1.43(d,J=32.4Hz,9H).

[0966] Example 187: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)-N-(3-(trihydroxysilyl)phenyl)tetrahydrothiophene-2-carboxamide (Compound a-82-A)

[0967] Compound a-79-A (20.0 mg, 0.04 mmol) was dissolved in ACN (3 mL) and H2O (3 mL) and stirred at room temperature. The reaction was complete and the target compound (15.9 mg, 0.03 mmol, yield 78.23%) was obtained by Pre-HPLC separation.

[0968] MS: m / z = 510.1, [M+H] + , 1H NMR (400MHz, DMSO) δ8.79(s,1H),7.58(dd,J=14.9,3.0Hz,1H),7.42(t,J=14.9H z,1H),7.13(dd,J=15.0,10.1Hz,1H),7.02(dd,J=14.9,3.0Hz,1H),6.90-6.79(m ,1H),5.00(d,J=20.9Hz,1H),4.89(s,3H),3.92(s,3H),3.69(dt,J=21.1,16.8Hz ,1H),3.00(dd,J=24.8,16.8Hz,1H),2.50(dd,J=24.8,16.8Hz,1H),1.38(s,3H).

[0969] Example 188: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-N-methylpicolinamide (Compound 253-A)

[0970] 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 4-amino-N-methylpicolinamide (63.42 mg, 0.42 mmol) was added, and TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After returning to room temperature naturally, stirring was continued. The reaction was complete and the target compound (28 mg, 0.06 mmol, yield 40.89%) was obtained by Pre-HPLC separation.

[0971] MS: m / z = 490.1, [M+H] + , 1 H NMR(400MHz,DMSO)δ9.92(s,1H),8.58(s,1H),8.22-8.00(m,2H),7.63-7.61(m,1H),6.86-6.92(m,2H),4.09- 4.07(m,2H),3.83(s,3H),3.48-3.46(m,1H),2.85(s,3H),2.17-1.92(m,2H),2.21-1.96(m,2H),1.38(s,3H).

[0972] Example 189: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-(hydroxymethyl)phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 254-A)

[0973] The experimental steps are as in Example 1.

[0974] MS: m / z=479.1,[M+H]+, 1 H NMR (400MHz, DMSO) δ10.31(s,1H),7.63(dd,J=6.7,2.6Hz,1H),7.48-7.41(m,1H),7.24-7.13(m,2H),7.10-7.03(m,1H),4.61(d,J=10. 7Hz,1H),4.50(d,J=5.7Hz,2H),4.28(tt,J=7.2,5.1Hz,1H),4.10-4.02(m,1H),3.99(d,J=1.8Hz,3H),2.49-2.29(m,2H),1.76(s,3H).

[0975] Example 190: Preparation of (2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(4-fluoro-3-formylphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-84-A)

[0976] Compound 254-A (100 mg, 0.21 mmol) was dissolved in anhydrous DCM (5 mL), and active MnO2 (55 mg, 0.63 mmol) was added. The mixture was stirred at room temperature. The reaction was completed and the target compound (68 mg, 0.05 mmol, yield 48.32%) was obtained by Pre-HPLC separation.

[0977] MS: m / z = 477.08, 1 H NMR (400MHz, DMSO) δ10.55(s,1H),10.19(s,1H),8.05(dd,J=6.2,2.8Hz,1H),7.78(ddd,J=8.8,4.5,2.9Hz,1H),7.42-7.31(m,1H),7 .26-7.11(m,2H),4.60(d,J=10.7Hz,1H),4.29(ddd,J=17.0,12.6,6.1Hz,1H),3.99(d,J=1.8Hz,3H),2.50-2.29(m,2H),1.76(s,3H).

[0978] Example 191: Preparation of (2R, 3S, 5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxabor-6-yl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-85-A)

[0979] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 6-amino-3,3-dimethylbenzo[c][1,2]oxaborin-1(3H)-ol (74.6 mg, 0.42 mmol) was added. TCFH (196.6 mg, 0.70 mmol) and NMI (92.1 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (28 mg, 0.05 mmol, yield 38.83%) was obtained by Pre-HPLC separation.

[0980] MS: m / z = 516.2, [M+H] + , 1 H NMR(400MHz,DMSO)δ10.02(s,1H),7.61-7.38(m,3H),7.07-6.98(m,2H),4.25-4.21( m,2H),3.83(s,3H),3.48-3.46(m,1H),2.17-1.92(m,2H),1.38(s,3H),1.35(s,6H).

[0981] Example 192: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-N-(N,N-dimethylsulfamoyl)picolinamide (Compound a-86-A)

[0982] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), and 4-amino-N-(N,N-dimethylsulfamoyl)picolinamide (102.5 mg, 0.42 mmol) was added. TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (39.5 mg, 0.07 mmol, yield 48.49%) was obtained by Pre-HPLC separation.

[0983] MS: m / z = 583.1, [M+H] + , 1H NMR (400MHz, DMSO) δ10.94(s,1H),8.53(d,J=5.5Hz,1H),8.21(d,J=1.8Hz,1H),7.73(dd,J=5.5,2.0Hz,1H),7.32(dd,J=12.4,5.2Hz, 2H),7.15(s,1H),4.29(td,J=13.0,6.2Hz,1H),4.19-4.10(m,1H),3.97(d,J=1.6Hz,3H),2.86(s,6H),2.39-2.21(m,2H),1.74(s,3H).

[0984] Example 193: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-3-methylpicolinamide (Compound 255-A)

[0985] Compound 1-7-2 (50.0 mg, 0.14 mmol) was dissolved in anhydrous DMF (2 mL), 4-amino-3-methylpicolinamide (63.4 mg, 0.42 mmol) was added, and TCFH (196.0 mg, 0.70 mmol) and NMI (91.8 mg, 1.12 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (40.0 mg, 0.08 mmol, yield 58.20%) was obtained by Pre-HPLC separation.

[0986] MS: m / z = 490.1, [M+H] + , 1 H NMR (400MHz, DMSO) δ9.83(s,1H),8.28(d,J=5.3Hz,1H),7.87(s,1H),7.57(d,J=5.3Hz,1H),7.48(s,1H),7.22-7.14( m,2H),4.81(d,J=10.7Hz,1H),4.31-4.16(m,1H),3.94(d,J=1.8Hz,3H),2.42-2.29(m,2H),2.13(s,3H),1.73(s,3H).

[0987] Example 194: Preparation of (2R,3S,5R)-N-(2-aminophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound 256-A)

[0988] Compound 1-7-2 (500 mg, 1.40 mmol) was dissolved in anhydrous DCM (2 mL), and benzene-1,2-diamine (910 mg, 8.42 mmol) was added. HATU (1.60 g, 4.21 mmol) and DIPEA (543 mg, 4.21 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was complete and the target compound (325 mg, 0.728 mmol, yield 52.03%) was obtained by Pre-HPLC separation.

