Amidine-derived compounds, their preparation methods and uses

Abstract

The present invention provides an amidine-derived compound of formula I, and its preparation method and uses. The amidine-derived compound of the present invention has Nav1.8 selective inhibitory activity, can be used as a Nav1.8 selective inhibitor, has good pharmacokinetic properties, can be used to treat or alleviate pain-related diseases, and has important clinical application value.

Description

[0001] Priority Information

[0002] This invention claims the priority of a Chinese patent application titled "Amidine Derivative Compounds and Their Preparation Methods and Uses", with the application number 202210176519X, filed with the China National Intellectual Property Administration on February 25, 2022, and the entire content of which is incorporated herein by reference. Technical Field

[0003] This invention relates to the field of pharmaceutical technology, and particularly relates to a class of amidine derivative compounds, their preparation methods, their use for preparing Nav1.8 inhibitors, and their use in preparing drugs for treating and / or alleviating pain and pain-related diseases. Background Art

[0004] Voltage-gated sodium channels (hereinafter referred to as VGSC or Nav) mediate the selective transmembrane flow of sodium ions and play a key role in the initiation, conduction, and transmission of action potentials in excitable cells such as neurons (Catterall et al., Pharmacol Rev. 2005; 57(4): 397-409.). Nav channels are important drug targets, and Nav channel inhibitors are used in the treatment of diseases such as pain, arrhythmia, epilepsy, anesthesia, and pruritus (Black et al., Neuron. 2013; 80(2): 280-91; Catterall et al., Annu Rev Pharmacol Toxicol. 2014; 54: 317-38; Bennett et al., Physiol Rev. 2019; 99(2): 1079-1151.).

[0005] Voltage-gated sodium channel 1.8 (hereinafter referred to as Nav1.8), as a subtype of voltage-gated sodium channels, plays an important role in the pathophysiology of pain. It is mainly expressed in neurons that transmit pain signals in the dorsal root ganglion (DRG). Inhibiting Nav1.8 may not produce adverse effects of drugs on the central nervous system (CNS). Because the Nav1.8 channel has relatively high activation and inactivation voltages, making it the main component of the rising phase of the action potential (other Nav channel subtypes are in a non-functional inactivated state) (Goodwin et al., Nat Rev Neurosci. 2021, 22(5):263-274.). The characteristics of slow inactivation and fast recovery of the Nav1.8 channel enable it to participate in the physiological and pathological processes of membrane potential depolarization and high-frequency neuronal firing such as pain (Alsaloum et al., Nat Rev Neurol. 2020, 16(12):689-705.). Human genetic studies have shown that mutations in the Nav1.8 gene lead to small fiber neuropathy and erythermalgia (Faber et al., Proc Natl Acad Sci U SA. 2012, 109(47):19444-9; Kaluza et al., Pflugers Arch. 2018, 470(12):1787-1801.). In rodents, gene knockout or knockdown of the Nav1.8 channel gene can relieve various inflammatory and neuropathic pains; while administration of Nav1.8 inhibitors such as A-803467 can effectively relieve pain responses (Jarvis et al., Proc Natl Acad Sci U S A. 2007, 104(20):8520-5.).

[0006] Diabetic neuropathy is one of the most common neuropathic pain diseases. Approximately 60% - 70% of diabetic patients are troubled by this disease, and more than 70% of patients do not receive effective treatment (Jensen et al., Brain. 2021, 144(6):1632-1645.). In a mouse model of diabetic neuropathy, methylglyoxal can directly enhance the function of the Nav1.8 channel, and gene knockout or knockdown of the Nav1.8 channel can effectively relieve the neuropathic pain increased by methylglyoxal (Bierhaus et al., Nat Med. 2012, 18(6):926-33.). In a rat model of streptozotocin (STZ)-induced diabetic neuropathy, intraperitoneal or plantar administration of the Nav1.8 inhibitor A-803467 can dose-dependently relieve the pain behavioral responses of animals (Mert et al., J Am Assoc Lab Anim Sci. 2012, 51(5):579-85.).

[0007] In addition to pain, the Nav1.8 channel is also associated with diseases such as multiple sclerosis, arrhythmia, cough, pruritus, and epilepsy.

[0008] Multiple sclerosis (MS) is an inflammatory demyelinating disease originating in the central nervous system, and its exact pathogenesis remains to be elucidated. The cerebellar Purkinje fibers of normal individuals do not express the Nav1.8 channel. The expression of Nav1.8 in the cerebellum of MS patients is upregulated, and the expression level of the channel shows a dependent increase with the progression of the disease. The single nucleotide polymorphism (SNP) of the Nav1.8 encoding gene is also related to the severity of MS (Craner et al., J Neuropathol Exp Neurol. 2003, 62(9):968-75; Roostaei et al., Neurology. 2016, 86(5):410-7.). Gene mice with Nav1.8 (overexpression) knocked into the cerebellar Purkinje fibers (L7-1.8TG) exhibit MS behavior, and administration of the Nav1.8 selective inhibitor PF-01247324 can alleviate the MS behavior of L7-1.8TG transgenic mice (Shields et al., Ann Neurol. 2012, 71(2):186-94; Shields et al., PLoS One. 2015, 10(3):e0119067.).

[0009] Osteoarthritis is a degenerative joint disease, and cartilage wear and pain are its main characteristics. Phosphorylated cAMP response element-binding protein (CREB) directly binds to the promoter of the Nav1.8 encoding gene, promotes the transcription of Nav1.8 protein, and upregulates the expression level of the Nav1.8 channel (Zhu et al., Elife. 2020, 9:e57656.).

[0010] In the cardiovascular system, the Nav1.8 channel has been shown to be expressed in cardiac nerves such as Purkinje fibers, and some studies also suggest that Nav1.8 is expressed in cardiomyocytes (Verkerk et al., Circ Res. 2012, 111(3):333-43.). Human genetic studies have found that Nav1.8 gene mutations are related to Brugada syndrome (Hu et al., J Am Coll Cardiol. 2014, 64(1):66-79.). Inhibition of the Nav1.8 channel can improve cardiac remodeling, and the Nav1.8 channel is considered a potential therapeutic target for cardiovascular diseases such as arrhythmia, atrial fibrillation, and heart failure (Dybkova et al., Cardiovasc Res. 2018, 114(13):1728-1737.).

[0011] The Nav1.8 channel is expressed in the cough-related vagus nerve plexus. During the pathological cough process, the phosphorylation level and expression of Nav1.8 increase, indicating its involvement in the cough reflex (Muroi et al., Lung. 2014, 192(1): 15-20.).

[0012] In the itch sensation of mammals, pruritogens such as histamine released by lymphocytes, mast cells, etc. can activate the Nav1.8 channel. Knocking out Nav1.8 in mice can effectively relieve the itching behavior induced by histamine and endothelin (Riol-Blanco et al., 2014, 510(7503): 157-61.).

[0013] In addition, congenital mutations of human Nav1.8 have been reported to cause epilepsy and convulsive diseases (Kambouris et al., Ann Clin Transl Neurol. 2016, 4(1): 26-35.). Therefore, inhibitors of the Nav1.8 channel are considered to be useful for treating, preventing, or controlling diseases associated with the participation or dysfunction of the Nav1.8 channel.

[0014] Since Nav1.8 is mainly distributed in the peripheral nervous system, selectively inhibiting Nav1.8 can effectively reduce side effects. In existing studies, the Nav1.8 sodium channel inhibitor VX-150 containing a pyridone structure reached the primary endpoint in a phase 2 clinical trial for treating patients with pain caused by small fiber neuropathy (SFN), and is used to treat moderate to severe pain and has been granted breakthrough therapy designation by the US FDA; in addition, WO2021018165 and CN202010932125.3 also disclose pyridone compounds for inhibiting the Nav1.8 sodium channel; in addition, WO2014120815, WO2014120820, US201901667, WO2020092187, CN202010889003.0, WO2020092187, CN202110107114.6, etc. respectively disclose compounds including arylcarboxylic acids, benzamides, arylsulfonamides, etc. for inhibiting the Nav1.8 sodium channel; in addition, WO2020169042 discloses a Nav1.8 sodium channel inhibitor containing a pyridazinone compound. None of the above studies have products on the market. Therefore, developing new Nav1.8 inhibitors has very important scientific value and clinical significance for treating diseases related to Nav1.8 expression disorders.

[0015] In view of this, the present invention is specifically proposed. Summary of the Invention

[0016] One object of the present invention is to provide an amidine-derived compound having selective inhibitory activity against Nav1.8.

[0017] The second object of the present invention is to provide a method for preparing an amidine-derived compound.

[0018] The third object of the present invention is to provide a pharmaceutical composition comprising the amidine-derived compound.

[0019] The fourth object of the present invention is to provide the use of the amidine-derived compound or the pharmaceutical composition in the preparation of a Nav1.8 inhibitor or a drug for treating and / or alleviating pain and pain-related diseases.

[0020] In order to achieve the above objects of the present invention, the following technical solutions are specifically adopted:

[0021] The present invention provides, on the one hand, a compound of formula I, its tautomer, meso form, racemate, enantiomer, diastereoisomer, its deuterated compound or its pharmaceutically acceptable salt,

[0022]

[0023] Wherein:

[0024] Ring A is a substituted or unsubstituted C6-C12 aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group containing 1 to 4 heteroatoms selected from N, O, S; preferably, ring A is a substituted or unsubstituted phenyl group; the substituents of the substitution are selected from halogen, C1-C6 alkyl group, deuterated C1-C6 alkyl group, halogenated C1-C6 alkyl group, C1-C6 alkoxy group, deuterated C1-C6 alkoxy group, halogenated C1-C6 alkoxy group, C3-C8 cycloalkyl group, deuterated C3-C8 cycloalkyl group, halogenated C3-C8 cycloalkyl group, C3-C8 cycloalkoxy group, deuterated C3-C8 cycloalkoxy group, halogenated C3-C8 cycloalkoxy group, preferably selected from F, Cl, C1-C3 alkyl group, deuterated C1-C3 alkyl group, halogenated C1-C3 alkyl group, C1-C3 alkoxy group, deuterated C1-C3 alkoxy group, halogenated C1-C3 alkoxy group, C3-C6 cycloalkyl group, deuterated C3-C6 cycloalkyl group, halogenated C3-C6 cycloalkyl group, C3-C6 cycloalkoxy group, deuterated C3-C6 cycloalkoxy group, halogenated C3-C6 cycloalkoxy group;

[0025] R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl group, C3-C6 cycloalkyl group, C(=O)R 1a , C(=O)OR 2a , wherein, R 1a is selected from hydrogen, C1-C6 alkyl group, C3-C6 cycloalkyl group, phenyl group, and R 2a is selected from C1-C6 alkyl group, C3-C6 cycloalkyl group, phenyl group;

[0026] R 3Selected from hydrogen, -CN, -OH or C1-C6 alkoxy;

[0027] X 1 and X 2 One of them is C, and the other is selected from N and CR g ;

[0028] R 4 、R 5 and R 6 Each independently is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl;

[0029] X 3 、X 4 and X 5 Each independently is selected from N and CR a and X 3 、X 4 and X 5 There is at most one N among them;

[0030] R 7 Is selected from hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy;

[0031] R g 、R a Each time it appears, it is independently selected from hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C1-C6 alkynyl, C2-C6 alkynyloxy, halo-C1-C6 alkynyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy;

[0032] Or, R 7 and R a Two adjacent substituents among them together with the carbon atom to which they are attached form a ring Or a substituted or unsubstituted benzene ring; the substituents of the substitution are selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, preferably selected from F, Cl, C1-C3 alkyl, C1-C3 alkoxy;

[0033] Y 1 and Y 2 Each independently is selected from O, CH 2 ;

[0034] R 8 Is selected from hydrogen, halogen or C1-C3 alkyl.

[0035] In some preferred embodiments, R 1 、R2 and R 3 At least one of them is H. In particular, R 1 , R 2 and R 3 are all hydrogen.

[0036] In some embodiments, is

[0037] In some embodiments, the compound of formula I is selected from:

[0038]

[0039] wherein,

[0040] X 1 , X 2 are each independently selected from N and CR g ,

[0041] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R g , A ring, X 3 , X 4 , X 5 are defined as above.

[0042] In some embodiments, the compound of formula I is selected from the compound of formula I-A and the compound of formula I-A':

[0043]

[0044] wherein,

[0045] X 1 , X 2 are each independently selected from N and CR g ;

[0046] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R g , X 3 , X 4 , X 5 are defined as above;

[0047] X 6 , X 7, X 8 Each independently selected from N and CR b , and X 6 , X 7 and X 8 There is at most one N among them;

[0048] R b , R 9 and R 10 Each independently selected from hydrogen, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, deuterated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C3-C8 cycloalkoxy, deuterated C3-C8 cycloalkoxy, halogenated C3-C8 cycloalkoxy when each appears; preferably selected from hydrogen, F, Cl, C1-C3 alkyl, deuterated C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkoxy, halogenated C1-C3 alkoxy, C3-C6 cycloalkyl, deuterated C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C3-C6 cycloalkoxy, deuterated C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.

[0049] In some embodiments, the compound of formula I is a compound of formula I-A:

[0050]

[0051] Wherein, X 2 is selected from N or CR g , preferably CR g , R g is selected from hydrogen, F, Cl, Br, C1-C6 alkyl or C1-C6 alkoxy, preferably hydrogen, F, Cl or Br, more preferably hydrogen or F, especially F;

[0052] X 3 , X 4 Each independently is CR a , X 5 is selected from N or CR a , R a is the same or different each time it appears, selected from hydrogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, preferably R 3 in X a is selected from trifluoromethyl or trifluoromethoxy, and R 4 in X 5 and R a in X

[0053] X 6 , X 7 , X8 each independently selected from CR b , R b are the same or different and are selected from hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl, preferably selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy;

[0054] R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3-C6 cycloalkyl, deuterated C3-C6 cycloalkyl;

[0055] R 7 is selected from halogen, C1-C6 alkoxy, preferably selected from F, Cl, Br or methoxy;

[0056] R 4 , R 5 , R 6 each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen;

[0057] R 1 and R 2 each independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen;

[0058] R 3 is selected from hydrogen, -CN, -OH or C1-C6 alkoxy, preferably -OH.

[0059] In some embodiments, the compound of formula I-A is selected from the following compounds of formula I-A-1:

[0060]

[0061] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , X 5 , R 6 , R 7 , R 9 , R 10 , R a , R b , R g are as defined above;

[0062] In particular, R 1 , R 2 and R 3 are hydrogen;

[0063] In particular, R 4 , R5 、R 6 、R g At least two of them are H, particularly at least three of them are H, and more particularly all of them are H;

[0064] Particularly, R 7 、R a At least one of them is H, particularly at least two of them are H;

[0065] Particularly, R 9 、R 10 、R b At least two of them are H, particularly at least three of them are H.

[0066] In some preferred embodiments, in the compound of formula I-A-1,

[0067] R g is selected from hydrogen, F, Cl, Br, C1-C6 alkyl or C1-C6 alkoxy, preferably hydrogen, F, Cl or Br, more preferably hydrogen or F, particularly F;

[0068] X 5 is selected from N or CR a ,R a is the same or different each time it appears and is selected from hydrogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, preferably the R 3 in X a is selected from trifluoromethyl or trifluoromethoxy, X 4 and X 5 in the R a is hydrogen;

[0069] R b is the same or different and is selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, preferably selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy;

[0070] R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3-C6 cycloalkyl, deuterated C3-C6 cycloalkyl;

[0071] R 7 is selected from halogen, C1-C6 alkoxy, preferably selected from F, Cl, Br or methoxy;

[0072] R 4 、R 5 、R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen;

[0073] R1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen;

[0074] R 3 is selected from hydrogen, -CN, -OH or C1-C6 alkoxy, preferably -OH.

[0075] In some embodiments, the compound of formula I-A-1 is selected from the following compounds of formula I-A-1A:

[0076]

[0077] X 5 、R 7 、R 9 、R 10 、R a 、R b are as defined above.

[0078] In some embodiments, in the compound of formula I-A-1A,

[0079] X 5 is selected from N or CR a ,R a is the same or different each time it appears and is selected from hydrogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, preferably R 3 in X a is selected from trifluoromethyl or trifluoromethoxy, X 4 and X 5 in R a is hydrogen;

[0080] R b is the same or different and is selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, preferably selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy;

[0081] R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3-C6 cycloalkyl, deuterated C3-C6 cycloalkyl;

[0082] R 7 is selected from halogen, C1-C6 alkoxy, preferably selected from F, Cl, Br or methoxy.

[0083] Those of ordinary skill in the art will understand that and are tautomers, so the compounds of the present invention containing structures can also be regarded as containing structure, the two are equivalent.

[0084] In some embodiments, Selected from the following structures:

[0085]

[0086] In some preferred embodiments, the compound of formula I is selected from the following compounds:

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094] The definitions of terms in this invention are as follows:

[0095] The "halogen" may be fluorine, chlorine, bromine or iodine.

[0096] The “C1-C6 alkyl” refers to a chain alkyl group having 1 to 6 carbon atoms; specific examples thereof may include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like, but are not limited thereto; the definition of “C1-C3 alkyl” is similar.

[0097] The "deuterated C1-C6 alkyl group" refers to a C1-C6 alkyl group as defined above in which one or more hydrogen atoms are replaced by deuterium.

[0098] The "halogenated C1-C6 alkyl" refers to a C1-C6 alkyl group as defined above in which one or more hydrogen atoms are replaced by halogen.

[0099] The "C2-C6 alkenyl" refers to a straight-chain or branched-chain group containing 2 to 6 carbon atoms and having at least one carbon-carbon double bond; specific examples thereof may include vinyl, propenyl, 2-propenyl, (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (E)-2-pentenyl, (Z)-2-hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2-hexenyl, (Z)-3-hexenyl, (E)-3-hexenyl, (E)-1,3-hexadienyl, 4-methyl-3-pentenyl or norbornene.

[0100] The "C2-C6 alkynyl" refers to a straight-chain or branched-chain group containing 2 to 6 carbon atoms and having at least one carbon-carbon triple bond; specific examples thereof may include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl.

[0101] The "C1-C6 alkoxy" refers to the RO-group, where R is a C1-C6 alkyl group as described above. Specific examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, etc. The definition of "C1-C3 alkoxy" can be deduced by analogy.

[0102] The "halo C1-C6 alkoxy" refers to a group obtained by substituting at least one hydrogen of the alkoxy as described above with a halogen; specific examples thereof include trifluoromethoxy, etc.

[0103] The "deuterated C1-C6 alkoxy" refers to the RO-group, where R is a deuterated C1-C6 alkyl group as described above.

[0104] The "C2-C6 alkenyloxy" refers to the RO-group, where R is a C2-C6 alkenyl group as described above; specific examples of alkenyloxy include vinyloxy, propenyloxy.

[0105] The "C2-C6 alkynyloxy" refers to the RO-group, where R is a C2-C6 alkynyl group as described above; specific examples of alkynyloxy include ethynyloxy, propynyloxy.

[0106] The "C3-C8 cycloalkyl" refers to a group of completely saturated cyclic hydrocarbon compounds containing 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0107] The "deuterated C3-C8 cycloalkyl group" refers to a group obtained by substituting one or more hydrogens of the C3-C8 cycloalkyl group as defined above with deuterium.

[0108] The "halogenated C3-C8 cycloalkyl group" refers to a group obtained by substituting one or more hydrogens of the C3-C8 cycloalkyl group as defined above with a halogen.

[0109] The "C3-C8 cycloalkyloxy group" refers to an RO-group, where R is the C3-C8 cycloalkyl group as described above.

[0110] The "deuterated C3-C8 cycloalkyloxy group" refers to a group obtained by substituting one or more hydrogens of the C3-C8 cycloalkyloxy group as defined above with deuterium.

[0111] The "halogenated C3-C8 cycloalkyloxy group" refers to a group obtained by substituting one or more hydrogens of the C3-C8 cycloalkyloxy group as defined above with a halogen.

[0112] The "C6-C12 aryl group" refers to a monocyclic or polycyclic aryl group having 6 to 12 carbon atoms; specific examples thereof include a phenyl group and a naphthyl group.

[0113] The "5-10 membered heteroaryl group" refers to a 5-10 membered aromatic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur in the ring, and specific examples thereof include pyridine, pyridazine, pyrimidine, etc.

[0114] The "pharmaceutically acceptable salts" are well-known in the art and include salts derived from suitable inorganic / organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or salts formed by reacting with an amino group using other methods employed in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0115] The "deuterated compound" refers to a structure in which one or more hydrogens ( 1 H) in the compound structure are replaced by deuterium ( 2 H).

[0116] The compounds and their pharmaceutically acceptable salts involved in this application may have isomers or racemates, such as optical isomers (including diastereoisomers and enantiomers), atropisomers, geometric isomers (cis-trans isomers), conformational isomers, tautomers, and mixtures thereof, etc., but are not limited thereto. These isomers are also included within the scope defined by the claims of the present invention.

[0117] On the other hand, the present invention provides a method for preparing the above-mentioned compound of formula I, which is achieved through the following reaction route:

[0118] Route 1:

[0119]

[0120] Compound II-A reacts with an alcohol under acid catalysis to form a Pinner salt, and then NR 1 R 2 R 3Prepare Compound I-A.

[0121] R in Compound II-A 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 has the same definition as the corresponding one in Compound I-A.

[0122] In some embodiments, the preparation method of the compound of formula II-A is one of the following Method 1 or Method 2:

[0123] Method 1:

[0124]

[0125] The first step: SM1 (where LG is a leaving group for nucleophilic reaction, such as halogen or S(O) 2 Me, Y is an ester group or a cyano group) and SM2 are heated in the presence of a base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. to carry out a nucleophilic substitution reaction to obtain the corresponding M1. The reaction is usually carried out at a temperature in the range of 50°C to 110°C.

[0126] The second step: M1 is hydrolyzed into an acid, and then reacted with SM3 through an amino acid condensation reaction to prepare II-A;

[0127] The amino acid condensation reaction is one of the following Scheme 1 to Scheme 3:

[0128] Scheme 1:

[0129] M1 and SM3 are subjected to an amino acid condensation reaction to obtain II-A. The amino acid condensation is carried out in the presence of a condensing agent, such as a conventional condensing agent such as HATU or HBTU, and a base, such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc., in a suitable solvent such as acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 100°C to obtain II-A.

[0130] Scheme 2:

[0131] At a certain temperature, POCl is slowly added dropwise to the pyridine system of M1 and SM3 3 to obtain II-A. The certain temperature is -10°C to 30°C, preferably about 0°C.

[0132] Scheme III:

[0133] First, M1 is prepared into acyl chloride under the action of thionyl chloride or phosphorus trichloride, and then reacts with SM2 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. to obtain II-A.

[0134] Method II:

[0135]

[0136] The first step: M2 is prepared by the amino acid dehydration reaction of SM1 and SM3;

[0137] The amino acid dehydration reaction is one of the following Schemes I to III:

[0138] Scheme I:

[0139] M2 is obtained by the amino acid condensation reaction of SM1 and SM3. The amino acid condensation is carried out in the presence of a condensing agent such as a conventional condensing agent like HATU or HBTU and a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. in a suitable solvent such as acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 100 °C to obtain M2.

[0140] Scheme II:

[0141] At a certain temperature, POCl is slowly added dropwise to the pyridine system of SM1 and SM3 3 to obtain M2, and the certain temperature is -10 °C to 30 °C, preferably about 0 °C.

[0142] Scheme III:

[0143] SM1 is prepared into acyl chloride under the action of thionyl chloride or phosphorus trichloride, and then reacts with SM3 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. to obtain M2.

[0144] The second step: M2 (where LG is a leaving group for nucleophilic reaction such as halogen or S(O) 2 Me, Y is an acid ester group or a cyano group) and SM2 are heated in the presence of a base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. to carry out a nucleophilic substitution reaction to obtain the corresponding II-A, and the reaction is usually carried out at a temperature in the range of 50 °C to 110 °C.

[0145] Route 2:

[0146]

[0147] The II-A’ compound reacts with an alcohol under acid catalysis to form a Pinner salt, and then NHR is added 1 R 2 To prepare the I-A’ compound.

[0148] R in the II-A’ compound 4 、R 5 、R 6 、R 7 、R 9 、R 10 、X 1 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 are defined the same as the corresponding definitions in the I-A’ compound.

[0149] In some embodiments, the preparation method of the formula II-A’ compound is one of the following Method 1 and Method 2:

[0150] Method 1:

[0151]

[0152] The first step: SM1 (where LG is a leaving group for nucleophilic reaction, such as halogen or S(O) 2 Me, Y is an ester group or a cyano group) and SM2 are heated in the presence of a base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. to carry out a nucleophilic substitution reaction to obtain the corresponding M1, and the reaction is usually carried out at a temperature in the range of 50 °C to 110 °C.

[0153] The second step: First, M1 is hydrolyzed to form an acid, and then II-A’ is prepared by an amine-acid condensation reaction with SM4;

[0154] The amine-acid condensation reaction is one of the following Scheme 1 to Scheme 3:

[0155] Scheme 1:

[0156] M1 and SM4 react through amino acid condensation reaction to obtain II-A'. The amino acid condensation is carried out in the presence of a condensing agent such as a conventional condensing agent like HATU or HBTU and a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc., in a suitable solvent such as acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 100 °C.

[0157] Scheme II:

[0158] At a certain temperature, POCl is slowly added dropwise to the pyridine system of M1 and SM4 3 to obtain II-A'. The certain temperature is -10 °C to 30 °C, preferably around 0 °C.

[0159] Scheme III:

[0160] First, M1 is prepared into acyl chloride under the action of thionyl chloride or phosphorus trichloride, and then reacts with SM4 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc., in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. to obtain II-A'.

[0161] Method II:

[0162]

[0163] The first step: SM1 and SM4 are prepared into M4 through amino acid condensation reaction;

[0164] The amino acid dehydration reaction is one of the following Schemes I to III:

[0165] Scheme I:

[0166] SM1 and SM4 react through amino acid condensation reaction to obtain M4. The amino acid condensation is carried out in the presence of a condensing agent such as a conventional condensing agent like HATU or HBTU and a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc., in a suitable solvent such as acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 100 °C.

[0167] Scheme II:

[0168] At a certain temperature, POCl is slowly added dropwise to the pyridine system of SM1 and SM4 3 to obtain M4. The certain temperature is -10 °C to 30 °C, preferably around 0 °C.

[0169] Scheme III:

[0170] First, SM1 is prepared into an acyl chloride under the action of thionyl chloride or phosphorus trichloride, and then reacted with SM4 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. to obtain M4.

[0171] Step 2: M4 (where LG is a leaving group for nucleophilic reaction, such as halogen or S(O) 2 Me, Y is an acid ester group or a cyano group) and SM2 are heated in the presence of a base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. to carry out a nucleophilic substitution reaction to obtain the corresponding II-A'. The reaction is usually carried out at a temperature in the range of 50 °C to 110 °C.

[0172] Route 3:

[0173]

[0174] Among them, R 1 , R 2 is H, R 3 is OH, R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 have the same definitions as those in the I-A compound;

[0175] The II-A compound reacts with hydroxylamine or a salt of hydroxylamine in the presence of an anhydrous solvent and a base to obtain the I-A compound;

[0176] Among them, the anhydrous organic solvent includes but is not limited to one or more mixtures of anhydrous methanol, anhydrous ethanol, anhydrous propanol, anhydrous butanol, anhydrous tetrahydrofuran, anhydrous ethyl acetate, etc.;

[0177] The base is an organic base, including but not limited to anhydrous triethylamine, anhydrous N,N-dimethylethylamine, anhydrous 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylenediamine, sodium methoxide, potassium ethoxide, potassium tert-butoxide, etc.;

[0178] The salts of hydroxylamine include but are not limited to hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, etc.

[0179] The preparation of the II-A compound is as described above.

[0180] Route 4:

[0181]

[0182] wherein R 1 and R 2 are H, R 3 is OH, and R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 are defined the same as the corresponding ones in the I-A' compound;

[0183] The I-A' compound is obtained by reacting the II-A' compound with hydroxylamine or a salt of hydroxylamine in the presence of an anhydrous solvent and a base;

[0184] wherein the anhydrous organic solvent includes but is not limited to one or a mixture of anhydrous methanol, anhydrous ethanol, anhydrous propanol, anhydrous butanol, anhydrous tetrahydrofuran, anhydrous ethyl acetate, etc.;

[0185] The base is an anhydrous organic base, including but not limited to anhydrous triethylamine, anhydrous N,N-dimethylethylamine, anhydrous 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylenediamine, sodium methoxide, potassium ethoxide, potassium tert-butoxide, etc.;

[0186] The salts of hydroxylamine include but are not limited to hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, etc.

[0187] The preparation of the II-A' compound is as described above.

[0188] On the other hand, the present invention provides a pharmaceutical composition, which comprises one or more selected from the group consisting of a compound of formula I, its tautomer, mesomer, racemate, enantiomer, diastereoisomer and its pharmaceutically acceptable salt, and optionally a pharmaceutically acceptable excipient.

[0189] Pharmaceutically acceptable excipients include any and all solvents, diluents, or other liquid excipients, dispersion or suspension aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. suitable for the particular dosage form desired. The use of any conventional carrier medium is contemplated within the scope of the present invention, provided that the conventional carrier medium is not incompatible with the compounds of the present invention, such as producing any undesired biological effects or otherwise interacting in a detrimental manner with any other component in the pharmaceutically acceptable composition. Examples of some materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchange agents, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates, glycine, sorbic acid or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polypropylene-block polymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), tragacanth powder, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol or polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffering agents (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water isotonic saline, Gifford's reagent, ethanol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), and, at the discretion of the formulator, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, and fragrances, preservatives, and antioxidants may also be present in the composition.

[0190] In yet another aspect, the present invention provides the use of a compound of formula I, its tautomer, meso form, racemate, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, in the preparation of a Nav1.8 inhibitor.

[0191] In yet another aspect, the present invention provides a method for inhibiting Nav1.8 in an individual, comprising administering to the individual one or more selected from a compound of formula I, its tautomer, meso form, racemate, enantiomer, diastereomer, and a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition.

[0192] In another aspect, the present invention provides the use of the compound of formula I, its tautomer, meso form, racemate, enantiomer, diastereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating and / or alleviating pain diseases and pain-related diseases.

