Novel sodium channel modulator

Abstract

Provided is a novel sodium channel modulator, and particularly an Nav1.8 channel modulator. The sodium channel modulator has a structure as shown in the following formula I.

Description

A new sodium channel modulator

[0001] This application claims the priority benefit of the prior application filed by the applicant with the State Intellectual Property Office of China on December 26, 2023, with patent application number CN202311805889.6 and title “A Novel Sodium Channel Regulator”. The full text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present invention relates to a novel sodium channel regulator, in particular to a Nav1.8 channel regulator. Background Art

[0003] Voltage-gated sodium channels (VGSCs) mediate the selective influx of sodium ions into excitable cells and play an important role in the initiation and propagation of action potentials. Voltage-gated sodium channels are ubiquitous in the central and peripheral nervous systems, as well as in skeletal and cardiac muscles.

[0004] Nav's form a subfamily of the voltage-gated ion channel superfamily and comprise nine isoforms, designated Nav1.1-Nav1.9. The tissue localization of each of the nine isoforms varies. Nav1.4 is the predominant sodium channel in skeletal muscle, and Nav1.5 is the predominant sodium channel in cardiac myocytes. Nav's 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system, while Nav's 1.1, 1.2, 1.3, and 1.6 are neural channels found in both the central and peripheral nervous systems. The nine isoforms exhibit similar functional behaviors but differ in specific aspects of their voltage-dependence and kinetic behavior.

[0005] The Nav1.8 voltage-gated sodium channel is thought to play a role in various diseases, including neuropathic pain, chronic itch, and inflammatory pain sensation.

[0006] There is still a need for effective inhibitors of Nav1.8 sodium channel activity that have selective activity against the Nav1.8 sodium channel. Therefore, the compounds of the present invention are useful in treating and preventing diseases, disorders and conditions involving the Nav1.8 receptor and the Nav1.8 voltage-gated sodium channel. Summary of the Invention

[0007] The present invention provides the following compounds for use in the treatment and prevention of diseases, disorders and conditions involving the Nav1.8 receptor and the Nav1.8 voltage-gated sodium ion channel.

[0008] In one aspect, the present application provides a compound of structural formula I:

[0009] Its isomers, racemates, pharmaceutically acceptable salts or prodrugs, wherein:

[0010] R1, R2, R3, R4, and R5 are independently selected from H, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylamino, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl, halogenated C 3-6 Cycloalkyloxy; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylamino, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl, halogenated C 3-6 Cycloalkyloxy may be further substituted by one or more independently selected from hydrogen, halogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Substitution by a cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0011] R6 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl;

[0012] R7, R8 are independently selected from H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl;

[0013] R9, R 10 Further cyclized with the carbon atoms to which they are attached to form a 5-10 membered heterocycloalkyl group; the 5-10 membered heterocycloalkyl group may be further substituted with one or more independently selected R 11 Substituents substituted; R 11 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -L1-OR 12 、-L1-NR 13 R 14 、C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkylene C 3-6 Cycloalkyl, C 1-6 Alkylene 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl; wherein, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, -L1-OR 12 、-L1-NR 13 R 14 、C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkylene C 3-6 Cycloalkyl, C 1-6 Alkylene 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl can be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Substitution by a cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0014] L1 is selected from a bond, C 1-6 Alkylene or C 3-6 cycloalkylene;

[0015] R 12 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0016] R 13 、R 14 are independently selected from hydrogen, C 1-6Alkyl, 3-7 membered heterocycloalkyl.

[0017] In one embodiment of the present invention, in the formula I, Selected from and its five-membered ring portion is optionally substituted by one or more independently selected from R 11 substituted by a substituent.

[0018] In one embodiment of the present invention, in the formula I, Selected from

[0019] In one embodiment of the present invention, R1, R2, R3, R4, and R5 are independently selected from H, FCH2O-, CH3O-, CH3S-, CH3CH2O-, CH3CH2S-, F,

[0020] In one embodiment of the present invention, Formula I has the structure of Formula II:

[0021] wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in Formula I.

[0022] In one embodiment of the present invention, The H is optionally further replaced by one or more independently selected R 11 Substituents substituted;

[0023] In one embodiment of the present invention, Selected from

[0024] In one embodiment of the present invention, Selected from

[0025] In one embodiment of the present invention, Formula I has the structure of Formula IIa, Formula IIb:

[0026] Among them, R1, R2, R3, R4, R5, R6, R7, R8, R 11 As defined above.

[0027] In some embodiments of the present invention,

[0028] R 11 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl, -L1-OR 12 、-L1-NR 13 R 14 、C 3-6Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkylene C 3-6 Cycloalkyl, C 1-6 Alkylene 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl; wherein, the C 1-6 Alkyl, halogenated C 1-6 Alkyl, -L1-OR 12 、-L1-NR 13 R 14 、C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkylene C 3-6 Cycloalkyl, C 1-6 Alkylene 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl can be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-6 Substitution by a cycloalkyl group or a 3-7 membered heterocycloalkyl group;

[0029] L1 is selected from a bond, C 1-6 Alkylene or C 3-6 cycloalkylene;

[0030] R 12 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0031] R 13 、R 14 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, 3-7 membered heterocycloalkyl;

[0032] In one embodiment of the present invention, the isomer is the isomer represented by formula I-YG:

[0033] In one embodiment of the present invention, the formula I-YG has the structure of formula II-YG:

[0034] In one embodiment of the present invention, the formula I-YG has the structure of formula IIa-YG, IIb-YG:

[0035] In one embodiment of the present invention, R6 is selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl.

[0036] In one embodiment of the present invention, Formula I has the structure of Formula III:

[0037] In one embodiment of the present invention, Formula I has the structure of Formula IIIa, Formula IIIb:

[0038] In one embodiment of the present invention, the formula I-YG has the structure of formula III-YG:

[0039] In one embodiment of the present invention, the formula I-YG has the structure of formula IIIa-YG, IIIb-YG:

[0040] In one embodiment of the present invention, R1, R2, R3, R4, and R5 are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy; wherein the C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 The alkoxy group may be further substituted by one or more independently selected from hydrogen, hydroxy, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The substituents of the cycloalkyl group and the 3- to 7-membered heterocycloalkyl group are substituted.

[0041] In one embodiment of the present invention, R 11 Selected from H, C 1-6 Alkyl, C 3-6 Cycloalkyl, -L1-OR 12 、-L1-NR 13 R 14 , 3-7 membered heterocycloalkyl; L1 is selected from a bond, C 1-6 Alkylene or C 3-6 Cycloalkylene; R 12 Selected from hydrogen.

[0042] In one embodiment of the present invention, C 3-6 Cycloalkyl, C 3-6 The cycloalkylene group is a 3-6 membered monocyclic, spirocyclic or bridged cycloalkyl group.

[0043] In one embodiment of the present invention, the 3-7 membered heterocycloalkyl group is a 3-7 membered N-containing heterocycloalkyl group.

[0044] In one embodiment of the present invention, the 3-7 membered heterocycloalkyl group is a 3-7 membered monocyclic, spirocyclic, or bridged ring N-containing heterocycloalkyl group.

[0045] In one embodiment of the present invention, R 11 Selected from H, -CH3,

[0046] In an optional embodiment of the present invention, the present invention further provides a compound of Formula I, Formula II, Formula III, its isomer, racemate, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from:

[0047] In some embodiments, according to the aforementioned compounds of Formula I, Formula II, Formula III, their isomers, racemates, or pharmaceutically acceptable salts or prodrugs, the compounds are selected from:

[0048] In some embodiments, according to the aforementioned compounds of Formula I, Formula II, Formula III, their isomers, racemates, or pharmaceutically acceptable salts or prodrugs, the compounds are selected from:

[0049] Definition of terms:

[0050] In the present invention, the term "C 1-6 The term "alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0051] In the present invention, the term "C 1-6 "Alkylene" refers to the removal of C 1-6 In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0052] In the present invention, the term "C 1-6 "Alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy. Preferably, C 1-4 Alkoxy.

[0053] In the present invention, the term "C 1-6"Alkylamino" refers to an alkyl group substituted with at least one amino group, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, n-hexylamino, etc.

[0054] In the present invention, the term "C 3-6 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring. 3-6 The cycloalkyl group may be a 3-6 membered monocyclic, spirocyclic, or bridged cycloalkane, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0055] The term "heterocycloalkyl" should be understood as a non-aromatic cyclic group containing heteroatoms, which can be a 5-10-membered, 3-7-membered, 3-8-membered, 5-6-membered heterocycloalkyl group, etc. The heteroatoms in the "heterocycloalkyl" can be one, two or more heteroatoms selected from N, O, and S. The term "5-10-membered heterocycloalkyl" is a 5-10-membered (5, 6, 7, 8, 9, 10-membered) heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, and S, which can be a monocyclic, spirocyclic, or bridged ring. Preferably, the 5-10-membered heterocyclic group contains one or more heteroatoms selected from NH, CO, C 1-6 an alkylene, O or SO2 group.

[0056] In the present invention, the term "3-7 membered heterocycloalkyl" refers to a 3-7 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S. Preferably, the 3-7 membered heterocycloalkyl is a 3-7 membered N-containing heterocycloalkyl. Preferably, the 3-7 membered heterocycloalkyl is a 3-7 membered monocyclic, spirocyclic or bridged N-containing heterocycloalkyl, including but not limited to the following groups:

[0057] It will be understood by those skilled in the art that when a linking group is clearly required in a compound structure, the Markush variable listed for that group should be understood to be a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "cycloalkyl", it should be understood that the "alkyl" or "cycloalkyl" represents a linked alkylene group or arylene group, respectively. Therefore, when used as a linking group, "alkyl" and "arylene" have equivalent definitions, for example, "C 1-6 Alkyl" and "C 1-6 "Alkylene" has an equivalent definition, "C 3-6 Cycloalkyl" and "C 3-6 "Cycloalkylene" has an equivalent definition.

[0058] In the present invention, the term "halogen" includes fluorine, chlorine, bromine and iodine.

[0059] In the present invention, the term "halogenated" refers to substitution with halogen. 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 3- 6-cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl refers to C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 One or more hydrogen atoms in the cycloalkyloxy group and the 3- to 7-membered heterocycloalkyl group are replaced by a halogen group.

[0060] In the present invention, the term "oxy group" is O.

[0061] In the present invention, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0062] In the present invention, the terms "aromatic heterocycle" and "heteroaryl" have the same meaning and refer to heteroaromatic groups containing one to multiple heteroatoms. For example, "heteroaryl" refers to an aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 3 to 10 carbon atoms. Non-limiting examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. Heteroaryl groups may be optionally substituted or unsubstituted.

[0063] In the present invention, the term "optionally substituted with one or more" or "optionally further substituted with one or more" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. Here, "plurality" includes two or more, for example, 2, 3, 4, 5, or 6.

[0064] In the present invention, the term "1-6" refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings.

[0065] In the present invention, the term "substituted" should be considered to include multiple degrees of substitution of the substituent indicated. When multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted with one or more of the disclosed or claimed substituent moieties, either singly or multiply. Independently substituted means that the (two or more) substituents can be the same or different.

[0066] The compounds of the present invention may contain one or more asymmetric centers and, therefore, may exist as isomers, racemates, etc., wherein racemates include racemates and racemic mixtures; and isomers include single enantiomers, diastereomeric mixtures, and individual diastereomers. The present invention is intended to include all such isomeric forms of the compounds of Formula I, II, or III.