[0989] MS:m / z=447.1,[M+H]+, 1 H NMR (400MHz, DMSO) δ9.44(s,1H),7.33-7.15(m,2H),7.06(dd,J=7.9,1.3Hz,1H),6.97-6.86(m,1H),6.69(dd,J=8.0,1.3Hz,1H),6.58-6.47 (m,1H),4.67(d,J=10.9Hz,3H),4.33-4.20(m,1H),3.98(d,J=1.8Hz,3H),2.42(t,J=12.8Hz,1H),2.33(dd,J=12.6,6.2Hz,1H),1.76(s,3H).

[0990] Example 195: Preparation of 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamido)-N-hydroxypicolinamide (Compound a-87-A)

[0991] Hydroxylamine hydrochloride (354 mg, 5.10 mmol) was dissolved in anhydrous THF (5 mL). Solid sodium hydroxide (164 mg, 4.10 mmol) was slowly added under ice-cooling. After reacting for 10 minutes under ice-cooling, compound a-90-1 (50 mg, 0.10 mmol) was added. The mixture was allowed to cool to room temperature and continued stirring. The reaction was complete, and the title compound (12.7 mg, 0.025 mmol, 25.84% yield) was obtained by pre-HPLC separation.

[0992] MS: m / z = 492.1. 1H NMR (400MHz, DMSO) δ11.35(s,1H),10.81(s,1H),9.06(s,1H),8.42(d,J=5.5Hz,1H),8.10(d,J=2.0Hz,1H),7.64(dd,J=5.5,2.2Hz,1H),7.24-7 .10(m,2H),4.60(d,J=10.6Hz,1H),4.33-4.22(m,1H),3.97(d,J=1.9Hz ,3H),2.45(d,J=12.9Hz,1H),2.33(dd,J=12.6,6.1Hz,1H),1.74(s,3H).

[0993] Example 196: Preparation of N-(2-aminophenyl)-4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide)picolinamide (a-88-A)

[0994] 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide)pyridine-2-carboxylic acid (200 mg, 0.42 mmol) was dissolved in anhydrous DCM (2 mL), and benzene-1,2-diamine (272 mg, 2.52 mmol) was added. HATU (479 mg, 1.26 mmol) and DIPEA (163 mg, 1.26 mmol) were added under ice bath. After naturally returning to room temperature, stirring was continued. The reaction was completed and the target compound (196 mg, 0.346 mmol, yield 82.70%) was obtained by Pre-HPLC separation.

[0995] MS: m / z = 567.1, [M+H] + . 1H NMR (400MHz, DMSO) δ10.92(s,1H),10.05(s,1H),8.59(d,J=5.5Hz,1H),8.27(d,J=2.0Hz,1 H),7.78(dd,J=5.5,2.2Hz,1H),7.52(dd,J=7.9,1.3Hz,1H),7.27-7.14(m,2H),6.99-6.93( m,1H),6.85(dd,J=7.9,1.3Hz,1H),6.75-6.62(m,1H),4.65(d,J=10.6Hz,1H),4.32(ddd,J =26.3,17.4,10.9Hz,1H),4.01(d,J=2.0Hz,3H),2.37(dd,J=12.6,6.0Hz,1H),1.78(s,3H).

[0996] Example 197: Preparation of (2R,3S,5R)-N-(3-((E)-3-amino-2-cyano-3-oxopropen-1-yl)-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide (Compound a-89-A)

[0997] Compound a-84-A (100 mg, 0.21 mmol) was dissolved in anhydrous EtOH (5 mL), and Et3N (64 mg, 0.63 mmol) was added. The temperature was raised to 80°C and stirred. The reaction was completed. Pre-HPLC separation gave the target compound (73 mg, 0.13 mmol, yield 64.13%).

[0998] MS: m / z=543.11, 1 H NMR (400MHz, DMSO) δ10.58 (s, 1H), 8.28 (dd, J = 6.5, 2.5Hz, 1H), 8.20 (s, 1H), 8.0 5(s,1H),7.88(s,1H),7.75(ddd,J=8.9,4.6,2.7Hz,1H),7.36(t,J=9.5Hz,1H),7 .26-7.12(m,2H),4.63(d,J=10.7Hz,1H),4.33(dq,J=10.9,6.2Hz,1H),4.00(d, J=1.7Hz, 3H), 2.46 (t, J=12.9Hz, 1H), 2.34 (dd, J=12.6, 6.1Hz, 1H), 1.76 (s, 3H).

[0999] Example 198: Preparation of 4-(N-methyl(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide)pyridine-2-carboxamide (Compound a-90-A)

[1000] Step 1: Synthesis of methyl 4-((2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-amide)pyridine-2-carboxylate (Compound a-90-1)

[1001] Compound 1-7-2 (50 mg, 0.14 mmol) was dissolved in anhydrous DMF (5 mL), and 4-amino-2-methylpyridine formate (64 mg, 0.42 mmol) was added. TCFH (197 mg, 0.70 mmol) and NMI (92 mg, 1.12 mmol) were added under ice bath. After returning to room temperature, stirring was continued. The reaction was complete. Pre-HPLC separation gave the title compound (65 mg, 0.133 mmol, yield 94%). MS: m / z = 491.10, [M+H] + .

[1002] Step 2: Synthesis of methyl 4-(N-methyl(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-amide)pyridine-2-carboxylate (a-90-2)

[1003] Compound a-90-1 (65 mg, 0.133 mmol) was dissolved in anhydrous DMF (5 mL), and Cs2CO3 (130 mg, 0.398 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Mel (28 mg, 0.199 mmol) was added under ice bath. The mixture was allowed to return to room temperature and continued to stir. The reaction was complete. Pre-HPLC separation gave the title compound (58 mg, 0.115 mmol, yield 87%). MS: m / z = 505.11, [M+H] + .

[1004] Step 3: Synthesis of 4-(N-methyl(2R,3S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide)pyridine-2-carboxamide (a-90-A)

[1005] Compound a-90-2 (58 mg, 0.115 mmol) was dissolved in NH3·MeOH (7 mol / L, 5 mL) and stirred at room temperature for 1 h. The reaction was complete and the target compound (33 mg, 0.067 mmol, yield 59%) was obtained by Pre-HPLC separation.

[1006] MS: m / z = 490.11, [M+H] + , 1 H NMR (400MHz, DMSO) δ8.56-8.32(m,3H),7.25-7.12(m,2H),6.23(s,2H),4.62(d,J=10.7Hz,1H),4.36-4.22(m ,1H),3.99(d,J=1.6Hz,3H),3.41(s,3H),2.44(t,J=12.9Hz,1H),2.33(dd,J=12.6,6.0Hz,1H),1.76(s,3H).