[0193] In yet another aspect, the present invention provides a method for treating or alleviating pain diseases and pain-related diseases or symptoms, the method comprising administering to a subject in need thereof one or more selected from the group consisting of the compound of formula I, its tautomer, meso form, racemate, enantiomer, diastereoisomer and its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition.

[0194] The pain diseases include but are not limited to nociceptive pain, inflammatory pain (including but not limited to rheumatoid arthritis pain or vulvodynia), neuropathic pain (including but not limited to postherpetic neuralgia, idiopathic small fiber neuropathy), musculoskeletal pain (including but not limited to osteoarthritis pain, back pain, cold pain, burn pain or toothache), postoperative pain (including but not limited to pain after bunionectomy, abdominoplasty pain, etc.) and visceral pain, functional pain, pain associated with muscle or bone injury, pelvic pain, abdominal pain, thoracic 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 neuropathy, erythromelalgia, etc.

[0195] The pain-related diseases include arthritis, pruritus, acute or chronic pruritus, asthma, multiple sclerosis, arrhythmia, atrial fibrillation, heart failure, Brugada syndrome, kidney stones, epilepsy, convulsion, Charcot-Marie-Tooth syndrome, incontinence, etc.

[0196] Beneficial effects

[0197] The present invention provides an amidine-derived compound different from the currently existing structures of Nav1.8 selective inhibitors, which has good Nav1.8 selective inhibitory activity, good pharmacokinetic properties, and good drug-likeness. As a Nav1.8 inhibitor, it can be used to treat or alleviate pain or pain-related diseases, and has important clinical application value.

[0198] The present invention has been described in detail above, but the above embodiments are essentially illustrative only and are not intended to limit the present invention. In addition, the present invention is not limited by any theory described in the foregoing prior art or the description of the invention content or the following examples. Detailed implementation manners

[0199] The present invention will be further described below in conjunction with embodiments. It should be noted that the following embodiments are provided for illustrative purposes only and do not constitute a limitation on the scope of protection required by the present invention.

[0200] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the embodiments are all conventional raw materials, reagents, and methods in the art.

[0201] Experimental materials and analytical instruments:

[0202] The thin-layer analysis (TLC) plate model is HSGF-254 (thickness 0.15 - 0.2 mm, produced by Yantai Chemical Experiment Factory); the column chromatography silica gel is 200 - 300 mesh commercial silica gel produced by Qingdao Ocean Chemical Factory; 1 H-NMR, 13 13C-NMR was recorded using Bruker AM-300 and Varian Mercury-500 nuclear magnetic resonance spectrometers, with tetramethylsilane (TMS) as the internal standard; the chemical shift is (ppm, δ:), and the proton coupling is marked as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad peak (br); low-resolution mass spectrometry was recorded using a Finning / MAT-95 instrument or an Agilent 6110 mass spectrometer.

[0203] Abbreviations and notes:

[0204] HEPES: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid or N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid);

[0205] EGTA: ethylene glycol bis(2-aminoethyl ether) tetraacetic acid;

[0206] All drugs were purchased from Sigma.

[0207] The hydrogen chloride-ethyl acetate system, hydrogen chloride-dioxane system, hydrochloric acid-ethyl acetate system, and hydrochloric acid-dioxane system all refer to anhydrous hydrogen chloride organic solutions.

[0208] Example 1 Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoylamino)phenyl)-4-(trifluoromethyl)benzamide (I-1)

[0209]

[0210] First step: Synthesis of 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzonitrile (1-a)

[0211] First, add 4-(trifluoromethyl)-2-fluorobenzonitrile (1-SM1) (10.0 g, 52.9 mmol), 4-fluoro-2-methylphenol (1-SM2) (6.7 g, 53.0 mmol), and cesium carbonate (34.5 g, 105.8 mmol) to anhydrous N,N-dimethylformamide (200 mL). Then, heat the reaction system to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. The organic phase is dried and concentrated to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 20:1 (v / v) to obtain 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzonitrile (1-a) (10.3 g, yield 66%). 1 H-NMR(400MHz,DMSO-d 6 )δ:8.19(d,J=8.0Hz,1H),7.64(d,J=8.4Hz,1H),7.30(d,J=9.2Hz,1H),7.24~7.28(q,1H),7.14~7.19(td,J=8.8,3.2Hz,1H),6.93(s,1H),2.16(s,3H);ESI[M+Na] + =317.7。

[0212] Step 2: Synthesis of 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b)

[0213] Add 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzonitrile (1-a) (6.0 g, 20.3 mmol) and sodium hydroxide (10 N, 20.3 mL, 203.2 mmol) to 95% ethanol and reflux until the raw materials completely disappear. Concentrate to remove ethanol, add water, and adjust the pH value to about 2 - 3 with 2 N hydrochloric acid. A large amount of solid precipitates. Let it stand and filter to obtain 5.3 g of solid 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b). 1 H-NMR(400MHz,DMSO-d 6 )δ:7.99(d,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),7.23(dd,J=9.2,2.8Hz,1H),7.05(tq,J=8.4,3.2Hz,1H),6.99(s,1H),6.92~6.96(m,1H),2.18(s,3H);ESI[M+1] + =314.7。

[0214] Step 3: Synthesis of N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1)

[0215] Under a dry system, 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) (1.0 g, 3.2 mmol) and 3-aminobenzonitrile (0.4 g, 3.34 mmol) were added to anhydrous pyridine (10 mL) for dissolution. After cooling to about 0 °C, phosphorus oxychloride (0.6 mL, 6.4 mmol) was slowly added dropwise while controlling the temperature below 10 °C. After the addition was completed, the reaction was continued until the raw materials were completely reacted. Subsequently, the reaction system was poured into ice water, and the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, and then extracted with dichloromethane. The organic phase was dried and concentrated to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) (1.1 g, yield 83.0%). 1 H-NMR(400MHz,CDCl 3 )δ: 9.79(s, 1H), 8.47(d, J = 8Hz, 1H), 8.07(s, 1H), 7.82(d, J = 7.2Hz, 1H), 7.43 - 7.49(q, 3H), 7.07 - 7.13(m, 3H), 6.86(s, 1H), 2.26(s, 3H); ESI[M+Na] + = 415.1。

[0216] Step 4: Synthesis of 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoylamino)phenyl)-4-(trifluoromethyl)benzamide (I-1)

[0217] N-(3-Cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) (200.0 mg, 0.482 mmol), triethylamine (0.4 mL, 2.90 mmol) and hydroxylamine hydrochloride (67.0 mg, 0.965 mmol) were added to 95% ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. After concentration, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then column chromatographed (200 - 300 mesh) with petroleum ether:ethyl acetate (v / v) = 2:1 to obtain the target compound (I-1) (180.0 mg, yield 83.5%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.59 (s, 1H), 9.66 (s, 1H), 8.04 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.33 - 7.39 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 6.0 Hz, 2H), 6.95 (s, 1H), 2.18 (s, 3H); MS(ESI) m / z [M + H] + = 447.7。

[0218] Example 2 Preparation of 2-(4-Fluoro-2-methylphenoxy)-N-(3-(N-methoxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-2)

[0219] N-(3-Cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) (200.0 mg, 0.48 mmol) obtained in Example 1, triethylamine (0.2 mL, 1.44 mmol) and methoxylamine hydrochloride (40.3 mg, 0.48 mmol) were added to 95% ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then passed through a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain the target compound (I-2) (170.0 mg, yield 84.6%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.92 (s, 1H, NH), 8.14 (s, 1H), 7.96 - 7.91 (m, 2H), 7.58 - 7.64 (m, 3H), 7.22 (d, J = 9.2 Hz, 1H), 7.11 (d, J = 6.8 Hz, 2H), 7.00 (s, 1H), 3.35 (s, 3H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 462.7。

[0220] Example 3 Preparation of N-(3-Carbamimidoyl)phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-3)

[0221] N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) (3.1 g, 7.5 mmol) obtained in Example 1, absolute ethanol (4.0 mL, 58.0 mmol) and hydrogen chloride-ethyl acetate system (10 N, 50.0 mL) were added to a sealed reaction flask, and the reaction was carried out at room temperature until the raw materials were completely converted into the intermediate Pinner salt. Subsequently, the solvent was concentrated to remove to obtain the crude intermediate Pinner salt (II-Aa). Silica gel column chromatography (200 - 300 mesh) was carried out with dichloromethane:methanol = 20:1 - 15:1 (v / v) to obtain 1.8 g of ethyl 3-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamidino)benzimidate hydrochloride (II-Aa) solid, MS (ESI) m / z [M+H] + = 461.1.

[0222] The intermediate II-Aa was dissolved in absolute methanol, ammonia-methanol system (7 N, 4.2 mL) and ammonium chloride (619.0 mg, 11.58 mmol) were added, and the reaction was carried out completely under reflux. Subsequently, the solvent was concentrated to obtain the crude product of I-3. Then silica gel column chromatography (200 - 300 mesh) was carried out with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-3) (1.3 g, yield 54.3%). 1 1H-NMR (400 MHz, DMSO-d 6 ) δ: 10.98 (s, H), 8.25 (s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.60 (t, J = 8.4, 7.8 Hz, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.23 - 7.25 (dd, J = 9.0, 2.4 Hz, 1H), 7.15 - 7.18 (m, 1H), 7.11 - 7.14 (m, 1H), 6.93 (s, 1H), 2.17 (s, 3H); MS (ESI) m / z [M+H] + = 431.7.

[0223] Example 4 Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxycarbamoylamino)pyridin-4-yl)-4-(trifluoromethyl)benzamide (I-4)

[0224] Under a dry system, 1-b (1.26 g, 4.0 mmol) obtained in Example 1 and 4-amino-2-cyanopyridine (480.0 mg, 4.0 mmol) were added to anhydrous pyridine (10.0 mL) for dissolution. After cooling to about 0 °C, phosphorus oxychloride (1.9 mL, 20.0 mmol) was slowly added dropwise while controlling the temperature below 5 °C. After the addition was complete, the reaction was continued until the raw materials reacted completely. Subsequently, the reaction system was poured into ice water, and the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, followed by extraction with dichloromethane. The organic phase was dried and concentrated to obtain 1.1 g of white solid of N-(2-cyanopyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-33), MS(ESI) m / z [M+H] + = 415.7.

[0225] II-A-33 (150.0 mg, 0.36 mmol), triethylamine (0.3 mL, 2.2 mmol) and hydroxylamine hydrochloride (50.0 mg, 0.72 mmol) were added to 95% ethanol, and the reaction was carried out under reflux until the raw materials reacted completely. After concentration, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-4) (120.0 mg, yield 74%). 1 1H-NMR (400 MHz, DMSO-d 6 ) δ: 10.98 (s, 1H), 9.93 (s, 1H), 8.45 (d, J = 5.2 Hz, 1H), 8.24 (s, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.60 - 7.64 (m, 2H), 7.19 (d, J = 9.2 Hz 1H), 7.10 (s, 1H), 7.09 (d, J = 5.2 Hz, 1H), 6.98 (s, 1H), 2.14 (s, 3H); MS(ESI) m / z [M+H] + = 448.7.

[0226] Example 5 Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-methylcarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-5)

[0227] II-A-1 (100.0 mg, 0.24 mmol) obtained in Example 1, absolute ethanol (0.14 mL, 2.4 mmol) and hydrogen chloride - ethyl acetate system (10N, 5.0 mL) were added to a sealed reaction flask, and the reaction was carried out at room temperature until the raw materials were completely converted into the intermediate. Subsequently, the solvent was removed by concentration to obtain the crude intermediate Pinner salt (II-Aa).

[0228] The crude intermediate was dissolved in anhydrous methanol, methylamine hydrochloride (27.2 mg, 0.4 mmol) and triethylamine (0.17 mL, 1.2 mmol) were added, and the reaction was carried out under reflux. After the reaction was complete, it was concentrated to obtain the crude product of I-5. Subsequently, it was passed through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-5) (30.0 mg, yield 28.1%). 1 H-NMR(400MHz,DMSO-d 6 )δ:10.9(brs,1H),9.88(s,1H),9.52(s,1H),9.02(s,1H),8.25(s,1H),7.84(d,J=8.0Hz,2H),7.59~7.62(m,2H),7.44(d,J=8.0Hz,1H),7.2(d,J=7.2Hz,1H),7.15(m,1H),6.93(s,1H),3.00(s,3H),2.16(s,3H);MS(ESI)m / z[M+H] + =446.2。

[0229] Example 6 Preparation of N-(3-(N-cyclopropylcarbamoyl)phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-6)

[0230] II-A-1 (100.0 mg, 0.24 mmol) obtained in Example 1, anhydrous ethanol (0.14 mL, 2.4 mmol) and hydrogen chloride-ethyl acetate system (10 N, 5.0 mL) were added to a sealed reaction flask, and the reaction was carried out at room temperature until the raw materials were completely converted into the intermediate. Subsequently, the solvent was removed by concentration to obtain the crude intermediate Pinner salt (II-Aa).

[0231] The crude intermediate was dissolved in anhydrous methanol (20.0 mL), cyclopropylamine (27.2 mg, 0.4 mmol) and triethylamine (0.17 mL, 1.2 mmol) were added, and the reaction was carried out under reflux. After the reaction was complete, it was concentrated to obtain the crude product of I-6. The crude product was passed through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the solid target compound (I-6) (40.0 mg, yield 36.4%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.04 (s, 1H), 9.72 (s, 1H), 9.27 (s, 1H), 8.21 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.55 - 7.61 (m, 2H), 7.43 (d, J = 8.0 Hz, 1H), 7.24 (m, 1H), 7.12 - 7.17 (m, 2H), 6.92 (s, 1H), 2.80 (m, 1H), 2.16 (s, 3H), 0.93 (m, 2H), 0.81 (m, 2H); MS(ESI) m / z [M + H] + = 472.2。

[0232] Example 7 Preparation of N-(3-(N,N-dimethylcarbamoyl)phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-7)

[0233] II-A-1 (100.0 mg, 0.24 mmol) obtained in Example 1, absolute ethanol (0.14 mL, 2.4 mmol) and hydrogen chloride - ethyl acetate system (10 N, 5.0 mL) were added to a sealed reaction flask and reacted at room temperature until the raw materials were completely converted into the intermediate. Subsequently, the solvent was removed by concentration to obtain the crude intermediate Pinner salt (II-Aa).

[0234] The crude intermediate was dissolved in absolute methanol (20.0 mL), N,N-dimethylhydrochloride (27.2 mg, 0.4 mmol) and triethylamine (0.17 mL, 1.2 mmol) were added and reacted under reflux. After the reaction was complete, the solvent was removed by concentration to obtain the crude product of I-7. The crude product was purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20:1 (v / v) to obtain the target compound (I-7) (45.0 mg, yield 40.8%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 11.9 (brs, 1H), 9.37 (s, 1H), 9.16 (s, 1H), 8.07 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.80 - 7.80 (m, 1H), 7.59 (q, 2H), 7.31 (d, J = 7.8 Hz, 1H), 7.21 - 7.23 (dd, J = 9.0, 3.0 Hz, 1H), 7.14 - 7.18 (m, 1H), 7.09 - 7.12 (td, J = 7.8, 3.0 Hz, 1H), 6.94 (d, J = 4.2 Hz, 1H), 3.23 (s, 3H), 2.98 (s, 3H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 460.2。

[0235] Example 8 Preparation of N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (I-8)

[0236]

[0237] First step: Methyl 4-chloro-6-methylnicotinate (8-SM1) (1.2 g, 6.5 mmol), 4-fluoro-2-methylphenol (897.0 mg, 7.11 mmol), cesium carbonate (4.2 g, 12.9 mmol), and copper(I) iodide (12.3 mg, 0.065 mmol) were added to toluene (10.0 mL), and the mixture was refluxed at 100 °C. After the reaction was complete, the pH was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by column chromatography using petroleum ether:ethyl acetate = 40:1 (v / v) to obtain methyl 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinate (8-a) (1.38 g, yield 77.25%). 1 1H-NMR (400 MHz, DMSO-d 6 ) δ: 8.18 (dd, J = 7.6, 2.4 Hz, 1H), 7.17 (dd, J = 9.5, 2.4 Hz, 1H), 7.12 - 7.03 (m, 3H), 3.85 (s, 3H), 2.29 (s, 3H), 2.07 (s, 3H); MS(ESI) m / z [M + H] + = 275.9.

[0238] Second step: Methyl 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinate (8-a) (1.38 g, 5.0 mmol) was dissolved in sodium hydroxide solution (10N, 5.0 mL), methanol (8.0 mL) was added, and the mixture was refluxed until the raw materials reacted completely. Methanol was removed by concentration, water was added, and the pH was adjusted to about 2 - 3 with 2N dilute hydrochloric acid. A large amount of white solid precipitated, and after standing, it was filtered to obtain 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid (8-b) (1.2 g, yield 91.5%). 1 1H-NMR (400 MHz, DMSO-d 6 ) δ: 13.02 (s, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.14 (dd, J = 9.2, 2.4 Hz, 1H), 7.06 - 6.98 (m, 3H), 2.25 (s, 3H), 2.04 (s, 3H); MS(ESI) m / z [M + H] + = 262.0.

[0239] Step 3: Dissolve 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid (8-b) (1.2 g, 4.57 mmol) and 3-aminobenzonitrile (567.0 mg, 4.8 mmol) in pyridine (12.0 mL). Slowly add phosphorus oxychloride (0.9 mL, 9.2 mol) dropwise at 0 °C, control the temperature below 10 °C. After the addition, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is recrystallized from ethyl acetate to obtain N-(3-benzonitrile)-2-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (II-A-2) (689.0 mg, yield 42%). 1 H-NMR(400MHz,DMSO-d 6 )δ:10.67(s,1H),8.21(s,1H),8.04(d,J=7.6Hz,1H),7.95(s,1H),7.58(s,2H),7.26~7.03(m,4H),2.31(s,3H),2.08(s,3H);MS(ESI)m / z[M+H] + =362.0。

[0240] Step 4: Add N-(3-benzonitrile)-2-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (II-A-2) (200.0 mg, 0.553 mmol), absolute ethanol (2.0 mL), and hydrochloric acid-ethyl acetate (10N, 6.0 mL) into a sealed tube and react at room temperature with the tube sealed. After the reaction is complete, evaporate the reaction system to dryness, add absolute methanol (3.0 mL), ammonia-methanol solution (7N, 5.0 mL), and 2eq ammonium chloride, and reflux at 65 °C. After the reaction is complete, directly evaporate to dryness, mix the sample, and elute through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 30:1 (v / v) to obtain the target compound (I-8) (92.0 mg, yield 43.9%). 1 H-NMR(400MHz,DMSO-d 6 )δ:10.72(s,1H),8.27(t,J=2.0Hz,1H),8.02(d,J=7.6Hz,1H),7.95(d,J=8.2Hz,1H),7.60(t,J=8.0Hz,1H),7.53~7.47(m,1H),7.24(dd,J=8.9,5.2Hz,1H),7.17(dd,J=9.5,3.2Hz,1H),7.14~7.05(m,2H),2.31(s,3H),2.09(s,3H);MS(ESI)m / z[M+H] + =379.1。

[0241] Example 9 Preparation of N-(3-carbamoylamino)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (I-9)

[0242]

[0243] First step: Dissolve 2-fluoro-4-trifluoromethylbenzoic acid (9-SM1) (2.08 g, 10.0 mmol) and 3-aminobenzonitrile (1.2 g, 10.0 mmol) in pyridine (16.0 mL). Slowly add phosphorus oxychloride (1.9 mL, 20.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition, continue the reaction until the raw materials react completely. Then pour the reaction system into ice water, adjust the pH to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 4:1 (v / v) to obtain N-(3-cyanophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (9-a) (1.5 g, yield 48.7%). 1 H-NMR(400MHz,CDCl 3 )δ:8.51(d,J=9.6Hz,1H),8.31(t,J=5.2Hz,1H),8.12(s,1H),7.83(d,J=5.2Hz,1H),7.63(d,J=9.6Hz,1H),7.51(d,J=5.2Hz,1H),7.47~7.50(m,2H);MS(ESI)m / z[M+H] + =309.1。

[0244] Second step: Add (9-a) (308.0 mg, 1.0 mmol), 4-trifluoromethoxyphenol (195.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) to N,N-dimethylformamide (7.0 mL), and react at 100 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:dichloromethane = 1:1 (v / v) to obtain N-(3-cyanophenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (II-A-3) (346.0 mg, yield 74.2%). 1 H-NMR(400MHz,CDCl 3)δ: 8.01 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.51 (t, 1H), 7.46 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 5.6 Hz, 2H), 7.17 (d, J = 6.8 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H); MS(ESI) m / z [M+H] + = 467.1。

[0245] Step 3: Add N-(3-cyanophenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (II-A-3) (149.0 mg, 0.32 mmol) into absolute ethanol (2.0 mL) and hydrochloric acid-ethyl acetate system (10 N, 0.6 mL), and react in a sealed tube at room temperature. After the reaction is complete, evaporate the reaction system to dryness, add absolute methanol (3.0 mL), ammonia-methanol system (7 N, 5.0 mL), and ammonium chloride (68.6.0 mg, 1.3 mmol), and reflux at 65 °C for 3 h. After the reaction is complete, directly evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 30:1 (v / v) to obtain the target compound (I-9) (50.0 mg, yield 32.7%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.92 (brs, 1H), 7.87 (brs, 1H), 7.66 - 7.74 (m, 3H), 7.54 (d, 2H), 7.44 - 7.48 (m, 2H), 7.27 (s, 1H), 7.06 (s, 2H); MS(ESI) m / z [M+H] + = 484.1。

[0246] Example 10 Preparation of N-(3-carbamoylamino)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenoxy)benzamide (I-10)

[0247] Step 1: 9-a (308.0 mg, 1.0 mmol) obtained in Example 9, 4-trifluoromethylphenol (178.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) were added to N,N-dimethylformamide (7.0 mL), and the reaction was carried out at 80 °C. After the reaction was complete, the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 4:1 (v / v) to obtain N-(3-cyanophenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenoxy)benzamide (II-A-4) (360.0 mg, yield 80%). 1 H-NMR(400MHz,CDCl 3 )δ:10.29(brs,1H),8.12(s,1H),7.66(d,J=8.4Hz,2H),7.62(d,J=7.8Hz,1H),7.53(t,J=7.8Hz,1H),7.45(s,1H),7.42(d,J=8.4Hz,1H),7.26(s,1H),7.25(d,J=8.4Hz,2H),7.20(d,J=8.4Hz,1H),6.80(d,J=7.8Hz,1H); MS(ESI)m / z[M+H] + =451.2。

[0248] Step 2: N-(3-cyanophenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenoxy)benzamide (II-A-4) (149.0 mg, 0.32 mmol) and absolute ethanol (2.0 mL) were added to a hydrochloric acid-ethyl acetate system (10N, 0.6 mL), and the reaction was carried out in a sealed tube at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, and anhydrous methanol (3.0 mL), ammonia-methanol solution (5.0 mL), and ammonium chloride (68.6 mg, 1.3 mmol) were added, and the reaction was refluxed at 65 °C. After the reaction was complete, it was directly evaporated to dryness, mixed with a sample, and purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-10) (55.0 mg, yield 35.7%). 1 H-NMR(400MHz,DMSO-d 6 )δ:9.28(brs,4H),7.84(s,1H),7.70(dm,3H),7.56(d,J=8.4Hz,2H),7.45~7.7.53(m,2H),7.32(t,J=7.8Hz,1H),7.06(td,2H); MS(ESI)m / z[M+H] + =468.1。

[0249] Example 11 Preparation of N-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)-4-(trifluoromethyl)benzamide (I-11)

[0250] First step: 9-a (308.0 mg, 1.0 mmol) obtained in Example 9, 4-fluoro-2-methoxyphenol (156.2 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) were dissolved in N,N-dimethylformamide (7.0 mL), and the reaction was carried out at 100 °C. After the reaction was complete, the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 6:1 (v / v) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-5) (360.0 mg, yield 83.7%). 1 H-NMR(400MHz,CDCl 3 )δ: 9.83(s, 1H), 8.33(d, J = 8.4Hz, 1H), 8.03(s, 1H), 7.87(dd, J = 7.6, 1.6Hz, 1H), 7.43 - 7.48(m, 3H), 7.21 - 7.24(q, 1H), 6.97(s, 1H), 6.85 - 6.88(dd, J = 7.2, 2.8Hz, 1H), 6.78 - 6.83(q, 1H), 3.83(s, 3H); MS(ESI) m / z[M + H] + = 431.1.

[0251] Second step: N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-5) (180.0 mg, 0.42 mmol), absolute ethanol (2 mL) and hydrochloric acid-ethyl acetate system (10N, 8.0 mL) were added to a sealed tube, and the reaction was carried out in the sealed tube at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, anhydrous methanol (3.0 mL), ammonia-methanol solution (5.0 mL), and ammonium chloride (89.4 mg, 1.68 mmol) were added, and the reaction was refluxed until the raw materials reacted completely. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-11) (93.0 mg, yield 49.7%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.87 (s, 1H), 8.28 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.61 (t, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H), 6.83 (s, 1H), 3.76 (s, 3H); MS(ESI) m / z [M+H] + = 448.2.

[0252] Example 12 Preparation of N-(3-carbamimidoyl phenyl)-2-(3-fluoro-4-methoxyphenoxy)-4-(trifluoromethyl)benzamide (I-12)

[0253] First step: Add 9-a (308.0 mg, 1.0 mmol) obtained in Example 9, 3-fluoro-4-methoxyphenol (156.3 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) to N,N-dimethylformamide (7.0 mL), and react at 100 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 6:1 (v / v) to obtain N-(3-cyanophenyl)-2-(3-fluoro-4-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-6) (217.0 mg, yield 50.5%). 1 H-NMR (400 MHz, CDCl 3 )δ: 7.97 (s, 2H), 7.51 (m, 1H), 7.44 - 7.46 (m, 3H), 7.15 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.81 - 6.93 (q, 4H), 3.86 (s, 3H); MS(ESI) m / z [M+H] + = 431.3.

[0254] Step 2: Add N-(3-cyanophenyl)-2-(3-fluoro-4-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-6) (175.0 mg, 0.42 mmol), absolute ethanol (2.0 mL) and hydrochloric acid-ethyl acetate system (10 N, 10.0 mL) into a sealed tube, and react in the sealed tube at room temperature. After the reaction is complete, evaporate the reaction system to dryness to obtain an intermediate. Dissolve it in absolute methanol (3.0 mL), add ammonia-methanol solution (5 mL) and ammonium chloride (87.0 mg, 1.67 mmol), and reflux until the raw materials react completely. Then directly evaporate to dryness, mix the sample, and elute through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-12) (67.0 mg, yield 36.8%). 1 H-NMR(600MHz,DMSO-d 6 )δ: 10.74(s, 1H), 9.40(brs, 1.5H), 9.15(brs, 1.5H), 7.80(s, 1H), 7.68(brs, 3H), 7.51(d, J = 7.8Hz, 1H), 7.30(brs, 1H), 7.03 - 7.14(m, 4H); MS(ESI) m / z[M + H] + = 448.1.

[0255] Example 13 Preparation of N-(5-carbamimidoyl-2-chlorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-13)

[0256] Step 1: Dissolve 1-b (628.0 mg, 2.0 mmol) obtained in Example 1 and 3-amino-4-chlorobenzonitrile (305.0 mg, 2.0 mmol) in pyridine (6.0 mL), slowly add phosphorus oxychloride (0.38 mL, 4.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the dropwise addition is complete, continue the reaction until the raw materials react completely. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is eluted through a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 4:1 (v / v) to obtain N-(2-chloro-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-7) (510.0 mg, yield 56.9%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.56 (s, 1H), 8.45 (s, 1H), 8.11 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.20 (d, J = 2.8 Hz, 1H), 7.15 (t, 1H), 6.92 (s, 1H), 2.20 (s, 3H); MS(ESI) m / z [M + H] + = 448.9。

[0257] Step 2: Add N-(2-chloro-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-7) (134.0 mg, 0.3 mmol), absolute ethanol (0.17 mL) and hydrochloric acid-ethyl acetate system (10 N, 7.0 mL) into a sealed tube and react at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, add absolute methanol (4.0 mL), ammonia-methanol solution (5.0 mL), ammonium chloride (62.0 mg, 0.6 mmol), and reflux until the intermediate reaction is complete, then directly evaporate to dryness, mix the sample, and elute through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-13), (70.0 mg, yield 50%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.60 (brs, 1H), 8.51 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8.8 Hz, 2H), 7.26 - 7.31 (tq, 2H), 7.14 - 7.19 (t, 1H), 6.90 (s, 1H), 2.20 (s, 3H); MS(ESI) m / z [M + H] + = 467.1, 469.2 (3:1).

[0258] Example 14 Preparation of N-(5-carbamimidoyl-2-methylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-14)

[0259] Step 1: Dissolve 1-b (628.0 mg, 2.0 mmol) obtained in Example 1 and 3-amino-4-methylbenzonitrile (285.8 mg, 2 mmol) in pyridine (6.0 mL). Slowly add phosphorus oxychloride (0.38 mL, 4.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials react completely. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 4:1 (v / v) to obtain N-(2-methyl-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-8) (624.0 mg, yield 72.9%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.20(s, 1H), 8.00(brs, 2H), 7.62(t, J = 8.4Hz, 2H), 7.47(d, J = 7.6Hz, 1H), 7.28(d, J = 8.4Hz, 1H), 7.16(m, 2H), 6.94(s, 1H), 2.28(s, 3H), 2.19(s, 3H); MS(ESI) m / z[M + H]+ = 429.1.

