Voltage-gated sodium channel inhibitor, pharmaceutical composition containing same and use thereof

Abstract

The present invention relates to a voltage-gated sodium channel inhibitor having a structure of formula (A), particularly formula (I) or formula (I'), a pharmaceutical composition containing same, and the use thereof.

Description

Voltage-gated sodium channel inhibitors, pharmaceutical compositions comprising them, and their uses Technical Field

[0001] This invention relates to voltage-gated sodium channel inhibitors, pharmaceutical compositions comprising the same, and their use for the prevention or treatment of diseases or conditions. Background Technology

[0002] The International Association for the Study of Pain (ISAP) defines pain as "an unpleasant sensory and emotional experience, often accompanied by actual or potential tissue damage." Pain is both a complex sensation and a warning signal, alerting healthy animals to avoid tissue damage and preventing further injury. Pain is also a common clinical symptom; after the external stimulus that triggered the pain disappears, intense or persistent pain can cause physiological dysfunction, severely impacting the quality of life of living organisms.

[0003] Pain originates from nociceptors in the peripheral nervous system, which are widely distributed throughout the skin, muscles, joints, and internal organs. These receptors convert perceived thermal, mechanical, or chemical stimuli into nerve impulses (action potentials), which are then transmitted via afferent nerve fibers to the cell bodies of the dorsal root ganglia (DRGs), ultimately reaching higher nerve centers and causing pain sensation. The generation and conduction of action potentials in neurons depend on voltage-gated sodium channels (VGSCs) on the cell membrane. When the cell membrane depolarizes, sodium channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity can help treat and alleviate pain.

[0004] Voltage-gated sodium ion channels (Na V It is widely present on the cell membranes of excitable cells such as neurons and skeletal muscle cells. It is a type of transmembrane glycoprotein complex, including 9 isoforms, named Na+. V 1,1-Na V 1.9. The nine isotypes have different tissue localizations. Na V 1.4 is a primary sodium channel in skeletal muscle, and Na V 1.5 is a primary sodium channel in cardiomyocytes. V 1.7, 1.8, and 1.9 are primarily located in the peripheral nervous system, while Na... V1.1, 1.2, 1.3, and 1.6 are neuronal channels found in the central and peripheral nervous systems. The nine isotypes are similar but different in the details of their voltage-dependent and kinetic behaviors (Catterall, WA, Goldin, AL, and Waxman, SG, International Union of Pharmacology. XL VII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57(4), p. 397 (2005).

[0005] Na v 1.8 is a highly selective target for pain treatment. It has been shown to act as a carrier of sodium currents, maintaining the action potential firing of neurons in the small dorsal root ganglion, and also participating in the spontaneous emission of electrical signals in damaged neurons, such as driving neuropathic pain. Currently reported sodium... v 1.8 Small molecule inhibitors include PF-01247324, A-803467, PF-06305591, VX-150, HRS-4800, JMKX-000623, HBW-004, and VX-548. PF-01247324, A-803467, and PF-06305591 suffer from poor selectivity, poor pharmacokinetic properties, and low bioavailability. Summary of the Invention

[0006] This invention provides a sodium channel (Na) for use as a voltage-gated channel. V Inhibitor compounds, especially Na V 1.8 Inhibitor, which has an effect on Na V 1.8 It exhibits excellent inhibitory activity and can be used to inhibit voltage-gated sodium channels, especially Na+, in biological samples or individuals. V 1.8, or used to treat, prevent, or alleviate voltage-gated sodium channels, especially Na+. V 1.8 Related diseases or symptoms.

[0007] The compounds of the present invention may also have voltage-gated sodium channel selectivity (e.g., for Na+). V1.8). The compounds of the application, e.g., the Example compounds, have superior pharmacokinetic properties. Surprisingly, the compounds of the application, e.g., some of the Example compounds, have improved pharmacokinetic properties (e.g., improved blood levels, exposure, bioavailability, half-life, and / or duration of action) compared to some prior art compounds. Thus, the compounds of the application, e.g., some of the Example compounds, are expected to have better in vivo therapeutic efficacy. The compounds of the application have been shown to have superior pharmacodynamic properties, exhibiting significant, rapid (onset times as short as about 0.5 hour) and long lasting (e.g., up to about 4-6 hours) in vivo analgesic efficacy. Also surprisingly, the compounds of the application, e.g., some of the Example compounds, exhibit comparable in vivo analgesic efficacy at lower doses and stronger in vivo analgesic efficacy (e.g., in terms of onset speed, peak intensity, and duration of action) at the same doses compared to some prior art compounds. The compounds of the application can also have better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved safety (lower toxicity and / or fewer side effects, wider therapeutic window), and other superior properties.

[0008] One aspect of the application provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of Formula (A):

[0009] wherein:

[0010] W is O, S, or NH;

[0011] Ring A is phenyl, 6-membered heteroaryl, or a saturated or partially unsaturated 6-membered carbocyclic or heterocyclic ring,

[0012] Ring B is 5-membered heteroaryl, or a saturated or partially unsaturated 5-membered carbocyclic or heterocyclic ring,

[0013] said Ring A and said Ring B are fused via sharing adjacent ring atoms X 2 and X 5 to form a fused bicyclic ring;

[0014] represents a single or double bond;

[0015] X 2 and X 5 are each independently selected from C, CH, and N, and no more than one of X 2 and X 5 is N;

[0016] R 1It is H, –OH, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio, –NR 13 -C 1-6 Alkyl, –NR 13 -C 1-6 Halogenated alkyl, –L 1 –(C 1-6 (alkylene)–OR 15 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–OR 15 –L 1 –(C 2-6 (alkenyl)–OR 15 –L 1 –(by one or more R) 15 'Replacement of C' 2-6 (alkenyl)–OR 15 –L 1 –(C 1-6 (alkylene)–SR 15 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–SR 15 –L 1 –(C 2-6 (alkenyl)–SR 15 –L 1 –(by one or more R) 15 'Replacement of C' 2-6 (alkenyl)–SR 15 –L 1 –(C 1-6 (alkylene)–NR 13 R 14 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–NR 13 R 14 –L 1 –(C 1-6 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 ;

[0017] R 2 and R 3 Each is independently H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0018] R 4 and R 5 Each is independently H, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0019] n is 0, 1, 2, or 3;

[0020] Each R a Independently, it is hydrogen, halogen, CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -S (=O) m -R 11 R 12 -C(=O)-NR 13 R 14 -C(=S)-R 11 R 12 -N(NR) 13 R 14 ) m -P (=O) m -R 11 R 12 -C(=N)-NR 13 R 14 -S(=O)2-NR 13 R 14 -C 1-6 Alkylene-R 11 R 12 、or -S(=O)(=NR) 11 )R 12 ;

[0021] m is 0, 1, or 2;

[0022] R 6 R 7 R 8 and R 9 H and C are independent of each other. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl;

[0023] L 1 Is it a key, O, or S?

[0024] L2 Is it a key or C? 1-6 Alkylene;

[0025] R 10 It is C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, 5 or 6 membered heteroaryl, –C(O)O(C 1-6 Alkyl), –COOH or –C(O)NR 17 R 18 Wherein C 3-6 Cycloalkyl, 3-7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl groups are optionally bonded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0026] R 11 and R 12 Each time it appears, it is independently selected from hydrogen, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkyl group, 3-7 membered carbon ring, or 3-7 membered heterocycle, wherein the 3-7 membered carbon ring or 3-7 membered heterocycle is optionally surrounded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0027] R 13 R 14 R 17 and R 18 Each time it appears, it is independently H, –OH, or C. 1-6 Alkyl or 3-7 membered heterocyclic alkyl, or R attached to the same N. 13 and R 14 Optionally, they can be linked to form a 3-7 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-7 membered heterocyclic alkyl group, or the 5 or 6 membered heteroaryl group, is optionally bonded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0028] R 15 Each time it appears, it is independently H or C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0029] Each R 15'Independently halogen, CN, -OH, -SH, -NR 13 R 14 C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; and

[0030] The C mentioned above 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 1-6 Alkylene and C 2-6 Any one or more of the alkenyl groups, either alone or as part of a substituent, may optionally be substituted with one or more deuterium (D).

[0031] In some embodiments, the compound of formula (A) has the structure of formula (I):

[0032] In some embodiments, the compound of formula (A) has the structure of formula (I'):

[0033] Another aspect of the invention provides a pharmaceutical composition comprising a preventatively or therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, and one or more pharmaceutically acceptable carriers. The pharmaceutical composition optionally comprises one or more additional therapeutic agents. The pharmaceutical composition is preferably a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0034] Another aspect of the invention provides the use of the compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs of the invention, or pharmaceutical compositions of the invention, in the preparation of a medicament used as a voltage-gated sodium channel inhibitor.

[0035] Another aspect of the invention provides compounds of the invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs of the invention, or pharmaceutical compositions of the invention, which are used as voltage-gated sodium channel inhibitors.

[0036] Another aspect of the invention provides a method for treating, preventing, or alleviating voltage-gated sodium channel-related diseases or conditions, the method comprising administering to an individual in need an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or pharmaceutical composition of the invention.

[0037] The voltage-gated sodium channel is preferably Na. V 1.8. The voltage-gated sodium channel-related diseases or conditions include, but are not limited to, pain (e.g., acute or chronic pain). Detailed Implementation

[0038] definition

[0039] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0040] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps (i.e., these terms also cover the terms “consistently made up of” and “comprises of”).

[0041] As used herein, the term "alkyl" refers to a straight-chain or branched monovalent saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example, 1 to 6 (e.g., 1, 2, 3, 4, 5, or 6) carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a straight-chain or branched group with 1 to 6 carbon atoms, including "C". 2-6 Alkyl", C 2-5 "alkyl" and "C" 1-4 Alkyl group. "C" 1-6 Examples of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. The term "C" 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl). The term "C"... 1-3 "Alkyl" refers to a straight-chain or branched aliphatic hydrocarbon chain with 1 to 3 carbon atoms (i.e., methyl, ethyl, n-propyl, or isopropyl).

[0042] As used herein, the term "alkylene" refers to a group obtained by further losing one hydrogen atom from an "alkyl" group as defined above. In some embodiments, the alkylene group has 1 to 12 carbon atoms, preferably 1, 2, 3, 4, 5, or 6 carbon atoms. For example, "C 1-6 Alkylene, C 2-6 Alkylene, C 2-5 "alkylene" and "C" 1-4 Alkylene. "C" 1-6 Examples of "alkylene" include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, and n-hexylene. The term "C" 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms.

[0043] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms, as defined herein. The term "C" 1-6 "Halogenated alkyl" and "C" 1-4 "Halogenated alkyl" refers to alkyl halogens having 1 to 6 carbon atoms and 1 to 4 carbon atoms, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl or -CH2CH2CF3, etc.

[0044] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein the alkyl group is as defined above. Alkoxy groups may optionally be substituted with one or more (such as 1 to 3) identical or different halogen atoms (i.e., "haloalkoxy").

[0045] As used herein, the term "alkathio" refers to a -S-alkyl group, wherein the alkyl group is as defined above. An alkathio group may optionally be substituted with one or more (such as 1 to 3) identical or different halogen atoms (i.e., "haloalkathio").

[0046] As used herein, the term “halogenated” or “halogenated” is defined as including F, Cl, Br or I.

[0047] As used herein, the term "alkenyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more double bonds. In some embodiments, the alkenyl group has 2, 3, 4, 5, or 6 carbon atoms ("C60"). 2-6 "Alkenyl", for example "C 2-4The alkenyl group is, for example, -CH=CH2, -CH2CH=CH2, -C(CH3)=CH2, -CH2-CH=CH-CH3, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the present invention contain an alkenyl group, the compounds may exist in pure E (iso-side), pure Z (iso-side), or any mixture thereof. The term "alkenyl" refers to the corresponding divalent group, including, for example, "C..." 2-6 "Ideinyl", "C" 2-4 "Alkenyl", etc., specific examples of which include, but are not limited to: -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, butenyl, pentenyl, hexenyl, cyclopentenyl, cyclohexenyl, etc.

[0048] As used herein, the term "alkynyl" refers to a straight-chain or branched monovalent aliphatic hydrocarbon group containing one or more triple bonds. In some embodiments, the alkynyl group has 2, 3, 4, 5, or 6 carbon atoms ("C60"). 2-6 "Alkyne group", for example "C 2-4 The term "alkynyl" refers to the corresponding divalent group, including, for example, -C≡CH, -CH2C≡CH, -C≡C-CH3, -CH2-C≡C-CH3, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 3-methyl-2-butynyl, and 2-methyl-3-pentynyl. The term "alkynyl" refers to the corresponding divalent group, including, for example, "C≡CH". 2-6 "Isynyne", "C" 2-4 "Immyneyl", etc., specific examples of which include, but are not limited to: -C≡C-, -CH2C≡C-, -C≡C-CH2-, -CH2-C≡C-CH2-, imyneylyl, imyneylyl, etc.

[0049] As used herein, the terms “carbocyclic” and “carbocyclic group” refer to a ring or ring system in which all ring members are carbon atoms, and said ring or ring system may be saturated (“cycloalkyl”), partially unsaturated (e.g., having one or more double bonds within the ring, i.e., “cycloalkenyl”), or aromatic (“aryl”). A carbocyclic ring has, for example, 3 to 10 (suitably 3 to 8, 3 to 7, 3 to 6, 4 to 6, or 5 to 6) cyclic carbon atoms.

[0050] As used herein, the terms “cycloalkylene group,” “cycloalkylene group,” and “hydrocarbon ring” refer to a saturated (i.e., “cycloalkylene group” and “cycloalkylene group”) or unsaturated (i.e., having one or more double and / or triple bonds within the ring) monocyclic or polycyclic (including spirocyclic, fused, or bridged systems) hydrocarbon ring having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) cyclic carbon atoms, including but not limited to (cycloalkylene group), cyclopropyl (ring), (cycloalkylene group), (cycloalkylene group), cyclopentyl (ring), (cyclohexyl (ring), (cycloalkylene group), (cycloheptyl (ring), (cycloalkylene group), (cyclooctyl (ring), (cycloalkylene group), (cyclohexenyl (ring), etc.

[0051] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.)) which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 10 carbon atoms. For example, the term "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 6 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0052] As used herein, the terms "cycloalkenyl" and "cycloalkenylidene" refer to a monocyclic or polycyclic (such as bicyclic) fused hydrocarbon ring having one or more double bonds within the ring (e.g., monocyclic, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cyclooctenyl, cyclononenyl, or bicyclic). The cycloalkenyl and "cycloalkenylidene" have 3 to 10 carbon atoms, suitably 3 to 8, for example 3 to 7, 3 to 6, 4 to 6, or 5 to 6.

[0053] As used herein, the terms “heterocyclic group,” “heterocycle,” and “hybrid heterocyclic group” refer to a monocyclic or bicyclic cyclic structure having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S, and the remaining ring atoms are saturated (i.e., “heterocyclic alkyl” and “hybrid heterocyclic alkyl”) or partially unsaturated (e.g., having one or more double bonds within the ring, i.e., “heterocyclic alkenyl” and “hybrid alkenyl”)) C. For example, “3-10 membered (hybrid)heterocyclic group” is a saturated or partially unsaturated (hybrid)heterocyclic group having 2 to 9 (e.g., 2, 3, 4, 5, 6, 7, 8, or 9) ring carbon atoms and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, and S. The heterocycle can be attached to the rest of the molecule by any of the carbon atoms or a nitrogen atom (if present). Specifically, 3-10 membered heterocycles are groups having 3-10 (e.g., 3-8, 3-7, 3-6, 4-9, 4-7, 4-6, 5-6, or 6-7) carbon atoms and heteroatoms in the ring. Examples of heterocyclic groups and heterocyclic groups include, but are not limited to: (heterocyclic)epoxyalkyl, (heterocyclic)aziridinyl, (heterocyclic)azetidinyl, (heterocyclic)oxetanyl, (heterocyclic)tetrahydrofuranyl, (heterocyclic)dioxolinyl, (heterocyclic)pyrrolylyl, (heterocyclic)pyrrolidone, (heterocyclic)imidazylyl, (heterocyclic)pyrrolinyl, (heterocyclic)tetrahydropyranyl, (heterocyclic)piperidinyl, (heterocyclic)morpholinyl, (heterocyclic)dithianyl, (heterocyclic)thiomorpholinyl, (heterocyclic)piperazinyl, or (heterocyclic)trithianyl. The groups also encompass bicyclic systems, including spirocyclic, fused, or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.). The heterocyclic and heterocyclic groups may optionally be substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0054] As used herein, the term “nitrogen-containing heterocycle” refers to a saturated or partially unsaturated monocyclic or bicyclic group having, for example, 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and at least one nitrogen atom in the ring, and optionally may also contain one or more (e.g., one, two, three, or four) additional heteroatoms selected from N, O, and S as ring members.

[0055] As used herein, the term "5-membered nitrogen-containing heterocyclic alkenyl" refers to a partially unsaturated monocyclic heterocycle having five ring atoms, containing at least one nitrogen atom in the ring, and having one or two double bonds in the ring, said double bonds being either carbon-carbon double bonds (C=C) or carbon-nitrogen double bonds (C=N). The 5-membered nitrogen-containing heterocyclic alkenyl may optionally also contain one, two, or three additional heteroatoms selected from N, O, and S.

[0056] As used in this article, the term "aromatic" refers to a ring structure having a conjugated π-electron system.

[0057] As used herein, the terms “(aryl)aryl” and “aromatic ring” refer to all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated π-electron system. For example, as used herein, the term “C…” 6-10 (Asyl) aryl" and "C 6-10 "Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or ()naphthyl (naphthalene ring). The ()aryl and aromatic rings are optionally substituented with one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted. (Aromatic) aryl and aromatic rings are optionally substituted with another ring (e.g., C10). 3-10 Fused groups (hydrocarbon rings, 3-10 membered heterocycles, or 5-14 membered heteroaromatic rings), the fused groups being, for example,...

[0058] As used herein, the terms “(sub)heteroaryl” and “heteroary ring” refer to monocyclic, bicyclic, or tricyclic aromatic ring systems having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, the "(hybrid)aryl" or "heteroary ring" is selected from (thiopheneyl), (furanyl), (pyrrolyl), (oxazolyl), (thiazolyl), (imidazolyl), (pyrazolyl), (imidazolyl), (pyrazolyl), (isooxazolyl), (isothiazolyl), (oxadiazolyl), (triazolyl), (thiazolyl), etc., and their benzo[derivatives], such as benzopyrazole (indazole); or (pyridyl), (pyridazinyl), (pyrimidinyl), (pyrazinyl), (triazinyl), etc., and their benzo[derivatives], such as benzopyrazole (indazole); or (pyridinyl), (pyridazinyl), (pyridinyl), (pyrazinyl), (triazinyl), etc., and their benzo[derivatives]. The "(hybrid)aryl" and "heteroary ring" may also optionally be combined with another ring (e.g., C14). 3-10 Hydrocarbon rings, 3-10 membered heterocycles, C 6-10 Fused aromatic rings (or 5-14 membered heteroaromatic rings), the fused groups being, for example, As an example, the "(hybrid)aryl" and "heteroary ring" can be fused with pyridine (pyridofused), such as pyridotriazole.

[0059] As used in this article, the term "fusion" means that two or more ring structures share two adjacent atoms with each other.

[0060] The term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0061] If a substituent is described as “optionally substituted,” then the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the carbon (to the extent that any hydrogens are present) may be substituted individually and / or together with independently selected optional substituents. If the nitrogen of the substituent is described as being optionally substituted with one or more of the substituents in the list, then one or more hydrogens on the nitrogen (to the extent that any hydrogens are present) may each be substituted with independently selected optional substituents.

[0062] If a substituent is described as being “independently selected” from a group, then each substituent is selected independently of the others. Therefore, each substituent may be the same as or different from another (other) substituent.

[0063] As used herein, the term "one or more" means one or more under reasonable conditions, such as two, three, four, five, or ten.

[0064] Unless otherwise specified, as used herein, the connection point of a substituent may be derived from any suitable location of the substituent.

[0065] When the bond of a substituent is such that it passes through the ring and connects two atoms, then such a substituent can be bonded to any cyclic atom in the substituted ring.

[0066] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., deuterium). 2 H), tritium ( 3 H); carbon isotopes (e.g., H); 11 C 13 C and14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125 I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes ... 32 P); and isotopes of sulfur (e.g. 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0067] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, racemic mixtures, single enantiomers, diastereomer mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of 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-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application covers all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0068] Solid lines may be used in this article. solid wedge Or virtual wedge The chemical bonds of the compounds of the present invention are depicted. Solid lines are used to depict bonds to asymmetric carbon atoms to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) at that carbon atom. Solid or dashed wedges are used to depict bonds to asymmetric carbon atoms to indicate the presence of the indicated stereoisomers. When present in racemic mixtures, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and may consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0069] When the substituent bond is shown as a bond that passes through the ring and connects two atoms (“floating bond”), such a substituent can be bonded to any substituted cyclic atom in the ring, unless otherwise stated. In cases where a substituted hydrogen atom is shown to be carried by a substituted ring member, when the floating bond is bonded to that substituted ring member, the substituted hydrogen atom is substantially substituted (i.e., not present). As an example, in the structure of formula (I) described above:

[0070] When n is not 0, each substituent R a It can independently bond to any substituted cyclic atom in ring A or ring B. As another example, in the formula described below... Part of (where, for example, X) 4 For CH and X 7 In N), substituents Can be linked to containing X 1 and X 6 A 6-membered ring, or containing X 4 and X 7 Any substituted cyclic atom in the 5-membered ring; for example, when the substituent Key to X 4 When the ring C atom is at the position, it acts as X in CH. 4 The H in the equation has been essentially replaced (i.e., it does not exist).

[0071] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0072] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0073] Pharmaceutically acceptable salts of the compounds of the present invention include their acid addition salts and base addition salts.

[0074] As used herein, the term "ester" means an ester derived from the various general formula compounds of this application, including physiologically hydrolyzable esters (the compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). The compounds of the present invention may themselves also be esters.

[0075] The compounds of the present invention can exist as solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent, particularly, for example, water, methanol, or ethanol, as a structural element of the lattice of the compound. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric.

[0076] Those skilled in the art will understand that not all nitrogen-containing heterocycles can form N-oxides because nitrogen requires available lone pairs of electrons to be oxidized into oxides; those skilled in the art will identify nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including the oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl peroxides such as tert-butyl peroxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see, for example: T.L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp. 748-750; A.R. Katritzky and A.J. Boulton, Eds., Academic Press; and G.W. H. Heeseman and E.S. G. Wierstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp. 390-392, A.R. Katritzky and A.J. Boulton, Eds., Academic Press.

[0077] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0078] This invention further includes, within its scope, prodrugs of the compounds of this invention, which are certain derivatives of the compounds of this invention that may themselves have little or no pharmacological activity, and which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of this invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that are readily converted in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). The prodrugs of this invention can be prepared, for example, by replacing suitable functional groups present in the compounds of this invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0079] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in T.W. Greene & P. ​​G. W. M. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0080] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0081] compound

[0082] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein said compound has the structure of formula (A):

[0083] in:

[0084] W represents O, S, or NH;

[0085] Ring A is a phenyl group, a 6-membered heteroaryl group, or a saturated or partially unsaturated 6-membered carbon ring or heterocycle.

[0086] Ring B is a 5-membered heteroaryl group, or a saturated or partially unsaturated 5-membered carbon ring or heterocycle.

[0087] Ring A and ring B share adjacent ring atoms X. 2 and X 5 This forms a fused double ring;

[0088] Indicates a single bond or a double bond;

[0089] Given the allowable valence, X 2 and X 5 Each is independently selected from C, CH, and N, and X 2 and X 5 At most one of them is N;

[0090] R 1 It is H, –OH, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio, –NR 13 -C 1-6 Alkyl, –NR 13 -C 1-6 Halogenated alkyl, –L 1 –(C 1-6 (alkylene)–OR 15 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–OR 15 –L 1 –(C 2-6 (alkenyl)–OR 15 –L 1 –(by one or more R) 15 'Replacement of C'2-6 (alkenyl)–OR 15 –L 1 –(C 1-6 (alkylene)–SR 15 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–SR 15 –L 1 –(C 2-6 (alkenyl)–SR 15 –L 1 –(by one or more R) 15 'Replacement of C' 2-6 (alkenyl)–SR 15 –L 1 –(C 1-6 (alkylene)–NR 13 R 14 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–NR 13 R 14 –L 1 –(C 1-6 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 ;

[0091] R 2 and R 3 Each is independently H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0092] R 4 and R 5 Each is independently H, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0093] n is 0, 1, 2, or 3;

[0094] Each R a Independently, it is hydrogen, halogen, CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -S (=O) m -R 11 R 12 -C(=O)-NR 13 R14 -C(=S)-R 11 R 12 -N(NR) 13 R 14 ) m -P (=O) m -R 11 R 12 -C(=N)-NR 13 R 14 -S(=O)2-NR 13 R 14 -C 1-6 Alkylene-R 11 R 12 、or -S(=O)(=NR) 11 )R 12 ;

[0095] m is 0, 1, or 2;

[0096] R 6 R 7 R 8 and R 9 H and C are independent of each other. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl;

[0097] L 1 Is it a key, O, or S?

[0098] L 2 Is it a key or C? 1-6 Alkylene;

[0099] R 10 It is C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, 5 or 6 membered heteroaryl, –C(O)O(C 1-6 Alkyl), –COOH or –C(O)NR 17 R 18 Wherein C 3-6 Cycloalkyl, 3-7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl groups are optionally bonded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0100] R 11 and R 12 Each time it appears, it is independently selected from hydrogen, OH, NH2, and C. 1-6 Alkyl, C 1-6Alkyl group, 3-7 membered carbon ring, or 3-7 membered heterocycle, wherein the 3-7 membered carbon ring or 3-7 membered heterocycle is optionally surrounded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0101] R 13 R 14 R 17 and R 18 Each time it appears, it is independently H, –OH, or C. 1-6 Alkyl or 3-7 membered heterocyclic alkyl, or R attached to the same N. 13 and R 14 Optionally, they can be linked to form a 3-7 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-7 membered heterocyclic alkyl group, or the 5 or 6 membered heteroaryl group, is optionally bonded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups;

[0102] R 15 Each time it appears, it is independently H or C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups;

[0103] Each R 15 'Independently halogen, CN, -OH, -SH, -NR 13 R 14 C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; and...

[0104] The C mentioned above 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 1-6 Alkylene and C 2-6 Any one or more of the alkenyl groups, either alone or as part of a substituent, may optionally be substituted with one or more deuterium (D).

[0105] In some embodiments, the present invention provides a compound of formula (A) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (I), or the compound has the structure of formula (I'):

[0106] In some embodiments, the present invention provides compounds of formula (A), including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 1 It is H, –OH, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio, –NR 13 -C 1-6 Alkyl, –NR 13 -C 1-6 Halogenated alkyl, –L 1 –(C 1-6 (alkylene)–OR 15 –L 1 –(C 2-6 (alkenyl)–OR 15 –L 1 –(C 1-6 (alkylene)–SR 15 –L 1 –(C 2-6 (alkenyl)–SR 15 –L 1 –(C 1-6 (alkylene)–NR 13 R 14 –L 1 –(C 1-6 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 .

[0107] In some embodiments, the compound of formula (I) has the structure of formula (IIA), formula (IIB), or formula (IIC):

[0108] In some embodiments, the compound of formula (I') has the structure of formula (II'A), formula (II'B), or formula (II'C):

[0109] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 4 Is it H or C? 1-4 Alkyl group. In a preferred embodiment, R 4 It is H, methyl, ethyl or isopropyl, more preferably H.

[0110] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 5 Is it H or C? 1-4 Alkyl group. In a preferred embodiment, R 5 It is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, more preferably H, methyl, ethyl, isopropyl or tert-butyl, and even more preferably H or methyl.

[0111] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein... The functional groups are -NH2 and -NH(C). 1-4 alkyl), or -N(C) 1-4 Alkyl)2, preferably -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH3)(CH2CH3), or -N(CH2CH3)2, more preferably -NH2.

[0112] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 13 and R 14 Each time it appears, it is independently H or C. 1-4Alkyl or 3-6 membered heterocyclic alkyl, or R attached to the same N. 13 and R 14 Optionally, they can be linked to form 3-6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups, wherein the 3- or 6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups, are optionally bonded by one or more halogens, –OH groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution. In a preferred embodiment, R... 13 and R 14 Each time it appears, it is independently either H or C. 1-4 Alkyl, more preferably H, methyl or ethyl.

[0113] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 11 and R 12 Each time it appears, it is independently selected from hydrogen, OH, NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl is optionally reacted with one or more halogens, –OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution. In a preferred embodiment, R... 11 and R 12 Each time it appears, it is independently selected from hydrogen, OH, NH2, and C. 1-4 Alkyl, or C 1-4 Alkyl group.

[0114] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein each R a Independently, it is hydrogen, halogen, CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Haloalkoxy group. In a preferred embodiment, each R aIndependently, it is H, F, Cl, Br, I, or C 1-4 Alkyl, more preferably H, F, Cl, methyl, ethyl, isopropyl or tert-butyl, and even more preferably H, F or Cl.

[0115] In some implementations, each R a It can be independently linked to any substituted cyclic atom in ring A. In some embodiments, each R a It is independently attached to any substituted cyclic atom in ring A.

[0116] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein n is 0; in other embodiments, n is 1; and in still other embodiments, n is 2.

[0117] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein ring A is cyclohexyl, a C6-cycloalkenyl having one or two double bonds, a 6-membered heterocyclic alkyl, a 6-membered heterocyclic alkenyl having one or two double bonds, a phenyl, or a 6-membered heteroaryl. In a preferred embodiment, ring A is phenyl or a 6-membered heteroaryl.

[0118] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein ring B is cyclopentyl, a C5-cycloalkenyl having one or two double bonds, a 5-membered heterocyclic alkyl, a 5-membered heterocyclic alkenyl having one or two double bonds, or a 5-membered heteroaryl. In a preferred embodiment, ring B is a C5-cycloalkenyl having one or two double bonds, a 5-membered heterocyclic alkenyl having one or two double bonds, or a 5-membered heteroaryl.