[1007] Experimental Example 1: Manual patch clamp technique to monitor the effect of test substances on the current of stably overexpressed Nav1.8 channels

[1008] Experimental methods:

[1009] 1. Reagent preparation

[1010] Test compounds were dissolved in dimethyl sulfoxide (DMSO).

[1011] The extracellular solution consisted of 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, and NaOH adjusted the pH to 7.4. The intracellular solution consisted of 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, and CsOH adjusted the pH to 7.2.

[1012] 2 Experimental materials and instruments

[1013] 1) Patch clamp amplifier: EPC 10 (HEKA)

[1014] 2) Micromanipulator: MP225 (Sutter Instrument)

[1015] 3) Inverted microscope: MF53 (Mshot)

[1016] 4) Microelectrode pulling instrument: P97 (Sutter Instrument)

[1017] 5) Capillary glass tube: BF150-86-10 (Sutter Instrument)

[1018] 3 Experimental steps

[1019] 1) After the compound is prepared into a solution of specified concentration, it is added to the drug delivery system pipeline in sequence and marked.

[1020] 2) Place the cell slide in the recording chamber, select appropriate cells under an inverted microscope and adjust the position of the dosing head.

[1021] 3) Use a microelectrode puller to pull a suitable recording electrode from a capillary glass tube. Then, place the electrode, filled with intracellular fluid, into a microelectrode holder. Under an inverted microscope, adjust the micromanipulator to bring the recording electrode into contact with the cell. Apply negative pressure to the electrode to create a high-resistance seal. At this point, perform fast capacitance compensation. Continue applying negative pressure to rupture the cell membrane, establishing whole-cell recording mode. Finally, perform slow capacitance compensation and record relevant parameters.

[1022] 4) Drug administration begins after the cell current stabilizes. Each drug concentration is allowed to act for five minutes or until the current stabilizes, and the next concentration is monitored. The drug solution flows through the recording bath in sequence from low to high concentrations by gravity administration to act on the cells. A peristaltic pump is used for fluid replacement during recording.

[1023] 4 Test voltage procedure (resting state) and results

[1024] After whole-cell blockade, the cell is voltage-clamped at -120 mV. A 50-ms square-wave pulse is then applied to 0 mV to obtain a Nav1.8 current. This procedure is repeated every 20 s. The maximum current induced by the square wave is monitored, and the test compound is administered after stabilization. When the response stabilizes, the magnitude of the current block is calculated.

[1025] 5 The test results are shown in Table 2-1, Table 2-2 and Table 3 below:

[1026] Table 2-1. Inhibitory rate determination results of the compounds of the present invention at a concentration of 10 nM

[1027] Table 2-2 Inhibitory rate determination results of the compounds of the present invention at a concentration of 1 nM

[1028] Table 3 Inhibition rate IC of some compounds of the present invention 50 Measurement results

[1029] The compounds of the present invention, such as the compounds in the Examples, have good Nav1.8 inhibitory effects.

[1030] Experimental Example 2: Pharmacokinetic study of the compound in SD rats

[1031] Experimental animals: SD rats, male, 6-8 weeks old.

[1032] Compound preparation: First, add 5% DMSO to the final volume to dissolve the test compound, and then add 10% CremophorEL and 85% Saline to the final volume in sequence.

[1033] Experimental Design: SD rats were administered a single intravenous or oral dose of the test compound (2 mg / kg for injection and 10 mg / kg for oral administration; n = 3). The injection group was fasted overnight (>12 hours) but not for water; food was resumed 4 hours after administration. Blood was collected from the jugular vein of SD rats 5 minutes, 15 minutes, 0.5, 1, 2, 4, 8, and 24 hours after injection, and 15 minutes, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. After anticoagulation (blood samples were placed in an ice bath after collection), the samples were centrifuged at 6000g for 5 minutes, and plasma was separated and stored at -70°C until analysis.

[1034] Sample monitoring: LC-MS / MS was used to determine the concentration of the designated compound in plasma; Winnolin 8.3 non-compartmental model was used to calculate the main pharmacokinetic parameters.

[1035] The test results are shown in Table 4 below:

[1036] Table 4. Pharmacokinetic test results of some compounds of the present invention in SD rats

[1037] From the data in Table 4, it can be seen that compound 139 of the present invention has better pharmacokinetic properties in rats, wherein the exposure after oral administration is 2 times that of VX-548, t 1 / 2 It is also twice that of VX-548, indicating that compound 139 has stronger efficacy and longer analgesic duration.

[1038] Experimental Example 3: Pharmacokinetic study of the compound in ICR mice

[1039] Experimental animals: ICR mice, male, 6-8 weeks old.

[1040] Compound preparation: First, add 5% DMSO to the final volume to dissolve the test compound, and then add 10% CremophorEL and 85% Saline to the final volume in sequence.

[1041] Experimental Design: ICR mice were administered a single intravenous or oral dose of the test compound (2 mg / kg for injection and 10 mg / kg for oral administration; n = 3). The injection group was fasted overnight (>12 hours) but not for water; food was resumed 4 hours after administration. Blood was collected from the jugular vein of ICR mice 5 minutes, 15 minutes, 0.5, 1, 2, 4, 8, and 24 hours after injection, and 15 minutes, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. After anticoagulation (blood samples were placed in an ice bath after collection), the samples were centrifuged for 5 minutes, and plasma was separated and stored at -70°C until analysis.

[1042] Sample testing: LC-MS / MS was used to determine the concentration of the designated compound in plasma; Winnolin 8.3 non-compartmental model was used to calculate the main pharmacokinetic parameters.

[1043] The test results are shown in Table 5 below:

[1044] Table 5 Pharmacokinetic test results of some compounds of the present invention in ICR mice

[1045] Experimental Example 4: Tissue distribution study of the compound in ICR mice

[1046] Experimental animals: ICR mice, male, 6-8 weeks old.

[1047] Compound preparation: First, add 5% DMSO to the final volume to dissolve the test compound, and then add 10% CremophorEL and 85% Saline to the final volume in sequence.

[1048] Experimental Design: ICR mice were orally administered a single dose of the test compound (20 mg / kg; n=3, 3 time points). 0.25, 2, and 12 hours after oral administration, the ICR mice were sacrificed after blood collection, and the dorsal root ganglia (DRG) were collected. Residual blood was rinsed with ice-cold saline, dried with absorbent paper, and stored at -70°C for testing.

[1049] Sample detection: LC-MS / MS method was used to determine the concentration of drug compounds in dorsal root ganglia.

[1050] The test results are shown in Table 6 below:

[1051] Table 6 Distribution test results of some compounds of the present invention in the dorsal root ganglion of ICR mice

[1052] Experimental Example 5: Tissue distribution study of the compound in SD rats

[1053] Experimental animals: SD rats, male, 6-8 weeks old.