[0067] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0068] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0069] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0070] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention can exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R, S)-configuration. In certain embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of (R)- or (S)-configuration. The independent synthesis of optical isomers and diastereomers or their chromatographic separation can be achieved as known in the art by appropriate modifications of the methods disclosed herein. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates, which, if necessary, are derivatized with reagents containing asymmetric centers or sufficiently heavy atoms of known absolute configuration for absolute distribution.

[0071] If desired, a racemic mixture of a compound can be separated to isolate the individual enantiomers. Separation can be performed by methods well known in the art, for example, by coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods (e.g., fractional crystallization or chromatography).

[0072] Racemic mixtures of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration using methods well known in the art.

[0073] The term "prodrug" refers to a structure that can be converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues.

[0074] In the compounds of formula I, II or III, the atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.

[0075] The present invention is intended to include all suitable isotopic variations of the compounds of formula I, II or III. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H) and tritium (3H).

[0076] Isotopically enriched compounds within structural formula I, II or III can be prepared by conventional techniques well known to those skilled in the art or by methods analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates without undue experimentation.

[0077] In another aspect, the present invention provides a pharmaceutical composition comprising any one of the above-mentioned compounds, its isomers, racemates, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0078] In another aspect, the present invention also discloses the use of a compound, an isomer, a racemate, or a pharmaceutically acceptable salt thereof as described above, and a pharmaceutical composition for the preparation of a medicament for treating a condition, illness, or disease responsive to inhibition of Nav1.8 channel activity in a mammal in need thereof. The compounds of the present invention have the ability to block, partially block, interfere with, reduce, or decrease the activity or expression of Nav1.8 in a subject, with "inhibition" encompassing complete and / or partial reduction of channel function, such as a reduction of at least 10%, in some embodiments a reduction of at least 20%, 30%, 50%, 75%, 95%, 98%, and up to and including 100%.

[0079] More specifically, the IC activity of the compounds of the present invention on Nav1.8 channels is 50 The inhibitory value or inhibitory activity is less than 10 μM, more preferably less than 1 μM, more preferably less than 50 nM, and more preferably less than 10 nM.

[0080] In another aspect, the present invention also discloses the use of any of the above-mentioned compounds, their isomers, racemates, or pharmaceutically acceptable salts, and pharmaceutical compositions in the preparation of drugs for treating, preventing or controlling pain conditions, cough conditions, acute itching conditions or chronic itching conditions.

[0081] In one embodiment of the invention, the condition comprises chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia, or a method of reducing the severity thereof.

[0082] In one embodiment of the invention, the pain comprises neuropathic pain, musculoskeletal pain (preferably osteoarthritis pain), acute pain (preferably acute postoperative pain), postoperative pain or visceral pain.

[0083] In one embodiment of the present invention, the neuropathic pain comprises one or more of postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy or diabetic neuropathy, preferably diabetic peripheral neuropathy.

[0084] In one embodiment of the invention, the postoperative pain comprises one or more of bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain.

[0085] The present invention also discloses treating the subject by administering one or more additional therapeutic agents simultaneously with, before or after treatment with any one of the above compounds, their isomers, racemates, or pharmaceutically acceptable salts or pharmaceutical compositions.

[0086] In another aspect, the present invention discloses any one of the above compounds, its isomers, racemates, or pharmaceutically acceptable salts thereof; and use of any one of the above pharmaceutical compositions as a medicine. Beneficial effects

[0087] The present invention provides a Nav1.8 selective inhibitor with novel structure, excellent pharmacokinetic properties, good efficacy and drugability, which can be used to treat, prevent or control Nav1.8-related pain symptoms, cough symptoms, acute itching symptoms or chronic itching symptoms, and has significant clinical application value. DETAILED DESCRIPTION

[0088] The present invention will be further described below with reference to the examples. It should be noted that the following examples are provided for illustrative purposes only and do not constitute a limitation on the scope of protection claimed in the present invention.

[0089] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples are conventional raw materials, reagents, methods in the art, and the experimental materials and reagents used can be obtained from commercial channels.

[0090] Experimental materials and analytical instruments:

[0091] The thin layer chromatography (TLC) plate model was HSGF-254 (thickness 0.15-0.2 mm, produced by Yantai Chemical Experimental Plant); the column chromatography silica gel was 200-300 mesh commercial silica gel produced by Qingdao Ocean Chemical Plant;

[0092] 1 H-NMR spectra were recorded using a Bruker Avance III-400 NMR spectrometer with tetramethylsilane (TMS) as the internal standard. Chemical shifts are in ppm, δ:, and proton coupling is labeled as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m).

[0093] Low-resolution mass spectra were recorded using an Agilent 6110 mass spectrometer.

[0094] Abbreviations and notes:

[0095] DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; psi: pounds per square inch; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; CDI: N,N'-carbonyldiimidazole; MTBE: methyl tert-butyl ether; DIBAL-H: diisobutylaluminum hydride; DMAP: 4-dimethylaminopyridine; LiHMDS: lithium hexamethyldisilazane; DCC: 1,3-dicyclohexylcarbodiimide; CuCl: cuprous chloride; THF: tetrahydrofuran; DCM: dichloromethane; EtOAC: ethyl acetate.

[0096] Example 1: Preparation of Compound P-1

[0097] The synthetic route of compound P-1 is as follows:

[0098] Step 1: Preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one

[0099] 2-(3,4-Difluoro-2-methoxyphenyl)acetic acid (Intermediate A, 10.00 g, 49.5 mmol) was dissolved in acetonitrile, followed by the addition of CDI (9.22 g, 56.9 mmol). The mixture was stirred at 40°C for 15 minutes. (R)-4,4,4-Trifluoro-3-hydroxy-3-methylbutan-2-one (Intermediate B, 7.72 g, 59.4 mmol) and potassium carbonate (8.46 g, 61.9 mmol) were added sequentially, and the temperature was raised to 60°C and stirred for 24 hours. The reaction was quenched with water, and the aqueous phase was extracted 2-3 times with MTBE. The organic phase was washed with 2M hydrochloric acid (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography yielded 11.5 g of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one as a white solid in a 72.1% yield. MS m / z calculated: 322.06; found: 323.1 [M+H] + .

[0100] Step 2: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[0101] To an autoclave, add (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (3.00 g, 9.3 mmol) and dissolve in anhydrous ethanol. Then, add palladium on carbon (10% wt, 0.99 g, 9.3 mmol) and palladium hydroxide on carbon (20% wt, 1.57 g, 11.16 mmol) in that order. After three gas replacements, introduce hydrogen to a pressure of 50 psi. Heat to 80°C and stir for 40 hours. After cooling the mixture to room temperature, open the autoclave and monitor the complete reaction of the starting materials using TLC. The mixture was filtered through diatomaceous earth under reduced pressure, and the filter cake was rinsed with anhydrous ethanol. The filtrate was concentrated under reduced pressure to give 2.75 g of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one as a white solid, with a yield of 91.1%. MS m / z calculated: 324.07; found: 325.08 [M+H] + .

[0102] Step 3: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

[0103] Under nitrogen at -78°C, DIBAL-H (2.30 g, 16.2 mmol) was slowly added dropwise to a dichloromethane solution containing (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (2.50 g, 7.7 mmol). The reaction was monitored by a microplate reader until completion. The reaction was then quenched by the addition of saturated ammonium chloride solution. The reaction mixture was extracted two to three times with ethyl acetate. The combined organic phases were washed with saturated brine and concentrated under reduced pressure to yield 2.50 g of a crude product, with (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol as the major diastereomer, in a yield of 99.2%. MS m / z calculated: 326.09; found: 327.1 [M+H] + .

[0104] Step 4: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate

[0105] At room temperature, acetic anhydride (4.69 g, 46.2 mmol) was added to a mixed solution of (3S,4S,5R)-3-(3-fluoro-4-hydroxy-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (2.50 g, 7.7 mmol) and DMAP (1.40 g, 11.6 mmol). The reaction was monitored with a microplate reader until completion. After completion, saturated sodium bicarbonate solution was added, and the reaction system was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 2.77 g of the stereoisomer, with (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate as the major diastereomer, in a yield of 98.5%. MS m / z calculated: 368.10; found: 369.1 [M+H] + .

[0106] Step 5: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile

[0107] Trimethylsilyl cyanide (1.86 g, 18.8 mmol) and boron trifluoride etherate (3.20 g, 22.5 mmol) were added sequentially to a dichloromethane solution of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (2.77 g, 7.5 mmol) at -78 °C. The reaction mixture was stirred for 30 minutes and then brought to room temperature until the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution (60 mL), and the mixture was extracted with dichloromethane. The organic compounds were combined, dried, and concentrated under reduced pressure to afford 2.48 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile as the major diastereomer in a 98.5% yield. MS m / z calculated: 335.09; found: 336.1 [M+H] + .

[0108] Step 6: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0109] To (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (2.00 g, 5.9 mmol) was added 10 mL of 2 M sodium hydroxide and 20 mL of methanol. The reaction was heated to 60°C and monitored with a microplate reader until completion. The reaction was partitioned between ethyl acetate and 1 M hydrochloric acid. The layers were separated, combined, and concentrated in vacuo to afford 2.02 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a clear oil in a 95.9% yield. MS m / z calculated: 354.08; found: 355.1 [M+H] + .

[0110] Step 7: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0111] At 0°C, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.1 g, 0.3 mmol) was dissolved in DMF (50 mL), and 4-amino-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Intermediate C, 0.11 g, 0.45 mmol), DIPEA (0.10 g, 0.9 mmol), and HATU (0.16 g, 0.45 mmol) were added respectively. The reaction mixture was brought to room temperature and reacted overnight. The reaction system was diluted with ethyl acetate and then washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to obtain 0.05 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(7-oxo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide as a white solid with a yield of 36.5%.

[0112] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.95(s,1H),8.60(d,J=5.4Hz,1H),7.97(d,J=5.4Hz,1H),7.18(q,J=3.3,2.8Hz,2H),5.28( d,J=10.2Hz,1H),4.35(d,J=8.0Hz,2H),3.95(d,J=2.2Hz,3H),3.93(d,J=2.1Hz,1H),1.99(s,1H),1.61(s,3H),0.77–0.71(m,3H).

[0113] Example 2: Preparation of Compound P-2

[0114] The synthetic route of compound P-2 is as follows:

[0115] Step 1: Preparation of (R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one

[0116] 2-(3-Fluoro-2,4-dimethoxyphenyl)acetic acid (Intermediate D, 30.00 g, 140.1 mmol) was dissolved in acetonitrile, followed by the addition of CDI (26.12 g, 161.1 mmol). The mixture was stirred at 40°C for 15 minutes. (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one (Intermediate B, 40.11 g, 168.1 mmol) and potassium carbonate (19.35 g, 175.1 mmol) were added sequentially, and the temperature was raised to 60°C and stirred for 24 hours. The reaction was quenched by the addition of water, and the aqueous phase was extracted 2-3 times with MTBE. The organic phase was washed with 2M hydrochloric acid (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure in vacuo. Purification by column chromatography yielded 27.85 g of (R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one as a white solid in a 59.5% yield. MS m / z calculated: 334.08; found: 335.1 [M+H] + .