[0119] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein ring A is phenyl or a 6-membered heteroaryl, and ring B is a C5-cycloalkenyl having one or two double bonds, a 5-membered nitrogen-containing heterocyclic alkenyl having one or two double bonds, or a 5-membered heteroaryl.

[0120] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein... A portion can be connected to the rest of the molecule via ring atoms of ring A. In a preferred embodiment, the... Part of the ring is connected to the rest of the molecule through the ring atoms of ring A.

[0121] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein... The group can be attached to the carbon ring atom of said ring B. In a preferred embodiment, the... The group is attached to the carbon ring atom of the ring B.

[0122] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein:

[0123] The Part of the structure is of formula (Cy1):

[0124] in:

[0125] The ring A is a phenyl or a 6-membered heteroaryl group.

[0126] This indicates that the indicated ring is aromatic;

[0127] This indicates that the indicated ring is aromatic or partially unsaturated;

[0128] X 1 X 2 X 5 X 6 X 8 and X 9 Each is independently selected from CH and N;

[0129] X 3 X 4 and X7 Each is independently selected from CH, CH2, O, S, N, and NR. 16 ;

[0130] R 16 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl or 3-7 membered heterocycloalkyl;

[0131] The conditions are:

[0132] (1) Given the allowable valence, X 1 X 2 X 5 X 6 X 8 and X 9 At most three atoms are selected from N, and there are no three consecutive N ring atoms in ring B; and

[0133] (2) Where the valence is permissible, X 2 X 3 X 4 X 5 and X 7 There are at most four atoms selected from N and NH, and at most two atoms selected from O and S, and there are no two adjacent O ring atoms, two adjacent S ring atoms, or adjacent O and S ring atoms in the ring C.

[0134] In some such implementations, R 16 H or C is preferred. 1-4 Alkyl, more preferably H, methyl, ethyl, isopropyl or tert-butyl, and even more preferably H or methyl.

[0135] When the When the group is attached to the carbon ring atom of ring B, X 3 X 4 and X 7 At least one of them is CH or CH2, and is related to the above. connect.

[0136] In some preferred embodiments, part of formula (Cy1) has the structure of formula (Cy2):

[0137] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein X 1 Let N be the number of elements, and X be the number of elements.6 For N; in other implementations, X 1 It is CH, and X 6 For N; in some other preferred embodiments, X 1 and X 6 Each is CH; in some other preferred embodiments, X 1 Let N be the number of elements, and X be the number of elements. 6 For CH.

[0138] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein X 2 and X 5 Each is designated C; in other implementations, X 2 Let C be the integer, and X be the integrity. 5 For N; in other implementations, X 2 Let N be the number of elements, and X be the number of elements. 5 The answer is C.

[0139] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy2) has the structure of formula (Cy3A):

[0140] in:

[0141] X 3 X 4 and X 7 Each is independently selected from CH, N, and NR. 16 O and S, and in X 3 X 4 and X 7 In the middle, at most two are N or NR. 16 And at least one of them is CH; or in X 3 X 4 and X 7 Among them, there is one and only one that is NR. 16 O or S. In a preferred embodiment, X 3 X 4 and X 7 At least one of them is CH.

[0142] In some implementations, in the structure of formula (Cy3A), X 3X 4 and X 7 Each is independently selected from CH, N, and NR. 16 O and S, and in X 3 X 4 and X 7 In the middle, at most two are N or NR. 16 And at least one of them is CH. In a preferred embodiment, in X 3 X 4 and X 7 In the given information, at most two values ​​are N, and at least one value is CH. In the preferred embodiment, X... 3 and X 4 Each is N, and X 7 For CH. In the preferred embodiment, X 3 It is CH, and X 4 and X 7 Each is N.

[0143] In some implementations, in the structure of formula (Cy3A), X 3 X 4 and X 7 Each is independently selected from CH, N, and NR. 16 O and S, and in X 3 X 4 and X 7 Among them, there is one and only one that is NR. 16 O or S. In a preferred embodiment, X 3 X 4 and X 7 At least one of them is CH.

[0144] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy2) has the structure of formula (Cy3B):

[0145] in:

[0146] Indicates a single or double bond, and the two bonds in ring B. At most one of them is a double bond; and

[0147] Given the allowable valence, X 3 X 4 and X 7 Each is independently selected from CH, CH2, O, S, N, and NR.16 And in X 3 X 4 and X 7 In the middle, at most two are N or NR. 16 There are at most two Os or Ss. In the preferred embodiment, X 3 X 4 and X 7 At least one of them is CH or CH2.

[0148] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy3A) has the structure of formula (Cy4):

[0149] Where: X 3 It is NR 16 O or S; X 4 It is CH or N; and X 7 It can be CH or N.

[0150] In some such implementations, preferably, X 1 It is CH and X 6 It is CH. In some other preferred embodiments, X 1 It is N and X 6 It is CH.

[0151] In some preferred embodiments, part of formula (Cy4) is More

[0152] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (IIIA), formula (IIIA'), formula (IIIB), (IIIB'), formula (IIIC) or formula (IIIC'):

[0153] The compounds of formula (I') have the structures of formula (III'A), (III'A'), (III'B), (III'B'), (III'C), or (III'C'):

[0154] In some such implementations, the formula The preferred part is:

[0155] In a more preferred embodiment, formula The part is:

[0156] In some such implementations, preferably, formula The part is:

[0157] In a more preferred embodiment, formula The part is:

[0158] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (IVA), formula (IVB), or formula (IVC):

[0159] The compounds of formula (I') have the structure of formula (IV'A), formula (IV'B), or formula (IV'C):

[0160] In some such implementations, preferably, formula The part is:

[0161] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the structure of formula (Cy3A) is the same as that of formula (Cy5):

[0162] Where: X 3 It is CH or N; X 4 It is CH or N; and X 7 For NR 16 O or S. In a preferred embodiment, X 3 and X 4 At least one of them is CH.

[0163] In some such implementations, preferably, X 1 It is CH and X 6 It is CH. In some other preferred embodiments, X 1 It is N and X 6 It is CH.

[0164] In some preferred embodiments, part of formula (Cy5) is More

[0165] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (VA), formula (VA'), formula (VB), (VB'), formula (VC), or formula (VC'):

[0166] The compound of formula (I') has the structure of formula (V'A), formula (V'A'), formula (V'B), (V'B'), formula (V'C), or formula (V'C'):

[0167] In some such implementations, the formula A preferred portion is:

[0168] In a more preferred embodiment, formula The part is:

[0169] In some such implementations, the formula The preferred part is

[0170] In some preferred embodiments, the compounds of formula (I) according to the invention have the structures of formula (VIA), formula (VIA'), formula (VIB), (VIB'), formula (VIC), or formula (VIC'):

[0171] The compounds of formula (I') have the structures of formula (VI'A), formula (VI'A'), formula (VI'B), (VI'B'), formula (VI'C), or formula (VI'C'):

[0172] In such implementations, X 1 It is CH or N. In some implementations, X 1 It is CH. In some other implementations, X 1 It is N.

[0173] In some such implementations, the formula The preferred part is

[0174] In a more preferred embodiment, formula Part of

[0175] In some such implementations, the formula The preferred part is

[0176] In a more preferred embodiment, formula Part of

[0177] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (VD), formula (VE), or formula (VF):

[0178] The compounds of formula (I') have the structures of formula (V'D), formula (V'E), or formula (V'F):

[0179] In some such implementations, the formula The preferred part is:

[0180] In a more preferred embodiment, formula The part is:

[0181] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy3A) has the structure of formula (Cy6):

[0182] Where: X 3 It is CH or N; X 4 For NR 16 O or S; and X 7 It is CH or N. In the preferred embodiment, X 3 and X 7 At least one of them is CH.

[0183] In some such implementations, preferably, X1 It is CH and X 6 It is CH. In some other preferred embodiments, X 1 It is N and X 6 It is CH.

[0184] In some preferred embodiments, part of formula (Cy6) is More

[0185] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (VIIA), formula (VIIA'), formula (VIIB), (VIIB'), formula (VIIC) or formula (VIIC'):

[0186] The compounds of formula (I') have the structures of formula (VII'A), (VII'A'), (VII'B), (VII'B'), (VII'C), or (VII'C'):

[0187] In some such implementations, the formula The preferred part is

[0188] In some such implementations, the formula The preferred part is:

[0189] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy3A) has the structure of formula (Cy7):

[0190] Where: X 3 X 4 and X 7 Each is independently selected from CH and N. In the preferred embodiment, X 3 X 4 and X 7 At least one of them is CH.

[0191] In some such implementations, preferably, X 1 It is CH and X 6It is CH. In some other preferred embodiments, X 1 It is N and X 6 It is CH.

[0192] In some preferred embodiments, part of formula (Cy7) is or (where X) 3 and X 4 At least one of them is CH), preferably (where X) 3 and X 4 At least one of them is CH), or (where X) 3 and X 4 At least one of them is CH).

[0193] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (VIIIA), formula (VIIIA'), formula (VIIIB), (VIIIB'), formula (VIIIC), or formula (VIIIC'):

[0194] The compound of formula (I') has the structure of formula (VIII'A), formula (VIII'A'), formula (VIII'B), (VIII'B'), formula (VIII'C), or formula (VIII'C'):

[0195] In some such implementations, the formula The preferred part is

[0196] In some such implementations, the formula The preferred part is

[0197] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy3A) has the structure of formula (Cy8):

[0198] Where: X 3 X 4 and X 7 Each is independently selected from CH and N. In the preferred embodiment, X 3 X4 and X 7 At least one of them is CH.

[0199] In some such implementations, preferably, X 1 It is CH and X 6 It is CH. In some other preferred embodiments, X 1 It is N and X 6 It is CH.

[0200] In some preferred embodiments, part of formula (Cy8) is In some preferred embodiments, part of formula (Cy8) is In some preferred embodiments, part of formula (Cy8) is

[0201] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (IX-1A), formula (IX-1A'), formula (IX-1B), (IX-1B'), formula (IX-1C) or formula (IX-1C'):

[0202] The compounds of formula (I') have the structures of formula (IX'-1A), (IX'-1A'), (IX'-1B), (IX'-1B'), (IX'-1C), or (IX'-1C'):

[0203] In some such implementations, the formula The preferred part is

[0204] In some such implementations, the formula The preferred part is

[0205] In some preferred embodiments, the compounds of formula (I) according to the invention have the structures of formula (IX-2A), formula (IX-2A'), formula (IX-2B), (IX-2B'), formula (IX-2C), or formula (IX-2C'):

[0206] The compounds of formula (I') have the structures of formula (IX'-2A), (IX'-2A'), (IX'-2B), (IX'-2B'), (IX'-2C), or (IX'-2C'):

[0207] In some such implementations, the formula The preferred part is

[0208] In some such implementations, the formula The preferred part is

[0209] In some preferred embodiments, the compounds of formula (I) according to the invention have the structures of formula (IX-3A), formula (IX-3A'), formula (IX-3B), (IX-3B'), formula (IX-3C), or formula (IX-3C'):

[0210] The compounds of formula (I') have the structures of formula (IX'-3A), (IX'-3A'), (IX'-3B), (IX'-3B'), (IX'-3C), or (IX'-3C'):

[0211] In such implementations, X 1 It is CH or N. In some implementations, X 1 It is CH. In some other implementations, X 1 It is N.

[0212] In some such implementations, the formula The preferred part is

[0213] In some such implementations, the formula The preferred part is

[0214] In some preferred embodiments, the compounds of formula (I) according to the invention have the structures of formula (IX-4A), formula (IX-4A'), formula (IX-4B), (IX-4B'), formula (IX-4C), or formula (IX-4C'):

[0215] The compounds of formula (I') have the structures of formula (IX'-4A), (IX'-4A'), (IX'-4B), (IX'-4B'), (IX'-4C), or (IX'-4C'):

[0216] In some such implementations, preferably, X 1 It is CH and X 6 It is CH. In some other implementations, X 1 It is N and X 6 It is CH. In some other implementations, X 1 It is N and X 6 It is CH.

[0217] In some such implementations, the formula The preferred part is

[0218] In some such implementations, the formula The preferred part is

[0219] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy3B) has the structure of formula (Cy9):

[0220] Where: X 3 X 4 and X 7 Each is independently selected from CH2, O, S and NR. 16 In the preferred embodiment, X 3 and X 4 At least one of them is CH2.

[0221] In some such implementations, preferably, X 1 It is CH and X 6 It is CH. In some other preferred embodiments, X 1 It is N and X 6 It is CH.

[0222] In some preferred embodiments, a portion of formula (Cy9) is selected from:

[0223] In a more preferred embodiment, part of formula (Cy9) is

[0224] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (XA), formula (XB) or formula (XC):

[0225] Alternatively, the compound of formula (I) may have the structure of formula (XD), formula (XE), or formula (XF):

[0226] The compounds of formula (I') have the structure of formula (X'A), formula (X'B), or formula (X'C):

[0227] Alternatively, the compound of formula (I') may have the structure of formula (X'D), formula (X'E), or formula (X'F):

[0228] In such implementations, X 1 It is CH or N. In some implementations, X 1 It is CH. In some other implementations, X 1 It is N.

[0229] In some such implementations, the formula Partially preferred

[0230] In some such implementations, the formula Partially preferred

[0231] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy3B) has the structure of formula (Cy10):

[0232] Where: X 3 and X 4 Each is independently selected from CH and N.

[0233] In some such implementations, preferably, X 1 It is CH and X 6 It is CH. In some other preferred embodiments, X 1 It is N and X 6 It is CH.

[0234] In some preferred embodiments, a portion of formula (Cy10) is selected from...

[0235] In a more preferred embodiment, part of formula (Cy10) is

[0236] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (XIA), formula (XIB) or formula (XIC):

[0237] Alternatively, the compound of formula (I) may have the structure of formula (XID), formula (XIE), or formula (XIF):

[0238] The compounds of formula (I') have the structure of formula (XI'A), formula (XI'B), or formula (XI'C):

[0239] Alternatively, the compound of formula (I') may have the structure of formula (XI'D), formula (XI'E), or formula (XI'F):

[0240] In such implementations, X 1 It is CH or N. In some implementations, X 1 It is CH. In some other implementations, X 1 It is N.

[0241] In some such implementations, the formula The preferred part is

[0242] In some such implementations, the formula The preferred part is

[0243] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein the portion of formula (Cy3B) has the structure of formula (Cy11):

[0244] Where: X 4 and X 7 Each is independently selected from CH and N.

[0245] In some such implementations, preferably, X 1 It is CH and X 6 It is CH. In some other preferred embodiments, X 1It is N and X 6 It is CH.

[0246] In some preferred embodiments, a portion of formula (Cy11) is selected from...

[0247] In a more preferred embodiment, the structure of formula (Cy11) is as follows:

[0248] In some preferred embodiments, the compound of formula (I) according to the invention has the structure of formula (XIIA), formula (XIIB), or formula (XIIC):

[0249] Alternatively, the compound of formula (I) may have the structure of formula (XIID), formula (XIIE), or formula (XIIF):

[0250] The compounds of formula (I') have the structure of formula (XII'A), formula (XII'B), or formula (XII'C):

[0251] Alternatively, the compound of formula (I') may have the structure of formula (XII'D), formula (XII'E), or formula (XII'F):

[0252] In such implementations, X 1 It is CH or N. In some implementations, X 1 It is CH. In some other implementations, X 1 It is N.

[0253] In some such implementations, the formula The preferred part is

[0254] In some such implementations, the formula The preferred part is

[0255] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 17 and R 18 Each time it appears, it is independently H or C. 1-4Alkyl or 3-6 membered heterocyclic alkyl, or R attached to the same N. 17 and R 18 Optionally, they can be linked to form 3-6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups, wherein the 3- or 6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups, are optionally bonded by one or more halogens, –OH groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution. In a preferred embodiment, R... 17 and R 18 Each is independently H or C 1-4 Alkyl, more preferably H, methyl or ethyl.

[0256] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 10 It is C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, –C(O)O(C 1-4 Alkyl groups), –COOH or –C(O)NH2, –C(O)NH(C 1-4 alkyl) or –C(O)NH(C 1-4 alkyl)2, wherein the C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, optionally bonded by one or more halogens, –OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups.

[0257] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 15 Each time it appears, it is independently H or C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

[0258] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein each R 15 'Independently, they are halogens, CN, –OH, -SH, NH2, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Halogenated alkyl, or –N(C) 1-4 alkyl)-C 1-4 Halogenated alkyl groups. In some preferred embodiments, each R 15 Independently, they are F, Cl, Br, I, CN, –OH, -SH, NH2, and C. 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, –NH-C 1-2 Alkyl, –N(C) 1-2 Alkyl)2、–NH-C 1-2 Haloalkyl, –N(C) 1-2 alkyl)-C 1-2 Halogenated alkyl groups. In a more preferred embodiment, each R 15 'Independently, it is F, Cl, CN, –OH, -SH, or NH2. In a further preferred embodiment, each R 15 'Independently, it is –OH, -SH, or NH2.

[0259] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 1 It is H, –OH, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Halogenated alkyl, –L 1 –(C1-4 (alkylene)–OR 15 –L 1 –(by one or two Rs) 15 'Replacement of C' 1-4 (alkylene)–OR 15 –L 1 –(C 2-4 (alkenyl)–OR 15 –L 1 –(by one or two Rs) 15 'Replacement of C' 2-4 (alkenyl)–OR 15 –L 1 –(C 1-4 (alkylene)–SR 15 –L 1 –(by one or two Rs) 15 'Replacement of C' 1-4 (alkylene)–SR 15 –L 1 –(C 2-4 (alkenyl)–SR 15 –L 1 –(by one or two Rs) 15 'Replacement of C' 2-4 (alkenyl)–SR 15 –L 1 –(C 1-4 (alkylene)–NR 13 R 14 –L 1 –(by one or two Rs) 15 'Replacement of C' 1-4 (alkylene)–NR 13 R 14 –L 1 –(C 1-4 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 L 1 Each occurrence is independently a key, an O, or an S, and L 2 Is it a key or C? 1-4 Alkylene. In some preferred embodiments, R 1 Is H, –OH, F, Cl, Br, I, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Haloalkyl, –(C 1-4 (alkylene)–OC 1-4 Alkyl, –(C 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 (alkylene)–OC 1-4 Alkyl group, –O (C group substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene) –OH, –O (C substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 alkylene)–OH, –O(C 1-4 (alkylene)–SC 1-4 Alkyl group, –O (C group substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 Alkylene)–SH,–O (C substituted with one or two substituents selected from F, Cl, CN,–OH, -SH and NH2) 1-4 alkylene)–SH,–S(C 1-4 (alkylene)–OC 1-4 Alkyl group, –S (C group substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–OC 1-4 Alkyl, –S(C 1-4 (alkylene) –OH, –S (C substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 alkylene)–OH, –S(C 1-4 (alkylene)–SC 1-4 Alkyl group, –S (C group substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 Alkylene) –SH, –S (C substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–SH,–L 1 –(C1-4 (alkylene)–NR 13 R 14 –L 1 –(C substituted by one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–NR 13 R 14 –O–(C 1-4 (alkylene)–R 10 、–S–(C 1-4 (alkylene)–R 10 , or -R 10 L 1 Each occurrence is independently a bond, O, or S. In a more preferred embodiment, R 1 It is C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Haloalkyl, –O(C) 1-4 (alkylene)–OC 1-4 Alkyl groups, –O (C atoms substituted with one or two substituents selected from –OH, -SH, and NH2) 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 Alkylene) –OH, –O (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 alkylene)–OH, –O(C 1-4 (alkylene)–SC 1-4 Alkyl groups, –O (C atoms substituted with one or two substituents selected from –OH, -SH, and NH2) 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 Alkylene) –SH, –O (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 alkylene)–SH,–S(C 1-4 (alkylene)–OC 1-4 Alkyl group, –S (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 (alkylene)–OC 1-4 Alkyl, –S(C 1-4Alkylene) –OH, –S (C substituted with one or two substituents selected from –OH, -SH and ) 1-4 alkylene)–OH, –S(C 1-4 (alkylene)–SC 1-4 Alkyl group, –S (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 Alkylene) –SH, –S (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 Alkylene)–SH, –O–(C 1-4 (alkylene)–NR 13 R 14 、–S–(C 1-4 (alkylene)–NR 13 R 14 –O– (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 (alkylene)–NR 13 R 14 –S– (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 (alkylene)–NR 13 R 14 –O–(C 1-4 (alkylene)–R 10 、–S–(C 1-4 (alkylene)–R 10 , or -R 10 In a further, more preferred embodiment, R 1 It is C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Haloalkyl, –O(C) 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene) –OH, –O (C substituted with one or two substituents selected from –OH and -SH) 1-4 alkylene)–OH, –O(C 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4Alkylene) –SH, –O (C substituted with one or two substituents selected from –OH and -SH) 1-4 alkylene)–SH,–S(C 1-4 (alkylene)–OC 1-4 Alkyl, –S(C 1-4 Alkylene) –OH, –S (C substituted with one or two substituents selected from –OH and -SH) 1-4 alkylene)–OH, –S(C 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 Alkylene) –SH, –S (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 Alkylene)–SH, –O–(C 1-4 (alkylene)–NR 13 R 14 、–S–(C 1-4 (alkylene)–NR 13 R 14 –O–(C 1-4 (alkylene)–R 10 、–S–(C 1-4 (alkylene)–R 10 , or -R 10 In the implementation scheme described above, the C... 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio group, C 1-4 Alkylene and C 2-4 Any one or more of the alkenyl groups, whether alone or as part of a substituent, are optionally substituted with one or more deuterium groups. In the embodiments described above, preferably, R 13 and R 14 Each time it appears, it is independently either H or C. 1-4 Alkyl, more preferably H, methyl or ethyl; or R attached to the same N 13 and R 14 Optionally linked to form a compound optionally connected by one or more halogens, –OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 The alkyl group is a 3-6 membered heterocyclic alkyl group substituted with a haloalkoxy group or a 5- or 6-membered heteroaryl group. In the embodiments described above, preferably, R 10Each time it appears, it is independently and optionally influenced by one or more halogens, –OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy-substituted C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl. In a further preferred embodiment, R 1 It includes methoxy, ethoxy, isopropoxy, tert-butoxy, -OCD3, -OCD2CD3, -OCD(CD3)2, -OC(CD3)3, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2Cl, -O-CHCl2, -O-CCl3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2Cl, -O-CH2CHCl2, -O-CH2CCl3, methylthio, ethylthio, isopropylthio, tert-butylthio, -SCD3, -SCD2CD3 , -SCD(CD3)2, -SC(CD3)3, -S-CH2F, -S-CHF2, -S-CF3, -S-CH2Cl, -S-CHCl2, -S-CCl3, -S-CH2CH2F, -S-CH2CHF2, -S-CH2CF3, -S-CH2CH2Cl, -S-CH2CHCl2, -S-CH2CCl3, –NHCH3, –N(CH3)2, –NHCH2CH3, –N(CH3)(CH2CH3), –N(CH2CH3)2, –NHCD3, –N(CD3) 2. -OCH2-OCH3, -OCH2-OCH2CH3, -OCH2CH2-OCH3, -OCH2CH2-OCH2CH3, -SCH2-OCH3, -SCH2-OCH2CH3, -SCH2CH2-OCH3, -SCH2 CH2-OCH2CH3, -OCH2-OH, -OCH2CH2-OH, -OCH2-CH(OH)-CH2-OH, -O-CH(-CH2-OH)2, -SCH2-OH, -SCH2CH2-OH, -S-CH2-CH(OH) -CH2-OH, -S-CH(-CH2-OH)2, -O-CH2-NH2, -O-CH2-NH(CH3), -O-CH2-N(CH3)2, -O-CH2CH2-NH2, -O-CH2CH2-NH(CH3), -O-CH2 CH2-N(CH3)2, -S-CH2-NH2, -S-CH2-NH(CH3), -S-CH2-N(CH3)2, -S-CH2CH2-NH2, -S-CH2CH2-NH(CH3), -S-CH2CH2-N(CH3)2, In a further preferred embodiment, R 1 It is methoxy, methylthio, -OCD3, -SCD3, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2Cl, -O-CHCl2, -O-CCl3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2Cl, -O-CH2CHCl2, -O-CH2CCl3, -S-CH2F, -S-CHF2, -S-CF3, -S-CH2Cl, -S-CHCl2, -S-CCl3, -S-CH2CH2F, -S-CH2CHF2, -S-CH2CF3, -S-CH2CH2Cl, -S-CH2CHCl2, -S-CH2CCl3, –NHCH3, –N (CH3)2, –NHCH2CH3, –N(CH3)(CH2CH3), –N(CH2CH3)2, –NHCD3, –N(CD3)2, -OCH2-OCH3, –OCH2-OCH2CH3, –OCH2CH2-OCH3, –OCH2CH2-OCH3, –OCH2-OH, –OCH2CH2 -OH, -OCH2-CH(OH)-CH2-OH, -O-CH(-CH2-OH)2, -O-CH2-NH2, -O-CH2-NH(CH3), -O-CH2-N(CH3)2, -O-CH2CH2-NH2, -O-CH2CH2-NH(CH3), -O-CH2CH2-N(CH3)2,

[0260] In other embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 1 It is H, –OH, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4Halogenated alkyl, –L 1 –(C 1-4 (alkylene)–OR 15 –L 1 –(C 2-4 (alkenyl)–OR 15 –L 1 –(C 1-4 (alkylene)–SR 15 –L 1 –(C 2-4 (alkenyl)–SR 15 –L 1 –(C 1-4 (alkylene)–NR 13 R 14 –L 1 –(C 1-4 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 L 1 It is a key, O or S, and L 2 Is it a key or C? 1-4 Alkylene. In some preferred embodiments, R 1 Is H, –OH, F, Cl, Br, I, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Haloalkyl, –(C 1-4 (alkylene)–OC 1-4 Alkyl, –(C 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 (alkylene)–OC 1-4 Alkyl, or –S(C 1-4 (alkylene)–SC 1-4 Alkyl group. In a more preferred embodiment, R 1 It is C 1-4Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –O(C 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 (alkylene)–OC 1-4 Alkyl, or –S(C 1-4 (alkylene)–SC 1-4 Alkyl group. In a more preferred embodiment, R 1 It is C 1-4 Alkoxy, C 1-4 Alkylthio, –O(C 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 (alkylene)–OC 1-4 Alkyl, or –S(C 1-4 (alkylene)–SC 1-4 Alkyl group. In the embodiments described above, the C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio group, C 1-4 Alkylene and C 2-4 Any one or more of the alkenyl groups, either alone or as part of a substituent, may optionally be substituted with one or more deuterium groups.

[0261] In a further preferred embodiment, R 1 It is methoxy, ethoxy, isopropoxy, tert-butoxy, -OCD3, -OCD2CD3, -OCD(CD3)2, -OC(CD3)3, -OCF3, -OCHF2, -OCH2F, methylthio, ethylthio, isopropylthio, tert-butylthio, -SCD3, -SCD2CD3, -SCD(CD3)2, -SC(CD3)3, -SCF3, -SCHF2, -SCH2F, -OCH2-OCH3, -OCH2-OCH2CH3, -OCH2CH2-OCH3, -OCH2CH2-OCH2CH3, and more preferably methoxy, -OCHF2, methylthio, -SCHF2, -OCD3, or -OCH2CH2-OCH3.

[0262] Even more preferably, R 1 It is methoxy, ethoxy, isopropoxy, tert-butoxy, -OCD3, -OCD2CD3, -OCD(CD3)2, -OC(CD3)3, -OCF3, -OCHF2, -OCH2F, methylthio, ethylthio, isopropylthio, tert-butylthio, -SCD3, -SCD2CD3, -SCD(CD3)2, -SC(CD3)3, -OCH2-OCH3, -OCH2-OCH2CH3, -OCH2CH2-OCH3, -OCH2CH2-OCH2CH3, and more preferably methoxy, methylthio, -OCD3, -OCHF2, or -OCH2CH2-OCH3.

[0263] In a further preferred embodiment, R 1 It is methoxy, ethoxy, isopropoxy, tert-butoxy, -OCD3, -OCD2CD3, -OCD(CD3)2, -OC(CD3)3, methylthio, ethylthio, isopropylthio, tert-butylthio, -SCD3, -SCD2CD3, -SCD(CD3)2, -SC(CD3)3, -OCH2-OCH3, -OCH2-OCH2CH3, -OCH2CH2-OCH3, -OCH2CH2-OCH2CH3, and more preferably methoxy, methylthio, -OCD3, or -OCH2CH2-OCH3.

[0264] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 2 and R 3 Each is independently H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups. In some preferred embodiments, R 2 and R 3 The individual choices are F, Cl, Br, and I, with F being the optimal choice.

[0265] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein Part of

[0266] In other embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein Part of

[0267] In other embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein Part of

[0268] In other embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein Part of

[0269] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 6 It is C 1-4 Alkyl, and R 7 It is C 1-4 Halogenated alkyl groups. In some preferred embodiments, R 6 It is methyl, and R 7 It's CF3.

[0270] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein R 8 It is H, and R 9 It is C 1-4 Alkyl group. In some preferred embodiments, R 8 It is H, and R 9It is CH3.

[0271] This invention covers compounds obtained by arbitrarily combining various embodiments.

[0272] In some embodiments, the present invention provides compounds of formula (A) as described above, including compounds of formula (I) and compounds of formula (I'), or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites, or prodrugs thereof, wherein said compounds are selected from:

[0273] Pharmaceutical compositions and treatment methods

[0274] In some embodiments, the present invention provides a pharmaceutical composition comprising a preventatively or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, and one or more pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition may further comprise one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are sodium channel inhibitors. The pharmaceutical composition is preferably a solid dosage form, a semi-solid dosage form, a liquid dosage form, or a gaseous dosage form.

[0275] In some embodiments, the present invention provides a pharmaceutical combination comprising a preventative or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more additional therapeutic agents. In some embodiments, said one or more additional therapeutic agents are sodium channel inhibitors.

[0276] In some embodiments, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the present invention in the preparation of a medicament used as a voltage-gated sodium channel inhibitor. In a preferred embodiment, the voltage-gated sodium channel is a Na+ channel. V 1.8.

[0277] In some embodiments, the present invention provides compounds of the present invention or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs, or pharmaceutical compositions of the present invention, which function as voltage-gated sodium channel inhibitors. In a preferred embodiment, the voltage-gated sodium channel is a Na+ channel. V 1.8.