[1054] Compound preparation: First, add 5% DMSO to the final volume to dissolve the test compound, and then add 10% CremophorEL and 85% Saline to the final volume in sequence.

[1055] Experimental design: SD rats were orally administered a single dose of the test compound (10 mg / kg; n=3, 3 time points). 0.5, 2, and 6 hours after oral administration, the SD rats were killed after blood was collected, and the dorsal root ganglia were collected. The residual blood was rinsed with ice-cold saline, dried with absorbent paper, and stored at -70°C for testing.

[1056] Sample detection: LC-MS / MS method was used to determine the concentration of designated drug compounds in plasma and tissues.

[1057] The test results are shown in Table 7 below:

[1058] Table 7 Distribution test results of some compounds of the present invention in the dorsal root ganglion of SD rats

[1059] It can be seen from the data in Tables 6 and 7 that the compounds of the present invention have a relatively high concentration distribution in the dorsal root ganglion for a long time.

[1060] Experimental Example 6: Study on the efficacy of compounds in the incisional pain model of ICR mice

[1061] Experimental animals: ICR mice, male, 28-35 g.

[1062] Compound preparation: First, add 5% DMSO to the final volume to dissolve the test compound, and then add 10% CremophorEL and 85% Saline to the final volume in sequence.

[1063] Experimental Design:

[1064] 1. Model building

[1065] Before drug administration, a plantar incisional pain model was established in mice through surgery. Mice were placed in an anesthesia induction box and anesthetized with 3%-4% isoflurane. After induction, they were connected to a breathing mask with the isoflurane concentration adjusted to 1%-2% to prevent pain during surgery. The mice were placed in a supine position, and the surgical area was disinfected with alcohol and iodine. Under sterile conditions, a 0.5 cm longitudinal incision was made with a blade at 0.2 cm from the heel of the left hind paw toward the fingertips. The skin and fascia were incised, the plantar muscles were separated, slightly elevated, and longitudinally incised. The skin was then sutured with 5-0 sutures and disinfected.

[1066] 2. Drug administration test

[1067] A Von Frey test was performed before surgery. On the second day after animal modeling, the animals were tested again. Animals that met the baseline requirements were selected and randomly divided into groups according to the 50% PWT value. Each group had 10 animals. Double-blind test administration was performed. The 50% PWT of the animals was tested before administration (baseline) and 0.5 h, 2 h, and 4 h after administration. A single dose was administered. The model control group was given normal saline, and the compound group was given the compound according to the dose in the table below.

[1068] The test results are shown in Table 8 below:

[1069] Table 8 PWT 50% values ​​of mice in each group treated with the compounds of the present invention at different time points (g, Mean ± SEM, n = 10)

[1070] It can be seen from the data in the above table that the compounds of the present invention have the properties of rapid onset of action and long-lasting analgesic effect.

[1071] Experimental Example 7: Study on the efficacy of the compound in the incisional pain model of SD rats

[1072] Experimental animals: SD rats, male, 180-220 g.

[1073] Compound preparation: First, add 5% DMSO to the final volume to dissolve the test compound, and then add 10% CremophorEL and 85% Saline to the final volume in sequence.

[1074] Experimental Design:

[1075] 1. Model building

[1076] Before drug administration, a rat plantar incisional pain model was established surgically. Rats were placed in an anesthesia induction box and anesthetized with 3%-4% isoflurane. After induction, they were connected to a breathing mask with the isoflurane concentration adjusted to 1%-2% to prevent pain during surgery. The rats were placed in the supine position, and the surgical area was disinfected with alcohol and iodine. Under sterile conditions, a 0.5 cm longitudinal incision was made with a blade toward the fingertips at a point 0.2 cm from the heel of the left hind paw. The skin and fascia were incised, the plantar muscles were separated, slightly elevated, and longitudinally incised. The skin was then sutured with 5-0 sutures and disinfected.

[1077] 2. Drug administration test

[1078] A Von Frey test was performed before surgery. The next day after modeling, animals were retested. Animals meeting baseline requirements were randomly divided into six groups of 10 animals each based on their 50% PWT values. Double-blind dosing was performed. 50% PWT values ​​were measured before dosing (baseline) and 0.5, 2, 4, 6, or 8 hours after dosing. A single dose was administered. The model control group received saline, and the compound group received the compound at the doses shown in the table below.

[1079] The test results are shown in Table 9 below:

[1080] Table 9 PWT 50% values ​​of rats in each group treated with the compounds of the present invention at different time points (g, Mean ± SEM, n = 10)

[1081] As can be seen from the data in the table above, compound 139-A exhibited a good dose-response relationship in the rat incisional pain model. At the same dose, compound 139-A had superior analgesic activity compared to VX-548.

[1082] Experimental Example 8: Study on the pharmacological effects of compounds in the rat spinal nerve ligation model (SNL)

[1083] Experimental animals: SD rats, male, 180-220 g.

[1084] Compound preparation: First, add 5% DMSO to the final volume to dissolve the test compound, and then add 10% Cremophor EL and 85% Saline to the final volume in sequence.

[1085] Experimental Design:

[1086] 1. Model building

[1087] SD rats were anesthetized with isoflurane and placed in the prone position. The surgical area was shaved and disinfected with alcohol and iodine. Under sterile conditions, a 3-4 cm longitudinal incision was made at the level of the lower lumbar region / superior sacrum to expose the left paraspinal muscles. Using small blunt-pointed scissors, the paraspinal muscles were bluntly dissected and the L6 transverse process was resected. The L4 and L5 spinal nerves were isolated and exposed. The L5 spinal nerve was ligated with 6-0 silk suture. Ceftriaxone was used to treat the wound and prevent infection. The muscles and skin were sutured layer by layer and disinfected with iodine. After the surgery, the animals were placed on a warm electric blanket for warmth and returned to their cages after they fully recovered. Postoperative behavioral observation was performed.

[1088] 2. Drug administration test

[1089] A Von Frey test was performed before surgery. Leg raises were performed on days 5 and 6 after surgery. Animals with a baseline weight of 2-5 g were enrolled and grouped according to 50% PWT values, with 10 animals per group. On the second day, a single dose was administered in a blinded manner. 50% PWT values ​​were measured before dosing (baseline) and 0.5, 2, 4, 6, or 8 hours after dosing. The model control group received saline, and the compound group received the compound at the doses shown in the table below.

[1090] The test results are shown in Table 10 below:

[1091] Table 10 PTW 50% values ​​of rats in each group of the compounds of the present invention at different time points (g, Mean ± SEM, n = 10)

[1092] As shown in Table 10, compound 139-A exhibited a good dose-effect relationship in the rat SNL model. Compound 139-A showed significant differences compared to the model group at each time point.

[1093] Experimental Example 9: Study on the efficacy of compounds in CFA-induced inflammatory pain model in rats

[1094] Experimental animals: SD rats, male, 180-220 g.