[0117] Step 2: Preparation of (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[0118] To an autoclave, add (R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (5.00 g, 14.9 mmol) and dissolve it in anhydrous ethanol. Then, add palladium on carbon (10% wt, 1.58 g, 14.9 mmol) and palladium hydroxide on carbon (20% wt, 2.51 g, 17.8 mmol) in that order. After three gas replacements, fill the autoclave with hydrogen to a pressure of 50 psi. Heat to 80°C and stir for 36 hours. After cooling the mixture to room temperature, open the autoclave and monitor the complete reaction of the starting materials using TLC. The mixture was filtered through diatomaceous earth under reduced pressure, and the filter cake was rinsed with anhydrous ethanol. The filtrate was concentrated under reduced pressure to yield 4.50 g of (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one as a white solid, with a yield of 89.3%. MS m / z calculated: 336.09; found: 337.1 [M+H] + .

[0119] Step 3: Preparation of (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

[0120] Under nitrogen at -78°C, DIBAL (6.34 g, 89.2 mmol) was slowly added dropwise to a dichloromethane solution containing (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (15.00 g, 44.6 mmol). The reaction was monitored by a microplate reader until completion. Saturated ammonium chloride solution was then added to quench the reaction. The reaction mixture was extracted two to three times with ethyl acetate. The combined organic phases were washed with saturated brine and concentrated under reduced pressure to yield 13.50 g of crude product, with (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol as the major diastereomer, in an 89.5% yield. MS m / z calculated: 338.11; found: 339.1 [M+H] + .

[0121] Step 4: Preparation of (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate

[0122] At room temperature, acetic anhydride (24.44 g, 239.4 mmol) was added to a mixed solution of (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (13.50 g, 39.9 mmol) and DMAP (7.31 g, 59.8 mmol). The reaction was monitored with a microplate reader until completion. After completion, saturated sodium bicarbonate solution was added, and the reaction system was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 13.20 g of the stereoisomer, with (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate as the major diastereomer, in an 87.0% yield. MS m / z calculated: 380.12; found: 381.1 [M+H] + .

[0123] Step 5: Preparation of (2R,3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile

[0124] Trimethylsilyl cyanide (8.61 g, 86.7 mmol) and boron trifluoride etherate (14.77 g, 104.1 mmol) were added sequentially to a dichloromethane solution of (3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (13.20 g, 34.7 mmol) at -78 °C. The reaction mixture was stirred for 30 minutes and then brought to room temperature until the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution (60 mL), and the mixture was extracted with dichloromethane. The organic compounds were combined, dried, and concentrated under reduced pressure to afford 11.50 g of the stereoisomers, with (2R,3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile as the major diastereomer, in a 95.4% yield. MS m / z calculated: 347.11; found: 348.1 [M+H] + .

[0125] Step 6: Preparation of (2R,3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0126] To (2R,3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (11.50 g, 33.1 mmol) was added 80 mL of 2 M sodium hydroxide and 160 mL of methanol. The reaction was heated to 60°C and monitored with a microplate reader until completion. The reaction was partitioned between ethyl acetate and 1 M hydrochloric acid. The layers were separated, combined, and concentrated in vacuo to afford 10.10 g of (2R,3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a clear oil in an 83.3% yield. MS m / z Calcd: 366.11; Found: 367.0 [M+H] + .

[0127] Step 7: Preparation of (2R,3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0128] At 0°C, (2R,3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.2 g, 0.5 mmol) was dissolved in DMF (50 mL), and 4-amino-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Intermediate C, 0.11 g, 0.75 mmol), DIPEA (0.19 g, 1.5 mmol), and HATU (0.28 g, 0.75 mmol) were added respectively. The reaction mixture was brought to room temperature and reacted overnight. The reaction system was diluted with ethyl acetate and then washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to obtain 0.08 g of (2R,3S,4S,5R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-N-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide as a white solid with a yield of 32.2%.

[0129] 1 H NMR (400MHz, DMSO-d6) δ9.73(s,1H),8.89(s,1H),8.52(d,J=5.4Hz,1H),7.63(d,J=5.5Hz,1H),6.95(t,J=9.9Hz,1H),6.75(t,J=8.5Hz,1H),5.01(d, J=9.2Hz,1H),3.99(t,J=2.4Hz,2H),3.96–3.92(m,3H),3.87–3.82(m,1H) ,3.73(s,3H),3.22–3.13(m,1H),1.44(s,3H),0.95(d,J=12.9,6.6Hz,3H).

[0130] Example 3: Preparation of compound P-3:

[0131] Step 1: Preparation of (R)-methyl 2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate

[0132] Oxalyl chloride (6.00 mL, 68.8 mmol) was added dropwise to a solution of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (Intermediate A, 6.00 g, 29.9 mmol) and DMF (100.0 μL, 1.3 mmol) in DCM (100 mL) at 0°C and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo, and then a solution of (R)-methyl 3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (Intermediate F, 4.40 g, 25.6 mmol) and triethylamine (7.8 mL, 55.9 mmol) in DCM (10 mL) was added. The mixture was stirred at room temperature overnight until the reaction was complete. The reaction was quenched by the addition of saturated ammonium chloride solution (50 mL). The aqueous phase was extracted with DCM (150 mL) two to three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography purification gave 4.30 g of a white solid product with a yield of 41.5%. MS m / z calculated: 356.07; found: 357.1 [M+H] + .

[0133] Step 2: Preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one

[0134] Methyl (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate (1.48 g, 4.2 mmol) was dissolved in THF (20 mL) and slowly added to a solution of LiHMDS (10 mL, 10.0 mmol) in THF (20 mL) at -78°C. The reaction mixture was stirred at -78°C for 5 h with a plate monitor until the reaction was complete. 2M HCl was added to quench the reaction, and the aqueous phase was extracted 2-3 times with EtOAc (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by column chromatography afforded 0.80 g of the product as a yellow oil in a 59.7% yield. MS m / z calculated: 324.04; found: 325.0 [M+H] + .

[0135] Step 3: Preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one

[0136] Under nitrogen, methanol (4 mL, 68.5 mmol) was added dropwise to a mixture of DCC (2.71 g, 13.1 mmol) and CuCl (0.04 g, 0.4 mmol) at 0°C. After stirring for 1 hour, the mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated in vacuo. Column chromatography afforded 2.1 g of 1,3-dicyclohexyl-2-methylisourea as a colorless oil. Subsequently, 1,3-dicyclohexyl-2-methylisourea (0.44 g, 1.7 mmol) was dissolved in THF and slowly added dropwise to a THF solution of methyl (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate (0.28 g, 0.8 mmol). The reaction mixture was heated at 85°C overnight. After completion of the reaction, the white precipitate was filtered. The mother liquor was collected and concentrated in vacuo. Column chromatography purification afforded 0.26 g of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one in an 86.4% yield. MS m / z calculated: 338.06; found: 339.1 [M+H] + .

[0137] The series of reactions from step 4) to step 9) of this example are similar to the reaction process from step 2) to step 7) in Example 2, except that the reaction starting material (R)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one in step 2 of Example 2 was replaced with (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one, and then a series of reactions were carried out to obtain 82 mg of the target compound (2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-N-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide in a yield of 60.7%.

[0138] 1 H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.94(s,1H),8.59(d,J=5.5Hz,1H),7.95(d,J=5.5Hz,1H),7.30–7.19(m,2H),5.26( d,J=10.6Hz,1H),4.43–4.23(m,2H),4.10(d,J=4.8Hz,1H),3.96(s,3H),2.93(s,3H),2.00(q,J=7.2Hz,1H),1.55(s,3H).

[0139] Example 4: Preparation of Compound P-4

[0140] In this reaction scheme, -PMB represents p-methoxybenzyl.

[0141] Step 1: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0142] Potassium carbonate (1.16 g, 8.5 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.0 g, 2.8 mmol) in N,N-dimethylformamide (50 mL). Methyl iodide (0.59 g, 4.2 mmol) was then added dropwise to the solution. After the addition was complete, the temperature was raised to 70°C. The reaction was monitored for completion by TLC. After cooling to room temperature, the reaction system was diluted with ethyl acetate (200 mL) and washed 3-5 times with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 0.92 g of crude methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate, in an 88.5% yield. MS m / z calculated: 368.10; found: 369.1 [M+H] + .

[0143] Step 2: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0144] Boron tribromide (1.87 g, 7.5 mmol) was slowly added dropwise to a solution of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.92 g, 2.5 mmol) in dichloromethane (100 mL) at 0°C. After completion of the reaction, the reaction system was slowly quenched by adding ice water dropwise. The pH of the solution was adjusted to 7-8 with saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted 2-3 times with dichloromethane (200 mL). The combined organic phases were washed 2-3 times with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by column chromatography afforded 0.71 g of a yellow oil in 80.2% yield. MS m / z Calcd: 354.08; Found: 355.1 [M+H]+ .

[0145] Step 3: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0146] Cesium carbonate (1.95 g, 6.0 mmol) was added to a solution of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.71 g, 2.0 mmol) in N,N-dimethylformamide (50 mL). 2-Bromoethyl methyl ether (0.42 g, 3.0 mmol) was then added dropwise to the solution. After the addition was complete, the temperature was raised to 100°C. The reaction was monitored by TLC for completion. After cooling to room temperature, the reaction system was diluted with ethyl acetate (200 mL) and washed 3-5 times with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography afforded 0.53 g of a light yellow oily liquid in a 65.2% yield. MS m / z Calcd: 412.13; Found: 413.1 [M+H] + .

[0147] Step 4: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0148] Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.53 g, 1.3 mmol) was dissolved in 7 M ammonia in methanol (10 mL). The reaction was stirred for 6 h and monitored by TLC for completion. The reaction was then concentrated in vacuo to afford 0.47 g of crude (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide, with a yield of 92.3%. MS m / z calculated: 397.13; found: 398.1 [M+H] + .

[0149] Step 5: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-N-(6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0150] Under nitrogen conditions, (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (0.15 g, 0.38 mmol), 4-bromo-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (0.14 g, 0.42 mmol), tris(dibenzylideneacetone)dipalladium (0.035 g, 0.038 mmol), 4,5 -bis(diphenylphosphino)-9,9-dimethylxanthene (0.044 g, 0.076 mmol) and cesium carbonate (0.25 g, 0.76 mmol) were added to the system after nitrogen substitution three times. Toluene (20 mL) was added to the system and the temperature was raised to 100°C for overnight reaction. After TLC monitoring, the reaction was completed and the system was naturally cooled to room temperature. Ethyl acetate (30 mL) was added to the reaction system for dilution and the system was washed 3-5 times with saturated brine (40 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography afforded 0.11 g of a white solid in a 44.9% yield. MS m / z calculated: 649.22; found: 650.2 [M+H] + .

[0151] Step 6: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-N-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0152] To a 50 mL round-bottom flask was added (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-N-(6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (0.11 g, 0.19 mmol) and acetonitrile (10 mL). Under an ice bath, an aqueous solution (5 mL) of ammonium cerium nitrate (0.37 g, 0.67 mmol) was added to the system in batches. After the addition was completed, the system was warmed to room temperature and reacted for 6 hours. After the reaction was completed by TLC monitoring, the system was transferred to a 250 mL beaker, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was filtered under reduced pressure. The filtrate was extracted three times with dichloromethane (30 mL), and the organic phase was washed three times with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography, 0.08 g of a white solid was obtained with a yield of 89.2%.