[0260] Step 2: Add N-(2-methyl-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-8) (214.0 mg, 0.5 mmol), absolute ethanol (1.5 mL) and hydrochloric acid-ethyl acetate system (10N, 7.0 mL) into a sealed tube, and react in the sealed tube at room temperature. After the reaction is complete and the intermediate is formed, evaporate the reaction system to dryness, add anhydrous methanol (3.0 mL), ammonia-methanol solution (5.0 mL), and ammonium chloride (53.0 mg, 1 mmol), and reflux until the intermediate reacts completely. After the reaction is complete, directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-14) (90.0 mg, yield 40.5%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.30 (s, 1H), 9.42 (s, 1H), 9.22 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 7.16 - 7.29 (q, 3H), 6.91 (s, 1H), 2.32 (s, 3H), 2.20 (s, 3H); MS(ESI) m / z [M + H] + = 446.1。

[0261] Example 15 Preparation of N-(5-carbamimidoyl-2-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-15)

[0262] First step: Dissolve 1-b (628.0 mg, 2.0 mmol) obtained in Example 1 and 3-amino-4-fluorobenzonitrile (285.8 mg, 2 mmol) in pyridine (6 mL). Slowly add phosphorus oxychloride (0.38 mL, 4.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 4:1 (v / v) to obtain N-(2-methyl-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-9) (520.0 mg, yield 60.2%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.65 (s, 1H), 8.41 (d, J = 6.4 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.76 (brs, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 10.0 Hz, 1H), 7.26 (d, J = 10.0 Hz, 1H), 7.10 - 7.15 (m, 2H), 6.95 (s, 1H), 2.18 (s, 3H); MS(ESI) m / z [M + H] + = 433.1。

[0263] Step 2: Add N-(2-methyl-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-9) (214.0 mg, 0.5 mmol), absolute ethanol (1.5 mL) and hydrochloric acid-ethyl acetate system (10 N, 5.0 mL) into a sealed tube, and react in the sealed tube at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, add ammonia-methanol solution (7 N, 5.0 mL) and ammonium chloride (53.0 mg, 1 mmol), and reflux until the intermediate reaction is complete. After the reaction is complete, directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-15) (97.0 mg, yield 43.6%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.66(s, 1H), 8.48(s, 1H), 7.95(s, 1H), 7.70(s, 1H), 7.60(s, 2H), 7.14 - 7.27(t, 3H), 6.92(s, 1H), 2.19(s, 3H); MS(ESI) m / z[M+H] + = 450.1.

[0264] Example 16 Preparation of N-(3-carbamoylphenyl)-4-chloro-2-(4-fluoro-2-methylphenoxy)benzamide (I-16)

[0265]

[0266] Step 1: Dissolve 2-fluoro-4-chlorobenzoic acid (16-SM1) (1.0 g, 5.73 mmol) and m-aminobenzonitrile (710.6 mg, 6.02 mmol) in pyridine (9.0 mL), slowly add phosphorus oxychloride (1.0 mL, 11.5 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials react completely. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2 N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain compound (16-a) (630.0 mg, yield 40.1%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.81 (s, 1H), 8.18 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 10.0 Hz, 1H), 7.60 (brs, 2H), 7.47 (d, J = 8.0 Hz, 1H); MS(ESI) m / z [M+H] + = 275.1.

[0267] Step 2: Dissolve 16-a (275.0 mg, 1.0 mmol), 4-fluoro-2-methylphenol (138.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) in N,N-dimethylformamide (7.0 mL), and react at 80 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 4:1 (v / v) to obtain 4-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-10) (264.0 mg, yield 69.5%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.74 (s, 1H), 8.14 (s, 1H), 7.90 (brs, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.56 (sq, 1H), 7.31 (dd, J = 8.4, 1.6 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.09 (dd, J = 6.4, 1.6 Hz, 2H), 6.75 (d, J = 2.0 Hz, 1H), 2.16 (s, 3H); MS(ESI) m / z [M+H] + = 381.1, 382.9 (3:1).

[0268] Step 3: Add 4-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-10) (197.0 mg, 0.5 mmol), absolute ethanol (0.2 mL) and hydrochloric acid-ethyl acetate system (10N, 5.0 mL) into a sealed tube, and react with the tube sealed at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, then add ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (53.0 mg, 1 mmol), and reflux until the intermediate reaction is complete. After the reaction is complete, directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the solid target compound (I-16) (104.0 mg, yield 68%). 1H-NMR(400MHz, DMSO-d 6 ) δ: 10.78 (s, 1H), 8.25 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.21 - 7.23 (dd, J = 9.6, 3.0 Hz, 1H), 7.09 - 7.17 (m, 2H), 6.70 (s, 1H), 2.16 (s, 3H), MS(ESI) m / z [M + H] + = 398.1 / 400.1 (3:1).

[0269] Example 17 Preparation of N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide (I-17)

[0270]

[0271] First step: Dissolve 2-fluoro-5-(trifluoromethyl)benzoic acid (17-SM1) (1.0 g, 4.81 mmol) and m-aminobenzonitrile (694.0 mg, 5.05 mmol) in pyridine (7 mL). Slowly add phosphorus oxychloride (0.9 mL, 9.6 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain compound (17-a) (850.0 mg, yield 57.4%). 1 H-NMR(400MHz, DMSO-d 6 ) δ: 10.95 (brs, 1H), 8.18 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.01 - 8.04 (sq, 1H), 7.93 - 7.96 (td, 1H), 7.60 - 7.67 (sq, 3H); MS(ESI) m / z [M + H] + = 309.1.

[0272] Step 2: Dissolve 17-a (275.0 mg, 1.0 mmol), 4-fluoro-2-methylphenol (138.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) in N,N-dimethylformamide (7.0 mL), and react at 80 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 4:1 (v / v) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide (II-A-11) (363.0 mg, yield 87.7%). 1 H-NMR(400MHz,DMSO-d 6 ) δ: 10.87 (s, 1H), 8.18 (s, 1H), 8.02 (sd, J = 2.4 Hz, 1H), 7.92 - 7.94 (q, 1H), 7.80 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (s, 1H), 7.58 (st, 1H), 7.24 (dd, J = 9.2, 2.4 Hz, 1H), 7.10 - 7.20 (q, 2H), 6.84 (d, J = 8.8 Hz, 1H), 2.12 (s, 3H); MS(ESI) m / z [M+H] + = 415.1。

[0273] Step 3: Add N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide (II-A-11) (197.0 mg, 0.5 mmol), absolute ethanol (0.2 mL) and hydrochloric acid-ethyl acetate system (10N, 5.0 mL) into a sealed tube, and react with the tube sealed at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, then add ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (53.0 mg, 1 mmol), and reflux until the intermediate reaction is complete. After the reaction is complete, directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-17) (118 mg, yield 57%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.94 (s, 1H), 8.24 (s, 1H), 7.96 (sd, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.61 (t, J = 8.4 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.22 - 7.27 (m, 2H), 7.15 (t, J = 8.4 Hz, 1H), 6.82 (d, J = 9.0 Hz, 1H), 2.15 (s, 3H); MS(ESI) m / z [M + H] + = 432.2。

[0274] Example 18 Preparation of 5-Chloro-N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (I-18)

[0275]

[0276] First step: Dissolve 2-fluoro-5-chlorobenzoic acid (18-SM1) (1.0 g, 5.73 mmol) and m-aminobenzonitrile (710.6 mg, 6.02 mmol) in pyridine (9.0 mL). Slowly add phosphorus oxychloride (1.0 mL, 11.5 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to precipitate a solid to obtain compound (18-a) (360.0 mg, yield 24.4%). 1 H-NMR(400 MHz, DMSO-d 6 )δ: 10.89 (brs, 1H), 8.18 (s, 1H), 7.93 - 7.95 (sd, 1H), 7.78 - 7.80 (sq, 1H), 7.67 - 7.70 (sq, 1H), 7.59 - 7.61 (sq, 2H), 7.46 (t, 1H); MS(ESI) m / z [M + H] + = 275.0, 277.0 (3:1).

[0277] Step 2: 18-a (275.0 mg, 1.0 mmol), 4-fluoro-2-methylphenol (138.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) were added to N,N-dimethylformamide (7.0 mL), and the reaction was carried out at 80 °C. After the reaction was complete, the pH was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 4:1 (v / v) to obtain 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-12) (126.0 mg, yield 33.1%). 1 H-NMR(400MHz,CDCl 3 ) δ: 10.79 (s, 1H), 8.13 (s, 1H), 7.89 (sq, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.57 (s, 1H), 7.56 - 7.57 (sq, 1H), 7.51 (dd, J = 8.8, 2.4 Hz, 1H), 7.17 (dd, J = 9.6, 2.4 Hz, 1H), 7.01 - 7.10 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 2.15 (s, 3H); MS(ESI) m / z [M+H] + = 381.8。

[0278] Step 3: 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-12) (97.0 mg, 0.25 mmol), absolute ethanol (0.1 mL) and hydrochloric acid-ethyl acetate system (10N, 5.0 mL) were added to a sealed tube, and the reaction was carried out in the sealed tube at room temperature. After the reaction was complete and the intermediate was formed, the reaction system was evaporated to dryness, and then ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (30.0 mg, 1.0 mmol) were added, and the reaction was refluxed until the intermediate reaction was complete. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-18) (46.0 mg, yield 45%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.87 (s, 1H), 9.42 (brs, 2H), 9.21 (brs, 2H), 8.23 (s, 1H), 7.91 (d, J=6.0 Hz, 1H), 7.67 (s, 1H), 7.59 (brs, 1H), 7.50 (brs, 2H), 7.21 (d, J=10.0 Hz, 1H), 7.10 (brs, 2H), 6.73 (d, J=8.4 Hz, 1H), 2.15 (s, 3H); MS(ESI) m / z [M + H] + = 398.1。

[0279] Example 19 Preparation of 4,5 - Dichloro - N - (3 - carbamoylphenyl) - 2 - (4 - fluoro - 2 - methylphenoxy)benzamide (I - 19)

[0280]

[0281] First step: Dissolve 2 - fluoro - 4,5 - dichlorobenzoic acid (19 - SM1) (2.0 g, 9.6 mmol) and m - aminobenzonitrile (1.2 g, 10.0 mmol) in pyridine (15.0 mL). Slowly add phosphorus oxychloride (1.8 mL, 19.2 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to precipitate a solid to obtain compound (19 - a) (1.6 g, yield 54.1%). 1 1H - NMR (400 MHz, DMSO - d 6 )δ: 10.9 (s, 1H, NH), 8.17 (s, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.93 (t, 2H), 7.61 (t, 2H); MS(ESI) m / z [M + H] + = 309.0, 311.0 (3:1).

[0282] Second step: Add 19 - a (309.0 mg, 1.0 mmol), 4 - fluorophenol (123.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) to N,N - dimethylformamide (10.0 mL), and react at 80 °C until the raw materials are completely reacted. Cool, pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate to precipitate a large amount of solid, and filter to obtain 4,5 - dichloro - N - (3 - cyanophenyl) - 2 - (4 - fluorophenoxy)benzamide (II - A - 13) (216.0 mg, yield 53.9%). 1H-NMR(400MHz,DMSO-d 6 )δ: 10.81(s, 1H, NH), 8.10(s, 1H), 7.99(s, 1H), 7.87(d, J = 8Hz, 1H), 7.58(st, 2H), 7.18 - 7.26(m, 5H); MS(ESI) m / z [M+H] + = 401.0, 402.9(3:1).

[0283] Step 3: Add 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluorophenoxy)benzamide (II-A-13) (202.0 mg, 0.49 mmol), absolute ethanol (1.0 mL) and hydrochloric acid-ethyl acetate system (10 N, 5.0 mL) into a sealed tube, and react with the tube sealed at room temperature. After the reaction is complete and the intermediate is formed, evaporate the reaction system to dryness. Then add ammonia-methanol solution (7 N, 5.0 mL) and ammonium chloride (52.4 mg, 1 mmol), and reflux until the intermediate reaction is complete. After the reaction is complete, directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-19) (110.0 mg, yield 52%). 1 H-NMR(600MHz,DMSO-d 6 )δ: 10.91(brs, 1H), 8.19(s, 1H), 7.93(s, 1H), 7.88(brs, 1H), 7.59(t, J = 7.8Hz, 1H), 7.48(d, J = 7.2Hz, 1H), 7.27(t, J = 8.4Hz, 2H), 7.22(brs, 2H), 7.17(s, 1H); MS(ESI) m / z [M+H] + = 418.1 / 420.1(3:1).

[0284] Example 20 Preparation of 4,5-chloro-N-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (I-20)

[0285] Step 1: Dissolve 19-a (309.0 mg, 1.0 mmol) obtained in Example 19, 4-fluoro-2-methoxyphenol (156.3 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) in N,N-dimethylformamide (5.0 mL), and react at 80 °C until the raw materials react completely. Cool down, pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate to precipitate a solid, and filter to obtain 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-14) (300.0 mg, yield 69.6%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.75(s, 1H), 8.16(s, 1H), 7.93(s, 2H), 7.59(s, 2H), 7.28(q, 1H), 7.12(q, 1H), 6.88(s, 1H), 6.84(q, 1H), 3.74(s, 3H); MS(ESI) m / z [M+H] + = 432.1。

[0286] Step 2: Add 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-14) (200.0 mg, 0.49 mmol), absolute ethanol (1.0 mL) and hydrochloric acid-ethyl acetate system (10N, 5.0 mL) into a sealed tube, and react in the sealed tube at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, then add ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (50.0 mg, 1 mmol), and reflux until the intermediate reacts completely. Cool down and directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-20) (74.0 mg, yield 35.2%). 1 H-NMR(400MHz,DMSO-d 6 ): 10.79(brs, 1H), 8.24(s, 1H), 7.88 - 7.92(brs, 2H), 7.60(t, J = 8.0 Hz, 1H), 7.49(d, J = 7.6 Hz, 1H), 7.31(t, J = 8.0 Hz, 1H), 7.15(dd, J = 10.4, 3.2 Hz, 1H), 6.87(dd, J = 10.4, 3.2 Hz, 1H), 6.84(s, 1H), 3.76(s, 3H); MS(ESI) m / z [M+H] + = 448.1 / 450.1(3:1)。

[0287] Example 21 Preparation of 4-chloro-N-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (I-21)

[0288] First step: 16-a (275.0 mg, 1.0 mmol) obtained in Example 16, 4-fluoro-2-methoxyphenol (156.3 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) were added to N,N-dimethylformamide (7.0 mL), and the reaction was carried out at 80 °C. After the reaction was complete, the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain 4-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-15) (260.0 mg, yield 65.6%). 1 H-NMR(400MHz,DMSO-d 6 ) δ: 10.64(s, 1H), 8.18(s, 1H), 7.92(brs, 1H), 7.68(d, J = 8.4Hz, 1H), 7.56(d, J = 5.2Hz, 2H), 7.25 - 7.32(m, 2H), 7.13(dd, J = 10.8, 2.8Hz, 1H), 6.85(td, J = 8.4, 2.8Hz, 1H), 6.65(s, 1H), 3.75(s, 3H); MS(ESI) m / z [M + H] + 397.1, 389.9(3:1).

[0289] Second step: 4-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-15) (200.0 mg, 0.47 mmol), absolute ethanol (1.0 mL) and hydrochloric acid-ethyl acetate system (10N, 10.0 mL) were added to a sealed tube, and the reaction was carried out in the sealed tube at room temperature. After the reaction was complete to form the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 10.0 mL) and ammonium chloride (55.0 mg, 1 mmol) were added, and the reflux reaction was carried out until the intermediate reaction was complete. Then it was directly concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the solid target compound (I-21) (80.0 mg, yield 38%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.70 (s, 1H), 8.25 (s, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.88 (t, 1H), 6.61 (s, 1H), 3.77 (s, 3H); MS(ESI) m / z [M + H] + = 414.1 / 416.1 (3:1).

[0290] Example 22 Preparation of N-(3-carbamimidoyl phenyl)-4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)benzamide (I-22)

[0291] First step: Dissolve 19-a (309.0 mg, 1.0 mmol) obtained in Example 19, 3-fluoro-4-methoxyphenol (161.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) in N,N-dimethylformamide (10.0 mL), and react at 80 °C until the raw materials react completely. Cool, pour the reaction system into ice water, adjust the pH to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate to precipitate a large amount of solid, and filter to obtain 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)benzamide (II-A-16) (216.0 mg, yield 50.1%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.77 (s, 1H), 8.11 (s, 1H), 7.96 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.57 (sq, 2H), 7.14 - 7.21 (m, 3H), 6.95 (d, J = 6.6 Hz, 1H), 3.82 (s, 3H); MS(ESI) m / z [M + H] + = 431.0, 433.1 (3:1).

[0292] Step 2: 4,5-Dichloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)benzamide (II-A-16) (100.0 mg, 0.23 mmol), absolute ethanol (0.1 mL) and hydrochloric acid-dioxane system (4N, 10.0 mL) were added into a sealed tube, and the reaction was carried out in the sealed tube at room temperature. After the reaction was complete to form the intermediate, the reaction system was concentrated. Subsequently, ammonia-methanol solution (4N, 10.0 mL) and ammonium chloride (24.0 mg, 0.46 mmol) were added, and the reaction was carried out under reflux until the intermediate reaction was complete. Then it was directly concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the solid target compound (I-22) (50.0 mg, yield 48%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.90(s, 1H), 9.40(brs, 2H), 7.91(s, 1H), 7.90(d, 1H), 7.59(t, J = 9.6Hz, 1H), 7.50(d, J = 8.0Hz, 1H), 7.19 - 7.24(m, 2H), 7.14(s, 1H), 7.98(d, 1H), 3.83(s, 3H); MS(ESI) m / z[M + H] + = 448.1 / 450.1(3:1).

[0293] Example 23 Preparation of N-(5-carbamimidoyl-2-methylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-23)

[0294] Step 1: 2-Fluoro-4-trifluoromethylbenzoic acid (9-SM1) (1.0 g, 4.8 mmol) and 3-amino-4-methylbenzonitrile (667.0 mg, 5.05 mmol) from Example 9 were dissolved in pyridine (10.0 mL). Phosphorus oxychloride (0.9 mL, 9.6 mmol) was slowly added dropwise at 0 °C, and the temperature was controlled below 10 °C. After the addition was complete, the reaction was continued until the raw materials reacted completely. Subsequently, the reaction system was poured into ice water, and the pH value was adjusted to about 2 - 3 with 2N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to precipitate a solid, and filtered to obtain N-(5-cyano-2-methylphenyl)-2-fluoro-4-(trifluoromethyl)benzamide (23-a) (450.0 mg, yield 24.6%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.27 (s, 1H), 7.91 - 8.01 (m, 3H), 7.77 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H); MS(ESI) m / z [M + H] + = 323.1.

[0295] Step 2: Add N-(5-cyano-2-methylphenyl)-2-fluoro-4-(trifluoromethyl)benzamide (23-a) (322.0 mg, 1.0 mmol), 4-fluorophenol (123.3 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) into N,N-dimethylformamide (7.0 mL), and react at 80 °C. After the reaction is complete, adjust the pH to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain N-(5-cyano-2-methylphenyl)-2-(4-fluorophenoxy)-4-(trifluoromethyl)benzamide (II-A-23) (330.0 mg, yield 79.7%). 1 H-NMR(400 MHz, DMSO-d 6 )δ: 10.18 (s, 1H), 8.00 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.25 - 7.34 (m, 4H), 7.15 (s, 1H), 2.27 (s, 3H); MS(ESI) m / z [M + H] + = 415.1.

[0296] Step 3: Add N-(5-cyano-2-methylphenyl)-2-(4-fluorophenoxy)-4-(trifluoromethyl)benzamide (II-A-23) (200.0 mg, 0.48 mmol) and anhydrous ethanol (0.3 mL) into a sealed tube containing hydrochloric acid-dioxane system (4N, 12.0 mL), and react at room temperature with the tube sealed. After the reaction is complete, concentrate the reaction system to dryness to obtain the intermediate, then add ammonia-methanol solution (4N, 10.0 mL) and ammonium chloride (51.6 mg, 0.46 mmol), and reflux until the intermediate reaction is complete. Concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-23) (20.0 mg, yield 9.6%). 1 H-NMR(400 MHz, DMSO-d 6)δ: 10.27 (brs, 1H), 8.10 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.33 (m, 4H), 7.13 (s, 1H), 2.29 (s, 3H); MS(ESI) m / z [M + H] + = 432.1。

[0297] Example 24 Preparation of N-(3-carbamimidoylphenyl)-5-chloro-2-(4-fluoro-2-methoxyphenoxy)benzamide (I-24)

[0298] First step: Add 18-a (275.0 mg, 1.0 mmol) obtained in Example 18, 4-fluoro-2-methoxyphenol (156.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) to N,N-dimethylformamide (7.0 mL), and react at 80 °C until the raw materials react completely. Adjust the pH to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-18) (50.0 mg, yield 12.6%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.72 (brs, 1H), 8.18 (s, 1H), 7.93 (brs, 1H), 7.68 (sd, J = 2.4 Hz, 1H), 7.57 (d, J = 5.2 Hz, 2H), 7.47 (dd, J = 9.2, 2.8 Hz, 1H), 7.24 (q, 1H), 7.11 (dd, J = 10.4, 2.8 Hz, 1H), 6.80 - 6.86 (td, J = 10.4, 4.0 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H); MS(ESI) m / z [M + H] + = 397.1, 389.9 (3:1).

[0299] Step 2: Add 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-18) (50.0 mg, 0.13 mmol) and absolute ethanol (0.1 mL) into a hydrochloric acid-dioxane system (4N, 10 mL), and seal the reaction tube at room temperature. After the reaction is complete, concentrate the reaction system to obtain an intermediate. Subsequently, add ammonia-methanol solution (4N, 5 mL) and ammonium chloride (22.0 mg, 0.26 mmol), and reflux until the intermediate reaction is complete. Concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-24) (10.0 mg, yield 19.8%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.71(s, 1H), 8.26(s, 1H), 7.91(d, J = 8.4Hz, 1H), 7.65(s, 1H), 7.60(t, J = 7.8Hz, 1H), 7.48(t, J = 7.8Hz, 2H), 7.27(q, 1H), 7.14(dd, J = 10.8, 2.4Hz, 1H), 6.85(t, 1H), 6.68(d, J = 9.0Hz, 1H), 3.75(s, 3H); MS(ESI) m / z [M+H] + = 414.1 / 416.1(3:1).

[0300] Example 25 Preparation of N-(3-carbamimidoyl phenyl)-4-ethynyl-2-(4-fluoro-2-methylphenoxy)benzamide (I-25)

[0301]

[0302] Step 1: Add 4-bromo-2-fluorobenzonitrile (19-SM1) (4.0 g, 20.0 mmol), 4-fluoro-2-methylphenol (2.52 g, 20.0 mmol) and cesium carbonate (13.0 g, 40.0 mmol) into N,N-dimethylformamide (60.0 mL), and react at 80 °C until the main raw materials react completely. Add ethyl acetate and water, stir and separate the layers. The ethyl acetate phase is dried with anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain compound (19-a) (5.7 g, yield 93.1%). 1 H-NMR(400MHz,DMSO-d 6)δ: 7.87 (d, J = 8.4 Hz, 1H), 7.47 - 7.49 (dd, J = 8.4, 2.0 Hz, 1H), 7.28 - 7.31 (dd, J = 9.2, 3.2 Hz, 1H), 7.21 - 7.24 (q, 1H), 7.13 - 7.18 (td, J = 8.4, 3.2 Hz, 1H), 6.85 (s, 1H), 2.15 (s, 3H); MS(ESI) m / z [M + H] + = 305.1, 307.1 (1:1).

[0303] Step 2: Add 19-a (5.0 g, 16.3 mmol) to methanol (100.0 mL), then add sodium hydroxide (6.6 g, 16.3 mmol) and water (20.0 mL), and reflux the reaction until complete hydrolysis. Concentrate, remove methanol, add water for dilution, adjust the pH value to acidic with dilute hydrochloric acid, a large amount of solid precipitates, and filter to obtain compound (19-b) (3.9 g, yield 73.4%). MS(ESI) m / z [M + H] + = 325.0, 327.0 (1:1).

[0304] Step 3: Dissolve 19-b (3.9 g, 12.0 mmol) and m-aminobenzonitrile (1.42 g, 12.0 mmol) in pyridine (20.0 mL), slowly add phosphorus oxychloride (2.25 mL, 24.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials react completely. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate to obtain the crude product, and recrystallize the crude product with ethyl acetate to obtain compound (19-c) (1.4 g, yield 27.5%). MS(ESI) m / z [M + H] + = 425.0, 427.0 (1:1).

[0305] Step 4: Under nitrogen protection, add 19-c (850.0 mg, 2.0 mmol), trimethylsilylacetylene (294.5 mg, 3.0 mmol), copper(I) iodide (76.0 mg, 0.02 mmol), tetrakis(triphenylphosphine)palladium(0) (206.0 mg, 0.2 mmol) and triethylamine (0.56 mL, 4.0 mmol) to toluene (10 mL), and reflux the reaction until the main raw materials react completely. Cool, pour the reaction system into ice water, extract with ethyl acetate, dry, and concentrate to obtain the crude product. The crude product is chromatographed on a column with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain compound (19-d) (600.0 mg, yield 67.8%). 1 H-NMR(400 MHz, DMSO-d 6)δ: 10.75 (s, 1H), 8.15 (s, 1H), 7.90 (brs, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.56 (sd, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 10.0 Hz, 1H), 7.09 (m, 2H), 6.69 (s, 1H), 2.15 (s, 3H), 0.20 (s, 9H); MS(ESI) m / z [M + H] + = 443.2。

[0306] Step 5: 19-d (331.0 mg, 0.75 mmol) was added to formic acid (10 mL) and reacted at 80 °C. After concentration, the crude product was obtained. The crude product was purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 4:1 (v / v) to obtain 110.0 mg of compound (II-A-19). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.75 (s, 1H), 8.14 (s, 1H), 7.90 (brs, 1H), 7.66 (d, J = 5.2 Hz, 1H), 7.56 (d, 2H), 7.33 (d, J = 5.2 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H), 7.07 - 7.08 (brs, 2H), 6.75 (s, 1H), 4.37 (s, 1H), 2.15 (s, 3H); MS(ESI) m / z [M + H] + = 371.2。

[0307] Step 6: N-(3-cyanophenyl)-4-ethynyl-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-19) (65.0 mg, 0.175 mmol) and absolute ethanol (0.1 mL) were added to a hydrochloric acid-ethyl acetate system (10 N, 10.0 mL), and the reaction was carried out in a sealed tube at room temperature. After the reaction was complete to form the intermediate, the reaction system was evaporated to dryness. Ammonia-methanol solution (4 N, 8.0 mL) and ammonium chloride (18.7 mg, 0.34 mmol) were added, and the reaction was refluxed until the intermediate reaction was complete. Subsequently, it was directly concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-25) (37.0 mg, yield 54.4%). 1 H-NMR (400 MHz, DMSO-d 6)δ: 10.79 (brs, 1H), 8.26 (s, 1H), 7.87 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 9.2 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.11 (brm, 2H), 6.70 (s, 1H), 4.38 (s, 1H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 388.2.

[0308] Example 26 Preparation of N-(3-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(4-methyl-1-pentyn-1-yl)benzamide (I-26)

[0309] First step: Under nitrogen protection, 19-c (425.0 mg, 1.0 mmol) obtained in Example 25, 4-methyl-1-pentyne (353 mg, 3.0 mmol), copper(I) iodide (38.0 mg, 0.01 mmol), tetrakis(triphenylphosphine)palladium(0) (103 mg, 0.1 mmol) and triethylamine (0.28 mL, 2.0 mmol) were added to toluene (10.0 mL) and reacted under reflux until the main raw materials reacted completely. After cooling, the reaction system was poured into ice water, extracted with ethyl acetate, dried, and concentrated to obtain a crude product. The crude product was column chromatographed with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(4-methyl-1-pentyn-1-yl)benzamide (II-A-20) (280.0 mg, yield 80.8%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.69 (s, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 4.8 Hz, 2H), 7.23 (d, J = 7.8 Hz, 1H), 7.17 - 7.19 (dd, J = 9.0, 2.4 Hz, 1H), 7.06 - 7.08 (q, 2H), 2.29 (d, J = 6.6 Hz, 2H), 2.15 (s, 3H), 1.79 - 1.83 (m, 1H), 0.96 (s, 3H), 0.95 (s, 3H); MS(ESI) m / z [M + H] + = 427.1.

[0310] Step 2: Add N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(4-methyl-1-pentyn-1-yl)benzamide (II-A-20) (140 mg, 0.34 mmol) and absolute ethanol (0.1 mL) to hydrochloric acid / ethyl acetate (10 N, 16.0 mL), and react in a sealed tube at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, add ammonia-methanol solution (7 N, 3.0 mL) and ammonium chloride (35.0 mg, 0.68 mmol), and reflux until the intermediate reaction is complete. Then directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-26) (65.0 mg, yield 44.6%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.75(brs,1H), 8.24(s,1H), 7.89(d,J = 8.0Hz,1H), 7.61(t,2H), 7.49(d,J = 7.6Hz,1H), 7.22(t,2H), 7.10(brs,2H), 6.59(s,1H), 2.29(d,J = 5.6Hz,2H), 2.16(s,3H), 0.95(sd,J = 5.6Hz,3H); MS(ESI) m / z [M+H] + = 443.8.

[0311] Example 27 Preparation of N-(3-carbamimidoyl phenyl)-6-chloro-5-fluoro-(4-fluoro-2-methylphenoxy)-nicotinamide (I-27)

[0312]

[0313] Step 1: Dissolve 2,6-dichloro-5-fluoronicotinic acid (27-SM1) (1.05 g, 5.0 mmol) and 3-aminobenzonitrile (587 mg, 5.0 mmol) in pyridine (4.0 mL), slowly add phosphorus oxychloride (0.9 mL, 2.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials react completely. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 4:1 (v / v) to obtain compound (27-a) (500.0 mg, yield 32.3%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.10 (s, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.60 - 7.66 (m, 2H); MS(ESI) m / z [M + H] + = 311.0, 311.9 (3:1).

[0314] Step 2: Add 27-a (310.0 mg, 1.0 mmol), 4-fluoro-2-methylphenol (126.0 mg, 1.1 mmol), copper(I) iodide (2.0 mg, 0.01 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) to toluene (7.0 mL), and react at 100 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N-(3-cyanophenyl)-6-chloro-5-fluoro-(4-fluoro-2-methylphenoxy)-nicotinamide (II-A-21) (100.0 mg, yield 25%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.96 (s, 1H), 8.38 (d, J = 9.2 Hz, 1H), 8.15 (s, 1H), 7.898 (td, 1H), 7.58 - 7.63 (m, 2H), 7.25 - 7.28 (dd, J = 6.8, 4.0 Hz, 2H), 7.12 - 7.17 (td, 8.0, 3.2 Hz, 1H), 2.14 (s, 3H); MS(ESI) m / z [M + H] + = 399.9, 401.9 (3:1).