[1095] Compound preparation: First, add 5% DMSO to the final volume to dissolve the test compound, then add 10% Cremophor EL and 85% Saline to the final volume. Weigh an appropriate amount of Celecoxib and first add 5% DMSO to the final volume to dissolve the test compound, then add 5% HS-15 and 90% Saline to the final volume.

[1096] Experimental Design:

[1097] 1. Model building

[1098] Sprague-Dawley rats were anesthetized with isoflurane, and the right hind paw was disinfected. A needle was inserted subcutaneously into the posterior half of the plantar surface, and 50 μL of complete Freund's adjuvant (CFA, 1 mg / mL) was injected subcutaneously into the mid-plantar region. The needle was then withdrawn with a slow rotation to avoid leakage. Following modeling, localized swelling and redness of the plantar surface, difficulty walking, and contraction of the affected foot were observed.

[1099] 2. Drug administration test

[1100] A Von Frey test was performed before surgery. The day after modeling, animals meeting baseline requirements were enrolled and randomly divided into six groups of 10 animals per group based on their 50% PWT values. Double-blind dosing was performed, and 50% PWT values ​​were measured before dosing (baseline) and 0.5, 2, and 8 hours after dosing. The model control group received saline, and the compound group received the compound at the doses shown in the table below.

[1101] The test results are shown in Table 11 below:

[1102] Table 11 PWT 50% values ​​of rats in each group treated with the compounds of the present invention at different time points (g, Mean ± SEM, n = 10)

[1103] As can be seen from the data in Table 11, compound 139-A exhibited good analgesic activity in the CFA-induced rat inflammatory pain model and was superior to the positive control Celecoxib.

[1104] Experimental Example 10: Study on the efficacy of compounds in the rat formalin pain model

[1105] Experimental animals: SD rats, male, 180-200 g.

[1106] Compound preparation: Dissolve the test compound by adding 5% DMSO to the final volume, followed by 10% Cremophor EL and 85% Saline. Weigh an appropriate amount of Etoricoxib and dissolve the test compound by adding 5% DMSO to the final volume, followed by 5% HS-15 and 90% Saline. Tramadol injection: Dilute with normal saline to the desired concentration.

[1107] Experimental Design:

[1108] 1. Model building

[1109] Each group had 10 rats, and 50 μL of 5% formalin solution was injected into the right sole of the foot using a micro syringe.

[1110] 2. Drug administration test

[1111] Based on the different pharmacokinetic properties of the drugs, the drugs were administered 0, 60, and 120 minutes before modeling. After formalin injection, the rats were observed for pain responses. Behavioral responses such as paw lifting, licking, and foot swinging were considered a pain response. Spontaneous pain responses were observed every 5 minutes, and the number of pain responses within 1 minute was counted for a total of 60 minutes. Inhibition rate = (number of pain responses in the control group - number of pain responses in the drug-treated group) / number of pain responses in the control group × 100%.

[1112] Specific dosing information is shown in Table 12 below.

[1113] Table 12 Dosage information of the compounds of the present invention in rat formalin model test

[1114] The test results are shown in Table 13 below:

[1115] Table 13. Number of pain reactions in rats of each group treated with the compound of the present invention (Mean±SD, n=10)

[1116] As shown in Table 13, Compound 139-A exhibits a good dose-response relationship in the rat formalin pain model. Formalin-induced inflammatory pain manifests in two distinct phases. The first phase is the immediate pain response following subcutaneous formalin injection, caused by stimulation of nerve endings. The second phase, which occurs approximately 15-20 minutes after subcutaneous formalin injection, is due to the continued transmission of nociceptive information from local chronic inflammation. In this model, tramadol and etoricoxib exhibit superior analgesic effects in the first and second phases, respectively. Compound 139-A of the present invention exhibits significant analgesic activity in both the first and second phases, surpassing VX-548.

[1117] Experimental Example 11: Study on the efficacy of compounds in the acetic acid writhing model in mice

[1118] Experimental animals: ICR mice, male, 20-24 g.

[1119] Compound preparation: First add 5% DMSO to the final volume to dissolve the test compound, then add 10% CremophorEL and 85% Saline to the final volume. Weigh an appropriate amount of Etoricoxib and first add 5% DMSO to the final volume to dissolve the test compound, then add 5% HS-15 and 90% Saline to the final volume.

[1120] Experimental Design:

[1121] 1. Model establishment The rats were randomly divided into groups according to body weight, with 10 rats in each group. 0.8% (v / v) acetic acid solution was injected intraperitoneally at a volume of 10 mL / kg.

[1122] 2. Drug administration test

[1123] Administration was performed 60 minutes before modeling. After injection of the acetic acid solution, the number of writhing reactions in the mice was observed. A complete writhing reaction was defined as a behavioral response, including abdominal indentation, extension of the trunk and hind limbs, and elevation of the buttocks. The number of writhing reactions in the mice was observed and recorded within 0-15 minutes and 15-30 minutes, for a total of 30 minutes. Inhibition rate = (number of writhings in the control group - number of writhings in the drug administration group) / number of writhings in the control group × 100%. The model control group was administered with normal saline, the positive control group 1 was administered with 20 mg / kg of etoricoxib, and the positive control group 2 was administered with 50 mg / kg of VX-548. The remaining groups were administered the compounds of the present invention according to the dosages shown in the table below.

[1124] The test results are shown in Table 14 below:

[1125] Table 14 Number of writhing reactions in each group of mice treated with the compound of the present invention (Mean±SD, n=10)

[1126] As shown in the data above, the compounds of the present invention, particularly compounds 119-A, 139-A, and a-20-A, are more effective in inhibiting writhing than VX-548. Compound 139-A exhibited a strong dose-response relationship in the mouse acetic acid writhing model; at a dose of 125 mg / kg, it significantly inhibited the number of writhing episodes.