[0278] In some embodiments, the present invention provides a method for inhibiting voltage-gated sodium channels in an isolated biological sample, the method comprising contacting the biological sample with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or pharmaceutical composition of the present invention. In a preferred embodiment, the voltage-gated sodium channel is Na V 1.8.

[0279] In some embodiments, the present invention provides a method for inhibiting voltage-gated sodium channels in an individual, the method comprising administering to the individual an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or pharmaceutical composition of the present invention. In a preferred embodiment, the voltage-gated sodium channel is Na V 1.8. In some embodiments, the method includes administering an effective amount of one or more additional therapeutic agents to the individual. The one or more additional therapeutic agents are administered concurrently, prior to, or subsequently with an effective amount of the compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, or a pharmaceutical composition of the present invention. In some embodiments, the one or more additional therapeutic agents are sodium channel inhibitors.

[0280] In some embodiments, the present invention provides a method for treating, preventing, or alleviating diseases or symptoms associated with voltage-gated sodium channels, the method comprising administering to an individual in need an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug, or a pharmaceutical composition of the present invention. In a preferred embodiment, the voltage-gated sodium channel is a Na V1.8. In some embodiments, the method includes administering an effective amount of one or more additional therapeutic agents to the individual. The one or more additional therapeutic agents are administered concurrently, prior to, or subsequently with treatment using an effective amount of the compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or pharmaceutical composition of the present invention. In some embodiments, the one or more additional therapeutic agents are sodium channel inhibitors.

[0281] In some implementations, the voltage-gated sodium channel-related diseases or conditions include, but are not limited to, pain, such as acute or chronic pain.

[0282] In this invention, "pharmaceutically acceptable carrier" refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0283] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The compositions may also contain small amounts of wetting agents, emulsifiers, or pH buffers as needed. Oral formulations may contain standard carriers such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0284] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered via suitable routes, such as by injection (e.g., intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, sublingual, nasal, transmucosal, topical, ophthalmic formulations or by inhalation.

[0285] For these routes of administration, the pharmaceutical compositions of the present invention can be administered in suitable dosage forms.

[0286] The dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, and syrups.

[0287] As used in this article, the term "effective amount" refers to the amount of a compound that, when administered, will alleviate one or more symptoms of the treated condition to some extent.

[0288] The dosing regimen can be adjusted to provide the optimal required response. For example, a single bolus injection can be administered, several fractions can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation. It should be noted that dosage values ​​can vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. To further understand, for any given individual, the specific dosing regimen should be adjusted over time based on individual needs and the professional judgment of the person administering the composition or supervising its administration.

[0289] The amount of the compounds of the present invention administered will depend on the individual being treated, the severity of the condition or illness, the rate of administration, the disposal of the compounds, and the prescribing physician's judgment. Generally, the effective dose is from about 0.0001 to about 50 mg per kg of body weight per day, for example, from about 0.01 to about 10 mg / kg / day (single or divided doses). For a 70 kg person, this would total from about 0.007 mg / day to about 3500 mg / day, for example, from about 0.7 mg / day to about 700 mg / day. In some cases, dose levels not exceeding the lower limit of the foregoing range may be sufficient, while in other cases, larger doses may still be used without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses administered throughout the day.

[0290] The content or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, preferably 0.1-500 mg, preferably 0.5-300 mg, more preferably 1-150 mg, particularly preferably 1-50 mg, such as 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, etc.

[0291] Unless otherwise stated, as used herein, the term “treating” means to reverse, alleviate, or inhibit the progression of a disease or condition or one or more symptoms of such a disease or condition to which such term is applied, or to prevent such a disease or condition or one or more symptoms of such a disease or condition.

[0292] As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include individuals suffering from a disease or ailment (such as those described herein) (referred to as patients) or healthy individuals. In this invention, “non-human animals” includes 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.). Beneficial effects

[0293] The compounds of the present invention, such as the compounds in the examples, are effective voltage-gated sodium channels (Na+). V Inhibitors, especially Na V 1.8 Inhibitor, which has an effect on Na V 1.8 exhibits excellent inhibitory activity. Surprisingly, compared to some known compounds, the compounds of the present invention, such as some of the example compounds, show enhanced Na+ inhibition. V 1.8 Inhibitory Activity. The compounds of the present invention, such as the compounds of the examples, exhibit excellent pharmacokinetic properties. Surprisingly, compared to some known compounds, the compounds of the present invention, such as some of the compounds of the examples, possess improved pharmacokinetic properties (e.g., improved plasma concentrations, exposure, bioavailability, half-life, and / or duration of action). Therefore, the compounds of the present invention, such as some of the compounds of the examples, are expected to have better in vivo therapeutic efficacy. The compounds of the present invention may also possess superior properties such as better physicochemical properties (e.g., solubility, physical and / or chemical stability), improved safety (lower toxicity and / or fewer side effects, wider therapeutic window), etc.

[0294] Example

[0295] The present invention is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0296] The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR). 1 Confirmation was performed using 1H NMR or mass spectrometry (MS).

[0297] Chemical shift (δ) is given in parts per million (ppm). 1 H NMR measurements were performed on a Bruker BioSpin GmbH 400 NMR spectrometer. The test solvents were deuterated methanol (CD3OD), deuterated chloroform (CDCl3), or hexadeuterated dimethyl sulfoxide (DMSO-d6), and the internal standard was tetramethylsilane (TMS).

[0298] LC-MS determinations were performed on a Shimadzu LC-MS-2020 liquid chromatography-mass spectrometry system (manufacturer: Shimadzu, model: Shimadzu LC-MS-2020).

[0299] Preparative high performance liquid chromatography was performed using a Waters 2767 (Waters Sunfire, C18 column).

[0300] Thin-layer chromatography (TLC) was performed using HSGF 254 (5×20cm) silica gel plates, while preparative thin-layer chromatography was performed using GF 254 (0.4~0.5nm) silica gel plates.

[0301] The reaction was detected using thin-layer chromatography (TLC) or LC-MS. Developing solvent systems included dichloromethane and methanol, n-hexane and ethyl acetate, and petroleum ether and ethyl acetate. The developing solvent system was adjusted according to the polarity of the compounds to be separated (by adjusting the solvent volume ratio or adding triethylamine, etc.). The mobile phase for LC-MS was water and acetonitrile (with 0.1% FA or TFA added depending on the method).

[0302] The microwave reaction was performed using a BiotageInitiator+ (400W, RT~300℃) microwave reactor.

[0303] Column chromatography typically uses 200-300 mesh silica gel as the stationary phase. Eluent systems include dichloromethane and methanol systems and n-hexane and ethyl acetate systems. The eluent system is adjusted according to the polarity of the compounds to be separated (by adjusting the volume ratio of the solvent or adding triethylamine, etc.).

[0304] Unless otherwise specified in the examples, the reaction temperature is room temperature (20℃~30℃).

[0305] The reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, or Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0306] The abbreviations used in this invention have the following meanings:

[0307] Example 1: Synthesis of (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0308] Step 1: Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-1, 104 mg, 0.29 mmol), 5-amino-2-fluorobenzonitrile (compound 1-2, 40 mg, 0.29 mmol), and N,N-diisopropylethylamine (DIPEA, 114 mg, 0.88 mmol) in DMF (3 mL). Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (111.8 mg, 0.29 mmol) at room temperature and stir for 3 hours at room temperature. After the reaction was complete, water (40 mL) was added. The aqueous phase was extracted three times with EA, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA:PE = 1:4) to obtain a colorless liquid (2R,3S,4S,5R)-N-(3-cyano-4-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compounds 1-3, 54 mg, yield 38.9%). ESI-MS: m / z = 473.1 [M+1] + .

[0309] Step 2: Compounds 1-3 (54 mg, 0.114 mmol) were dissolved in 1,4-dioxane (5 mL) and hydrazine hydrate (1 mL). The mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the mixture was diluted with water and extracted three times with EA. The organic phase was washed three times with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA:PE = 1:1) by reverse phase separation to obtain (2R,3S,4S,5R)-N-(3-amino-1H-indazole-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 1, 6.8 mg, yield 12.3%) in the form of a white solid.

[0310] ESI-MS: m / z = 485.1 [M+1] + . 1H NMR (400MHz, MeOD) δ7.92(d,J=1.1Hz,1H),7.36(dd,J=8.9,1.8Hz,1H),7.27(d,J=8.9Hz,1H),7.23-7.15(m,1H),7.07-6.96(m,1H ), 5.09 (d, J = 10.6Hz, 1H), 4.34 (dd, J = 10.4, 8.1Hz, 1H), 4.02 (d, J = 2.1Hz, 3H), 2.88-2.74 (m, 1H), 1.70 (s, 3H), 0.92-0.79 (m, 3H). 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),10.11(s,1H),7.99(s,1H),7.29-7.21(m,1H),7.20-7.12(m,3H),5.25(s,2H),5 .07(d,J=10.5Hz,1H),4.31-4.22(m,1H),3.96(d,J=1.9Hz,3H),2.81-2.71(m,1H),1.60(s,3H),0.73(d,J=5.9Hz,3H).

[0311] Example 2: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0312] Compounds 1-3 (60.0 mg, 127 μmol), K2CO3 (35.1 mg, 254 μmol), and N-hydroxyacetamide (11.4 mg, 152 μmol) prepared according to the method described in step 1 of Example 1 were added sequentially to a mixture of DMF (2 mL) and water (0.2 mL). The reaction mixture was then stirred at 45 °C for 16 hours. After the reaction was completed, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 35%-65%) to obtain (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 2, 22.0 mg, yield 35.6%) as a yellow solid.

[0313] ESI-MS: [M+H] + =486.1. 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.22(d,J=1.9Hz,1H),7.50(dd,J=2.0,9.0Hz,1H),7.39(d,J=8.9Hz,1H),7.23-7.12(m,2H) ,6.37(s,2H),5.09(d,J=10.4Hz,1H),4.27(dd,J=7.5,10.4Hz,1H),3.95(d,J=2.1Hz,3H),2.79-2.70(m,1H),1.61(s,3H),0.73(br d,J=6.3Hz,3H).

[0314] Example 3: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isothiazo-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0315] Step 1: 5-Nitrobenzo[d]isothiazol-3-amine (compound 3-1, 1.80 g, 9.22 mmol), Boc anhydride (6.04 g, 27.6 mmol, 6.36 mL), TEA (1.87 g, 18.4 mmol), and 4-dimethylaminopyridine (112 mg, 922 μmol) were sequentially added to 10 mL of THF. The reaction mixture was then stirred at 25 °C for 16 hours. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with 10 mL of THF, and the filter cake was dried to give a red solid tert-butyl (tert-butoxycarbonyl) (5-nitrobenzo[d]isothiazol-3-yl)carbamate (compound 3-2, 3.00 g, yield 55.6%). ESI-MS: m / z = 396.2 [M+1] + .

[0316] Step 2: Compound 3-2 (1.00 g, 2.53 mmol), ammonium chloride (541 mg, 10.1 mmol), and reduced iron powder (564 mg, 10.1 mmol) were added sequentially to a mixture of EtOH (8 mL) and water (2 mL). The reaction mixture was then stirred at 80 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. 3 mL of water was added to the residue, and the mixture was extracted three times with EA. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 51%–81%) to obtain a brown solid tert-butyl(5-aminobenzo[d]isothiazo-3-yl)(tert-butyloxycarbonyl)carbamate (compound 3-3, 450 mg, yield 46.1%).

[0317] ESI-MS: m / z = 366.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ8.03(br d,J=9.0Hz,1H),7.19(d,J=2.3Hz,1H),7.15(dd,J=2.4,9.0Hz,1H),5.46(s,2H),1.63-1.48(m,18H).

[0318] Step 3: Compound 3-3 (61.8 mg, 169 μmol), compound 1-1, and T4P (122 mg, 169 μmol) were added sequentially to DCM (2 mL), and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, 3 mL of water was added to the reaction mixture, and the aqueous layer was separated. The organic phase was dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown crude product: (tert-butyloxycarbonyl)(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-formylamino)benzo[d]isothiazo-3-yl)tert-butyl carbamate (compound 3-4, 130 mg). ESI-MS: m / z = 702.3 [M+1] + .

[0319] Step 4: Compounds 3-4 (100 mg, 142 μmol) and HCl / 1,4-dioxane (4 M, 1.0 mL) were added sequentially to DCM (1.0 mL), and the reaction mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (3 mL), and TEA was slowly added dropwise to the mixture until the pH of the system was 8. The mixture was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 40-80%) to give (2R,3S,4S,5R)-N-(3-aminobenzo[d]isothiazo-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 3, 41.0 mg, yield 57.3%) as a gray solid.

[0320] ESI-MS: m / z = 502.0 [M+1] + . 1H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.14(s,1H),7.55(s,2H),7.25-7.12(m,4H),5.09(d,J=10.5H z,1H),4.28(dd,J=7.6,10.4Hz,1H),3.97(d,J=2.0Hz,3H),2.81-2.73(m,1H),1.62(s,3H),0.74(br d,J=6.0Hz,3H).

[0321] Example 4: Synthesis of (2R,3S,4S,5R)-N-(3-aminopyrazolo[1,5-a]pyridin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0322] Step 1: 5-Bromopyrazolo[1,5-a]pyridine (compound 4-1, 2.0 g, 10.15 mmol) was dissolved in sulfuric acid (10 mL). A mixture of nitric acid (7.00 g, 111 mmol, 5 mL) and sulfuric acid (5 mL) was added dropwise to the reaction solution at 0 °C. The reaction solution was then stirred at 0 °C for 30 minutes. After the reaction was completed, the reaction solution was poured into ice water (50 mL) and stirred for 10 minutes. The reaction mixture was filtered, and the filter cake was dried to give 5-bromo-3-nitropyrazolo[1,5-a]pyridine (compound 4-2, 1.6 g, 6.61 mmol, yield 65.13%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ9.03-8.91 (m, 2H), 8.41 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 2.1, 7.3 Hz, 1H).

[0323] Step 2: Compound 4-2 (1.2 g, 4.96 mmol, 1.0 eq) and benzophenone imine (1.35 g, 7.44 mmol, 1.25 mL) were dissolved in toluene (12.0 mL). Then, Cs₂CO₃ (4.85 g, 14.87 mmol, 3.0 eq) and SPhos (203.54 mg, 495.81 μmol) were added sequentially at 20 °C. The reaction system was purged with nitrogen three times. Then, Pd₂(dba)₃ (454 mg, 495.81 μmol) was added to the reaction system under a nitrogen atmosphere. After the addition was complete, the reaction solution was heated to 110 °C and stirred at 110 °C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: industrial hexane: EA = 100:1 to 0:1) to obtain N-(3-nitropyrazolo[1,5-a]pyridin-5-yl)-1,1-diphenylmethyleneimine (compound 4-3, 650 mg, 1.90 mmol, yield 38.3%) as a yellow solid. 1 H NMR (400MHz, CDCl3-d) δ8.42 (s, 1H), 8.21 (d, J = 7.3Hz, 1H), 7.74-7.27 (m, 10H), 7.16-7.05 (m, 1H), 6.52 (dd, J = 2.3, 7.3Hz, 1H).

[0324] Step 3: Compound 4-3 (650 mg, 1.90 mmol) was dissolved in THF (26 mL). Dilute hydrochloric acid (1 M, 22.78 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove THF. The residue was dispersed in a saturated sodium bicarbonate solution (10 mL) and extracted with EA (5 mL * 3). The organic phase was washed with a saturated NaCl solution (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 10%–40%) to give 3-nitropyrazolo[1,5-a]pyridine-5-amine (compound 4-4, 100 mg, 561.33 μmol, yield 29.6%) as a yellow solid. ESI-MS: m / z = 179.0 [M+H] + .

[0325] Step 4: Compound 4-4 (26 mg, 145.95 μmol, 1.0 eq) and compound 1-1 (62.04 mg, 175.14 μmol) were dissolved in DMF (1.0 mL). Then, N-methylimidazole (83.88 mg, 1.02 mmol, 81.43 μL) was added to the reaction solution at room temperature. After cooling the reaction system to 0 °C, TCFH (106.47 mg, 379.46 μmol) was added to the reaction solution in a partitioned manner. After the addition was complete, the reaction solution was stirred at 20 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 55%-85%) to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(3-nitropyrazolo[1,5-a]pyridin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 4-5, 30 mg, 58.32 μmol, yield 40.0%) as a white solid. ESI-MS: m / z = 515.0 [M+H] + .

[0326] Step 5: Compound 4-5 (30 mg, 58.32 μmol) was dissolved in EtOH (1.0 mL). Anhydrous stannous chloride (16.59 mg, 87.48 μmol, 2.27 μL) was added to the reaction solution at room temperature. The reaction solution was then stirred at 90 °C for 16 hours. LCMS showed approximately 89.39% of the starting material remaining. After cooling the reaction solution to room temperature, anhydrous stannous chloride (22.12 mg, 116.64 μmol, 3.03 μL) was added to the reaction system, and the reaction solution was stirred at 90 °C for 24 hours. After the reaction was completed, the system was cooled to room temperature, and the reaction solution was poured into a saturated sodium bicarbonate solution (3 mL). Extraction was performed using EA (2 mL * 2). The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 3%-73%) to obtain (2R,3S,4S,5R)-N-(3-aminopyrazolo[1,5-a]pyridin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 4, 8.05 mg, 16.43 μmol, yield 28.2%) in the form of a yellow solid.

[0327] ESI-MS: m / z = 485.2 [M+H] + . 1H NMR (400MHz, CDCl3-d) δ8.33(s,1H),8.20(d,J=7.6Hz,1H),7.96(d,J=1.7Hz,1H),7.63(s,1H),7.14-7.08(m,1H),6.97-6.87(m,1H),6.56(dd,J =2.2,7.6Hz,1H),5.04(d,J=11.0Hz,1H),4.11(dd,J=8.0,11.0Hz,1H),4 .02(d,J=2.7Hz,3H),2.83-2.47(m,3H),1.70(s,3H),0.86-0.74(m,3H).

[0328] Example 5: Synthesis of (2R,3S,4S,5R)-N-(3-amino-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0329] Step 1: 2-Chloro-5-nitronicotinamide (compound 5-1, 600 mg, 3.27 mmol), iron powder (182.63 mg, 32.7 mmol), and ammonium chloride (1.75 g, 32.7 mmol) were dissolved in THF (10 mL) and water (10 mL). The mixture was stirred at 80 °C for 4 hours. After the reaction was complete, water (100 mL) and EA (100 mL) were added. The mixture was filtered and separated. The organic phase was washed three times with saturated NaCl solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM = 1:10) to obtain 5-amino-2-chloronicotinic acid (compound 5-2, 173 mg, yield 34%) as a brown solid. ESI-MS: m / z = 154.1 [M+1] + .

[0330] Step 2: Dissolve compound 1-1, compound 5-2 (43 mg, 0.28 mmol) and DIPEA (108.5 mg, 0.84 mmol) in DMF (5 mL), add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (106.45 mg, 0.28 mmol) at room temperature, and stir at room temperature for 3 hours. After the reaction was complete, water (50 mL) was added. The aqueous phase was extracted three times with EA, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA:PE = 1:4) to give a colorless liquid form of (2R,3S,4S,5R)-N-(6-chloro-5-cyanopyridin-3-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 5-3, 76 mg, yield 55%). ESI-MS: m / z = 490.0 [M+1] + .

[0331] Step 3: Compound 5-3 (76 mg, 0.15 mmol) was dissolved in 1,4-dioxane (5 mL) and hydrazine hydrate (1 mL), stirred at 100 °C for 5 hours. After the reaction was complete, water was added for dilution, and the mixture was extracted three times with EA. The organic phase was washed three times with saturated NaCl solution, dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (eluent: EA:PE = 1:1) to obtain a white solid (2R,3S,4S,5R)-N-(3-amino-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 5, 14.51 mg, yield 20%).

[0332] ESI-MS: m / z = 486.1 [M+1] + . 1 H NMR (400MHz, MeOD) δ8.45-8.43(m,J=2.3Hz,1H),8.40(d,J=2.3Hz,1H),7.23-7.16(m,1H),7.01(dd,J=16.7,9.7Hz, 1H), 5.12 (d, J = 10.6Hz, 1H), 4.40-4.27 (m, 1H), 4.02 (s, 3H), 2.90-2.73 (m, 1H), 1.71 (s, 3H), 0.85 (d, J = 5.4Hz, 3H).

[0333] Example 6: Synthesis of (2R,3S,4S,5R)-N-(3-aminoisoxazolo[5,4-b]pyridin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0334] N-hydroxyacetamide (44.73 mg, 595.81 μmol) was dissolved in DMF (2.28 mL). t-BuOK (66.86 mg, 595.81 μmol) was added to the resulting solution at 15 °C. After stirring at 15 °C for 20 minutes, compound 5-3 (114 mg, 232.74 μmol) was added in portions, and the mixture was stirred at 50 °C for 13 hours. After the reaction was complete, the reaction solution was cooled to 15 °C and diluted with DMSO (1.5 mL). The resulting solution was purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 45%-75%) to obtain (2R,3S,4S,5R)-N-(3-aminoisoxazolo[5,4-b]pyridin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 6, 18.93 mg, 38.44 μmol, yield 16.52%) as a white solid.

[0335] ESI-MS: m / z = 487.1 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.72(d,J=2.3Hz,1H),8.51(d,J=2.4Hz,1H),7.23-7.14(m,2H),6.63(s,2H),5.14( d,J=10.5Hz,1H),4.27(dd,J=7.7,10.3Hz,1H),3.95(d,J=1.9Hz,3H),2.82-2.72(m,1H),1.62(s,3H),0.78-0.69(m,3H).

[0336] Example 7: Synthesis of (2R,3S,4S,5R)-N-(3-amino-1H-indazol-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0337] Step 1: Dissolve compound 1-1 (50 mg, 0.15 mmol), 4-amino-2-fluorobenzonitrile (compound 7-1, 38 mg, 0.28 mmol) and pyridine (44 mg, 0.56 mmol) in DCM (20 mL), add phosphorus oxychloride (22 mg, 0.14 mmol) at 0 °C, and react at 0 °C for 2 hours. After the reaction was complete, the system was slowly added dropwise to ice water. The aqueous phase was extracted three times with EA, and the organic phase was washed once with saturated NaCl solution. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA = 3:1) to give (2R,3S,4S,5R)-N-(4-cyano-3-fluorophenyl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 7-2, 60 mg, yield 90%), which was a yellow oil. ESI-MS: m / z = 473.1 [M+1] + .

[0338] Step 2: Compound 7-2 (60 mg, 0.13 mmol) was dissolved in 1,4-dioxane (2.5 mL), and hydrazine hydrate (0.5 mL) was added. The mixture was stirred at 100 °C for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (eluent: ACN:water (FA) = 30%–60%) to give (2R,3S,4S,5R)-N-(3-amino-1H-indazole-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 7, 8.6 mg, yield 12.9%) as a white solid.

[0339] ESI-MS: [M+H] + =485.1. 1 HNMR(400MHz,DMSO-d6)δ11.28(s,1H),10.27(s,1H),7.76(s,1H),7.57(d,J=8.6Hz,1H),7.25-7.12(m,2H),6.92(dd,J=8.7,1.6Hz,1H),5.2 9(s,2H),5.08(d,J=10.5Hz,1H),4.26(dd,J=10.3,7.7Hz,1H),3.96(d,J=2.0Hz,3H),2.82-2.74(m,1H),1.60(s,3H),0.73(d,J=6.1Hz,3H).

[0340] Example 8: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0341] Compound 7-2 (74 mg, 0.16 mmol) was dissolved in DMF (1 mL), and N-hydroxyacetamide (12 mg, 0.16 mmol), K2CO3 (43 mg, 0.31 mmol), and water (0.3 mL) were added. The mixture was stirred at 50 °C for 16 hours. After the reaction was completed, the mixture was diluted with saturated ammonium chloride solution, extracted three times with EA, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (eluent: ACN: water (0.1% FA) = 0%–30%) to give (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 8, 11.5 mg, yield 15.1%) as a white solid.

[0342] ESI-MS: [M+H] + =486.1. 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),7.88(s,1H),7.71(d,J=8.5Hz,1H),7.33(dd,J=8.6,1.5Hz,1H),7.24-7.10(m,2H),6.34(s,2H ), 5.11 (d, J = 10.3Hz, 1H), 4.27 (dd, J = 10.2, 7.7Hz, 1H), 3.96 (d, J = 2.0Hz, 3H), 2.85-2.71 (m, 1H), 1.60 (s, 3H), 0.73 (d, J = 6.0Hz, 3H).

[0343] Example 9: Synthesis of (2R,3S,4S,5R)-N-(3-aminoisothiazo[4,5-b]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0344] Step 1: 3-Fluoro-4-iodocyanopyridine (compound 9-1, 500 mg, 2.02 mmol), tert-butyl carbamate (236 mg, 2.02 mmol), XPhos (96.1 mg, 201 μmol), Pd2(dba)3 (115 mg, 201 μmol), and Cs2CO3 (1.97 g, 6.05 mmol) were sequentially added to toluene (5 mL), and nitrogen was applied three times. The reaction mixture was then stirred at 100 °C under nitrogen protection for 16 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA = 1:1) to obtain (2-cyano-3-fluoropyridin-4-yl)tert-butyl carbamate (compound 9-2, 310 mg, yield 64.8%) as a white solid. ESI-MS: m / z = 238.1 [M+1] + .

[0345] Step 2: Compound 9-2 (300 mg, 1.26 mmol) and HCl / 1,4-dioxane (4 M, 1.5 mL) were added sequentially to DCM (3.0 mL), and the reaction mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure to give 4-amino-3-fluorocyanopyridine (compound 9-3, 200 mg, yield 91.1%, hydrochloride) as a white solid. ESI-MS: m / z = 138.1 [M+1] + .

[0346] Step 3: Compound 1-1 (120 mg, 338 μmol), TEA (68.5 mg, 677 μmol), 2-chloro-1,3-dimethyl-4,5-dihydroimidazolium hydrochloride (114 mg, 677 μmol), and compound 9-3 (55.7 mg, 406 μmol) were added sequentially to DCM (2 mL). The reaction mixture was then stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE:EA = 3:1) to give (2R,3S,4S,5R)-N-(2-cyano-3-fluoropyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 9-4, 97.0 mg, yield 60.5%) as a white solid. ESI-MS: m / z = 474.2 [M+1] + .

[0347] Step 4: Dissolve compound 9-4 (85.0 mg, 179 μmol) and Na₂S (14.0 mg, 179 μmol) in DMSO (1 mL). Stir the reaction solution at 70 °C for 16 hours, then cool to room temperature. Add NaOH (17.9 mg, 448 μmol), NH₃·H₂O (377 mg, 2.69 mmol, 25% purity) and NaClO (267 mg, 359 μmol, 221 μL, 10% purity) to the reaction solution sequentially, and then stir the reaction solution at 25 °C for 2 hours. After the reaction was completed, 3 mL of water was added to dilute the reaction solution, and the mixture was extracted three times with EA. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by high performance liquid chromatography (eluent: ACN: water (NH4HCO3) = 45%–75%) to give (2R,3S,4S,5R)-N-(3-aminoisothiazo[4,5-b]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 9, 36.0 mg, yield 39.9%) as a white solid.

[0348] ESI-MS: [M+H] + =503.1. 1 H NMR (400MHz, DMSO-d6) δ10.85 (s, 1H), 8.55 (d, J = 5.1Hz, 1H),

[0349] 7.68(d,J=5.1Hz,1H),7.25-7.13(m,2H),6.68(s,2H),5.26(d,J=10.2Hz,1H),4.27( dd,J=7.8,9.9Hz,1H),3.96(d,J=2.1Hz,3H),2.87-2.73(m,1H),1.62(s,3H),0.75(br d,J=6.3Hz,3H).

[0350] Example 10: Synthesis of (2R,3S,4S,5R)-N-(3-aminoisoxazolo[4,5-b]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0351] Step 1: Compound 9-4 (50.0 mg, 105 μmol), N-hydroxyacetamide (10.3 mg, 137 μmol), and K2CO3 (29.2 mg, 211 μmol) were added sequentially to a mixture of DMF (0.9 mL) and water (0.1 mL). The reaction mixture was then stirred at 45 °C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 45%–80%) to give (2R,3S,4S,5R)-N-(3-aminoisoxazolo[4,5-b]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 10, 28.0 mg, yield 54.5%) as a white solid.

[0352] ESI-MS: [M+H] + =487.4. 1 H NMR: (400MHz, DMSO-d6) δ11.01-10.79(m,1H),8.44(d,J=5.3Hz,1H),8.12(d,J=5.1Hz,1H),7.23-7.16(m,2H),6.59(s,2 H),5.37(d,J=10.3Hz,1H),4.27(dd,J=7.6,10.2Hz,1H),3.95(d,J=2.1Hz,3H),2.82–2.70(m,1H),1.61(s,3H),0.73(br d,J=6.4Hz,3H).

[0353] Example 11: Synthesis of (2R,3S,4S,5R)-N-(7-amino-6,7-dihydro-5H-cyclopentadieno[b]pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0354] Step 1: 4-Chloro-6,7-dihydro-5H-cyclopentadieno[b]pyridine-7-ol (compound 11-1, 1.5 g, 8.84 mmol) and imidazole (1.2 g, 17.68 mmol) were dissolved in DMF (20 mL). Tert-butyldimethylchlorosilane (1.6 g, 10.61 mmol) was added at room temperature, and the reaction was continued for 3 h at room temperature. After the reaction was complete, water (50 mL) was added. The aqueous phase was extracted three times with EA, and the organic phase was washed once with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA:PE = 1:4) to obtain 7-((tert-butyldimethylsilyl)oxy)-4-chloro-6,7-dihydro-5H-cyclopentadieno[b]pyridine (compound 11-2, 1.8 g, yield 71.7%), a yellow liquid. ESI-MS: m / z = 284.0 [M+1] + .

[0355] Step 2: Compound 11-2 (1.8 g, 6.34 mmol) and tert-butyl carbamate (890.34 mg, 7.6 mmol) were dissolved in 1,4-dioxane (20 mL). Under nitrogen protection, palladium acetate (142.3 mg, 0.63 mmol), Cs2CO3 (4.13 g, 12.68 mmol) and XPhos (604.5 mg, 1.27 mmol) were added. The mixture was stirred at 95 °C for 16 hours. After the reaction was complete, the mixture was diluted with water and extracted three times with EA. The organic phase was washed three times with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EA:PE = 1:2) to give tert-butyl (7-(tert-butyldimethylsiloxy)-6,7-dihydro-5H-cyclopentadien[b]pyridin-4-yl)carbamate as a yellow solid (compound 11-3, 1.6 g, yield 69%). ESI-MS: m / z = 365.2 [M+1] + .