[0315] Step 3: Add N-(3-cyanophenyl)-6-chloro-5-fluoro-(4-fluoro-2-methylphenoxy)-nicotinamide (II-A-21) (100.0 mg, 0.25 mmol) and absolute ethanol (0.2 mL) to the hydrochloric acid-ethyl acetate system (10N, 16.0 mL), and react in a sealed tube at room temperature. After the reaction is complete, evaporate the reaction system to dryness, add ammonia-methanol solution (7N, 5.0 mL), ammonium chloride (27.0 mg, 0.5 mmol), and reflux until the raw materials react completely. Then directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-27) (40.0 mg, yield 38.4%). 1 1H-NMR (600 MHz, DMSO-d 6)δ: 11.03 (brs, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 8.4 Hz, 7.8 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.26 - 7.28 (dt, 2H), 7.13 - 7.17 (td, J = 9.0, 3.0 Hz, 1H), 2.15 (s, 3H); MS(ESI) m / z [M + H] + = 416.7.

[0316] Example 28 Preparation of N-(3-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (I-28)

[0317]

[0318] First step: Dissolve 2-fluorobenzoic acid (28-SM1) (1.4 g, 10.0 mmol) and m-aminobenzonitrile (1.2 g, 10.0 mmol) in pyridine (8.0 mL). Slowly add phosphorus oxychloride (1.9 mL, 20.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain 1.0 g of compound (28-a). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.77 (s, 1H), 8.21 (s, 1H), 7.96 (brm, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.58 - 7.64 (m, 3H), 7.38 (q, J = 7.6 Hz, 2H); MS(ESI) m / z [M + H] + = 241.1.

[0319] Step 2: Under nitrogen protection, 28-a (480.0 mg, 2.0 mmol), 4-fluoro-2-methylphenol (252.0 mg, 2.0 mmol), cesium carbonate (1.3 mg, 4.0 mmol) and copper(I) iodide (38.0 mg, 0.2 mmol) were added to toluene (20.0 mL), and the reaction was carried out at 90 °C. After the reaction was complete, it was poured into ice water, and the pH was adjusted to about 2 - 3 with 2N dilute hydrochloric acid. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain 320.0 mg of N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-22). 1 H-NMR(400MHz,DMSO-d 6 )δ:10.70(s,1H),8.15(s,1H),7.92(brs,1H),7.65(dd,J=7.6,1.6Hz,1H),7.55(d,J=5.2Hz,2H),7.47(t,J=8.4Hz,1H),7.23(t,J=8.0Hz,1H),7.16(dd,J=9.2,2.8Hz,1H),6.99~7.06(q,2H),6.77(d,J=8.4Hz,1H),2.16(s,3H);MS(ESI)m / z[M+H] + =346.8。

[0320] Step 3: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-22) (250.0 mg, 0.72 mmol) and absolute ethanol (0.4 mL) were added to a hydrochloric acid-ethyl acetate system (10N, 14.0 mL), and the reaction was carried out in a sealed tube at room temperature. After the reaction was complete to form the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (77.0 mg, 1.4 mmol) were added, and the reaction was refluxed until the intermediate reaction was complete. Subsequently, it was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-28) (74.0 mg, yield 28.6%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.74 (s, 1H), 8.27 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.64 (dd, J = 7.6, 1.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.44 - 7.50 (q, 2H), 7.18 - 7.24 (q, 2H), 7.08 (d, J = 6.4 Hz, 2H), 6.72 (d, J = 8.4 Hz, 1H), 2.17 (s, 3H); MS(ESI) m / z [M + H] + = 363.8.

[0321] Example 29 Preparation of N-(3-carbamimidoyl phenyl)-5-fluoro-(4-fluoro-2-methyl phenoxy)-6-methyl nicotinamide (I-29)

[0322]

[0323] First step: Ethyl 5-chloro-2-fluoro-6-methyl nicotinate (29-SM1) (434.0 mg, 2.0 mmol), 4-fluoro-2-methyl phenol (252.0 mg, 2.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and copper(I) iodide (38.0 mg, 0.2 mmol) were added to toluene (20.0 mL), and the mixture was refluxed at 100 °C. After the reaction was complete, the pH was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain the target compound (29-a) (440.0 mg, yield 67%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 8.24 (s, 1H), 7.17 (dd, J = 9.2, 2.4 Hz, 1H), 7.05 - 7.12 (q, 2H), 4.31 (q, 2H), 2.33 (s, 3H), 2.08 (s, 3H), 1.30 (t, J = 6.8 Hz, 3H); MS(ESI) m / z [M + H]+ = 323.8.

[0324] Second step: Ethyl 5-chloro-2-(4-fluoro-2-methyl phenoxy)-6-methyl nicotinate (29-a) (323.0 mg, 1.0 mmol) was dissolved in sodium hydroxide solution (10N, 5.0 mL), methanol (8.0 mL) was added, and the mixture was refluxed at 80 °C for 1 h. Methanol was removed by concentration, water was added, and the pH was adjusted to about 2 - 3 with 2N dilute hydrochloric acid. A large amount of white solid precipitated, and after standing, it was filtered and dried to obtain 290.0 mg of 5-chloro-2-(4-fluoro-2-methyl phenoxy)-6-methyl nicotinic acid (29-b) for direct use in the next step;

[0325] Dissolve 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid (29-b) (140.0 mg, 0.5 mmol) and 3-aminobenzonitrile (59.2 mg, 0.5 mmol) in pyridine (4 mL). Slowly add phosphorus oxychloride (0.1 mL, 1.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate to dryness, and recrystallize from ethyl acetate to obtain compound (II-A-23) (150.0 mg, yield 78.9%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.85 (s, 1H), 8.90 (s, 1H), 8.52 (brs, 1H), 8.22 (s, 1H), 8.21 (s, 1H), 7.95 - 8.02 (dd, 2H), 7.59 (s, 1H), 7.58 (s, 1H), 7.20 - 7.24 (q, 1H), 7.10 - 7.18 (dd, 1H), 7.05 - 7.10 (td, 1H), 2.34 (s, 3H), 2.09 (s, 3H); MS (ESI) m / z [M + H]+ = 395.7.

[0326] Step 3: Add N-(3-cyanophenyl)-5-fluoro-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (II-A-23) (100.0 mg, 0.25 mmol) and absolute ethanol (0.2 mL) to a hydrochloric acid - ethyl acetate system (10N, 10.0 mL), and react in a sealed tube at room temperature. After the reaction is complete to form the intermediate, concentrate the reaction system. Then add ammonia - methanol solution (7N, 5.0 mL) and ammonium chloride (27.0 mg, 0.5 mmol), and reflux until the intermediate is completely reacted. Then directly concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-29) (32 mg, yield 30.7%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 10.91 (brs, 1H), 8.26 (brs, 1H), 8.19 (s, 1H), 7.96 (d, 1H), 7.61 (t, 1H), 7.53 (d, 1H), 7.08 - 7.24 (q, 3H), 2.36 (s, 3H), 2.09 (s, 3H); MS (ESI) m / z [M + H] + = 413.7.

[0327] Preparation of Example 30 N-(3-carbamoylphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (I-30)

[0328]

[0329] First step: Dissolve 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (30-SM1) (628.0 mg, 2.2 mmol) and m-aminobenzonitrile (272.0 mg, 2.3 mmol) in pyridine (3.5 mL). Slowly add phosphorus oxychloride (0.4 mL, 4.4 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain compound (30-a) (430.0 mg, yield 50.6%). 1 H-NMR(400MHz,CDCl 3 )δ:11.31(brs,1H),8.15(s,1H),7.90(brs,3H),7.65(brs,2H);MS(ESI)m / z[M+H] + =387.0,389.0(1:1).

[0330] Second step: Add 30-a (200.0 mg, 0.52 mmol), 4-fluoro-2-methylphenol (1-SM2) (78.2 mg, 0.62 mmol), cesium carbonate (336.0 mg, 2.0 mmol), and copper(I) iodide (9.0 mg, 0.05 mmol) to toluene (10.0 mL), and reflux the reaction at 100 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain compound (II-A-24) (90.0 mg, yield 67%). 1 H-NMR(400MHz,DMSO-d 6 )δ:11.28(s,1H),8.16(s,1H),7.90(d,J=7.6Hz,1H),7.82(t,J=9.2Hz,1H),7.58~7.62(m,2H),7.14~7.28(td,3H),6.63(d,J=8.8Hz,1H),2.13(s,3H);MS(ESI)m / z[M+H]+=433.1.

[0331] Step 3: Add N-(3-cyanophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (II-A-24) (90.0 mg, 0.21 mmol) and absolute ethanol (0.1 mL) to a hydrochloric acid-ethyl acetate system (10 N, 10.0 mL), and seal the reaction tube at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, then add ammonia-methanol solution (7 N, 8.0 mL) and ammonium chloride (23.0 mg, 1.4 mmol), and reflux until the intermediate reaction is complete. Then directly concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-30) (30.0 mg, yield 30%). 1 H-NMR(600MHz,DMSO-d 6 )δ: 11.34(s, 1H), 9.41(s, 1.5H), 9.07(s, 1.5H), 8.24(s, 1H), 7.91(d, J = 7.8 Hz, 1H), 7.81(t, J = 9.0 Hz, 1H), 7.63(t, J = 7.8 Hz, 1H), 7.52(d, J = 7.8 Hz, 1H), 7.27 - 7.29(dd, J = 9.0, 3.0 Hz, 1H), 7.23 - 7.25(q, 1H), 7.15 - 7.18(td, J = 8.4, 3.0 Hz, 1H), 6.61(d, J = 9.0 Hz, 1H), 2.14(s, 3H); MS(ESI) m / z [M + H] + = 450.1。

[0332] Preparation of N-(3-carbamimidoyl phenyl)(4-fluoro-2-methylphenoxy)-nicotinamide (I-31) in Example 31

[0333] Step 1: Dissolve 2-chloronicotinic acid (31-SM1) (3.0 g, 19.04 mmol) and m-aminobenzonitrile (2.25 g, 19.04 mmol) in pyridine (20.0 mL), slowly add phosphorus oxychloride (3.55 mL, 38.08 mmol) dropwise at 0 °C, control the temperature below 10 °C, after the addition is complete, continue the reaction until the raw materials react completely, then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2 N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is recrystallized from ethyl acetate to obtain 2-chloro-N-(3-benzonitrile)nicotinamide (31-a) (301 mg, yield 6.13%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.02 (s, 1H), 8.57 (dd, J = 4.8, 1.9 Hz, 1H), 8.19 - 8.17 (m, 1H), 8.13 (dd, J = 7.6, 1.9 Hz, 1H), 7.92 (dt, J = 6.7, 2.4 Hz, 1H), 7.65 - 7.57 (m, 3H); MS(ESI) m / z [M + H]+ = 257.8.

[0334] Step 2: Add 2-chloro-N-(3-cyanophenyl)nicotinamide (31-a) (250.0 mg, 0.97 mmol), 4-fluoro-2-methylphenol (122.4 mg, 0.97 mmol), cesium carbonate (632.2 mg, 1.94 mmol), and copper(I) iodide (1.85 mg, 0.0097 mmol) into toluene (6.0 mL), and reflux the reaction at 100 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 20:1 (v / v) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-nicotinamide (II-A-25) (158 mg, yield 46.89%). 1 1H-NMR(400MHz, DMSO-d 6 )δ: 10.82 (s, 1H), 8.22 (dd, J = 4.8, 2.0 Hz, 2H), 8.13 (dd, J = 7.4, 2.0 Hz, 1H), 7.97 (q, J = 4.8, 4.0 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.25 (ddd, J = 13.8, 8.1, 5.0 Hz, 2H), 7.16 (dd, J = 9.4, 3.2 Hz, 1H), 7.08 (td, J = 8.6, 3.2 Hz, 1H), 2.07 (s, 3H); MS(ESI) m / z [M + H]+ = 347.8.

[0335] Step 3: Add N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-nicotinamide (II-A-25) (100.0 mg, 0.2 mmol) and absolute ethanol (0.2 mL) into a hydrochloric acid-ethyl acetate system (10N, 10.0 mL), and react in a sealed tube at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, add ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (21 mg, 0.4 mmol), and reflux the reaction until the intermediate reaction is complete. Then directly concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-31) (34 mg, yield 48.4%). 1H-NMR(400MHz,DMSO-d 6 )δ:10.88(brs,1H),8.30(brs,1H),8.24(brs,1H),8.11(brs,1H),7.96(brs,1H),7.62(brs,1H),7.52(brs,1H),7.27(brs,2H),7.18(brs,1H),7.09(s,1H),2.08(s,3H); MS(ESI) m / z [M+H] + = 365.8。

[0336] Preparation of methyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)phenyl)(imino)methyl)carbamate (I-32) in Example 32

[0337] Dissolve N-(3-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-3) (215 mg, 0.5 mmol) obtained in Example 3 in tetrahydrofuran (10.0 mL), cool to about 0 °C, add sodium hydroxide (10 N, 74.76 mmL), and then slowly add methyl chloroformate (56.5 mg, 0.6 mmol). React at room temperature until the raw materials react completely. Then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-32) (160.0 mg, yield 65.6%). 1 H-NMR(400MHz,DMSO-d 6 )δ:10.73(brs,1H),9.10(brs,2H),8.33(s,1H),7.84(s,2H),7.64(s,1H),7.59(s,1H),7.47(s,1H),7.22(s,1H),7.11(s,2H),6.95(s,1H),3.62(s,3H),2.17(s,3H); MS(ESI) m / z [M+H] + = 489.7。

[0338] Preparation of ethyl N-(3-carbamimidoyl phenyl)methyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)phenyl)(imino)methyl)carbamate (I-33) in Example 33

[0339] Dissolve N-(3-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-3) (215.0 mg, 0.5 mmol) obtained in Example 3 in tetrahydrofuran (10.0 mL). Cool to about 0 °C and add sodium hydroxide (10 N, 74.8 mmol). Subsequently, slowly add ethyl chloroformate (64.8 mg, 0.6 mmol) and react at room temperature until the raw materials are completely reacted. Then extract with ethyl acetate, dry the organic phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-33) (70 mg, yield 27.9%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.76(brs,1H), 9.15(brs,2H), 8.37(brs,1H), 7.87~7.89(brs,2H), 7.68(brs,1H), 7.60(t,1H), 7.48(q,1H), 7.22(t,1H), 7.13(brs,2H), 6.97(s,1H), 4.00(brs,2H), 3.37(s,3H), 2.19(brs,3H); MS(ESI) m / z[M + H] + = 503.7。

[0340] Example 34 Preparation of N-(3-carbamimidoyl phenyl)-5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-34)

[0341] First step: Dissolve 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (34-SM1) (485.0 mg, 2.0 mmol) and m-aminobenzonitrile (268.3 mg, 2.0 mmol) in pyridine (6.0 mL). Slowly add phosphorus oxychloride (0.38 mL, 4.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to precipitate a solid to obtain off-white 5-chloro-N-(3-cyanophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (34-a) (469.0 mg, yield 58.3%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.04 (s, 1H), 8.17 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 14.4 Hz, 1H), 7.91 - 7.94 (dt, J = 10.8, 2.4 Hz, 1H), 7.64 (s, 1H), 7.60 (q, 1H); MS(ESI) m / z [M + H] + = 343.1.

[0342] Step 2: Add 5-chloro-N-(3-cyanophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (34-a) (342.0 mg, 1.0 mmol), 4-fluoro-2-methylphenol (140.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) into N,N-dimethylformamide (7.0 mL), and react at 100 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-26) (380.0 mg, yield 84.8%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.93 (s, 1H), 8.07 (s, 1H), 8.05 (s, 1H), 7.82 - 7.8 (dt, 1H), 7.56 (t, 2H), 7.17 (d, J = 8.8 Hz, 1H), 7.05 - 7.09 (q, 3H), 2.13 (s, 3H); MS(ESI) m / z [M + H] + = 448.8..

[0343] Step 3: Add 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-26) (224.0 mg, 0.5 mmol) and absolute ethanol (0.2 mL) into a hydrochloric acid-ethyl acetate system (10N, 10.0 mL), and react in a sealed tube at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness, add ammonia-methanol solution (4N, 10 mL) and ammonium chloride (54.0 mg, 1 mmol), and reflux until the intermediate reaction is complete, then concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-34) (120.0 mg, yield 51.6%); 1 1H-NMR (400 MHz, DMSO-d 6)δ: 11.06 (brs, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.23 (dd, J = 9.6, 3.2 Hz, 1H), 7.11 - 7.17 (m, 2H), 7.05 (s, 1H), 2.17 (s, 3H); MS(ESI) m / z [M + H] + = 465.9。

[0344] Example 35 Preparation of N-(3-(N-cyanoaminocarbonimidoyl)phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-35)

[0345] N-(3-Cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) (115.0 mg, 0.25 mmol) obtained in Example 1 and absolute ethanol (0.2 mL) were added to a hydrochloric acid - ethyl acetate system (10 N, 10.0 mL), and the reaction was carried out in a sealed tube at room temperature. After the reaction was complete to form the intermediate, the residue obtained by evaporating the reaction system to dryness was dissolved in ethanol, and then 50% aqueous cyanamide solution (0.21 mL) was added and the reaction was refluxed until the intermediate reaction was complete. Subsequently, ammonia - methanol solution (4 N, 10.0 mL) was added and the reflux reaction was continued. After the reaction was complete, it was concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 4 - 2:1 (v / v) to obtain N-(3-(N-cyanoaminocarbonimidoyl)phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-35) (43.0 mg, yield 37.7%); 1 1H-NMR (400 MHz, DMSO-d6) δ: 10.75 (s, 1H), 8.69 (brs, 1H), 8.24 (brs, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.48 (t, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 7.2 Hz, 2H), 6.95 (s, 1H), 6.21 (brs, 1H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 456.9。

[0346] Example 36 Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-formylaminocarbonimidoyl)phenyl)-4-(trifluoromethyl)benzamide (I-36)

[0347] Dissolve N-(3-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-3) (43.0 mg, 0.01 mmol) obtained in Example 3 in acetonitrile (5.0 mL), then add formic acid (13.8 mg, 0.03 mmol) and zinc powder (1.3 mg, 0.2 eq), and react under reflux until completely clear. Then extract with ethyl acetate, dry the organic phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20:1 (v / v) to obtain the target compound (I-36) (45.0 mg, yield 98%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.93(s, 1H), 10.03(brs, 1H), 9.19(brs, 1H), 8.30(s, 1H), 8.22(s, 1H), 7.84 - 7.90(q, 2H), 7.57 - 7.62(q, 2H), 7.48(d, J = 7.2Hz, 1H), 7.23(d, J = 8.0Hz, 1H), 7.13(q, 2H), 6.94(s, 1H), 2.17(s, 3H); MS(ESI) m / z[M - 29] + = 432.0。

[0348] Preparation of N-(2-carbamoylpyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-37) in Example 37

[0349] Dissolve 2-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxycarbamoylamino)pyridin-4-yl)-4-(trifluoromethyl)benzamide (I-4) (112.0 mg, 0.25 mmol) obtained in Example 4 in methanol (10.0 mL), then add ammonium formate (157.0 mg, 2.5 mmol) and freshly prepared magnesium powder (60.0 mg, 2.5 mmol) washed with 0.5N dilute hydrochloric acid and acetone and dried, and react at 40 °C until the raw materials are completely reacted. Then extract with ethyl acetate, dry the organic phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20:1 (v / v) to obtain the target compound (I-37) (20.0 mg, yield 18.5%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.47 (brs, 1H), 9.55 (brs, 1H), 9.30 (brs, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 7.79 - 7.90 (m, 2H), 7.64 (s, 1H), 7.24 (s, 1H), 7.13 - 7.17 (m, 2H), 6.95 (s, 1H), 4.43 (1H, NH), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 433.0.

[0350] Example 38 Synthesis of N-(3-carbamoylphenyl)-2-(2-cyclopropyl-4-fluorophenoxy)-4-(trifluoromethyl)benzamide (Preparation of I-38)

[0351] First step: Add 2-bromo-4-fluorophenol (1.33 g, 6.96 mmol), potassium phosphate (5.12 g, 24.4 mmol), tricyclohexylphosphine (218.2 mg, 0.696 mmol), and cyclopropylboronic acid (897.0 mg, 10.4 mmol) to a mixture of toluene (30.0 mL) and water (1.5 mL), and displace with argon 3 times. Add palladium acetate (78.1 mg, 0.35 mmol), displace with argon 3 times, and reflux at 100 °C for 16 h. After the reaction is complete, extract with ethyl acetate, dry the ethyl acetate phase with anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is purified by passing through a silica gel column (200 - 300 mesh) with petroleum ether to obtain 2-cyclopropyl-4-fluorophenol (38-a) (943.0 mg, yield 89.0%). 1 H-NMR (400 MHz, CDCl 3 )δ: 6.8 - 6.71 (m, 3H), 1.87 - 1.78 (m, 1H), 1.04 - 0.95 (m, 2H), 0.68 - 0.60 (m, 2H); MS(EI) m / z [M] + = 153.

[0352] Step 2: Add N-(3-benzonitrile)-2-fluoro-4-(trifluoromethyl)benzamide (9-a) (1.0 g, 3.24 mmol), 2-cyclopropyl-4-fluorophenol (38-a) (518.4 mg, 3.41 mmol), and cesium carbonate (2.11 g, 6.49 mmol) into N,N-dimethylformamide (10.0 mL), and react at 100 °C. After the reaction is complete, add water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by column chromatography with petroleum ether:ethyl acetate = 40:1 (v / v) to obtain N-(3-benzonitrile)-2-(2-cyclopropyl-4-fluorophenoxy)-4-(trifluoromethyl)benzamide (II-A-27) (840.0 mg, yield 58.8%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.92(s, 1H), 8.20~8.14(m, 1H), 7.96~7.85(m, 2H), 7.64~7.56(m, 3H), 7.20~7.12(m, 1H), 7.07(td, J = 8.4, 3.0Hz, 1H), 6.94(d, J = 1.6Hz, 1H), 6.85(dd, J = 10.1, 3.0Hz, 1H), 2.06~1.97(m, 1H), 0.88~0.78(m, 2H), 0.73~0.64(m, 2H); MS(ESI) m / z[M+H] + = 441.0。

[0353] Step 3: Add N-(3-benzonitrile)-2-(2-cyclopropyl-4-fluorophenoxy)-4-(trifluoromethyl)benzamide (II-A-27) (200.0 mg, 0.454 mmol) and absolute ethanol (2.6 mL) into a hydrochloric acid-ethyl acetate system (10N, 7.0 mL), and react in a sealed tube at room temperature. After the reaction is complete, concentrate to obtain the intermediate for the next step directly. Add absolute methanol (4.0 mL), ammonia-methanol solution (5.0 mL), and 2eq ammonium chloride to the intermediate, and reflux until the intermediate reacts completely. After the reaction is complete, concentrate directly to obtain the crude product. The crude product is purified by silica gel column chromatography with dichloromethane:methanol = 20:1 (v / v) (200 - 300 mesh) to obtain the target compound (I-38) (91 mg, yield 43.8%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.03 (s, 1H), 9.41 (s, 2H), 9.29 (s, 2H), 8.28 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 9.0, 5.1 Hz, 1H), 7.08 (td, J = 8.4, 3.0 Hz, 1H), 6.86 (q, J = 3.6 Hz, 2H), 2.02 - 1.97 (m, 1H), 0.86 - 0.80 (m, 2H), 0.69 (d, J = 5.4 Hz, 2H); MS(ESI) m / z [M + H] + = 458.0

[0354] Example 39 Preparation of N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4,5-dimethoxybenzamide (I-39)

[0355] First step: Dissolve 2-bromo-4,5-dimethoxybenzoic acid (3.0 g, 11.5 mmol) and m-aminobenzonitrile (1.43 g, 12.1 mmol) in pyridine (8.0 mL). Slowly add phosphorus oxychloride (2.14 mL, 23 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain 3.2 g of crude 2-bromo-N-(3-cyanophenyl)-4,5-dimethoxybenzamide (39-a), which is directly used in the next step. MS(ESI) m / z [M + H] + = 362.9

[0356] Second step: Dissolve 2-bromo-N-(3-cyanophenyl)-4,5-dimethoxybenzamide (39-a) (3.0 g, 8.31 mmol), 4-fluoro-2-methylphenol (1.1 g, 8.72 mmol), cesium carbonate (5.4 g, 16.6 mmol), and copper(I) iodide (15.8 mg, 0.083 mmol) in N,N-dimethylformamide (10 mL) and react at 80 °C. After the reaction is completed, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:dichloromethane = 1:1 (v / v) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4,5-dimethoxybenzamide (II-A-28) (832 mg, yield 24.6%). 1 1H-NMR(400 MHz, DMSO-d6 )δ: 10.42 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 6.7 Hz, 1H), 7.54 - 7.46 (m, 2H), 7.27 (dd, J = 8.0, 3.2 Hz, 1H), 7.06 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.70 (td, J = 9.0, 4.6 Hz, 1H), 6.62 (dd, J = 8.0, 3.2 Hz, 1H), 3.81 (s, 3H), 3.72 (s, 3H), 2.22 (s, 3H); MS(ESI) m / z [M + H] + = 407.0。

[0357] Step 3: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4,5-dimethoxybenzamide (II-A-28) (200.0 mg, 0.492 mmol) and absolute ethanol (2.0 mL) were added to a hydrochloric acid-ethyl acetate system (10 N, 6.0 mL), and the reaction was carried out in a sealed tube at room temperature. After the raw materials were completely reacted, the reaction system was evaporated to dryness to obtain the crude intermediate. Subsequently, absolute methanol (3.0 mL), ammonia-methanol solution (5.0 mL), and 2 eq ammonium chloride were added, and the reaction was refluxed until the intermediate was completely converted. After the reaction was complete, it was concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20:1 (v / v) to obtain the target compound (I-39) (93 mg, yield 44.6%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.43 (s, 1H), 9.35 (s, 2H), 9.06 (s, 2H), 8.33 (s, 1H), 8.19 (t, J = 2.0 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.27 (s, 1H), 7.12 (dd, 1H), 6.78 (dd, 1H), 6.57 (s, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 2.25 (s, 3H); MS(ESI) m / z [M + H]+ = 424.1。

[0358] Example 40 Preparation of N-(4-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-40)

[0359] Step 1: Under a dry system, 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) (314.0 mg, 1.0 mmol) obtained in Example 1 and m-aminobenzonitrile (0.4 g, 3.34 mmol) were added to anhydrous pyridine (4.0 mL) for dissolution. After cooling to about 0 °C, phosphorus oxychloride (0.5 mL, 5 mmol) was slowly added dropwise while controlling the temperature below 10 °C. After the addition was complete, the reaction was continued until the raw materials reacted completely. Subsequently, the reaction system was poured into ice water, and the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, and then extracted with dichloromethane. The organic phase was dried and concentrated to obtain N-(4-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-B-1) (295 mg, yield 71.3%). 1 H-NMR(400MHz,CDCl 3 )δ:10.17(s,1H),8.75(d,J=8.4Hz,1H),8.97(d,J=8.8Hz,2H),7.94(d,J=8.8Hz,2H),7.77(d,J=8.4Hz,1H),7.33~7.42(m,3H),7.15(s,1H),2.54(s,3H);MS(ESI)m / z[M+H]+=451.1。

[0360] Step 2: N-(4-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-B-1) (250.0 mg, 0.6 mmol), absolute ethanol (0.1 mL) and hydrogen chloride - ethyl acetate system (10N, 20.0 mL) were added to a sealed reaction flask and reacted at room temperature until the raw materials were completely converted into the intermediate. Subsequently, the solvent was concentrated to remove to obtain the crude intermediate, and the corresponding Pinner salt intermediate 163 mg of solid was obtained by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 40:1 (v / v). 1 H-NMR(400MHz,CDCl 3 )δ:9.77(s,1H),8.87(d,J=8.4Hz,1H),7.77(d,J=8.8Hz,2H),7.70(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,1H),7.00~7.12(m,3H),6.87(s,1H),4.31(q,J=7.2Hz,2H),2.26(s,3H),1.43(t,J=7.2Hz,3H);MS(ESI)m / z[M+H] + =461.1。

[0361] The Pinner salt intermediate (92.0 mg, 0.2 mmol) and ammonium chloride (20.8 mg, 0.4 mmol) were added to an ammonia - methanol system (12 mL) and reacted under reflux. The reaction mixture was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20:1 - 15:1 (v / v) to obtain the solid N-(4-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-40) (45 mg, yield 47.4%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 11.04(brs,1H), 7.84~7.89(q,5H), 7.62(d,J = 8.0Hz,1H), 7.21(d,J = 8.0Hz,1H), 7.10(d,2H), 7.00(s,1H), 2.16(s,3H); MS(ESI) m / z [M+H] + = 432.1。

[0362] Example 41 Preparation of N-(3-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)-4-methoxybenzamide (I-41)

[0363] First step: 2-Bromo-4-methoxybenzoic acid (41-SM1) (300.0 mg, 1.30 mmol) and 3-aminobenzonitrile (153.4 mg, 1.30 mmol) were dissolved in pyridine (4.0 mL). Phosphorus oxychloride (0.242 mL, 2.60 mmol) was slowly added dropwise at 0 °C, and the temperature was controlled below 10 °C. After the addition was complete, the reaction was continued until the raw materials were completely reacted. Subsequently, the reaction system was poured into ice water, and the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain 2-bromo-N-(3-cyanophenyl)-4-methoxybenzamide (41-a) (150 mg, yield 34.9%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.73(s,1H), 8.18(s,1H), 7.94(td,J = 4.8,2.2Hz,1H), 7.59~7.52(m,3H), 7.30(d,J = 2.4Hz,1H), 7.08(dd,J = 8.6,2.4Hz,1H), 3.83(s,3H); MS(ESI) m / z [M+H] + = 332.7。

[0364] Step 2: Dissolve 2-bromo-N-(3-benzonitrile)-4-methoxybenzamide (41-a) (250.0 mg, 0.755 mmol), 4-fluoro-2-methylphenol (95.2 mg, 0.755 mmol), cesium carbonate (491.9 mg, 1.51 mmol), and copper(I) iodide (1.4 mg, 0.00755 mmol) in toluene (7.35 mL), and reflux the reaction mixture at 100 °C. After the reaction is complete, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 20:1 (v / v) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-methoxybenzamide (II-A-29) (239.0 mg, yield 84.1%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.44(s, 1H), 8.13(s, 1H), 7.90(s, 1H), 7.70(d, J = 8.8Hz, 1H), 7.53(d, J = 4.8Hz, 2H), 7.17(d, J = 9.2Hz, 1H), 7.02(d, J = 5.8Hz, 2H), 6.84(d, J = 9.2Hz, 1H), 6.24(s, 1H), 3.74(s, 3H), 2.17(s 3H); MS(ESI) m / z [M + H] + = 376.8。

