Substituted benzimidazole derivative as well as preparation method and application thereof

Abstract

The invention provides a substituted benzimidazole derivative as well as a preparation method and application thereof. The substituted benzimidazole derivative is shown as a formula (I). The compound has a good Nav1.8 inhibition effect, and can be used for preventing and / or treating diseases, such as pain, related to Nav1.8 channel activity abnormity.

Description

Technical Field

[0001] This invention belongs to the pharmaceutical field and relates to a class of compounds used as specific inhibitors of the voltage-gated sodium ion channel subtype Nav1.8 and their use in treating diseases related to pain associated with the Nav1.8 target. Background Technology

[0002] Pain is the fifth vital sign after breathing, pulse, blood pressure, and body temperature. It is originally a warning mechanism of the body, but when pain becomes persistent, unbearable, or even severely affects normal work and life, it is no longer a simple warning signal, but a disease requiring treatment. Pain is a major reason why people seek medical attention; chronic pain alone affects more than one-fifth of the world's population. Currently, pain has become the third leading health problem after cardiovascular disease and cancer.

[0003] Pain perception is a complex physiological process, but the transmission of pain signals is inseparable from the participation of voltage-gated sodium channels (VGSCs, or Nav). The generation of pain in the human body originates from the conversion of harmful stimuli (mechanical, thermal, cold, and chemical stimuli) into nerve impulses (action potentials) by pain receptors distributed throughout the body's peripheral nerve endings. These impulses are transmitted via afferent nerves to the dorsal root ganglion (DRG), and then via efferent nerves to the central nervous system, thus allowing the perception of pain. Nav plays a role in triggering and transmitting nerve impulse signals, and is the main mediator for the initiation and rise of DRG action potentials. When the cell membrane depolarizes, sodium channels are activated, opening and causing an influx of sodium ions, further depolarizing the cell membrane and leading to the generation of action potentials. Inhibiting Nav can effectively block pain signal transmission and exert an analgesic effect; however, currently used clinical Nav inhibitors (such as lidocaine, carbamazepine, and mexiletine) have significant toxic side effects due to their inhibition of non-pain-related subtypes, limiting their application. Therefore, specifically inhibiting pain-related subtypes is an important direction for developing highly effective and safe analgesics.

[0004] Nav neurons are classified into nine subtypes, namely Nav1.1 to 1.9. Among them, Nav1.7, Nav1.8, and Nav1.9 are the main subtypes involved in action potential generation in the peripheral nervous system. Their involvement in action potentials primarily involves the following process: After the pain signal is transmitted to the dorsal root ganglion, Nav1.7 amplifies the threshold depolarization current, causing the action potential to reach the threshold, which is a crucial step in initiating action potentials in DRG neurons. Subsequently, Nav1.8 is activated, generating an inward current that promotes the rise of the action potential. During this process, Nav1.8 provides the Navs required for sustained action potential discharge. +More than 70% of the current is the main contributor to the rising phase of the action potential. The effectiveness of Nav1.8 as an analgesic target has been verified by genetic, animal model and clinical studies: (1) At the genetic level, human genetic studies have shown that Nav1.8 gain-of-function mutations lead to small fiber neuralgia and erythematous pain, while in rodents, knocking out or knocking down the Nav1.8 channel gene can relieve various inflammatory pain and neuralgia; (2) Nav1.8 inhibitors have significant efficacy in pain animal models. Abbott's A-803467 showed an analgesic effect of more than 50% compared with the model group in carrageenan model, complete Freund's adjuvant model, chronic sciatic nerve compression pain model, spinal nerve ligation pain model and acute mechanical pain model, while Pfizer's PF-01247324 also showed significant pain relief effect in complete Freund's adjuvant model and spinal nerve ligation pain model; (3) Clinical studies have also proven that Nav1.8 is the most effective analgesic target for analgesia. V Nav1.8 inhibitors are effective analgesics, as evidenced by the fact that Vertex's selective Nav1.8 inhibitor, VX-150, met its primary clinical endpoints in three Phase II proof-of-concept (PoC) studies, including those for acute and chronic pain. Furthermore, multiple clinical trials of its next-generation candidate drug, VX-548, have also yielded positive results. These studies strongly demonstrate that Nav1.8 is an effective analgesic target.

[0005]

[0006] However, currently reported small-molecule Nav1.8 inhibitors have significant shortcomings and require further improvement to deliver maximum clinical benefits to patients. First-generation Nav inhibitors, such as A-803467, PF-04531083, VX-150, VX-128, and VX-961, suffer from low activity, poor subtype selectivity, poor pharmacokinetic properties, and low oral bioavailability. Second-generation inhibitor VX-548 also exhibits significant shortcomings in metabolic properties; it is metabolized extremely rapidly in male rats, resulting in very low drug exposure. Furthermore, VX-548 exhibits moderate analgesic activity in animals, requiring further enhancement. These factors may limit the potential clinical application of VX-548, especially given that the majority of participants in its Phase II and III clinical trials were female. Therefore, developing Nav1.8 inhibitors with stronger analgesic activity, higher selectivity, and particularly superior metabolic properties (higher drug exposure) is of great value. Summary of the Invention

[0007] The purpose of this invention is to propose a benzimidazole derivative with high subtype selectivity, strong inhibitory activity, and excellent metabolism towards Nav1.8. This class of compounds exhibits strong Nav1.8 inhibitory activity and extremely high Nav1.8 subtype selectivity in vitro. More importantly, the compounds of this invention demonstrate excellent metabolic properties and analgesic activity in animals (rats), and can be used to prepare drugs for treating, relieving, or preventing pain. The pain referred to includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain, as well as any pain related to the Nav1.8 pathway.

[0008] A first aspect of the present invention provides a compound of general formula (I), or a tautomer, stereoisomer, or mixture thereof, a deuterated derivative, a hydrate, a solvate, a prodrug, a pharmaceutically acceptable salt, or a eutectic:

[0009]

[0010] In the formula, X is selected from O and S; Y is selected from CR. 5 , N, N + -O - ;where R 5 Selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy;

[0011] R 1 Selected from: hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, -C(O)NR 01 R 02 -C(O)NR 03 -NR 01 R 02 -C(=NR) 04 )NR 01 R 02 -C(=NR) 04 )NR 01 -OR 02 -S(O)R 05 -S(O)2R 05 -S(=NR) 01 (=O)R 05 S(O)2NR 01 R 02 NHR 06 OR 06 SR 06 Wherein, the substitution refers to substitution by one or more substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, and halo-C1-C6 alkyl; wherein: R01 R 02 R 03 R 05 Each is independently selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C6 cycloalkyl; R 04 Selected from hydrogen and hydroxyl groups; R 06 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups; wherein, the substitution refers to being substituted by one or more substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, halo-C1-C6 alkyl, amide, ester.

[0012] R 2 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to being substituted by one or more substituents selected from the group consisting of: halogens, deuterium;

[0013] R 3a and R 3b They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, cyano, or halo-C1-C6 alkyl;

[0014] R 4a and R 4b They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, and halo-C1-C6 alkyl;

[0015] Or, R 3a R 4a The carbon atom or R atom on the attached five-membered ring 3b R 4b It forms a 3-6 membered carbon ring with the carbon atom on the attached five-membered ring, wherein the 3-6 membered carbon ring is optionally substituted by one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy.

[0016] The condition is that the compound represented by formula (I) is not a

[0017] In another preferred embodiment, Y is N, R 1 Not -CONH2.

[0018] In another preferred embodiment, the compound has the following structure:

[0019] The definitions of each group are as described above.

[0020] In another preferred embodiment, the structural unit Selected from the following group:

[0021]

[0022] R 1 The definition is the same as that described in equation (I).

[0023] In another preferred embodiment, Y is a C-halogen or CH;

[0024] R 1 Selected from: hydrogen, cyano, hydroxy-substituted or unsubstituted C1-C4 alkyl groups, -C(O)NR 01 R 02 -C(O)NR 03 -NR 01 R 02 -C(=NR) 04 )NR 01 R 02 -C(=NR) 04 )NR 01 -OR 02 -S(O)R 05 -S(O)2R 05 -S(=NR) 01 (=O)R 05 S(O)2NR 01 R 02 OR 06 NHR 06 SR 06 Where: R 01 R 02 R 03 R 05 Each is independently selected from hydrogen and C1-C4 alkyl groups; R 04 Selected from hydrogen and hydroxyl groups; R 06 Selected from substituted or unsubstituted C1-C4 alkyl groups; wherein the substitution refers to being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, halo-C1-C4 alkyl, amide, ester.

[0025] In another preferred embodiment, R 1 Selected from one of the following structures: CN, -S (C1-C4 alkyl),

[0026]

[0027] In another preferred embodiment, Y is N or N0 + -O - ;

[0028] R 1 Selected from: hydrogen, cyano, hydroxy-substituted or unsubstituted C1-C4 alkyl groups, -C(O)NR 01 (C1-C4 alkyl), -C(O)NR 03 -NR01 R 02 -C(=NR) 04 )NR 01 R 02 -C(=NR) 04 )NR 01 -OR 02 -S(O)R 05 -S(O)2R 05 -S(=NR) 01 (=O)R 05 S(O)2NR 01 R 02 OR 06 NHR 06 SR 06 Where: R 01 R 02 R 03 R 05 Each is independently selected from hydrogen and C1-C4 alkyl groups; R 04 Selected from hydrogen and hydroxyl groups; R 06 Selected from substituted or unsubstituted C1-C4 alkyl groups; wherein the substitution refers to being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, halo-C1-C4 alkyl, amide, ester.

[0029] In another preferred embodiment, R 1 Choose from one of the following structures:

[0030]

[0031] In another preferred embodiment, R 2 Selected from substituted or unsubstituted C1-C4 alkyl groups, wherein the substitution refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogens and deuterium.

[0032] In another preferred embodiment, R 2 It is selected from methyl, difluoromethyl, difluorodeuterated methyl, deuterated methyl, and dideuterated methyl.

[0033] In another preferred embodiment, R 3a R 3b Each is independently selected from: hydrogen, C1-C4 alkyl, cyano, and halo-C1-C4 alkyl;

[0034] R 4a R 4b Each is independently selected from: hydrogen, C1-C4 alkyl, and halo-C1-C4 alkyl;

[0035] Or, R 3a R 4aThe carbon atom or R atom on the attached five-membered ring 3b R 4b It forms a 3-6 membered carbon ring with the carbon atom on the attached five-membered ring, optionally substituted by one or more (e.g., 2, 3, 4 or 5) substituents selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl.

[0036] In another preferred embodiment, R 3a R 3b Each is independently selected from: H, methyl, ethyl;

[0037] R 4a R 4b Each is independently selected from: hydrogen, methyl, ethyl, and trifluoromethyl;

[0038] Or, R 3a R 4a The carbon atom or R atom on the attached five-membered ring 3b R 4b It forms a 3-6 membered carbon ring with the carbon atom on the attached five-membered ring, and is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of: F, Cl, Br, trifluoromethyl, and difluoromethyl.

[0039] In another preferred embodiment, R 3a R 3b One is H, and the other is methyl.

[0040] In another preferred embodiment, R 4a R 4b One is methyl, and the other is trifluoromethyl.

[0041] In another preferred embodiment, R 3a R 3b R 4a R 4b It forms with the carbon atom on the attached tetrahydrofuran ring.

[0042] In another preferred embodiment, the compound is selected from the group consisting of:

[0043]

[0044]

[0045] Those skilled in the art will understand that and It is a tautomer, therefore contains The compounds of this invention with the structure can also be considered to contain The structures are equivalent.

[0046] Those skilled in the art should also understand that and It is a tautomer, therefore contains The compounds of this invention with the structure can also be considered to contain The structures are equivalent, and so on.

[0047] The compounds of this invention exhibit strong Nav1.8 inhibitory activity and extremely high Nav1.8 subtype selectivity in vitro. More importantly, these compounds demonstrate excellent metabolic properties and analgesic activity in animals (rats), and can be used to prepare drugs for treating, relieving, or preventing pain. The pain includes acute pain, chronic pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, and idiopathic pain, as well as any pain associated with the Nav1.8 pathway.

[0048] A second aspect of the present invention provides a method for preparing a compound represented by general formula (I) as described in the first aspect, comprising the following steps:

[0049]

[0050] The substituted tetrahydrofuran-2-carboxylic acid or the substituted tetrahydrothiophene-2-carboxylic acid undergoes a condensation reaction with an o-diamine to form an amide, which then undergoes cyclization under the action of an acid or base to form a benzimidazole; wherein the acid is selected from: formic acid, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, sulfuric acid, and hydrochloric acid; the base is selected from potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, and sodium ethoxide; the definitions of each substituent are as described above.

[0051] In another preferred embodiment, the condensation reaction occurs under the action of a condensing agent selected from the group consisting of: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-n-propylphosphonic anhydride, and carbonyldiimidazole.

[0052] In other preferred embodiments, the synthesis method involves the following route:

[0053]

[0054] The target product is prepared by heating a cyano-containing intermediate with a free substituted hydroxylamine or a substituted hydroxylamine salt in a solvent. The solvent includes, but is not limited to, methanol, ethanol, propanol, water, tetrahydrofuran, 1,4-dioxane, and ethyl acetate. The definitions of each substituent are as described above.

[0055] In other preferred embodiments, the synthesis method involves the following route:

[0056]

[0057] A cyanide-containing intermediate reacts with hydrogen chloride gas or an organic solvent solution of hydrogen chloride in an anhydrous solvent to form a Pinner salt, which then reacts with ammonia or a substituted amine to form a compound. The organic solvent and anhydrous solvent include, but are not limited to, one or more mixtures of anhydrous methanol, anhydrous ethanol, anhydrous propanol, anhydrous butanol, anhydrous tetrahydrofuran, anhydrous ethyl acetate, and anhydrous diethyl ether. The definitions of each substituent are as described above.

[0058] In another preferred embodiment, the organic solvent is the same as the anhydrous solvent.