[1127] The above-described embodiments do not limit the solutions of the present application in any way. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A compound or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein the compound has the following structure: in: R a Selected from Y 1 , Y 2 , Y 3 , Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ; R a1 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and -S(O)2R 1 ; R a2 Each is independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl, -NR 2 R 3 、-NHC(O)R 4 、-C(O)OR 5 、-C(O)NR 6 R 7 、-SR 8 、-S(O)R 9 、-S(O)2R 10 、-S(O)2NR 11 R 12 、-S(O)(NR 13 )R 14 、-P(O)R 15 R 16 and The C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 19 R 20 substituted by a substituent; Or the adjacent R a1 and R a2 Or two R a2 The carbon atom to which it is attached forms a 5-6 membered heteroaromatic ring; R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , R 20 Each independently selected from H and C 1-6 alkyl; R 2 , R 3 Each independently selected from H, C 1-6 Alkyl and carbonyl substituted C 1-6 alkyl; R 4 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 2-6 alkenyl; R 17 , R 18 Each independently selected from H and C 1-6 Alkyl, or R 17 , R 18 Together with the attached boron and oxygen atoms, it forms a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-6 substituted by an alkyl substituent; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ; R a3 Each is independently selected from H, halogen, hydroxyl, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 3-6 Cycloalkyl, -NR 21 R 22 、-NHC(O)R 23 、-C(O)OR 24 、-C(O)NR 25 R 26 、-SR 27 、-S(O)R 28 、-S(O)2R 29 、-S(O)2NR 30 R 31 、-S(O)(NR 32 )R 33 、-P(O)R 34 R 35 and The C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 38 R 39 substituted by a substituent; Or two adjacent R a3 The carbon atom connected thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally substituted by one or more OH, C 1-6 alkyl; R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 38 , R 39 Each independently selected from H and C 1-6 alkyl; R 21 , R 22 Each independently selected from H, C 1-6 Alkyl, carbonyl substituted C 1-6 Alkyl and -C(O)OC 1-6 alkyl; R 23 Each independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl and C 2-6 alkenyl; R 36 , R 37 Each independently selected from H and C 1-6 Alkyl, or R 36 , R 37 Together with the attached boron and oxygen atoms, it forms a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-6 substituted by an alkyl substituent; V is selected from N, N + -O - and CR a4 ; R a4 Selected from H and C 1-6 alkyl; R a5 Selected from H and C 1-6 alkyl; R a6 Selected from H and C 1-6 alkyl; R b1 and R b2 are each independently selected from H and deuterium; R b3 and R b4 are each independently selected from H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl; R b5 and R b6 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl, or R b5 , R b6 Together with the attached carbon atom, it forms C 3-5 Cycloalkyl and 4-6 membered heterocyclic groups; R c Selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 , C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one or more halogen, C 1-6 Alkyl substitution; R 40 , R 41 Each independently selected from H and C 1-6 alkyl; X 1 , X 2 , X 3 , X 4 Each independently selected from N and CR c1 ; R c1 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

2. The compound according to any one of claims 1 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein: R a Selected from Y 1 , Y 2 , Y 3 , Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ; R a1 Each independently selected from H, C 1-4 Alkyl (e.g. methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g. CF3, CHF2, CH2F) and -S(O)2R 1 (e.g. -S(O)2CH3); R a2 are each independently selected from H, halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, -CN, C 1-4 Alkyl (e.g. methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g. CF3, CHF2, CH2F), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, C 1-4 Cycloalkyl, -NR 2 R 3 、-NHC(O)R 4 、-C(O)OR 5 、-C(O)NR 6 R 7 , SR 8 、-S(O)R 9 、-S(O)2R 10 、-S(O)2NR 11 R 12 、-S(O)(NR 13 )R 14 、-P(O)R 15 R 16 and The C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 19 R 20 substituted by a substituent; Or the adjacent R a1 and R a2 Or two R a2 The carbon atom to which it is attached forms a 5-6 membered heteroaromatic ring; R 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 19 , R 20 Each independently selected from H and C 1-4 alkyl; R 2 , R 3 Each independently selected from H, C 1-4 Alkyl and carbonyl substituted C 1-4 alkyl; R 4 Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl and C 2-6 alkenyl; R 17 , R 18 Each independently selected from H and C 1-4 Alkyl, or R 17 , R 18 Together with the attached boron and oxygen atoms, it forms a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-4 substituted by an alkyl substituent; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ; R a3 are each independently selected from H, halogen (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, -CN, C 1-4 Alkyl (e.g. methyl, ethyl, propyl, butyl), C 1-4 Haloalkyl (e.g. CF3, CHF2, CH2F), C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, C 1-4 Cycloalkyl, -NR 21 R 22 、-NHC(O)R 23 、-C(O)OR 24 、-C(O)NR 25 R 26 、-SR 27 、-S(O)R 28 、-S(O)2R 29 、-S(O)2NR 30 R 31 、-S(O)(NR 32 )R 33 、-P(O)R 34 R 35 and The C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 The haloalkoxy group is optionally substituted with one or more hydroxyl groups, -NR 38 R 39 substituted by a substituent; Or two adjacent R a3 The carbon atom connected thereto forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-6 membered heteroaromatic ring is optionally substituted by one or more OH, C 1-6 Alkyl substitution; R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 38 , R 39 Each independently selected from H and C 1-4 alkyl; R 21 , R 22 Each independently selected from H, C 1-4 Alkyl, carbonyl substituted C 1-4 Alkyl and -C(O)OC 1-4 alkyl; R 23 Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl and C 2-6 alkenyl; R 36 , R 37 Each independently selected from H and C 1-4 Alkyl, or R 36 , R 37 Together with the attached boron and oxygen atoms, it forms a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-4 substituted by an alkyl substituent; V is selected from N, N + -O - and CR a4 ; R a4 Selected from H and C 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl); R a5 Selected from H and C 1-4 Alkyl (e.g., methyl, ethyl, propyl, butyl); R a6 Selected from H and C 1-4 Alkyl (eg, methyl, ethyl, propyl, butyl).

3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein: R a Selected from Y 1 , Y 2 , Y 3 , Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ; R a1 Each independently selected from H, methyl, CF3, CHF2 and -S(O)2CH3; R a2 Each independently selected from H, fluorine, chlorine, methyl, CF3, CHF2, -C(O)NH2, -NH2 and Or the adjacent R a1 and R a2 Or two R a2 The carbon atom to which it is attached forms a 5-6 membered heteroaromatic ring; R 17 , R 18 Each independently selected from H and C 1-4 Alkyl, or R 17 , R 18 Together with the attached boron and oxygen atoms, it forms a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-4 substituted by an alkyl substituent; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ; R a3 Each is independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -NR 21 R 22 、-NC(O)R 23 、-C(O)OR 24 、-C(O)NR 25 R 26 、-SR 27 、-S(O)R 28 、-S(O)2R 29 、-S(O)2NR 30 R 31 、-S(O)(NR 32 )R 33 、-P(O)R 34 R 35 and Or two adjacent R a3 The carbon atom to which it is connected forms a 5-6 membered heterocyclic group or a 5-6 membered heteroaromatic ring, wherein the heterocyclic group is optionally substituted by one or more hydroxyl groups or methyl groups; R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 Each independently selected from H and C 1-4 alkyl; R 21 , R 22 Each independently selected from H, C 1-4 Alkyl and carbonyl substituted C 1-4 alkyl; R 23 Each independently selected from C 1-4 Alkyl, C 1-4 Haloalkyl and C 2-6 alkenyl; R 36 , R 37 Each independently selected from H and C 1-4 Alkyl, or R 36 , R 37 Together with the attached boron and oxygen atoms, it forms a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by one or more selected from H, halogen, C 1-4 substituted by an alkyl substituent; V is selected from N, N + -O - and CR a4 ; R a4 is selected from H and methyl; R a5 is selected from H and methyl; R a6 Selected from H and methyl.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein: R a3 each independently selected from H, fluorine, chlorine, bromine, hydroxyl, -CN, methyl, CF3, CHF2, methoxy, trifluoromethoxy, vinyl, cyclopropyl, -CH2OH, -C(CH3)2OH, -CH(OH)CH2(OH), -CH(OH)CH2F, -CH(NH2)CH2(OH), -N(CH3)-Boc, -NH(CH3), -N(CH3)2, -C(O)OCH3, -C(O)NH2, -SH, -S(O)CH3, -S(O)2CH3, -S(O)2NH2, -S(O)(NH)CH3, -S(O)(NCH3)CH3, -P(O)(CH3)2, and Or two adjacent R a3 The carbon atom to which it is attached forms 5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R b3 and R b4 are each independently selected from H, deuterium, C 1-4 Alkyl (such as methyl, ethyl, propyl and butyl), C 1-4 Haloalkyl and C 3-6 Cycloalkyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R b5 and R b6 Each independently selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl and C 3-6 Cycloalkyl, or R b5 , R b6 Together with the attached carbon atom, it forms C 3-5 Cycloalkyl and 4-6 membered heterocyclic group (eg 4-6 membered oxygen-containing heterocyclic group).