[0153] 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.13(d,J=2.0Hz,1H),7.85(t,J=4.9Hz,1 H),7.78(dd,J=8.4,2.0Hz,1H),7.51(d,J=8.4Hz,1H),7.17(d,J=6.7Hz,2H),5. 11(d,J=10.7Hz,1H),4.35(dd,J=9.5,6.1Hz,3H),4.31–4.13(m,2H),3.61(q,J= 4.5Hz,2H),3.27(s,3H),2.83(t,J=7.3Hz,1H),1.61(s,3H),0.74–0.67(m,3H).

[0154] Example 5: Preparation of Compound P-5

[0155] The preparation method of the compound is similar to that of Example 4, except that the 2-bromoethyl methyl ether in step 3) is replaced by an equal molar amount of iodomethane to obtain 0.10 g of a white solid compound with a yield of 82.6%.

[0156] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.11(d,J=1.9Hz,1H),7.85(t,J=4.9Hz ,1H),7.77(dd,J=8.5,2.0Hz,1H),7.50(d,J=8.4Hz,1H),7.41–7.22(m,2H),5 .93–5.86(m,1H),5.76(dt,J=5.3,2.6Hz,1H),5.11(d,J=10.3Hz,1H),4.33(d d,J=11.4,6.9Hz,3H),2.79(p,J=7.5Hz,1H),1.61(s,3H),0.78–0.71(m,3H).

[0157] Example 6: Preparation of Compound P-6

[0158] The preparation method is similar to that of Example 4, except that 2-bromoethyl methyl ether in step 3) is replaced by 3-(iodomethyl)oxetane to obtain 0.09 g of a white solid compound with a yield of 89.2%.

[0159] 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),8.94(s,1H),8.60(d,J=5.5Hz,1H),7.98(s,1H),7.25–7.16(m,2H),5.29(d,J=10.4Hz,1H),4.73(ddd ,J=8.0,6.0,2.0Hz,2H),4.52–4.41(m,3H),4.37–4.25(m,4H),3.43–3.37(m,1H),2.77(t,J=7.3Hz,1H),1.60(s,3H),0.73(d,J=7.2Hz,3H).

[0160] Example 7: Preparation of compound P-7:

[0161] The synthetic route of compound P-7 is as follows:

[0162] Step 1: Preparation of methyl 4-bromo-3-methylpicolinate

[0163] To a 500 mL round-bottom flask, 4-bromo-3-methylpyridinic acid (5.00 g, 23.2 mmol), iodomethane (6.50 g, 46.5 mmol), potassium carbonate (9.50 g, 69.7 mmol), and N,N-dimethylformamide (250 mL) were added. The resulting solution was heated to 80°C overnight. The reaction was monitored for completion by a microplate reader. The reaction system was transferred to a separatory funnel and ethyl acetate (500 mL) was added. The product was washed three times with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4.56 g of the product as a pale yellow oil in an 85.8% yield. MS m / z calculated: 228.97; found: 230.9 [M+H] + .

[0164] Step 2: Preparation of 4-bromo-3-(bromomethyl)picolinic acid

[0165] To a 500 mL round-bottom flask, methyl 4-bromo-3-methylpicolinate (4.56 g, 19.9 mmol), N-bromophthalimide (4.80 g, 29.8 mmol), azobisisobutyronitrile (0.30 g, 2.0 mmol), and carbon tetrachloride (150 mL) were added. The temperature was raised to 80°C and the reaction was allowed to react overnight. The reaction was monitored for completion by a microplate reader. The reaction system was transferred to a beaker and saturated sodium sulfite solution (100 mL) was added and stirred for 1 hour. The reaction system was then transferred to a separatory funnel, and dichloromethane (200 mL) was added. The mixture was washed three times with saturated brine (500 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5.15 g of the title compound as a yellow oil in an 86.9% yield. MS m / z calculated: 294.86; found: 295.7 [M+H] + .

[0166] Step 3: Preparation of tert-butyl 3-(4-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)azetidine-1-carboxylate

[0167] To a 500 mL round-bottom flask, 4-bromo-3-(bromomethyl)picolinic acid (5.06 g, 17.3 mmol) and tetrahydrofuran (200 mL) were added, followed by tert-butyl 3-aminoazetidine-1-carboxylate (4.57 g, 26.6 mmol). The temperature was raised to 80°C and stirred for 3 hours. The reaction was monitored for completion by a plate count. The reaction system was concentrated under reduced pressure to obtain the crude product. After slurrying with n-hexane, 4.57 g of the off-white title compound was obtained, with a yield of 72.2%. MS m / z calculated: 367.05; found: 368.09 [M+H] + .

[0168] Step 4: Preparation of tert-butyl 3-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)azetidine-1-carboxylate

[0169] Under nitrogen conditions, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (0.20 g, 0.56 mmol), tert-butyl 3-(4-bromo-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)azetidine-1-carboxylate (0.24 g, 0.67 mmol), tris(dibenzylideneacetone)dipalladium (0.051 g, 0.056 mmol), 4,5-bis(diphenylphosphine-9,9-dimethylxanthene) (0.065 g, 0.112 mmol), cesium carbonate 0.36 g, 1.12 mmol) were added to a Schlk tube. After three replacements, toluene (50 mL) was added to the system, and the temperature was raised to 100°C for overnight reaction. After completion of the reaction as monitored by TLC, the system was naturally cooled to room temperature. Ethyl acetate (200 mL) was added to the reaction system for dilution, and the mixture was washed 3-5 times with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. After column chromatography, 0.18 g of tert-butyl 3-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)azetidine-1-carboxylate was obtained as a white oil in a yield of 50.2%. MS m / z calculated: 640.23; found: 641.2 [M+H]. + .

[0170] Step 5: Preparation of (2R,3S,4S,5R)-N-(6-(azetidin-3-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (hydrochloride)

[0171] tert-Butyl 3-(4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)azetidine-1-carboxylate (0.18 g, 0.28 mmol) was dissolved in ethyl acetate (5 mL) with hydrochloric acid. After completion of the reaction, monitored by TLC, the reaction was concentrated in vacuo to afford 0.13 g of (2R,3S,4S,5R)-N-(6-(azetidin-3-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (hydrochloride) in an 81.6% yield. MS m / z calculated: 576.15; found: 577.17 [M+H]. + .

[0172] 1 H NMR (400MHz, DMSO-d6) δ10.48 (s, 1H), 8.75 (s, 2H), 8.60 (d, J = 5.5Hz, 1H), 8.0 6(d,J=5.5Hz,1H),7.17(dd,J=8.4,4.9Hz,2H),5.28(d,J=10.1Hz,1H),5.16– 5.05(m,1H),4.80–4.59(m,2H),4.30(dd,J=10.1,7.5Hz,1H),4.25–4.03(m,4 H),3.96(d,J=2.1Hz,3H),2.85–2.75(m,1H),1.61(s,3H),0.79–0.72(m,3H).

[0173] Example 8: Preparation of compound P-8:

[0174] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced with tert-butyl 4-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate to obtain 0.13 g of a white solid compound with a yield of 81.6%.

[0175] 1H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.50(s,2H),8.62(d,J=5.5Hz,1H),8.01(d,J=5.5H z,1H),7.22–7.09(m,2H),5.40(d,J=10.3Hz,1H),4.62(d,J=8.7Hz,2H),4.28(dd,J=10.3 ,7.4Hz,1H),3.96(d,J=2.1Hz,3H),3.50(t,J=5.2Hz,2H),2.78(q,J=7.2Hz,1H),2.73–2. 63(m,1H),2.38(s,2H),2.11(ddd,J=9.4,5.3,1.9Hz,2H),1.61(s,3H),0.81–0.72(m,3H).

[0176] Example 9: Preparation of compound P-9:

[0177] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced with tert-butyl (2-aminoethyl)carbamate to obtain 0.12 g of a white solid compound with a yield of 78.1%.

[0178] 1 H NMR (400MHz, DMSO-d6) δ11.23–11.07(m,1H),8.64(d,J=5.6Hz,1H),8.09(s,3H),8.06(d ,J=5.6Hz,1H),7.39(ddd,J=8.5,5.9,1.8Hz,1H),7.28–7.16(m,1H),5.53(d,J=10.4Hz, 1H),4.74–4.52(m,2H),4.28(dd,J=10.4,7.4Hz,1H),3.98(d,J=2.1Hz,3H),3.85(t,J=6 .0Hz,2H),3.13(q,J=5.9Hz,2H),2.80(p,J=7.4Hz,1H),1.62(s,3H),0.81–0.72(m,3H).

[0179] Example 10: Preparation of compound P-10:

[0180] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced by tert-butyl (2-aminoethyl)(methyl)carbamate to obtain 0.13 g of a white solid compound with a yield of 83.2%.

[0181] 1 H NMR (400MHz, DMSO-d6) δ10.97(s,1H),8.76(s,2H),8.63(d,J=5.6Hz,1H),8.00(d ,J=5.5Hz,1H),7.45–7.14(m,2H),5.45(d,J=10.3Hz,1H),4.62–4.51(m,2H),4.2 8(dd,J=10.4,7.4Hz,1H),3.97(d,J=2.0Hz,3H),3.89(s,2H),3.23(t,J=6.0Hz,2 H),2.80(p,J=7.5Hz,1H),2.58(q,J=5.3Hz,3H),1.62(s,3H),0.80–0.71(m,3H).

[0182] Example 11: Preparation of compound P-11:

[0183] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced with tert-butyl 3-aminobicyclo[1.1.1]pentylcarboxylate to obtain 0.16 g of a white solid compound with a yield of 85.3%.

[0184] 1 H NMR (400MHz, DMSO-d6) δ10.95 (s, 1H), 9.11 (s, 3H), 8.63 (d, J = 5.6Hz, 1H), 8.06 (d,J=5.6Hz,1H),7.33(ddd,J=8.1,5.8,1.9Hz,1H),7.25–7.11(m,1H),5.46(d, J=10.4Hz,1H),4.55(d,J=5.7Hz,2H),4.29(dd,J=10.3,7.4Hz,1H),3.97(d,J= 2.0Hz,3H),2.79(t,J=7.4Hz,1H),2.47(s,6H),1.62(s,3H),0.81–0.71(m,3H).

[0185] Example 12: Preparation of Compound P-12

[0186] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced with methylamine to obtain 0.13 g of a white solid compound with a yield of 81.6%.

[0187] 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),8.58(d,J=5.5Hz,1H),7.92(d,J=5.5Hz,1H),7.21–7.15(m,2H),5.28(d,J=10.3Hz,1H),4.45(d,J =7.3Hz,2H),4.26(dd,J=10.2,7.4Hz,1H),3.96(d,J=2.2Hz,3H),3.11(s,3H),2.78(h,J=7.9Hz,1H),1.61(s,3H),0.76(t,J=8.6Hz,3H).

[0188] Example 13: Preparation of Compound P-13

[0189] The synthetic route of compound P-13 is as follows:

[0190] Step 1: Preparation of rac-(4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid ethyl ester

[0191] Ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (Intermediate E, 10.2 g, 26.3 mmol) and (3,4-difluoro-2-(methylthio)phenyl)boronic acid (Intermediate F, 8 g, 39.4 mmol) were dissolved in toluene (90 mL) and water (10 mL) solution, potassium phosphate (11.17 g, 52.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.04 g, 2.63 mmol) were added thereto, nitrogen was replaced three times, and the mixture was stirred at 100°C for 1 hour. TLC confirmed the complete reaction of the starting material. After cooling to room temperature, the reaction mixture was added with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 8.6 g of rac-(4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid ethyl ester, a yellow solid, in a yield of 78.0%. MS m / z calculated: 396.08; found: 397.1 [M+H] + .