[0059] A third aspect of the present invention provides a pharmaceutical composition comprising: a compound of formula (I) as described in the first aspect, or a tautomer, stereoisomer, or mixture thereof, a deuterated derivative, a hydrate, a solvate, a prodrug, a pharmaceutically acceptable salt, or a cocrystal, or one or more thereof; and a pharmaceutically acceptable carrier.

[0060] The pharmaceutical compositions of the present invention may, depending on the method of administration and the nature of the dosage form, contain at least one pharmaceutically acceptable carrier selected from the following: diluents, adjuvants, excipients, preservatives, fillers, binders, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, thermosensitive materials, adhesives, stabilizers, suspending agents, etc.

[0061] The drug combination can be prepared into tablets, capsules, sachets, sugar-coated pills, powders, granules, lozenges, powder injections, liquid preparations, or suppositories.

[0062] A fourth aspect of the invention provides the use of a compound of general formula (I) as described in the first aspect, or a tautomer, stereoisomer, or mixture thereof, a deuterated derivative, a hydrate, a solvate, a prodrug, a pharmaceutically acceptable salt, or a cocrystal, or a pharmaceutical composition as described in the third aspect, for the preparation of a medicament for treating, alleviating, or preventing diseases related to sodium channel regulation; or for the preparation of Nav1.8 inhibitors.

[0063] In another preferred embodiment, the sodium channel is Nav1.8.

[0064] In another preferred embodiment, the use is for preparing a drug for diseases associated with abnormal Nav1.8 channel activity.

[0065] In another preferred embodiment, the disease includes pain, multiple sclerosis, pathological cough, but is not limited to the types of diseases listed above.

[0066] The pain conditions mentioned include, but are not limited to, nociceptive pain, inflammatory pain (including but not limited to rheumatoid arthritis pain or vulvar pain), neuropathic pain (including but not limited to postherpetic neuralgia, idiopathic small fiber neuralgia), musculoskeletal pain (including but not limited to osteoarthritis pain, back pain, cold pain, burn pain or toothache), postoperative pain (including but not limited to post-hamstring surgery pain, abdominoplasty pain, etc.), internal pain, functional pain, muscle or bone injury-related pain, pelvic pain, abdominal pain, chest pain, lumbosacral neuralgia, preoperative pain, intraoperative pain, postoperative pain, intestinal pain (including but not limited to inflammatory bowel disease pain, Crohn's disease pain or interstitial cystitis), acute or chronic pain, migraine, trigeminal neuralgia, pancreatitis, renal colic, cancer pain, pain caused by chemotherapy or drug therapy, diabetic neuropathy, postherpetic neuralgia, back pain, phantom limb pain, sciatica, small fiber neuralgia, erythromelalgia, primary pain, idiopathic pain, etc. Diseases associated with abnormal expression of Nav1.8 channel activity include pruritus, acute or chronic pruritus, asthma, multiple sclerosis, arrhythmia, atrial fibrillation, heart failure, Brugada syndrome, kidney stones, epilepsy, seizures, Shayma-Tuss syndrome, and incontinence.

[0067] Furthermore, the drug may be administered alone or in combination with other therapeutic agents.

[0068] Furthermore, the drug can be administered orally, parenterally, intravenously, by inhalation, or transdermally.

[0069] This invention provides a novel substituted benzimidazole derivative. This class of compounds exhibits potent inhibitory activity against Nav1.8 and extremely high Nav1.8 isoform selectivity, with minimal impact on other sodium ion channels. It is expected to reduce cardiac, muscular, and central nervous system side effects, thereby improving the therapeutic efficacy and safety for Nav1.8-mediated diseases. Another major advantage of this invention is that the compounds provided have better pharmacokinetic properties than VX-548 (longer half-life, greater drug exposure, and higher oral bioavailability), and demonstrate stronger analgesic activity than VX-548 in animal models, potentially providing greater and more sustained clinical benefits to all patients. Therefore, this type of substituted benzimidazole derivative has significant advantages and promising application prospects in the preparation of drugs for the treatment, relief, or prevention of diseases related to abnormal expression of Nav1.8 channel activity.

[0070] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Due to space limitations, these will not be elaborated upon here. Attached Figure Description

[0071] Figure 1 The results show the analgesic effect of the compound in a rat incision pain model.

[0072] Figure 2 The results show the analgesic effect of the compound in a humanized mouse postoperative pain model.

[0073] In the accompanying drawings of this invention, * indicates P < 0.05; ** indicates P < 0.01; *** indicates P < 0.001. Detailed Implementation

[0074] the term

[0075] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0076] In this invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5, or 6 carbon atoms, and so on. "3-6" refers to having 3, 4, 5, or 6 ring atoms, and so on.

[0077] In the compounds of this invention, "hydrogen," "carbon," and "oxygen" include all their isotopes. Isotopes should be understood as including atoms having the same number of atoms but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include... 13 C and 14 C, oxygen isotopes include 16 O and 18 O etc.

[0078] "Halogen" refers to fluorine, chlorine, bromine, or iodine; "halogenated" refers to fluorinated, chlorinated, bromine, or iodinated substances.

[0079] "Cyano" refers to -CN. "Carboxyl" refers to -C(=O)OH. "Hydroxy" refers to -OH.

[0080] "Amide group" refers to RCONH, where R is H or a hydrocarbon group. Examples of amide groups include, but are not limited to, -CONH2, -CONH (C1-C6 alkyl), and -CONH (C3-C6 cycloalkyl).

[0081] "Ester group" refers to -COOR, where R is a non-H group such as an alkyl group. Examples of R include, but are not limited to, C1-C6 alkyl groups and C3-C6 cycloalkyl groups.

[0082] "alkyl" refers to a group formed by the loss of a hydrogen atom from any carbon atom in a saturated hydrocarbon composed only of C and H elements, including straight-chain and branched aliphatic hydrocarbons. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.

[0083] The term "C1-C6 alkyl" refers to a chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Specific examples may include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, 1-methylbutyl, 1-ethylbutyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, and similar groups. The meaning of C1-C3 alkyl follows the same principle.

[0084] "Heteroalkyl" means an alkyl group containing at least one (e.g., 1, 2, 3 or 4) heteroatoms (e.g., N, O, S, P or Se).

[0085] In this invention, the term "alkoxy" refers to an -O-(alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, and butoxy groups.

[0086] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group. For example, the term "C3-C6 cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms on the ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0087] "Substitution" refers to the independent replacement of one or more groups, such as hydrogen atoms, in a group by a corresponding number of substituents; the substitution is monosubstituted or polysubstituted, preferably disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted. Disubstituted means having two substituents, and so on.

[0088] "Independently" means that when the number of substituents exceeds one, these substituents can be the same or different;

[0089] In this invention, "isomers" refers to compounds having the same molecular formula but differing in properties, the bond sequence of their atoms, or the spatial arrangement of their atoms. Stereoisomers are isomers whose atoms differ in spatial arrangement. Stereoisomers that are not mirror images of each other are diastereomers, and stereoisomers that are non-overlapping mirror images of each other are enantiomers. Chiral compounds can exist as single enantiomers or mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0090] "Deuterated compounds" refer to compounds with one or more hydrogen atoms in their structure. 1 H) was deuterium ( 2 The structure formed by H / D substitution, wherein the content of "deuterium" can be 20% to 100%, preferably 90% to 100%.

[0091] "Pharmaceutically acceptable salts" refer to salts that retain the biological potency of a specific compound as a free acid or base without any adverse biological effects, such as acid (including organic and inorganic acids) addition salts or base (including organic and inorganic bases) addition salts. The pharmaceutically acceptable salts of this invention can be synthesized from a parent compound containing an acid radical or base using conventional chemical methods. Generally, their preparation involves reacting a parent compound in its free acid or base form with a stoichiometric base or acid in water or an organic solvent or a mixture of both.

[0092] The compounds involved in this application, as well as their pharmaceutically usable salts, esters, and prodrugs, may have isomers, such as stereoisomers, tautomers, and mixtures thereof, but are not limited thereto. These isomers are also included within the scope defined by the claims of this invention.

[0093] The present invention will be further illustrated below with reference to specific embodiments. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions (such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.

[0094] This invention was completed through extensive compound design, synthesis, in vitro and in vivo bioactivity testing, and drug development studies including metabolism. The following examples are merely illustrative of the invention and do not constitute any limitation thereof. Any minor modifications made to this invention by those skilled in the art using well-known techniques, methods, or combinations thereof are within the scope of protection of this invention.

[0095] Method for synthesizing the compounds of the present invention

[0096] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR data were acquired on a BRUKER AVANCE III 400, BRUKER AVANCE III 500, or BRUKER AVANCE III 600 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD) as the solvent. Chemical shifts are expressed as δ (ppm). The abbreviations used to describe peak signals are as follows: br = broad signal, s = singlet, d = doublet, dd = doublet peak, t = triplet, q = quartet, m = multiplet. Mass spectrometry was performed using a Finnigan LTQ linear ion trap mass spectrometer. 200-300 mesh silica gel was used for column chromatography, and all eluent ratios were volume ratios. Commercially available raw materials, reagents, and solvents used in the synthesis were purchased directly from reagent companies and used directly in the reaction without additional purification.

[0097] Example 1: Preparation of Compound 1

[0098] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (1)-1H-benzo[d]imidazol-6-carboxamide (2-yl)-1H-benzo[d]imidazol-6-carboxamide

[0099]

[0100] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (WO2022256660A1) (100 mg, 0.282 mmol) and 3,4-diaminobenzonitrile (37.58 mg, 0.282 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (72 mg, 0.564 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (214 mg, 0.564 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared (2 h), then 20 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in an oil bath at 65 °C for 12 h. After concentration to remove acetic acid, the crude product was separated by column chromatography (DCM / MeOH = 15 / 1) to give intermediate 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-benzo[d]imidazolium-6-onitrile (62 mg), yield 46%. ESI-MS m / z = 452.2 [M+H] + .

[0101] Step 2: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-benzo[d]imidazolium-6-onitrile (50 mg, 0.110 mmol) was dissolved in 1 mL of dimethyl sulfoxide, and potassium carbonate (182 mg, 1.304 mmol) and 30% hydrogen peroxide (10 mL) were added. The mixture was stirred at room temperature for 12 h. After the reaction starter disappeared as monitored by TLC, 20 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 1 (30 mg), yield 59%. 1 H NMR(400MHz,DMSO-d6)δ12.91&12.85(s,1H),8.16&8.02(s,1H),7.97&7.9 1(s,1H),7.78&7.71(d,J=8.6Hz,1H),7.60&7.51(d,J=8.5Hz,1H),7.28&7. 22(s,1H),7.19–7.07(m,2H),5.74(d,J=11.1Hz,1H),4.59–4.46(m,1H),3 .97(d,J=2.1Hz,3H), 2.89(p,J=7.6Hz,1H), 1.66(s,3H), (d,J=6.4Hz,3H). ESI-MS m / z=470.2[M+H] + .

[0102] Example 2: Preparation of Compound 2

[0103] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (2)-N-hydroxy-1H-benzo[d]imidazolium-6-carboximide

[0104]

[0105] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-benzo[d]imidazolium-6-onitrile (50 mg, 0.11 mmol) was dissolved in methanol (5 mL), and hydroxylamine hydrochloride (16 mg, 0.22 mol) and triethylamine (67 mg, 0.66 mol) were added. The mixture was then stirred in an oil bath at 65 °C for 4 h. The volatiles were removed by concentration, and the product was dissolved in ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative TLC (DCM / MeOH = 15 / 1) to give compound 2 (30 mg), yield 56%. 1H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.69(d,J=8.6Hz,1H),7.55(d,J=8.5Hz,1H),7.00–6.93(m,1H),6.84(q,J=8.6Hz,1H),5.69(d, J=10.8Hz,1H),4.98(s,2H),4.54(dd,J=10.8,7.9Hz,1H),4.04(d,J=2.6Hz,3H),2.92(p,J=7.6Hz,1H),1.73(s,3H),0.89(d,J=6.8Hz,3H). ESI-MS m / z=485.2[M+H] + .

[0106] Example 3: Preparation of Compound 3

[0107] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (3)-1H-benzo[d]imidazol-6-carboximide

[0108]

[0109] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (50 mg, 0.110 mmol) was dissolved in anhydrous methanol (2 mL) and cooled in an ice-water bath, followed by the introduction of hydrogen chloride gas (10 min). The reaction mixture was stirred in the ice-water bath until the starting material disappeared (approximately 2 h), then the solvent was removed under reduced pressure, and NH3 (7N in MeOH, 3 mL) was added. The reaction mixture was then reacted in an oil bath at 40 °C until the intermediate disappeared. 10 mL of water was added to the reaction mixture, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 3 (32 mg), with a yield of 61%. 1 H NMR (600MHz, DMSO-d6) δ8.10(s,1H),7.62(d,J=8.4Hz,1H),7.58(d,J=8.5Hz,1H),7.15–7.10(m,1H),7.06(q,J=8.7Hz,1H),5.72 (d, J=11.1Hz, 1H), 4.64 (dd, J=11.1, 7.4Hz, 1H), 3.97 (d, J=1.8Hz, 3H), 2.88 (p, J=7.5Hz, 1H), 1.67 (s, 3H), 0.79 (d, J=7.4Hz, 3H). ESI-MS m / z=469.2[M+H] + .

[0110] Example 4: Preparation of Compound 4

[0111] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl Hydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-carboxamide (4)

[0112]

[0113] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (136 mg, 0.384 mmol) and 4,5-diamino-2-fluorobenzonitrile (70 mg, 0.461 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of triethylamine (78 mg, 0.768 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 291 mg, 0.768 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared (3 h), then 20 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. ESI-MS m / z = 486.2 [MH] + .

[0114] The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in an oil bath at 70 °C for 12 h. Acetic acid was removed by concentration, and the crude product was separated by column chromatography (DCM / MeOH = 10 / 1) to give intermediate 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (70 mg), yield 38%. ESI-MS m / z = 470.2 [M+H] + .