[0356] Step 3: Compound 11-3 (1.6 g, 4.39 mmol) was dissolved in 10 mL of 4 M HCl solution of 1,4-dioxane, and the reaction was stirred at 20 °C for 3 hours. The reaction solution was concentrated under reduced pressure to give 4-amino-6,7-dihydro-5H-cyclopentadien[b]pyridine-7-ol as a yellow solid (compound 11-4, 600 mg, yield 91%). ESI-MS: m / z = 151.2 [M+1] + .

[0357] Step 4: Compound 11-4 (600 mg, 3.99 mmol) and imidazole (543.3 mg, 7.98 mmol) were dissolved in DMF (10 mL). Tert-butyldimethylchlorosilane (723.5 mg, 4.8 mmol) was added at room temperature, and the reaction was continued for 24 h at room temperature. After the reaction was complete, water (50 mL) was added. The aqueous phase was extracted three times with EA, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: MeOH:DCM = 1:10) to obtain 7-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopentadien[b]pyridine-4-amine (compound 11-5, 380 mg, yield 36%), a yellow liquid. ESI-MS: m / z = 265.1 [M+1] + .

[0358] Step 5: Dissolve compound 1-1 (533 mg, 1.5 mmol) in DCM (10 mL), add oxalyl chloride (228.5 mg, 1.8 mmol) and DMF (catalytic amount) at 0 °C, continue the reaction at 0 °C for 2 h, and then concentrate under reduced pressure to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl chloride (compound 11-6, 670 mg, crude product), which is a yellow oil.

[0359] Step 6: Dissolve compound 11-5 (380 mg, 1.44 mmol) and TEA (145.71 mg, 14.4 mmol) in DCM (10 mL), add compound 11-6 (670 mg, crude product) dropwise at 0 °C, and continue the reaction at room temperature for 2 h. After the reaction was complete, water (30 mL) was added. The aqueous phase was extracted three times with DCM, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM = 1:10) to give (2R,3S,4S,5R)-N-(7-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopentadieno[b]pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 11-7, 548 mg, yield 63%), as a colorless liquid. ESI-MS: m / z = 601.2 [M+1] + .

[0360] Step 7: Compound 11-7 (548 mg, 0.91 mmol) was dissolved in hydrogen chloride / EA solution (4 M, 10 mL), stirred at room temperature for 2 h, and filtered to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(7-hydroxy-6,7-dihydro-5H-cyclopentadieno[b]pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 11-8, 320 mg, yield 72%) as a white solid. ESI-MS: m / z = 487.1 [M+1] + .

[0361] Step 8: Dissolve compound 11-8 (208 mg, 0.42 mmol) in DCM (10 mL), add Dess-Martin reagent (356.3 mg, 0.84 mmol) in portions at 0 °C, and continue the reaction at 0 °C for 2 h. After the reaction was complete, 10 mL of saturated thio-Na₂SO₄ aqueous solution and 10 mL of saturated sodium bicarbonate solution were added, and the mixture was stirred for another 30 minutes. The aqueous phase was extracted three times with DCM, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol:DCM = 1:10) to give (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-dihydro-5H-cyclopentadieno[b]pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 11-9, 84 mg, yield 41%) as a white solid. ESI-MS: m / z = 485.1 [M+1] + .

[0362] Step 9: Compound 11-9 (79 mg, 0.16 mmol) and 2,4-dimethoxybenzamine (53.5 mg, 0.32 mmol) were dissolved in anhydrous MeOH (10 mL) and stirred at room temperature for 16 h. Sodium cyanoborohydride (20.1 mg, 0.32 mmol) was added in portions at 0 °C, and the reaction was continued at 0 °C for 2 h. After the reaction was complete, 10 mL of saturated ammonium chloride aqueous solution was added. The aqueous phase was extracted three times with DCM, and the organic phase was washed once with saturated NaCl aqueous solution. The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH:DCM = 1:10) to obtain (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(7-((2,4-dimethoxybenzyl)amino)-6,7-dihydro-5H-cyclopentadieno[b]pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 11-11, 40 mg, yield 39%), as a yellow liquid. ESI-MS: m / z = 636.2 [M+1]+.

[0363] Step 10: Compound 11-11 (40 mg, 0.06 mmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 50 °C for 3 h. The mixture was concentrated under reduced pressure, and the residue was reverse-phase to prepare a white solid (2R,3S,4S,5R)-N-(7-amino-6,7-dihydro-5H-cyclopentadieno[b]pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 11, 5.62 mg, yield 21%).

[0364] ESI-MS: m / z = 486.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δ10.11-9.83(m,1H),8.44-8.23(m,

[0365] 2H),7.81-7.69(m,1H),7.30-7.12(m,2H),5.31(dd,J=10.4,3.0Hz,1H),4.47-4.34(m,1H),4.32-4.16(m,1H ), 3.94 (s, 3H), 3.00-2.62 (m, 3H), 2.48-2.36 (m, 1H), 1.88-1.74 (m, 1H), 1.60 (s, 3H), 0.74 (d, J = 6.3Hz, 3H).

[0366] Example 12: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0367] Step 1: 2-Hydroxy-5-bromopyridine (compound 12-1, 1 g, 5.3 mmol) was slowly added to an anhydrous EtOH:water solution of cyanogen bromide (0.67 g, 6.3 mmol) in a ratio of 5:1 (25 mL). The system was stirred at 25 °C for 16 hours. The EtOH was then removed by rotary evaporation under reduced pressure. The pH was adjusted to 7 with an aqueous sodium bicarbonate solution, resulting in a yellow precipitate. This precipitate was filtered, and the filter cake was dried to obtain a yellow solid compound, 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-amine (compound 12-2, 540 mg, yield 47.2%). ESI-MS: m / z = 214 [M+1] + .

[0368] Step 2: 6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-amine (compound 12-2, 540 mg, 2.5 mmol) was dissolved in DCM (20 mL), and DIPEA (645 mg, 5 mmol) and Boc anhydride (817 mg, 3.8 mmol) were slowly added. The system was stirred at 25 °C for 4 hours. The solvent was removed by rotary evaporation under reduced pressure, followed by purification by rapid silica gel column chromatography (EA-PE, 0–40%) to obtain a white solid (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl) tert-butyl carbamate (compound 12-3, 350 mg, yield 44.8%). ESI-MS: m / z = 314.0 [M+1] + .

[0369] Step 3: Pd2(dba)3 (102.35 mg, 0.12 mmol) was added to a solution of tert-butyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)carbamate (compound 12-3, 350 mg, 1.12 mmol), diphenylmethyleneimine (243.1 mg, 1.34 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene (129.34 mg, 0.22 mmol) and Cs2CO3 (1092.5 mg, 3.35 mmol) in 1,4-dioxane (5 mL). The system was heated to 100 °C under a nitrogen atmosphere and reacted for 12 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with EA, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure and purified by rapid silica gel column chromatography (EA-PE, 0–80%) to obtain a yellow solid (6-((diphenylmethylene)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)carbamate tert-butyl ester (compound 12-4, 183 mg, yield 35.64%). ESI-MS: m / z = 414.0 [M+1] + .

[0370] Step 4: A 1,4-dioxane solution of hydrochloric acid (4 mol / L, 1.5 mL) was added dropwise to a DCM (3 mL) solution of (6-((diphenylmethylene)amino)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)carbamate (compound 12-4, 183 mg, 0.44 mmol). The system was stirred at 25 °C for 1 hour. The DCM was removed by rotary evaporation under reduced pressure. The pH was adjusted to 7 with sodium bicarbonate aqueous solution, resulting in a yellow precipitate. The precipitate was filtered, and the filter cake was dried to obtain a yellow solid compound [1,2,4]triazolo[4,3-a]pyridin-3,6-diamine (compound 12-5, 70 mg, yield 84.8%). ESI-MS: m / z = 150.2 [M+1] + .

[0371] Step 5: 1H-benzotriazol-1-yloxytripyrrolyl hexafluorophosphate (366.3 mg, 0.70 mmol) was added to a DCM (3 mL) solution of [1,2,4]triazolo[4,3-a]pyridine-3,6-diamine (compound 12-5, 70 mg, 0.47 mmol), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-1, 166.3 mg, 0.469 mmol) and diisopropylethylamine (181.9 mg, 1.4 mmol). The system was stirred at 25 °C for 1 hour. The reaction solution was added to water (10 mL), extracted twice with EA (5 mL), and the organic phases were combined. The mixture was washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and the residue obtained by rotary evaporation under reduced pressure was purified by C18 column chromatography (water-ACN, 0–10%, 0.1% formic acid) to yield the target compound (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 12, 2.27 mg, yield 0.89%). ESI-MS: m / z = 486.4 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.34(s,1H),8.70(s,1H),7.44(d,J=9.8Hz,1H),7.22-7.11(m,2H),7.04(dd,J=9.8,1.7Hz,1H),6.27(s,2H),5 .10(d,J=10.5Hz,1H),4.26(dd,J=10.3,7.7Hz,1H),3.96(d,J=2.1Hz,3H),2.77(t,J=7.5Hz,1H),1.60(s,3H),0.73(d,J=5.5Hz,3H).

[0372] Example 13: (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0373] Step 1: Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 1-1, 3 g, 8.47 mmol) in DCM (40 mL), add boron tribromide (6.36 g, 25.4 mmol) dropwise at 0 °C, react for 30 min, and then stir at room temperature for 3 hours. After the reaction was complete, the temperature was lowered to 0°C, and 30 mL of MeOH was added dropwise while stirring for 2 hours. The reaction solution was then evaporated to dryness, concentrated, and purified by silica gel column chromatography (eluent: EA:PE = 1:4) to obtain a colorless liquid (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (compound 13-1, 3 g, yield 100%). ESI-MS: m / z = 355.1 [M+1] + .

[0374] Step 2: Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (compound 13-1, 3 g, 8.47 mmol), deuterated iodomethane (1.47 g, 10.16 mmol), and Cs₂CO₃ (4.14 g, 12.7 mmol) were dissolved in ACN (50 mL) and reacted at 70 °C for 2 h. The reaction was monitored for completeness by liquid chromatography-mass spectrometry (LC-MS). Water (100 mL) was added, and the aqueous phase was extracted three times with EA. The obtained organic phase was washed three times with saturated NaCl solution, dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: EA:PE = 1:4) to obtain a colorless liquid (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (compound 13-2, 2.82 g, yield 89%). ESI-MS: m / z = 372.1 [M+1] + .

[0375] Step 3: Dissolve methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (compound 13-2, 2.82 g, 7.59 mmol) in anhydrous MeOH (20 mL) and water (6 mL). Add sodium hydroxide (607.2 mg, 15.18 mmol) at 0 °C and react at room temperature for 2 hours to allow the starting material to react completely. Then pour the reaction solution into ice water and adjust the pH to 1 with 1 N hydrochloric acid. The aqueous phase was extracted three times with EA, and the resulting organic phase was washed three times with saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:1) to obtain a colorless liquid (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 13-3, 2.7 g, 99%). ESI-MS: m / z = 358.0 [M+1] + .

[0376] Step 4: Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (2.7 g, 7.55 mmol), 5-amino-2-fluorobenzonitrile (1.03 g, 7.55 mmol), and DIPEA (2.93 g, 22.65 mol) in DMF (30 mL). Add 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.87 g, 7.55 mmol) at room temperature and stir for 16 hours at room temperature. After the reaction was complete, water (500 mL) was added. The aqueous phase was extracted three times with EA, and the resulting organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:4) to obtain a colorless liquid (2R,3S,4S,5R)-N-(3-fluorocyano-4-fluorophenyl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 13-4, 3 g, 83%). ESI-MS: m / z = 476.0 [M+1] + .

[0377] Step 5: (2R,3S,4S,5R)-N-(3-fluorocyano-4-fluorophenyl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 13-4, 1.46 g, 3.07 mmol) was dissolved in 1,4-dioxane (20 mL) and hydrazine hydrate (2 mL). The mixture was stirred at 100 °C for 4 hours. After the reaction was complete, the mixture was diluted with water and extracted three times with EA. The resulting organic phase was... Wash three times with saturated NaCl solution, dry to anhydrous Na₂SO₄, concentrate under reduced pressure, and purify the concentrate by silica gel column chromatography (eluent: EA:PE = 1:1) three times, yielding a white solid (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 13,772 mg, 51%). ESI-MS: m / z = 488.1 [M+1] + . 1 H NMR (400MHz, DMSO) δ11.33(s,1H),10.13(s,1H),7.99(d,J=1.3Hz,1H),7.31-7.12(m,4H),5.27(s,2H),5. 08(d,J=10.5Hz,1H),4.27(dd,J=10.4,7.6Hz,1H),2.81-2.71(m,1H),1.61(s,3H),0.73(d,J=6.1Hz,3H).

[0378] Example 14: (2R,3S,4S,5R)-N-(3-amino-1,2-benzoxazol-5-yl)-3-[3,4-difluoro-2-(methoxy-d3)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0379] Step 1: At room temperature (20°C), DMF (0.80 mL) and MeOH (0.10 mL) were added to the reaction flask, followed by (2R,3S,4S,5R)-N-(3-cyano-4-fluoro-phenyl)-3-[3,4-difluoro-2-(methoxy-d3)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 13-4, 40.0 mg, 84.1 μmol), acetohydroxylamine (16.2 mg, 215 μmol), and t-BuOK (24.2 mg, 215 μmol). After the addition was complete, the reaction mixture was stirred at 50°C for 16 hours. LC-MS analysis showed that approximately 40% of the starting material and approximately 57% of the product remained. The reaction was stopped, and the reaction solution was filtered. The filtrate was purified by prep-HPLC (eluent: ACN / water (NH4HCO3) = 50%-80%). The resulting fraction was freeze-dried under vacuum to give a white solid product (2R,3S,4S,5R)-N-(3-amino-1,2-benzoxazol-5-yl)-3-[3,4-difluoro-2-(methoxy-d3)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 14, 23 mg, yield: 55.6%). ESI-MS: [M+H] + =489.3. 1 H NMR (400MHz, CDCl3) δ8.47 (s, 1H), 8.18 (d, J = 1.8Hz, 1H), 7.41-7.30 (m, 2H), 7.1 6-7.08(m,1H),6.96-6.82(m,1H),5.31(s,1H),5.06(d,J=11.0Hz,1H),4.32(br d, J=2.0Hz, 2H), 4.12 (dd, J=8.0, 11.0Hz, 1H), 2.81 -2.70 (m, 1H), 1.70 (s, 3H), 0.90-0.71 (m, 3H).

[0380] Example 15: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazo-5-yl)-3-[3,4-difluoro-2-(methylthio)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide and (2S,3R,4R,5S)-N-(3-aminobenzo[d]isoxazo-5-yl)-3-[3,4-difluoro-2-(methylthio)phenyl]-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0381] Step 1: Under nitrogen protection at 15°C, potassium acetate (1.52 g, 15.53 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (189.43 mg, 258.89 μmol) were added to a 20 mL solution of compound 15-1 (2.0 g, 5.18 mmol) and bis(diphenylphosphine)ferrocene palladium dichloride. After the addition was complete, the reaction solution was stirred at 80°C under nitrogen protection for 16 hours. After the reaction was completed, the reaction solution was cooled to 20°C and then poured into water (50 mL). The resulting solution was extracted with EA (20 mL * 2), the combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (eluent: industrial hexane / EA = 100 / 3 to 100 / 5) to give a pale yellow oily compound 15-2 (1.4 g, yield: 74.25%). 1 H NMR (400MHz, CDCl3-d) δ4.38-4.16(m,2H),3.21-3.08(m,1H),1.48(s,3H),1.28-1.23(m,12H),1.23-1.18(m,6H).

[0382] Step 2: Under nitrogen protection at 15°C, potassium phosphate (2M, 1.20mL) and the [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride DCM complex (41.15mg, 50.39μmol) were added to a solution of compound 15-2 (400mg, 1.10mmol) and 1-bromo-3,4-difluoro-2-methylthiobenzene (240.92mg, 1.01mmol) in 1,4-dioxane (8.0mL). The reaction solution was stirred at 100°C under nitrogen protection for 2 hours. After cooling the reaction solution to 20°C, it was poured into water (20mL) and then extracted with EA (10mL*2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by prep-TLC (evolving solvent: industrial hexane / EA = 5 / 1) to give a pale yellow oily compound 15-3 (180 mg, yield: 36.05%, purity: 80%). 1 H NMR(400MHz, CDCl3-d)δ7.19-7.08(m,1H),6.88(ddd,J=1.7,5.0,8.5Hz,1H),4.17-4.09(m,2H),3.58(br s,1H),2.44(s,3H),1.75(s,3H),1.17-1.06(m,6H).

[0383] Step 3: Magnesium filings (0.47 g, 19.33 mmol) were added in portions to a MeOH (10 mL) solution of compound 15-3 (180 mg, 454.12 μmol) at 60 °C. After the reaction was initiated, the reaction solution was stirred at 60 °C for 6 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. EA (15 mL) and saturated citric acid aqueous solution (20 mL) were added to the crude product to dissolve it. The organic phase was separated, and the aqueous phase was extracted with EA (10 mL * 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by prep-HPLC (eluent: ACN / water (NH4HCO3) = 55%-85%) to give compound 15-4 (33 mg, yield: 18.91%) as a white solid. 1 H NMR (400MHz, CDCl3-d) δ7.19-7.10(m,1H),7.08-7.01(m,1H),4.97(d,J=10.5Hz,1H),4.57(dd,J=8. 1,10.4Hz,1H),3.73(s,3H),2.80(quin,J=7.7Hz,1H),2.46(s,3H),1.68(s,3H),0.82-0.68(m,3H).

[0384] Step 4: At 20°C, lithium hydroxide monohydrate (10.81 mg, 257.57 μmol) was added to a solution of compound 15-4 (66 mg, 171.71 μmol) in THF (2 mL) / MeOH (0.2 mL) / water (0.2 mL). After the addition was complete, the reaction solution was stirred at 20°C for 14 hours. After the reaction was completed, the pH of the reaction solution was adjusted to ~2 with dilute hydrochloric acid (4N, 0.5 mL), and then extracted with EA (5 mL * 2). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid compound 15-5 (64 mg, crude product). 1 H NMR (400MHz, CDCl3-d) δ7.11-7.03(m,1H),7.02-6.95(m,1H),4.91(d,J=10.9Hz,1H),4.47(d d,J=8.0,10.8Hz,1H),2.71(quin,J=7.7Hz,1H),2.37(s,3H),1.59(s,3H),0.69-0.61(m,3H).

[0385] Step 5: At 30°C, N-methylimidazole (NMI, 99.32 mg, 1.21 mmol, 96.43 μL) was added to a DMF (2.0 mL) solution of compound 15-5 (64 mg, 172.82 μmol) and 5-amino-2-fluorobenzonitrile (32.00 mg, 235.08 μmol). Then, TCFH (126.07 mg, 449.32 μmol) was added in a single addition at 0°C. After the addition was complete, the reaction mixture was stirred at 30°C for 8 hours. After the reaction was complete, saturated brine (5 mL) was added to the reaction mixture, and extraction was performed using EA (5 mL * 3). The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by prep-TLC (evolving solvent: industrial hexane / EA = 3 / 1) to give a colorless oily compound 15-6 (racemic mixture, 64 mg, yield: 75.82%). 1 H NMR(400MHz, CDCl3-d)δ8.35(s,1H),7.91(dd,J=2.8,5.4Hz,1H),7.64(ddd,J=2.8,4.5,9.1Hz,1H),7.16-7.06(m,3H) ,4.98(d,J=11.2Hz,1H),4.40(dd,J=7.9,11.2Hz,1H),2.76-2.66(m,1H),2.37(s,3H),1.64(s,3H),0.73-0.63(m,3H).

[0386] Step 6: At 20°C, t-BuOK (198.49 mg, 1.77 mmol) and acetohydroxylamine (132.83 mg, 1.77 mmol) were added to a DMF (1.6 mL) / water (0.2 mL) solution of compound 15-6 (64.00 mg, 131.03 μmol). After the addition was complete, the reaction solution was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was directly purified by prep-HPLC (eluent: ACN / water (NH4HCO3) = 50%-80%) to obtain a white solid compound 15 (racemic, 40 mg, yield: 60.88%). This compound was further separated by prep-SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); mobile phase: A: CO2, B: MeOH (0.1% NH3H2O); elution conditions: B%: 50%, isogradient elution, flow rate: 80 ml / min) to obtain white solid compounds 15-P1 (RT: 1.339 min; 19 mg) and 15-P2 (RT: 1.667 min; 15 mg).

[0387] Compound 15-1: ESI-MS: [M+H] +=502.1. 1 H NMR (400MHz, CDCl3-d) δ8.56 (s, 1H), 8.25 (d, J = 1.7Hz, 1H), 7.49-7.37 (m, 2H), 7 .33-7.22(m,2H),5.16(d,J=11.3Hz,1H),4.59(dd,J=7.8,11.3Hz,1H),4.40(br s,2H),2.95-2.80(m,1H),2.52(s,3H),1.81(s,3H),0.85(br dd,J=2.1,7.3Hz,3H).

[0388] Compound 15-2: ESI-MS: [M+H] + =502.1. 1 H NMR (400MHz, CDCl3-d) δ8.41 (s, 1H), 8.09 (d, J = 1.6Hz, 1H), 7.33-7.24 (m, 2H), 7 .19-7.06(m,2H),5.01(d,J=11.1Hz,1H),4.44(dd,J=7.8,11.2Hz,1H),4.26(br s,2H),2.73(quin,J=7.6Hz,1H),2.37(s,3H),1.66(s,3H),0.73-0.66(m,3H).

[0389] Example 16: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0390] Step 1: Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (compound 13-1, 275 mg, 0.78 mmol), 1-bromo-2-methoxyethane (129 mg, 0.93 mmol), and Cs2CO3 (506 mg, 1.55 mmol) were dissolved in ACN (5 mL) and reacted at 70 °C for 5 hours. After the reactants reacted completely, water (100 mL) was added. The aqueous phase was extracted three times with EA, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The concentrate was then subjected to silica gel column chromatography (eluent: EA:PE = 1:3) to give methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (compound 16-1, 225 mg, yield 70.29%). ESI-MS: m / z = 413.1 [M+1] + .

[0391] Step 2: Dissolve methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (225 mg, 0.55 mmol) in anhydrous MeOH (4 mL) and water (1 mL). Add sodium hydroxide (83 mg, 2.08 mmol) at 0 °C and react at room temperature for 5 hours until the reactants are completely reacted. Pour the reaction mixture into ice water and adjust the pH to 1 N hydrochloric acid. 6. The aqueous phase was extracted three times with EA, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:1) to obtain a white solid (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 16-2, 180 mg, yield 82.81%). ESI-MS: m / z = 339.1 [M+1] + .

[0392] Step 3: Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (compound 16-2, 150 mg, 0.38 mmol), 5-amino-2-fluorobenzonitrile (51 mg, 0.37 mmol), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (TCFH, 159 mg, 0.57 mmol) in ACN (4 mL). Add N-methylimidazole (46 mg, 0.56 mmol) at room temperature and stir at room temperature for 5 hours until the starting materials are fully reacted. After the reaction was complete, water (10 mL) was added. The aqueous phase was extracted three times with EA, and the organic phase was washed three times with saturated NaCl solution. The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:4) to obtain a white solid (2R,3S,4S,5R)-N-(3-cyano-4-fluorophenyl)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 16-3, 110 mg, yield 56.56%). ESI-MS: m / z = 517.1 [M+1] + .

[0393] Step 4: Dissolve (2R,3S,4S,5R)-N-(3-cyano-4-fluorophenyl)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (110 mg, 0.21 mmol) and methoxyamine (20 mg, 0.43 mmol) in DMF (1 mL) and water (0.2 mL), add K2CO3 (88 mg, 0.64 mmol), stir at 50 °C for 18 hours, after the reaction is complete, dilute with water, extract three times with EA, and use the organic phase... Wash three times with saturated NaCl solution, dry to anhydrous Na₂SO₄, concentrate under reduced pressure, and purify the concentrate by Prep-HPLC column (mobile phase: water (0.1% formic acid) / ACN, 10 min, ACN 50% to 80%) to give a white solid (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (compound 16, 54.2 mg, yield 48.05%). ESI-MS: m / z = 530.1 [M+1] + . 1H NMR (400MHz, DMSO) δ10.32(s,1H),8.22(d,J=1.8Hz,1H),7.52(dd,J=8.9,2 .1Hz,1H),7.39(d,J=8.9Hz,1H),7.21-7.12(m,2H),6.36(s,2H),5.11(d,J =10.9Hz,1H),4.36(dd,J=10.8,7.2Hz,1H),4.32-4.17(m,2H),3.68-3.58( m,2H),3.29(s,3H),2.90-2.80(m,1H),1.61(s,3H),0.71(d,J=5.9Hz,3H).

[0394] Example 17: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0395] Step 1: Hydrazine hydrate (5.68 g, 113.5 mmol) was added dropwise to a solution of 2-chloro-5-nitropyridine (17-1, 6 g, 37.8 mmol) in EtOH (100 mL) at room temperature. The mixture was stirred at 60 °C for 3 hours, and the reaction was confirmed to be complete by liquid chromatography-mass spectrometry (LC-MS). The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with EtOH to give a yellow solid compound, 2-hydrazino-5-nitropyridine (17-2, 5 g, yield 85.6%). ESI-MS: m / z = 155.1 [M+1] + .

[0396] Step 2: Compound 17-2 (5 g, 32.4 mmol) was dissolved in DCM (300 mL), and TEA (16.4 g, 162 mmol), 4-dimethylaminopyridine (5.94 g, 48.6 mmol), and di-tert-butyl dicarbonate (35.4 g, 162 mmol) were added at room temperature. After stirring at room temperature for 16 hours, the reaction was complete as indicated by LC-MS. The reaction solution was evaporated to dryness, concentrated, and purified by silica gel column chromatography (eluent: EA:PE = 1:10) to obtain a yellow solid compound, 2-(5-nitropyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tri-tert-butyl ester (17-3, 3.5 g, crude product). ESI-MS: m / z = 455.4 [M+1] + .

[0397] Step 3: Compound 17-3 (3.5 g, crude) was dissolved in THF (50 mL), and 10% Pd / C (1 g) was added at room temperature. The mixture was then stirred at room temperature under hydrogen atmosphere for 16 hours. Liquid chromatography-mass spectrometry (LC-MS) showed the reaction was complete. The filtrate was filtered through diatomaceous earth, evaporated to dryness, concentrated, and purified by silica gel column chromatography (eluent: EA:PE = 1:1) to obtain a white solid compound, 2-(5-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tritert-butyl ester (17-4, 2.2 g, overall yield of two steps: 16.0%). ESI-MS: m / z = 425.0 [M+1] + . 1 H NMR (400MHz, DMSO-d6) δppm 7.63 (d, J = 2.8 Hz, 1H), 7.34-7.32 (m, 1H), 6.98-6.95 (m, 1H), 5.21 (s, 2H), 1.43 (s, 9H), 1.39 (s, 18H).

[0398] Step 4: Compounds 17-4 (500 mg, 1.17 mmol), (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-D3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (13-3, 543 mg, 1.52 mmol), and N-methylimidazole (672 mg, 8.19 mmol) were dissolved in DMF (10 mL). TCFH (853 mg, 3.04 mmol) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, EA (50 mL) was added for dilution, and the mixture was washed with water (20 mL * 3) and saturated NaCl aqueous solution (20 mL), respectively. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:3) to give a yellow solid compound, 2-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tritert-butyl ester (17-5, 850 mg, yield 94.4%). ESI-MS: m / z = 764.3 [M+1] + .

[0399] Step 5: Compound 17-5 (825 mg, 1.08 mmol) was dissolved in DCM (10 mL), and boron trifluoride diethyl ether solution (2 mL) was added at room temperature. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction solution was concentrated under reduced pressure, the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, and then extracted three times with EA (30 mL). The organic phase was washed with saturated NaCl aqueous solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow solid compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-N-(6-hydrazinopyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (17-6, 450 mg, crude product). ESI-MS: m / z = 464.0 [M+1] + .

[0400] Step 6: Compound 17-6 (450 mg crude) was dissolved in a mixed solvent of EtOH (10 mL) and water (2 mL). DIPEA (376 mg, 2.91 mmol) and cyanogen bromide (206 mg, 1.94 mmol) were added at 0 °C, and the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, water (20 mL) was added, and then extracted three times with EA (30 mL). The organic phase was washed with a saturated NaCl aqueous solution (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The concentrate was purified by HPLC (ACN / water, 0.1% TFA) to give a white solid compound (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (17,224.8 mg, yield 47.4%). ESI-MS: m / z = 489.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.32(s,1H),8.70(s,1H),7.43(d,J=9.8Hz,1H),7.18-7.14(m,2H),7.04(d,J=8.1Hz,1H),6.25(s,2 H), 5.10 (d, J = 10.4Hz, 1H), 4.29-4.24 (m, 1H), 2.79-2.67 (m, 1H), 1.60 (s, 3H), 0.73 (d, J = 6.4Hz, 3H).

[0401] Example 18: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0402] Step 1: Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (13-1, 15 g, 42.4 mmol) was dissolved in DMF (600 mL). Cs2CO3 (137.7 g, 423.7 mmol) and sodium 2-chloro-2,2-difluoroacetate (32.5 g, 32.5 mmol) were added at 25 °C. After stirring at 90 °C for 12 hours, the reaction was complete as indicated by liquid chromatography-mass spectrometry. The reaction solution was cooled to 25°C, diluted with water (2 L), and extracted with EA (200 mL * 3). The organic phases were combined, washed once with saturated brine (500 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EA:PE = 1:5) to give a pale yellow liquid compound (2R,3S,4S,5R)-3-(2-difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxylate (18-1, 11.2 g, 65.5%). ESI-MS: m / z = 405.0 [M+1] + . 1 H NMR(400MHz,DMSO)δppm 7.52–7.07(m,3H),5.19(d,J=10.5Hz,1H),4.14(dd,J=10.4,7.6Hz,1H),3.60(s,3H),2.69–2.65(m,1H),1.52(s,3H),0.73(d,J=5.5Hz,3H).