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R c Selected from H, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 , C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one or more halogen, C 1-4 Alkyl substitution; R 40 , R 41 Each independently selected from H and C 1-4 alkyl.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein: X 1 , X 2 , X 3 , X 4 Each independently selected from N and CR c1 ; R c1 are each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R a Selected from:

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R c Selected from: H, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -OCH2CF3, -OCH2CF2CH3, -OCH2CHF2, -OCHF2, 11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein the compound is selected from:

12. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein the compound is selected from:

13. A compound of formula II or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein the compound has the following structure: in, R a Selected from Y 1 , Y 2 , Y 3 , Y 4 Each independently selected from O, S, N, NR a1 and CR a2 ; R a1 Each independently selected from -S(O)2-R 42 ; R a2 Each independently selected from H and C 1-6 alkyl; R 42 Each independently selected from C 1-6 Haloalkyl and C 3-6 Cycloalkyl; Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ; R a3 Each is independently selected from H, halogen, -N3, -NO2, -SCN, -S(F)5, -CH(O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)NR 43 R 44 、-C(O)NR 45 S(O)2NR 46 R 47 、-C(S)NR 48 R 49 、-C(=NR 50 )NR 51 R 52 、-C(=NR 53 )R 54 、-NR 55 R 56 、-NR 57 S(O)2R 58 、-NR 59 S(O)2NR 60 R 61 、-N=S(O)R 62 R 63 、-OS(O)2R 64 、-S(O)2R 65 、-S(O)2NR 66 R 67 、-Si(OR 68 )3. The C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, optionally substituted with one or more halogen, hydroxyl, -CN, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)OR 71 、-C(O)NR 72 R 73 Substituents are substituted; Or two adjacent R a3 The carbon atom connected thereto forms a 5-6 membered heterocyclic group or a 5-10 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-10 membered heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, amino, -CN, =O, C 1-6 Alkyl, -C 1-6 Alkyl NR 74 R 75 Substituents are substituted; R 43 , R 44 , R 50 , R 53 Each independently selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy; R 45 , R 46 , R 47 , R 48 , R 49 , R 51 , R 52 , R 54 , R 57 , R 59 , R 62 , R 63 , R 68 , R 71 , R 72 , R 73 , R 74 , R 75 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; R 55 , R 56 , R 66 , R 67 Each independently selected from H, hydroxyl, -CN, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 2-6 Alkenyl, -C(O)C 2-6 Alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The 3- to 6-membered cycloalkyl and heterocyclic groups are optionally substituted by halogen, hydroxyl, amino, -CN, N3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino substitution; R 58 independently selected from halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, N3 substituent substitution; R 60 , R 61 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, N3 substituent substitution; R 64 are independently selected from halogen, amino and C 1-6 Alkylamino; R 65 Independently selected from halogen, N3, C 1-6 Alkyl and C 1-6 Haloalkyl; R 69 , R 70 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl is optionally substituted with hydroxyl and amino; or R 69 , R 70 Together with the attached boron and oxygen atoms, it forms a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl and =O substituents substituted; L 1 , L 2 are each independently selected from O and N; V is selected from N, N + -O - and CR a4 ; R a4 Selected from H and C 1-6 alkyl; R a5 Selected from H and C 1-6 alkyl; R a6 Selected from H and C 1-6 alkyl; R a7 Selected from H and C 1-6 alkyl; R b1 and R b2 are each independently selected from H and deuterium; R b3 and R b4 are each independently selected from H, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl; R b5 and R b6 Each independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl and C 3-6 Cycloalkyl, or R b5 , R b6 Together with the attached carbon atom, it forms C 3-5 Cycloalkyl and 4-6 membered heterocyclic groups; R c Selected from H, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 3-6 The cycloalkyl group is optionally substituted with one or more hydroxyl, carboxyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, -NR 40 R 41 , C 3-6 The 3-6 membered heterocyclic group and the 5-6 membered heteroaryl group are optionally substituted by one or more halogen, C 1-6 Alkyl substitution; R 40 , R 41 Each independently selected from H and C 1-6 alkyl; X 1 , X 2 , X 3 , X 4 Each independently selected from N and CR c1 ; R c1 are each independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy and C 1-6 Halogenated alkoxy.