[0115] Step 2: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (50 mg, 0.106 mmol) was dissolved in 1 mL of dimethyl sulfoxide, followed by the addition of potassium carbonate (182 mg, 1.31 mmol) and 30% hydrogen peroxide (10 mL). The mixture was stirred at room temperature for 12 h. After the reaction starter disappeared as monitored by TLC, 20 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 15 / 1) to give compound 4 (33 mg), yield 64%.1 H NMR (600MHz, DMSO-d6) δ7.83(d,J=6.4Hz,1H),7.59(s,1H),7.53(s,1H),7.41(dd,J=9.9,4.5Hz,1H),7.18–7.07(m,2H),5.74(d ,J=11.0Hz,1H),4.49(dd,J=11.1,7.6Hz,1H),3.96(d,J=1.9Hz,3H),2.88(p,J=7.7Hz,1H),1.65(s,3H),0.80(d,J=7.5Hz,3H). ESI-MS m / z=488.2[M+H] + .

[0116] Example 5: Preparation of Compound 5

[0117] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (5)-5-fluoro-N-hydroxy-1H-benzo[d]imidazolium-6-carboximide

[0118]

[0119] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (30 mg, 0.063 mmol) was dissolved in methanol (10 mL), and hydroxylamine hydrochloride (8.89 mg, 0.128 mol) and triethylamine (38 mg, 0.376 mol) were added. The mixture was then stirred in an oil bath at 65 °C for 3 h. The volatiles were removed by concentration, and the product was dissolved in ethyl acetate. The organic phase was washed successively with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 5 (8 mg), yield 24%. 1 HNMR(600MHz,DMSO-d6)δ12.91(s,1H),9.75(s,1H),7.71–7.56(m,1H),7.50–7.35(m,1H),7.19–7.07(m,2H),5.72(d ,J=10.9Hz,1H),4.49(dd,J=11.2,7.0Hz,1H),3.96(s,3H),2.88(p,J=7.3Hz,1H),1.66(s,3H),0.80(d,J=7.3Hz,3H). ESI-MS m / z=503.2[M+H] + .

[0120] Example 6: Preparation of Compound 6

[0121] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (6)-5-fluoro-1H-benzo[d]imidazol-6-carboximide

[0122]

[0123] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (130 mg, 0.277 mmol) was dissolved in anhydrous methanol (2 mL) and cooled in an ice-water bath, followed by the introduction of hydrogen chloride gas (10 min). The reaction mixture was stirred in the ice-water bath until the starting material disappeared (approximately 2 h), then the solvent was removed under reduced pressure, and NH3 (7N in MeOH, 6 mL) was added. The mixture was reacted in an oil bath at 40 °C until the intermediate disappeared. 10 mL of water was added to the reaction mixture, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 6 (20 mg), with a yield of 14.9%. 1 H NMR (600MHz, DMSO-d6) δ9.36 (s, 3H), 7.91 (s, 1H), 7.61 (s, 1H), 7.19–7.06 (m, 2H), 5.78 (d, J = 11.1Hz, 1H), 4. 53 (dd, J = 11.1, 7.6 Hz, 1H), 3.96 (d, J = 1.9 Hz, 3H), 2.90 (p, J = 7.6 Hz, 1H), 1.68 (s, 3H), 0.81 (d, J = 7.5 Hz, 3H). ESI-MS m / z=487.4[M+H] + .

[0124] Example 7: Preparation of Compound 7

[0125] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (7)-5-fluoro-6-(methylsulfinyl)-1H-benzo[d]imidazolium

[0126]

[0127] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (45 mg, 0.127 mmol) and 4-fluoro-5-(methylsulfinyl)phenyl-1,2-diamine (24 mg, 0.127 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of triethylamine (51 mg, 0.50 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 67 mg, 0.152 mmol). The reaction mixture was stirred at room temperature for 3 h, then 50 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 6 mL of glacial acetic acid, then stirred in an oil bath at 100 °C for 1 h, concentrated to remove acetic acid, and the crude product was separated by column chromatography (DCM / MeOH = 100 / 1) to give compound 7 (28 mg), with a yield of 43%. 1 H NMR(500MHz,DMSO-d6)δ13.10(s,1H),7.84(s,1H),7.55(s,1H),7.20–7.05(m,2H),5.77(d,J=11.0Hz,1H),4.5 4–4.46(m,2H),3.96(dd,J=2.1Hz,3H),2.88(p,J=7.5Hz,1H),2.79(s,3H),1.65(s,3H),0.80(d,J=6.6Hz,3H). ESI-MS m / z=507.2[M+H] + .

[0128] Example 8: Preparation of Compound 8

[0129] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (8)-5-fluoro-6-(methylsulfonyl)-1H-benzo[d]imidazolium

[0130]

[0131] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (104 mg, 0.294 mmol) and 4-fluoro-5-(methanesulfonyl)phenyl-1,2-diamine (60 mg, 0.294 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (114 mg, 0.88 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 143 mg, 0.32 mmol). The reaction mixture was stirred at room temperature for 2 h, then 40 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 6 mL of glacial acetic acid, then stirred in an oil bath at 100 °C for 1 h, concentrated to remove acetic acid, and the crude product was separated by column chromatography (PE / EA = 5 / 1 to 1 / 1) to give compound 8 (108 mg), with a yield of 70%. 1 H NMR (500MHz, DMSO-d6) δ13.30&13.23(s,1H),8.01&7.97(d,J=6.2Hz,1H),7.72&7.61(d,J=11.1Hz,1H),7.22–7.06(m,2H),5.83&5.77(d ,J=11.1Hz,1H),4.53–4.43(m,1H),3.95(s,3H),3.30&3.28(d,J=6.4Hz,3H),2.88(p,J=7.5Hz,1H),1.65(s,3H),0.80(d,J=6.5Hz,3H). ESI-MS m / z=523.1[M+H] + .

[0132] Example 9: Preparation of Compound 9 (2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5- dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)(imino)(methyl)-λ 6 - Sulfophenone (9)

[0133]

[0134] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (354 mg, 1.0 mmol) and 4-fluoro-5-methylthiophenyl-1,2-diamine (172 mg, 1.0 mmol) were dissolved in anhydrous N,N-dimethylformamide (8 mL), followed by the addition of N,N-diisopropylethylamine (258 mg, 2.0 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 442 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 h, then 60 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 6 mL of glacial acetic acid, then stirred in an oil bath at 100 °C for 1 h. The acetic acid was removed by concentration, and the crude product was separated by column chromatography (PE / EA = 5 / 1) to give 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-6-(methylthio)-1H-benzimidazole (356 mg), yield 73%. 1 H NMR(500MHz,DMSO-d6)δ12.75(d,J=19.1Hz,1H),7.62–7.31(m,2H),7.13–7.05(m,2H),5.70(d,J=11.1Hz,1H),4.48( dd,J=11.1,7.5Hz,1H),3.96(d,J=1.9Hz,3H),2.87(p,J=7.5Hz,1H),2.47(s,3H),1.64(s,3H),0.79(d,J=6.6Hz,3H). ESI-MS m / z=491.1[M+H] + .

[0135] Step 2: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-6-(methylthio)-1H-benzi[d]imidazole (100 mg, 0.204 mmol) was dissolved in methanol (3 mL), followed by the sequential addition of ammonium carbamate (24 mg, 0.306 mmol) and iodobenzene diacetate (138 mg, 0.428 mmol). The reaction mixture was stirred at room temperature for 1.5 h, and then concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH = 50 / 1) to give compound 9 (70 mg), yield 66%. 1H NMR (500MHz, DMSO-d6) δ13.16(s,1H),8.03(d,J=6.3Hz,1H),7.65–7.48(m,1H),7.20–7.05(m,2H),5.77(d,J=11.0Hz,1H),4. 60(s,1H),4.48(dd,J=11.0,7.5Hz,1H),3.95(s,3H),3.16(s,3H),2.88(p,J=7.5Hz,1H),1.65(s,3H),0.80(d,J=6.5Hz,3H). ESI-MS m / z=522.2[M+H] + .

[0136] Example 10: Preparation of Compound 10

[0137] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl Hydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-sulfonamide (10)

[0138]

[0139] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (230 mg, 0.649 mmol) and 4,5-diamino-2-fluorobenzenesulfonamide (133 mg, 0.648 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (165 mg, 1.27 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 490 mg, 1.28 mmol). The reaction mixture was stirred at room temperature for 2 h until the starting material disappeared, then 50 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in an oil bath at 120 °C for 12 h. After the starting material disappeared as monitored by TLC, the mixture was concentrated to remove acetic acid. The crude product was then separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 10 (160 mg), with a yield of 47%. 1H NMR (800MHz, DMSO-d6) δ13.14(s,1H),7.95(s,1H),7.56(s,3H),7.19–7.15(m,1H),7.13–7.08(m,1H),5.84–5.72(m ,1H),4.48(dd,J=11.1,7.6Hz,1H),3.96(d,J=1.9Hz,3H),2.89(p,J=7.6Hz,1H),1.66(s,3H),0.81(d,J=6.9Hz,3H). ESI-MS m / z=524.2[M+H] + .

[0140] Example 11: Preparation of Compound 11

[0141] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl Hydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine (11)

[0142]

[0143] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (354 mg, 1.0 mmol) and 3,4-diaminopyridine (218 mg, 2.0 mmol) were dissolved in anhydrous N,N-dimethylformamide (6 mL), followed by the addition of N,N-diisopropylethylamine (516 mg, 4.0 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 570 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 4 h, then 50 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. ESI-MS m / z = 446.2 [M+H] + The crude product was dissolved in 6 mL of glacial acetic acid, then stirred in an oil bath at 80 °C for 20 min, concentrated to remove acetic acid, and the crude product was separated by column chromatography (DCM / MeOH = 30 / 1) to give compound 11 (242 mg), with a yield of 57%. 1H NMR (500MHz, DMSO-d6) δ13.09(s,1H),8.88(s,1H),8.28(d,J=5.5Hz,1H),7.54(d,J=5.1Hz,1H),7.20–7.13(m,1H),7.10(q,J=8.9Hz,1H ), 5.78 (d, J = 11.1Hz, 1H), 4.50 (dd, J = 11.0, 7.5Hz, 1H), 3.96 (d, J = 2.0Hz, 3H), 2.89 (p, J = 7.5Hz, 1H), 1.65 (s, 3H), 0.80 (d, J = 6.4Hz, 3H). ESI-MS m / z=428.2[M+H] + .

[0144] Example 12: Preparation of Compound 12

[0145] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (12)-1H-imidazo[4,5-c]pyridine-5-oxide

[0146]

[0147] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine (80 mg, 0.187 mmol) was dissolved in dichloromethane (6 mL) and methanol (3 mL), followed by the addition of m-chloroperoxybenzoic acid (76 mg, 37 mmol, 85%). The reaction mixture was stirred at room temperature for 5 h, concentrated, dissolved in ethyl acetate (50 mL), washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 15 / 1) to give compound 12 (37 mg), yield 44%. 1 H NMR(500MHz,DMSO-d6)δ13.25(s,1H),8.66(s,1H),8.02(s,1H),7.57(s,1H),7.19–7.06(m,2H),5.76(d,J=11.1Hz, 1H), 4.46 (dd, J = 11.1, 7.6Hz, 1H), 3.95 (d, J = 2.0Hz, 3H), 2.87 (p, J = 7.5Hz, 1H), 1.64 (s, 3H), 0.79 (d, J = 6.4Hz, 3H). ESI-MS m / z=444.4[M+H] + .

[0148] Example 13: Preparation of Compound 13

[0149] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (13)-N-methyl-1H-imidazo[4,5-c]pyridine-6-carboxamide

[0150]

[0151] Step 1: Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (450 mg, 1.27 mmol) in DCM. Add 0.3 mL of DMF, then add 241 mL of oxaloyl chloride dropwise under ice bath conditions. Slowly restore to room temperature and stir for 1 h. After evaporating the solvent, add 10 mL of DCM, then add ethyl 4,5-diaminopyridinecarboxylate (402 mg, 1.905 mmol) reaction solution and stir at room temperature (2 h). Add 50 mL of water, then extract twice with ethyl acetate. Wash the obtained organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH = 10 / 1) to yield intermediate ethyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-nitropyridine-2-carboxylate (350 mg), yield 80.3%. ESI-MS m / z = 548.2 [M+H] + .

[0152] Step 2: Ethyl 4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-5-nitrotholinate (350 mg, 0.639 mmol) was dissolved in ethanol, and 10% Pd / C (350 mg) was added. The mixture was then heated and stirred in a hydrogen atmosphere at 60 °C for 6 h. After the reaction was complete, the crude product was filtered and separated by column chromatography (DCM / MeOH = 10 / 1) to obtain the intermediate ethyl 5-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-pyridine-2-carboxylate (300 mg), yield 91%. ESI-MS m / z = 518.2 [M+H] + .

[0153] Step 3: Dissolve in 10 mL of glacial acetic acid, then place in a 65°C oil bath and stir for 12 h. Concentrate to remove acetic acid, and separate the crude product by column chromatography (DCM / MeOH = 10 / 1) to obtain intermediate ethyl 5-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine-2-carboxylate (280 mg), yield 96%. ESI-MS m / z = 500.2 [M+H] + .

[0154] Step 4: Ethyl 5-amino-4-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)pyridine-2-carboxylate (50 mg, 0.106 mmol) was dissolved in MeOH (2 mL), followed by the addition of methylamine (5 mL, 2 M methanol solution). The reaction mixture was stirred at room temperature for 12 h and then concentrated. The crude product was separated by preparative TLC (DCM / MeOH = 20 / 1) to give compound 13 (25 mg), yield 52%. 1 H NMR (600MHz, DMSO-d6) δ13.35(s,1H),8.89(s,1H),8.73(s,1H),8.17(s,1H),7.23–7.18(m,1H),7.12(q,J=8.9Hz,1H),5.85(d,J=11.0Hz, 1H), 4.52 (dd, J = 11.0, 7.6Hz, 1H), 3.97 (d, J = 1.9Hz, 3H), 2.90 (p, J = 7.5Hz, 1H), 2.84 (d, J = 4.8Hz, 3H), 1.66 (s, 3H), 0.81 (d, J = 7.6Hz, 3H). ESI-MS m / z=485.2[M+H] + .