[0403] Step 2: Compound 18-1 (1.4 g, 3.95 mmol) was dissolved in DCM (7 mL), and an aqueous solution of KOH (2.77 g, 49.3 mmol) (7 mL) was added dropwise at 0 °C. The reaction was allowed to proceed for 16 h. The pH was adjusted to 2 by adding 1 N HCl at 0 °C. The aqueous phase was extracted three times with EA, and the organic phase was washed three times with a saturated NaCl aqueous solution. The mixture was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a yellow liquid compound (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (18-2, 0.4 g, yield 25%). ESI-MS: m / z = 389.1 [M-1] + .

[0404] Step 3: Compound 18-2 (217 mg, 0.55 mmol), 5-amino-2-fluorobenzonitrile (75 mg, 0.55 mmol), and DIPEA (213.2 mg, 1.6 mmol) were dissolved in DMF (3 mL). 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (209.1 mg, 0.55 mmol) was added at room temperature, and the mixture was stirred for 2 hours at room temperature. After the reaction was complete, water (50 mL) was added, and the aqueous phase was extracted three times with EA. The organic phase was washed three times with a saturated NaCl solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:4) to give a colorless liquid compound (2R,3S,4S,5R)-N-(3-cyano-4-fluorophenyl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (18-3, 200 mg, yield 71%). ESI-MS: m / z = 509.0 [M+1] + .

[0405] Step 4: Compound 18-3 (200 mg, 0.39 mmol) was dissolved in DMF (3 mL) and water (1 mL). K2CO3 (108.7 mg, 0.787 mmol) and N-hydroxyacetamide (59 mg, 0.787 mmol) were added at room temperature, and the mixture was stirred at 50 °C for 16 hours. After the reaction was complete, the reaction solution was diluted with water, extracted three times with EA, and the organic phase was washed three times with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:2) to prepare a white solid compound (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (18, 37.72 mg, yield 18%). ESI-MS: m / z = 521.8 [M+1] + . 1 H NMR (400MHz, DMSO) δ10.35 (s, 1H), 8.23 ​​(d, J = 1.8Hz, 1H), 7.53–7.44 (m, 2H), 7.41–7.09 (m, 3H), 6.37 (s, 2H), 5.14(d,J=10.4Hz,1H),4.31(dd,J=10.3,7.6Hz,1H),2.81–2.71(m,1H),1.60(s,3H),0.77(d,J=6.1Hz,3H).

[0406] Example 19: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0407] Step 1: Compound 18-2 (712 mg, 1.82 mmol), 2-(5-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (17-4, 600 mg, 1.40 mmol), and N-methylimidazole (806 mg, 9.82 mmol) were dissolved in DMF (10 mL), and TCFH (1025 mg, 3.64 mmol) was added at 0 °C. The reaction was allowed to proceed for 2 h. After the reaction was complete, water (30 mL) was added, and the aqueous phase was extracted three times with EA (30 mL). The organic phase was washed three times with a saturated NaCl aqueous solution (30 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:5) to give a yellow solid compound 2-(5-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-trifluoromethyltetrahydrofuran-2-carboxamido)pyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (19-1, 800 mg, yield 71.27%). ESI-MS: m / z = 797.0 [M+1] + .

[0408] Step 2: Compound 19-1 (800 mg, 1.0 mmol) was dissolved in DCM (20 mL), and boron trifluoride diethyl ether (1 mL) was added at 0 °C. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The solution was then extracted three times with EA (30 mL). The organic phase was washed with saturated NaCl aqueous solution (10 mL), dried over anhydrous Na2SO4, and then concentrated under reduced pressure to give a yellow solid compound (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(6-hydrazylpyridin-3-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (19-2, 800 mg, crude product). ESI-MS: m / z = 497.0 [M+1] + .

[0409] Step 3: Compound 19-2 (800 mg) was dissolved in EtOH (10 mL) and water (2 mL). DIPEA (624 mg, 4.83 mmol) and cyanogen bromide (204 mg, 1.93 mmol) were added at 0 °C, and the mixture was stirred for 2 hours. After the reaction was complete, the reaction solution was diluted with water (20 mL) and extracted three times with EA (30 mL). The organic phase was washed three times with a saturated NaCl aqueous solution (30 mL), dried over anhydrous Na₂SO₄, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by Prep-HPLC (ACN / water, 0.1% TFA) to give a white solid compound (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (19,333.3 mg, yield 38.47%). ESI-MS: m / z = 522.0 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δppm 10.32(s,1H),8.69(s,1H),7.52-7.42(m,2H),7.35-7.08(m,2H),7.06-7.04(m,1H),6.25(s,2H), 5.12(d,J=10.4Hz,1H),4.32-4.28(m,1H),2.79-2.74(m,1H),1.59(s,3H),0.75(d,J=6.4Hz,3H).

[0410] Example 20: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0411] Step 1: Under nitrogen protection at 0°C, ethyl 2-(diethoxy-phosphoryl)-propionate (20-1, 552.76 g, 2.32 mol, 505.26 mL) was dissolved in THF (2.0 L). Then, sodium hydride (92.81 g, 2.32 mol, 38.67 mL, 60% purity) was added to the reaction solution in portions. The reaction solution was stirred at 0°C under nitrogen protection for 30 minutes. Then, a solution of 1,1,1-trifluoroacetone (20-2, 200 g, 1.78 mol, 159.74 mL) in THF (200 mL) was added dropwise to the reaction system. After the addition was complete, the reaction solution was naturally heated to 25°C under a nitrogen atmosphere and stirred at 25°C for 18 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 7-8 with 1N dilute hydrochloric acid under ice bath conditions, and then extracted with EA (1500mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated at room temperature. The concentrate was purified by silica gel column chromatography (eluent: hexane / EA = 100 / 1 to 0 / 1) to give ethyl 4,4,4-trifluoro-2,3-dimethylbut-2-enoate (20-3g, 140.9g, yield 40.24%). 1 H NMR (400MHz, CDCl3-d) δ = 4.20 (q, J = 7.2Hz, 2H), 1.98 (dd, J = 1.6, 2.6Hz, 3H), 1.86 (d, J = 1.5Hz, 3H), 1.26 (t, J = 7.2Hz, 3H).

[0412] Step 2: Under nitrogen protection at 0°C, 2-mercapto-EA (20-4, 202.84 g, 1.69 mol, 185.07 mL) was added to a round-bottom flask, followed by piperidine (28.74 g, 337.59 mmol, 33.34 mL). Compound 20-3 (140.9 g, 718.27 mmol) was added dropwise to the reaction system. After the addition was complete, the reaction mixture was stirred at 50°C under nitrogen protection for 24 hours. TLC (evolving solvent: hexane / EA = 5 / 1) showed complete consumption of the starting material. After the reaction was complete, 0.1 N hydrochloric acid (400 mL) was added dropwise to quench the reaction. The aqueous phase was extracted with PE (800 mL × 3), the combined organic phases were washed with saturated brine (800 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: hexane / EA = 100 / 1 to 0 / 1) to give a yellow oily compound 3-[(2-ethoxy-2-oxoylethyl)thiol]-4,4,4-trifluoro-2,3-dimethylbutyrate ethyl ester (20-5, 68.5 g, yield 30.15%). 1H NMR (400MHz, CDCl3-d) δ = 4.20-4.03 (m, 4H), 3.41-3.30 (m, 2H), 2.77 (q, J = 7.1Hz, 1H), 1.44 (s, 3H), 1.32 (d, J = 7.1Hz, 3H), 1.23-1.17 (m, 6H).

[0413] Step 3: Under nitrogen protection at 0°C, t-BuOK (1M, 281.50mL) was added dropwise to a solution of compound 20-5 (68.5g, 216.54mmol) in diethyl ether (1360mL). After the addition was complete, the reaction mixture was stirred at 0°C for 10 minutes. TLC (electrolyte: hexane / EA = 5 / 1) showed that the reaction was complete. Under nitrogen protection at 0°C, glacial acetic acid (500mL) and water (1.0L) were added dropwise to quench the reaction mixture. The aqueous phase was extracted with EA (500mL × 3). The combined organic phases were washed with saturated brine (1.0L), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow oily compound 20-6 (59.5g, crude product). The crude product was used directly in the next reaction step. 1 H NMR (400MHz, CDCl3-d) δ = 4.40 (s, 1H), 4.21-4.18 (m, 2H), 2.84 (q, J = 7.2Hz, 1H), 1.48 (s, 3H), 1.26-1.22 (m, 6H).

[0414] Step 4: Under nitrogen protection at -70°C, DIPEA (34.14 g, 264.18 mmol, 46.02 mL) was added dropwise to a DCM (595 mL) solution of compound 20-6 (59.5 g, 220.15 mmol). Then, a DCM (60 mL) solution of trifluoromethanesulfonic anhydride (62.11 g, 220.15 mmol, 36.32 mL) was added dropwise to the reaction solution at -70°C. After the addition was complete, the reaction solution was stirred at -70°C for 1 hour. TLC (developing solvent: hexane / EA = 10 / 1) showed that the starting material was completely consumed. After the reaction was complete, a saturated sodium bicarbonate solution (500 mL) was added dropwise to the reaction solution, and then the aqueous phase was extracted with DCM (800 mL × 2). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: hexane / EA = 100 / 1 to 10 / 1) to give a pale yellow oily compound 20-7A (4.31 g, yield 4.87%). 1¹H NMR (400 MHz, CDCl₃-d) δ 4.39 (q, J = 7.1 Hz, 2H), 3.30 (q, J = 7.3 Hz, 1H), 1.67 (d, J = 0.6 Hz, 3H), 1.43–1.34 (m, 6H). A pale yellow oily compound 20-7B (21.43 g, yield 24.19%) was also obtained. 1 H NMR (400MHz, CDCl3-d) δ = 4.24 (q, J = 7.2Hz, 2H), 3.37 (q, J = 7.2Hz, 1H), 1.48 (s, 3H), 1.31-1.23 (m, 6H).

[0415] Step 5: Under nitrogen protection, potassium phosphate (2.0 M, 7.46 mL) and tetraphenylphosphine palladium (287.22 mg, 248.55 μmol) were added sequentially to a toluene (20 mL) solution of compound 20-7A (2.00 g, 4.97 mmol) and 3,4-difluoro-2-methoxyphenylboronic acid (20-8, 1.03 g, 5.47 mmol). After the addition was complete, the reaction mixture was stirred at 100 °C under nitrogen protection for 16 hours. LCMS showed complete consumption of the starting materials. After the reaction was complete, the reaction mixture was cooled to 20 °C and then poured into water (50 mL). The resulting solution was extracted with EA (20 mL × 2), the combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: hexane / EA = 100 / 1 to 100 / 5) to give compound 20-9 (1.87 g, yield 94.1%). 1 H NMR(400MHz, CDCl3-d)δ=6.83-6.75(m,1H),6.68-6.60(m,1H),4.05-3.97(m,2H),3.86-3 .82(m,3H),3.31(q,J=7.4Hz,1H),1.70(s,3H),1.07(t,J=7.1Hz,3H),1.01-0.98(m,3H).

[0416] Step 6: Under argon protection at 20°C, compound 20-9 (200 mg, 504.58 μmol) was dissolved in MeOH (20 mL), and then wet Pd / C (1.07 g, 10% Pd) was added to the reaction solution. After the addition was complete, the reaction solution was reacted at 90°C under a hydrogen atmosphere (2.5 MPa) for 24 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered through diatomaceous earth, and then the filtrate was concentrated. The concentrate was purified by Prep-HPLC (eluent: ACN / water (NH4HCO3) = 55%-85%) to give a pale yellow oily compound 20-10 (91 mg, yield 45.27%).1 H NMR (400MHz, CDCl3-d) δ = 7.74-7.63 (m, 1H), 6.73 (dd, J = 7.7, 9.2Hz, 1H), 4.31 (t, J = 7.2Hz, 1H), 3.94 (t,J=2.8Hz,1H),3.93-3.87(m,2H),3.86(d,J=1.9Hz,3H),2.67-2.57(m,1H),1.65(s,3H),0.95(br dd,J=2.0,7.5Hz,3H),0.88(t,J=7.1Hz,3H)

[0417] Step 7: At 0°C, a t-BuOK THF solution (1 mol / L, 753.79 μL, 3.3 eq) was added to a THF solution of compound 20-10 (91 mg, 228.42 μmol) in 0.91 mL. After the addition was complete, the reaction mixture was stirred at 0°C for 4 hours. LC-MS showed that the starting material was completely consumed. After the reaction was complete, the pH of the reaction mixture was adjusted to approximately 1 with dilute hydrochloric acid (1 N, 0.5 mL), and then extracted with EA (5 mL × 2). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain a pale yellow solid compound 20-11 (63 mg, crude product). The crude product was used directly in the next reaction step. 1 H NMR (400MHz, CDCl3-d) δ = 6.83-6.69 (m, 2H), 4.38 (br d, J = 11.4Hz, 1H), 4.29-4.14 (m, 1H), 3.93 (br s, 3H), 2.47 (br s, 1H), 1.74 (br s,3H),0.79-0.64(m,3H).

[0418] Step 8: At 25°C, NMI (97.77 mg, 1.19 mmol, 94.92 μL) was added to a DMF (0.63 mL) solution of compound 20-11 (63 mg, 170.12 μmol) and 5-amino-2-fluorobenzonitrile (30.10 mg, 221.15 μmol). Then, TCFH (119.33 mg, 425.29 μmol) was added in portions at 0°C. After the addition was complete, the reaction solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was poured into saturated brine (5 mL) and then extracted with EA (5 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and then the filtrate was concentrated under reduced pressure. The concentrate was purified by Prep-TLC (evolving solvent: hexane / EA = 3 / 1) to give colorless oily compound 20-12 (racemic mixture, 48 mg, yield 57.77%). 1H NMR (400MHz, CDCl3-d))δ=8.15(br s,1H),7.87-7.79(m,1H),7.60-7.54(m,1H),7.08(br t,J=8.7Hz,1H),6.98-6.88(m,1H),6.83-6.76(m,1H),4.53-4.47(m,1H),4.40(br dd,J=5.4,11.1Hz,1H),3.97(d,J=2.3Hz,3H),2.59-2.53(m,1H),1.85(s,3H),0.80(br d,J=4.8Hz,3H).

[0419] Step 9: At 25°C, t-BuOK (28.23 mg, 251.57 μmol) and acetic acid (8.88 mg, 251.57 μmol) were added to a DMF (0.8 mL) / water (0.1 mL) solution of compound 20-12 (48.00 mg, 98.27 μmol). After the addition was complete, the reaction solution was stirred at 80°C for 14 hours. After the reaction was completed, the reaction solution was directly purified by Prep-HPLC (eluent: ACN / water (NH4HCO3) = 50%-80%) to obtain a white solid racemic compound 20 (24 mg). This was then purified by Prep-SFC (Column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1%)). [NH3H2O]; B%: 35%, isogradient elution) further resolved to give compounds 20-P1 and 20-P2, namely compounds (2R,3S,4S,5R)-N-(3-amino-1,2-benzoxazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)thiapentyl-2-carboxamide and compounds (2S,3R,4R,5S)-N-(3-amino-1,2-benzoxazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)thiapentyl-2-carboxamide.

[0420] Compound 20-P1 (white solid, 12.0 mg): RT: 1.011 min. ESI-MS: [M+H] + =502.2. 1H NMR (400MHz, CDCl3-d) δ = 8.07 (s, 2H), 7.35 (d, J = 9.0Hz, 1H), 7.24-7.21 (m, 1H), 7.09-7.03 (m, 1H), 6.89 (br d,J=8.0Hz,1H),4.62-4.55(m,1H),4.52-4.44(m,1H),4.31(br s, 2H), 4.04 (d, J = 2.3Hz, 3H), 2.71-2.59 (m, 1H), 1.93 (s, 3H), 0.91-0.88 (m, 3H).

[0421] Compound 20-P2 (white solid, 10.7 mg): RT: 1.236 min. ESI-MS: [M+H] + =502.2. 1 H NMR (400MHz, CDCl3-d) δ = 8.11-8.04 (m, 2H), 7.35 (d, J = 8.9Hz, 1H), 7.24-7.22 (m, 1H), 7.07 -7.02(m,1H),6.92-6.85(m,1H),4.63-4.54(m,1H),4.49(dd,J=5.4,11.1Hz,1H),4.32(br s, 2H), 4.04 (d, J = 2.4Hz, 3H), 2.69-2.60 (m, 1H), 1.93 (s, 3H), 0.89 (br d, J = 6.1Hz, 3H).

[0422] Example 21: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0423] Step 1: 2-Chloro-4-nitropyridine (21-1, 1.0 g, 6.31 mmol) and di-tert-butyl azide dicarboxylate (2.22 g, 9.46 mmol) were dissolved in toluene (50 mL). Cs₂CO₃ (4.11 g, 12.62 mmol), 1,1'-bis(diphenylphosphine)ferrocene (1.05 g, 1.89 mmol), and Pd₂(dba)₃ (577 mg, 0.63 mmol) were added, and the mixture was stirred at 100 °C under nitrogen protection for 16 hours. After the reaction was complete, the reaction solution was cooled back to room temperature, concentrated under reduced pressure, diluted with water (50 mL), and extracted three times with EA (50 mL). The organic phase was washed with saturated NaCl aqueous solution (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:5) to give a yellow solid compound, 1-(4-nitropyridin-2-yl)hydrazine-1,2-dicarboxylic acid di-tert-butyl ester (21-2, 1.1 g, yield 49.1%). ESI-MS: m / z = 199.1 [M-156+H] + .

[0424] Step 2: Compound 21-2 (1.1 g, 3.09 mmol) was dissolved in THF (20 mL), and 10% Pd / C (200 mg) was added at room temperature. After stirring at room temperature under hydrogen atmosphere for 16 hours, the reaction was complete as indicated by LC-MS. The reaction solution was filtered, the filtrate was evaporated to dryness, concentrated, and purified by silica gel column chromatography (eluent: EA:PE = 2:1) to give a white solid compound, 1-(4-aminopyridin-2-yl)hydrazine-1,2-dicarboxylic acid di-tert-butyl ester (21-3, 850 mg, yield 85.0%). ESI-MS: m / z = 325.1 [M+H] + .

[0425] Step 3: Compound 21-3 (600 mg, 1.84 mmol), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1-1, 1.17 g, 3.31 mmol), and N-methylimidazolium (1.06 g, 12.9 mmol) were dissolved in DMF (30 mL). N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (1.34 g, 4.78 mmol) was added at room temperature, and the mixture was stirred for 2 hours at room temperature. After the reaction was complete, EA (100 mL) was added for dilution, and the mixture was washed with water (30 mL x 3) and saturated NaCl aqueous solution (30 mL), respectively. The organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:3) to give a yellow solid compound, 1-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)hydrazine-1,2-dicarboxylic acid di-tert-butyl ester (21-4, 450 mg, yield 36.8%). ESI-MS: m / z = 660.9 [M+H] + .

[0426] Step 4: Compound 21-4 (440 mg, 0.66 mmol) was dissolved in DCM (10 mL), and boron trifluoride diethyl ether solution (1 mL) was added at room temperature. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted three times with EA (30 mL). The organic phase was washed with saturated NaCl aqueous solution (10 mL) and dried over anhydrous Na2SO4 to give a yellow solid compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-N-(2-hydrazylpyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (21-5, 260 mg, yield 84.8%). ESI-MS: m / z = 461.0 [M+H] + .

[0427] Step 5: Compound 21-5 (260 mg, 0.56 mmol) was dissolved in a mixed solvent of EtOH (5 mL) and water (1 mL). TEA (284 mg, 2.80 mmol) and cyanogen bromide (119 mg, 1.12 mmol) were added at 0 °C, and the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, then water (20 mL) was added, and the mixture was extracted three times with EA (30 mL). The organic phase was washed with a saturated NaCl aqueous solution (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The concentrate was purified by Prep-HPLC (ACN / water, 0.1% TFA) to give a white solid compound (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (21, 49.9 mg, 18.2%). ESI-MS: m / z = 486.1 [M+1] + . 1 H NMR(400MHz,DMSO-d6)δppm 11.08(s,1H),8.40(d,J=7.6Hz,1H),8.13(s,1H),7.58(s,2H),7.32–7.30(m,1H),7.19–7.16(m,2H),5.17(d,J =10.0Hz,1H),4.30–4.26(m,1H),3.96(d,J=2.0Hz,3H),2.81–2.77(m,1H),1.61(s,3H),0.74(d,J=6.4Hz,3H).

[0428] Example 22: Synthesis of (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0429] Step 1: Hydrazine hydrate (1.10 g, 21.5 mmol, 1.06 mL, 98% pure) was added to a solution of intermediate 20-12 (210 mg, 429 μmol) in EtOH (2.1 mL) at 20 °C. After the addition was complete, the reaction solution was stirred at 90 °C for 5 hours. LCMS showed that intermediate 20-12 was completely consumed. After the reaction was complete, the reaction solution was cooled and filtered. The resulting filtrate was directly purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 50%–80%) to obtain a white solid racemic compound 22 (60 mg).

[0430] Step 2: The obtained racemic mixture was separated by prep-SFC (separation conditions: column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-EtOH]; B%: 35%, isocratic elution mode), yielding white solids 22-P1 (Peak 1, SFC RT = 1.154 min, 24.28 mg) and 22-P2 (Peak 2, SFC). RT = 1.330 min, 13.56 mg), namely the compound (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and the white solid (2S,3R,4R,5S)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: [M+H]+ = 501.1.

[0431] Compound 22-P1 (i.e., Peak 1): 1 H NMR (400MHz, chloroform-d) δ8.15-8.01(m,1H),8.00-7.88(m,1H),7.27-7.21(m,1H),7.20-7.12(m,1H),7.12-7.04(m,1H ),6.94-6.84(m,1H),4.66-4.57(m,1H),4.56-4.48(m,1H),4.05(s,3H),2.72-2.61(m,1H),1.95(s,3H),0.91(br d,J=5.0Hz,3H).

[0432] Compound 22-P2 (i.e., Peak 2): 1¹H NMR (400MHz, chloroform-d) δ 8.06–7.90 (m, 1H), 7.90–7.80 (m, 1H), 7.18–7.13 (m, 1H), 7.11–7.04 (m, 1H), 7.02–6.95 (m, 1H), 6.87–6.74 (m, 1H), 4.59–4.48 (m, 1H), 4.46–4.38 (m, 1H), 3.96 (d, J = 2.1 Hz, 3H), 2.64–2.50 (m, 1H), 1.92–1.80 (m, 3H), 0.82 (br d, J = 5.4 Hz, 3H).

[0433] Example 23: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazol[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazol[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0434] Step 1: Dissolve intermediate 20-11 (300 mg, 810 μmol) in DMF (2.0 mL). Then, at 0 °C, add N-methylimidazolium (465 mg, 5.67 mmol, 451 μL), 2-(5-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (intermediate 17-4, 343 mg, 810 μmol), and TCFH (590 mg, 2.11 mmol) sequentially to the reaction solution. After the addition is complete, stir the reaction solution at room temperature (25 °C) for 16 hours. TLC (developing solvent: industrial hexane / EA = 3 / 1, raw material R) f =0.02, Product R f =0.34) and LCMS showed that the starting material was completely consumed. After the reaction was complete, the reaction solution was poured into 50 mL of water, and then extracted three times with EA (20 mL * 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1 to 0 / 1) to give a pale yellow solid compound 23-1 (250 mg, 321 μmol, yield: 39.73%). 1¹H NMR (400 MHz, chloroform-d) δ = 9.81–9.40 (m, 1H), 8.64–8.44 (m, 2H), 7.99–7.68 (m, 1H), 6.94–6.59 (m, 2H), 5.03–4.93 (m, 1H), 4.64–4.58 (m, 1H), 4.07 (d, J = 2.0 Hz, 3H), 2.70–2.62 (m, 1H), 1.95 (s, 3H), 1.53–1.29 (m, 27H), 0.88 (br d, J = 5.1 Hz, 3H).

[0435] Step 2: Compound 23-1 (250 mg, 321 μmol) was dissolved in MeOH (5.0 mL), and then MeOH hydrochloric acid (4 M, 1.0 mL) was added in a single batch at 25 °C. The reaction mixture was then stirred at 25 °C for 16 hours. LC-MS showed that the starting material was completely consumed. After the reaction was complete, the reaction mixture was concentrated under reduced pressure at approximately 40 °C to obtain a white solid compound 23-2 (150 mg, crude product, HCl).

[0436] Step 3: Compound 23-2 (150 mg, crude product, HCl) was dissolved in EtOH (15 mL). Then, N,N-diisopropylethylamine (188.98 mg, 1.46 mmol, 254.68 μL) and di(1H-imidazol-1-yl)imine (61.27 mg, 380.17 μmol) were added sequentially to the reaction solution at 20 °C. After the addition was complete, the reaction solution was stirred at 90 °C for 16 hours. LCMS showed that the starting materials were completely consumed. After the reaction was completed, the reaction solution was concentrated under reduced pressure at approximately 40 °C to obtain the crude product. The crude product was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7um; mobile phase: [H2O(10mM NH4HCO3)-ACN]; gradient: 46%-76% B, for 8.0 min) to obtain racemic 23 (36 mg, racemic).

[0437] Step 4: The obtained racemic 23 was separated by prep-SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 25%, isocratic elution mode), yielding a pair of corresponding isomers 23-P1 (Peak 1, SFC RT = 0.954min, 15.13mg) and 23-P2 (Peak 2, SFC). RT = 1.126 min, 10.90 mg), namely compounds (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: [M+H]+ = 502.1.

[0438] Compound 23-P1 (i.e., Peak 1): 1 H NMR (400MHz, chloroform-d)δ=10.18(br s,1H),8.58(br s,1H),7.27(br s,1H),7.15-7.04(m,1H),6.93(br s,1H),6.73(q,J=8.0Hz,1H),5.55-4.57(m,3H),4.48(br dd,J=4.9,11.0Hz,1H),3.96(s,3H),2.56-2.47(m,1H),1.82(br s,3H),0.74(br s,3H).

[0439] Compound 23-P2 (i.e., Peak 2): 1 H NMR (400MHz, DMSO-d6) δ=10.51(s,1H),8.69(s,1H),7.44(d,J=9.8Hz,1H),7.20(q,J=9.0Hz,1H ),7.14-7.05(m,1H),6.90(dd,J=1.3,9.8Hz,1H),6.25(s,2H),4.87(d,J=11.6Hz,1H),4.51(br dd,J=5.3,11.6Hz,1H),4.01(d,J=1.5Hz,3H),2.71-2.57(m,1H),1.86(s,3H),0.80(br d,J=4.4Hz,3H).

[0440] Example 24: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0441] Step 1: Compound 21-2, namely 1-(5-nitropyridin-2-yl)hydrazine-1,2-dicarboxylic acid tert-butyl ester (21-2, 30.0 g, 87.2 mmol), was dissolved in 1,4-dioxane (1000 mL). TEA (34.08 g, 336.8 mmol) and Boc2O (55.13 g, 252.6 mmol) were added at room temperature. After stirring at 80 °C for 16 hours, the reaction was monitored for completeness using LC-MS. The reaction solution was concentrated by rotary evaporation and purified by silica gel column chromatography (eluent: EA:PE = 1:3) to obtain a yellow solid compound 24-1, namely 2-(4-nitropyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (24-1, 22.0 g, yield: 57.1%). ESI-MS: m / z = 344.0 [M-256+1] + .

[0442] Step 2: Compound 2-(4-nitropyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (24-1, 22.0 g, 48.1 mmol) was dissolved in EA (0.8 L), and 10% Pd / C (9.4 g) was added at room temperature. After stirring at room temperature under hydrogen atmosphere for 2 hours, the reaction was monitored by liquid chromatography-mass spectrometry until complete. The mixture was filtered, and the filtrate was concentrated by rotary evaporation to obtain a white solid compound 24-2, namely 2-(4-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (24-2, 15.0 g, yield 72.9%). ESI-MS: m / z = 425.0 [M+H] + . 1 H NMR (400MHz, DMSO) δ7.72 (d, J = 4.9 Hz, 1H), 6.97 (s, 1H), 6.27 (d, J = 3.2 Hz, 1H), 6.11 (s, 2H), 1.43 (s, 18H), 1.38 (s, 9H).

[0443] Step 3: At 25°C, N-methylimidazole (NMI, 434.52 mg, 5.29 mmol, 421.86 μL) was added to a DMF (DMF, 3 mL) solution of compound 2-(4-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (24-2, 385.13 mg, 907.29 μmol) and compound 20-11 (280.00 mg, 756.07 μmol). Then, TCFH (551.56 mg, 1.97 mmol) was added to the reaction solution in portions at 0°C. After the addition was complete, the reaction solution was stirred at 25°C for 16 hours. LCMS showed that compound 20-11 was completely consumed. After the reaction was complete, the reaction solution was poured into saturated brine (10 mL) and then extracted with EA (5 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by prep-TLC (eluent: industrial hexane / EA = 3 / 1) to give a pale yellow solid compound 24-3 (racemic mixture, 400 mg, yield: 66.06%). ESI-MS: [M+H] + =777.2.

[0444] Step 4: Compound 24-3 (0.4 g, 514.93 μmol) and hydrochloric acid / methyl tert-butyl ether (5 M, 8.0 mL) were added to the reaction flask at 15 °C. The reaction mixture was then stirred at 15 °C for 16 hours. LC-MS showed complete consumption of the starting material. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain a yellow solid compound 24-4 (racemic mixture, 310 mg, crude hydrochloride).

[0445] Step 5: At 15°C, N,N-diisopropylethylamine (DIEA, 341.94 mg, 2.65 mmol, 460.83 μL) was added to a 3.0 mL EtOH solution of compound 24-4 (310 mg, 529.15 μmol). After stirring the reaction solution at 15°C for 5 minutes, cyanogen bromide (0.08 g, 755.29 μmol, 55.44 μL) was added in portions at the same temperature. After the addition was complete, the reaction solution was stirred at 15°C for 16 hours. LCMS showed that the starting material 24-4 was completely consumed. After the reaction was complete, an ammonia / MeOH solution (7 M, 1 mL) was added to the reaction solution to quench the reaction. The resulting solution was then directly purified by prep-HPLC (eluent: ACN / water (NH4HCO3) = 40%-70%) to give off-white solid compound 24 (racemic mixture, 100 mg, yield: 37.69%).