14. The compound of claim 13 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R a Selected from Z 1 , Z 2 , Z 3 , Z 4 , Z 5 Each independently selected from N, N + -O - and CR a3 ; R a3 Each is independently selected from H, halogen, -N3, -NO2, -SCN, -S(F)5, -CH(O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)NR 43 R 44 、-C(O)NR 45 S(O)2NR 46 R 47 、-C(S)NR 48 R 49 、-C(=NR 50 )NR 51 R 52 、-C(=NR 53 )R 54 、-NR 55 R 56 、-NR 57 S(O)2R 58 、-NR 59 S(O)2NR 60 R 61 、-N=S(O)R 62 R 63 、-OS(O)2R 64 、-S(O)2R 65 、-S(O)2NR 66 R 67 、-Si(OR 68 )3. The C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, optionally substituted with one or more halogen, hydroxyl, -CN, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)OR 71 、-C(O)NR 72 R 73 Substituents are substituted; Or two adjacent R a3 The carbon atom connected thereto forms a 5-6 membered heterocyclic group or a 5-10 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-10 membered heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, amino, -CN, =O, C 1-6 Alkyl, -C 1-6 Alkyl NR 74 R 75 Substituents are substituted; R 43 , R 44 , R 50 , R 53 Each independently selected from H, hydroxyl, C 1-6 Alkyl and C 1-6 Alkoxy; R 45 , R 46 , R 47 , R 48 , R 49 , R 51 , R 52 , R 54 , R 57 , R 59 , R 62 , R 63 , R 68 , R 71 , R 72 , R 73 , R 74 , R 75 Each independently selected from H, C 1-6 Alkyl and C 1-6 Haloalkyl; R 55 , R 56 , R 66 , R 67 Each independently selected from H, hydroxyl, -CN, C 1-6 Alkyl, -C(O)C 1-6 Alkyl, -C(O)C 2-6 Alkenyl, -C(O)C 2-6 Alkynyl, C 3-6 cycloalkyl and 3-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 The 3- to 6-membered cycloalkyl and heterocyclic groups are optionally substituted by halogen, hydroxyl, amino, -CN, N3, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino substitution; R 58 independently selected from halogen, C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, N3 substituent substitution; R 60 , R 61 Each independently selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more halogen, hydroxy, amino, C 1-6 Alkoxy, C 1-6 Alkylamino, N3 substituent substitution; R 64 are independently selected from halogen, amino and C 1-6 Alkylamino; R 65 Independently selected from halogen, N3, C 1-6 Alkyl and C 1-6 Haloalkyl; R 69 , R 70 are each independently selected from H, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -C(O)OC 1-6 Alkyl, -C(O)NH2, -C(O)NHC 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Haloalkyl is optionally substituted with hydroxyl and amino; or R 69 , R 70 Together with the attached boron and oxygen atoms, it forms a 5-10 membered heterocyclic group (e.g., a 5-6 membered heterocyclic group), wherein the heterocyclic group is optionally substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl and =O substituents substituted; L 1 , L 2 are each independently selected from O and N.

15. The compound according to any one of claims 13 to 14, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R a Selected from one or more R 3a Substituted phenyl, pyridine and pyridazine, wherein R 3a Each is independently selected from H, halogen, -N3, -NO2, -SCN, -S(F)5, -CH(O), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, -C(O)NR 43 R 44 、-C(O)NR 45 S(O)2NR 46 R 47 、-C(S)NR 48 R 49 、-C(=NR 50 )NR 51 R 52 、-C(=NR 53 )R 54 、-NR 55 R 56 、-NR 57 S(O)2R 58 、-NR 59 S(O)2NR 60 R 61 、-N=S(O)R 62 R 63 、-OS(O)2R 64 、-S(O)2R 65 、-S(O)2NR 66 R 67 、-Si(OR 68 )3. The C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, optionally substituted with one or more halogen, hydroxyl, -CN, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C(O)OR 71 、-C(O)NR 72 R 73 or two adjacent R a3 The carbon atom connected thereto forms a 5-6 membered heterocyclic group or a 5-10 membered heteroaromatic ring, wherein the 5-6 membered heterocyclic group or the 5-10 membered heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, amino, -CN, =O, C 1-6 Alkyl, -C 1-6 Alkyl NR 74 R 75 substituted by a substituent.

16. The compound according to any one of claims 13 to 15, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R a Selected from one or more R 3a Substituted phenyl, pyridine and pyridazine, wherein R 3a Each independently selected from H, F, N3, -SCN, N(H)CN, -S(O)2CHF2, -S(O)2CF3, SF5, -NO2, -S(O)2N(H)CN, -N=S(O)(CH3)2, -OS(O)2NH2, -NH(OH), -NHS(O)2NH2, -NHS(O)2CH2CH3, C(S)NH2, -S(O)2N3, -OS(O)2F, -NHS(O)2F, -S(O)2NH2, -CH(O), -C(O)NH(OH), Or two adjacent R a3 The carbon atom to which it is attached forms 17. The compound according to any one of claims 13 to 16, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R a Selected from one or more R 3a Replaced Where R 3a Each independently selected from Or, R a Selected from in, R a6 Each selected from H; Or, R a Selected from Y 1 , Y 2 , Y 3 , Y 4 Each independently selected from O, S, N, NR a1 and CR a2 If present, R a1 Each independently selected from -S(O)2-C 3-6 Cycloalkyl, -S(O)2-C 1-6 Haloalkyl; R a2 Each independently selected from C 1-6 alkyl; Or, R a Selected from R a1 Each is independently selected from -S(O)2-cyclopropyl; R a2 are each independently selected from methyl.

18. The compound according to any one of claims 13 to 17, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein R a Selected from:

19. The compound according to any one of claims 13 to 18 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein the compound is selected from:

20. The compound according to any one of claims 13 to 19 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, wherein the compound is selected from:

21. A pharmaceutical composition comprising a preventively and / or therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, and one or more pharmaceutically acceptable carriers.

22. Use of the compound according to any one of claims 1-20 or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph, or the pharmaceutical composition according to claim 21, in the preparation of a medicament for treating and / or alleviating NaV1.8-related diseases. Preferably, the NaV1.8-related diseases are pain, multiple sclerosis, Chuck-Mare-Dodds syndrome, incontinence, pathological cough or arrhythmia.

23. The compound according to any one of claims 1-20 or its pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph, or the pharmaceutical composition according to claim 21, for treating and / or alleviating NaV1.8-related diseases. Preferably, the NaV1.8-related diseases are pain, multiple sclerosis, Chuck-Marie-Dodds syndrome, incontinence, pathological cough or arrhythmia.

24. A method for treating and / or alleviating NaV1.8-related diseases, comprising administering to an individual a therapeutically effective amount of a compound according to any one of claims 1-20 or a pharmaceutically acceptable salt, stereoisomer, solvate, isotope-labeled compound or polymorph thereof, or a pharmaceutical composition according to claim 21. Preferably, the NaV1.8-related disease is pain, multiple sclerosis, Chuck-Mare-Dodds syndrome, incontinence, pathological cough or arrhythmia.

25. The use of claim 22 or 23 or the method of claim 24, wherein the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, ICU analgesia, fracture or postoperative pain (e.g., bunionectomy pain, hernia repair pain, and abdominoplasty pain), neuropathic pain (e.g., peripheral neuropathy, postherpetic neuralgia, peripheral neuropathy, small fiber neuropathy pain, trigeminal neuralgia, idiopathic small fiber neuralgia, or diabetic neuropathy), visceral pain (e.g., intestinal pain), musculoskeletal pain, primary pain, idiopathic pain, osteoarthritis pain, gouty arthritis pain, rheumatic or rheumatoid arthritis pain, toothache, joint pain, labor pain, fibromyalgia, chronic low back pain, bladder pain syndrome, sciatica; Preferably, the pain is selected from postoperative pain, neuropathic pain (eg, postherpetic neuralgia, small fiber neuropathy pain, diabetic neuropathy), osteoarthritis pain, bladder pain syndrome, cancer pain.

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