[0155] Example 14: Preparation of Compound 14

[0156] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl (14)-1H-imidazo[4,5-c]pyridine-6-carbazide

[0157]

[0158] Ethyl 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (50 mg, 0.106 mmol) was dissolved in MeOH (2 mL), followed by the addition of hydrazine hydrate (3 mL, 40% aqueous solution). The reaction mixture was stirred at room temperature for 12 h and then concentrated. The crude product was preparatively separated by TLC (DCM / MeOH = 10 / 1) to give compound 14 (28 mg), yield 57%. 1 H NMR (600MHz, DMSO-d6) δ13.33(s,1H),9.77(s,1H),8.13(s,1H),7.24–7.17(m,1H),7.12(q,J=8.9Hz,1H),5.85(d, J=11.0Hz,1H),4.67–4.44(m,3H),3.96(d,J=2.0Hz,3H),2.90(p,J=7.6Hz,1H),1.66(s,3H),0.81(d,J=6.2Hz,3H). ESI-MS m / z=486.3[M+H] + .

[0159] Example 15: Preparation of Compound 15 (2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4, 5-Dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-6-yl)(imino)(methyl)- λ 6 -Sulfophenone (15)

[0160]

[0161] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (137 mg, 0.39 mmol) and 6-(methylthio)pyridine-3,4-diamine (60 mg, 0.39 mmol) were dissolved in anhydrous N,N-dimethylformamide (8 mL), followed by the addition of N,N-diisopropylethylamine (116 mg, 0.90 mmol) and 2-(7-azabenzotriazole)-N,N,N,N'-tetramethylurea hexafluorophosphate (HATU, 343 mg, 0.90 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared (1 h), then 50 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. ESI-MS m / z = 492.2 [M+H] + .

[0162] The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in an oil bath at 120 °C for 36 h. After concentration to remove acetic acid, the crude product was separated by column chromatography (DCM / MeOH = 8 / 1–4 / 1) to give intermediate 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-(methylthio)-1H-imidazo[4,5-c]pyridine (152 mg), yield 83%. ESI-MS m / z = 474.1 [M+H] + .

[0163] Step 2: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-(methylthio)-1H-imidazo[4,5-c]pyridine (150 mg, 0.32 mmol) was dissolved in methanol (5 mL), followed by the sequential addition of ammonium carbamate (37 mg, 0.48 mmol) and iodobenzene diacetate (214 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 1.5 h, and then concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH = 50 / 1) to give compound 15 (121 mg), yield 76%. 1 H NMR (500MHz, DMSO-d6) δ13.54(s,1H),8.99(s,1H),8.20(s,1H),7.22(q,J=7.7,6.7Hz,1H),7.17–7.07(m,1H),5.87(d,J=10. 9Hz,1H),4.57–4.43(m,1H),4.27(s,1H),3.95(s,3H),3.14(s,3H),2.89(p,J=7.5Hz,1H),1.66(s,2H),0.81(d,J=6.5Hz,3H). ESI-MS m / z=505.1[M+H] + .

[0164] Example 16: Preparation of Compound 16

[0165] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrafluorophenyl Hydrofuran-2-yl)-6-(methanesulfonyl)-1H-imidazo[4,5-c]pyridine (16)

[0166]

[0167] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-(methylthio)-1H-imidazo[4,5-c]pyridine (50 mg, 0.1057 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of m-chloroperoxybenzoic acid (49 mg, 0.244 mmol, 85%) under ice bath conditions. The reaction mixture was stirred at room temperature for 1.5 h, then diluted with dichloromethane (50 mL), followed by washing with saturated sodium bicarbonate and saturated sodium chloride, and finally dried over anhydrous sodium sulfate. The crude product was concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH = 50 / 1) to give compound 16 (20 mg), yield 37%. 1 H NMR (400MHz, DMSO-d6) δ13.66(s,1H),9.05(s,1H),8.19(s,1H),7.28–7.20(m,1H),7.17–7.08(m,1H),5.90(d,J=10.9Hz,1H) ,4.50(dd,J=11.0,7.5Hz,1H),3.95(d,J=2.2Hz,3H),3.24(s,3H),2.90(p,J=7.5Hz,1H),1.67(s,3H),0.82(d,J=6.7Hz,3H). ESI-MS m / z=506.3[M+H] + .

[0168] Example 17: Preparation of Compound 17 (S)-1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxybenzene) 2-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)ethane-1,2- Diol (17)

[0169]

[0170] Step 1: (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (317 mg, 0.897 mmol) and 4-bromo-5-fluorobenzene-1,2-diamine (202 mg, 0.986 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (230 mg, 1.789 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 680 mg, 1.789 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared (1 h), then 20 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. ESI-MS m / z = 561.2 [M+H]+ .

[0171] The crude product was dissolved in 10 mL of glacial acetic acid and then stirred in an oil bath at 65 °C for 12 h. After concentration to remove acetic acid, the crude product was separated by column chromatography (DCM / MeOH = 10 / 1) to give the intermediate 6-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazole (370 mg), yield 79%. ESI-MS m / z = 523.2 [M+H] + .

[0172] Step 2: Dissolve 6-bromo-2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzis[d]imidazole (200 mg, 0.383 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxoborane (76 mg, 0.498 mmol) in a 1:1 mixture of 1,4-dioxane / water (20 ml). Add cesium carbonate (249 mg, 0.766 mol). Under nitrogen protection, add Pd(dppf)Cl2 (28 mg, 0.038 mmol) and stir at 80 °C until the starting material disappears (4 h). Add 10 mL of water, then extract twice with ethyl acetate. Wash the resulting organic phase with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. Separate the crude product by column chromatography (PE / EQ = 3 / 1) to give compound 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-6-vinyl-1H-benzo[d]imidazole (110 mg), yield 61%. ESI-MS m / z = 471.2 [M+H] + .

[0173] Step 3: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-6-vinyl-1H-benzis[d]imidazole (50 mg, 0.106 mmol) was dissolved in tBuOH / H2O (1:1, 2 mL), followed by the addition of AD-mix-alpha (150 mg). The reaction mixture was stirred at room temperature for 12 h, then 20 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH = 10 / 1) to give compound 17 (20 mg), yield 37%. 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),7.62&7.55(d,J=6.4Hz,1H),7.31&7.22(d,J= 10.2Hz,1H),7.16–7.05(m,2H),5.69(d,J=11.0Hz,1H),5.39&5.31(d,J=4.6Hz,1H) ,4.92–4.83(m,1H),4.81–4.73(m,1H),4.55–4.43(m,1H),3.97(s,3H),3.55–3.44( m,1H),3.42–3.36(m,1H),2.87(p,J=7.3Hz,1H),1.65(s,3H),0.80(d,J=7.3Hz,3H). ESI-MSm / z=505.2[M+H] + .

[0174] Example 18: Preparation of Compound 18 (R)-1-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxybenzene) 2-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)ethane-1,2- Diol (18)

[0175]

[0176] 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-6-vinyl-1H-benzis[d]imidazole (50 mg, 0.106 mmol) was dissolved in tBuOH / H2O (1:1, 2 mL), followed by the addition of AD-mix-beta (150 mg). The reaction mixture was stirred at room temperature for 12 h, then 20 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM / MeOH = 10 / 1) to give compound 18 (22 mg), yield 41%. 1 H NMR(400MHz, DMSO-d6)δ12.67(s,1H),7.61&7.55(d,J=6.4Hz,1H),7.31&7.22(d, J=11.0Hz,1H),7.16–7.04(m,2H),5.70(d,J=11.1Hz,1H),5.40&5.29(d,J=4.8Hz ,1H),4.93–4.82(m,1H),4.81–4.73(m,1H),4.53–4.42(m,1H),3.97(d,J=2.1Hz, 3H), 3.54–3.35 (m, 2H), 2.88 (p, J = 7.5Hz, 1H), 1.65 (s, 3H), 0.80 (d, J = 6.3Hz, 3H). ESI-MS m / z=505.2[M+H] + .

[0177] Example 19: Preparation of Compound 19 (R)-3-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy) phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)oxy)propane Alkane-1,2-diol (19)

[0178]

[0179] (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (114 mg, 0.322 mmol) and (S)-4-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-5-fluorobenzene-1,2-diamine (80 mg, 0.312 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (83 mg, 0.643 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 244 mg, 0.643 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared (2 h), then 50 mL of water was added. The mixture was then extracted twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. ESI-MS m / z = 593.3 [M+H] + .

[0180] The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in an oil bath at 100 °C for 30 min. Acetic acid was removed by concentration, and the crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 19 (28 mg), yield 16%. 1 H NMR (400MHz, DMSO-d6) δ12.62&12.61(s,1H),7.43&7.34(d,J=11.3Hz,1H),7.31&7.16(d, J=7.7Hz,1H),7.12–7.06(m,2H),5.67(d,J=11.1Hz,1H),5.04&4.98(d,J=5.2Hz,1H),4.7 3&4.69(t,J=5.6Hz,0H),4.54–4.45(m,1H),4.11–4.01(m,1H),3.99–3.89(m,4H),3.87–3 .78(m,1H),3.50–3.43(m,2H),2.87(p,J=7.3Hz,1H),1.64(s,3H),0.79(d,J=6.5Hz,3H). ESI-MS m / z=535.2[M+H] + .

[0181] Example 20: Preparation of Compound 20 (R)-3-((2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy) phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-1H-imidazo[4,5-c]pyridin-6-yl)oxy)propane Alkane-1,2-diol (20)

[0182]

[0183] Step 1: Dissolve (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (135 mg, 0.381 mmol) and (S)-6-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)pyridine-3,4-diamine (90 mg, 0.381 mmol) in anhydrous N,N-dimethylformamide (6 mL), then add N,N-diisopropylethylamine (98 mg, 0.759 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 286 mg, 0.752 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared (2 h), then 20 mL of water was added. The mixture was subsequently extracted twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. ESI-MS m / z = 576.3 [M+H] + .

[0184] Step 2: The crude intermediate obtained in the previous step was dissolved in isopropanol (5 mL), followed by the addition of potassium tert-butoxide (42.6 mg, 0.381 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared (2 h), and then concentrated to obtain the crude product 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-(((R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1H-imidazo[4,5-c]pyridine, which was directly used for the next step of the reaction. ESI-MS m / z = 558.3 ​​[M+H] + .

[0185] Step 3: 2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-6-(((R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-1H-imidazo[4,5-c]pyridine was dissolved in tetrahydrofuran (20 mL), followed by the addition of 1N hydrochloric acid (4.6 mL, 4.6 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared (2 h), then 30 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 20 (110 mg), with an overall yield of 56% for the three steps. 1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),8.46(s,1H),7.20–7.04(m,2H),6.78(s,1H),5.70(d,J =11.1Hz,1H),4.88(d,J=5.1Hz,1H),4.62(t,J=5.7Hz,1H),4.46(dd,J=11.1,7.6Hz,1H),4.26 (dd,J=10.8,4.4Hz,1H),4.14(dd,J=10.8,6.4Hz,1H),3.96(d,J=2.1Hz,3H),3.79(h,J=5.5H z, 1H), 3.43 (td, J = 5.7, 1.7Hz, 2H), 2.88 (p, J = 7.5Hz, 1H), 1.65 (s, 3H), 0.79 (d, J = 6.3Hz, 3H). ESI-MS m / z=518.3[M+H] + .

[0186] Example 21: Preparation of compound 21

[0187] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoro) Methyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-carboxamide (21)

[0188]

[0189] Step 1: (2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (CN118388466) (350 mg, 0.90 mmol) and 4,5-diamino-2-fluorobenzonitrile (162 mg, 1.1 mmol) were dissolved in anhydrous N,N-dimethylformamide (10 mL), followed by the addition of N,N-diisopropylethylamine (231 mg, 1.8 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 682 mg, 1.8 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared, then 50 mL of water was added, followed by extraction twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 6 mL of glacial acetic acid and then stirred in a 100°C oil bath. After the starting material disappeared as monitored by TLC, the mixture was concentrated to remove acetic acid. The crude product was then separated by column chromatography (PE / EA = 5 / 1) to give intermediate 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-nitrile (387 mg), with a yield of 91%. 1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),8.27–8.06(m,1H),7.79–7.54(m,1H),7.47–7.35(m,2H),5.85(d, J=10.9Hz, 1H), 4.45 (dd, J=11.0, 7.6Hz, 1H), 2.87 (p, J=7.5Hz, 1H), 1.64 (s, 3H), 0.84 (d, J= 6.3Hz, 3H). ESI-MS m / z=507.2[M+H] + .

[0190] Step 2: 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (80 mg, 0.158 mmol) was dissolved in 2 mL of dimethyl sulfoxide, and potassium carbonate (400 mg, 2.9 mmol) and 30% hydrogen peroxide (2.5 mL) were added. The mixture was stirred at room temperature for 12 h. After the reaction starter disappeared as monitored by TLC, 30 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 20 / 1) to give compound 21 (71 mg), yield 85%. 1 H NMR (400MHz, DMSO-d6) δ12.94&12.92(s,1H),7.88–7.77(m,1H),7.65–7.31(m,5H),5.82&5.80(d,J= 10.8Hz, 1H), 4.47 (dd, J = 10.9, 7.6Hz, 1H), 2.87 (p, J = 7.5Hz, 1H), 1.64 (s, 3H), 0.84 (d, J = 6.4Hz, 3H). ESI-MS m / z=525.2[M+H] + .