[0446] Step 6: The obtained racemic mixture 24 (100 mg) was further resolved by prep-SFC (column: DAICEL CHIRALPAK IK (250 mm * 25 mm, 10 μm); mobile phase: [CO2–EtOH (0.1% NH3H2O)]; B%: 40%, isocratic elution mode) to obtain pale yellow solid compounds 24-P1 (Peak 1, SFC RT = 1.087 min, 45 mg) and 24-P2 (Peak 2, SFC) RT = 1.304 min, 46 mg), namely compounds (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: [M+H]+ = 502.2.

[0447] Compound 24-P1 (i.e., Peak 1): ESI-MS: [M+H] + =502.1. 1 H NMR (400MHz, DMSO-d6) δ = 10.70 (s, 1H), 8.01 (d, J = 7.5Hz, 1H), 7.76 (s, 1H), 7.25-7.15 (m, 1H), 7.15-7.06 (m, 1H), 6.77-6.69 (m, 1H) ,6.41(s,2H),4.87(d,J=11.5Hz,1H),4.50(dd,J=5.3,11.5Hz,1H),4.01(d,J=1.8Hz,3H),2.69-2.57(m,1H),1.86(s,3H),0.80(br d,J=4.8Hz,3H).

[0448] Compound 24-P2 (i.e., Peak 2): ESI-MS: [M+H] + =502.2. 1H NMR (400MHz, DMSO-d6) δ = 10.60 (s, 1H), 7.96 (d, J = 7.5Hz, 1H), 7.72 (d, J = 1.0Hz, 1H), 7.25-7.15 (m, 1H), 7.14-7.04 (m, 1H), 6.68 (dd, J = 1.9, 7 .5Hz,1H),6.26(s,2H),4.85(d,J=11.6Hz,1H),4.50(dd,J=5.4,11.5Hz,1H),4.01(d,J=1.9Hz,3H),2.67-2.58(m,1H),1.86(s,3H),0.79(br d,J=4.6Hz,3H).

[0449] Example 25: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0450] Step 1: Dissolve compound 20-10 (1.0 g, 2.51 mmol) in DCM (10 mL), then add boron tribromide (2 M, 6.28 mL) dropwise to the reaction solution at 0 °C. After the addition is complete, stir the reaction solution at room temperature (20 °C) for 2 hours. TLC (developing solvent: industrial hexane / EA = 3 / 1, starting material R) f =0.42, Product R f =0.40) indicates that the raw materials were completely consumed. After the reaction was completed, EtOH (5.0 mL) was added to the reaction solution to quench the reaction, and then the mixture was concentrated to obtain the crude product. The obtained crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1 to 0 / 1) to give a yellow solid compound 25-1 (300 mg, 700 μmol, yield: 28.2%). 1 ¹H NMR (400MHz, chloroform-d) δ=6.90-6.84(m,1H), 6.78-6.70(m,1H), 5.62(d,J=4.8Hz,1H), 4.62-4.56(m,1H), 4.53-4.46(m,1H), 4.17(t,J=7.1Hz,2H), 2.81(dd,J=5.8,6.9Hz,1H), 1.90(s,3H), 1.24(t,J=7.1Hz,3H), 0.91-0.83(m,3H).

[0451] Step 2: Dissolve compound 25-1 (200 mg, 520 μmol) in ACN (4.0 mL). Then, add K2CO3 (143 mg, 1.04 mmol) and deuterated iodomethane (377 mg, 2.60 mmol) sequentially to the reaction solution at 25 °C. After the addition is complete, stir the reaction solution at 45 °C for 14 hours. TLC (developing solvent: industrial hexane / EA = 3 / 1, starting material R) f =0.30, Product R f =0.52) and LCMS showed that the starting material 25-1 was completely consumed. After the reaction was complete, the reaction solution was filtered, and the filter cake was washed with EA (3 mL*3). The filtrate was concentrated at 40 °C to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1~0 / 1) to give a white solid compound 25-2 (racemic mixture, 180 mg, 448 μmol, yield: 86.18%).

[0452] Step 3: Dissolve compound 25-2 (180 mg, 448 μmol) in THF (1.8 mL) and start stirring. Then, at 0 °C, add t-BuOK / t-BuOH solution (1.0 M, 582 μL) dropwise to the reaction solution. After the addition is complete, stir the reaction solution at 0 °C for 2 hours. LCMS showed that the starting material was completely consumed, and the target MS peak was the main peak. After the reaction was completed, adjust the pH of the reaction solution to 2-3 with 1 M hydrochloric acid aqueous solution. Then, extract twice with EA (50 mL), wash the organic phase once with saturated NaCl solution (30 mL), dry with anhydrous Na2SO4, concentrate under reduced pressure, and obtain a yellow oily crude compound 25-3 (racemic mixture, 170 mg, crude).

[0453] Step 4: Compound 25-3 (350 mg, 937.45 μmol) was dissolved in DMF (7.0 mL). Then, at 0 °C, N-methylimidazole (538 mg, 6.56 mmol, 523 μL), 5-amino-2-fluorobenzonitrile (165 mg, 1.22 mmol), and TCFH (683.88 mg, 2.44 mmol) were added sequentially to the reaction solution. After the addition was complete, the reaction solution was stirred at 25 °C for 12 hours. LCMS showed that compound 25-3 was completely consumed. After the reaction was complete, the reaction solution was poured into 30 mL of water and extracted twice with EA (10 mL * 2). The organic phases were combined, dried, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1 to 0 / 1) to give a white solid compound 25-4 (420 mg, yield: 91.16%). 1H NMR (400MHz, chloroform-d) δ = 8.47 (br s,1H),7.93(dd,J=2.7,5.3Hz,1H),7.78-7.63(m,1H),7.18(t,J=8.7Hz,1H),7.06-6.99(m,1H), 6.96-6.85(m,1H),4.65-4.59(m,1H),4.54-4.49(m,1H),2.73-2.61(m,1H),1.95(s,3H),0.90(br d,J=4.7Hz,3H).

[0454] Step 5: Compound 25-4 (200 mg, 406 μmol) was dissolved in a mixed solution of DMF (2.0 mL) and water (0.6 mL). Then, K₂CO₃ (112 mg) and ethane-hydroxyxamic acid (30.5 mg, 0.407 mmol) were added to the reaction solution. After the addition was complete, the reaction solution was stirred at 45 °C for 16 hours. LC-MS showed that the starting material 25-4 was completely consumed, and the target MS peak was the dominant peak. After the reaction was complete, the reaction solution was filtered, and the filtrate was directly purified by Prep-HPLC (eluent: ACN:water (NH₄HCO₃) = 57%-87%) to obtain a white solid compound 25 (racemic mixture, 80 mg).

[0455] Step 6: The obtained racemic mixture 25 (80 mg) was further separated by prep-SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode): white solid compounds 25-P1 (Peak 1, SFC RT = 1.032 min, 31.79 mg) and 25-P2 (Peak 2, SFC) were obtained. RT = 1.257 min, 33.34 mg), namely compounds (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: [M+H]+ = 505.1.

[0456] Compound 25-P1 (i.e., Peak 1): 1H NMR (400MHz, DMSO-d6) δ = 10.48 (s, 1H), 8.19 (s, 1H), 7.45-7.35 (m, 2H), 7.24-7.16 (m, 1H), 7.15-7.07 (m, 1H), 6.3 5(s,2H),4.88(d,J=11.7Hz,1H),4.53(dd,J=5.0,11.9Hz,1H),2.67-2.58(m,1H),1.87(s,3H),0.86-0.71(m,3H).

[0457] Compound 25-P2 (i.e., Peak 2): 1 H NMR (400MHz, DMSO-d6)δ=10.49(s,1H),8.19(s,1H),7.43-7.35(m,2H),7.24-7.15(m,1H),7.14-7.08(m,1H) ,6.35(s,2H),4.88(d,J=11.5Hz,1H),4.53(dd,J=5.2,11.8Hz,1H),2.66-2.59(m,1H),1.87(s,3H),0.80(br d,J=4.4Hz,3H).

[0458] Example 26: Synthesis of (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0459] Step 1: Hydrazine hydrate (1.04 g, 20.35 mmol, 1.01 mL, 98% pure) was added to a solution of compound 25-4 (200 mg, 406 μmol) in EtOH (2.0 mL), and the reaction mixture was stirred at 90 °C for 12 hours. LCMS showed that compound 25-4 was completely consumed. After cooling the reaction mixture to room temperature, it was filtered, and the resulting filtrate was directly purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 52%–82%) to obtain a white solid compound 26 (racemic mixture, 70 mg).

[0460] Step 2: The obtained racemic mixture (70 mg) was further separated by prep-SFC (column: DAICEL CHIRALPAK IG (250 mm * 30 mm, 10 μm); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 50%, isocratic elution mode) to obtain white solid compounds 26-P1 (Peak 1, SFC RT = 1.233 min, 37.14 mg) and 26-P2 (Peak 2, SFC). RT = 1.456 min, 32.41 mg), namely the enantiomers (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-1H-indazol-5-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: [M+H]+ = 504.1.

[0461] Compound 26-P1 (i.e., Peak 1): 1 H NMR (400MHz, DMSO-d6) δ = 11.30 (s, 1H), 10.24 (s, 1H), 7.97 (s, 1H), 7.49-6.88 (m, 4H), 5.23 (s, 2H) ),4.89(d,J=11.5Hz,1H),4.52(dd,J=5.2,11.7Hz,1H),2.65-2.57(m,1H),1.87(s,3H),0.79(br d,J=5.1Hz,3H).

[0462] Compound 26-P2 (i.e., Peak 2): 1 H NMR (400MHz, DMSO-d6) δ = 11.30 (s, 1H), 10.24 (s, 1H), 7.97 (s, 1H), 7.16 (br d,J=4.1Hz,4H),5.23(s,2H),4.90(d,J=11.6Hz,1H),4.52(dd,J=5.1,11.6Hz,1H),2.64-2.57(m,1H),1.87(s,3H),0.79(br d,J=4.4Hz,3H).

[0463] Example 27: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0464] Step 1: Compound 25-3 (170 mg, crude) was dissolved in DMF (3.4 mL). Then, N-methylimidazolium (261 mg, 3.19 mmol, 254 μL), 2-(5-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (17-4, 193 mg, 455 μmol), and TCFH (332.17 mg, 1.18 mmol) were added sequentially to the reaction solution at 0 °C. After the addition was complete, the reaction solution was stirred at room temperature (20 °C) for 16 hours. TLC (developing solvent: industrial hexane / EA = 3 / 1, raw material R) f =0.02, Product R f =0.51) and LCMS showed that the starting material 25-3 was completely consumed. After the reaction was complete, the reaction solution was poured into 50 mL of water and extracted three times with EA (20 mL * 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1 to 0 / 1) to give compound 27-1 (racemic mixture, 260 mg, 333 μmol, yield: 73.22%).

[0465] Step 2: Dissolve compound 27-1 (260 mg, 333 μmol) in MeOH (5.2 mL). Then, add hydrochloric acid methanol solution (4 M, 1.3 mL) in a single step at 25 °C. After the addition is complete, stir the reaction mixture at 25 °C for 16 hours. TLC (electrolyte: industrial hexane / EA = 3 / 1, raw material R) f =0.51, Product R f =0.02) indicates that the raw materials were completely consumed. After the reaction was completed, the reaction solution was concentrated under reduced pressure at about 40°C to obtain crude compound 27-2 (170 mg, crude hydrochloride).

[0466] Step 3: Compound 27-2 (170 mg, crude hydrochloride) was dissolved in EtOH (17 mL). Then, N,N-diisopropylethylamine (187 mg, 1.45 mmol, 253 μL) and di(1H-imidazol-1-yl)imine (60.9 mg, 377 μmol) were added sequentially to the reaction solution at 20 °C. After the addition was complete, the reaction solution was stirred at 90 °C for 16 hours. HPLC analysis confirmed complete consumption of the starting materials. After the reaction was complete, the reaction solution was concentrated under reduced pressure at approximately 40 °C to obtain the crude product. The crude product was purified by prep-HPLC (column: WePure Biotech XP tC18 150*40*7 μm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 35%-65% B, for 8.0 min) to obtain compound 27 (racemic mixture, 50 mg).

[0467] Step 4: The obtained racemic compound 27 was resolved by prep-SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10µm); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 15%-30% B, for 14.0 min) to obtain the corresponding isomers 27-P1 (Peak 1, SFC RT = 0.959 min, 15.7 mg, 30.8 μmol) and 27-P2 (Peak 2, SFC). RT = 1.128 min, 16.76 mg, 32.8 μmol), namely compounds (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: [M+H]+ = 505.2.

[0468] Compound 27-P1 (Peak 1): 1H NMR (400MHz, DMSO-d6) δ=10.52(s,1H),8.69(s,1H),7.44(d,J=9.9Hz,1H),7.25-7.15(m,1H),7.13-7.07(m,1H),6.90(dd,J =1.7,9.9Hz,1H),6.25(s,2H),4.88(d,J=11.6Hz,1H),4.51(dd,J=5.2,11.6Hz,1H),2.67-2.60(m,1H),1.86(s,3H),0.80(br d,J=4.4Hz,3H).

[0469] Compound 27-P2 (Peak 2): 1 H NMR (400MHz, DMSO-d6) δ=10.52(s,1H),8.69(s,1H),7.44(d,J=9.7Hz,1H),7.25-7.15(m,1H),7.13-7.06(m,1H),6.90(dd,J =1.7,9.9Hz,1H),6.25(s,2H),4.88(d,J=11.6Hz,1H),4.51(dd,J=5.4,11.6Hz,1H),2.67-2.59(m,1H),1.86(s,3H),0.80(br d,J=4.9Hz,3H).

[0470] Example 28: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0471] Step 1: At 25°C, N-methylimidazole (NMI, 307.86 mg, 3.75 mmol, 298.89 μL) was added to a DMF (DMF, 2.0 mL) solution of compound 25-3 (200 mg, 535.69 μmol) and compound 2-(4-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (24-2, 250.00 mg, 588.94 μmol). Then, TCFH (390.79 mg, 1.39 mmol) was added in portions to the reaction solution at 0°C. After the addition was complete, the reaction solution was stirred at 25°C for 16 hours. LCMS showed that compound 25-3 was completely consumed. After the reaction was complete, the reaction solution was poured into saturated brine (10 mL) and then extracted with EA (5 mL × 2). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by prep-TLC (eluent: industrial hexane / EA = 3 / 1) to give a pale yellow oily compound 28-1 (racemic mixture, 200 mg, yield: 47.88%). ESI-MS: [M+H] + =780.5.

[0472] Step 2: At 15°C, hydrochloric acid / methyl tert-butyl ether (4M, 5.27mL) and compound 28-1 (145mg, 185.94μmol) were added sequentially to a 40mL reaction flask. The reaction mixture was then stirred at 15°C for 6 hours. LC-MS showed complete consumption of the starting materials. After the reaction was complete, the reaction mixture was directly concentrated under reduced pressure to obtain a pale yellow solid compound 28-2 (racemic mixture, 100mg, crude hydrochloride). ESI-MS: [M+H] + =480.1.

[0473] Step 3: At 15°C, N,N-diisopropylethylamine (DIEA, 172.84 mg, 1.34 mmol, 232.94 μL) was added to a solution of compound 28-2 (138 mg) in EtOH (2.0 mL). After the addition was complete, the reaction solution was stirred at 15°C for 5 minutes, and then cyanogen bromide (42.50 mg, 401.21 μmol, 29.45 μL) was added to the reaction solution at the same temperature. After the addition was complete, the reaction solution was stirred at 15°C for 16 hours. LCMS showed that the starting material was completely consumed. After the reaction was complete, ammonia / MeOH solution (7 M, 0.5 mL) was added to the reaction solution, and then the resulting solution was directly purified by prep-HPLC (eluent: ACN / water (NH4HCO3) = 40%-70%) to give a white solid compound 28 (racemic mixture, 65 mg, yield: 47.89%). MS: [M+H] + =505.0.

[0474] Step 4: The obtained racemic compound 28 (80 mg) was then further separated by prep-SFC (column: Daicel ChiralPak IM (250*25mm id10um); mobile phase: [CO2-EtOH (0.1% NH3H2O)]; B%: 30%, isocratic elution mode) to obtain a white solid compound 28-P1 (Peak 1, SFC RT=1.115min, 35 mg) and a pale yellow solid compound 28-P2 (Peak 2, SFC). RT = 1.297 min, 35 mg), namely compounds (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: [M+H] + =505.1.

[0475] Compound 28-P1 (Peak 1, RT = 2.932): 1 H NMR (400MHz, DMSO-d6) δ = 10.60 (s, 1H), 7.96 (d, J = 7.5Hz, 1H), 7.72 (s, 1H), 7.24-7.14 (m, 1H), 7.12-7.05 (m, 1H), 6.68 (dd, J =1.7,7.6Hz,1H),6.26(s,2H),4.85(d,J=11.5Hz,1H),4.50(dd,J=5.3,11.4Hz,1H),2.66-2.60(m,1H),1.86(s,3H),0.79(br d,J=4.5Hz,3H).

[0476] Compound 28-P2 (Peak 2, RT = 2.932): 1H NMR (400MHz, DMSO-d6) δ=10.64(s,1H),7.97(d,J=7.5Hz,1H),7.73(s,1H),7.23-7.15(m,1H),7.14-7.06(m,1H),6.70(dd,J =1.6,7.5Hz,1H),6.29(s,2H),4.87(d,J=11.5Hz,1H),4.50(dd,J=5.2,11.6Hz,1H),2.66-2.59(m,1H),1.86(s,3H),0.79(br d,J=4.6Hz,3H).

[0477] Example 29: Synthesis of (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0478] Step 1: At 25°C, Cs₂CO₃ (509 mg, 1.56 mmol) and sodium difluorochloroacetate (238 mg, 1.56 mmol) were added to a DMF (6.0 mL) solution of compound 25-1 (300 mg, 781 μmol). After the addition was complete, the reaction solution was stirred at 100°C for 14 hours. TLC (developing solvent: industrial hexane / EA = 5 / 1, starting material Rf = 0.48, product Rf = 0.61, potassium permanganate for color development) showed that the starting material was completely consumed. After the reaction was complete, 10 mL of water and 10 mL of EA were added to the reaction solution. The aqueous phase was extracted three times with EA (20 mL), and the organic phase was washed once with saturated NaCl solution (20 mL). The solution was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain the crude compound. The crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1 to 0 / 1) to give brown oily compound 29-1 (200 mg, 460 μmol, yield: 59%). 1H NMR (400MHz, CDCl3-d) δ = 7.06-6.96 (m, 1H), 6.94-6.87 (m, 1H), 6.61 (t, J = 74.0Hz, 1H), 4.47-4.40 (m, 2H), 4.05 (ddd d,J=3.6,7.1,10.7,17.8Hz,2H),2.60(dd,J=4.4,7.1Hz,1H),1.79(s,3H),1.12(t,J=7.1Hz,3H),0.83-0.75(m,3H).

[0479] Step 2: At 0°C, lithium hydroxide (22.1 mg, 921 μmol) was added to a mixed solution of compound 29-1 (200 mg, 460 μmol) in water (2.0 mL) and THF (2.0 mL). After the addition was complete, the reaction solution was stirred at 25°C for 2 hours. TLC (evolving solvent: industrial hexane / EA = 5 / 1, starting material Rf = 0.54, product Rf = 0.24, potassium permanganate for color development) showed that the starting material was completely consumed. After the reaction was complete, the pH of the reaction solution was adjusted to 2-3 with 1M dilute hydrochloric acid. The aqueous phase was extracted twice with EA (20 mL), and the organic phase was washed once with saturated NaCl solution (20 mL). The solution was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a brown oily product, compound 29-2 (racemic mixture, 200 mg). 1 H NMR (400MHz, CDCl3-d)δ=7.01-6.94(m,1H),6.90(br d,J=4.4Hz,1H),6.77-6.36(m,1H),4.40-4.26(m,2H),2.66-2.49(m,1H),1.73(s,3H),0.74(br d,J=4.9Hz,3H).

[0480] Step 3: At 25°C, N-methylimidazole (283 mg, 3.45 mmol, 275 μL) and 5-amino-2-fluorobenzonitrile (87.1 mg, 640 μmol) were added to a DMF (2.0 mL) solution of compound 29-2 (200 mg, crude product). The reaction solution was cooled to 0°C, and then TCFH (359 mg, 1.28 mmol) was added to the reaction solution in portions. After the addition was complete, the reaction solution was stirred at 25°C under nitrogen protection for 12 hours. TLC (electrolyte: industrial hexane / EA = 2 / 1, starting material Rf = 0.01, product Rf = 0.44) and LCMS showed that starting material 29-2 was completely consumed. After the reaction was completed, the reaction solution was poured into 50 mL of water and then extracted three times with EA (20 mL * 3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1 to 0 / 1) to give compound 29-3 (150 mg, 272 μmol, yield: 55.2%). ESI-MS: m / z = 423.0 [M-1] - . 1 H NMR (400MHz, CDCl3-d) δ = 8.11 (s, 1H), 7.77 (dd, J = 2.8, 5.4Hz, 1H), 7.53 (ddd, J = 2.8, 4.4, 9.0Hz, 1H), 7.15-7.04 (m ,3H),6.80-6.40(m,1H),4.58-4.48(m,1H),4.44-4.37(m,1H),2.66-2.56(m,1H),1.87(s,3H),0.87-0.80(m,3H).

[0481] Step 4: At 25°C, K₂CO₃ (58.0 mg, 420 μmol) was added to a solution of compound 29-3 (110 mg, 210 μmol) in DMF (1.1 mL) and water (0.33 mL). Then, acetyloxyoxime acid (15.8 mg, 210 μmol) was added to the reaction solution. After the addition was complete, the reaction solution was stirred at 45°C for 16 hours. TLC (eluent: industrial hexane / EA = 2 / 1, starting material Rf = 0.69, product Rf = 0.41) and LCMS showed that starting material 29-3 was completely consumed. After the reaction was complete, the reaction solution was cooled and filtered. The resulting filtrate was directly purified by Prep-HPLC (eluent: ACN:water (NH₄HCO₃) = 45%–85%) to obtain a white solid compound 29 (racemic mixture, 42 mg).

[0482] Step 5: The obtained racemic compound 29 was separated by prep-SFC (separation conditions: column: DAICEL CHIRALPAK AD (250mm*30mm, 10um); mobile phase: [CO2-MeOH]; B%: 5%-25%, isocratic elution mode), yielding white solid compound 29-P1 (Peak 1, SFC RT = 2.10min, 17.5mg) and white solid 29-P2 (Peak 2, SFC). RT = 2.70 min, 21.8 mg, 40.4 μmol), namely compounds (2R,3S,4S,5R)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-aminobenzo[d]isoxazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: m / z = 537.9 [M+1] + .

[0483] Compound 29-P1 (i.e., Peak 1): 1 H NMR (400MHz, DMSO-d6) δ = 10.51 (s, 1H), 8.23 ​​(s, 1H), 7.54-7.44 (m, 1H), 7.39 (d, J = 1.1 Hz,2H),7.32(s,1H),7.30-7.24(m,1H),6.37(s,2H),4.93(d,J=11.4Hz,1H),4.58(br dd,J=5.2,11.3Hz,1H),2.70-2.67(m,1H),1.85(s,3H),0.83(br d,J=4.6Hz,3H).

[0484] Compound 29-P2 (i.e., Peak 2): 1 H NMR (400MHz, DMSO-d6) δ = 10.51 (s, 1H), 8.22 (s, 1H), 7.49 (br d,J=6.4Hz,1H),7.39(d,J=1.0Hz,2H),7.33-7.12(m,2H),6.36(s,2H),4.92(d,J= 11.5Hz,1H),4.57(dd,J=5.3,11.6Hz,1H),2.69-2.65(m,1H),1.85(s,3H),0.82(br d,J=4.5Hz,3H).

[0485] Example 30: Synthesis of (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-1H-indazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0486] Step 1: At 25°C, hydrazine hydrate (955 mg, 19.1 mmol, 925 μL, 50 eq.) was added to a solution of compound 29-3 (200 mg, 381 μmol) in EtOH (2.0 mL). After the addition was complete, the reaction mixture was stirred at 80°C for 12 hours. TLC (eluent: industrial hexane / EA = 2 / 1, starting material Rf = 0.69, product Rf = 0.11) and LCMS showed that the starting material was completely consumed. After the reaction was complete, the reaction mixture was cooled and filtered. The resulting filtrate was directly purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 45%–75%) to obtain a white solid compound 30 (racemic mixture, 75 mg).

[0487] Step 2: The obtained racemic compound 30 was separated by prep-SFC (separation conditions: column: DAICEL CHIRALPAK IG (250mm*30mm, 10um); mobile phase: [CO2-MeOH]; B%: 0.1% NH3H2O, isocratic elution mode), yielding the corresponding isomers 30-P1 (Peak 1, SFC RT = 1.07min, 31.3mg) and 30-P2 (Peak 2, SFC). RT = 1.19 min, 40.27 mg), namely compounds (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-1H-indazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: m / z = 537.1 [M+1] + .

[0488] Compound 30-P1 (i.e., Peak 1): 1H NMR (400MHz, DMSO-d6) δ = 11.31 (s, 1H), 10.23 (s, 1H), 7.99 (s, 1H), 7.53-7. 47(m,1H),7.46-7.11(m,4H),5.25(s,2H),4.92(d,J=11.5Hz,1H),4.56(br dd,J=5.1,11.4Hz,1H),2.71-2.60(m,1H),1.84(s,3H),0.82(br d,J=4.1Hz,3H).

[0489] Compound 30-P2 (i.e., Peak 2): 1 H NMR (400MHz, DMSO-d6) δ = 11.31 (s, 1H), 10.23 (s, 1H), 7.99 (s, 1H), 7.53-7. 47(m,1H),7.46-7.11(m,4H),5.25(s,2H),4.92(d,J=11.5Hz,1H),4.56(br dd,J=5.1,11.4Hz,1H),2.71-2.60(m,1H),1.84(s,3H),0.82(br d,J=4.1Hz,3H).

[0490] Example 31: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0491] Step 1: At 25°C, N-methylimidazole (382 mg, 4.65 mmol, 371 μL) and tert-butyl 2-(5-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid (17-4, 86 mg, 665 μmol) were added to a 2.0 mL DMF solution (270 mg, 665 μmol) of compound 29-2. The reaction solution was cooled to 0°C, and then TCFH (359 mg, 1.28 mmol) was added to the reaction solution in portions. After the addition was complete, the reaction solution was stirred at 25°C under nitrogen protection for 16 hours. TLC (electrolyte: industrial hexane / EA = 2 / 1, starting material Rf = 0.01, product Rf = 0.44) and LCMS showed that the starting material was completely consumed. After the reaction was completed, the reaction solution was poured into 50 mL of water and extracted three times with EA (20 mL * 3). The combined organic phases were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1 to 0 / 1) to give a yellow solid compound 31-1 (racemic mixture, 420 mg, 517 μmol, yield: 77.7%). ESI-MS: m / z = 811.3 [M⁻¹] - . 1 H NMR (400MHz, CDCl3-d)δ=9.53-9.09(m,1H),8.61-8.47(m,1H),8.42(br s,1H),7.95-7.64(m,1H),7.45-7.35(m,1H),7.09-6.98(m,1H),6.73(t,J=74.0Hz,1H),5.15-4.95(m,1H),4.65(br dd,J=5.3,11.9Hz,1H),2.78-2.67(m,1H),1.95(s,3H),1.58(s,9H),1.36(s,18H),0.90(br d,J=5.6Hz,3H).

[0492] Step 2: At 15°C, 1,4-dioxane hydrochloride (4M, 2.1mL) was added to a DCM solution (4.2mL) of compound 31-1 (420mg, 492μmol). After addition, the reaction mixture was stirred at 25°C for 2 hours. TLC (electrolyte: industrial hexane / EA = 2 / 1, starting material Rf = 0.44, product Rf = 0.00) and LCMS showed complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to obtain a white solid crude compound 31-2 (racemic mixture, 400mg, crude hydrochloride). ESI-MS: m / z = 513.2 [M+1] - .

[0493] Step 3: At 25°C, N,N-diisopropylethylamine (502 mg) and di(1H-imidazol-1-yl)imine (163 mg) were added sequentially to an EtOH (8.0 mL) solution of compound 31-2 (400 mg, crude hydrochloride). After the addition was complete, the reaction mixture was stirred at 90°C for 16 hours. LCMS showed that starting material 20 was completely consumed. After the reaction was complete, the reaction mixture was directly purified by Prep-HPLC (eluent: ACN:water (NH4HCO3) = 35%-65%) to obtain a white solid compound 31 (racemic mixture, 50 mg).

[0494] Step 4: The obtained racemic mixture 31 (45 mg) was further resolved by Prep-SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: [CO2-EtOH]; B%: 10%-30%) to obtain white solid compounds 31-P1 (Peak 1, SFC RT = 2.14 min, 15.8 mg) and 31-P2 (Peak 2, SFC). RT = 2.74 min, 16.32 mg), namely compounds (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: [M+H] + =538.1.

[0495] Compound 31-P1 (i.e., Peak 1): 1 H NMR(400MHz,DMSO-d6)δ=10.52(br s,1H),8.70(s,1H),7.53-7.46(m,1H),7.44(d,J=9.8Hz,1H),7.35-7.13(m,2H),6.89(dd,J=1.7,9.8Hz,1H) ,6.26(s,2H),4.91(d,J=11.4Hz,1H),4.55(dd,J=5.2,11.4Hz,1H),2.69-2.66(m,1H),1.84(s,3H),0.82(br d,J=4.8Hz,3H).

[0496] Compound 31-P2 (i.e., Peak 2): 11H NMR(400MHz,DMSO-d6)δ=10.52(br s,1H),8.70(s,1H),7.53-7.46(m,1H),7.44(d,J=10.0Hz,1H),7.34-7.12(m, 2H),6.89(dd,J=1.6,9.8Hz,1H),6.26(s,2H),4.91(d,J=11.4Hz,1H),4.55(br dd,J=5.1,11.5Hz,1H),2.68(br d,J=5.0Hz,1H),1.84(s,3H),0.82(br d,J=4.1Hz,3H).