[0365] Step 3: Add N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-methoxybenzamide (II-A-29) (100 mg, 0.27 mmol) to anhydrous ethanol (0.1 mL) and hydrochloric acid - ethyl acetate (6 mL), and seal the reaction tube at room temperature. After the reaction is complete, evaporate the reaction system to dryness, add anhydrous methanol (3 mL), ammonia - methanol solution (5 mL), and 2eq ammonium chloride, and reflux the reaction mixture at 65 °C. After the reaction is complete, concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20:1 (v / v) to obtain N-(3-carbamimidoyl phenyl)-2-(4-fluoro-2-methylphenoxy)-4-methoxybenzamide (I-41) (35.0 mg, yield 33.5%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.49 (s, 1H), 8.23 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.20 (d, J = 9.2 Hz, 1H), 7.08 (sd, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.18 (s, 1H), 3.72 (s, 3H), 2.18 (s, 3H); MS(ESI) m / z [M + H] + = 393.8。

[0366] Example 42 Preparation of N-(2-(N-Acetamidino)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-42)

[0367] 2-(4-Fluoro-2-methylphenoxy)-N-(2-(N-hydroxycarbamimidoyl)pyridin-4-yl)-4-(trifluoromethyl)benzamide (I-4) (112.0 mg, 0.25 mmol), acetic anhydride (30.6 mg, 0.3 mmol) and 5% palladium / carbon (10 mg) were added to acetic acid (5 mL). The mixture was purged with nitrogen three times, then purged with hydrogen three times and hydrogenated until the raw material was completely converted. After filtration and concentration, the crude product was obtained. The crude product was purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20:1 - 15:1 (v / v) to obtain N-(2-(N-acetamidino)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-42) (45.0 mg, yield 38.9%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 8.62 (d, J = 5.6 Hz, 1H), 8.47 (s, 1H), 7.88 (t, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 9.2, 2.0 Hz, 1H), 7.11 - 7.15 (m, 2H), 6.95 (s, 1H), 2.16 (s, 3H), 1.77 (s, 3H); MS(ESI) m / z [M + H] + = 475.1。

[0368] Example 43 Preparation of N-(3-Aminimidoyl-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-43)

[0369] Step 1: Synthesis of N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-30)

[0370] Under a dry system, 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) (628.0 mg, 2.0 mmol) obtained in Example 1 and 4-amino-2-fluorobenzonitrile (286.0 mg, 2.1 mmol) were added to anhydrous pyridine (3.0 mL) for dissolution. After cooling to about 0 °C, phosphorus oxychloride (0.4 mL, 4.1 mmol) was slowly added dropwise, controlling the temperature below 10 °C. After the addition was complete, the reaction was continued until the raw materials were completely reacted. Subsequently, the reaction system was poured into ice water, and the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, and then extracted with dichloromethane. The organic phase was dried and concentrated to obtain a crude product. The crude product was chromatographed on a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-30) (558.0 mg, yield 64.6%). 1 H-NMR(400MHz,DMSO-d 6 )δ:10.93(brs,1H),8.17(brs,1H),7.90(brs,2H),7.60(brs,2H),7.12(t,4H),2.14(s,3H);ESI[M+H] + =433.0。

[0371] Step 2: Synthesis of N-(3-carbamimidoyl-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-43)

[0372] N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-30) (216 mg, 0.5 mmol) and anhydrous ethanol (0.3 mL) were added to a hydrochloric acid-ethyl acetate system (10N, 10.0 mL), and the reaction was carried out in a sealed tube at room temperature. After the raw materials were completely reacted, the reaction system was evaporated to dryness to obtain a Pinner salt. Subsequently, anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 5.0 mL), and 2eq ammonium chloride were added, and the reaction was refluxed until the intermediate was completely reacted. After the reaction was complete, it was directly concentrated to obtain a crude product. The crude product was chromatographed on a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20:1 (v / v) to obtain the target compound (I-43) (38 mg, yield 16.9%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.96 (brs, 1H), 9.54 (brs, 2H), 9.25 (brs, 1H), 8.09~8.11 (m, 1H), 7.83~7.78 (m, 2H), 7.61 (d, J=8.8 Hz, 1H), 7.49 (t, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.11~7.15 (m, 2H), 6.95 (s, 1H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 450.1。

[0373] Example 44 Preparation of N-(3-carbamoylphenyl)-2-(2-chloro-4-fluorophenoxy)-4-(trifluoromethyl)benzamide (I-44)

[0374] First step: Add N-(3-benzonitrile)-2-fluoro-4-(trifluoromethyl)benzamide (9-a) (1.0 g, 3.24 mmol), 2-chloro-4-fluorophenol (523 mg, 3.57 mmol), and cesium carbonate (2.11 g, 6.49 mmol) to N,N-dimethylformamide (10.0 mL), and react at 60 °C. After the reaction is complete, extract with ethyl acetate, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, dry with anhydrous sodium sulfate, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:dichloromethane = 1:1 (v / v) to obtain 2-(2-chloro-4-fluorophenoxy)-N-(3-benzonitrile)-4-(trifluoromethyl)benzamide (II-A-31) (180 mg, yield 12.8%). 1 H-NMR(400 MHz, DMSO-d 6 )δ: 10.91 (s, 1H), 8.13 (s, 1H), 7.97~7.88 (m, 3H), 7.68 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.5, 2.5 Hz, 1H), 7.58 (s, 1H), 7.31 (dd, J=7.6, 3.7 Hz, 2H), 7.12 (s, 1H); MS(ESI) m / z [M + H] + = 434.9。

[0375] Step 2: 2-(2-Chloro-4-fluorophenoxy)-N-(3-benzonitrile)-4-(trifluoromethyl)benzamide (II-A-31) (170 mg, 0.391 mmol) and absolute ethanol (2.0 mL) were added to a hydrochloric acid-ethyl acetate system (10 N, 6.0 mL), and the reaction was carried out in a sealed tube at room temperature. After the reaction was complete, the reaction system was concentrated to obtain the Pinner salt. Subsequently, absolute methanol (3.0 mL), ammonia-methanol solution (7 N, 5.0 mL), and 2 eq of ammonium chloride were added, and the reaction was refluxed until the Pinner salt reaction was complete. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 30:1 (v / v) to obtain the target compound (I-44), (21 mg, yield 11.9%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 11.00(s, 1H), 9.39(s, 2H), 9.17(s, 2H), 8.25(s, 1H), 7.88(t, J = 8.4 Hz, 2H), 7.69~7.64(m, 2H), 7.60(t, J = 8.0 Hz, 1H), 7.50(d, J = 7.8 Hz, 1H), 7.44~7.39(m, 1H), 7.34(td, J = 8.4, 2.9 Hz, 1H), 7.06(s, 1H); MS(ESI) m / z [M + H] + = 451.9.

[0376] Example 45 Preparation of N-(3-carbamimidoyl-4-fluorophenyl)-4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide (I-45)

[0377] Step 1: 2-Fluoro-4,5-dichlorobenzoic acid (1.0 g, 4.8 mmol) and 5-amino-2-fluorobenzonitrile (684.0 mg, 5.0 mmol) were dissolved in pyridine (15.0 mL). Phosphorus oxychloride (1.8 mL, 19.2 mmol) was slowly added dropwise at 0 °C, and the temperature was controlled below 10 °C. After the addition was complete, the reaction was continued until the raw materials reacted completely. Subsequently, the reaction system was poured into ice water, and the pH value was adjusted to about 2 - 3 with 2 N hydrochloric acid. It was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to precipitate a solid to obtain 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-fluorobenzamide (45-a) (1.1 g, yield 74.3%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.96 (s, 1H), 8.21 (brs, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.98 (brs, 1H), 7.93 (d, J = 9.6 Hz, 1H), 7.57 (t, J = 8.8 Hz, 1H); MS(ESI) m / z [M + H] + = 326.9, 328.9 (3:1).

[0378] Step 2: Add 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-fluorobenzamide (45-a) (327.0 mg, 1.0 mmol), 4-fluoro-2-methylphenol (132 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) into N,N-dimethylformamide (5.0 mL), and react at 80 °C until the raw materials are completely reacted. Cool down, pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N dilute hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate to precipitate a large amount of solid, and filter to obtain 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-32) (220 mg, yield 50.8%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.84 (s, 1H), 8.14 (brs, 1H), 7.98 (s, 1H), 7.93 (brs, 1H), 7.54 (t, J = 8.8 Hz, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 6 Hz, 2H), 6.98 (s, 1H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 432.8, 434.6 (3:1).

[0379] Step 3: Add 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-32) (200 mg, 0.46 mmol) and absolute ethanol (0.25 mL) into a hydrochloric acid-ethyl acetate system (10N, 10.0 mL), and react in a sealed tube at room temperature. After the reaction is complete, evaporate the reaction system to dryness to obtain the Pinner salt, then add absolute methanol (3.0 mL), ammonia-methanol solution (7N, 13 mL), 2eq ammonium chloride, and reflux until the Pinner salt is completely reacted. After the reaction is complete, directly concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol = 20:1 (v / v) to obtain the target compound (I-45) (15 mg, yield 7.2%). 1 H-NMR (400 MHz, DMSO-d 6)δ: 10.93 (brs, 1H), 9.55 (brs, 2H), 9.31 (brs, 2H), 8.08 (s, 1H), 7.86 - 7.94 (brs, 2H), 7.49 (s, 1H), 7.13 - 7.20 (brs, 3H), 6.93 (s, 1H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 449.9, 451.9 (3:1).

[0380] Example 46 Preparation of N-(3-carbamimidoylphenyl)-6-(4-fluoro-2-methylphenoxy)benzene[d][1,3]dioxole-5-carboxamide (I-46)

[0381] First step: Dissolve 6-bromobenzene[d][1,3]dioxole-5-carboxylic acid (46-SM1) (735 mg, 3.0 mmol) and 3-aminobenzonitrile (372 mg, 3.2 mmol) in pyridine (10.0 mL). Slowly add phosphorus oxychloride (0.6 mL, 2.0 mmol) dropwise at 0 °C, control the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 4:1 (v / v) to obtain compound (46-a) (200.0 mg). 1 H-NMR(400MHz, DMSO-d 6 )δ: 10.73 (s, 1H), 8.17 (s, 1H), 7.93 (brs, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.33 (s, 1H), 7.23 (s, 1H), 6.15 (s, 2H); MS(ESI) m / z [M + H] + = 344.7, 346.7 (1:1).

[0382] Step 2: 46-a (200.0 mg, 0.58 mmol), 4-fluoro-2-methylphenol (87.8 mg, 0.7 mmol), copper(I) iodide (11.0 mg, 0.06 mmol) and cesium carbonate (377.6 mg, 1.2 mmol) were added to toluene (10.0 mL), and the reaction was carried out at 100 °C. After the reaction was complete, the pH value was adjusted to about 2 - 3 with 2N dilute hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain N-(3-cyanophenyl)-6-(4-fluoro-2-methylphenoxy)benzo[d][1,3]dioxole-5-carboxamide (II-A-34) (80.0 mg, yield 30.6%). 1 H-NMR(400MHz,DMSO-d 6 ) δ: 10.50 (brs, 1H), 8.08 (s, 1H), 7.50 (s, 1H), 7.52 (d, 4.8 Hz, 2H), 7.24 (s, 1H), 7.08 - 7.11 (dd, J = 9.2, 2.8 Hz, 1H), 6.9 - 7.01 (td, J = 8.8, 3.2 Hz, 1H), 6.80 - 6.83 (q, 1H), 6.59 (s, 1H), 6.12 (s, 2H), 2.19 (s, 3H); MS(ESI) m / z [M+H] + = 391.0.

[0383] Step 3: N-(3-cyanophenyl)-6-(4-fluoro-2-methylphenoxy)benzo[d][1,3]dioxole-5-carboxamide (II-A-34) (50.0 mg, 0.13 mmol) and absolute ethanol (0.2 mL) were added to a hydrochloric acid-ethyl acetate system (10N, 10.0 mL), and the reaction was carried out in a sealed tube at room temperature. After the reaction was complete, the reaction system was evaporated to dryness to obtain the crude Pinner salt. Subsequently, ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (10.0 mg, 0.24 mmol) were added, and the reaction was refluxed until the Pinner salt reaction was complete. Then it was directly concentrated to obtain the crude product. The crude product was purified by silica gel column (200 - 300 mesh) with dichloromethane:methanol = 20 - 15:1 (v / v) to obtain the target compound (I-46) (10.0 mg). 1 H-NMR(600MHz,DMSO-d 6)δ: 10.53 (s, 1H), 8.21 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 7.23 (s, 1H), 7.13 - 7.15 (dd, J = 9.0, 3.0 Hz, 1H), 7.00 - 7.03 (td, J = 9.0, 3.0 Hz, 1H), 6.89 - 6.91 (q, 1H), 6.53 (s, 1H), 6.12 (s, 2H), 2.22 (s, 2H); MS(ESI) m / z [M + H] + = 408.0。

[0384] Example 47 Preparation of 2-(4-Fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-47)

[0385] First step: First, add methyl 2-chloro-6-(trifluoromethyl)nicotinate (478.0 mg, 2.00 mmol), 4-fluoro-2-methylphenol (251.9 mg, 2.00 mmol), cesium carbonate (1.3 g, 4.0 mmol) and copper(I) iodide (38.0 mg, 0.2 mmol) to toluene (20 mL), displace with nitrogen, and then heat to 100 °C for reaction until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. The organic phase is dried and concentrated to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 100 - 50:1 (v / v) to obtain methyl 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinate (468.0 mg, yield 71%). 1 H-NMR(400 MHz, CDCl 3 )δ: 8.38 d, J = 7.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.03 - 7.07 (q, 1H), 6.96 (dd, J = 9.2, 2.4 Hz, 1H), 6.90 (td, J = 8.4, 3.2 Hz, 1H), 3.98 (s, 3H), 2.15 (s, 3H); ESI [M + Na] + = 330.1。

[0386] Step 2: Methyl 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinate (400.0 mg, 1.21 mmol) was added to 95% ethanol (20 mL), and then sodium hydroxide (5 N, 2.43 mL, 12.15 mmol) was added. The reaction was carried out under reflux until the raw material was completely hydrolyzed into an acid. The mixture was concentrated, water was added, and then the pH value was adjusted to about 2 - 3 with hydrochloric acid to precipitate a large amount of white solid. The solid was filtered and dried to obtain 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinic acid (329.0 mg, yield 85.9%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 8.48 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.19 - 7.22 (dd, J = 9.2, 3.2 Hz, 1H), 7.17 (t, 3.6 Hz, 1H), 7.06 - 7.11 (td, J = 8.4, 3.2 Hz, 1H), 2.07 (s, 3H); MS(ESI) m / z [M+H] + = 316.1。

[0387] Step 3: In a reaction flask equipped with a drying tube, 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinic acid (325.0 mg, 1.03 mmol) was first dissolved in dichloromethane (20 mL). After adding a catalytic amount of DMF, the reaction system was cooled to about 0 °C, and then oxalyl chloride (0.8 mL, 10.31 mmol) was slowly added dropwise. After the addition was complete, the reaction was carried out at room temperature until all the acid was converted into an acyl chloride. The reaction system was concentrated to remove the excess oxalyl chloride and dichloromethane, and the residue was dissolved in dichloromethane and cooled to about 0 °C. Triethylamine (0.29 mL, 2.06 mmol) was slowly added, and then 5-amino-2-fluorobenzonitrile (140.4 mg, 1.03 mmol) was added. The reaction was carried out at room temperature until the reaction was complete. Water was added, and it was neutralized with dilute hydrochloric acid. The dichloromethane phase was separated by standing and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 4:1 (v / v) was used to elute through a silica gel column (200 - 300 mesh) to obtain N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinamide (358.0 mg, yield 80%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.04 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.23 - 8.25 (q, J = 5.6, 2.8 Hz, 1H), 7.96 - 8.00 (m, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 8.8 Hz, 1H), 7.25 - 7.29 (q, J = 8.8, 5.2 Hz, 1H), 7.20 (dd, J = 9.6, 3.2 Hz, 1H), 7.08 - 7.13 (td, J = 8.4, 3.2 Hz, 1H), 2.08 (s, 3H); MS(ESI) m / z [M + H] + = 434.1。

[0388] Step 4: N-(3-Cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinamide (100.0 mg, 0.23 mmol), triethylamine (140.1 mg, 1.38 mmol) and hydroxylamine hydrochloride (32.1 mg, 0.46 mmol) were added to absolute ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then columned (200 - 300 mesh) with dichloromethane:methanol (v / v) = 10 - 20:1 to obtain 2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(trifluoromethyl)nicotinamide (I-47) (55.0 mg, yield 51%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.75 (s, 1H), 9.68 (s, 1H), 8.35 (d, J = 7.2 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J = 7.2 Hz, 2H), 7.26 - 7.30 (m, 2H), 7.20 (d, J = 9.2 Hz, 1H), 7.11 (t, J = 8.4 Hz, 1H), 5.85 (brs, 2H), 2.09 (s, 3H); MS(ESI) m / z [M + H] + = 467.0。

[0389] Example 48 Preparation of 2-Fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-methoxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-48)

[0390] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.00 g, 6.97 mmol), 4-fluoro-2-methylphenol (1-SM2) (1.05 g, 8.36 mmol), cesium carbonate (4.54 g, 13.94 mmol) and copper(I) iodide (265.4 mg, 1.39 mmol) to toluene (50 mL). Replace the air with nitrogen, then heat to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (2.3 g, yield 64.8%), which is directly used for the next step. MS (ESI) m / z [M+H] + = 332.9.

[0391] Step 2: Dissolve 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (210.0 mg, 1.00 mmol) and 5-amino-2-fluorobenzonitrile (143.6 mg, 1.06 mmol) in anhydrous pyridine (4 mL, 49.71 mmol). Cool to about 0 °C and slowly add phosphorus oxychloride (0.2 mL, 2.01 mmol) while controlling the temperature below 10 °C. After the addition is complete, continue the reaction until the raw materials are completely reacted. Then pour the reaction system into ice water, adjust the pH value to about 2 - 3 with 2N hydrochloric acid, extract with ethyl acetate, dry with anhydrous sodium sulfate, and evaporate to dryness to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (150.0 mg, yield 33%). 1 1H-NMR (400 MHz, DMSO-d 6 ) δ: 11.30 (s, 1H), 8.19 (s, 1H), 7.92 - 7.96 (m, 1H), 7.82 (t, J = 8.8 Hz, 1H), 7.57 (t, J = 9.2 Hz, 1H), 7.26 (dd, J = 9.2, 2.8 Hz, 1H), 7.13 - 7.22 (m, 2H), 6.63 (d, J = 9.2 Hz, 1H), 2.13 (s, 3H); MS (ESI) m / z [M+H] + = 450.9

[0392] Step 3: Add N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (250.0 mg, 0.55 mmol), absolute ethanol (0.16 mL, 2.8 mmol), and hydrogen chloride-ethyl acetate system (10 N, 50.0 mL) into a sealed reaction flask and react at room temperature until the raw material is completely converted into the intermediate Pinner salt. Subsequently, concentrate to remove the solvent to obtain the crude intermediate Pinner salt. Then dissolve it in absolute ethanol, and then add triethylamine (1.54 mL, 11.10 mmol) and methoxylamine hydrochloride (463.6 mg, 5.55 mmol) and react under reflux until the Pinner salt is completely converted. Then add ammonia-methanol system (7 N, 4.2 mL) and react under reflux to obtain the target product. Subsequently, concentrate to obtain the crude product, and then use petroleum ether:ethyl acetate = 10:1 - 4:1 (v / v) to pass through a silica gel column (200 - 300 mesh) to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-methoxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-48) (31.0 mg, yield 11.0%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 11.01(s, 1H), 7.77~7.83(q, 2H), 7.71~7.75(m, 1H), 7.24~7.29(m, 2H), 7.20~7.23(m, 1H), 7.13~7.18(m, 1H), 6.60(d, J = 8.8Hz, 1H), 6.15(brs, 2H), 3.70(s, 3H), 2.14(s, 3H); MS(ESI)m / z[M + H] + = 497.8。

[0393] Example 49 Preparation of 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)-6-(2-(trifluoromethyl)phenoxy)benzamide (I-49)

[0394] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0 mg, 1.0 mmol), 2-(trifluoromethyl)phenol (194.5 mg, 1.20 mmol), cesium carbonate (651.6 mg, 2.00 mmol), and copper(I) iodide (38.1 mg, 0.2 mmol) to toluene (50.00 mL). Replace the air with nitrogen, then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) using petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl)phenoxy)benzoic acid (110.0 mg, yield 27%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 7.80 (d, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 8.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 8.4 Hz, 1H); MS(ESI) m / z [M+H] + = 269.0。

[0395] Step 2: In a reaction flask equipped with a drying tube, dissolve 2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl)phenoxy)benzoic acid (95.0 mg, 0.26 mmol) in dichloromethane (10 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, then slowly add oxalyl chloride (327.5 mg, 2.58 mmol). After the addition is complete, react at room temperature until the acid is completely converted to the acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (52.2 mg, 0.52 mmol), then add 5-amino-2-fluorobenzonitrile (38.6 mg, 0.28 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) using petroleum ether:ethyl acetate = 8 - 4:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl)phenoxy)benzamide (74.0 mg, yield 58.9%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.30 (s, 1H), 8.12 - 8.14 (q, 1H), 7.88 - 7.91 (m, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H); MS(ESI) m / z [M + H] + = 487.1。

[0396] Step 3: N-(3-Cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl)phenoxy)benzamide (70.0 mg, 0.14 mmol), triethylamine (145.65 mg, 1.44 mmol) and hydroxylamine hydrochloride (40.0 mg, 0.58 mmol) were added to absolute ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then chromatographed on a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 40 - 20:1 (v / v) to obtain 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)-6-(2-(trifluoromethyl)phenoxy)benzamide (44.0 mg, 58.8%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.96 (s, 1H), 9.68 (s, 1H), 7.88 (t, J = 8.4 Hz, 1H), 7.84 - 7.75 (m, 3H), 7.65 (m, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 5.86 (brs, 2H); MS(ESI) m / z [M + H] + = 520.1。

[0397] Example 50 Preparation of 2-(4-Fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-5-(trifluoromethyl)nicotinamide (I-50)

[0398] Step 1: First, add methyl 2-chloro-5-(trifluoromethyl)nicotinate (586.0 mg, 2.45 mmol), 4-fluoro-2-methylphenol (1-SM2) (308.8 mg, 2.45 mmol), cesium carbonate (1.6 g, 4.89 mmol) and copper(I) iodide (46.6 mg, 0.24 mmol) to toluene (20 ml), displace with nitrogen, and then heat to 100 °C for reaction until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. The organic phase is dried and concentrated to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 100 - 50:1 (v / v) to obtain methyl 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinate (667.0 mg, yield 82.8%). 1 H-NMR(400MHz,CDCl 3 )δ: 8.50(s, 1H), 8.47(s, 1H), 6.99 - 7.06(m, 2H), 6.92 - 6.97(m, 1H), 4.00(s, 3H), 2.15(s, 3H); MS(ESI) m / z [M + H] + = 330.1。

[0399] Step 2: Add methyl 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinate (500.0 mg, 1.52 mmol) to 95% ethanol (20 mL), then add sodium hydroxide (5N, 607.4 mg, 15.2 mmol) and react under reflux until the raw material is completely hydrolyzed into acid. Concentrate, add water, and then adjust the pH value to about 2 - 3 with hydrochloric acid to precipitate a large amount of white solid. Filter and dry to obtain 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinic acid (440.0 mg, yield 91.9%). MS(ESI) m / z [M + H] + =(316.1)。

[0400] Step 3: In a reaction flask equipped with a drying tube, first dissolve 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinic acid (315.0 mg, 1.0 mmol) in dichloromethane (10 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (1.27 g, 10.00 mmol). After the addition is complete, react at room temperature until the acid is completely converted to acyl chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (202.2 mg, 2.00 mmol), and then add 5-amino-2-fluorobenzonitrile (136.0 mg, 1.0 mmol). React at room temperature until the reaction is complete, add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 5:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinamide (230.0 mg, yield 53%). 1 H-NMR(400MHz,DMSO-d 6 )δ:9.83(s,1H),8.97(d,J=2.4Hz,1H),8.54(d,J=2.0Hz,1H),8.09~8.11(q,1H),7.85~7.89(m,1H),7.27(t,J=8.8Hz,1H),7.04~7.16(m,3H),2.22(s,3H);MS(ESI)m / z[M+H] + =434.1。

[0401] Step 4: Add N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinamide (185.0 mg, 0.43 mmol), triethylamine (432.0 mg, 4.27 mmol) and hydroxylamine hydrochloride (118.7 mg, 1.71 mmol) to absolute ethanol, and react under reflux until the raw materials react completely. Concentrate, add water, and extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product, and then purify it by column chromatography (200 - 300 mesh) with dichloromethane:methanol = 40 - 20:1 to obtain 2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-5-(trifluoromethyl)nicotinamide (120.0 mg, yield 60%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.72 (s, 1H), 9.67 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 7.88 (s, 1H), 7.77 (s, 1H), 7.24 - 7.29 (m, 2H), 7.19 (d, J = 9.2 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 5.84 (s, 1H), 2.09 (s, 3H); MS(ESI) m / z [M + H] + = 467.1。

[0402] Example 51 Preparation of 2 - fluoro - 6 - (4 - fluoro - 2 - methylphenoxy) - N - (4 - fluoro - 3 - (N - hydroxycarbamoyl)phenyl) - 3 - (trifluoromethyl)benzamide (I - 51)

[0403] N - (3 - Cyano - 4 - fluorophenyl) - 2 - fluoro - 6 - (4 - fluoro - 2 - methylphenoxy) - 3 - (trifluoromethyl)benzamide (112.0 mg, 0.25 mmol) [see Step 2 of Example 48], triethylamine (151.0 mg, 1.49 mmol) and hydroxylamine hydrochloride (34.6 mg, 0.50 mmol) were added to absolute ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then chromatographed on a column (200 - 300 mesh) with dichloromethane:methanol = 40 - 20:1 (v / v) to obtain 2 - fluoro - 6 - (4 - fluoro - 2 - methylphenoxy) - N - (4 - fluoro - 3 - (N - hydroxycarbamoyl)phenyl) - 3 - (trifluoromethyl)benzamide (I - 51) (80.0 mg, yield 66.5%). 1 H - NMR (400 MHz, DMSO - d 6 )δ: 10.98 (brs, 1H), 9.67 (brs, 1H), 7.85 - 7.87 (dd, 1H), 7.79 (t, 1H), 7.69 - 7.72 (m, 1H), 7.26 (t, 2H), 7.21 (t, 1H), 7.15 (td, 1H), 6.61 (d, J = 8.8 Hz, 1H), 5.84 (brs, 2H), 2.13 (s, 3H); MS(ESI) m / z [M + H] + = 483.9。

[0404] Example 52 Preparation of 2 - fluoro - N - (4 - fluoro - 3 - (N - hydroxycarbamoyl)phenyl) - 6 - (2 - methyl - 4 - (trifluoromethoxy)phenoxy) - 3 - (trifluoromethyl)benzamide (I - 52)

[0405] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (340.0 mg, 1.2 mmol), 2-methyl-4-(trifluoromethoxy)phenol (230.6 mg, 1.2 mmol), cesium carbonate (771.9 mg, 2.4 mmol) and copper(I) iodide (45.1 mg, 0.24 mmol) to toluene (20 mL). Replace the air with nitrogen, then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 2-fluoro-6-(2-methyl-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzoic acid (320.0 mg, yield 67.8%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 7.79 (t, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 2.18 (s, 3H); MS(ESI) m / z [M+H] + = 399.1。

[0406] Step 2: In a reaction flask equipped with a drying tube, dissolve 2-fluoro-6-(2-methyl-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzoic acid (289.0 mg, 0.73 mmol) in dichloromethane (10 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, then slowly add oxalyl chloride (921.1 mg, 7.26 mmol). After the addition is complete, react at room temperature until the acid is completely converted to the acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (146.9 mg, 1.45 mmol), then add 5-amino-2-fluorobenzonitrile (108.7 mg, 0.80 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 4:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(2-methyl-4-trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (280 mg, yield 74%). 1 H-NMR(600MHz,DMSO-d 6)δ: 11.30 (s, 1H), 8.16 (q, J = 12.0, 3.0 Hz, 1H), 7.91 - 7.94 (m, 1H), 7.85 (t, J = 9.0 Hz, 1H), 7.56 (t, J = 9.6 Hz, 1H), 7.42 (s, 1H), 7.31 (d, J = 10.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 2.18 (s, 3H); MS(ESI) m / z [M + H] + = 517.1。

[0407] Step 3: N-(3-Cyano-4-fluorophenyl)-2-fluoro-6-(2-methyl-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (143.0 mg, 0.28 mmol), triethylamine (168.1 mg, 1.66 mmol) and hydroxylamine hydrochloride (38.5 mg, 0.55 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials reacted completely. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then columned (200 - 300 mesh) with dichloromethane:methanol (v / v) = 40 - 20:1 to obtain 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(2-methyl-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (I-52) (66.0 mg, yield 43.4%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.99 (s, 1H), 9.66 (s, 1H), 7.79 - 7.86 (m, 2H), 7.67 - 7.71 (m, 1H), 7.42 (s, 1H), 7.22 - 7.30 (m, 3H), 6.69 (d, J = 8.8 Hz, 1H), 5.83 (brs, 2H), 2.18 (s, 3H); MS(ESI) m / z [M + H] + = 550.1。

[0408] Example 53 Preparation of 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (I-53)

[0409] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (345.0 mg, 1.20 mmol), 2-methoxy-4-(trifluoromethoxy)phenol (249.7 mg, 1.20 mmol), cesium carbonate (783.3 mg, 2.40 mmol) and copper(I) iodide (45.8 mg, 0.24 mmol) to toluene (20.0 mL). Replace the air with nitrogen, then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 2:1 (v / v) to obtain 2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzoic acid (342.0 mg, yield 68.7%). 1 H-NMR(400MHz,DMSO-d 6 )δ:7.74(t,J=8.8Hz,1H),7.32(d,J=8.8Hz,1H),7.28(sd,J=2.8Hz,1H),7.03(d,J=8.8Hz,1H),6.61(d,J=8.8Hz,1H),3.79(s,3H);MS(ESI)m / z[M+H] + =415.1。

[0410] Step 2: In a reaction flask equipped with a drying tube, first dissolve 2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzoic acid (324.0 mg, 0.78 mmol) in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, then slowly add oxalyl chloride (0.6 mL, 7.82 mmol). After the addition is complete, react at room temperature until all the acid is converted to the acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (158.3 mg, 1.56 mmol), then add 5-amino-2-fluorobenzonitrile (117.1 mg, 0.86 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 2:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(2-methoxy-4-trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (334.0 mg, yield 82.6%). 1 H-NMR(400MHz,CDCl 3)δ: 8.42 (s, 1H), 7.92 - 7.94 (m, 1H), 7.81 - 7.85 (q, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.19 - 7.26 (q, J = 8.4 Hz, 2H), 6.96 (d, 2H), 6.56 (d, J = 8.8 Hz, 1H), 3.87 (s, 3H); MS(ESI) m / z [M + H] + = 533.1。

[0411] Step 3: N-(3-Cyano-4-fluorophenyl)-2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (188.0 mg, 0.35 mmol), triethylamine (107.2 mg, 1.06 mmol) and hydroxylamine hydrochloride (49.1 mg, 0.70 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then chromatographed on a column (200 - 300 mesh) with dichloromethane:methanol (v / v) = 40 - 20:1 to obtain 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (I-53) (77.0 mg, yield 38.6%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.85 (s, 1H), 9.66 (s, 1H), 7.86 (dd, J = 6.4, 2.8 Hz, 1H), 7.77 (t, J = 8.4 Hz, 1H), 7.70 - 7.74 (m, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 7.25 (t, J = 9.2 Hz, 1H), 7.05 (d, J = 10.4 Hz, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.83 (brs, 2H), 3.80 (s, 3H); MS(ESI) m / z [M + H] + = 566.1。

[0412] Example 54 Preparation of 6-(4-Bromo-2-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-54)

[0413] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0 mg, 1.0 mmol), 4-bromo-2-(trifluoromethyl)phenol (289.2 mg, 1.20 mmol), cesium carbonate (651.6 mg, 2.00 mmol) and copper(I) iodide (38.1 mg, 0.2 mmol) to toluene (20 mL). Replace the air with nitrogen, then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 4 - 2:1 (v / v) to obtain 6-(4-bromo-2-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (244.0 mg, yield 53.7%). 1 H-NMR(400MHz,DMSO-d 6 )δ:8.03(s,1H),7.92(d,J=8.4Hz,1H),7.87(m,1H),7.24(d,J=8.8Hz,1H),7.02(d,J=8.8Hz,1H);MS(ESI)m / z[M+H] + =447.0,448.9(1:1).