[0192] Step 2: Preparation of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester

[0193] Ethyl rac-(4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (5 g, 12.6 mmol) was dissolved in methanol (50 mL), and magnesium chips (1.53 mL, 63 mmol) and 1,2-dibromoethane (2.37 g, 12.6 mmol) were added thereto. The mixture was stirred at 70 ° C for 3 days, filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure and purified by column chromatography and HPLC to obtain 0.5 g of ethyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a yellow solid compound with a yield of 9.52%. MS m / z calculated: 398.10; found: 399.1 [M+H] + .

[0194] Step 3: Preparation of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0195] Ethyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (500 mg, 1.30 mmol) was dissolved in a solution of tetrahydrofuran (9 mL) and water (3 mL), and lithium hydroxide monohydrate (2.18 g, 5.19 mmol) was added thereto. After stirring at room temperature for 2 hours, water (10 mL) was added to the reaction solution, and the pH value was adjusted to ~2 with 1 M dilute hydrochloric acid. The solution was extracted with ethyl acetate (10 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 480 mg of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a light yellow solid with a yield of 92%. MS m / z calculated: 370.07; found: 371.1 [M+H] + .

[0196] Step 4: Separation of chiral isomers

[0197] rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (480 mg) was separated by SFC column chromatography using an eluent of 40% IPA (0.2% NH4OH):60% CO2 to afford two single isomers. The first eluting isomer, P1 (RT = 2.18 min), was a white solid (116.48 mg of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid) in a 24.2% yield. MS m / z Calcd: 370.07; Found: 371.1 [M+H] + Second eluting isomer P2 (RT = 2.37 min): 166.73 mg of (2S,3R,4R,5S)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a white solid, 34.7% yield. MS m / z calculated: 370.07; found: 371.1 [M+H] + .

[0198] Step 5: Preparation of tert-butyl 3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate

[0199] At 0°C, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthiophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.1 g, 0.3 mmol) was dissolved in DMF (50 mL), and 4-amino-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (Intermediate C, 0.11 g, 0.45 mmol), DIPEA (0.10 g, 0.9 mmol), and HATU (0.16 g, 0.45 mmol) were added respectively. The reaction mixture was brought to room temperature and reacted overnight. The reaction system was diluted with ethyl acetate and then washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to obtain 0.04 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methylthiophenyl)-4,5-dimethyl-N-(7-oxo-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-4-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide as a white solid in a 29.6% yield. MS m / z calculated: 501.47; found: 502.4 [M+H] + .

[0200] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),8.90(s,1H),8.53(d,J=5.4Hz,1H),7.92(d,J=5.4Hz,1H),7.18(q,J=3.3,2.8Hz,2H),5.28( d,J=10.2Hz,1H),4.35(d,J=8.0Hz,2H),3.93(d,J=2.1Hz,1H),2.48(d,J=2.2Hz,3H),1.99(s,1H),1.61(s,3H),0.77–0.71(m,3H).

[0201] Example 14: Preparation of compound P-14:

[0202] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced by an equimolar amount of 3-aminooxetane, and step 5) is omitted to obtain 0.15 g of a white solid compound with a yield of 0.1%.

[0203] 1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),8.60(d,J=5.4Hz,1H),7.96(d,J=5.6Hz,1H),7.22–7.14(m,2H),5.40(d,J=10.4Hz,1H),4.64(s,1H),4.4 6(m,2H),4.28(d,J=12.1Hz,1H),3.96(m,2H),3.85(s,3H),3.73–3.43( m,2H),2.70–2.53(m,1H),1.60(d,J=23.5Hz,3H),0.80(d,J=7.3Hz,3H).

[0204] Example 15: Preparation of compound P-15:

[0205] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced by an equimolar amount of 2-(tert-butyldimethylsilyloxy)ethylamine to obtain 0.10 g of a white solid compound with a yield of 79.4%.

[0206] 1H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.62(d,J=5.5Hz,1H),8.07(d,J=5.6Hz,1H),7.54-7.16(m,2H),5.53(d,J=10.3Hz,1H),4.80(t,J=5.9Hz,1H ),4.66–4.54(m,2H),4.29(dd,J=10.4,7.4Hz,1H),3.98(d,J=2.0Hz,3H), 3.64-3.49(m,4H),2.79(t,J=7.4Hz,1H),1.60(s,3H),0.80–0.72(m,3H).

[0207] Example 16: Preparation of compound P-16:

[0208] The preparation method was similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) was replaced with an equimolar amount of 2-((tert-butyldimethylsilyloxy)-2-methylaziridine to obtain 0.14 g of a white solid compound with a yield of 82.3%.

[0209] 1 H NMR(400MHz,DMSO-d6)δ10.95(s,1H),8.65(d,J=5.6Hz,1H),8.01(d,J=5.6Hz,1H), 7.48(ddd,J=8.5,5.8,1.9Hz,1H),7.27–7.16(m,1H),5.44(d,J=10.4Hz,1H),4.76( t,J=5.7Hz,1H),4.54(d,J=7.1Hz,2H),4.27(dd,J=10.2,7.4Hz,1H),3.98(d,J=2.1 Hz,3H),3.54(s,2H),2.79(t,J=7.4Hz,1H),1.61(s,3H),1.18(s,6H),0.80(m,3H).

[0210] Example 17: Preparation of compound P-17:

[0211] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced with tert-butyl N-methyl-N-(trans-3-aminocyclobutyl)carbamate to obtain 0.16 g of a white solid compound with a yield of 85.4%.

[0212] 1H NMR (400MHz, DMSO) δ10.87(s,1H),9.29(s,2H),8.60(d,J=5.5Hz,1H),8.05(d,J=5.5Hz,1H ),7.32(t,J=7.5Hz,1H),5.45(d,J=10.3Hz,1H),5.08(p,J=8.0Hz,1H),4.76–4.60(m,2H),4 .29(dd,J=10.4,7.4Hz,1H),3.96(d,J=2.1Hz,3H),3.76(s,1H),2.80(q,J=7.5Hz,1H),2.76 –2.65(m,2H),2.63–2.56(m,2H),2.53(t,J=5.5Hz,3H),1.61(s,3H),0.75(d,J=5.5Hz,3H).

[0213] Example 18: Preparation of compound P-18:

[0214] The preparation method is similar to that of Example 7, except that tert-butyl 3-aminoazetidine-1-carboxylate in step 3) is replaced with tert-butyl ((1R, 2R)-2-aminocyclopropyl)carbamate to obtain 0.03 g of a white solid compound with a yield of 23.0%.

[0215] 1 H NMR (400MHz, DMSO) δ11.07 (s, 1H), 8.87–8.73 (m, 3H), 8.59 (d, J = 5.4Hz, 1H), 7. 99(d,J=5.2Hz,1H),7.40(d,J=9.5Hz,1H),7.19(d,J=9.2Hz,1H),5.52(d,J=10. 4Hz,1H),4.52(s,2H),4.32–4.22(m,1H),3.96(s,3H),2.99(s,1H),2.82–2.73 (m,1H),2.09(s,1H),1.61(s,3H),0.85(d,J=9.1Hz,2H),0.75(d,J=7.3Hz,3H).

[0216] Comparative Example 1

[0217] The preparation method of Comparative Example 1 is similar to that of Example 1, except that 4-amino-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one in step 7 is replaced by an equimolar amount of 4-aminoisoindol-1-one to obtain 0.04 g of a white solid compound with a yield of 30.0%.

[0218] 1 H NMR (400MHz, DMSO-d6) δ10.04(s,1H),8.55(s,1H),7.76(d,J=7.4Hz,1H),7.53–7.42(m,2H),7.20(t,J=8.1Hz,2H),5.19(d ,J=10.4Hz,1H),4.20(s,2H),3.95(d,J=2.7Hz,3H),2.75(q,J=7.4Hz,1H),1.62(s,3H),1.23(s,1H),0.74(d,J=7.3Hz,3H).

[0219] Preparation of intermediate A

[0220] The synthetic route of intermediate A is as follows:

[0221] Step 1: Preparation of ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate

[0222] Ethyl 2-bromoacetate (23.12 g, 127.7 mmol), potassium carbonate (44.12 g, 319.2 mmol), tetrakistriphenylphosphine palladium (0.26 g, 0.2 mmol), and cuprous oxide (0.46 g, 3.2 mmol) were added to a reaction tube. The atmosphere was purged with nitrogen three times, followed by the addition of a toluene solution containing (3,4-difluoro-2-methoxyphenyl)boronic acid (20.00 g, 106.4 mmol). The reaction was allowed to proceed overnight at 100°C, with a microplate reader monitoring the reaction for completion. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The product was washed two to three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 18.49 g of ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate in a 75.5% yield. MS m / z calculated: 230.07; found: 231.1 [M+H] + .

[0223] Step 2: Preparation of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid

[0224] Lithium aluminum hydride (2.08 g, 52.2 mmol) was added to a solution of ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate (4.00 g, 17.4 mmol) in THF (50 mL) at room temperature. The temperature was then raised to 50°C and the reaction monitored until completion. Hydrochloric acid (1 M) was added to the reaction mixture to adjust the pH to 2. The mixture was extracted with ethyl acetate 2-3 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 3.54 g of crude 2-(3,4-difluoro-2-methoxyphenyl)acetic acid as a white solid in a 99.6% yield. MS m / z calculated: 202.04; found: 203.2 [M+H] + .

[0225] Preparation of intermediate B

[0226] The synthetic route of intermediate B is as follows:

[0227] Step 1: Preparation of (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one

[0228] (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (50.00 g, 316.3 mmol) and diethyl ether (10 L) were placed in a dry, nitrogen-filled reaction flask. Methyllithium bromide complex (27.54 g, 253.04 mmol) was slowly added under an ice bath, and the reaction mixture was stirred overnight at room temperature. Citric acid (121.53 g, 632.6 mmol) was added to neutralize the mixture and stirred for 30 minutes. The aqueous phase was separated and extracted with diethyl ether 2-3 times. The combined organic phases were distilled under reduced pressure (200 mbar, 70°C) to a colorless oil. Solid potassium carbonate pellets were added, the product was dried, allowed to stand for 6 hours, and then filtered through a glass filter to obtain 32.24 g of (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one as a colorless oil with a yield of 65.3%. MS m / z calculated: 156.03; found: 157.1 [M+H] + .

[0229] Preparation of intermediate C

[0230] The synthetic route of intermediate C is as follows:

[0231] In this reaction scheme, Boc- represents tert-butyloxycarbonyl, and PMB- represents p-methoxybenzyl.

[0232] Step 1: Preparation of methyl 4-bromo-3-methylpicolinate

[0233] To a 500 mL round-bottom flask, 4-bromo-3-methylpyridinic acid (5.00 g, 23.2 mmol), iodomethane (6.50 g, 46.5 mmol), potassium carbonate (9.50 g, 69.7 mmol), and N,N-dimethylformamide (250 mL) were added. The resulting solution was heated to 80°C overnight. The reaction was monitored for completion by a microplate reader. The reaction system was transferred to a separatory funnel and ethyl acetate (500 mL) was added. The product was washed three times with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4.56 g of the product as a pale yellow oil in an 85.8% yield. MS m / z calculated: 228.97; found: 230.9 [M+H] + .