[0191] Example 22: Preparation of compounds 22-a and 22-b

[0192] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoro) (22-a)-(E / Z)-tetrahydrofuran-2-yl)-5-fluoro-N-hydroxy-1H-benzo[d]imidazol-6-carboximide (22-a) and (E / Z)-2- ((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydro (2-furan-2-yl)-5-fluoro-N,N'-dihydroxy-1H-benzo[d]imidazol-6-carboximide (22-b)

[0193]

[0194] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (80 mg, 0.158 mmol) was dissolved in methanol (10 mL), and hydroxylamine hydrochloride (98 mg, 1.4 mmol) and triethylamine (95 mg, 0.95 mmol) were added. The reaction system was stirred in an oil bath at 65 °C for 15 h. After concentrating the reaction solution to remove volatiles, it was dissolved in ethyl acetate (50 mL), and then washed successively with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 15 / 1) to give compound 22-a (39 mg, yield 46%) and compound 22-b (8 mg, yield 9%).

[0195] Compound 22-a: 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),9.57&9.52(s,1H),7.62&7.55(d,J=6.3Hz,1H),7.47–7.30(m,3H),5.83– 5.74 (m, 3H), 4.46 (dd, J = 10.9, 7.5Hz, 1H), 2.87 (p, J = 7.5Hz, 1H), 1.65 (d, J = 2.2Hz, 3H), 0.84 (d, J = 6.4Hz, 3H). ESI-MS m / z=540.2[M+H] + Compound 22-b: ESI-MS m / z = 556.2 [M+H] + .

[0196] Example 23: Preparation of compound 23

[0197] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoro) (23)Methyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-carboximide

[0198]

[0199] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (100 mg, 0.198 mmol) was dissolved in anhydrous methanol (2 mL) and cooled in an ice-water bath, followed by the introduction of hydrogen chloride gas (10 min). The reaction mixture was stirred in the ice-water bath until the starting material disappeared (approximately 2 h), then the solvent was removed under reduced pressure, and NH3 (7N in MeOH, 3 mL) was added. The mixture was reacted in an oil bath at 40 °C until the intermediate disappeared. 10 mL of water was added to the reaction mixture, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 23 (36 mg), yield 35%. 1 H NMR(400MHz,DMSO-d6)δ13.41(s,1H),9.35(s,3H),7.91(s,1H),7.61(s,1H),7.48–7.35(m,2H),5.86(d ,J=10.9Hz,1H),4.50(dd,J=10.9,7.5Hz,1H),2.87(p,J=7.5Hz,1H),1.66(s,3H),0.85(d,J=6.9Hz,3H). ESI-MS m / z=524.2[M+H] + .

[0200] Example 24: Preparation of compound 24

[0201] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoro) Methyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-sulfonamide (24)

[0202]

[0203] (2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (70 mg, 0.18 mmol) and 4,5-diamino-2-fluorobenzenesulfonamide (41 mg, 0.18 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (46 mg, 0.36 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 137 mg, 0.36 mmol). The reaction mixture was stirred at room temperature for 2 h until the starting material disappeared, then 50 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in an oil bath at 100 °C for 30 min. After the starting material disappeared as monitored by TLC, the mixture was concentrated to remove acetic acid. The crude product was then separated by preparative TLC (PE / EA = 4 / 1 to 1 / 1) to give compound 24 (55 mg), with a yield of 55%. 1 H NMR(400MHz, DMSO-d6)δ13.10(s,1H),7.93(d,J=6.4Hz,1H),7.55(s,3H),7.47–7.36(m,2H),5.84(d,J =10.8Hz, 1H), 4.46 (dd, J = 10.9, 7.6Hz, 1H), 2.87 (p, J = 7.5Hz, 1H), 1.65 (s, 3H), 0.84 (d, J = 6.4Hz, 3H). ESI-MS m / z=561.1[M+H] + .

[0204] Example 25: Preparation of Compound 25 (R)-3-((2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)- (3,4-Difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl) (25)propane-1,2-diol

[0205]

[0206] (2R,3S,4S,5R)-3-(2-(difluoromethoxy-d)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (100 mg, 0.26 mmol) and (S)-4-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-5-fluorobenzene-1,2-diamine (78 mg, 0.30 mmol) were dissolved in anhydrous N,N-dimethylformamide (6 mL), followed by the addition of N,N-diisopropylethylamine (66 mg, 0.51 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 194 mg, 0.51 mmol). After stirring the reaction mixture at room temperature until the starting material disappeared (2 h), 50 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in an oil bath at 100 °C for 30 min. Acetic acid was removed by concentration, and the crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 25 (38 mg), with a yield of 26%. 1 H NMR (400MHz, DMSO-d6) δ12.59(s,1H),7.47–7.10(m,4H),5.74(d,J=10.9Hz,1H),5.08–4.90(m,1H),4.78–4.62(m,1H),4.49(dd,J=10.6,7.6H z,1H),4.13–4.02(m,1H),4.00–3.89(m,1H),3.88–3.77(m,1H),3.54– 3.42(m,2H),2.86(p,J=7.3Hz,1H),1.63(s,3H),0.83(d,J=6.2Hz,3H). ESI-MS m / z=572.2[M+H] + .

[0207] Example 26: Preparation of Compound 26 (R)-3-((2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3, (4-Difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)oxy (26) propane-1,2-diol

[0208]

[0209] (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (WO2021113627A1) (160 mg, 0.41 mmol) and (S)-4-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-5-fluorobenzene-1,2-diamine (158 mg, 0.61 mmol) were dissolved in anhydrous N,N-dimethylformamide (8 mL), followed by the addition of triethylamine (82 mg, 0.82 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 311 mg, 0.82 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared. 50 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 8 mL of glacial acetic acid and then stirred in a 100°C oil bath for 30 min. Acetic acid was removed by concentration. The crude product was then separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 26 (66 mg), with a yield of 28%. 1 H NMR(400MHz,DMSO-d6)δ12.60&12.58(s,1H),7.51–7.27(m,4H),7.19–7.11(m ,1H),5.73(d,J=11.0Hz,1H),5.05–4.93(m,1H),4.74–4.62(m,1H),4.49(dd, J=11.0,7.5Hz,1H),4.13–4.03(m,1H),3.98–3.89(m,1H),3.87–3.76(m,1H), 3.52–3.42(m,2H),2.86(p,J=7.5Hz,1H),1.63(s,3H),0.83(d,J=6.7Hz,3H). ESI-MS m / z = 571.2 [M+H] + .

[0210] Example 27: Preparation of Compound 27

[0211] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl) (27) Tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-carboxamide

[0212]

[0213] Step 1: (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (500 mg, 1.28 mmol) and 4,5-diamino-2-fluorobenzonitrile (151 mg, 1.54 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of triethylamine (260 mg, 2.56 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 977 mg, 2.56 mmol). The reaction mixture was stirred at room temperature for 2 h, then 50 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 10 mL of glacial acetic acid and then stirred in an oil bath at 100 °C for 1 h. After the starting material disappeared as monitored by TLC, the mixture was concentrated to remove acetic acid. The crude product was then separated by column chromatography (PE / EA = 3 / 1) to obtain intermediate 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-nitrile (560 mg), with a yield of 87%. 1 H NMR (400MHz, DMSO-d6) δ13.32(s,1H),8.28–8.05(m,1H),7.76–7.57(m,1H),7.45–7.35(m,2H),7.28(t,J=72.2Hz,1 H), 5.85 (d, J = 10.9Hz, 1H), 4.46 (dd, J = 10.9, 7.6Hz, 1H), 2.87 (p, J = 7.5Hz, 1H), 1.64 (s, 3H), 0.84 (d, J = 6.4Hz, 3H). ESI-MS m / z=506.2[M+H] + .

[0214] Step 2: 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (80 mg, 0.158 mmol) was dissolved in 2 mL of dimethyl sulfoxide, and potassium carbonate (218 mg, 1.58 mmol) and 30% hydrogen peroxide (2 mL) were added. The mixture was stirred at room temperature for 12 h. After the reaction starter disappeared as monitored by TLC, 30 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 20 / 1) to give compound 27 (76 mg), yield 91%.1 H NMR (400MHz, DMSO-d6) δ12.94&12.91(s,1H),7.85&7.80(d,J=6.4Hz,1H),7.64–7.33(m,5H),7.30(t,J=72.2Hz, 1H),5.82&5.80(d,J=11.2Hz,1H),4.52–4.43(m,1H),2.87(p,J=7.5Hz,1H),1.64(s,3H),0.84(d,J=6.6Hz,3H). ESI-MS m / z=524.2[M+H] + .

[0215] Example 28: Preparation of Compound 28

[0216] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl) (28) Tetrahydrofuran-2-yl)-5-fluoro-N-hydroxy-1H-benzo[d]imidazol-6-carboximide

[0217]

[0218] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (120 mg, 0.24 mmol) was dissolved in ethanol (5 mL), and 50% hydroxylamine aqueous solution (1 mL) was added. The mixture was refluxed for 2 h. The volatiles were removed by concentration, and the crude product was separated by preparative TLC (DCM / MeOH = 15 / 1) to give compound 28 (87 mg), yield 68%. 1 H NMR (400MHz, DMSO-d6) δ12.82(s,1H),9.57&9.53(s,1H),7.62&7.55(d,J=6.3Hz,1H),7.49–7.30(m,3H),7.30(t,J=72 .2Hz,1H),5.87–5.70(m,3H),4.46(dd,J=11.0,7.5Hz,1H),2.87(p,J=7.6Hz,1H),1.65(s,3H),0.84(d,J=6.3Hz,3H). ESI-MS m / z=539.2[M+H] + .

[0219] Example 29: Preparation of compound 29

[0220] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl) (29) Tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-carboximide

[0221]

[0222] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazolium-6-onitrile (100 mg, 0.198 mmol) was dissolved in anhydrous methanol (2 mL) and cooled in an ice-water bath, followed by the introduction of hydrogen chloride gas (10 min). The reaction mixture was stirred in the ice-water bath until the starting material disappeared (approximately 2 h), then the solvent was removed under reduced pressure, and NH3 (7N in MeOH, 2 mL) was added. The mixture was reacted in an oil bath at 40 °C until the intermediate disappeared. 10 mL of water was added to the reaction mixture, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 29 (47 mg), yield 45%. 1 H NMR(400MHz, DMSO-d6)δ9.39(s,3H),7.90(d,J=6.1Hz,1H),7.60(d,J=10.7Hz,1H),7.47–7.35(m,2H),7.32(t,J= 72.3Hz, 1H), 5.85 (d, J = 10.9Hz, 1H), 4.57–4.45 (m, 1H), 2.87 (p, J = 7.5Hz, 1H), 1.66 (s, 3H), 0.85 (d, J = 6.2Hz, 3H). ESI-MS m / z=523.2[M+H] + .

[0223] Example 30: Preparation of compound 30

[0224] 2-((2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl) (30) Tetrahydrofuran-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-sulfonamide

[0225]

[0226] (2R,3S,4S,5R)-3-(2-(difluoromethoxy)-3,4-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (79 mg, 0.20 mmol) and 4,5-diamino-2-fluorobenzenesulfonamide (42 mg, 0.20 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of N,N-diisopropylethylamine (52 mg, 0.40 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 195 mg, 0.51 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared, then 50 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in an oil bath at 100 °C for 30 min. After the starting material disappeared as monitored by TLC, the mixture was concentrated to remove acetic acid. The crude product was then separated by preparative TLC (PE / EA = 4 / 1 to 1 / 1) to give compound 30 (58 mg), with a yield of 51%. 1 H NMR (400MHz, DMSO-d6) δ13.14&13.07(s,1H),7.95&7.92(d,J=6.4Hz,1H),7.68–7.35(m,5H),7.28(t,J=72.1Hz, 1H),5.87&5.82(d,J=10.9Hz,1H),4.51–4.41(m,1H),2.87(p,J=7.6Hz,1H),1.65(s,3H),0.84(d,J=6.6Hz,3H). ESI-MS m / z=560.1[M+H] + .

[0227] Example 31: Preparation of compounds 31-a and 31-b (R)-3-((2-((2R,3S,4S,5R)-3-(3,4-difluoro- (2-Methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl) (31-a)propane-1,2-diol and (R)-3-((2-((2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)- 4,5-Dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)oxy)propane-1,2- Diol (31-b)

[0228]

[0229] A mixture of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid and (2S,3R,4R,5S)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrothiophene-2-carboxylic acid (prepared using the method disclosed in Example 2 of WO2024146632) (100 mg, 0.27 mm) (ol) and (S)-4-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-5-fluorobenzene-1,2-diamine (77 mg, 0.30 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of triethylamine (55 mg, 0.54 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 205 mg, 0.54 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared, then 30 mL of water was added, followed by extraction with ethyl acetate (10 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in a 100 °C oil bath for 30 min. Acetic acid was removed by concentration, and the crude product was preparatively separated by TLC (DCM / MeOH = 10 / 1) to give a mixture of compounds 31-a and 31-b (56 mg), in 38% yield. ESI-MS m / z = 551.2 [M+H] + .

[0230] Example 32: Preparation of compound 32 (R)-3-(re-(2-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxy) (2-(trifluoromethyl)tetrahydrothiophene-2-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)oxy) Propane-1,2-diol (32)

[0231]

[0232] re-(2R,3S,3aS,6aR)-3-(3,4-difluoro-2-methoxyphenyl)-6,6-difluoro-6a-methylhexahydro-2H-cyclopentathiophene-2-carboxylic acid (prepared according to the method disclosed in Example 2 of WO2024217528) (83 mg, 0.228 mmol) and (S)-4-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-5-fluorophenyl-1,2-diamine (59 mg, 0.228 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of triethylamine (46 mg, 0.46 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 175 mg, 0.46 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared. 30 mL of water was added, followed by extraction with ethyl acetate (15 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in a 100°C oil bath for 30 min. Acetic acid was removed by concentration. The crude product was then separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 32 (55 mg), yield 44%. ESI-MS m / z = 545.3 [M + H]. + .