[0414] Step 2: In a reaction flask equipped with a drying tube, dissolve 6-(4-bromo-2-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (199.0 mg, 0.46 mmol) in dichloromethane (10 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, then slowly add oxalyl chloride (564.9 mg, 4.45 mmol). After the addition is complete, react at room temperature until all the acid is converted to the acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (90.1 mg, 0.89 mmol), then add 5-amino-2-fluorobenzonitrile (66.6 mg, 0.49 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 4:1 (v / v) to obtain 6-(4-bromo-2-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (163.0 mg, yield 64.8%). 1 H-NMR(400MHz,CDCl 3)δ: 8.00 - 8.02 (q, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.87 (s, J = 2.4 Hz, 1H), 7.72 - 7.78 (m, 2H), 7.64 (t, J = 8.4 Hz, 1H), 7.22 (t, J = 8.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H); MS(ESI) m / z [M + H] + = 565.0, 567.0 (1:1).

[0415] Step 3: 6-(4-Bromo-2-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (130.0 mg, 0.23 mmol), triethylamine (69.8 mg, 0.69 mmol) and hydroxylamine hydrochloride (32.0 mg, 0.46 mmol) were added to absolute ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then columned (200 - 300 mesh) with dichloromethane:methanol (v / v) = 40 - 20:1 to obtain 6-(4-bromo-2-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-54) (61.0 mg, yield 44.3%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.96 (s, 1H), 9.66 (s, 1H), 8.00 (s, 1H), 7.96 (dd, J = 9.2, 2.0 Hz, 1H), 7.89 (t, J = 8.4 Hz, 1H), 7.79 (dd, J = 6.0, 2.4 Hz, 1H), 7.61 - 7.66 (m, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 5.83 (brs, 1H); MS(ESI) m / z [M + H] + = 598.0, 600.0 (1:1).

[0416] Example 55 Preparation of 2-Fluoro-6-(4-fluoro-2-methoxyphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide

[0417] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0 mg, 1.0 mmol), 4-fluoro-2-methoxyphenol (170.6 mg, 1.20 mmol), cesium carbonate (651.6 mg, 2.00 mmol) and copper(I) iodide (38.1 mg, 0.2 mmol) into toluene (20.0 mL). Replace the air with nitrogen, then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-3-(trifluoromethyl)benzoic acid (190.0 mg, yield 54.5%). 1 H-NMR(600MHz,DMSO-d 6 )δ: 7.71 (t, J = 9.0 Hz, 1H), 7.24 (dd, J = 9.0, 6.0 Hz, 1H), 7.19 (dd, J = 10.2, 2.4 Hz, 1H), 6.86 (td, J = 3.0, 8.4 Hz, 1H), 6.54 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H); MS(ESI) m / z[M + H] + = 349.1。

[0418] Step 2: In a reaction flask equipped with a drying tube, first dissolve 2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-3-(trifluoromethyl)benzoic acid (172.0 mg, 0.49 mmol) in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, then slowly dropwise add oxalyl chloride (626.9 mg, 4.94 mmol). After the addition is complete, react at room temperature until all the acid is converted to acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (99.97 mg, 0.99 mmol), then add 5-amino-2-fluorobenzonitrile (74.0 mg, 0.54 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 2:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-3-(trifluoromethyl)benzamide (106.0 mg, yield 46.0%). 1 H-NMR(400MHz,CDCl 3)δ: 8.50 (s, 1H), 7.91 - 7.93 (q, J = 8.0 Hz, 1H), 7.82 - 7.86 (m, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.22 (d, J = 9.2 Hz, 1H), 7.19 (t, J = 5.6 Hz, 1H), 6.82 - 6.85 (dd, J = 9.6, 2.8 Hz, 1H), 6.76 - 6.80 (td, J = 8.4, 2.8 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 3.85 (s, 3H); MS(ESI) m / z [M + H] + = 467.1。

[0419] Step 3: Add N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-3-(trifluoromethyl)benzamide (100.0 mg, 0.21 mmol), triethylamine (65.1 mg, 0.63 mmol) and hydroxylamine hydrochloride (29.8 mg, 0.42 mmol) into absolute ethanol, and react under reflux until the raw materials are completely reacted. Concentrate, add water, and extract with ethyl acetate. Dry the organic phase, concentrate to obtain the crude product, and then column chromatograph (200 - 300 mesh) with dichloromethane:methanol (v / v) = 40 - 20:1 to obtain 2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-55) (44.0 mg, yield 41.1%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.93 (s, 1H), 9.66 (s, 1H), 7.86 (dd, J = 2.8, 6.4 Hz, 1H), 7.71 - 7.78 (m, 2H), 7.23 - 7.29 (m, 2H), 7.18 (dd, J = 10.4, 3.2 Hz, 1H), 6.84 - 6.90 (td, J = 8.4, 2.8 Hz, 1H), 6.59 (d, J = 9.2 Hz, 1H), 5.84 (brs, 1H), 3.77 (s, 3H); MS(ESI) m / z [M + H] + = 500.7。

[0420] Example 56 Preparation of 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-56)

[0421] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (340.0 mg, 1.2 mmol), 3-chloro-2-fluoro-5-(trifluoromethyl)phenol (250.0 mg, 1.2 mmol), cesium carbonate (772.0 mg, 2.4 mmol) and copper(I) iodide (45.1 mg, 0.24 mmol) to toluene (20 mL). Replace the air with nitrogen, then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 2:1 (v / v) to obtain 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (72.0 mg, yield 14.5%). 1 H-NMR(600MHz,DMSO-d 6 )δ:7.67(t,J=7.8Hz,1H),7.61(d,J=9.0Hz,1H),7.37(d,J=6Hz,1H),6.68(d,J=9.0Hz,1H);MS(ESI)m / z[M+H] + =421.1。

[0422] Step 2: In a reaction flask equipped with a drying tube, dissolve 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (70.0 mg, 0.17 mmol) in dichloromethane (10 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, then slowly add oxalyl chloride (211.2 mg, 1.66 mmol). After the addition is complete, react at room temperature until all the acid is converted to acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane. Then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (33.68 mg, 0.32 mmol), then add 5-amino-2-fluorobenzonitrile (24.9 mg, 0.18 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 4:1 (v / v) to obtain 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (50.0 mg, yield 55.7%). 1 H-NMR(400MHz in CDCl 3)δ: 8.01 (sq, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.83 (sq, 1H), 7.67 (t, J = 8.8 Hz, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.23 (t, 1H), 6.71 (d, J = 8.8 Hz, 1H); MS(ESI) m / z [M + H] + = 539.0。

[0423] Step 3: 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (50.0 mg, 0.09 mmol), triethylamine (28.2 mg, 0.28 mmol) and hydroxylamine hydrochloride (12.9 mg, 0.18 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then columned (200 - 300 mesh) with dichloromethane:methanol (v / v) = 40 - 20:1 to obtain 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-56) (30.0 mg, yield 56.5%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 11.00 (s, 1H), 9.67 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.89 (t, J = 8.8 Hz, 1H), 7.78 - 7.84 (m, 2H), 7.64 - 7.66 (m, 1H), 7.24 (t, J = 9.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.83 (brs, 1H); MS(ESI) m / z [M + H] + = 572.1, 574.1 (3:1).

[0424] Example 57 Preparation of 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)benzamide (I-57)

[0425] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0 mg, 1.0 mmol), 4-(trifluoromethyl)phenol (194.5 mg, 1.2 mmol), cesium carbonate (651.6 mg, 2.0 mmol), and copper(I) iodide (38.1 mg, 0.2 mmol) to toluene (50 mL). Replace the air with nitrogen, then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 4 - 2:1 (v / v) to obtain 2-fluoro-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)benzoic acid (183.0 mg, yield 49.7%). 1 H-NMR(400MHz,DMSO-d 6 )δ:7.90(t,J=8.8Hz,1H),7.82(d,J=8.8Hz,2H),7.33(d,J=8.8Hz,2H),7.08(d,J=8.8Hz,1H);MS(ESI)m / z[M+H] + =368.9。

[0426] Step 2: In a reaction flask equipped with a drying tube, first dissolve 2-fluoro-3-(trifluoromethyl)-6-(4-(trifluoroethyl)phenoxy)benzoic acid (67.0 mg, 0.18 mmol) in dichloromethane (10 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, then slowly add oxalyl chloride (231.0 mg, 1.82 mmol). After the addition is complete, react at room temperature until the acid is completely converted to the acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (36.8 mg, 0.26 mmol), then add 5-amino-2-fluorobenzonitrile (27.3 mg, 0.2 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, and let it stand for liquid separation to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 20 - 10:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)benzamide (20.0 mg, yield 22%). 1 H-NMR(400MHz,DMSO-d 6)δ: 8.12 (s, 1H), 7.96 (dd, J = 5.4, 2.7 Hz, 1H), 7.77 (ddd, J = 9.1, 4.6, 2.8 Hz, 1H), 7.70 - 7.59 (m, 3H), 7.22 - 7.16 (m, 3H), 6.79 (d, J = 8.8 Hz, 1H); MS(ESI) m / z [M+H] + = 487.1.

[0427] Step 3: Add N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)benzamide (20.0 mg, 0.041 mmol), triethylamine (12.48 mg, 0.12 mmol) and hydroxylamine hydrochloride (5.7 mg, 0.082 mmol) into absolute ethanol, and react under reflux until the raw materials are completely reacted. Concentrate, add water, and extract with ethyl acetate. Dry the organic phase, concentrate to obtain the crude product, and then column chromatograph (200 - 300 mesh) with dichloromethane:methanol (v / v) = 40 - 20:1 to obtain 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)benzamide (I-57) (10.0 mg, yield 46%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 11.00 (s, 1H), 9.66 (s, 1H), 7.89 (t, J = 8.8 Hz, 1H), 7.79 - 7.84 (q, 3H), 7.62 - 7.66 (m, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.23 (t, J = 8.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.83 (brs, 2H); MS(ESI) m / z [M+H] + = 520.1.

[0428] Example 58 Preparation of 6-(2,4-dimethylphenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-58)

[0429] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0 mg, 1.0 mmol), 2,4-dimethylphenol (146.6 mg, 1.2 mmol), cesium carbonate (651.6 mg, 2.00 mmol) and copper(I) iodide (38.1 mg, 0.2 mmol) to toluene (20.0 mL). Replace the air with nitrogen, then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 4 - 2:1 (v / v) to obtain 6-(2,4-dimethylphenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (160.0 mg, yield 48.7%), which is directly used in the next step. MS(ESI) m / z [M+H] + = 329.1.

[0430] Step 2: In a reaction flask equipped with a drying tube, dissolve 6-(2,4-dimethylphenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (100.0 mg, 0.3 mmol) in dichloromethane (10 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, then slowly add oxalyl chloride (386.6 mg, 3.0 mmol). After the addition is complete, react at room temperature until all the acid is converted to acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (61.7 mg, 0.61 mmol), then add 5-amino-2-fluorobenzonitrile (49.7 mg, 0.36 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 20 - 4:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-6-(2,4-dimethylphenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (69.0 mg, yield 50.7%). 1 H-NMR (400 MHz in CDCl 3 ) δ: 8.34 (s, 1H), 7.99 (s, 1H), 7.80 - 7.84 (m, 1H), 7.49 (t, J = 8.4 Hz, 1H), 7.18 (t, J = 8.4 Hz, 1H), 7.09 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 2.33 (s, 3H), 2.13 (s, 3H); MS(ESI) m / z [M+H] + = 447.2.

[0431] Step 3: N-(3-Cyano-4-fluorophenyl)-6-(2,4-dimethylphenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (69.0 mg, 0.15 mmol), triethylamine (46.9 mg, 0.46 mmol) and hydroxylamine hydrochloride (21.5 mg, 0.31 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials reacted completely. It was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then column chromatographed (200 - 300 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 to obtain 6-(2,4-dimethylphenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-58) (38.0 mg, 51.3%). 1 H-NMR(400MHz,DMSO-d 6 ) δ: 10.97 (s, 1H), 9.66 (s, 1H), 7.85 - 7.88 (dd, J = 6.4, 2.8 Hz, 1H), 7.77 (t, J = 8.4 Hz, 1H), 7.68 - 7.73 (m, 1H), 7.25 (t, J = 9.6 Hz, 1H), 7.18 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 9.2 Hz, 1H), 5.83 (brs, 2H), 2.29 (s, 3H), 2.09 (s, 3H); MS(ESI) m / z [M+H] + = 480.1.

[0432] Preparation of Example 59 N-(3-(N-Cyanoaminocarbonyl)-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (I-59)

[0433] Weigh N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (450.0 mg, 1.0 mmol) prepared in Example 48 and add absolute ethanol (0.2 mL) to the hydrochloric acid-ethyl acetate system (10 N, 10.0 mL), and carry out the reaction in a sealed tube at room temperature. After the reaction is complete to form the intermediate, evaporate the reaction system to dryness to obtain the residue. Dissolve the residue in ethanol, then add 50% aqueous cyanamide solution (840.18 mg, 10.0 mmol) and reflux until the intermediate reaction is complete. Then add ammonia-methanol solution (4 N, 10.0 mL) and continue the reflux reaction. After the reaction is complete, concentrate to obtain the crude product. The crude product is purified by column chromatography (200 - 300 mesh) with dichloromethane:methanol (v / v) = 40 - 20:1 to obtain N-(3-(N-cyanoaminocarbonyl)-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (I-59) (60.0 mg, yield 12.2%). 1 H-NMR(600MHz,DMSO-d 6 )δ:11.19(s,1H),9.04(brs,1H),8.84(brs,1H),7.90(brs,1H),7.79~7.84(q,2H),7.43(brs,1H),7.26~7.28(dd,J=9.0,3.0Hz,1H),7.20~7.22(q,1H),7.14~7.17(td,J=8.4,3.0Hz,1H),6.61(d,J=9.0Hz,1H),2.14(s,3H);MS(ESI)m / z[M+H] + =493.1。

[0434] Example 60 Preparation of 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxyaminocarbonyl)phenyl)-3-(trifluoromethoxy)benzamide (I-60)

[0435] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (250.0 mg, 0.83 mmol), 4-fluoro-2-methylphenol (156.1 mg, 1.24 mmol), cesium carbonate (537.6 mg, 1.65 mmol) and copper(I) iodide (157.1 mg, 0.83 mmol) to toluene (20.0 mL), displace with nitrogen, and then heat to 100 °C for reaction until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. The organic phase is dried and concentrated to obtain a crude product. The crude product is chromatographed on a column (200 - 300 mesh) with dichloromethane:methanol (v / v) = 100 - 10:1 to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethoxy)benzoic acid (150 mg, yield 52%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 7.59(t, J = 8.4Hz, 1H), 7.25(d, J = 9.2Hz, 1H), 7.10(d, J = 5.6Hz, 2H), 6.55(d, J = 9.2Hz, 1H), 2.13(s, 3H); MS(ESI) m / z[M + H] + = 348.9。

[0436] Step 2: In a reaction flask equipped with a drying tube, first dissolve 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethoxy)benzoic acid (140.0 mg, 0.4 mmol) in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (510.3 mg, 4.02 mmol). After the addition is complete, react at room temperature until the acid is completely converted to the acyl chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (81.4 mg, 1.12 mmol), and then add 5-amino-2-fluorobenzonitrile (54.7 mg, 0.4 mmol). React at room temperature until the reaction is complete, add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain a crude product. The crude product is chromatographed on a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 4:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethoxy)benzamide (110.0 mg, yield 58%). 1 H-NMR(400MHz,DMSO-d 6)δ: 8.17 (d, J = 5.6 Hz, 1H), 7.91 - 7.95 (q, 1H), 7.63 (t, J = 8.8 Hz, 1H), 7.57 (t, J = 8.8 Hz, 1H), 7.22 (dd, J = 2.4, 9.2 Hz, 1H), 7.11 - 7.15 (q, 2H), 6.60 (dd, J = 1.2, 9.2 Hz, 1H), 2.14 (s, 3H); MS(ESI) m / z [M + H] + = 466.9。

[0437] Step 3: N-(3-Cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethoxy)benzamide (100.0 mg, 0.22 mmol), triethylamine (130.2 mg, 1.29 mmol) and hydroxylamine hydrochloride (29.8 mg, 0.43 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials reacted completely. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then columned (200 - 300 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethoxy)benzamide (I-60) (68.0 mg, yield 63.5%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.96 (s, 1H), 9.67 (s, 1H), 7.85 (dd, J = 6.4, 2.8 Hz, 1H), 7.68 - 7.72 (m, 1H), 7.60 (t, J = 9.2 Hz, 1H), 7.21 - 7.27 (m, 2H), 7.09 - 7.17 (q, 2H), 6.58 (d, J = 8.8 Hz, 1H), 5.83 (brs, 2H), 2.15 (s, 3H); MS(ESI) m / z [M + H] + = 499.9。

[0438] Example 61 Preparation of 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-61)

[0439] Step 1: In a reaction flask equipped with a drying tube, first dissolve 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (968.0 mg, 4.0 mmol) in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (3.8 mL, 40.0 mmol). After the addition is complete, react at room temperature until all the acid is converted to acyl chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (807.7 mg, 8.0 mmol), then add 5-amino-2-fluorobenzonitrile (570.4 mg, 4.2 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is eluted through a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 20 - 4:1 (v / v) to obtain 5-chloro-N-(3-cyano-4-fluorophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (1.1 g, yield 76.4%). 1 H-NMR(400MHz,DMSO-d 6 )δ:11.06(brs,1H),8.19~8.21(dd,J=7.6,2.8Hz,1H),8.12(d,J=7.6Hz,1H),8.06(d,J=7.6Hz,1H),7.59(t,J=8.8Hz,1H);MS(ESI)m / z[M+H] + =360.9。

[0440] Step 2: First add 5-chloro-N-(3-cyano-4-fluorophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (360.00 mg, 1.0 mmol), 4-fluoro-2-methylphenol (138.49 mg, 1.10 mmol), cesium carbonate (650.43 mg, 2.00 mmol) and copper(I) iodide (38 mg, 0.2 mmol) to toluene (20 mL). Replace the air with nitrogen, then heat to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is eluted through a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10:1 (v / v) to obtain 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (218.0 mg, yield 68%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.99 (s, 1H), 8.12 - 8.14 (q, 1H), 8.08 (s, 1H), 7.88 - 7.92 (q, 1H), 7.556 (t, J = 9.2 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.18 (s, 1H), 7.08 - 7.10 (d, 2H) 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 466.8, 468.9 (3:1).

[0441] Step 3: 5-Chloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (638.0 mg, 1.37 mmol), triethylamine (276.6 mg, 2.73 mmol) and hydroxylamine hydrochloride (189.9 mg, 2.73 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then column chromatographed (200 - 300 mesh) with dichloromethane:methanol = 100 - 40:1 (v / v) to obtain 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-61) (360.0 mg, yield 52.7%). 1 H-NMR (400 MHz, DMSO-d 6 )δ: 10.69 (s, 1H), 9.65 (s, 1H), 8.04 (s, 1H), 7.81 (sq, 1H), 7.68 (s, 1H), 7.23 (t, J = 10.0 Hz, 2H), 7.08 - 7.11 (t, 3H), 5.82 (s, 2H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 499.8, 501.9 (3:1).

[0442] Preparation of N-(4-Chloro-3-(N-hydroxycarbamoyl)phenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (I-62) in Example 62

[0443] Step 1: Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0 mg, 0.45 mmol) prepared in Example 48 and place it in a round-bottom flask. Add N,N-dimethylformamide (5 mL) as the solvent, then add HATU (206.0 mg, 0.54 mmol). Stir at room temperature for 15 min, then add 3-cyano-4-chloroaniline (75.6 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.25 mg, 1.36 mmol), and continue to stir at room temperature for 5 h. Monitor the reaction by TLC. After the reaction is complete, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify by column chromatography (200 - 300 mesh) with n-hexane:ethyl acetate = 8:1 (v / v) to obtain N-(4-chloro-3-cyanophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (130 mg, yield 60%). 1 H-NMR(400MHz,CDCl 3 )δ:8.07(d,J=2.5Hz,1H),7.80(dd,J=8.9,2.6Hz,1H),7.54(t,J=8.4Hz,1H),7.49(d,J=8.8Hz,1H),7.04~6.98(m,2H),6.96(dd,J=7.9,2.9Hz,1H),6.49(d,J=8.9Hz,1H),2.18(s,3H);MS(ESI)m / z[M+H] + =466.8。

[0444] Step 2: Weigh N-(4-chloro-3-cyanophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (140.0 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add 5 mL of absolute ethanol, then add triethylamine (151.8 mg, 1.5 mmol), and react at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and purify by column chromatography. Use dichloromethane:methanol = 100 - 50:1 (v / v) for column chromatography (200 - 300 mesh) to obtain N-(4-chloro-3-(N-hydroxycarbamoyl)phenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (I-62) (105 mg, yield 70%). 1 H-NMR(400MHz in Methanol-d 4)δ: 7.81 - 7.78 (m, 2H), 7.68 (t, J = 8.5 Hz, 1H), 7.47 - 7.44 (m, 1H), 7.13 - 7.10 (m, 1H), 7.10 - 7.07 (m, 1H), 7.01 (td, J = 8.4, 3.1 Hz, 1H), 6.60 (d, J = 8.9 Hz, 1H), 2.18 (s, 3H); MS(ESI) m / z [M + H] + = 500.0。

[0445] Example 63 Preparation of 2-Fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (I-63)

[0446] First step: Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0 mg, 0.45 mmol) prepared in Example 48 and place it in a round-bottom flask. Add N,N-dimethylformamide (5 mL) as the solvent, then add HATU (206.0 mg, 0.54 mmol). Stir at room temperature for 15 min, then add 5-amino-2-methylbenzonitrile (65.6 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.25 mg, 1.36 mmol). Continue to stir at room temperature for 5 h. Monitor the reaction by TLC. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify by column chromatography (200 - 300 mesh) with n-hexane:ethyl acetate = 8:1 (v / v) to obtain N-(3-cyano-4-methylphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (121 mg, yield 60%). 1 H-NMR(400 MHz, CDCl 3 )δ: 8.18 (s, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 8.4, 2.4 Hz, 1H), 7.51 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.00 (dt, J = 7.5, 3.7 Hz, 2H), 6.93 (td, J = 8.2, 3.0 Hz, 1H), 6.47 (d, J = 8.9 Hz, 1H), 2.49 (s, 3H), 2.17 (s, 3H); MS(ESI) m / z [M + H] + = 446.8。

[0447] Step 2: Weigh N-(3-cyano-4-methylphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (133.8 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add 5 mL of absolute ethanol, then add triethylamine (151.8 mg, 1.5 mmol). React overnight at 80 °C under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and pass through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)-4-methylphenyl)-3-(trifluoromethyl)benzamide (I-63) (100.6 mg, yield 70%). 1 H-NMR (400 MHz in Methanol-d 4 ) δ: 7.73 - 7.66 (m, 3H), 7.28 (d, J = 8.9 Hz, 1H), 7.13 (m, 2H), 7.05 (dt, J = 9.0, 4.5 Hz, 1H), 6.62 (d, J = 8.9 Hz, 1H), 2.42 (s, 3H), 2.22 (s, 3H); MS(ESI) m / z [M + H] + = 480.0。

[0448] Example 64 Preparation of 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxyamino)pyridin-4-yl)-3-(trifluoromethyl)benzamide (I-64)

[0449] Step 1: Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0 mg, 0.45 mmol) prepared in Example 48 and place it in a round-bottom flask. Add dichloromethane (15 mL) as the solvent, stir for 10 min in an ice-water bath, then add oxalyl chloride (171.4 mg, 1.35 mmol) and a catalytic amount of N,N-dimethylformamide. After the addition is complete, react at room temperature until all the acid is converted to acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (91.0 mg, 0.9 mmol), and then add 4-amino-2-cyanopyridine (54.0 mg, 0.45 mmol). React at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Purify it by passing through a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N-(2-cyanopyridin-4-yl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (117 mg, yield 60%). 1 H-NMR(400MHz,DMSO-d 6 )δ:11.74(s,1H),8.68(d,J=5.6Hz,1H),8.19(d,J=2.0Hz,1H),7.91(dd,J=5.6,2.1Hz,1H),7.84(t,J=8.7Hz,1H),7.29~7.20(m,2H),7.15(td,J=8.5,3.1Hz,1H),6.65(d,J=8.9Hz,1H),2.13(s,3H);MS(ESI)m / z[M+H] + =433.8。

[0450] Step 2: Weigh N-(2-cyanopyridin-4-yl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (130.0 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add 5 mL of absolute ethanol, then add triethylamine (151.8 mg, 1.5 mmol). React at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and purify it by passing through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxyamino)pyridin-4-yl)-3-(trifluoromethyl)benzamide (I-64) (98 mg, yield 70%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.35 (s, 1H), 9.94 (s, 1H), 8.49 (d, J = 5.6 Hz, 1H), 8.28 (d, J = 2.0 Hz, 1H), 7.81 (t, J = 8.7 Hz, 1H), 7.63 (dd, J = 5.6, 2.1 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.15 (td, J = 8.5, 3.1 Hz, 1H), 6.63 (d, J = 8.9 Hz, 1H), 5.83 (s, 2H), 2.13 (s, 3H); MS(ESI) m / z [M + H] + = 466.9。

[0451] Example 65 Preparation of 2 - fluoro - 6 - (4 - fluoro - 2 - methylphenoxy) - N - (3 - (N - hydroxycarbamimidoyl) - 4 - methoxyphenyl) - 3 - (trifluoromethyl)benzamide (I - 65)

[0452] First step: Weigh 2 - fluoro - 6 - (4 - fluoro - 2 - methylphenoxy) - 3 - (trifluoromethyl)benzoic acid (150.0 mg, 0.45 mmol) prepared in Example 48 and place it in a round - bottom flask. Add N,N - dimethylformamide (5 mL) as the solvent, then add HATU (206.0 mg, 0.54 mmol). Stir at room temperature for 15 min, then add 5 - amino - 2 - methoxybenzonitrile (73.6 mg, 0.50 mmol) and N,N - diisopropylethylamine (129.25 mg, 1.36 mmol), and continue to stir at room temperature for 5 h. Monitor the reaction by TLC. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N - dimethylformamide with water, and purify by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N - (3 - cyano - 4 - methoxyphenyl) - 2 - fluoro - 6 - (4 - fluoro - 2 - methylphenoxy) - 3 - (trifluoromethyl)benzamide (125 mg, yield 60%). 1 H - NMR(400 MHz, CDCl 3 )δ: 8.12 (s, 1H), 7.83 (dd, J = 9.0, 2.7 Hz, 1H), 7.80 (d, J = 2.6 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.01 - 6.91 (m, 4H), 6.46 (d, J = 8.9 Hz, 1H), 3.92 (s, 3H), 2.17 (s, 3H); MS(ESI) m / z [M + H] + = 462.8。

[0453] Step 2: Weigh N-(3-cyano-4-methoxyphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (138.6 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add 5 mL of absolute ethanol, then add triethylamine (151.8 mg, 1.5 mmol). React at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and pass through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:(v / v) to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoylamino)-4-methoxyphenyl)-3-(trifluoromethyl)benzamide (I-65) (103.9 mg, yield 70%). 1 H-NMR(400MHz inMethanol-d 4 )δ:7.88~7.82(m,1H),7.74~7.67(m,2H),7.14(m,3H),7.09~7.00(m,1H),6.62(d,J=8.9Hz,1H),3.91(s,3H),2.22(s,3H);MS(ESI)m / z[M+H] + =496.1。

[0454] Example 66 Preparation of 6-chloro-5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)nicotinamide (I-66)

[0455] Step 1: First, add 2,6-dichloro-5-fluoronicotinic acid (1.46 g, 6.97 mmol), 4-fluoro-2-methylphenol (1-SM2) (1.05 g, 8.36 mmol), cesium carbonate (4.54 g, 13.94 mmol) and copper(I) iodide (265.43 mg, 1.39 mmol) to toluene (50 mL). Replace the air with nitrogen, then heat up to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. Pass the crude product through a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1(v / v) to obtain 6-chloro-5-fluoro-2-(4-fluoro-2-methylphenoxy)nicotinic acid (1.35 g, yield 64.8%). 1 H-NMR(400MHz,DMSO-d 6 )δ:8.31(d,J=9.6Hz,1H),7.25(m,2H),7.12(td,J=8.7,3.2Hz,1H),2.11(s,3H);MS(ESI)m / z[M+H]+ = 300.6。

[0456] Step 2: Weigh 6-chloro-5-fluoro-2-(4-fluoro-2-methylphenoxy)nicotinic acid (135.0 mg, 0.45 mmol) and place it in a round-bottom flask. Add N,N-dimethylformamide (5 mL) as the solvent, then add HATU (206.0 mg, 0.54 mmol). Stir at room temperature for 15 min, then add 3-cyano-4-fluoroaniline (68 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.2 mg, 1.36 mmol). Continue to stir at room temperature for 5 h. Monitor the reaction by TLC. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify it by column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain 6-chloro-N-(3-cyano-4-fluorophenyl)-5-fluoro-2-(4-fluoro-2-methylphenoxy)nicotinamide (113 mg, yield 60%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.00 (s, 1H), 8.37 (d, J = 9.4 Hz, 1H), 8.18 (dd, J = 5.8, 2.7 Hz, 1H), 7.93 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.56 (t, J = 9.1 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.14 (td, J = 8.5, 3.1 Hz, 1H), 2.14 (s, 3H); MS (ESI) m / z [M+H] + = 417.8。

[0457] Step 3: Weigh 6-chloro-N-(3-cyano-4-fluorophenyl)-5-fluoro-2-(4-fluoro-2-methylphenoxy)nicotinamide (125.1 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add 5 mL of absolute ethanol, then add triethylamine (151.8 mg, 1.5 mmol). React at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and purify it by column chromatography. Use dichloromethane:methanol = 100 - 50:1 (v / v) for column chromatography (200 - 300 mesh) to obtain 6-chloro-5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)nicotinamide (I-66) (95 mg, yield 70%). 1 H-NMR (400 MHz, DMSO-d 6)δ: 10.74 (s, 1H), 9.70 (s, 1H), 8.39 (d, J = 9.4 Hz, 1H), 7.88 (dd, J = 6.5, 2.7 Hz, 1H), 7.73 (dt, J = 7.8, 3.8 Hz, 1H), 7.34 - 7.24 (m, 3H), 7.18 (td, J = 8.5, 3.1 Hz, 1H), 5.87 (s, 2H), 2.18 (s, 3H); MS(ESI) m / z [M + H] + = 450.8.