[0234] Step 2: Preparation of 4-bromo-3-(bromomethyl)picolinic acid

[0235] To a 500 mL round-bottom flask, methyl 4-bromo-3-methylpicolinate (4.56 g, 19.9 mmol), N-bromophthalimide (4.80 g, 29.8 mmol), azobisisobutyronitrile (0.30 g, 2.0 mmol), and carbon tetrachloride (150 mL) were added. The temperature was raised to 80°C and the reaction was allowed to react overnight. The reaction was monitored for completion by a microplate reader. The reaction system was transferred to a beaker and saturated sodium sulfite solution (100 mL) was added and stirred for 1 hour. The reaction system was then transferred to a separatory funnel, and dichloromethane (200 mL) was added. The mixture was washed three times with saturated brine (500 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 5.15 g of the title compound as a yellow oil in an 86.9% yield. MS m / z calculated: 294.86; found: 295.7 [M+H] + .

[0236] Step 3: Preparation of 4-bromo-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0237] To a 500 mL round-bottom flask, 4-bromo-3-(bromomethyl)picolinic acid (5.06 g, 17.3 mmol) and tetrahydrofuran (200 mL) were added, followed by p-methoxybenzylamine (3.55 g, 26.6 mmol). The temperature was raised to 80°C and stirred for 3 hours. The reaction was monitored for completion by a plate-drip. The reaction system was concentrated under reduced pressure to obtain the crude product. After slurrying with n-hexane, 4.14 g of the off-white title compound was obtained, with a yield of 72.2%. MS m / z calculated: 332.01; found: 334.1 [M+H] + .

[0238] Step 4: Preparation of tert-butyl (6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)carbamate

[0239] To a 500 mL three-necked flask, 4-bromo-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (4.14 g, 12.5 mmol), tert-butyloxycarbonylamine (2.20 g, 18.70 mmol), trisdibenzylideneacetone dipalladium (1.14 g, 1.2 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.44 g, 2.5 mmol), and cesium carbonate (6.09 g, 18.7 mmol) were added. After the addition was completed, the atmosphere was replaced with argon three times, toluene (200 mL) was added, the temperature was raised to 100 ° C, and the reaction was allowed to proceed overnight. After the reaction was completed, the reaction was monitored by plate spotting and filtered under reduced pressure. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 1.88 g of a yellow oily compound with a yield of 41.2%. MS m / z calculated: 369.16; found: 370.1 [M+H] + Step 5: Preparation of tert-butyl (7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)carbamate

[0240] To a 250 mL round-bottom flask, tert-butyl (6-(4-methoxybenzyl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)carbamate (1.88 g, 5.1 mmol) was added. Acetonitrile (100 mL) was stirred at room temperature. Cerium ammonium nitrate (8.12 g, 20.5 mmol) was dissolved in water (50 mL). The reaction was allowed to react overnight at room temperature. After completion, the system was transferred to a 1000 mL beaker and saturated sodium bicarbonate solution (200 mL) was added. The mixture was filtered under reduced pressure and the filtrate was extracted three times with dichloromethane (500 mL). The organic phase was washed three times with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.92 g of a crude yellow product in a 41.5% yield. MS m / z calculated: 249.11; found: 250.3 [M+H] + Step 6: Preparation of 4-amino-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one

[0241] To a 100 mL round-bottom flask, tert-butyl (7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-4-yl)carbamate (0.92 g, 3.7 mmol) and an ethanol solution of hydrochloric acid (40 mL) were added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was monitored by plate monitoring and concentrated under reduced pressure. The crude product was purified by beating with dichloromethane to give 0.61 g of a light yellow solid compound with a yield of 65.1%.

[0242] 1 H NMR (400MHz, DMSO-d6) δ9.50(s,1H),8.63(s,2H),8.20(d,J=6.9Hz,1H),6.95(dd,J=6.8,1.5Hz,1H),4.35(s,2H).

[0243] Preparation of intermediate D

[0244] The synthetic route of intermediate D is as follows:

[0245] Step 1: Preparation of ethyl 2-(3-fluoro-2,4-dimethoxyphenyl)acetate

[0246] Ethyl 2-bromoacetate (21.72 g, 120.0 mmol), potassium carbonate (41.46 g, 300.0 mmol), tetrakistriphenylphosphine palladium (0.12 g, 0.1 mmol), and cuprous oxide (0.43 g, 30.0 mmol) were added to a reaction tube. The atmosphere was purged with nitrogen three times, followed by the addition of a toluene solution containing (3-fluoro-2,4-dimethoxyphenyl)boronic acid (20.00 g, 100.0 mmol). The reaction was allowed to proceed overnight at 100°C, with a microplate reader monitoring the reaction for completion. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The product was washed two to three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 15.58 g of ethyl 2-(3-fluoro-2,4-dimethoxyphenyl)acetate in a 64.3% yield. MS m / z calculated: 242.09; found: 243.1 [M+H] + .

[0247] Step 2: Preparation of 2-(3-fluoro-2,4-dimethoxyphenyl)acetic acid

[0248] Lithium aluminum hydride (2.34 g, 61.8 mmol) was added to a solution of ethyl 2-(3-fluoro-2,4-dimethoxyphenyl)acetate (5.00 g, 20.6 mmol) in THF (50 mL) at room temperature. The temperature was then raised to 50°C and the reaction monitored until completion. Hydrochloric acid (1 M) was added to the reaction mixture to adjust the pH to acidic. The mixture was extracted with ethyl acetate 2-3 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 4.05 g of crude 2-(3-fluoro-2,4-dimethoxyphenyl)acetic acid as a white solid in a 91.8% yield. MS m / z calculated: 214.06; found: 215.0 [M+H] + .

[0249] Preparation of intermediate E

[0250] The synthetic route of intermediate E is as follows:

[0251] Step 1: Preparation of ethyl 2-diazo-3-oxopentanoate

[0252] Ethyl propionyl acetate (28.8 g, 200 mmol) was dissolved in dichloromethane (250 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to 0°C and TEA (60.6 g, 600 mmol) was added. The mixture was stirred at 0°C for 5 minutes. 4-Methylbenzenesulfonyl azide (47.3 g, 240 mmol) was then added and the mixture was slowly returned to room temperature and stirred for 6 hours. The reaction was quenched with water (300 mL) and dichloromethane (1000 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography yielded 17.3 g of ethyl 2-diazo-3-oxopentanoate as a colorless oil in a 51% yield. MS m / z calculated: 170.17; found: 171.1 [M+H] + .

[0253] Step 2: Preparation of ethyl (Z)-2-diazo-3-((trimethylsilyl)oxy)pent-3-enoate

[0254] Dissolve ethyl 2-diazo-3-oxopentanoate (60.0 g, 353 mmol) in dichloromethane (720 mL) and cool to -10°C-0°C. Add TEA (57.0 g, 79.4 mL, 564 mmol) and slowly add trimethylsilyl trifluoromethanesulfonate (TMSOTf) (102.0 g, 82.8 mL, 458 mmol). Stir the reaction mixture at 0°C for 60 minutes. The reaction is nearly complete as determined by TLC. Wash the reaction mixture with saturated sodium bicarbonate (1000 mL). The organic layer is separated, washed with water (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 72 g of crude ethyl (Z)-2-diazo-3-(trimethylsilyl)oxy)pent-3-enoate in a 67% yield. The crude product was used directly in the next step without further purification.

[0255] Step 3: Preparation of rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoic acid ethyl ester

[0256] A solution of trifluoroacetone (47.0 g, 37.5 mL, 416 mmol) in dichloromethane (300 mL) was cooled to -78°C. A solution of titanium tetrachloride (78.9 g, 416 mmol) in dichloromethane (340 mL) was added dropwise to the stirred reaction mixture. The reaction mixture was stirred at -78°C for 10 minutes, followed by the dropwise addition of a solution of ethyl (Z)-2-diazo-3-((trimethylsilyl)oxy)pent-3-enoate (72.0 g, 297 mmol) in dichloromethane (300 mL). The reaction mixture was stirred at -78°C for 2 hours. Saturated aqueous sodium bicarbonate (1000 mL) was added, and the aqueous phase was extracted with dichloromethane (300 mL x 2). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 51 g of rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoic acid ethyl ester, a pale yellow liquid, in a yield of 57.6%. MS m / z calculated: 282.08; found: 283.1 [M+H] + .

[0257] Step 4: Preparation of rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester

[0258] Ethyl rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (20.0 g, 70.9 mmol, 1.00 eq) was dissolved in toluene (100 mL) and dimeric rhodium acetate (470 mg, 1.06 mmol, 0.015 eq) was added. The reaction mixture was stirred at 100°C for 2 hours. The solvent was removed under vacuum to yield 18.0 g of crude green oily product, ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate, which was used directly in the next reaction.

[0259] Step 5: Preparation of rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylic acid ethyl ester

[0260] Ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (18.0 g crude product, 70.5 mmol) was dissolved in anhydrous dichloromethane (200 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to -78°C and a solution of diisopropylethylamine (10.9 g, 84.6 mmol) and trifluoromethanesulfonic anhydride (23.9 g, 84.6 mmol) in anhydrous dichloromethane (50 mL) was added. The mixture was stirred at this temperature for 1 hour. The reaction mixture was gradually warmed to 0°C and stirred for 0.5 hours. The reaction was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (150 mL). The organic phases were combined. The residue was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 15 g of rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylic acid ethyl ester as a colorless oil in a 54.6% yield. MS m / z calculated: 386.03; found: 387.1 [M+H] + .

[0261] Preparation of intermediate F

[0262] The synthetic route of intermediate F is as follows:

[0263] Step 1: Preparation of (6-bromo-2,3-difluorophenyl)(methyl)sulfane

[0264] 4-Bromo-1,2-difluorobenzene (20 g, 103.6 mmol) was dissolved in tetrahydrofuran (200 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to -78°C and LDA (62 mL, 124 mmol, 2 M) was added. The mixture was stirred at this temperature for half an hour. Dimethyl disulfide (11.7 g, 124 mmol) was then added. The reaction mixture was gradually warmed to room temperature and stirred for 2.5 hours. The reaction was quenched with saturated ammonium chloride solution (400 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography afforded 12 g of (6-bromo-2,3-difluorophenyl)(methyl)sulfane as a colorless oil in a 46% yield. MS m / z calculated: 239.92; found: 238.9 [MH] - .

[0265] Step 2: Preparation of (3,4-difluoro-2-(methylthio)phenyl)boronic acid

[0266] (6-Bromo-2,3-difluorophenyl)(methyl)sulfane (12 g, 50.2 mmol) was dissolved in tetrahydrofuran (120 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to 0°C and i-PrMgBr.LiCl (30.1 mL, 60.2 mmol, 2 M) was added. The mixture was stirred at 0°C for half an hour. Triisopropyl borate (18.88 g, 100.4 mmol) was added and stirred at 0°C for 2.5 hours. The reaction was quenched with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 8 g of (3,4-difluoro-2-(methylthio)phenyl)boronic acid as a colorless oil in a 52% yield. MS m / z calculated: 204.02; found: 203.0 [MH] - .

[0267] Biological part of the test:

[0268] Test Example 1: Blocking activity of the compound of the present invention on sodium ion channel 1.8 (Nav1.8)

[0269] 1. Detection method: Whole-cell manual patch clamp technique to detect the effect of compounds on voltage-gated Nav1.8 channel current

[0270] 2. Preparation and Analysis of Test Compounds

[0271] Blank control: Take an appropriate amount of DMSO and add it to the extracellular solution to obtain an extracellular solution containing 0.1% DMSO as the blank control working solution.