[0233] Example 33: Preparation of compound 33 (R)-3-(re-(2-((1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxy) (3.2.0)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]hept-3-yl)-5-fluoro-1H-benzo[d]imidazol-6- 1,2-propane-1,2-diol (33)

[0234]

[0235] re-(1R,3R,4S,5R)-4-(3,4-difluoro-2-methoxyphenyl)-5-methyl-1-(trifluoromethyl)-2-oxabicyclo[3.2.0]heptane-3-carboxylic acid (prepared according to the method disclosed in Example 85 of WO2024046253) (65 mg, 0.176 mmol) and (S)-4-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-5-fluorobenzene-1,2-diamine (54 mg, 0.212 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL), followed by the addition of triethylamine (36 mg, 0.35 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 81 mg, 0.212 mmol). The reaction mixture was stirred at room temperature until the starting material disappeared. 30 mL of water was added, followed by extraction with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was dissolved in 5 mL of glacial acetic acid and then stirred in a 100°C oil bath until the starting material disappeared. Acetic acid was removed by concentration. The crude product was then separated by preparative TLC (DCM / MeOH = 10 / 1) to give compound 33 (24 mg), yield 25%. ESI-MS m / z = 547.2 [M+H] + .

[0236] Compounds 34-39 of the following examples were synthesized according to the methods of Examples 1-33.

[0237]

[0238]

[0239] Preparation of intermediate A

[0240]

[0241] 4-Bromo-5-fluorobenzodiamine (3.0 g, 14.778 mmol) was dissolved in DMF (50 mL), and Pd(PPh3) (850 mg, 0.735 mmol) and Zn(CN)2 (3.42 g, 29.230 mmol) were added. The reaction was carried out at 120 °C for 12 h. After the reactants disappeared as monitored by TLC, 150 mL of water was added, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by column chromatography (PE:EA = 5 / 1) to give 4-bromo-5-fluorobenzodiamine (900 mg) in 41% yield. ESI-MS m / z = 152.1 [M+H] + .

[0242] Preparation of intermediate B

[0243]

[0244] Step 1: 4-Bromo-5-fluorophenyl-1,2-diamine (0.5 g, 2.44 mmol) and di-tert-butyl dicarbonate (2.66 g, 12.2 mmol) were dissolved in ethanol (10 mL), and Amberlyst 15(H) acidic resin (1.0 g) was added. The reaction mixture was stirred at room temperature for 80 h, and the solid was removed by filtration. The filtrate was concentrated to obtain a crude product, which was then subjected to column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain di-tert-butyl(4-bromo-5-fluoro-1,2-phenyl)dicarbamate (0.84 g), with a yield of 84%. 1 H NMR (400MHz, DMSO-d6) δ 8.75 (s, 1H), 8.71 (s, 1H), 7.75 (d, J = 7.4Hz, 1H), 7.62 (d, J = 10.9Hz, 1H), 1.48 (s, 9H), 1.47 (s, 9H).

[0245] Step 2: Di-tert-butyl(4-bromo-5-fluoro-1,2-phenyl)dicarbamate (500 mg, 1.23 mmol), methyl 2-3-mercaptopropionate (163 mg, 1.34 mmol), Pd2(dba)3 (112 mg, 0.12 mmol), and Xantphos (143 mg, 0.24 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen three times. Then, N,N-diisopropylethylamine (480 mg, 3.7 mmol) was added. The reaction mixture was stirred in an oil bath at 100 °C for 3 h, cooled to room temperature, and concentrated. The crude product was then subjected to column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain methyl 3-((4,5-bis((tert-butoxycarbonyl)amino)-2-fluorophenyl)thio)propionate (0.51 g), with a yield of 94%. 1 H NMR(400MHz,Chloroform-d)δ7.62(d,J=10.2Hz,1H),7.38(d,J=7.4Hz,1H),7.02(s,1H),6. 36 (s, 1H), 3.69 (s, 3H), 3.10 (t, J = 7.3Hz, 2H), 2.61 (t, J = 7.3Hz, 2H), 1.53 (d, J = 1.7Hz, 18H).

[0246] Step 3: Methyl 3-((4,5-bis((tert-butoxycarbonyl)amino)-2-fluorophenyl)thio)propionate (0.75 g, 1.68 mmol) was dissolved in tetrahydrofuran (10 mL), and potassium tert-butoxide (566 mg, 5.0 mmol) was added under cooling in an ice-water bath. The reaction mixture was stirred at 0 °C for 30 min, diluted with ethyl acetate (10 mL), and then the pH was adjusted to 6-7. The mixture was separated. The aqueous phase was extracted once with ethyl acetate (20 mL), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated to obtain crude product, and subjected to column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain di-tert-butyl(4-fluoro-5-mercapto-1,2-phenyl)dicarbamate (0.34 g), yield 55%. 1 H NMR (400MHz, DMSO-d6) δ8.58(s,1H),8.53(s,1H),7.52(d,J=8.1Hz,1H),7.42(d,J=11.3Hz,1H),5.53(s,1H),1.47(s,18H).

[0247] Di-tert-butyl(4-fluoro-5-mercapto-1,2-phenyl)dicarbamate (0.32 g, 0.89 mmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (238 mg, 1.72 mmol) was added. The reaction solution was stirred at room temperature for 10 min, filtered, concentrated, and subjected to column chromatography (PE / EA = 5 / 1) to obtain di-tert-butyl(4-fluoro-5-(methylthio)-1,2-phenyl)dicarbamate (0.33 g), with a yield of 99%. 1 H NMR (400MHz, Chloroform-d) δ7.51 (s, 1H), 7.32 (d, J = 7.5Hz, 1H), 6.84 (s, 1H), 6.39 (s, 1H), 2.45 (s, 3H), 1.53 (s, 18H).

[0248] Step 4: Di-tert-butyl(4-fluoro-5-(methylthio)-1,2-phenyl)dicarbamate (200 mg, 0.54 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of m-chloroperoxybenzoic acid (272 mg, 1.34 mmol, 85%). The reaction mixture was stirred at room temperature for 12 h, then diluted with dichloromethane (20 mL), followed by washing with saturated sodium bicarbonate, saturated sodium thiosulfate, and saturated sodium chloride sequentially. Finally, the solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative column chromatography (PE / EA = 5 / 1–2 / 1) to obtain di-tert-butyl(4-fluoro-5-(methylsulfinyl)-1,2-phenyl)dicarbamate (203 mg), with a yield of 97%. 1H NMR (400MHz, Chloroform-d) δ7.87 (d, J = 11.6 Hz, 1H), 7.64 (d, J = 6.9 Hz, 1H), 7.44 (s, 1H), 6.66 (s, 1H), 2.83 (s, 3H), 1.54 (d, J = 1.1 Hz, 18H).

[0249] Step 5: Di-tert-butyl(4-fluoro-5-(methylsulfinyl)-1,2-phenyl)dicarbamate (190 mg, 0.49 mmol) was dissolved in dichloromethane (4 mL), followed by trifluoroacetic acid (1 mL). The reaction mixture was stirred at 38 °C for 2 h, concentrated, and subjected to preparative column chromatography (DCM / MeOH = 10 / 1) to give 4-fluoro-5-(methylsulfinyl)phenyl-1,2-diamine (45 mg), yield 49%. ESI-MS m / z = 189.2 [M+H] + .

[0250] Preparation of intermediate C

[0251]

[0252] Step 1: Di-tert-butyl(4-fluoro-5-(methylthio)-1,2-phenyl)dicarbamate (200 mg, 0.54 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of m-chloroperoxybenzoic acid (660 mg, 3.24 mmol, 85%). The reaction mixture was stirred at room temperature for 18 h, then diluted with dichloromethane (20 mL), followed by washing with saturated sodium bicarbonate, saturated sodium thiosulfate, and saturated sodium chloride sequentially. Finally, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to preparative column chromatography (PE / EA = 5 / 1–2 / 1) to obtain di-tert-butyl(4-fluoro-5-(methylsulfonyl)-1,2-phenyl)dicarbamate (180 mg), yield 83%. ESI-MS m / z = 405.3 [M+H] + .

[0253] Step 2: 160 mg (0.40 mmol) of tert-butyl(4-fluoro-5-(methylsulfonyl)-1,2-phenyl)dicarbamate was dissolved in dichloromethane (4 mL), followed by trifluoroacetic acid (1 mL). The reaction mixture was stirred at 38 °C for 2 h, concentrated, and subjected to preparative column chromatography (DCM / MeOH = 50 / 1) to obtain 60 mg (4-fluoro-5-(methylsulfonyl)phenyl-1,2-diamine) in 74% yield. 1H NMR (400MHz, DMSO-d6) δ6.89 (d, J = 7.2 Hz, 1H), 6.41 (d, J = 12.5 Hz, 1H), 5.73 (s, 2H), 4.75 (s, 2H). ESI-MS m / z=205.2[M+H] + .

[0254] Preparation of intermediate D

[0255]

[0256] Di-tert-butyl(4-fluoro-5-(methylthio)-1,2-phenyl)dicarbamate (500 mg, 1.24 mmol) was dissolved in dichloromethane (10 mL), followed by trifluoroacetic acid (2.5 mL). The reaction mixture was stirred at 38 °C for 2 h, concentrated, and subjected to preparative column chromatography (DCM / MeOH = 50 / 1) to give 4-fluoro-5-(methylsulfonyl)phenyl-1,2-diamine (142 mg), yield 61%. ESI-MS m / z = 173.2 [M+H] + .

[0257] Preparation of intermediate E

[0258]

[0259] Step 1: 5-Fluoro-2-nitroaniline (2 g, 12.8 mmol) was slowly added to chlorosulfonic acid (10 mL) and stirred at 120 °C for 4 h. After the reactants disappeared as monitored by TLC, 40 mL of water was slowly added to the reaction system, followed by extraction twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product 4-amino-2-fluoro-5-nitrobenzenesulfonyl chloride. The obtained crude product was added to a methanol solution of ammonia (10 mL, 7 M) and stirred at room temperature. After the reactants disappeared as monitored by TLC, the mixture was concentrated to remove volatiles. The obtained crude product was slurried and filtered with DCM:MeOH = 10:1 to obtain compound 4-amino-2-fluoro-5-nitrobenzenesulfonamide (1.4 g), yield 46%. ESI-MS m / z = 236.1 [M+H] + .

[0260] Step 2: 4-Amino-2-fluoro-5-nitrobenzenesulfonamide (700 mg, 2.978 mmol) was dissolved in 20 mL of EA, and 10% Pd / C (700 mg) was added. The mixture was then stirred at room temperature under a hydrogen atmosphere for 6 h. After the reaction was complete, the crude product was filtered off, and 4-amino-2-fluoro-5-nitrobenzenesulfonamide (460 mg) was obtained by column chromatography (DCM / MeOH = 10 / 1), with a yield of 76%. ESI-MS m / z = 206.2 [M+H] + .

[0261] Preparation of intermediate F

[0262]

[0263] Step 1: 2,4-Dichloro-5-nitropyridine (5.0 g, 26.2 mmol) was dissolved in ammonia-methanol solution (7 N, 26 mL). After stirring at room temperature for 1 h, the solution was concentrated to remove volatiles. Water was then added and the mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. Ethyl acetate (10 mL) was then added, and the mixture was heated. Petroleum ether (10 mL) was then added, and the mixture was stirred at room temperature to precipitate a solid. The solid was filtered to give 2-chloro-5-nitropyridine-4-amine (3.6 g), with a yield of 80%. 1 HNMR (400MHz, DMSO-d6) δ8.83(s,1H),8.38(s,1H),8.00(s,1H),7.05(s,1H).

[0264] Step 2: Dissolve 2-chloro-5-nitropyridine-4-amine (2.0 g, 26.2 mmol) in N,N-dimethylformamide (20 mL), and add 8 mL of 20% sodium methanethiol aqueous solution. The reaction mixture was stirred at 80 °C for 8 h, then cooled to room temperature. Water was added, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phase was washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to column chromatography (PE / EA = 5 / 1–2 / 1) to give 1.4 g of 2-(methylthio)-5-nitropyridine-4-amine, with a yield of 66%. 1 H NMR (600MHz, DMSO-d6) δ8.87(s,1H),7.84(s,2H),6.71(s,1H),2.48(s,3H).

[0265] Step 3: Dissolve 2-(methylthio)-5-nitropyridine-4-amine (500 mg, 2.7 mmol) in ethyl acetate (20 mL), and add 20% Pd(OH)₂ / C (400 mg, 50% purity). The reaction mixture was stirred at 50 °C for 6 h, then cooled to room temperature and filtered. The crude product was subjected to column chromatography (PE / EA = 5 / 1–2 / 1) to give 6-(methylthio)pyridine-3,4-diamine (163 mg), yield 39%. ESI-MS m / z = 156.1 [M+H] + .

[0266] Preparation of intermediate G

[0267]

[0268] Step 1: 4,5-Difluoro-2-nitroaniline (4 g, 22.988 mmol) was dissolved in methanol (80 mL), and KOH (24 mL, 2 M) was added. The mixture was stirred at room temperature. After the reactants disappeared as monitored by TLC, 50 mL of water was slowly added to the reaction mixture. The mixture was then extracted twice with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. 4-fluoro-5-methoxy-2-nitroaniline (4.1 g) was obtained by column chromatography, with a yield of 95%. ESI-MS m / z = 187.2 [M+H] + .

[0269] Step 2: 4-Fluoro-5-methoxy-2-nitroaniline (4.6 g, 24.73 mmol) was dissolved in dichloromethane (100 mL), and aluminum trichloride (14 g, 105.26 mmol) was added. The mixture was stirred at 40 °C for 12 h. After the reaction starter disappeared as monitored by TLC, the reaction mixture was slowly added to a 100 g ice-water mixture. The mixture was then extracted twice with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was obtained by slurry mixing with DCM (46 mL, 10 V) to yield 5-amino-2-fluoro-4-nitrophenol (3.65 g), with a yield of 86%. ESI-MS m / z = 173.1 [M+H] + .

[0270] Step 3: A mixture of DIAD (2.2 g, 10.89 mmol) and (S)-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methanol (1.13 g, 8.56 mmol) was dissolved in toluene (10 mL) and slowly added dropwise to a toluene (10 mL) solution of 5-amino-2-fluoro-4-nitrophenol (1.26 g, 7.32 mmol) and triphenylphosphine (2.83 g, 10.80 mmol). After the reaction mixture disappeared under TLC monitoring, the solution was directly concentrated to obtain the crude product. The crude product was separated by column chromatography (DCM:MeOH = 10:1) to obtain compound (S)-5-((2,2-dimethyl-1,3-dioxacyclopentan-4-yl)methoxy)-4-fluoro-2-nitroaniline (2.1 g), yield 61%. ESI-MS m / z = 287.2 [M+H] + .