[0458] Example 67 Preparation of 2-Fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-(trifluoromethyl)benzamide (I-67)

[0459] First step: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0 g, 6.97 mmol), 4-fluoro-3-(trifluoromethyl)phenol (1.5 g, 8.36 mmol), cesium carbonate (4.54 g, 13.94 mmol) and copper(I) iodide (265.4 mg, 1.4 mmol) to toluene (50 mL), displace with nitrogen, and then heat to 100 °C for reaction until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate, dry the organic phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3-(trifluoromethyl)benzoic acid (1.75 g, yield 64.8%), and directly proceed to the next step. MS(ESI) m / z [M + H] + = 386.8.

[0460] Second step: Weigh 2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3-(trifluoromethyl)benzoic acid (173.7 mg, 0.45 mmol) and place it in a round-bottom flask, add N,N-dimethylformamide (5 mL) as the solvent, then add HATU (206.0 mg, 0.54 mmol), stir at room temperature for 15 min, then add 3-cyano-4-fluoroaniline (68.0 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.3 mg, 1.36 mmol), and continue to stir at room temperature for 5 h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3-(trifluoromethyl)benzamide (136 mg, yield about 60%). 1H-NMR(400MHz,DMSO-d 6 )δ:11.28(s,1H),8.15(dd,J=5.7,2.7Hz,1H),7.95~7.83(m,2H),7.69~7.65(m,1H),7.65~7.61(m,2H),7.55(t,J=9.1Hz,1H),6.97(d,J=8.8Hz,1H);MS(ESI)m / z[M+H] + =504.8。

[0461] Step 3: Weigh N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-(trifluoromethyl)benzamide (151.2 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add 5 mL of absolute ethanol, then add triethylamine (151.8 mg, 1.5 mmol), and react at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and pass it through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(4-fluoro-3-(trifluoromethyl)phenoxy)-3-(trifluoromethyl)benzamide (I-67) (112.8 mg, yield about 70%). 1 H-NMR(400MHz inMethanol-d 4 )δ:7.81(tdd,J=8.1,5.7,3.1Hz,3H),7.56(dd,J=5.8,2.9Hz,1H),7.53~7.41(m,2H),7.21(dd,J=10.0,8.7Hz,1H),6.89(d,J=8.8Hz,1H);MS(ESI)m / z[M+H] + =537.8。

[0462] Example 68 Preparation of 6-(2,3-difluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-68)

[0463] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0 g, 6.97 mmol), 2,3-difluorophenol (1.09 g, 8.36 mmol), cesium carbonate (4.5 g, 14.0 mmol) and copper(I) iodide (265.43 mg, 1.4 mmol) to toluene (50 mL), displace with nitrogen, and then heat to 100 °C for reaction until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate, dry the organic phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (1.52 g, yield 64.8%), and directly proceed to the next step. MS(ESI) m / z [M+H] + = 336.8.

[0464] Step 2: Weigh 6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (151.2 mg, 0.45 mmol) and place it in a round-bottom flask, add N,N-dimethylformamide (5 mL) as the solvent and HATU (206.0 mg, 0.54 mmol), stir at room temperature for 15 min, then add 3-cyano-4-fluoroaniline (68.0 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.25 mg, 1.36 mmol), and continue to stir at room temperature for 5 h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (122.58 mg, yield 60%). 1 H-NMR(400MHz,DMSO-d 6 ) δ: 11.35 (s, 1H), 8.18 (dd, J = 5.7, 2.7 Hz, 1H), 7.93 (ddd, J = 9.2, 4.8, 2.7 Hz, 1H), 7.88 (t, J = 8.6 Hz, 1H), 7.55 (t, J = 9.1 Hz, 1H), 7.40 (dddd, J = 10.3, 8.6, 6.9, 1.7 Hz, 1H), 7.31 (tdd, J = 8.3, 5.8, 1.8 Hz, 1H), 7.20 (ddt, J = 8.4, 6.7, 1.7 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H); MS(ESI) m / z [M+H] + = 455.1.

[0465] Step 3: Weigh N-(3-cyano-4-fluorophenyl)-6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (136.2 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add 5 mL of absolute ethanol, then add triethylamine (151.8 mg, 1.5 mmol). React overnight at 80 °C under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and pass it through a silica gel column (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 6-(2,3-difluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-68) (102.3 mg, yield 70%). 1 H-NMR(400MHz,DMSO-d 6 )δ:11.03(s,1H),9.67(s,1H),7.90~7.81(m,2H),7.70(ddd,J=8.9,4.4,2.8Hz,1H),7.40(dddd,J=10.2,8.6,6.9,1.6Hz,1H),7.31(tdd,J=8.5,5.9,2.0Hz,1H),7.28~7.17(m,2H),6.98(d,J=8.8Hz,1H),5.83(s,2H);MS(ESI)m / z[M+H] + =487.8。

[0466] Example 69 Preparation of 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-69)

[0467] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0 g, 6.97 mmol), 4-bromo-2-fluoro-6-(trifluoromethyl)phenol (2.2 g, 8.36 mmol), cesium carbonate (4.54 g, 13.94 mmol) and copper(I) iodide (265.43 mg, 1.39 mmol) to toluene (50 mL). Replace the air with nitrogen, then heat up to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is passed through a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (2.10 g, yield 64.8%), and directly proceed to the next step. MS(ESI)m / z[M+H] += 465.0。

[0468] Step 2: Weigh 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (208.8 mg, 0.45 mmol) and place it in a round-bottom flask. Add N,N-dimethylformamide (5 mL) as the solvent, then add HATU (206 mg, 0.54 mmol). Stir at room temperature for 15 min, then add 3-cyano-4-fluoroaniline (68.0 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.25 mg, 1.36 mmol), and continue to stir at room temperature for 5 h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify it by column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (157.14 mg, yield 60%). 1 H-NMR (400 MHz, DMSO-d 6 ) δ: 11.34 (s, 1H), 8.27 (dd, J = 9.9, 2.3 Hz, 1H), 8.18 (dd, J = 5.7, 2.7 Hz, 1H), 7.99 - 7.91 (m, 2H), 7.84 (t, J = 8.6 Hz, 1H), 7.57 (t, J = 9.1 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H); MS (ESI) m / z [M+H] + = 582.9。

[0469] Step 3: Weigh 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (174.6 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add 5 mL of absolute ethanol, then add triethylamine (151.8 mg, 1.5 mmol), and react at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and purify it by column chromatography (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-69) (129.2 mg, yield 70%). 1 H-NMR (400 MHz, DMSO-d 6)δ: 10.49 (s, 1H), 9.15 (s, 1H), 7.76 (dd, J = 9.9, 2.3 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.18 (ddd, J = 8.9, 4.4, 2.8 Hz, 1H), 6.74 (dd, J = 10.2, 9.0 Hz, 1H), 6.44 (d, J = 8.9 Hz, 1H), 5.32 (s, 2H); MS(ESI) m / z [M + H] + = 615.9。

[0470] Example 70 Preparation of 2,3,4 - Trifluoro - 6 - (4 - fluoro - 2 - methylphenoxy) - N - (4 - fluoro - 3 - (N - hydroxycarbamoyl)phenyl)benzamide (I - 70)

[0471] First step: First, add 6 - bromo - 2,3,4 - trifluorobenzoic acid (1.77 g, 6.97 mmol), 4 - fluoro - 2 - methylphenol (1 - SM2) (1.05 g, 8.36 mmol), cesium carbonate (4.54 g, 13.94 mmol) and copper(I) iodide (265.43 mg, 1.39 mmol) to toluene (50 mL), displace with nitrogen, and then heat to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate, dry the organic phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 2,3,4 - trifluoro - 6 - (4 - fluoro - 2 - methylphenoxy)benzoic acid (1.35 g, yield 64.8%), and directly proceed to the next step. MS(ESI) m / z [M + H] + = 300.8。

[0472] Second step: Weigh 2,3,4 - trifluoro - 6 - (4 - fluoro - 2 - methylphenoxy)benzoic acid (135.0 mg, 0.45 mmol) and place it in a round - bottom flask, add N,N - dimethylformamide (5 mL) as the solvent, then add HATU (206.0 mg, 0.54 mmol), stir at room temperature for 15 min, then add 3 - cyano - 4 - fluoroaniline (68.0 mg, 0.50 mmol) and N,N - diisopropylethylamine (129.3 mg, 1.36 mmol), and continue to stir at room temperature for 5 h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N - dimethylformamide with water, and purify by chromatography column (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N - (3 - cyano - 4 - fluorophenyl) - 2,3,4 - trifluoro - 6 - (4 - fluoro - 2 - methylphenoxy)benzamide (112.9 mg, yield 60%). 1H-NMR(400MHz, DMSO-d 6 ) δ: 11.24 (s, 1H), 8.14 (dd, J = 5.8, 2.7 Hz, 1H), 7.89 (ddd, J = 9.2, 4.8, 2.7 Hz, 1H), 7.54 (t, J = 9.1 Hz, 1H), 7.18 (dd, J = 8.9, 1.9 Hz, 1H), 7.09 (d, J = 1.7 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.79 (ddd, J = 11.7, 6.0, 2.0 Hz, 1H), 2.14 (s, 3H); MS(ESI) m / z [M+H] + = 419.1。

[0473] Step 3: Weigh N-(3-cyano-4-fluorophenyl)-2,3,4-trifluoro-6-(4-fluoro-2-methylphenoxy)benzamide (125.4 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add anhydrous ethanol (5 mL), then add triethylamine (151.8 mg, 1.5 mmol). React overnight at 80 °C under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and chromatograph on a column (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 2,3,4-trifluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)benzamide (I-70) (94.7 mg, yield 70%). 1 H-NMR(400MHz, DMSO-d 6 ) δ: 10.93 (s, 1H), 9.67 (s, 1H), 7.82 (dd, J = 6.4, 2.7 Hz, 1H), 7.67 (ddd, J = 8.9, 4.3, 2.7 Hz, 1H), 7.29 - 7.18 (m, 2H), 7.10 (d, J = 1.8 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.76 (ddd, J = 11.7, 5.9, 2.1 Hz, 1H), 5.83 (s, 2H), 2.15 (s, 3H); MS(ESI) m / z [M+H] + = 451.8。

[0474] Example 71 Preparation of 6-(2-ethyl-4-fluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-71)

[0475] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0 g, 6.97 mmol), 2-ethyl-4-fluorophenol (1.2 g, 8.36 mmol), cesium carbonate (4.54 g, 13.94 mmol), and copper(I) iodide (265.43 mg, 1.39 mmol) to toluene (50 mL). Replace the air with nitrogen, and then heat the mixture to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (1.57 g, yield 64.8%), which is directly used for the next step. MS (ESI) m / z [M+H] + = 347.0.

[0476] Step 2: Weigh 6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (155.7 mg, 0.45 mmol) and place it in a round-bottom flask. Add N,N-dimethylformamide (5 mL) as the solvent, then add HATU (206 mg, 0.54 mmol), and stir at room temperature for 15 min. Then add 3-cyano-4-fluoroaniline (68 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.3 mg, 1.36 mmol), and continue to stir at room temperature for 5 h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify by column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (125.3 mg, yield 60%). 1 1H-NMR (400 MHz, DMSO-d 6 ) δ: 11.34 (s, 1H), 8.20 (dd, J = 5.7, 2.7 Hz, 1H), 7.95 (ddd, J = 9.3, 4.9, 2.7 Hz, 1H), 7.81 (t, J = 8.7 Hz, 1H), 7.56 (t, J = 9.1 Hz, 1H), 7.25 (dd, J = 9.5, 3.0 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.65 (d, J = 8.9 Hz, 1H), 2.56 - 2.44 (m, 2H), 1.05 (t, J = 7.6 Hz, 3H); MS (ESI) m / z [M+H] + = 465.1.

[0477] Step 3: Weigh N-(3-cyano-4-fluorophenyl)-6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (139.2 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add anhydrous ethanol (5 mL), then add triethylamine (151.8 mg, 1.5 mmol). React at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and chromatograph on a column (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 6-(2-ethyl-4-fluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-71) (104.4 mg, yield 70%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 11.03(s, 1H), 9.72(s, 1H), 7.91(dd, J = 6.4, 2.7Hz, 1H), 7.83(t, J = 8.7Hz, 1H), 7.75(ddd, J = 8.9, 4.4, 2.8Hz, 1H), 7.34 - 7.16(m, 4H), 6.67(d, J = 8.9Hz, 1H), 5.88(s, 2H), 2.55(q, J = 7.5Hz, 2H), 1.10(t, J = 7.5Hz, 3H); MS(ESI) m / z [M + H] + = 497.9。

[0478] Example 72 Preparation of 6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-72)

[0479] Step 1: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0 g, 6.97 mmol), 2-cyclopropyl-4-fluorophenol (38-a) (1.27 g, 8.36 mmol), cesium carbonate (4.54 g, 13.94 mmol), and copper(I) iodide (265.43 mg, 1.39 mmol) to toluene (50 mL). Replace the air with nitrogen, then heat to 100 °C and react until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. Chromatograph the crude product on a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (1.62 g, yield 64.8%), and directly proceed to the next step. MS(ESI) m / z [M + H] + = 359.1。

[0480] Step 2: Weigh 6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (161.1 mg, 0.45 mmol) and place it in a round-bottom flask. Add N,N-dimethylformamide (5 mL) as the solvent, then add HATU (206 mg, 0.54 mmol). Stir at room temperature for 15 min, then add 3-cyano-4-fluoroaniline (68.0 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.2 mg, 1.36 mmol). Continue to stir at room temperature for 5 h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify it by column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (128.5 mg, yield 60%). 1 1H-NMR (400 MHz, DMSO-d 6 ) δ: 11.37 (s, 1H), 8.22 (dd, J = 5.7, 2.7 Hz, 1H), 8.00 - 7.92 (m, 1H), 7.82 (t, J = 8.7 Hz, 1H), 7.56 (t, J = 9.1 Hz, 1H), 7.21 (dd, J = 8.9, 5.0 Hz, 1H), 7.08 (td, J = 8.4, 3.0 Hz, 1H), 6.88 (dd, J = 10.0, 3.1 Hz, 1H), 6.64 (d, J = 8.9 Hz, 1H), 1.97 - 1.88 (m, 1H), 0.90 - 0.82 (m, 2H), 0.74 - 0.67 (m, 2H); MS (ESI) m / z [M + H] + = 476.9。

[0481] Step 3: Weigh N-(3-cyano-4-fluorophenyl)-6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (142.8 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add anhydrous ethanol (5 mL), then add triethylamine (151.8 mg, 1.5 mmol). React at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and purify it by column chromatography (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-72) (106.9 mg, yield 70%). 1H-NMR(400MHz,DMSO-d 6 )δ:11.09(s,1H),8.01(dd,J=6.3,2.8Hz,1H),7.87~7.66(m,4H),7.40(t,J=8.6Hz,1H),7.29(t,J=9.5Hz,1H),7.22(dd,J=9.3,2.0Hz,1H),6.89(d,J=8.9Hz,1H),3.87(s,3H),3.36(s,2H),2.50(s,2H);MS(ESI)m / z[M+H] + =510.1。

[0482] Example 73 Preparation of 2-Fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-73)

[0483] First step: First, add 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.00 g, 6.97 mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy)phenol (1.89 g, 8.36 mmol), cesium carbonate (4.54 g, 13.94 mmol) and copper(I) iodide (265.43 mg, 1.39 mmol) to toluene (50 mL), displace with nitrogen, and then heat to 100 °C for reaction until the raw materials are completely reacted. Pour the reaction system into ice water, then extract with ethyl acetate, dry the organic phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 2:1 (v / v) to obtain 2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzoic acid (1.96 g, yield 64.8%), and directly proceed to the next step; MS(ESI) m / z[M+H] + =433.1。

[0484] Step 2: Weigh 2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzoic acid (194.8 mg, 0.45 mmol) and place it in a round-bottom flask. Add N,N-dimethylformamide (5 mL) as the solvent, then add HATU (206 mg, 0.54 mmol). Stir at room temperature for 15 min, then add 3-cyano-4-fluoroaniline (68 mg, 0.50 mmol) and N,N-diisopropylethylamine (129.25 mg, 1.36 mmol), and continue to stir at room temperature for 5 h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash away the solvent N,N-dimethylformamide with water, and purify it by column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 8:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (148.8 mg, yield 60%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 11.34(s, 1H), 8.18(dd, J = 5.7, 2.7Hz, 1H), 7.94(ddd, J = 9.2, 4.8, 2.7Hz, 1H), 7.85(t, J = 8.6Hz, 1H), 7.56(t, J = 9.1Hz, 1H), 7.39(ddd, J = 9.4, 8.0, 1.4Hz, 1H), 7.21(dd, J = 9.3, 2.1Hz, 1H), 6.91(d, J = 8.9Hz, 1H), 3.86(s, 3H); MS(ESI) m / z[M + H] + = 551.0。

[0485] Step 3: Weigh N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (165.0 mg, 0.3 mmol) and hydroxylamine hydrochloride (104.3 mg, 1.5 mmol) and place them in a sealed tube. Add absolute ethanol (5 mL), then add triethylamine (151.8 mg, 1.5 mmol), and react at 80 °C overnight under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and purify it by column chromatography (200 - 300 mesh) with dichloromethane:methanol = 100 - 50:1 (v / v) to obtain 2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-73) (122.4 mg, yield 70%). 1 H-NMR(400MHz,DMSO-d 6)δ: 11.03 (s, 1H), 9.68 (s, 1H), 7.86 (dt, J = 6.0, 2.9 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.71 (ddd, J = 8.9, 4.3, 2.8 Hz, 1H), 7.41 (ddd, J = 9.3, 8.0, 1.3 Hz, 1H), 7.30 - 7.19 (m, 2H), 6.88 (d, J = 8.8 Hz, 1H), 5.85 (s, 2H), 3.87 (s, 3H); MS(ESI) m / z [M + H]+ = 583.9。

[0486] Example 74 Preparation of 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-74)

[0487] 5-Chloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-26) (141.00 mg, 0.32 mmol) obtained in Example 34, triethylamine (190.75 mg, 1.89 mmol) and hydroxylamine hydrochloride (43.66 mg, 0.64 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. Concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then chromatographed on a column (200 - 300 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 to obtain 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-74) (80.0 mg, yield 52.8%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 10.64 (s, 1H), 9.66 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.35 - 7.40 (q, 2H), 7.21 (dd, J = 1.6, 9.6 Hz, 1H), 7.09 - 7.12 (q, 2H), 7.07 (s, 1H), 5.78 (s, 2H), 2.17 (s, 3H); MS(ESI) m / z [M + H] + = 482.2。

[0488] Example 75 Preparation of 2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-75)

[0489] Step 1: In a reaction flask equipped with a drying tube, dissolve 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) (628.0 mg, 2.00 mmol) obtained in Example 1 in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (1.7 mL, 20.00 mmol). After the addition is complete, react at room temperature until all the acid is converted to acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, and then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (404.5 mg, 4.00 mmol), and then add 5-amino-2-fluorobenzonitrile (285.7 mg, 2.10 mmol). React at room temperature until the reaction is complete, add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 2:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (437.0 mg, yield 50.4%). 1 H-NMR(400MHz,DMSO-d 6 )δ:10.93(s,1H),8.16~8.18(sq,1H),7.91~7.95(sq,1H),7.87(d,J=8.0Hz,1H),7.62(d,J=7.2Hz,1H),7.55(t,9.2Hz,1H),7.21(d,J=8.0Hz,1H),7.10(dd,J=8.0,2.4Hz,2H),6.99(s,1H),2.15(s,3H);MS(ESI)m / z[M+H] + =433.0。

[0490] Step 2: Add N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (43.00 mg, 0.1 mmol), triethylamine (20.13 mg, 0.2 mmol) and hydroxylamine hydrochloride (13.82 mg, 0.2 mmol) to absolute ethanol, and react under reflux until the raw materials react completely. Concentrate, add water, and extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product. Subsequently, purify by silica gel column chromatography (200 - 300 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 to obtain 2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-75) (25.0 mg, yield 54.0%). 1 H-NMR(600MHz,DMSO-d 6)δ: 10.98 (s, 1H), 8.06 (s, 1H), 7.89 (d, J = 5.4 Hz, 1H), 7.84 (s, 1H), 7.60 (d, J = 5.4 Hz, 1H), 7.48 (s, 1H), 7.23 (d, J = 5.4 Hz, 1H), 7.14 (s, 1H), 7.12 (s, 1H), 6.94 (s, 1H), 2.16 (s, 3H); MS(ESI) m / z [M + H] + = 466.1.

[0491] Example 76 Preparation of 4-Bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)benzamide (I-76)

[0492] First step: First, methyl 4-bromo-2,6-difluorobenzoate (474.0 mg, 1.89 mmol), 4-fluoro-2-methylphenol (262.0 mg, 2.08 mmol), and cesium carbonate (1.23 g, 3.78 mmol) were added to N,N-dimethylformamide (20.0 mL). After purging with nitrogen, the temperature was raised to 100 °C and the reaction was carried out until the raw materials were completely reacted. The reaction system was poured into ice water, and then extracted with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography (200 - 300 mesh) using petroleum ether:ethyl acetate = 20:1 (v / v) to obtain methyl 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzoate (420.0 mg, yield 62.8%). 1 1H-NMR (400 MHz in CDCl 3 )δ: 6.91 - 7.02 (m, 4H), 6.52 (s, 1H), 3.92 (s, 3H), 2.19 (s, 3H); MS(ESI) m / z [M + H] + = 356.9, 358.9 (1:1).

[0493] Methyl 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzoate (350.0 mg, 0.98 mmol) was added to 95% ethanol (20 mL), and then sodium hydroxide (10.00 M, 391.96 mg, 9.80 mmol) was added. The reaction was carried out under reflux until the raw material was completely hydrolyzed into an acid. The mixture was concentrated, water was added, and then the pH value was adjusted to about 2 - 3 with hydrochloric acid to precipitate a large amount of white solid. The solid was filtered and dried to obtain 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzoic acid (300.0 mg, yield 94%), which was directly used in the next step.

[0494] Step 2: In a reaction flask equipped with a drying tube, first dissolve 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzoic acid (350.0 mg, 1.0 mmol) in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (1.3 g, 10.2 mmol). After the addition is complete, react at room temperature until the acid is completely converted to acyl chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, dissolve the residue in dichloromethane and cool to about 0 °C, slowly add triethylamine (206.4 mg, 2.0 mmol), then add 5-amino-2-fluorobenzonitrile (138.9 mg, 1.0 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 20 - 4:1 (v / v) to obtain 4-bromo-N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzamide (200.0 mg, yield 42.5%). 1 H-NMR(600MHz,DMSO-d 6 )δ:11.16(s,1H),8.16(sq,1H),7.91(sq,1H),7.55(t,J=9.0Hz,1H),7.52(d,J=8.4Hz,1H),7.21(dd,J=2.4,9.0Hz,1H),7.11~7.14(m,2H),6.68(s,1H),2.14(s,3H);MS(ESI)m / z[M+H] + =460.9,462.8(1:1)。

[0495] Step 3: Add 4-bromo-N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzamide (112.00 mg, 0.24 mmol), triethylamine (147.43 mg, 1.5 mmol) and hydroxylamine hydrochloride (33.75 mg, 0.48 mmol) to absolute ethanol, and reflux until the raw materials react completely. Concentrate, add water, and extract with ethyl acetate. Dry the organic phase and concentrate to obtain the crude product, and then purify by column chromatography (200 - 300 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 to obtain 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)benzamide (I-76) (52.0 mg, yield 43.3%). 1 H-NMR(400MHz,DMSO-d 6)δ: 10.88 (brs, 1H), 9.68 (brs, 1H), 7.83 (brs, 1H), 7.69 (brs, 1H), 7.49 (d, J = 5.2 Hz, 1H), 7.22 (brs, 2H), 7.14 (brs, 2H), 6.64 (brs, 1H), 5.85 (brs, 2H), 2.15 (s, 3H); MS(ESI) m / z [M+H] + = 493.8, 495.8 (1:1).

[0496] Example 77 Preparation of 2-Fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-77)

[0497] First step: In a reaction flask equipped with a drying tube, dissolve 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (471.0 mg, 1.5 mmol) prepared according to Example 48 in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (1.27 mL, 14.99 mmol). After the addition is complete, react at room temperature until the acid is completely converted to acyl chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, dissolve the residue in dichloromethane and cool to about 0 °C, slowly add triethylamine (303.4 mg, 3.0 mmol), then add 5-amino-2-fluorobenzonitrile (214.2 mg, 1.6 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:dichloromethane = 1:1 (v / v) to obtain N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (437.0 mg, yield 67%). MS(ESI) m / z [M+H] + = 433.0.

[0498] Step 2: N-(3-Cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (43.0 mg, 0.1 mmol), triethylamine (20.1 mg, 0.2 mmol) and hydroxylamine hydrochloride (13.8 mg, 0.2 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials reacted completely. It was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then columned (200 - 300 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-77) (25.0 mg, yield 54%). 1 H-NMR(600MHz,DMSO-d 6 )δ: 10.93(s, 1H), 8.16 - 8.18(sq, 1H), 7.91 - 7.95(sq, 1H), 7.87(d, J = 8.0 Hz, 1H), 7.62(d, J = 7.2 Hz, 1H), 7.55(t, 9.2 Hz, 1H), 7.21(d, J = 8.0 Hz, 1H), 7.10(dd, J = 2.4, 8 Hz, 2H), 6.99(s, 1H), 2.15(s, 3H); MS(ESI) m / z [M + H] + = 466.1.

[0499] Example 78 Preparation of 6-(4-Chloro-2-trifluoromethyl)phenoxy-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-trifluoromethylbenzamide (I-78)

[0500] Step 1: First, 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid (1.0 g, 3.5 mmol), 4-chloro-2-trifluoromethylphenol (720.0 mg, 3.7 mmol), cesium carbonate (2.3 g, 7.0 mmol) and copper(I) iodide (130.0 mg, 0.7 mmol) were added to toluene (50 mL), the nitrogen was displaced, and then the temperature was raised to 100 °C for reaction until the raw materials reacted completely. The reaction system was poured into ice water, and then extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product. The crude product was columned (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 2:1 (v / v) to obtain 6-(4-chloro-2-trifluoromethyl)phenoxy-2-fluoro-3-trifluoromethylbenzoic acid (990.0 mg, yield 70.6%). 1 H-NMR(400MHz,DMSO-d 6)δ: 7.94 (s, 1H), 7.87 (t, J = 8.4 Hz, 1H), 7.80 (dd, J = 2.4, 8.8 Hz, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H); MS(ESI) m / z [M + H] + = 425.1, 427.1 (3:1).

[0501] Step 2: In a reaction flask equipped with a drying tube, dissolve 6-(4-chloro-2-trifluoromethyl)phenoxy-2-fluoro-3-trifluoromethylbenzoic acid (776.0 mg, 2.0 mmol) in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (1.63 mL, 20.0 mmol). After the addition is complete, react at room temperature until the acid is completely converted to the acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, dissolve the residue in dichloromethane and cool to about 0 °C, slowly add triethylamine (0.84 mL, 5.8 mmol), then add 5-amino-2-fluorobenzonitrile (275.5 mg, 2.0 mmol) and react at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:dichloromethane = 20 - 4:1 (v / v) to obtain 6-(4-chloro-2-trifluoromethyl)phenoxy-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzamide (320.0 mg, yield 32%). 1 1H-NMR (400 MHz, DMSO-d 6 )δ: 11.30 (s, 1H), 8.12 (s, 1H), 7.92 - 7.94 (m, 2H), 7.87 - 7.91 (m, 1H), 7.83 - 7.86 (dd, J = 8.8, 2.4 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H); MS(ESI) m / z [M + H] + = 521.0, 523.0 (3:1).