[0497] Example 32: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide

[0498] Step 1: Compound 29-2 (200 mg, 492 μmol) was dissolved in DMF (4.0 mL). Then, N-methylimidazole (268 mg, 3.27 mmol, 260 μL), 2-(4-aminopyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid tert-butyl ester (24-2, 250 mg), and TCFH (341 mg, 1.22 mmol) were added sequentially to the reaction solution at 0 °C. After the addition was complete, the reaction solution was stirred at 25 °C for 16 hours. TLC (developing solvent: industrial hexane / EA = 2 / 1, raw material R) f =0.10, Product R f =0.52) and LCMS showed that the starting material 29-2 was completely consumed. After the reaction was completed, ammonium chloride aqueous solution (20 mL) was added to the reaction solution, the aqueous phase was extracted twice with EA (20 mL), the organic phase was washed once with saturated NaCl aqueous solution (20 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure, and a yellow oily crude product (400 mg) was obtained. The crude product was purified by silica gel column chromatography (eluent: industrial hexane / EA = 100 / 1 to 0 / 1) to obtain a yellow solid compound 32-1 (racemic mixture, 280 mg, 313.49 μmol, yield: 67.04%).

[0499] Step 2: Compound 32-1 (260 mg, 319 μmol) was dissolved in MeOH (5.2 mL). Then, a 4 M methanol hydrochloric acid solution (1.3 mL) was added to the reaction solution at 25 °C. After the addition was complete, the reaction solution was stirred at 25 °C for 16 hours. LC-MS showed that the starting material was completely consumed. After the reaction was completed, the reaction solution was concentrated to obtain a yellow solid crude product, compound 32-2 (racemic mixture, 200 mg, crude hydrochloride).

[0500] Step 3: Compound 32-2 (200 mg, crude hydrochloride) was dissolved in EtOH (4.0 mL). Then, N,N-diisopropylethylamine (235 mg, 1.82 mmol) and bis(imidazol-1-yl)methyleneimine (76.2 mg, 472 μmol) were added sequentially to the reaction solution at 25 °C. After the addition was complete, the reaction system was heated to 90 °C and stirred for 16 hours. LCMS showed that the starting materials were completely consumed. After the reaction was completed, the reaction solution was concentrated under reduced pressure at about 40 °C to obtain the crude product. The obtained crude product was purified by prep-HPLC (column: Phenomenex Luna C18 100*30 mm*5 μm; mobile phase: [H2O (0.2% FA)-ACN]; gradient: 30%-65% B, for 8.0 min) to obtain compound 32 (racemic mixture, 40 mg).

[0501] Step 4: The obtained racemic 32 was separated by prep-SFC (separation conditions: column: Daicel ChiralPak IM (250*25mm id10um); mobile phase: [CO2-MeOH (0.1% NH3H2O)]; B%: 35%, isocratic elution mode), yielding the corresponding isomers 32-P1 (Peak 1, SFC RT=1.06min, 15.45mg) and 32-P2 (Peak 2, SFC). RT = 1.25 min, 13.37 mg), namely compounds (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide and (2S,3R,4R,5S)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxamide. ESI-MS: m / z = 538.0 [M+1]+.

[0502] Compound 32-P1 (i.e., Peak 1): 1H NMR (400MHz, DMSO-d6) δ = 10.64 (s, 1H), 7.96 (d, J = 7.5Hz, 1H), 7.70 (s, 1H), 7.52-7. 13(m,3H),6.70(dd,J=1.7,7.6Hz,1H),6.27(s,2H),4.90(d,J=11.4Hz,1H),4.53(br dd,J=5.4,11.4Hz,1H),2.67(br d,J=6.8Hz,1H),1.84(s,3H),0.81(br d,J=4.8Hz,3H).

[0503] Compound 32-P2 (i.e., Peak 2): 1 H NMR (400MHz, DMSO-d6) δ = 10.63 (s, 1H), 7.96 (d, J = 7.3Hz, 1H), 7.70 (s, 1H), 7.53-7.11 (m, 3H), 6.70 (dd,J=1.8,7.6Hz,1H),6.27(s,2H),4.90(d,J=11.4Hz,1H),4.53(dd,J=5.3,11.3Hz,1H),2.67(br d,J=7.3Hz,1H),1.84(s,3H),0.81(br d,J=4.0Hz,3H).

[0504] Example 33: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0505] Step 1: Compound 13-3 (1.57 g, 4.4 mmol), compound 21-3 (1.44 g, 4.4 mmol), and N-methylimidazole (2.53 g, 30.8 mmol) were dissolved in DMF (30 mL). N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (3.21 g, 11.44 mmol) was added at room temperature, and the mixture was stirred for 2 hours at room temperature. After the reaction was complete, EA (100 mL) was added for dilution, and the mixture was washed with water (30 mL x 3) and saturated NaCl aqueous solution (30 mL), respectively. The organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:3) to obtain a yellow solid compound 1-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)hydrazine-1,2-dicarboxylic acid tert-butyl ester (33-1,660 mg, yield: 22.53%). ESI-MS: m / z = 664 [M+H] + .

[0506] Step 2: Compound 33-1 (660 mg, 0.66 mmol) was dissolved in DCM (10 mL), and boron trifluoride diethyl ether solution (3 mL) was added at room temperature. The mixture was stirred at room temperature for 20 minutes. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted three times with EA (30 mL). The organic phase was washed with saturated NaCl aqueous solution (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a yellow solid compound (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-N-(2-hydrazylpyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (33-2, 280 mg), yield: 60.94%. ESI-MS: 464 m / z = [M+H] + .

[0507] Step 3: Compound 33-2 (280 mg, 0.604 mmol) was dissolved in a mixed solvent of EtOH (5 mL) and water (1 mL). TEA (183.4 mg, 1.81 mmol) and cyanogen bromide (128.0 mg, 1.21 mol) were added at 0 °C, and the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure, water (20 mL) was added, and the solution was extracted three times with EA (30 mL). The organic phase was washed with 20 mL of saturated NaCl aqueous solution, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The concentrate was purified by Prep-HPLC (ACN / water, 0.1% TFA) to give a white solid compound (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(3,4-difluoro-2-(methoxy-d3)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (33,55.24 mg, yield: 18.72%). ESI-MS: m / z = 489.0 [M+H] + . 1 H NMR (400MHz, DMSO) δ11.08(s,1H),8.39(d,J=7.6Hz,1H),8.12(s,1H),7.56(s,2H),7.23(m,J=12.9,7.6,2. 4Hz, 3H), 5.17 (d, J = 10.1Hz, 1H), 4.29–4.15 (m, 1H), 2.81–2.74 (m, 1H), 1.60 (s, 3H), 0.74 (d, J = 6.3Hz, 3H).

[0508] Example 34: Synthesis of (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0509] Step 1: Compound 18-2 (1.0 g, 2.56 mmol), compound 24-2 (1.09 g, 2.56 mmol), and N-methylimidazole (1.05 g, 12.82 mmol) were dissolved in DMF (10 mL). N,N,N',N'-tetramethylchloromethamine hexafluorophosphate (5.04 mg, 17.9 mmol) was added at room temperature, and the mixture was stirred for 2 hours at room temperature. After the reaction was complete, EA (100 mL) was added for dilution, and the mixture was washed with water (30 mL x 3) and saturated NaCl aqueous solution (30 mL), respectively. The organic phase was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: EA:PE = 1:5) to obtain tert-butyl 2-(4-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridin-2-yl)hydrazine-1,1,2-tricarboxylic acid (34-1, 1.5 g, yield: 73.52%). ESI-MS: m / z = 797.1 [M+H] + .

[0510] Step 2: Compound 34-1 (1.5 g, 1.88 mmol) was dissolved in DCM (15 mL), and boron trifluoride diethyl ether solution (3 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a yellow oily crude compound (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-N-(2-hydrazylpyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (34-2, 2.4 g). ESI-MS: m / z = 497.2 [M+H] + .

[0511] Step 3: Compound 34-2 (2.4 g) was dissolved in a mixed solvent of EtOH (20 mL) and water (4 mL). N,N-diisopropylethylamine (1.87 g, 14.5 mmol) and cyanogen bromide (358 mg, 3.3 mmol) were added at 0 °C, and the mixture was stirred at 0 °C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and water (20 mL) was added. The mixture was extracted three times with EA (30 mL). The organic phase was washed with a saturated NaCl aqueous solution (20 mL), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The concentrate was purified by Prep-HPLC (ACN / water, 0.1% FA) to give a white solid compound (2R,3S,4S,5R)-N-(3-amino-[1,2,4]triazolo[4,3-a]pyridin-7-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (34,587.5 mg, yield: 36.67%). ESI-MS: m / z = 522.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ10.45(s,1H),7.99(d,J=7.6Hz,1H),7.80(d,J=0.8Hz,1H),7.49(q,J=9.6Hz,1H),7.35–7.08(m,2H),6.86(dd,J=7.6 ,1.9Hz,1H),6.32(s,2H),5.12(t,J=14.3Hz,1H),4.29(dd,J=10.1,7.8Hz,1H),2.76(d,J=7.4Hz,1H),1.59(s,3H),0.76(d,J=6.3Hz,3H).

[0512] Example 35: Synthesis of (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0513] Compound 18-3 (420 mg, 0.82 mmol) was dissolved in anhydrous ethanol (12 mL) and hydrazine hydrate (4 mL, 98%), and the reaction was stirred overnight at 80 °C. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain a white solid compound (2R,3S,4S,5R)-N-(3-amino-1H-indazol-5-yl)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (35, 124.8 mg, yield: 29.67%). ESI-MS: m / z = 520.41, [M+1] + 521.1. 1 H NMR (400MHz, DMSO) δ11.33(s,1H),10.12(s,1H),8.00(d,J=1.4Hz,1H),7.53-7.45(m,J=9.4Hz,1H),7.40-7.11(m,4H),5. 29(brs,2H),5.12(d,J=10.4Hz,1H),4.33-4.28(m,1H),2.79-2.73(m,1H),1.56(d,J=27.6Hz,3H),0.76(d,J=6.2Hz,3H).

[0514] Biological tests

[0515] Experimental Example 1: Inhibitory Activity against hNav1.8

[0516] The presence of a analyte on voltage-gated sodium ion channels was evaluated using a manual patch-clamp technique. The dose-response curve of the analyte was obtained by detecting the effect of five consecutive non-zero concentration points of the analyte on the resting potential current of the sodium channel, and the IC50 was calculated. 50 The experiment included two parallel sample measurements.

[0517] Cell lines and cell culture

[0518] A stable cell line expressing the human sodium ion channel family (hNav1.8) was constructed and its function was verified. Cell information and culture conditions were as follows: HEK293 (90% DMEM, 10% fetal bovine serum, 100 U / mL penicillin-streptomycin, 0.75 μg / mL puromycin, 100 μg / mL hygromycin).

[0519] When the cell density reaches 40%–80% of the bottom area of ​​the culture dish, use TrypLE... TM Cells were digested using Express and passaged three times a week. Prior to the experiment, cells were cultured at 5 × 10⁻⁶ cells / week. 5The total number of seeded samples were inoculated into 3.5cm culture dishes covered with glass slides for subsequent manual patch-clamp experiments.

[0520] Solution preparation

[0521] Extracellular fluid: 132 mM NaCl, 4 mM potassium chloride, 3 mM calcium chloride, 0.5 mM magnesium chloride, 11.1 mM glucose, 10 mM HEPES, 40 mM tetraethylammonium chloride, 0.0002 mM tetrodotoxin; pH adjusted to 7.35 using sodium hydroxide.

[0522] Intracellular fluid: 10 mM EGTA, 10 mM HEPES, 10 mM cesium chloride, 10 mM NaCl, 110 mM cesium fluoride; pH adjusted to 7.2 using cesium hydroxide.

[0523] The osmotic pressure of the solution should be controlled between 280 and 300 mOsmol / kg. The solution should be filtered and stored at 4°C before use.

[0524] Preparation of test compound solution

[0525] Following the internal SOP (Standard Operating Procedure), the test compound was dissolved in DMSO to prepare a stock solution with a final concentration of 10 or 30 mM. The stock solution was then diluted with DMSO to create intermediate gradient solutions at a concentration 1000 times the test concentration. Before the experiment, the intermediate gradient solutions of the test compound were diluted again with extracellular fluid at a ratio of 1:1000 to prepare a series of working solutions. The concentration of DMSO in the working solutions was 0.1% (volume ratio).

[0526] Following the internal SOP, the positive control compound was dissolved in DMSO to prepare intermediate gradient solutions with a final concentration of 1000x. Before the experiment, the intermediate gradient solutions of the positive control compound were diluted again with extracellular fluid at a ratio of 1:1000 to prepare a series of working solutions. The concentration of DMSO in the working solutions was 0.1% (volume ratio).

[0527] Positive control compound:

[0528] (1) VX-548 (purchased from MedChemExpress (MCE))

[0529] (2) The control compound 1 was synthesized according to the method of Example 2 (WO2024046409A1):

[0530] (3) Comparative compound 2 was synthesized according to the method of Example 157 (WO2025092922A1):

[0531] (4) Comparative compound 3 was synthesized according to the method of Example 432 of WO2022256702A1:

[0532] Experimental steps

[0533] 1) Place the small glass slide containing HEK293 cells in the culture dish into the perfusion tank of the micromanipulation table.

[0534] 2) Using an Olympus IX71 or IX73 inverted microscope, position the appropriate cells in the center of the field of view. Use a ×10 objective lens to locate the tip of the glass electrode and center it in the field of view. Then, use the micromanipulator to move the electrode down while adjusting the coarse focus knob to slowly bring the electrode closer to the cells.

[0535] 3) When you get close to the cell, switch to a 40x objective lens for observation. Use the micromanipulator to fine-tune the setting so that the electrode gradually gets closer to the cell surface.

[0536] 4) Apply negative pressure to form a seal with a resistance higher than 1 GΩ between the electrode tip and the cell membrane.

[0537] 5) In voltage clamping mode, the instantaneous capacitive current C fast Compensation is then performed. Short bursts of negative pressure are then repeatedly applied to rupture the membrane, eventually forming a whole-cell recording pattern.

[0538] 6) Under the condition that the membrane potential is clamped at -60mV, the slow capacitive current C slow The cell membrane capacitance (Cm) and input membrane resistance (Ra) are compensated separately.

[0539] 7) After the cells stabilize, change the clamping voltage to -80mV, set the sampling frequency to 20kHz, and the filtering frequency to 10kHz. The leakage current detection conditions are: clamping voltage changed to -80mV, time duration 200ms.

[0540] 8) The sodium channel resting-state current test method is as follows: Apply a 20-millisecond depolarization command voltage to depolarize the membrane potential from -80mV to -10mV, then repolarize the membrane potential to -80mV to close the channel. Stimulate once every 15 seconds. The instantaneous peak current at the depolarization voltage is the magnitude of the sodium channel current.

[0541] 9) Sodium channel currents used to detect the test compounds were continuously recorded for 120 seconds before drug administration to assess the stability of sodium channel current generation in the test cells. Only stable cells within the acceptable range of the evaluation criteria were allowed to proceed to subsequent compound detection.

[0542] 10) Testing the inhibitory effect of the test compound on sodium channel current: First, the resting current of the sodium channel, measured in extracellular fluid containing 0.1% DMSO, is used as the baseline. After the current stabilizes for at least 5 minutes, the solution containing the test compound is sequentially perfused around the cells from low to high concentration. After each perfusion, wait at least 3 minutes to allow the compound to fully act on the cells while simultaneously recording the sodium channel current. Once the recorded current stabilizes, the average of the last 5 stable current values ​​is taken as the current value at that specific concentration. After testing the test compound, the highest test concentration of the positive control compound is added to the same cell to completely inhibit its current, serving as the positive control for that cell. Simultaneously, before and after the test compound experiment, the positive control compound is tested in parallel using the same patch-clamp system, and concentration-effect curves are plotted to ensure the reliability and sensitivity of the entire detection system. All the above test steps must be repeated on two separate test cells (n=2).

[0543] Data Analysis

[0544] Only data that meets the above criteria can be analyzed according to the following steps, and the data will be output by PatchMaster software.

[0545] After injecting blank solvent or a compound gradient solution, the average of five consecutive current values ​​obtained after the current tends to stabilize is taken as the "current". 空白 "and current" 化合物 The current suppression percentage is calculated using the following formula:

[0546] The dose-response curves were obtained by fitting using Graphpad Prism 8.0 software, and the IC was calculated. 50 Value. IC 50 The values ​​are shown in Table 1 below.

[0547] Table 1. Inhibitory activity of the compounds of the present invention against hNav1.8

[0548] Experimental results show that the compound of the present invention has a positive effect on hNa. V 1.8 It exhibits excellent inhibitory activity.

[0549] Experimental Example 2: Mouse Pharmacokinetic Experiment

[0550] experimental animals

[0551] Six male CD1 mice (6-8 weeks old, 20-30g; Beijing Vital River Laboratory Animal Technology Co., Ltd.) were randomly divided into two groups (n=3 / group).

[0552] Drug preparation and administration

[0553] Single oral (PO) administration: The test compound was weighed and added to a certain volume of polyethylene glycol 400, polyethylene glycol-15 hydroxystearate, and water for injection to prepare a clear solution. Three male CD1 mice were administered the solution by gavage after an overnight fast at a dose of 20 mg / kg.

[0554] Sample collection

[0555] Following drug administration, approximately 30 μL of blood was collected via the dorsal pedis vein at each time point. The blood was anticoagulated with dipotassium EDTA, placed on ice, and centrifuged within 0.5 hours (4000 g / min; 5 min; 4 °C). Blood collection time points were 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored at -80 °C.

[0556] Sample processing

[0557] Add 30 μL of plasma sample to 200 μL of ice-cold ACN containing internal standard, vortex for 30 seconds, and centrifuge at 4000 g / min for 15 minutes. Transfer 100 μL of supernatant to a 96-well plate, add 200 μL of ultrapure water, vortex for 30 seconds, and then inject the supernatant into LC-MS / MS for analysis.

[0558] The results showed that the compounds of the present invention exhibited excellent pharmacokinetic properties, demonstrating a significantly longer half-life and higher C60% C60 compared to the control. max and a significantly higher AUC 0～t This suggests better in vivo analgesic efficacy and bioavailability.

[0559] Experiment Example 3: Rat Pharmacokinetic Experiment

[0560] experimental animals

[0561] Six male SD rats (6-8 weeks old, 200-300g; SPAF (Beijing) Biotechnology Co., Ltd.) were randomly divided into two groups (n=3 / group).

[0562] Drug preparation and administration

[0563] Single oral (PO) administration: The test compound was weighed and added to a certain volume of polyethylene glycol 400, polyethylene glycol-15 hydroxystearate, and water for injection to prepare a clear solution. Three male SD rats were administered the solution by gavage after an overnight fast at a dose of 10 mg / kg.

[0564] Sample collection

[0565] Following drug administration, approximately 50 μL of blood was collected via the jugular vein at each time point. The blood was anticoagulated with dipotassium EDTA, placed on ice, and centrifuged within 0.5 hours to separate the plasma (centrifugation conditions: 4000 g / min; 5 minutes; 4°C). Blood collection time points were 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Samples were stored at -80°C.

[0566] Sample processing

[0567] Add 50 μL of plasma sample to 200 μL of ice-cold ACN containing internal standard, vortex for 30 seconds, and centrifuge at 4000 g / min for 15 minutes. Transfer 100 μL of supernatant to a 96-well plate, add 200 μL of ultrapure water, vortex for 30 seconds, and then inject the supernatant into LC-MS / MS for analysis.

[0568] The results showed that the compounds in the examples of the present invention have excellent pharmacokinetic properties, exhibiting significantly higher C60% compared to the control. max and a significantly higher AUC 0～t This suggests better in vivo analgesic efficacy and bioavailability.

[0569] Experimental Example 4: Pharmacodynamic Study in a Rat Incision Pain Model

[0570] Experimental animals: SPF-grade male SD rats, 6-8 weeks old, purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0571] Drug preparation: Prepare homogeneous suspensions of the test compound in 0.5% CMC-Na at concentrations of 2.5 mg / mL (25 mg / kg) or 5.0 mg / mL (50 mg / kg), and temporarily store on wet ice before use. The control group is a 0.5% CMC-Na carrier.

[0572] Model Establishment: One day prior to modeling, the animal was acclimatized to the foot analgesia testing procedure, and preoperative baseline data were collected. On the day of modeling, the animal's weight was recorded before modeling. The animal was anesthetized with isoflurane, routinely disinfected, and a 1cm long longitudinal skin incision was made on the left hind foot, approximately 0.2cm distal to the tibiotalar joint, extending towards the toes. The plantar muscles were dissected, slightly elevated, and then longitudinally incised, without damaging the muscle's origin and insertion. The incision was sutured intermittently horizontally with 5-0 nylon sutures (2 stitches).

[0573] Experimental grouping and administration: Animals were randomly divided into groups of 8 based on their baseline pain threshold before administration. The animals were administered the drug via a single gavage, with a volume of 10 mL / kg.

[0574] Mechanical pain threshold measurement: The mechanical pain threshold (PWT) was measured 2 hours after modeling, before drug administration. After measurement, animals were randomly assigned to receive drug administration based on their postoperative PWT, and mechanical pain threshold was measured again using a plantar analgesia meter at the following times: before surgery, before drug administration (Pre), and 0.5h, 1h, 2h, 4h, and 6h after drug administration. The measurement site was on the inside of the surgical incision site. Each animal was measured 3 times, with an interval of at least 3 minutes between each measurement, and the average value was taken. The end of the experiment was after the last pain test. After the experiment, the experimental animals were euthanized according to the animal euthanasia standard operating procedure (SOP).

[0575] Data Analysis: Data were processed using Office Excel 2013 and GraphPad Prism 9.0. Results are expressed as mean ± standard error (Mean ± SEM). Two-way ANOVA was used for analysis, and Tukey's method and two-tailed t-tests were used for comparisons between groups. A p-value < 0.05 was considered statistically significant. The results are shown in the table below.

[0576] Experiment 1: PWT Changes (Mean±SEM)

[0577] Experiment 2: PWT Changes (Mean±SEM) Note: Two-way ANOVA: #### p<0.0001 vs. Pre; **** p<0.0001, *** p<0.001, ** p<0.01, * p<0.05 vs. carrier.

[0578] The results showed that the compounds of the present invention exhibited significant analgesic efficacy, and all of them significantly reversed hyperalgesia, with compound 30-P1 taking effect 0.5 h after administration. The compounds of the present invention all showed potent analgesic effects at a dose of 25 mg / kg, with compound 30-P1 suggesting dose-dependent analgesic efficacy.

[0579] Experimental Example 5: Pharmacodynamic Study in a Rat Model of Selective Sciatic Nerve Branch Injury (SNI)

[0580] Experimental animals: SPF-grade male SD rats, weighing 160-180g (purchased from Hunan Slack Jingda Experimental Animal Co., Ltd.), were raised in a barrier environment animal laboratory.

[0581] Drug preparation: Prepare solutions of the test compound in the carrier (25% PEG400 + 10% Solutol HS-15 + 65% water) at a concentration of 2.5 mg / mL (25 mg / kg) or 5.0 mg / mL (50 mg / kg).

[0582] Experimental Methods: Male SPF-grade SD rats, weighing 180–220 g, were selected after quarantine. All animals were anesthetized with Supra-50 and placed on the operating table. The main sciatic nerve, tibial nerve, common peroneal nerve, and sural nerve were exposed. The tibial and common peroneal nerves were severed distal to their bifurcation to replicate the SNI model. On postoperative day 7, animals were randomly divided into stratified groups (n=8 per group) based on pain threshold and body weight. Each group received either the test substance or control substance orally at a dose of 10 mL / kg, as a single administration. The left paw pain threshold of each group was measured using an electronic analgesia device before administration (Pre), and at 0.5 h, 1.5 h, 2.5 h, 4 h, and 6 h after administration.

[0583] Data Processing and Statistical Analysis: SPSS 23.0 was used for statistical analysis, and results are expressed as mean ± standard deviation (MEAN ± SEM). Leven's test was used to test for normality and homogeneity of variance. If there was no statistical significance (p > 0.05), one-way ANOVA was used. If the ANOVA was statistically significant (p ≤ 0.05), the LSD test (parametric method) was used for comparative analysis. If the variances were unequal (p ≤ 0.05), the Kruskal-Wallis test was used. If the Kruskal-Wallis test was statistically significant (p ≤ 0.05), Dunnett's test (non-parametric method) was used for comparative analysis. The statistical results were compared with α = 0.05, where p ≤ 0.05 indicated statistical significance, and p ≤ 0.01 indicated a highly significant difference. The results are shown in the table below.

[0584] Changes in plantar pain threshold in rats (MEAN±SEM, n=8) Note: Compared with the carrier group. + p≤0.05, ++ p≤0.01.

[0585] The results showed that the compounds of the present invention exhibited significant, rapid (onset of action 0.5 h after administration) and sustained (approximately 6 hours) analgesic efficacy, suggesting dose dependence. The analgesic efficacy of compound 17 at 25 mg / kg was comparable to that of VX-548 at 50 mg / kg. Compound 17 at 50 mg / kg demonstrated superior analgesic efficacy compared to the same dose of VX-548 in terms of onset rate, peak intensity, and duration of action.

[0586] Experimental Example 6: Pharmacodynamic Study in a Mouse Model of Chronic Sciatic Nerve Compression Injury (CCI)

[0587] Laboratory animals: SPF grade C57BL / 6 mice (male, 6-8 weeks old), purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0588] Drug preparation: Prepare a solution of the test compound at a concentration of 5.0 mg / mL (50 mg / kg) in the carrier (25% PEG400 + 10% solubil HS-15 + 65% water).

[0589] Model establishment: Mice were placed in an anesthesia induction box filled with 3.0% isoflurane for anesthesia induction. After anesthesia induction, the animals were transferred to the operating table, and anesthesia was maintained with 2.0% isoflurane at a rate of 200 mL / min. Eyelid reflexes and pain responses were observed. Surgery was initiated after the disappearance of eyelid reflexes and pain responses in the limbs and tail. Before surgery, the surgical site was shaved and disinfected with povidone-iodine. A longitudinal incision of approximately 1 cm was made behind the greater trochanter of the left femur of the mouse. The muscles were bluntly dissected to fully expose the sciatic nerve and its three terminal branches: the sural nerve, the common peroneal nerve, and the tibial nerve. The sciatic nerve was intermittently ligated with 6-0 silk suture softened by physiological saline (ligation began 2 mm from the branch), with three ligatures spaced approximately 1 mm apart, and the intensity was such that there was a slight tremor in the calf muscles.

[0590] Experimental grouping and administration: Animals were randomly assigned to groups of 7 based on their baseline pain threshold before administration. Administration was performed via a single gavage, with a volume of 10 mL / kg.

[0591] Mechanical pain threshold measurement: Before testing, animals were placed in the testing box for 3 consecutive days, 30 minutes each day. For each test, the animal was placed in the testing box for 5-10 minutes to acclimatize, and then the mechanical pain threshold of the animal's left hind limb was measured using an electronic Von Frey analgesic device. Each animal was measured 3 times consecutively at 5-minute intervals, and the average value was taken. Measurements were performed before surgery, before drug administration on day 6 post-surgery (Pre), and at 0.5h, 1.5h, 2.5h, 4h, and 6h post-surgery (day 7). The day of surgical modeling was defined as day 0.

[0592] Data Analysis: Data were processed using Office Excel 2013 and GraphPad Prism 9.0. Results are expressed as mean ± standard error (Mean ± SEM). Two-way ANOVA was used for analysis, and Tukey's method and two-tailed t-tests were used for comparisons between groups. A p-value < 0.05 was considered statistically significant. The results are shown in the table below.

[0593] PWT variation (Mean±SEM) Note: Two-way ANOVA: *** p<0.001, ** p<0.01, * p<0.05 vs. carrier.

[0594] The results showed that the compounds of the present invention exhibit significant, rapid and long-lasting analgesic efficacy.

[0595] In addition to those described herein, various modifications to the 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. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (A): in: W represents O, S, or NH; Ring A is a phenyl group, a 6-membered heteroaryl group, or a saturated or partially unsaturated 6-membered carbon ring or heterocycle. Ring B is a 5-membered heteroaryl group, or a saturated or partially unsaturated 5-membered carbon ring or heterocycle. Ring A and ring B share adjacent ring atoms X. 2 and X 5 This forms a fused double ring; Indicates a single bond or a double bond; Given the allowable valence, X 2 and X 5 Each is independently selected from C, CH, and N, and X 2 and X 5 At most one of them is N; R 1 It is H, –OH, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio, –NR 13 -C 1-6 Alkyl, –NR 13 -C 1-6 Halogenated alkyl, –L 1 –(C 1-6 (alkylene)–OR 15 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–OR 15 –L 1 –(C 2-6 (alkenyl)–OR 15 –L 1 –(by one or more R) 15’ Replacement C 2-6 (alkenyl)–OR 15 –L 1 –(C 1-6 (alkylene)–SR 15 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–SR 15 –L 1 –(C 2-6 (alkenyl)–SR 15 –L 1 –(by one or more R) 15 'Replacement of C' 2-6 (alkenyl)–SR 15 –L 1 –(C 1-6 (alkylene)–NR 13 R 14 –L 1 –(by one or more R) 15 'Replacement of C' 1-6 (alkylene)–NR 13 R 14 –L 1 –(C 1-6 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 ; R 2 and R 3 Each is independently H, halogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R 4 and R 5 Each is independently H, -OH, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; n is 0, 1, 2, or 3; Each R a Independently, it is hydrogen, halogen, CN, -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy groups, -S (=O) m -R 11 R 12 -C(=O)-NR 13 R 14 -C(=S)-R 11 R 12 -N(NR) 13 R 14 ) m -P (=O) m -R 11 R 12 -C(=N)-NR 13 R 14 -S(=O)2-NR 13 R 14 -C 1-6 Alkylene-R 11 R 12 、or -S(=O)(=NR) 11 )R 12 ; m is 0, 1, or 2; R 6 R 7 R 8 and R 9 H and C are independent of each other. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 3-6 cycloalkyl; L 1 Is it a key, O, or S? L 2 Is it a key or C? 1-6 Alkylene; R 10 It is C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, 5 or 6 membered heteroaryl, –C(O)O(C 1-6 Alkyl), –COOH or –C(O)NR 17 R 18 Wherein C 3-6 Cycloalkyl, 3-7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl groups are optionally bonded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R 11 and R 12 Each time it appears, it is independently selected from hydrogen, OH, NH2, and C. 1-6 Alkyl, C 1-6 Alkyl group, 3-7 membered carbon ring, or 3-7 membered heterocycle, wherein the 3-7 membered carbon ring or 3-7 membered heterocycle is optionally surrounded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R 13 R 14 R 17 and R 18 Each time it appears, it is independently H, –OH, or C. 1-6 Alkyl or 3-7 membered heterocyclic alkyl, or R attached to the same N. 13 and R 14 Optionally, they can be linked to form a 3-7 membered heterocyclic group or a 5-10 membered heteroaryl group, wherein the 3-7 membered heterocyclic alkyl group, or the 5 or 6 membered heteroaryl group, is optionally bonded by one or more halogens, –OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy groups; R 15 Each time it appears, it is independently H or C. 1-6 Alkyl or C 1-6 Halogenated alkyl groups; Each R 15 'Independently halogen, CN, -OH, -SH, -NR 13 R 14 C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups; and The C mentioned above 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio group, C 1-6 Alkylene and C 2-6 Any one or more of the alkenyl groups, either alone or as part of a substituent, may optionally be substituted with one or more deuterium groups.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (I) or has the structure of formula (I'):

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 1 It is H, –OH, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylthio, C 1-6 Haloalkylthio, –NR 13 -C 1-6 Alkyl, –NR 13 -C 1-6 Halogenated alkyl, –L 1 –(C 1-6 (alkylene)–OR 15 –L 1 –(C 2-6 (alkenyl)–OR 15 –L 1 –(C 1-6 (alkylene)–SR 15 –L 1 –(C 2-6 (alkenyl)–SR 15 –L 1 –(C 1-6 (alkylene)–NR 13 R 14 –L 1 –(C 1-6 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 .