[0272] Test compound: Weigh an appropriate amount of the test substance, dissolve it with DMSO to obtain a test compound stock solution, and then further dilute it with extracellular fluid to a final concentration of 10nM, 50nM, 0.1μM, 1μM and 10μM test compound working solution (the DMSO concentration in the working solution does not exceed 0.3%).

[0273] 3. Cell Culture

[0274] CHO cell lines stably expressing Nav1.8 (gene information: SCN10A, NM_006514; SCN1B, NM_199037; SCN3B, NM_018400) were cultured and passaged in HAM'S / F-12 medium (supplemented with 10% fetal bovine serum, 10 μg / mL blasticidin, 200 μg / mL hygromycin B, and 100 μg / mL zeocin) in a 37°C incubator with 5% carbon dioxide. To maintain electrophysiological activity, the cell density in the culture dish should not exceed 80%.

[0275] Before the patch clamp test, cells were detached with 0.25% trypsin-EDTA and 6.5 × 10 3 Cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After induction with tetracycline for 24-72 hours, the assay was performed.

[0276] 4. Electrophysiological Experiments

[0277] (1) Fluids used in electrophysiological experiments

[0278] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH.

[0279] Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH adjusted to 7.2 with CsOH.

[0280] (2) Patch clamp assay

[0281] The voltage stimulation protocol for whole-cell patch-clamp recording of sodium currents was as follows: After whole-cell seal formation, the cell was voltage-clamped at -120 mV. The voltage was first stepped from -130 mV to -10 mV in 10 mV steps and held for 5 seconds. A depolarizing pulse of 0 mV was then applied to obtain the half-inactivation voltage (Vhalf). The resting and half-inactivated states of sodium current were monitored using a double-pulse protocol. The first depolarizing pulse (TP1) was applied to 0 mV for 50 ms to measure the resting sodium current. The voltage was then adjusted to Vhalf and held for 5 seconds. The voltage was then returned to -120 mV and held for 20 ms. A second depolarizing pulse (TP2) was applied to 0 mV for 50 ms to measure the half-inactivated sodium current. Finally, the voltage was returned to the holding voltage of -120 mV. Data were collected repeatedly every 20 seconds to observe the effects of drugs on the peak sodium currents in the two different states. The experimental data were collected by EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0282] The patch clamp procedure begins by pulling a recording electrode from a glass capillary using a microelectrode puller. The electrode, filled with intracellular fluid, is then placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in extracellular fluid and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a high-resistance GΩ seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is performed.

[0283] When the sodium current recorded in the whole cell is stable, the drug is administered. Each drug concentration is allowed to act for 5 minutes (or the current is stable) before the next concentration is detected. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the compound to be tested are administered by gravity perfusion from low concentration to high concentration through the recording bath to act on the cells. At the same time, a peristaltic pump is used for liquid replacement during the recording. The current detected in the external solution without compound for each cell serves as its own control group. At least two cells are used for each concentration and the test is repeated twice independently. All electrophysiological experiments are performed at room temperature.

[0284] 5. Data Analysis

[0285] First, the peak sodium current after each drug concentration is compound ) and blank control current peak (Peakcurrent control ) normalized, and then calculated the inhibition rate corresponding to each drug concentration under different conditions, that is, The inhibition rate at each concentration was averaged.

[0286] The dose-effect curve was fitted using the Hill equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)), where Bottom and Top represent the minimum and maximum values ​​of inhibition, respectively, X represents the logarithm of the compound concentration, and Y represents the Peak-current compound / Peak-current Control Value, IC 50 It represents the drug concentration that produces half-maximal inhibition effect, and HillSlope represents the Hill coefficient.

[0287] The percentage blocking activity results and IC of some compounds of the present invention on Nav1.8 channels 50 The values ​​are shown in Table 1-3. TP1 is the Resting state, and TP2 is the Half-inactivated state.

[0288] Table 1 Percent blocking activity of some compounds of the present invention on Nav1.8 channels at a concentration of 100 nM

[0289] The inhibition rates of P-1, P-3, P-4, P-5, P-6, P-7, P-8, P-9, P-10, P-11, P-12, P-13, P-17, and P-18 on TP1 and TP2 were >50% at a concentration of 100 nM.

[0290] Table 2 Percent blocking activity of some compounds of the present invention on Nav1.8 channels at a concentration of 10 nM

[0291] The inhibition rates of P-1, P-4, P-5, P-7, P-8, P-9, P-10, and P-11 on TP1 and TP2 were >50% at a concentration of 10 nM.

[0292] Table 3 IC values ​​of representative compounds for Nav1.8 channels 50 Value (nM)

[0293] Test Example 2 hERG activity test:

[0294] 1. Sample Preparation

[0295] Preparation of blank control substance: Take an appropriate amount of DMSO and add it to the extracellular solution to obtain an extracellular solution containing 0.3% DMSO as the blank control substance working solution.

[0296] Preparation of positive control: Weigh an appropriate amount of Cisapride, dissolve it with an appropriate amount of dimethyl sulfoxide (DMSO), and then dilute it with extracellular fluid to prepare working solutions with concentrations of 1000 nM, 100 nM, 10 nM, 1 nM and 0.1 nM (make sure the DMSO concentration is 0.3%).

[0297] Preparation of test substances: Weigh an appropriate mass of the test substance, dissolve it with an appropriate amount of DMSO, and then use extracellular fluid to prepare working solutions of the test substance with concentrations of 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM, ensuring that the DMSO concentration in each working solution is 0.3%.

[0298] 2. Cell Culture

[0299] HEK-293 cells stably expressing the hERG potassium channel were used. hERG potassium channel cells were purchased from Creacell (Cat. No. A-0320). Cells were cultured and passaged in DMEM supplemented with 10% fetal bovine serum and 0.8 mg / mL G418 in a cell culture dish in an incubator at 37°C and 5% CO2. To maintain electrophysiological activity, the cell density must not exceed 80%.

[0300] Before patch clamp testing, cells were stained with TrypLE TM Express separation, 4×10 3 The cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the assay was performed.

[0301] 3. Electrophysiological Recording

[0302] Extracellular solution: K-007-1, 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, NaOH adjusted to pH = 7.4.

[0303] Intracellular solution: K-002-2, 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl2·6H2O, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, pH adjusted to 7.2 with KOH.

[0304] Patch clamp detection: The voltage stimulation scheme for whole-cell patch clamp recording of hERG current is as follows: After the whole-cell seal is formed, the cell membrane voltage is clamped at -80mV. The clamping voltage is depolarized from -80mV to -50mV for 0.5s (as a leakage current detection), then stepped to 30mV for 2.5s, and then quickly restored to -50mV for 4s to stimulate the tail current of the hERG channel. Data is collected repeatedly every 10s to observe the effect of drugs on the hERG tail current. A 0.5s stimulation of -50mV is used as a leakage current detection. The experimental data are collected by an IPA amplifier (Sutter Instrument) and stored in SutterPatch (with Igor Pro) software.

[0305] The patch clamp procedure begins by pulling a recording electrode from a glass capillary using a microelectrode puller. The electrode, filled with intracellular fluid, is then placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in extracellular fluid and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a high-resistance GΩ seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is performed.

[0306] When the hERG current recorded by the whole cell is stable, the drug is administered. After each drug concentration is applied for 5 minutes (or the current is stable), the next concentration is detected. Multiple concentrations are detected for each test compound. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the test compound are flowed through the recording bath from low concentration to high concentration by gravity perfusion to act on the cells. A peristaltic pump is used for liquid exchange during recording. The current detected in the external solution without compound for each cell serves as its own control group. At least three cells are used for each concentration and the test is repeated three times independently. All electrophysiological experiments are performed at room temperature.

[0307] 4. Data Analysis

[0308] First, the peak tail current after each drug concentration is compound ) and blank control tail current (Peak tail current control ) normalized, and then calculated the inhibition rate corresponding to each drug concentration The average inhibition rate was calculated for each concentration.

[0309] The dose-effect curve was fitted using the Hill equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50=X)*HillSlope)), where Bottom and Top represent the minimum and maximum values ​​of inhibition, respectively; X represents the logarithm of the compound concentration; and Y represents the Peak tail current. compound / Peak tail current Control Value, IC 50 It represents the drug concentration that produces half-maximal inhibition effect, and HillSlope represents the Hill coefficient.

[0310] Table 4 Inhibitory activity of representative compounds on hERG

[0311] The results showed that the compound of the present invention had very weak inhibitory activity on hERG (potassium ion channel) and exhibited high ion channel selectivity.

[0312] Test Example 3 Liver microsome metabolic stability test:

[0313] 1. Sample Preparation

[0314] Working solutions of test compounds and positive control compounds: The test compounds and positive control compound (dextromethorphan) were dissolved in DMSO to prepare 1 mM intermediate working solutions, which were then diluted with acetonitrile (ACN) to 200 μM working solutions.

[0315] Phosphate buffer: Dissolve 8.709g of potassium dihydrogen phosphate (K2HPO4) in 950mL of water. Adjust the pH of the solution to 7.4 with hydrochloric acid, then add water to 1000mL. Filter through a 0.22μm filter and store in a refrigerator at 4°C until needed.

[0316] Incubation matrix working solution: After various types of liver microsomes (protein concentration 20 mg / mL) were melted in a 37-degree water bath, they were diluted with phosphate buffer solution to obtain liver microsome working solution with a protein concentration of 0.629 mg / mL.

[0317] NADPH working solution: Use the above phosphate buffer to prepare a 5mM NADPH solution for later use.

[0318] Reaction stop solution: Prepare a 1 mg / mL stock solution of terfenadine / tolbutamide in DMSO, and then dilute it with a mixture of 50% methanol / 50% acetonitrile to a reaction stop solution containing 5 / 10 ng / mL (terfenadine / tolbutamide) as internal standard.

[0319] 2. Incubation and Detection

[0320] 238.5 μL of liver microsome working solution from different species was added to a 1.1 mL microtube. 1.5 μL of the test compound working solution or the positive control compound (dextromethorphan) working solution (200 μM) was added to each tube. Mix thoroughly and pre-incubate in a 37°C waterbath for 5 minutes. The reaction was initiated by adding 60 μL of NADPH solution. After thorough mixing, 30 μL of the reaction solution was pipetted into 300 μL of the reaction stop solution at 0, 5, 15, 30, and 60 minutes after the reaction. Samples at all time points were vortexed vigorously for 1 minute and centrifuged at 4000 rpm for 15 minutes at 4°C. The supernatant was analyzed by LC-MS / MS.

[0321] 3. Data Analysis

[0322] The slope (ke) was measured by plotting the natural logarithm of the percentage of the remaining compound against time, and T was calculated according to the first-order kinetic formula. 1 / 2 and intrinsic clearance (CL int ):

[0323] The compound residual rate is calculated as follows: C t =C0*e -ke*t lnC t =lnC o –ke*t

[0324] According to the above formula, when When

[0325] Intrinsic clearance CL int (μL / min / mg protein)=0.693*1000 / T 1 / 2 / Protein concentration (0.5mg protein / mL)

[0326] The unbound fraction (Fu) in the liver microsomal mixture was assumed to be 100%.

[0327] The following physiological variables were used for prediction calculations:

[0328] The results of the liver microsome stability test are shown in Table 5.

[0329] Table 5 Representative compounds for the stability of Nav1.8 channels in liver microsomes

[0330] The results showed that the compound of the present invention exhibited good metabolic stability in human and rat liver microsomes.