[0271] Step 4: (S)-5-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-4-fluoro-2-nitroaniline (2.1 g, 7.317 mmol) was dissolved in 10 mL of EA, and 10% Pd / C (1 g) was added. The mixture was then stirred at room temperature under a hydrogen atmosphere for 6 h. After the reaction starter disappeared as monitored by TLC, the crude product was filtered off and separated by column chromatography (DCM / MeOH = 10 / 1) to obtain (S)-4-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-5-fluorobenzene-1,2-diamine (1.5 g), yield 66%. ESI-MS m / z = 257.3 [M+H] + .

[0272] Preparation of intermediate H

[0273]

[0274] Step 1: (S)-(2,2-dimethyl-1,3-dioxolane-4-yl)methanol (1.52 g, 11.5 mmol) was dissolved in N-methylpyrrolidone (20 mL). The solution was cooled to 0 °C under a nitrogen atmosphere, and NaH (460 mg, 11.5 mmol, 60% purity) was slowly added while stirring in an ice bath for 30 min. Then, 2-chloro-5-nitropyridine-4-amine (1 g, 5.8 mmol) was added. The mixture was transferred to 100 °C and reacted for 12 h. After the reaction starter disappeared as monitored by TLC, the crude product was obtained by diatomaceous earth filtration. The crude product (470 mg) was obtained by column chromatography (DCM / MeOH = 10 / 1), yielding (S)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-5-nitropyridine-4-amine (470 mg), with a yield of 20%. ESI-MS m / z = 270.2 [M+H] + .

[0275] Step 2: (S)-2-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-5-nitropyridine-4-amine (1 g, 3.72 mmol) was dissolved in 10 mL of ethyl acetate, and 10% Pd / C (0.5 g) was added. The mixture was then stirred at room temperature under a hydrogen atmosphere for 6 h. After the reaction starter disappeared as monitored by TLC, the crude product was filtered off and separated by column chromatography (DCM / MeOH = 10 / 1) to obtain 6-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)pyridine-3,4-diamine (533 mg), yield 60%. ESI-MS m / z = 240.2 [M+H] + .

[0276] Biological evaluation

[0277] Test Example 1: Nav1.8 Manual Patch Clamp Test

[0278] Experimental objective: To test the inhibitory / blocking activity of the compounds of this invention on sodium ion channel 1.8 (Nav1.8).

[0279] Detection method: Whole-cell manual patch-clamp technique was used to detect the effect of compounds on the Nav1.8 channel current.

[0280] 1. Preparation and analysis of the detected compounds

[0281] Control: Electrophysiological extracellular fluid containing 0.5% DMSO

[0282] Test Compound: Weigh a certain mass of the compound and dissolve it in dimethyl sulfoxide (DMSO) to prepare a 20 mM DMSO stock solution. On the day of testing, serially dilute the 20 mM stock solution with extracellular fluid to the final concentration required for detection, ensuring that the DMSO content in the test drug solution does not exceed 0.5%. This concentration of DMSO has no effect on the detected Nav1.8 channel current. For example, to prepare 100 nM and 1 μM compound solutions, the serial dilution method is as follows: First, add 5 μL of the DMSO stock solution to 10 mL of extracellular fluid and dissolve thoroughly to obtain a 10 μM compound solution; then, add 1 mL of the 10 μM compound to 9 mL of extracellular fluid and dissolve thoroughly to obtain a 1 μM compound solution; finally, add 1 mL of the 1 μM compound to 9 mL of extracellular fluid and dissolve thoroughly to obtain a 100 nM compound solution.

[0283] All positive controls in this experiment used VX-150, with a half-maximal inhibitory concentration (IC50) of 33.45 ± 0.86 nM, consistent with the results reported in the original literature. The negative control used in this experiment was extracellular fluid containing 0.5% DMSO, with a channel current change ≤5% 10 minutes after administration.

[0284] 2. Cell Culture

[0285] (1) Nav1.8 cell line: HEK293 (Flp-In T-Rex-293) cells that stably express human Nav1.8 sodium channel, with the following encoding gene information: NM_001293306.2.

[0286] (2) Culture and passage conditions and methods: Nav1.8 cell lines were cultured in a constant temperature incubator at 37℃ and 5% CO2. Stable Nav1.8 cells were cultured in complete medium containing 10% tetracycline-free fetal bovine serum (HyClone) and 100 μg / mL Hygromycin B in DMEM (Gibco) high glucose. The day before the experiment, when the cells reached approximately 90% confluence, they were digested and passaged. The medium was first aspirated, and the cells were washed with phosphate-buffered saline (PBS) preheated to 37℃. After discarding the PBS buffer, trypsin was added for digestion, and the cells were transferred to centrifuge tubes. The cells were centrifuged at 800 rpm for 3 minutes, the supernatant was discarded, and the cells were resuspended in complete medium containing 1 μg / mL Doxcycline. The cells were then passaged into 6-well plates and induced for 20 hours. After 20 hours of induction culture, the cells were isolated and passaged into coverslips coated with poly-L-lysine and cultured for another 1-2 hours before being used for electrophysiological recording experiments.

[0287] 3. Electrophysiological experiments

[0288] (1) The Nav1.8 channel current was recorded at room temperature (23-25℃) using whole-cell voltage clamp technique.

[0289] (2) Whole-cell voltage-clamp recording experiments were performed using an Axon patch 700B patch-clamp amplifier (Molecular Devices), a Digidata 1440A digital-to-analog converter (Molecular Devices), and glass microelectrodes were drawn from glass electrode blanks (World Precision Instruments) using a drawing machine (P97, Sutter). The tip resistance after perfusion with electrode fluid was approximately 1.5-2.5 MΩ. The glass microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier probe. Clamp voltage and data recording were controlled and recorded by computer using pClamp 10 software (Molecular Devices), with a sampling frequency of 20 kHz and a filtering frequency of 2 kHz.

[0290] (3) Extracellular and intracellular fluids used in electrophysiological experiments:

[0291] Extracellular fluid formulation (mM): 140 NaCl, 3 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES and 20 Glucose, adjusted to pH 7.3 with NaOH.

[0292] Intracellular fluid formulation (mM): 140 CsF, 10 NaCl, 10 HEPES, 1.1 EGTA and 20 Glucose, pH adjusted to 7.3 with CsOH.

[0293] (4) Electrophysiological stimulation protocol: After obtaining whole-cell recordings, hold the cells at -80mV for 4-5 minutes until the intracellular fluid and electrode fluid reach equilibrium, then begin electrophysiological recording. Current stimulation and compound activity assay protocol: Hold the cells at -80mV, apply a 20ms depolarization voltage of +10mV, then repolarize to -80mV at a stimulation frequency of 0.5Hz. Once the Nav1.8 sodium channel current is stable (approximately 1 minute), begin the drug administration process until the cell current no longer changes (compound inhibition reaches steady state). Test at least 3 cells (n≥3) for each compound concentration. After all compounds are tested, administer a single concentration of 1nMVX-548 as a positive control.

[0294] 4. Data Analysis

[0295] Data acquisition, analysis, and processing were performed using pClamp10 (Molecular Devices), GraphPad Prism 5 (GraphPad Software), and Excel (Microsoft). All data are expressed as mean ± standard error (Mean ± SEM). The effect of the compound on the current was calculated using the following formula:

[0296] Inhibition rate (%) = [1 - magnitude of current after drug administration (I)] Drug ) / Magnitude of current before drug administration (I) Control )]×100.

[0297] The dose-response curve was fitted using the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^(X – LogIC)) 50 In this context, Bottom and Top represent the minimum and maximum inhibition values, respectively, X represents the logarithm of the compound concentration, and Y represents the IC50 value. 50 Indicate I Drug / I Control Value, IC 50 This indicates the drug dose that produces a half-maximal inhibitory effect.

[0298] The results are shown in Table 1 and Table 2.

[0299] Table 1. Inhibition rate of representative compounds of the present invention against Nav1.8 at 10 nM

[0300] compound Inhibition rate compound Inhibition rate compound Inhibition rate 1 42％ 11 51％ 22-b 89％ 3 54％ 12 42％ 23 69％ 4 66％ 14 13％ 24 45％ 5 79％ 17 37％ 25 86％ 6 85％ 18 31％ 26 76％ 7 44％ 19 81％ 27 46％ 8 26％ 20 21％ 28 65％ 9 45％ 21 49％ 29 70％ 10 69％ 22-a 71％ 30 64％

[0301] Table 2. Inhibitory activity of representative compounds of the present invention against Nav1.8 channels (IC50, 100 mg / L). 50 ,nM))

[0302] compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> VX-150 33.45 23 3.27 19 1.08 25 2.98 22-a 4.72 26 2.94 22-b 2.15 29 4.18

[0303] As shown in Tables 1 and 2, the representative compounds of this invention exhibit strong Nav1.8 inhibitory activity, with an IC50 value of [missing information]. 50 All were less than 5 nM and significantly superior to compound VX-150 in the Phase II clinical trial.

[0304] Test Example 2: Sodium Ion Channel Subtype Inhibition Test

[0305] Inhibition of sodium ion channel 1.5 (Nav1.5) by compounds may cause cardiac side effects. This study tests and evaluates the selectivity of the compounds of the present invention for Nav1.5.

[0306] Nav1.5 cell line: CHL (Chinese hamster lung cells) cells that stably express the human Nav1.5 sodium channel, with the following encoding gene information: NM_198056.2.

[0307] Culture and passage conditions and methods: Nav1.5 stable transgenic cells were cultured in DMEM (Gibco) high-glucose complete medium containing 10% fetal bovine serum (Gibco) and 500 μg / mL G418 (Invitrogen). The day before the experiment, when cells reached approximately 90% confluence, they were digested and passaged. The medium was first aspirated, and the cells were washed with pre-warmed phosphate-buffered saline (PBS) at 37°C. After discarding the PBS, trypsin was added for digestion, and the cells were transferred to centrifuge tubes. The supernatant was discarded, and the cells were resuspended in complete medium containing 1 μg / mL doxcycline. The cells were then passaged into 6-well plates and induced for 20 hours. Afterward, the cells were isolated and passaged into poly-L-lysine-coated coverslips and cultured for another 1-2 hours before being used for electrophysiological recording experiments.

[0308] The testing conditions were the same as those for Nav1.8 in Test Example 1, and the test results are shown in Table 3.

[0309] Table 3. Inhibitory effect of the compounds of this invention on Navl.5

[0310] compound <![CDATA[IC 50 (μM)]]> Relative to Nav 1.8 multiple <![CDATA[VX-150 # ]]> / >400 19 9.17 8490 22-b 6.02 2800 23 20.48 6263

[0311] # Data source: Hemme J.Hijm, et al. Pain Medicine, 22(8), 2021, 1814–1826.

[0312] As shown in Table 3, the compounds of this invention have excellent selectivity (thousands of times) for the sodium ion channel Navl.5, which may cause cardiac side effects, far superior to the compound VX-150 in the Phase II clinical trial. Therefore, it is expected that they will show better safety in clinical trials.

[0313] Test Example 3: hERG Suppression Test

[0314] (1) Cell culture and compound preparation

[0315] hERG-CHO cells were cultured at 37°C and 5% CO2 until they reached a maximum confluence of 70-80%. The culture medium (F-12 medium containing 10% fetal bovine serum, 100 μg / mL G418, and 100 μg / mL hygromycin B) was then discarded, and the cells were washed with 7 mL of phosphate-buffered saline. They were then dissociated in a 37°C incubator for 3 minutes with 3 mL of dissociation reagent, and resuspended in 7 mL of serum-free medium. Finally, the cells were harvested by centrifugation at 800 rpm and adjusted to a concentration of 2-5 × 10⁶ / mL for subsequent automated Qpatch 16X experiments.

[0316] (2) Preparation of compounds.

[0317] First, 10 μL of the stock solution of the compound (20 mM) was added to 4990 μL of extracellular fluid. Then, the extracellular fluid containing 0.2% DMSO was serially diluted 3-fold using a Bravo instrument to obtain 6 test concentrations: 40, 13.33, 4.44, 1.48, 0.49, and 0.16 μM, where the DMSO content did not exceed 0.2%, and this concentration had no effect on the hERG potassium channel.

[0318] (3) Electrophysiological recording process

[0319] The Qpatch 16X fully automated patch-clamp assay was performed. The Qpatch instrument automatically performed single-cell high-impedance sealing and whole-cell pattern formation. After obtaining the whole-cell recording pattern, the cells were clamped at -80 mV. A -50 mV pre-voltage for 50 mV was applied, followed by repolarization to -50 mV for 5 seconds, then back to -80 mV. This voltage stimulation was applied every 15 seconds. A +40 mV depolarization stimulus was then applied for 5 seconds. The assay started at the lowest test concentration of the drug, with each assay lasting 2.5 minutes. At least three cells (n≥3) were tested for each concentration. Cisapride was used as a positive control compound. The test results are shown in Table 4.

[0320] Table 4. hERG inhibitory activity of the compounds of the present invention

[0321] compound <![CDATA[hERG(IC 50 ,μM)]]> 5 >40 22-b >40 23 >40 30 39.2

[0322] Inhibition of hERG potassium channels may cause cardiac-related side effects in clinical practice. As shown in Table 4, the compounds of this invention do not inhibit hERG potassium channels and exhibit excellent off-target selectivity, indicating a very low likelihood of causing cardiotoxicity.

[0323] Test Example 4: Rat Pharmacokinetic Properties of Compounds

[0324] 1. Experimental methods and conditions: Male SD rats, 3 rats per group, were fasted for 12 hours before the gavage experiment, but allowed free access to water. They were fed uniformly 4 hours after administration of the drug. For intravenous administration, the rats were not fasted.