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (IIA), (IIB), or (IIC), or the structure of formula (II'A), (II'B), or (II'C):

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: R 4 Is it H or C? 1-4 Alkyl, preferably H, methyl, ethyl or isopropyl, more preferably H; and / or R 5 Is it H or C? 1-4 Alkyl, preferably H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, more preferably H, methyl, ethyl, isopropyl or tert-butyl, and even more preferably H or methyl.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein... The functional groups are -NH2 and -NH(C). 1-4 alkyl), or -N(C) 1-4 Alkyl)2, preferably -NH2, -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH3)(CH2CH3), or -N(CH2CH3)2, more preferably -NH2.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 13 and R 14 Each time it appears, it is independently H or C. 1-4 Alkyl or 3-6 membered heterocyclic alkyl, or R attached to the same N. 13 and R 14 Optionally, they can be linked to form 3-6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups, wherein the 3- or 6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups, are optionally bonded by one or more halogens, –OH groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy substitution; preferably, R 13 and R 14 Each time it appears, it is independently either H or C. 1-4 Alkyl, more preferably H, methyl or ethyl; and / or R 11 and R 12 Each time it appears, it is independently selected from hydrogen, OH, NH2, and C. 1-4 Alkyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, or 3-6 membered heterocycloalkyl, wherein the 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl is optionally reacted with one or more halogens, –OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution, preferably hydrogen, OH, NH2, or C. 1-4 Alkyl, or C 1-4 Alkoxy, more preferably H, methyl or ethyl.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein each R a Independently, it is hydrogen, halogen, CN, -OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl or C 1-4 Haloalkoxy groups, preferably H, F, Cl, Br, I, or C. 1-4 Alkyl, more preferably H, F, Cl, methyl, ethyl, isopropyl or tert-butyl, and even more preferably H, F or Cl.

9. The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein n is 0; or n is 1; or n is 2.

10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein ring A is cyclohexyl, C6 cycloalkenyl having one or two double bonds, 6-membered heterocyclic alkyl, 6-membered heterocyclic alkenyl having one or two double bonds, phenyl or 6-membered heteroaryl; Preferably, ring A is phenyl or a 6-membered heteroaryl group.

11. The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein the ring B is cyclopentyl, C5 cycloalkenyl having one or two double bonds, 5-membered heterocyclic alkyl, 5-membered heterocyclic alkenyl having one or two double bonds, or 5-membered heteroaryl; Preferably, the ring B is a C5 cycloalkenyl group having one or two double bonds, a 5-membered heterocyclic alkenyl group having one or two double bonds, or a 5-membered heteroaryl group.

12. The compound according to any one of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein ring A is phenyl or a 6-membered heteroaryl, and ring B is a C5 cycloalkenyl having one or two double bonds, a 5-membered nitrogen-containing heterocyclic alkenyl having one or two double bonds, or a 5-membered heteroaryl.

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: The Part of the structure is of formula (Cy1): in: The ring A is a phenyl or a 6-membered heteroaryl group. This indicates that the indicated ring is aromatic; This indicates that the indicated ring is aromatic or partially unsaturated; X 1 X 2 X 5 X 6 X 8 and X 9 Each is independently selected from CH and N; X 3 X 4 and X 7 Each is independently selected from CH, CH2, O, S, N, and NR. 16 ; R 16 It is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-7 membered heterocyclic alkyl, preferably H or C 1-4 Alkyl, more preferably H, methyl, ethyl, isopropyl or tert-butyl; The conditions are: (1) Given the allowable valence, X 1 X 2 X 5 X 6 X 8 and X 9 At most three atoms are selected from N, and there are no three consecutive N ring atoms in ring B; and (2) Where the valence is permissible, X 2 X 3 X 4 X 5 and X 7 There are at most four atoms selected from N and NH, and at most two atoms selected from O and S, and there are no two adjacent O ring atoms, two adjacent S ring atoms, or adjacent O and S ring atoms in the ring C.

14. The compound of claim 13 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: The part of formula (Cy1) has the structure of formula (Cy2):

15. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: X 1 Let N be the number of elements, and X be the number of elements. 6 For N; or, X 1 It is CH, and X 6 For N; or, X 1 and X 6 Each is CH; or, X 1 Let N be the number of elements, and X be the number of elements. 6 For CH.

16. The compound according to any one of claims 13-15, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: X 2 and X 5 Each is C; or, X 2 Let C be the integer, and X be the integrity. 5 For N; or, X 2 Let N be the number of elements, and X be the number of elements. 5 The answer is C.

17. The compound according to any one of claims 13-16, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the portion of formula (Cy2) comprises: (1) The structure of formula (Cy3A): in: X 3 X 4 and X 7 Each is independently selected from CH, N, and NR. 16 O and S, and in X 3 X 4 and X 7 In the middle, at most two are N or NR. 16 And at least one of them is CH; or in X 3 X 4 and X 7 Among them, there is one and only one that is NR. 16 O or S, and preferably at least one of them is CH; or (2) The structure of formula (Cy3B): in: Indicates a single or double bond, and the two bonds in ring B. At most one of them is a double bond; and Given the allowable valence, X 3 X 4 and X 7 Each is independently selected from CH, CH2, O, S, N, and NR. 16 And in X 3 X 4 and X 7 In the middle, at most two are N or NR. 16 It has at most two O or S, and preferably at least one of them is CH or CH2.

18. The compound according to any one of claims 13-17, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the structure of formula (Cy3A) has the structure of formula (Cy4): in: X 3 It is NR 16 O or S; X 4 It is CH or N; and X 7 For CH or N; and / or Preferably, X 1 It is CH and X 6 It is CH, or, preferably, X. 1 It is N and X 6 It is CH; Preferably, part of formula (Cy4) is Preferred (1) More preferably, the compound has the structure of formula (IIIA), formula (IIIA'), formula (IIIB), (IIIB'), formula (IIIC) or formula (IIIC'), or the structure of formula (III'A), formula (III'A'), formula (III'B), (III'B'), formula (III'C) or formula (III'C'): Where, formula The preferred part is: More preferably, formula The part is: Where, formula The preferred part is: More preferably, formula The part is: or (2) More preferably, the compound has the structure of formula (IVA), formula (IVB) or formula (IVC), or the structure of formula (IV'A), formula (IV'B) or formula (IV'C): Where, formula The preferred part is:

19. The compound according to any one of claims 13-17, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the structure of formula (Cy3A) is the structure of formula (Cy5): in: X 3 It is CH or N; X 4 It is CH or N; and X 7 For NR 16 O or S; preferably, X 3 and X 4 At least one of them is CH; and / or Preferably, X 1 It is CH and X 6 It is CH, or, preferably, X. 1 It is N and X 6 It is CH; Preferably, part of formula (Cy5) is Preferred (1) More preferably, the compound has the structure of formula (VA), formula (VA'), formula (VB), (VB'), formula (VC) or formula (VC'), or the structure of formula (V'A), formula (V'A'), formula (V'B), (V'B'), formula (V'C) or formula (V'C'): Where, formula The preferred part is: More preferably, formula The part is: Where, formula The preferred part or (2) More preferably, the compound has the structure of formula (VIA), formula (VIA'), formula (VIB), (VIB'), formula (VIC) or formula (VIC'), or the structure of formula (VI'A), formula (VI'A'), formula (VI'B), (VI'B'), formula (VI'C) or formula (VI'C'): Where, formula The preferred part More preferably, formula Part of Where, formula The preferred part More preferably, formula Part of or (3) More preferably, the compound has the structure of formula (VD), formula (VE), or formula (VF), or the structure of formula (V'D), formula (V'E), or formula (V'F): Where, formula The preferred part is: More preferably, formula The part is:

20. The compound according to any one of claims 13-17, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the portion of formula (Cy3A) has the structure of formula (Cy6): in: X 3 It is CH or N; X 4 For NR 16 O or S; and X 7 It is CH or N; preferably, X 3 and X 7 At least one of them is CH; and / or Preferably, X 1 It is CH and X 6 It is CH, or, preferably, X. 1 It is N and X 6 It is CH; Preferably, part of formula (Cy6) is Preferred More preferably, the compound has the structure of formula (VIIA), formula (VIIA'), formula (VIIB), (VIIB'), formula (VIIC) or formula (VIIC'), or the structure of formula (VII'A), formula (VII'A'), formula (VII'B), (VII'B'), formula (VII'C) or formula (VII'C'): Where: formula The preferred part Mode The part is:

21. The compound according to any one of claims 13-17, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the portion of formula (Cy3A) has the structure of formula (Cy7): in: X 3 X 4 and X 7 Each is independently selected from CH and N, and preferably, X 3 X 4 and X 7 At least one of them is CH; and / or Preferably, X 1 It is CH and X 6 It is CH, or, preferably, X. 1 It is N and X 6 It is CH; Preferably, part of formula (Cy7) is (where X) 3 and X 4 At least one of them is CH), preferably (where X) 3 and X 4 At least one of them is CH), or (where X) 3 and X 4 At least one of them is CH); More preferably, the compound has the structure of formula (VIIIA), formula (VIIIA'), formula (VIIIB), (VIIIB'), formula (VIIIC), or formula (VIIIC'), or the structure of formula (VIII'A), formula (VIII'A'), formula (VIII'B), (VIII'B'), formula (VIII'C), or formula (VIII'C'): Where, formula The preferred part is Mode The preferred part 22. The compound according to any one of claims 13-17, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the portion of formula (Cy3A) has the structure of formula (Cy8): in: X 3 X 4 and X 7 Each is independently selected from CH and N, and preferably, X 3 X 4 and X 7 At least one of them is CH; and / or Preferably, X 1 It is CH and X 6 It is CH, or, preferably, X. 1 It is N and X 6 It is CH; Preferably, part of formula (Cy8) is Preferred (1) More preferably, the compound has the structure of formula (IX-1A), formula (IX-1A'), formula (IX-1B), (IX-1B'), formula (IX-1C), or formula (IX-1C'), or the structure of formula (IX'-1A), formula (IX'-1A'), formula (IX'-1B), (IX'-1B'), formula (IX'-1C), or formula (IX'-1C'): Where, formula The preferred part is Mode The preferred part is or (2) More preferably, the compound has the structure of formula (IX-2A), formula (IX-2A'), formula (IX-2B), (IX-2B'), formula (IX-2C), or formula (IX-2C'), or the structure of formula (IX'-2A), formula (IX'-2A'), formula (IX'-2B), (IX'-2B'), formula (IX'-2C), or formula (IX'-2C'): Where, formula The preferred part is Mode The preferred part is or (3) More preferably, the compound has the structure of formula (IX-3A), formula (IX-3A'), formula (IX-3B), (IX-3B'), formula (IX-3C), or formula (IX-3C'), or the structure of formula (IX'-3A), formula (IX'-3A'), formula (IX'-3B), (IX'-3B'), formula (IX'-3C), or formula (IX'-3C'): Where, formula The preferred part is Mode The preferred part is or (4) More preferably, the compound has the structure of formula (IX-4A), formula (IX-4A'), formula (IX-4B), (IX-4B'), formula (IX-4C), or formula (IX-4C'), or the structure of formula (IX'-4A), formula (IX'-4A'), formula (IX'-4B), (IX'-4B'), formula (IX'-4C), or formula (IX'-4C'): Where, formula The preferred part is Mode The preferred part is 23. The compound according to any one of claims 13-17, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: (1) Part of the formula (Cy3B) has the structure of formula (Cy9): Where: X 3 X 4 and X 7 Each is independently selected from CH2, O, S and NR. 16 Preferably, X 3 X 4 and X 7 At least one of them is CH2; and / or Preferably, X 1 It is CH and X 6 It is CH, or, preferably, X. 1 It is N and X 6 It is CH; Preferably, a portion of formula (Cy9) is selected from: More preferably, part of formula (Cy9) is More preferably, the compound has a structure of formula (XA), formula (XB), or formula (XC): or The compound has a structure of formula (XD), formula (XE), or formula (XF): or The compound has a structure of formula (X'A), formula (X'B), or formula (X'C): or The compound has a structure of formula (X'D), formula (X'E), or formula (X'F): Where, formula Partially preferred Mode Partially preferred or (2) Part of the formula (Cy3B) has the structure of formula (Cy10): Where: X 3 and X 4 Each is independently selected from CH and N; and / or Preferably, X 1 It is CH and X 6 It is CH, or, preferably, X. 1 It is N and X 6 It is CH; Preferably, a portion of the formula (Cy10) is selected from... More preferably, part of the formula (Cy10) is More preferably, the compound has a structure of formula (XIA), formula (XIB), or formula (XIC): or The compound has a structure of formula (XID), formula (XIE), or formula (XIF): or The compound has a structure of formula (XI'A), formula (XI'B), or formula (XI'C): or The compound has a structure of formula (XI'D), formula (XI'E), or formula (XI'F): Where, formula The preferred part is Mode The preferred part is or (3) Part of the formula (Cy3B) has the structure of formula (Cy11): Where: X 4 and X 7 Each is independently selected from CH and N; and / or Preferably, X 1 It is CH and X 6 It is CH, or, preferably, X. 1 It is N and X 6 It is CH; Preferably, a portion of the formula (Cy11) is selected from... More preferably, part of the formula (Cy11) is More preferably, the compound has a structure of formula (XIIA), formula (XIIB), or formula (XIIC): or The compound has a structure of formula (XIID), formula (XIIE), or formula (XIIF): or The compound has a structure of formula (XII'A), formula (XII'B), or formula (XII'C): or The compound has a structure of formula (XII'D), formula (XII'E), or formula (XII'F): Where, formula The preferred part is Mode Part of 24. The compound according to any one of claims 1-23, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 17 and R 18 Each time it appears, it is independently H or C. 1-4 Alkyl or 3-6 membered heterocyclic alkyl, or R attached to the same N. 17 and R 18 Optionally, they can be linked to form 3-6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups, wherein the 3- or 6-membered heterocyclic alkyl groups, or 5- or 6-membered heteroaryl groups, are optionally bonded by one or more halogens, –OH groups, C groups, etc. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy substitution; preferably, R 17 and R 18 Each is independently H or C 1-4 Alkyl, more preferably H, methyl or ethyl.

25. The compound according to any one of claims 1-24, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 10 It is C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl, –C(O)O(C 1-4 Alkyl groups), –COOH or –C(O)NH2, –C(O)NH(C 1-4 alkyl) or –C(O)NH(C 1-4 alkyl)2, wherein the C 3-6 Cycloalkyl, 3-6-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, optionally bonded by one or more halogens, –OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups.

26. The compound according to any one of claims 1-25, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 15 Each time it appears, it is independently H or C. 1-4 Alkyl or C 1-4 Halogenated alkyl groups.

27. The compound according to any one of claims 1-26, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein each R 15’ Independently, it is halogen, CN, –OH, -SH, NH2, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Halogenated alkyl, or –N(C) 1-4 alkyl)-C 1-4 Halogenated alkyl groups, Preferably, each R 15’ Independently, they are F, Cl, Br, I, CN, –OH, -SH, NH2, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, –NH-C 1-2 Alkyl, –N(C) 1-2 Alkyl)2、–NH-C 1-2 Haloalkyl, –N(C) 1-2 alkyl)-C 1-2 Halogenated alkyl groups, More preferably, each R 15’ It can be F, Cl, CN, –OH, -SH, or NH2 independently. More preferably, each R 15 'Independently, it is –OH, -SH, or NH2.

28. The compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: R 1 It is H, –OH, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Halogenated alkyl, –L 1 –(C 1-4 (alkylene)–OR 15 –L 1 –(by one or two Rs) 15 'Replacement of C' 1-4 (alkylene)–OR 15 –L 1 –(C 2-4 (alkenyl)–OR 15 –L 1 –(by one or two Rs) 15 'Replacement of C' 2-4 (alkenyl)–OR 15 –L 1 –(C 1-4 (alkylene)–SR 15 –L 1 –(by one or two Rs) 15 'Replacement of C' 1-4 (alkylene)–SR 15 –L 1 –(C 2-4 (alkenyl)–SR 15 –L 1 –(by one or two Rs) 15 'Replacement of C' 2-4 (alkenyl)–SR 15 –L 1 –(C 1-4 (alkylene)–NR 13 R 14 –L 1 –(by one or two Rs) 15 'Replacement of C' 1-4 (alkylene)–NR 13 R 14 –L 1 –(C 1-4 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 L 1 Each occurrence is independently a key, an O, or an S, and L 2 Is it a key or C? 1-4 Alkylene Preferably, R 1 Is H, –OH, F, Cl, Br, I, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Haloalkyl, –(C 1-4 (alkylene)–OC 1-4 Alkyl, –(C 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 (alkylene)–OC 1-4 Alkyl group, –O (C group substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene) –OH, –O (C substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 alkylene)–OH, –O(C 1-4 (alkylene)–SC 1-4 Alkyl group, –O (C group substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 Alkylene)–SH,–O (C substituted with one or two substituents selected from F, Cl, CN,–OH, -SH and NH2) 1-4 alkylene)–SH,–S(C 1-4 (alkylene)–OC 1-4 Alkyl group, –S (C group substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–OC 1-4 Alkyl, –S(C 1-4 (alkylene) –OH, –S (C substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 alkylene)–OH, –S(C 1-4 (alkylene)–SC 1-4 Alkyl group, –S (C group substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 Alkylene) –SH, –S (C substituted with one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–SH,–L 1 –(C 1-4 (alkylene)–NR 13 R 14 –L 1 –(C substituted by one or two substituents selected from F, Cl, CN, –OH, -SH and NH2) 1-4 (alkylene)–NR 13 R 14 –O–(C 1-4 (alkylene)–R 10 、–S–(C 1-4 (alkylene)–R 10 , or -R 10 L 1 Each time it appears, it is independently a key, an O, or an S. More preferably, R 1 It is C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Haloalkyl, –O(C) 1-4 (alkylene)–OC 1-4 Alkyl groups, –O (C atoms substituted with one or two substituents selected from –OH, -SH, and NH2) 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 Alkylene) –OH, –O (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 alkylene)–OH, –O(C 1-4 (alkylene)–SC 1-4 Alkyl groups, –O (C atoms substituted with one or two substituents selected from –OH, -SH, and NH2) 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 Alkylene) –SH, –O (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 alkylene)–SH,–S(C 1-4 (alkylene)–OC 1-4 Alkyl group, –S (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 (alkylene)–OC 1-4 Alkyl, –S(C 1-4 Alkylene) –OH, –S (C substituted with one or two substituents selected from –OH, -SH and ) 1-4 alkylene)–OH, –S(C 1-4 (alkylene)–SC 1-4 Alkyl group, –S (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 Alkylene) –SH, –S (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 Alkylene)–SH, –O–(C 1-4 (alkylene)–NR 13 R 14 、–S–(C 1-4 (alkylene)–NR 13 R 14 –O– (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 (alkylene)–NR 13 R 14 –S– (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 (alkylene)–NR 13 R 14 –O–(C 1-4 (alkylene)–R 10 、–S–(C 1-4 (alkylene)–R 10 , or -R 10 , Even more preferably, R 1 It is C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Haloalkyl, –O(C) 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene) –OH, –O (C substituted with one or two substituents selected from –OH and -SH) 1-4 alkylene)–OH, –O(C 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 Alkylene) –SH, –O (C substituted with one or two substituents selected from –OH and -SH) 1-4 alkylene)–SH,–S(C 1-4 (alkylene)–OC 1-4 Alkyl, –S(C 1-4 Alkylene) –OH, –S (C substituted with one or two substituents selected from –OH and -SH) 1-4 alkylene)–OH, –S(C 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 Alkylene) –SH, –S (C substituted with one or two substituents selected from –OH, -SH and NH2) 1-4 Alkylene)–SH, –O–(C 1-4 (alkylene)–NR 13 R 14 、–S–(C 1-4 (alkylene)–NR 13 R 14 –O–(C 1-4 (alkylene)–R 10 、–S–(C 1-4 (alkylene)–R 10 , or -R 10 , The C mentioned above 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio group, C 1-4 Alkylene and C 2-4 Any one or more of the alkenyl groups, whether alone or as part of a substituent, may optionally be substituted with one or more deuterium groups; Preferably, where R 13 and R 14 Each time it appears, it is independently either H or C. 1-4 Alkyl, more preferably H, methyl or ethyl, or R attached to the same N 13 and R 14 Optionally linked to form a compound optionally connected by one or more halogens, –OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Haloalkoxy-substituted 3-6-membered heterocyclic alkyl groups or 5- or 6-membered heteroaryl groups; and / or Preferably, where R 10 Each time it appears, it is independently and optionally influenced by one or more halogens, –OH, C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy-substituted C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5 or 6 membered heteroaryl; Even more preferably, R 1 It includes methoxy, ethoxy, isopropoxy, tert-butoxy, -OCD3, -OCD2CD3, -OCD(CD3)2, -OC(CD3)3, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2Cl, -O-CHCl2, -O-CCl3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2Cl, -O-CH2CHCl2, -O-CH2CCl3, methylthio, ethylthio, isopropylthio, tert-butylthio, -SCD3, -SCD2CD3 , -SCD(CD3)2, -SC(CD3)3, -S-CH2F, -S-CHF2, -S-CF3, -S-CH2Cl, -S-CHCl2, -S-CCl3, -S-CH2CH2F, -S-CH2CHF2, -S-CH2CF3, -S-CH2CH2Cl, -S-CH2CHCl2, -S-CH2CCl3, –NHCH3, –N(CH3)2, –NHCH2CH3, –N(CH3)(CH2CH3), –N(CH2CH3)2, –NHCD3, –N(CD3) 2. -OCH2-OCH3, -OCH2-OCH2CH3, -OCH2CH2-OCH3, -OCH2CH2-OCH2CH3, -SCH2-OCH3, -SCH2-OCH2CH3, -SCH2CH2-OCH3, -SCH2 CH2-OCH2CH3, -OCH2-OH, -OCH2CH2-OH, -OCH2-CH(OH)-CH2-OH, -O-CH(-CH2-OH)2, -SCH2-OH, -SCH2CH2-OH, -S-CH2-CH(OH) -CH2-OH, -S-CH(-CH2-OH)2, -O-CH2-NH2, -O-CH2-NH(CH3), -O-CH2-N(CH3)2, -O-CH2CH2-NH2, -O-CH2CH2-NH(CH3), -O-CH2 CH2-N(CH3)2, -S-CH2-NH2, -S-CH2-NH(CH3), -S-CH2-N(CH3)2, -S-CH2CH2-NH2, -S-CH2CH2-NH(CH3), -S-CH2CH2-N(CH3)2, Even more preferably, R 1 It is methoxy, methylthio, -OCD3, -SCD3, -O-CH2F, -O-CHF2, -O-CF3, -O-CH2Cl, -O-CHCl2, -O-CCl3, -O-CH2CH2F, -O-CH2CHF2, -O-CH2CF3, -O-CH2CH2Cl, -O-CH2CHCl2, -O-CH2CCl3, -S-CH2F, -S-CHF2, -S-CF3, -S-CH2Cl, -S-CHCl2, -S-CCl3, -S-CH2CH2F, -S-CH2CHF2, -S-CH2CF3, -S-CH2CH2Cl, -S-CH2CHCl2, -S-CH2CCl3, –NHCH3, –N (CH3)2, –NHCH2CH3, –N(CH3)(CH2CH3), –N(CH2CH3)2, –NHCD3, –N(CD3)2, -OCH2-OCH3, –OCH2-OCH2CH3, –OCH2CH2-OCH3, –OCH2CH2-OCH3, –OCH2-OH, –OCH2CH2 -OH, -OCH2-CH(OH)-CH2-OH, -O-CH(-CH2-OH)2, -O-CH2-NH2, -O-CH2-NH(CH3), -O-CH2-N(CH3)2, -O-CH2CH2-NH2, -O-CH2CH2-NH(CH3), -O-CH2CH2-N(CH3)2, 29. The compound according to any one of claims 1-27, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: R 1 It is H, –OH, halogen, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Halogenated alkyl, –L 1 –(C 1-4 (alkylene)–OR 15 –L 1 –(C 2-4 (alkenyl)–OR 15 –L 1 –(C 1-4 (alkylene)–SR 15 –L 1 –(C 2-4 (alkenyl)–SR 15 –L 1 –(C 1-4 (alkylene)–NR 13 R 14 –L 1 –(C 1-4 Alkylene)-N=S(O)(C 1-3 alkyl)2 or –L 1 –L 2 –R 10 L 1 It is a key, O or S, and L 2 Is it a key or C? 1-4 Alkylene Preferably, R 1 Is H, –OH, F, Cl, Br, I, C 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –NH-C 1-4 Alkyl, –N(C) 1-4 Alkyl)2、–NH-C 1-4 Haloalkyl, –N(C) 1-4 alkyl)-C 1-4 Haloalkyl, –(C 1-4 (alkylene)–OC 1-4 Alkyl, –(C 1-4 (alkylene)–SC 1-4 Alkyl, –O(C) 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 (alkylene)–OC 1-4 Alkyl, or –S(C 1-4 (alkylene)–SC 1-4 alkyl, More preferably, R 1 It is C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio groups, –O(C 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 (alkylene)–OC 1-4 Alkyl, or –S(C 1-4 (alkylene)–SC 1-4 alkyl, More preferably, R 1 It is C 1-4 Alkoxy, C 1-4 Alkylthio, –O(C 1-4 (alkylene)–OC 1-4 Alkyl, –O(C) 1-4 (alkylene)–SC 1-4 Alkyl, –S(C 1-4 (alkylene)–OC 1-4 Alkyl, or –S(C 1-4 (alkylene)–SC 1-4 alkyl, The C mentioned above 1-4 Alkyl, C 2-4 alkenyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio group, C 1-4 Alkylene and C 2-4 Any one or more of the alkenyl groups, whether alone or as part of a substituent, may optionally be substituted with one or more deuterium groups; Even more preferably, R 1 It is methoxy, ethoxy, isopropoxy, tert-butoxy, -OCD3, -OCD2CD3, -OCD(CD3)2, -OC(CD3)3, -OCF3, -OCHF2, -OCH2F, methylthio, ethylthio, isopropylthio, tert-butylthio, -SCD3, -SCD2CD3, -SCD(CD3)2, -SC(CD3)3, -SCF3, -SCHF2, -SCH2F, -OCH2-OCH3, -OCH2-OCH2CH3, -OCH2CH2-OCH3, -OCH2CH2-OCH2CH3, and more preferably methoxy, -OCHF2, methylthio, -SCHF2, -OCD3, or -OCH2CH2-OCH3; Even more preferably, R 1 It is methoxy, ethoxy, isopropoxy, tert-butoxy, -OCD3, -OCD2CD3, -OCD(CD3)2, -OC(CD3)3, -OCF3, -OCHF2, -OCH2F, methylthio, ethylthio, isopropylthio, tert-butylthio, -SCD3, -SCD2CD3, -SCD(CD3)2, -SC(CD3)3, -OCH2-OCH3, -OCH2-OCH2CH3, -OCH2CH2-OCH3, -OCH2CH2-OCH2CH3, and more preferably methoxy, methylthio, -OCD3, -OCHF2, or -OCH2CH2-OCH3.

30. The compound according to any one of claims 1-29, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: R 2 and R 3 Each is independently H, halogen, C 1-4 Alkyl or C 1-4 Halogenated alkyl groups; Preferably, R 2 and R 3 The individual choices are F, Cl, Br, and I, with F being the optimal choice.

31. The compound according to any one of claims 1-30, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein... Part of 32. The compound according to any one of claims 1-30, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein... Part of 33. The compound according to any one of claims 1-32, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R 6 It is C 1-4 Alkyl, and R 7 It is C 1-4 Halogenated alkyl groups; Preferably, R 6 It is methyl, and R 7 It's CF3.

34. The compound according to any one of claims 1-33, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein: R 8 It is H, and R 9 It is C 1-4 alkyl; Preferably, R 8 It is H, and R 9 It is CH3.

35. The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from:

36. A pharmaceutical composition comprising a preventive or therapeutically effective amount of the compound of any one of claims 1-35 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier, wherein the pharmaceutical composition optionally comprises one or more additional therapeutic agents.

37. Use of any compound of claims 1-35 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug, or the pharmaceutical composition of claim 36 in the preparation of a medicament used as a voltage-gated sodium channel inhibitor. Preferably, the voltage-gated sodium channel is Na V 1.8; and / or The drug is used to treat, prevent or alleviate diseases or conditions related to voltage-gated sodium channels, wherein the disease or condition is preferably pain (e.g., acute or chronic pain).

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