[0331] Test Example 4 CYP450 enzyme inhibition test

[0332] An in vitro test system was used to evaluate the effects of the test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A). Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory ability of the test substance on each CYP enzyme subtype was evaluated.

[0333] The specific results are shown in Table 6.

[0334] Table 6 CYP450 enzyme inhibition test results

[0335] Test Example 5 Solubility Test:

[0336] Solubility determination in pH 7.4 phosphate buffer: Excess DMSO stock solution of the test compound was placed in pH 7.4 phosphate buffer, shaken at 25°C and 350 rpm for 4 hours, then sampled and filtered through a 0.22 μm filter. The filtrate was then used to determine the concentration. The results are shown in the following table:

[0337] Table 7 Solubility of representative compounds

[0338] The results showed that the representative compounds exhibited good solubility.

[0339] Test Example 6 Spinal Nerve Ligation (SNL)-induced Neuropathic Pain Model in Mice

[0340] The model was established after one week of adaptive breeding of female SPF-grade C57BL / 6J mice. The specific establishment method is as follows:

[0341] 1. Spinal Nerve Ligation (SNL) Model

[0342] (1) Sterilization of surgical instruments;

[0343] (2) The experimental animals were anesthetized with isoflurane using a small animal gas anesthesia machine and placed in a prone position on the operating table. The hair at the lumbar spine and hip bones were trimmed and the skin was disinfected.

[0344] (3) After disinfection with iodine, a 2-cm incision is made along the spine near the hip bone, the fascia and muscles are separated, and the L5 transverse process is exposed;

[0345] (4) Use forceps to carefully bite off the L5 transverse process and expose the L5 nerve;

[0346] (5) The L5 nerve was separated by a glass needle and ligated using a 5-0 ligature;

[0347] (6) Suture the muscles and skin and disinfect.

[0348] (7) After surgery, observe the overall recovery of the mice, as well as their gait, spontaneous pain, and weight-bearing preference, and pay attention to whether the skin on the back of the mice has healed well.

[0349] 2. Observation of general clinical symptoms

[0350] After modeling, the activity of the right hind limb of the mice was observed during movement. The mice with successful modeling had abnormal gait, manifested as dragging or lameness of the right hind limb; spontaneous pain behavior, manifested as licking or stroking the affected limb; weight-bearing preference, manifested as the mice tended to avoid placing weight on the affected hind limb.

[0351] 3. Mechanical Pain Measurement

[0352] The mechanical withdrawal threshold (MPT) of mice was measured using the classic up-down test. The 50% paw withdrawal threshold (50% PTT) is determined by the mechanical force required to elicit a 50% paw withdrawal response after repeated mechanical stimulation. After the mice were acclimated to the Plexiglas box for 30 minutes, Von Frey fibers were used to vertically stimulate the mid-plantar aspect of the hind limb for ≤4 seconds. A positive response was considered if the mouse lifted its paw or licked its paw; a negative response was considered otherwise.

[0353] Start with a force of 0.4. If there is no withdrawal, stimulate the hind toe at a force above 0.6. If there is a withdrawal, stimulate the hind toe at a force below 0.16, and so on. Continue stimulating four times in sequence until a different response occurs, from withdrawal to no withdrawal, or from no withdrawal to withdrawal, for a total of six times, to determine the 50% withdrawal threshold. If the force required exceeds 2.0 or is less than 0.02, the threshold for that side will be recorded as 2.0 or 0.02. Leave 30 seconds between each stimulation. Maintain consistent measurement techniques throughout the experiment, such as force direction, force application speed, fiber bending degree, force stability, and force removal speed. Additionally, ensure consistent criteria for judging the mouse's response. The 50% paw withdrawal threshold was calculated using the formula 50% paw withdrawal threshold = 10log(X) + κδ (X is the intensity of the final stimulus used; κ is the coefficient of different stimulus methods, which can be found in the coefficient table; δ refers to the average of the adjacent intervals of each stimulus intensity, here δ = 0.224).

[0354] The 50% paw withdrawal threshold was measured and recorded at 0.5 h, 1 h, 3 h, 6 h, and 8 h after iv administration.

[0355] 4. Data Analysis

[0356] All experimental data were analyzed using GraphPad Prism 9 and IBM SPSS Statistics 19 software. The data were expressed as mean ± standard deviation (x ± s). The independent sample t test was used for comparison between groups. P < 0.05, p < 0.01, and p < 0.001 indicated statistically significant differences.

[0357] 5. Conclusion

[0358] The compounds of the present invention, such as the example compounds, have significant analgesic effects. For example, compounds P-1, P-4, P-5, P-7, P-9 and P-10 all have significant analgesic effects at a dosage of 15 mg / kg or 45 mg / kg.

[0359] The above embodiments are based on the numbers and corresponding structural formulas and are only used to illustrate the technical solutions of the present invention, not to limit them. Although the present invention has been described in detail with reference to the above embodiments, it should be understood by those skilled in the art that the technical solutions described in the above embodiments may be modified, or some or all of the technical features therein may be replaced with equivalents, without departing from the spirit and essence of the claims of the present invention; and such modifications or replacements are still within the scope of the claims of the present invention.

Claims

1. Compound of structural formula I: Its isomers, racemates, pharmaceutically acceptable salts or prodrugs, wherein: R1, R2, R3, R4, and R5 are each independently selected from H, deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, C 1-6 alkylamino, -S-halo-C 1-6 alkyl, deuterated C 1-6 alkyl, deuterated C 1-6 alkoxy, -S-deuterated C 1-6 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 3-6 cycloalkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 3-6 cycloalkyl, halo-3-7 membered heterocycloalkyl, halo-C 3-6 cycloalkoxy; wherein the C 1-6 alkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, C 1-6 alkylamino, -S-halo-C 1-6 alkyl, deuterated C 1-6 alkyl, deuterated C 1-6 alkoxy, -S-deuterated C 1-6 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 3-6 cycloalkoxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 3-6 cycloalkyl, halo-3-7 membered heterocycloalkyl, halo-C 3-6 cycloalkoxy may optionally be further substituted by one or more substituents independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl; R6 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 3-6 cycloalkyl, halo-C 3-6 cycloalkyloxy, halo-3- to 7-membered heterocycloalkyl; R7 and R8 are each independently selected from H, halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-7 membered heteroalkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 3-6 cycloalkyl, halo 3-7 membered heteroalkyl; R9, R 10 Further cyclize with the carbon atoms to which they are attached to form a 5- to 10-membered heteroalkyl group; the 5- to 10-membered heteroalkyl group may be further substituted by one or more substituents independently selected from R 11 ; R 11 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, -L1-OR 12 , -L1-NR 13 R 14 , C 3-6 cycloalkyl, 3- to 7-membered heteroalkyl, C 1-6 alkylene C 3-6 cycloalkyl, C 1-6 alkylene 3- to 7-membered heteroalkyl, 5- to 6-membered heteroaryl; wherein, the C 1- 6 alkyl, halo C 1-6 alkyl, -L1-OR 12 , -L1-NR 13 R 14 , C 3-6 cycloalkyl, 3- to 7-membered heteroalkyl, C 1-6 alkylene C 3-6 cycloalkyl, C 1- 6 alkylene 3- to 7-membered heteroalkyl, 5- to 6-membered heteroaryl may be optionally substituted by one or more substituents independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 7-membered heteroalkyl; L1 is selected from a bond, C 1-6 an alkylene group or C 3-6 a cycloalkylene group; R 12 selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl; R 13 and R 14 are each independently selected from hydrogen, C 1-6 alkyl, and 3- to 7-membered heterocycloalkyl.

2. The compound of structural formula I according to claim 1, its isomers, racemates, pharmaceutically acceptable salts or prodrugs thereof, characterized in that, In the formula I, is selected from and the five-membered ring moiety thereof is optionally substituted by one or more substituents independently selected from R 11 Preferably, in the formula I, is selected from Preferably, the formula I has the structures of formula IIa and formula IIb: wherein, R1, R2, R3, R4, R5, R6, R7, R8, R 11 as defined in claim 1 or 2; Preferably, the formula I has the structures of formula IIa-YG and IIb-YG:

3. The compound, its isomers, racemates, pharmaceutically acceptable salts or prodrugs according to claim 1 or 2, wherein: R6 is selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl; Preferably, the formula I has the structures of formula IIIa and formula IIIb: Preferably, the formula I has the structures of formula IIIa-YG and IIIb-YG:

4. The compound, its isomers, racemates, pharmaceutically acceptable salts or prodrugs according to any one of claims 1-3, wherein: R1, R2, R3, R4, and R5 are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy; wherein the C 1-6 alkyl, C 1-6 alkoxy, halo-C 1-6 alkoxy may optionally be further substituted by one or more substituents independently selected from hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 3- 6-cycloalkyl, 3-7-membered heterocycloalkyl; preferably, R1, R2, R3, R4, and R5 are each independently selected from H, FCH2O-, CH3O-, CH3S-, CH3CH2O-, CH3CH2S-, F, 5. The compound according to claim 1, its isomers, racemates, pharmaceutically acceptable salts or prodrugs thereof, wherein: R 11 selected from H, C 1- 6-alkyl, C 3-6 cycloalkyl, -L1-OR 12 、-L1-NR 13 R 14 、3- to 7-membered heteroalkyl; L1 is selected from a bond, C 1-6 alkylene or C 3-6 cycloalkylene; R 12 is selected from hydrogen; Preferably, C 3-6 cycloalkyl, C 3-6 subcycloalkyl is a 3- to 6-membered monocyclic, spiro, or bridged cycloalkyl; Preferably, the 3- to 7-membered heterocycloalkyl is a 3- to 7-membered N-containing heterocycloalkyl; Preferably, the 3- to 7-membered heterocycloalkyl is a 3- to 7-membered monocyclic, spirocyclic or bridged N-containing heterocycloalkyl; Preferably, R 11 is selected from H, -CH3, 6. A compound of structural formula I according to any one of claims 1-5, its isomers, racemates, pharmaceutically acceptable salts or prodrugs, wherein the compound of structural formula I is selected from:

7. A pharmaceutical composition comprising the compound according to any one of claims 1-6, its isomers, racemates, pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1-6, its isomers, racemates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to claim 7 in the manufacture of a medicament for treating a condition, disorder or disease responsive to inhibition of Nav1.8 channel activity in a mammalian subject in need thereof.

9. Use of the compound according to any one of claims 1-6, its isomers, racemates, pharmaceutically acceptable salts or prodrugs, or the pharmaceutical composition according to claim 7 in the manufacture of a medicament, preferably for treating, preventing or controlling pain conditions, cough disorders, acute pruritus disorders or chronic pruritus disorders.

10. The use according to claim 9, characterized in that: The conditions include chronic pain, visceral pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or arrhythmia or a method for reducing their severity; Preferably, the pain includes neuropathic pain, musculoskeletal pain (preferably osteoarthritis pain), acute pain (preferably acute postoperative pain), postoperative pain or visceral pain; Preferably, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy or diabetic neuropathy, preferably one or more of diabetic peripheral neuropathy; Preferably, the postoperative pain includes one or more of pain after bunionectomy, abdominoplasty pain or hernia repair pain; Preferably, one or more additional therapeutic agents are administered to the subject simultaneously with, before or after treatment with the compound, its isomers, racemates, or pharmaceutically acceptable salts or pharmaceutical composition.

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