[0325] The intravenous solvent is 5% DMSO / 10% HS15 / 10% EtOH / 75% physiological saline (volume ratio), with a dosage of 1 mg / kg and an administration volume of 5 mL / kg; the oral solvent is 0.5% CMC-Na (mass fraction), with a dosage of 5 mg / kg and an administration volume of 10 mL / kg.

[0326] 2. Sampling Information: At 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, and 24 hours after gavage administration, 0.2 mL of blood was collected via the jugular vein and placed in EDTA-K2 tubes. After collection, the whole blood was temporarily stored in an ice-water bath and centrifuged at 11000 rpm for 5 min within 30 min to separate the plasma. The plasma was then frozen at -70℃ for analysis. At 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 10, and 24 hours after intravenous administration, 0.2 mL of blood was collected via the jugular vein and placed in EDTA-K2 tubes. After collection, the whole blood was temporarily stored in an ice-water bath and centrifuged at 11000 rpm for 5 min within 30 min to separate the plasma. The plasma was then frozen at -70℃ for analysis. Ice-water bath operation was used. The concentration of the original drug in the samples was quantitatively determined using LC-MS / MS.

[0327] 3. Detection Information: The concentrations of the parent drug in rat / mouse plasma after intravenous administration and gavage administration of the test compound were determined using LC / MS / MS. The plasma pharmacokinetic parameters of the compound in rats were calculated using WinNonlin software under both administration routes, and the bioavailability of the compound in rats was calculated. max The measured maximum blood drug concentration is given by the area under the blood drug concentration-time curve, AUC(0→t), which is calculated using the trapezoidal method. T max The time to peak plasma concentration is given by F / %, which represents oral bioavailability. The results are shown in Table 5 below.

[0328] Table 5. Pharmacokinetic parameters

[0329]

[0330] Pharmacokinetic studies showed that the compounds of this invention exhibited excellent pharmacokinetic properties in rats, significantly superior to VX-548 (the only marketed Nav1.8 inhibitor), a representative second-generation Nav1.8 inhibitor. Table 5 data indicates that the compounds of this invention were well absorbed orally. At the same dose, the drug exposure of compound 25 after oral administration was more than 10 times that of VX-548, with nearly 3 times higher oral bioavailability and a nearly 5-fold longer half-life. In contrast, the drug exposure of compound 30 after oral administration was more than 23 times that of the same dose of VX-548.

[0331] The above pharmacokinetic results indicate that the compounds of the present invention have significantly better pharmacokinetic properties (longer half-life, greater drug exposure, and higher oral bioavailability) than VX-548, a representative second-generation Nav1.8 inhibitor. They are expected to provide patients with greater and more sustained clinical analgesic benefits. Therefore, the novel substituted benzimidazole derivatives of the present invention have significant advantages and better clinical application prospects in the preparation of drugs for the treatment, relief, or prevention of diseases related to the Nav1.8 channel.

[0332] Test Example 5: Analgesic effect of the compound in a rat incision pain model

[0333] The SD rats used in this embodiment of the invention were purchased from Zhejiang Vital River Co., Ltd.

[0334] Establishment of a rat model of postoperative pain: Male rats weighing 200–220 g were used. Rats were anesthetized with isoflurane, and their right hind paw was fixed and wiped with povidone-iodine. At a distance of 1 cm from the heel, the skin and fascia of the foot were longitudinally incised with a scalpel. The toe muscles were lifted with forceps and longitudinally incised 1 cm with a scalpel. The skin was then sutured with 4-0 sutures. 0.3 mL of 25% penicillin was injected intraperitoneally to prevent infection.

[0335] Behavioral testing in rats: Von Frey behavioral tests were performed one day after modeling. Baseline thresholds were first measured after modeling, and rats with a paw withdrawal threshold (PWT) greater than 4g were excluded.

[0336] Experimental group: administered via gavage (solvent: 20% PEG400 + 10% PG + 10% Kolliphor HS15 + 60% double-distilled water, volume ratio), 6-7 rats, tested at 1, 2, 4, and 8 hours after administration. Vehicle group: administered via gavage, 6 rats. Sham group (sham operation group), 9 rats. Each rat was placed in an independent glass partition on a wire mesh for 15 minutes to acclimatize. At the start of the test, the middle of the paw pad of the right paw of the rat was stimulated with fibers of 0.4, 0.6, 1, 2, 4, 6, 8, and 15 g respectively until the rat withdrew its paw. The response corresponding to each fiber was recorded, and the PWT of each rat was calculated. The area under the curve (AUC, g·h) was calculated using Graph software based on the PWT-time curve, and the percentage of maximum possible effect (%MPE) was calculated from the AUC value. The formula is: %MPE = (AUC / g·h) / (G / h) * ... 实验组 -AUC vehicle ) / (AUC Sham -AUC vehicle The results are shown in Table 6 and appendix. Figure 1 As shown.

[0337] Table 6. Results of in vivo drug efficacy evaluation in rats with postoperative pain model

[0338]

[0339] Table 6 shows that the compounds of this invention have significant analgesic effects in a rat postoperative pain model, exhibiting a clear dose-response relationship. Compound 25, at the same dose, showed twice the analgesic effect of VX-548, significantly outperforming VX-548, which may be attributed to the superior metabolic properties of compound 25. In conclusion, this experiment demonstrates that the compounds of this invention can be used to treat postoperative pain. Test Example 6: Analgesic effect of the compound in a humanized mouse postoperative pain model

[0340] In this embodiment of the invention, the humanized mice were constructed by Beijing Biosetu Co., Ltd., and bred and raised in the animal facility of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

[0341] Construction of a humanized mouse model of postoperative pain: Half male and half female mice, weighing 22–28 g. Mice were anesthetized with isoflurane, their right hind paw was fixed, and wiped with povidone-iodine. At a distance of 0.5 cm from the heel, the skin and fascia of the foot were longitudinally incised with a scalpel. The toe muscles were lifted with forceps, and a 0.5 cm longitudinal incision was made with a scalpel. The skin was then sutured with 6-0 sutures. 0.2 mL of 25% penicillin was injected intraperitoneally to prevent infection.

[0342] Humanized mouse behavioral testing: Von Frey behavioral tests were performed one day after modeling. The baseline thresholds after modeling were first measured, and mice with a paw withdrawal threshold (PWT) greater than 0.4g were screened out.

[0343] Experimental group: Mice were administered the drug via gavage (solvent: 20% PEG400 + 10% PG + 10% Kolliphor HS15 + 60% double-distilled water, volume ratio), and tests were conducted at 1, 2, 4, and 8 hours post-administration. Vehicle group: The drug was administered via gavage. Sham group: 5-7 mice per group. Each mouse was placed in an independent glass partition on a wire mesh for 15 minutes to acclimatize. At the start of the test, the middle of the paw pad on the right side of the mouse was stimulated with 0.02, 0.04, 0.07, 0.16, 0.4, 0.6, 1, and 1.4 g of fiber filaments until the mouse withdrew its paw. The response corresponding to each fiber filament was recorded, and the PWT (partial total weight) of each mouse was calculated. The area under the curve (AUC, g·h) is calculated using Graph software based on the PWT-time curve. Then, the percentage of maximum possible effect (%MPE) is calculated from the AUC value. The formula is: %MPE = (AUC / (g·h)) 实验组 -AUC vehicle ) / (AUC Sham -AUC vehicle The results are shown in Table 7 and appendix. Figure 2 As shown.

[0344] Table 7. Results of in vivo drug efficacy evaluation in rats with postoperative pain model

[0345]

[0346] From Table 7 and Appendix Figure 2 It is evident that the compounds of this invention exhibit extremely strong analgesic effects in a humanized mouse postoperative pain model, with a clear dose-response relationship. The analgesic activity of compound 25 is significantly higher than that of VX-548; at the same dose, the analgesic activity of compound 25 is at least twice that of VX-548. This experiment demonstrates that the analgesic effect of the compounds of this invention is significantly superior to that of VX-548.

[0347] Although the present invention has been described in detail above, those skilled in the art will understand that various modifications and changes can be made to the invention without departing from its spirit and scope. The scope of the invention is not limited to the detailed description above, but is as set forth in the appended claims.

Claims

1. A compound of general formula (I), or a tautomer, stereoisomer, mixture thereof, deuterated derivative, hydrate, solvate, prodrug, pharmaceutically acceptable salt, or cocrystal thereof, In the formula, X is selected from O and S; Y is selected from CR 5 , N, N + -O - ;where R 5 Selected from: H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 deuterated alkyl, C1-C6 deuterated alkoxy; R 1 Selected from: hydrogen, cyano, substituted or unsubstituted C1-C6 alkyl, -C(O)NR 01 R 02 -C(O)NR 03 -NR 01 R 02 -C(=NR) 04 )NR 01 R 02 -C(=NR) 04 )NR 01 -OR 02 -S(O)R 05 -S(O)2R 05 -S(=NR) 01 (=O)R 05 S(O)2NR 01 R 02 NHR 06 OR 06 SR 06 ;in, The substitution refers to substitution by one or more substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, and halo-C1-C6 alkyl; Where: R 01 R 02 R 03 R 05 Each is independently selected from hydrogen, C1-C6 alkyl, deuterated C1-C6 alkyl, and C3-C6 cycloalkyl; R 04 Selected from hydrogen and hydroxyl groups; R 06 Selected from substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 heteroalkyl groups; wherein, the substitution refers to being substituted by one or more substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, C1-C6 alkyl, halo-C1-C6 alkyl, amide, ester. R 2 Selected from substituted or unsubstituted C1-C6 alkyl groups, wherein the substitution refers to being substituted by one or more substituents selected from the group consisting of: halogens, deuterium; R 3a and R 3b They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, cyano, or halo-C1-C6 alkyl; R 4a and R 4b They may be the same or different, and each is independently selected from hydrogen, C1-C6 alkyl, and halo-C1-C6 alkyl; Or, R 3a R 4a or R 3b R 4b It forms a 3-6 membered carbon ring with the carbon atom on the attached five-membered ring, wherein the 3-6 membered carbon ring is optionally substituted by one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy. The condition is that the compound represented by formula (I) is not a 2. The compound according to claim 1, characterized in that, Y is either C-halogen or CH; R 1 Selected from: hydrogen, cyano, hydroxy-substituted or unsubstituted C1-C4 alkyl groups, -C(O)NR 01 R 02 -C(O)NR 03 -NR 01 R 02 -C(=NR) 04 )NR 01 R 02 -C(=NR) 04 )NR 01 -OR 02 -S(O)R 05 -S(O)2R 05 -S(=NR) 01 (=O)R 05 S(O)2NR 01 R 02 NHR 06 OR 06 SR 06 ; Where: R 01 R 02 R 03 R 05 Each is independently selected from hydrogen and C1-C4 alkyl groups; R 04 Selected from hydrogen and hydroxyl groups; R 06 Selected from substituted or unsubstituted C1-C4 alkyl groups; wherein the substitution refers to being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, halo-C1-C4 alkyl, amide, ester.

3. The compound according to claim 1, characterized in that, Y is N or N + -O - ; R 1 Selected from: hydrogen, cyano, hydroxy-substituted or unsubstituted C1-C4 alkyl groups, -C(O)NR 01 (C1-C4 alkyl), -C(O)NR 03 -NR 01 R 02 -C(=NR) 04 )NR 01 R 02 -C(=NR) 04 )NR 01 -OR 02 -S(O)R 05 -S(O)2R 05 -S(=NR) 01 (=O)R 05 S(O)2NR 01 R 02 NHR 06 OR 06 SR 06 ; Where: R 01 R 02 R 03 R 05 Each is independently selected from hydrogen and C1-C4 alkyl groups; R 04 Selected from hydrogen and hydroxyl groups; R 06 Selected from substituted or unsubstituted C1-C4 alkyl groups; wherein the substitution refers to being substituted by 1, 2 or 3 substituents selected from the group consisting of: deuterium, halogen, hydroxyl, amino, C1-C4 alkyl, halo-C1-C4 alkyl, amide, ester.

4. The compound according to claim 1, characterized in that, R 2 Selected from substituted or unsubstituted C1-C4 alkyl groups, wherein the substitution refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogens and deuterium.

5. The compound according to claim 1, characterized in that, R 3a R 3b Each is independently selected from: hydrogen, C1-C4 alkyl, cyano, and halo-C1-C4 alkyl; R 4a R 4b Each is independently selected from: hydrogen, C1-C4 alkyl, and halo-C1-C4 alkyl; Or, R 3a R 4a or R 3b R 4b It forms a 3-6 membered carbon ring with the carbon atom on the attached five-membered ring, wherein the 3-6 membered carbon ring is optionally substituted by one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy.

6. The compound according to claim 1, characterized in that, The compounds are selected from the group consisting of:

7. The method for preparing the compound of general formula (I) as described in claim 1, characterized in that, The preparation method includes the following steps: Substituted tetrahydrofuran-2-carboxylic acid or substituted tetrahydrothiophene-2-carboxylic acid undergoes a condensation reaction with o-diamine to form an amide, which then undergoes cyclization under the action of acid or base to form benzimidazole; The acid is selected from: formic acid, acetic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, sulfuric acid, and hydrochloric acid; The alkali is selected from potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, and sodium ethoxide; The definitions of each substituent are as described above.

8. A pharmaceutical composition, characterized in that, It comprises one or more of the compound of general formula (I) as claimed in claim 1, or tautomers, stereoisomers, or mixtures thereof, deuterated derivatives, hydrates, solvates, prodrugs, pharmaceutically acceptable salts or cocrystals; and a pharmaceutically acceptable carrier.

9. Use of the compound of formula (I) as claimed in claim 1, or a tautomer, stereoisomer, or mixture thereof, a deuterated derivative, a hydrate, a solvate, a prodrug, a pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition of claim 8, characterized in that, Used to prepare drugs for the treatment, relief or prevention of diseases related to sodium channel regulation, or to prepare Nav1.8 channel inhibitor drugs.

10. The use as described in claim 9, characterized in that, The sodium channel is Nav1.8.

Images