[0502] Step 3: 6-(4-Chloro-2-trifluoromethyl)phenoxy-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzamide (300.0 mg, 0.58 mmol), triethylamine (0.24 mL, 1.7 mmol) and hydroxylamine hydrochloride (400.0 mg, 12.0 mmol) were added to absolute ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. It was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then chromatographed on a silica gel column (300 - 400 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 to obtain 6-(4-chloro-2-trifluoromethyl)phenoxy-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-trifluoromethylbenzamide (I-78) (130.0 mg, yield 40.8%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.99(brs,1H), 9.67(brs,1H), 7.90(d,J = 8.8Hz,2H), 7.85(t,J = 5.6Hz,1H), 7.79(d,J = 5.6Hz,1H), 7.65(s,1H), 7.39(d,J = 8.8Hz,1H), 7.24(t,J = 9.6Hz,1H), 7.03(d,J = 8.8Hz,1H), 5.84(brs,2H); MS(ESI)m / z[M + H] + = 554.1, 556.1(3:1).

[0503] Example 79 Preparation of 6-(4-Fluoro-2-trifluoromethyl)phenoxy-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-trifluoromethylbenzamide (I-79)

[0504] Step 1: First, 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid (1.2 g, 4.2 mmol), 4-fluoro-2-trifluoromethylphenol (790.0 mg, 4.4 mmol), cesium carbonate (2.7 g, 7.0 mmol) and copper(I) iodide (160.0 mg, 0.2 mmol) were added to toluene (50 mL), the nitrogen was replaced, and then the temperature was raised to 100 °C and the reaction was carried out until the raw materials were completely reacted. The reaction system was poured into ice water, and then extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product. The crude product was chromatographed on a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 2:1 (v / v) to obtain 6-(4-chloro-2-trifluoromethyl)phenoxy-2-fluoro-3-trifluoromethylbenzoic acid (1.27 g, yield 78.6%). 1 H-NMR(400MHz,DMSO-d 6)δ: 7.81 - 7.85 (m, 2H), 7.64 (t, J = 8.4 Hz, 1H), 7.42 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H); MS(ESI) m / z [M + H]+ = 386.8.

[0505] Step 2: In a reaction flask equipped with a drying tube, dissolve 6-(4-fluoro-2-trifluoromethyl)phenoxy-2-fluoro-3-trifluoromethylbenzoic acid (1.16 g, 3.0 mmol) in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (2.54 mL, 30.0 mmol). After the addition is complete, react at room temperature until all the acid is converted to acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (1.25 mL, 9.0 mmol), and then add 5-amino-2-fluorobenzonitrile (430.0 mg, 3.15 mmol). React at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, let it stand and separate the layers to obtain the dichloromethane phase. Concentrate to obtain the crude product. Purify the crude product by silica gel column chromatography (200 - 300 mesh) with petroleum ether:dichloromethane = 20 - 4:1 (v / v) to obtain 6-(4-fluoro-2-trifluoromethyl)phenoxy-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzamide (1.0 g, yield 66.7%). 1 1H-NMR(400 MHz, DMSO-d 6 ): 11.30 (s, 1H), 8.14 (s, 1H), 7.88 - 7.93 (q, 2H), 7.80 (dd, J = 2.0, 8.4 Hz), 7.68 (td, J = 8.8, 2.8 Hz, 1H), 7.56 (t, J = 9.2 Hz, 1H), 7.46 (q, 1H), 6.95 (d, J = 8.8 Hz, 1H); MS(ESI) m / z [M + H]+ = 504.7;

[0506] Step 3: 6-(4-Fluoro-2-(trifluoromethyl))phenoxy-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (850.0 mg, 1.7 mmol), triethylamine (0.7 mL, 5.0 mmol) and hydroxylamine hydrochloride (234.0 mg, 3.4 mmol) were added to absolute ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. The mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then passed through a silica gel column (300 - 400 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 (v / v) to obtain 6-(4-fluoro-2-(trifluoromethyl))phenoxy-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-79) (590.0 mg, yield 65%). 1 H-NMR(400MHz,DMSO-d 6 )δ: 10.97(s, 1H), 9.66(s, 1H), 7.87(t, J = 8.8Hz, 1H), 7.78 - 7.82(td, J = 8.4, 2.8Hz, 2H), 7.64 - 7.70(td, J = 8.4, 2.8Hz, 2H), 7.44 - 7.47(dd, J = 9.2, 4.4Hz, 1H), 7.24(t, J = 9.6Hz, 1H), 6.93(d, J = 8.8Hz, 1H), 5.84(brs, 2H); MS(ESI) m / z[M + H] + = 538.1。

[0507] Example 80 Preparation of 6-(2-Cyclopropyl-4-(trifluoromethoxy)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-80)

[0508] Step 1: First, 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (600 mg, 2.1 mmol), 2-cyclopropyl-4-(trifluoromethoxy)phenol (501.6 mg, 2.3 mmol), cesium carbonate (1.36 g, 4.2 mmol) and copper(I) iodide (39.6 mg, 0.21 mmol) were added to toluene (25 mL). After purging with nitrogen, the temperature was raised to 100 °C and the reaction was carried out until the raw materials were completely reacted. The reaction system was poured into ice water, and then the pH was adjusted to 2 - 3. The mixture was extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the crude product. The crude product was passed through a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 8 - 6:1 (v / v) to obtain 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (570 mg, yield 64.2%). 11H NMR (400 MHz, Chloroform-d) δ: 7.56 (t, J = 8.3 Hz, 1H), 7.06 (s, 2H), 6.80 (s, 1H), 6.51 (d, J = 8.9 Hz, 1H), 1.96 (tt, J = 8.4, 5.2 Hz, 1H), 0.96~0.89 (m, 2H), 0.67~0.61 (m, 2H); MS (ESI) m / z [M+H]+ = 424.8。

[0509] Step 2: Dissolve 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (550.0 mg, 1.3 mmol) in thionyl chloride (20 mL), and reflux the reaction system at 80 °C for 2 h until all the acid is converted into acyl chloride. Concentrate the reaction system to remove the excess thionyl chloride, then dissolve the residue in dichloromethane (20 mL), add triethylamine (0.360 mL, 2.60 mmol), and then add 5-amino-2-fluorobenzonitrile (176.0 mg, 1.30 mmol) and react at room temperature until the reaction is complete. Add water, extract with ethyl acetate, dry the organic phase, and concentrate to obtain the crude product. The crude product is purified by silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 20~6:1 (v / v) to obtain 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (606.0 mg, yield 86.2%). 1 1H NMR (400 MHz, DMSO-d 6 ) δ: 11.32 (s, 1H), 8.21~8.15 (m, 1H), 7.97~7.89 (m, 1H), 7.86 (t, J = 8.7 Hz, 1H), 7.57 (t, J = 9.1 Hz, 1H), 7.29~7.25 (m, 2H), 7.01 (s, 1H), 6.73 (d, J = 8.9 Hz, 1H), 1.96 (tt, J = 8.6, 4.8 Hz, 1H), 0.92~0.81 (m, 2H), 0.74~0.68 (m, 2H); MS (ESI) m / z [M+H]+ = 542.7;

[0510] Step 3: 6-(2-Cyclopropyl-4-(trifluoromethoxy)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (100.0 mg, 0.18 mmol), triethylamine (0.08 mL, 0.55 mmol) and hydroxylamine hydrochloride (25.6 mg, 0.37 mmol) were added to anhydrous ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. It was concentrated, water was added, and it was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, and then the crude product was chromatographed on a silica gel plate with dichloromethane:methanol = 30:1 (v / v) to obtain 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-80) (63.0 mg, yield 60.0%). 1 H NMR(600MHz,DMSO-d 6 )δ:11.02(s,1H),9.72(s,1H),7.87(d,J=6.2Hz,1H),7.82(t,J=8.7Hz,1H),7.71(d,J=9.0Hz,1H),7.29~7.25(m,3H),7.02(s,1H),6.69(d,J=8.9Hz,1H),5.91(s,2H),2.03~1.92(m,1H),0.94~0.85(m,2H),0.77~0.67(m,2H);MS(ESI)m / z[M+H] + =575.7。

[0511] Example 81 Preparation of 6-(2,4-Bis(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-81)

[0512] Step 1: First, 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (500.0 mg, 1.74 mmol), 2,4-bis(trifluoromethyl)phenol (421.0 mg, 1.83 mmol), cesium carbonate (1.14 g, 3.48 mmol) and copper(I) iodide (66.0 mg, 0.35 mmol) were added to toluene (20 mL). After purging with nitrogen, the temperature was raised to 100 °C and the reaction was carried out until the raw materials were completely reacted. The reaction system was poured into ice water, and then extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product. The crude product was chromatographed on a silica gel column (200 - 300 mesh) with petroleum ether:ethyl acetate = 10 - 2:1 (v / v) to obtain 6-(2,4-bis(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (540.0 mg, yield 71.0%). 1 H-NMR(400MHz,DMSO-d 6)δ: 8.15 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.95 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H); MS(ESI) m / z [M+H] + = 437.1.

[0513] Step 2: In a reaction flask equipped with a drying tube, dissolve 6-(2,4-bis(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (400.0 mg, 9.2 mmol) in dichloromethane (20 mL). After adding a catalytic amount of DMF, cool the reaction system to about 0 °C, and then slowly add oxalyl chloride (0.78 mL, 9.2 mmol). After the addition, react at room temperature until the acid is completely converted to the acyl chloride. Concentrate the reaction system to remove the excess oxalyl chloride and dichloromethane, and then dissolve the residue in dichloromethane and cool to about 0 °C. Slowly add triethylamine (0.38 mL, 2.7 mmol), and then add 5-amino-2-fluorobenzonitrile (131.0 mg, 0.96 mmol). React at room temperature until the reaction is complete. Add water, neutralize with dilute hydrochloric acid, and let it stand for liquid separation to obtain the dichloromethane phase, and concentrate the crude product. The crude product is purified by silica gel column chromatography (200 - 300 mesh) with petroleum ether:ethyl acetate = 20 - 4:1 (v / v) to obtain 6-(2,4-bis(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (330.0 mg, yield 64.9%). 1 1H-NMR (400 MHz, DMSO-d 6 6): 11.32 (s, 1H), 8.12 (brs, 2H), 8.06 (s, 1H), 8.00 (t, J = 8.4 Hz, 1H), 7.84~7.88 (m, 1H), 7.55 (t, J = 9.2 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H); MS(ESI) m / z [M+H] + = 554.6;

[0514] Step 3: 6-(2,4-Bis(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)benzamide (140.0 mg, 0.25 mmol), triethylamine (0.1 mL, 0.75 mmol) and hydroxylamine hydrochloride (25.7 mg, 0.50 mmol) were added to absolute ethanol, and the reaction was carried out under reflux until the raw materials were completely reacted. It was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then chromatographed on a column (300 - 400 mesh) with dichloromethane:methanol (v / v) = 100 - 20:1 to obtain 6-(2,4-bis(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-81) (103.0 mg, yield 70%). 1 H-NMR(600MHz,DMSO-d 6 ) δ: 11.61(s, 1H), 9.75(s, 1H), 8.29(d, J = 7.8Hz, 1H), 8.23(s, 1H), 7.80(d, J = 7.8Hz, 1H), 7.54(t, J = 9.6Hz, 1H), 7.47(s, 1H), 7.34(brs, 1H), 7.18(t, J = 9.6Hz, 1H); MS(ESI) m / z [M + H] + = 587.6。

[0515] Experimental Example Biological Part Test: Blocking Activity of the Compounds of the Present Invention against Sodium Channel 1.8 (Nav1.8)

[0516] 1. Detection Method: The whole-cell manual patch-clamp technique was used to detect the effect of the compound on the voltage-gated Nav1.8 channel current

[0517] 2. Preparation and Analysis of the Test Compounds

[0518] Negative Control: Electrophysiological extracellular fluid containing 0.5% DMSO

[0519] Test compound: Weigh a certain mass of the compound and dissolve it in DMSO to prepare a 20 mM DMSO stock solution. On the day of the test, dilute the 20 mM compound stock solution with extracellular fluid to the final concentration to be detected, ensuring that the DMSO content in the test drug solution does not exceed 0.5%. DMSO at this concentration has no effect on the detected Nav1.8 channel current. For example, to prepare 100 nM and 1 μM compound solutions, the gradient dilution method is as follows: First, pipette 5 μL of the DMSO stock solution into 10 mL of extracellular fluid and dissolve it evenly to obtain a 10 μM compound solution; then pipette 1 mL of the 10 μM compound and add it to 9 mL of extracellular fluid and dissolve it evenly to obtain a 1 μM compound solution; then pipette 1 mL of the 1 μM compound and add it to 9 mL of extracellular fluid and dissolve it evenly to obtain a 100 nM compound solution. All positive controls in this experiment use VX-150 as the positive control drug, and its half-maximal inhibitory concentration is 33.45 ± 0.86 nM, which is consistent with the results reported in the original literature. The negative control used in this experiment is extracellular fluid containing 0.5% DMSO, and the change value of the channel current ≤ 5% after 10 minutes of drug administration.

[0520] 3. Cell culture

[0521] (1) Nav1.8 cell line: HEK293 (Flp-In T-Rex-293) cells stably expressing human Nav1.8 sodium channels, and the coding gene information is as follows: NM_001293306.2.

[0522] (2) Culture and subculture conditions and methods: The cell line is cultured in a constant temperature incubator at 37 °C and 5% CO 2 The Nav1.8 stable transfected cells are cultured in a complete medium of high-glucose DMEM (Gibco) containing 10% tetracycline-free fetal bovine serum (HyClone) and 100 μg / mL Hygromycin B. One day before the experiment, when the cell density grows to about 90%, digest and subculture. First, aspirate the medium, wash the cells with pre-warmed phosphate buffer (PBS) at 37 °C, discard the PBS buffer, add trypsin to digest and transfer to a centrifuge tube, centrifuge at 800 rpm for 3 minutes, discard the supernatant, add a complete medium containing 1 μg / mL Doxcycline to resuspend, subculture into a 6-well plate, after inducing culture for 20 hours, separate and subculture into coverslips coated with polylysine and continue to culture for 1 - 2 hours for electrophysiological recording experiments.

[0523] 4. Electrophysiological experiment

[0524] (1) Record the Nav1.8 sodium channel current using the whole-cell voltage clamp technique at room temperature (23 - 25 °C).

[0525] (2) For whole-cell voltage clamp recording experiments, an Axon patch 700B patch clamp amplifier (Molecular Devices) was used, and the digital-to-analog converter was a Digidata 1440A (Molecular Devices). The glass microelectrodes were pulled from glass electrode blanks (World Precision Instrunents) using a puller (P97, Sutter). The tip resistance after filling with the internal electrode solution was about 1.5 - 2.5 MΩ. The glass microelectrodes could be connected to the patch clamp amplifier by inserting them into the amplifier probe. The clamping voltage and data recording were controlled and recorded by pClamp 10 software (Molecular Devices) via a computer. The sampling frequency was 20 kHz, and the filtering frequency was 2 kHz.

[0526] (3) Extracellular and intracellular solutions for electrophysiological experiments:

[0527] Composition of extracellular solution (mM): 140 NaCl, 3 KCl, 1 CaCl 2 , 1 MgCl 2 , 10 HEPES and 20 Glucose, pH was adjusted to 7.3 with NaOH.

[0528] Composition of intracellular solution (mM): 140 CsF, 10 NaCl, 10 HEPES, 1.1 EGTA and 20 Glucose, pH was adjusted to 7.3 with CsOH.

[0529] (4) Electrophysiological stimulation protocol: After obtaining a whole-cell recording (reaching the GΩ seal condition with high impedance), the voltage was clamped at -80 mV and waited for 4 - 5 minutes until the internal electrode solution and the intracellular solution were balanced, and then electrophysiological recording began. Current stimulation and compound activity detection protocol: The cell was clamped at -80 mV, a depolarizing voltage stimulation of +10 mV with a duration of 20 ms was given, and then repolarized to -80 mV. The stimulation frequency was 0.5 Hz. After determining that the Nav1.8 sodium channel current was stable (about 1 minute), the drug administration process was started until the cell current no longer changed (compound inhibition reached a steady state). Each concentration of the compound was tested on at least 3 cells (n≥3). After detecting all compounds, a single concentration of 100 nM VX-150 was given as a positive control.

[0530] 5. Data analysis

[0531] Data acquisition, analysis, and processing were performed using pClamp10 (Molecular Devices), GraphPad Prism 5 (GraphPad Software), and Excel (Microsoft) software. All data were expressed as mean ± standard error of the mean (Mean ± SEM). The effect of the compound on current was calculated using the following formula:

[0532] Inhibition rate (%) = [1 - magnitude of current after adding the drug (I Drug ) / magnitude of current before adding the drug (I Control )] × 100.

[0533] The dose - effect curve was fitted using the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC 50 -X) × k), where Bottom and Top represent the minimum and maximum values of inhibition, X represents the logarithm of the compound concentration, Y represents the I Drug / I Control value, IC 50 represents the drug dose that produces a 50% inhibitory effect, and k represents the Hill coefficient.

[0534] The results are shown in the following table.

[0535] Table 1 Activity IC 50 values (nM) of the compounds of the present invention against Navl.8 channels

[0536]

[0537] Table 2 Percent blockage activity of the compounds of the present invention against Nav1.8 channels at a concentration of 1 nM

[0538] Compound Number Percent Inhibition at 1 nM (%) Compound Number Percent Inhibition at 1 nM (%) I-52 77％ I-67 57％ I-53 90％ I-71 67％ I-54 72％ I-72 54％ I-55 90％ I-73 90％ I-60 72％ I-78 70％ I-62 65％ I-80 84％

[0539] Table 3 Percent blockage activity of the compounds of the present invention against Nav1.8 channels at a concentration of 10 nM

[0540]

[0541]

[0542] Table 4 Percent blockage activity of the compounds of the present invention against Nav1.8 channels at a concentration of 30 nM

[0543] Compound Number Percent Inhibition at 30 nM (%) I-25 57％ I-34 98％ I-35 36％ I-36 83％ I-37 72％ I-38 70％ I-39 6％ I-41 22％ I-42 65％ I-45 77％ I-56 47％ I-57 66％

[0544] Table 5 Percent blockage activity of some compounds of the present invention against Nav1.8 channels at a concentration of 100 nM

[0545]

[0546]

[0547] Pharmacokinetic part test:

[0548] In this experimental example, the in vivo pharmacokinetics of rats was evaluated by single intravenous injection or intragastric administration of drugs.

[0549] 1. Test methods and conditions: Male SD rats were fasted overnight. The test compound was administered intravenously at a single dose of 2 mg / kg or 1 mg / kg (intravenous solvent: 5% DMSO / 10% Solutol / 10% EtOH / 75% Saline, administration volume: 5 mL / kg), and intragastrically at a single dose of 10 mg / kg or 5 mg / kg (administration solvent: 0.5% CMC-Na, administration volume: 10 mL / kg).

[0550] 2. Sampling information: Blood samples were collected from the retro-orbital venous plexus at 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 24 h (an additional sampling point at 5 min for the intravenous administration group) before and after drug administration. At each of the above time points, 0.2 ml of blood was collected and placed in an EDTA-K2 tube, centrifuged at 11000 rpm for 5 min to separate plasma, and frozen in a -20°C refrigerator.

[0551] 3. Detection information: The LC / MS / MS method was used to determine the concentration of the prototype drug in the plasma of rats / mice after intravenous administration of the test compound and intragastric administration. The pharmacokinetic parameters of the plasma of rats / mice under the two administration methods were calculated, and the bioavailability of each compound in rats was calculated. The results are shown in Tables 6 and 7 below.

[0552] Table 6 Intravenous pharmacokinetic information of representative compounds

[0553]

[0554] Table 7 Intragastric pharmacokinetic information of representative compounds

[0555]

[0556] For each of the above embodiments, the number and the corresponding structural formula shall prevail, and they are only used to illustrate the technical solutions of the present invention by way of example, rather than to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: within the scope not departing from the spirit and essence defined by the claims of the present invention, the technical solutions recorded in the foregoing embodiments may be modified, or some or all of the technical features may be equivalently replaced; and such modifications or replacements are still within the scope defined by the claims of the present invention.

Claims

1. A compound of formula I, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein: Ring A is a substituted or unsubstituted phenyl; the substituents of the substitution are selected from halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, deuterated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C3-C8 cycloalkoxy, deuterated C3-C8 cycloalkoxy, halogenated C3-C8 cycloalkoxy; R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, C(=O)R 1a , C(=O)OR 2a , wherein R 1a is selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, and R 2a is selected from C1-C6 alkyl, C3-C6 cycloalkyl; R 3 selected from hydrogen, -CN, -OH or C1-C6 alkoxy; X 1 and X 2 One of them is C, and the other is selected from N and CR g ; R g independently selected from hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, and halo-C1-C6 alkoxy each time it appears; R 4 、R 5 、R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, and C1-C3 alkoxy; X 3 、X 4 and X 5 are each independently selected from N and CR a and, among X 3 、X 4 and X 5 there is at most one N; R 7 selected from hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy; R a independently selected from hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C2-C6 alkenyl, halo-C2-C6 alkenyl, C2-C6 alkenyloxy, halo-C2-C6 alkenyloxy, C2-C6 alkynyl, halo-C1-C6 alkynyl, C2-C6 alkynyloxy, halo-C1-C6 alkynyloxy each time it appears; Alternatively, R 7 and R a Two adjacent substituents in and together with the carbon atom to which they are attached form a ring Y 1 and Y 2 Each independently selected from O, CH 2 ; R 8 selected from hydrogen, a halogen or a C1-C3 alkyl group provided that the compound of formula I does not include the following compounds:

2. The compound according to claim 1, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, Ring A is a substituted or unsubstituted phenyl; the substituents of the substitution are selected from F, Cl, C1-C3 alkyl, deuterated C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkoxy, halogenated C1-C3 alkoxy, C3-C6 cycloalkyl, deuterated C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C3-C6 cycloalkoxy, deuterated C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.

3. The compound according to claim 1, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 1 、R 2 and R 3 at least one of them is H; and / or For 4. The compound according to claim 1, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 1 、R 2 and R 3 are all hydrogen.

5. The compound according to any one of claims 1-4, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The compound of formula I is selected from: wherein, X 1 、X 2 each independently selected from N and CR g , R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、Ring A, X 3 、X 4 、X 5 are defined the same as the corresponding claims.

6. The compound according to claim 1, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The compound of formula I is selected from the following formula I-A compound and formula I-A' compound: wherein, X 1 、X 2 are each independently selected from N and CR g ; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R g 、X 3 、X 4 、X 5 are defined the same as in claim 1; X 6 、X 7 、X 8 Each independently selected from CR b ; R b 、R 9 and R 10 each independently represents, each time it appears, hydrogen, halogen, C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, deuterated C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C3-C8 cycloalkoxy, deuterated C3-C8 cycloalkoxy, or halogenated C3-C8 cycloalkoxy.

7. The compound according to claim 6, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R b 、R 9 and R 10 each independently represents, each time it appears, hydrogen, F, Cl, C1-C3 alkyl, deuterated C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, deuterated C1-C3 alkoxy, halogenated C1-C3 alkoxy, C3-C6 cycloalkyl, deuterated C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C3-C6 cycloalkoxy, deuterated C3-C6 cycloalkoxy, or halogenated C3-C6 cycloalkoxy.

8. The compound according to claim 6, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, In the I-A compound, X 2 selected from N or CR g , R g is selected from hydrogen, F, Cl, Br, C1-C6 alkyl or C1-C6 alkoxy; X 3 、 X 4 are each independently CR a , X 5 is selected from N or CR a , R a is the same or different each time it appears and is selected from hydrogen, halo-C1-C6 alkyl, halo-C1-C6 alkoxy; X 6 、 X 7 、 X 8 are each independently selected from CR b , R b being the same or different and being selected from hydrogen, halogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl; R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3-C6 cycloalkyl, and deuterated C3-C6 cycloalkyl; R 7 selected from halogen, C1-C6 alkoxy groups; R 4 、R 5 、R 6 Each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy; R 1 and R 2 each independently selected from hydrogen, C1-C6 alkyl; R 3 Selected from hydrogen, -CN, -OH or C1-C6 alkoxy groups.

9. The compound according to claim 8, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, X 2 is CR g , and R g is defined in the same way as in claim 8.

10. The compound according to claim 9, its tautomer, meso form, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R g is hydrogen, F, Cl or Br.

11. The compound according to claim 9, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R g is F.

12. The compound according to claim 8, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, X 3 、 X 4 are each independently CR a , X 5 is selected from N or CR a , X 3 wherein R a is selected from trifluoromethyl or trifluoromethoxy, X 4 and X 5 wherein R a is hydrogen.

13. The compound according to claim 8, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, X 6 , X 7 , X 8 are each independently selected from CR b , where R b is the same or different and is selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy.

14. The compound according to claim 8, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 7 selected from F, Cl, Br or methoxy.

15. The compound according to claim 8, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 4 、R 5 、R 6 is hydrogen.

16. The compound according to claim 8, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 1 and R 2 is hydrogen.

17. The compound according to claim 8, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 3 is -OH.

18. The compound according to any one of claims 6 - 8, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, The compound of formula I-A is selected from the following compounds of formula I-A-1: Among them, R 1 , R 2 , R 3 , R 4 , R 5 , X 5 , R 6 , R 7 , R 9 , R 10 , R a , R b , R g are defined in the corresponding claims.

19. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 1 、R 2 and R 3 are hydrogen.

20. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 4 、R 5 、R 6 、R g At least two of them are H.

21. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 4 、R 5 、R 6 、R g At least three of them are H.

22. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 4 、R 5 、R 6 、R g All are H.

23. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 7 、R a At least one of them is H.

24. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 7 、R a At least two of them are H.

25. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 9 、R 10 、R b At least two of them are H.

26. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 9 、R 10 、R b At least three of them are H.

27. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, In the compound of formula I-A-1, R g selected from hydrogen, F, Cl, Br, C1-C6 alkyl or C1-C6 alkoxy; X 5 selected from N or CR a , R a , which is the same or different each time it appears, and is selected from hydrogen, halo-C1-C6 alkyl, halo-C1-C6 alkoxy; R b identical or different, and are selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3-C6 cycloalkyl, and deuterated C3-C6 cycloalkyl; R 7 selected from halogen, C1-C6 alkoxy groups; R 4 、R 5 、R 6 Each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy; R 1 and R 2 each independently selected from hydrogen, C1-C6 alkyl; R 3 Selected from hydrogen, -CN, -OH or C1-C6 alkoxy groups.

28. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R g is hydrogen, F, Cl or Br.

29. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R g is hydrogen or F.

30. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R g is F.

31. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, X 5 wherein R a is hydrogen.

32. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R b identical or different and selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy.

33. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 7 Selected from F, Cl, Br or methoxy group.

34. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 4 、R 5 、R 6 is hydrogen.

35. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 1 and R 2 is hydrogen.

36. The compound according to claim 27, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R 3 is -OH.

37. The compound according to claim 18, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, The compound of formula I-A-1 is selected from the following compound of formula I-A-1A: Among them, X 5 , R 7 , R 9 , R 10 , R a , R b are defined in the same way as in claim 18.

38. The compound according to claim 37, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, In the compound of formula I-A-1A, X 5 selected from N or CR a , R a , which is the same or different each time it appears, and is selected from hydrogen, halogen, halo-C1-C6 alkyl, and halo-C1-C6 alkoxy; R b identical or different, and are selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl; R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3-C6 cycloalkyl, deuterated C3-C6 cycloalkyl; R 7 Selected from halogen, C1-C6 alkoxy groups.

39. The compound according to claim 37, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, X 5 selected from N or CR a , X 5 wherein R a is hydrogen.

40. The compound according to claim 37, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or its pharmaceutically acceptable salt, wherein, R b identical or different and selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy.

41. A compound according to claim 37, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, R 7 selected from F, Cl, Br or methoxy.

42. A compound according to claim 37, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein ， Selected from the following structures:

43. A compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The compound of formula I is selected from the following compounds:

44. A method for preparing a compound according to any one of claims 1-43, which is one of the following methods: Method 1: The II-A compound reacts with an alcohol under acid catalysis to form a Pinner salt, and then NR is added 1 R 2 R 3 Prepare the I-A compound; wherein, The definitions of each substituent are the same as those defined in the corresponding claim; Method 2: The II-A’ compound reacts with an alcohol under acid catalysis to form a Pinner salt, and then NR is added 1 R 2 R 3 Prepare the I-A’ compound; wherein the definitions of each substituent are the same as those defined in the corresponding claim; Method 3: Compound II-A reacts with hydroxylamine or a salt of hydroxylamine in the presence of an anhydrous solvent and a base to obtain compound I-A; wherein, R 1 , R 2 is H, R 3 is OH, and the definitions of other substituents are the same as those in the corresponding claims; Method 4: Compound II-A' reacts with hydroxylamine or a salt of hydroxylamine in the presence of an anhydrous solvent and a base to obtain compound I-A'; wherein, R 1 and R 2 are H, R 3 is OH, and the definitions of other substituents are the same as those in the corresponding claims.

45. A pharmaceutical composition, which comprises one or more selected from the compounds according to any one of claims 1-43, its tautomers, mesomers, racemates, enantiomers, diastereoisomers, and pharmaceutically acceptable salts thereof, and optionally pharmaceutically acceptable excipients.

46. Use of a compound according to any one of claims 1-43, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 45 in the preparation of a Nav1.8 inhibitor.

47. Use of a compound according to any one of claims 1-43, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 45 in the preparation of a drug for treating and / or alleviating pain and pain-related diseases.

48. According to the use of claim 47, wherein, The pain and pain-related diseases include nociceptive pain, inflammatory pain, neuropathic pain, functional pain, pain related to muscle or bone injury, pelvic pain, abdominal pain, thoracic pain, lumbosacral neuralgia, preoperative pain, intraoperative pain, postoperative pain, 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 neuropathy, erythromelalgia, arthritis, pruritus, acute or chronic pruritus, asthma, multiple sclerosis, arrhythmia, atrial fibrillation, heart failure, Brugada syndrome, kidney stones, epilepsy, convulsion, Charcot-Marie-Tooth syndrome, incontinence.

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